ORCID Profile
0000-0002-4200-7476
Current Organisations
University of Sydney
,
Anzac Research Institute
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Publisher: AMPCo
Date: 02-2010
DOI: 10.5694/J.1326-5377.2010.TB03456.X
Abstract: To describe the prevalence of depressive symptoms in older male Italian-born Australian immigrants. Cross-sectional study of 335 Italian-born and 849 Australian-born men aged 70 years and over who completed written questionnaires and were interviewed in the baseline phase of the Concord Health and Ageing in Men Project (CHAMP). Depressive symptoms assessed by the short (15-item) form of the Geriatric Depression Scale associations between depressive symptoms and country of birth. The prevalence of depressive symptoms in Italian-born men was 18%, almost twice the prevalence of 10% in Australian-born men (odds ratio [OR], 1.9 95% CI, 1.2-3.0). After adjusting for socioeconomic and health factors, the relationship between country of birth and depressive symptoms was attenuated and no longer statistically significant (OR, 1.7 95% CI, 0.9-3.0). The strongest confounders of the relationship between country of birth and depressive symptoms were source of income and satisfaction with social support. Male Italian-born immigrants aged over 70 years report more depressive symptoms than their Australian-born counterparts. This association appears to be explained by increased reliance on a government pension as the sole source of income and lower satisfaction with social support among Italian-born men. However, these findings need to be confirmed longitudinally.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2012
DOI: 10.1007/S12672-012-0107-9
Abstract: Hormones, notably estrogens, are pivotal in the origins of breast cancer but androgenic effects, while supported by persistence of AR expression in breast cancers, remain controversial. This study determined the role of the androgen actions via androgen receptor (AR) in experimental mammary cancer. Androgen-resistant female and male mice (ARKO) were generated using Cre/loxP technique and featured a global AR inactivation. The effect of AR inactivation and influence of genetic background on 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis was confirmed using two separate ARKO models with different genetic backgrounds. The onset of palpable mammary tumors was significantly faster in ARKO females (median time 22 vs 34 weeks, respectively (p = 0.0024 multivariate Cox regression) compared to WT and independent of the mouse genetic background. The cumulative incidence at 9 months was 81 ± 10% [mean ± SE] for ARKO compared to 50 ± 13% in WT females. The increased DMBA susceptibility of ARKO females was associated with a higher epithelial proliferation index but not with major structural or receptor (estrogen or progesterone) expression differences between the virgin WT or ARKO female mammary glands. AR inactivation allowed substantial ductal extension in ARKO males while WT males displayed only rudimentary epithelial branches or complete regression of epithelial structures. Yet, DMBA did not induce epithelial mammary tumors in WT or ARKO males, demonstrating that AR inactivation alone is insufficient to promote mammary tumors. These results demonstrate that AR inactivation accelerates mammary carcinogenesis in female mice exposed to the chemical carcinogen DMBA regardless of mouse genetic background but require prior exposure to endogenous ovarian hormones.
Publisher: Oxford University Press (OUP)
Date: 08-2008
DOI: 10.1373/CLINCHEM.2008.105726
Abstract: Background: The utility of insulinlike growth factor (IGF) axis and collagen markers for a growth hormone (GH) doping test in sport depends on their stability and reproducibility. We sought to determine short-term within-subject variability of these markers in a large cohort of healthy in iduals. Methods: We measured IGF-I, IGF binding protein 3 (IGFBP-3), acid labile subunit (ALS), and the collagen markers N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), and N-terminal propeptide of type III procollagen (PIIINP) in serum s les obtained on multiple occasions (median 3 per participant) over a 2- to 3-week period from 1103 elite athletes (699 men, 404 women) ages 22.2 (5.2) years [mean (SD)]. We estimated between-subject and within-subject variances by mixed–effects ANOVA. Results: Within-subject variance accounted for 32% to 36% and 4% to 13% of the total variance in IGF markers and collagen markers, respectively. The within-subject CV ranged from 11% to 21% for the IGF axis markers and from 13% to 15% for the collagen markers. The index of in iduality for the IGF axis markers was 0.66–0.76, and for the collagen markers, 0.26–0.45. For each marker, in iduals with initial extreme measured values tended to regress toward the population mean in subsequent repeated measurements. We developed a Bayesian model to estimate the long-term probable value for each marker. Conclusions: These results indicate that in healthy in iduals the within-subject variability was greater for IGF-I than for the collagen markers, and that where a single measurement is available, it is possible to estimate the long-term probable value of each of the markers by applying the Bayesian approach. Such an application can increase the reliability and decrease the cost of detecting GH doping.
Publisher: The Endocrine Society
Date: 03-2016
DOI: 10.1210/JC.2015-4139
Abstract: Advancing age is accompanied by an accumulation of ill health and shortening of chromosomal telomeres signifying biological aging. T is metabolized to DHT by 5α-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro. The objective of the study was to establish whether circulating T or its metabolites, DHT or E2, and single-nucleotide polymorphisms in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men. Early-morning serum T, DHT, and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 single-nucleotide polymorphisms and LTL analyzed by PCR in 980 men from the Western Australian Busselton Health Survey who participated in the study. LTL was expressed as the T/S ratio. Men were aged (mean ± SD) 53.7 ± 15.6 years. LTL decreased linearly with age, from the T/S ratio of 1.89 ± 0.41 at younger than 30 years to 1.50 ± 0.49 at 70 to younger than 80 years (r = -0.225, P < .0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT, r = 0.069, P = .030 E2, r = 0.068, P = .034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2, 59.3 vs 68.6 pmol/L, P < .0001 T/S ratio, 1.54 vs 1.62, P = .045), rs10046 C (60.5 vs 68.1 pmol/L, P = .0005, 1.54 vs 1.62, P = .035), and rs700518 A (59.9 vs 68.9 pmol/L, P < .0001, 1.54 vs 1.63, P = .020). A single-copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL. In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo, thus warranting further studies to examine whether hormonal interventions might slow biological aging in men.
Publisher: Wiley
Date: 20-01-2019
DOI: 10.1111/CEN.13918
Abstract: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men. We used cross-sectional data from 2913 men aged 76.7 ± 3.2 years with morning blood s les assayed for T, DHT, E2 (mass spectrometry), and sex hormone-binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history. Average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r = 0.038, P = 0.039) and SHBG was inversely correlated (r = -0.053, P = 0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, P = 0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P = 0.014) and SHBG inversely (coefficient -0.013, P = 0.037) associated with T/S ratio. In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.
Publisher: Public Library of Science (PLoS)
Date: 24-09-2012
Publisher: The Endocrine Society
Date: 17-04-2020
Abstract: Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine, reproductive, and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, the etiology of PCOS is poorly understood, so there is no cure and symptomatic treatment is suboptimal. Hyperandrogenism is the most consistent feature observed in PCOS patients, and recently aberrant neuroendocrine signaling and adipose tissue function have been proposed as playing a role in the development of PCOS. To investigate the role of adipose tissue and the brain as key sites for androgen receptor (AR)-mediated development of PCOS, we combined a white and brown adipose and brain-specific AR knockout (AdBARKO) mouse model with a dihydrotestosterone (DHT)-induced mouse model of PCOS. As expected, in wildtype (WT) control females, DHT exposure induced the reproductive PCOS traits of cycle irregularity, ovulatory dysfunction, and reduced follicle health, whereas in AdBARKO females, DHT did not produce the reproductive features of PCOS. The metabolic PCOS characteristics of increased adiposity, adipocyte hypertrophy, and hepatic steatosis induced by DHT in WT females were not evident in DHT-treated AdBARKO females, which displayed normal white adipose tissue weight and no adipocyte hypertrophy or liver steatosis. Dihydrotestosterone treatment induced increased fasting glucose levels in both WT and AdBARKO females. These findings demonstrate that adipose tissue and the brain are key loci of androgen-mediated actions involved in the developmental origins of PCOS. These data support targeting adipocyte and neuroendocrine AR-driven pathways in the future development of novel therapeutic strategies for PCOS.
Publisher: The Endocrine Society
Date: 06-2010
DOI: 10.1210/EN.2009-1477
Publisher: Bioscientifica
Date: 10-1993
Abstract: This study aimed at determining the relationship of sex steroids, particularly in the perinatal period, to the pubertal insulin-like growth factor-I (IGF-I) surge in male mice. We used hypogonadal ( hpg ) mice, which have a major deletion in the gonadotrophin-releasing hormone (GnRH) gene, in order to have a model lacking all GnRH-induced gonadotrophin and sex steroid secretion throughout pre- and postnatal life. Cross-sectional data on body weights and weights of testes, seminal vesicles, kidneys, liver and spleen from 9 to 77 days of age were obtained in male hpg , heterozygous (Hz) and homozygous normal (N/N) littermates ( n = 75–78/group). These data did not reveal any difference between Hz and N/N mice. Hpg mice had decreased body weights which by 70–77 days of age were approximately 18% less than normal controls. Testes and seminal vesicles of hpg mice did not demonstrate any significant postnatal growth. Relative to body weight, kidney weights were also markedly reduced in hpg mice ( P ·0001), deviating significantly from normal by 28–35 days of age, reflecting the impact of androgen deficiency on a non-reproductive organ. From the cross-sectional data it was concluded that puberty commenced soon after weaning (21 days) in the male and that maturity was achieved within 4–5 weeks. Longitudinal study showed that, compared with normal controls, untreated hpg mice had an exaggerated pubertal IGF-I surge ( P ·005) which peaked in mid-puberty. This, together with their reduced body weights ( P ·05), were normalized by treatment from 21 to 70 days of age with two 1 cm s.c. implants of testosterone ( n =6) or dihydrotestosterone ( n =7). There was no difference in IGF-I levels or in weights of testes, seminal vesicles, kidney, liver or spleen between testosterone and dihydrotestosterone treatments ( P ·05). Prolonged high levels of androgen also restored testicular and seminal vesicle weights to 40% of phenotypically normal controls, while kidney, liver and spleen weights were also significantly increased. The pubertal IGF-I surge in mice does not, therefore, require androgens in either the pre- or postnatal periods, and it is exaggerated in androgen-deficient male mice and d ened to normal regardless of aromatization. Journal of Endocrinology (1993) 139, 57–65
Publisher: The Endocrine Society
Date: 11-2005
DOI: 10.1210/JC.2005-1214
Abstract: Age and androgens are key determinants of benign prostate hyperplasia, but the mechanisms remain unclear. We examine the relationship between androgens and total, central, and peripheral prostate volume with a focus on early life factors. We conducted a cross-sectional observational study of 406 community-dwelling Australian men aged 20-82 yr old without known prostate disease. Prostate zonal (total, central, and peripheral) volumes were measured by planimetric transrectal ultrasound. Participants completed questionnaires, underwent physical examination, and provided blood s les to measure total, free, and bioavailable testosterone, dihydrotestosterone, estradiol, SHBG, LH, FSH, and prostate-specific antigen. Prostate zonal volumes were positively associated with age, prostate-specific antigen, early onset of puberty, current height, body surface area, lean body mass, hip and waist circumference as well as recalled height and weight during puberty and adolescence but not current weight, fat mass, or body mass index. Stepwise multivariate regression modeling indicated that age and height were the only independent predictors of prostate zonal volumes. When adjusted for age and s ling time of day, the negative correlations of age-adjusted prostate zonal volumes with current blood total, free, and bioavailable testosterone and the positive correlation with blood SHBG were no longer significant. This study suggests that early and long-term androgen exposure may have long-acting effects on mature prostate zonal volumes, whereas relationships with current blood androgens and related hormones levels were mostly a result of confounding by age. Additional studies on the mechanism of androgen effects on late-life prostate diseases should consider lasting effects of early-life androgen exposure.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2012
Publisher: Oxford University Press (OUP)
Date: 06-2005
DOI: 10.1530/EJE.1.01920
Abstract: Objective : Androgen deficiency (AD) leads to bone loss and contributes to osteoporotic fractures in men. Although low bone mineral density (BMD) in AD men is improved by testosterone replacement, the responses vary between in iduals but the determinants of this variability are not well defined. Design and methods : Retrospective review of dual energy X-ray absorptiometry (DEXA) of the lumbar spine and proximal femur in men with established AD requiring regular androgen replacement therapy (ART). After a DEXA scan all men were treated with testosterone implants (800 mg, ~6 month intervals). Patients were classified as having a congenital, childhood, or post-pubertal onset, as well as according to the adequacy of treatment prior to their first DEXA scan as untreated, partially treated or well treated. Results : Men with AD requiring regular ART ( n = 169, aged 46.3±1.1 years, range 22–84 years) underwent a DEXA scan prior to being treated with testosterone implants (800 mg, ~6 month intervals). In cross-sectional analysis at the time of the first DEXA scan untreated men ( n = 24) had significantly reduced age-adjusted BMD at all four sites (L1–L4, femoral neck, Ward’s triangle and trochanter). Well-treated men ( n = 77) had significantly better age-adjusted BMD at all four sites compared with those who were partially treated ( n = 66) or untreated ( n = 24) with their age-adjusted BMD being normalized. In a longitudinal assessment of men ( n = 60) who had two or more serial DEXA scans, at the second DEXA scan after a median of 3 years, men who were previously partially treated ( n = 19) or untreated ( n = 11) had proportionately greater improvements in BMD, significantly for Ward’s triangle ( P = 0.025) and the trochanter ( P = 0.044) compared with men ( n = 30) previously well treated. Conclusions : The present study demonstrates a positive relationship between adequacy of testosterone replacement and BMD in men with overt organic AD. Additionally, the BMD of well-treated AD men approximates that of age-matched non-AD controls. The greatest BMD gains are made by those who have been either untreated or partially treated, and optimal treatment over time (median 3 years) normalizes BMD to the level expected for healthy men of the same age.
Publisher: The Endocrine Society
Date: 11-1986
Abstract: To determine the antisteroidogenic effect of ketoconazole (KTZ) in the human testis, we measured the plasma delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, dehydroepiandrosterone (DHEA), progesterone, 17 alpha-hydroxyprogesterone, androstenedione (A), and testosterone (T) concentrations in three men with previously untreated metastatic prostate cancer at various time intervals for 24 h before and 48 h after the administration of 200 mg oral KTZ every 8 h. The adrenal glands of these three patients were suppressed (as measured by the plasma cortisol levels) by the administration of 1.0 mg dexamethasone daily for 7 days before and during the study. After six doses of KTZ, bilateral orchiectomy was performed, and the intratesticular concentration of the aforementioned seven steroids and the intratesticular activities of the 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase enzymes in the delta 4-steroidogenic pathway were determined. These seven intratesticular steroids and three intratesticular enzyme activities were compared to those in five men with previously untreated prostate cancer who underwent orchiectomy as primary treatment for their disease. Plasma A, DHEA, and T all significantly decreased during KTZ therapy. There was no significant change in the other four steroids in the plasma. In the testis, delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, and delta 4-17 alpha-hydroxyprogesterone were all significantly elevated, whereas intratesticular DHEA, A, and T were significantly decreased in the three KTZ-treated patients compared to levels in the five non-KTZ-treated patients. Measurement of the enzyme activities demonstrated a significant reduction in both 17 alpha-hydroxylase and 17,20-desmolase, but no change in 17 beta-hydroxysteroid dehydrogenase, in the KTZ-treated patients compared to the levels in the non-KTZ-treated patients. We conclude that oral KTZ decreases testicular T production by inhibiting the 17,20-desmolase and also the 17 alpha-hydroxylase steps in both the delta 4- and delta 5-T biosynthetic pathways.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.RBMO.2018.10.006
Abstract: Can IVF outcomes be predicted from the steroid profile generated by liquid chromatography-mass spectrometry (LC-MS/MS) from follicular fluid collected from a single dominant follicle and serum after ovarian stimulation. Prospective observational cohort study in which serum and follicular fluid were collected from women and used to generate steroid profiles by LC-MS/MS. A total of 93 consecutive women enrolled for IVF treatment were recruited at the Fertility Unit, Royal Prince Alfred Women and Babies Hospital, Sydney between September 2014 and July 2015. Baseline and serum levels at oocyte retrieval, as well as follicular fluid s les from the largest single antral follicle, were collected. All s les underwent steroid analysis within a single batch to measure progesterone (P4), oestradiol (E2), oestrone (E1), dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), and 3 α, 5α androstanediol (3α-diol) and 3β, 5α androstanediol (3β-diol). P4, E2, E1, A4, T, DHEA and A4 were detectable in all baseline serum levels, at oocyte retrieval and in follicular fluid s les, whereas DHT, 3α-diol and 3β-diol were only detectable in a minority of s les. The most consistent predictor of pre-transfer (number of follicles >14mm in diameter, oocytes retrieved or fertilized, day-5 blastocysts) outcomes was baseline serum anti-Müllerian hormone. In follicular fluid, E2 was a negative predictor of the number of oocytes retrieved and the number of day-5 blastocysts but no follicular fluid steroids predicted pregnancy outcome. None of the nine steroids measured in follicular fluid predicted pregnancy outcome in women undergoing IVF.
Publisher: Medknow
Date: 2016
Publisher: Oxford University Press (OUP)
Date: 03-2022
DOI: 10.1530/EJE-21-0608
Abstract: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known. The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections. Men ( n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later. In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since the last injection. After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.
Publisher: Oxford University Press (OUP)
Date: 12-03-2021
Abstract: Although characteristic changes in amino acid concentrations occur in obesity and sarcopenia, amino acids concentrations have not been reported in sarcopenic obesity. We studied n = 831 men aged 75 years and older from the 5-year follow-up of the Concord Health and Ageing in Men Project. Sarcopenia was defined using the Foundation of the National Institutes of Health criteria and obesity was defined as & % fat mass. There were 31 men (3.7%) who had sarcopenic obesity. Branched chain amino acids were elevated in the obese (but not sarcopenic) group (n = 348) but reduced in both the sarcopenic (but not obese) (n = 44) and the sarcopenic obese groups. Apart from this, most of the amino acid concentrations were between those for the obese and the sarcopenic groups. Yet despite low concentrations of branched chain amino acids, the sarcopenic obese group had indications of insulin resistance and diabetes mellitus (fasting glucose and insulin concentrations, homeostatic model assessment, and percentage of participants taking diabetes medications) that were similar to the obese group. In summary, sarcopenic obese participants did not have a unique amino acid signature. In obesity, elevated branched chain amino acids are not a prerequisite for insulin resistance and diabetes if obesity is associated with sarcopenia.
Publisher: Walter de Gruyter GmbH
Date: 20-05-2021
Abstract: Clinical evaluation of vitamin D status is conventionally performed by measuring serum levels of a single vitamin D metabolite, 25-hydroxyvitamin D predominantly by immunoassay methodology. However, this neglects the complex metabolic pathways involved in vitamin D bioactivity, including two canonical forms D3 and D2, bioactive 1,25-dihydroxy metabolites and inactive 24-hydroxy and other metabolites. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can measure multiple analytes in a s le during a single run with high sensitivity and reference level specificity. We therefore aimed to develop and validate a LC-MS/MS method to measure simultaneously 13 circulating vitamin D metabolites and apply it to 103 human serum s les. The LC-MS/MS method using a Cookson-type derivatization reagent phenyl-1,2,4-triazoline-3,5-dione (PTAD) quantifies 13 vitamin D metabolites, including mono and dihydroxy-metabolites, as well as CYP11A1-derived D3 and D2 metabolites in a single run. The lower limit of quantitation was 12.5 pg/mL for 1,25(OH) 2 D3 with accuracy verified by analysis of National Institute of Standards and Technology (NIST) 972a standards. Quantification of seven metabolites (25(OH)D3, 25(OH)D2, 3-epi-25(OH)D3, 20(OH)D3, 24,25(OH) 2 D3, 1,25(OH) 2 D3 and 1,20 S (OH) 2 D3) was consistently achieved in human serum s les. This profiling method can provide new insight into circulating vitamin D metabolite pathways forming the basis for improved understanding of the role of vitamin D in health and disease.
Publisher: AMPCo
Date: 09-2016
DOI: 10.5694/MJA16.00448
Abstract: Part 1 of this position statement dealt with the assessment of male hypogonadism, including the indications for testosterone therapy. This article, Part 2, focuses on treatment and therapeutic considerations for male hypogonadism and identifies key questions for future research. Key points and recommendations are:Excess cardiovascular events have been reported in some but not all studies of older men without pathological hypogonadism who were given testosterone treatment. Additional studies are needed to clarify whether testosterone therapy influences cardiovascular risk.Testosterone is the native hormone that should be replaced in men being treated for pathological hypogonadism. Convenient and cost-effective treatment modalities include depot intramuscular injection and transdermal administration (gel, cream or liquid formulations).Monitoring of testosterone therapy is recommended for efficacy and safety, focusing on ameliorating symptoms, restoring virilisation, avoiding polycythaemia and maintaining or improving bone mineral density.Treatment aims to relieve an in idual's symptoms and signs of androgen deficiency by administering standard doses and maintaining circulating testosterone levels within the reference interval for eugonadal men.Evaluation for cardiovascular disease and prostate cancer risks should be undertaken as appropriate for eugonadal men of similar age. Nevertheless, when there is a reasonable possibility of substantive pre-existing prostate disease, digital rectal examination and prostate-specific antigen testing should be performed before commencing testosterone treatment.Changes in management as result of the position statement: Treatment aims to relieve symptoms and signs of androgen deficiency, using convenient and effective formulations of testosterone. Therapy should be monitored for efficacy and safety.
Publisher: Wiley
Date: 04-1991
DOI: 10.1111/J.1365-2826.1991.TB00261.X
Abstract: Abstract The regulation of gonadotropin-releasing hormone (GnRH) secretion from the medial basal hypothalamus (MBH) of adult male rats has been studied using two types of in vitro methods, the dynamic superfusion and static incubation systems. We compared both systems for methodological features including stability of baseline GnRH release and technical limitations or artifacts as well as for response to norepinephrine and naloxone, an opiate antagonist, which represent the two major physiological neuromodulators regulating the GnRH neuron. Baseline GnRH release rate per MBH was similar in both systems for at least 6 h, although owing to dilution of effluent s les by flow-through medium, the dynamic superfusion system required six MBH per chamber compared with the static incubation system which required only one MBH per chamber. Procedural losses of GnRH were low with either system without the need for proteolytic enzyme inhibitors and were mainly due to adhesion to plastic surfaces of chambers and tubings in the dynamic superfusion system. Mechanical agitation of chambers by either manual swinging or continuous shaking increased GnRH release rate. Addition of hypertonic KCl (final 50 mM) or equivalent NaCl or mannitol solution in a minimal volume directly into the tissue chambers, induced a non-specific GnRH release due to osmotic effects in the dynamic superfusion system. In contrast, the static incubation system, where hypothalamic tissue is exposed to the exact final concentration of solute by complete change of media, was more resistant to GnRH release by hypertonic stimulus. Thus, only in the static incubation system did 50 mM KCl concentrations cause GnRH release through depolarization alone. Using systems optimized to avoid technical artifacts, stimulation with naloxone demonstrated dose-dependent GnRH release in both systems whereas norepinephrine gave a clear dose-dependent GnRH release only in the static system. Thus both incubation systems produce stable and similar baseline GnRH release for at least 6 h. The static incubation system proved superior requiring fewer hypothalami, a shorter preincubation stabilization period, allowing more accurate concentration of additives and was less prone to mechanical and osmotic artifacts while preserving responsiveness to physiological stimuli. The static incubation system, being technically simpler, more robust and accurate, provided a more valid approach to the in vitro study of GnRH release and its regulation by neurochemicals.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.IJCARD.2015.05.045
Abstract: Guideline recommended management of ischemic heart disease (IHD) suggests the concomitant use of antiplatelet, beta-blocker, renin angiotensin system blocker and statin therapy. In older people exposure to multiple medications has been associated with adverse events and geriatric syndromes. The study aimed to investigate the use of medications for IHD in older men with and without geriatric syndromes, and whether adherence to medication guidelines impacts on adverse outcomes. Community-dwelling men, aged ≥ 70 years and enrolled in the Concord Health and Ageing in Men Project were studied. Data on self-reported IHD, number of guideline recommended medications (use of four guideline medications considered optimal medical therapy) and geriatric syndromes (frailty, falls, cognitive impairment and urinary incontinence) were obtained. Cox regression was used to assess the relationship between optimal medical therapy and adverse outcomes (mortality and institutionalization), stratifying by geriatric syndromes. At baseline, 462 (27%) men self-reported a history of IHD and of these, 226 (49%) had at least one geriatric syndrome. Among men with IHD, no significant difference was observed in patterns of prescribing between those with and without geriatric syndromes. Compared to zero medications, optimal medical therapy among men with IHD was associated with lower mortality [hazard ratio, HR = 0.40 (95% CI: 0.21-0.95)] and institutionalization risk (HR=0.31 95% CI: 0.09-0.81). The presence of geriatric syndromes did not modify the association of increasing use of guideline recommended medications and clinical outcomes. In older men with IHD, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of geriatric syndromes.
Publisher: Oxford University Press (OUP)
Date: 06-1999
Abstract: In order to evaluate the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH) in combination with urinary human chorionic gonadotrophin (HCG) to induce spermatogenesis and fertility in gonadotrophin-deficient men, we conducted a prospective, open, non-comparative multicentre study in two Australian academic medical centres. Ten men with gonadotrophin deficiency requiring induction of spermatogenesis and fertility were treated with HCG for 3-6 months followed by the s.c. self-administration of injections of r-hFSH in combination with HCG for 18 months. Among the eight men who commenced r-hFSH treatment, seven demonstrated sperm output at a median of 6 months and five achieved the target sperm output of 1. 5x10(6) per ml at a median of 9 months of FSH treatment. Mean testicular volume increased by 4.2 ml during FSH treatment. Three men produced pregnancies in their partners, two of which resulted in the birth of healthy babies and a third patient's partner had a miscarriage. We conclude that r-hFSH is well tolerated and effective in inducing testis growth, spermatogenesis and fertility in gonadotrophin-deficient men. The efficacy of r-hFSH seems comparable with urinary FSH at restoring normal fertility in gonadotrophin-deficient men.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.JSBMB.2019.105528
Abstract: Long-term studies investigating hormone-dependent cancers and reproductive health often require prolonged frozen storage of serum which assumes that the steroid molecules and measurements are stable over that time. Previous studies of reproducibility of circulating steroids have relied upon flawed historical rather than contemporaneous controls. We measured serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) in 150 randomly selected serum s les by liquid chromatography-mass spectrometry (LC-MS) from men 70 years or older (mean age 77 years) in the CHAMP study. The original measurements in 2009 were repeated 10 years later using the identical serum aliquot (having undergone 2-4 freeze-thaw cycles in the interim) in 2019 together with another never-thawed aliquot of the same serum s le. The results of all three sets of measurements were evaluated by Passing-Bablok regression and Bland-Altman difference analysis. Serum androgens (T, DHT) and estrogens (E2, E1) measured by LC-MS display excellent reproducibility when stored for 10 years at -80 C without thawing. Serum T and DHT displayed high level of reproducibility across all three sets of measurements. Multiple freeze-thaw cycles over those storage conditions do not significantly affect serum T, DHT and E1 concentrations but produce a modest increase (21%) in serum E2 measurements.
Publisher: Wiley
Date: 10-1999
DOI: 10.1046/J.1365-2265.1999.00827.X
Abstract: It has previously been shown that testosterone implantation is an effective and well accepted form of androgen replacement therapy, but that pellet extrusion was the most frequent side-effect. The present study aimed to reduce the extrusion rate. To determine whether the washing of testosterone pellets to remove potentially surface-adherent particles decreased the rate of extrusion of pellet implants. Prospective, randomized parallel group design in a single centre with consecutive procedures to be randomized (1 : 1) into a wash or control group. The study included 251 testosterone implantation procedures in men with known androgen deficiency. The primary endpoint, extrusion rate per procedure, was evaluated prospectively by telephone contact at 1 week and then 3 and 6 month intervals. Secondary end-points included peri-procedure adverse events (bleeding, skin reaction, excessive discomfort) noted at the time of implant. Bruising, bleeding and infection were also evaluated as later adverse events by telephone and personal follow-up. Explanatory variables recorded as possible covariables included the number of implants used, production batch number of the implants, the operator, as well as other demographic and medical factors. In the wash group, the extrusion rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects), indicating no evidence of any benefit of the wash procedure (OR = 1. 09 [95% CI 0.47-2.6] per procedure). There was no evidence of benefit in secondary endpoints including total adverse events (7.1%, OR 1.28 [0.44-3.9], bleeding/bruising (8.8%, 1.23 [0.47-3.3]) and infection (4.0%, 1.54 [0.35-7.6]) per procedure. Among men reporting an infection requiring antibiotic treatment according to their own general practitioners, six/ten (60%) subsequently experienced an extrusion. There were no significant differences in extrusion rate between four different operators (P = 0.24) nor among 12 different batches of pellets used during the course of the study (P = 0.77). The pellet washing procedure used during implantation does not reduce the subsequent extrusion rate. The higher rate of both primary and secondary adverse events in this prospective study compared with the previous retrospective survey may reflect either more rigorous follow-up or a secular trend.
Publisher: American Thoracic Society
Date: 12-1992
DOI: 10.1164/AJRCCM/146.6.1389
Abstract: As sleep apnea is more prevalent in men and testosterone has known effects on sleep apnea and chemosensitivity, reduction of androgen activity may influence sleep-disordered breathing and respiratory control. We studied the effect of 1 wk of treatment with flutamide, a nonsteroidal antiandrogen, on sleep, respiration, and ventilatory control in eight men with sleep apnea. Results on flutamide were compared with two baseline studies performed before and after the drug treatment period. Although effective androgen blockade was achieved as evidenced by increased hormone levels, flutamide had no effect on sleep architecture or chemoresponsiveness to hypoxia and hypercapnia. There was a trend towards a reduction in respiratory disturbance index in both NREM and REM sleep (41 +/- 4 baseline versus 34 +/- 3 flutamide, p = 0.09 NREM 53 +/- 4 baseline versus 48 +/- 3 flutamide, p = 0.16 REM), but this was not significant. Our results indicate that androgen blockade had no clinically significant effect on sleep, sleep-disordered breathing, or chemosensitivity in patients with moderate to severe sleep apnea. More specific blockers such as gonadotrophin-releasing hormone analogs may have more clinical effect or, alternatively, androgen blockade may be more beneficial in patients with milder sleep apnea.
Publisher: American College of Physicians
Date: 09-2023
DOI: 10.7326/M23-0342
Publisher: Wiley
Date: 26-07-2016
DOI: 10.1002/JBMR.2904
Abstract: This study aimed to examine progressive temporal relationships between changes in major reproductive hormones across three waves of a cohort study of older men and (1) changes in bone mineral density (BMD) and (2) incident fractures (any, hip or non-vertebral) over an average of 6 years of follow-up. The CHAMP cohort of men aged 70 years and older were assessed at baseline (2005 to 2007, n = 1705), 2-year follow-up (n = 1367), and 5-year follow-up (n = 958). Serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) (by liquid chromatography-tandem mass spectrometry [LC-MS/MS]), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (by immunoassay) were measured at all time-points, whereas free testosterone (cFT) was calculated using a well-validated formula. Hip BMD was measured by dual-energy X-ray absorptiometry (DXA) at all three time-points, and fracture data were verified radiographically. Statistical modeling was done using general estimating equations (GEEs). For total hip BMD, univariable analyses revealed inverse associations with temporal changes in serum SHBG, FSH, and LH and positive associations for serum E1 and cFT across the three time-points. In models adjusted for multiple covariables, serum SHBG (β = -0.029), FSH (β = -0.065), LH (β = -0.049), E1 (β = 0.019), and cFT (β = 0.033) remained significantly associated with hip BMD. However for femoral neck BMD, only FSH (β = -0.048) and LH (β = -0.036) remained associated in multivariable-adjusted models. Temporal change in serum SHBG, but not T, E2, or other hormonal variables, was significantly associated with any, nonvertebral or hip fracture incidence in univariable analyses. In multivariable-adjusted models, temporal increase in serum SHBG over time remained associated with any fracture (β = 0.060) and hip fracture (β = 0.041) incidence, but not nonvertebral fracture incidence. These data indicate that a progressive increase in circulating SHBG over time predicts bone loss and fracture risk in older men. Further studies are warranted to further characterize changes in circulating SHBG as a mechanism and/or biomarker of bone health during male ageing. © 2016 American Society for Bone and Mineral Research.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2014
Publisher: Oxford University Press (OUP)
Date: 03-2000
Abstract: The aim of this study was to determine for the first time in humans, the efficacy of adding a low dose oestradiol to a suboptimally suppressive testosterone dose in a depot hormonal regimen to suppress spermatogenesis in healthy eugonadal men. Twenty-six healthy men were randomized into groups that were treated by a single subdermal implantation of either 600 mg testosterone alone (T n = 11) or together with 10 mg (TE10, n = 7) or 20 mg (TE20, n = 8) oestradiol. Administration of oestradiol produced a dose-dependent increase in peak plasma oestradiol at 1 month and prolonged suppression of plasma LH and FSH leading to significantly enhanced suppression of sperm output. Despite the augmented spermatogenic suppression, there was no significant difference in the proportions achieving azoospermia (6/26, 23%) or severe oligozoospermia (<1 or <3 x 10(6) spermatozoa per ml, 7/26, 27%) and overall these proportions were inadequate to provide reliable contraception according to the standards identified in World Health Organization male contraceptive efficacy studies. Total and free testosterone remained within the eugonadal reference range for young men throughout the study. While the lower oestradiol dosage had minimal spermatogenic suppression effects, the higher dose produced dose-limiting adverse effects of androgen deficiency and/or oestrogen excess between the fourth and sixth month of the study. This appeared to be due to the unexpectedly prolonged, low concentration of oestradiol release from the oestradiol implants. There were no significant treatment-related changes in body composition, lipids, prostate-specific antigen, haematological or biochemical variables. Thus oestradiol has a low therapeutic window and dose-limiting side-effects at dosages that fail to achieve the uniform azoospermia required of an effective male hormonal contraceptive regimen.
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/RD16022
Abstract: Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.
Publisher: American Diabetes Association
Date: 10-1988
Abstract: The modern management of diabetes relies heavily on self-monitoring of blood glucose (SMBG), and therefore SMBG records are an important source of clinical data for management decision making. The development of a memory Glucometer has provided the opportunity to verify the validity of glucose records thus generated and observe the effects of different educational approaches on compliance with SMBG. Thirty-four patients without previous experience of SMBG were randomized into one of the following experimental groups differing in the model of diabetes care: mutual decision making, didactic, and authoritarian. Patients, unaware of the memory capacity of the glucose meter, were required to perform four glucose measurements per day over a 14-day observation period. Patient-generated blood glucose records were then compared with objective records stored in the glucose-meter memory. Patients with gestational diabetes mellitus recorded a lower proportion of correct results (63 vs. 79%, P = .049) and exhibited a tendency to invent results with lower blood glucose levels (5.3 vs. 7.5 mM, P & .0001) than the results omitted compared with patients with non-insulin-dependent diabetes mellitus. Predictors of greater validity of records were perceived intelligence of the subject (χ2 = 4.56, P & .02) and private health-insurance status (χ2 = 4.52, P & .04), whereas the experimental group assignment was not significant. These findings reflect potential motivational and sociodemographic limitations in the validity of SMBG recordings within the management and education of patients with gestational and nongestational diabetes.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Proceedings of the National Academy of Sciences
Date: 20-03-2017
Abstract: The cause of polycystic ovary syndrome (PCOS) is unknown, but androgen excess is a key feature. We combined a hyperandrogenized PCOS mouse model with global and tissue- and cell-specific androgen-resistant mouse lines to uncover the sites of androgen action that initiate PCOS. We demonstrate that direct androgen actions, particularly in neurons but less so in granulosa cells, are required for the development of key reproductive and metabolic PCOS features. These data highlight the previously overlooked importance of extraovarian neuroendocrine androgen action in the origins of PCOS. Targeting androgen-driven mechanisms may represent new options for developing a mechanism-based treatment of PCOS.
Publisher: Wiley
Date: 21-04-2013
DOI: 10.1002/DTA.1481
Abstract: Urine provides a convenient non-invasive alternative to blood s ling for measurement of certain hormones. Urinary luteinizing hormone (LH) measurements have been used for endocrinology research and anti-doping testing. However, the commercially available LH immunoassays are developed and validated for human blood s les but not urine so that LH assays intended for use with urine s les need thorough validation. Therefore, the present study evaluated the measurement of urinary LH immunoreactivity using previously validated immunofluorometric (IF) and immunochemiluminometric (ICL) LH assays after prolonged frozen storage. LH was measured in serial urine s les following administration of a single injection of one of two doses of recombinant human chorionic hormone (rhCG) with assays run at the end of study (2008) and again after four years of frozen (-20 °C) storage where s les were stored without adding preservatives. The ICL assay showed quantitatively reproducible LH measurements after prolonged -20 °C storage. However, the IF immunoassay gave consistently lower LH levels relative to ICL (2008) with a further proportionate reduction after four years of s le storage (2012). Yet, both the assays displayed similar patterns of the time-course of urine LH measurement both before and after four years of frozen storage. In conclusion, we found that both immunoassays are suitable for urinary LH measurements with ICL assay being more robust for quantitative urinary LH measurement such as for anti-doping purposes, whereas the IF could be applicable for research studies where urine LH levels are compared within-study but not in absolute terms.
Publisher: The Endocrine Society
Date: 02-2009
DOI: 10.1210/EN.2008-0760
Abstract: Arterial calcification has prognostic significance for cardiovascular outcomes, but its pathogenesis remains unclear. Calcification increases with age, but its prevalence in men suggests hormonal influence. In this study we analyzed the effect of exogenous androgens on calcification of advanced atherosclerotic lesions in the arterial tree of gonadally intact 34-wk-old male and female apolipoprotein E-null mice. Testosterone (T) increased calcification 3- to 4-fold (P & 0.05) in lesions of the innominate artery and aortic sinus. A nonaromatizable androgen, dihydrotestosterone, also increased lesion calcification in the innominate artery (2.4-fold, P & 0.05) but not the aortic sinus. The androgen-induced effects were independent of sex and occurred despite corresponding reductions in plaque area, the latter correlating inversely with increased serum high-density lipoprotein cholesterol levels. Androgen-induced calcification in the innominate artery was observed with up-regulation of local androgen receptor (AR) expression in response to T and dihydrotestosterone for both males and females but neither androgen influenced innominate artery estrogen receptor (ER)-α or -β expression in either sex. Conversely, T-induced calcification in the aortic sinus was associated with down-regulation of ERα but not ERβ expression in both sexes, whereas androgen-induced AR expression was increased in female but decreased in male mice. This study demonstrates for the first time that calcification of advanced atherosclerotic lesions is an androgen-sensitive process and postulates potential roles for both AR- and ER-mediated pathways in androgen-induced vascular calcification. We demonstrate a novel direct link between vascular calcification and the major male hormone, T, uncoupled from conventional relationships with plaque growth and lipid levels. Calcification of advanced atherosclerotic lesions is an androgen-sensitive process whereby testosterone uncouples conventional relationships between plaque growth and lipid levels.
Publisher: Oxford University Press (OUP)
Date: 27-10-2015
Abstract: Comorbidity and multimorbidity are common in older people. Here we used a novel analytic approach called Association Rules together with network analysis to evaluate multimorbidity (two or more disorders) and comorbidity in old age. A population-based cross-sectional study was undertaken where 17 morbidities were analyzed using network analysis, cluster analysis, and Association Rules methodology. A comorbidity interestingness score was developed to quantify the richness and variability of comorbidities associated with an index condition. The participants were community-dwelling men aged 70 years or older from the Concord Health and Ageing in Men Project, Sydney, Australia, with complete data (n = 1,464). The vast majority (75%) of participants had multimorbidity. Several morbidity clusters were apparent (vascular cluster, metabolic cluster, neurodegenerative cluster, mental health and other cluster, and a musculoskeletal and other cluster). Association Rules revealed unexpected comorbidities with high lift and confidence linked to index diseases. Anxiety and heart failure had the highest comorbidity interestingness scores while obesity, hearing impairment, and arthritis had the lowest (zero) scores. We also performed Association Rules analysis for the geriatric syndromes of frailty and falls to determine their association with multimorbidity. Frailty had a very complex and rich set of frequent and interesting comorbidities, while there were no frequent and interesting sets associated with falls. Old age is characterized by a complex pattern of multimorbidity and comorbidity. Single disease definitions do not account for the prevalence and complexity of multimorbidity in older people and a new lexicon may be needed to underpin research and health care interventions for older people.
Publisher: Medknow
Date: 05-2008
DOI: 10.1111/J.1745-7262.2008.00406.X
Abstract: Androgens remain the most effective and widely abused ergogenic drugs in sport. Although androgen doping has been prohibited for over 3 decades with a ban enforced by mass spectrometric (MS)-based urine testing for synthetic and exogenous natural androgens, attempts continue to develop increasingly complex schemes to circumvent the ban. A prominent recent approach has been the development of designer androgens. Such never-marketed androgens evade detection because mass spectrometry relies on identifying characteristic chemical signatures requiring prior knowledge of chemical structure. Although once known, designer androgens are readily detected and added to the Prohibited List. However, until their structures are elucidated, designer androgens can circumvent the ban on androgen doping. To combat this, in vitro androgen bioassays offer powerful new possibilities for the generic detection of unidentified bioactive androgens, regardless of their chemical structure. Another approach to circumvent the ban on androgen doping has been the development of indirect androgen doping, the use of exogenous drugs to produce a sustained increase in endogenous testosterone (T) production. Apart from estrogen blockers, however, such neuroendocrine active drugs mostly provide only transient increases in blood T. Finally the ban on androgen doping must allow provision for rare athletes with incidental, proven androgen deficiency who require T replacement therapy. The Therapeutic Use Exemption mechanism makes provision for such necessary medical treatment, subject to rigorous criteria for demonstrating a genuine ongoing need for T and monitoring of T dosage. Effective deterrence of sports doping requires novel, increasingly sophisticated detection options calibrated to defeat these challenges, without which fairness in sport is tarnished and the social and health idealization of sporting ch ions devalued.
Publisher: AMPCo
Date: 10-2004
DOI: 10.5694/J.1326-5377.2004.TB06364.X
Abstract: To analyse temporal trends and geographical variations in testosterone prescribing in Australia. An analysis of testosterone prescribing over the past 11 years according to products and region, determined by Pharmaceutical Benefits Scheme (PBS) expenditure in Australian states and territories. Patterns of monthly PBS expenditure on injectable, oral and implantable testosterone products from 1 January 1991 to 30 December 2001, classified by state or territory. There were two periods (1993-1994 and 1998-1999) of striking upsurge followed by declines in national total prescribing of testosterone. These changes were more prominent for oral than injectable testosterone products, and patterns were similar in all regions, apart from a disproportionately higher peak in Western Australia in 1998. On a per-capita basis, Western Australia showed a dramatic increase in prescribing of oral and implantable, but not injectable, testosterone coinciding with the opening of a franchised men's sexual health clinic in Perth. The two striking upsurges in testosterone prescribing despite no convincing new evidence to justify them appear to reflect promotional activity to prescribe testosterone for older men, rather than overcoming the underdiagnosis of androgen deficiency related to pituitary or testicular disease in younger men. The curtailments after the introduced restrictions to PBS prescribing for older men without overt androgen deficiency were partial and temporary, suggesting that such regulatory barriers are only partly successful in counteracting the commercial and populist pressure driving excessive testosterone prescribing. Professional and community education is needed for appropriate diagnosis of genuine androgen deficiency in younger men, while discouraging unproven testosterone treatment for ageing men.
Publisher: Wiley
Date: 04-2001
DOI: 10.1046/J.1365-2265.2001.01240.X
Abstract: Androgens play a key role in prostate development and disease. However the effects of androgen deficiency and replacement on the prostate during mid-life are not well understood, and there is no information on their effects on prostate zonal volumes. This study aimed to define the effects of androgen deficiency and androgen replacement therapy on prostate zonal volumes (central, peripheral & total) using planimetric prostate ultrasound with particular emphasis on the central zone of the prostate, the most hormonally sensitive and fastest growing region of the prostate and the zone where nodular benign prostate hyperplasia originates. Central and total prostate volume were measured directly, and peripheral prostate volume calculated, by a single observer using transrectal ultrasound in 71 hypogonadal men (aged 40 +/- 2, range 18-78 years) who were compared with in idually age-matched health controls without prostate or gonadal disease. Among the men with androgen deficiency, 17 men had untreated androgen deficiency (never treated or no treatment for at least 6 months) and 54 men were receiving long-term androgen replacement therapy (median 32 months, 93% > or = 6 months) with testosterone implants (n = 27), testosterone ester injections (n = 24) or other testosterone treatment (n = 3). Compared with in idually age-matched controls, untreated androgen deficient men (n = 17) had reduced central (4.0 +/- 0.5 vs. 6.2 +/- 0.5 ml, P < 0.001) and total (23.4 +/- 2.6 vs. 29.2 +/- 1.6 ml, P < 0.001) prostate volumes whereas the reduction in peripheral prostate volume (19.4 +/- 2.1 vs. 23.0 +/- 1.3 ml, P = 0.15) was not statistically significant. Men with treated androgen deficiency (n = 54) also still had significantly reduced central (4.8 +/- 0.4 vs. 6.8 +/- 0.4, P < 0.001), peripheral prostate volume (19.6 +/- 0.8 vs. 21.6 +/- 0.7 ml, P = 0.06) and total (24.4 +/- 1.1 vs. 28.4 +/- 1.0 ml, P = 0.008) despite prolonged restoration of physiological testosterone concentrations. Neither modality of testosterone treatment nor type of hypogonadism influenced prostate zonal volumes before or after treatment. In contrast, central, peripheral and total prostate volume increased with age among healthy controls and men with androgen deficiency regardless of androgen replacement therapy. Plasma PSA concentrations were reduced in men with untreated androgen deficiency and were similar to age-matched controls in men with treated androgen deficiency. We conclude that, during mid-life, chronic androgen deficiency due to hypogonadism is associated with reduced central, peripheral and total prostate volumes. Reduced prostate volumes persist even during long-term maintenance of effective androgen replacement therapy with physiological testosterone concentrations until the fourth decade of life. After that, prostate volumes increase with age regardless of androgen deficiency or replacement. These findings suggest that, during mid-life, age is a more important determinant of prostate growth than ambient testosterone concentrations maintained in the physiological range. The persistently subnormal prostate volumes despite adequate androgen replacement therapy may explain the apparent paucity of cases of overt prostate disease among testosterone-treated androgen deficient men who retain protection against prostate disease despite physiological androgen replacement therapy.
Publisher: Walter de Gruyter GmbH
Date: 14-05-2019
Abstract: In large community-based studies of puberty, Tanner staging by a clinician is often not possible. We compared self-rated Tanner staging and other subjective ratings of pubertal development with serum hormone levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to reassess the utility of self-rated pubertal stage using highly sensitive and specific hormone analysis. Adolescents and their parents enrolled in the Adolescent Rural Cohort study of Hormones and health, Education, environments and Relationships (ARCHER) answered annual survey questions on pubertal development. Annually, adolescents provided blood s les for serum testosterone and estradiol measured by LC-MS/MS. Longitudinally, self-rated Tanner stage was positively associated with serum testosterone and estradiol levels in both sexes. Confirmation by adolescent and parent that puberty had commenced was associated with higher gonadal hormone levels in both sexes. Parent and adolescent responses demonstrated ‘fair’ to ‘moderate’ agreement. Over a 3-year follow-up, self-rated Tanner staging and simple questions regarding pubertal onset and development are positively associated with adolescent gonadal hormone concentrations in serum measured by mass spectrometry. Thus, self-report of puberty stage still has a role in large community-based studies where physical examination is not feasible.
Publisher: Springer Science and Business Media LLC
Date: 02-2012
Abstract: Evidence about the association between treatment with high-risk medicines and frailty in older in iduals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ≥70 years of age. High-risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men.
Publisher: The Endocrine Society
Date: 03-2009
DOI: 10.1210/JC.2008-1648
Abstract: Background: The induction of spermatogenesis and fertility with gonadotropin therapy in gonadotropin-deficient men varies in rate and extent. Understanding the predictors of response would inform clinical practice but requires multivariate analyses in sufficiently large clinical cohorts that are suitably detailed and frequently assessed. Design, Setting, and Participants: A total of 75 men, with 72 desiring fertility, was treated at two academic andrology centers for a total of 116 courses of therapy from 1981–2008. Outcomes: Semen analysis and testicular examination were performed every 3 months. Results: A total of 38 men became fathers, including five through assisted reproduction. The median time to achieve first sperm was 7.1 months [95% confidence interval (CI) 6.3–10.1]) and for conception was 28.2 months (95% CI 21.6–38.5). The median sperm concentration at conception for unassisted pregnancies was 8.0 m/ml (95% CI 0.2–59.5). Multivariate correlated time-to-event analyses show that larger testis volume, previous treatment with gonadotropins, and no previous androgen use each independently predicts faster induction of spermatogenesis and unassisted pregnancy. Conclusions: Larger testis volume is a useful prognostic indicator of response. The association of slower responses after prior androgen therapy suggests that faster pregnancy rates might be achieved by substituting gonadotropin for androgen therapy for pubertal induction, although a prospective randomized trial will be required to prove this.
Publisher: The Endocrine Society
Date: 12-2014
DOI: 10.1210/JC.2014-2464
Abstract: The causal relationship between metabolic syndrome and reproductive hormones is unclear. This study sought to examine the cross-sectional, longitudinal, and predictive associations between reproductive hormones and SHBG and metabolic syndrome in older men. Men ages 70 years and older from the Concord Health and Ageing in Men Project study (n = 1705) were assessed at baseline and 2-year follow-up. At baseline, T, dihydrotestosterone (DHT), estradiol, and estrone were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH by immunoassay. Metabolic syndrome was defined using the P National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. In cross-sectional data, significant associations between each of T, SHBG, DHT, and calculated free testosterone (cFT) with the metabolic syndrome remained significant after multivariate adjustment. In longitudinal analyses, however, only lower SHBG was significantly associated with incident metabolic syndrome over the 2-year follow-up (P for linear trend = .04). Although low serum T, DHT, SHBG, and cFT were associated cross-sectionally with metabolic syndrome among community-dwelling older men, over a 2-year follow-up period only SHBG remained significant after multivariate adjustment. This suggests that lowered circulating androgens (T and DHT) may be biomarkers rather than causally related to incident metabolic syndrome.
Publisher: Massachusetts Medical Society
Date: 12-09-2013
DOI: 10.1056/NEJME1305307
Publisher: The Endocrine Society
Date: 12-2014
DOI: 10.1210/ER.2014-1067
Publisher: Wiley
Date: 03-09-2019
DOI: 10.1002/DTA.2689
Abstract: Testosterone doping remains a prevalent and potent form of drug cheating among elite athletes. In men, the urine testosterone (T) to epitestosterone (E) ratio (T/E ratio) can identify administration of exogenous T by its suppression of endogenous T production through strong negative feedback on endogenous T and E production as well as spill over into urine of extra testosterone. However, this mechanism may be partially inoperative in females whose much lower circulating T derives from three sources, none subject to powerful negative T feedback. Hence, additional methods to detect T doping in females are required. In this study we report two cases of elite female athletes who were sanctioned for T doping proven by measurement of serum T using liquid chromatography-mass spectrometry (LC-MS), when serial urine T and T/E ratio in one were not indicative of T doping, and in the other were nullified by incidental genetic inactivation of T glucuronidation through the uridine diphosphoglucuronosyl transferase 2B17 (UGT2B17) deletion genotype-phenotype. These findings indicate the potential for serum T measurement by LC-MS to detect T doping in female athletes, especially if implemented in the Bayesian format of an athlete biological passport.
Publisher: Wiley
Date: 14-01-2002
DOI: 10.1046/J.1440-1681.2002.03606.X
Abstract: 1. To evaluate interventions aiming to increase muscle strength in older men, it is necessary to use an objective and reproducible method to measure strength. The most reliable method to evaluate muscle strength is isokinetic peak torque (PT) measured by a dynamometer however, raw PT varies with differences in body size and an optimal scaling for body physique to control confounding effects of body size is necessary to make the most valid comparisons. 2. The present study was designed to estimate the effects of age (part A) and androgen administration (part B) on muscle strength and to estimate reproducibility and evaluate various scaling methods in order to optimize comparisons of isokinetic PT measurements. 3. A single isokinetic exercise protocol was used to compare the muscle strength of 31 healthy men of two age groups ( 60 years part A) and change in strength due to administration of dihydrotestosterone (DHT 70 mg/day) or placebo gel for 3 months in 35 healthy older (> or = 60 years) men (part B). 4. Muscle strength was assessed by a total of 16 PT measurements using a Cybex NORM dynamometer (Cybex, Ronkonkoma, NY, USA). Age-related differences in muscle strength were estimated by using PT evaluated as raw data or scaled by normalizing methods, including simple ratio (PT/weight), allometric PT (PT/weight(0.67)) and adjustment of PT by weight, height, body mass index and body surface area (BSA). The goodness-of-fit for various scaling methods was compared using the Akaike Information Criterion (AIC) as an objective measure of model-based entropy reduction. 5. The effects of DHT administration according to different scaling methods were estimated by eta-squared measure of effect size in treatment models. In part A, older men were weaker than younger men in five knee PT, consistently by all eight analysis models but not in shoulder PT. In part B, DHT treatment resulted in an increase one knee PT (dominant knee flexion at 120 degrees/s) with the difference consistent in all seven models. 6. The scaling model using BSA proved superior to other comparison models throughout both parts of the present study according to entropy minimization criteria (AIC) for goodness-of-fit of the model or eta-squares for treatment effect size. 7. We conclude that differences in muscle strength due to age or androgen administration in older men are restricted to a minority of lower limb contractions and that use of BSA scaling for PT values is considered the best scaling method for muscle strength comparisons in either cross-sectional or longitudinal studies.
Publisher: Oxford University Press (OUP)
Date: 10-2014
DOI: 10.1111/JSM.12550
Publisher: Oxford University Press (OUP)
Date: 12-1997
DOI: 10.1093/HUMREP/12.12.2701
Abstract: Controversial claims, based on a meta-analysis aggregating 61 heterogeneous observational studies, have been made that human sperm output has decreased by 50% over the last six decades and that this trend may be due to global pollution. If true, such effects should be evident in all areas of the globe however, longitudinal studies within single centres in Europe and America have produced conflicting results and there are no reports from the southern hemisphere. We therefore reviewed semen analyses obtained from 1980-1995 from 689 healthy men volunteering for screening either as potential sperm donors for a donor insemination programme (n = 509) or to participate in five male contraception research studies (studies no. 1-5, n = 180). All were recruited through the Andrology Unit of the Royal Prince Alfred Hospital, Sydney, by the same doctors using standard methods of recruiting, screening and laboratory examination throughout the period 1980-1995. Recruitment was by advertising without regard to marital or fertility status except in two contraceptive efficacy studies (no. 1 and no. 3) where participants had to be in a stable relationship requiring contraception. Analysing the first semen s le in idually or when grouped by year of ejaculation, there was no significant difference in sperm concentration over time or between years or according to year of birth. During the second half of this period, 180 consecutive volunteers were recruited by the same doctors and staff for five male contraception studies. The median sperm concentration for studies no. 1 (103 x 10(6) ml) and no. 2 (142 x 10(6) ml) were significantly (P < 0.05) higher than for studies no. 3-5 (84, 67 and 63 x 10(6) ml, respectively) and for potential sperm donors (median 69 x 10(6) ml). The inconsistency of these estimates illustrates the magnitude of bias (up to 100%) in sperm output that may occur in recruiting groups of self-referred volunteers within a single centre. This highlights the invalidity of extrapolating similar findings on sperm output of self-selected volunteers to the general male community or in using such study groups to characterize sperm output in supposedly 'normal' men.
Publisher: Wiley
Date: 08-1989
DOI: 10.1111/J.1365-2826.1989.TB00110.X
Abstract: Abstract We have investigated some requirements for valid estimates of pulsatile luteinizing hormone (LH) secretion in the castrate male rat. The choice of cannulation route and the minimal s ling intensity required to produce stable, unbiased estimates of parameters of pulsatile LH secretion were examined. Castrate mature male Wistar rats with unilateral ligation of a carotid artery (an inevitable consequence of carotid artery cannulation) had a 47% reduction in mean LH levels (1.8 vs 3.4 ng/ml, P< 0.011) attributable to a 40% reduction in LH pulse frequency (6.2 vs 10.4 peaks/6 h P<0.006) without change in LH pulse litude or other parameters of pulsatile LH secretion. In another study, a range of s ling intensities were examined to derive estimates of pulsatile LH secretion. Parameter estimates derived from the most intensive regime (q10 min s ling for 6 h) were compared with estimates of pulsatile LH secretion parameters determined from less intensive derivative sub-series composed of either fixed s ling frequency, but variable total study duration (i.e. the first 1, 2, 3, 4 and 5 h at 10 min intervals), or a fixed total study duration but variable s ling frequency. LH pulse frequency (or its inverse, interpulse interval) was quite sensitive to s ling intensity whereas pulse litude, maximum, minimum and overall mean LH were estimated accurately at even relatively low s ling intensity (q20 min for one h duration). Lower frequency s ling (q20 min) gave marked underestimates of LH pulse frequency (4.9 vs 10.4 peaks/6 h, P<0.05) compared with q10min s ling over a 6h study. These results indicated that for stable and unbiased estimates of pulsatile LH secretion in the castrate mature male rat it is necessary (but may not be sufficient) to (1) avoid carotid artery cannulation and (2) undertake blood s ling at intervals of not more than 10 min for at least 3 h.
Publisher: Wiley
Date: 04-2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2019
Publisher: The Endocrine Society
Date: 08-2017
Publisher: Elsevier BV
Date: 06-1997
DOI: 10.1016/S0735-1097(97)00063-6
Abstract: We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males. Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown. We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject. Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03). Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.
Publisher: The Endocrine Society
Date: 05-1995
DOI: 10.1210/ENDO.136.5.7720654
Abstract: We demonstrate that androgens rapidly and specifically increase intracellular calcium in Sertoli cells, investigate the mechanism, and suggest the unifying hypothesis that calcium might be a common intracellular molecular effector to explain the known synergism between FSH and testosterone (T) action on Sertoli cells in support of spermatogenesis. In freshly isolated Sertoli cells, T and its 5 alpha-reduced metabolite dihydrotestosterone increased intracellular calcium from 83 +/- 4 to 147 +/- 8 and 167 +/- 29 nM, respectively, whereas estradiol had minor (117 +/- 9 nM) and progesterone no (80 +/- 6 nM) effect. The effect of T was rapid (20-40 sec) and inhibited by 1) preincubation with either a pure nonsteroidal antiandrogen (hydroxyflutamide) or a 5 alpha-reductase inhibitor (finasteride) or 2) removal of extracellular calcium (47 +/- 4 nM) or pharmacological blockade of voltage-activated (62 +/- 5 nM) or voltage-independent (55 +/- 14 nM) membrane calcium channels. These findings suggest that the T-induced rise in Sertoli cell cytosolic calcium involves sequential 5 alpha-reduction, binding to a classical androgen receptor, and activation of transmembrane influx of extracellular calcium. Immobilization of T by conjugation to a large carrier molecule (BSA) to prevent steroid entry into Sertoli cells also resulted in a rapid increase in cytosolic calcium to a similar magnitude as unconjugated T, consistent with a plasma membrane site of action. This finding together with the rapid cytosolic calcium rise caused by T argues for the possible existence of a short term, nongenomic effects in hormonal regulation of Sertoli cell function in addition to the well known, slower genomic response.
Publisher: Wiley
Date: 06-2008
DOI: 10.1038/BJP.2008.150
Publisher: Oxford University Press (OUP)
Date: 30-03-2022
Abstract: Nutritional intake could influence the development of frailty. The aim was to evaluate the associations between dietary iron intakes and changes in dietary iron intakes with frailty. Cross-sectional analyses involved 785 men with Fried frailty phenotype (FP) and 758 men with Rockwood frailty index (FI) data aged 75 years and older at nutrition assessment from the Concord Health and Ageing in Men Project prospective cohort study. Of these, 563 men who were FP robust or prefrail, and 432 men who were FI nonfrail were included in the longitudinal analyses for more than 3 years. Dietary intake was assessed at both timepoints using a validated diet history questionnaire. The dietary calculation was used to derive heme iron and nonheme iron intakes from total iron intakes. The associations were evaluated through binary logistic regression. Incidence of FP frailty was 15.3% (n = 86). In longitudinal analyses, maintaining total iron intakes (medium tertile −2.61–0.81 mg/d), increases in total iron and nonheme iron intakes (high tertiles ≥0.82 mg/d and ≥0.80 mg/d), and changes in nonheme iron intake (1 mg increment) were associated with reduced risks of incident FP frailty (OR: 0.47 [95% confindence interval (CI): 0.24, 0.93, p = .031], OR 0.48 [95% CI: 0.23, 0.99, p = .048], OR 0.41 [95% CI: 0.20, 0.88, p = .022], and OR 0.89 [95% CI: 0.82, 0.98, p = .017]). Maintaining or increases in total dietary iron and increases or changes in dietary nonheme iron intakes more than 3 years were associated with reduced incidence of FP frailty in older men.
Publisher: The Endocrine Society
Date: 12-2014
DOI: 10.1210/EN.2014-1226
Abstract: The androgen receptor (AR) is widely expressed in mammary cells of female mammals including humans and mice, indicating a possible role for AR-mediated androgen actions in breast development, function, and pathology, although the specific mechanisms remain unclear. To elucidate the mechanisms of androgen action in mammary gland physiology and development, we used AR-knockout (ARΔex3KO) female mice with a universally expressed, transcriptionally inactive AR protein harboring an in-frame deletion of its second zinc finger. Although in sexually mature wild-type (WT) and ARex3ΔKO females, the mammary epithelial growth was fully extended to the edge of the fat pad, during puberty, ARex3ΔKO females exhibit significantly accelerated mammary ductal growth and an increased number of terminal end buds compared with WT females. Accelerated ARex3ΔKO female mammary growth was associated with significantly increased mammary epithelial ERα expression and activated Wnt/β-catenin signaling as shown by increased Wnt4 expression and accumulation of nuclear β-catenin. These findings are consistent with increased mammary estrogen exposure although ovarian estradiol content was unchanged compared with WT females. Furthermore, treatment with the potent pure androgen DHT markedly reduced ductal extension and terminal end bud numbers in WT but not in ARΔex3KO females, further supporting the concept that AR-mediated, androgen-induced suppression of murine mammary growth is a physiological characteristic of puberty. In summary, our findings reveal an inhibitory role of AR-mediated androgen actions in pubertal mammary gland development by reducing epithelial cell proliferation and could be mediated by regulation of Wnt/β-catenin signaling.
Publisher: American College of Physicians
Date: 16-11-2010
DOI: 10.7326/0003-4819-153-10-201011160-00004
Abstract: Benign prostatic hypertrophy increases with age and can result in substantially decreased quality of life for older men. Surgery is often required to control symptoms. It has been hypothesized that long-term administration of a non lifiable pure androgen might decrease prostate growth, thereby decreasing or delaying the need for surgical intervention. To test the hypothesis that dihydrotestosterone (DHT), a non lifiable and nonaromatizable pure androgen, reduces late-life prostate growth in middle-aged men. Randomized, placebo-controlled, parallel-group trial. (Australian New Zealand Clinical Trials Registry number: ACTRN12605000358640) SETTING: Ambulatory care research center. Healthy men (n = 114) older than 50 years without known prostate disease. Transdermal DHT (70 mg) or placebo gel daily for 2 years. Prostate volume was measured by ultrasonography bone mineral density (BMD) and body composition were measured by dual-energy x-ray absorptiometry and blood s les and questionnaires were collected every 6 months, with data analyzed by mixed-model analysis for repeated measures. Over 24 months, there was an increase in total (29% [95% CI, 23% to 34%]) and central (75% [CI, 64% to 86%] P 0.2). Dihydrotestosterone treatment decreased spinal BMD (1.4% [CI, 0.6% to 2.3%] P 0.2) and increased serum aminoterminal propeptide of type I procollagen in the second year of the study compared with placebo. Dihydrotestosterone increased serum DHT levels and its metabolites (5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol) and suppressed serum testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels. Dihydrotestosterone increased hemoglobin levels (7% [CI, 5% to 9%]), serum creatinine levels (9% [CI, 5% to 11%]), and lean mass (2.4% [CI, 1.6% to 3.1%) but decreased fat mass (5.2% [CI, 2.6% to 7.7%]) (P <0.001 for all). Protocol-specific discontinuations due to DHT were asymptomatic increased hematocrit (n = 8), which resolved after stopping treatment, and increased prostate-specific antigen levels (n = 3 none with prostate cancer) in the DHT group. No serious adverse effects due to DHT occurred. Negative findings on prostate growth cannot exclude adverse effects on the natural history of prostate cancer. Dihydrotestosterone treatment for 24 months has no beneficial or adverse effect on prostate growth but causes a decrease in spinal but not hip BMD. These findings have important implications for the wider use of nonsteroidal pure androgens in older men. BHR Pharma.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-05-2017
DOI: 10.1097/J.PAIN.0000000000000952
Abstract: Older adults are largely under-represented in low back pain (LBP) research. In light of the ageing population, it is crucial to understand the influence of comorbidities and lifestyle factors on the risk and prognosis of LBP in older adults. The aims of this study were to describe the course of LBP in older men to investigate whether comorbidities/lifestyle factors can predict the course of LBP in older men to assess if comorbidities/lifestyle factors increase the risk of developing LBP in older men. The study s le comprised 1685 older men living in suburban Sydney, Australia. Low back pain, sociodemographic measures, lifestyle factors, and comorbidities were assessed. Of the 1012 men with LBP at baseline, 58% still reported having pain at the 24-month follow-up. Of those without pain at baseline (n = 673), 28% reported pain at follow-up. The odds of persistent pain at 24 months increased with each additional alcoholic drink/wk (odds ratio [OR] = 1.10, 95% confidence interval [CI]: 1.01-1.22 P = 0.03) and each additional unit of body mass index (OR = 1.28, 95% CI: 1.04-1.60 P = 0.02), but reduced for men who speak English at home (OR = 0.58, 95% CI: 0.35-0.96 P = 0.03). In older men, free of LBP at baseline (n = 673), for every additional comorbidity there was an increased risk of developing LBP (OR = 1.17, 95% CI: 1.00-1.37 P = 0.05). These results demonstrate the influence of lifestyle factors and comorbidities on LBP in older men and suggest that the consideration of these issues in management may improve outcomes.
Publisher: Wiley
Date: 05-03-2015
DOI: 10.1111/CEN.12738
Abstract: Lower circulating androgens and poorer lung function are associated with increased cardiovascular risk and mortality in men. The association between androgens and lung function is unclear. We tested the hypothesis that circulating testosterone (T) and its metabolites dihydrotestosterone (DHT) and oestradiol (E2) are differentially associated with lung function in men. Early-morning serum T, DHT and E2 were assayed using mass spectrometry in 1768 community-dwelling men from Busselton, Western Australia. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured using spirometry. Linear regression models adjusting for age, height, smoking, exercise, body mass index, respiratory conditions and cardiovascular risk factors were used. Mean age was 50.1 ± 16·8 years. 16·0% were current smokers, 14·1% reported a history of asthma and 2·7% reported chronic obstructive pulmonary disease. Current smokers had higher T compared with never smokers (age-adjusted mean 14·5 vs 13·5 nmol/l, P = 0·002) and higher E2 (65·3 vs 60·1 pmol/l, P = 0·017). In fully adjusted analyses, T was associated with FEV1 (51 ml per 1 SD increase, P < 0·001) as was DHT (62 ml, P < 0·001), E2 was not (P = 0·926). Similar results were seen for FVC (T: 76 ml, P < 0·001 DHT: 65 ml, P < 0·001 E2 P = 0·664). Higher DHT was marginally associated with the ratio FEV1/FVC (0·3% per 1 SD increase, P = 0·047). Both T and DHT were independently associated with higher FEV1 and FVC in predominantly middle-aged community-dwelling men. Androgens may contribute to, or be biomarkers for, better lung function in men. Further research is needed to clarify whether androgens preserve lung function in ageing men.
Publisher: The Endocrine Society
Date: 02-2021
Abstract: Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by a range of endocrine, reproductive, and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signaling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight white and brown fat pad weights fasting serum triglyceride and glucose levels, and blood glucose incremental area under the curve. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity, and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.
Publisher: The Endocrine Society
Date: 02-2014
DOI: 10.1210/EN.2013-1755
Abstract: Age-specific incidence of ischemic heart disease in men is higher than in women, although women die more frequently without previous symptoms the molecular mechanism(s) are poorly understood. Most studies focus on protection by estrogen, with less attention on androgen receptor-mediated androgen actions. Our aim was to determine the role of androgens in the sex differences in cardiac damage during myocardial infarction. Mature age-matched male and female Sprague Dawley rats, intact or surgically gonadectomized (Gx), received testosterone (T) or 17β-estradiol (E2) via subdermal SILASTIC (Dow Corning Corp.) implants a subset of male rats received dihydrotestosterone. After 21 days, animals were anesthetized, and hearts were excised and subjected to ex vivo regional ischemia-reperfusion (I-R). Hearts from intact males had larger infarcts than those from females following I-R Gx produced the opposite effect, confirming a role for sex steroids. In Gx males, androgens (dihydrotestosterone, T) and E2 aggravated I-R-induced cardiac damage, whereas in Gx females, T had no effect and E2 reduced infarct area. Increased circulating T levels up-regulated androgen receptor and receptor for advanced glycation end products, which resulted in enhanced apoptosis aggravating cardiac damage in both males and females. In conclusion, our study demonstrates, for the first time, that sex steroids regulate autophagy during myocardial infarction and shows that a novel mechanism of action for androgens during I-R is down-regulation of antiapoptotic protein Bcl-xL (B cell lymphoma-extra large), a key controller for cross talk between autophagy and apoptosis, shifting the balance toward apoptosis and leading to aggravated cardiac damage.
Publisher: Springer Science and Business Media LLC
Date: 02-2015
Publisher: Oxford University Press (OUP)
Date: 17-03-2022
Abstract: Aging and multimorbidity are associated with inflammation. Polypharmacy is common in older people with multimorbidity. Given the potential for interactions between polypharmacy and inflammation, the relationship between inflammation and polypharmacy were studied in older adults with multimorbidity and in healthy aging mice. A cross-sectional analysis of data from the 5-year wave of the Concord Health and Ageing in Men Project, a population-based study of community-dwelling men aged ≥70 years. Serum concentrations of 27 cytokines were measured using a multiplex immunoassay. Associations between polypharmacy (≥5 medications) and cytokines were evaluated using multivariable linear regression adjusting for age, frailty, comorbidities, and in idual drug classes. Interaction between polypharmacy and Drug Burden Index (DBI―drugs with anticholinergic and sedative effects) was analyzed. Effects of polypharmacy and DBI on serum levels of 23 cytokines were determined in aging male mice treated with chronic polypharmacy or control. Compared to the nonpolypharmacy group (n = 495), CHAMP participants with polypharmacy (n = 409) had significantly higher concentrations of IL-8, IL-6, CCL3, Eotaxin, IL-1ra, IL-1β, IP-10, and lower concentrations of anti-inflammatory cytokine IL-4. In fully-adjusted multivariable models, polypharmacy was positively associated with concentrations of IL-8 and CCL3. There were no significant differences in inflammatory profiles between control and polypharmacy-treated mice. The relationship was not influenced by DBI in men or in mice. Inflammatory markers associated with polypharmacy in older adults were not seen in healthy aged mice administered polypharmacy, and may be related to underlying diseases. The polypharmacy mouse model provides opportunities for mechanistic investigations in translational research.
Publisher: The Endocrine Society
Date: 10-04-2020
Abstract: Activin A promotes fetal mouse testis development, including driving Sertoli cell proliferation and cord morphogenesis, but its mechanisms of action are undefined. We performed ribonucleic acid sequencing (RNA-seq) on testicular somatic cells from fetal activin A-deficient mice (Inhba KO) and wildtype littermates at embryonic day (E) E13.5 and E15.5. Analysis of whole gonads provided validation, and cultures with a pathway inhibitor discerned acute from chronic effects of altered activin A bioactivity. Activin A deficiency predominantly affects the Sertoli cell transcriptome. New candidate targets include Minar1, Sel1l3, Vnn1, Sfrp4, Masp1, Nell1, Tthy1 and Prss12. Importantly, the testosterone (T) biosynthetic enzymes present in fetal Sertoli cells, Hsd17b1 and Hsd17b3, were identified as activin-responsive. Activin-deficient testes contained elevated androstenedione (A4), displayed an Inhba gene dose-dependent A4/T ratio, and contained 11-keto androgens. The remarkable accumulation of lipid droplets in both Sertoli and germ cells at E15.5 indicated impaired lipid metabolism in the absence of activin A. This demonstrated for the first time that activin A acts on Sertoli cells to determine local steroid production during fetal testis development. These outcomes reveal how compounds that perturb fetal steroidogenesis can function through cell-specific mechanisms and can indicate how altered activin levels in utero may impact testis development.
Publisher: Oxford University Press (OUP)
Date: 09-2013
DOI: 10.1530/EJE-13-0406
Abstract: In hypopituitary men, oral delivery of unesterified testosterone in doses that result in a solely hepatic androgen effect enhances protein anabolism during GH treatment. In this study, we aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women. Eight healthy postmenopausal women received 2-week treatment with oral testosterone at a dose of 40 mg/day (crystalline testosterone USP). This dose increases portal concentrations of testosterone, exerting androgenic effects on the liver without a spillover into the systemic circulation. The outcome measures were whole-body leucine turnover, from which leucine rate of appearance (LRa, an index of protein breakdown) and leucine oxidation (Lox, a measure of irreversible protein loss) were estimated, energy expenditure and substrate utilization. We measured the concentration of liver transaminases as well as of testosterone, SHBG and IGF1. Testosterone treatment significantly reduced LRa by 7.1±2.5% and Lox by 14.6±4.5% ( P .05). The concentration of liver transaminases did not change significantly, while that of serum SHBG fell within the normal range by 16.8±4.0% and that of IGF1 increased by 18.4±7.7% ( P .05). The concentration of peripheral testosterone increased from 0.4±0.1 to 1.1±0.2 nmol/l ( P .05), without exceeding the upper normal limit. There was no change in energy expenditure and fat and carbohydrate utilization. Hepatic exposure to unesterified testosterone by oral delivery stimulates protein anabolism by reducing protein breakdown and oxidation without inducing systemic androgen excess in women. We conclude that a small oral dose of unesterified testosterone holds promise as a simple novel treatment of protein catabolism and muscle wasting.
Publisher: Oxford University Press (OUP)
Date: 07-1999
DOI: 10.1095/BIOLREPROD61.1.200
Abstract: Perinatal sex-steroid exposure may result in permanent modifications in the structure and function of the prostate gland. The mechanism of such long-range alterations in hormonal sensitivity is not known. This study aimed to define the molecular requirements for neonatal sex-steroid imprinting and to investigate whether combined administration of neonatal androgens and estrogens had synergistic effects upon the mature mouse prostate. Since the interaction between endogenous and exogenous sex steroids in normal mice makes it difficult to dissociate direct from indirect effects, we used the hypogonadal (hpg) mouse, characterized by congenital androgen deficiency yet still fully responsive to exogenous androgens. Newborn mice (Days 1-2) were administered a single s.c. injection of androgens alone or in combination with an estrogen followed by testosterone-induced maximal prostate growth at maturity. The final effects were determined in 7-wk-old mice through study of ductal architecture in microdissected ventral prostates (VP) and quantitation of volume densities and diameters of prostate tissue components. A single neonatal dose of androgens, but not of estrogen, increased branching morphogenesis and VP weights at adulthood. These effects did not differ significantly between various androgens in addition, combined androgen and estrogen treatment failed to demonstrate any synergistic effects on the prostate. We conclude that neonatal androgens induce long-range effects upon the mature VP structure as well as its secretory function and that this imprinting occurs via the androgen receptor without requiring aromatization of androgens. However, these conclusions, based on a specific treatment protocol, are confined only to the distal segment of VP, and effects of neonatal sex-steroid exposure in other regions or lobes of VP may differ.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-12-2010
Abstract: Elevated follicle-stimulating hormone (FSH) activity is proposed to directly cause bone loss independent of estradiol deficiency in aging women. Using transgenic female mice expressing human FSH (TgFSH), we now reveal that TgFSH dose-dependently increased bone mass, markedly elevating tibial and vertebral trabecular bone volume. Furthermore, TgFSH stimulated a striking accrual of bone mass in hypogonadal mice lacking endogenous FSH and luteinizing hormone (LH) function, showing that FSH-induced bone mass occurred independently of background LH or estradiol levels. Higher TgFSH levels increased osteoblast surfaces in trabecular bone and stimulated de novo bone formation, filling marrow spaces with woven rather than lamellar bone, reflective of a strong anabolic stimulus. Trabecular bone volume correlated positively with ovarian-derived serum inhibin A or testosterone levels in TgFSH mice, and ovariectomy abolished TgFSH-induced bone formation, proving that FSH effects on bone require an ovary-dependent pathway. No detectable FSH receptor mRNA in mouse bone or cultured osteoblasts or osteoclasts indicated that FSH did not directly stimulate bone. Therefore, contrary to proposed FSH-induced bone loss, our findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism, which is independent of LH activity, and does not involve direct FSH actions on bone cells.
Publisher: The Endocrine Society
Date: 08-1994
DOI: 10.1210/ENDO.135.2.8033822
Abstract: The recent development of an ultrasensitive immunofluorometric rat LH assay makes possible evaluation of pulsatile LH secretion in intact male rats under physiological conditions of minimal volume blood s ling without requiring orchidectomy. Specifically, we applied this assay to determine the effect of macronutrient restriction on pulsatile LH secretion in the presence or absence of testes. In testes-intact rats, halving of food intake for 7 days while maintaining micronutrient supply caused a reduction of mean, maximal, and basal LH levels and LH pulse litude (all P < 0.05) compared with those in ad libitum fed controls. The loss of body weight was positively correlated with decreases in mean LH level, pulse litude, and area under the curve (all P < 0.009). In contrast, the same food restriction in castrated rats caused an increase in pulse length and area under the curve and a decrease in pulse frequency, but did not change mean, maximal, and basal LH levels or LH pulse litude compared to castrated ad libitum fed controls (all P < 0.02). The observed positive correlations between body weight and the LH secretion parameters in intact rats were absent or reversed in castrated rats. This study demonstrates qualitatively different effects of macronutrient restriction on pulsatile LH secretion in castrated and intact rats, indicating that it is not necessary valid to extrapolate consequences of undernutrition on LH secretion from castrate to intact male rats. We conclude that undernutrition-induced inhibition of LH secretion involves both an indirect suppression of LH secretion via lification of endogenous testicular negative feedback as well as more direct suppression of GnRH release.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.FERTNSTERT.2021.12.026
Abstract: To determine the semen quality and reproductive hormones of men conceived by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) compared with men conceived without assisted reproductive technology (ART). Cohort study. IVF centers in Victoria and the Western Australian Raine Study. Men conceived with IVF/ICSI and men conceived without ART aged 18-25 years. Clinical review. The primary outcome was the prevalence of severe oligozoospermia (sperm concentration, <5 million/mL). The secondary outcomes were total sperm count, total and progressive motility, total motile count, normal morphology, and serum testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). There was no difference in the prevalence of severe oligozoospermia between 120 men conceived with IVF/ICSI and 356 men conceived without ART (9% vs. 5.3%). Men conceived with IVF/ICSI had similar sperm concentration, total sperm count, and total motile count but lower mean total (55.3% vs. 60.6%) and progressive (44.7% vs. 53.9%) sperm motility with higher mean normal morphology (8.5% vs. 5.4%). Differences in progressive motility (ß, -9.9 95% confidence interval [CI], -16.7 - -3.0), normal morphology (ß, 4.3 95% CI, 3.0-5.7), and proportion with abnormal morphology (adjusted odds ratios, 0.1 95% CI, 0.04-0.5) remained significant after adjusting for confounders. Men conceived with IVF/ICSI had lower mean FSH (3.3 IU/L) and LH (3.9 IU/L) levels and higher mean testosterone levels (19.1 nmol/L) than controls (4.2 IU/L, 11.0 IU/L, and 16.8 nmol/L). This study of men conceived with IVF/ICSI found similar sperm output to men conceived without ART. Overall, the results are reassuring.
Publisher: Public Library of Science (PLoS)
Date: 23-11-2015
Publisher: The Endocrine Society
Date: 11-1990
Abstract: Having recently demonstrated highly vectorial and FSH-stimulated inhibin secretion by immature rat Sertoli cells in vitro, we wished to determine if vectorial secretion of inhibin was also characteristic of primate Sertoli cells. By adapting techniques for isolation of Sertoli cells from testes of the immature rat and cynomolgus monkey. Sertoli cells were isolated from immature baboon testes. Sertoli cells were then plated onto matrix-impregnated porous filters and cultured in twin chamber assemblies in fully defined, supplemented HEPES-buffered Eagles medium. Inhibin was measured in conditioned culture media by an heterologous RIA validated for primate inhibins. Throughout 28 days of culture immunoreactive inhibin was readily detectable in the upper chambers whereas inhibin was undetectable or just detectable in the lower chambers. The median ratio of upper to lower chamber inhibin content was 15.3 under basal conditions rising to 41 under FSH stimulation. Inhibin secretion into the upper chamber was increased 2.5 +/- 0.4 times by stimulation with ovine FSH (100 ng/ml). We conclude that immature Sertoli cells from a nonhuman primate demonstrate FSH-responsive and highly vectorial secretion of inhibin almost exclusively into the upper chamber. These data suggest that during maturation mammalian Sertoli cells secrete inhibin vectorially mainly from the apical surface of the cell towards the seminiferous tubular lumen. The predominance of inhibin secretion into the seminiferous tubule during testicular maturation suggests that inhibin may have an important paracrine or autocrine role in the developmental biology of spermiogenesis.
Publisher: Bioscientifica
Date: 07-1999
Abstract: Estrogens play an important role in prostate physiology and neonatal exposure to estrogens has profound effects on the mature structure and hormonal sensitivity of rodent prostate. We aimed to determine the long-term effects of neonatal estrogens on the ductal architecture, morphology and hormonal sensitivity of the mature mouse prostate. Newborn mice (day 1-2) were administered a single injection (s.c.) of estrogens (estradiol benzoate (EB), diethylstilbestrol (DES)) with or without concomitant anti-estrogens (tamoxifen (TAM) or ICI 182 780 (ICI)) TAM or ICI alone, GnRH-antagonist (GnRH-A) or vehicle. At 7 weeks of age, ventral prostates (VP) were microdissected to estimate branch tip numbers and processed for stereologic analysis of volume fractions and diameters of various tissue components. Estrogens induced permanently reduced branching morphogenesis leading to reduced VP weights and these effects were fully reproduced by GnRH-A, consistent with an indirect effect. Stereologically, neonatal estrogens induced epithelial and stromal hyperplasia and significantly reduced (P .05) the diameters of VP glandular tubules and lumen compared with controls and these regressive effects were not reversed either by TAM or ICI. These studies confirm that a single neonatal dose of both DES and EB produces imprinting in the mature mouse prostate and indicate that neonatal estrogen effects involve both direct as well as indirect effects. In addition, both TAM and ICI act as partial agonists to the estrogen receptor in the ventral prostate of neonatal mouse.
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/RD17100
Abstract: As the transient postnatal hormone surge in humans, known as ‘minipuberty’, occurs simultaneously with key steps in germ-cell development, we investigated whether similar changes occur in the hypothalamic–pituitary–testicular axis of neonatal mice at a time that would coincide with gonocyte transformation into spermatogonial stem cells (SSC). Serum and testes were collected from C57Bl/6 mice at embryonic Day 17 (E17), birth (postnatal Day 0 P0) and daily until P10. Serum FSH and testosterone levels in both serum and testes were analysed and gene expression of FSH receptor (Fshr), luteinising hormone receptor (Lhr), anti-Müllerian hormone (Amh), octamer-binding transcription factor 4 (Oct-4), membrane type 1 metalloprotease (Mt1-mmp), proto-oncogene C-kit and promyelocytic leukaemia zinc finger (Plzf ) was quantified by real-time polymerase chain reaction. We found a transient surge of serum and testicular testosterone levels between P1 and P3 and a gradual increase in FSH from P1 to P10. Testis Lhr expression remained low from P0 until P10 but Fshr expression peaked between P3 and P6 (P 0.01). The same was found for Oct-4 expression (a gonocyte marker), which surged between P3 and P6 (P 0.01). Mt1-mmp expression peaked at P3 (P 0.05). The expression pattern of both C-kit and Plzf (SSC markers) was similar with a steady increase from P1 to P10. These results show a transient activation of the hypothalamic–pituitary–testicular axis postnatally with increases in serum and testicular testosterone at P1–P3 and testicular Fshr (but not Lhr) at P3–P6. These changes coincide with increases in gene expression of Oct4, Mt1-mmp, Plzf and C-kit, reflecting gonocyte activation, migration and transformation into SSC. In conclusion, these findings suggest that ‘minipuberty’ does occur in mice and that gonocyte transformation may be driven by a transient FSH signalling pathway.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2010
DOI: 10.1007/S00198-010-1478-9
Abstract: Aging alone is not the only factor accounting for poor bone health in older men. There are modifiable factors and lifestyle choices that may influence bone health and result in higher bone density and lower fracture risk even in very old men. The aim of this cross-sectional analysis was to identify the factors associated with areal bone mineral density (BMD) and their relative contribution in older men. The Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia, involving 1,705 men aged 70-97. Data were collected using questionnaires and clinical assessments. BMD of the hip and spine was measured by dual X-ray absorptiometry. In multivariate regression models, BMD of the hip was associated with body weight and bone loading physical activities, but not independently with age. The positive relationship between higher BMD and recreational activities is attenuated with age. Factors independently associated with lower BMD at the hip were inability to stand from sitting, a history of kidney stones, thyroxine use, and Asian birth and at the spine, chronic obstructive pulmonary disease, paternal fracture history, and thyroxine use. Higher body weight, participation in dancing, tennis or jogging, quadriceps strength, alcohol consumption, and statin use were associated with higher hip BMD, while older age, osteoarthritis, higher body weight, and aspirin use were associated with higher spinal BMD. Maintaining body weight, physical activity, and strength were positively associated with BMD even in very elderly men. Other parameters were also found to influence BMD, and once these were included in multivariate analysis, age was no longer associated with BMD. This suggests that age-related diseases, lifestyle choices, and medications influence BMD rather than age per se.
Publisher: Oxford University Press (OUP)
Date: 08-1987
Abstract: Abstract. The effect of short-term exposure to the insulin-like growth factors (IGF-I and IGF-II) on testosterone production by rat testicular interstitial cells in primary culture has been examined. Both peptides, when present during a 1-h pre-incubation period, increased human chorionic gonadotropin (hCG)-stimulated testosterone release over the following 16-h period. The effect of exposure to IGFs was most marked on maximally hCG-stimulated testosterone release. Maximal stimulation following IGF exposure was 80– 85% above that seen without IGFs, and the IGF effect was half-maximal at 1.5–2 μg/l of IGF-I or IGF-II. Pre-incubation with IGFs did not alter the concentration of hCG (0.1 μg/l) at which half-maximal stimulation of testosterone release was seen. Increasing cell density had a marked effect on the testosterone production rate per 10 5 cells, and the stimulatory effect of IGFs was only seen at relatively high cell density (2.8 × 10 5 cells/ml). Varying the period of pre-incubation with IGFs between 0.5 and 16 h, it was found that a 1-h period gave maximal stimulation. We conclude that a short exposure to IGFs is capable of increasing hCG-stimulated steroidogenesis in Leydig cells, and postulate that this effect may be part of an intratesticular paracrine control mechanism.
Publisher: Wiley
Date: 17-08-2010
DOI: 10.1002/PROS.21242
Abstract: Glucocorticoids influence prostate development and pathology, yet the underlying mechanisms including possible direct glucocorticoid effect on the prostate are not well characterized. We evaluated the expression of the glucocorticoid receptor (GR) together with the effects of supraphysiological glucocorticoid (corticosterone) on mouse prostate morphology and epithelial proliferation. Mature male mice were treated by weekly subdermal implantation of depot pellets containing either 1.5 mg corticosterone or placebo providing steady-state release for 4 weeks. Corticosterone treatment significantly increased dorsolateral and anterior prostate weights as well as prostate epithelial cell proliferation while epithelial apoptosis remained low upon corticosterone treatment. Histological analysis of the anterior lobe demonstrated abnormal, highly disorganized luminal epithelium with frequent formation of bridge-like structures lined by continuous layer of basal cells not observed following placebo treatment. Molecular analysis revealed corticosterone-induced increase in expression of stromal growth factor Fgf10 which, together with prominent stromal GR expression, suggest that glucocorticoid modify stromal-to-epithelial signaling in the mouse prostate. The mitogenic effects were prostate specific and not mediated by systemic effects on testosterone production suggesting that corticosterone effects were primarily mediated via prostate GR expression. These data demonstrate that murine prostate is significantly and directly influenced by corticosterone treatment via aberrant stromal-to-epithelial growth factor signaling.
Publisher: The Endocrine Society
Date: 17-02-2023
Abstract: Thyroid hormone (TH) abuse for performance enhancement in sport remains controversial and it is not prohibited in sports under the World Anti-Doping Code. However, the prevalence of TH usage in athletes is not known. We investigated TH use among Australian athletes undergoing antidoping tests for competition in World Anti-Doping Agency (WADA)–compliant sports by measuring TH in serum and surveying mandatory doping control form (DCF) declarations by athletes of all drugs used in the week prior to the antidoping test. Serum thyroxine (T4), triiodothyronine (T3), and reverse T3 were measured by liquid chromatography–mass spectrometry and serum thyrotropin, free T4, and free T3 by immunoassays in 498 frozen serum s les from antidoping tests together with a separate set of 509 DCFs. Two athletes had biochemical thyrotoxicosis giving a prevalence of 4 per 1000 athletes (upper 95% confidence limit [CL] 16). Similarly, only 2 of 509 DCFs declared usage of T4 and none for T3, also giving a prevalence of 4 (upper 95% CL 16) per 1000 athletes. These estimates were consistent with DCF analyses from international competitions and lower than the estimated T4 prescription rates in the age-matched Australian population. There is minimal evidence for TH abuse among Australian athletes being tested for competing in WADA-compliant sports.
Publisher: Elsevier BV
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 07-01-2015
DOI: 10.1007/S12672-014-0210-1
Abstract: Men are significantly more susceptible to non-melanoma skin cancers than women, and the androgen receptor (AR) is widely distributed in the skin, suggesting a ro\\le for androgens acting via AR. Therefore, we explored the role of androgen action via AR in susceptibility to experimental 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis and in skin structural development of male and female mice. We demonstrate that both the male gender and androgen action via AR modify the susceptibility to carcinogen-induced skin cancer, but the effect depends on the carcinogenesis model used. Following systemic DMBA exposure, males were significantly (p 35 weeks (wild-type [WT] vs. AR knockout [ARKO], p 35 weeks, p = 0.008)) mice. In contrast, following DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multistage local skin carcinogenesis, AR inactivation protected against formation of DMBA-induced skin cancers in both male and female mice. The skin structure was also affected by gender effect as well as the AR inactivation and could at least partly explain the different responses between the carcinogenesis models (systemic vs. topical). In addition, AR inactivation modified Cox-1 and Cox-2 expression in the skin, suggesting possible molecular mechanism for the AR effect on skin. Finally, some gender differences are observed also in ARKO mice insensitive to androgens, suggesting that factors other than androgens also play a role in gender-dependent skin carcinogenesis.
Publisher: Oxford University Press (OUP)
Date: 06-2016
Abstract: The longitudinal association between progressive temporal change in sexual (dys)function and mortality in older men. Community-dwelling men aged 70 years and older from the Concord Health and Ageing in Men Project were assessed at baseline (2005-2007, n = 1,705), 2-years follow-up (n = 1,367), and 5-years follow-up (n = 958). Self-reported sexual function (erectile function and sexual activity) using standardized questions were analyzed by generalized estimating equations to examine the longitudinal prediction of mortality according to change in sexual function across three time-points. Men reported to have erectile dysfunction increased from 64% to 80%, and to be sexually inactive increased from 56% to 59% over the course follow-up. In univariate analyses, erectile dysfunction (hazard ratio: 2.02, 95% confidence interval [CI]: 1.45-2.81) or having no sexual activity (hazard ratio: 2.31, 95% CI: 1.82-2.93) at baseline predicted increased mortality over the subsequent 7 years. Models adjusted for multivariate and major reproductive hormones had negligible impact on mortality prediction, but neither statistically significantly predicted mortality after adjusting for depression. Similarly, change in erectile dysfunction over time was associated with mortality over 7 years in univariate (odds ratio: 1.69, 95% CI: 1.34-2.14) and multivariate analysis, including hormones, but not after adjusting for depression (odds ratio: 1.24, 95% CI: 0.95-1.62). Change in sexual activity was associated with mortality over 7 years in univariate analysis (odds ratio: 2.37, 95% CI: 1.33-4.20) but not after adjusting for age (odds ratio: 1.45, 95% CI: 0.79-2.64). Our analyses suggest sexual dysfunction was not an independent risk factor of, but rather may be a biomarker for, all-cause mortality in older men.
Publisher: Oxford University Press (OUP)
Date: 03-2005
DOI: 10.1530/EJE.1.01844
Abstract: Background : The growing interest in measuring blood free testosterone (FT) is constrained by the unsuitability of the laborious reference methods for wider adoption in routine diagnostic laboratories. Various alternative derived testosterone measures have been proposed to estimate FT from either additional assay steps or calculations using total testosterone (TT) and sex hormone-binding globulin (SHBG) measured in the same s le. However, none have been critically validated in large numbers of blood s les. Methods : We analyzed a large dataset comprising over 4000 consecutive blood s les in which FT as well as TT and SHBG were measured. Dividing the dataset into s les with blood TT above and below 5 nM, using a bootstrap regression modeling approach guided by Akaike Information Criterion for model selection to balance parsimony against reduction of residual error, empirical equations were developed for FT in terms of TT and SHBG. Results : Comparison between the empirical FT equations with the laboratory FT measurements as well as three widely used calculated FT methods showed the empirical FT formulae had superior fidelity with laboratory measurements while previous FT formulae overestimated and deviated systematically from the laboratory FT values. Conclusion : We conclude that these simple, assumption-free empirical FT equations can estimate accurately blood FT from TT and SHBG measured in the same s les with the present assay methods and have suitable properties for wider application to evaluate the clinical utility of blood FT measurements.
Publisher: Oxford University Press (OUP)
Date: 08-06-2018
Abstract: previous cross-sectional studies have reported bidirectional associations between sexual activity and cognitive function among older people. However, the temporal associations have not been studied. community-dwelling men aged 70+ from the Concord Health and Ageing in Men Project were assessed. This study was based on 986 men at baseline, 829 men at 2 year and 595 men at 5-year follow-up. Sexual function using a standardised questionnaire (erectile function, sexual activity, sexual satisfaction, sexual desire) was analysed by generalised estimating equations to examine associations between changes in sexual function and changes in mini-mental state examination (MMSE) across three time points over 5 years. Age, BMI, comorbidity, self-rated health, smoking, number of medications, country of birth, education, marital status, depression and reproductive hormones were also measured at all time points. in unadjusted models, declines in erectile function (β = -0.317) and sexual activity (β = -0.575) over time were statistically significantly associated with a decline in MMSE over time. The associations observed in the unadjusted models remained after adjusting for a range of covariables. Declines in sexual satisfaction and sexual desire over time were not associated with changes in MMSE. our findings provide evidence of a longitudinal temporal relationship between sexual activity and cognitive function. Further studies are warranted to examine whether maintaining a healthy sexual life has a positive effect on cognitive function in older men.
Publisher: Wiley
Date: 13-09-2012
DOI: 10.1002/PROS.22570
Abstract: Regulation of steroid synthesis within the prostate is not well understood. In this study, we examined androgen synthesis and metabolism in the mouse prostate. Using LC-MSMS steroid assays, immunohistochemistry and real-time PCR we examined the role of prostate epithelial AR in regulating 5αR expression and subsequent androgen metabolism by analyzing natural differences in epithelial AR expression between lobes as well as in the prostate epithelial AR knockout (PEARKO) mouse model. Subsequently, the role of intraprostatic androgen metabolism and epithelial AR in the generation and progression of prostate epithelial pathology was examined using long-term exogenous testosterone (T) + estradiol (E2) exposure. Epithelial AR and 5αR2 expression as well as intraprostatic DHT followed the same lobe-specific pattern being lower in anterior than the other lobes (n = 6-8, P < 0.05). Lobe-specific 5αR2 expression was similar in PEARKO and wild-type (WT) prostate. However, PEARKO prostate had higher intraprostatic DHT content with significantly increased 5αR2 expression localized in abnormal epithelium. T + E2 treatment induced epithelial pathology was more common in PEARKO prostate compared to WT (20% vs. 2%), and was associated with increased 5αR2 expression (n = 6, P < 0.001). We suggest that androgen synthesis via 5αR2 expression is driven by its own product (DHT) acting on adjacent stromal cells in a paracrine loop leading to increased in situ androgen levels in the PEARKO prostate. This may form part of a feed-forward loop that promotes the development of epithelial pathology.
Publisher: The Endocrine Society
Date: 09-2001
Abstract: Clinical trials of hormonal male contraceptive regimens have identified a consistent population polymorphism in susceptibility to hormone-induced azoospermia. Using identical hormonal regimens, fewer men of European origin (approximately two thirds) become azoospermic compared with Asian men who virtually all become azoospermic. This variation within and between populations remains unexplained. To investigate pharmacogenetic differences in androgen metabolism or action that might explain variable susceptibility to hormonal-induced azoospermia, we studied single nucleotide polymorphism in the CYP3A4 gene, which encodes the major hepatic T-inactivating enzyme, and CAG and GGC triplet repeats in the AR gene in 75 Australian volunteers participating in a male hormonal contraceptive study and 106 population controls. These men were classified into groups according to whether 6 months of weekly T enanthate injections produced azoospermia (n = 54), near-azoospermia (n = 7), and nonazoospermia (n = 14). Mutagenically differentiated PCR was designed to identify A/G variants in the promoter region of the CYP3A4 gene. Fluorescent-labeled DNA fragments containing either CAG or GGC repeats were lified from the genomic DNA, and their sizes were determined based on the capillary electrophoresis. The G allele of CYP3A4 gene was absent from the nonazoospermia and near-azoospermia groups, but overall this single nucleotide polymorphism distribution did not differ significantly between men in the azoospermia group or population controls. There were no significant differences in distribution of CAG and GGC triplet repeats among three groups or between them and the population controls based on the maximum likelihood estimate of the odds ratio and CLUMP II analyses. These results suggested that neither genetic polymorphisms in the AR gene (CAG and GGC repeats) nor that in hepatic androgen metabolism (CYP3A4 A/G variant) were the major contributors to the within-population variations in susceptibility to T-induced azoospermia.
Publisher: The Endocrine Society
Date: 12-2010
DOI: 10.1210/JC.2010-2369
Publisher: Elsevier BV
Date: 10-2012
Publisher: American Medical Association (AMA)
Date: 11-02-2008
Publisher: Wiley
Date: 20-09-2017
DOI: 10.1002/NAU.23415
Abstract: To describe the natural history of post-void residual urine volume (PVR) in community-dwelling older men. The Concord Health and Ageing in Men Project involves a representative s le of community-dwelling men aged 70 and older in a defined geographic area of Sydney, Australia. PVR were measured at baseline and 2-year and 5-year follow-up. The measurements were considered valid when the voided volumes were 150 mL and over. Three-hundred twenty-nine men without conditions that are likely to alter PVR (neurological disorders, prostate cancer, and a history of urological treatment) were included in the analyses. Baseline PVR were 0-49 mL in 183 men, 50-99 mL in 59 men, 100-199 mL in 72 men, 200-399 mL in 11 men, and 400 mL and over in 4 men. Thirteen out of 314 (4%) men with a baseline PVR of 0-199 mL and 2 out of 11 (18%) men with a baseline PVR of 200-399 mL had surgery for benign prostate enlargement (BPE) or indwelling catheterization over 5 years compared to three out of four men (75%) with a PVR of 400 mL and over. In all 101 men with a baseline PVR of less than 400 mL who did not receive urological treatment during follow-up and had valid PVR data for both 2-year and 5-year follow-up, PVR did not exceed 400 mL at either follow-up time point. Conservative management may be appropriate for most older men with incidentally found elevated PVR of up to 400 mL.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2017
Publisher: Oxford University Press (OUP)
Date: 2003
Abstract: Although male factors contribute to over half of all cases of infertility, most infertile men are described as 'idiopathic oligo/asthenozoospermic' rather than diagnosed precisely hence, specific medical treatment is not possible. One uncommon but treatable cause of male infertility is gonadotrophin deficiency in which gonadotrophin replacement therapy is highly effective at inducing spermatogenesis and fertility. Hormonal therapy is a logical approach for empirical drug therapy given the fundamental role of hormonal regulation in spermatogenesis. However, treatment with GnRH analogues, gonadotrophins, androgens, anti-estrogens, aromatase inhibitors, growth hormone- and prolactin-suppressing drugs is ineffective in unselected infertile men. Prolonged high-dose glucocorticoid therapy for sperm autoimmunity may improve pregnancy rates modestly, but the risks are generally unacceptable compared with IVF or ICSI. For these reasons, modern reproductive technologies, notably ICSI/IVF, have become the de-facto standard empirical treatment of male infertility, despite involving significant though infrequent risks to the fetus and mother. There remains a potential for hormonal methods to improve sperm quality or ultrastructure in subgroups of infertile men more responsive to hormonal manipulation or using novel protein or gene-targeted therapies or biochemical approaches based on post-hormonal receptor mechanisms that stimulate spermatogenesis. How such novel hormonal methods will develop in conjunction with improved ICSI/IVF or cloning technologies, and the potential role of adjunctive hormonal therapy remains to be clarified.
Publisher: The Endocrine Society
Date: 07-2003
Abstract: Long-term glucocorticoid therapy in men is associated with loss of bone and muscle mass as well as a decrease in serum testosterone. We tested the effect of two androgens, testosterone and its minimally aromatizable analog nandrolone, on muscle mass (dual x-ray absorptiometry), muscle strength (knee flexion and extension by isokinetic dynamometry), bone mineral density (BMD), and quality of life (Qualeffo-41 questionnaire) in 51 men on a mean daily prednisone dose of 12.6 +/- 2.2 mg. Men were randomized, double blind, to testosterone (200 mg mixed esters), nandrolone decanoate (200 mg), or placebo given every fortnight by im injection for 12 months. At 12 months, both androgens increased muscle mass (mean change from baseline +3.5%, +5.8%, and -0.9% in testosterone, nandrolone, and placebo groups, respectively, P < 0.0001) and muscle strength (P < 0.05). Lumbar spine BMD increased significantly only in men treated with testosterone (4.7 +/- 1.1%, P < 0.01). There was no significant change in hip or total body BMD. Testosterone, but not nandrolone or placebo, improved overall quality of life (P < 0.001). These results suggest that androgen therapy may have a role in ameliorating adverse effects of glucocorticoid therapy such as muscle and bone loss and aromatization is necessary for androgen action on bone but not on muscle.
Publisher: The Endocrine Society
Date: 07-08-2019
Abstract: Whether serum androgen levels can identify women with “androgen insufficiency” or “androgen excess” is unresolved thus, what constitutes “normal” remains uncertain. We sought to determine whether androgens, including 11-oxygenated C19 steroids, vary with age, menstrual cycle, or body mass index (BMI), during the reproductive years. Cross-sectional study recruited from eastern Australian states. A total of 588 women, aged 18 to 39 years, who were not pregnant, lactating, or using systemic hormone therapy, with regular menstrual cycles and no previous diagnosis of polycystic ovarian syndrome. Sex steroids measured using liquid chromatography-tandem mass spectrometry. Testosterone and androstenedione concentrations were significantly higher during the menstrual cycle mid- and luteal phases than in the early follicular phase, with median values across the cycle of 0.34 nmol/L (range, 0.04 to 1.01) and 1.97 nmol/L (range, 0.53 to 7.89), respectively. No cyclical variations were found in dehydroepiandrosterone (DHEA 4.91 nmol/L range, 0.08 to 23.51), 11-ketoandrostenedione (11KA 7.99 nmol/L range, 0.07 to 31.67), or 11-ketotestosterone (11KT 1.27 nmol/L range, 0.03 to 7.61). Overweight women had lower median testosterone (P 0.05), DHEA (P 0.05), and 11KA (P 0.01) levels than normal-weight women. All C19 steroids were significantly lower (P 0.01) in those aged 35 to 39 years than in those aged 18 to 25 years. The median 11KA/androstenedione (4.3:1) and 11KT/testosterone (3.9:1) ratios did not change with age, after adjustment for BMI and cycle stage. We have demonstrated that 11KA and 11KT are stable across the menstrual cycle and make major quantitative contributions to the circulating androgen pool. All C19 androgens declined with age before menopause hence, age-specific reference ranges are required for the interpretation of androgen levels in premenopausal women.
Publisher: Wiley
Date: 08-1988
DOI: 10.1111/J.1365-2605.1988.TB00999.X
Abstract: We have compared the pharmacokinetics and pharmacodynamics of the three commonly used testosterone formulations in a prospective, randomized cross-over clinical trial. Plasma free and total testosterone and their ratio (proportion of unbound testosterone), sex hormone-binding globulin (SHBG), oestradiol, LH and FSH were measured in 15 hypogonadal men (nine hyper- and six hypogonadotrophic) who underwent, in a randomized sequence, three treatment periods each separated by an intervening washout period. The treatments were: (i) intramuscular injection of 250 mg mixed testosterone esters at 2-weekly intervals, (ii) oral testosterone undecanoate 120 mg bd, and (iii) subcutaneous testosterone pellets (6 x 100 mg). Pellet implantation gave the most prolonged effect with free and total testosterone levels being elevated for up to 4 months. This was accompanied by prompt and sustained suppression of plasma LH and FSH, an increase in plasma levels of oestradiol but no change in SHBG levels. In contrast, intramuscular injections induced marked but reproducible week-to-week fluctuations in free and total testosterone, which resulted in a small decrease in plasma SHBG levels, less marked suppression of LH and FSH and a smaller increase in plasma levels of oestradiol. Oral testosterone undecanoate produced the most variable plasma levels of free and total testosterone with a peak in the first treatment week and a fall thereafter and, despite maintenance of testosterone levels within the physiological range, there was no significant suppression of plasma levels of LH and FSH, and oestradiol levels were unchanged but levels of SHBG and total cholesterol were decreased. Free testosterone levels were increased disproportionately during testosterone treatment as the proportion of unbound testosterone was increased by all three treatments. All three testosterone preparations lowered plasma levels of urea and all were without biochemical or haematological toxicity. Reported sexual function was better maintained and side-effects were fewer with parenteral compared with oral treatments. The marked decrease in SHBG and cholesterol levels during oral testosterone undecanoate, when compared with parenteral treatments, occurred despite lesser androgenic effects (suppression of gonadotrophin levels and reported sexual function), which suggests that the liver is exposed to excessive androgenic load via the portal vein during oral treatment with testosterone esters. It is concluded that testosterone pellets give the closest approximation to zero-order (steady-state) delivery conditions for up to 4 months after a single insertion.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: The Endocrine Society
Date: 06-2001
Abstract: Gonadal function is wholly reliant on the two pituitary-derived gonadotropins, FSH and LH. Identifying the specific effects of FSH has been difficult because of the intimate relationship between LH and FSH action and inherent limitations of classic research paradigms. We describe a novel transgenic model to characterize the definitive actions of FSH alone, distinct from LH effects, created by combining transgenic FSH expression with the gonadotropin-deficient background of the hypogonadal (hpg) mouse. A tandem transgene construct encoding each alpha- and beta-subunit of human FSH, under the rat insulin II promoter, expressed biologically active heterodimers at serum levels, by immunoassay, equivalent to circulating FSH concentrations in fertile humans (0.1-25 IU/liter). Transgenic mice were crossed into the hpg mouse genotype to obtain LH-deficient animals secreting FSH alone. Testis weights of adult FSHxhpg mice were increased up to 5-fold, relative to nontransgenic hpg controls (P < 0.001). However, only transgenic males with serum FSH levels more than 1 IU/liter showed testis weights increased relative to hpg controls, indicating a physiological FSH threshold for the testicular response. Histology of enlarged FSHxhpg testes revealed round spermatids and sparse numbers of elongated spermatids, demonstrating that the testosterone-independent FSH response targeting the Sertoli cell can facilitate completion of meiosis and minimal initiation, but not completion, of spermiogenesis. Transgenic FSH also induced inhibin B secretion in FSHxhpg mice, but showed a distinct sexual dimorphism with only females exhibiting a strong FSH dose-dependent increase in serum inhibin B levels (r(2) = 0.84). In addition, ovaries of FSHxhpg females were enlarged up to 10-fold (P < 0.001), characterized by increased follicular recruitment and development to type 7 antral follicles. Thus, these findings show that the transgenic FSHxhpg mouse provides a unique model for detailed investigations of the definitive in vivo actions of FSH alone.
Publisher: American Physiological Society
Date: 06-1993
DOI: 10.1152/AJPENDO.1993.264.6.E863
Abstract: The prompt rise in cytosolic calcium induced by follicle-stimulating hormone (FSH) in rat Sertoli cells suggests a role for calcium in FSH signal transduction. To evaluate the requirement for sodium in transmembrane calcium fluxes in Sertoli cells, we measured intracellular calcium concentration under sodium-free conditions and during stimulation by monensin and veratridine, used to elevate cytosolic sodium. Cytosolic calcium levels were measured by dual-wavelength spectrofluorimetry using freshly isolated cells loaded with fura-2 acetoxymethyl ester. Whereas, removal of extracellular sodium lowered cytosolic calcium in unstimulated cells from 89 +/- 4 to 75 +/- 8 nM, treatment with monensin and veratridine increased cytosolic calcium to 142 +/- 19 and 126 +/- 13 nM, respectively. Without extracellular calcium, monensin still produced 47% of the rise in cytosolic calcium observed in the presence of extracellular calcium, indicating approximately equal contributions of calcium from intracellular and extracellular sources. Blockade of voltage-sensitive or/and voltage-insensitive calcium channels by verapamil and ruthenium red was unable to completely prevent the monensin-induced elevation of cytosolic calcium. In addition tetrodotoxin failed to block the FSH-induced rise in cytosolic calcium. These observations, together with the considerable reduction in monensin-induced rise in cytosolic calcium under extracellular sodium-free condition, support the hypothesis that sodium-calcium exchange rather than the specific calcium or sodium channels regulate basal and monensin-induced transmembrane sodium and calcium fluxes in Sertoli cells.
Publisher: Springer Science and Business Media LLC
Date: 05-12-2012
DOI: 10.1007/S00198-012-2226-0
Abstract: Though bone loss tends to accelerate with age there are modifiable factors that may influence the rate of bone loss even in very old men. The aim of this 2-year longitudinal study was to examine potential predictors of change in total hip bone mineral density (BMD) in older men. The Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia. For this study, 1,122 men aged 70-97 years had baseline and follow-up measures of total hip BMD measured with dual X-ray absorptiometry. Data about mobility, muscle strength, balance, medication use, cognition, medical history and lifestyle factors were collected using questionnaires and clinical assessments. Serum 25-hydroxyvitamin D [25(OH)D] was also measured. Multivariate linear regression models were used to assess relationships between baseline predictors and change in BMD. Over a mean of 2.2 years, there was a mean annualised loss of total hip BMD of 0.006 g/cm(2)/year (0.6 %) and hip BMC of 0.14 g/year (0.3 %). Annual BMD loss accelerated with increasing age, from 0.4 % in men aged between 70 and 75 years, to 1.2 % in men aged 85+ years. In multivariate regression models, predictors of faster BMD loss were anti-androgen, thiazolidinedione and loop-diuretic medications, kidney disease, poor dynamic balance, larger hip bone area, older age and lower serum 25(OH)D. Factors associated with attenuated bone loss were walking for exercise and use of beta-blocker medications. Change in BMD was not associated with baseline BMD, smoking, alcohol consumption, BMI, frailty, or osteoarthritis. There was considerable variation in the rate of hip bone loss in older men. Walking, better balance and beta blockers may attenuate the acceleration of BMD loss that occurs with age.
Publisher: MDPI AG
Date: 13-08-2019
DOI: 10.3390/NU11081882
Abstract: Protein and branched-chain amino acid (BCAA) intake are associated with changes in circulating BCAAs and influence metabolic health in humans and rodents. However, the relationship between BCAAs and body composition in both species is unclear, with many studies questioning the translatability of preclinical findings to humans. Here, we assessed and directly compared the relationship between circulating BCAAs, body composition, and intake in older mice and men. Body weight and body fat were positively associated with circulating BCAA levels in both mouse and human, which remained significant after adjustments for age, physical activity, number of morbidities, smoking status, and source of income in the human cohort. Macronutrient intakes were similarly associated with circulating BCAA levels however, the relationship between protein intake and BCAAs were more pronounced in the mice. These findings indicate that the relationship between circulating BCAAs, body composition, and intakes are comparable in both species, suggesting that the mouse is an effective model for examining the effects of BCAAs on body composition in older humans.
Publisher: The Endocrine Society
Date: 09-2007
DOI: 10.1210/JC.2007-0862
Abstract: Background: Cross-sectional studies from different populations show a variable decline in blood testosterone concentrations as men age. Few population representative cohorts have been followed up over time. Objective: The objective of the study was to quantify longitudinally the change in serum testosterone and SHBG concentrations with age in two well-defined, representative but geographically widely separated regional Australian cohorts. Subjects and Setting: The Busselton cohort comprises in iduals aged 18–90 yr residing in Western Australia assessed prospectively since 1981. Sera were assayed from 910 men, from whom further s les were available 14 yr later in 480. The Dubbo cohort involves in iduals aged 61–90 yr living in Eastern Australia. Baseline sera were collected from 610 men and additional sera on a second (n = 370) and third (n = 200) occasion from 1989 to 2004. Men from both cohorts are community dwelling and of predominately European origin. Results: Longitudinal analyses show the following: 1) total testosterone declines comparably (P & 0.9) by 1.3% (Busselton) and 0.9% (Dubbo) per annum with the same rates of decline when analyses were restricted to men older than 60 yr of age 2) annual changes in SHBG were also very similar in age-restricted analyses (2.3% vs. 2.5%, P = 0.48) and 3) the annual increase in SHBG was steeper in middle-aged and older men (P & 10−3vs. young men). These longitudinal changes were all up to 4-fold greater in magnitude, compared with cross-sectional analyses of baseline data. Conclusion: In two separate regional Australian populations, blood testosterone fell and SHBG increased comparably with age. Age-related changes in blood testosterone and SHBG previously described in urban-dwelling men are the same in men who reside in smaller regional cities of another continent.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
DOI: 10.1016/J.PAIN.2010.11.022
Abstract: The role of anxiety in pain is less well understood than the role of depression. Based on recent conceptual thinking about worry and pain, we explored the relationship between pain status and worry about health and anxiety in 1217 community-dwelling men aged 70 years or older who participated in the baseline phase of the Concord Health and Ageing in Men Project study, a large population-based epidemiological study of healthy ageing based in Sydney, Australia. We hypothesised that worry about health would be associated with having persistent pain, and that the association would be stronger in the presence of co-existing pain-related interference with activities (intrusive pain). Of men in the study, 12.5% had persistent and intrusive pain, 22.4% were worried about their health, and 6.3% had anxiety. We found a strong association between worry about health and pain that was both persistent and intrusive, and that remained after accounting for age, number of comorbidities, depression, self-rated health status, arthritis, and gait speed (adjusted odds ratio 2.9 95% confidence interval 1.8-4.7), P<0.0001). The corresponding adjusted odds ratio for the association between anxiety and pain was 2.3 (95% confidence interval 1.0-4.8 P=0.0363). These findings suggest that at a population level, subthreshold anxiety and pain are strongly related, and worry about health occurs much more commonly than anxiety itself. To our knowledge, this is the first study to explore, specifically, the relationship between pain status and worry about health in older men. In older community-dwelling men, pain was robustly associated with worry about health, highlighting the potential importance of subthreshold anxiety-related psychological factors.
Publisher: The Endocrine Society
Date: 09-2014
DOI: 10.1210/ME.2013-1405
Publisher: The Endocrine Society
Date: 03-1991
Abstract: Previous studies have shown that male rats with experimental uremia manifest profound suppression of circulating LH and testosterone levels, yet, paradoxically, after castration gonadotropin levels are elevated greatly above those of nonuremic castrate control rats. To investigate further this phenomenon, we characterized pulsatile LH secretion in experimental uremia. Mature orchidectomized male Wistar rats with subtotal nephrectomy demonstrated a 43% reduction of LH pulse frequency, but a 157% increase in pulse litude and a 335% increase in mean LH levels compared with sham-operated controls. All pulse parameters were highly correlated with plasma creatinine (r = 0.53-0.75). To determine the mechanism of the increased pulse litude, we tested responsiveness of the postcastration uremic pituitary to exogenous GnRH (0.01-10 micrograms/kg) in a Latin square design. Plasma LH response was linearly related to the logarithm of the GnRH dose in uremic and control rats, but was markedly increased in uremic rats. We conclude that the uremia causes decreased LH pulse frequency independent of testicular feedback. Pituitary hypersensitivity to GnRH magnifies LH pulse litude and thereby is the major factor causing the paradoxical LH hyperelevation after castration.
Publisher: The Endocrine Society
Date: 05-2014
DOI: 10.1210/JC.2013-3984
Abstract: Self-rated health and health-related quality of life are inversely associated with increased morbidity and mortality however, the temporal relationship with reproductive hormones is poorly understood. The objective of the study was to examine relationships between reproductive hormones, self-rated health, and quality of life in older men at baseline as well as changes over a 2-year follow-up. One thousand six hundred thirty-seven men aged 70 years and older from the Concord Health and Ageing in Men Project were assessed at baseline and 1316 men returned for the 2-year follow-up. Serum T, dihydrotestosterone, estradiol, and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry and SHBG, LH, and FSH by immunoassay. Logistic regression and multivariate linear regression models were performed. Self-rated health and health-related quality of life measures (12-Item Short Form Health Survey) were determined. In the cross-sectional baseline data, univariate analyses revealed significant associations between many of the hormones and quality-of-life scores and self-rated health. In a multivariable analysis, the associations between T, E1, and calculated free T and self-rated health remained statistically significant. Compared with men in the highest T quartile, men in the lowest T quartile had an odds ratio of 1.47 (95% confidence interval 1.04-2.06) for reporting fair, poor, or very poor health vs excellent or good health. The findings for E1 and calculated free T were similar. In the longitudinal data, the only significant relationship was that between E1 and self-rated health. Compared with those in the highest E1 quartile, those in the lowest quartile experienced deterioration in self-rated health: adjusted odds ratio of 1.84 (95% confidence interval 1.10-3.06). Low serum T and E1 are associated with poorer self-rated health in older men, whereas lower serum levels of E1 are predictive of subsequent deterioration in self-rated health over time. Therefore, serum E1 is a novel potential risk factor for poor self-rated health in older men that warrants further investigation.
Publisher: Bioscientifica
Date: 10-2015
DOI: 10.1530/ERC-15-0203
Abstract: Haploinsufficient inactivating phosphatase and tensin homolog ( Pten ) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P 4 ) is assumed protective in uterine cancers, serum P 4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.
Publisher: Medknow
Date: 02-2010
DOI: 10.1038/AJA.2010.1
Publisher: Wiley
Date: 05-10-2012
DOI: 10.1111/J.1365-2265.2012.04432.X
Abstract: To determine serum concentrations, intra-in idual variability and impact of age-related co-morbidities on serum testosterone (T), dihydrotestosterone (DHT), estradiol (E(2)) and estrone (E(1)) in older men. Observational, repeated measures study. Men (n = 325) with 40 years and older self-reporting very good or excellent health. Standardized history, physical examination and collection of nine blood s les at fixed time intervals were measured over 3 months (three at 20 min intervals on days 1 (fasting) and 2 (non-fasting), one at days 7, 30 and 90). Serum T, DHT, E(2) and E(1) (n = 2900, > 99% of scheduled s les) measured by liquid chromatography-tandem mass spectrometry (LC-MS) were analysed by linear mixed model analysis with fasting, age and obesity as covariables. Mean serum T did not vary with age (P = 0·76) but obesity (-0·35 nM per body mass index (BMI) unit, P < 0·0001) and ex-smoker status (-1·6 nM, P < 0·001) had significant effects. Serum DHT was increased with age (+0·011 nM per year, P = 0·001) but decreased with obesity (-0·05 nM per BMI unit, P < 0·0001). Serum E(2) did not vary with age (P = 0·31) or obesity (P = 0·12). Overnight fasting increased (by 9-16%, all P 0·28). Serum T, DHT and E(2) displayed no decrease associated with age among men over 40 years of age who self-report very good or excellent health although obesity and ex-smoking status were associated with decreased serum androgens (T and DHT) but not E(2). These findings support the interpretation that the age-related decline in blood T accompanying non-specific symptoms in older men may be due to accumulating age-related co-morbidities rather than a symptomatic androgen deficiency state.
Publisher: Wiley
Date: 09-1997
DOI: 10.1046/J.1365-2605.1997.D01-285.X
Abstract: Abuse of anabolic-androgenic steroids (AAS) is reportedly increasing in prevalence and spreading from sportsmen to cosmetic and recreational use, though there are few accurate estimates of the extent of AAS use outside North America. In order to identify the prevalence of, and risk factors for, 'ever' (lifetime) or 'recent' (within last month) use of AAS among Australian high school students, 13,355 students (51.3% male, median age 13.8 years) in 203 schools constituting a stratified random s le of all high schools in New South Wales and Victoria completed a self-report questionnaire about drug use. Lifetime ('ever') use of AAS was reported by 213 boys (3.2% 95% CI, 2.7-3.6%) and 74 girls (1.2% 95% CI, 0.9-1.5%). Factors associated with 'ever' use were truancy [odds ratio (OR) 17.7 (95% CI, 9.4-31.6) for 7 or more truant days compared with no trauncy over the last fortnight], unsupervised recreation [OR 8.4 (5.9-11.9) for 6 or more compared with 2 or fewer nights per week], speaking only a non-English language at home [OR 7.75 (4.4-13.1)], Aboriginality [OR 3.4 (2.0-5.5)], male gender [OR 2.8 (2.1-3.7)], higher student income [OR 2.3 (1.7-3.0)], overseas born [OR 2.2 (1.6-3.0)] and low level of social support [OR 2.5 (1.7-3.5)]. Use of AAS within the last month ('recent') was reported by 113 boys (1.7% 95% CI, 1.4-2.0%) and 28 girls (0.4% 95% CI, 0.3-0.6%) and virtually identical risk factor patterns except ORs were uniformly higher. We conclude that AAS abuse is relatively uncommon among Australian high school students but has distinctive and strong socio-economic and cultural predictors. Further studies of the behavioural epidemiology of AAS abuse are required to clarify the origins and significance of our findings and to identify potentially effective interventions.
Publisher: The Endocrine Society
Date: 02-1987
Abstract: The marked increase in circulating insulin-like growth factor-I (IGF-I) levels during puberty observed in primates indicates an important functional relationship between hypothalamic-pituitary gonadal function and hormonal regulation of peripubertal circulating IGF-I levels. Recent studies demonstrating local production and secretion of gonadal peptides including IGF-I suggest that increased circulating IGF-I levels during puberty might be due to direct gonadal secretion of IGF-I or alternatively to indirect effects of increased gonadal steroid secretion on nongonadal tissues including the hypothalamus, pituitary, and liver. We therefore studied the effects of prepubertal castration on the pubertal IGF-I surge and demonstrate that castration provokes a further increase rather than ablation of the pubertal IGF-I surge in the rat. Furthermore, neonatal treatment with monosodium glutamate, a hypothalamic neurotoxin, abolishes the pubertal IGF-I surge when commenced on postnatal day 1 but not on day 5, whereas treatment with a GnRH antagonist commencing within 12 h of birth significantly reduces but does not abolish the pubertal IGF-I surge. We therefore propose that the pubertal IGF-I surge in the rat is not due to direct gonadal secretion of IGF-I or other gonadal hormones during puberty but may involve hypothalamic and/or hepatic programming by events during prenatal or very early postnatal life.
Publisher: AMPCo
Date: 10-2006
DOI: 10.5694/J.1326-5377.2006.TB00642.X
Abstract: Testosterone is among the oldest drugs in medicine. It has a long efficacy and safety record for its prime role of androgen replacement therapy in men with androgen deficiency. Testosterone and synthetic analogue androgens have also been used in pharmacological androgen therapy (PAT) to produce androgenic effects on marrow, muscle or bone. Although PAT is increasingly being superseded by newer, more expensive drugs, androgens remain cost-effective in many older applications. Androgen misuse is the systematic over-prescribing for unproven medical indications. Misuse is increasingly evident for male ageing ("andropause") and some other clinical conditions. Further trials for new indications for androgens require reliable safety data, but rising costs may make it increasingly attractive to circumvent the need for evidence by promoting off-label mass marketing. Androgen abuse is the illicit self-administration of often massive doses of androgens for non-medical purposes - notably power sports and body building. In parallel with effective detection reducing androgen abuse in elite sports, more focus is needed on non-sporting cosmetic, recreational and occupational androgen abuse. Despite ongoing androgen misuse and abuse, testosterone remains under-prescribed for younger men with classical androgen deficiency that frequently remains undiagnosed.
Publisher: The Endocrine Society
Date: 03-2014
DOI: 10.1210/EN.2013-1940
Abstract: We determined the functional role of the Sertoli cell glucocorticoid receptor (GR) in vivo using a transgenic Cre-loxP approach to conditionally disrupt GR expression. Sertoli cell GR knockout (SCGRKO) was shown by absent Sertoli cell-specific GR immunolocalization and reduced levels of glucocorticoid-responsive Stc1 and Tsc22d3 mRNA in SCGRKO relative to control testes. Adult SCGRKO testes exhibited distinct morphological changes, including reduced seminiferous tubular lumen formation, decreased total Sertoli cell numbers, and parallel reductions in meiotic spermatocyte and postmeiotic spermatid numbers. Conversely, tubular diameter was increased and testis size was normal in SCGRKO males. Decreased serum FSH and testicular Fshr mRNA levels were consistent with reduced Sertoli cell number. Adult SCGRKO testes also displayed atypical germ cells and interstitial focal accumulations of hypertrophic lipid-laden, immature-like Leydig cells. Circulating LH, and testicular Lhr mRNA, testosterone, dihydrotestosterone, and 3α/3β-diol levels were all reduced in mature SCGRKO mice, whereas serum testosterone and dihydrotestosterone levels remained normal. Moreover, Sertoli cell GR disruption caused differential changes to steroidogenic enzyme transcripts, with down-regulated testicular Cyp11a1 contrasting with up-regulated Hsd17b3 expression. Reduced SCGRKO testicular expression of Hsd11b2, encoding an enzyme for corticosterone inactivation, supports a dynamic coupling between Hsd11b and androgen production. Our novel SCGRKO model has revealed that Sertoli cell-mediated GR actions support normal testicular function. Sertoli cell GR is required to maintain normal testicular Sertoli/germ cell numbers and circulating gonadotropin levels, as well as optimal Leydig cell maturation and steroidogenesis, providing new insight into gluocorticoid-mediated impact on male reproduction.
Publisher: Wiley
Date: 31-01-2014
DOI: 10.1111/CEN.12407
Abstract: Lower testosterone (T) levels are associated with poorer health outcomes in older men, but associations in younger or middle-aged men are uncertain, and data for dihydrotestosterone (DHT) and oestradiol (E2) are limited. We assessed the associations of circulating T, DHT and E2 with physical and health-related factors in a cohort comprising men aged 17-97 years. Serum from 2143 community-dwelling men from the 1994/95 Busselton Health Survey was assayed for T, DHT and E2 using liquid chromatography-tandem mass spectrometry. Men receiving hormonal therapy or reporting the use of testosterone, or with prostate cancer or orchidectomy were excluded. Of the men, 43% had never smoked, 6·1% had diabetes and 16·8% cardiovascular disease (CVD). Mean (±SD) age was 50·3 ± 17·0 years. Total T was moderately correlated with DHT (r = 0·56), E2 (r = 0·35) and sex hormone-binding globulin (r = 0·53). In age-, smoking-, body mass index (BMI)- and sex hormone-binding globulin (SHBG)-adjusted analyses, T was inversely associated with metabolic syndrome score, while DHT and E2 were not associated. In multivariable models, higher total T was associated with lower age, BMI and C-reactive protein, and with higher creatinine and haemoglobin, independently of SHBG. Higher DHT was associated with lower age, BMI and glucose level, and higher creatinine and haemoglobin. E2 was positively associated with age, BMI and haemoglobin. In men spanning younger, middle and older ages, circulating androgens are more related to age and metabolic factors than CVD or chronic disease. Further investigation is required to clarify whether androgens and oestrogens have contrasting roles as risk predictors for CVD.
Publisher: Wiley
Date: 16-06-2003
DOI: 10.1046/J.1365-2265.2003.01796.X
Abstract: The vascular effects of fluctuations in testosterone levels within the physiological range in otherwise healthy men are not known. We therefore aimed to study arterial function in hypogonadal men receiving long-term physiological androgen replacement therapy, at trough and peak testosterone levels. We recruited nine hypogonadal men (aged 35 +/- 4 years) receiving androgen replacement therapy, each treated with 800 mg testosterone (T) depot preparations every 6 months. Serum lipid and hormone levels and arterial reactivity were measured, prior to (trough T) and 2-4 weeks following testosterone administration (peak T). Each subject therefore served as their own control. Vessel diameter was measured by ultrasound at rest, during reactive hyperaemia [leading to flow-mediated dilatation (FMD), an endothelium-dependent response] and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Serum T (13 +/- 2 nmvs. 27 +/- 3 nm for trough and peak serum T, respectively, P < 0.001 normal adult male range 11-35 nm), and free T (195 +/- 23 pmvs. 510 +/- 93 pm, P < 0.005) significantly increased following subcutaneous depot T administration, as did serum oestradiol (100 +/- 10 pmvs. 175 +/- 9 pm, P = 0.001 normal adult male range < 250 pm). There was a significant decrease in FMD (3.6 +/- 1.1%vs. 3.0 +/- 0.8%, P 0.2). Lipid, blood pressure and vessel diameter measurements were also similar before and after testosterone administration. Physiological replacement of testosterone is associated with decreased endothelium-dependent dilatation, in hypogonadal men.
Publisher: The Endocrine Society
Date: 23-07-2020
Publisher: Oxford University Press (OUP)
Date: 08-05-2013
Abstract: Poor vitamin D status and frailty are common in older people and associated with adverse health outcomes. The aim of this study was to examine the associations between serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels and frailty and components of frailty in older Australian men. Cross-sectional analysis of the Concord Health and Ageing in Men Project, a large epidemiological study conducted in Sydney, Australia, between January 2005 and May 2007. Participants included 1,659 community-dwelling men. Main outcome measurements were frailty (assessed using the Cardiovascular Health Study), frailty criteria comprising five core components: weight loss reduced muscular strength/weakness slow walking speed exhaustion and low activity level, and the separate components of frailty. Covariates included serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels measured by radioimmunoassay, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, income, measures of health, parathyroid hormone, estimated glomerular function. Frailty was present in 9.2% of the s le. Low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were independently associated with frailty and with four of the five components of frailty (except weight loss). 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels were independently associated with frailty in older men. This suggests that there might be a number of different biological mechanisms for how low vitamin D status might contribute to the frailty syndrome. In addition, the possibility that improving vitamin D status may specifically influence the incidence and progression of frailty needs to be explored.
Publisher: Oxford University Press (OUP)
Date: 12-2012
DOI: 10.1095/BIOLREPROD.112.102012
Abstract: Ovarian granulosa cells display strong androgen receptor (AR) expression, suggesting a functional role for direct AR-mediated actions within developing mammalian follicles. By crossing AR-floxed and anti-Müllerian hormone (AMH)-Cre recombinase mice, we generated granulosa cell-specific androgen receptor knockout mice (GCARKO). Cre expression, assessed by lacZ activity, localized to 70%-100% of granulosa cells in most preantral to antral follicles, allowing for selected evaluation of granulosa cell AR-dependent actions during follicle development. Relative to wild-type (WT) females, GCARKO females were subfertile, producing a 24% reduction in the number of litters (P < 0.05) over 6 mo and an age-dependent decrease in total number of pups born, evident from 6 mo of age (P < 0.05). Follicle dynamics were altered in GCARKO ovaries at 3 mo of age, with a significant reduction in large preantral and small antral follicle numbers compared to WT ovaries (P < 0.05). Global premature follicle depletion was not observed, but increased follicular atresia was evident in GCARKO ovaries at 6 mo of age, with an 81% increase in unhealthy follicles and zona pellucida remnants (P < 0.01). Cumulus cell expansion was decreased (P < 0.01) and oocyte viability was diminished in GCARKO females, with a significant reduction in the percentage of oocytes fertilized after natural mating and, thus, in the rate of progression to the two-cell embryo stage (P < 0.05). In addition, compared with age-matched WT females, 6-mo-old GCARKO females exhibited significantly prolonged estrous cycles (P ≤ 0.05), suggesting altered hypothalamic-pituitary-gonadal feedback signaling. In conclusion, our findings revealed that selective loss of granulosa cell AR actions during preantral and antral stages of development leads to a premature reduction in female fecundity through reduced follicle health and oocyte viability.
Publisher: Wiley
Date: 27-02-2004
Publisher: The Endocrine Society
Date: 09-1999
Abstract: We showed previously that testosterone (T) alone could induce spermatogenesis and produce normally fertile spermatozoa in the absence of circulating gonadotropins. These studies used the hpg mouse, which is characterized by a congenital gonadotrophin deficiency due to a major deletion in the GnRH gene. Administering T by a subdermal implant of a SILASTIC brand tube impregnated with crystalline T showed that the androgenic requirement for full induction of spermatogenesis was a 1-cm length implant. Using this unique model of spermatogenesis without gonadotropins, we have now investigated the quantitative requirement for androgens to maintain spermatogenesis by testing the hypothesis that the androgenic threshold required for induction and maintenance of spermatogenesis are the same. Spermatogenesis was induced in homozygous hpg mice by T administration for 6 weeks. The first experiment determined the time-course of the regression of spermatogenesis after removal of the T-impregnated SILASTIC brand implant. Elongated spermatids were absent by 3 weeks and testicular weight regression was maximal by 4 weeks after androgen withdrawal. The second experiment examined the effects on maintenance of spermatogenesis of reducing the T dose. After full induction of spermatogenesis in homozygous hpg mice, the T implants were replaced with a range of smaller size T-impregnated SILASTIC brand implants for a further 4 weeks. All androgen-sensitive end-points (testis weight, tubular, and luminal diameters, round spermatids) were fully maintained with T implants of 0.06 cm and elongated spermatids with T implants of 0.25 cm. A further experiment showed that at very low T doses (0.06, 0.125 cm) the T effects observed at 4 weeks were maintained at 6 and 11 weeks duration. We conclude that the androgenic threshold to maintain spermatogenesis in the mouse is an order of magnitude lower than the threshold required for inducing spermatogenesis. This distinction suggests that the mechanism of action of testosterone in inducing spermatogenesis may involve regulation of a genetic switch to complete meiosis, whereas the maintenance involves a different locus of action. These findings suggest that further studies of androgen-dependent meiotic genes may be central to understanding the regulation and molecular basis of androgen-driven induction and maintenance of spermatogenesis.
Publisher: Elsevier BV
Date: 04-1987
DOI: 10.1016/0024-3205(87)90331-6
Abstract: It has been reported previously that 12-0-tetradecanoylphorbol-13-acetate is capable of stimulating the release of insulin from adult and neonatal pancreatic tissue. The data from this study show that this agent at a concentration of 1.3 uM, in the presence of 2.8 mM glucose, was unable to cause significant secretion of insulin from cultured human fetal pancreatic explants. By contrast 20 mM glucose was able to cause a small but significant immediate increase in secretion of insulin, but was unable to maintain this response beyond ten minutes. When the two agents were combined, a synergistic effect was seen throughout the entire 50 minute period of stimulation. The reason for this synergism is unclear since, whilst both secretagogues were able to cause a rise in the levels of diacylglycerol, together no extra effect was observed.
Publisher: Oxford University Press (OUP)
Date: 25-09-2015
Abstract: By investigating a birth cohort with a high ongoing participation rate to derive an unbiased population, what are the parameters and influences upon testicular function for a population not selected with regard to fertility? While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have no or minimal adverse impact. The majority of previous attempts to develop valid reference populations for spermatogenesis have relied on potentially biased sources such as recruits from infertility clinics, self-selected volunteer sperm donors for research or artificial insemination or once-fertile men seeking vasectomy. It is well known that studies requiring semen analysis have low recruitment rates which consequently question their validity. However, there has been some concern that a surprisingly high proportion of young men may have semen variables that do not meet all the WHO reference range criteria for fertile men, with some studies reporting that up to one half of participants have not meet the reference range for fertile men. Reported median sperm concentrations have ranged from 40 to 60 million sperm/ml. The Western Australian Pregnancy Cohort (Raine) was established in 1989. At 20-22 years of age, members of the cohort were contacted to attend for a general follow-up, with 753 participating out of the 913 contactable men. Of these, 423 men (56% of participants in the 20-22 years cohort study, 46% of contactable men) participated in a testicular function study. Of the 423 men, 404 had a testicular ultrasound, 365 provided at least one semen s le, 287 provided a second semen s le and 384 provided a blood s le. Testicular ultrasound examinations were performed at King Edward Memorial Hospital, Subiaco, Perth, for testicular volume and presence of epididymal cysts and varicoceles. Semen s les were provided and analysed by standard semen assessment and a sperm chromatin structural assay (SCSA) at Fertility Specialists of Western Australia, Claremont, Perth. Serum blood s les were provided at the University of Western Australia, Crawley, Perth and were analysed for serum luteinizing hormone (LH), follicular stimulating hormone (FSH), inhibin B, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), estradiol, estrone and the primary metabolites of DHT: 5α-androstane-3α,17β-diol (3α-diol) and 5-α androstane-3-β-17-beta-diol (3β-diol). Serum steroids were measured by liquid chromatography, mass spectrometry and LH, FSH and inhibin B were measured by ELISA assays. Cryptorchidism was associated with a significant reduction in testicular (P = 0.047) and semen (P = 0.027) volume, sperm concentration (P = 0.007) and sperm output (P = 0.003). Varicocele was associated with smaller testis volume (P < 0.001), lower sperm concentration (P = 0.012) and total sperm output (P = 0.030) and lower serum inhibin B levels (P = 0.046). Smoking, alcohol intake, herniorrhaphy, an epididymal cyst, medication and illicit drugs were not associated with any significant semen variables, testicular volume or circulating reproductive hormones. BMI had a significantly negative correlation with semen volume (r = -0.12, P = 0.048), sperm output (r = -0.13, P = 0.02), serum LH (r = -0.16, P = 0.002), inhibin B (r = -0.16, P < 0.001), testosterone (r = -0.23, P < 0.001) and DHT (r = -0.22, P < 0.001) and a positive correlation with 3αD (r = 0.13, P = 0.041) and DHEA (r = 0.11, P = 0.03). Second semen s les compared with the first semen s les in the 287 participants who provided two s les, with no significant bias by Bland-Altman analysis. Testis volume was significantly correlated positively with sperm concentration (r = 0.25, P < 0.001) and sperm output (r = 0.29, P < 0.001) and inhibin B (r = 0.42, P < 0.001), and negatively correlated with serum LH (r = -0.24, P < 0.001) and FSH (r = -0.32, P < 0.001). SCSA was inversely correlated with sperm motility (r = -0.20, P < 0.001) and morphology (r = -0.16, P = 0.005). WHO semen reference criteria were all met by only 52 men (14.4%). Some criteria were not met at first analysis in 15-20% of men, including semen volume (<1.5 ml, 14.8%), total sperm output (<39 million, 18.9%), sperm concentration (<15 million/ml, 17.5%), progressive motility (<32%, 14.4%) and morphologically normal sperm (<4%, 26.4%), while all five WHO criteria were not met in four participants (1.1%). This was a large cohort study however, potential for recruitment bias still exists. Men who did not participate in the testicular evaluation study (n = 282) did not differ from those who did (n = 423) with regard to age, weight, BMI, smoking or circulating reproductive hormones (LH, FSH, inhibin B, T, DHT, E2, E1, DHEA, 3α-diol, 3β-diol), but were significantly shorter (178 versus 180 cm, P = 0.008) and had lower alcohol consumption (P = 0.019) than those who did participate. This study demonstrated the feasibility of establishing a birth cohort to provide a relatively unbiased insight into population-representative sperm output and function and of investigating its determinants from common exposures. While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have little adverse impact, and this study suggests that discrepancies from the WHO reference ranges are expected, due to its derivation from non-population-representative fertile populations.
Publisher: Oxford University Press (OUP)
Date: 19-03-2010
Abstract: to describe the prevalence and impact on quality of life of urinary incontinence in a population-based cohort of older community-dwelling Australian men. the population comprised 1,705 men aged >or=70 years participating in the Concord Health and Ageing in Men Project, a population-based study of urban older Australian men. data were collected between January 2005 and June 2007, and the participation rate was 47%. Data on demographics, medical history and from the 12-item Short Form Health Survey (SF-12) and International Consultation on Incontinence Questionnaire were collected. Urinary incontinence was defined as urinary leakage at least two times a week over the past 4 weeks. the prevalence of urinary incontinence was 14.8%, increasing from 12.0% for men aged 70-74 years old to 16.3% for those aged >or=90 years, with urgency incontinence being the most frequent type of urinary incontinence. Daily urine leakage was reported by 3% of men. Men with incontinence had lower overall SF-12 scores with greater impact on the physical (PCS) than the mental (MCS) components of that scale. After adjusting for age, number of co-morbidities, enlarged prostate and prostate cancer, men with incontinence had worse PCS (43.6 vs 45.9) and MCS scores (52.2 vs 54.6) compared with continent men. urinary incontinence is common among older community-dwelling men and is associated with worse quality of life with greater impact on physical than mental factors. As the population ages, urinary incontinence prevalence will increase and increased resources will be needed to address this growing problem.
Publisher: Massachusetts Medical Society
Date: 20-02-1986
DOI: 10.1056/NEJM198602203140802
Abstract: Purpose. p38 mitogen-activated protein kinase (MAPK) is known to play a regulatory role in inflammatory processes in disease. Inflammation has been linked also to the development of diabetic retinopathy in rodents. This study was conducted to evaluate the effect of a p38 MAPK inhibitor on the development of early stages of diabetic retinopathy in rats. Methods. Streptozotocin-diabetic rats were assigned to two groups-treated with the p38 MAPK inhibitor PHA666859 (Pfizer, New York, NY) and untreated-and compared with age-matched nondiabetic control animals. Results. At 2 months of diabetes, insulin-deficient diabetic control rats exhibited significant increases in retinal superoxide, nitric oxide (NO), cyclooxygenase (COX)-2, and leukostasis within retinal microvessels. All these abnormalities were significantly inhibited by the p38 MAPK inhibitor (25 mg/kgBW/d). At 10 months of diabetes, significant increases in the number of degenerate (acellular) capillaries and pericyte ghosts were measured in control diabetic rats versus those in nondiabetic control animals, and pharmacologic inhibition of p38 MAPK significantly inhibited all these abnormalities (all P < 0.05). This therapy also had beneficial effects outside the eye in diabetes, as evidenced by the inhibition of a diabetes-induced hypersensitivity of peripheral nerves to light touch (tactile allodynia). Conclusions. p38 MAPK plays an important role in diabetes-induced inflammation in the retina, and inhibition of p38 MAPK offers a novel therapeutic approach to inhibiting the development of early stages of diabetic retinopathy and other complications of diabetes.
Publisher: The Royal Society
Date: 07-10-2015
Abstract: Prenatal testosterone may have a powerful masculinizing effect on postnatal physical characteristics. However, no study has directly tested this hypothesis. Here, we report a 20-year follow-up study that measured testosterone concentrations from the umbilical cord blood of 97 male and 86 female newborns, and procured three-dimensional facial images on these participants in adulthood (range: 21–24 years). Twenty-three Euclidean and geodesic distances were measured from the facial images and an algorithm identified a set of six distances that most effectively distinguished adult males from females. From these distances, a ‘gender score’ was calculated for each face, indicating the degree of masculinity or femininity. Higher cord testosterone levels were associated with masculinized facial features when males and females were analysed together ( n = 183 r = −0.59), as well as when males ( n = 86 r = −0.55) and females ( n = 97 r = −0.48) were examined separately ( p -values 0.001). The relationships remained significant and substantial after adjusting for potentially confounding variables. Adult circulating testosterone concentrations were available for males but showed no statistically significant relationship with gendered facial morphology ( n = 85, r = 0.01, p = 0.93). This study provides the first direct evidence of a link between prenatal testosterone exposure and human facial structure.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2013
DOI: 10.1007/S12603-013-0013-Z
Abstract: Inadequate vitamin D status (25-hydroxyvitamin D (25(OH)D) concentrations <50 nmol/L) is an increasingly important public health issue in Australia. The aim of this analysis is to describe 25(OH)D levels in community dwelling men aged ≥70 years in Sydney, Australia, and to determine associations between serum 25(OH)D levels and socioeconomic and lifestyle factors. A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. 1659 non-institutionalised men aged ≥70 years. The cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. Participants included 1659 community dwelling men who were interviewed and had clinical assessments. Main outcome measurements included serum 25(OH)D levels measured in blood s les using a radioimmunoassay kit (DiaSorin Inc., Stillwater, MN). Covariates included age, socioeconomic measures, season of blood s le, physical activity, sun exposure, vitamin D supplement use, cigarette smoking status, alcohol consumption, obesity and measures of health. Prevalence of vitamin D insufficiency was 43.0% highest in winter (55.5%) and spring (53.9%), and was associated with season (winter and spring), low physical activity, avoidance of sun exposure, current smoking and obesity, even after adjustment for confounding factors. Inadequate vitamin D status is highly prevalent among Australian older men and is associated with specific lifestyle factors. These findings emphasize the need to screen and monitor 25(OH)D levels in this population group, despite living in a sunny country such as Australia.
Publisher: The Endocrine Society
Date: 07-04-2021
Abstract: Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder however, the etiology and pathogenesis of PCOS are poorly understood and current management is symptom-based. Defining the pathogenesis of PCOS traits is important for developing early PCOS detection markers and new treatment strategies. Hyperandrogenism is a defining characteristic of PCOS, and studies support a role for androgen-driven actions in the development of PCOS. Therefore, we aimed to determine the temporal pattern of development of PCOS features in a well-characterized dihydrotestosterone (DHT)-induced PCOS mouse model after 2, 4, and 8 weeks of DHT exposure. Following 2 weeks of treatment, DHT induced the key PCOS reproductive features of acyclicity, anovulation, and multifollicular ovaries as well as a decrease in large antral follicle health. DHT-treated mice displayed the metabolic PCOS characteristics of increased body weight and exhibited increased visceral adiposity after 8 weeks of DHT treatment. DHT treatment also led to an increase in circulating cholesterol after 2 weeks of exposure and had an overall effect on fasting glucose levels, but not triglycerides, aspartate transaminase (AST) and alanine transaminase (ALT) levels, or hepatic steatosis. These data reveal that in this experimental PCOS mouse model, acyclicity, anovulation, and increased body weight are early features of a developing PCOS phenotype whereas adiposity, impaired glucose tolerance, dyslipidemia, and hepatic steatosis are later developing features of PCOS. These findings provide insights into the likely sequence of PCOS trait development and support the addition of body weight criteria to the early diagnosis of PCOS.
Publisher: Informa UK Limited
Date: 18-11-2016
DOI: 10.1080/07853890.2016.1252053
Abstract: Anticholinergic and sedative medications are associated with acute cognitive impairment, but the long-term impact on change in cognition is unclear. This study investigated the effect of anticholinergic and sedative medications, quantified using the Drug Burden Index (DBI), on change in cognition over time in community-dwelling older men. This was a prospective cohort study of men aged ≥70 years in Sydney, Australia. DBI was assessed at baseline, 2, and 5 years. Cognitive performance was assessed using the Mini-Mental State Exam (MMSE) at each wave. Logistic quantile mixed-effects modelling was used to assess the adjusted effect of DBI on the median MMSE-time profile. Analyses were restricted to men with English-speaking backgrounds (n = 1059, 862, and 611 at baseline, 2, and 5 years). Overall, 292 (27.7%), 258 (29.9%), and 189 (31.3%) men used anticholinergic or sedative medications at baseline, 2, and 5 years. There was a concave relationship between MMSE and time, where higher DBI corresponded to lower MMSE scores (coefficient: -0.161 95% CI: -0.250 to -0.071) but not acceleration of declining MMSE over time. Exposure to anticholinergic and sedative medications is associated with a small impairment in cognitive performance but not decline in cognition over time. KEY MESSAGES Exposure to anticholinergic and sedative medications, quantified using the Drug Burden Index, is associated with small cross-sectional impairments in cognitive performance. There was no evidence that exposure to anticholinergic and sedative medications is associated with accelerating decline in cognitive performance over a 5-year follow-up. Older people taking anticholinergic and sedative medications may derive immediate but small benefits in cognitive performance from clinical medication reviews to minimize or cease prescribing of these medications.
Publisher: S. Karger AG
Date: 20-05-2023
DOI: 10.1159/000524311
Abstract: b i Introduction: /i /b This study aimed to assess the extent to which a single item of self-reported hearing difficulties is associated with future risk of falling among community-dwelling older adults. b i Methods: /i /b We used data from two Australian population-based cohorts: three waves from the PATH Through Life study (PATH i n /i = 2,048, 51% men, age 66.5 ± 1.5 SD years) and three waves from the Concord Health and Ageing in Men Project (CHAMP i n /i = 1,448, 100% men with mean age 77.3 ± 5.3 SD years). Hearing difficulties were recorded on a four-point ordinal scale in PATH and on a dichotomous scale in CHAMP. The number of falls in the past 12 months was reported at each wave in both studies. In CHAMP, incident falls were also ascertained by triannual telephone call cycles for up to four years. Multivariable-adjusted random intercept negative binomial regression models were used to estimate the association between self-reported hearing difficulties and number of falls reported at the following wave or 4-monthly follow-ups. b i Results: /i /b In PATH, self-reported hearing difficulties were associated with a higher rate of falls at follow-up (incidence rate ratio = 1.15, 95% CI = 1.03–1.27 per a one-level increase in self-reported hearing difficulties), after adjusting for sociodemographic characteristics, health behaviours, physical functioning, balance, mental health, medical conditions, and medications. There were no significant associations between hearing difficulties and the rate of falls based on either repeated survey or 4-monthly follow-ups in CHAMP. b i Conclusion: /i /b Though we find mixed results, findings from PATH data indicate an ordinal measure of self-reported hearing loss may be predictive of falls incidence in young-old adults. However, the null findings in the male-only CHAMP preclude firm conclusions of a link between hearing loss and falls risk.
Publisher: Medknow
Date: 17-06-2013
DOI: 10.1038/AJA.2013.71
Publisher: Oxford University Press (OUP)
Date: 2022
DOI: 10.1530/EJE-21-0663
Abstract: Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatization to estradiol (E2). However, no controlled study has assessed the effects of E2 in the absence of testosterone. Six-month randomized, placebo-controlled trial with the hypothesis that men randomized to E2 would reduce their fat mass. Seventy-eight participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3, and month 6. The primary outcome was total fat mass. Serum E2 increased in the estradiol group over 6 months compared to placebo, and mean-adjusted difference (MAD) was 207 pmol/L (95% CI: 123–292), P 0.001. E2 treatment changed total fat mass, MAD 1007 g (95% CI: 124–1891), but not significantly, so P = 0.09. There were other consistent non-significant trends toward increased proportional fat mass, MAD 0.8% (95% CI: 0.0–1.6), P = 0.15 gynoid fat, MAD 147 g (95% CI: 2–293), P = 0.08 visceral fat, 53 g (95% CI: 1–105) P = 0.13 and subcutaneous fat, MAD 65 g (95% CI: 5–125), P = 0.11. Android fat increased, MAD 164 g (95% CI: 41–286), P = 0.04. Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of testosterone, may increase total and regional fat mass in men. Given the premature closure of clinical trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether E2 promotes fat expansion in the absence of testosterone.
Publisher: AMPCo
Date: 10-2013
DOI: 10.5694/MJA13.10111
Abstract: To provide the first multinational survey of temporal trends in testosterone prescribing, given that anecdotal evidence indicates that it is increasing in some countries, including Australia. Sales data for all testosterone products were obtained for 41 countries for each year from 2000 to 2011. For each testosterone product type (injectable, implantable, oral, transdermal), units sold were converted into defined monthly doses per year, reflecting total testosterone prescribing per product. National testosterone prescribing rate overall and per product type on a per capita basis. For every region and 37 of 41 countries, there was a major and progressive increase in defined monthly doses per year per capita over the 11 years surveyed. In most countries, the increases were steeper for the last half of the survey period. The proportion of testosterone prescribing represented by transdermal testosterone products, a surrogate measure of prescribing for older men, increased even more than did the total usage of testosterone products. In the absence of any new indications, off-label testosterone prescribing has increased in most countries in 2000-2011, especially over the last half of the period. The increased testosterone prescribing appears to be primarily for older men and driven by clinical guidelines that endorse testosterone prescribing for age-related functional androgen deficiency (andropause). By eliminating the fundamental distinction between pathological and functional androgen deficiency, these guidelines tacitly promote increased testosterone prescribing, bypassing the requirement for high-quality clinical evidence of safety and efficacy and creating dramatic increases in prescription of testosterone products.
Publisher: Wiley
Date: 08-1994
DOI: 10.1111/J.1365-2826.1994.TB00599.X
Abstract: Hypothalamo-pituitary inhibition of reproductive function during undernutrition is well known, however, the physiological mechanisms leading to suppression of gonadotrophin secretion are not clear. A variety of studies have indicated that testicular negative feedback on LH secretion is enhanced during food restriction. To evaluate directly the suppression by endogenous androgens on hypothalamic GnRH pulse generator activity during food restriction and examine the mechanism underlying the increased testicular steroidal feedback, we examined (1) circulating bioactive LH (bLH) levels in response to selective cerebral androgen blockade by intraventricular administration of an androgen receptor antagonist (hydroxyflutamide, SCH 16423) and (2) the binding capacity and affinity of androgen receptors in medio-basal hypothalamus, pituitary and prostate during undernutrition of intact mature male rats. Hydroxyflutamide (20 micrograms in 10 microliters vehicle), but not vehicle alone, markedly increased bLH levels in both food restricted and ad-lib fed rats. However, the faster (geometric mean 11.4 vs 27.7 min) and greater (47.2 vs 21.9 ng/ml) increase in bLH level in food restricted compared with ad-lib fed controls demonstrates an enhanced sensitivity to blockade of androgenic negative feedback during undernutrition. Food restriction increased androgen receptor binding capacity in pituitary (3.36 vs 0.77 fmol/mg protein) but not in medio-basal hypothalamus or prostate while binding affinity was unchanged by undernutrition in all 3 tissues. These studies reveal that undernutrition both enhances tonic, androgen receptor-mediated feedback suppression of GnRH secretion and increases in pituitary (but not hypothalamic) androgen receptor numbers to cause inhibition of LH secretion.
Publisher: The Endocrine Society
Date: 10-07-2020
Abstract: Accurate measurement of very low circulating estradiol (E2) (& pg/ml) in postmenopausal women and in mice is essential to investigating sex steroid action in target tissues. However, direct immunoassays are too inaccurate and conventional mass spectrometry-based measurement too insensitive at these serum E2 levels. We report application of an ultrasensitive method using a novel estrogen-selective derivatization in liquid chromatography-mass spectrometry to measure serum E2, with a detection limit of 0.25 pg/ml in small (0.2 ml) serum volumes that can quantify serum E2 in 98% and serum E1 in 100% of healthy postmenopausal women. Aromatase inhibitor (AI) treatment of postmenopausal women with breast cancer further reduces serum E2 by 85% and serum estrone (E1) by 80%. The wide scatter of circulating E2 in AI-treated women suggests that the degree of sustained E2 depletion, now quantifiable, may be an efficacy or safety biomarker of adjuvant AI treatment. This ultrasensitive method can also measure serum E2 in most (65%) female but not in any male mice. Further studies are warranted using this and comparable ultrasensitive liquid chromatography-mass spectrometry estrogen measurements to investigate the relationship of circulating E2 (and E1) in male, postmenopausal female, and childhood health where accurate quantification of serum estrogens was not previously feasible. This will focus on the direct impact of estrogens as well as the indirect effects of androgen aromatization on reproductive, bone, and brain tissues and, notably, the efficacy and safety of AIs in adjuvant breast cancer treatment.
Publisher: The Endocrine Society
Date: 04-2004
DOI: 10.1210/EN.2003-1164
Publisher: The Endocrine Society
Date: 09-04-2009
DOI: 10.1210/EN.2008-1750
Abstract: Female androgen receptor (AR) knockout mice (AR−/−) generated by an in-frame Ar exon 3 deletion are subfertile, but the mechanism is not clearly defined. To distinguish between extra- and intraovarian defects, reciprocal ovarian transplants were undertaken. Ovariectomized AR−/− hosts with wild-type (AR+/+) ovary transplants displayed abnormal estrus cycles, with longer cycles (50%, P & 0.05), and 66% were infertile (P & 0.05), whereas AR+/+ hosts with either AR−/− or surgical control AR+/+ ovary transplants displayed normal estrus cycles and fertility. These data imply a neuroendocrine defect, which is further supported by increased FSH (P & .05) and estradiol (P & .05), and greater LH suppressibility by estradiol in AR−/− females at estrus (P & .05). Additional intraovarian defects were observed by the finding that both experimental transplant groups exhibited significantly reduced pups per litter (P & 0.05) and corpora lutea numbers (P & 0.05) compared with surgical controls. All groups exhibited normal uterine and lactation functions. AR−/− uteri were morphologically different from AR+/+ with an increase in horn length (P & 0.01) but a reduction in uterine diameter (P & 0.05), total uterine area (P & 0.05), endometrial area (P & 0.05), and myometrial area (P & 0.01) at diestrus, indicating a role for AR in uterine growth and development. Both experimental transplant groups displayed a significant reduction in uterine diameter (P & 0.01) compared with transplanted wild-type controls, indicating a role for both AR-mediated intraovarian and intrauterine influences on uterine physiology. In conclusion, these data provide direct evidence that extraovarian neuroendocrine, but not uterine effects, as well as local intraovarian AR-mediated actions are important in maintaining female fertility, and a disruption of AR signaling leads to altered uterine development.
Publisher: Oxford University Press (OUP)
Date: 19-12-2017
Abstract: How well does multi-analyte steroid mass spectrometry (MS) profiling classify women with and without polycystic ovary syndrome (PCOS)? Our liquid chromatography MS (LC-MS) steroid profiling only minimally improves discrimination of women with and without PCOS compared with a direct testosterone immunoassay (T_IA) and the free androgen index (FAI). Blood testosterone measured by direct (non-extraction) immunoassay overlaps between women with and without PCOS. Multi-analyte MS provides greater specificity and accuracy for steroid measurement so might improve the classification. An observational, cross-sectional study of women with PCOS (n = 152) defined by Rotterdam criteria and matched non-PCOS (n = 45) control women was conducted. Serum steroid profiles of testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), androstenedione (A Serum testosterone by immunoassay demonstrated levels more than 100% higher than that measured by LC-MS. Compared with the controls, women with PCOS had higher serum T, DHEA, A The study cohort is limited in size and only unconjugated steroids were measured. Multi-analyte steroid profiling of unconjugated circulating steroids provides only limited improvement on direct T_IA in classifying women with and without PCOS. None. N/A.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.4158/EP14034.CR
Publisher: Oxford University Press (OUP)
Date: 03-1995
DOI: 10.1093/OXFORDJOURNALS.HUMREP.A135997
Abstract: To minimize overestimation of motility, it is recommended that fresh semen be diluted with seminal plasma prior to automated analysis. However, for glycerolated or cryopreserved semen this is impractical, and alternative methods are needed to minimize automated motility bias. In the present study, the proportion of motile spermatozoa was determined in fresh, diluted and cryopreserved semen (n = 25 ejaculates) using visual and automated methods. The effect of software settings on motility was investigated by assessing s les at a range of modified settings. At standard settings, automated motility was biased in fresh semen (+7.2%) after dilution with cryopreservative (-2.9%) and after cryopreservation (-7.8%) (P < 0.0001 versus visual). Automated motility was inversely related to the minimum number of frames for motility s ling (P < 0.0001), with mean estimates of 41.0, 46.1, 52.0 and 58.2% generated at settings of 8, 4, 2 and 1 frame(s) respectively (n = 15 fresh, diluted and cryopreserved s les). Based on an arbitrary ordinal scale, a method was developed whereby motility s ling was adjusted prior to analysis according to sperm density. Analysis of an independent set of semen s les with density-adjusted software settings reduced bias in automated estimates (n = 30) before and after freezing (P < 0.0001). In addition, bias was no longer related to sperm density. In conclusion, modification of software settings is an effective alternative to dilution to minimize bias in automated motility estimates in fresh, diluted and cryopreserved human semen.
Publisher: The Endocrine Society
Date: 07-1988
Abstract: The pulse frequency, litude, and mode of administration of GnRH all influence gonadotropin secretion and, ultimately, pituitary-gonadal function. We studied plasma LH responses to repetitive iv administration of GnRH given hourly for 5 h as a 2-microgram rapid (less than 15 s) bolus dose or a 2-microgram dose infused for 15 min of each hour in seven women deficient in endogenous GnRH and sex steroids. Plasma LH levels, measured at 10-min intervals throughout the 5-h period, rose more briskly (pattern X time course interactions: F = 3.33 P less than 0.0001) to higher levels overall (F = 11.7 P = 0.014) after rapid bolus GnRH administration than after GnRH infusion. Plasma FSH levels increased during both modes of delivery, with higher responses to rapid bolus GnRH administration (P = 0.005). Plasma estradiol levels did not change during either 5-h study. We conclude that the pattern of delivery of GnRH is a determinant of pituitary LH and FSH secretion in untreated hypogonadotropic women, and therefore, that alterations in the GnRH wave form and/or peak plasma GnRH concentrations consequent upon different rates of GnRH entry into the blood-stream may explain the different responses that occur when GnRH is given by different routes.
Publisher: Wiley
Date: 17-08-2010
DOI: 10.1111/J.1365-2265.2010.03804.X
Abstract: As reference laboratory methods for measuring free testosterone (FT) by equilibrium dialysis (ED) are laborious, costly and nonautomatable, FT levels are often calculated (cFT) rather than measured. However, the predictive accuracy of such estimates in routine use relative to laboratory measurements is not well defined. We provide a large-scale evaluation of the predictive accuracy for different FT formulae compared with laboratory ED measurement and an analysis of clinical factors that may influence accuracy. The accuracy of five different cFT formulae (two equilibrium binding, three empirical) based on immunoassays of total testosterone (TT) and SHBG was evaluated by comparing those estimates with FT measurement by ED in 2159 serum s les from men at a single research laboratory over several years. cFT formulae show systematic discrepancies from the two equilibrium-binding formulae. One empirical formula overestimated FT relative to ED measurements, whereas two newer empirical cFT formulae were more concordant. These discrepancies persisted after correction for serum albumin and were not influenced by obesity, ethnicity or gonadal status. Commonly used cFT formulae significantly overestimate FT relative to laboratory measurement by ED in male serum s les. The accuracy of the formulae is not influenced by correction for serum albumin, obesity, ethnicity or gonadal status. Such inaccuracy relative to the reference method renders some cFT estimates unreliable for evaluating androgen deficiency as recommended by clinical best practice guidelines.
Publisher: The Endocrine Society
Date: 04-2015
DOI: 10.1210/JC.2014-4104
Abstract: It is unclear whether declining sexual function in older men is a cause or consequence of reduced androgen status. Longitudinal associations were examined between reproductive hormones and sexual function in older men. Men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (n = 1705) and 2-year follow-up (n = 1367), with a total of 1226 men included in the final analyses. At both visits, serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH were measured by immunoassay. Sexual functions (erectile function, sexual activity, and sexual desire) were self-reported via standardized questions. In longitudinal analyses, although baseline hormones (T, DHT, E2, and E1) did not predict decline in sexual function, the decline in serum T (but not DHT, E2, or E1) over 2 years was strongly related to the change in sexual activity and desire (but not erectile function). For each 1-SD decrease in T from baseline to 2-year follow-up, there was a multivariate-adjusted odds ratio of 1.23 (95% confidence interval, 1.12-1.36) for an additional risk of further decline in sexual activity. However, the magnitude of the decrease in serum T was strikingly small (<10%). Similar associations were found for changes over 2 years in serum T and decline in sexual desire, but not for erectile function. We found a consistent association among older men followed over 2 years between the decline in sexual activity and desire, but not in erectile function, with a decrease in serum T. Although these observational findings cannot determine causality, the small magnitude of the decrease in serum T raises the hypothesis that reduced sexual function may reduce serum T rather than the reverse.
Publisher: The Endocrine Society
Date: 2015
DOI: 10.1210/JC.2014-3019
Abstract: In mice, undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesized that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers. PARTICIPANTS were community-dwelling men aged 70 to 89 years resident in Perth, Western Australia. Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, DHT, and estradiol (E2) were assayed by mass spectrometry. Excluding men with osteoporosis or conditions affecting sex hormones or on bisphosphonates, glucocorticoids, or warfarin, 2966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase = 0.55, P < .001). Similar results were seen for TOC (OR = 0.60, P < .001), P1NP (OR = 0.64, P < .001), and CTX (OR = 0.60, P < .001) but not ucOC/TOC. When all 4 markers were included in the fully adjusted model, higher ucOC (OR = 0.56, P < .001) and CTX (OR = 0.76, P = .008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient -0.04, P = .031), TOC (-0.05, P = .001) and CTX (-0.04, P = .016) and positively with ucOC/TOC (0.05, P = .002). DHT was inversely associated with ucOC/TOC (-0.04, P = .040). T was not associated with bone turnover. Higher bone remodeling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodeling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.CLNU.2021.10.010
Abstract: Mediterranean dietary patterns may exert favourable effects on various health conditions. This study aimed to determine associations of adherence to Mediterranean diet as well as its components, with circulating cytokine levels, musculoskeletal health and incident falls in community-dwelling older men. Seven hundred ninety-four (794) community-dwelling men with mean age 81.1 ± 4.5 years, who participated in the five-year follow-up of the Concord Health and Ageing in Men Project (CHAMP) were included in the cross-sectional analysis, and 616 attended follow-up three years later. Adherence to Mediterranean diet was assessed using MEDI-LITE (literature-derived Mediterranean diet) score which was obtained using a validated diet history questionnaire. Twenty-four evaluable circulating cytokines were analyzed using Bio-Plex Pro Human Cytokine 27-plex Assay kit. Appendicular lean mass (ALM) and bone mineral density (BMD) were measured using dual-energy x-ray absorptiometry (DXA). Three-year changes in gait speed and hand grip strength were assessed by walking a 6-m course and using a dynamometer respectively and analyzed using linear mixed-effects models. Incident falls over three years were determined through telephone interviews every four months. Multivariable linear regression was utilized to determine the cross-sectional associations between MEDI-LITE scores and circulating cytokines, bone mineral density, ALM, and ALM A higher MEDI-LITE score, indicating greater adherence to Mediterranean diet, was associated with higher appendicular lean mass adjusted for body mass index (ALM Adherence to a Mediterranean diet is associated with higher ALM
Publisher: Elsevier BV
Date: 04-2006
Publisher: Oxford University Press (OUP)
Date: 07-08-2014
Abstract: Although there is a conflicting evidence for an association between low serum 25-hydroxyvitamin D (25D) levels and pain, the relationship between pain and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25D), has not been investigated. The aim of this study was to examine the associations between serum vitamin D metabolites: 25D and 1,25D with intrusive or chronic pain in community-living men aged ≥70 years. Population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project, a large epidemiological study conducted in Sydney between January 2005 and May 2007. Participants included 1,659 community dwelling men aged ≥70 years, taking part in Concord Health and Ageing in Men Project. Main outcome measurements were symptoms of chronic or intrusive pain. Covariates included 25D and 1,25D, parathyroid hormone, estimated glomerular filtration rate as well as age, country of birth, season of blood collection, body mass index, health conditions, and medication, including nonsteroidal anti-inflammatory drugs and statins. The prevalence of intrusive pain was 22.9% and of chronic pain was 29.7%. Low serum 25D concentrations were associated with intrusive and chronic pain in unadjusted analysis, but after adjustment, the associations were no longer significant. Low 1,25D levels (<62.0 pmol/L) remained independently associated with chronic pain (odds ratio: 1.53 [1.05, 2.21, p = .02]), even after adjustment for a wide range of potential confounders and covariates of clinical significance. Low serum 1,25D concentrations are associated with chronic pain in older men. This raises the question whether vitamin D metabolites may influence pain states, mediated through different biological mechanisms and pathways.
Publisher: The Endocrine Society
Date: 08-11-2021
Abstract: Ovarian hyperthecosis (OHT), severe hyperandrogenism after menopause in the absence of ovarian or adrenal tumors, is usually treated by surgical excision. We report a 58-year-old woman presenting with severe hyperandrogenism (serum testosterone 15.7-31.0 nmol/L, normal female & .8 nmol/L) with menopausal gonadotropins and virilization but no adrenal or ovarian lesions. Multisteroid profiling by liquid chromatography mass spectrometry (LCMS) of adrenal and ovarian vein s les identified strong gradients in the left ovarian vein (10- to 30-fold vs peripheral blood in 17OHP4, 17 hydroxyprogesterone, 17 hydroxypregnenolone, androstenedione, testosterone, dehydroepiandrosterone) but the right ovarian vein could not be cannulated with the same findings in a second ovarian vein cannulation. OHT diagnosis was confirmed by an injection of a depot pure gonadotropin-releasing hormone (GnRH) antagonist (80 mg Degarelix, Ferring) producing a rapid (& hour) and complete suppression of ovarian steroidogenesis as well as serum luteinizing hormone and follicle-stimulating hormone lasting at least 8 weeks, with reduction in virilization but injection site reaction and flushing and vaginal spotting ameliorated by an estradiol patch. Serum testosterone remained suppressed at 313 days after the first dose despite recovery of menopausal gonadotropins by day 278 days. This illustrates use of multisteroid LCMS profiling for confirmation of the OHT diagnosis by ovarian and adrenal vein s ling and monitoring of treatment by peripheral blood s ling. Injection of a depot pure GnRH antagonist produced rapid and long-term complete suppression of ovarian steroidogenesis maintained over 10 months. Hence a depot pure GnRH antagonist can not only rapidly confirm the OHT diagnosis but also induce long-term remission of severe hyperandrogenism without surgery.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.PEPTIDES.2008.08.009
Abstract: Kisspeptins, the products of KiSS-1 gene acting via G protein-coupled receptor 54 (GPR54), have recently emerged as fundamental gatekeepers of gonadal function by virtue of their ability to stimulate gonadotropin secretion. Indeed, since the original disclosure of the reproductive facet of the KiSS-1/GPR54 system, an ever-growing number of studies have substantiated the extraordinary potency of kisspeptins to elicit gonadotropin secretion in different mammalian species, under different physiologic and experimental conditions, and through different routes of administration. In this context, studies conducted in laboratory rodents have been enormously instrumental to characterize: (i) the primary mechanisms of action of kisspeptins in the control of gonadotropin secretion (ii) the pharmacological consequences of acute vs. continuous activation of GPR54 (iii) the roles of specific populations of kisspeptin-producing neurons at the hypothalamus in mediating the feedback effects of sex steroids (v) the function of kisspeptins in the generation of the pre-ovulatory surge of gonadotropins and (iv) the influence of sex steroids on GnRH/gonadotropin responsiveness to kisspeptins. While some of those aspects of kisspeptin function will be covered elsewhere in this Special Issue, we summarize herein the most salient data, obtained in laboratory rodents, that have helped to define the physiologic roles and putative pharmacological implications of kisspeptins in the control of male and female gonadotropic axis.
Publisher: Bioscientifica
Date: 15-05-2013
DOI: 10.1530/JOE-13-0056
Abstract: Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family and signals through GDNF family receptor alpha 2 (GFRα2). We hypothesised that epithelial atrophy reported in the reproductive organs of Ntn ( Nrtn )- and Gfr α 2 ( Gfra2 )-deficient mice could be due to NTN affecting the hormonal environment. To investigate this, we compared the reproductive organs of Ntn - and Gfr α 2 -deficient male mice in parallel with an analysis of their circulating reproductive hormone levels. There were no significant structural changes within the organs of the knockout mice however, serum and intratesticular testosterone and serum LH levels were very low. To reconcile these observations, we tested androgen sensitivity by creating a dihydrotestosterone (DHT) cl (castration plus DHT implant) to create fixed circulating levels of androgens, allowing the evaluation of androgen-sensitive endpoints. At the same serum DHT levels, serum LH levels were lower and prostate and seminal vesicle weights were higher in the Ntn knockout (NTNKO) mice than in the wild-type mice, suggesting an increased response to androgens in the accessory glands and hypothalamus and pituitary of the NTNKO mice. Testicular and pituitary responsiveness was unaffected in the NTNKO males, as determined by the response to the human chorionic gonadotrophin or GNRH analogue, leuprolide, respectively. In conclusion, our results suggest that NTN inactivation enhances androgen sensitivity in reproductive and neuroendocrine tissues, revealing a novel mechanism to influence reproductive function and the activity of other androgen-dependent tissues.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.JCLINEPI.2012.02.018
Abstract: This study aimed to determine an optimal discriminating number of concomitant medications associated with geriatric syndromes, functional outcomes, and mortality in community-dwelling older men. Older men aged ≥ 70 years (n=1,705), enrolled in the Concord Health and Aging in Men Project were studied. Receiver operating characteristic curve analysis using the Youden Index and the area under the curve was performed to determine discriminating number of medications in relation to each outcome. The highest value of the Youden Index for frailty was obtained for a cutoff point of 6.5 medications compared with a cutoff of 5.5 for disability and 3.5 for cognitive impairment. For mortality and incident falls, the highest value of Youden Index was obtained for a cutoff of 4.5 medications. For every one increase in number of medications, the adjusted odds ratios were 1.13 (95% confidence interval [CI]=1.06-1.21) for frailty, 1.08 (95% CI=1.00-1.15) for disability, 1.09 (95% CI=1.04-1.15) for mortality, and 1.07 (95% CI=1.03-1.12) for incident falls. There was no association between increasing number of medications and cognitive impairment. The study supports the use of five or more medications in the current definition of polypharmacy to estimate the medication-related adverse effects for frailty, disability, mortality, and falls.
Publisher: AMPCo
Date: 02-1991
DOI: 10.5694/J.1326-5377.1991.TB121077.X
Abstract: We compared prevalence rates and correlates of substance use among high school students in South Africa and the United States. We used weighted data from 2 nationally representative surveys of high school students. We conducted bivariate and multivariate analyses and examined between-country differences in rates and correlates of substance use were examined. Rates of past-month alcohol and marijuana use were lower among South African students than among US students, but rates of illicit hard drug use were higher. Correlates of use in the 2 countries differed. For ex le, female gender was protective against tobacco, alcohol, and marijuana use in South Africa, whereas in the United States it was protective only against marijuana use. Black race/ethnicity was associated with lower rates of past-month cigarette and alcohol use in both countries, but the protective effect for alcohol use was stronger in South Africa. Crosscultural studies can elucidate common and culturally unique pathways to drug use. Our results can inform future research, policies, and behavioral interventions in South Africa.
Publisher: Public Library of Science (PLoS)
Date: 11-03-2014
Publisher: Wiley
Date: 08-1991
DOI: 10.1111/J.1365-2826.1991.TB00302.X
Abstract: Abstract The aim of this study was to determine whether testicular products of non-Leydig cell origin modulate rat luteinizing hormone (LH) secretion in vivo. We therefore compared the effects of ethane dimethane sulphonate (EDS), a toxin regarded as highly selective for Leydig cells, with that of bilateral orchidectomy on LH secretion in mature male Wistar rats. The intention was thereby to compare the effects of selective removal of Leydig cells with that of removing both Leydig cells and seminiferous tubules, respectively. Following a single dose of EDS (75 mg/kg, ip), plasma LH concentrations rose equally with those of castrated rats for the first 3 days. After that time, however, plasma LH concentrations in the EDS-treated rats fell progressively below those of the orchidectomized rats despite the continuing castrate level of circulating testosterone until Day 17. The effects of EDS treatment or orchidectomy on pulsatile LH secretion were then compared after 11 days to castrate levels of testosterone. EDS-treated rats demonstrated reduced LH pulse litude, mean plasma LH levels and net LH secretion compared with castrate rats, although LH pulse frequency was unaltered. However, a further group of rats treated with EDS and orchidectomized failed to demonstrate that these changes were fully reversed by the castration and therefore EDS may have direct effects upon pituitary LH secretion. In order to determine the mechanism of the reduced LH pulse litude after EDS treatment, a further study was conducted to determine whether EDS treatment resulted in reduced pituitary sensitivity to gonadotropin-releasing hormone (GnRH). Responsiveness of pituitary LH to exogenous GnRH (0.01 to 10 mug/kg body wt) was studied 11 days after removal of testicular testosterone feedback by either EDS or castration. Plasma LH response was linearly related to the log of the GnRH dose. At 10 min after GnRH administration, the plasma LH response in EDS-treated rats was less sensitive than in castrate rats. We conclude that the lesser augmentation of LH secretion between Days 3 and 17 after EDS treatment compared with castrate rats cannot be explained solely by changes in Leydig cell secretion but may involve direct effects of EDS on pituitary LH secretion or non-Leydig cell testicular products. D ening of LH pulse litude without change in LH pulse frequency together with the reduced sensitivity to GnRH in EDS-treated rats suggests that this toxin may have direct effects on pituitary LH secretion independent of its effects on Leydig cell function.
Publisher: Wiley
Date: 09-1997
DOI: 10.1046/J.1365-2265.1997.2521050.X
Abstract: To review 13 years of experience using fused crystalline testosterone implants for androgen replacement therapy in order to identify pattern of usage (including continuation rates) and adverse events emerging during therapy and factors associated with adverse events including implant extrusions. Retrospective review of prospectively collected data on characteristics of patients and implant procedures performed as well as adverse events reported during routine follow-up. Over 13 years 973 implant procedures using fused crystalline testosterone implants were performed in 221 men. Continuation rates and adverse events such as extrusions, bleeding, infection or others were recorded and analysed in relationship to characteristics of the patient and the implant procedure performed. Overall rate of adverse events (108/73, 11.1%) was significantly related to increased numbers of implants (4.2 +/- 0.1 vs 4.0 +/- 0.03, P = 0.031) and higher levels of physical activity at work (P = 0.030). The most common adverse effect was extrusion (83/973, 8.5%) which was related to occupational classification (P = 0.033) and increasing work activity (P = 0.044) and occurred more frequently than by chance in multiple (16 vs 3.3 expected) rather than single (65 vs 76.1 expected) episodes. Bleeding (22/973, 2.3%) was significantly associated with an increased number of implants (4.5 +/- 0.2 vs 4.0 +/- 0.03, P = 0.020) but even in the worst cases (3/22) it was of minor clinical importance. Infection was rare (6/973, 0.6%) but occurred more among thinner men. The overall continuation rate was 92.7% increasing from 86% after the first implantation to > 99% after the tenth implant. This study demonstrates the very satisfactory clinical acceptability of testosterone pellet implants for androgen replacement therapy within a single unit with experienced operators. The only regular adverse effect is extrusion, which may be related to mechanical factors such as habitual work activity but also possibly procedural factors. Other adverse effects such as bleeding, infection and fibrosis were rare. An improved method of implant delivery would enhance this old but durable technology.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2007
DOI: 10.1016/J.JURO.2007.05.163
Abstract: We evaluated the transperineal ultrasound method to measure total and central prostate volume compared with the standard transrectal ultrasound. Healthy men without prostate disease underwent transperineal and transrectal ultrasound at a single session to calculate total and central prostate volume by the ellipsoidal formula from maximal measured dimensions. Reproducibility within and between methods was evaluated by ICC, CV and Bland-Altman plots. In 13 men measured on 3 occasions within 2 weeks transperineal and transrectal ultrasound had high within method (ICC 0.92 and 0.97, and CV 7.2% and 5.1%, respectively) and between method (ICC 0.98 and CV 5.4%) agreement. Agreement for central prostate volume was good but it was lower within method (ICC 0.74 and 0.73, and CV 20.5% and 20.3%, respectively) and between method (ICC 0.85 and CV 19.7%). Transperineal ultrasound bias was -2.7% for total and -8.9% for central prostate volume. Of 287 healthy men the methods highly correlated for total prostate volume in 245 (ICC 0.92, 95% CI 0.90 to 0.94) and for central prostate volume in 217 (ICC 0.87, 95% CI 0.83 to 0.90). Transperineal ultrasound had minimal bias for total prostate volume (-3.7%, mean -1.0 ml, 95% CI -1.7 to -0.2 ml) and no bias for central prostate volume (-3.0%, mean bias 0.10 ml, 95% CI -0.3 to 0.5 ml). Transperineal ultrasound was more acceptable but it had a higher technical failure rate for total and central prostate volume (13.6% vs 1.4% and 23.7% vs 3.5%, respectively). Transperineal ultrasound provides an accurate, less invasive and more acceptable alternative but with a higher technical failure rate than transrectal ultrasound, especially for central prostate volume. By trading off acceptability for the failure rate transperineal ultrasound may enhance the feasibility of valid studies requiring repeat prostate volume measurement in asymptomatic men.
Publisher: Medknow
Date: 27-08-2012
DOI: 10.1038/AJA.2012.88
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2010
DOI: 10.1159/000253431
Publisher: The Endocrine Society
Date: 05-2011
DOI: 10.1210/EN.2010-1501
Publisher: The Endocrine Society
Date: 09-1988
Abstract: A comparison of serum inhibin levels in men and women was undertaken using a sensitive sheep pituitary cell in vitro bioassay and a newly developed heterologous RIA. The RIA was based on an antiserum raised to bovine 31K inhibin using [125I]31K inhibin as tracer. Bovine inhibin alpha- and beta-subunits, bovine activin-A, transforming growth factor-beta, and Mullerian inhibitory substance did not cross-react in the RIA. In both assays, dilutions of serum gave response lines parallel to that of the partially purified human follicular fluid inhibin preparation used as standard. Negligible levels of both bio (B)- and immuno (I) activities were found in serum from women with premature ovarian failure or castrated men. In ovulation-induced cycles, serum B inhibin levels increased progressively from the early to the late follicular phase and remained at the late follicular phase level during the early and midluteal phases. Serum I inhibin levels also rose during the follicular phase, but declined during the early luteal phase before increasing again in the midluteal phase. As a consequence, inhibin B:I ratios varied during the treatment cycle, with high ratios in early follicular (2.86) and early luteal (2.25) phases and a low ratio in the midluteal phase (1.09). Similar changes in serum B:I ratios also occurred during the midcycle and midluteal phases of normal cycles. The B:I ratio was lower (0.35) in normal men. We conclude that the largely similar pattern of inhibin biological and immunological activities in serum obtained during a variety of physiological conditions support the validity of the RIA procedure, and the B:I ratio of serum inhibin varies during the follicular and luteal phases of the cycle and is low in men. Potential reasons for these changes in B:I ratio include the presence of interfering substances in either the bioassay or the RIA, the presence of inhibin isoforms, and/or modulation of secreted forms by sex steroids.
Publisher: Oxford University Press (OUP)
Date: 10-1998
Publisher: Wiley
Date: 08-2005
DOI: 10.1111/J.1365-2265.2005.02342.X
Abstract: Measurement of biochemical markers of the IGF-system and of collagen turnover is a potential approach to detect GH abuse in sport. These markers are increased in patients on dialysis treated with recombinant human erythropoietin (r-HuEPO), mimicking the effects of GH. The aim was to determine whether r-HuEPO induces similar effects on the IGF-system and collagen turnover in healthy athletes. Young male Caucasian recreational athletes were administered 50 U/kg r-HuEPO (n=14) or placebo (n=16) three times a week for 25 days, followed by a 4-week wash-out period. IGF-I, IGFBP-3, the acid labile subunit (ALS), N-terminal propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III collagen (PIIINP) were measured in s les collected at baseline (two s les), after 10, 22 and 24 days of r-HuEPO treatment and at the end of the 4-week wash-out period. Treatment with r-HuEPO resulted in approximately threefold elevation of serum EPO and marked elevation of markers of erythropoiesis. There was no significant treatment effect of r-HuEPO compared to baseline on IGF-I, IGFBP-3, ALS, PINP, ICTP or PIIINP. r-HuEPO administration did not change markers of the IGF-system and of collagen turnover in young healthy male athletes. Therefore, use of r-HuEPO in athletes should not affect the validity of a GH doping test using these GH-responsive markers.
Publisher: The Endocrine Society
Date: 02-07-2020
Abstract: After menopause, estradiol (E2) is predominately an intracrine hormone circulating in very low serum concentrations. The objective of this work is to examine determinants of E2 concentrations in women beyond age 70 years. A cross-sectional, community-based study was conducted. A total of 5325 women participated, with a mean age of 75.1 years (± 4.2 years) and not using any sex steroid, antiandrogen/estrogen, glucocorticoid, or antiglycemic therapy. Sex steroids were measured by liquid chromatography–tandem mass spectrometry. Values below the limit of detection (LOD E2 11 pmol/L [3 pg/mL] were assigned a value of LOD/√2 to estimate total E2. E2 and estrone (E1) were below the LOD in 66.1% and 0.9% of women, respectively. The median (interdecile ranges) for E1 and detectable E2 were 181.2 pmol/L (range, 88.7-347.6 pmol/L) and 22.0 pmol/L (range, 11.0-58.7 pmol/L). Women with undetectable E2 vs detectable E2 were older (median age 74.1 years vs 73.8, P = .02), leaner (median body mass index [BMI] 26.8 kg/m2 vs 28.5, P & .001), and had lower E1, testosterone and DHEA concentrations (P & .001). A linear regression model, including age, BMI, E1, and testosterone, explained 20.9% of the variation in total E2, but explained only an additional 1.2% of variation over E1 alone. E1 and testosterone made significant contributions (r2 = 0.162, P & .001) in a model for the subset of women with detectable E2. Our findings support E1 as a principal circulating estrogen and demonstrate a robust association between E1 and E2 concentrations in postmenopausal women. Taken together with prior evidence for associations between E1 and health outcomes, E1 should be included in studies examining associations between estrogen levels and health outcomes in postmenopausal women.
Publisher: Informa UK Limited
Date: 24-01-2023
Publisher: The Endocrine Society
Date: 05-2007
DOI: 10.1210/EN.2006-1223
Abstract: Prostate development and maturation requires stromal-epithelial interactions and androgen action via the androgen receptor (AR) within these compartments. However, the specific roles of epithelial and stromal AR in postnatal prostate differentiation are unclear. We used Cre-LoxP technology to determine the prostate phenotype in mice with epithelial-selective genetic inactivation of the AR leaving the stromal AR functionally intact. We find that prostate development abolished in mice globally lacking a functional AR can be rescued by restricting the AR knockout to the postnatal prostate epithelium. We show that, at 8 wk of age, prostate epithelial AR knockout (PEARKO) mice exhibit prostate development with normal branching morphogenesis but lobe-specific decrease in prostate weight and hindered structural and functional differentiation of the mature prostate epithelium. No change was observed in PEARKO testis weight or serum testosterone compared with littermate controls. The most striking change was increased proliferation and abnormal lesions of epithelial cells predominantly in the anterior lobe of PEARKO mice. These findings highlight the vital role of stromal AR in postnatal prostate growth and structural differentiation and emphasize the requirement of epithelial AR in maintaining functional differentiation and restraining proliferation of epithelial cells in a lobe-specific manner. This unique PEARKO mouse provides a new paradigm with which to define the molecular mechanisms of the androgen signaling in mature prostate lobes in vivo and provides insight into the identification of better targets for treatment of prostate cancer and hyperplasia.
Publisher: The Endocrine Society
Date: 1996
DOI: 10.1210/JCEM.81.1.8550796
Abstract: To examine the role of androgens in initiating the pubertal rise in circulating insulin-like factor-I (IGF-I) levels, a longitudinal study of puberty in 13 male hamadryas baboons was conducted over 3 yr. The five control baboons commenced puberty (initial testicular enlargement) at a mean +/- SE age of 4.2 +/- 0.4 yr. Another eight baboons were castrated prepubertally of those four received testosterone pellets (dose equivalent: 12.5-50 mg every 6 weeks) implanted se from the time of puberty. Body weight, crown-rump length, and limb length measurements, synchronized to pubertal onset, suggest that a pubertal growth spurt occurs in male baboons. Control baboons had a marked rise (4- to 5-fold P 0.99 chronological age ED50 controls, 4.4 +/- 0.1 yr and castrate + testosterone, 4.3 +/- 0.1 yr). Serum IGF binding protein-3 levels paralleled the rise in IGF-I consistent with a common regulatory mechanism. In another study, castration of four sexually mature male baboons aged 11.12 +/- 1.16 yr had no effect on serum IGF-I levels (P = 0.5). This indicates that androgens are the predominant determinant of circulating IGF-I in the male baboon, and that this is an uniquely pubertal phenomenon.
Publisher: AMPCo
Date: 06-2012
DOI: 10.5694/MJA11.11277
Abstract: To describe patterns of testosterone prescribing in Australia over the past two decades by state or territory and by product type. Observational analysis of testosterone prescribing data obtained from two independent data sources--the Pharmaceutical Benefits Scheme (PBS) and IMS, a source of commercial pharmaceutical sales data. Temporal trends in testosterone prescribing--measured as units prescribed (converted into monthly defined doses) and expenditure--to state or territory and product type (injectable, implantable, transdermal and oral). Over two decades, total annual expenditure on testosterone products increased ninefold to $12.7 million according to PBS data and fivefold to $16.3 million according to IMS data. When adjusted for inflation and population growth, expenditure increased 4.5-fold according to PBS data and 2.5-fold according to IMS data. The patterns of testosterone prescribing according to PBS and IMS data were highly congruent. When converted into monthly defined dose units, testosterone prescribing increased over the two decades with approximately twofold differences in total testosterone prescribed per capita between the states and territories with the highest and lowest rates of prescribing. When analysed by product type, the stable market patterns over the first 15 years were disrupted by sharp changes to create market dominance owing to introduction of two new testosterone products--a depot injectable testosterone and a transdermal testosterone gel. The progressive increase in PBS-subsidised testosterone prescribing without changes in proven medical indications or improvements in diagnosis of pathologically based androgen deficiency are likely to be due to promotion-driven non-compliance with PBS prescribing criteria, indicating that more effective implementation of the criteria is needed.
Publisher: American Chemical Society (ACS)
Date: 18-02-2011
DOI: 10.1021/AC102845Y
Abstract: Androgenic steroids marketed online as nutraceuticals are a growing concern in sport doping. The inability of conventional mass spectrometry (MS)-based techniques to detect structurally novel androgens has led to the development of in vitro androgen bioassays to identify such designer androgens by their bioactivity. The objective of this study was to determine the androgenic bioactivity of novel steroidal compounds isolated from nutraceuticals using both yeast and mammalian cell-based androgen bioassays. We developed two new in vitro androgen bioassays by stably transfecting HEK293 and HuH7 cells with the human androgen receptor (hAR) expression plasmid together with a novel reporter gene vector (enhancer/ARE/SEAP). The yeast β-galactosidase androgen bioassay was used for comparison. Our new bioassay featuring the enhancer/ARE/SEAP construct (-S) displayed simpler assay format and higher specificity with lower sensitivity compared with the commonly used mouse mammary tumour virus (MMTV)-luciferase. The relative potencies (RP), defined as [EC(50)] of testosterone/[EC(50)] of steroid, of nutraceutical extracts in the yeast, HEK293-S, and HuH7-S, were 34, 333, and 80,000 for Hemapolin 208, 250, and 80 for Furazadrol 0.38, 10, and 106 for Oxyguno 2.7, 0.28, and 15 for Trena and 4.5, 0.1, and 0.4 for Formadrol, respectively. The wide discrepancies in rank RP of these compounds was reconciled into a consistent potency ranking when the cells were treated with meclofenamic acid, a nonselective inhibitor of steroid metabolizing enzymes. These findings indicate that steroids extracted from nutraceuticals can be converted in vitro into more or less potent androgens in mammalian but not in yeast cells. We conclude that the putative androgenic bioactivity of a new compound may depend on the bioassay cellular format and that mammalian cell bioassays may have an added benefit in screening for proandrogens but sacrifice specificity for sensitivity in quantitation.
Publisher: Oxford University Press (OUP)
Date: 05-2015
DOI: 10.1530/EJE-14-0891
Abstract: Injectable testosterone undecanoate (TU) was marketed within the last decade, but its complications in routine clinical practice are not well defined. Prospective observational study of consecutive TU injections in an Andrology Clinic to estimate the incidence of i) immediate cough/syncope due to pulmonary oil microembolisation (POME), ii) post-injection haematoma and iii) the prevalence of secondary polycythaemia. In 3022 injections given to 347 patients over 3.5 years, POME was observed after 56 injections (66% mild, 19% severe 40% with onset before injection completed) in 43 patients. The incidence of 19 (95% CI 14–24) per 1000 injections did not differ between three experienced nurse injectors, but recurrences were more frequent than by chance. No post-injection haematoma was reported including after 269 injections to men taking antiplatelet, anticoagulant or both drugs (upper 95% confidence limit 1%) with 56 not withholding drugs prior to TU administration (upper 95% confidence limit 5.4%). Mean haematocrit was 0.44±0.04 ( s.d. ) with 25 (7%) .50, 14 (4%) .52 and 3 (1%) .54. TU injections produce a low incidence of POME with injections by experienced nurses, but recurrence is more frequent than by chance. Post-injection haematoma was not observed even among men using anticoagulant and/or antiplatelet drugs, and polycythaemia was a minor problem rarely requiring treatment other than optimising inter-injection interval.
Publisher: The Endocrine Society
Date: 10-07-2020
Abstract: Estimating breeding performance from mouse mating trials has focused on lifetime mating trials, which are too slow and costly for characterizing the many novel genetic mouse lines produced in fertility research, an underpinning of reproductive pathophysiology research. This study introduces the fertility index, defined as the slope of the regression of cumulative number of pups produced by a female over elapsed time in a monogamous mating trial. By using a robust res ling technique, the Theil-Sen estimator (widely available in free or niche statistical software), to estimate the fertility index, the present study of 410 mating trials of mice from 7 genotypes lasting a median of 10 litters shows that it is possible to estimate the fertility index reliably over as few as 4 litters.
Publisher: The Endocrine Society
Date: 11-1996
Publisher: The Endocrine Society
Date: 02-2003
Abstract: We recently created a novel transgenic (tg) model to examine the specific gonadal actions of FSH, distinct from LH effects, by expressing tg-FSH in gonadotropin-deficient hypogonadal (hpg) mice. Using this unique in vivo paradigm, we now describe the postnatal cellular development in seminiferous tubules selectively stimulated by tg-FSH alone or combined with testosterone (T). In the αβ.6 line, tg-FSH stimulated the maturation and proliferation (∼2-fold) of Sertoli cells in hpg testes. Total Sertoli cell numbers were also significantly increased (1.5-fold) independently of FSH effects by T treatment alone. Selective FSH activity in αβ.6 hpg testes increased total spermatogonia numbers 3-fold, which established a normal spermatogonia/Sertoli cell ratio. FSH also elevated meiotic spermatocyte numbers 7-fold, notably at pachytene (28-fold), but induced only limited numbers of postmeiotic haploid cells (absent in hpg controls) that arrested during spermatid elongation. In contrast, T treatment alone had little effect on postnatal spermatogonial proliferation but greatly enhanced meiotic progression with total spermatocytes increased 12-fold (pachytene 53-fold) relative to hpg testes, and total spermatid numbers 11-fold higher than tg-FSH hpg testes. Combining tg-FSH and T treatment had no further effect on Sertoli or spermatogonia numbers relative to FSH alone but had marked additive and synergistic effects on meiotic cells, particularly pachytene (107-fold more than hpg), to establish normal meiotic germ cell/Sertoli cell ratios. Furthermore, tg-FSH had a striking synergistic effect with T treatment on total spermatid numbers (19-fold higher than FSH alone), although spermatid to Sertoli cell ratios were not fully restored to normal, indicating elevated Sertoli cell numbers alone are insufficient to establish a maximal postmeiotic germ cell capacity. This unique model has allowed a detailed dissection of FSH in vivo activity alone or with T and provided compelling evidence that FSH effects on spermatogenesis are primarily via Sertoli and spermatogonial proliferation and the stimulation of meiotic and postmeiotic germ cell development in synergy with and dependent on T actions.
Publisher: Oxford University Press (OUP)
Date: 12-2015
DOI: 10.1530/EJE-15-0380
Abstract: The age-specific population profiles in men of circulating testosterone and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E 2 ) across the adult lifespan and its determinants are not well described. Our objective was to deduce smoothed age-specific centiles of circulating testosterone, DHT, and E 2 in men using pooled data from population-based studies in three Australian cities from liquid chromatography–mass spectrometry steroid measurements in a single laboratory. We pooled data of 10 904 serum s les (serum testosterone, DHT, E 2 , age, height, and weight) from observational population-based studies in three major cities across Australia. Age-specific smoothed centiles for serum testosterone, DHT, and E 2 in men aged 35–100 years were deduced by large s le data analysis methods. We found that serum testosterone, DHT, and E 2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, BMI, and body surface area as well as shorter stature are associated with reduced serum testosterone, DHT, and E 2 . Among Australian men, there is a gradual progressive population-wide decline in androgen status during male aging until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status. Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.
Publisher: SAGE Publications
Date: 14-09-2019
Abstract: Foot growth is part of overall pubertal growth but its relation to other anthropometric and hormonal changes is unclear. Our objective was to determine how foot length changes relate to changes in other growth parameters (height and weight), Tanner stage, and serum hormones. Adolescents (n = 342) were recruited to a 3-year longitudinal cohort study, underwent annual anthropometric assessments (height, weight, and foot length), and provided self-rated Tanner staging. They also provided blood s les that were analyzed using liquid chromatography-tandem mass spectrometry for serum testosterone and estradiol and classified as pre-pubertal or pubertal based on circulating hormone levels. Average annual percent increase in foot length was greater for pre-pubertal adolescents compared with pubertal. Increased foot length was associated with increases in height, weight, Tanner stage, and serum hormones in males and pre-menarcheal females but not post-menarcheal females. Foot length offers a novel, noninvasive, cost-effective, and easily demonstrable marker of early pubertal changes.
Publisher: AMPCo
Date: 10-2010
Publisher: Elsevier BV
Date: 05-2010
Publisher: The Endocrine Society
Date: 12-1996
Publisher: The Endocrine Society
Date: 08-2014
DOI: 10.1210/EN.2014-1196
Abstract: Polycystic ovary syndrome (PCOS) affects 5–10% of women of reproductive age, causing a range of reproductive, metabolic and endocrine defects including anovulation, infertility, hyperandrogenism, obesity, hyperinsulinism, and an increased risk of type 2 diabetes and cardiovascular disease. Hyperandrogenism is the most consistent feature of PCOS, but its etiology remains unknown, and ethical and logistic constraints limit definitive experimentation in humans to determine mechanisms involved. In this study, we provide the first comprehensive characterization of reproductive, endocrine, and metabolic PCOS traits in 4 distinct murine models of hyperandrogenism, comprising prenatal dihydrotestosterone (DHT, potent nonaromatizable androgen) treatment during days 16–18 of gestation, or long-term treatment (90 days from 21 days of age) with DHT, dehydroepiandrosterone (DHEA), or letrozole (aromatase inhibitor). Prenatal DHT-treated mature mice exhibited irregular estrous cycles, oligo-ovulation, reduced preantral follicle health, hepatic steatosis, and adipocyte hypertrophy, but lacked overall changes in body-fat composition. Long-term DHT treatment induced polycystic ovaries displaying unhealthy antral follicles (degenerate oocyte and/or & 10% pyknotic granulosa cells), as well as anovulation and acyclicity in mature (16-week-old) females. Long-term DHT also increased body and fat pad weights and induced adipocyte hypertrophy and hypercholesterolemia. Long-term letrozole-treated mice exhibited absent or irregular cycles, oligo-ovulation, polycystic ovaries containing hemorrhagic cysts atypical of PCOS, and displayed no metabolic features of PCOS. Long-term dehydroepiandrosterone treatment produced no PCOS features in mature mice. Our findings reveal that long-term DHT treatment replicated a breadth of ovarian, endocrine, and metabolic features of human PCOS and provides the best mouse model for experimental studies of PCOS pathogenesis.
Publisher: American Physiological Society
Date: 05-2009
DOI: 10.1152/AJPENDO.90941.2008
Abstract: We have characterized the in vivo actions of human wild-type FSH receptor (FSHR) overexpressed in Sertoli cells of transgenic (Tg) mice ( TgFSHRwt) compared with transgenic overexpression of the human activated mutant FSHR*D567G ( TgFSHR*D567G). Testicular TgFSHRwt expression significantly elevated specific FSH binding ( -fold, P 0.01) relative to nontransgenic testes, similar to increased FSH binding in TgFSHR*D567G testes. Isolated TgFSHRwt Sertoli cells exhibited higher FSH-stimulated cAMP levels compared with non- Tg or TgFSHR*D567G cells but did not display the elevated FSH-independent basal cAMP levels found in TgFSHR*D567G Sertoli cells. Furthermore, Sertoli cell overexpression of TgFSHR*D567G but not TgFSHRwt allowed promiscuous cAMP responses to human chorionic gonadotropin (300 IU/ml) and TSH (30 mIU/ml), demonstrating increased constitutive signaling and altered glycoprotein hormone specificity via the intracellular D567G substitution rather than FSHR overexpression. Despite elevating Sertoli cell FSH sensitivity, overexpression of TgFSHRwt had no detectable effect upon normal testis function and did not stimulate Sertoli and germ cell development in testes of gonadotropin-deficient hypogonadal ( hpg) mice, in contrast to the increased meiotic and postmeiotic germ cell development in TgFSHR*D567G hpg testes. Increased steroidogenic potential of TgFSHR*D567G hpg testes was demonstrated by elevated Cyp11a1 and Star expression, which was not detected in TgFSHRwt hpg testes. Androgen-regulated and Sertoli cell-specific Rhox5 gene expression was increased in TgFSHR*D567G but not TgFSHRwt hpg testes, providing evidence of elevated LH-independent androgen activity due to mutant FSHR*D567G. Hence, transgenic FSHR overexpression in Sertoli cells revealed that the D567G mutation confers autonomous signaling and steroidogenic activity in vivo as well as promiscuous glycoprotein hormone receptor activation, independently of FSHR overexpression alone.
Publisher: Bioscientifica
Date: 06-2020
DOI: 10.1530/JOE-19-0530
Abstract: As the mechanistic basis of polycystic ovary syndrome (PCOS) remains unknown, current management relies on symptomatic treatment. Hyperandrogenism is a major PCOS characteristic and evidence supports it playing a key role in PCOS pathogenesis. Classically, androgens can act directly through the androgen receptor (AR) or, indirectly, following aromatization, via the estrogen receptor (ER). We investigated the mechanism of androgenic actions driving PCOS by comparing the capacity of non-aromatizable dihydrotestosterone (DHT) and aromatizable testosterone to induce PCOS traits in WT and Ar -knockout (ARKO) mice. DHT and testosterone induced the reproductive PCOS-like features of acyclicity and anovulation in WT females. In ARKO mice, DHT did not cause reproductive dysfunction however, testosterone treatment induced irregular cycles and ovulatory disruption. These findings indicate that direct AR actions and indirect, likely ER, actions of androgens are important mediators of PCOS reproductive traits. DHT, but not testosterone, induced an increase in body weight, body fat, serum cholesterol and adipocyte hypertrophy in WT mice, but neither androgen induced these metabolic features in ARKO mice. These data infer that direct AR-driven mechanisms are key in driving the development of PCOS metabolic traits. Overall, these findings demonstrate that differing PCOS traits can be mediated via different steroid signaling pathways and indicate that a phenotype-based treatment approach would ensure effective targeting of the underlying mechanisms.
Publisher: Bioscientifica
Date: 06-1994
Abstract: In many mammalian species, circulating levels of insulinlike growth factor-I (IGF-I) rise during puberty. Previous studies manipulating testosterone levels in rats with normal GH secretion suggested that the pubertal IGF-I rise is regulated by an interaction between GH and sex steroids. Therefore, in a reciprocal study, IGF-I levels were examined during sexual maturation of the GH-deficient dwarf ( dw/dw ) rat which has a selective genetic deficiency of GH but normal sex steroid levels. Male dw/dw rats were treated with daily injections of recombinant human GH (200 μg/100 g body weight) or saline vehicle, from 28 to 70 days of age. Sexual maturation was determined to occur primarily between 42 and 63 days of age based on testis and seminal vesicle growth and plasma testosterone levels. GH treatment had no effect on seminal vesicle weights, plasma testosterone or gonadotrophins. GH administration resulted in a 7% increase in absolute testes weight ( P ·05), but a 50% increase in body weight ( P ·0001). These results supported previous findings that the reproductive development of dw/dw rats is essentially normal. Untreated dw/dw rats had no rise in IGF-I levels during sexual maturation. In contrast, treatment with GH produced a marked sustained rise in IGF-I levels ( P ·0001). Ligand blots demonstrated GH induction of IGF-binding protein-3 (IGFBP-3) and an IGFBP cluster at 32 kDa. The initially high immunoreactive IGFBP-1 levels ( ng/ml) decreased by 49 days of age after which untreated dw/dw rats had significantly higher IGFBP-1 levels than GH-treated dw/dw rats ( P ·01). We conclude that GH secretion, rather than sex steroids, may be the predominant determinant of pubertal IGF-I levels in rats and that the rise in circulating IGF-I levels during puberty is not an indispensible event for normal reproductive development. Journal of Endocrinology (1994) 141, 393–401
Publisher: Medknow
Date: 23-04-2012
DOI: 10.1038/AJA.2012.2
Publisher: Wiley
Date: 12-1995
DOI: 10.1111/J.1445-5994.1995.TB02885.X
Abstract: During the second half of the 20th century, progress in developing novel, practical contraceptive methods for men has lagged significantly behind developments for women. Despite the lack of reliable, reversible methods, men throughout the world continue to be strongly involved in family planning but a greater involvement will require more attractive and reliable contraceptive options for men. The closest to fruition are hormonal methods the features of which are reviewed. Landmark WHO contraceptive efficacy studies have established that hormonally-induced azoospermia provides highly effective and reversible contraception for at least 12 months with minimal short-term side effects. Even among the small subgroup of men who remain oligozoospermic during hormonal suppression, good contraceptive efficacy is achieved. The present goals are to develop improved second generation hormonal regimens which provide more uniform azoospermia to obviate the need for monitoring of sperm output and to develop long-acting depot testosterone formulations used alone or with additional gonadotrophin suppressive agents such as progestins or GnRH antagonists. Significant obstacles to progress are the flight of industry from contraceptive R&D dur to the financial deterrent posed by the product liability crisis as well as the low priority accorded male reproductive health. Together those will determine whether the range of contraceptive options available to our children in the 21st century will improve, or whether the historically recent unbalanced increase in reliance on women for family planning will continue.
Publisher: Oxford University Press (OUP)
Date: 14-01-2010
Abstract: frailty is a concept used to describe older people at high risk of adverse outcomes, including falls, functional decline, hospital or nursing home admission and death. The associations between frailty and use of specific health and community services have not been investigated. the cross-sectional relationship between frailty and use of several health and community services in the last 12 months was investigated in 1,674 community-dwelling men aged 70 or older in the Concord Health and Ageing in Men study, a population-based study conducted in Sydney, Australia. Frailty was assessed using a modified version of the Cardiovascular Health Study criteria. overall, 158 (9.4%) subjects were frail, 679 (40.6%) were intermediate (pre-frail) and 837 (50.0%) were robust. Frailty was associated with use of health and community services in the last 12 months, including consulting a doctor, visiting or being visited by a nurse or a physiotherapist, using help with meals or household duties and spending at least one night in a hospital or nursing home. Frail men without disability in activities of daily living were twice more likely to have seen a doctor in the previous 2 weeks than robust men (adjusted odds ratio 2.04, 95% confidence interval 1.21-3.44), independent of age, comorbidity and socio-economic status. frailty is strongly associated with use of health and community services in community-dwelling older men. The high level of use of medical services suggests that doctors and nurses could play a key role in implementation of preventive interventions.
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/J.JACC.2003.07.002
Abstract: This study investigated the effects of androgens on gene expression in male- and female-donor macrophages. Men have more severe coronary disease than women. Androgen exposure increases foam cell formation in male but not female macrophages, and male macrophages express >4-fold more androgen receptor messenger ribonucleic acid than female macrophages. Therefore, androgen exposure may have gender-specific and potentially pro-atherogenic effects in macrophages. Utilizing complementary deoxyribonucleic acid arrays, we studied the effects of a pure androgen (dihydrotestosterone, 40 nmol/l) on human monocyte-derived macrophages from healthy male and female donors (n = 4 hybridizations 2 men, 2 women). Differential expression of atherosclerosis-related genes was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in five male and five female donors. Functional corroboration of foam cell formation-related findings was undertaken by experiments using (125)I-acetylated low-density lipoprotein (AcLDL). In male macrophages, androgen treatment produced differential up-regulation of 27 genes concentrated in five functional classes: 1) lipoprotein processing 2) cell-surface adhesion 3) extracellular signaling 4) coagulation and fibrinolysis and 5) transport protein genes. By contrast, none of 588 genes were up-regulated in female macrophages. By RT-PCR, we confirmed the gender-specific up-regulation of six of these atherosclerosis-related genes: acyl coenzyme A:cholesterol acyl transferase I, lysosomal acid lipase (LAL), caveolin-2, CD40, vascular endothelial growth factor-165 receptor, and tissue factor pathway inhibitor. Functionally, androgen-treated male macrophages showed increased rates of lysosomal AcLDL degradation, by 45% to 75% after 15 to 20 h of (125)I-AcLDL incubation (p = 0.001), consistent with increased LAL activity. Androgens increase expression of atherosclerosis-related genes in male but not female macrophages, with functional consequences. These findings may contribute to the male predisposition to atherosclerosis.
Publisher: Oxford University Press (OUP)
Date: 27-04-2019
Abstract: while both negative and positive impacts of caregiving on health have been reported, findings regarding caregiver's mortality may be biased by the lack of consideration of changes in their health and caregiving status during follow-up. This study examines the impact of caregiving on the risk of death in older men, allowing for caregiving-transition by in iduals and adjusting for changes over time in their health status. data from 1639 men age ≥70 years old from the Concord Health and Ageing in Men Project (CHAMP) were collected between baseline (2005-07), 2-year and 5-year follow-up and linked to death records up to 30 September 2015. A time-varying Cox proportional hazards model was used to examine the risk of death from caregiving between 2005 and 2015, adjusting for baseline education, history of myocardial infarction, congestive heart failure, and risk factors which may change over time (age, income, self-rated overall health, number of morbidities, physical disability, depression and anxiety). the average follow-up was 7.39 years (SD = 2.95) with 495 deaths observed. There was no significant difference in all-cause mortality between caregivers and non-caregivers in the multivariable model (HR: 0.95, 95% CI: 0.67-1.32, P = 0.73). this study addressed the dynamic caregiving role and covariates which has been rarely considered in the literature. While there is concern that when older people take on a caring role their health suffers, we found no difference in mortality between older male caregivers and non-caregivers when we accounted for transitions in their caregiving status.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2016
DOI: 10.1007/S12672-016-0272-3
Abstract: Phosphatase and tensin homologue (PTEN) is a known tumour suppressor. To explore the role of Pten in ovarian tumorigenesis, we used transgenic (Tg) SOX2. Cre and AMH. Cre mouse models to direct global Pten haploinsufficiency (Pten
Publisher: Springer Science and Business Media LLC
Date: 06-03-2019
DOI: 10.1007/S10903-019-00874-W
Abstract: Italian migrants are one of the largest groups of older migrants in Australia. Past research has found lower mortality rates in Italian migrants but it is unclear if this persists into older age. Data came from 334 Italian-born and 849 Australian-born men aged 70 years and over participating in a longitudinal study of men's ageing. Male Italian migrants were more likely to smoke, be overweight, and have lower socio-economic status (SES). They also had higher morbidity from diabetes, chronic pain, dementia and depressive symptoms but lower morbidity from heart disease and cancer. There was no age-adjusted mortality difference. However, adjusting for SES, lifestyle and morbidity differences revealed a 25% lower mortality rate (adjusted HR = 0.75 95% CI 0.57, 0.98) in Italian-born men. Compared to their Australian-born counterparts, older Italian-born men have a lower mortality than expected considering their lower SES, higher smoking and higher morbidity.
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1016/J.JCLINEPI.2019.04.009
Abstract: The aim of the study was to compare the response rates and costs of phone call vs. short message service (SMS) screening reminders to prospective randomized controlled trial (RCT) participants. This study was a randomized evaluation within a large Australian diabetes prevention RCT. Participants were men aged 50-74 years, overweight or obese, without a previous type 2 diabetes diagnosis. Those eligible on a prescreening questionnaire who did not attend a further screening assessment within 4 weeks were randomized to receive an SMS or phone call reminder (N = 709). The primary outcome was attendance for further screening assessment within 8 weeks of prescreening. Attendance was 18% (62/354) in the SMS reminder group, and 23% (80/355) in the phone reminder group, with no statistically significant difference in response according to reminder type (relative risk = 1.29, 95% confidence interval [CI]: 0.96-1.73, P = 0.09). The lower confidence limits for response to SMS (95% CI: 14-22%) and phone reminders (95% CI: 18-27%) did not include the 8-week attendance rate before this evaluation, 12%. Phone reminders cost substantially more than SMS reminders (AU$6.21 vs. AU$0.53 per reminder). SMS reminders were as adequate a method as phone reminders to boost RCT screening uptake and were considerably more affordable.
Publisher: The Endocrine Society
Date: 04-2006
DOI: 10.1210/JC.2006-0156
Publisher: Bioscientifica
Date: 07-2021
DOI: 10.1530/EC-21-0109
Abstract: To define the optimized inter-injection interval of injectable testosterone undecanoate (TU) treatment for hypogonadal and transmen based on in idual dose titration in routine clinical practice. A prolective observational study of consecutive TU injections in men undergoing testosterone replacement therapy for pathological hypogonadism or masculinization of female-to-male transgender (transmen) subject to in idual dosing titration to achieve a stable replacement regimen. From 2006 to 2019, 6899 injections were given to 325 consecutive patients. After excluding the 6-week loading dose, 6300 injections were given to 297 patients who had at least three and a median of 14 injections. The optimal injection interval (mean of last three injection intervals) had a median of 12.0 weeks (interquartile range 10.4–12.7 weeks). The interval was significantly influenced by age and body size (body surface area, BSA) but not by diagnosis or trough serum LH, FSH, and SHBG. Longer (≥14 weeks 68/297, 23%), but not shorter (≤10 weeks 22/297, 7.4%), intervals were weakly correlated with age but not diagnosis or other covariables. Low blood hemoglobin increased with trough serum testosterone to reach plateau once testosterone was about 10 nmol/L or higher. Optimal intervals between TU injection after in idual titration resulted in the approved 12-week interval in 70% of patients with only minor influence for clinical application of BSA and not of trough serum LH, FSH, and SHBG. In idually optimized inter-injection interval did not differ between men with primary or secondary hypogonadism or transmen.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1986
Publisher: Wiley
Date: 04-01-2019
DOI: 10.1111/DOM.13601
Abstract: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT). To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years. Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT). Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments. Fasting insulin, HbA1c, body composition, maximal handgrip strength sexual function and lower urinary tract symptoms serum sex steroids and sex hormone binding globulin mood and psychosocial function adherence to lifestyle intervention and healthcare utilization and costs. Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2012
Abstract: Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17β-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5α-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol- O -methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5α-reductase mRNA levels. We find ERα and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT) increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ERα mRNA down-regulation and ERβ mRNA up-regulation by testosterone was found. 5α reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting conversion of T to DHT and increasing AR mRNA. Further, testosterone may increase local dopamine synthesis and metabolism, thereby changing dopamine regulation within the substantia nigra. We show that testosterone action through both AR and ERs modulates synthesis of sex steroid receptor by altering AR and ER mRNA levels in normal adolescent male substantia nigra. Increased sex steroids in the brain at adolescence may alter substantia nigra dopamine pathways, increasing vulnerability for the development of psychopathology.
Publisher: Oxford University Press (OUP)
Date: 10-2005
DOI: 10.1095/BIOLREPROD.105.039602
Abstract: Inhibin is secreted in two distinct heterodimeric forms, A and B, but the mechanism for the differential control of these two forms is unclear. To evaluate the relationship between secretion of inhibin forms and folliculogenesis, the effects of gonadotropins on inhibin concentrations were studied in parallel with stereological enumeration of ovarian follicle types in gonadotropin-deficient hypogonadal (hpg) female mice treated with recombinant human FSH (10 IU/day), hCG (1 IU/day), or both for 20 days. Treatment with FSH alone significantly increased blood concentrations of both inhibin A and inhibin B, whereas hCG alone had no effect on either inhibin. The combination of FSH and hCG further increased the concentration of inhibin A but had no effect on the concentration of inhibin B beyond that of FSH. The number of primordial follicles per ovary was significantly reduced in FSH-treated hpg mice, but was not affected by hCG treatment. Antral follicles were absent in the untreated hpg mice, present following treatment with FSH, and were present in only limited numbers following hCG treatment alone. Preovulatory follicles were observed only in the wild-type and combined FSH and hCG treatment groups. These results demonstrate that secretion of both inhibins is associated with the presence of antral follicles. Inhibin A secretion is increased by the presence of preovulatory follicles, whereas the concentration of inhibin B is not affected. The observed effects of gonadotropins on inhibin A and B secretion may be explained by corresponding gonadotropin effects on follicle development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
Publisher: The Endocrine Society
Date: 08-06-2020
Publisher: Oxford University Press (OUP)
Date: 03-2014
DOI: 10.1373/CLINCHEM.2013.213363
Abstract: Steroid immunoassays originally required solvent extraction, chromatography, and structurally authentic tracers to avoid interference from steroid cross-reactivity and matrix effects. The demand for steroid assays has driven assay simplification, bypassing this triplet of validity criteria to allow use of unextracted serum, which has introduced bias and nonspecificity at low steroid concentrations. We aimed to evaluate the performance of commercial direct estradiol (E2) immunoassays relative to the reference method of LC-MS and compared serum E2 measurements from each assay with biomarkers of estrogen action. We measured serum E2 in duplicate using 5 commercial direct immunoassays and LC-MS in a nested cohort of 101 healthy, asymptomatic men & years old from the Healthy Man Study. For each immunoassay, we evaluated the detectability and distribution of serum E2 measurements, CV, and bias (relative to LC-MS) by Passing–Bablok regression and deviance plots. Three assays detected E2 in all s les, whereas E2 was detected in only 53% and 72% of s les by 2 other assays. All 5 assays had positive biases, ranging from 6% to 74%, throughout their ranges. CVs were lower with 4 immunoassays than with LC-MS. LC-MS, but none of the direct immunoassays, correlated with serum testosterone and sex steroid–binding globulin. The positive bias of direct E2 immunoassays throughout their working range reflects the nonspecific effects of steroid cross-reactivity and/or matrix interference arising from the violation of the triplet validity criteria for steroid immunoassay.
Publisher: Elsevier BV
Date: 04-1996
Publisher: American Chemical Society (ACS)
Date: 02-07-2015
DOI: 10.1021/ACS.ANALCHEM.5B01042
Abstract: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is described that employs a novel derivatization reagent for the measurement of serum estradiol (E2), with simultaneous analysis of underivatized testosterone (T) and dihydrotestosterone (DHT). The main advantage of the new derivatization reagent 1,2-dimethylimidazole-5-sulfonyl chloride is its analyte-specific fragmentation that enables monitoring of confirmatory mass transitions with high sensitivity. The reaction mixture can be analyzed without additional purification steps using a 9.5 min gradient run, and sensitive detection is achieved with a triple quadrupole mass spectrometer using atmospheric pressure photoionization. Method validation was performed with human serum s les, including a comparison with a standard LC-MS/MS method using 120 s les from a clinical study, and analysis of certified E2 serum reference materials BCR-576, BCR-577, and BCR-578. The lower limits of quantification for E2, T, and DHT were 0.5 pg/mL, 25 pg/mL, and 0.10 ng/mL, respectively, from a 200-μL s le. Validation results indicated good accuracy and agreement with established, conventional LC-MS/MS assays, demonstrating suitability for analysis of s les containing E2 in the low pg/mL range, such as serum from men, children, and postmenopausal women.
Publisher: Springer Science and Business Media LLC
Date: 23-02-2017
DOI: 10.1007/S12672-017-0287-4
Abstract: Advancing age is associated with increased cancer incidence, but the role of sex hormones as risk predictors for common cancers in older men remains uncertain. This study was performed to assess associations of testosterone (T), dihydrotestosterone (DHT) and estradiol (E2), with incident prostate, lung and colorectal cancer in community-dwelling older men. Plasma T, DHT and E2 were assayed using liquid chromatography-mass spectrometry between 2001 and 2004 in 3690 men. Cancer outcomes until 20 June 2013 were ascertained using data linkage. Analyses were performed using proportional hazards competing-risks models, and adjustments were made for potential confounding factors including smoking status. Results are expressed as subhazard ratios (SHR). There were 348, 107 and 137 cases of prostate, lung and colorectal cancers respectively during a median of 9.1-year follow-up. Mean T was comparable in current and non-smokers, whilst mean DHT was lower in ex- and current smokers compared to non-smokers. After adjusting for confounders including smoking, higher T or DHT was associated with an increased incidence of lung cancer (SHR = 1.30, 95% CI 1.06-1.60 p = 0.012 per 1 SD increase in T and SHR = 1.29, 95% CI 1.08-1.54 p = 0.004 for DHT). Sex hormones were not associated with prostate or colorectal cancer. In older men, higher T or DHT predict increased incidence of lung cancer over the next decade. Sex hormones are not associated with incident prostate or colorectal cancer. Further studies are warranted to determine if similar associations of sex hormones with lung cancer are present in other populations and to investigate potential underlying mechanisms.
Publisher: Elsevier BV
Date: 1995
Publisher: Informa UK Limited
Date: 06-11-2018
DOI: 10.1080/13697137.2017.1392504
Abstract: The menopausal transition may have significant consequences for respiratory health, risk of chronic respiratory disease and management strategies. To systematically summarize the literature regarding the impact of menopause status on respiratory health outcomes. PubMed was searched systematically to identify population-based studies investigating the associations between menopause status and respiratory outcomes including asthma, chronic obstructive pulmonary disease (COPD), respiratory symptoms and lung function. Ten publications were identified for full review. Evidence on menopause and asthma was conflicting, while studies on COPD were scarce. The findings generally support an association between menopause and clinically significant reductions in lung function in a non-obstructive pattern. However, the effects of menopause are clouded by aging, menopausal hormone therapy use, and increased risk of metabolic syndrome during this period. As the global burden associated with respiratory conditions continues to rise, the need to understand the associations between menopause and respiratory health is essential to identify potentially modifiable risk factors for respiratory disease in adult women. More studies are needed to clarify the impact of menopause on obstructive lung disease.
Publisher: Wiley
Date: 22-10-2010
DOI: 10.1002/DTA.175
Abstract: Gas chromatography‐combustion‐isotope ratio mass spectrometry (GC‐C‐IRMS) is the preferred method of confirming the administration of exogenous testosterone by athletes. This relies on synthetic testosterone preparations being depleted in 13 C compared to natural testosterone. There is concern, however, about the existence of synthetic testosterone products that are unexpectedly 13 C‐enriched and which may allow athletes to circumvent the current GC‐C‐IRMS test. Further to the reported studies of legitimate pharmaceutical‐grade testosterone products, a detailed analysis of seized materials from border‐level seizures was required to obtain intelligence concerning trends in ‘black market’ testosterone manufacture and distribution. The s le set collected for this study between 2006 and 2009 inclusive provided a δ 13 C range (n = 266) of − 22.9‰ to − 32.6‰ with mean and median values of − 28.4‰ and − 28.6‰, respectively. Within this distribution there were 24 s les (9%) confirmed to have δ 13 C values in the range reported for endogenous urinary steroid metabolites (≥− 25.8‰). The benefit of δ 13 C profiling for testosterone preparations was demonstrated by the ability to identify specific seized products that can be target tested for future intelligence purposes. In addition, the potential of stable hydrogen isotope ratio ( 2 H/ 1 H δ 2 H) discrimination to complement δ 13 C analysis was investigated. Methodologies for the determination of δ 2 H values by gas chromatography‐thermal conversion‐isotope ratio mass spectrometry (GC‐TC‐IRMS) were developed to provide a δ 2 H range (n = 173) of − 177‰ to − 268‰ with mean and median values of − 231‰ and − 234‰, respectively. Copyright © 2010 John Wiley & Sons, Ltd.
Publisher: AMPCo
Date: 08-2016
DOI: 10.5694/MJA16.00393
Abstract: This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings.
Publisher: Ivyspring International Publisher
Date: 2018
DOI: 10.7150/IJBS.27378
Publisher: American Medical Association (AMA)
Date: 21-02-2017
Publisher: Wiley
Date: 23-05-2014
DOI: 10.1002/PROS.22825
Abstract: Glucocorticoids are used as a last resort treatment for prostate cancer but the cell-specific glucocorticoid receptor (GR) mediated actions and the role of endogenous glucocorticoids in prostate are not understood. We evaluated the influence of prostate epithelial GR mediated actions of glucocorticoids in prostate structural development by comparing the intact wild-type (WT) and prostate epithelia selective GR knockout (peGRKO) males at 8, 20, and 35 weeks of age. We also determined the cell-specific role of GR on corticosterone treatment induced prostate abnormalities by treating peGRKO and WT male mice with corticosterone depot pellets or placebo for 4 weeks. GR was not expressed in the epithelial cells of peGRKO prostate unlike WT but was expressed in stromal of both peGRKO and WT mice. Nevertheless, prostate weights, histological appearance, and secretory protein probasin expression in peGRKO were no different from WT. Despite lacking epithelial GR, the peGRKO prostate demonstrated corticosterone treatment induced hyperplasia similar to WT suggesting that stromal rather than epithelial GR mediates the hyperproliferative mouse prostate response to corticosterone. As circulating androgen levels were not affected by corticosterone treatment, this effect is likely to be mediated directly via prostate GR. Sustained administration of corticosterone induces prostate hyperplasia, which is mediated via GR expressed predominantly in the stroma. Thus GR mediated actions in the prostate may have significant cell-specific effects that could be utilized for more rational therapeutic approaches in prostate cancer treatment. This also illustrates the paracrine hormonal mechanisms in prostate pathophysiology.
Publisher: AMPCo
Date: 04-2011
Publisher: Elsevier BV
Date: 10-2021
Publisher: The Endocrine Society
Date: 07-02-2020
Abstract: Androgen abuse impairs male reproductive and cardiac function, but the rate, extent, and determinants of recovery are not understood. To investigate recovery of male reproductive and cardiac function after ceasing androgen intake in current and past androgen abusers compared with healthy non-users. Cross-sectional, observational study recruited via social media 41 current and 31 past users (≥3 months since last use, median 300 days since last use) with 21 healthy, eugonadal non-users. Each provided a history, examination, and serum and semen s le and underwent testicular ultrasound, body composition analysis, and cardiac function evaluation. Current abusers had suppressed reproductive function and impaired cardiac systolic function and lipoprotein parameters compared with non- or past users. Past users did not differ from non-users, suggesting full recovery of suppressed reproductive and cardiac functions after ceasing androgen abuse, other than residual reduced testicular volume. Mean time to recovery was faster for reproductive hormones (anti-Mullerian hormone [AMH], 7.3 months luteinizing hormone [LH], 10.7 months) than for sperm variables (output, 14.1 months) whereas spermatogenesis (serum follicle-stimulating hormone [FSH], inhibin B, inhibin) took longer. The duration of androgen abuse was the only other variable associated with slower recovery of sperm output (but not hormones). Suppressed testicular and cardiac function due to androgen abuse is effectively fully reversible (apart from testis volume and serum sex hormone binding globulin) with recovery taking between 6 to 18 months after ceasing androgen intake with possible cumulative effects on spermatogenesis. Suppressed serum AMH, LH, and FSH represent convenient, useful, and underutilized markers of recovery from androgen abuse.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2014
DOI: 10.1007/S00345-013-1201-5
Abstract: We aim to determine the relationship between season, personal solar UV exposure, serum 25(OH)D and 1,25(OH)2D and serum prostate-specific antigen (PSA) levels. Questionnaire data and blood s les were collected at baseline from participants of the Concord Health and Ageing in Men Project (n = 1,705), aged 70 and above. They were grouped as men 'free of prostate disease' for those with no record of having prostate cancer, benign prostatic hyperplasia, or prostatitis and with serum PSA levels below 20 ng/mL, and 'with prostate disease' for those with a record of either of these diseases or with serum PSA levels 20 ng/mL or above. Personal solar UV exposure (sUV) was estimated from recalled hours of outdoor exposure and weighted against ambient solar UV radiation. Sera were analysed to determine levels of PSA, 25(OH)D and 1,25(OH)2D, and analysed using multiple regression, adjusting for age, BMI and region of birth. The association between sUV and serum PSA levels was conditional upon season (p interaction = 0.04). There was no direct association between serum PSA and 25(OH)D in both groups of men. There was a positive association between serum PSA and 1,25(OH)2D in men with prostate disease (mean = 110.6 pmol/L p heterogeneity = 0.03), but there was no such association in men free of prostate disease (mean = 109.3 pmol/L p heterogeneity = 0.8). The association between PSA and sUV may only be evident at low solar UV irradiance, and this effect may be independent of serum vitamin D levels.
Publisher: Wiley
Date: 06-04-2016
DOI: 10.1111/LIV.13122
Abstract: Circulating testosterone is usually reduced in men with cirrhosis, but there has not been a comprehensive analysis of androgen status or circulating oestrogens. Little is known about associations between circulating sex steroids with aspects of health in this population. We report data from men with cirrhosis and low serum testosterone (<12 nmol/L or calculated free testosterone <230 pmol/L). Comprehensive circulating sex steroid profiles were measured by liquid chromatography-mass spectrometry and compared with age-matched controls. Relationships between sex hormone levels, severity of liver disease, biochemistry and clinical outcomes were assessed. Serum oestrone and oestradiol were significantly elevated in men with cirrhosis compared with controls (median, 869.1 pmol/L vs. 133.8 pmol/L and 166.7 pmol/L vs. 84.6 pmol/L respectively). Serum oestrone correlated with MELD score (correlation +0.306, P < 0.001) and inversely correlated with serum sodium (correlation -0.208, P = 0.004) and haemoglobin (correlation -0.177, P = 0.012). No such correlations were observed for oestradiol. Serum testosterone levels inversely correlated with MELD score (correlation -0.294, P < 0.001) and positively with handgrip strength (correlation +0.242, P < 0.001), physical activity (correlation +0.276, P = 0.012), haemoglobin (correlation +0.282, P < 0.001) and serum sodium (+0.344, P < 0.001). Dihydrotestosterone inversely correlated with MELD score (correlation -0.225, P = 0.002) and shared similar significant relationships to testosterone. Low serum androgens and elevated serum oestrone (but not oestradiol) are associated with higher MELD and in idual adverse health outcomes in cirrhotic cohort of men selected for low testosterone. Serum oestrone may be a novel marker of ill health in this population. Whether low androgens are markers or mediators of ill health requires further investigation.
Publisher: Elsevier BV
Date: 03-1993
Publisher: Oxford University Press (OUP)
Date: 08-2001
Abstract: This is the first report of human exposure to the novel compound follicle stimulating hormone (FSH)-C-terminal peptide (CTP) 'FSH-CTP' (Org 36286), a long-acting recombinant FSH like substance, consisting of the alpha-subunit of human FSH and a hybrid beta-subunit. The latter is composed of the beta-subunit of human FSH and the C-terminus part (CTP) of the beta-subunit of human chorionic gonadotrophin (HCG). In this phase I, non-blind, multi-centre study, 13 hypogonadotrophic hypogonadal male subjects were enrolled to test the safety of FSH-CTP in terms of antibody formation in humans. Furthermore, the pharmacokinetic profile of this new compound was determined. Subjects were injected four times with 15 microg FSH-CTP with an interval of approximately 4 weeks between each injection. No drug related (serious) adverse events occurred. No antibodies against FSH-CTP or chinese hamster ovary (CHO)-cell derived proteins were detected and measurement of local tolerance demonstrated that s.c. administration of FSH-CTP is well tolerated and no increase in intensity of injection-site responses was observed after repeated exposure to FSH-CTP. After the first and third injection, FSH-CTP serum concentrations were determined. Overall mean (+/- SD) C(max) was 0.426 (+/- 0.116) ng/ml, mean t(1/2) and AUC(0-infinity) were 94.7 (+/- 26.2) h and 81.5 (+/- 18.8) ng.h/ml respectively. Compared with recFSH (Puregon), the half life of FSH-CTP was increased 2-3 times. Following the first and third injection a clear rise in serum inhibin-B concentrations were observed. The use of FSH-CTP is safe and does not lead to detectable formation of antibodies. Furthermore, the pharmacokinetic and dynamic profile of FSH-CTP may lead to the development of new, more convenient regimens for the treatment of male and female infertility.
Publisher: Wiley
Date: 31-07-2012
DOI: 10.1111/J.1472-8206.2012.01063.X
Abstract: The aim of this cross-sectional study was to investigate the association between sedative load and functional outcomes in community-dwelling older Australian men. A total of 1696 males aged ≥ 70 years, enrolled in the Concord Health and Ageing in Men Project, were studied. Participants underwent assessments during 2005-2007. Sedative load was computed using a published model. Outcomes included activities of daily living (ADL), instrumental activities of daily living (IADL), physical performance measures and a clinical diagnosis of cognitive impairment. Of the participants, 15.3% took medications with sedative properties. After adjusting for age, education, depressive symptoms and comorbidities, participants who took one medication with sedation as a prominent side effect (sedative load = 1) had odds ratio (OR) of 2.15 (95% confidence interval, CI: 1.20-3.85) for ADL disability, compared with participants with sedative load = 0. Participants who took at least one primary sedative or two medications with sedation as a prominent side effect (sedative load ≥ 2) had an OR of 1.55 (95% CI: 1.02-2.35) for IADL disability, compared with participants with sedative load = 0. The mean 6-m walking speed (P = 0.001) and grip strength (P = 0.003) were significantly different between sedative load groups in unadjusted models only. No association between sedative load and poorer performance on balance and chair stands tests or cognitive impairment was observed. Participants with sedative load of one were more likely to report ADL disability, whereas participants with sedative load of ≥2 were more likely to report IADL disability. Higher sedative load was not associated with poorer physical performance or cognitive impairment in older Australian men.
Publisher: The Endocrine Society
Date: 11-2005
DOI: 10.1210/JC.2005-0962
Abstract: Context: Management of male infertility and/or androgen deficiency requires accurate hormonal measurements with valid reference intervals. Objective: The objective of this study was to develop a valid reference panel of blood s les from healthy eugonadal young men with verified normal reproductive function and to use this panel to evaluate the performance of seven fully automated, commercial multiplex immunoassay platforms used to measure serum total testosterone (T), LH, and FSH. Design: This was an observational study of consistency among seven different automated immunoassays for each of total T, LH, and FSH. Each method was implemented in two laboratories, with each repeating the analysis of the full reference panel s les twice. Serum T concentrations were also measured by gas chromatography/mass spectrometry (GC/MS), and serum inhibin B levels were determined by an ELISA. Setting: The study was performed at commercial, high-volume, clinical pathology laboratories. Participants: From 147 men screened, sera from 124 healthy, reproductively normal men (age, 21–35 yr) with normal sperm output were used as a reference panel. All laboratories selected for elite performance in the national immunoassay quality assurance program agreed to participate. Main Outcome Measure(s): For each of the 868 assays, descriptive statistics were calculated in the natural and log-transformed scales and were analyzed by nested, repeated measures ANOVA after log transformation. Reference intervals, defined as 95% confidence limits, were calculated using arithmetic (natural scale), geometric (log scale) and nonparametric methods. Results: Descriptive statistics and reference intervals for serum T, LH, and FSH differed widely and significantly between methods, but variation between laboratories for the same assay was negligible. All T methods showed significant differences in regression slope and intercept in deviance plots as well as in estimated reference ranges compared with the independent GC/MS reference method. Although similar between-method differences existed for gonadotropin assays, the smaller quantitative discrepancies allowed assignment of consensus reference intervals for serum FSH (1.3–8.4 IU/liter) and LH (1.6–8.0 IU/liter), although these differed from manufacturers’ currently quoted expected values. Conclusions: Using a reference panel of sera from healthy eugonadal young men with verified normal reproductive function, major differences exist between commercial T immunoassays as well as ergence from the GC/MS standard. This impairs their clinical diagnostic utility and requires substantial improvements in automated T immunoassay technologies or a switch to GC/MS methods. Gonadotropin assays showed less variability, but current high-throughput immunoassays remain suboptimal to confirm accurate diagnosis of azoospermia or androgen deficiency.
Publisher: The Endocrine Society
Date: 18-04-2012
DOI: 10.1210/EN.2011-2003
Abstract: Age-related depletion of estrogens and androgens is associated with an increase in Alzheimer's disease (AD) brain pathology and diminished cognitive function. Here we investigated AD-associated molecular and cellular changes in brains of aged hypogonadal (hpg) male and female mice. hpg Mice have a spontaneous, inactivating genetic mutation in the GnRH gene resulting in life-long deficiency of gonadotropins and gonadal sex hormones. Western blot analysis revealed low levels of amyloid precursor protein and high levels of presenilin 1, amyloid precursor protein C-terminal fragment, and β-amyloid 42 in brains of aged male, but not female, hpg mice. Changes were confined to the hippoc us and were not evident in the cerebellum or other brain tissues. Male hpg mice tended to have lower levels of IL-1β protein than male littermate controls. Immunohistochemical staining of the basal forebrain revealed that male hpg mice had lower choline acetyltransferase levels per neuron compared with controls. These AD-like changes specific to male hpg mice supports a link between androgen depletion and the development of AD pathology.
Publisher: Elsevier BV
Date: 07-1987
DOI: 10.1016/S0015-0282(16)59287-5
Abstract: Pulsatile intravenous gonadotropin releasing hormone (IV-GnRH) was used in 36 infertile patients with primary amenorrhea (n = 5), secondary amenorrhea due to hypothalamic chronic anovulation (HCA) (n = 22), hyperprolactinemia (n = 1) or polycystic ovary syndrome (PCOS) (n = 5), and oligomenorrhea (n = 3), using several dosage and timing regimens. Early follicular phase responses showed four patterns: type 1 consisted of a delayed follicle-stimulating hormone (FSH) peak and was seen with severe hypothalamic suppression (n = 4) type 2 consisted of a brisk and dominant FSH peak on the first day of treatment, and occurred with mild to moderate hypothalamic suppression (n = 19) type 3, which consisted of an FSH peak accompanied by an immediate and exaggerated luteinizing hormone (LH) rise, occurred with mild PCOS and some cases of HCA (n = 5) and type 4, in which LH levels were high to begin with and neither FSH nor LH levels rose with GnRH, occurred with severe PCOS (n = 2). Exaggerated estradiol responses within 24 hours of therapy were seen in eight cycles: in four cases no ovarian abnormality was apparent in three cases a dominant follicle was already present and in one case ovarian hyperstimulation was diagnosed ultrasonographically. With standard human chorionic gonadotropin luteal phase support, luteal phase defects were rare with HCA but common with PCOS.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.JAMDA.2015.02.006
Abstract: Sarcopenia is associated with an increased risk of adverse outcomes. The aim of this study was to explore the relationship between severity of sarcopenia and incident activities of daily living (ADL) disability, institutionalization, and all-cause mortality among community-dwelling older men participating in the Concord Health and Ageing in Men Project (CHAMP). Longitudinal analysis of 1705 participants aged 70 years or older at baseline (2005-2007) living in the community in Sydney, Australia. The main outcome measures were incident ADL disability, institutionalization, and mortality. Of the 1705 participants who completed the baseline assessments, a total of 1678 men (mean age 77 years) had complete measures by dual-energy x-ray absorptiometry, to assess sarcopenia in terms of low appendicular lean mass (ALM), using the Foundation for the National Institutes of Health (FNIH) criteria. To differentiate between severity of sarcopenia we used low ALM alone (sarcopenia I), low ALM with weakness (sarcopenia II), and sarcopenia with weakness and poor gait speed (sarcopenia III). Cox proportional hazard models and logistic regression models were used to assess the risk of mortality and institutionalization, and incidence of ADL disability. From baseline to follow-up, 103 (11.3%) men had incident ADL disability, 191 (11.2%) men were institutionalized, and 535 (31.9%) had died. At baseline, 14.2% had sarcopenia I, 5.3% had sarcopenia II, and 3.7% had sarcopenia III. Fully adjusted analysis (adjusted for demographics, lifestyle factors, comorbidities and health conditions, and blood measures) showed that sarcopenia I, II, and III were associated with increased risk of disability, institutionalization, and mortality. Associations between sarcopenia I, II, and III and risk of incident disability were as follows: odds ratio (OR) 2.77 95% confidence interval (CI) 1.30-5.87, OR 3.78 95% CI 1.23-11.64, and OR 4.53 95% CI 0.90-22.72 associations with institutionalization were hazard ratio (HR) 1.96 95% CI 1.14-3.35, HR 2.53 95% CI 1.31-4.90, and HR 2.27 95% CI 1.08-4.80 and with mortality were HR 1.65 95% CI 1.30-2.09, HR 1.50 95% CI 1.08-2.08, and HR 1.69 95% CI 1.17-2.44. This study shows that, in community-dwelling older men, sarcopenia defined by the FNIH criteria is associated with increased risk of incident disability, institutionalization, and mortality.
Publisher: The Endocrine Society
Date: 05-2004
DOI: 10.1210/JC.2004-0033
Abstract: Tetrahydrogestrinone (THG) was recently identified as a novel steroid used illicitly to improve athletic performance. Although its structure is closely related to gestrinone, a 19-nor progestin, and resembles that of trenbolone, THG was never marketed, so information on its hormonal properties is not known. In this study, we demonstrate that THG is a highly potent androgen and progestin in a yeast-based in vitro bioassay system expressing human androgen and progesterone receptors. It has no estrogenic activity and no antagonism for any of the three steroid receptor classes.
Publisher: Oxford University Press (OUP)
Date: 24-05-2010
Publisher: The Endocrine Society
Date: 08-1989
Abstract: We have studied the regulation of inhibin secretion by rat Sertoli cells grown on extracellular matrix-impregnated porous filters in a twin chamber assembly. Previous studies have established that rat Sertoli cells cultured under these conditions reproduce the morphological and functional polarization observed in the Sertoli cell in situ. Sertoli cells isolated from 18- to 22-day-old Wistar rats were cultured for up to 8 days with daily changes of fully defined supplemented Eagle's Minimum Essential Medium (MEM). Rat inhibin was measured by RIA and pituitary cell bioassay, and transferrin by RIA. Inhibin measured by immunoassay or bioassay was always readily detectable in the upper, but not the lower, chamber. Inhibin secretion into the upper chamber exhibited a dose-dependent stimulation of up to 3.7-fold by ovine FSH, with a medium effective dose of 2.2 micrograms/liter and a constant bio- to immunoreactive ratio (3.6 +/- 0.4). Apically directed secretion accounted for over 80% of inhibit output under basal conditions and over 94% with FSH stimulation. Insulin also stimulated upper chamber inhibin secretion at a high dose (5 mg/liter) but not at lower doses or in conjunction with FSH exposure of Sertoli cells. Testosterone augmented FSH-induced stimulation of inhibin secretion, but was ineffective without FSH exposure. In contrast to inhibin secretion, for which FSH is the principal regulator, transferrin secretion by Sertoli cells is more evenly bidirectional (overall mean upper to lower chamber ratio of 1.5) and requires exposure to other stimuli (insulin, retinoic acid, and testosterone) in addition to FSH to achieve maximal secretion. Both submaximal and maximal FSH stimulation of inhibin output were augmented by a phosphodiesterase inhibitor, isobutylmethylxanthine, and these effects were fully reproduced by forskolin, which suggests the involvement of cAMP in the vectorial secretion of inhibin. The marked polarization of Sertoli cell inhibin secretion in vitro could not be explained by restricted transmembrane passage of inhibin. It is, therefore, suggested that the bulk of inhibin secretion by the immature rat Sertoli cell in vivo may be directed primarily into the seminiferous tubular lumen. Thus, in addition to its role in endocrine negative feedback signaling to the pituitary, inhibin may also have important functions in seminiferous tubular function and the support of spermatogenesis.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2018
DOI: 10.1007/S12672-018-0346-5
Abstract: Androgens, notably testosterone (T), have been implicated in development of several common cancers and prostate cancer however, precise mechanisms remain unclear. This study assessed prospective associations of serum T, dihydrotestosterone (DHT) and estradiol (E2) with overall cancer (excluding skin cancer), prostate, colorectal and lung cancer risk in 1574 community-dwelling men aged 25-84 years. Sex hormones were assayed using mass spectrometry and men were followed for 20 years with outcomes ascertained using data linkage. Over 20 years, there were 289, 116, 48 and 22 men who developed any cancer, prostate cancer, colorectal cancer and lung cancer, respectively. Androgens in the lowest quartile were associated with an increased overall cancer risk (HR = 1.36, 95% CI 1.05-1.76, p = 0.020 for T and HR = 1.30, 95% CI 1.00-1.69, p = 0.049 for DHT comparing the lowest vs other quartiles). T in the lowest quartile was associated with an increased risk of prostate cancer (HR = 1.53, 95% CI 1.02-2.29, p = 0.038 comparing the lowest vs other quartiles). The association between androgens and overall cancer risk remained similar after excluding prostate cancer outcomes however, results were not significant. There were no associations of T, DHT or E2 with colorectal or lung cancer risk however, LH in the highest quartile was associated with an increased risk of lung cancer (HR = 4.55, 95% CI 1.70-12.19, p = 0.003 for the highest vs other quartiles). Whether T is a biomarker of poor health in men with any cancer or prostate cancer requires further confirmation as does the nature and mechanism of the association of a high LH with future lung cancer.
Publisher: AMPCo
Date: 08-1992
DOI: 10.5694/J.1326-5377.1992.TB137073.X
Abstract: Investigating food-limitation in generalist predators is difficult, because they can switch to alternative prey, when one of their staple prey becomes scarce. Apart from data on the dynamics of the predator population, a robust study requires: (i) a documentation of the predator's entire prey base and (ii) an experimental or natural situation, where profitable dietary shifts are impossible, because several preferred prey species decline simultaneously. Here, we provide a detailed description of how food-supply has limited a generalist avian top predator, the northern goshawk Accipiter gentilis. In our study area, populations of several principal goshawk prey species crashed simultaneously during 1975-2000, whereas other extrinsic factors remained essentially unchanged. The breeding and non-breeding segments of the local goshawk population declined markedly, associated with a significant increase in nest failures. Brood size of successful pairs remained unaffected by changes in prey availability. Breeding recruitment ceased at a time when potential replacement birds ('floaters') were still present, providing a rare empirical demonstration of an 'acceptance threshold' in raptor territory choice. To investigate how goshawk diet changed in response to varying food-supplies, we make novel use of an analytical tool from bio ersity research-'abundance-biomass-comparison curves' (ABC curves). With increasing levels of food-stress, the dominance of principal prey species in the diet decreased, and the number of small-bodied prey species increased, as did intra-guild predation. Our finding that breeder and non-breeder segments declined in concert is unexpected. Our results carry the management implication that, in food-limited raptor populations, externally induced breeder mortality can rapidly depress population size, as losses are no longer buffered when floaters reject breeding opportunities.
Publisher: Cambridge University Press (CUP)
Date: 07-1987
DOI: 10.1079/BJN19870064
Abstract: 1. Adipose tissue lipoprotein lipase ( EC 3.1.1.34 AT-LPL), a rate-limiting enzyme in triglyceride storage in adipose tissue, is hormonally regulated and may be important in the maintenance of obesity. 2. In twelve obese women, AT-LPL activity was measured before weight loss, during weight loss and after 1 and 2 weeks of weight maintenance on either a high-carbohydrate or a high-protein diet. 3. When related to tissue weight, AT-LPL activity during the 2 weeks of weight maintenance was higher than the initial AT-LPL activity there was no difference when activity was expressed per cell. 4. Changes in AT-LPL activity were not affected by diet composition. AT-LPL activity correlated with insulin levels and a change in the insulin sensitivity of AT-LPL was observed after weight loss.
Publisher: Wiley
Date: 2001
DOI: 10.1002/PROS.1056
Abstract: To understand the molecular mechanisms underlying prostate cancer, we have utilized the gene expression array to search for genes whose expression is altered in this disease. RNA quality from manual microdissected tissue was compared with that from microselected tissue by electrophoresis. For array analysis, malignant and normal prostate epithelium was enriched using microselection technique from prostate cancer and the peripheral zone of a normal prostate. Identical array membrane was hybridized to labeled cancer and normal cDNA, respectively. The differentially expressed gene was further evaluated by RT-PCR. Microdissection, but not microselection, causes visible degradation to RNA. Of the 588 genes on the membrane, 87 genes yielded significant signals. Based on a three fold difference relative to normal prostate tissue, 1 gene was overexpressed and 12 genes underexpressed in prostate cancer. Of them, five showed statistically significant reduction in mRNA levels in six prostate cancer specimens compared with seven normal prostate specimens. These five genes are glutathione S-transferase M1 (GSTM1), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha receptor-1 (TNFR-1), transforming growth factor beta3 (TGF-beta3), and inhibitor of DNA binding-1 (ID-1). GST-based metabolism, cytokine MCP-1 and TNFR-1, and TGF-beta3 signaling pathways, and some helix-loop-helix nuclear proteins could be potentially important in organ-confined prostate cancer and deserve further investigation.
Publisher: Elsevier BV
Date: 1987
DOI: 10.1016/S0168-8227(87)80049-9
Abstract: Glycosylated hemoglobin was compared with fasting blood glucose as a screening test for diabetes mellitus and as an index of the severity of diabetes in biethnic (Melanesian and Indian) Fiji. Age-adjusted diabetes prevalence in the test s le was higher in Indians by either criterion. According to the hemoglobin A1 criterion, Melanesians had prevalence rates of 8.2% (males) and 15.8% (females) compared to 17.0% (males) and 24.3% (females) in Indians. In contrast, fasting blood glucose criteria (WHO) gave higher rates in each group. Hemoglobin A1 levels were higher overall in Indians and females. The predictive value of an elevated fasting blood glucose test for an elevated hemoglobin A1 was 20.0% in Melanesians and 60.7% in Indians while that of a normal fasting blood glucose test for a normal hemoglobin A1 was 89.4% in Melanesians and 89.3% in Indians. The proportion of Indians with elevated hemoglobin A1 who were severely hyperglycemic was almost 7 times higher (40.9% vs. 5.8%) than that of Melanesians. The ethnic difference in the predictive value of fasting blood glucose levels for hemoglobin A1 levels appears to be related to the greater severity of hyperglycemia of diabetic Indians compared to diabetic Melanesians. Hemoglobin A1 levels provide information on both the qualitative as well as quantitative differences in diabetes between ethnic groups.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2017
DOI: 10.1038/S41467-017-00920-X
Abstract: Long bone strength is determined by its outer shell (cortical bone), which forms by coalescence of thin trabeculae at the metaphysis (corticalization), but the factors that control this process are unknown. Here we show that SOCS3-dependent cytokine expression regulates bone corticalization. Young male and female Dmp1Cre.Socs3 f/f mice, in which SOCS3 has been ablated in osteocytes, have high trabecular bone volume and poorly defined metaphyseal cortices. After puberty, male mice recover, but female corticalization is still impaired, leading to a lasting defect in bone strength. The phenotype depends on sex-steroid hormones: dihydrotestosterone treatment of gonadectomized female Dmp1Cre.Socs3 f/f mice restores normal cortical morphology, whereas in males, estradiol treatment, or IL-6 deletion, recapitulates the female phenotype. This suggests that androgen action promotes metaphyseal corticalization, at least in part, via IL-6 signaling.
Publisher: Wiley
Date: 2011
DOI: 10.1016/J.EJPAIN.2010.05.009
Abstract: Back pain is common in older people and is associated with functional disability and poor self-rated health. Older persons are under-represented in back pain research, and research on back pain in older persons from ethnic minorities is particularly sparse. We investigated differences in back pain characteristics, effects and medication use in a population-based s le of 335 Italian-born immigrants and 849 Australian-born men aged 70 years and over. There were 189 (62%) Italian-born men and 507 (63%) Australian-born men who reported experiencing back pain in the past 12 months. Despite no difference in the reported prevalence of back pain between the two groups of men, Italian-born men were more likely to report that their pain was frequent, severe and chronic. Italian-born men were also more likely to report having other sites of pain and that they had limited their activities in the past 12 months due to back pain. Despite these differences, the use of analgesic medication was the same in both groups. Multivariate analyses showed that differences in pain characteristics and effects between the two groups of men were explained by socioeconomic factors such as years of education and occupation history.
Publisher: The Endocrine Society
Date: 11-2012
DOI: 10.1210/JC.2012-1154
Publisher: American Medical Association (AMA)
Date: 25-06-2007
DOI: 10.1001/ARCHINTE.167.12.1252
Abstract: Sex steroid levels are related to metabolic outcomes that could convey higher risk of premature death. We examined whether total or free testosterone, dihydrotestosterone, and sex hormone-binding globulin levels are related to all-cause or cause-specific mortality in men. Data were obtained from the Massachusetts Male Aging Study, a population-based cohort study of 1709 men aged 40 to 70 years. Men were followed up for all-cause and cause-specific mortality. Complete data were available for 1686 men, with 395 deaths occurring during 15.3 years of follow-up. With age adjustment, dihydrotestosterone and sex hormone-binding globulin levels were associated with ischemic heart disease mortality, and free testosterone level was associated with respiratory mortality. In multivariate-adjusted models, higher free testosterone (P=.02) and lower dihydrotestosterone (P=.04) levels were significantly associated with ischemic heart disease mortality, although the latter association was not robust to differences in model selection. The relative risk of death from ischemic heart disease per 1-SD lower free testosterone level was 0.80 (95% confidence interval, 0.64-0.99). Free testosterone level was significantly associated with respiratory mortality (P=.002), with a multivariate-adjusted relative risk per 1-SD lower free testosterone level of 1.90 (95% confidence interval, 1.24-2.92). Total testosterone level was unrelated to mortality, and sex hormone-binding globulin was not significantly associated with mortality after multivariate adjustment. In men, endogenous sex steroid levels seem to have relatively weak associations with mortality. These data provide little support for the hypothesis that endogenous sex steroid levels are associated with risk of premature death but suggest that further investigation of the relationship between sex steroids and mortality from ischemic heart disease and respiratory disease may be warranted.
Publisher: The Endocrine Society
Date: 1994
DOI: 10.1210/ENDO.134.1.8275946
Abstract: FSH signal transduction in Sertoli cells involves the generation of cAMP and calcium as second messengers however, the relationship between these two signals is not clear. In order to determine whether these were serial or parallel signals, we studied cytosolic calcium levels in freshly isolated rat Sertoli cells using maneuvers to dissociate generation of endogenous cAMP from cytosolic calcium. Pretreatment with 1 mM MDL 12,330A, an adenylate cyclase inhibitor, reduced by greater than 90% increases in cytosolic calcium induced by FSH (97 +/- 6 vs. 213 +/- 16 nM), whereas, despite adenylate cyclase blockade, 1 mM (Bu)2cAMP continued to elevate cytosolic calcium (from 87 +/- 6 to 182 +/- 23 nM), indicating the involvement of adenylate cyclase in the FSH-induced rise of cytosolic calcium. A cAMP antagonist, 1 mM Rp-cAMP, reduced by 75% the FSH-induced rise of cytosolic calcium (115 +/- 14 vs. 213 +/- 16 nM), suggesting that endogenous cAMP levels generated by FSH are sufficient to activate the cytosolic calcium response to FSH. Pretreatment with pertussis toxin (1 mg/liter) to dissociate the FSH-receptor interaction from its G-protein-mediated linkage to adenylate cyclase also suppressed the FSH-induced rise in cytosolic calcium (97 +/- 11 vs. 213 +/- 16 nM). Sertoli cells preincubated with 1 mM staurosporine, an inhibitor of protein kinases, exhibited a reduced calcium response to FSH (125 +/- 14 vs. 213 +/- 16 nM), suggesting that FSH-induced calcium flux might be mediated by protein kinase, presumably cAMP-dependent protein kinase A. The present findings therefore strengthen the premise that the cytosolic calcium response to FSH in Sertoli cells is predominantly attributable to serial signaling after the generation of endogenous cAMP.
Publisher: Wiley
Date: 02-2001
DOI: 10.1046/J.1365-2265.2001.01176.X
Abstract: To assess prospectively the effects of low dose oestradiol on arterial endothelial and smooth muscle function in healthy men. Oestrogen use is associated with reduced cardiovascular disease in oestrogen-deficient women, however, the vascular effects of low-dose oestradiol in healthy men have not been investigated previously. Twenty-three men (aged 32 +/- 8 years) were randomized to receive depot implants of testosterone (T) alone (group 1, n = 10), or T with either 10 mg (group 2, n = 7) or 20 mg (group 3, n = 6) of oestradiol (E). Hormone levels, lipids and vascular reactivity were measured before, 1 month and 6 months after hormone implantation. Using high-resolution ultrasound, brachial artery diameter was measured at rest, during reactive hyperaemia (leading to flow-mediated dilatation, FMD, which is endothelium-dependent) and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Oestradiol produced a dose-dependent increase in plasma oestradiol (at 1 month 96 +/- 7, 149 +/- 6, 192 +/- 23 pmol/l in the 3 groups, respectively, P < 0.001 by ANOVA for trend). Minor side-effects (gynaecomastia, nipple tenderness) indicated that 20 mg oestradiol was the maximum tolerated dose. There was also a dose-dependent increase in FMD with oestradiol dose: at 1 month, - 0.2, + 0.2 and + 1.8% for groups 1-3, respectively (P = 0.31 by ANOVA for trend) and at 6 months, - 0.8, + 0.4 and + 2.2% (P = 0.02). The rise in oestradiol levels following treatment correlated with the improvement in FMD (P = 0.01). GTN responses were similar in the 3 groups throughout the study. In healthy young men, oestradiol supplementation is associated with enhanced arterial endothelial function, a key marker of vascular health.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-05-1999
DOI: 10.1161/01.CIR.99.17.2317
Abstract: Background —Male sex is an independent risk factor for coronary artery disease. Owing to the importance of monocyte adhesion to endothelial cells in the development of atherosclerosis, we hypothesized that androgens might promote this process. We therefore studied the effects of the nonaromatizable androgen dihydrotestosterone (DHT) on human monocyte adhesion to human endothelial cells and on endothelial cell–surface expression of adhesion molecules. Methods and Results —Human umbilical vein endothelial cells (HUVECs) were grown to confluence in media supplemented with postmenopausal female serum, then exposed for 48 hours to either DHT (40 and 400 nmol/L), with or without the androgen receptor blocker hydroxyflutamide (HF) (4 μmol/L) HF alone or vehicle control (ethanol 0.1%). Human monocytes obtained by elutriation were incubated for 1 hour with the HUVECs at 37°C, and adhesion was measured by light microscopy. Compared with vehicle control, monocyte adhesion was increased in the androgen-treated HUVECs in a dose-dependent manner (116±6% and 128±3% for DHT 40 and 400 nmol/L respectively P .001). HF blocked this increase ( P ≥0.3 compared with control). Surface expression of endothelial cell adhesion molecules was measured by ELISA and revealed an increased expression of vascular cell adhesion molecule-1 (VCAM-1) in the DHT-treated HUVECs (125±5% versus 100±4% in controls P =0.002), an effect also antagonized by HF ( P ≥0.3 compared with controls). Furthermore, the DHT-related increase in adhesion was completely blocked by coincubation with anti–VCAM-1 antibody. Comparable results were obtained in arterial endothelial cells and in endothelium stimulated with the cytokine tumor necrosis factor-α. Conclusions —Androgen exposure is associated with increased human monocyte adhesion to endothelial cells, a proatherogenic effect mediated at least in part by an increased endothelial cell–surface expression of VCAM-1.
Publisher: Oxford University Press (OUP)
Date: 21-02-2018
Abstract: to determine whether pain increases the risk of developing the frailty phenotype and whether frailty increases the risk of developing chronic or intrusive pain, using longitudinal data. longitudinal data from the Concord Health and Ageing in Men Project (CHAMP), a prospective population based cohort study. a total of 1,705 men aged 70 years or older, living in an urban area of New South Wales, Australia. data on the presence of chronic pain (daily pain for at least 3 months), intrusive pain (pain causing moderate to severe interference with activities) and the criteria for the Cardiovascular Health Study (CHS) frailty phenotype were collected in three waves, from January 2005 to October 2013. Data on age, living arrangements, education, smoking status, alcohol consumption, body mass index, comorbidities, cognitive function, depressive symptoms and history of vertebral or hip fracture were also collected and included as covariates in the analyses. a total of 1,705 participants were included at baseline, of whom 1,332 provided data at the 2-year follow-up and 940 at the 5-year follow-up. Non-frail (robust and pre-frail) men who reported chronic pain were 1.60 (95% confidence interval (CI): 1.02-2.51, P = 0.039) times more likely to develop frailty at follow-up, compared to those with no pain. Intrusive pain did not significantly increase the risk of future frailty. Likewise, the frailty status was not associated with future chronic or intrusive pain in the adjusted analysis. the presence of chronic pain increases the risk of developing the frailty phenotype in community-dwelling older men.
Publisher: Springer Science and Business Media LLC
Date: 29-07-2020
DOI: 10.1186/S12877-020-01648-Y
Abstract: Conflicting evidence exists regarding the association of socioeconomic status (SES) with mortality among older people and little is known about the mechanisms underlying this association. We investigated the association of SES with mortality among older Australian men. We also investigated potential mediating effects of health-related behaviours in SES-mortality associations. We used data from a prospective population-based cohort (the Concord Health and Aging in Men Project), in Sydney, Australia. The main outcomes were all-cause and cause-specific mortality. Educational attainment, occupational position, source of income, housing tenure, and a cumulative SES score were assessed at baseline. Longitudinally assessed alcohol consumption, smoking, physical activity, and body mass index were investigated as potential mediators. Associations were quantified using Cox regression. We evaluated 1527 men (mean age: 77.4 ± 5.5 years). During a mean follow-up time of 9.0 years, 783 deaths occurred. For deaths from all causes, the adjusted hazard ratio (HR) for the lowest tertile of cumulative SES score versus the highest tertile was 1.44 (95% CI 1.21 to 1.70) the corresponding sub-HRs were 1.35 (0.96 to 1.89) for cardiovascular disease (CVD) mortality 1.58 (1.15 to 2.18) for cancer mortality, and 1.86 (1.36 to 2.56) for non-CVD, non-cancer mortality. SES-mortality associations were attenuated by 11–25% after adjustment for mediating health-related behaviours. Low SES is associated with increased mortality in older Australian men and health-related behaviours accounted for less than one-fourth of these associations. Further research is needed to fully understand the mechanisms underlying SES inequalities in mortality among older people.
Publisher: Oxford University Press (OUP)
Date: 05-09-2014
DOI: 10.1093/AJE/KWU199
Abstract: Balance training is the most efficacious exercise to prevent falls. This study examined the associations between common sporting activities and the incidence of falls, and whether lower risks can be attributed to the superior balance of sports participants. We studied a population-based cohort of 1,667 older Australian men (mean age = 76.8 years) in the Concord Health and Ageing in Men Project (CHAMP) between 2005 and 2011. Data on incident falls were captured by 12 triannual telephone call cycles per participant and were analyzed using negative binomial regression. The length of follow-up averaged 43.8 months (median, 48 months), during which time 2,662 falls were recorded. In unadjusted models, golfers (n = 160 incidence rate ratio (IRR) = 0.65, 95% confidence interval (CI): 0.47, 0.89) and swimmers (n = 88 IRR = 0.47, 95% CI: 0.30, 0.71) had significantly lower risks of falling. After adjustment for leisure-time physical activity, walking, lifestyle physical activity score (e.g., chores, gardening), and conventional risk factors for falling, swimming was the only activity that was associated with a protective effect (IRR = 0.67, 95% CI: 0.45, 1.00). Swimmers had significantly lower postural sway (β = -5.23 cm(2), P < 0.05) and shorter time to complete a narrow walk test than men who took part in only lifestyle physical activities. Balance indicators were strong predictors of the incidence of falls. The IRR for swimmers was 0.71 (95% CI: 0.48, 1.06) after adding balance measures to the adjusted model.
Publisher: The Endocrine Society
Date: 08-2004
DOI: 10.1210/JC.2004-0143
Publisher: Medknow
Date: 18-02-2013
DOI: 10.1038/AJA.2013.17
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.JAMDA.2015.02.014
Abstract: Anemia and frailty are both common in older people and are associated with adverse health outcomes. There have been some cross-sectional studies of anemia and frailty but no longitudinal studies. The objectives of this study were to examine cross-sectional and longitudinal associations between anemia and frailty in older Australian men. A total of 1666 men aged 70 years and older from the Concord Health and Aging in Men Project were assessed at baseline (2005-2007), 1314 men came for the 2-year follow-up between 2007 and 2009, and of those, 917 men returned for the 5-year follow-up between 2012 and 2013. The main outcome measurement was frailty, assessed using the Cardiovascular Health Study method. Anemia was defined as a hemoglobin levels <13.0 g/dL. Covariates included age, income, body mass index, measures of health, estimated glomerular filtration rate, and inflammatory markers (white cell count and albumin). The prevalence of anemia was 14.6% at baseline, 16.2% at 2-year follow-up, and 19.4% at 5-year follow-up. Prevalence of frailty was 9.1% at baseline and 9.7 % at both 2- and 5-year follow-up. Among men aged 70-74 at baseline, prevalence of frailty was 4.5%, but at 5-year follow-up the prevalence was 9.0%. There were significant cross-sectional associations between anemia and frailty in unadjusted [odds ratio, [OR 5.03 (95% confidence interval, CI 3.50, 7.25, P < .0001)] and in fully adjusted analysis [OR 2.90 (95% CI 1.87, 4.51, P < .0001)]. Generalized estimating equations time-lag models were used to examine the longitudinal associations between repeated measurements of hemoglobin and frailty. There were significant associations between measurements of anemia and frailty in unadjusted [OR 2.51 (95% CI 1.58, 4.00, P < .0001] and in fully adjusted analysis (OR 1.80, 95% CI 1.14, 2.85, P = .01). Anemia was associated with frailty in both cross-sectional and longitudinal analyses, and anemia precedes frailty in men who were nonfrail at baseline. Low hemoglobin levels among patients may alert clinicians to the increased risk of frailty.
Publisher: Wiley
Date: 24-03-2015
DOI: 10.1111/JGS.13391
Publisher: The Endocrine Society
Date: 24-06-2016
DOI: 10.1210/JC.2016-1646
Abstract: The impact of early life events on testicular function in adulthood is not well understood. To study the early influences of fetal growth, exposures to cigarette smoke in utero and cord blood estrogens, and the influences of growth and adiposity in childhood through adolescence on testicular function in adulthood. Male members of the Western Australian Pregnancy Cohort (Raine) were contacted at 20-22 years of age. Of 913 contacted, 423 (56%) agreed to participate 404 underwent a testicular ultrasound, 365 provided a semen s le, and reproductive hormones were measured (384). Fetal growth measurements (n = 137), umbilical cord estrogen concentrations (n = 128), cord testosterone (T) (n = 125), and child-adulthood growth charts (n = 395) were available. Median sperm output for the 18.6% of men exposed in utero to smoking was lower than nonexposed (82.4 × 10(6) vs 123.1 × 10(6) P = .029). Sperm output in adulthood was inversely correlated with cord serum estradiol (P = .019) and estrone (P = .018). The sperm output of men whose cord blood estradiol and estrone were less than 50th percentile vs more than 50th percentile was 191.1 × 10(6) vs 100.5 × 10(6) (P = .002) and 190.0 × 10(6) vs 106.0 × 10(6) (P = .012), respectively. Men with favorable fetal growth patterns in utero were less likely to have total motile sperm counts within the lowest quartile (P = .011), and men born prematurely had reduced serum T levels in adulthood (13.4 vs 16.6nmol/L, P = .024). Consistent height above the 50th percentile for age through childhood was associated with larger adult mean testicular volume (P < .001). Optimal body mass index trajectory through childhood and adolescence was associated with larger testicular volume (P = .009) and higher serum inhibin B (P = .010) and T (P = .003) in adulthood. Exposures to maternal smoking and higher cord blood estrogens at delivery were associated with a reduced sperm output in adulthood. Optimal adult testicular function depends on being born at or above average weight, and maintaining optimal growth and adiposity into adulthood.
Publisher: Medknow
Date: 2017
Publisher: The Endocrine Society
Date: 20-03-2008
DOI: 10.1210/EN.2007-1805
Abstract: Androgen action on sex accessory organs influences rodent fertility, but the mechanisms remain unclear and investigation is difficult without the ability to restrict androgen action in specific tissues. We used Cre-LoxP technology to generate male mice with prostate epithelial-specific androgen receptor deficiency (denoted PEARKO). In addition to prostate, these males have reduced androgen action due to tissue-selective androgen receptor inactivation in seminal vesicle, epididymis, and vas deferens, whereas the testis is unaffected. We find that fertility of PEARKO males was severely reduced, compared with littermates with prominent defects in copulatory plug formation, which were smaller, softer, and more friable than controls. Despite normal testis sperm production, sperm numbers were reduced in caput but increased in cauda epididymis, suggesting alterations in sperm epididymal transit kinetics associated with increased rate of spontaneous acrosome reaction and abnormal flagellar morphology in PEARKO cauda epididymal sperm. Whereas the quantitative in vitro fertilizing ability of PEARKO epididymal sperm was normal, fewer fertilized oocytes were flushed from the oviducts of females after natural mating with PEARKO males. These data show that sperm formed in mice with impaired androgen action restricted to accessory glands and epididymis are quantitatively normal in number and in vitro fertilizing function but that severe in vivo subfertility reflects other functions related to sperm transport and survival in female reproductive tract that determine fertility in vivo.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.JSBMB.2021.106049
Abstract: Recent studies have highlighted the potential role of 11oxygenated (keto or hydroxy) androgens in human reproductive function with 11keto androgens circulating at concentrations comparable with testosterone in women and children. However, the intrinsic androgenic bioactivities of 11 keto and hydroxy androgens are not fully characterized. We therefore investigated the full androgen dose-response curves using complementary in vitro yeast and mammalian (HEK293) host cell bioassays of 11 keto and hydroxy derivatives of the potent androgens, testosterone (T) and dihydrotestosterone (DHT), compared with their parent non-11 oxygenated steroids together with the pro-androgen precursor (androstenedione (A
Publisher: The Endocrine Society
Date: 12-2014
DOI: 10.1210/JC.2014-2664
Abstract: Older men have lower T levels, but whether differences in circulating T or its metabolites dihydrotestosterone (DHT) or estradiol (E2) contribute to cardiovascular disease remains controversial. We tested the hypothesis that plasma T, DHT, and E2 are differentially associated with the incidence of myocardial infarction (MI) and stroke in older men. Plasma total T, DHT, and E2 were assayed using liquid chromatography-mass spectrometry in early-morning s les from 3690 community-dwelling men aged 70-89 years. Outcomes of the first hospital admission or death due to MI or stroke were ascertained by data linkage. Mean follow-up was 6.6 years. Incident MI occurred in 344, stroke in 300, and neither in 3046 men. In a multivariate analysis adjusting for age and other risk factors, T, DHT, and E2 were not associated with incident MI [fully adjusted hazard ratio (HR) for T in quartile (Q) 4 vs Q1: 0.92, 95% confidence interval (CI) 0.66-1.28 DHT: 0.83, 95% CI 0.59-1.15 E2: 0.84, 95% CI 0.62-1.15]. Higher T or DHT was associated with a lower incidence of stroke (T: Q4: Q1 fully adjusted HR 0.56, 95% CI 0.39-0.81, P = .002 DHT: 0.57, 95% CI 0.40-0.81, P = .002). E2 was not associated with stroke (HR 0.76, 95% CI 0.54-1.08, P = .123). Higher plasma T or DHT is a biomarker for reduced risk of stroke but not MI. Androgen exposure may influence outcomes after rather than the incidence of MI, whereas androgens but not E2 are independent predictors of stroke risk. Randomized clinical trials are needed to clarify the impact of modifying T or DHT on the risk of stroke in aging men.
Publisher: American Physiological Society
Date: 09-2006
DOI: 10.1152/AJPENDO.00058.2006
Abstract: Androgens promote anabolism in skeletal muscle however, effects on subsequent muscle function are less well defined because of a lack of reliable experimental models. We established a rigorous model of androgen withdrawal and administration in male mice and assessed androgen regulation of muscle mass, structure, and function. Adult C57Bl/6J male mice were orchidectomized (Orx) or sham-operated (Sham) and received 10 wk of continuous testosterone (T) or control treatment (C) via intraperitoneal implants. Mass, fiber cross-sectional area (CSA), and in vitro contractile function were assessed for fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles. After 10 wk, Orx+C mice had reduced body weight gain ( P 0.05), seminal vesicle mass ( P 0.01), and levator ani muscle mass ( P 0.001) compared with Sham+C mice, and these effects were prevented with testosterone treatment. Orx+T mice had greater EDL ( P 0.01) and SOL ( P 0.01) muscle mass compared with Orx+C mice however, median fiber CSA was not significantly altered in these muscles. EDL and SOL muscle force was greater in Sham+T compared with Orx+C mice ( P 0.05) in proportion to muscle mass. Unexpectedly, Orx+T mice had increased fatigue resistance of SOL muscle compared with Orx+C mice ( P 0.001). We used a rigorous model of androgen withdrawal and administration in male mice to demonstrate an essential role of androgens in the maintenance of muscle mass and force. In addition, we showed that testosterone treatment increases resistance to fatigue of slow- but not fast-twitch muscle.
Publisher: The Endocrine Society
Date: 27-09-2021
Abstract: Vitamin D status is conventionally defined by measurement of unconjugated circulating 25-hydroxyvitamin D (25OHD), but it remains uncertain whether this isolated analysis gives sufficient weight to vitamin D’s erse metabolic pathways and bioactivity. Emerging evidence has shown that phase II endocrine metabolites are important excretory or storage forms however, the clinical significance of circulating phase II vitamin D metabolites remains uncertain. In this study we analyzed the contribution of sulfate and glucuronide vitamin D metabolites relative to unconjugated levels in human serum. An optimized enzyme hydrolysis method using recombinant arylsulfatase (Pseudomonas aeruginosa) and beta-glucuronidase (Escherichia coli) was combined with liquid chromatography mass spectrometry (LC-MS/MS) analysis to measure conjugated and unconjugated vitamin D metabolites 25OHD3, 25OHD2, 3-epi-25OHD3, and 24,25(OH)2D3. The method was applied to the analysis of 170 human serum s les from community-dwelling men aged over 70 years, categorized by vitamin D supplementation status, to evaluate the proportions of each conjugated and unconjugated fraction. As a proportion of total circulating vitamin D metabolites, sulfate conjugates (ranging between 18% and 53%) were a higher proportion than glucuronide conjugates (ranging between 2.7% and 11%). The proportion of conjugated 25OHD3 (48 ± 9%) was higher than 25OHD2 conjugates (29.1 ± 10%) across all supplementation groups. Conjugated metabolites correlated with their unconjugated forms for all 4 vitamin D metabolites (r = 0.85 to 0.97). Sulfated conjugates form a high proportion of circulating vitamin D metabolites, whereas glucuronide conjugates constitute a smaller fraction. Our findings principally in older men highlight the differences in abundance between metabolites and suggest a combination of both conjugated and unconjugated measurements may provide a more accurate assessment of vitamin D status.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-01-2000
Abstract: Background —Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. Methods and Results —Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64±0.06 versus 0.15±0.02 amol/μg total RNA P .001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women ( P =0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (n=9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109±10%, 117±3%, and 120±4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, P =0.002 95±8% for DHT with hydroxyflutamide, P =0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages ( P .2 versus controls). Conclusions —Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2013
Publisher: Visagaa Publishing House
Date: 19-08-2021
Publisher: Wiley
Date: 27-06-2017
DOI: 10.1002/DTA.2000
Abstract: Sport supplements containing steroids never approved for therapeutic use have the potential for abuse by athletes. Most are marketed online and may contain undisclosed steroids yet are readily available despite lacking toxicological or pharmacological evaluation. In this study, 18 supplements purchased online underwent organic solvent extraction to isolate any steroids they contained. From the 18 supplements, 19 steroids were identified and for each, its intrinsic androgenic potency was determined by a yeast cell (Saccharomyces cerevisiae) androgen bioassay and its potential androgenic potency was determined by a liver (HuH7) cell androgen bioassay. The yeast bioassay showed that of the 19 steroids tested, 6 demonstrated strong intrinsic bioactivity, with 4 metabolically activated to even stronger androgens. Moreover, 4 steroids with moderate and 1 with intrinsically weak androgenic bioactivity were activated to more potent androgens. Finally, 8 steroids were metabolically inactivated or deactivated into weaker androgens. Our results show that Internet-sourced sport supplements may contain intrinsically strong androgens, or precursors that can be metabolized to them. These potentially potent pharmacologically active steroids are being used without regulatory control or consumer awareness of their potential adverse effects. Copyright © 2016 John Wiley & Sons, Ltd.
Publisher: AMPCo
Date: 03-2002
Publisher: Wiley
Date: 09-06-2022
DOI: 10.1002/DTA.3331
Abstract: The high sensitivity of antidoping detection tests creates the possibility of inadvertent doping due to an athlete's unknowing ingestion of contaminated environmental sources such as dietary supplements, food, or drinks. Recently, athletes denying use of a prohibited substance have claimed that the positive antidoping tests was due to exchange of bodily fluids with a nonathlete partner using a prohibited substance. Measurement of drugs in semen is largely limited to one or very few s les due to the inaccessibility of sufficiently frequent semen s les for detailed pharmacokinetics. An emerging issue in semen drug measurements is that semen s les may contain residual urine from ejaculation left in the urethra however, the urine content in semen s les has not been studied. In the present study, we employed concurrent creatinine measurements in urine and seminal plasma to determine the urine content of semen s les.
Publisher: Wiley
Date: 03-2007
DOI: 10.1359/JBMR.061117
Abstract: The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative microCT at 6, 12, and 32 weeks of age (n=8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. microCT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p<0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p<0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p<0.01) and an increase in trabecular separation (p<0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. These findings show that inactivation of the DNA binding-dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding-dependent actions of the AR in mature osteoblasts.
Publisher: Wiley
Date: 08-04-2022
Publisher: Elsevier BV
Date: 07-1987
DOI: 10.1016/S0015-0282(16)59286-3
Abstract: Pulsatile intravenous gonadotropin-releasing hormone (IV-GnRH) was used in 36 infertile patients with primary amenorrhea (n = 5), secondary amenorrhea due to hypothalamic chronic anovulation (HCA) (n = 22), hyperprolactinemia (n = 1) or polycystic ovary syndrome (PCOS) (n = 5), and oligomenorrhea (n = 3). Treatment was commonly initiated in the hospital but was then continued outside, with patients and local physicians accepting responsibility for maintaining IV-GnRH delivery systems. Twenty-eight of 113 treatment cycles (24.8%) resulted in pregnancy, with four spontaneous abortions (14.3%) and four twin pregnancies (16.7%) among 24 births. Probability of pregnancy per treatment cycle was significantly higher for primary amenorrhea (0.30) and for HCA (0.33) than for PCOS (0.07 P less than 0.05) and for oligomenorrhea (no conceptions P = 0.01). Ovulatory cycles were not achieved in five patients (primary amenorrhea, n = 1 PCOS, n = 3 oligomenorrhea, n = 1). There were no serious complications six patients recorded eight febrile episodes, which responded quickly to antibiotic therapy and cannula change. The authors conclude that outpatient IV-GnRH is safe, practical, and effective for follicular stimulation and ovulation induction in women presumed to have GnRH deficiency and in whom clomiphene therapy fails, and that less intensive monitoring is needed compared with gonadotropin ovulation induction therapy.
Publisher: Medknow
Date: 06-06-2011
DOI: 10.1038/AJA.2011.55
Publisher: Springer Science and Business Media LLC
Date: 23-06-2010
DOI: 10.1007/S00198-010-1332-0
Abstract: The association between socioeconomic status (SES) and bone health, specifically in men, is unclear. Based upon data from the large prospective Concord Health in Ageing Men Project (CHAMP) Study of community-dwelling men aged 70 years or over, we found that specific sub-characteristics of SES, namely, marital status, living circumstances, and acculturation, reflected bone health in older Australian men. Previous studies reported conflicting results regarding the relationship between SES and bone health, specifically in men. The main objective of this study was to investigate associations of SES with bone health in community-dwelling men aged 70 years or over who participated in the baseline phase of the CHAMP Study in Sydney, Australia. The Australian Socioeconomic Index 2006 (AUSEI06) based on the Australian and New Zealand Standard Classification of Occupations was used to determine SES in 1,705 men. Bone mineral density and bone mineral content (BMC) were determined by dual-energy X-ray absorptiometry. Bone-related biochemical and hormonal parameters, including markers of bone turnover, parathyroid hormone, and vitamin D, were measured in all men. General linear models adjusted for age, weight, height, and bone area revealed no significant differences across crude AUSEI06 score quintiles for BMC at any skeletal site or for any of the bone-related biochemical measures. However, multivariate regression models revealed that in Australian-born men, marital status was a predictor of higher lumbar BMC (β = 0.07, p = 0.002), higher total body BMC (β = 0.05, p = 0.03), and lower urinary NTX-I levels (β=-0.08, p = 0.03), while living alone was associated with lower BMC at the lumbar spine (β=-0.05, p = 0.04) and higher urinary NTX-I levels (β=0.07, p = 0.04). Marital status was also a predictor of higher total body BMC (β = 0.14, p = 0.003) in immigrants from Eastern and South Eastern Europe. However, in immigrants from Southern Europe, living alone and acculturation were predictors of higher femoral neck BMC (β = 0.11, p = 0.03) and lumbar spine BMC (β = 0.10, p = 0.008), respectively. Although crude occupation-based SES scores were not significantly associated with bone health in older Australian men, specific sub-characteristics of SES, namely, marital status, living circumstances, and acculturation, were predictors of bone health in both Australia-born men and European immigrants.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2021
DOI: 10.1186/S12877-021-02169-Y
Abstract: Unintended weight loss and the reduction in appetite are common phenomenon among older people. Reduced appetite has been linked to medication related reductions in saliva production, reduced taste ability and poor oral health. Poor appetite can result in reduced nutrient intake ensuing weight loss. It is possible that poor appetite is a mediating step on the causal pathway between oral health and weight loss. This study investigates whether poor oral health and loss of appetite are related to weight loss. This is an observational study where data were obtained from the Concord Health and Ageing in Men Project (CHAMP). Information on socio-demographics, appetite and health related behavior was collected by self-completed questionnaire. Intraoral assessment was conducted by calibrated oral health therapists. Height and weight were measured by trained staff. Regression analysis investigated associations between oral health and appetite as risk factors for weight loss. Participants included 542 community dwelling older males. 99 older men (18.3%) experienced 5% or more weight loss over 3 years. Men who lost weight from baseline had lower BMI and lower body weight, had higher prevalence of frailty and depression, reported poorer appetite, and had fewer teeth (13.8 ± 9.5) than those who did not lose weight (16.3 ± 9.3). Before adjustment, the prevalence ratio (PR) for weight loss was 1.76 (95% Confidence Interval (CI), 1.19–2.59) for participants with 0–19 natural teeth present compared to those with 20 or more teeth. When adding appetite and other variables to the model, the PR for number of teeth and weight loss was unchanged: 1.78 (95% CI, 1.06–3.00). The mediation analysis showed that the indirect effect of appetite on the association between number of natural teeth on weight loss was not found to be significant. This study found that number of natural teeth present and appetite are independently related to weight change among elderly men in Australia. Tooth loss can increase the risk of swallowing difficulty leading to change in food preference, avoidance of foods and a decrease in energy intake. Our study showed the importance of oral health interventions to encourage maintenance of 20 or more natural teeth in older people.
Publisher: The Endocrine Society
Date: 07-2014
DOI: 10.1210/JC.2014-1243
Abstract: Testosterone (T) and nandrolone (N) esters require deep im injections by medical personnel but these often deposit injectate into sc fat so that more convenient sc self-administration may be feasible. To investigate the feasibility and pharmacology of sc injection of N decanoate in healthy men using dried blood spot (DBS) for frequent blood s ling without clinic visits. Healthy male volunteers received 100 mg N decanoate by a single sc injection. Finger-prick capillary blood was spotted onto filter paper before injection daily at home for 21 d and stored at room temperature. Venous whole blood was also spotted onto filter paper before and weekly for 3 wk after injection. DBS were extracted for assay of N and T by liquid chromatography tandem mass spectrometry in a single batch with serum concentrations estimated with adjustment for capillary blood s le volume and hematocrit to define peak (N) or nadir (T) time and concentration from in idual daily measurements. Daily serum N peaked 2.50 ± 0.25 (SEM) ng/mL at a median (range) of 6 (4-13) days causing a reduction in serum T from 3.50 ± 0.57 ng/mL at baseline to a nadir of 0.38 ± 0.13 (SEM) ng/mL (89 ± 3% suppression) at a median (range) of 8 (5-16) days. Simultaneously s led capillary, venous whole blood, and serum gave almost identical results for serum T and N. Finger-pricks and sc injections were well tolerated. This study demonstrates that A) DBS s ling with liquid chromatography mass spectrometry steroid analysis achieves frequent time s ling in the community without requiring clinic visits, venesection, or frozen serum storage, and B) androgen esters in an oil vehicle can be delivered effectively by sc injection, thus avoiding the need for medically supervised deep-im injections.
Publisher: The Endocrine Society
Date: 06-2008
DOI: 10.1210/JC.2008-0402
Abstract: IGF axis proteins and collagen peptides are promising markers of GH abuse. Our objective was to investigate whether responses of serum IGF axis and collagen markers to GH differ between men and women, and are influenced by testosterone (T). This was a randomized, double-blind, placebo-controlled study of 8-wk treatment followed by 6-wk washout. The study was performed at a clinical research facility. A total of 96 recreationally trained healthy athletes (63 men, 33 women), aged 18-40 yr, were studied. All subjects received GH (2 mg/d sc) or placebo for 8 wk men also received T (250 mg/wk im) or placebo for 5 wk. Serum IGF axis proteins (IGF-I, IGF binding protein-3, and acid labile subunit) and collagen peptides (N-terminal propeptide of type I procollagen, C-terminal telopeptide of type I collagen, and N-terminal propeptide of type III procollagen) were measured. GH induced significant increases in IGF axis and collagen markers that were greater in men than women (P < 0.001). Of the IGF axis markers, IGF-I showed the greatest increase. The relative incremental responses of the collagen markers in general were greater than the IGF markers, especially for PIIINP. The collagen markers increased and decreased more slowly with most remaining elevated (P < 0.01) after 6 wk, in comparison to IGF markers, which returned to baseline within 1 wk. Addition of T to GH lified the response of PIIINP by more than 1.5-fold but did not affect any other marker. T alone did not affect IGF axis markers but modestly increased collagen markers. These markers of GH abuse are less responsive in women. The increases in collagen markers have a different time course to the IGF markers and extend the window of detection in both sexes. The response of PIIINP is increased by coadministration of T.
Publisher: Oxford University Press (OUP)
Date: 03-2002
Abstract: Predictors of fertility or spermatogenesis during gonadotrophin therapy of gonadotrophin-deficient men remain poorly defined. In order to evaluate potential predictors, this study evaluated 29 consecutive gonadotrophin-deficient men all desiring paternity who received 43 courses of therapy in one centre between 1982 and 1998. The Kaplan-Meier survival analysis estimates of median (SE) time to a sperm concentration of >0, >5 and >20 x 10(6)/ml were 5.5 (1.1), 12.4 (2.3) and 29.1 (1.9) months respectively. Conception occurred in 22/43 cycles (with eight men achieving two pregnancies) with a median (SE) Kaplan-Meier estimate of 20.5 (4.7) months. The median sperm concentration at conception was 5.0 (SE 2.0 range 0.0-59.5) x 10(6)/ml. Multivariate correlated Cox proportional hazards models predicting these same sperm thresholds and conception were developed by forward stepwise variable selection with verification of the model by backward stepping. Larger testicular volume, prior gonadotrophin therapy, completion of puberty, older age, the absence of adverse fertility factors and the absence of multiple pituitary hormone deficiency predicted a favourable response. Multivariate modelling suggests that the two most important predictors of sperm output are testicular volume and pubertal status. The most important potentially modifiable predictor was prior gonadotrophin therapy. The efficacy of recombinant and urinary FSH were similar. Prior androgen therapy and partner's age did not appear to be significant. Since prolonged treatment may be required to induce spermatogenesis, attention to these predictors may allow appropriate early use of advanced reproductive technologies.
Publisher: The Endocrine Society
Date: 12-2014
DOI: 10.1210/JC.2014-3424
Publisher: The Endocrine Society
Date: 09-2014
DOI: 10.1210/JC.2014-1124
Abstract: The relationship between functional disability and reproductive hormones and whether it is mediated by muscle mass and strength in older men are unclear. The objective of the study was to identify the relationships between hormones and change in functional disability over a 2-year follow-up and to examine whether muscle mass and strength explain any of the observed relationships. A total of 1318 men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at both baseline and 2-year follow-up. T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry and SHBG, LH, and FSH by immunoassay. Functional disability was measured by basic Activities of Daily Living scale at both time points. Grip and quadricep strength were measured using dynamometers and lean (muscle) mass was determined by dual X-ray absorptiometry. All hormones were significantly associated with functional decline in univariate analyses. Only T, E2, E1, and calculated free T remained associated in multivariate analyses. Men in the lowest T quartile (vs the highest quartile) had an increased risk functional decline (odds ratio 1.96, 95% confidence interval 1.01-3.82). Similar associations were observed in E2, E1, and calculated free T. When muscle variables were added into the multivariate model, the associations between these hormones and functional decline were no longer statistically significant. Low T, E2, and E1 were significantly associated with prospective functional decline over 2 years. This relationship was no longer significant when muscle mass or strength were added, suggesting that the hormonal associations are mediated through their sequential effect on muscle mass and strength.
Publisher: Elsevier BV
Date: 08-2007
Publisher: Oxford University Press (OUP)
Date: 05-2012
DOI: 10.1095/BIOLREPROD.111.097808
Abstract: Polycystic ovary syndrome (PCOS) is the most frequent female endocrine disorder, affecting 5%-10% of women, causing infertility due to dysfunctional follicular maturation and ovulation, distinctive multicystic ovaries and hyperandrogenism, together with metabolic abnormalities including obesity, hyperinsulinism, an increased risk of type 2 diabetes, and cardiovascular disease. The etiology of PCOS is unclear, and decisive clinical studies are limited by ethical and logistic constraints. Consequently treatment is palliative rather than curative and focuses on symptomatic approaches. Hence, a suitable animal model could provide a valuable means with which to study the pathogenesis of the characteristic reproductive and metabolic abnormalities and thereby identify novel and more effective treatments. So far there is no consensus on the best experimental animal model, which should ideally reproduce the key features associated with human PCOS. The prenatally androgenized rhesus monkey displays many characteristics of the human condition, including hyperandrogenism, anovulation, polycystic ovaries, increased adiposity, and insulin insensitivity. However, the high cost of nonhuman primate studies limits the practical utility of these large-animal models. Rodent models, on the other hand, are inexpensive, provide well-characterized and stable genetic backgrounds readily accessible for targeted genetic manipulation, and shorter reproductive life spans and generation times. Recent rodent models display both reproductive and metabolic disturbances associated with human PCOS. This review aimed to evaluate the rodent models reported to identify the advantages and disadvantages of the distinct rodent models used to investigate this complex endocrine disorder.
Publisher: Wiley
Date: 03-01-2021
DOI: 10.1002/DTA.3202
Abstract: The ready detectability of synthetic androgens by mass spectrometry (MS)‐based antidoping tests has reoriented androgen doping to using testosterone (T), which must be distinguished from its endogenous counterpart making detection of exogenous T harder. We investigated urine and serum steroid and hematological profiling in idually and combined to determine the optimal detection model for T administration in women. Twelve healthy females provided six paired blood and urine s les over 2 weeks prior to treatment consisting of 12.5‐mg T in a topical transdermal gel applied daily for 7 days. Paired blood and urine s les were then obtained at the end of treatment and Days 1, 2, 4, 7, and 14 days later. Compliance with treatment and s ling was high, and no adverse effects were reported. T treatment significantly increased serum and urine T, serum dihydrotestosterone (DHT), urine 5α‐androstane‐3α,17β‐diol (5α‐diol) epitestosterone (E), and urine T/E ratio with a brief window of detection (2–4 days) as well as total and immature (medium and high fluorescence) reticulocytes that remained elevated over the full 14 posttreatment days. Carbon isotope ratio MS and the OFF score and Abnormal Blood Profile score (ABPS) were not discriminatory. The optimal multivariate model to identify T exposure combined serum T, urine T/E ratio with three hematological variables (% high fluorescence reticulocytes, mean corpuscular hemoglobin, and volume) with the five variables providing 93% correct classification (4% false positive, 10% false negatives). Hence, combining select serum and urine steroid MS variables with reticulocyte measures can achieve a high but imperfect detection of T administration to healthy females.
Publisher: The Endocrine Society
Date: 11-2012
DOI: 10.1210/JC.2012-2265
Abstract: Testosterone (T) levels decline with increasing age. Controversy exists over the threshold for classifying T as low vs. normal in older men. The relevance of assessing dihydrotestosterone (DHT) and estradiol (E2) remains unclear. We assessed the associations of T, DHT, and E2 in men aged 70 yr or older and established reference ranges for these in healthy older men. Community-dwelling men aged 70–89 yr residing in Perth, Western Australia, Australia, participated in the study. Plasma T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning s les from 3690 men. Increasing age, higher body mass index and waist to hip ratio, dyslipidemia, diabetes, and higher LH were independently associated with lower levels of T and DHT. Increasing age, diabetes, and higher LH were associated with lower E2. In a reference group of 394 men aged 76.1 ± 3.2 yr reporting excellent or very good health with no history of smoking, diabetes, cardiovascular disease, cancer, depression, or dementia, the 2.5th percentile for T was 6.4 nmol/liter (184 ng/dl) DHT, 0.49 nmol/liter and E2, 28 pmol/liter. Applying these cutoffs to all 3690 men, those with low T or DHT had an increased odds ratio for frailty, diabetes, and cardiovascular disease. Men with both low T and DHT had a higher odds ratio for these outcomes. The 2.5th percentile in a reference group of healthy older men provides age-appropriate thresholds for defining low T, DHT, and E2. Additional studies are needed to test their potential applicability and clinical utility in older men.
Publisher: SAGE Publications
Date: 05-10-2015
Abstract: Age-specific trends of serum testosterone and sex hormone-binding globulin across the full lifespan have not been reported. We deduced age-specific trends in serum testosterone and sex hormone-binding globulin in males and females between ages 10 and 90 from a large s le of consecutive results from a single large pathology laboratory. Coded results of 110,712 consecutive blood s les requesting serum testosterone over seven years (2007–2013) comprising blood testosterone, sex hormone-binding globulin and calculated free testosterone together with gender and age were analysed create smoothed age-specific centiles (2.5%, 5%, 25%, 50%, 75%, 95%, 97.5%) for males and females. These identified the pubertal increases in serum testosterone in males peaking at 20 years of age and remaining stable thereafter until the eighth decade. In females, circulating testosterone peaked in late adolescence and declined gradually over the next two decades but remained stable across menopause and beyond. After early childhood, serum sex hormone-binding globulin declines to a nadir in males at the age of 20 years and remains stable till the sixth decade with a gradual, progressive rise thereafter. In females, the sex hormone-binding globulin nadir is reached earlier with levels rising gradually and progressively with age thereafter and accelerating after the age of 70 years. Females also exhibit a second sex hormone-binding globulin peak during reproductive ages reflected only in upper centiles due to effects of pregnancy and oral contraceptive use in a significant minority of females. This large s le of clinical data provides a comprehensive profile of androgen status across the lifespan from early adolescence to late old age.
Publisher: Wiley
Date: 21-12-2019
DOI: 10.1111/CEN.13905
Abstract: Low endogenous sex hormones and low physical activity (PA) levels have been associated with CVD risk. Whether these interact to influence CVD outcomes remains unclear. We assessed whether sex hormone concentrations and PA were additively associated with lower central adiposity and CVD risk. 3351 community-dwelling men, mean age 77 years. Baseline testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Levels of PA were ascertained by questionnaire. Men were stratified using median splits into high hormone + high PA (H/H), high hormone + low PA (H/L) low hormone + high PA (L/H) and low hormone + low PA (L/L) groups. A total of 865 CVD events and 499 CVD deaths occurred during 10-year mean follow-up. Men with higher T, DHT or SHBG and higher PA had the lowest BMI, waist circumference and risk of metabolic syndrome. Men with higher T had the lowest risk of incident CVD events, irrespective of PA level. Men with higher T or DHT and higher PA had the lowest risk of dying from CVD (eg, hazard ratios for T/PA H/H 0.76 P = 0.031 H/L 0.85 P = 0.222 L/H 0.80 P = 0.075 L/L 1.00). Higher circulating androgens and higher PA were associated with less central adiposity at baseline and fewer CVD deaths during follow-up. These findings are consistent with a potential additive effect of androgens and PA on cardiometabolic outcomes in older men.
Publisher: AMPCo
Date: 10-2010
DOI: 10.5694/J.1326-5377.2010.TB03964.X
Abstract: To determine the proportion of older Australian men who meet the Pharmaceutical Benefits Scheme (PBS) criteria for osteoporosis treatment and are receiving effective treatment. A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study focusing on the health of older men. Data were collected through questionnaires and clinical assessments. Bone mineral density (BMD) of the hip and spine was measured by dual x-ray absorptiometry (DXA). Vertebral deformities were identified from DXA lateral vertebral fracture assessment images. The study was conducted at Concord Hospital, Sydney, between January 2005 and May 2007. 1705 community-dwelling men aged 70 years or over from a defined geographical region around Concord Hospital. Prevalence of vertebral deformities previous minimal trauma fractures BMD T-scores ≤ - 3 falls in the previous 12 months use of bisphosphonates and calcium and vitamin D supplements. Of the 1705 men seen at baseline, 1626 completed all DXA scans and 401 (25%) met one or more of the PBS criteria for osteoporosis treatment. Ninety per cent of the men who met the PBS criteria were unaware they had osteoporosis. Of the men eligible for PBS-subsidised treatment, 39 (10%) reported use of a bisphosphonate, 56 (14%) had taken calcium supplements, and 28 (7%) had taken vitamin D supplements. Only three men had taken calcium, vitamin D and bisphosphonates in combination. Despite a high prevalence of osteoporosis in elderly Australian men, awareness, diagnosis and treatment of the condition remain very low.
Publisher: The Endocrine Society
Date: 29-11-2019
Abstract: The study of gonadal hormone effects on adolescent wellbeing has been limited by logistical challenges. Urine hormone profiling offers new opportunities to understand the health and behavioral implications of puberty hormones. To characterize pubertal change in urinary testosterone and estradiol among male and female adolescents, respectively. Three-year prospective cohort study. Australian regional community. 282 (163 male) normally developing adolescents aged 11.8 ± 1.0 years at baseline. Quarterly urine measurements of testosterone and estradiol (mass spectrometry) annual anthropometric assessment and Tanner stage (TS) self-report. Two-class sigmoidal and quadratic growth mixture models (centered on age at TS3) were identified as best-fit for describing testosterone (male) and estradiol (female) change. Classes 1 (male: 63% female: 82%) and 2 (male: 37% female: 18%) were respectively named the “stable” and “unstable” trajectories, characterized by different standard deviation of quarterly hormone change and magnitude of hormone peaks and troughs (all P & 0.001). Compared with class 1 (stable), class 2 males were taller at baseline (154 vs 151 cm), reported earlier and faster TS progression (P & 0.01), and showed higher serum testosterone levels at baseline and 3 years (P ≤ 0.01). Class 2 females exhibited smaller height and weight gains over the 3 years and had higher baseline serum estradiol (249 vs 98 pmol/L P = 0.002) than class 1. Adolescents showed 2 distinct urinary gonadal hormone trajectories, characterized by stability of change over time, which were not associated with consistent anthropometric differences. Results provide a methodology for studying gonadal hormone impacts on other aspects of biopsychosocial wellbeing. Identification of potential “at-risk” hormone groups would be important for planning supportive interventions.
Publisher: Wiley
Date: 08-1997
DOI: 10.1046/J.1365-2605.1997.00051.X
Abstract: The biological basis for the remarkably wide variation in sperm output between and within men remains unclear. Although some contributing factors have been identified, the familial and genetic contributions to variation in human sperm output have been little studied, although such sources of variation are known to be significant in experimental animals. In order to identify such familial and genetic factors in a classical twin study design, we recruited monozygotic and dizygotic twins aiming to study the degree of resemblance between genetically identical and non-identical twins in sperm output, testis size and testicular endocrine function. From an approach to 160 twin pairs on the Australian Twin Register database, eventually 17 pairs of male twins (11 monozygotic and six dizygotic) participated in this study. Sperm concentration and output, right testis size and SHBG all exhibited a strong familial effect but a genetic component could not be confirmed. Total and free testosterone exhibited a genetic component. Although identifying for the first time a clear familial component to normal human spermatogenesis, this study had insufficient power to determine whether there was a genetic component, nor could its design distinguish between genetic or shared (early) environmental determinants for these familial effects. Implications for future twin studies of human testicular function including stronger recruitment strategies, multi-centre studies and surrogate variables for human spermatogenesis are suggested.
Publisher: Future Science Ltd
Date: 07-2012
DOI: 10.4155/BIO.12.128
Abstract: Although significant progress has been achieved during the past few years with the introduction of new assays and analytical methodologies, the detection and quantification of protein analytes, in particular of peptide hormones, continues to pose analytical challenges for the World Anti-Doping Agency-accredited anti-doping laboratories. In this article, the latest achievements in the application of MS-based methodologies and specific biochemical and immunological assays to detect some of the prohibited substances listed in section S2 of the World Anti-Doping Agency List of Prohibited Substances and Methods are reviewed. In addition, we look towards the future by focusing on some of the most promising analytical approaches under development for the detection of so-called ‘biomarkers of doping’.
Publisher: Medknow
Date: 18-02-2013
DOI: 10.1038/AJA.2013.8
Publisher: Elsevier BV
Date: 12-2006
Publisher: Oxford University Press (OUP)
Date: 27-06-2022
DOI: 10.1530/EJE-22-0227
Abstract: In men, many effects of testosterone (T) on the skeleton are thought to be mediated by estradiol (E2), but trial evidence is largely lacking. This study aimed to determine the effects of E2 on bone health in men in the absence of endogenous T. This study is a 6-month randomized, placebo-controlled trial with the hypothesis that E2 would slow the decline of volumetric bone mineral density (vBMD) and bone microstructure, maintain areal bone mineral density (aBMD), and reduce bone remodelling. 78 participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel daily or matched placebo. The outcome measures were vBMD and microarchitecture at the distal tibia and distal radius by high-resolution peripheral quantitative CT, aBMD at the spine and hip by dual-energy x-ray absorptiometry, and serum bone remodelling markers. For the primary endpoint, total vBMD at the distal tibia, there was no significant difference between groups, mean adjusted difference (MAD) 2.0 mgHA/cm3 (95% CI: −0.8 to 4.8), P = 0.17. Cortical vBMD at the distal radius increased in the E2 group relative to placebo, MAD 14.8 mgHA/cm3 (95% CI: 4.5 to 25.0), P = 0.005. Relative to placebo, E2 increased estimated failure load at tibia, MAD 250 N (95% CI: 36 to 465), P = 0.02, and radius, MAD 193 N (95% CI: 65 to 320), P = 0.003. Relative to placebo, E2 increased aBMD at the lumbar spine, MAD 0.02 g/cm2 (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm2 (95% CI: 0.00 to 0.02), P = 0.01, and reduced serum bone remodelling markers. Relative to placebo, E2 treatment increases some measures of bone density and bone strength in men and reduces bone remodelling, effects that occur in the absence of endogenous T.
Publisher: Oxford University Press (OUP)
Date: 11-2015
DOI: 10.1095/BIOLREPROD.115.132241
Abstract: While estrogen action is the major driver of uterine development, androgens acting via the androgen receptor (AR) may also promote uterine growth as suggested by uterine phenotypes in global AR knockout (ARKO) female mice. Because AR is expressed in uterine endometrial glands, we generated (Cre/loxP) uterine gland epithelium-specific ARKO (ugeARKO) to determine the role of endometrial gland-specific androgen actions. However, AR in uterine gland epithelium may not be required for normal uterine development and function because ugeARKO females had normal uterine development and fertility. To determine if exogenous androgens acting via AR can fully support uterine growth in the absence of estrogens, the ARKO and ugeARKO females were ovariectomized and treated with supraphysiological doses of testosterone or dihydrotestosterone (nonaromatizable androgen). Both dihydrotestosterone and testosterone supported full uterine regrowth in wild-type females while ARKO females had no regrowth (comparable to ovariectomized only). These findings suggest that androgens acting via AR can promote full uterine regrowth in the absence of estrogens. The ugeARKO had 50% regrowth when compared to intact uterine glands, and histomorphologically, both the endometrial and myometrial areas were significantly (P < 0.05) reduced, suggesting glandular epithelial AR located in the endometrium may indirectly modify myometrial development. Additionally, to confirm Cre function in endometrial glands, we generated uge-specific PTEN knockout mouse model. The ugePTEN knockout females developed severe endometrial hyperplasia and therefore present a novel model for future research.
Publisher: Oxford University Press (OUP)
Date: 28-04-2005
Abstract: Practical hormonal male contraceptive regimens are likely to have delayed onset and offset of reliable contraception dictated by the length of the spermatogenic cycle and clearance rate of pre-formed sperm from the ductular system. While delayed onset of contraceptive efficacy is an accepted feature of vasectomy, reliable time estimates for a hormonal male contraceptive of time to onset and offset of reliable contraception and of resumption of normal male fertility are required. We utilized the sperm output data from three male contraceptive efficacy studies to define quantitative estimates of suppression and recovery rates from an androgen alone (testosterone enanthate) and an androgen rogestin (testosterone/depot medroxyprogesterone acetate) study. Using nearly 14,000 semen s les from World Health Organization (WHO) studies #85921 and #89903 with identical protocols, the rate of suppression of sperm output was best modelled as a two-parameter, single exponential decay function with effective half-time to suppression of 5.5 weeks and times of 6.8 weeks to 10 x 10(6)/ml, 8.7 weeks to 5 x 10(6)/ml, 10.0 weeks to 3 x 10(6)/ml and 13.0 weeks to 1 x 10(6)/ml. The rate of recovery using absolute sperm concentration was best modelled as a three-parameter, sigmoidal curve with effective time to reach half of the recovery plateau of 10.5 weeks and times of 9.0 weeks to 3 x 10(6)/ml, 9.9 weeks to 5 x 10(6)/ml, 11.5 weeks to 10 x 10(6)/ml, and 13.6 weeks to 20 x 10(6)/ml. Using relative sperm output, defined as a percentage of the participants' own baseline, recovery approached an asymptotic plateau of approximately 85% of geometric mean pre-treatment sperm concentration. In the combination androgen rogestin study, suppression rate was significantly faster (effective time to reach half maximal suppression of 3.0 weeks) and recovery significantly slower (effective time to reach half of recovery plateau of 14.7 weeks) and less complete (asymptotic recovery plateau of 43% of baseline) than in the androgen-alone WHO studies. These findings therefore provide large s le estimates of the suppression and recovery rates from an androgen-alone hormonal male contraceptive regimen as a basis for comparison with other second-generation combination androgen rogestin regimens that are the most promising approach to developing practical male hormonal regimens.
Publisher: Springer Science and Business Media LLC
Date: 10-2006
DOI: 10.1038/NCPURO0599
Publisher: Bioscientifica
Date: 10-1996
Abstract: We previously demonstrated that androgens alone, in the complete absence of gonadotropins, initiated qualitatively complete spermatogenesis in hypogonadal ( hpg ) mice. Although germ cell to Sertoli cell ratios were normal in hpg mice with androgen-induced spermatogenesis, testicular size, Sertoli cell and germ cell numbers only reached 40% of those of non- hpg mice, and Sertoli cell numbers were unaffected by androgen treatment started at 21 days of age. We postulated that these observations were due to diminished gonadotropin-dependent Sertoli cell proliferation during perinatal life while the Sertoli cells still exhibited normal carrying capacity for mature germ cells. In order to test this hypothesis, we examined the effects of administering androgens and gonadotropins to hpg mice during the first 2 weeks of postnatal life when Sertoli cells normally continue to proliferate. The study end-points were Sertoli and germ cell numbers in hpg mice following induction of spermatogenesis by 8 weeks treatment with 1 cm subdermal silastic testosterone implants. Newborn pups (postnatal day 0–1) were injected s.c. with recombinant human FSH (rhFSH) (0·5 IU/20 μl) or saline once daily for 14 days, with or without a single dose of testosterone propionate (TP) (100 μg/20 μl arachis oil) or human chorionic gonadotropin (hCG) (1 IU/20 μl). Untreated hpg and phenotypically normal littermates were studied as concurrent controls. At 21 days of age, all treated weanling mice received a 1 cm silastic subdermal testosterone implant and, finally, 8 weeks after testosterone implantation, all mice were killed. As expected, qualitatively complete spermatogenesis was induced in all groups by testosterone despite undetectable circulating FSH levels. Exogenous rhFSH increased testis size by 43% ( P ·002) but a single neonatal dose of either TP or hCG reduced the FSH effect although neither TP nor hCG had any effect alone. In contrast, a single neonatal dose of TP or hCG increased final seminal vesicle size whereas FSH had no effect. FSH and TP treatment significantly increased absolute numbers of testicular spermatids compared with saline treatment, whereas hCG and TP significantly increased testicular sperm when expressed relative to testis size. Stereological evaluation of Sertoli and germ cell numbers demonstrated a rise in the absolute numbers of Sertoli and all germ cell populations induced by neonatal administration of hormones. When expressed per Sertoli cells the numbers of germ cells in the treated mice were between 85 and 90% of non- hpg controls. We conclude that exogenous FSH treatment during the first 2 weeks of postnatal life, coinciding with the natural time of Sertoli cell proliferation, increases Sertoli cell numbers and thereby the ultimate size of the mature testis and its germ cell production. Thus neonatal gonadotropin secretion may be a critical determinant of the sperm-producing capacity of the mature testis. In addition, neonatal exposure to androgens could be important for the imprinting of sex accessory organs in hpg mice, with the long-term effects of altering the sensitivity of the accessory organs to exogenous testosterone later in life. Journal of Endocrinology (1996) 151, 37–48
Publisher: Wiley
Date: 05-2016
DOI: 10.1111/WRR.12420
Abstract: The aims of this work were to define the role of androgens in female wound healing and to develop and characterize a novel wound dressing with antiandrogens. Androgens retard wound healing in males, but their role in female wound healing has not been established. To understand androgen receptor (AR)-mediated androgen actions in male and female wound healing, we utilized the global AR knockout (ARKO) mouse model, with a mutated AR deleting the second zinc finger to disrupt DNA binding and transcriptional activation. AR inactivation enhanced wound healing rate in males by increasing re-epithelialization and collagen deposition even when wound contraction was eliminated. Cell proliferation and migration in ARKO male fibroblasts was significantly increased compared with wild-type (WT) fibroblasts. However, ARKO females showed a similar healing rate compared to WT females. To exploit local antiandrogen effects in wound healing, while minimizing off-target systemic effects, we developed a novel electrospun polycaprolactone (PCL) scaffold wound dressing material for sustained local antiandrogen delivery. Using the antiandrogen hydroxyl flutamide (HF) at 1, 5, and 10 mg/mL in PCL scaffolds, controlled HF delivery over 21 days significantly enhanced in vitro cell proliferation of human dermal fibroblasts and human keratinocytes. HF-PCL scaffolds also promoted in vivo wound healing in mice compared with open wounds but not to PCL scaffolds.
Publisher: Oxford University Press (OUP)
Date: 21-12-2019
Abstract: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood? Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder. Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function. The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen s le. Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood s les were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA >4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk. Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P < 0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P 4 was associated with a lower serum testosterone (P = <0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015). This study is limited by the s le size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment. Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume. This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2008
DOI: 10.1016/J.PAIN.2008.08.011
Abstract: Intrusive pain is likely to have a serious impact on older people with limited ability to respond to additional stressors. Frailty is conceptualised as a functional and biological pattern of decline accumulating across multiple physiological systems, resulting in a decreased capacity to respond to additional stressors. We explored the relationship between intrusive pain, frailty and comorbid burden in 1705 community-dwelling men aged 70 or more who participated in the baseline phase of the CHAMP study, a large epidemiological study of healthy ageing based in Sydney, Australia. 9.4% of men in the study were frail (according to the commonly-used Cardiovascular Health Study frailty criteria).Using a combination of self-report and clinical measures, we found an association between frailty and intrusive pain that remained after accounting for demographic characteristics, number of comorbidities, self-reported depressed mood and arthritis (adjusted odds ratio 1.7 (95% confidence interval (CI) 1.1-2.7), p=0.0149). The finding that adjusting for depressed mood, but not a history of arthritis, attenuated the relationship between frailty and intrusive pain points to a key role for central mechanisms. Additionally, men with the highest overall health burden (frail plus high comorbid burden) were most likely to report intrusive pain (adjusted odds ratio 3.0 (95% CI 1.6-5.5), p=0.0004). These findings provide support for the concept that intrusive pain is an important challenge for older men with limited capacity to respond to additional physical stressors. To our knowledge, this is the first study to explore specifically the relationship between pain and frailty.
Publisher: Oxford University Press (OUP)
Date: 27-09-2022
Abstract: Is the metabolic health of men conceived using ICSI different to that of IVF and spontaneously conceived (SC) men? ICSI-conceived men aged 18–24 years, compared with SC controls, showed differences in some metabolic parameters including higher resting diastolic blood pressure (BP) and homeostasis model assessment for insulin resistance (HOMA-IR) scores, although the metabolic parameters of ICSI- and IVF-conceived singleton men were more comparable. Some studies suggest that IVF-conceived offspring may have poorer cardiovascular and metabolic profiles than SC children. Few studies have examined the metabolic health of ICSI-conceived offspring. This cohort study compared the metabolic health of ICSI-conceived men to IVF-conceived and SC controls who were derived from prior cohorts. Participants included 121 ICSI-conceived men (including 100 singletons), 74 IVF-conceived controls (all singletons) and 688 SC controls (including 662 singletons). Resting systolic and diastolic BP (measured using an automated sphygmomanometer), height, weight, BMI, body surface area and fasting serum metabolic markers including fasting insulin, glucose, total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, triglycerides, highly sensitive C-reactive protein (hsCRP) and HOMA-IR were compared between groups. Data were analysed using multivariable linear regression adjusted for various covariates including age and education level. After adjusting for covariates, compared to 688 SC controls, 121 ICSI-conceived men had higher diastolic BP (β 4.9, 95% CI 1.1–8.7), lower fasting glucose (β −0.7, 95% CI −0.9 to −0.5), higher fasting insulin (ratio 2.2, 95% CI 1.6–3.0), higher HOMA-IR (ratio 1.9, 95% CI 1.4–2.6), higher HDLC (β 0.2, 95% CI 0.07–0.3) and lower hsCRP (ratio 0.4, 95% CI 0.2–0.7) levels. Compared to 74 IVF-conceived singletons, only glucose differed in the ICSI-conceived singleton men (β −0.4, 95% CI −0.7 to −0.1). No differences were seen in the paternal infertility subgroups. The recruitment rate of ICSI-conceived men in this study was low and potential for recruitment bias exists. The ICSI-conceived men, the IVF-conceived men and SC controls were from different cohorts with different birth years and different geographical locations. Assessment of study groups and controls was not contemporaneous, and the measurements differed for some outcomes (BP, insulin, glucose, lipids and hsCRP). These observations require confirmation in a larger study with a focus on potential mechanisms. Further efforts to identify whether health differences are due to parental characteristics and/or factors related to the ICSI procedure are also necessary. This study was funded by an Australian National Health and Medical Research Council Partnership Grant (NHMRC APP1140706) and was partially funded by the Monash IVF Research and Education Foundation. S.R.C. was supported through an Australian Government Research Training Program Scholarship. R.J.H. is supported by an NHMRC project grant (634457), and J.H. and R.I.M. have been supported by the NHMRC as Senior and Principal Research Fellows respectively (J.H. fellowship number: 1021252 R.I.M. fellowship number: 1022327). L.R. is a minority shareholder and the Group Medical Director for Monash IVF Group, and reports personal fees from Monash IVF Group and Ferring Australia, honoraria from Ferring Australia and travel fees from Merck Serono and MSD and Guerbet R.J.H. is the Medical Director of Fertility Specialists of Western Australia and has equity in Western IVF R.I.M. is a consultant for and shareholder of Monash IVF Group and S.R.C. reports personal fees from Besins Healthcare and nonfinancial support from Merck outside of the submitted work. The remaining authors have no conflicts of interest to declare. N/A.
Publisher: Wiley
Date: 13-01-2020
DOI: 10.1111/AJAG.12763
Abstract: To investigate whether poorer oral health, tooth loss and lower usage of dental services are associated with depressive symptoms in older Australian men. Cross-sectional study of data collected from participants of the Concord Health and Ageing in Men Project. Depressive symptoms were evaluated by the Geriatric Depression Scale. Chewing capacity was estimated by ability to chew 11 food items. The prevalence of depressive symptoms was 17.5%. Self-evaluated oral health, chewing capacity and the number of natural and decayed teeth were associated with depressive symptoms. After adjusting for multiple confounders, chewing capacity (PR 1.93 95% CI 1.34-2.79) and decayed teeth (PR 1.68 95% CI 1.03-2.75) maintained a significant association with depressive symptoms. The direction of causality between oral health and depression is unclear however, oral health may contribute to depression in older Australian men and depressive symptoms may limit chewing capacity and be aggravated by untreated dental decay.
Publisher: BMJ
Date: 13-10-2019
DOI: 10.1136/HEARTJNL-2019-315449
Abstract: Low levels of total cholesterol (TC) are associated with adverse outcomes in older populations. Whether this phenomenon is independent of statin use is unknown. We investigated the association between low TC levels and long-term major adverse cardiovascular events (MACE) in a prospective study of men aged ≥70 years without ischaemic heart disease (IHD) and whether this was influenced by statin use. The CHAMP (Concord Health and Ageing in Men Project) cohort is a prospective cohort study of community-dwelling men aged ≥70 years. The relationship between TC and long-term MACE was analysed using Cox-regression modelling adjusted for comorbidities and stratified by statin use. The study cohort comprised 1289 men (mean (±SD) age, 77.0±5.5 years mean follow-up, 6.4±2.7 years). Decreasing TC level was associated with increased comorbidity burden, frailty and MACE (linear trend p .001). In men not on statin therapy (n=731), each 1 mmol/L decrease in TC was associated with increased MACE (HR 1.27, 95% CI 1.10 to 1.45, p=0.001) and mortality (HR 1.22, 95% CI 1.03 to 1.44, p=0.02) adjusted for comorbidities. In contrast, low TC in men on statins (n=558) was not associated with MACE (HR 0.91, 95% CI 0.74 to 1.11) or mortality (HR 0.86, 95% CI 0.68 to 1.09). Low TC is associated with increased risk of MACE in older men without IHD who are not taking statin therapy but not in those on statins.
Publisher: Wiley
Date: 14-06-2010
DOI: 10.1111/J.1365-2265.2009.03744.X
Abstract: Life-long testosterone replacement therapy (TRT) for younger men with organic androgen deficiency is best provided by depot testosterone (T) products. This study compared directly the two long-acting depot T products, subdermal T implants (TI) and injectable T undecanoate (TU) for maintenance of TRT. Men with organic androgen deficiency (n = 38) undergoing regular TRT at an academic Andrology centre were recruited for a two period, randomized sequence, cross-over clinical trial without intervening wash-out period of TRT maintenance. For both depot T products, their pharmacokinetics and pharmacodynamics were evaluated using a range of androgen sensitive clinical, laboratory and quality of life measures as well as preference for ongoing treatment after experience of both products. The two depot T products had distinct pharmacokinetics and were not bioequivalent. However, there were no consistent clinical differences in a comprehensive range of pharmacodynamic measures reflecting androgen effects on biochemistry and haematology, muscle mass and strength, and quality of life, mood and sexual function. The majority (91%) of participants chose TU over TI at study completion. Despite significant pharmacokinetic differences, the two depot T products are clinically interchangeable allowing for choice dependent on patient and physician delivery preference in practice but most patients preferred the injectable over the implantable form.
Publisher: The Endocrine Society
Date: 08-2003
Abstract: Androgen therapy may precipitate obstructive sleep apnea in men. Despite increasing androgen use in older men, few studies have examined sleep and breathing. Randomized, double-blind, placebo-controlled studies examining effects of testosterone simultaneously on sleep, breathing, and function in older men are not available. Seventeen community-dwelling healthy men over the age of 60 yr were randomized to receive three injections of im testosterone esters at weekly intervals (500 mg, 250 mg, and 250 mg) or matching oil-based placebo and then crossed over to the other treatment after 8 wk of washout. Polysomnography, anthropometry, and physical, mental, and metabolic function were assessed at baseline and after each treatment period. Testosterone treatment reduced total time slept ( approximately 1 h), increased the duration of hypoxemia ( approximately 5 min/night), and disrupted breathing during sleep (total and non-rapid eye movement respiratory disturbance indices both increased by approximately seven events per hour) (all P < 0.05). Despite expected effects on body composition (increase in total and lean mass, reduction in fat mass, P < 0.05, bioimpedance method), upper airway dimensions did not change (acoustic reflectometry). Driving ability (computer simulation), physical activity (accelerometry, Physical Activity Scale in the Elderly), quality of life (SF36, Functional Outcomes of Sleep Questionnaire), mood (Profile of Mood States Questionnaire), sleepiness (Epworth, Stanford scales), and insulin resistance (homeostasis model) also were not changed by treatment. Short-term administration of high-dose testosterone shortens sleep and worsens sleep apnea in older men but did not alter physical, mental, or metabolic function. These changes did not appear to be due to upper airway narrowing. Further study of longer-term lower-dose androgen therapy on sleep and breathing is needed to evaluate its safety in older men.
Publisher: Wiley
Date: 21-02-2022
DOI: 10.1111/CEN.14689
Abstract: Roles for estradiol in modulating cognition in men remain uncertain. We assessed the isolated effects of estradiol on cognition in men in the absence of testosterone. Randomized trial of transdermal estradiol 0.9 mg daily, or matched placebo, for 6 months, hypothesizing that estradiol would improve verbal learning, verbal memory, and spatial problem solving over time. Men receiving androgen deprivation therapy (ADT) for prostate cancer. Cognition was assessed by a tablet‐based cognitive battery (Cogstate) at baseline, Month 1, Month 3, and Month 6. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale. Seventy‐eight participants were randomized. Baseline mean scores were 21.0 (standard deviation [ SD ] 4.1) for the International Shopping List test (ISL), assessing verbal learning and memory (higher scores better), and 60.4 ( SD 19.5) for the Groton Maze Learning test (GML), assessing spatial problem solving (lower scores better). There was no significant difference in performance over time for the estradiol group versus the placebo group for the ISL, mean adjusted difference (MAD) 0.7 (95% confidence interval [CI] −1.2 to 2.5), p = .36, or the GML, MAD −3.2 (95% CI −12.0 to 5.6), p = 0.53. There was no significant difference between groups over time in performance in any other cognitive domain, or on depression or anxiety scores. We found no major effects of estradiol on cognition in men with castrate testosterone concentrations. Although the cognitive effects of ADT are debated, this study suggests that any such effects are unlikely to be prevented by the administration of estradiol.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2009
Publisher: Wiley
Date: 08-05-2017
DOI: 10.1111/CEN.13350
Abstract: Male performance in athletic events begins to exceed that of age-matched females during early adolescence, but the timing of this ergence relative to the onset of male puberty and the rise in circulating testosterone remains poorly defined. This study is a secondary quantitative analysis of four published sources which aimed to define the timing of the gender ergence in athletic performance and relating it to the rise in circulating testosterone due to male puberty. Four data sources reflecting elite swimming and running and jumping track and field events as well as hand-grip strength in nonathletes were analysed to define the age-specific gender differences through adolescence and their relationship to the rising circulating testosterone during male puberty. The onset and tempo of gender ergence were very similar for swimming, running and jumping events as well as the hand-grip strength in nonathletes, and all closely paralleled the rise in circulating testosterone in adolescent boys. The gender ergence in athletic performance begins at the age of 12-13 years and reaches adult plateau in the late teenage years with the timing and tempo closely parallel to the rise in circulating testosterone in boys during puberty.
Publisher: The Endocrine Society
Date: 10-2003
Abstract: WHO studies provided proof of concept for hormonal male contraception using a prototype androgen-alone regimen. Combined testosterone plus progestin regimens offer more practical promise, but no contraceptive efficacy studies have been completed. The objective of this study was to establish the proof of principle for depot hormonal androgen rogestin combination as a male contraceptive. We performed a contraceptive efficacy study of 55 healthy men in stable fertile relationships seeking a change in contraceptive method. Testosterone (four 200-mg implants, every 4 or 6 months) and 300 mg depot medroxyprogesterone acetate, im, every 3 months were administered. Once sperm output was suppressed (<1 million/ml for 2 consecutive months), men entered a 12-month contraceptive efficacy period, ceasing other contraception. The main outcome measure was contraceptive failure (pregnancy) rate. No pregnancies occurred in 426 person-months (35.5 person-years 95% confidence limits for contraceptive failure rate, 0-8%/annum), superior to the first year failure rate of condoms, the only reversible male method. Sperm density fell rapidly, so 94% of men entered the efficacy phase by 3 months, with only 2 of 55 (3.6%) men not sufficiently suppressed to enter efficacy. A few men treated with testosterone implants at 6-month intervals demonstrated androgen deficiency symptoms and/or escape of gonadotropin and spermatogenic suppression between months 5 and 6 after a protocol amendment, all men receiving testosterone implants at 4-month intervals avoided androgen deficiency or loss of gonadotropin and sperm output suppression. Recovery was complete (median, 3.6 months to sperm reappearance and 5.0 months to 20 million sperm/ml) in all but one man with an incidental testicular disorder. Discontinuations were for protocol-related reasons (n = 15) or altered personal circumstances (n = 12), but there were no serious adverse effects related to drug exposure. The first male contraceptive efficacy study using a prototype depot androgen rogestin combination demonstrates high contraceptive efficacy with satisfactory short-term safety and recovery of spermatogenesis. Further studies of purpose-developed products are required to extend the overall safety and efficacy experience with depot androgen rogestin combinations, the most promising approach to hormonal male contraception.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JSBMB.2014.01.011
Abstract: Non-steroidal drugs that increase endogenous testosterone (T) may be used to exploit ergogenic effects of androgens in power sports. While superactive GnRH analog use is suspected, neither screening nor detection tests are developed. This study aimed to determine if (a) stimulation for 5 days by leuprolide (a superactive GnRH analog) of serum and urine steroids and urine LH is reproducible at a 2 week interval, (b) nandrolone decanoate (ND) co-administration masks responses to leuprolide administration, (c) performance of urine measurement of leuprolide and M1, its major metabolite, as a detection test. Healthy men were randomized into a 4 week parallel group, open label clinical study in which all men had daily sc injections of leuprolide (1mg) for 4 days in the 1st and 3rd weeks with hormone-free 2nd and 4th weeks. In the 3rd week, men were randomized to either ND injections or no extra treatment. Serum steroids were determined by liquid chromatography, tandem mass spectrometry (LC-MS), urine steroids by gas chromatography, mass spectrometry (GC-MS), urine leuprolide and M1 by high resolution LC-MS and urine LH by immunoassay. Leuprolide stimulated striking, reproducible increases in serum and urine LH and steroids (serum T, dihydroT (DHT), 3α diol urine T, epitestosterone (E) and androsterone (A). ND suppressed basal serum T, E2, 3α diol, and urinary E but did not mask or change the magnitude of responses to leuprolide. Urine leuprolide and M1 measurement had 100% sensitivity and specificity in detecting leuprolide administration up to one day after cessation of injections with the detection window between 1 and 3 days after last dose. Screening using urine steroid and LH measurements, optimally by urinary log10(LHxT), correctly classified 82% of urine s les. It is concluded that leuprolide stimulation of endogenous testosterone is reproducible after a 10-day interval, is not masked by ND and is reliably detected by urine leuprolide or M1 measurement for at least 1 day after administration.
Publisher: The Endocrine Society
Date: 2014
DOI: 10.1210/JC.2013-3272
Abstract: Testosterone (T) levels decline with age and lower T has been associated with increased mortality in aging men. However, the associations of its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with mortality are poorly defined. We assessed associations of T, DHT, and E2 with all-cause and ischemic heart disease (IHD) mortality in older men. Participants were community-dwelling men aged 70 to 89 years who were residing in Perth, Western Australia. Plasma total T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning s les collected in 2001 to 2004 from 3690 men. Deaths to December 2010 were ascertained by data linkage. There were 974 deaths (26.4%), including 325 of IHD. Men who died had lower baseline T (12.8±5.1 vs 13.2±4.8 nmol/L [mean±SD], P=.013), DHT (1.4±0.7 vs 1.5±0.7 nmol/L, P=.002), and E2 (71.6±29.3 vs 74.0±29.0 pmol/L, P=.022). After allowance for other risk factors, T and DHT were associated with all-cause mortality (T: quartile [Q] Q2:Q1, adjusted hazard ratio [HR]=0.82, P=.033 Q3:Q1, HR=0.78, P=.010 Q4:Q1, HR=0.86, P>.05 DHT: Q3:Q1, HR=0.76, P=.003 Q4:Q1, HR=0.84, P>.05). Higher DHT was associated with lower IHD mortality (Q3:Q1, HR=0.58, P=.002 Q4:Q1, HR=0.69, P=.026). E2 was not associated with either all-cause or IHD mortality. Optimal androgen levels are a biomarker for survival because older men with midrange levels of T and DHT had the lowest death rates from any cause, whereas those with higher DHT had lower IHD mortality. Further investigations of the biological basis for these associations including randomized trials of T supplementation are needed.
Publisher: The Endocrine Society
Date: 08-2007
DOI: 10.1210/EN.2007-0248
Abstract: The role of classical genomic androgen receptor (AR) mediated actions in female reproductive physiology remains unclear. Female mice homozygous for an in-frame deletion of exon 3 of the Ar (AR−/−) were subfertile, exhibiting delayed production of their first litter (AR+/+ = 22 d vs. AR−/− = 61 d, P & 0.05) and producing 60% fewer pups/litter (AR+/+: 8.1 ± 0.4 vs. AR−/−: 3.2 ± 0.9, P & 0.01). Heterozygous females (AR+/−) exhibited an age-dependent 55% reduction (P & 0.01) in pups per litter, evident from 6 months of age (P & 0.05), compared with AR+/+, indicating a significant gene dosage effect on female fertility. Ovulation was defective with a significant reduction in corpora lutea numbers (48–79%, P & 0.01) in 10- to 12- and 26-wk-old AR+/− and AR−/− females and a 57% reduction in oocytes recovered from naturally mated AR−/− females (AR+/+: 9.8 ± 1.0 vs. AR−/−: 4.2 ± 1.2, P & 0.01) however, early embryo development to the two-cell stage was unaltered. The delay in first litter, reduction in natural ovulation rate, and aromatase expression in AR+/− and AR−/− ovaries, coupled with the restored ovulation rate by gonadotropin hyperstimulation in AR−/− females, suggest aberrant gonadotropin regulation. A 2.7-fold increase (AR+/+: 35.4 ± 13.4 vs. AR−/−: 93.9 ± 6.1, P & 0.01) in morphologically unhealthy antral follicles demonstrated deficiencies in late follicular development, although growing follicle populations and growth rates were unaltered. This novel model reveals that classical genomic AR action is critical for normal ovarian function, although not for follicle depletion and that haploinsufficiency for an inactivated AR may contribute to a premature reduction in female fecundity.
Publisher: Wiley
Date: 2016
DOI: 10.1111/JGS.13877
Abstract: To investigate the effects of number of medications and Drug Burden Index (DBI) on transitions between frailty stages and death in community-dwelling older men. Cohort study. Sydney, Australia. Community-dwelling men aged 70 and older (N=1,705). Self-reported questionnaires and clinic visits were conducted at baseline and 2 and 5 years. Frailty was assessed at all three waves according to the modified Fried frailty phenotype. The total number of regular prescription medications and DBI (a measure of exposure to sedative and anticholinergic medications) were calculated over the three waves. Data on mortality over 9 years were obtained. Multistate modeling was used to characterize the transitions across three frailty states (robust, prefrail, frail) and death. Each additional medication was associated with a 22% greater risk of transitioning from the robust state to death (adjusted 95% confidence interval (CI)=1.06-1.41). Every unit increase in DBI was associated with a 73% greater risk of transitioning from the robust state to the prefrail state (adjusted 95% CI=1.30-2.31) and a 2.75 times greater risk of transitioning from the robust state to death (adjusted 95% CI=1.60-4.75). There was no evidence of an adjusted association between total number of medications or DBI and the other transitions. Although the possibility of confounding by indication cannot be excluded, additional medications were associated with greater risk of mortality in robust community-dwelling older men. Greater DBI was also associated with greater risk of death and transitioning from the robust state to the prefrail state.
Publisher: Oxford University Press (OUP)
Date: 14-05-2008
DOI: 10.1093/IJE/DYN071
Publisher: CSIRO Publishing
Date: 2001
DOI: 10.1071/RD00103
Abstract: Extravagant claims have been made repeatedly in recent years that human sperm counts are falling and that global exposure to environmental estrogens are responsible. The basis for these two distinct claims is reviewed. The claims of falling human sperm output, reviving an old debate, are prompted by a paper by Carlsen et al. (1992). This meta-analysis, however, is marred by numerous flaws that invalidate its claims. Major defects include severe heterogeneity of component studies, rendering them unsuitable for aggregation, and defective data analysis based on arithmetic mean rather than median, which showed no significant changes over time. This debate is likely to remain unresolved until valid, representative population-based studies of human sperm output can be achieved. None have been reported, or seem feasible in the near future, and so alternative strategies, based on surrogate variables for human male fertility not requiring sperm counts, need to be developed and validated. The plausible hypothesis that prenatal estrogen exposure might influence development of the human testis through effects on Sertoli cell replication and sperm carrying capacity has, however, been conclusively refuted by studies of boys born to women exposed to high doses of oral diethylstilbestrol during pregnancy. Neither fertility nor sperm output were adversely influenced by massive maternal estrogen exposure during pregnancy, although minor urogenital malformations did occur. The still wider claims of deteriorating male reproductive health, notably changes in prevalence or incidence of hypospadias or cryptorchidism, also lack convincing population-based evidence, although cancer registry data indicate a gradual increase in testis cancer in some countries. In summary, the available evidence does not support claims of falling sperm counts or any general deterioration in male reproductive health. Population-based studies of valid surrogate variables for male fertility not requiring semen analysis are needed. If population-based evidence regarding male fertility or sperm output could be generated, it is highly unlikely that prenatal estrogen exposure could be a valid explanation of any deterioration as massive maternal exposure to oral estrogen has negligible effects on male fertility or sperm output.
Publisher: The Endocrine Society
Date: 13-08-2019
Abstract: There is a lack of understanding of what is normal in terms of sex steroid levels in older women. To determine whether sex steroid levels vary with age in and establish reference ranges for women years of age. Cross-sectional, community-based study. Included 6392 women ≥70 years of age. Sex steroids measured by liquid chromatography–tandem mass spectrometry. A reference group, to establish sex steroid age-specific reference ranges, excluded women using systemic or topical sex steroid, antiandrogen or glucocorticoid therapy, or an antiglycemic agent. The reference group of 5326 women had a mean age of 75.1 (±4.2) years, range of 70 to 94.7 years. Median values (range) were 181.2 pmol/L (3.7 to 5768.9) for estrone (E1), 0.38 nmol/L (0.035 to 8.56) for testosterone (T), 2.60 nmol/L (0.07 to 46.85) for dehydroepiandrosterone (DHEA), and 41.6 nmol/L (2.4 to 176.6) for SHBG. Estradiol and DHT were below method sensitivity in 66.1% and 72.7% of the s les, respectively. Compared with women aged 70 to 74 years, women aged ≥85 years had higher median levels of E1 (11.7%, P = 0.01), T (11.3%, P = 0.02), and SHBG (22.7%, P 0.001) and lower DHEA (30% less, P 0.001). Women with overweight and obesity had higher E1 (P 0.001) and T (P 0.03) and lower SHBG (P 0.001) than did women with normal body mass index. Smokers had 17.2% higher median T levels (P = 0.005). From the age of 70 years, T and E1 increase with age, despite a steady decline in DHEA. Whether E1 and T are biomarkers for longevity or contribute to healthy aging merits investigation.
Publisher: Wiley
Date: 22-12-2005
DOI: 10.1111/J.1365-2265.2004.02173.X
Abstract: There is evidence that male sex hormones influence the rate of progression of inflammatory and cardiovascular diseases. We have previously shown that human leucocytes and arterial cells isolated from male donors express more androgen receptor (AR) than those from female cells, with potentially pro-atherogenic effects. We now investigate whether the gender difference in AR expression is due to genetic or hormonal regulation. The influence of hormones on AR expression were studied in hpg mice (a mouse model of androgen deficiency) treated with testosterone, oestradiol or dihydrotestosterone (DHT). Blood s les were obtained for leucocyte AR expression and hormone levels from 53 subjects, grouped into: 12 male [six young adult (27-45 years), six elderly (71-79 years)] and six female (young adult 25-45 years) healthy controls six male-to-female transsexuals (M2F 20-50 years) receiving stable pharmacological oral oestrogen treatment six female-to-male transsexuals (F2M 31-51 years) receiving stable androgen replacement therapy five younger men (18-56 years) who had been receiving long-term androgen replacement therapy for hypogonadal disease six elderly men (72-88 years) who had undergone medical castration for prostate cancer treatment and 12 male bone marrow transplant recipients (BMT 23-65 years) from either male or female donors. Serum testosterone and oestradiol concentrations were measured by established immunoflurometric assays from unextracted human serum. AR mRNA levels were measured by RT-PCR and AR protein levels by western blot (cell culture) or immunohistochemistry (mouse arteries). We found that AR mRNA levels were significantly down-regulated in the leucocytes of hpg mice that were treated with exogenous testosterone, oestradiol or DHT. AR protein levels were also lower in aortic tissue from the same mice. In humans, we found AR expression was significantly down-regulated by exogenous treatment with testosterone in F2M (31 +/- 13%, compared with control) or oestradiol in M2F (22 +/- 5%) but was significantly up-regulated by endogenous testosterone in BMT (128 +/- 17%). Low androgen levels measured in castrated older men were associated with markedly increased AR expression (207 +/- 26%, P < 0.05) compared with age-matched older male controls (100 +/- 2%). Our results indicate a regulated ability of vascular cells to respond to sex hormones, with the effects of exogenous therapies differing markedly from those due to endogenous sex hormones. We conclude that the gender difference in AR expression in vascular cells is hormonally, rather than genetically, controlled.
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.BONE.2011.08.026
Abstract: Weight loss is associated with bone loss however, it is unclear whether loss of fat or loss of lean body mass plays the key role in this relationship. The aim of this longitudinal analysis was to clarify the relationship between hip BMD, hip BMC and whole body BMC with changes in fat and lean tissue mass in older men. The Concord Health and Aging in Men Project (CHAMP) is a population-based study in Sydney, Australia, involving 1705 men aged 70-97 years. Bone mineral density (BMD) of the total hip, and bone mineral content (BMC) of the hip and whole body (WB), lean mass and fat mass were measured with Dual X-ray Absorptiometry (DXA). Multivariate linear regression models were used to assess relationships. Over 2.2 years of follow-up, 368(33%) men lost at least 2% of their body weight, which included a mean loss of 0.8 kg/year of lean body mass and 0.9 kg/year of fat body mass. Fat loss was strongly associated with BMD loss in men who lost weight. As a group, weight losers lost 1.0% of hip BMD annually compared to 0.2% in men who gained weight, with each kilo of fat loss associated with 0.6%/year hip BMD loss (p<0.0001). Lean mass was not associated with hip BMD loss in weight losers, however, lean mass change was associated with BMD change in men who gained weight (0.3% hip BMD increase per kilo increase of lean mass p<0.01). Maintaining body weight is important for bone health in elderly men. Body fat plays an important role in this relationship, which may reflect the additional metabolic function of adipose tissue.
Publisher: The Endocrine Society
Date: 02-2005
DOI: 10.1210/JC.2004-2362
Publisher: Elsevier BV
Date: 11-1998
DOI: 10.1016/S0735-1097(98)00416-1
Abstract: To assess the vascular effects of high-dose androgen treatment in genetic females. Male gender is an independent risk factor for coronary artery disease, suggesting either a protective effect of estrogens and/or a deleterious effect of androgens. We have recently demonstrated that androgen deprivation is associated with enhanced vascular reactivity in adult men, however, the effects of androgen excess on vascular function in humans has not been reported previously. We studied vascular reactivity in two groups of genetic females: 12 female-to-male transsexuals receiving long-term high-dose androgens, and 12 healthy female control subjects, matched for age and smoking history. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (leading to flow-mediated dilatation [FMD], which depends on normal endothelial function) and after sublingual nitroglycerin (NTG), an endothelium-independent dilator. Testosterone levels were higher (15.2+/-8.7 vs. 1.9+/-1.3 mmol/L, p < 0.001) and high-density lipoprotein cholesterol levels were lower (1.2+/-0.2 vs. 1.6+/-0.4 mmol/L, p=0.02) in the transsexuals compared with the control subjects. In each group, nine of 12 subjects were current or ex-smokers, leading to impaired FMD in both groups (5.1+/-3.7% in the transsexuals vs. 6.9+/-4.1% in controls, p=0.28). The NTG response was significantly decreased in the transsexuals (15.9+/-4.9% vs. 22+/-5.8% in controls, p=0.01), independent of the effects of age, cholesterol or vessel size. Long-term treatment with high-dose androgens is associated with impaired vascular reactivity in genetic females, consistent with a deleterious effect of androgen excess on arterial physiology.
Publisher: Wiley
Date: 10-10-2018
DOI: 10.1111/CEN.13484
Abstract: Sex hormone trajectories in ageing men and their health implications remain unclear. We examined longitudinal trajectories and associations of testosterone (T), dihydrotestosterone (DHT), oestradiol (E2), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) in oldest old men. Prospective cohort study. We studied 1025 community-dwelling men median age 75.1 years at baseline with 8.6 years of follow-up. Baseline and follow-up T, DHT and E2 were assayed using mass spectrometry. Physical performance was assessed at follow-up. Correlations and covariate-adjusted P-values were determined. Longitudinal change in T was -2.0%/year, DHT -7.2%/year, LH +7.5%/year, SHBG +5.6%/year while E2 remained stable. Annualized increases in LH correlated with decreases in T and DHT (r = -.20, P 16 IU/L) at follow-up, 175 (17.4%) had high LH of whom 70 had low T (<6.4 nmol/L). Annualized increases in LH are associated with declines in T and DHT, and predict poorer subsequent physical performance in oldest old men. Men transitioning from 8th to 9th decades exhibit biochemical evidence of progressively impaired testicular endocrine function, warranting further evaluation.
Publisher: Springer Science and Business Media LLC
Date: 12-03-2021
DOI: 10.1038/S41430-021-00893-7
Abstract: To compare the Australian Dietary Guideline Index (DGI-2013) and the Pyramid-based Mediterranean Diet Score (pyrMDS) as measures of diet quality in an ethnically erse group of older men. Seven hundred and ninety-four older men aged ≥75 participated in wave 3 (2012-2013) of the Concord Health and Ageing in Men Project. Dietary intake was assessed using a validated diet history questionnaire. Ethnicity was based on self-reported country of birth and categorised as Australian-born (418 men), Italian or Greek migrants (188), and other migrants (188). Incident cardiovascular outcomes until March 2018 were measured using the composite of major adverse cardiovascular events (MACE), which comprises all-cause mortality, acute myocardial infarction, congestive cardiac failure, coronary revascularisation and/or ischaemic stroke. Ability to predict incident cardiovascular outcomes and all-cause mortality were compared between standardised DGI-2013 pyrMDS scores by comparison of hazard ratios, discrimination (Harrell's C-statistic) and calibration (calibration plots). Italian and Greek migrant men had significantly lower DGI-2013 scores (91.7 vs. 93.9 p = 0.01) but significantly higher pyrMDS scores (8.8 vs. 8.2 p < 0.0001) than Australian-born men. In the whole s le (794 men), the pyrMDS was a better predictor of both MACE (age-adjusted HR = 0.84 95% CI = 0.75-0.94 vs. HR = 0.92 95% CI = 0.82-1.03 for DGI-2013) and all-cause mortality (age-adjusted HR = 0.69 95% CI = 0.60-0.80 vs. HR = 0.86 95% CI = 0.74-0.99). The pyrMDS also demonstrated superior discrimination for predicting all-cause mortality and superior calibration for MACE and all-cause mortality. The DGI-2013 appears to underestimate diet quality in older Italian and Greek migrant men. The pyrMDS appears superior to the DGI-2013 for prediction of incident cardiovascular disease and mortality regardless of ethnic background.
Publisher: Elsevier BV
Date: 06-1992
Publisher: Oxford University Press (OUP)
Date: 08-1997
DOI: 10.1093/CLINCHEM/43.8.1408
Abstract: Field studies of androgen pharmacology are complicated by the necessity to collect, process, and store blood s les in a central facility. We have assessed the feasibility of using capillary blood spots collected by fingerprick and dried on filter paper for pharmacokinetics and pharmacodynamic measurements with nandrolone and testosterone RIAs modified for extracts from capillary blood spots. Assays on punched spots of 7.9-mm diameter (14.9 μL of dried blood) permitted accurate quantification of testosterone down to 0.4 nmol/L from a single spot and nandrolone down to 0.9 nmol/L from two spots. Stability of the steroids in dried blood spots to adverse environmental conditions, notably increased temperatures, was investigated both in the laboratory and in field studies of dried spots sent through the postal system. Storage or postal transport under moderate conditions appeared to have no deleterious effects on apparent androgen concentrations. However, under extreme conditions of storage at 50 °C for a week or more, or transport to a very hot tropical location, a rise in the final concentration of nandrolone, and, to a lesser extent, testosterone when corrected for tracer recovery, was noticed. These effects were largely due to apparent susceptibility of tritiated tracer, but not unlabeled androgens, to thermal degradation. In a pilot pharmacological study involving intramuscular injection of 100 mg of nandrolone decanoate in 1 mL of arachis oil, nandrolone concentrations in concurrently collected plasma as well as venous and capillary blood spots showed good agreement. Testosterone concentrations in contemporaneously collected plasma and venous blood spots also showed very good agreement. We propose that these methods may allow patients and experimental subjects to self-collect s les at remote or field locations for convenient mailing to a central laboratory for androgen assay. Applications of this methodology are now under way.
Publisher: The Endocrine Society
Date: 06-2003
DOI: 10.1210/ER.2003-0005
Abstract: Globally, cardiovascular disease will continue causing most human deaths for the foreseeable future. The consistent gender gap in life span of approximately 5.6 yr in all advanced economies must derive from gender differences in age-specific cardiovascular death rates, which rise steeply in parallel for both genders but 5-10 yr earlier in men. The lack of inflection point at modal age of menopause, contrasting with unequivocally estrogen-dependent biological markers like breast cancer or bone density, makes estrogen protection of premenopausal women an unlikely explanation. Limited human data suggest that testosterone exposure does not shorten life span in either gender, and oral estrogen treatment increases risk of cardiovascular death in men as it does in women. Alternatively, androgen exposure in early life (perinatal androgen imprinting) may predispose males to earlier onset of atherosclerosis. Following the recent reevaluation of the estrogen-protection orthodoxy, empirical research has flourished into the role of androgens in the progression of cardiovascular disease, highlighting the need to better understand androgen receptor (AR) coregulators, nongenomic androgen effects, tissue-specific metabolic activation of androgens, and androgen sensitivity. Novel therapeutic targets may arise from understanding how androgens enhance early plaque formation and cause vasodilatation via nongenomic androgen effects on vascular smooth muscle, and how tissue-specific variations in androgen effects are modulated by AR coregulators as well as metabolic activation of testosterone to lify (via 5alpha-reductase to form dihydrotestosterone acting on AR) or ersify (via aromatization to estradiol acting upon estrogen receptor alpha/beta) the biological effects of testosterone on the vasculature. Observational studies show that blood testosterone concentrations are consistently lower among men with cardiovascular disease, suggesting a possible preventive role for testosterone therapy, which requires critical evaluation by further prospective studies. Short-term interventional studies show that testosterone produces a modest but consistent improvement in cardiac ischemia over placebo, comparable to the effects of existing antianginal drugs. By contrast, testosterone therapy has no beneficial effects in peripheral arterial disease but has not been evaluated in cerebrovascular disease. Erectile dysfunction is most frequently caused by pelvic arterial insufficiency due to atherosclerosis, and its sentinel relationship to generalized atherosclerosis is insufficiently appreciated. The commonality of risk factor patterns and mechanisms (including endothelial dysfunction) suggests that the efficacy of antiatherogenic therapy is an important challenge with the potential to enhance men's motivation for prevention and treatment of cardiovascular diseases.
Publisher: Wiley
Date: 10-2001
DOI: 10.1046/J.1365-2265.2001.01357.X
Abstract: Implantation of testosterone pellets under the lateral abdominal wall skin is an old but popular and effective form of androgen replacement therapy. Extrusion of one or more pellets remains the most frequent adverse event. To determine whether an alternative implantation site (hip) and/or track geometry (two vs. four tracks) would reduce extrusion rates compared with the standard of a four-track abdominal site. Additionally, the study aimed to evaluate the effects of site and track geometry on other adverse effects (bruising, infection) and the pharmacology of testosterone release from the implants. A prospective, parallel-group unmasked study design in a single centre. The primary objective was to evaluate sites, with evaluation of track geometry a subordinate objective made necessary by anatomical differences. Accordingly, androgen deficient men requiring testosterone implantation with the standard dose (four 200 mg pellets) were randomized into one of three groups (ratio 1 : 1 : 2): a four-track abdomen site (standard), a two-track abdomen site or a two-track hip site. The pharmacological substudy was to evaluate the impact of site and track geometry on testosterone implant pharmacology by monthly hormone assays following implantation. Two hundred and forty-six implantation procedures involving 96 androgen deficient men. The primary end-point, extrusion rate per procedure, and secondary end-points (bruising or infection post procedure) were evaluated prospectively by self-report from the participants, and verified when they returned next for implantation. The pharmacology substudy involved monthly blood s ling for hormone (total and free testosterone, LH, FSH) measurements. The extrusion rate was significantly higher [odds ratio (OR) = 2.6, 95% confidence interval (CI) 1.1-7.1] for the hip site (15/125, 12%) compared with the abdominal site (6/121, 5%). Track geometry made no significant difference (OR = 1.05, 95% CI 0.2-5.4) to the extrusion rate. No secondary end-points (bruising, infection) were significantly different according to either site or track geometry. One operator who performed the implant procedures had significantly less primary and secondary adverse events than the other operators (P = 0.006). Neither implantation site, nor track geometry influenced pharmacokinetics [peak plasma total and free testosterone concentrations and net hormone release (area-under-curve, AUC)] or pharmacodynamics [nadir plasma LH and FSH and net suppression (AUC) in men with hypergonadotrophic hypogonadism]. We conclude that the hip site has a higher extrusion rate than the standard abdominal wall site but that track geometry does not increase the risk of extrusion. Neither implantation site, nor track geometry influenced either other adverse effects or the pharmacokinetics or pharmacodynamics of testosterone pellet implants.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
DOI: 10.1016/J.PAIN.2014.06.009
Abstract: The evidence on the patterns of nonsteroidal anti-inflammatory drug (NSAID) use according to pain prevalence and clinical guidelines in older people is sparse. This cross-sectional study examined the patterns of NSAID use according to pain prevalence and concordance with clinical guideline recommendations for safe NSAID use in older people, in relation to duration of use, patterns of use, concomitant use of proton pump inhibitors (PPIs), and prevalence of specific drug interactions. Community-dwelling men (n=1696) age ≥ 70 years living in Sydney were studied. 8.2% (n=139) of participants reported regular NSAID use compared with 2.9% (n=50) reporting as-needed use. The mean treatment duration for regular NSAID use was 4.9 years, suggesting long-term rather than short-term use as recommended by the guidelines. Although guidelines recommend use of PPIs together with an NSAID, only 25.2% of regular NSAID users reported PPI use. Regular NSAID users were significantly more likely to report use of opioid analgesics (P<.0001) compared with nonregular users. In relation to pain prevalence, regular NSAID users were significantly more likely to report chronic pain (P<.0001), recent pain (P=.0001), and chronic intrusive pain (P<.0001) compared with nonregular users. The findings of this study indicate that NSAID prescribing practices do not align with clinical guidelines for safe use in older people. This difference between the guideline recommendations and what is happening in the real world should be explored further.
Publisher: Oxford University Press (OUP)
Date: 19-08-2019
Abstract: Off-label testosterone prescribing for androgen deficiency (AD)-like sexual and energy symptoms of older men without pathologic hypogonadism has increased dramatically without convincing evidence of efficacy. In a randomized, double-blind, placebo-controlled study with three phases, we entered 45 men aged at least 40 years without pathologic hypogonadism but with AD-like energy and/or sexual symptoms to either daily testosterone or placebo gel treatment for 6 weeks in a cross-over study design with a third, mandatory extension phase in which participants chose which previous treatment they preferred to repeat while remaining masked to their original treatment. Primary endpoints were energy and sexual symptoms as assessed by a visual analog scale (Lead Symptom Score [LSS]). Increasing serum testosterone to the healthy young male range produced no significant benefit more than placebo for energy or sexual LSS. Covariate effects of age, body mass index, and pretreatment baseline serum testosterone on quality-of-life scales were detected. Only 1 out of 22 indices from seven quality-of-life scales was significantly improved by testosterone treatment over placebo. Participants did not choose testosterone significantly more than placebo as their preferred treatment in the third phase. Six-week testosterone treatment does not improve energy or sexual symptoms more than placebo in symptomatic men without pathologic hypogonadism.
Publisher: Wiley
Date: 27-02-2014
DOI: 10.1111/JGS.12693
Abstract: To explore associations between serum 25-hydroxyvitamin D (25(OH)D) levels and a wide range of health conditions, physical performance measures, disability, and mortality in a large epidemiological study to identify an optimum range for 25(OH)D concentrations. Cross-sectional study, with additional prospective data on falls and mortality. Concord Health and Ageing in Men Project, Sydney, Australia. Community-dwelling men aged 70 and older (N = 1,659). Serum 25(OH)D levels, general health status, self-reported diseases, physical performance measures, disability (activities of daily living and instrumental activities of daily living) and falls. Fair, poor, and very poor health self-reported diabetes mellitus hyperglycemia depression muscle weakness poor balance and all-cause mortality were all associated with serum 25(OH)D levels less than 50 nmol/L, even after adjustment for confounding. The findings also suggest that, in older men, for a wide range of health conditions, physical performance measures, disability, falls, and mortality, the optimum range of 25(OH)D is between 50.0 and 74.9 nmol/L, with no additional benefit for 25(OH)D levels of 75.0 nmol/L or greater. Programs aimed at achieving an optimum range of serum 25(OH)D at levels between 50.0 and 74.9 nmol/L may have overall health benefits and such levels are adequate for older men.
Publisher: Wiley
Date: 04-1992
DOI: 10.1111/J.1365-2265.1992.TB01466.X
Abstract: We aimed to concurrently characterize serial changes in circulating immunoreactive inhibin (irINH) and testosterone (T) as reflections of Sertoli and Leydig cell responses to acute critical illness in man. Blood s les were drawn within 24 hours of admission to an Intensive Care Unit and at weekly intervals thereafter for up to 4 weeks while the patient remained in Intensive Care Unit or after discharge to a general ward. We studied 13 male subjects with critical illness requiring intensive therapy. Plasma levels of irINH, T, LH, FSH and sex hormone binding globulin (SHBG) were analysed in relation to (i) the severity of illness as indicated by a sepsis score, acute physiology and chronic health evaluation score, and reverse triiodothyronine (rT3) levels and (ii) the outcome of illness as determined by discharge from Intensive Care Unit and the two-month mortality. Overall irINH levels remained normal and correlated negatively with rT3 (r = -0.63, P = 0.001) but not with sepsis, acute physiology and chronic health evaluation score, or gonadotrophin levels. Neither admission nor serial irINH levels significantly distinguished between the different clinical outcomes. In contrast, T levels were depressed and inversely correlated with both sepsis and acute physiology and chronic health evaluation scores (P less than 0.02), and positively with gonadotrophins (P less than 0.01), but not rT3 levels. Men eventually discharged from the Intensive Care Unit showed a rise, while those remaining showed a fall, in T levels (P = 0.02, time-course interaction). Similarly, T levels were lower in patients who died than in survivors, despite the comparable T levels on admission (P = 0.02, time-course interaction). Despite the fall in T levels, gonadotrophin levels remained inappropriately in the eugonadal range but higher in men who were discharged from Intensive Care Unit (P = 0.02, time-course interaction). FSH but not LH levels were correlated with sepsis score (P = 0.02) but not acute physiology and chronic health evaluation score or rT3. Sertoli cell function as judged by circulating irINH levels is much less affected by acute critical illness than is Leydig cell function as judged by circulating T levels. The suppressive effect of acute critical illness on Leydig cell function is consistent with a hypothalamic-pituitary lesion.
Publisher: S. Karger AG
Date: 2018
DOI: 10.1159/000487762
Abstract: The androgen receptor (AR) is expressed throughout the hypothalamic-pituitary-gonadal (HPG) axis, and findings from female global AR knockout mice confirm that AR-mediated androgen actions play important roles in regulating female reproductive function. We generated neuron-specific AR knockout mice (NeurARKO) to investigate the functional role of neuronal AR-mediated androgen action in regulating the female HPG axis and fertility. Relative to control females, NeurARKO females exhibited elevated luteinizing hormone (LH) levels at diestrus ( i /i & #x3c 0.05) and a compromised serum LH response to ovariectomy and E2 priming ( i /i & #x3c 0.01). Furthermore, NeurARKO females displayed reduced i Kiss1 /i mRNA expression in the anteroventral periventricular nucleus at diestrus ( i /i & #x3c 0.05) and proestrus ( i /i & #x3c 0.05), but elevated i Kiss1 /i ( i /i & #x3c 0.05) and neurokinin B ( i Tac2 /i , i /i & #x3c 0.05) mRNA expression in the arcuate nucleus at proestrus compared to WT controls. Ovarian follicle dynamics were also altered in NeurARKO ovaries at 3 months of age, with a significant reduction in large antral follicle numbers at the proestrus stage compared to control WT ovaries ( i /i & #x3c 0.05). Increased follicular atresia was evident in NeurARKO ovaries with a 4-fold increase in unhealthy large preantral follicles ( i /i & #x3c 0.01). Despite the findings of aberrant neuroendocrine and ovarian characteristics in the NeurARKO females, estrous cyclicity and overall fertility were comparable between NeurARKO and WT females. In conclusion, our findings revealed that selective loss of neuronal AR actions impacts the kisspeptin/GnRH/LH cascade leading to compromised ovarian follicle dynamics.
Publisher: The Endocrine Society
Date: 13-07-2018
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.MCE.2017.06.026
Abstract: It has been well established for decades that androgens, namely testosterone (T) plays an important role in female reproductive physiology as the precursor for oestradiol (E
Publisher: Wiley
Date: 30-03-2020
DOI: 10.1111/GER.12469
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.TEM.2005.01.002
Abstract: There is a growing interest, as well as a booming industry, in the use of testosterone therapy for middle-aged and older men. This interest has led to the definition of a new condition, termed 'andropause', meaning the putative somatic consequences of gradually falling blood testosterone concentrations during male aging. This trend risks replicating both the rejuvenation fads of a century ago and the recent experience in estrogen therapy for menopause that has been propelled for decades by advocacy substituting for reliable scientific evidence. The current status and prospects for androgen therapy in middle-aged and older men should be evaluated critically from the perspective of male reproductive health during aging. This review appraises current knowledge with a focus on the questionable basis for using androgen therapy to improve male reproductive health during aging.
Publisher: Oxford University Press (OUP)
Date: 03-2008
DOI: 10.1095/BIOLREPROD.107.064089
Abstract: Although androgens and the androgen receptor (AR) have defining roles in male reproductive development and function, previously no role in female reproductive physiology beyond testosterone (T) as the precursor in estradiol (E(2)) biosynthesis was firmly established. Understanding the role and specific mechanisms of androgen action via the AR in the ovary has been limited by confusion on how to interpret results from pharmacological studies, because many androgens can be metabolized in vivo and in vitro to steroids that can also exert actions via the estrogen receptor (ESR). Recent genetic studies using mouse models with specific disruption of the Ar gene have highlighted the role that AR-mediated actions play in maintaining female fertility through key roles in the regulation of follicle health, development, and ovulation. Furthermore, these genetic studies have revealed that AR-mediated effects influence age-related female fertility, possibly via mechanisms acting predominantly at the hypothalamic-pituitary axis in a dose-dependent manner. This review focuses on combining the findings from pharmacological studies and novel genetic mouse models to unravel the roles of ovarian androgen actions in relation to female fertility and ovarian aging, as well as creating new insights into the role of androgens in androgen-associated reproductive disorders such as polycystic ovarian syndrome.
Publisher: Oxford University Press (OUP)
Date: 20-08-2019
Abstract: Increased blood levels of branched chain amino acids (BCAAs) have been associated with cardiometabolic risk factors. Here, we studied 918 community-dwelling older men to determine the relationship between BCAAs and other amino acids with cardiometabolic risk factors, major cardiovascular endpoints (MACE), and mortality. BCAAs had robust associations with many adverse metabolic risk factors (increased glucose, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), triglycerides decreased high-density lipoprotein cholesterol). However, paradoxically, participants with lower levels of BCAAs had greater mortality and MACE possibly because increasing age and frailty, both of which were associated with lower BCAA levels, are powerful risk factors for these outcomes in older people. Overall, amino acids that were lowest in frail subjects (BCAAs, α-aminobutyric acid [AABA], histidine, lysine, methionine, threonine, tyrosine) were inversely associated with mortality and MACE. In conclusion, BCAAs are biomarkers for important outcomes in older people including cardiometabolic risk factors, frailty, and mortality. In old age, frailty becomes a dominant risk factor for MACE and mortality.
Publisher: AMPCo
Date: 16-08-2004
Publisher: The Endocrine Society
Date: 10-2013
DOI: 10.1210/JC.2013-3375
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.GENE.2004.12.047
Abstract: Prostate cancer deaths are due to functional escape of prostate cancer cells from their original androgen-dependent growth. To better understand the origin and evolution of hormone-refractory prostate cancer, it is important to identify and characterize genes expressed in the androgen-deprived prostate. We have verified that the rudimentary prostate of congenital androgen deficient mice (hpg) is indeed androgen independent. Using suppression subtractive hybridization between mRNA derived from prostates of hypogonadal (hpg) with or without 14 days of testosterone replacement we have cloned a novel gene from the hpg prostate, termed ADMP (for androgen down regulated gene expressed in mouse prostate), that is down regulated by androgens. ADMP expression is strong in hpg mouse prostate, weak in mature castrated mouse prostate and absent in normal intact or androgen-replaced hpg mouse prostates. While ADMP expression is androgen independent in the hpg prostate, it appears to be androgen-dependent in the kidney and brain of normal intact mouse suggesting tissue specific regulation of ADMP by androgens. Human ADMP mRNA expression is suppressed by androgens in the androgen-sensitive LNCaP cell line. The predicted mouse and human protein of 76 amino acids shares sequence similarity to a putative G-protein coupled receptor indicating its possible role in signal transduction. Human ADMP expression was seen predominantly in the prostate epithelium with weaker expression in the fibroblasts and endothelial cells. Cloning and characterization of ADMP has made it feasible to determine its prospective role in the absence of androgens in prostate cancer.
Publisher: Wiley
Date: 21-11-2021
DOI: 10.1111/JHN.12965
Abstract: The association between dietary protein intake and the risk of mortality is still controversial. The present study aimed to examine the associations between dietary total, animal and plant protein intake and all‐cause and cause‐specific mortality. Community‐dwelling men aged ≥ 70 years were recruited from local government areas surrounding Concord Hospital in Sydney, New South Wales for the Concord Health and Ageing in Men Project (CHAMP). The research dietitian administered a standardised validated diet history questionnaire to capture baseline dietary intake. In total, 794 men participated in a detailed diet history interview at the third wave. Adequacy of protein intake was assessed by comparing participant intake with the Nutrient Reference Values. Total protein intake was categorised into quintiles. Sources of protein were also captured. Mortality was ascertained through the New South Wales death registry. Cox proportional hazard models were used to assess the association between dietary total, animal and plant protein intake and risk of mortality. The mean age of the CHAMP men was 81 years. In total, 162 men died during a median follow‐up of 3.7 years. Of these, 54 (33.3%) and 49 (30.2%) men died due to cancer and cardiovascular disease, respectively. There were U‐shaped associations between protein intake and all‐cause and cancer mortality. In multiple adjusted analysis, the second (hazard ratio [HR] = 0.38 95% confidence interval [CI] = 0.18–0.82) and third (HR = 0.36 95% CI = 0.16–0.82) quintiles of protein intakes were significantly associated with reduced risk of all‐cause and only second quintile (HR = 0.47 95% CI = 0.10–0.93) of protein intake was significantly associated with cancer mortality. Each serve increase in animal protein was significantly associated with 12% (HR = 1.12 95% CI = 1.00–1.26) and 23% (HR = 1.23 95% CI = 1.02–1.49) increased risk of all‐cause mortality and cancer mortality respectively. Conversely, each serve increase in plant protein intake was significantly associated with 25% (HR = 0.75 95% CI 0.61–0.92) and 28% (HR = 0.72 95% CI = 0.53–0.97) reduced risk of all‐cause and cancer mortality, respectively. No such associations were observed for cardiovascular disease mortality. Both second and third quintiles of total protein intake were associated with reduced all‐cause and cancer mortality. Plant protein was inversely associated with all‐cause and cancer mortality, whereas animal protein intake was positively associated with mortality.
Publisher: The Endocrine Society
Date: 27-10-2016
DOI: 10.1210/JC.2016-2141
Abstract: The development of a safe and effective reversible method of male contraception is still an unmet need. Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone. Prospective multicentre study. Ten study centers. Healthy men, aged 18–45 years, and their 18- to 38-year-old female partners, both without known fertility problems. Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks. Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate. Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8–97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59–4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5–97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early. The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high.
Publisher: American College of Physicians
Date: 21-02-2006
DOI: 10.7326/0003-4819-144-4-200602210-00005
Abstract: Clinically important rapid bone loss occurs within 3 to 6 months after liver transplantation and may be associated with osteoporotic fractures. To determine whether bisphosphonate treatment with zoledronic acid reduces transplant-related bone loss more than placebo in adults having liver transplantation for chronic liver disease. 12-month randomized, double-blind, placebo-controlled trial. 2 large liver transplantation centers in Australia. 62 adults having liver transplantation for chronic liver disease. Infusions of zoledronic acid, 4 mg (n = 32), or saline (n = 30) were given within 7 days of transplantation and again at months 1, 3, 6, and 9 after transplantation. All patients received supplementation with calcium carbonate, 600 mg/d, and ergocalciferol, 1000 U/d. The primary outcome was bone mineral density (BMD) measured by dual x-ray absorptiometry before transplantation and 3, 6, and 12 months later. Secondary outcomes included bone turnover markers that were measured before transplantation and 1, 3, 6, 9, and 12 months later. There were statistically significant interactions between treatment effects and time for BMD measurements at the lumbar spine (P = 0.002), femoral neck (P = 0.001), and total hip (P < 0.001). Differences in acute bone loss 3 months after transplantation favored zoledronic acid over placebo. Differences between groups in percentage change from baseline adjusted for baseline weight and serum parathyroid hormone (PTH) level were 4.0% (95% CI, 1.1% to 7.0%) for the lumbar spine, 4.7% (CI, 1.9% to 7.6%) for the femoral neck, and 3.8% (CI, 1.7% to 6.0%) for the total hip. At 12 months after transplantation, the difference in percentage change from baseline between the 2 groups adjusted for baseline weight and serum PTH level was 1.1% (CI, -2.1% to 4.4%) for the lumbar spine, 2.7% (CI, 0.0% to 5.4%) for the femoral neck, and 2.4% (CI, 0.1% to 4.7%) for the total hip. Treatment with zoledronic acid induced temporary secondary hyperparathyroidism and postinfusion hypocalcemia statistically significantly more often than did placebo. The trial was not powered to assess fractures, and 10 of 62 (16%) patients were not included in adjusted analyses because of missing weight or serum PTH measurements. Treatment with zoledronic acid can prevent bone loss within the first year after liver transplantation.
Publisher: Elsevier BV
Date: 04-2021
Publisher: The Endocrine Society
Date: 09-2001
Abstract: The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5alpha reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency lification by 5alpha reduction. Therefore, the effects of dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T < or =15 nmol/liter) were randomized to undergo daily dermal application of 70 mg dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 month after treatment. Among 33 (17 dihydrotestosterone, 16 placebo) men completing the study with a high degree of compliance, dihydrotestosterone had significant effects on circulating hormones (increased dihydrotestosterone decreased total and free testosterone, LH, and FSH unchanged SHBG and estradiol), lipid profiles (decreased total and low-density lipoprotein cholesterols unchanged high-density lipoprotein cholesterol and triglycerides), hematopoiesis (increased hemoglobin, hematocrit, and red cell counts), and body composition (decreased skinfold thickness and fat mass unchanged lean mass and waist to hip ratio). Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction, nor was there any significant change in gait, balance, or mobility tests, in cognitive function, or in quality of life scales. Dihydrotestosterone treatment had no adverse effects on prostate (unchanged prostate volumes and prostate-specific antigen) and cardiovascular (no adverse change in vascular reactivity or lipids) safety markers. We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected androgenic effects, short-term safety, and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function.
Publisher: SAGE Publications
Date: 22-01-2009
Abstract: Serum free testosterone (FT) concentrations are commonly requested, but because reference FT methods are too laborious various calculational algorithms for FT based on total testosterone (TT) and sex hormone-binding globulin (SHBG) are frequently used. This study provides the first large-scale evaluation of the predictive accuracy and sources of variability for different FT formulae compared with direct laboratory measurements. Using a large data-set of direct FT measurements by centrifugal ultrafiltration, the predictive accuracy of five different formulas for cFT (four existing plus a new formula) is evaluated in 3975 consecutive blood s les. In a second data-set of 124 s les from a reference panel of healthy eugonadal young men, we estimate the relative influence of the five algorithms and eight different TT and two SHBG assays including all available commercial total TT and SHBG assays together with a gas chromatography/mass spectrometry T reference method. cFT formulae show wide discrepancies with equilibrium-binding algorithms showing systematic overestimation relative to direct FT measurements, whereas two empirical cFT methods were more concordant. Variations between commercially available TT immunoassays have a strong impact on calculation of FT with TT assays contributing 82.2% of overall variance compared with 13.7% for the cFT algorithms and 4.1% for the SHBG assays. If FT measurements are requested and direct measurement impractical, cFT formulae using TT and SHBG immunoassays provide an approximation to direct FT measurement that is strongly dependent on the TT, cFT formula used and, to a lesser extent, SHBG immunoassays.
Publisher: The Endocrine Society
Date: 06-06-2022
Abstract: Clinical evaluations that require excluding androgen abuse, a secretive, illicit activity, rely on the drug history, but its veracity for androgen abuse has neither been verified nor has any objective corroborating laboratory test been validated. In a high-risk population, to (a) validate the drug history of androgen abuse objectively using state-of-the-art World Anti-Doping Agency–accredited antidoping laboratory urine mass spectrometry tests and (b) to determine what biochemical tests best distinguish androgen abuse from nonuse in this population. Urine s les from current (n = 41) and past (n = 31) androgen abusers and nonusers (n = 21) were analyzed by comprehensive mass spectrometry-based detection tests for androgens and related drugs (ARD). No prohibited ARDs were identified among nonusers. Current users had a median of 5 (range 1-13) drugs detected comprising 176 ARDs among 220 drug identifications. Past users had a median of 1 (range 0-9) drugs detected comprising 21 ARDs among 43 drugs. Negative predictive value was high (& .8) for those denying drug usage while positive predictive value was good (& .6) for both those reporting currently using (current) and not using (nonusers plus past users) ARD. Serum luteinizing hormone (LH) alone had high, but imperfect, discriminatory power (89%) to distinguish between current and noncurrent androgen use. We demonstrates that a negative drug history in a high-risk group has high reliability and that even a single suppressed serum LH exhibits high discrimination for objectively detecting androgen abuse.
Publisher: The Endocrine Society
Date: 19-04-2022
Abstract: Abuse of androgens and erythropoietin has led to hormones being the most effective and frequent class of ergogenic substances prohibited in elite sports by the World Anti-Doping Agency (WADA). At present, thyroid hormone (TH) abuse is not prohibited, but its prevalence among elite athletes and nonprohibited status remains controversial. A corollary of prohibiting hormones for elite sports is that endocrinologists must be aware of a professional athlete’s risk of disqualification for using prohibited hormones and/or to certify Therapeutic Use Exemptions, which allow in idual athletes to use prohibited substances for valid medical indications. This narrative review considers the status of TH within the framework of the WADA Code criteria for prohibiting substances, which requires meeting 2 of 3 equally important criteria of potential performance enhancement, harmfulness to health, and violation of the spirit of sport. In considering the valid clinical uses of TH, the prevalence of TH use among young adults, the reason why some athletes seek to use TH, and the pathophysiology of sought-after and adverse effects of TH abuse, together with the challenges of detecting TH abuse, it can be concluded that, on the basis of present data, prohibition of TH in elite sport is neither justified nor feasible.
Publisher: Wiley
Date: 25-01-2021
DOI: 10.1111/AJAG.12896
Abstract: To investigate the association between home ownership and health in older men. Cross‐sectional analysis of 909 community‐dwelling Australian men (mean age: 81.3 ± 4.6) from the Concord Health and Ageing in Men Project (CHAMP, 2012‐2013). We considered self‐rated health, frailty status, multimorbidity, and anxiety and depressive symptoms which identify different dimensions of health. Most participants were owner‐occupiers (89.7%). In age‐ and country of birth–adjusted analyses, not being an owner‐occupier was associated with an increased likelihood of depressive symptoms [prevalence ratio: 1.82, 95% confidence intervals 1.17 to 2.84]. There were no associations between home ownership and other health conditions. Lack of home ownership was associated with a higher prevalence of depressive symptoms, largely explained by poorer social support. Thus, targeting mental health programs at older orced or separated men who do not own their own home could be an appropriate community‐based intervention.
Publisher: The Endocrine Society
Date: 28-06-2019
Abstract: Can injectable testosterone undecanoate (TU) be administered effectively and acceptably by the subcutaneous (SC) route? To investigate the acceptability and pharmacokinetics (PK) of SC injection of TU. Randomized sequence, crossover clinical study of SC vs IM TU injections. Ambulatory clinic of an academic andrology center. Twenty men (11 hypogonadal, 9 transgender men) who were long-term users of TU. injections. Intervention: Injection of 1000 mg TU (in 4 mL castor oil vehicle) by SC or IM route. Main Outcome Measures: Patient-reported pain, acceptability, and preference scales. PK by measurement of serum testosterone, dihydrotestosterone (DHT), and estradiol (E2) concentrations with application of population PK methods and dried blood spot (DBS) s ling. Pain was greater after SC compared with IM injection 24 hours (but not immediately) after injection but both routes were equally acceptable. Ultimately 11 preferred IM, 6 preferred SC, and 3 had no preference. The DBS-based PK analysis of serum testosterone revealed a later time of peak testosterone concentration after SC vs IM injection (8.0 vs 3.3 days) but no significant route differences in model-predicted peak testosterone concentration (8.4 vs 9.6 ng/mL) or mean resident time (183 vs 110 days). The PK of venous serum testosterone, DHT, and E2 did not differ according to route of injection. We conclude that SC TU injection is acceptable but produces greater pain 24 hours after injection that may contribute to the overall majority preference for the IM injection. The PK of testosterone, DHT, or E2 did not differ substantially between SC and IM routes. Hence whereas further studies are required, the SC route represents an alternative to IM injections without a need to change dose for men for whom IM injection is not desired or recommended.
Publisher: Elsevier BV
Date: 12-1994
Publisher: Wiley
Date: 08-01-2007
DOI: 10.1111/J.1365-2265.2006.02715.X
Abstract: Androgens have striking effects on skeletal muscle, but the effects on human cardiac muscle function are not well defined, neither has the role of metabolic activation (aromatization, 5alpha reduction) of testosterone on cardiac muscle been directly studied. To assess the effects of testosterone and nandrolone, a non- lifiable and non-aromatizable pure androgen, on cardiac muscle function in healthy young men. Double-blind, randomized, placebo-controlled, three-arm parallel group clinical trial. Ambulatory care research centre. Healthy young men randomized into three groups of 10 men. Weekly intramuscular injections of testosterone (200 mg mixed esters), nandrolone (200 mg nandrolone decanoate) or matching (2 ml arachis oil vehicle) placebo for 4 weeks. Comprehensive measures of cardiac muscle function involving transthoracic cardiac echocardiography measuring myocardial tissue velocity, peak systolic strain and strain rates, and bioimpedance measurement of cardiac output and systematic vascular resistance. Left ventricular (LV) function (LV ejection fraction, LV modified TEI index), right ventricular (RV) function (ejection area, tricuspid annular systolic planar motion, RV modified TEI index) as well as cardiac afterload (mean arterial pressure, systemic vascular resistance) and overall cardiac contractility (stroke volume, cardiac output) were within age- and gender-specific reference ranges and were not significantly (P < 0.05) altered by either androgen or placebo over 4 weeks of treatment. Minor changes remaining within normal range were observed solely within the testosterone group for: increased LV end-systolic diameter (30 +/- 7 vs. 33 +/- 5 mm, P = 0.04) and RV end-systolic area (12.8 +/- 1.3 vs. 14.6 +/- 3.3 cm(2), P = 0.04), reduced LV diastolic septal velocity (Em, 9.5 +/- 2.6 vs. 8.7 +/- 2.0 cm/s, P = 0.006), increased LV filling pressure (E/Em ratio, 7.1 +/- 1.6 vs. 8.3 +/- 1.8, P = 0.02) and shortened PR interval on the electrocardiogram (167 +/- 13 vs. 154 +/- 12, P = 0.03). Four weeks of treatment with testosterone or nandrolone had no beneficial or adverse effects compared with placebo on cardiac function in healthy young men.
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1016/S0950-351X(98)80248-6
Abstract: Chronic renal failure, dialysis and transplantation have major effects on male reproductive health because of the impairment of spermatogenesis, steroidogenesis and sexual function. Hypothalamo-pituitary testicular dysfunction in uraemia is manifest clinically as delayed growth and puberty, sexual dysfunction, androgen deficiency, impaired spermatogenesis and infertility. Apart from renal anaemia, there are at present no proven indications for androgen therapy in chronic renal failure. This chapter reviews the basis and scope for various clinical applications of gonadotropin and androgen therapy as an adjunct to the standard medical care of chronic renal failure. The therapeutic possibilities implied by experimental and clinical findings suggesting that uraemic hypogonadism may be a functional state of gonadotropin deficiency are emphasized.
Publisher: Wiley
Date: 15-09-2008
DOI: 10.1002/PROS.20809
Abstract: MRP4/ABCC4 is an ATP-binding cassette transporter expressed in normal prostate. This study aimed to define the pattern of MRP4/ABCC4 expression in normal and malignant prostate tissue and the relationship of MRP4/ABCC4 expression and function in response to androgen signaling. Eighty-four radical prostatectomy specimens from patients with localized prostate cancer (PC) (22 neoadjuvant androgen ablation, AA, 62 no AA), 42 non-cancer and 16 advanced PCs were assessed for MRP4/ABCC4 mRNA rotein expression. The effect of DHT and bicalutamide on LNCaP cells was assessed by immunoblotting. HEK293 cells (+/-MRP4/ABCC4) were assessed for the ability to efflux androgens and anti-androgens. MRP4/ABCC4 mRNA rotein levels were higher in localized PC compared to non-cancer (P = 0.006). MRP4/ABCC4 levels were significantly decreased in PCs treated with AA compared to cancers exposed to normal testosterone levels (P < 0.0001). MRP4/ABCC4 expression in normal human tissues was limited to the prostate and the renal tubules. MRP4/ABCC4 protein levels increased in LNCaP cells after DHT which was partially blocked by bicalutamide. However, DHT did not alter the activation of the MRP4/ABCC4 promotor in luciferase reporter assays and testosterone, DHT, flutamide and hydroxy-flutamide were not substrates for MRP4/ABCC4. Elevated MRP4/ABCC4 expression is found in malignant compared to benign prostate tissue while lower MRP4/ABCC4 expression is seen after AA. Furthermore, MRP4/ABCC4 is upregulated by androgen and downregulated by anti-androgen treatment in vitro potentially through an indirect mode of action. These data strongly suggest that MRP4/ABCC4 is an androgen-regulated gene important in the progression to PC and may be a potential drug target.
Publisher: Wiley
Date: 12-01-2016
DOI: 10.1002/NAU.22951
Abstract: To describe the natural history of non-neurogenic overactive bladder (OAB) and urgency incontinence in community-dwelling older men. A representative s le of 1,705 community-dwelling men aged 70 and older in a defined geographic area of Sydney, Australia, had their urinary symptoms assessed using the International Prostate Symptom Scores (IPSS) and the International Consultation of Incontinence Questionnaire (ICIQ) at baseline, 2-year follow-up, and 5-year follow-up. Four hundred and eighty-eight men without neurological diseases or prostate cancer during follow-up, or history of urological treatment at baseline were included in the analysis. Urgency incontinence was defined as leakage of urine occurring more than weekly in the above-defined population. OAB was defined as either urgency or urgency incontinence according to 2002 International Continence Society consensus. Of the men with OAB at baseline, 29% received treatment for OAB or benign prostatic enlargement over 5 years. Of the remaining men, 33% had sustained remission at 2-year and 5-year follow-ups without treatment. Of the men with OAB at 2-year follow-up, remission rate at 5-year follow-up was 53% in men without OAB at baseline and 27% in men with OAB at baseline (P = 0.23). No statistically significant difference was found in baseline characteristics between men with sustained remission and men with persistent symptoms. One in three older men with non-neurogenic OAB had sustained remission of symptoms without medical or surgical interventions. No significant predictor of sustained remission was identified. Neurourol. Urodynam. 36:443-448, 2017. © 2016 Wiley Periodicals, Inc.
Publisher: The Endocrine Society
Date: 30-11-2018
Abstract: The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function affects the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone–binding globulin (SHBG). The liver senses the body’s metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction. Sex steroids impact the pathogenesis of nonalcoholic fatty liver disease, including development of hepatic steatosis, fibrosis, and carcinogenesis. Preclinical studies in male rodents demonstrate that androgens protect against hepatic steatosis and insulin resistance both via androgen receptor signaling and, following aromatization to estradiol, estrogen receptor signaling, through regulating genes involved in hepatic lipogenesis and glucose metabolism. In female rodents in contrast to males, androgens promote hepatic steatosis and dysglycemia, whereas estradiol is similarly protective against liver disease. In men, hepatic steatosis is associated with modest reductions in circulating testosterone, in part consequent to a reduction in circulating SHBG. Testosterone treatment has not been demonstrated to improve hepatic steatosis in randomized controlled clinical trials. Consistent with sex-dimorphic preclinical findings, androgens promote hepatic steatosis and dysglycemia in women, whereas endogenous estradiol appears protective in both men and women. In both sexes, androgens promote hepatic fibrosis and the development of hepatocellular carcinoma, whereas estradiol is protective.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.PHRS.2016.12.018
Abstract: The aim of this study was to apply Association Rule and Frequent-Set analysis, and novel means of data visualisation to ascertain patterns of medication use and medication combinations contributing to medication group clusters according to geriatric syndrome status in older adults. Participants were community-dwelling men (aged ≥70 years, n=1686), Sydney, Australia. Medication exposure was categorised at medication class level and data were analysed according to geriatric syndrome status (presence of at least one syndrome including frailty, falls, cognitive impairment and urinary incontinence). Association Rule and Frequent-Set analysis were performed to identify "interesting" patterns of medication combinations that occur together. This analysis involves advanced computer algorithms that investigated all possible combinations of medications in the dataset in order to identify those which are observed more or much less frequently than expected. Frequent-Set Analysis demonstrated one unexpected medication combination, antiulcer and antidiabetic medications (3.5% of participants) in the overall population (n=1687). Frequency of medication combinations was similar in participants with (n=666) and without (n=1020) geriatric syndromes. Among participants with geriatric syndromes, the most frequent combinations included antigout with lipid-lowering agents (5.7%) followed by angiotensin II and diuretics combination (22%). This novel methodology can be used to detect common medication combinations overall by data visualisation, and against specific adverse drug reactions such as geriatric syndromes. This methodology may be a valuable pharmacovigilance approach to monitor large databases for the safety of medications.
Publisher: Elsevier BV
Date: 04-2011
Publisher: Springer Science and Business Media LLC
Date: 08-05-2020
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.JSBMB.2021.105900
Abstract: Non-invasive self-testing using an objective chemical method to detect ovulation is valuable for women planning conception, practising contraception or undergoing infertility investigations or treatment. Based on luteal phase secretion of progesterone (P Urine PDG with and without creatinine adjustment was stable during the follicular phase with the expected striking rise in the luteal phase peaking at 5 days after ovulation. Using a single spot urine s le (100 μL) or a DUS (<20 μL urine) and an optimal threshold to distinguish pre- from post-ovulatory s les, in ROC analysis urine PDG adjusted for creatinine accurately identified ovulation in 92 % of s les was comparable with P3G immunoassay and superior to urine P This method holds promise as a non-invasive self-test method for women to determine by an objective chemical method their ovulatory status.
Publisher: The Endocrine Society
Date: 07-2002
Abstract: Despite partial androgen deficiency, the safety and efficacy of androgen therapy in older men remains controversial because controlled studies of testosterone have given equivocal results. Human chorionic gonadotropin (hCG) can be conveniently and infrequently self-administered, and it increases not only circulating testosterone but also estradiol and other testicular steroids. We evaluated the efficacy and safety of 3 months of treatment with sc recombinant hCG (r-hCG, Ovidrel) on muscle mass, strength, mobility, and physical activity in ambulant, community-dwelling men more than 60 yr old having partial androgen deficiency (testosterone < or = 15 nmol/liter, twice). Forty eligible men (mean age, 67 yr range, 60-85 yr) were randomized to receive r-hCG (5000 IU, 250 microg) or placebo by twice weekly sc self-injection and were studied before treatment, monthly during treatment, and 1 month after treatment. All completed the study, and treatment groups were well matched. r-hCG significantly increased body weight (approximately 1 kg P < 0.05) and lean body mass ( approximately 2 kg P < 0.001) and reduced fat mass (approximately 1 kg, P < 0.05). However, anthropometric measures of skinfold thickness (biceps, triceps, subscapular, suprailiac) and circumferences (midarm, waist, hip, and midthigh), including the waist-hip ratio, did not change significantly. Shoulder and knee strength (peak torque), as measured by isokinetic and isometric dynamometry, was not significantly increased, nor was physical activity (accelerometry and Physical Activity Scale for Elderly self-report) or gait and balance (modified Guralnik and Frailty and Injuries: Cooperative Studies of Intervention Techniques performance batteries) altered. Total and free testosterone and estradiol were markedly (150% P < 0.001) and stably increased, whereas LH, FSH, and urea were significantly decreased. Testis volume was significantly decreased (approximately 5 ml P < 0.05). There were no significant changes in hemoglobin, osteocalcin, or prostate-specific antigen, and the International Prostate Symptom Score did not change. Three men developed nipple tenderness that did not progress to gynecomastia. We conclude that 3 months of treatment with twice weekly r-hCG demonstrates sustained androgenic effects on hormones and muscle mass but has no effect on muscle strength or physical functioning.
Publisher: Oxford University Press (OUP)
Date: 05-04-2019
Abstract: What is the natural history of outcomes of sperm cryostorage at an Australian tertiary academic centre? Cryostorage is feasible in virtually all men facing gonadotoxic therapy but the timing of sperm disposal varies according to the reason for it. Gonadotoxic treatment for cancer or non-cancer diseases damages spermatogenesis and impairs male fertility. Sperm cryopreservation is an established technique to preserve male fertility prior to gonadotoxic treatment. A retrospective review of clinical, anthropometric, semen analysis and hormonal data from 1978 to 2017 involving 2717 men comprising 2085 men with cancer, 234 non-cancer disease and 398 healthy controls, in a single tertiary academic centre with the same clinic and laboratory staff. Sperm output was analysed according to diseases, the feasibility of sperm cryostorage notably for adolescents, regional access to an urban cryostorage facility, the determinants of sperm output and time-dependent disposal of cryostored sperm. Semen s les were assessed by contemporaneous WHO methods. Of 2085 men with cancer, 904 (43%) had haematological malignancies, 680 (33%) testicular cancers and 136 (6.5%) were adolescents. Most men (89%) and adolescents (80%) could collect sperm. Sperm output for all cancers and non-cancer diseases was lower than controls. Sperm output correlated positively with total testicular volume (r = 0.44, P < 0.0001) and negatively with serum FSH and LH (r = -0.24, -0.12, respectively, both P < 0.0001) but not testosterone. For all stored s les, the median time in cryostorage was 8.5 years, 7% were transferred for use to induce pregnancy (median time 2.5 years) and 62.2% were discarded as no longer needed (return of fertility, 35.9% median 3.5 years death, 26.3%, median 6.5 years), the high disposal rate reflecting regular annual follow-up to establish ongoing need for continued cryostorage. Cryostorage facilities are not available in remote and rural areas of the State and the proportion of outer regional and remote area residents cryostoring sperm was only about half that compared with urban residents. This study does not report the pregnancy outcomes of the patients who used the cryostored sperm, due to recent limitations on health data privacy. Sperm cryostorage is feasible for virtually all men, including sufficiently mature adolescents, who can collect semen to insure future paternity as well as making positive psychological preparation for the patient's survival. Disposal of cryostored material when no longer required is efficient with regular follow-up. Sperm cryopreservation should be an integral part of comprehensive treatment plan in men receiving gonadotoxic treatment but remains underutilized. There was no external funding for this study and there were no relevant conflicts of interest.
Publisher: Wiley
Date: 10-1988
DOI: 10.1111/J.1365-2605.1988.TB01015.X
Abstract: In order to test the hypothesis that pretreatment with gonadotropin-releasing hormone (GnRH) analogs might ameliorate cytotoxic drug-induced testicular damage, mature male Wistar rats were pretreated for 2 weeks with a GnRH superactive agonist or a pure GnRH antagonist prior to, and for 1 week after, a 5 mg/kg intraperitoneal dose of cis-platinum. Despite inhibition of testicular function by both GnRH analogs prior to cis-platinum administration, there was no evidence of protection or enhanced recovery of spermatogenesis at 6 and 12 weeks after cis-platinum treatment, and spermatogenesis was significantly further depressed at both time-points by both GnRH agonist and antagonist pretreatment. This suggests that pretreatment with GnRH analogs in the rat does not protect spermatogenesis from cis-platinum-induced testicular damage within up to two spermatogenic cycles and that hypogonadism at the time of cytotoxic drug treatments may aggravate testicular damage.
Publisher: Oxford University Press (OUP)
Date: 28-04-2020
Abstract: APOE genotype has been associated with various age-related outcomes including Alzheimer’s disease, frailty, and mortality. In this study, the relationship between health, particularly cognitive function, and APOE was investigated in older men from the Concord Health and Ageing in Men Project (n = 1,616 age 76.9 ± 5.5 years [range 70–97 years] Australia). Baseline characteristics and survival up to 12 years were determined. Frailty was measured using Cardiovascular Health study (CHS) criteria and Rockwood frailty index, and cognition using Mini-Mental State Examination (MMSE) and Addenbrookes Cognitive Examination. APOE ε4 was less common in the oldest men and those born in Mediterranean countries. APOE ε2 was beneficially associated with cholesterol, creatinine, gamma-glutamyl transaminase, glucose, and HDL cholesterol while APOE ε4 was adversely associated with cholesterol and albumin. APOE ε4 was associated with a clinical diagnosis of Alzheimer’s disease when adjusted for age and region of birth (ε4 homozygotes Odds ratio (OR) 7.0 ε4 heterozygotes OR 2.4, p & .05), and APOE ε2 had a small positive association with cognition. On multivariate regression, overall cognitive function in the entire cohort was associated with age, country of birth, education, and frailty (all p & .001). APOE was not associated with frailty or survival. In conclusion, age and region of birth influenced distribution of APOE genotype in older men. Although APOE ε4 was associated with Alzheimer’s disease, overall cognitive function in the cohort was associated more strongly with frailty than APOE genotype.
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1111/IDJ.12623
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/J.JACC.2003.07.024
Abstract: We studied the effects of dehydroepiandrosterone (DHEA), an abundant adrenal androgen on two key early events of atherogenenis: 1) human monocyte adhesion to vascular endothelium, and 2) human foam cell formation. In the U.S., where DHEA is available without prescription, there has recently been a rapid increase in unsupervised self-administration of DHEA. The vascular biologic effects of DHEA are largely unknown, however. Regarding adhesion, human umbilical vein endothelial cells (HUVECs), exposed to either DHEA (42 or 420 nmol/l) or control, were incubated with human monocytes, and adhesion was measured by hemocytometry. Surface expression of endothelial cell adhesion molecules was measured by ELISA. Regarding foam cell formation, studies of lipid loading were performed on macrophages treated with DHEA or control and/or the androgen receptor antagonist hydroxyflutamide (HF) (4 micromol/l). Intracellular cholesterol and cholesteryl esters (CE) were quantified by high-performance liquid chromatography. Expression of foam cell formation-related genes was measured by reverse-transcription polymerase chain reaction. DHEA produced a dose-dependent receptor-mediated increase in the male macrophage CE content (up to 120 +/- 4% of control values, p = 0.015). DHEA upregulated messenger ribonucleic acid expression of the lipoprotein-processing enzymes acyl coenzyme A:cholesterol acyltransferase I and lysosomal acid lipase by 3.4- and 5.3-fold, respectively (p 0.2). There was no significant effect of DHEA on monocyte-endothelial adhesion ( 0.1). DHEA increases human macrophage foam cell formation, a potentially pro-atherogenic effect. This effect appears to be mediated via the androgen receptor and involves the upregulation of lipoprotein-processing enzymes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
Publisher: The Endocrine Society
Date: 04-2004
DOI: 10.1210/EN.2003-0789
Publisher: American Physiological Society
Date: 08-2016
DOI: 10.1152/AJPENDO.00159.2016
Abstract: Recently, we created a unique gain-of-function mouse model with Sertoli cell-specific transgenic androgen receptor expression (TgSCAR) showing that SCAR activity controls the synchronized postnatal development of somatic Sertoli and Leydig cells and meiotic-postmeiotic germ cells. Moderate TgSCAR (TgSCAR m ) expression reduced testis size but had no effect on male fertility. Here, we reveal that higher TgSCAR expression (TgSCAR H ) causes male infertility. Higher SCAR activity, shown by upregulated AR-dependent transcripts ( Rhox5, Spinw1), resulted in smaller adult TgSCAR H testes (50% of normal) despite normal or elevated circulating and intratesticular testosterone levels. Unlike fertile TgSCAR m males, testes of adult TgSCAR H males exhibited focal regions of interstitial hypertrophy featuring immature adult Leydig cells and higher intratesticular dihydrotestosterone and 5α-androstane 3α,17β-diol levels that are normally associated with pubertal development. Mature TgSCAR H testes also exhibited markedly reduced Sertoli cell numbers (70%), although meiotic and postmeiotic germ cell/Sertoli cell ratios were twofold higher than normal, suggesting that elevated TgSCAR activity supports excessive spermatogenic development. Concurrent with the higher germ cell load of TgSCAR H Sertoli cells were increased levels of apoptotic germ cells in TgSCAR H relative to TgSCAR m testes. In addition, TgSCAR H testes displayed unique morphological degeneration that featured accumulated cellular and spermatozoa clusters in dilated channels of rete testes, consistent with reduced epididymal sperm numbers. Our findings reveal for the first time that excessive Sertoli cell AR activity in mature testes can reach a level that disturbs Sertoli/germ cell homeostasis, impacts focal Leydig cell function, reduces sperm output, and disrupts male fertility.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.SCHRES.2015.05.040
Abstract: Late adolescence in males is a period of increased susceptibility for the onset of schizophrenia, coinciding with increased circulating testosterone. The cognitive deficits prevalent in schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions of depleted (monkey and rat) and replaced (rat) testosterone over adolescence, changes in gene expression of cortical BDNF and TrkB transcripts and interneuron markers and the relationships between these mRNAs and circulating testosterone. Testosterone removal by gonadectomy reduced gene expression of some BDNF transcripts in monkey and rat frontal cortices and the BDNF mRNA reduction was prevented by testosterone replacement. In rat, testosterone replacement increased the potential for classical TrkB signalling by increasing the full length to truncated TrkB mRNA ratio, whereas in the monkey cortex, circulating testosterone was negatively correlated with the TrkB full length/truncated mRNA ratio. We did not identify changes in interneuron gene expression in monkey frontal cortex in response to gonadectomy, and in rat, we showed that only somatostatin mRNA was decreased by gonadectomy but not restored by testosterone replacement. We identified complex and possibly species-specific, relationships between BDNF/TrkB gene expression and interneuron marker gene expression that appear to be dependent on the presence of testosterone at adolescence in rat and monkey frontal cortices. Taken together, our findings suggest there are dynamic relationships between BDNF/TrkB and interneuron markers that are dependent on the presence of testosterone but that this may not be a straightforward increase in testosterone leading to changes in BDNF/TrkB that contributes to interneuron health.
Publisher: Oxford University Press (OUP)
Date: 06-04-2019
Abstract: The objective of the study is to evaluate the prospective associations between antioxidant intake and incident frailty among older Australian men aged ≥75 years. Seven hundred and ninety-four men participated in a detailed diet history interview at the Concord Health and Ageing in Men Project (CHAMP) study third wave (considered baseline nutrition here) and 781 men participated at the fourth wave (considered 3-year follow-up here). The main outcome measurement was incident frailty at 3-year follow-up, using the Cardiovascular Health Study definition. Dietary adequacy of antioxidant intake was assessed by comparing participants' median intakes of four dietary antioxidants (vitamin A, E, C, and zinc) to the nutrient reference values (NRVs). Attainment of the NRVs was incorporated into a dichotomized variable "poor" (meeting ≤2 antioxidants) or "good" (meeting ≥3 antioxidants) as the independent variable using the cut-point method. Also, intakes of each in idual dietary antioxidant at baseline nutrition were categorized into quartiles. Analyses were performed using multinomial logistic regression. Incidence of pre-frailty was 53.0% and frailty was 6.4% at 3-year follow-up. Poor dietary antioxidant intake (meeting ≤2) at baseline nutrition was associated with incident frailty at 3-year follow-up in unadjusted (OR: 2.59 [95% CI: 1.47, 4.59, p = .001]) and adjusted (OR: 2.46 [95% CI: 1.10, 5.51, p = .03]) analyses. The lowest quartile of vitamin E intake (<7.08 mg/d) was significantly associated with incident frailty (OR: 2.46 [95% CI: 1.01, 6.00, p = .05]). Poor antioxidant intake, particularly vitamin E, is a plausible factor associated with incident frailty among older men. This supports the need for clinical trials of diets rich in antioxidants or possibly low-dose antioxidant supplements, for prevention of frailty.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-03-2015
Abstract: A fundamental tenet of life-history theory is that reproduction and longevity trade off against one another. Experiments on invertebrates show that, rather than competing for limiting resources, reproduction and lifespan are optimized on different dietary macronutrient compositions. In mice, studies have yet to establish the relationship between macronutrient balance, reproduction, and lifespan. We evaluated the effects of macronutrients and energy on lifespan and reproductive function. Indicators of reproductive function (uterine mass, ovarian follicle number, testes mass, epididymal sperm counts) were optimized by high protein (P), low carbohydrate (C) diets whereas lifespan was greatest on low P:C diets. Corpora lutea and estrous cycling were higher in females on lower P:C diets. Macronutrient balance has profound and opposing effects on reproduction and longevity.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2016
Publisher: Wiley
Date: 08-07-2003
DOI: 10.1002/J.1939-4640.2003.TB02712.X
Abstract: A multicenter, open-label, randomized efficacy and safety study was performed with combined human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) (Puregon(R)) treatment to induce spermatogenesis in hypogonadotropic hypogonadal male patients. Patients were pretreated for 16 weeks with hCG to normalize testosterone levels. A total of 30 of 49 (61%) subjects had normalized testosterone levels but were still azoospermic after the hCG-alone phase. These patients were randomized into 2 treatment schemes with recFSH (2 x 225 IU recFSH per week [group A] or 3 x 150 IU recFSH per week [group B]), in combination with hCG for a period of 48 weeks. Total testosterone increased during the hCG-alone period from 1.08 and 1.22 ng/mL to 6.26 and 4.52 ng/mL for groups A and B, respectively. Combined gonadotropin treatment was effective in inducing spermatogenesis (sperm count >/=1 x 10(6)/mL) in 14 of 30 subjects (47%) and this was achieved after a median duration of treatment of approximately 5.5 months. Treatment time necessary for first sperm cells to appear in the ejaculate was related to the initial testicular volume. Subjects with a history of maldescended testes (11 of 30 subjects, 37%) showed a lower mean response to treatment as indicated by the relatively lower number of subjects reaching levels of at least 1 x 10(6) sperm cells per milliliter. Combined testicular volume increased during combined gonadotropin treatment from 11.4 to 24.0 mL. Although subjects with a history of maldescended testes had a lower starting testicular volume, subjects with and without a history of maldescended testes showed approximately the same relative increase in testicular volume. Total testosterone levels showed only a minor further increase during the combined gonadotropin treatment period. In conclusion, a weekly dose of 450 IU (3 x 150 IU or 2 x 225 IU) recFSH, in addition to hCG, was able to induce spermatogenesis in many hypogonadotropic azoospermic men who failed to respond to treatment with hCG alone.
Publisher: The Endocrine Society
Date: 05-1995
DOI: 10.1210/JCEM.80.5.7745014
Abstract: Gonadotropin treatment of hypogonadotropic infertile men usually requires regular im administration of human urinary FSH (uFSH) however, testicular function is rarely normalized despite years of treatment. As the pharmacokinetics of standard FSH doses (75 IU, two or three times weekly) in gonadotropin-deficient men are poorly characterized, we studied 10 gonadotropin-deficient men by measuring plasma FSH levels with an ultrasensitive fluoroimmunoassay (Delfia, Pharmacia) in single dose and multidose studies. The single dose studies involved blood s les taken 15 min before and 0, 1, 2, 4, 6, 8, 10, 12, 15, 18, 21, 24, 48, 72, and 96 h after the injection of 75 IU uFSH in 1 mL diluent, either sc under the abdominal wall skin or im into the deltoid muscle, in a random sequence, cross-over design (n = 7 men) and after the injection of 150 IU, sc, with additional blood s ling at 120 and 168 h (n = 7 men). The multidose studies used a fixed ascending dose sequence, with blood s led at 24-h intervals posttreatment after at least 1 month of regular administration of either 75 or 150 IU uFSH, sc, at injection intervals of 72, 48, and 24 h (n = 6 men). From the single dose studies, pharmacokinetic variables were estimated from a one-compartment open model fitted by a weighted polyexponential curve fit of plasma FSH over time. The bioavailability of uFSH via the sc route was high (mean area under the curve, 90% for 75 IU and 143% for 150 IU vs. 75 IU, im). Peak plasma FSH levels were later (21.1 vs. 7.1 h P < 0.001) and lower (2.0 vs. 2.7 IU/L P < 0.001) after sc compared with im administration of 75 IU due to a slower absorption half-time (6.1 h vs. 1.4 h P < 0.001), whereas mean residence times and clearance half-times were similar. The pharmacokinetic features of the 150- and 75-IU doses sc were essentially identical, apart from expected dose-dependent increases in peak plasma FSH level (2.8 vs. 2.0 IU/L P < 0.001) and area under the curve (206 vs. 129 IU.h/L P < 0.05). Multidose simulations based on the single dose pharmacokinetic models predicted that during chronic sc administration of standard FSH doses, plasma FSH levels would be in the lower half of the eugonadal range and fluctuate less than with im administration. The multidose study confirmed empirically these predictions. These studies form a pharmacological basis for a more flexible, cost-effective, and convenient self-administered sc regimen.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: Oxford University Press (OUP)
Date: 02-2010
DOI: 10.1530/EJE-09-0717
Abstract: Testosterone formulations that have more steady-state pharmacokinetics, such as subcutaneously implanted testosterone pellets, may cause less erythrocytosis than i.m. injections of shorter acting androgen esters. We, therefore, sought to define the prevalence, predictors, and proximate basis (role of erythropoietin) for polycythemia (hematocrit .50) in hypogonadal men receiving testosterone implants long term. A cross-sectional study was conducted in an academic andrology center with a longitudinal subgroup analysis. A total of 158 hypogonadal men aged 14–84 years (mean age 46.7 years) treated on average for 8 years (range 0–21 years). Trough blood testosterone and hematocrit. Serial serum erythropoietin concentrations were measured in 16 volunteers. Positive univariate associations between polycythemia (hematocrit .50) and log(testosterone) (odds ratio (OR) 24.7, 95% confidence interval (CI): 4.3, 141.2, P .01) and age (OR 1.1, 95% CI: 1.0, 1.1, P =0.03) and a borderline relationship with current smoking (OR 4.2, 95% CI: 0.9, 20.0, P =0.08) were unveiled. A sensitivity analysis using alternate definitions of polycythemia was performed to capture all potential covariants. Multivariate regression analysis incorporating all potential covariants disclosed the independent OR of developing polycythemia (after adjusting for smoking and age) for log(testosterone) to be 15.0 (95% CI: 2.5, 90.8). Duration of testosterone therapy did not alter the risk of polycythemia. A direct relationship between testosterone and erythropoietin was observed ( P =0.05). Higher trough serum testosterone concentrations but not duration of treatment predict the development of polycythemia in men receiving long-acting depot testosterone treatment.
Publisher: The Endocrine Society
Date: 11-2006
DOI: 10.1210/JC.2006-0612
Abstract: Context: GH-responsive markers of the IGF system and of collagen turnover hold promise as the basis of a GH doping test. Objective: The purpose of this study was to determine the influence of age, gender, body mass index (BMI), ethnicity, and sporting type on GH-responsive serum markers in a large cohort of elite athletes from different ethnic backgrounds. Design: The study was designed as a cross-sectional study. Participants: A total of 1103 elite athletes (699 males, 404 females), aged 22.2 ± 5.2 yr, from 12 countries and 10 major sporting categories participated in this study. Main Outcome Measures: Serum IGF-I, IGF binding protein-3 (IGFBP-3), acid labile subunit (ALS), and collagen markers [N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), N-terminal propeptide of type III procollagen (PIIINP)] were measured. Results: There was a significant negative correlation (r = −0.14 to −0.58, P & 0.0005) between age and each of the GH-responsive markers. Serum IGF-I, IGFBP-3, and ALS were all lower (P & 0.05), whereas the collagen markers PINP, ICTP, and PIIINP were higher (P & 0.05) in men than in women. Multiple regression analysis indicated that age, gender, BMI, and ethnicity accounted for 23–54% of total between-subject variability of the markers. Age and gender cumulatively accounted for 91% of the attributable variation of IGF-I and more than 80% for PINP, ICTP, and PIIINP. Gender exerted the greatest effect on ALS (48%), and BMI accounted for less than 12% attributable variation for all markers. The influence of ethnicity was greatest for IGFBP-3 and ALS however, for the other markers, it accounted for less than 6% attributable variation. Analysis of 995 athletes indicated that sporting type contributed 5–19% of attributable variation. Conclusions: Age and gender were major determinants of variability of GH-responsive markers except for IGFBP-3 and ALS. Ethnicity is unlikely to confound the validity of a GH doping test based on IGF-I and these collagen markers.
Publisher: The Endocrine Society
Date: 22-03-2018
Abstract: The impact of testosterone (T) treatment on antidoping detection tests in female-to-male (F2M) transgender men is unknown. We investigated urine and serum sex steroid and luteinizing hormone (LH) profiles in T-treated F2M men to determine whether and, if so, how they differed from hypogonadal and healthy control men. Healthy transgender (n = 23) and hypogonadal (n = 24) men aged 18 to 50 years treated with 1000 mg injectable T undecanoate provided trough urine and blood s les and an additional earlier postinjection s le (n = 21). Healthy control men (n = 20) provided a single blood and urine s le. Steroids were measured by mass spectrometry-based methods in urine and serum, LH by immunoassay, and uridine 5'-diphospho-glucuronosyltransferase 2B17 genotype by polymerase chain reaction. Urine LH, human chorionic gonadotropin, T, epitestosterone (EpiT), androsterone (A), etiocholanolone (Etio), A/Etio ratio, dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and 5α,3α- and 5β,3α-androstanediols did not differ between groups or by time since last T injection. Urine T/EpiT ratio was <4 in all controls and 12/68 (18%) s les from T-treated men, but there was no difference between T-treated groups. Serum estradiol, estrone, and DHEA were higher in transgender men, and serum T and DHT were higher in earlier compared with trough blood s les, but serum LH, follicle-stimulating hormone, and 3α- and 3β,5α-diols did not differ between groups. Urine antidoping detection tests in T-treated transgender men can be interpreted like those of T-treated hypogonadal men and are unaffected by time since last T dose. Serum steroids are more sensitive to detect exogenous T administration early but not later after the last T dose.
Publisher: Bioscientifica
Date: 08-1992
Abstract: This study was undertaken to compare various extraction methods for insulin-like growth factor-binding proteins (IGFBPs) from insulin-like growth factor-I (IGF-I) in rat serum systematically, before measurement of IGF-I by radioimmunoassay (RIA). The values obtained in the IGF-I RIA following acid–ethanol (AE), acid-ethanol cryoprecipitation (AEC) and formic acid-acetone (FA) extraction methods were compared with the IGF-I values obtained following high-performance liquid chromatography (HPLC), which was the reference method. Radio-ligand blots were used to determine the pattern and degree of IGFBP removal by these methods. Over a wide range of circulating IGF-I levels, AE and AEC extraction gave IGF-I levels comparable with those obtained following HPLC. FA extraction resulted in IGF-I levels that were consistently higher ( P ·01) than those obtained following HPLC and gave non-parallel displacement curves in comparison with recombinant IGF-I standards ( P ·01). Ligand blots demonstrated a similar pattern of IGFBP removal among the three methods with almost complete removal of IGFBP-3 but only 30–40% removal of the lower molecular weight IGFBPs. These lower molecular weight IGFBPs did not interfere with the RIA measurements of IGF-I from AE and AEC extracts. Therefore the AE extraction method of Daughaday, originally validated for use in human serum, is also satisfactory for use in rat serum. The complete removal of IGF-binding activity does not appear essential for accurate measurement of IGF-I by RIA, although this may depend on the specific binding characteristics of the IGF-I antiserum. Journal of Endocrinology (1992) 134, 169–176
Publisher: Oxford University Press (OUP)
Date: 27-04-2017
Publisher: The Endocrine Society
Date: 04-2016
DOI: 10.1210/JC.2015-3810
Abstract: Although androgen status decreases with aging in unselected men, the contemporaneous relationship over time between circulating hormones and androgen-sensitive outcomes has not been reported. To investigate the temporal relationships between age-specific androgen status and muscle (mass, strength), hemoglobin, and prostate-specific antigen (PSA). Men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (2005–2007 n = 1705) and at 2-year (n = 1367) and 5-year follow-up (n = 958). At all assessments, serum T, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and serum SHBG, LH, and FSH were measured by immunoassay together with calculation of free T (cFT). Muscle mass, strength of upper (hand grip) and lower (walking speed) limbs, hemoglobin, and prostate size (serum PSA) were measured. Serum hormones showed longitudinal, within-man decreases in serum T (−2.6%/y), DHT (−2.6%/y), E1 (−3.2%/y), and cFT (−2.8%/y) but increases in serum E2 (2.6%/y), SHBG (1.3%/y), LH (1.9%/y), and FSH (1.8%/y). Significant positive correlation was observed between changes in serum T with muscle mass, strength, and hemoglobin but not with PSA across the three time-points. Changes in serum DHT, cFT, and E1 had significant correlation with muscle mass, strength, and hemoglobin, but not with PSA. These extended observational data are consistent with the impact of reduced androgen status on some somatic features of male aging. However, they do not exclude reverse causality or independent effects of aging on both androgen status and androgen-sensitive outcomes.
Publisher: BMJ
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 13-08-2019
Abstract: Weight loss increases fracture risk in older adults. We aimed to determine associations of 2-year body composition trajectories with subsequent falls and fractures in older men. We measured appendicular lean mass (ALM) and total fat mass (FM) by dual-energy X-ray absorptiometry at baseline and Year 2 in 1,326 community-dwelling men aged ≥70 and older. Body composition trajectories were determined from residuals of a linear regression of change in ALM on change in FM (higher values indicate maintenance of ALM over FM), and a categorical variable for change in ALM and FM (did not lose [≥−5% change] versus lost [& −5% change]). Bone mineral density (BMD), hand grip strength, and gait speed were assessed at Years 2 and 5. After Year 2, incident fractures (confirmed by radiographical reports) and falls were recorded for 6.8 years. Compared with men who did not lose ALM or FM, men who did not lose ALM but lost FM, and men who lost both ALM and FM, had reduced falls (−24% and −34%, respectively both p & .05). Men who lost ALM but did not lose FM had increased falls (incidence rate ratio = 1.73 95% CI 1.37–2.18). ALM/FM change residuals were associated with improved lumbar spine BMD (B = 0.007 95% CI 0.002–0.012 g/cm2 per SD increase) and gait speed (0.015 0.001–0.029 m/s), and reduced hip fractures (hazard ratio = 0.68 95% CI 0.47–0.99). Fracture risk may be increased in older men who lose higher ALM relative to FM. Weight loss interventions for obese older men should target maintenance of lean mass.
Publisher: Wiley
Date: 14-05-2015
DOI: 10.1002/JBMR.2493
Abstract: The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow-up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2 years follow-up (2007-2009), and 5 years follow-up (2010-2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X-ray absorptiometry (DXA) at all three time-points. Fracture data were collected at 4-monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (β = -0.071), FSH (β = -0.085), LH (β = -0.070), and E1 (β = 0.107) remained significantly associated with BMD loss in multivariate-adjusted models however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n = 171 hip, n = 44 and nonvertebral, n = 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate-adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging.
Publisher: Wiley
Date: 22-04-2022
DOI: 10.1002/CPT.2254
Abstract: We reviewed the available animal and human reproductive function studies of recently approved noncytotoxic oncology drugs. We reviewed the oncofertility information in the prescribing information for the US Food and Drug Administration (FDA)‐approved products and/or the product information and consumer medicine information for Therapeutic Goods Administration (TGA)‐approved drugs of 32 novel oncology drugs approved between 2014 and 2018 in the United States and/or Australia supplemented by a literature review for additional reproductive effects. No human studies were available on the reproductive effects of all 32 drugs. A systematic literature review of animal reproductive toxicity studies provided only very limited data with nine drugs displaying impaired male fertility, three impaired female fertility, and nine producing impaired fertility in both male and female animals. Two drugs in the study are reported to have no demonstrable impact on fertility in animal reproductive toxicity studies and nine are reported to have unknown effects on fertility. Of the 32 newly listed drugs, only 4 had recommendations regarding potential human fertility risks and accordingly advised clinicians about fertility preservation procedures for patients. The lack of human data and limited animal reproductive toxicity data raises concerns about the potential impact of these novel oncology drugs on human fertility and reproductive function. Consequently, adequate oncofertility recommendations, including for fertility preservation procedures, counselling for psychological or cost implications, and future prognosis for fertility are hindered by this paucity of relevant data. More data on human reproductive effects of novel oncology drugs is urgently required to facilitate effective use of the growing array of oncofertility care options available.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JAMDA.2017.08.018
Abstract: The study aimed to examine the contemporaneous temporal association between changes in total physical activity, sports intensity, muscle strengthening exercise, and walking speed as predictors of all-cause, cardiovascular, cancer and other cause-specific mortality in older men. Community-dwelling men aged 70 years and older from Concord Health and Aging in Men Project were assessed at baseline (2005-2007, n = 1705), 2 years (n = 1367), and 5 years follow-up (n = 958). At all time points, Physical Activity Scale for the Elderly questionnaire, walking speed over a 6-m walk, and potential confounders were assessed. Mortality was ascertained through the state death registry with a median follow-up of 7 years. As the Physical Activity Scale for the Elderly score increased by 1 standard deviation over the follow-up period, the relative risk (RR) for mortality was 0.78 [95% confidence interval (CI) 0.69-0.88] for all-cause, 0.66 (95% CI 0.55-0.79) for cardiovascular and 0.75 (95% CI 0.61-0.94) for other cause-specific mortality, but no association was observed in cancer mortality. The RR for undertaking strenuous sports during follow-up was 0.44 (95% CI 0.26-0.72) for all-cause mortality and 0.31 (95% CI 0.13-0.70) for cancer mortality when compared with no sports participation. Increases in walking speed per standard deviation over time were also associated with a decrease in all-cause mortality (RR 0.69, 95% CI 0.61-0.78), with similar associations for cardiovascular (RR 0.60, 95% CI 0.48-0.74), but not cancer mortality. Older men who engage in strenuous sports and those who increase their walking speed over time may have lower risk of all-cause and some cause-specific mortality.
Publisher: Wiley
Date: 11-03-2016
DOI: 10.1111/AJAG.12310
Abstract: To describe the age at which the geriatric syndromes and frailty become common in community-dwelling men. The Concord Health and Ageing in Men Project involves a population-based s le of 1705 community-dwelling men aged 70 and over from a defined geographic region in Sydney. Data were obtained by physical performance tests, clinical examinations, and questionnaire to determine the prevalence of the following conditions by five-year age group. Poor mobility, recurrent falls, urinary incontinence, dementia and frailty phenotype were all uncommon (less than 10%) in men in their 70s, but the prevalence of each of these conditions exceeded 10% in men aged 85-89. The prevalence of Frailty Index-defined frailty, multimorbidity, polypharmacy and instrumental activities of daily living dependence was constantly high in all age groups. The different health-care needs of the 'old old' aged 85 years and older should be accounted for in health service planning.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.CANLET.2005.06.008
Abstract: In silico methods and array technologies have identified genes differentially expressed in prostate cancer. Biological functions of the identified genes are often unclear. Considering the biological significance of androgens in prostate cancer, we profiled the prostate transcripts of congenital androgen-deficient mice with or without androgen replacement in vivo using murine gene expression array. In parallel genes differentially expressed in human prostate cancer were identified by Digital Differential Display and the Serial Analysis of Gene Expression. Androgen dependence of the identified genes was then determined by the steady-state mRNA levels of the murine orthologs in response to androgen treatment. The annotation is supported by the finding that some of the androgen target genes have been reported previously with independent experiments.
Publisher: Oxford University Press (OUP)
Date: 2004
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.DIABET.2014.03.006
Abstract: Low-circulating testosterone is associated with development of type 2 diabetes in obese men. In this study, we examined the effects of experimental overfeeding and weight gain on serum levels of sex hormones and skeletal muscle expression of steroidogenic enzymes in healthy men with (FH+) and without (FH-) a family history of type 2 diabetes. Following a 3-day lead in energy balanced diet, FH+ (n = 9) and FH- men (n = 11) were overfed by 5200 kJ/day (45% fat) for 28 days. Body weight, fasting glucose, insulin, sex steroid, sex hormone binding globulin (SHBG) levels, insulin sensitivity (hyperinsulinaemic-euglycaemic cl ) and body fat (DXA) were assessed in all in iduals at baseline and day 28, and sex steroidogenesis-related enzyme expression in vastus lateralis biopsies was examined in a subset (n = 11). Body weight, fat mass and fasting insulin levels were increased by overfeeding (P < 0.01) and insulin was increased significantly more in FH+ men (P<0.01). Serum sex hormone binding globulin (SHBG) and 5α-dihydrotestosterone (DHT) were reduced with overfeeding (P < 0.05), and serum testosterone and DHT were reduced to a greater extent in FH+ men (P < 0.05). Overfeeding reduced mRNA expression of 3β-hydroxysteroid dehydrogenase (HSD) and 17βHSD (P ≤ 0.007), independently of group. 5α-Reductase (SRD5A1) mRNA expression was not changed overall, but a time by group interaction was observed (P = 0.04). Overfeeding reduced SHBG and muscle expression of enzymes involved in the formation of testosterone in skeletal muscle. Men with a family history of T2DM were more susceptible to deleterious outcomes of overfeeding with greater reductions in serum testosterone and DHT and greater increases in markers of insulin resistance, which may contribute to increased risk of developing type 2 diabetes.
Publisher: Elsevier BV
Date: 07-2005
Publisher: Wiley
Date: 06-1997
DOI: 10.1111/J.1600-0684.1997.TB00047.X
Abstract: The semi-longitudinal collection of growth measurements in male and female hamadryas baboons has enabled documentation of the timing of puberty and the development of sexually dimorphic growth patterns in body weight, crown-rump length (CRL), limb lengths, and muscle mass. In addition, another sexually dimorphic characteristic appears to be the presence of a pubertal growth spurt in body weight, and possibly CRL, in male but not female baboons. Serum testosterone levels rose during male development however, there was a progressive decrease in dehydroepiandrosterone sulfate levels indicating the absence of adrenarche. Insulin-like growth factor-I (IGF-I) and its major binding protein, IGFBP-3, both rose during pubertal development however, a simultaneous rise in the IGF-I:IGFBP-3 molar ratio suggests other factors may enhance the bioactivity of IGF-I during puberty. A distinct rise in serum osteocalcin levels was also associated with puberty in male baboons. These growth and hormonal changes during puberty in the hamadryas baboon indicate that this species provides a close primate model for human puberty.
Publisher: The Endocrine Society
Date: 14-06-2019
Abstract: Hormone assay results below the assay detection limit (DL) can introduce bias into quantitative analysis. Although complex maximum likelihood estimation methods exist, they are not widely used, whereas simple substitution methods are often used ad hoc to replace the undetectable (UD) results with numeric values to facilitate data analysis with the full data set. However, the bias of substitution methods for steroid measurements is not reported. Using a large data set (n = 2896) of serum testosterone (T), DHT, estradiol (E2) concentrations from healthy men, we created modified data sets with increasing proportions of UD s les (≤40%) to which we applied five different substitution methods (deleting UD s les as missing and substituting UD s le with DL, DL/√2, DL/2, or 0) to calculate univariate descriptive statistics (mean, SD) or bivariate correlations. For all three steroids and for univariate as well as bivariate statistics, bias increased progressively with increasing proportion of UD s les. Bias was worst when UD s les were deleted or substituted with 0 and least when UD s les were substituted with DL/√2, whereas the other methods (DL or DL/2) displayed intermediate bias. Similar findings were replicated in randomly drawn small subsets of 25, 50, and 100. Hence, we propose that in steroid hormone data with ≤40% UD s les, substituting UD with DL/√2 is a simple, versatile, and reasonably accurate method to minimize left censoring bias, allowing for data analysis with the full data set.
Publisher: Medknow
Date: 2010
DOI: 10.1038/AJA.2009.49
Publisher: American Medical Association (AMA)
Date: 14-01-2008
DOI: 10.1001/ARCHINTERNMED.2007.2
Abstract: Data on the influence of gonadal hormones on incident fracture risk in elderly men are limited. We prospectively examined the relationship between serum levels of testosterone and estradiol and future fracture risk in community-dwelling men. A total of 609 men older than 60 years had been observed between January 1989 and December 2005, with the median duration being 5.8 years (up to 13 years). Clinical risk factors, including bone mineral density and lifestyle factors, were assessed at baseline. Serum testosterone and estradiol levels were measured by tandem mass spectrometry. The incidence of a low-trauma fracture was ascertained during follow-up. During follow-up, 113 men had at least 1 low-trauma fracture. The risk of fracture was significantly increased in men with reduced testosterone levels (hazard ratio [HR], 1.33 95% confidence interval [CI], 1.09-1.62). After adjustment for sex hormone-binding globulin, serum testosterone (HR, 1.48 95% CI, 1.22-1.78) and serum estradiol (HR, 1.21 95% CI, 1.00-1.47) levels were associated with overall fracture risk. After further adjustment for major risk factors of fractures (age, weight or bone mineral density, fracture history, smoking status, calcium intake, and sex hormone-binding globulin), lower testosterone was still associated with increased risk of fracture, particularly with hip (HR, 1.88 95% CI, 1.24-2.82) and nonvertebral (HR, 1.32 95% CI, 1.03-1.68) fractures. In community-dwelling men older than 60 years, serum testosterone is independently associated with the risk of osteoporotic fracture and its measurement may provide additional clinical information for the assessment of fracture risk in elderly men.
Publisher: Medknow
Date: 22-11-2010
DOI: 10.1038/AJA.2010.154
Publisher: Oxford University Press (OUP)
Date: 05-2018
DOI: 10.1530/EJE-17-1072
Abstract: There is increasing recognition that, in men, some biological actions attributed to testosterone (TS) are mediated by estradiol (E2). This study used two low doses of daily transdermal E2 gel to assess the effects on circulating E2 concentrations in men with prostate cancer with suppressed endogenous E2 production arising from androgen deprivation therapy (ADT). Secondarily, we aimed to assess short-term biological effects of E2 add-back without increasing circulating TS. 28-day randomised, placebo-controlled trial. 37 participants were randomised to either 0.9 or 1.8 mg of 0.1% E2 gel per day or matched placebo gel. Fasting morning serum hormones, quality of life questionnaires, and treatment side effects were evaluated at baseline, days 14 and 28. Hot flush diaries and other biochemical measurements were completed at baseline and study end. Transdermal E2 significantly raised serum E2 from baseline to day 28 compared to placebo in the 0.9 mg dose group (median: 208 pmol/L interquartile range: 157–332) and in the 1.8 mg dose group (median: 220 pmol/L interquartile range: 144–660). E2 treatment reduced hot flush frequency and severity as well as beta carboxyl-terminal type 1 collagen telopeptide. In men with castrate levels of E2 and TS, daily transdermal E2: 0.9–1.8 mg increased median serum E2 concentrations into the reference range reported for healthy men, but with substantial variability. E2 treatment reduced hot flushes and bone resorption. Larger studies will be required to test whether low-dose E2 treatment can mitigate ADT-associated adverse effects without E2-related toxicity.
Publisher: Wiley
Date: 10-07-2005
Publisher: Oxford University Press (OUP)
Date: 04-1995
DOI: 10.1093/OXFORDJOURNALS.HUMREP.A136051
Abstract: We undertook a prospective survey of the tolerability of deep i.m. injections of testosterone enanthate in a castor oil vehicle, the most widely used form of androgen replacement therapy. Over a period of 8 months, 26 men received 551 weekly injections into the gluteal, deltoid or thigh muscle and side-effects were recorded immediately and 1 week after each injection by the same nurse using a standardized questionnaire. Most injections caused no complaints [389/551, 70.6% (95% confidence interval 66.6-74.4%)] but minor local side-effects, mostly pain and bleeding, were common [162/551, 29.4% (25.6-33.4%)] no serious side-effects were observed. Considering all side-effects, the gluteal site had fewer complaints and was less prone to bleeding but was painful more often than deltoid or thigh injection sites. The laterality of injection at any site had no significant effect on side-effects. The only systemic side-effect was episodes of sudden-onset, non-productive cough associated with faintness following eight injections [1.5% (0.6-2.9%)] which we speculate may have been due to pulmonary oil microembolism. We conclude that, when administered by an experienced nurse, deep i.m. injection of testosterone enanthate in a castor oil vehicle is generally safe and well tolerated but causes relatively frequent minor side-effects, including pain and bleeding. An improved depot form of testosterone would be highly desirable for androgen replacement therapy and hormonal male contraception.
Publisher: Wiley
Date: 07-08-2012
DOI: 10.1111/J.1465-3362.2012.00496.X
Abstract: To explore the association between psychotropic drug use and alcohol drinking in community-dwelling older Australian men. We conducted a cross-sectional population-based study using baseline data collected between 2005 and 2007 from 1705 participants in the Concord Health and Ageing in Men Project (CHAMP) conducted in Sydney, Australia. All participants were men aged ≥70 years. The prevalence of antidepressant and sedative or anxiolytic drug use was ascertained at clinical examinations and alcohol drinking was self-reported. Logistic regression models were used to compute the unadjusted and adjusted prevalence ratios and 95% confidence intervals for the association between sedative or anxiolytic use and antidepressant use with drinking patterns. In the study s le, 8.0% used an antidepressant, 5.7% used a sedative or anxiolytic, 33.7% were daily drinkers, 13.9% were binge drinkers, 19.2% were heavy drinkers and 11.0% were problem drinkers. Overall, 27.1% of antidepressant users were daily drinkers and 42.7% of sedative or anxiolytic users were daily drinkers. Sedative or anxiolytic use was associated with daily drinking (prevalence ratio = 1.42 95% confidence intervals 1.09-1.76) but not with other drinking patterns. The associations between antidepressant use and alcohol drinking were not statistically significant. Potential psychotropic drug-alcohol interactions were common in older Australian men. Users of sedative or anxiolytic drugs were more likely to engage in daily drinking compared with non-users of sedative or anxiolytic drugs. Clinicians should monitor patients prescribed sedative or anxiolytic drugs for possible adverse events arising from concomitant use with alcohol.
Publisher: Elsevier BV
Date: 10-1991
DOI: 10.1016/0303-7207(91)90208-A
Abstract: Within the seminiferous tubules, the Sertoli cells create an impermeable blood-testis barrier and an unique intratubular microenvironment that fosters the development of spermatozoa. The functional differentiation of spermatozoa therefore requires vectorial secretion by Sertoli cells of substances that cannot cross the blood-testis barrier. We investigated the role of epidermal (EGF) and insulin-like growth factors I and II (IGF-I and IGF-II) in the regulation of vectorial secretion of transferrin by Sertoli cells. In order to study the regulation of vectorial transferrin secretion, we modified culture conditions in the twin chamber culture system to maximise gradients of transferrin secretion. Sertoli cells were plated at high density (3-4 x 10(6) cells/well) into chambers of near equal volume, cultured at 37 degrees C and maintained in simple, fully defined media omitting standard supplements (insulin, EGF, FSH) which affect vectorial transferrin secretion. Using this optimised culture system, maximum gradients of transferrin secretion occurred between days 2 and 3 of culture with preferential secretion (mean ratio 3.7 +/- 0.2) directed towards the apical compartment. The transferrin ratio (ratio of transferrin secreted into the upper over the lower chamber) was decreased by insulin and FSH but not by retinoic acid or testosterone, yet all four stimuli increased total transferrin secretion. IGF-I and IGF-II were effective at physiological concentrations (ED50 = 1 ng/ml) in lowering transferrin ratio and were 100-fold more potent than insulin suggesting that insulin effects on vectorial transferrin secretion by Sertoli cells is mediated through type 1 IGF receptors. EGF also reduced the transferrin ratio (ED50 = 50 ng/ml) as well as stimulating total transferrin secretion. The hormonally mediated reduction in transferrin ratio was consistently due to enhanced secretion of transferrin into the lower chamber. In the first demonstration of a highly polarised response of Sertoli cells to hormonal stimuli, the effects of insulin, FSH and EGF on vectorial transferrin secretion were effected primarily via the basal membrane of the Sertoli cell and operated independent of mechanisms controlling total transferrin secretion. These results establish a potential role for epidermal and insulin-like growth factors in the paracrine regulation of vectorial secretion by the Sertoli cell, in particular the developmental regulation of vectorial transferrin secretion by Sertoli cells. These findings also indicate that previous studies which included insulin and EGF routinely in culture media have systematically underestimated apically directed transferrin secretion.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.BEEM.2018.03.008
Abstract: Polycystic ovarian syndrome (PCOS) is the most common endocrine condition in women, and is characterized by reproductive, endocrine and metabolic features. However, there is no simple unequivocal diagnostic test for PCOS, its etiology remains unknown and there is no cure. Hence, the management of PCOS is suboptimal as it relies on the ad hoc empirical management of its symptoms only. Decisive studies are required to unravel the origins of PCOS, but due to ethical and logistical reasons these are not possible in humans. Experimental animal models for PCOS have been established which have enhanced our understanding of the mechanisms underlying PCOS and propose novel mechanism-based therapies to treat the condition. This review examines the findings from various animal models to reveal the current knowledge of the mechanisms underpinning the development of PCOS, and also provides insights into the implications from these studies for improved clinical management of this disorder.
Publisher: American Physiological Society
Date: 08-1993
DOI: 10.1152/AJPENDO.1993.265.2.E304
Abstract: The effect of food restriction on circulating luteinizing hormone (LH) levels in orchidectomized rats is controversial. The present study demonstrates that decreasing food intake by 50% for 3-10 days in orchidectomized rats increases LH pulse litude, length, area under pulse curve, and mean levels but decreases LH pulse frequency compared with ad-lib fed, orchidectomized controls. The effects on pulsatile LH secretion of food reduction by 50% with or without dilution by cellulose to maintain food volume in orchidectomized rats were also examined. Food volume influences pulsatile LH secretion independent of macronutrient effect after 3 days of food restriction, but subsequently macronutrient deprivation predominates. The exaggerated increase in LH levels in orchidectomized rats subject to food restriction for 7 days was not due to immunochemical or chromatographic heterogeneity or alteration in biopotency of circulating LH molecules. Intravenously injected 125I-labeled rat LH analyzed by noncompartmental modeling revealed that neither LH clearance nor mean residence time was reduced by food restriction. We conclude that during food restriction in orchidectomized rats, increases in LH pulse litude exceed and precede the decreases in LH pulse frequency, although the early changes in pulse litude are predominantly due to reduced food volume rather than macronutrient deprivation.
Publisher: Oxford University Press (OUP)
Date: 2005
Publisher: Springer Science and Business Media LLC
Date: 2005
Publisher: Wiley
Date: 21-01-2010
Publisher: Wiley
Date: 09-1995
DOI: 10.1111/J.1365-2265.1995.TB02040.X
Abstract: Gonadal dysfunction is common in chronic liver disease, but most of the previous studies have been restricted to men with alcohol-induced liver disease. We have evaluated hypothalamic-pituitary-testicular function in patients with end-stage non-alcoholic liver disease before and at 6 and 12 months after hepatic transplantation. A prospective study of hypothalamic-pituitary-testicular endocrine function before and after cadaveric hepatic transplantation. Fifty four consecutive patients with end-stage, non-alcoholic liver disease were evaluated before and after liver transplantation. Hypothalamic-pituitary-testicular (HPT) axis function was evaluated under basal conditions by single morning measurements of plasma total and free testosterone, sex hormone-binding globulin and by plasma LH and FSH responses to 100 micrograms i.v. GnRH. Men with chronic non-alcoholic liver disease had reduced levels of total and free testosterone and increased levels of SHBG compared with controls with normal liver function. Total and free testosterone were positively correlated with basal and stimulated LH (but not FSH) concentrations. Gonadotrophin responses to GnRH were preserved but delayed compared with healthy controls consistent with a predominantly hypothalamic defect in regulation of pituitary-testicular function. Increasing severity of underlying liver disease was associated with declining total and free testosterone as well as peak GnRH-stimulated LH concentrations. Spironolactone treatment was associated with decreased circulating testosterone levels only in men with liver disease of intermediate severity (Child-Pugh class B). Following hepatic transplantation, total and free testosterone and SHBG concentrations returned progressively towards eugonadal control levels over the first 12 months but total and free testosterone levels remained subnormal. Hypothalamic-pituitary regulation of testicular function is impaired in end-stage non-alcoholic liver disease in proportion to the severity of underlying liver disease. Spironolactone reduces circulating testosterone but only among men with Child-Pugh B liver cirrhosis. Gonadal function improves, but is not normalized, over the first year following successful liver transplantation.
Publisher: CSIRO Publishing
Date: 2008
DOI: 10.1071/RD08144
Abstract: Spermatogenesis requires androgen but, paradoxically, oestradiol (E2) treatment stimulates spermatogenic development in gonadotrophin- and androgen-deficient hypogonadal (hpg) mice. The mechanisms of E2-induced spermatogenesis were investigated by determining intratesticular E2 levels and testis cell populations in E2-treated hpg male mice, and E2 spermatogenic actions were determined in androgen receptor-knockout (ARKO) mice. Despite increased serum E2 concentrations (150–300 pmol L–1), intratesticular E2 concentrations declined fivefold (P 0.001) in E2-treated v. untreated hpg male mice. Serum FSH reached 40% of normal and total testicular numbers of known FSH-responsive Sertoli, spermatogonia and meiotic spermatocyte populations were significantly (P 0.001) elevated 1.7-, 4- and 13-fold, respectively. However, E2 administration also increased androgen-dependent pachytene spermatocytes and post-meiotic spermatids to levels comparable with testosterone-treated hpg testes. Selective investigation of androgen receptor involvement used E2-treated ARKO mice, which were found to exhibit increased (1.6-fold P 0.05) intratesticular E2 concentrations and suppression of the elevated serum gonadotrophins, although FSH remained twofold higher than normal. However, testis size and total Sertoli, spermatogonia and spermatocyte numbers were not increased in E2-treated ARKO male mice. Therefore, E2-stimulated murine spermatogenic development occurs with markedly suppressed and not elevated intratesticular E2 levels and displays an absolute requirement for functional androgen receptors. We propose that this paradoxical E2 spermatogenic response is explained by predominantly extratesticular E2 actions, increasing FSH to combine with residual androgen activity in hpg testes to stimulate pre- to post-meiotic development.
Publisher: Therapeutic Guidelines Limited
Date: 04-1998
Publisher: Oxford University Press (OUP)
Date: 04-2005
Publisher: Wiley
Date: 30-08-2018
DOI: 10.1111/GGI.13516
Abstract: The aim of the present longitudinal study of community-dwelling older men was to examine the association between cognitive status at baseline, and falls, fractures and bone loss over time. In the Concord Health and Aging in Men Project, 1705 community-dwelling men aged 70-97 years had detailed baseline clinical assessment of cognitive status (dementia, mild cognitive impairment [MCI] and normal cognition), as well as depression, physical activity, neuromuscular function, health status, sociodemographics, comorbidities, medication use and serum 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D and parathyroid hormone levels. During a mean follow-up period of 6 years, participants were contacted 4-monthly to ascertain incident falls and fractures, the latter being confirmed by radiographic reports. Bone mineral density was measured by dual X-ray absorptiometry at multiple time-points. At baseline, 120 men were assessed to have MCI and 93 men to have dementia. Over time, there were 162 first incident fractures, including 43 hip and 32 vertebral fractures. In univariate models, baseline dementia, but not MCI, predicted an increased incidence of hip fracture (HR 6.95, 95% CI 3.47-13.96), but not vertebral (HR 2.26, 95% CI 0.79-6.46) or non-hip non-vertebral fracture (HR 0.73, 95% CI 0.27-1.99). The strong risk of hip fractures associated with dementia remained after accounting for potential confounders (HR 4.44, 95% CI 1.97-9.98). In multivariate analyses, dementia (incidence rate ratio 2.26, 95% CI 1.70-2.99), but not MCI, was associated with an increased risk of falls compared with normal cognition. There was no association between baseline dementia and change in bone mineral density. Older men with dementia, but not MCI, have a greater tendency to fall and sustain hip fractures, but not any other types of fractures. Geriatr Gerontol Int 2018 18: 1479-1484.
Publisher: S. Karger AG
Date: 1988
DOI: 10.1159/000125045
Abstract: The gonadotropin-releasing hormone (GnRH) waveform arrives at the pituitary gonadotropes via the pituitary portal blood and provides the immediate suprapituitary stimulus to luteinizing hormone (LH) secretion. Despite their importance, nature and influence of the physiological GnRH waveform in vivo have been difficult to study. Recent pharmacological and in vitro studies have suggested the potential importance of the wave contour as a specific and independent factor in the pharmacodynamic effects of GnRH on pituitary gonadotrope LH secretion in vivo, and it has been hypothesized that the steepness of the rising edge of the GnRH wave contour is a specific determinant of pituitary LH secretion. In order to investigate the pharmacodynamic influence of GnRH pulse wave contour on pituitary LH secretion in vivo, variations in plasma LH responses to alterations in GnRH wave contour were measured in chronic ovariectomized, hypothalamopituitary-disconnected sheep undergoing physiological pulsatile GnRH maintenance regimen at a fixed dose (250 ng ulse) and frequency (interpulse interval 120 min). Variable wave contours were then generated by administration of the same total GnRH pulse dose over various lengths of time from near-instantaneous bolus to increasing lengths of constant-rate infusion time up to 8 min. This model allowed specific examination of pulse wave contour in the absence of concurrent changes in endogenous GnRH or sex steroid secretion and holding constant GnRH pulse dose, frequency, and route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Oxford University Press (OUP)
Date: 10-1994
Abstract: Crawford BA, Handelsman DJ. Recombinant growth hormone and insulin-like growth factor I do not alter gonadotrophin stimulation of the baboon testis in vivo. Eur J Endocrinol 1994 :405–12. ISSN 0804–4643 In vitro studies indicate a physiological role for insulin-like growth factor I (IGF-I) in paracrine regulation of testicular function and recent clinical studies suggest a potential role for growth hormone (GH) and/or IGF-I in the treatment of hypogonadotrophic states in males. This study aimed to examine the effects of pretreatment with recombinant human GH (rhGH) or rhIGF-I on the response to gonadotrophins of the non-human primate testis in vivo. Using a balanced Latin square design with repeated measures, six prepubertal male hamadryas baboons ( Papio hamadryas hamadryas ) were treated in a cross-over sequence for periods of 18 days with daily im injections of rhGH (0.4 IU·kg −1 · day −1 ), rhIGF-I (0.1 mg·kg −1 · day −1 ) or saline with a 2-week washout period between each treatment. A single im injection of hCG (1500 IU) increased serum testosterone (p = 0.0002) but neither rhGH nor rhIGF-I influenced the timing or magnitude of this response (p 0.5). A single im dose of FSH (75 IU) stimulated immunoreactive inhibin (p = 0.01) but also was unaffected in magnitude or timing by pretreatment with rhGH or rhIGF-I (p 0.2). Circulating IGF-I levels were increased independently by hCG (p = 0.01) and FSH (p 0.0001) administration. These findings indicate that neither GH nor IGF-I pre-treatment enhance acute gonadal responses to gonadotrophin stimulation of the prepubertal non-human primate testis in vivo. These findings suggest that GH or IGF-I treatment of hypogonadotrophic men without somatotrophin deficiency is unlikely to be beneficial. David J Handelsman, Andrology Unit, Royal Prince Alfred Hospital, Departments of Medicine and Obstetrics and Gynaecology, University of Sydney, Sydney 2006, Australia
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.EXGER.2018.04.006
Abstract: Previous cross-sectional studies investigating associations of sarcopenic obesity with metabolic syndrome (MetS) and insulin resistance have not utilised consensus definitions of sarcopenia. We aimed to determine associations of sarcopenic obesity with MetS and insulin resistance over five years in community-dwelling older men. 1231 men aged ≥70 years had appendicular lean mass (ALM) and body fat percentage assessed by dual-energy X-ray absorptiometry and hand grip strength and gait speed tests. Sarcopenia was defined as low ALM/height (m Men with sarcopenic obesity (odds ratio, 95% CI: 2.07, 1.21-3.55) and non-sarcopenic obesity (4.19, 3.16-5.57) had higher MetS likelihood than those with non-sarcopenic non-obesity at baseline. Higher gait speed predicted lower odds for prevalent MetS (0.45, 0.21-0.96 per m/s). Higher body fat predicted increased odds for prevalent and incident MetS (1.14, 1.11-1.17 and 1.11, 1.02-1.20 per kg, respectively) and deleterious 5-year changes in MetS fasting glucose, high-density lipoprotein cholesterol and triglycerides (all P < 0.05). Compared with non-sarcopenic non-obesity, estimated marginal means for HOMA-IR at 5-years were higher in non-sarcopenic obesity only (1.0, 0.8-1.1 vs 1.3, 1.2-1.5 P < 0.001). Similar results were observed when sarcopenic obesity was defined by waist circumference. Sarcopenic obesity does not appear to confer greater risk for incident MetS or insulin resistance than obesity alone in community-dwelling older men.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JSBMB.2010.02.001
Abstract: Accurate measurement of sex steroids is essential to evaluate mouse models for human reproductive development and disorders. The recent advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays that match the sensitivity of steroid immunoassay could overcome problems arising from the limited specificity of steroid immunoassay. In this current study we validate a LC-MS/MS assay for the measurement of key sex steroids from murine serum and reproductive tissues. The assay gave excellent dilutional linearity (r(2)> or =0.98) and reproducibility (CV< or =10% of replicate s les) in serum and reproductive tissues with sensitive quantitation limits testosterone (T 2pg), dihydrotestosterone (DHT 10pg), 5alpha-androstane-3alpha,17beta-diol (3alphaDiol 40pg), 5alpha-androstane-3beta,17beta-diol (3betaDiol 40pg), estradiol (E2 0.5pg) and estrone (E1 0.3pg). Using 0.1mL s le, T was the only consistently detectable steroid (detection limit 20pg/ml) in both male and female mouse serum. In the testis, T and DHT were quantifiable as were both diols at relatively high levels. Prostatic T levels were low and DHT was determined to be the most abundant androgen in this tissue. Uterine and ovarian levels of E2, E1 and T were measurable, with levels varying according to estrous cycle stage. Hence, we demonstrate that this LC-MS/MS method has the sensitivity, specificity and multi-analyte capability to offer accurate steroid profiling in mouse serum and reproductive tissues.
Publisher: The Endocrine Society
Date: 12-1995
DOI: 10.1210/ENDO.136.12.7588276
Abstract: Using a new experimental model for studying the hormonal induction of spermatogenesis, the hpg mouse, which has congenital functional gonadotropin deficiency due to a major deletion in the GnRH gene, we investigated the roles of testosterone (T) and dihydrotestosterone (DHT) in the initiation of spermatogenesis. Weanling homozygous hpg male mice were implanted subdermally with SILASTIC brand implants of varying lengths (0-2 cm) filled with T or DHT, using phenotypically normal (N/N or N/hpg) and untreated hpg/hpg mice as positive and negative controls. After 8 weeks, both T and DHT equally stimulated (approximately 14-fold) testis size and induced qualitatively complete spermatogenesis despite low intratesticular androgen levels and undetectable circulating FSH. Stereological quantitation of Sertoli and germ cells demonstrated a dose-dependent rise in the absolute numbers of all germ cell types induced by both T and DHT. At maximal androgen doses, germ cell numbers expressed per Sertoli cell and homogenization-resistant elongated spermatids expressed per mg testis were increased to more than 80% of non-hpg control values. An in vitro fertilization assay confirmed that both T and DHT induced quantitatively normal fertilizing capacity of the sperm in hpg males. We conclude that androgens, acting through the androgen receptor without need for aromatization, initiate qualitatively complete spermatogenesis in the mouse, including fertile sperm despite low intratesticular androgen levels and the absence of blood FSH levels. The hpg mouse model is a useful new paradigm to study the molecular basis of the hormonal induction of spermatogenesis.
Publisher: Oxford University Press (OUP)
Date: 04-2002
Abstract: OBJECTIVE: Testosterone pellet implantation is a safe, effective and convenient form of depot androgen replacement, with extrusion of pellets following about 10% of procedures the most frequent adverse effect. This study aimed to determine whether extrusion rate could be reduced by antibiotic impregnation of pellets immediately prior to implantation. DESIGN: Prospective, randomised, parallel-group, open-label study design in a single centre. One hundred and eighty-six androgen-deficient men (400 implantation procedures) were randomised into either a group who had their pellets soaked for approximately 2 min in gentamicin solution prior to implantation, or a control group who had the standard implantation procedure. METHODS: Extrusion, infection and/or bruising were evaluated prospectively by self-report from the participants, and retrospectively at subsequent implantation. Other variables (site, shaving, skin preparation, operator, pellet batch, bruising) were collected at implantation time. RESULTS: The extrusion rate was 20% lower (odds ratio=0.80, 95% confidence interval (CI) 0.40-1.62) but not statistically different between the two groups (extrusion rate 23/205 (11.2%) for the control group vs 18/195 (9.2%) for the antibiotic-soak group, P=0.42). One operator experienced more total (P=0.0002) and infection-related (P=0.0008) extrusions and marginally more bruising (P=0.06) than other operators. The operator effect did not appear to be explained by differences in experience or implantation style. There was a 4.6-fold excess (95% CI 1.6-18.6) of multiple (19 vs 4 expected) over single (22 vs 10 expected) and no (359 vs 386 expected) extrusions. Extrusion was not related to batch number (P=0.15), location (P=0.15), shaving (P=0.32), old or new site (P=0.59), or the presence of suppuration or not (P=0.42) however, povidone-iodine skin disinfectant had statistically fewer extrusions than mixed alcohol solution. CONCLUSIONS: Antibiotic impregnation prior to implantation does not significantly decrease testosterone pellet extrusion rate. An operator effect, not due to experience or procedural style, an excess of multiple extrusions and disinfectant effects were confirmed. Neither location, nor preparation of the site, nor pellet batch, influences extrusion rate.
Publisher: Wiley
Date: 20-08-2014
DOI: 10.1002/JBMR.2230
Abstract: The aim of this population-based, prospective, observational study was to examine the relationship between serum levels of 25-hydroxyvitamin D (25OHD) and fracture risk in a cohort of 1662 community-dwelling men aged 70 to 97 years followed for a mean of 4.3 years. Data about mobility, muscle strength, balance, medication use, cognition, medical history, lifestyle factors, renal function, and serum 25OHD were collected at baseline. Data on radiologically verified fractures were collected every 4 months. The relationship between fractures and serum 25OHD levels was analyzed using Cox's proportional hazard regression. We accounted for bone mineral density, falls, physical activity, sun exposure, and season of blood draw, in addition to anthropometric and lifestyle factors, medical history, muscle strength, balance, and medication and supplement use. There were 123 first-incident fragility fractures. The relationship between baseline 25OHD and fracture risk was U-shaped, with increased fracture risk in men with either low or high serum 25OHD levels. In multivariate analysis, the risk of fracture was greatest in men with 25OHD levels in the lowest quintile (25OHD ≤36 nmol/L hazard ratio [HR] = 3.5 95% confidence interval [CI] 1.7-7.0) and in men in the highest quintile (25OHD >72 nmol/L HR = 2.7 95% CI 1.4-5.4) compared with men in the 4th quintile (25OHD ≥60 to ≤72 nmol/L). These associations were not explained by lower BMD, increased physical activity, fall risk, or other lifestyle or anthropomorphic factors. In community-dwelling older men, there appears to be a healthy target range for serum 25OHD concentrations. Thus, serum 25OHD levels too high and too low may be harmful in regard to fracture risk.
Publisher: Cambridge University Press (CUP)
Date: 07-10-2020
DOI: 10.1017/S1368980020003547
Abstract: To assess the associations between nutrient intake and dietary patterns with different sarcopenia definitions in older men. Cross-sectional study. Sarcopenia was defined using the Foundation for the National Institutes of Health (FNIH), the European Working Group on Sarcopenia in Older People (EWGSOP) and the European Working Group on Sarcopenia in Older People 2 (EWGSOP2). Dietary adequacy of fourteen nutrients was assessed by comparing participants’ intakes with the Nutrient Reference Values (NRV). Attainment of NRV for nutrients was incorporated into a variable ‘poor’ (meeting ≤ 9) v. ‘good’ (meeting ≥ 10) using the cut-point method. Also, two different dietary patterns, monounsaturated:saturated fat and n- 6: n- 3 fatty acids ratio and in idual nutrients were used as predictor variables. A total of 794 men aged ≥75 years participated in this study. The prevalence of sarcopenia by the FNIH, EWGSOP and EWGSOP2 definitions was 12·9 %, 12·9 % and 19·6 %, respectively. With the adjustment, poor nutrient intake was significantly associated with FNIH-defined sarcopenia (OR: 2·07 (95 % CI 1·16, 3·67)), but not with EWGSOP and EWGSPOP2 definitions. The lowest and second-lowest quartiles of protein, Mg and Ca and the lowest quartiles of n -6 PUFA and n -3 PUFA intakes were significantly associated with FNIH-defined sarcopenia. Each unit decrease in n- 6: n- 3 ratio was significantly associated with a 9 % increased risk of FNIH-defined sarcopenia (OR: 1·09 (95 % CI 1·04, 1·16)). Inadequate intakes of nutrients are associated with FNIH-defined sarcopenia in older men, but not with the other two sarcopenia definitions. Further studies are required to understand these relationships.
Publisher: Wiley
Date: 05-10-2009
DOI: 10.1111/J.1365-2265.2009.03524.X
Abstract: Fat mass is increased in hypogonadal men and the changes are reversed by testosterone replacement. Testosterone administration enhances whole body fat oxidation (Fox). Fat is oxidized in the liver and in extra-hepatic tissues. To determine whether the stimulation of Fox by testosterone arises primarily from the liver or from extra-hepatic tissues. This was an open-label cross-over study. Thirteen men with hypopituitarism (age 53.1 +/- 4.1 years) with both growth hormone (GH) and testosterone deficiency were studied sequentially after 2 weeks of treatment with transdermal testosterone (5 mg), no treatment, and stepwise incremental doses of oral crystalline testosterone (10, 20, 40 and 80 mg) in the absence of GH replacement. Serum testosterone, IGF-I, metabolic effects [resting energy expenditure (REE) and Fox], SHBG, and thyroid binding globulin (TBG) as markers of excessive hepatic androgen exposure, were measured at the end of each treatment period. When compared to the no-treatment phase, mean blood testosterone levels rose into the physiological range after transdermal testosterone delivery but did not significantly change after 10, 20, 40 or 80 mg oral testosterone treatment. Blood SHBG and TBG fell significantly with 80 mg oral testosterone dose but were unaffected by any other testosterone treatment. Fox increased significantly with transdermal but not with any dose of oral testosterone. Mean plasma IGF-I and REE were unaffected by testosterone, regardless of the route or dose. Short-term testosterone administration does not stimulate hepatic fat oxidation but enhances whole body fat oxidation by acting on extra-hepatic tissues.
Publisher: Wiley
Date: 03-01-2022
DOI: 10.1002/ALZ.12529
Abstract: The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone–binding globulin (SHBG) with incidence of dementia and Alzheimer's disease. Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables. In 159,411 community‐dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P = .001, lowest vs highest quintile: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.13‐1.81), and AD ( P = .017, HR = 1.80, CI = 1.21‐2.66). Lower SHBG was associated with a lower incidence of dementia ( P .001, HR = 0.66, CI = 0.51‐0.85) and AD ( P = .012, HR = 0.53, CI = 0.34‐0.84). Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older men. Additional research is needed to determine causality.
Publisher: The Endocrine Society
Date: 13-06-2013
DOI: 10.1210/EN.2012-2273
Abstract: We recently created a mouse model displaying precocious Sertoli cell (SC) and spermatogenic development induced by SC-specific transgenic androgen receptor expression (TgSCAR). Here we reveal that TgSCAR regulates the development, function, and absolute number of Leydig cells (LCs). Total fetal and adult type LC numbers were reduced in postnatal and adult TgSCAR vs control testes, despite normal circulating LH levels. Normal LC to SC ratios found in TgSCAR testes indicate that SC androgen receptor (SCAR)-mediated activity confers a quorum-dependent relationship between total SC and LC numbers. TgSCAR enhanced LC differentiation, shown by elevated ratios of advanced to immature LC types, and reduced LC proliferation in postnatal TgSCAR vs control testes. Postnatal TgSCAR testes displayed up-regulated expression of coupled ligand-receptor transcripts (Amh-Amhr2, Dhh-Ptch1, Pdgfa-Pdgfra) for potential SCAR-stimulated paracrine pathways, which may coordinate LC differentiation. Neonatal TgSCAR testes displayed normal T and dihydrotestosterone levels despite differential changes to steroidogenic gene expression, with down-regulated Star, Cyp11a1, and Cyp17a1 expression contrasting with up-regulated Hsd3b1, Hsd17b3, and Srd5a1 expression. TgSCAR males also displayed elevated postnatal and normal adult serum testosterone levels, despite reduced LC numbers. Enhanced adult-type LC steroidogenic output was revealed by increased pubertal testicular T, dihydrotestosterone, 3α-diol and 3β-diol levels per LC and up-regulated steroidogenic gene (Nr5a1, Lhr, Cyp11a1, Cyp17a1, Hsd3b6, Srd5a1) expression in pubertal or adult TgSCAR vs control males, suggesting regulatory mechanisms maintain androgen levels independently of absolute LC numbers. Our unique gain-of-function TgSCAR model has revealed that SCAR activity controls temporal LC differentiation, steroidogenic function, and population size.
Publisher: Wiley
Date: 14-08-2009
DOI: 10.1111/J.1365-2265.2008.03516.X
Abstract: The administration of gonadotrophins is prohibited in sport but the effect in men of recently available recombinant hCG and LH on serum and urine concentrations of gonadotrophins and androgens has not been systematically evaluated in the antidoping context. To determine the time-course of recombinant LH (rhLH) and hCG (rhCG) on blood and urine hormone profiles in men to develop effective tests to detect rhLH and rhCG doping. Two randomized controlled studies with a 2 x 2 factorial design. Academic research centre. Healthy male volunteers aged 18-45 years. In the rhLH study, men were randomized into (i) either of two single doses of rhLH (75 IU or 225 IU), and (ii) suppression of endogenous LH and testosterone by nandrolone or no suppression. In the rhCG study, men were randomized into (i) either of two single doses of rhCG (250 or 750 microg), and (ii) suppression of endogenous LH and testosterone by nandrolone decanoate (ND) or no suppression. ND suppression comprised a single dose of 200 mg ND 3 days prior to, and in the rhCG study an additional dose 1 day after gonadotrophin injection. Serum and urine hCG, LH, T, T : LH ratio, urine epitestosterone (E) and urine T : E ratio. Neither rhLH dose produced a significant increase in serum or urine LH or T or in the T : E or T : LH ratios regardless of ND-induced suppression of endogenous LH and T. Nor did an even higher dose (750 IU) in three healthy men with unsuppressed gonadal axis. These findings were confirmed with two different commercial LH immunoassays together with adjustment for any influence of urine sediment and dilution. Both rhCG doses produced a steep, dose-proportional increase in serum and urine hCG with increases in serum and urine T and suppression of serum and urine LH, regardless of hCG dose. Serum but not urine T was lowered by ND suppression. The T : LH ratio showed a progressive increase unrelated to rhCG dose or ND suppression, whereas both rhCG and ND suppression minimally increased T : E ratio. Both rhCG doses produce a striking increase in serum hCG and T with suppression of serum LH but, at single doses up to 750 IU, rhLH has no influence on serum or urine LH or T. Effective rhLH doping, which relies on a sustained increases in endogenous T, would require much higher and more frequent daily rhLH doses. Use of LH immunoassays optimized for serum to detect rhLH doping by urine LH measurement requires more standardization and validation and, at present, is unreliable. The T : LH ratio is, however, a useful screening test for hCG doping although its utility requires further evaluation.
Publisher: SAGE Publications
Date: 16-03-2015
Abstract: Urinary hormone concentrations are often adjusted to correct for hydration status. We aimed to determine whether first morning void urine hormones in growing adolescents require adjustments and, if so, whether urinary creatinine or specific gravity are better adjustments. The study population was adolescents aged 10.1 to 14.3 years initially who provided fasting morning blood s les at 0 and 12 months ( n = 343) and first morning urine every three months ( n = 644). Unadjusted, creatinine and specific gravity-adjusted hormonal concentrations were compared by Deming regression and Bland–Altman analysis and grouped according to self-rated Tanner stage or chronological age. F-ratios for self-rated Tanner stages and age groups were used to compare unadjusted and adjusted hormonal changes in growing young adolescents. Correlations of paired serum and urinary hormonal concentration of unadjusted and creatinine and specific gravity-adjusted were also compared. Fasting first morning void hormone concentrations correlated well and were unbiased between unadjusted or adjusted by either creatinine or specific gravity. Urine creatinine concentration increases with Tanner stages, age and male gender whereas urine specific gravity was not influenced by Tanner stage, age or gender. Adjustment by creatinine or specific gravity of urinary luteinizing hormone, estradiol, testosterone, dihydrotestosterone and dehydroepiandrosterone concentrations did not improve correlation with paired serum concentrations. Urine steroid and luteinizing hormone concentrations in first morning void s les of adolescents are not significantly influenced by hydration status and may not require adjustments however, if desired, both creatinine and specific gravity adjustments are equally suitable.
Publisher: Wiley
Date: 06-10-2020
DOI: 10.1111/GER.12438
Abstract: To examine whether frailty in older men is associated with poorer oral health and lower levels of dental service utilisation. Poor oral health has been associated with some frailty components. Less is known about the link between frailty and oral health outcomes. A cross-sectional analysis. Data were collected from 601 older men with both frailty status and oral health information. Frailty was defined as meeting three or more of the Cardiovascular Health Study criteria: weight loss, weakness, exhaustion, slowness and low activity. Dental service utilisation (DSU) behaviour was collected from self-response questionnaires and face-to-face interviews. Oral status (number of remaining and functional teeth, periodontal disease, active coronal decayed surface [ACDS] and self-rated oral health [SROH]) was recorded by two oral health therapists. The association between frailty and oral health behaviour and risk markers was modelled using logistic regression. Nineteen per cent of the participants were identified as frail. There were significant associations between frailty and dentition status (odds ratio [OR]: 2.49, 95% confidence interval [CI]: (1.17-5.30), and frailty and ACDS (OR: 3.01, CI: 1.50-6.08) but only ACDS remained significant after adjusting for confounders (adjusted OR: 2.46, CI: 1.17-5.18). There was no association between frailty and DSU and frailty and SROH. Frailty was independently associated with the presence of dental caries. However, DSU, SROH and other oral health markers were not significantly associated with frailty after adjusting for confounders. The prevalence of periodontal disease was high regardless of their frailty status.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.JSBMB.2011.10.009
Abstract: Metabolism of sex steroids within the prostate is an important factor affecting its growth and pathology. Mouse models with genetic gain- and especially loss-of-function have characterised different steroid metabolic pathways and their contribution to prostate pathology. With reference to the human prostate, this review aims to summarize the steroidogenic pathways in the mouse prostate as the basis for using the mouse as a model for intraprostatic steroid signalling. In this review we summarize the current information for three main components of the steroid signalling pathway in the mouse prostate: circulating steroids, steroid receptors and steroidogenic enzymes with regard to signalling via androgen, estrogen, progesterone and glucocorticoid pathways. This review reveals many opportunities for characterisation steroid metabolism in various mouse models. The knowledge of steroid metabolism within prostate tissue and in a lobe (rodent)/region (human) specific manner, will give valuable information for future, novel hypotheses of intraprostatic control of steroid actions. This review summarizes knowledge of steroid metabolism in the mouse prostate and its relevance to the human.
Publisher: Oxford University Press (OUP)
Date: 25-05-2018
DOI: 10.1634/THEONCOLOGIST.2018-0157
Abstract: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The “Checkpoint Inhibitor Safety Working Group,” a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer.
Publisher: Wiley
Date: 05-2011
DOI: 10.1002/JBMR.286
Abstract: Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross-sectional analysis consisted of 1705 community-dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population-based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (β = 0.12 to 0.14, p < .001), serum calcium (β = 0.11, p = .001), parathyroid hormone (β = 0.09, p = .002), 25-hydroxyvitamin D (β = 0.09, p = .005), and was negatively associated with urinary excretion amino-terminal cross-linked telopeptide of type 1 collagen (β = -0.09, p = .006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R(2) = 0.10 to 0.22). In multiple logistic regression analyses, above-median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.22-0.81, p = .010) and lumbar spine (OR = 0.44, 95% CI 0.23-0.86, p = .016) and a lower prevalence of vertebral (OR = 0.62, 95% CI 0.43-0.91, p = .015) and nonvertebral (OR = 0.51, 95% CI 0.29-0.89, p = .018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men.
Publisher: The Endocrine Society
Date: 08-2011
DOI: 10.1210/JC.2011-0143
Abstract: Frailty, a syndrome of multiple morbidity, weakness, and immobility in aging, is an increasingly urgent threat to public health. Single measures of low serum androgen have been associated with frailty in men, but the contributory role of hormonal changes with time is unassessed. The objective of the study was to examine, using longitudinal measurements, the relations of serum androgens, estrogens, gonadotropins, and SHBG to the prevalence and progression of frailty in older men. Concord Health and Ageing in Men Project is an observational cohort study of 1705 men (aged 70 yr or older) living in the suburb of Concord, Sydney, Australia. Measurements were obtained at baseline (2005-2007) and 2-yr follow-up (2007-2009). Testosterone (T), dihydrotestosterone, estradiol, and estrone were obtained by liquid chromatography-tandem mass spectrometry, whereas SHBG, LH, and FSH were measured by immunoassay. Subjects from the general community were s led. A total of 1645 subjects constituting a representative s le of community-dwelling men aged 70 yr old or older participated in the study. The frailty syndrome was measured according to the Cardiovascular Health Study (CHS) and Study of Osteoporotic Fractures (SOF) indices. Androgens and estrogens showed significant age-adjusted associations with concurrent frailty. Subjects in the lowest T quintile had 2.2-fold odds of exhibiting greater CHS frailty as compared with the highest T quintile (P < 0.001) results for dihydrotestosterone, estradiol, estrone, and calculated free T were similar, and were unchanged when the SOF frailty index was substituted for the CHS frailty index. A 1 sd, 2-yr decrease in T, calculated free T, or LH was associated with a 1.2- to 1.3-fold increase in the odds of progression (increase in severity) of frailty. The control for comorbid medical conditions did not affect results. Age-related changes in blood androgens and estrogens may contribute to the development or progression of frailty in men.
Publisher: The Endocrine Society
Date: 05-2016
DOI: 10.1210/JC.2016-1025
Abstract: The dynamic temporal relationship between changes in serum reproductive hormones and mortality in men has not been reported. The objective of the study was to examine the relationship between progressive changes in circulating reproductive hormones over time with all-cause and cause-specific mortality in older men. Community-dwelling men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (2005-2007, n = 1705) and at 2-year (n = 1367) and 5-year follow-up (n = 958). At all three time-points, T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH were determined by immunoassay and calculated free T (cFT) was calculated. Mortality was ascertained through the state death registry. Statistical modeling was by general estimating equations with the Poisson regression. Serum T over time (relative risk [RR] per 1 SD decrease in concentration: 1.18, 95% confidence interval [CI] 1.05-1.32), DHT (RR 1.17, 95% CI 1.05-1.32), and E2 (RR 1.46, 95% CI 1.30-1.63) as well as cFT (RR 1.27, 95% CI 1.13-1.41) was associated with all-cause mortality. After adjusting for multiple covariables, the decline in serum T (RR 1.17, 95% CI 1.03-1.32), DHT (RR 1.17, 95% CI 1.03-1.32), and cFT (RR 1.13, 95% CI 1.08-1.19) remained significantly associated with all-cause mortality. Similar relationships were observed for cancer but not cardiovascular mortality. Progressive decline in serum E2 levels remained significantly associated with all-cause (RR 1.49, 95% CI 1.31-1.69), cancer (RR 1.82, 95% CI 1.45-2.28), and cardiovascular (RR 1.37, 95% CI 1.13-1.66) mortality, even after adjustment for covariables. Serum E1, LH, FSH, and SHBG were not associated with all-cause, cancer, or cardiovascular mortality. Dynamic temporal changes in serum T, cFT, DHT, and E2 (but not E1, LH, FSH, and SHBG) in older men are associated with all-cause and cause-specific mortality in distinct patterns.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2020
DOI: 10.1186/S12939-020-01277-2
Abstract: Among older people, the extent to which psychosocial factors explain socioeconomic inequalities in mortality is debated. We aimed to investigate the potential mediating effect of psychosocial factors on socioeconomic inequalities in mortality. We used data from a prospective population-based cohort (the Concord Health and Ageing in Men Project baseline recruitment in 2005–2007), in Sydney, Australia. The main outcomes were all-cause and cause-specific mortality. Socioeconomic status (SES educational attainment, occupational position, source of income, housing tenure, and a cumulative SES score) was assessed at baseline. Measures of structural and functional social support, as well as depressive and anxiety symptoms were assessed three times during follow-ups. Associations were quantified using Cox regression. Mediation was calculated using “change-in-estimate method”. 1522 men (mean age at baseline: 77·4 ± 5·5 years) were included in the analyses with a mean (SD) follow-up time of 9·0 (3·6) years for all-cause and 8·0 (2·8) years for cause-specific mortality. At baseline, psychosocial measures displayed marked social patterning. Being unmarried, living alone, low social interactions, and elevated depressive symptoms were associated with higher risk of all-cause and cardiovascular disease (CVD) mortality. Psychosocial factors explained 35% of SES inequalities in all-cause mortality, 29% in CVD mortality, 12% in cancer mortality, and 39% in non-CVD, non-cancer mortality. Psychosocial factors may account for up to one-third of SES inequalities in deaths from all and specific causes (except cancer mortality). Our findings suggest that interventional studies targeting social relationships and/or psychological distress in older men aiming to reduce socioeconomic inequalities in mortality are warranted.
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000445159
Abstract: Androgen abuse is the most potent and prevalent form of sports doping detected. It originated from the early years of the Cold War as an epidemic confined to drug cheating within elite power sports. In the decades following the end of the Cold War, it has become disseminated into an endemic based within the illicit drug subcultures serving recreational abusers seeking cosmetic body sculpting effects. Within sports, both direct androgen abuse (administration of androgens), as well as indirect androgen abuse (administration of nonandrogenic drugs to increase endogenous testosterone), is mostly readily detectable with mass spectrometry-based anti-doping urine tests. The ongoing temptation of fame and fortune and the effectiveness of androgen abuse in power sports continue to entice cheating via renewed approaches aiming to exploit androgens. These require ongoing vigilance, inventiveness in anti-doping science, and targeting coaches as well as athletes in order to build resilience against doping and maintain fairness in elite sport. The challenge of androgen abuse in the community among recreational abusers has barely been recognized and effective approaches remain to be developed.
Publisher: Wiley
Date: 30-09-2013
DOI: 10.1111/J.2047-2927.2013.00133.X
Abstract: Semen is collected to evaluate male fertility or cryostore sperm preferentially in laboratories but such collection facilities have no standard fit-out. It is widely believed but untested whether providing erotic material (EM) is required to collect semen by masturbation in the unfamiliar environment. To test this assumption, 1520 men (1046 undergoing fertility evaluation, 474 sperm cryostorage, providing 1932 semen collection episodes) consecutively attending the semen laboratory of a major metropolitan teaching hospital for semen analysis were eligible for randomization to be provided or not with printed erotic material EM (X-rated, soft-core magazines) during semen collection. Randomization was performed by providing magazines in the collection rooms (as a variation on non-standard fit-out) on alternate weeks using a schedule concealed from participants. In the pilot study, men were randomized without seeking consent. In the second part of the study, which continued on from the first without interruption, an approved informed consent procedure was added. The primary outcome, the time to collect semen defined as the time from receiving to returning the s le receptacle, was significantly longer (by ~6%, 14.9 ± 0.3 [mean ± standard error of mean] vs. 14.0 ± 0.2 minutes, p = 0.02) among men provided with EM than those randomized to not being provided. There was no significant increase in the failure to collect semen s les (2.6% overall) nor any difference in age, semen volume or sperm concentration, output or motility according to whether EM was provided or not. The significantly longer time to collect was evident in the pilot study and the study overall, but not in the main study where the informed consent procedure was used. This study provides evidence that refutes the assumption that EM needs to be provided for semen collection in a laboratory. It also provides an ex le of a usually unobservable participation bias influencing study outcome of a randomized controlled trials.
Publisher: Oxford University Press (OUP)
Date: 03-06-2004
Publisher: The Endocrine Society
Date: 02-2003
Publisher: Elsevier BV
Date: 07-2022
Publisher: The Endocrine Society
Date: 18-08-2023
Publisher: Oxford University Press (OUP)
Date: 18-07-2018
Abstract: It is unclear whether older men with osteopenia/osteoporosis and sarcopenia (so-called osteosarcopenia) are at greater risk of falls and fractures than those with either condition alone. One thousand five hundred seventy-five community-dwelling men aged ≥70 years had appendicular lean mass, total hip and lumbar spine bone mineral density determined by dual-energy x-ray absorptiometry, and completed hand grip strength and gait speed tests. Osteopenia/osteoporosis was defined as a T-score at any site ≤-1.0 SD. Sarcopenia was defined using the European Working Group on Sarcopenia algorithm. Participants were contacted every 4 months for 6 ± 2 years to ascertain incident fractures (confirmed by radiographic reports) and for 2 years for incident falls. Prevalence of osteosarcopenia was 8%, while 34% of participants had osteopenia/osteoporosis alone and 7% had sarcopenia alone. Men with osteosarcopenia had significantly increased fall (incidence rate ratio: 1.41 95% confidence interval [CI]: 1.02 to 1.95) and fracture risk (hazard ratio: 1.87 95% CI: 1.07 to 3.26) compared with men with neither osteopenia/osteoporosis nor sarcopenia. There was no statistical interaction between osteopenia/osteoporosis and sarcopenia, and falls and fracture risk were not different for osteosarcopenia compared with either condition alone (all p > .05). Community-dwelling older men with combined osteopenia/osteoporosis and sarcopenia do not have increased falls and fracture risk compared with those with either condition. Further research is required to clarify whether the term "osteosarcopenia" has any meaning above and beyond either term alone and therefore potential clinical utility for falls and fracture prediction.
Publisher: Frontiers Media SA
Date: 18-01-2022
Publisher: S. Karger AG
Date: 1991
DOI: 10.1159/000125913
Abstract: Defective regulation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion is the primary defect leading to the inhibition of pituitary gonadotropin secretion and its consequences such as androgen deficiency and infertility in experimental uremia. Previous studies using indirect methods to study presumptive GnRH release and the function of GnRH-secreting neurons have suggested functional disturbances of GnRH neurosecretion however, the precise biochemical mechanisms involved were not defined. Therefore, in order to clarify the mechanisms of aberrant regulation of hypothalamic GnRH secretion in experimental uremia, we examined basal secretion of GnRH from mediobasal hypothalamus (MBH) in vitro and the GnRH-secretory responses to naloxone, an opiate receptor antagonist in experimental uremia. Using a static incubation system, adult male rats, either intact or castrate, with subtotal nephrectomy demonstrated a significant reduction of GnRH secretion by 25% in intact and by 40% in castrate uremic male rats compared with their nonuremic controls. In contrast, hypothalamic GnRH content of uremic animals was increased significantly (6% in intact and 14% in castrate uremic rats). Despite the fall in basal GnRH release from MBH, the MBH GnRH release response to in vitro stimulation by an opioid blocker (naloxone) and a membrane-depolarizing agent (veratrine) were not diminished in uremic male rats. These findings suggest that the inhibition of pituitary gonadotropin secretion in experimental uremia is likely to be due to a functional defect in suprahypothalamic regulation of GnRH secretion rather than an intrinsic defect in the GnRH-secreting neurons. Further studies are required to clarify the nature of the neuromodulator interactions involved.
Publisher: The Endocrine Society
Date: 25-08-2023
Abstract: The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with T treatment reducing diabetes diagnosis by 40%. A follow-up email survey after a median of 5.1 years since last injection obtained 599 (59%) completed surveys (316 T, 283 P) with participants in follow-up survey like non-participants in 23 anthropometric and demographic variables. Randomization to TU associated with stronger belief in study benefits during (64% vs 49%, p & 0.001) but no longer after the study (44% vs 40%, p = 0.07) and high interest in future studies. At T4DM entry, 25% had sleep apnea with new diagnosis more frequent on TU (3.0% vs 0.4%, p = 0.03) during, but not after, the study. Post-study resuming prescribed testosterone treatment was more frequent among TU treated men (6% vs 2.8%, p = 0.03). Five years after cessation of TU treatment there was no difference in self-reported rates of new diagnosis of diabetes, prostate or cardiovascular disease nor change in weight maintenance or weight loss behaviours. We conclude that randomized T treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism was associated with higher levels of self-reported benefits and diagnosis of sleep apnea during, but not after, the study as well as more frequent prescribed post-study testosterone treatment consistent with androgen dependence in some men receiving prolonged injectable TU.
Publisher: The Endocrine Society
Date: 18-10-2016
DOI: 10.1210/EN.2016-1301
Abstract: Increasing evidence indicates that androgens regulate ischemia-induced neovascularization. However, the role of genomic androgen action mediated by androgen receptor (AR), a ligand-activated nuclear transcription factor, remains poorly understood. Using an AR knockout (KO) mouse strain that contains a transcriptionally inactive AR (AR
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.YHBEH.2015.02.005
Abstract: Although sex steroids are known to modulate brain dopamine, it is still unclear how testosterone modifies locomotor behaviour controlled, at least in part, by striatal dopamine in adolescent males. Our previous work suggests that increasing testosterone during adolescence may bias midbrain neurons to synthesise more dopamine. We hypothesised that baseline and hetamine-induced locomotion would differ in adult males depending on testosterone exposure during adolescence. We hypothesised that concomitant stimulation of estrogen receptor signaling, through a selective estrogen receptor modulator (SERM), raloxifene, can counter testosterone effects on locomotion. Male Sprague-Dawley rats at postnatal day 45 were gonadectomised (G) or sham-operated (S) prior to the typical adolescent testosterone increase. Gonadectomised rats were either given testosterone replacement (T) or blank implants (B) for six weeks and sham-operated (i.e. intact or endogenous testosterone group) were given blank implants. Subgroups of sham-operated, gonadectomised and gonadectomised/testosterone-replaced rats were treated with raloxifene (R, 5mg/kg) or vehicle (V), daily for the final four weeks. There were six groups (SBV, GBV, GTV, SBR, GBR, GTR). Saline and hetamine-induced (1.25mg/kg) locomotion in the open field was measured at PND85. Gonadectomy increased hetamine-induced locomotion compared to rats with endogenous or with exogenous testosterone. Raloxifene increased hetamine-induced locomotion in rats with either endogenous or exogenous testosterone. Amphetamine-induced locomotion was negatively correlated with testosterone and this relationship was abolished by raloxifene. Lack of testosterone during adolescence potentiates and testosterone exposure during adolescence attenuates hetamine-induced locomotion. Treatment with raloxifene appears to potentiate hetamine-induced locomotion and to have an opposite effect to that of testosterone in male rats.
Publisher: SAGE Publications
Date: 04-05-2021
DOI: 10.1177/02601060211011798
Abstract: Data in the Offspring Framingham Osteoporosis Study (FOS) suggested that higher intake of dietary fiber was modestly protective against loss of bone mineral density at the femoral neck in men but not in women. To examine the relationship of fiber intake with risk of hip fractures in men. We included 367 men from the FOS Original cohort, 1730 men from the FOS Offspring cohort, and 782 men from the Concord Health and Ageing in Men Project (CHAMP) in the analysis. Incident fractures were defined as medically confirmed first occurrence of osteoporotic fractures at the proximal femur. Fiber intake was estimated via a validated food frequency questionnaire (FFQ) or diet history. Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate the pooled relative risk in meta-analysis. Seventy-two incident hip fractures were identified, of which 24 occurred in the FOS Original cohort [mean (SD): age 75.3 (5.1) years follow-up time: 8.5 (6.2) years dietary fiber: 19 (8) (g/d)], 19 in the FOS Offspring cohort [58.8 (9.8) years 11.0 (5.9) years 19 (8) (g/d)], and 29 in CHAMP [81.4 (4.5) years 5.2 (1.5) years 28 (10) (g/d)]. We did not find significant associations within each cohort between fiber intake and risk of hip fractures. The pooled HR (95% CI) was 0.80 (0.39, 1.66) comparing energy-adjusted dietary fiber at tertile 3 vs. tertile 1 (I 2 = 0, p = 0.56). These data suggested that dietary fiber was not associated with risk of incident hip fractures in men.
Publisher: MDPI AG
Date: 28-08-2020
DOI: 10.3390/IJMS21176231
Abstract: Androgens have been known to inhibit cutaneous wound healing in men and male mice. However, in children with major burn injuries, a synthetic androgen was reported clinically to improve wound healing. The aim of this study is to investigate the role of dihydrotestosterone (DHT) as a new therapeutic approach in treating major burn injury. In the present study, mice received systemic androgen treatment post major burn injury. Wound healing rate and body weight were monitored over 21 days. The serum level of inflammatory cytokines/chemokines were measured using multiplex immunoassays. In addition, splenocyte enumeration was performed by flow cytometry. Healing phases of inflammation, re-epithelialization, cell proliferation and collagen deposition were also examined. In results, DHT treated mice lost less weight and displayed accelerated wound healing but has no impact on hypermetabolism. Mice, after burn injury, displayed acute systemic inflammatory responses over 21 days. DHT treatment shortened the systemic inflammatory response with reduced splenic weight and monocyte numbers on day 14 and 21. DHT treatment also reduced wound infiltrating macrophage numbers. In conclusion, DHT treatment facilitates local wound healing by accelerating the resolution of inflammation, but not through alterations of post-burn hypermetabolic response.
Publisher: The Endocrine Society
Date: 04-2015
DOI: 10.1210/EN.2014-1887
Abstract: Polycystic ovary syndrome (PCOS) is associated with reproductive, endocrine, and metabolic abnormalities. Because hyperandrogenism is the most consistent PCOS feature, we used wild-type (WT) and androgen receptor (AR) knockout (ARKO) mice, together with a mouse model of PCOS, to investigate the contribution of genomic AR-mediated actions in the development of PCOS traits. PCOS features were induced by prenatal exposure to dihydrotestosterone (250 μg) or oil vehicle (control) on days 16-18 of gestation in WT, heterozygote, and homozygote ARKO mice. DHT treatment of WT mice induced ovarian cysts (100% vs 0%), disrupted estrous cycles (42% vs 100% cycling), and led to fewer corpora lutea (5.0±0.4 vs 9.8±1.8). However, diestrus serum LH and FSH, and estradiol-induced-negative feedback as well as hypothalamic expression of kisspeptin, neurokinin B, and dynorphin, were unaffected by DHT treatment in WT mice. DHT-treated WT mice exhibited a more than 48% increase in adipocyte area but without changes in body fat. In contrast, heterozygous and homozygous ARKO mice exposed to DHT maintained comparable ovarian (histo)morphology, estrous cycling, and corpora lutea numbers, without any increase in adipocyte size. These findings provide strong evidence that genomic AR signaling is an important mediator in the development of these PCOS traits with a dose dependency that allows even AR haplosufficiency to prevent induction by prenatal androgenization of PCOS features in adult life.
Publisher: The Endocrine Society
Date: 23-01-2021
Abstract: Androgens are potent drugs requiring prescription for valid medical indications but are misused for invalid, unproven, or off-label reasons as well as being abused without prescription for illicit nonmedical application for performance or image enhancement. Following discovery and first clinical application of testosterone in the 1930s, commercialization of testosterone and synthetic androgens proliferated in the decades after World War II. It remains among the oldest marketed drugs in therapeutic use, yet after 8 decades of clinical use, the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the male reproductive system. Nevertheless, wider claims assert unproven, unsafe, or implausible benefits for testosterone, mostly representing wishful thinking about rejuvenation. Over recent decades, this created an epidemic of testosterone misuse involving prescription as a revitalizing tonic for anti-aging, sexual dysfunction and/or obesity, where efficacy and safety remains unproven and doubtful. Androgen abuse originated during the Cold War as an epidemic of androgen doping among elite athletes for performance enhancement before the 1980s when it crossed over into the general community to become an endemic variant of drug abuse in sufficiently affluent communities that support an illicit drug industry geared to bodybuilding and aiming to create a hypermasculine body physique and image. This review focuses on the misuse of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription or valid indications, typically by athletes, bodybuilders and others for image-oriented, cosmetic, or occupational reasons.
Publisher: The Endocrine Society
Date: 02-07-2009
DOI: 10.1210/EN.2009-0416
Abstract: We examined the biological importance of Sertoli cell androgen receptor (AR) genomic interaction, using a Cre-loxP approach to selectively disrupt the AR DNA-binding domain (AR-DBD). Sertoli cell (SC)-specific transgenic Abpa or AMH promoters targeted Cre-mediated inframe excision of mouse Ar exon-3, encoding the AR-DBD second zinc-finger (ZF2), generating SC-specific mutant AR(DeltaZF2) lines designated Abp.SCAR(DeltaZF2) and AMH.SCAR(DeltaZF2), respectively. Both SCAR(DeltaZF2) lines produced infertile males exhibiting spermatogenic arrest, despite normal SC numbers and immunolocalized SC nuclear AR. Adult homozygous TgCre((+/+)) SCAR(DeltaZF2) or double-TgCre((+/-)) Abp/AMH.SCAR(DeltaZF2) males displayed equivalent small testes 30% of normal size, representing maximal Cre-loxP-disruption of Sertoli AR function. Hemizygous TgCre((+/-)) vs. homozygous TgCre((+/+)) Abp.SCAR(DeltaZF2) testes were larger (47% normal size) with more postmeiotic development, indicating dose-dependent Cre-mediated disruption of SC-specific AR-DBD activity. SCAR(DeltaZF2) males exhibited adult Leydig cell hypertrophy but normal serum testosterone levels. Sertoli cell-specific Rhox5 and Spinlw1 transcription, regulated by ergent or classical androgen-response elements, respectively, were both decreased in postnatal SCAR(DeltaZF2) vs. control testes, demonstrating SC-specific AR-DBD function as early as postnatal d 5. However, Rhox5 expression declined dose-dependently, whereas Spinlw1 expression increased, in adult TgCre((+/-)) and TgCre((+/+)) SCAR(DeltaZF2) testes, revealing differential temporal control for distinct AR-regulated transcripts. Androgen-repressed Ngfr was not up-regulated in SCAR(DeltaZF2) testes, suggesting maintenance of a nonclassical mechanism independent of AR-DBD. Thus, our unique SCAR(DeltaZF2) paradigm provided dose-dependent Cre-mediated disruption of testicular development and gene expression revealing that the AR-DBD is essential for SC function and postmeiotic spermatogenesis. Nongenomic or AR-DBD-independent pathways appear secondary or play no major independent role in SC function.
Publisher: Rockefeller University Press
Date: 13-01-2010
DOI: 10.1084/JEM.20091924
Abstract: Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men.
Publisher: The Endocrine Society
Date: 11-1992
DOI: 10.1210/JCEM.75.5.1430094
Abstract: Hormonally induced azoospermia is an effective, reversible form of male contraception however, some men treated with weekly im testosterone enanthate (TE) injections fail to become azoospermic. As weekly injections cause widely fluctuating and supraphysiological testosterone levels, we tested the hypothesis that more stable, physiological testosterone levels would consistently produce azoospermia. Using a depot testosterone formulation which provides stable, physiological range testosterone levels for up to 6 months, we studied nine men before and after insertion of six 200 mg testosterone implants under the abdominal wall skin and compared the results with 38 men treated in a previous study with weekly im injections of 200 mg TE. Testosterone implants suppressed sperm output to near-azoospermia between the second to fourth postimplant months returning to normal by the sixth postimplant month. The fall in sperm output at the first month was greater after testosterone implants than TE injections (58% vs. 17%, P = 0.011) but similar proportions of men became azoospermic (5/9 vs. 25/38) or severely oligozoospermic (< 1 million/ml 9/9 vs. 37/38). Plasma testosterone and estradiol levels remained mostly within the eugonadal range after implants but were markedly supraphysiological during TE injections. Both treatments suppressed immunoreactive LH and FSH to undetectable levels by ultrasensitive fluoroimmunoassay. Sex hormone-binding globulin levels were decreased and PRL levels increased by TE injections but neither was changed by testosterone implants. Prostate-specific antigen demonstrated a small rise of marginal significance (P = 0.065) after testosterone implants. Fewer men experienced acne after implants (0/9 vs. 25/38, p = 0.0004). Therefore a depot testosterone preparation with quasi-zero-order release demonstrates higher dose efficiency with similar (but not uniform) efficacy at inducing azoospermia but may cause fewer androgenic side-effects than weekly TE injections.
Publisher: Oxford University Press (OUP)
Date: 2019
Abstract: Is exposure to gestational stress in the critical time window for the normal differentiation and growth of male reproductive tissue associated with male reproductive function in offspring in later life? Exposure to stressful life events (SLEs) in early, but not late gestation, are associated with reduced adult male reproductive function, consistent with the hypothesis that events during early prenatal life programme adult male reproductive function. Animal studies suggest that gestational stress may impact on the reproductive function of male offspring, but human evidence is sparse. Using a prospective longitudinal cohort, we examined the association between number and type of maternal stressors during pregnancy in both early and late gestation and reproductive function in 643 male Generation 2 (offspring) at age 20 years. Mothers and their male Generation 2 (offspring) from The Raine Study participated. Mothers prospectively reported SLEs during pregnancy recorded at gestational weeks 18 and 34 using a standardized 10-point questionnaire. The 643 male Generation 2 (offspring) underwent testicular ultrasound examination and semen analysis and provided serum for reproductive hormone analysis. Multivariate linear regression analysis was used to examine associations. Of 643 recruited males, 407 (63%) were exposed to at least one SLE in early gestation. Fewer SLEs were reported in late gestation (n = 343, 53%). Maternal SLE exposure in early gestation was negatively associated with total sperm count (β = -0.31, 95% CI -0.58 -0.03), number of progressive motile sperm (β = -0.15, 95% CI -0.31 0.00) and morning serum testosterone concentration (β = -0.04, 95% CI -0.09 -0.00). No similar effects of maternal SLE exposure in late pregnancy were detected. The large s le size and an objective detailed direct assessment of adult male reproductive function with strict external quality control for sperm quality, as well as detailed prospectively collected information on prenatal SLEs in two distinct time windows of pregnancy reported by the women in early and late gestation along with other risk factors, imply minimal possibility of recall, information bias and selection bias. When assessing our results, we adjusted for a priori chosen confounders, but residual confounding or confounding by factors unbeknown to us cannot be ruled out. It is not possible to measure how SLEs impacted differently on the mother's experience or perception of stress. Resilience (coping) gradients may alter cortisol levels and thus modify the associations we observed and the mothers' own perception of stress severity may have provided a more precise estimate of her exposure. Our findings suggest that exposure to SLEs in early, but not late gestation, are associated with reduced adult male reproductive function. Improved support for women with exposure to SLEs during pregnancy, particularly during the first trimester, may improve the reproductive health of their male offspring in later life. Intervention studies of improved pregnancy support could provide more insight into this association and more information is needed about the potential specific epigenetic mechanisms underlying this association. The male fertility sub-study was funded by NHMRC Grant 634 457. The core management of the Raine Study is funded by University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and Raine Medical Research foundation. Dr Bräuner's salary was supported by Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis foundation in Denmark. All authors declare no competing interests. N/A.
Publisher: Wiley
Date: 28-07-2017
DOI: 10.1111/CEN.13407
Abstract: Male ageing is associated with lower circulating testosterone (T) and increased incidence of cardiovascular disease (CVD). Whether physical activity (PA) interacts with hormones to modify CVD risk is unclear. We assessed whether PA and sex hormone concentrations were independently associated with measures of CVD risk. A total of 1649 men. Leisure, home, work and total PA were ascertained. At baseline, serum T, dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Men were stratified into high PA+high hormone (H/H) low PA+high hormone (L/H) high PA+low hormone (H/L) and low PA+low hormone (L/L). Mean age was 49.8 years at outset with 415 CVD events and 127 CVD deaths occurring during 20-year follow-up. Men with higher PA and higher T or DHT had lower odds of metabolic syndrome (eg leisure H/H vs L/L odds ratio [OR] 0.17 P<.001 for T, 0.26 P<.001 for DHT). Men with higher PA and E2 had lower risk of metabolic syndrome (eg leisure PA H/H vs L/L OR 0.51, P=.001). Men with higher leisure, work or total PA and higher DHT had the lowest risk of CVD death (eg leisure H/H hazard ratio [HR] 0.55 vs L/L, P=.033). Men with lower leisure, home or work PA and higher E2 were at greater risk of CVD death (eg leisure L/H HR 1.60 vs L/L, P=.039). Considering T, DHT and E2 in the context of PA better informs consideration of cardiovascular risk. A 2×2 factorial RCT assessing PA and androgens would illuminate the scope for preventing CVD in men.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
Publisher: Oxford University Press (OUP)
Date: 06-2006
Publisher: The Endocrine Society
Date: 11-2003
Abstract: The prostate strongly expresses type 2 5α-reductase, which avidly converts on entry most testosterone (T) to 5α-dihydrotestosterone (DHT). However, the quantitative contribution of the prostate to blood DHT is uncertain. We evaluated prostatic contribution to blood DHT by comparing the blood DHT concentrations in androgen-deficient patients with or without a prostate while they were receiving standard dose of T replacement. Androgen-deficient males (ADM) and female to male (F2M) transsexuals were studied in 2 centers, with both groups receiving either testosterone ester injections (250 mg mixed T esters) every 1 wk (Amsterdam) or 800 mg subdermal T implantation (Sydney). Among 39 Dutch patients, F2M (n = 21) were younger and smaller in physique than ADM (n = 18). One week (±1 d) after an injection, plasma DHT concentrations were 1.6 ± 0.2 (F2M) vs. 1.4 ± 0.2 (ADM) nmol/liter (P = 0.47), but the postinjection time interval to blood s ling was shorter in F2M (5.9 ± 0.4 vs. 7.2 ± 0.3 d P = 0.01). Covariance adjustment for time since last injection, age, and physique did not change the lack of significant difference in postinjection plasma DHT concentration. The rapid and wide excursions in plasma T concentrations after an im T ester injection make the timing of blood s ling critical. To remove confounding by this variable, the experiment was repeated at a second site in similar patients, but using a depot T that achieves steady-state delivery for prolonged periods. Among 29 Australian patients, before and 1 month after subdermal implantation of 800 mg T, plasma DHT concentrations were not significantly different between groups [F2M, 1.1 ± 0.1 (n = 14) ADM, 1.3 ± 0.1 (n = 15) P = 0.28]. Correction for covariates, including age, height, weight, body surface area, and body mass index, did not influence the lack of significant difference between treated groups. As both modes of T administration yielded similar plasma DHT concentrations regardless of the presence of a prostate, this study indicates that the normal human prostate is not a major contributor to circulating blood DHT concentrations.
Publisher: BMJ
Date: 15-12-2011
DOI: 10.1136/BMJ.D7679
Publisher: Oxford University Press (OUP)
Date: 25-05-2017
Abstract: To explore the associations between serum 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) levels at baseline and incidence of sarcopenia over time in older Australian community-dwelling older men. Of the 1,705 men aged ≥70 years (2005-2007) participating in the Concord Health and Ageing in Men Project, those without sarcopenia at baseline (n = 1,312 for 25D and n = 1,231 for 1,25D), 2 years (n = 1,024 for 25D and n = 956 for 1,25D), and 5-year follow-up (n = 709 for 25D and n = 663 for 1,25D) were included in the study. The main outcome measurement was the incidence of sarcopenia defined as appendicular lean mass adjusted for body mass index <0.789 and grip strength <26.0 kg. Serum 25D and 1,25D levels were measured at baseline by radioimmunoassay (Diasorin, Stillwater, MN) and categorized into quartiles as predictor variables. Covariates included age, income, season of blood collection, physical activity, vitamin D supplement and medication use, measures of health, serum parathyroid hormone (PTH), estimated glomerular filtration rate (eGFR), albumin, and white blood cell count. In this study, incidence of sarcopenia was 3.9% in men at the 2-year follow-up and 8.6% at the 5-year follow-up. In adjusted analysis, men with vitamin D levels in the lowest quartiles (25D <40nmol/L 1,25D <62 pmol/L) showed significant associations with increased odds of incident sarcopenia compared to those with vitamin D levels in the highest quartiles over 5 years. [25D: odds ratio (OR) 2.53 (95% confidence interval (CI) 1.14, 5.64) p = .02 1,25D: OR 2.67 (95% CI 1.28, 5.60) p = .01]. After further adjustments for the respective other serum vitamin D measure, (either 25D or 1,25D), the association remained significant [25D: OR 2.40 (95% CI 1.02, 5.64) p = .04 1,25D: OR 2.23 (95% CI 1.04, 4.80) p = .04]. Low serum 1,25D and 25D concentrations at baseline are independently associated with the incidence of sarcopenia over the subsequent 5 years. Although our data do not prove any causal relationship, it is conceivable that maintaining vitamin D sufficiency may reduce the incidence of sarcopenia in ageing men.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
DOI: 10.1161/ATVBAHA.117.309054
Abstract: Vascular calcification is associated with increased risk of myocardial infarction and stroke. The objective of this work was to examine the ability of 17β-estradiol (E2) to stimulate calcification of vascular smooth muscle cells (VSMC) in vivo, using aged apolipoprotein E-null mice with advanced atherosclerotic lesions, and subsequently to explore underlying mechanisms in vitro. Silastic E2 capsules were implanted into male and female apolipoprotein E-null mice aged 34 weeks. Plaque and calcified area were measured in the aortic sinus and innominate artery after 8 weeks. Immunohistochemical analysis examined expression of the estrogen receptors (estrogen receptor alpha and estrogen receptor beta [ERβ]). VSMC expression of osteogenic markers was examined using digital polymerase chain reaction. Advanced atherosclerotic lesions were present in all mice at the end of 8 weeks. In both male and female mice, E2 increased calcified area in a site-specific manner in the aortic sinus independently of plaque growth or lipid levels and occurred in association with a site-specific decrease in the proportion of ERβ-positive intimal cells. Calcified lesions expressed collagen I and bone sialoprotein, with decreased matrix Gla protein. In vitro, E2 suppressed ERβ expression and increased VSMC mineralization, demonstrating increased collagen I and II, osteocalcin and bone sialoprotein, and reduced matrix Gla protein and osteopontin. Antagonism or RNA silencing of estrogen receptor alpha, ERβ, or both further increased VSMC mineralization. We have demonstrated that E2 can drive calcification in advanced atherosclerotic lesions by promoting the differentiation of VSMC to osteoblast-like cells, a process which is augmented by inhibition of estrogen receptor alpha or ERβ activity.
Publisher: American Physiological Society
Date: 06-2009
DOI: 10.1152/AJPENDO.00017.2009
Abstract: Postnatal inactivation of epithelial androgen receptor (AR) in prostate epithelial AR knockout (PEARKO) mice results in hindered differentiation but enhanced proliferation of epithelial cells. As this resembles the precancerous proliferative atrophy of human prostates with undifferentiated but intensively replicating epithelial cells, we utilized the PEARKO mice to characterize the epithelial response to castration-induced involution with a focus on identifying the potential role of stromal AR and responsiveness of the androgen-deprived epithelia to the aromatizable androgen testosterone (T) or its nonaromatizable metabolite dihydrotestosterone (DHT). PEARKO and littermate control mice were orchidectomized at 8 wk of age and treated 2 wk later with subdermal implantation of 1-cm Silastic tubing filled with T or DHT for a week. Following castration, the prostatic involution and epithelial apoptosis did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution following castration is mediated primarily via stromal AR-dependent apoptotic signals. Androgen replacement (T/DHT) for 7 days induced significant growth and epithelial proliferation in all prostate lobes in both control and PEARKO, but full regrowth was observed only in controls treated with T. In PEARKO, prostate androgen (T and DHT) treatment induced significant epithelial cell “shedding” into the lumen, with T treatment resulting in acinar disorganization, cyst formation, and aberrant epithelial structures, described as a “gland within a gland.” These data suggest that epithelial AR inactivation during postnatal prostate development sensitizes prostate epithelial cells to paracrine signaling mediated by stromal AR activity leading to indirectly androgen-induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens.
Publisher: The Endocrine Society
Date: 03-1990
Abstract: Previous studies have demonstrated that abolition of the naloxone-stimulated increase in plasma LH levels is characteristic of hypothalamic dysfunction in experimental uremia. This study aimed to further characterize the nature of the defect in hypothalamic opiatergic mechanisms in experimental uremia. Specifically, we have tested the hypothesis that naloxone resistance was due to either opioid receptor dysfunction or diminished opioid peptide levels. Administration of naloxone (2 mg/kg, iv) to cannulated freely mobile rats confirmed previous observations that despite marked increases in plasma LH in control rats, plasma LH levels were unaffected in uremic male rats (P = 0.001 for group x time interaction). In a second experiment, morphine (2 mg/kg) or saline diluent was given quasi-continuously as small aliquots before each blood s le during the pulse studies of castrate mature male rats that had undergone either subtotal nephrectomy or sham operation. After the administration of morphine, uremic rats exhibited a 60% reduction in mean LH levels (14.9 +/- 1.4 vs. 6.0 +/- 0.7 ng/ml) attributable to a 42% reduction in LH pulse frequency (3.6 +/- 0.4 vs. 2.1 +/- 0.5 peaks/3 h) and a 60% reduction in LH pulse litude (4.7 +/- 0.5 vs. 1.9 +/- 0.3 ng/ml). The preservation of sensitivity to morphine despite complete naloxone resistance raised the alternate hypothesis of depletion of endogenous opiate peptide levels in the uremic hypothalamus. This hypothesis was tested by measuring the beta-endorphin content of the medial basal hypothalamus (MBH) in a rat beta-endorphin RIA. Rat MBH beta-endorphin content was not significantly altered specifically by either uremia or castration. We conclude, therefore, that naloxone resistance of plasma LH in experimental uremia is not due to either defects in opioid receptor function or reduced hypothalamic beta-endorphin content. Instead, we suggest that uremia may diminish the release of endogenous opioid peptides that interact with GnRH neurons from the MBH.
Publisher: Elsevier BV
Date: 1987
DOI: 10.1016/S0168-8227(87)80050-5
Abstract: Epidemiological risk factor patterns for diabetes mellitus determined by hemoglobin A1 and fasting blood glucose criteria were compared in the biethnic (Melanesian and Indian) nation of Fiji. The 2 diagnostic criteria elicited essentially similar risk factor patterns in Indians but ranking of predictors was altered in Melanesians. By either criterion age was a dominant risk factor for diabetes in both ethnic groups with age2 a predictor in Indians of elevated hemoglobin A1 (chi 2 = 7.8, P less than 0.005) and fasting blood glucose (chi 2 = 25.3, P less than 0.0001). Age- and sex-adjusted prevalence of diabetes was higher in Indians than in Melanesians [RR = 2.5 (1.9-3.3)]. A positive family history was associated with increased risk of diabetes in both ethnic groups by the hemoglobin A1 criterion [pooled RR = 2.3 (2.0-2.6)] but was not significant in Melanesians under the fasting blood glucose criterion. A positive family history was a strong predictor of severe hyperglycemia in both ethnic groups. The relative risk for diabetes was greater in females [1.5 (1.2-9.1)], with no ethnic difference. There was no urban-rural difference in either ethnic group. The similar risk factor patterns for diabetes diagnosed by hemoglobin A1 and severe hyperglycemia suggest that elevated hemoglobin A1 may constitute a useful screening test for 'high risk' diabetic subjects.
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1111/CEN.13885
Abstract: Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5α-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5α-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. Cross-sectional analysis of 1865 community-dwelling men aged 50.4 ± 16.8 years. Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P < 0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P < 0.001). These haplotypes were associated primarily with differences in E2 in men <65 years and LH in men ≥65 years. A 5α-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.
Publisher: Bioscientifica
Date: 08-2019
DOI: 10.1530/JOE-19-0096
Abstract: In the last decade, it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar -knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.
Publisher: Cambridge University Press (CUP)
Date: 27-11-2021
Publisher: Cold Spring Harbor Laboratory
Date: 03-2023
DOI: 10.1101/2023.02.28.530435
Abstract: Despite the importance of the mouse in biomedical research, the levels of circulating gonadal steroids across the estrous cycle are not established with any temporal precision. Using liquid chromatography-mass spectrometry, now considered the gold standard for steroid hormone analysis, we aimed to generate a detailed profile of gonadal steroid levels across the estrous cycle of C57BL/6J mice. For reference, luteinizing hormone (LH) and prolactin concentrations were measured in the same s les by sandwich ELISA. Terminal blood s les were collected at 8-hour intervals (10 am, 6 pm, 2 am) throughout the four stages of the estrous cycle. As expected, the LH surge was detected at 6 pm on proestrus with a mean (±SEM) concentration of 11±3 ng/mL and occurred coincident with the peak in progesterone levels (22±4 ng/mL). Surprisingly, estradiol concentrations peaked at 10 am on diestrus (51±8 pg/mL), with levels on proestrus 6 pm reaching only two-thirds of this value (31±5 pg/mL). We also observed a proestrous peak in prolactin concentrations (132.5±17 ng/mL) that occurred earlier than expected at 2 am. Estrone and androstenedione levels were often close to the LOD and showed no consistent changes across the estrous cycle. Testosterone levels were rarely above the LOD (0.01 ng/mL). These observations provide the first detailed assessment of fluctuating gonadal steroid and reproductive hormone levels across the mouse estrous cycle and indicate that species differences exist between mice and other spontaneously ovulating species.
Publisher: Wiley
Date: 02-08-2020
DOI: 10.1002/PDS.5080
Publisher: Oxford University Press (OUP)
Date: 19-09-2005
Abstract: With limited information regarding fertility and sexual activity in the older population, men's behaviour, attitudes and concerns were explored in a representative population of middle-aged and older men using the Men in Australia, Telephone Survey (MATeS). A stratified random national s le of 5990 men participated in a standardized computer-assisted telephone interview. Equal numbers in the age strata 40-49, 50-59, 60-69 and >or=70 years were surveyed with findings census-standardized to the national population. Broad aspects of men's health and well-being, including reproductive health, were explored. The majority of men were sexually active in the last 12 months (age-standardized proportion, 78.3%) with approximately 37% of men aged >or=70 years still continuing sexual activity. Overall, 12.2% of men had never fathered children, of whom most (7.7%) had chosen not to have children. Questioning on failed attempts to produce a pregnancy suggested an involuntary infertility rate of 7.6%. The age-standardized vasectomy rate was 25.1%, with 5.6% of vasectomized men having no children. Although 9.2% of vasectomized men regretted sterilization, only 1.4% had undergone vasectomy reversal. Continuing sexual activity, fertility and contraception needs in middle-aged and older men suggests that education and service delivery must be more appropriately directed to an ageing population.
Publisher: Wiley
Date: 12-08-2014
DOI: 10.1111/JGS.12975
Abstract: To examine the associations between serum 25-hydroxyvitamin D (25OHD) levels and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25OHD), with type 2 diabetes mellitus (DM) in community-living men aged 70 and older. Cross-sectional. A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. Community dwelling men aged 70 and older taking part in CHAMP (N = 1,659). Serum 25OHD and 1,25OHD levels, presence of DM, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, statin use, income, measures of health, depression, activity of daily living disabilities, parathyroid hormone, estimated glomerular filtration rate, phosphate, and calcium. The prevalence of DM was 20.0%. There was a significant association between low 25OHD and 1,25OHD levels and DM that remained after adjustment for a wide range of confounders and covariates of clinical significance such as comorbidity, renal function, calciotropic hormones, and medications. 25OHD and 1,25OHD levels were associated with DM. The independent association between serum 25OHD and 1,25OHD concentrations and DM raises the question of whether each of the two vitamin D metabolites may influence DM through different biological mechanisms and pathways.
Publisher: Cambridge University Press (CUP)
Date: 20-08-2202
DOI: 10.1017/S1368980021003566
Abstract: Inadequate nutrient intakes have been linked with poor dentition in older adults. The aim of this study was to investigate the associations between the composition of functional tooth units (FTU) and nutrient intakes in older men. A cross-sectional study with a standardised validated diet history assessment and comprehensive oral health assessments. FTU were categorised by dentition type: (i) Group A (Natural FTU Only), (ii) Group B (Natural and Replaced FTU) and (iii) Group C (No Natural FTU). Attainment of nutrient reference values (NRV) for sixteen micronutrients was incorporated into a micronutrient risk variable, dichotomised ‘good’ (≥ 12) or ‘poor’ (≤ 11), and for seven macronutrients into a macronutrient risk variable, dichotomised ‘good’ (≥ 5) or ‘poor’ (≤ 4). Subjects selected from the local Sydney geographical areas. Community-dwelling older men ( n 608). 32 % ( n 197) of participants were categorised as Group A, 27 % ( n 167) as Group B and 40 % ( n 244) as Group C. In adjusted logistic regression analysis, being in Group C, compared with Group A, was associated with intakes below NRV recommendations for fibre (OR: 2·30, 95 % CI 1·30, 4·05). Adjusted analysis also showed that men in Group C, compared with Group A, were more likely to have poor intake of macronutrients (OR: 2·00, 95 % CI 1·01, 3·94). Our study shows statistically significant associations between the composition of FTU and poor macronutrient intakes. Maintaining natural pairs of occluding FTU may be important for attaining adequate nutrient intakes in older men.
Publisher: Informa UK Limited
Date: 04-05-2018
DOI: 10.1080/17446651.2018.1475227
Abstract: Age-related decline in serum testosterone (T) has been suggested in some studies to be associated with in idual components of frailty: diminished energy, muscle strength and physical function. The aim of this study is to comprehensively review evidence from observational and interventional studies on the relationship of T to frailty in older men. We reviewed observational studies exploring the relationship between circulating T and its potent metabolite dihydrotestosterone (DHT) with frailty. We further reviewed the effects of T treatment on lean mass, muscle strength and physical function in both frail and non-frail older men. T treatment may provide modest improvements in lean mass among both frail and non-frail older men, but current evidence on the T effect on muscle strength is conflicting and the effect on physical function is weak.
Publisher: Oxford University Press (OUP)
Date: 15-09-2017
Abstract: To determine whether calculated free testosterone (cFT) provides prognostic information independent of serum T for predicting morbidity and mortality in older men in cross-sectional and 5-year longitudinal analyses. We studied men aged ≥70 years at baseline (n = 1,705), 2-year and 5-year measuring serum T (liquid chromatography-mass spectrometry), SHBG (immunoassay), cFT (an assumption-free empirical formula) together with 24 morbidity and 4 mortality outcomes. For cross-sectional and longitudinal analyses we employed a joint prediction model using generalized estimating equation models adjusted for age, smoking, comorbidities, and body mass index (BMI) with men having both normal T and normal cFT as referent group. Most morbidity and mortality outcomes were predicted by a combination of low T and cFT (LL). By contrast, only a single morbidity outcome in cross-sectional and none in longitudinal analysis was predicted by low T/normal cFT (LN) or normal T/low cFT (NL) without significant LL associations (isolated discordance). While for the few outcomes that predicted morbidity in men with discordances (LN or NL), these predictions only occurred when LL was also significant. Hence, for morbidity or mortality prediction in older men, discordance between cFT and T is unusual and isolated discordance is rare, so that cFT provides minimal independent prognostic information over serum T.
Publisher: Wiley
Date: 13-04-2013
DOI: 10.1111/CEN.12208
Abstract: In men, testosterone (T) levels decline with age, and lower T predicts all-cause and cardiovascular mortality. However, the associations of T and its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with symptomatic peripheral arterial disease remain unclear. We assessed associations of T, DHT and E2 with lower limb intermittent claudication in older men. Cross-sectional study. Community-dwelling men aged 70-89 years resident in Perth, Western Australia. Intermittent claudication was ascertained by the Edinburgh Claudication Questionnaire. Early morning, plasma T, DHT and E2 were assayed using liquid chromatography-tandem mass spectrometry. There were 268 men with intermittent claudication and 2435 without claudication or any leg pain. Men with nonspecific leg pain (n = 986) were excluded. After adjusting for age, smoking, BMI, waist/hip ratio, hypertension, dyslipidaemia, diabetes, creatinine and prevalent cardiovascular disease (CVD), higher T was associated with reduced risk of having claudication (per 1 SD increase, odds ratio [OR] = 0·80, 95% confidence interval [CI] = 0·69-0·94, P = 0·006 quartiles, Q4/Q1, OR = 0·54, 95% CI = 0·36-0·81). Higher DHT was associated with reduced risk of having claudication (per 1 SD increase, OR = 0·86, 95% CI = 0·73-1·00, P = 0·048 Q4/Q1, OR = 0·64, 95% CI = 0·43-0·95). E2 was not associated with claudication (per 1 SD increase, OR = 0·96, 95% CI = 0·83-1·11, P = 0·565 Q4/Q1, OR = 0·88, 95% CI = 0·60-1·29). Lower T or DHT levels, but not E2, are associated with symptoms of intermittent claudication in older men. Reduced exposure to androgens may represent a causal factor or biomarker for symptomatic peripheral arterial disease. Further studies are needed to examine underlying mechanisms and evaluate therapeutic options in ageing men.
Publisher: Wiley
Date: 11-2010
DOI: 10.1111/J.1532-5415.2010.03145.X
Abstract: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men. Cross-sectional study of older men participating in the Concord Health and Ageing in Men Project (CHAMP). Elderly men living in a defined geographical region in Sydney, Australia. One thousand seven hundred five community-dwelling men aged 70 and older who participated in the baseline assessments of CHAMP. Upper and lower extremity strength were measured using dynamometers for grip and quadriceps strength. Appendicular skeletal lean mass was assessed using dual X-ray absorptiometry. Muscle quality was defined as the ratio of strength to mass in upper and lower extremities. For each parameter, subjects in the lowest 20% of the distribution were defined as below normal. Functional limitation was assessed according to self-report and objective lower extremity performance measures. Physical disability was measured according to self-report questionnaire. After adjusting for important confounders, the prevalence ratio (PR) for poor quadriceps strength and self-reported functional limitation was 1.91 (95% confidence interval (CI) = 1.10-2.40) for performance-based functional limitation the PR was 1.81 (95% CI = 1.45-2.24). The adjusted PR for poor grip strength and physical disability in instrumental activities of daily living (IADLs) was 1.37 (95% CI = 1.20-1.56). The adjusted PR for low skeletal lean mass (adjusted for fat mass) and physical disability in basic activities of daily living was 2.08 (95% CI = 1.37-3.15). For muscle quality, the PR for lower extremity specific force and functional limitation and physical disability was stronger than upper extremity specific force. Muscle strength is the single best measure of age-related muscle change and is associated with physical disability in IADLs and functional limitation.
Publisher: Wiley
Date: 02-01-2000
Publisher: Wiley
Date: 06-1993
DOI: 10.1111/J.1440-1746.1993.TB01195.X
Abstract: Patients with end-stage liver disease have significant mortality often associated with intercurrent episodes of bleeding or sepsis. Intact adrenal function is essential in such situations. In order to test the hypothesis that adrenal insufficiency might be present in severe liver disease, hypothalamic-pituitary adrenal function was evaluated in patients with end-stage liver disease awaiting transplantation. The study had a prospective, open comparative design with patients restricted to those having non-alcoholic liver disease in order to avoid the confounding direct effects of alcohol on adrenocortical function. Fifty-one consecutive patients with end-stage, non-alcoholic liver disease undergoing evaluation for liver transplantation and 40 healthy controls were studied. Patients who had used corticosteroids (n = 8) or who were unable to complete the investigations (n = 5) were excluded leaving 38 patients eligible for analysis. Adrenal function was evaluated under basal conditions by single morning measurements of plasma total and free cortisol, corticosteroid-binding globulin, dehydroepiandrosterone sulfate and by adrenal stimulation indirectly using insulin-induced (0.1 U/kg, i.v.) hypoglycaemia and/or directly by adrenocorticotrophic hormone (ACTH) 250 micrograms tetracosactrin, i.v.) stimulation. Compared with healthy controls, patients with liver disease had a 64% reduction in maximal increments of plasma cortisol to indirect adrenal stimulation via insulin-induced hypoglycaemia and a 39% reduction to direct adrenal stimulation by ACTH (all P < 0.001). There was a significant negative correlation between the severity of underlying liver disease as assessed by Child-Pugh scores and peak control responses to ACTH (r = -0.647, P < 0.0001) and insulin-induced hypoglycaemia (r = -0.597, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Oxford University Press (OUP)
Date: 12-2001
DOI: 10.1093/HUMREP/16.12.2632
Abstract: Sperm cryopreservation allows men with threatened fertility to preserve their progenitive potential, but there is little data on long-term outcomes of elective sperm cryostorage programmes. Over 22 years, 930 men sought semen cryostorage in a single academic hospital, of which 833 (90%) had spermatozoa cryostored. Among 692 (74%) men surviving their illness, sperm s les were discarded for 193 (21% of all applicants, 28% of survivors) and cryostored spermatozoa were used for 64 men (7% of all applicants, 9% of survivors) in 85 treatment cycles commencing at a median of 36 months post-storage (range 12-180 months) with nearly 90% of usage started within 10 years of storage and none after 15 years. Pregnancy was most efficiently produced by intracytoplasmic sperm injection (median three cycles) compared with conventional IVF (median eight cycles) or artificial insemination (median more than six cycles P < 0.05). A total of 141 (15%) of men had died and of these, 120 (85% of those dying) had their spermatozoa discarded requests to prolong cryostorage were received from relatives of 21 men (2% of all applicants, 15% of deceased) of which three cases had spermatozoa transferred for use with no pregnancies reported. Sperm concentration was lower for all cryostorage groups compared with healthy sperm donor controls (P < 0.05). Following orchidectomy, men with testicular cancer had sperm density approximately half that of all other groups of men seeking cryostorage (P < 0.05), the lowering attributable to removal of one testis rather than in defects in spermatogenesis. Elective sperm cryopreservation is an effective, if sparsely used, form of fertility insurance for men whose fertility is threatened by medical treatment and is an essential part of any comprehensive cancer care programme.
Publisher: Medknow
Date: 05-2008
Publisher: Wiley
Date: 03-11-2017
DOI: 10.1002/JBMR.3016
Abstract: Body composition and muscle function have important implications for falls and fractures in older adults. We aimed to investigate longitudinal associations between sarcopenic obesity and its components with bone mineral density (BMD) and incident falls and fractures in Australian community-dwelling older men. A total of 1486 men aged ≥70 years from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2-year follow-up (2007-2009 n = 1238), and 5-year follow-up (2010-2013 n = 861). At all three time points, measurements included appendicular lean mass (ALM), body fat percentage and total hip BMD, hand-grip strength, and gait speed. Participants were contacted every 4 months for 6.1 ± 2.1 years to ascertain incident falls and fractures, the latter being confirmed by radiographic reports. Sarcopenic obesity was defined using sarcopenia algorithms of the European Working Group on Sarcopenia (EWGSOP) and the Foundation for the National Institutes of Health (FNIH) and total body fat ≥30% of total mass. Sarcopenic obese men did not have significantly different total hip BMD over 5 years compared with non-sarcopenic non-obese men (p > 0.05). EWGSOP-defined sarcopenic obesity at baseline was associated with significantly higher 2-year fall rates (incidence rate ratio [IRR] 1.66 95% confidence interval [CI] 1.16-2.37), as were non-sarcopenic obesity (1.30 1.04-1.62) and sarcopenic non-obesity (1.58 1.14-2.17), compared with non-sarcopenic non-obese. No association with falls was found for sarcopenic obesity using the FNIH definition (1.01 0.63-1.60), but after multivariable adjustment, the FNIH-defined non-sarcopenic obese group had a reduced hazard for any 6-year fracture compared with sarcopenic obese men (hazard ratio 0.44 95% CI 0.23-0.86). In older men, EWGSOP-defined sarcopenic obesity is associated with increased fall rates over 2 years, and FNIH-defined sarcopenic obese men have increased fracture risk over 6 years compared with non-sarcopenic obese men. © 2016 American Society for Bone and Mineral Research.
Publisher: The Endocrine Society
Date: 08-2009
DOI: 10.1210/EN.2009-0438
Publisher: Wiley
Date: 23-03-2017
DOI: 10.1111/ANDR.12357
Abstract: Scrotal skin is thin and has high steroid permeability, but the pharmacokinetics of testosterone via the scrotal skin route has not been studied in detail. The aim of this study was to define the pharmacokinetics of testosterone delivered via the scrotal skin route. The study was a single-center, three-phase cross-over pharmacokinetic study of three single doses (12.5, 25, 50 mg) of testosterone cream administered in random sequence on different days with at least 2 days between doses to healthy eugonadal volunteers with endogenous testosterone suppressed by administration of nandrolone decanoate. Serum testosterone, DHT and estradiol concentrations were measured by liquid chromatograpy, mass spectrometry in extracts of serum taken before and for 16 h after administration of each of the three doses of testosterone cream to the scrotal skin. Testosterone administration onto the scrotal skin produced a swift (peak 1.9-2.8 h), dose-dependent (p < 0.0001) increase in serum testosterone with the 25 mg dose maintaining physiological levels for 16 h. Serum DHT displayed a time- (p < 0.0001), but not dose-dependent, increase in concentration reaching a peak concentration of 1.2 ng/mL (4.1 nm) at 4.9 h which was delayed by 2 h after peak serum testosterone. There were no significant changes in serum estradiol over time after testosterone administration. We conclude that testosterone administration to scrotal skin is well tolerated and produces dose-dependent peak serum testosterone concentration with a much lower dose relative to the non-scrotal transdermal route.
Publisher: Wiley
Date: 10-03-2019
DOI: 10.1111/ANDR.12598
Abstract: Controversial speculation suggestions that dietary intake may affect semen quality and testicular function, however, there are limited comprehensive studies observing dietary patterns. To study associations between major dietary patterns and markers of testicular function in adulthood. Observational cross-sectional study of two hundred and ninety men with an average age of 20 years, from the Western Australian Pregnancy Cohort (Raine) Study. Usual dietary intake assessed using a semi-quantitative food frequency questionnaire at 20 years of age. Two dietary patterns previously identified using exploratory factor analysis ("Healthy" or "Western") and participants received z-scores for each dietary pattern. Primary endpoints were testicular volume, total sperm per ejaculate, morning serum testosterone concentration. Secondary endpoints were semen s le parameters, inhibin B and sex steroids (DHT: 3α-diol, 3β-diol LH FSH DHEA estradiol estrone). Participants were on average 20.0 ± 0.4 years old, had a median of 2 days sexual abstinence and a body mass index of 24.1 ± 3.9 kg/m Despite associations between greater intake of the "Western" dietary pattern and a decreased male reproductive health markers, our lack of consistent associations of either a "Healthy" or a "Western" dietary pattern, limit clinical or biological significance in isolation. A potential negative association of a "Western" dietary pattern with male reproductive health was detected and should be studied further in population-based studies.
Publisher: Massachusetts Medical Society
Date: 17-05-2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1988
DOI: 10.1097/00005053-198803000-00003
Abstract: Oral contraceptive (ORC)-related depression and irritability are among the most commonly reported drug-induced psychiatric symptoms. To investigate the etiological role of genetic factors in ORC-related symptoms, we studied questionnaire responses in 715 monozygotic and 416 dizygotic volunteer twin pairs concordant for ORC usage. Biometrical genetic analysis indicated that the liability to ORC-related depression was clearly influenced by genetic but not familial-environmental factors. Similar, but less definitive, results were found for ORC-related irritability. Multivariate genetic analysis indicated that both the genetic and the in idual-specific environmental factors that influenced the liability to ORC-related depression and irritability were largely distinct from those that influence baseline levels of psychiatric symptoms. Genes play an important etiological role in ORC-related psychiatric side effects. The genes that influence liability to these side effects appear to differ from those that are etiologically important in baseline psychiatric symptomatology.
Publisher: American Physiological Society
Date: 15-09-2013
DOI: 10.1152/AJPENDO.00263.2013
Abstract: Homozygous androgen receptor (AR)-knockout (ARKO) female mice are subfertile due to both intra- and extraovarian (neuroendocrine) defects as defined by ovary transplantation. Using ARKO mice, this study set out to reveal the precise AR-regulated pathways required for optimal androgen-regulated ovulation and fertility. ARKO females exhibit deficient neuroendocrine negative feedback, with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) ( P 0.01). Positive feedback is also altered as intact ARKO females, at late proestrus, exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, at late proestrus, intact ARKO females display diminished preovulatory serum estradiol (E 2 P 0.01) and LH ( P 0.05) surge levels and reduced Kiss1 mRNA expression in the anteroventral periventricular nucleus ( P 0.01) compared with controls. However, this reduced ovulatory LH response in intact ARKO females can be rescued by OVX and E 2 priming or treatment with endogenous GnRH. These findings reveal that AR regulates the negative feedback response to E 2 , E 2 -positive feedback is compromised in ARKO mice, and AR-regulated negative and positive steroidal feedback pathways impact on intrahypothalamic control of the kisspeptin/GnRH/LH cascade. In addition, intraovarian AR-regulated pathways controlling antral to preovulatory follicle dynamics are disrupted because adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte/follicle diameter ratios ( P 0.01) and increased proportions of unhealthy large antral follicles ( P 0.05) compared with controls. As a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle ( P 0.05) and corpora lutea numbers ( P 0.01). However, embryo development to the blastocyst stage is unchanged in ARKO females, and hence, the subfertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in neuroendocrine regulation and timing of the ovulatory LH surge as well as antral reovulatory follicle development.
Publisher: Wiley
Date: 23-12-2021
DOI: 10.1002/JBMR.4228
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.ECL.2007.03.002
Abstract: Impaired gonadal function, obesity, metabolic syndrome, and obstructive sleep apnea commonly occur together in men. We propose that this arises due to two interlinked cycles. Understanding the molecular mechanisms by which these relationships occur may lead to novel therapeutic strategies. Although obesity is not gender specific and the effectiveness of current antiobesity interventions have predominantly been verified in women, promoting weight loss in men is an urgent concern because men are have proportionally worse health consequences. In addition, avoiding excessive weight may maintain optimal male reproductive health.
Publisher: Oxford University Press (OUP)
Date: 08-12-2016
Abstract: to explore the longitudinal associations between body composition measures, sarcopenic obesity and outcomes of frailty, activities of daily living (ADL) and instrumental ADL (IADL) disability, institutionalisation and mortality. men aged ≥ 70 years (2005-07) from the Concord Health and Ageing in Men Project were assessed at baseline (n = 1,705), 2 (n = 1,366) and 5 years (n = 954). The main outcome measures were frailty (adapted Fried criteria), ADL, including personal care and mobility and IADL disability (ability to perform tasks for independent living), institutionalisation and mortality. The Foundation for the National Institutes of Health cut-points were used for low muscle mass: appendicular lean mass (ALM):Body Mass Index (BMI) ratio (ALMBMI) 30% fat. Generalised estimating equations were used to examine the longitudinal associations between the independent variables (obesity alone, low muscle mass and sarcopenic obesity) and frailty, ADL and IADL disability. in unadjusted, age adjusted and fully adjusted analysis, men with low muscle mass showed increased risk of frailty and IADL disability. In fully adjusted analysis, men with sarcopenic obesity had an increased risk of frailty (odds ratio (OR): 2.00 (95% confidence of interval (CI): 1.42, 2.82)) ADL disability (OR: 1.58 (95% CI: 1.12, 2.24)) and IADL disability (OR: 1.36 (95% CI: 1.05, 1.76)). Obesity alone was protective for institutionalisation (OR: 0.51 (95% CI: 0.31, 0.84)) but was not associated with any other outcomes. low muscle mass and sarcopenic obesity were associated with poor functional outcomes, independent of confounders. This would suggest that future trials on frailty and disability prevention should be designed to intervene on both muscle mass and fat mass.
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/RD10308
Publisher: Springer Science and Business Media LLC
Date: 27-03-2020
Publisher: Springer Science and Business Media LLC
Date: 24-02-2010
Publisher: The Endocrine Society
Date: 06-2015
DOI: 10.1210/JC.2015-1016
Abstract: The longitudinal relationship between declining levels of reproductive hormones and cognitive function remains unclear in older men. The objective of this study was to examine the temporal relationship between changes in major reproductive hormone levels and cognitive decline over time. Men age 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) were assessed at baseline (2005-2007 n = 1705), 2-year followup (2007-2009 n = 1367), and 5-year followup (2010-2013 n = 958). At all assessments, T, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH by immunoassay. Dementia was diagnosed at baseline by clinical assessment and review by a specialist panel. Cognitive function was measured at all three assessments by the Mini Mental State Examination. None of the baseline reproductive hormones predicted cognitive decline in men without dementia over 5 years. However, the change in serum hormones over time was associated with cognitive decline. In univariate analysis, change in all the studied hormones, except for E2, was significantly associated with cognitive decline. However, in multivariate-adjusted models accounting for potential confounders, only change in serum T (β = 0.067), DHT (β = 0.394), calculated free T (β = 0.005), and E1 (β = 0.009) remained significantly associated (P < .05) with cognitive decline. Men who had dementia at baseline had significantly greater decline in serum T levels, but not in other studied hormones, over the 5 years. Our findings show that decline in androgen status is associated with cognitive decline in older men, but the causality of this association requires further elucidation.
Publisher: Wiley
Date: 10-03-2022
DOI: 10.1111/JNE.13110
Abstract: Polycystic ovary syndrome (PCOS) is associated with androgen excess and, frequently, hyperactive pulsatile luteinizing hormone (LH) secretion. Although the origins of PCOS are unclear, evidence from pre‐clinical models implicates androgen signalling in the brain in the development of PCOS pathophysiology. Chronic exposure of female mice to dihydrotestosterone (DHT) from 3 weeks of age drives both reproductive and metabolic impairments that are ameliorated by selective androgen receptor (AR) loss from the brain. This suggests centrally driven mechanisms in hyperandrogen‐mediated PCOS‐like pathophysiology that remain to be defined. Acute prenatal DHT exposure can also model the hyperandrogenism of PCOS, and this is accompanied by increased LH pulse frequency and increased GABAergic innervation of gonadotrophin‐releasing hormone (GnRH) neurons. We aimed to determine the impact of chronic exposure of female mice to DHT, which models the hyperandrogenism of PCOS, on pulsatile LH secretion and putative GABAergic input to GnRH neurons. To do this, GnRH‐green fluorescent protein (GFP) female mice received either DHT or blank capsules for 90 days from postnatal day 21 ( n = 6 or 7 per group). Serial tail‐tip blood s ling was used to measure LH dynamics and perfusion‐fixed brains were collected and immunolabelled for vesicular GABA transporter (VGAT) to assess putative GABAergic terminals associated with GFP‐labelled GnRH neurons. As expected, chronic DHT resulted in acyclicity and significantly increased body weight. However, no differences in LH pulse frequency or the density of VGAT appositions to GnRH neurons were identified between ovary‐intact DHT‐treated females and controls. Chronic DHT exposure significantly increased the number of AR expressing cells in the hypothalamus, whereas oestrogen receptor α‐expressing neuron number was unchanged. Therefore, although chronic DHT exposure from 3 weeks of age increases AR expressing neurons in the brain, the GnRH neuronal network changes and hyperactive LH secretion associated with prenatal androgen excess are not evident. These findings suggest that unique central mechanisms are involved in the reproductive impairments driven by exposure to androgen excess at different developmental stages.
Publisher: SAGE Publications
Date: 03-10-2019
Abstract: Participant recruitment to diabetes prevention randomised controlled trials is challenging and expensive. The T4DM study, a multicentre, Australia-based, Phase IIIb randomised controlled trial of testosterone to prevent Type 2 diabetes in men aged 50–74 years, faced the challenge of screening a large number of prospective participants at a small number of sites, with few staff, and a limited budget for screening activities. This article evaluates a high-volume, low-cost, semi-automated approach to screen and enrol T4DM study participants. We developed a sequential multi-step screening process: (1) web-based pre-screening, (2) laboratory screening through a network of third-party pathology centres, and (3) final on-site screening, using online data collection, computer-driven eligibility checking, and automated, email-based communication with prospective participants. Phone- and mail-based data collection and communication options were available to participants at their request. The screening process was administered by the central coordinating centre through a central data management system. Screening activities required staffing of approximately 1.6 full-time equivalents over 4 years. Of 19,022 participants pre-screened, 13,108 attended a third-party pathology collection centre for laboratory screening, 1217 received final, on-site screening, and 1007 were randomised. In total, 95% of the participants opted for online pre-screening over phone-based pre-screening. Screening costs, including both direct and staffing costs, totalled AUD1,420,909 (AUD75 per subject screened and AUD1411 per randomised participant). A multi-step, semi-automated screening process with web-based pre-screening facilitated low-cost, high-volume participant enrolment to this large, multicentre randomised controlled trial. Centralisation and automation of screening activities resulted in substantial savings compared to previous, similar studies. Our screening approach could be adapted to other randomised controlled trial settings to minimise the cost of screening large numbers of participants.
Publisher: Wiley
Date: 16-02-2017
DOI: 10.1111/AJAG.12376
Abstract: To explore differences between older male caregivers and non-caregivers on health status, health behaviours and well-being, including symptoms of anxiety. Data were collected through self-completed questionnaires and face-to-face interviews with 1705 community living men aged ≥70 in the Concord Health and Ageing in Men Project. Eleven per cent of older men were caregivers, of whom 81.7% were looking after their wives or partners. Older male caregivers did not have worse physical health or more depressive symptoms than non-caregivers, but being a caregiver was associated with increased likelihood of reporting anxiety symptoms (OR: 2.32, 95% CI: 1.39-3.87). Caregivers had similar levels and frequencies of leisure activities but did more housework activities than non-caregivers. Higher anxiety levels were the main adverse health condition in older male caregivers. Strategies to assist minimising anxiety for caregivers should be a target of interventions.
Publisher: Springer Science and Business Media LLC
Date: 2001
Publisher: Wiley
Date: 30-10-2017
DOI: 10.1111/ADJ.12564
Publisher: AMPCo
Date: 05-2004
DOI: 10.5694/J.1326-5377.2004.TB06060.X
Abstract: Androgen deficiency is a clinical diagnosis confirmed by hormone assays. Among younger men, androgen deficiency is usually due to underlying hypothalamopituitary or testicular disorders. Androgen replacement therapy should be started after proof of androgen deficiency and should continue lifelong with monitoring. Men presenting with erectile dysfunction should be evaluated for androgen deficiency, but it is an uncommon cause if overt androgen deficiency is confirmed, an underlying disorder needs further specialist investigation. In the absence of characteristic underlying testicular or pituitary disorders, new diagnosis of androgen deficiency in older men is difficult because of the non-specific symptoms and the decline in blood testosterone levels seen in healthy ageing and chronic medical disorders. There remains no convincing evidence that androgen therapy is either effective treatment or safe for older men unless they have frank androgen deficiency.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2002
DOI: 10.1161/01.ATV.0000022167.80130.A6
Abstract: Objective — Because male sex is an independent risk factor for the severity of atherosclerosis, it is possible that androgens may be proatherogenic. There is evidence that sex hormones, particularly estrogens, regulate (or modulate) inflammation, a process integral to atherogenesis. Because levels of serum inflammatory markers predict cardiovascular outcomes, we prospectively assessed the effects of androgen therapy on these markers in older men. Methods and Results — Levels of high-sensitivity C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured from sera collected at baseline and at the end of 2 randomized double-blind placebo-controlled trials evaluating the effects of 3 months of androgen treatment with either dihydrotestosterone (DHT) or recombinant human chorionic gonadotropin (rhCG) in healthy men aged years with partial androgen deficiency (serum testosterone levels nmol/L). For the DHT study (70 mg transdermally daily), 33 men completed 3 months of treatment (16 men were treated with DHT, and there were 17 controls). For the rhCG (250 μg twice weekly) study, 20 men were treated with rhCG, and there were 20 controls. In both studies, groups were well matched for age and vascular risk factors. Androgen levels (DHT and testosterone) were consistently maintained at eugonadal levels throughout the trials, with estradiol markedly increased by rhCG but not DHT. Baseline CRP levels were 0.74 to 1.49 mg/L, sVCAM-1 levels were 847 to 950 ng/mL, and sICAM-1 levels were 256 to 292 ng/mL in all groups. Neither DHT nor rhCG resulted in significant changes in CRP, sVCAM-1, or sICAM-1 compared with placebo ( P .3 in both studies). Conclusions — Exogenous androgen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women. These data provide a measure of reassurance concerning potential adverse cardiovascular effects of androgen therapy in older men.
Publisher: Massachusetts Medical Society
Date: 31-07-1986
DOI: 10.1056/NEJM198607313150513
Abstract: Controversy has attended the relationship between risk-adjusted mortality and process-of-care. There would be advantage in the establishment, at the data-base level, of global quantitative indices subsuming the ersity of process-of-care. A retrospective, cohort study of patients identified in the Australian and New Zealand Intensive Care Society Adult Patient Database, 1993-2003, at the level of geographic and ICU-level descriptors (n = 35), for both hospital survivors and non-survivors. Process-of-care indices were established by analysis of: (i) the smoothed time-hazard curve of in idual patient discharge and determined by pharmaco-kinetic methods as area under the hazard-curve (AUC), reflecting the integrated experience of the discharge process, and time-to-peak-hazard (TMAX, in days), reflecting the time to maximum rate of hospital discharge and (ii) in idual patient ability to optimize output (as length-of-stay) for recorded data-base physiological inputs estimated as a technical production-efficiency (TE, scaled [0,(maximum)1]), via the econometric technique of stochastic frontier analysis. For each descriptor, multivariate correlation-relationships between indices and summed mortality probability were determined. The data-set consisted of 223129 patients from 99 ICUs with mean (SD) age and APACHE III score of 59.2(18.9) years and 52.7(30.6) respectively 41.7% were female and 45.7% were mechanically ventilated within the first 24 hours post-admission. For survivors, AUC was maximal in rural and for-profit ICUs, whereas TMAX (>or= 7.8 days) and TE (>or= 0.74) were maximal in tertiary-ICUs. For non-survivors, AUC was maximal in tertiary-ICUs, but TMAX (>or= 4.2 days) and TE (>or= 0.69) were maximal in for-profit ICUs. Across descriptors, significant differences in indices were demonstrated (analysis-of-variance, P <or= 0.0001). Total explained variance, for survivors (0.89) and non-survivors (0.89), was maximized by combinations of indices demonstrating a low correlation with mortality probability. Global indices reflecting process of care may be formally established at the level of national patient data-bases. These indices appear orthogonal to mortality outcome.
Publisher: The Endocrine Society
Date: 02-1990
Abstract: We have compared the time courses of serum inhibin and estradiol responses to ovarian hyperstimulation in patients undergoing in vitro fertilization and embryo transfer as well as their predictive value for outcome of intermediate variables and pregnancy in in vitro fertilization and embryo transfer. Blood s les (n = 749) were collected for up to 6 days before hCG administration in 100 consecutive treatment cycles, of which 44 resulted in pregnancy, as defined by elevated luteal phase serum hCG beta levels. Inhibin and estradiol levels increased markedly in parallel during hyperstimulation and were highly correlated (r = 0.89 P less than 0.001). Inhibin responses were significantly lower in women 35 yr of age or older (P less than 0.001), although estradiol responses were not influenced by age. Gravidity and tubal disease also had marginal effects on the time course of inhibin responses, but not on overall mean inhibin levels or estradiol responses. The time course of hormonal responses to hyperstimulation was not influenced by any other demographic or etiological factors. Peak values of both hormones correlated with the total number of follicles (inhibin, r = 0.70 estradiol, r = 0.65 P less than 0.001) and oocytes retrieved per cycle (inhibin, r = 0.49 estradiol, r = 0.39 P less than 0.001). The time course and peak values of inhibin and estradiol responses to hyperstimulation did not differ significantly between conception or nonconception cycles whether judged by biochemical (luteal hCG beta) or clinical (viable ongoing pregnancy) criteria. Luteal phase serum inhibin, estradiol, progesterone, and hCG levels were significantly higher in conception than in nonconception cycles (P less than 0.001). These data suggest that the rises in serum inhibin and estradiol levels during hyperstimulation have similar predictive properties for IVF-ET outcomes and could, therefore, be used interchangeably to monitor hyperstimulation regimens. The age-related reduction in inhibin, but not estradiol, responses suggests that these two hormones reflect different granulosa cell functions and that serum inhibin responses to maximal ovarian stimulation may be a sensitive and early index of declining ovarian function with advancing age.
Publisher: Bioscientifica
Date: 03-2006
DOI: 10.1677/JOE.1.06614
Abstract: Ovarian primordial follicle reserve is considered hormonally independent or subject to depletion by FSH-driven follicle recruitment. To explore specific in vivo effects of FSH on early follicle populations in the absence of luteinizing hormone (LH) activity, we examined mature hypogonadal ( hpg ), gonadotrophin-deficient mice expressing transgenic (tg) human FSH. Sustained expression of tg-FSH (5.3 ± 0.3 IU/l) increased ovary weights fourfold and significantly elevated total primordial follicle numbers twofold in tg-FSH hpg (4209 ± 457) relative to non-tg hpg (2079 ± 391) and wild-type (2043 ± 195) age-matched ovaries. Absolute primary follicle numbers in tg-FSH hpg ovaries were similar to non-tg hpg and wild-type ovaries. Furthermore, tg-FSH quantitatively increased secondary and antral follicles in hpg ovaries to numbers equivalent to wild-type, but did not induce ovulation, indicating a selective FSH response without LH. Circulating inhibin B and inhibin A levels were significantly increased in tg-FSH hpg females compared with hpg controls, and inhibin B correlated with antral number, consistent with FSH-driven antral follicle formation. These findings revealed that sustained pituitary-independent FSH activity, in the absence of endogenous gonadotrophins, promotes an increase in primordial follicle reserve despite also stimulating follicular growth in mature females. Therefore, the tg-FSH hpg ovary presents a novel paradigm to evaluate specific gonadotrophin effects on follicle reserve and recruitment.
Publisher: BMJ
Date: 30-11-2016
DOI: 10.1136/BMJ.I5968
Abstract: To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk. Population based case-control study SETTING: 370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality. 19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013. Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was sub ided into duration of more or less than six months. Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for comorbidities and all matching factors. The adjusted rate ratio of venous thromboembolism was 1.25 (95% confidence interval 0.94 to 1.66) for current versus no testosterone treatment. In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10 000 person years. The rate ratio after more than six months' treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07). Increased rate ratios within the first six months of treatment were observed in all strata: the rate ratio was 1.52 (0.94 to 2.46) for patients with pathological hypogonadism and 1.88 (1.02 to 3.45) for those without it, and 1.41 (0.82 to 2.41) for those with a known risk factor for venous thromboembolism and 1.91 (1.13 to 3.23) for those without one. Starting testosterone treatment was associated with an increased risk of venous thromboembolism, which peaked within six months and declined thereafter.
Publisher: Bioscientifica
Date: 05-2016
DOI: 10.1530/ERC-16-0039
Abstract: Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT ( n =8) and ugeARKO ( n =7) uteri. Uterine weight was significantly ( P =0.002) increased in ugePTENARKO (374±97 mg (mean± s.e. )) compared with WT (97±6 mg), ugeARKO (94±12 mg), and ugePTENKO (205±33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.
Publisher: Walter de Gruyter GmbH
Date: 1997
DOI: 10.1515/JPEM.1997.10.4.401
Abstract: The effect of androgens on changes in circulating LH and FSH during pubertal development was examined longitudinally in a 3 year study in male hamadryas baboons. Baboon LH and FSH were measured by a species-specific radioimmunoassay and bioactive LH (B-LH) was measured by the mouse in vitro Leydig cell bioassay. Control baboons (n = 5) progressed normally through puberty. Eight baboons were castrated prepubertally of these four received testosterone implants at the chronological age (CA) of clinical puberty (4.0 +/- 0.1 yr, mean +/- SEM). The timing of the postcastration rise in B-LH levels ranged between 1 and 15 months later (median 3.5 months) (CA 3.5 +/- 0.2 yr) thus supporting the hypothesis that central activation of gonadotrophins occurs at the time of puberty, independent of gonadal influences. Similar results were seen for immunoreactive-LH (IR-LH) and IR-FSH levels. IR- and B-LH levels continued to rise with age (P < 0.0003) in the untreated castrated baboons, associated with an increased LH B/I ratio. Administration of testosterone resulted in temporary suppression of B-LH, IR-LH and IR-FSH levels however gonadotrophin levels subsequently rose with age despite increased testosterone levels. Thus the mechanisms initiating puberty involve both gonad-independent events as well as alterations in negative androgenic feedback sensitivity on gonadotrophin secretion.
Publisher: The Endocrine Society
Date: 08-03-2021
Abstract: Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. We aimed to determine the effect of testosterone treatment on bone microarchitecture using high resolution–peripheral quantitative computed tomography (HR-pQCT). Men ≥ 50 years of age were recruited from 6 Australian centers and were randomized to receive injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. The primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (1 center). Secondary endpoints included other HR-pQCT parameters and bone remodeling markers. Areal BMD (aBMD) was measured by dual-energy x-ray absorptiometry (DXA) in 601 men (5 centers). Using a linear mixed model for repeated measures, the mean adjusted differences (95% CI) at 12 and 24 months between groups are reported as treatment effect. Over 24 months, testosterone treatment, versus placebo, increased tibial cortical vBMD, 9.33 mg hydroxyapatite (HA)/cm3) (3.96, 14.71), P & 0.001 or 3.1% (1.2, 5.0) radial cortical vBMD, 8.96 mg HA/cm3 (3.30, 14.62), P = 0.005 or 2.9% (1.0, 4.9) total tibial vBMD, 4.16 mg HA/cm3 (2.14, 6.19), P & 0.001 or 1.3% (0.6, 1.9) and total radial vBMD, 4.42 mg HA/cm3 (1.67, 7.16), P = 0.002 or 1.8% (0.4, 2.0). Testosterone also significantly increased cortical area and thickness at both sites. Effects on trabecular architecture were minor. Testosterone reduced bone remodeling markers CTX, −48.1 ng/L [−81.1, −15.1], P & 0.001 and P1NP, −6.8 μg/L[−10.9, −2.7], P & 0.001. Testosterone significantly increased aBMD at the lumbar spine, 0.04 g/cm2 (0.03, 0.05), P & 0.001 and the total hip, 0.01 g/cm2 (0.01, 0.02), P & 0.001. In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.
Publisher: Wiley
Date: 05-06-2013
DOI: 10.1111/AJAG.12048
Abstract: To describe the prevalence and correlates of alcohol consumption and tobacco smoking among older Australian men. Self-reported alcohol and tobacco use was assessed among a random s le of community-dwelling men aged ≥70 years living in Sydney (n = 1705) from 2005 to 2007. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with alcohol and tobacco use. The prevalence of heavy/excessive drinking was 19.2%, daily drinking 33.7%, and binge drinking 14.1%. Daily drinking was associated with chronic pain (OR = 1.38, 95% CI: 1.07-1.78). Binge drinking was associated with anxiety (OR = 1.93, 95% CI: 1.05-3.54) and being widowed (OR = 1.74, 95% CI: 1.11-2.73). Six per cent of men were current smokers and 56.7% were former smokers. Former smoking was associated with polypharmacy (OR = 1.47, 95% CI: 1.14-1.91) and each additional comorbid condition (OR = 1.11, 95% CI: 1.03-1.19). Nearly one-fifth of older men drank heavily or excessively. This highlights the need for public health initiatives to reduce alcohol consumption in older people.
Publisher: The Endocrine Society
Date: 02-1989
Abstract: We studied the effects of sleep apnea on neuroendocrine function in a cross-sectional study of 225 consecutive men undergoing sleep studies and in a longitudinal study of 43 men with severe obstructive sleep apnea before and after 3 months of successful treatment with nasal continuous positive airways pressure to eliminate upper airways obstruction. Blood s les were collected at 0600-0630 h on awakening for measurement of plasma insulin-like growth factor I (IGF-I), total and free testosterone, sex hormone-binding globulin (SHBG), LH, FSH, PRL, T4, T4-binding globulin, and cortisol. The plasma hormone levels were analyzed in relation to the severity of sleep apnea, as indicated by the desaturation index (the hourly rate of episodes of arterial oxygen desaturation greater than 4% of the stable baseline) and the mean minimal oxygen saturation during the desaturation episodes. In the cross-sectional study plasma IGF-I, free and total testosterone, and SHBG levels were significantly lower in relation to the severity of sleep apnea, whereas plasma LH, FSH, PRL, T4, T4-binding globulin, and cortisol were not. The decreases in plasma IGF-I and total and free testosterone were independent of the effects of aging and adiposity by covariance analysis. In the longitudinal study plasma IGF-I, total testosterone, and SHBG, but not free testosterone, significantly increased after 3 months of nasal continuous positive airways pressure treatment. We conclude that sleep apnea causes reversible neuroendocrine dysfunction in men, which is manifested by decreased plasma. IGF-I, testosterone, and SHBG levels. This neuroendocrine dysfunction is related to the severity of the sleep apnea, as indicated by the nadir levels of arterial oxygen desaturation and the rate of desaturation episodes. These hormonal measurements may provide biochemical markers for both the severity of sleep apnea and its response to therapeutic intervention. In addition, sleep apnea may be a previously unrecognized confounder of the neuroendocrine correlates of aging.
Publisher: Wiley
Date: 02-01-2021
DOI: 10.1111/CEN.14401
Publisher: Oxford University Press (OUP)
Date: 2014
Abstract: participation restriction, defined as 'problems an in idual may experience in involvement in life situations' (e.g. work and leisure), reflects difficulty functioning at a societal level and is a key component of disability. Our objective was to describe changes in participation in older men over a 2-year period and to identify baseline variables associated with participation and change in participation over the 2-year period. one thousand and three hundred and twenty-seven community-dwelling men aged 70 years or over who completed the baseline and 2-year follow-up phases of the Concord Health and Ageing in Men Project, a population-based cohort study in Sydney, Australia, were studied. Participation restriction and a range of other variables were measured using self-report and performance measures. Regression analyses were conducted to examine factors associated with participation and change in participation. over the 2-year period, participation in life roles deteriorated in 47.3% (627/1,327) of men, stayed the same in 20.7% (275/1,327) and improved in the remainder (32.0%). Overall, there was a significant deterioration in participation (P < 0.001). Reduced participation at 2-year follow-up was significantly associated with the following baseline factors: age, more comorbidities, mild cognitive impairment or dementia, lower mood, weakness, slower gait, worse activities of daily living performance, driving and baseline participation score. These variables explained 56% of the variance in participation at 2 years. participation in life roles worsened over a 2-year period in some community-dwelling older men. A number of associated factors were identified, which may provide targets for intervention to improve participation among older men.
Publisher: The Endocrine Society
Date: 09-2007
DOI: 10.1210/EN.2007-0046
Abstract: Rising serum FSH levels is one of the earliest signs of human female reproductive aging. Whether or not elevated FSH remains a passive reflection of a diminishing ovarian follicle pool or actively contributes to declining female fertility with age has not been established. We therefore investigated female reproduction in mice expressing progressively rising serum levels of transgenic human FSH (Tg-FSH, 2.5–10 IU/liter) independently of follicle depletion. We show that serum LH and estradiol levels and uterine size remained normal in Tg-FSH females, whereas ovarian weight and corpora lutea number were significantly increased up to 1.3- and 5-fold, respectively. Furthermore, the monotrophic FSH rise produced a striking biphasic effect on female fertility. Tg-FSH females less than 22 wk old delivered increased litter sizes, then beyond 23 wk, litter sizes decreased rapidly culminating in premature infertility despite continued ovary follicle development, and increased ovulation and uterine embryo implantation sites as well as normal serum levels of anti-Mullerian hormone, a marker of ovarian follicle reserve. We found that rising circulating Tg-FSH produced premature infertility by increasing embryo-fetal resorption and parturition failure with age. Thus, our Tg-FSH mice present a novel paradigm to investigate selective contributions of elevated FSH to age-related female infertility, which revealed that rising FSH levels, despite no exhaustion of ovarian reserve, actively accelerates female reproductive aging primarily by postimplantation reduction of embryo-fetal survival.
Publisher: The Endocrine Society
Date: 04-2016
DOI: 10.1210/ER.2016-1025
Publisher: The Endocrine Society
Date: 1998
DOI: 10.1210/JC.83.1.107
Publisher: The Endocrine Society
Date: 04-2011
DOI: 10.1210/JC.2010-2521
Abstract: GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared. Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation. Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment. In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone. In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction.
Publisher: Wiley
Date: 09-05-2019
DOI: 10.1111/ADJ.12694
Abstract: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative s le of older Australian men. The aim of this paper is to describe the oral health behaviours and dental service use of CHAMP participants and explore associations between oral health behaviours with and general health status. Information collected related to socio-demographics, general health, oral health service-use and oral health behaviours. Key general health conditions were ascertained from the health questionnaire and included physical capacity and cognitive status. Fifty-seven percent of the men reported visiting a dental provider at least once or more a year and 56.7% did so for a "dental check-up". Of those with some natural teeth, 59.3% claimed to brush their teeth at least twice or more a day. Most men (96%) used a standard fluoride toothpaste. Few participants used dental floss, tooth picks or mouth-rinses to supplement oral hygiene. Cognitive status and self-rated general health were associated with dental visiting patterns and toothbrushing behaviour. Most older men in CHAMP perform favourable oral health behaviours. Smoking behaviour is associated with less favourable dental visiting patterns, and cognitive status with toothbrushing behaviour.
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.STEROIDS.2005.07.003
Abstract: Anti-convulsant treatment is associated with a high prevalence of reproductive dysfunction compared with age-matched non-epileptics. We examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a yeast-based steroid receptor-beta-galactosidase reporter assay for the androgen receptor (AR), progesterone receptor (PR) or estrogen receptor (ER). Bioassays were performed (a) to detect agonist activity by exposing yeast to 100 microM CBZ or VPA or (b) to detect antagonist activity by exposing yeast stimulated with testosterone (5 x 10(-9) M, AR), progesterone (1.6 x 10(-9) M, PR) or estradiol (2.6 x 10(-11) M, ER) together with either VPA or CBZ for 4 (PR) or 16 (AR, ER) hours. VPA showed dose-dependent (1-800 microM) inhibition of progesterone-induced PR- and testosterone-induced AR activity but had no ER antagonist bioactivity and no significant PR, AR or ER agonist bioactivity. VPA also showed a dose-dependent (1-200 microM) blockade of DHT's suppression of AR-mediated NF-kappaB activation in human mammalian cells. By contrast, CBZ had no significant PR, AR or ER agonist or AR and ER antagonist bioactivity but at the highest concentration tested (800 microM) it did antagonize PR activity. We conclude that VPA is a non-steroidal antagonist for human AR and PR but not ER. VPA's androgen and progesterone antagonism at concentrations within therapeutic blood levels (350-700 microM) seems likely to contribute to the frequency of reproductive endocrine disturbances among patients treated with VPA.
Publisher: Wiley
Date: 23-05-2007
Publisher: American Physiological Society
Date: 03-2006
DOI: 10.1152/AJPENDO.00311.2005
Abstract: Although testosterone (T) has striking effects on mature skeletal size and structure, it is not clear whether this depends exclusively on adult circulating levels of T or whether additional early-life factors also play a role. We have compared the androgen-deficient hypogonadal ( hpg) mutant mouse with intact, orchidectomized, and T-treated non- hpg mice to determine relative contributions of adult and perinatal T to bone growth and development. At 3 wk of age, although trabecular and cortical bone structure was normal, bone turnover was significantly altered in hpg male mice osteoid volume (OV/BV) and osteoblast surface (ObS/BS) were significantly lower and osteoclast surface (OcS/BS) significantly higher in hpg mice compared with age-matched non- hpg mice, pointing to a role for the perinatal T surge in determining bone turnover levels before sexual maturity. At 9 wk of age, the hpg bone phenotype mimicked closely that of age-matched non- hpg mice that had been orchidectomized at 3 wk of age, including low trabecular bone mass and high bone turnover. These bone phenotypes of hpg and orchidectomized non- hpg mice were all prevented by replacement doses of T or dihydrotestosterone (DHT), suggesting that these are determined by adult sex steroid hormones. In contrast, a short bone phenotype that could not be prevented by T or DHT treatment was observed in 9-wk-old hpg mice yet not in intact or castrated non- hpg mice. These data suggest a role for the perinatal T surge in determining adult bone length and confirms that adult circulating T determines adult bone density.
Publisher: Elsevier BV
Date: 2019
Publisher: The Endocrine Society
Date: 2012
DOI: 10.1210/ME.2012-1219
Abstract: Sertoli cell (SC) androgen receptor (AR) activity is vital for spermatogenesis. We created a unique gain-of-function transgenic (Tg) mouse model to determine the temporal role of SCAR expression in testicular development. The SC-specific rat Abpa promoter directed human Tg AR [Tg SC-specific AR (TgSCAR)] expression, providing strong premature postnatal AR immunolocalized to SC nuclei. Independent Tg lines revealed that TgSCAR dose dependently reduced postnatal and mature testis size (to 60% normal), whereas androgen-dependent mature seminal vesicle weights and serum testosterone levels remained normal. Total SC numbers were reduced in developing and mature TgSCAR testes, despite normal or higher Fshr mRNA and circulating FSH levels. Postnatal TgSCAR testes exhibited elevated levels of AR-regulated Rhox5 and Spinlw1 transcripts, and precocious SC function was demonstrated by early seminiferous tubular lumen formation and up-regulated expression of crucial SC tight-junction (Cldn11 and Tjp1) and phagocytic (Elmo1) transcripts. Early postnatal Amh expression was elevated but declined to normal levels in peripubertal-pubertal TgSCAR vs. control testes, indicating differential age-related regulation featuring AR-independent Amh down-regulation. TgSCAR induced premature postnatal spermatogenic development, shown by increased levels of meiotic (Dmc1 and Spo11) and postmeiotic (Capza3 and Prm1) germ cell transcripts, elevated meiotic-postmeiotic germ:Sertoli cell ratios, and accelerated spermatid development. Meiotic germ:Sertoli cell ratios were further increased in adult TgSCAR mice, indicating predominant SCAR-mediated control of meiotic development. However, postmeiotic germ:Sertoli cell ratios declined below normal. Our unique TgSCAR paradigm reveals that atypical SC-specific temporal AR expression provides a direct molecular mechanism for induction of precocious testicular development, leading to reduced adult testis size and decreased postmeiotic development.
Publisher: Elsevier BV
Date: 12-1990
Publisher: Wiley
Date: 27-10-2023
DOI: 10.1111/ANDR.13546
Publisher: Informa UK Limited
Date: 03-02-2014
DOI: 10.3109/13685538.2013.843167
Abstract: To identify lifestyle factors associated with healthy aging in middle-aged and older Australian men. A cross-sectional, population-based, computer-assisted telephone interview study explored self-reported health outcomes, and associated determinants for general and reproductive health (the Men in Australia Telephone Survey) in men aged 40 years and older (n = 5990). "Good health" was defined by self-reported health (excellent/very good) combined with absence of self-reported high blood pressure, heart disease, stroke, diabetes and depression symptoms. Categories of sexual activity frequency in the previous four weeks ranged from zero to 12+ times. "Good health" declined with increasing age with 17% of men over 70 years reporting "good health". In multivariable logistic regression models, significant inverse associations were found between modifiable lifestyle factors - both underweight and overweight/obesity, physical inactivity, smoking and high alcohol consumption - and "good health". Low-risk alcohol intake and living with a partner were positively associated with "good health". Sexual activity was also positively associated with "good health" (p < 0.001) with elevated odds ratios (ORs) for each category of frequency of sexual activity (1-4, 5-8, 9-12 or 12+ times in the past 4 weeks) relative to zero frequency (ORs 1.68 to 2.16). This study suggests that sexual activity is an important correlate of retaining good health in middle- and older-aged men, independent of other behavioral determinants.
Publisher: The Endocrine Society
Date: 05-2008
DOI: 10.1210/JC.2007-2768
Publisher: Oxford University Press (OUP)
Date: 22-01-2018
Abstract: Human female reproductive aging features declining ovarian follicle reserve and oocyte quality, and rising levels of circulating follicle-stimulating hormone (FSH). We determined the effects of elevated FSH on oocyte-embryo development in mature mice exhibiting premature infertility caused by progressively rising transgenic human FSH (TgFSH) levels. Oocyte-embryo developmental competence and quality were examined using oocyte maturation and aneuploidy rates, biomarkers of oocyte quality, and reciprocal embryo transfers assessed for implantation and pregnancy. In vitro maturation suggested that TgFSH exposure only hindered oocyte developmental competence in old females, as significantly more oocytes from ≥12-month-old TgFSH females remained at germinal vesicle stage compared with age-matched control oocytes. Aneuploidy rates were equivalent in oocytes from aging TgFSH compared with wildtype females. Cumulus cell expression levels of candidate biomarker Inhba, Egfr, and Rgs2 transcripts were elevated in associated aneuploid vs euploid oocytes from both TgFSH and wildtype females. In vivo, embryos transferred from subfertile 6-month-old TgFSH females to wildtype recipients yielded normal implantation rates and more pups born compared with controls. Transfer of wildtype embryos rescued the fertility of 6-month-old TgFSH-recipient females, although pup birth weight was reduced in TgFSH vs wildtype recipients. Our current findings show that elevated FSH had minimal disruption of either embryo developmental capacity or uterine function when examined in isolation, and the subfertility of TgFSH female mice was not caused by altered oocyte aneuploidy or quality.
Publisher: Cambridge University Press (CUP)
Date: 28-07-2017
DOI: 10.1017/S0007114517001738
Abstract: The revised Dietary Guideline Index (DGI-2013) scores in iduals’ diets according to their compliance with the Australian Dietary Guideline (ADG). This cross-sectional study assesses the diet quality of 794 community-dwelling men aged 74 years and older, living in Sydney, Australia participating in the Concord Health and Ageing in Men Project it also examines sociodemographic and lifestyle factors associated with DGI-2013 scores it studies associations between DGI-2103 scores and the following measures: homoeostasis model assessment – insulin resistance, LDL-cholesterol, HDL-cholesterol, TAG, blood pressure, waist:hip ratio, BMI, number of co-morbidities and medications and frailty status while also accounting for the effect of ethnicity in these relationships. Median DGI-2013 score was 93·7 (54·4, 121·2) most in iduals failed to meet recommendations for vegetables, dairy products and alternatives, added sugar, unsaturated fat and SFA, fluid and discretionary foods. Lower education, income, physical activity levels and smoking were associated with low scores. After adjustments for confounders, high DGI-2013 scores were associated with lower HDL-cholesterol, lower waist:hip ratios and lower probability of being frail. Proxies of good health (fewer co-morbidities and medications) were not associated with better compliance to the ADG. However, in participants with a Mediterranean background, low DGI-2013 scores were not generally associated with poorer health. Older men demonstrated poor diet quality as assessed by the DGI-2013, and the association between dietary guidelines and health measures and indices may be influenced by ethnic background.
Publisher: The Endocrine Society
Date: 11-2002
DOI: 10.1210/ME.2002-0032
Abstract: FSH mediates its testicular actions via a specific Sertoli cell G protein-coupled receptor. We created a novel transgenic model to investigate a mutant human FSH receptor (FSHR(+)) containing a single amino acid substitution (Asp567Gly) equivalent to activating mutations in related glycoprotein hormone receptors. To examine the ligand-independent gonadal actions of FSHR(+), the rat androgen-binding protein gene promoter was used to direct FSHR(+) transgene expression to Sertoli cells of gonadotropin-deficient hypogonadal (hpg) mice. Both normal and hpg mouse testes expressed FSHR(+) mRNA. Testis weights of transgenic FSHR(+) hpg mice were increased approximately 2-fold relative to hpg controls (P < 0.02) and contained mature Sertoli cells and postmeiotic germ cells absent in controls, revealing FSHR(+)-initiated autonomous FSH-like testicular activity. Isolated transgenic Sertoli cells had significantly higher basal ( approximately 2-fold) and FSH-stimulated ( approximately 50%) cAMP levels compared with controls, demonstrating constitutive signaling and cell-surface expression of FSHR(+), respectively. Transgenic FSHR(+) also elevated testosterone production in hpg testes, in the absence of circulating LH (or FSH), and it was not expressed functionally on steroidogenic cells, suggesting a paracrine effect mediated by Sertoli cells. The FSHR(+) response was additive with a maximal testosterone dose on hpg testicular development, demonstrating FSHR(+) activity independent of androgen-specific actions. The FSHR(+) response was male specific as ovarian expression of FSHR(+) had no effect on hpg ovary size. These findings reveal transgenic FSHR(+) stimulated a constitutive FSH-like Sertoli cell response in gonadotropin-deficient testes, and pathways that induced LH-independent testicular steroidogenesis. This novel transgenic paradigm provides a unique approach to investigate the in vivo actions of mutated activating gonadotropin receptors.
Publisher: Cambridge University Press (CUP)
Date: 08-09-2021
DOI: 10.1017/S1368980020003249
Abstract: To examine changes in micronutrient intake over 3 years and identify any associations between socio-economic, health, lifestyle and meal-related factors and these changes in micronutrient intakes among older men. Prospective study. Dietary adequacy of in idual micronutrient was compared to the estimated average requirement of the nutrient reference values (NRV). Attainment of the NRV for twelve micronutrients was incorporated into a dichotomised variable ‘not meeting’ (meeting ≤ 6) or ‘meeting’ (meeting ≥ 7) and categorised into four categories to assess change in micronutrient intake over 3 years. The multinomial logistic regression analyses were conducted to model predictors of changes in micronutrient intake. Seven hundred and ninety-four men participated in a detailed diet history interview at the third wave (baseline nutrition) and 718 men participated at the fourth wave (3-year follow-up). The mean age was 81 years (range 75–99 years). Median intakes of the majority of micronutrients decreased significantly over a 3-year follow-up. Inadequacy of the NRV for thiamine, dietary folate, Zn, Mg, Ca and I were significantly increased at a 3-year follow-up than baseline nutrition. The incidence of inadequate micronutrient intake was 21 % and remained inadequate micronutrient intake was 16·4 % at 3-year follow-up. Changes in micronutrient intakes were significantly associated with participants born in the UK and Italy, low levels of physical activity, having ≥2 medical conditions and used meal services. Micronutrient intake decreases with age in older men. Our results suggest that strategies to improve some of the suboptimal micronutrient intakes might need to be developed and implemented for older men.
Publisher: Oxford University Press (OUP)
Date: 24-04-2019
Abstract: Advanced kidney disease is associated with reduced muscle strength and physical performance. However, associations between early stages of renal impairment and physical outcomes are unclear. The Concord Health and Ageing in Men Project is a prospective study of 1,705 community-dwelling men aged 70 years and older. Participants with estimated glomerular filtration rate (eGFR) more than 30 mL/min/1.73 m2 were included and further ided into four eGFR categories. Physical parameters including grip strength, gait speed, appendicular lean mass (ALM, a sum of skeletal mass of arms and legs), ALM adjusted for body mass index (ALMBMI), and muscle function (measured using grip strength ided by arm lean mass) were assessed at both baseline and 5-year follow-up. Associations between kidney function and changes in physical parameters were analyzed using linear and logistic regression models. Our study included 789 men with a median age of 75 years and median eGFR of 72 mL/min/1.73 m2 at baseline. Over 5 years, grip strength, gait speed, ALMBMI, and muscle function all declined in the whole cohort, compared with baseline. The multivariable analyses showed that poorer renal function was associated with more rapid declines in grip strength, gait speed, and muscle function in participants with mild-to-moderate renal impairment (GFR category stage G3, eGFR 60 mL/min/1.73 m2) (p = .01, p .01, p = .02, respectively) but less so in those with eGFR more than 60 mL/min/1.73 m2, whereas eGFR category did not have a significant impact on declines in ALMBMI. These results remained unchanged with or without adjustment for age. In community-dwelling older men, mild-to-moderate renal impairment at baseline was associated with declines in grip strength, gait speed, and muscle function over time despite preservation of muscle mass.
Publisher: Oxford University Press (OUP)
Date: 02-07-2011
Abstract: past research suggests that fall rates in older persons may differ by ethnicity. The aim of this study was to compare the incidence of falls between older male Italian-born immigrants and their Australian-born counterparts. this study analysed data from 335 Italian-born and 848 Australian-born men aged 70 years and over participating in the Concord Health and Ageing in Men Project (CHAMP). Prospective falls data were collected by 4 monthly phone calls (mean follow-up time: 26.7 months). Negative binomial regression compared falls incidence rate ratios (IRR) between the two groups of men. there were 37 (11%) Italian-born men and 185 (22%) Australian-born men who had two or more falls during follow-up (P < 0.001). Negative binomial analysis demonstrated that Italian-born men had half the incidence rate of falls compared with Australian-born men (IRR = 0.51, 95% CI = 0.38-0.67). After adjustment for falls risk factors, Italian-born men remained significantly less likely to fall with a 43% lower fall rate (IRR = 0.57, 95% CI = 0.39-0.85). older male Italian-born immigrants are less likely to fall than their Australian-born counterparts. Differences in fall rates between the two groups are not explained by established falls risk factors.
Publisher: The Endocrine Society
Date: 12-2007
DOI: 10.1210/JC.2007-1431
Abstract: This is an invited review based on a presentation at the 2007 Annual Scientific Meeting of The Endocrine Society. The objective of the review was to highlight a selection of the most important peer-reviewed papers in andrology published over the last 1-2 yr. This was a comprehensive survey of all papers published in major endocrinology journals over the last 2 yr augmented by personal knowledge and literature searching as well as an e-mail survey of more than 40 leading andrologists. From the list of suggested papers, the findings of a short list considered the most important were reviewed, aiming to focus on findings that influence thinking and practice in the field of andrology. Important advances highlighted included establishing genetic paternity for men with Klinefelter's syndrome as a realistic therapeutic option via testicular sperm aspiration coupled with intracytoplasmic sperm injection in vitro fertilization, using population registry linkage data to define the natural history of Klinefelter's syndrome in the community and identifying active cellular uptake mechanisms for SHBG-bound testosterone challenging the quasiaxiomatic status of the free hormone hypothesis. Other important recent contributions reviewed are on testosterone effects on the prostate, hormonal male contraception, possible temporal trends in blood testosterone concentrations in American men, and The Endocrine Society's position papers on testosterone assays and guidelines on testosterone prescribing.
Publisher: The Endocrine Society
Date: 2014
DOI: 10.1210/JC.2013-3108
Abstract: Secondary erythrocytosis due to androgens is most commonly seen in the context of T replacement therapy in men. Leydig cell ovarian tumors are a rare cause of virilization, erythrocytosis, and thromboembolism. We describe the case of a 55-year-old postmenopausal woman who presented with a 3-year history of frontal balding and virilization and a 5-year history of obstructive sleep apnea. She had not experienced significant alteration in libido or mood. Menstruation had ceased at age 46. She had a history of recurrent pulmonary embolism and unexplained secondary erythrocytosis. Past hematological investigations had not revealed any evidence of malignancy or thrombophilia, and the JAK2 mutation was negative. The serum erythropoietin was mildly elevated at 20.3 mIU/mL (normal range, 3.6-16.6 mIU/mL). The serum T was initially reported (by immunoassays) as >1600 ng/dL (>55 nmol/L). Similarly, serum androstenedione (>1000 ng/dL >35 nmol/L), estradiol (169 pg/mL 621 pmol/L), and dehydroepiandrosterone sulfate (348 μg/dL 9.4 μmol/L) were all elevated for a postmenopausal woman. Repeat analysis of the serum T by mass spectrometry showed an extremely elevated level of 4270 ng/dL (148 nmol/L). Computed tomography scan revealed a 5.0-cm right ovarian tumor. After surgical removal of an ovarian Leydig cell tumor, her virilization, erythrocytosis, and sleep apnea resolved. Hyperandrogenism in women should be considered as a rare but important cause of erythrocytosis, recurrent thromboembolism, and sleep apnea. The diagnosis of hyperandrogenism requires a careful history and physical examination because in postmenopausal women, menstrual disturbance does not occur and cosmetic measures may mask overt clinical features.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.RBMO.2017.11.009
Abstract: Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20-22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum s les for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum s les. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18 P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2000
Publisher: Wiley
Date: 05-1999
DOI: 10.1046/J.1365-2265.1999.00742.X
Abstract: The ratio of urinary testosterone (T) to epitestosterone (EpiT) is used to detect T abuse in sport. Also, plasma or urinary concentrations of EpiT have been measured to assess testicular steroidogenesis during hormonal male contraception. Further investigations are required to evaluate the relative contributions of the testis and adrenal to EpiT production. To this purpose, we have compared basal urinary EpiT glucuronide and plasma EpiT and the response to synthetic adrenocorticotrophic hormone (ACTH) stimulation between eugonadal and hypogonadal men. The basal urinary excretion rate of EpiT glucuronide was determined in 34 eugonadal men. Six men, clinically diagnosed as hypogonadal, and 6 out of the 34 eugonadal men previously described, received an intramuscular injection of synthetic ACTH depot (1 mg) at 0800 h on two consecutive days. Blood s les were collected prior to and then at 1.5, 8, 24, 25.5, 32 and 48 h with respect to the first administration (0 h). 24-h urine specimens were collected from 0800 h on days 1 and 2 (baseline) and 3 and 4 (stimulation). Plasma EpiT, T and cortisol were measured by RIA and urinary EpiT and T, following glucuronide hydrolysis, by gas chromatography-mass spectrometry (extract combines aglycones with a minor amount of urinary free steroids). Basal excretion rates of EpiT glucuronide in eugonadal men (range: 62-751 nmol/24 h) were considerably greater than in hypogonadal men (range: 3-34 nmol/24 h). Mean basal plasma EpiT in eugonadal men (1.32 +/- 0.08 nmol/l) were greater than in hypogonadal men (0.68 +/- 0.04 nmol/l). In each group, synthetic ACTH stimulation increased plasma cortisol 4-fold. In eugonadal men, plasma and urinary EpiT were unchanged whereas plasma and urinary T glucuronide decreased in response to ACTH. In hypogonadal patients, ACTH increased plasma and urinary EpiT while plasma T remained unchanged. The testes are the major source of epitestosterone, the adrenal contribution being relatively modest. Following adrenal stimulation, urinary epitestosterone glucuronide increases considerably in hypogonadal men but this increase is masked in eugonadal men because testicular production is probably suppressed by the ACTH-induced rise in cortisol. Activation of the adrenal cortex results in no change or only a small decrease in the urinary T/EpiT ratio in eugonadal men.
Publisher: Informa UK Limited
Date: 1989
DOI: 10.3109/09513598909152450
Abstract: In a retrospective international study 223 pregnancies induced with pulsatile hormone-releasing hormone (LH-RH) were evaluated. In patients with hypothalamic amenorrhea (HA) and polycystic ovarian disease (PCOD) the abortion rate was similar (10% vs 8.7%). The premature delivery rate was significantly higher, however, in the patients with HA, but this could be explained by the higher incidence of multiple pregnancies in this group. Thirty multiple pregnancies were observed in the HA group (n = 174) compared with none in the PCOD group (n = 24 p less than 0.05). The incidence of multiple pregnancies in the HA group correlated to the pulse dose (p less than 0.05). The 1st treatment cycle resulted in more multiple pregnancies than did subsequent cycles (p less than 0.05). Difference in pulse interval did not affect the incidence of multiple pregnancies, nor did the route of administration (intravenous or subcutaneous). The incidence of congenital anomalies was comparable to that with spontaneously achieved pregnancies.
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.JSBMB.2007.10.008
Abstract: The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for in idual steroids by their progestin bioactivity. 17alpha-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17beta-substituents were strong progestins but generally weak androgens. 17alpha-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17alpha-ethynyl group of each of these progestins produces 17alpha-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17alpha-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.PSYNEUEN.2020.104916
Abstract: While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippoc al (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippoc al and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.
Publisher: Wiley
Date: 23-06-2016
DOI: 10.1002/DTA.1832
Abstract: In 2012, seized capsules containing white powder were analyzed to show the presence of unknown steroid-related compounds. Subsequent gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) investigations identified a mixture of 3α- and 3β- isomers of the novel compound 3-chloro-17α-methyl-5α-androstan-17β-ol. Synthesis of authentic reference materials followed by comparison of NMR, GC-MS and gas chromatography-tandem mass spectrometry (GC-MS/MS) data confirmed the finding of a new 'designer' steroid. Furthermore, in vitro androgen bioassays showed potent activity highlighting the potential for doping using this steroid. Due to the potential toxicity of the halogenated steroid, in vitro metabolic investigations of 3α-chloro-17α-methyl-5α-androstan-17β-ol using equine and human S9 liver fractions were performed. For equine, GC-MS/MS analysis identified the diagnostic 3α-chloro-17α-methyl-5α-androstane-16α,17β-diol metabolite. For human, the 17α-methyl-5α-androstane-3α,17β-diol metabolite was found. Results from these studies were used to verify the ability of GC-MS/MS precursor-ion scanning techniques to support untargeted detection strategies for designer steroids in anti-doping analyses. Copyright © 2015 John Wiley & Sons, Ltd.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.PSYNEUEN.2015.11.012
Abstract: Depression in older men has been associated with low circulating testosterone concentration but data from prospective studies are limited. We conducted a prospective longitudinal study in a community representative cohort of 3179 older men free of clinically significant depressive symptoms at baseline. The main objective of this study was to determine if low serum testosterone, dihydrotestosterone and estradiol concentrations are associated with the development of depressive symptoms. Incident depression was assessed with the Patient Health Questionnaire and via an electronic health record database (The West Australian Data Linkage System). The main exposures of interest were serum testosterone, dihydrotestosterone and estradiol measured by liquid chromatography-mass spectrometry and calculated free testosterone in baseline blood s les (collected between 2001 and 2004). One hundred and thirty five men (4.2%) developed depression over a median follow up time of 9.4 years (range 8.4-10.9). Men with incident depression were older (median age 77.7 vs 76.1 years, z=-3.82, p=0<0.001) and were more likely to have cardiovascular disease (43.0% vs 32.6%, χ(2)=6.32, p=0.012) and diabetes (22.2% vs 13.2%, χ(2)=8.95, p=0.003). Low serum total testosterone (<6.4 nmol/L) was associated with incident depression (HR 2.07, 95%CI 1.17-3.68) and this remained significant after adjustment for relevant potential confounding factors (HR 1.86, 95%CI 1.05-3.31). Low serum dihydrotestosterone, estradiol and calculated free testosterone were not associated with risk of depression. Low serum total testosterone, but not calculated free testosterone, was associated with incident depression in this s le of older men.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1016/S0735-1097(00)01083-4
Abstract: The study examined arterial and cardiac structure and function in bodybuilders using androgenic anabolic steroids (AAS), compared to non-steroid-using bodybuilder controls. Adverse cardiovascular events have been reported in bodybuilders taking anabolic steroids. The cardiovascular effects of AAS, however, have not been investigated in detail. We recruited 20 male bodybuilders (aged 35 +/- 3 years), 10 actively using AAS and 10 who denied ever using steroids. Serum lipid and hormone levels, carotid intima-media thickness (IMT), arterial reactivity, and left ventricular (LV) dimensions were measured. Vessel diameter was measured by ultrasound at rest, during reactive hyperemia (an endothelium-dependent response, leading to flow-mediated dilation, FMD), and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Arterial reactivity was also measured in 10 age-matched non-bodybuilding sedentary controls. Use of AAS was associated with significant decreases in high density lipoprotein cholesterol, sex hormone binding globulin, testosterone and gonadotrophin levels, and significant increases in LV mass and self-reported physical strength (p 0.2). The GTN responses were significantly lower and carotid IMT significantly higher in both bodybuilding groups, however, compared with the non-bodybuilding sedentary controls (p = 0.01). Although high-level bodybuilding is associated with impaired vascular reactivity and increased arterial thickening, the use of AAS per se is not associated with significant abnormalities of arterial structure or function.
Publisher: The Endocrine Society
Date: 11-2014
DOI: 10.1210/JC.2014-1913
Abstract: Aberrant sex steroid signaling is suggested to promote endometriosis growth by several mechanisms, and the tissue concentrations of sex steroids are key determinants of the hormone action. However, their concentrations are only superficially known in the endometrium and endometriosis lesions. This study sought to evaluate whether the tissue steroid hormone concentrations in endometriosis differ from the endometrium or serum. Steroid analysis of serum and tissue specimens of women with endometriosis (n = 60) and healthy controls (n=16) was measured, and supporting data from quantitative RT-PCR for steroidogenic enzymes and explant cultures of a subset of specimens is provided. Endometrial tissue progesterone (P4) concentrations reflected the serum P4 levels during the menstrual cycle, whereas in endometriosis lesions, the cycle-dependent change was missing. Remarkably high tissue T concentrations were measured in endometriosis lesions independent of the cycle phase, being 5-19 times higher than the corresponding serum levels. Tissue/serum ratio of T was further increased in patients with contraceptive medication. The altered tissue steroid concentrations in endometriosis were in line with the expression of various steroidogenic enzymes in the lesions, of which HSD3B2 showed constantly high expression, whereas CYP11A1 expression was low. Furthermore, the high concentration of sex steroids detected in the ovarian lesions involves their production by the lesion and by the adjacent ovarian tissue. Endometriosis lesions present with progestin and androgen metabolism, which are different from that of the endometrium, and the lesions are characterized by high tissue T and a loss of cyclical changes in tissue P4 concentration.
Publisher: Wiley
Date: 20-11-2018
DOI: 10.1111/CDOE.12435
Abstract: To describe the associations between chewing function with oral health and certain general health characteristics, in a population of community-dwelling older Australian men. Analysis of data obtained from a cross-sectional analysis of the 4th wave of the Concord Health and Ageing in Men Project cohort of 614 participants, 524 whom were dentate, aged 78 years and over. Their chewing capacity was assessed using three main indicators: capacity to chew eleven food items ranging from boiled eggs through to fresh carrots and nuts discomfort when eating and interruption of meals. Associations with chewing were tested for dentate vs edentate participants, numbers of teeth present, active dental disease and key general health conditions such as disabilities, comorbidities and cognitive status. Log binomial regression models adjusted for age, country of birth, income, education and marital status. Prevalence ratios and 95% confidence intervals were estimated. Twenty-one per cent of participants could not eat hard foods, while 23.1% reported discomfort when eating, and 8.8% reported interrupted meals when eating. There was a threefold difference in the capacity of dentate men to chew firm meat over that of edentulous men (95% CI, 2.0-4.9) a 2.5 times greater likelihood of edentate men reporting discomfort when eating (95% CI: 1.5-4.3) and 1.9 times greater likelihood of edentate participants reporting having meals interrupted (95% CI: 1.4-2.6). Chewing/eating difficulties were associated with both dental status (number of teeth, active dental caries) and self-rated dental health. Fewer than 20 teeth and the presence of active coronal or root decay were associated with more discomfort when eating. General health conditions associated with chewing function included disability, physical activity, comorbidities, cognitive status and depression. Older men's self-rated oral health and general health perceptions were also associated with aspects of chewing function. Poorer self-reported oral health was associated with inability to eat hard foods (95% CI: 1.3-2.7) and with discomfort when eating (95% CI: 2.6-5.1), while poorer self-reported general health was associated with discomfort when eating (95% CI: 1.2-2.2). Falling rates of edentulism may lead to improved chewing and eating function in older men. Maintaining 20 or more natural teeth, and preventing active coronal and root caries should enhance chewing function and promote self-reported health and oral health. Lower capacity to chew hard foods and a higher reporting of discomfort when eating is associated with co-morbidity in older Australian men.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-08-2004
Abstract: The recent identification of tetrahydrogestrinone (THG), the first true "designer androgen," as a sports doping agent reflects both an alarmingly sophisticated illicit manufacturing facility and an underground network of androgen abusers in elite sports, as well as the still untapped potential for designer androgens in medicine. Never marketed, THG was apparently developed as a potent androgen that was undetectable by conventional International Olympic Committee–mandated urinary sports doping tests. As a potent androgen and progestin with unspecified contaminants, its distribution for use at high doses without any prior biological or toxicological evaluation poses significant health risks. Yet this ersion of science also highlights the prospect of designer androgens for use in human medicine. Designer androgens also offer the possibility of tissue-specific effects enhancing the beneficial effects of androgens while mitigating the undesirable ones. Further developments require better understanding of the postreceptor tissue selectivity of androgens, comparable to the mechanism underlying that of partial estrogen agonists (SERMs). This experience highlights the ongoing need for vigilance to detect novel drug doping strategies in order to maintain fairness and safety in elite sports. This will require the deployment of generic catch-all tests, such as sensitive and specific in vitro androgen bioassays, coupled with the development of mass spectrometry–based tests for specific doping agents.
Publisher: Elsevier BV
Date: 02-2022
Publisher: The Endocrine Society
Date: 14-04-2010
DOI: 10.1210/EN.2009-1456
Abstract: The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days. And yet, some effects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.CCA.2009.09.003
Abstract: Immunoassays are widely used to quantify steroid hormones in biological s les. However, they lack specificity, especially at low levels. This study aimed to develop a sensitive LC-MS/MS method to measure serum androgens and estrogens without derivatization within a single run. A stable-isotope dilution LC-MS/MS method was established using atmospheric pressure photoionization to quantify testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) from serum. S le preparation involved liquid-liquid extraction (LLE) with hexane:ethyl acetate (3:2) containing deuterated internal standards. Accuracy was assessed by spiked recovery of serum pools, and imprecision by quality controls. Using 200 microL serum, limits of quantification were 0.3 pg (1.5 pg/mL) E(1), 0.5 pg (2.5 pg/mL) E(2), 2 pg (10 pg/mL) T and 10 pg (50 pg/mL) DHT. Accuracy (93-110%) and precision (median 4%, all <15%) were determined to be well within acceptable limits for bioanalytical method validation. An analysis time of less than 10 min allowed up to 150 s les (600 analytes) to be processed per day. The method is sufficiently sensitive and precise to accurately quantify serum T levels in females and E(2) in males, and is readily adapted to tissue and non-human s les.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.AJPATH.2017.08.036
Abstract: The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P < 0.05) and the AR splice variants 1 (threefold, P < 0.05) and 7 (threefold, P < 0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2015
Publisher: Springer Science and Business Media LLC
Date: 16-10-2020
DOI: 10.1038/S41467-020-19003-5
Abstract: Lifestyle, mainly dietary, interventions are first-line treatment for women with polycystic ovary syndrome (PCOS), but the optimal diet remains undefined. We combined a hyperandrogenized PCOS mouse model with a systematic macronutrient approach, to elucidate the impact of dietary macronutrients on the development of PCOS. We identify that an optimum dietary macronutrient balance of a low protein, medium carbohydrate and fat diet can ameliorate key PCOS reproductive traits. However, PCOS mice display a hindered ability for their metabolic system to respond to diet variations, and varying macronutrient balance did not have a beneficial effect on the development of metabolic PCOS traits. We reveal that PCOS traits in a hyperandrogenic PCOS mouse model are ameliorated selectively by diet, with reproductive traits displaying greater sensitivity than metabolic traits to dietary macronutrient balance. Hence, providing evidence to support the development of evidence-based dietary interventions as a promising strategy for the treatment of PCOS, especially reproductive traits.
Publisher: Oxford University Press (OUP)
Date: 14-03-2017
Publisher: Bioscientifica
Date: 10-1991
Abstract: This study aimed to determine the effect of streptozotocin (STZ)-induced diabetes on pulsatile LH secretion in the mature male rat. LH pulse frequency was reduced by 56% and pulse litude by 54%, with a consequential decrease of 72% in mean LH levels 8 days after i.v. administration of STZ (55 mg/kg) to castrated Wistar rats compared with castrated non-diabetic controls. Twice daily insulin treatment completely reversed all parameters of pulsatile LH secretion to control values. Food-restricted non-diabetic controls, studied to distinguish the metabolic effect of diabetes from that of concurrent weight loss, demonstrated a 34% reduction in LH pulse frequency but no significant changes in LH pulse litude or mean LH levels compared with non-diabetic controls given free access to food. To distinguish whether the decreased LH pulse litude in diabetes was due to a reduction in either the quantity of hypothalamic gonadotrophin-releasing hormone (GnRH) released per secretory episode or to decreased pituitary responsiveness to GnRH, the responsiveness of the pituitary to exogenous GnRH (1–1000 ng/kg body weight) was tested in diabetic rats after castration, using a full Latin square experimental design. The net LH response (total area under response curve over 40 min following GnRH) was decreased by 33% ( P =0·001) in diabetic compared with control rats. The decreased LH pulse frequency in STZ-induced diabetes therefore suggests that the metabolic effect of diabetes is to decelerate directly the firing rate of the hypothalamic GnRH pulse generator independent of testicular feed-back. These effects were fully reversed by insulin treatment and were only partly due to the associated weight loss. The impaired pituitary responsiveness to GnRH is at least partly involved in the reduction of LH pulse litude. Journal of Endocrinology (1991) 131, 49–55
Publisher: The Endocrine Society
Date: 16-06-2023
Abstract: Multiple changes occur across various endocrine systems as an in idual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older in iduals. Each section describes the natural history and observational data in older in iduals, available therapies, clinical trial data on efficacy and safety in older in iduals, key points, and scientific gaps. The goal of this statement is to inform future research that refines prevention and treatment strategies in age-associated endocrine conditions, with the goal of improving the health of older in iduals.
Publisher: The Endocrine Society
Date: 05-2006
DOI: 10.1210/JC.2005-2569
Abstract: The objective of the study was to review the rationale underlying the banning of human chorionic gonadotropin (hCG) and estrogen blockers (antiestrogens, specific estrogen receptor modulators, aromatase inhibitors) in sports for male and female athletes in the light of gender differences in regulation of reproductive physiology. We reviewed well-controlled clinical studies of exogenous testosterone effects on human muscle size and strength in men and all available evidence relevant to the effects of hCG and estrogen blockers on blood testosterone in men and women. Well-designed placebo-controlled clinical studies in men with suppressed pituitary-testicular axis establish a strong case that, across a wide range from sub- to supraphysiological doses, muscle growth and strength is proportional to exogenous testosterone dose and resulting blood testosterone concentrations. In men, there is unequivocal evidence that hCG and estrogen blockers cause consistent and sustained rise in blood testosterone concentrations. In women, although there has been no direct testing of ergogenic or myotrophic properties of exogenous testosterone in healthy women, either hCG or estrogen blockers do not produce any consistent or biologically significant increase blood testosterone concentrations. In men undergoing potential stimulation of endogenous blood testosterone concentrations, blood testosterone concentration is a reasonable surrogate measure for muscle growth and increased strength in men. Because hCG and estrogen blockers produce marked increase in blood testosterone concentration in men, this provides strong evidence to support the banning of hCG and estrogen blockers in men. In women, however, the negligible effect on blood testosterone suggests that drug-induced performance enhancement by hCG or estrogen blockers is highly unlikely. Furthermore, routine urinary hCG testing in young women risks invasion of privacy by detecting unrecognized pregnancy. These considerations suggest that prohibition of hCG and estrogen blockers should be restricted to men in which they are well justified.
Publisher: Oxford University Press (OUP)
Date: 2003
Abstract: OBJECTIVE: In order to assess the hormonal determinants of insulin sensitivity and related components of the metabolic syndrome, we evaluated the effect of subcutaneous recombinant human chorionic gonadotropin (r-hCG Ovidrel) on insulin sensitivity, vascular reactivity, leptin, insulin-like growth factor-I (IGF-I) and lipids in ambulant, community dwelling men Years of age with serum testosterone or= 15 nmol/l on two occasions. DESIGN: Forty eligible men were randomized to receive 250 microg (5000 IU) r-hCG subcutaneously twice each week (n=20) or placebo (n=20) injections for 3 Months, and all subjects (mean age 67 (range 60-85) Years) completed the study. METHODS AND RESULTS: Groups were well matched for height, weight, anthropometry and insulin sensitivity. Insulin sensitivity was assessed by homeostasis model (HOMA) and euglycemic hyperinsulinemic cl at baseline and at the end of the treatment period in the first 30 men who did not have diabetes mellitus. Insulin sensitivity (HOMA and euglycemic cl ) or beta cell function (HOMA) were not significantly changed by r-hCG despite a significant increase in lean body mass (approximately 2 kg, P .001) and reduced fat mass (approximately 1 kg, P .05). Subcutaneous fat (skinfold measurements), abdominal girth and serum leptin all decreased and IGF-I tended to increase, but these changes were not significant. Recombinant hCG significantly reduced total and low density lipoprotein cholesterol, and triglycerides, but did not significantly alter high density lipoprotein cholesterol. Endothelial function (vascular reactivity) was not significantly worsened. We conclude that three-Months of treatment with r-hCG demonstrates expected hormonal effects, improved lipids and did not worsen vascular endothelial function. Insulin sensitivity was not altered despite suggestive changes in body composition. CONCLUSIONS: These findings suggest short-term metabolic and cardiovascular safety and argue against an important role for androgens in the hormonal control of insulin sensitivity in older men.
Publisher: American Physiological Society
Date: 10-2011
DOI: 10.1152/AJPENDO.00580.2010
Abstract: Androgens influence prostate growth and development, so androgen withdrawal can control progression of prostate diseases. Although estrogen treatment was originally used to induce androgen withdrawal, more recently direct estrogen effects on the prostate have been recognized, but the nature of androgen-estrogen interactions within the prostate remain poorly understood. To characterize androgen effects on estrogen sensitivity in the mouse prostate, we contrasted models of castration-induced androgen withdrawal in the prostate stromal and epithelial compartments with a prostate epithelial androgen receptor (AR) knockout (PEARKO) mouse model of selective epithelial AR inactivation. Castration markedly increased prostate epithelial estrogen receptor (ER)α immunoreactivity compared with very low ERα expression in intact males. Similarly, strong basal and luminal ERα expression was detected in PEARKO prostate of intact males, suggesting that epithelial AR activity regulated epithelial ERα expression. ERβ was strongly expressed in intact, castrated, and PEARKO prostate. However, strong clusters of epithelial ERβ positivity coincided with epithelial stratification in PEARKO prostate. In vivo estrogen sensitivity was increased in PEARKO males, with greater estradiol-induced prostate growth and epithelial proliferation leading to squamous metaplasia, featuring markedly increased epithelial proliferation, thickening, and keratinization compared with littermate controls. Our results suggest that ERα expression in the prostate epithelial cells is regulated by local, epithelia-specific, androgen-dependent mechanisms, and this imbalance in the AR- and ER-mediated signaling sensitizes the mature prostate to exogenous estrogens.
Publisher: The Endocrine Society
Date: 04-05-2021
Publisher: American College of Physicians
Date: 02-2022
DOI: 10.7326/M21-0551
Publisher: The Endocrine Society
Date: 10-2004
DOI: 10.1210/EN.2004-0440
Abstract: Suppression of intratesticular testosterone (ITT) levels is required for spermatogenic recovery in rats after irradiation, but maintenance of peripheral testosterone (T) levels is important for many male functions. Considering the preservation of peripheral T while suppressing ITT, we tested the effects of a combination of a progestin, medroxyprogesterone acetate (MPA), plus T on spermatogenic recovery after irradiation, and compared its effects to those of T alone or T combined with estradiol (E2). Rats were given testicular irradiation (6 Gy) and treated during wk 3–7 after irradiation with MPA + T, or the in idual steroids with or without GnRH antagonist (GnRH-ant), or GnRH-ant alone, or T + E2. Whereas GnRH-ant alone stimulated differentiation in 55% of tubules 13 wk after irradiation compared with 0% in irradiated-only rats, the addition of MPA reduced the percentage of tubules showing differentiation to 18%. However, T or MPA alone or the combination of the two induced germ cell differentiation in only 2–4% of tubules. In contrast, E2 stimulated differentiation in 88% of tubules, and T combined with E2 still resulted in differentiation in 30% of tubules. Although both MPA and E2 suppressed ITT levels to approximately 2% of control (2 ng/g testis), MPA was a less effective stimulator of spermatogenic recovery than E2 or GnRH-ant alone. MPA’s function as a weak androgen was likely responsible for inhibiting spermatogenic recovery, as was the case for all other tested androgens. Thus, for clinical protection or restoration of spermatogenesis after radiation or chemotherapy by suppressing T production, MPA, at least in the doses used in the present study, is suboptimal. The combination of an estrogen with T appears to be most effective for stimulating such recovery.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.TEM.2018.08.005
Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-aged women. It is characterized by reproductive, endocrine, metabolic, and psychological features. The cause of PCOS is unknown, thus there is no cure and its management remains suboptimal because it relies on the ad hoc empirical management of symptoms only. We review here the strong support for PCOS having a neuroendocrine origin. In particular, we focus on the role of aberrant hypothalamic-pituitary function and associated hyperandrogenism, and their role as major drivers of the mechanisms underpinning the development of PCOS. This important information now provides a target site and a potential mechanism for the future development of novel, targeted, and mechanism-based effective therapies for the treatment of PCOS.
Publisher: The Endocrine Society
Date: 2015
DOI: 10.1210/EN.2014-1664
Abstract: Accurate measurement of testosterone is important for reproductive endocrinology research, but the validity of direct (nonextraction) testosterone immunoassays, developed and validated for human serum, has not been appraised for application to mouse serum or steroidogenic tissue extracts. Testosterone was measured in serum and extracts of testis or ovary from male and female wild-type mice by 2 commercial direct testosterone immunoassays, with and without preassay extraction, and by the liquid chromatography, tandem mass spectrometry reference method. Results were compared hierarchically by correlation (Kendall's τ), regression (Passing-Bablok), and deviance (Bland-Altman) analysis, under the null hypothesis of perfect agreement between assays (slope = 1, intercept and deviation = 0). For mouse serum, immunoassays displayed an upward bias with performance better for male vs female sera and, within gender, improved by preassay extraction relative to liquid chromatography, tandem mass spectrometry. Testosterone was detectable in all serum s les, but few (male 54%, female 9%) were accurate (within 20% of the reference measurement). For mouse testis extracts, immunoassays were biased upwards, and preassay extraction improved immunoassay performance. Although testosterone was detectable in all extracts, a minority (45%) was accurate. For mouse ovary extracts, all correlations were poor with severe, upward bias, and while testosterone was detectable in all s les, virtually none were accurate. We conclude that these direct testosterone immunoassay kits provide relatively, but not absolutely, accurate results with male mouse serum and testis extracts but not with female mouse serum and ovary extracts, with performance improved by preassay extraction. Whether relative accuracy is fit for purpose depends on the experimental aims, design, and interpretation.
Publisher: AMPCo
Date: 09-2012
DOI: 10.5694/MJA12.10981
Publisher: Wiley
Date: 08-11-2019
DOI: 10.1111/ANDR.12557
Abstract: Surgical sperm retrieval, requiring local anesthetic injection, is the most frequent surgical procedure in male infertility. However, needle phobia is common and may contribute to negative experiences or refusal of procedures employing needle injection. The aim of this study was to compare the acceptability, safety, and efficacy of needle-free jet anesthetic technique (MadaJet) with conventional needle injection for surgical sperm retrievals in patients with azoospermia. This single-blind randomized controlled trial (RCT) was included of 59 participants who underwent surgical sperm retrievals. Patients were randomly assigned to the needle-free jet (n = 29) or needle injection (n = 30) groups prior to undergoing the surgery. The primary endpoint was the pain score. Baseline characteristics were comparable between the two groups. The safety and adverse outcomes were also not statistically significant difference (p > 0.05). The pain score in patients using needle-free jet was significantly lower than that in patients using needle injection (p < 0.05). Patients in MadaJet group had a significantly lower discomfort score during (p < 0.001) and after (p = 0.01) injection than those in the needle injection group. However, there was no significant difference in the fear score (before, during, and after) of MadaJet and needle injection (p = 0.98, p = 0.74, and p = 0.94, respectively). The mean time to onset of anesthesia was much shorter in the MadaJet group as compared with needle injection (10 ± 4 vs. 157.5 ± 71 s, p < 0.001). However, the duration of anesthesia in patients using MadaJet was shorter compared with those using needle injection (44 ± 13 vs. 63 ± 26 min, p < 0.001). In conclusion, for local anesthesia in patients undergoing surgical sperm retrieval, MadaJet produces less pain and discomfort with quicker time to onset and offset of anesthesia compared with conventional needle injection.
Publisher: The Endocrine Society
Date: 07-1990
Abstract: We studied the pharmacokinetics and pharmacodynamics of sc implanted pellets of fused crystalline testosterone. Three different regimens (6 x 100 mg, 6 x 200 mg and 3 x 200 mg) were compared in a prospective, cross-over clinical trial in which androgen deficient men were administered the three-dose combinations in a randomized starting order at intervals of at least 6 months. Plasma free and total testosterone, sex hormone-binding globulin, LH, and FSH were measured before and at monthly intervals for at least 6 months after 111 pellet implantation in 43 men with hypergonadotropic (n = 22) or hypogonadotropic (n = 21) hypogonadism. Total and free testosterone levels peaked at the first month and were maintained at physiological levels for 4 to 5 (600 mg doses) or 6 (1200 mg dose) months after a single implantation. Absorption of testosterone from 100 mg and 200 mg pellets closely approximated zero-order throughout the effective life of the pellets and exhibited a half-duration of 2.5 months. The estimated rate of release of testosterone was 1.5 (95% confidence limits 1.3-1.6) mg/day.200 mg pellet as determined from direct measurement of residue in pellets recovered after extrusion and confirmed independently from percent absorbed-time plots. The bioavailability of testosterone was virtually complete and the time course was predictable from the total implant dose and, to a lesser extent, total initial surface areas of pellets. Despite wide fluctuations in testosterone, SHBG levels were not changed during 6 months. In men with hypergonadotropic hypogonadism, both LH and FSH levels were uniformly and markedly suppressed by increased testosterone after pellet implants. LH and FSH were highly correlated with each other (r = 0.87) and inversely with total (r = 0.47 and 0.45, respectively) and free (r = 0.46 and 0.47) testosterone levels. Nadir LH levels occurred at 1-3 months (600 mg) and 1-4 months (1200 mg) reaching levels comparable with eugonadal controls. In contrast nadir FSH levels occurred at similar times but remained elevated compared with eugonadal controls. We conclude that fused pellets of crystalline testosterone provides very satisfactory depot androgen replacement exhibiting many desirable features for androgen replacement.
Publisher: Elsevier BV
Date: 08-2011
Publisher: Wiley
Date: 23-08-2017
DOI: 10.1002/PDS.4284
Abstract: To estimate the impact of the first year of new Pharmaceutical Benefits Scheme (PBS) prescribing criteria that dictate eligibility for national health scheme subsidy of testosterone prescribing. Analysis of cumulative PBS data. Retrospective analysis of testosterone prescribing from PBS data. Nil MAIN OUTCOME MEASURES: PBS expenditure analysed by total expenditure, by state, and by product type as well as the age, indication, and prescriber type for new testosterone treatment. Total PBS expenditure continued to exceed $20 million in 2014 before declining from 2015 with changes that were uniform by state and product type. Prior to 2015, over 80% were for men aged over 40 years of age for low circulating testosterone in the absence of reproductive system disorders ("Low T") initiated by GPs. From 2015, these features were markedly reduced without changing the numbers of new prescriptions for pathological reproductive disorders or specialist initiations. The short-term impact of 2015 PBS criteria showed highly effective and well-targeted curbing of off-label testosterone prescribing. The findings indicate that the main driver for the recent upsurge in testosterone prescribing was treatment of middle-aged men for "Low T" initiated by GPs.
Publisher: Bioscientifica
Date: 15-04-2010
DOI: 10.1677/JOE-10-0026
Abstract: We used our genomic androgen receptor (AR) knockout (ARKO) mouse model, in which the AR is unable to bind DNA to: 1) document gender differences between males and females 2) identify the genomic (DNA-binding-dependent) AR-mediated actions in males 3) determine the contribution of genomic AR-mediated actions to these gender differences and 4) identify physiological genomic AR-mediated actions in females. At 9 weeks of age, control males had higher body, heart and kidney mass, lower spleen mass, and longer and larger bones compared to control females. Compared to control males, ARKO males had lower body and kidney mass, higher splenic mass, and reductions in cortical and trabecular bone. Deletion of the AR in ARKO males abolished the gender differences in heart and cortical bone. Compared with control females, ARKO females had normal body weight, but 14% lower heart mass and heart weight/body weight ratio. Relative kidney mass was also reduced, and relative spleen mass was increased. ARKO females had a significant reduction in cortical bone growth and changes in trabecular architecture, although with no net change in trabecular bone volume. In conclusion, we have shown that androgens acting via the genomic AR signaling pathway mediate, at least in part, the gender differences in body mass, heart, kidney, spleen, and bone, and play a physiological role in the regulation of cardiac, kidney and splenic size, cortical bone growth, and trabecular bone architecture in females.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2015
DOI: 10.1007/S12672-015-0222-5
Abstract: BRCA1 mutations are associated with ovarian cancer. Previous studies reported that murine granulosa cell (GC) Brca1 loss caused ovarian-uterine tumors resembling serous cystadenomas, but the pathogenesis of these tumors may have been confounded by ectopic Brca1 expression and altered estrous cycling. We have used Tg.AMH.Cre conferring proven ovarian and GC-specific Cre activity to selectively target Brca1 disruption, denoted Brca1(GC-/-). Furthermore, ovary-specific Brca1(GC-/-) was combined with global Trp53 haploinsufficiency (Trp53(+/-)) and transgenic follicle-stimulating hormone (Tg.FSH) overexpression as a multi-hit strategy to investigate additional genetic and hormonal ovarian tumorigenesis mechanisms. However, 12-month-old Brca1(GC-/-) mice had no detectable ovarian or uterine tumors. Brca1(GC-/-) mice had significantly increased ovary weights, follicles exhibiting more pyknotic granulosa cells, and fewer corpora lutea with regular estrous cycling compared to controls. Isolated Brca1(GC-/-) mutation lengthened the estrous cycle and proestrus stage however, ovarian cystadenomas were not observed, even when Brca1(GC-/-) was combined with Trp53(+/-) and overexpressed Tg.FSH. Our Brca1(GC-/-) models reveal that specific intra-follicular Brca1 loss alone, or combined with cancer-promoting genetic (Trp53 loss) and endocrine (high serum FSH) changes, was not sufficient to cause ovarian tumors. Our findings show that the ovary is remarkably resistant to oncogenesis, and support the emerging view of an extragonadal, multi-hit origin for ovarian tumorigenesis.
Publisher: Oxford University Press (OUP)
Date: 18-03-2016
Abstract: The objective of this study is to examine associations between Hb levels and sarcopenia, low muscle strength, functional measures, and activities of daily living (ADL) and instrumental ADL (IADL) disabilities in older Australian men. Men aged 70 years and older (2005-2007) from the Concord Health and Ageing in Men Project were assessed at baseline (n = 1,705), 2 years (n = 1,367), and 5 years (n = 958). The main outcome measurements were walking speed, muscle strength, ADL and IADL disabilities, and sarcopenia using the Foundation for the National Institutes of Health criteria (low appendicular lean mass adjusted for body mass index < 0.789 and poor grip strength < 26kg). Analysis was performed using Hb levels as a continuous measure, unadjusted and adjusted by age, income, body mass index, measures of health, estimated glomerular function, inflammatory markers, and medication use. Receiver operating characteristic curve analysis was performed to determine a threshold of Hb for each outcome. In cross-sectional and longitudinal analysis, for every 1g/dL increase in Hb, there was a significant reduction in risk of sarcopenia, slow walking speed, poor grip strength, inability to perform chair stands, and ADL and IADL disabilities in unadjusted, age-adjusted, and multivariate-adjusted analysis. The highest value of the Youden Index for Hb was 14.2g/dL for sarcopenia and grip strength, 14.5g/dL for walking speed, and 14.4g/dL for all other outcomes. Declines in Hb levels over time are associated with poor functional outcomes. The risks and benefits of interventions to increase Hb among older men warrant further investigation to differentiate whether this is an active contributor to age-related debility or a passive biomarker of it.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2014
Publisher: AMPCo
Date: 03-2000
DOI: 10.5694/J.1326-5377.2000.TB123913.X
Abstract: Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17 alpha-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks [corrected]. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended.
Publisher: Wiley
Date: 04-2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1016/J.JURO.2016.06.085
Abstract: We sought to determine which lower urinary tract symptoms are associated with incident falls in community dwelling older men. The Concord Health and Ageing in Men Project involves a representative s le of community dwelling men 70 years old or older in a defined geographic region in Sydney, New South Wales, Australia. Included in analysis were 1,090 men without neurological diseases, poor mobility or dementia at baseline. Lower urinary tract symptoms were assessed using I-PSS (International Prostate Symptom Score) and incontinence was assessed using ICIQ (International Consultation on Incontinence Questionnaire) at baseline. I-PSS subscores were calculated for storage and voiding symptoms. Incident falls in 1 year were determined by telephone followup every 4 months. I-PSS storage and voiding subscores were associated with falls. Urgency incontinence was associated with falls (adjusted incidence rate ratio 2.57, 95% CI 1.54-4.30). In addition, intermediate to high I-PSS storage subscores without urgency incontinence were associated with falls (adjusted incidence rate ratio 1.72, 95% CI 1.24-2.38). Other types of incontinence and urgency alone without urgency incontinence were not associated with falls. Lower urinary tract storage and voiding symptoms were associated with falls in community dwelling older men. Of the symptoms of overactive bladder urgency incontinence carried a high risk of falls. Storage symptoms also contributed to the fall risk independently of urgency incontinence. Circumstances of falls among men with lower urinary tract symptoms should be explored to understand how lower urinary tract symptoms increase the fall risk and generate hypotheses regarding potential interventions. Furthermore, trials to treat lower urinary tract symptoms in older men should include falls as an end point.
Publisher: Wiley
Date: 30-08-2013
DOI: 10.1002/JMS.3252
Abstract: Accurate measurement of estradiol (E2) is important in clinical diagnostics and research. High sensitivity methods are critical for specimens with E2 concentrations at low picomolar levels, such as serum of men, postmenopausal women and children. Achieving the required assay performance with LC-MS is challenging due to the non-polar structure and low proton affinity of E2. Previous studies suggest that ionization has a major role for the performance of E2 measurement, but comparisons of different ionization techniques for the analysis of clinical s les are not available. In this study, female serum and endometrium tissue s les were used to compare electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI) in both polarities. APPI was found to have the most potential for E2 analysis, with a quantification limit of 1 fmol on-column. APCI and ESI could be employed in negative polarity, although being slightly less sensitive than APPI. In the presence of biological background, ESI was found to be highly susceptible to ion suppression, while APCI and APPI were largely unaffected by the s le matrix. Irrespective of the ionization technique, background interferences were observed when using the multiple reaction monitoring transitions commonly employed for E2 (m/z 271 > 159 m/z 255 > 145). These unidentified interferences were most severe in serum s les, varied in intensity between ionization techniques and required efficient chromatographic separation in order to achieve specificity for E2.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1093/JN/NXZ256
Abstract: The relations between diet, chronic inflammation, and musculoskeletal health are unclear, especially among older men. This study aimed to determine associations of the Dietary Inflammatory Index (DII) with inflammatory biomarkers, musculoskeletal health, and falls risk in community-dwelling older men. The cross-sectional analysis included 794 community-dwelling men, mean age 81.1 ± 4.5 y, who participated in the 5-y follow-up of the Concord Health and Aging in Men Project. Of these, 616 were seen again 3 y later for the longitudinal analysis. Energy-adjusted DII (E-DII) was calculated from a validated diet history questionnaire. Bone mineral density (BMD) was measured using DXA. Twenty-four inflammatory biomarkers were analyzed. Incident falls over 3 y were determined through telephone interviews every 4 mo. Multiple regression, linear mixed effects models, negative binomial regression, and mediation analysis were utilized in this study. A higher E-DII score (indicating a more proinflammatory diet) was associated with higher concentrations of IL-6 (β: 0.028 pg/mL 95% CI: 0.003, 0.053), IL-7 (β: 0.020 pg/mL 95% CI: 0.002, 0.037), and TNF-α (β: 0.027 pg/mL 95% CI: 0.003, 0.051). A higher E-DII score was also associated with lower appendicular lean mass adjusted for BMI (ALMBMI) (β: -0.006 kg/m2 95% CI: -0.010, -0.001). For every unit increase in E-DII (range: -4.91 to +3.66 units), incident falls rates increased by 13% (incidence rate ratio: 1.13 95% CI: 1.05, 1.21) over 3 y. Mediation analysis showed that the association between E-DII and 3-y incident falls was influenced by the concentrations of IL-7 by 24%. There was no association between E-DII and BMD. Consumption of a proinflammatory diet was associated with increased concentrations of IL-6, IL-7, and TNF-α increased falls risk and lower ALMBMI in community-dwelling older men. The association between incident falls and E-DII was partly mediated by concentrations of IL-7.
Publisher: The Endocrine Society
Date: 10-1999
Publisher: The Endocrine Society
Date: 06-2004
Abstract: Several randomized trials of androgen supplementation in older men have been undertaken. However, the relative contributions of testosterone (T) and estrogens on bone metabolism in aging men are controversial. Within the setting of two double-blind, placebo-controlled studies, we evaluated the effect of dihydrotestosterone (DHT) and recombinant human chorionic gonadotropin (rhCG) on bone turnover in healthy, community-dwelling older men with partial androgen deficiency (total T ≤ 15 nmol/liter). In the first study, 35 men (age 68.3 ± 6.8 yr baseline T, 13.9 ± 3.3 nmol/liter) were randomized to receive either daily transdermal DHT (n = 17) or placebo for 3 months. In the second study, 40 men (age 67.4 ± 5.4 yr baseline T, 11.4 ± 2.2 nmol/liter) were randomized to receive either rhCG sc (n = 20), two injections weekly, or placebo for 3 months. The following parameters were measured before, monthly during, and 1 month after treatment: serum T, estradiol (E2), and LH markers of bone formation, serum amino-terminal propeptide of type I procollagen (S-PINP) and osteocalcin markers of bone resorption, serum carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline. Compared with placebo, treatment with DHT significantly increased serum DHT and suppressed LH and T levels, whereas E2 concentrations and markers of bone turnover did not change. In contrast, rhCG therapy significantly increased both T and E2, with the increases in E2 being supraphysiological. At the same time, rhCG significantly increased S-PINP concentrations with peak levels after 1 month (Δ40% P = 0.02 compared with placebo). In contrast, serum osteocalcin and carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline levels did not change. The change in S-PINP levels correlated with the change in E2 levels (r = 0.59 P = 0.02) but not with a change in T. We conclude that in older men with partial age-related androgen deficiency, rhCG treatment stimulates osteoblastic collagen formation proportionally to increased E2 concentrations but does not alter markers of mature osteoblastic function or bone resorption. In contrast, treatment with a pure, nonaromatizable androgen (DHT) has no effect on bone turnover despite a 20-fold increase in serum levels. Bone resorption was not accelerated during unchanged (DHT) or increased (rhCG) E2 levels, suggesting that minimal E2 levels are needed to maintain stable resorption, although direct androgen receptor-mediated effects cannot be excluded. If androgen supplementation is required for aging men, aromatizable androgens with sufficient endogenous estrogenic activity may have the most beneficial effects on bone.
Publisher: Copernicus GmbH
Date: 08-01-2013
Abstract: Abstract. The Southern Ocean (44° S–75° S) plays a critical role in the global carbon cycle, yet remains one of the most poorly s led ocean regions. Different approaches have been used to estimate sea-air CO2 fluxes in this region: synthesis of surface ocean observations, ocean biogeochemical models, and atmospheric and ocean inversions. As part of the RECCAP (REgional Carbon Cycle Assessment and Processes) project, we combine these different approaches to quantify and assess the magnitude and variability in Southern Ocean sea-air CO2 fluxes between 1990–2009. Using all models and inversions (26), the integrated median annual sea-air CO2 flux of −0.42 ± 0.07 Pg C yr−1 for the 44° S–75° S region is consistent with the −0.27 ± 0.13 Pg C yr−1 calculated using surface observations. The circumpolar region south of 58° S has a small net annual flux (model and inversion median: −0.04 ± 0.07 Pg C yr−1 and observations: +0.04 ± 0.02 Pg C yr−1), with most of the net annual flux located in the 44° S to 58° S circumpolar band (model and inversion median: −0.36 ± 0.09 Pg C yr−1 and observations: −0.35 ± 0.09 Pg C yr−1). Seasonally, in the 44° S–58° S region, the median of 5 ocean biogeochemical models captures the observed sea-air CO2 flux seasonal cycle, while the median of 11 atmospheric inversions shows little seasonal change in the net flux. South of 58° S, neither atmospheric inversions nor ocean biogeochemical models reproduce the phase and litude of the observed seasonal sea-air CO2 flux, particularly in the Austral Winter. Importantly, no in idual atmospheric inversion or ocean biogeochemical model is capable of reproducing both the observed annual mean uptake and the observed seasonal cycle. This raises concerns about projecting future changes in Southern Ocean CO2 fluxes. The median interannual variability from atmospheric inversions and ocean biogeochemical models is substantial in the Southern Ocean up to 25% of the annual mean flux with 25% of this inter-annual variability attributed to the region south of 58° S. Trends in the net CO2 flux from the inversions and models are not statistically different from the expected increase of –0.05 Pg C yr−1 decade−1 due to increasing atmospheric CO2 concentrations. However, resolving long term trends is difficult due to the large interannual variability and short time frame (1990–2009) of this study.
Publisher: The Endocrine Society
Date: 06-1996
DOI: 10.1210/ENDO.137.6.8641216
Abstract: We have examined the cAMP-independent regulation of cytosolic calcium concentration in rat Sertoli cells using the effect of vasoactive hormones, known as testicular paracrine regulators operating via the non-cAMP pathway, on cytosolic calcium. Calcium concentrations were estimated with dual excitation fluorimetry, using freshly isolated, fura-2/AM-loaded cells. No increase in the cellular cAMP concentration was detected after stimulation with angiotensin II (AII), vasopressin, PGF2 alpha, or atrial natriuretic peptide. Whereas both AII and vasopressin evoked a rise in cytosolic calcium from a basal level of 81.4 +/- 4 to 142.5 +/- 18 and 154.4 +/- 11 nM, respectively, PGF2 alpha had only a minimal effect (98 +/- 5 nM), and atrial natriuretic peptide no effect (86.6 +/- 9 nM). The effect of AII on calcium was blocked by the the selective AT2, but not by the AT1, receptor antagonist, indicating the selective presence on Sertoli cells of AT2 AII receptor. Similarly, the vasopressin-induced calcium response was blocked by vasopressin V1, but not by V2 receptor antagonist, consistent with the presence of V1 receptor subtype in these cells. Removal of extracellular calcium or blockade of calcium channels did not inhibit the calcium increase due to AII and vasopressin, suggesting the involvement of intracellular calcium. Thapsigargin increased the basal cytosolic calcium concentration to 137 +/- 10 nM. Depletion of intracellular calcium stores with thapsigargin before stimulation with AII or vasopressin abolished both the AII-mediated and the vasopressin-mediated calcium rise in the presence as well as the absence of extracellular calcium, indicating that the increase in calcium is predominantly derived from the thapsigargin-sensitive endoplasmic reticulum. This study indicates that calcium homeostasis of Sertoli cells might also be regulated by cAMP-independent metabolism apart from the well known cAMP-dependent pathway. Furthermore, our findings support the idea that angiotensin and vasopressin might be important paracrine regulators of Sertoli cells functions.
Publisher: Oxford University Press (OUP)
Date: 28-07-2017
Abstract: Previous studies demonstrated associations between IL-6 and frailty, but associations between a wide range of cytokines, chemokines, and growth factors with prevalent and incident frailty has not been studied. Community-dwelling men aged more than 75 enrolled in the 5-year and 8-year follow-up of the CHAMP study were assessed. Twenty-seven inflammatory biomarkers were measured using the Bio-Plex Pro Human Cytokine 27-plex Assay kit at 5-year follow-up. Frailty was determined using the Fried frailty phenotype (FP) and Rockwood frailty index (FI) at both time-points. Age, body mass index, smoking, alcohol, and comorbidity were also assessed. In cross-sectional analysis of the 5-year follow-up, the unadjusted odds ratio (OR) for frail versus robust evaluated by the FP showed significant associations for IL-6 (OR: 1.56, 95% confidence interval [CI]: 1.23-1.98) and IL-8 (OR: 1.28, 95% CI: 1.00-1.63). IL-6 remained significantly associated in the age-adjusted (OR: 1.58, 95% CI: 1.21-2.05) and multivariable-adjusted model (OR: 1.54, 95% CI: 1.16-2.05). No associations were observed between pre-frail versus robust. In longitudinal unadjusted analysis, IL-8 (OR: 1.32, 95% CI: 1.03-1.70) and IP-10 (OR: 1.32, 95% CI: 1.03-1.70) at 5-year predicted incident frailty at 8-year follow-up. IL-8 remained longitudinally associated with incident frailty after age (OR: 1.34, 95% CI: 1.03-1.75) but not multivariable (OR: 1.20, 95% CI: 0.98-1.70) adjustment. Similar results were seen using the FI. None of the other biomarkers had significant associations with incident frailty. Our findings suggest that IL-6 and IL-8 may be cross-sectionally associated with frailty and that all measured inflammatory biomarkers were not causally related to frailty. Together with previous studies, the results suggest that frailty is specifically linked to IL-6 and IL-8 rather than simply representing a nonspecific pan-inflammatory condition.
Publisher: Wiley
Date: 07-2009
Publisher: Oxford University Press (OUP)
Date: 27-02-2021
Abstract: Type 2 diabetes mellitus (T2DM) increases falls and fracture risk. Our objective was to compare incidence and risk factors for falls and fractures in community-dwelling older men with and without T2DM. A total of 1705 men (471 with T2DM 1234 without T2DM) aged ≥70 years were assessed at baseline. Men were contacted every 4 months for 6.0 ± 2.2 years to ascertain incident falls and fractures, with the latter being confirmed by radiographic reports. Hip fractures were ascertained via data linkage (follow-up: 8.8 ± 3.6 years). Risk factors for falls and fractures included physical activity and function, body composition, medications, and vision measures. Men with T2DM had similar fall (incident rate ratio [IRR]: 0.92 [95% confidence interval {CI}: 0.70, 1.12], n = 1246) and fracture rates (hazard ratio [HR]: 0.86 [95% CI: 0.56, 1.32], n = 1326) compared to men without T2DM after adjustment for significant risk factors. In men with T2DM, depression (IRR: 1.87 [95% CI: 1.05, 3.34], n = 333), sulphonylurea usage (IRR: 2.07 [95% CI: 1.30, 3.27]) and a greater number of prescription medications (IRR: 1.13 [95% CI: 1.03, 1.24]) were independently associated with increased fall rates, and higher total hip bone mineral density was independently associated with lower fracture rates (HR: 0.63 [95% CI: 0.47, 0.86], n = 351). Interaction terms demonstrated that better contrast sensitivity was independently associated with lower fracture rates (HR: 0.14 [95% CI: 0.02, 0.87]) in men with T2DM compared to men without T2DM. Fall and fracture rates were similar in men with and without T2DM after adjusting for significant risk factors. Vision assessments including contrast sensitivity measures may improve fracture prediction in older men with T2DM.
Publisher: Public Library of Science (PLoS)
Date: 08-03-2018
Publisher: Elsevier BV
Date: 08-2020
Publisher: Oxford University Press (OUP)
Date: 12-2001
Publisher: Informa UK Limited
Date: 04-07-2022
No related grants have been discovered for David Handelsman.