ORCID Profile
0000-0002-0678-3187
Current Organisation
Edith Cowan University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 15-06-2006
DOI: 10.1111/J.1365-2826.2006.01452.X
Abstract: The effect of circulating oestrogen deficiency on sleep regulation and locomotor activity was investigated in aromatase cytochrome P450 deficient mice (ArKO) and wild-type (WT) controls. Sleep was recorded in 3-month old mice during a 24-h baseline day, 6-h sleep deprivation (SD) and 18-h recovery, and activity was recorded at the age of 3, 9 and 12 months. In mice deficient of oestrogen, the total amount of sleep per 24 h was the same as in WT controls. However, in ArKO mice, sleep was enhanced in the dark period at the expense of sleep in the light phase, and was more fragmented than sleep in WT mice. This redistribution of sleep resulted in a d ed litude of slow-wave activity (SWA power between 0.75-4.0 Hz) in non-rapid eye movement sleep across 24 h. After SD, the rebound of sleep and SWA was similar between the genotypes, suggesting that oestrogen deficiency does not affect the mechanisms maintaining the homeostatic balance between the amount of sleep and its intensity. Motor activity decreased with age in both genotypes and was lower in ArKO mice compared to WT at all three ages. After SD, the amount of rest in 3-month old WT mice increased above baseline and was more consolidated. Both effects were less pronounced in ArKO mice, reflecting the baseline differences between the genotypes. The results indicate that despite the pronounced redistribution of sleep and motor activity in oestrogen deficient mice, the basic homeostatic mechanisms of sleep regulation in ArKO mice remain intact.
Publisher: Springer Science and Business Media LLC
Date: 08-2006
DOI: 10.1007/S00213-006-0472-6
Abstract: The aim of this study was to investigate the interaction of sex steroid hormones, particularly oestrogen, in the regulation of prepulse inhibition (PPI) by serotonin-1A (5-HT1A) receptors. We studied aromatase knockout (ArKO) mice, which are unable to produce oestrogen but have high levels of testosterone, and the effects of castration. Treatment of male ArKO mice with the 5-HT1A receptor agonist, 8-hydroxy-dipropyl-aminotetralin (8-OH-DPAT), caused an increase in PPI that was significantly greater than in male wild-type controls. Castration of male mice caused a significant enhancement of the effect of 8-OH-DPAT in control mice however, there was no change in the effect of this drug in ArKO mice. There was no significant effect of 8-OH-DPAT on PPI in either female ArKO or wild-type controls. In all experiments, the effects of 8-OH-DPAT on startle were not different between the groups. [3H]8-OH-DPAT autoradiography showed no differences in 5-HT1A receptor binding densities in areas of the forebrain, hippoc us or raphe region that could explain the PPI results. These data show that the absence of oestrogen in male ArKO mice leads to a greater effect of 5-HT1A receptor stimulation on PPI. This effect can be mimicked in male control mice by castration. The differential involvement of oestrogen and testosterone in these animal models is discussed.
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.MCN.2004.04.012
Abstract: The aromatase knockout (ArKO) mouse is unable to synthesize estrogens. Immunohistochemical studies on active caspase-3 and tyrosine hydroxylase (TH) revealed apoptosis of dopaminergic neurons in the medial preoptic area (MPO) and arcuate nucleus (Arc) of the hypothalamus of 1-year-old (1yo) male ArKO mice while no active caspase-3 was detected in wild type (WT). Furthermore, the number of TH-positive cells in the MPO and caudal Arc was significantly decreased in 1yo ArKO compared to WT. RNase protection assays support the presence of apoptosis in 1yo ArKO hypothalamus, revealing an up-regulation of pro-apoptotic genes: FASL, FADD, and caspase-8. Concomitantly, the ratio of bcl-2-related anti-apoptotic genes to pro-apoptotic genes in the hypothalamus of 1yo ArKO mice was significantly down-regulated. Previously, we have reported that no such changes were observed in the hypothalamus of female ArKO mice. Thus, we have provided direct evidence that estrogen is required to maintain the survival and functional integrity of dopaminergic neurons in the MPO and Arc of male, but not female mice.
Publisher: Elsevier BV
Date: 07-1000
DOI: 10.1016/S1043-2760(00)00254-X
Abstract: Natural (human) and experimental (mouse) models of estrogen insufficiency have revealed hitherto unexpected roles for estrogens in both males and females. In postmenopausal women, and in men, estrogen no longer has a major role as a circulating hormone, but rather it functions locally as a paracrine or even 'intracrine' factor in tissue sites where it is formed. As a consequence, the tissue-specific nature of aromatase production assumes physiological and pathophysiological significance. The availability of circulating precursors is also important in sites where there is no local supply of C19 precursors, particularly in elderly women. The potential clinical significance of these findings in terms of the development of new therapeutic modalities is discussed.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0960-0760(01)00158-3
Abstract: Targeted disruption of exon 9 of the cyp19 gene gives rise to a non-functional aromatase enzyme incapable of converting androgens to oestrogens. The aromatase knockout (ArKO) mouse is, thus, characterised by a dysfunctional pituitary-gonadal axis, which manifests in non-detectable levels of oestrogen in serum. These mice also exhibit elevated levels of circulating gonadotrophins (luteinising hormone (LH) and follicle stimulating hormone (FSH)) and testosterone. The ArKO mouse is infertile due to folliculogenic disruption and a failure to ovulate. The age-dependent ovarian phenotype revealed a block in follicular development at the antral stage and a complete absence of corpora lutea. By 21-23 weeks of age haemorrhagic cystic follicles were present and by 1 year there were abnormal follicles, an absence of secondary and antral follicles and atretic primary follicles. Interstitial tissue remodelling was extensive and exemplified by an increase in collagen deposition and an influx of macrophages, coincident with the loss of follicles. In mice, maintained on a soy-free and, thus, phytoestrogen-free diet, the ovarian phenotype was accelerated and exacerbated. In conclusion, the ovarian phenotype of the ArKO mouse can be attributed to the altered hormonal environment brought about by the absence of aromatase and the failure of androgens to be converted to oestrogens in the presence of elevated gonadotropins.
Publisher: S. Karger AG
Date: 2005
DOI: 10.1159/000086864
Abstract: The mechanism of regulation of growth hormone (GH) secretion by oestrogens and androgens is still controversial. Available data on the action of oestrogens on GH expression and secretion in somatotropes is poorly understood. We previously reported that the aromatase knockout (ArKO) mouse with oestrogen deficiency and excessive androgen levels had dysfunctional somatotropes. In order to clarify the influence of androgen and oestrogen, we investigated the in vivo treatment of ovariectomised (OVX) ArKO mice with exogenous oestradiol (E sub /sub ) on the mRNA expression of GH, GH-secretagogue receptor (GHS-R), GH-releasing hormone receptor (GHRH-R), pituitary-specific transcription factor (Pit-1), and somatostatin receptors (sst1–5) in pituitary glands. Circulating plasma GH levels were also evaluated. The results showed that ArKO/OVX mice have a low expression of pituitary GH, GHRH-R, GHS-R and Pit-1, and significantly reduced GH levels. Treatment of female ArKO/OVX (E sub /sub -deficient without excessive androgen) mice with E sub /sub for 21 days enhanced expression of pituitary GHRH-R and Pit-1 to 151 and 168%, respectively, of that in mice without treatment. E sub /sub treatment increased GH expression and plasma levels in ArKO/OVX mice to levels comparable with those in wild-type female mice. We conclude therefore that long-term E sub /sub replacement rescues the dysfunction of somatotropes in ArKO/OVX mice through increases in expression of GH, GHRH-R, and Pit-1 in the pituitary somatotropes, whereas the level of androgen in this oestrogen-deficient female mouse does not significantly influence the function of somatotropes.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2008
DOI: 10.1038/CR.2008.291
Abstract: Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0016-6480(90)90208-4
Abstract: A sensitive radioimmunoassay was developed to measure circulating levels of the neurohypophysial peptide lysine vasopressin (LVP) in the marsupial quokka (Setonix brachyurus), which is abundant on Rottnest Island off the coast of Western Australia. Animals from locations on the island where free water is completely absent were compared in midsummer with animals from sites where brackish water is available and utilized by the quokkas. In the animals from West End, where free water is absent, circulating levels of LVP averaged 89.2 +/- 19.6 pg/ml, which was significantly higher than the mean level of 35.6 +/- 15.8 pg/ml measured in in iduals collected from the Lakes site with access to brackish drinking water. Rates of water and sodium turnover, measured with isotopes, were significantly greater in Lakes than West End animals, as were renal clearances of sodium, chloride, urea, and total osmolytes. Despite an obvious osmotic diuresis resulting from the ingestion of salty water, the Lakes animals were in better physical condition at the end of summer than the West End animals which lack free water, and these latter in iduals showed signs of slight dehydration with elevated plasma and urinary electrolyte concentrations and osmolalities.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-12-2003
DOI: 10.1161/01.RES.0000103172.98986.25
Abstract: The consequences of estrogen deficiency on the cardiovascular system have been widely examined in females. The effects of endogenous estrogen deficiency in males are less clear. The aromatase-knockout (ArKO) mouse lacks a functional Cyp19 gene, which encodes aromatase, and is thus incapable of synthesizing endogenous estrogen. In the present study, we examined the effect of lack of endogenous estrogens on vascular function in aortic rings isolated from male ArKO mice and compared these effects to rings from wild-type (WT) littermates. Full concentration-response curves to norepinephrine, acetylcholine, isoprenaline, and sodium nitroprusside were obtained in the absence and presence of the nitric oxide synthase inhibitor N ω -nitro- l -arginine in aortic segments set up in isometric myographs. Responses to noradrenaline were not different in aorta from ArKO compared with WT mice. Both N ω -nitro- l -arginine and endothelium denudation significantly shifted the noradrenaline concentration-response curve to the left however, this shift was not different in ArKO compared with WT. Responses to the endothelium-dependent vasodilator acetylcholine were significantly blunted in aortic rings from ArKO mice (E max , 58.2±0.9% and 34.0±0.5% in wild-type and ArKO, respectively P .05), whereas responses to the endothelium-independent agonist sodium nitroprusside and to the partial endothelium-dependent agonist isoprenaline were not affected. These findings suggest that endogenous estrogen facilitate vasorelaxation in males. This may be via modulating endothelial function rather than vascular smooth muscle cell responsiveness.
Publisher: Wiley
Date: 10-2007
Abstract: Estrogen regulates tissue development, function, and aging by regulating expression of critical genes. Recent studies suggest that estrogen promotes cell proliferation by stimulating telomerase activity, an enzyme that plays a key role in extending cell life span. In some estrogen-responsive tissues, estrogen appears important in regulating telomerase activity in vivo. Further characterization will provide a greater understanding of the link between estrogen, telomerase, and aging.
Publisher: Georg Thieme Verlag KG
Date: 2005
Abstract: The aromatase (ArKO) knockout mouse develops obesity marked by increased gonadal fat depots. This obesity is characterized by pronounced hypertrophy and hyperplasia in adipocytes with corresponding increases in transcripts involved in fat development. Aromatase deficiency in mice and humans with natural mutations of the aromatase gene also leads to metabolic syndrome, particularly hepatic steatosis. In ArKO mice, this hepatic steatosis, the increased body weight and serum triglycerides are surprisingly prevented by cholesterol feeding. We sought to investigate whether the reduction in body weight upon cholesterol feeding is reflected in gonadal fat depots, which account for a large percentage of body weight in the ArKO mouse. Indeed, gonadal fat depots in female ArKO mice were significantly reduced after cholesterol feeding. Concomitantly, adipocyte hyperplasia and hypertrophy were dramatically reduced upon cholesterol feeding in ArKO mice. Real-time PCR analysis revealed concurrent changes with adipocyte volume in the levels of lipoprotein lipase, caveolin-1 and CD59 transcripts. Little change was observed in levels of transcripts involved in de novo fatty acid synthesis, beta-oxidation, lipolysis, differentiation and cholesterol metabolism, suggesting that cholesterol feeding prevents hyperplasia and hypertrophy of ArKO adipocytes, possibly as a consequence of changes in transcript levels of lipoprotein lipase and therefore fatty acid uptake.
Publisher: Elsevier BV
Date: 06-1995
Publisher: Oxford University Press (OUP)
Date: 04-2011
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.BIOPSYCH.2006.01.012
Abstract: Aromatase converts androgen to estrogen. Thus, the aromatase knockout (ArKO) mouse is estrogen deficient. We investigated the compulsive behaviors of these animals and the protein levels of catechol-O-methyltransferase (COMT) in frontal cortex, hypothalamus and liver. Grooming was analyzed during the 20-min period immediately following a water-mist spray. Running wheel activity over two consecutive nights and barbering were analyzed. COMT protein levels were measured by Western analysis. Six-month old male but not female ArKO mice develop compulsive behaviors such as excessive barbering, grooming and wheel-running. Excessive activities were reversed by 3 weeks of 17beta-estradiol replacement. Interestingly, the presentation of compulsive behaviors is accompanied by concomitant decreases (p < .05) in hypothalamic COMT protein levels in male ArKO mice. These values returned to normal upon 17beta-estradiol treatment. In contrast, hepatic and frontal cortex COMT levels were not affected by the estrogen status, indicating region- and tissue-specific regulation of COMT levels by estrogen. No differences in COMT levels were detectable between female animals of both genotypes. This study describes the novel observation of a possible link between estrogen, COMT and development of compulsive behaviors in male animals which may have therapeutic implications in obsessive compulsive disorder (OCD) patients.
Publisher: The Endocrine Society
Date: 09-2004
DOI: 10.1210/EN.2004-0421
Publisher: Wiley
Date: 06-2001
Publisher: The Endocrine Society
Date: 07-04-2005
DOI: 10.1210/ER.2004-0020
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.MCN.2008.12.009
Abstract: The aromatase knockout (ArKO) mouse is completely estrogen deficient. We previously detected apoptosis in the hypothalamus of 1 year-old male ArKO mice. This study shows that 12 week-old female ArKO mice display spontaneous apoptosis of pyramidal neurons in the frontal cortex while wild-type (WT) littermates show no signs of apoptosis. Concomitantly, bcl-2 related anti-apoptotic genes are down-regulated whereas the pro-apoptotic gene TRADD is up-regulated in the female ArKO frontal cortex. This phenotype can be rescued by 3-week replacement of 17beta-estradiol. Furthermore, the apoptosis phenotype is exacerbated in 12-15 month-old female ArKO mice, which have 30% less neurons in the frontal cortex and lower brain weights than WT counterparts. These data show that estrogens are essential for the survival of female cortical neurons even in the absence of pathological conditions or external assaults. Our observations also demonstrate the sexually dimorphic susceptibility of neurons to estrogen deficiency.
Publisher: Bioscientifica
Date: 06-1999
Abstract: It is now apparent that in men and in postmenopausal women, estrogens have important physiological and pathophysiological roles. However, importantly, these actions are at a local level, namely paracrine, autocrine, and even 'intracrine' rather than endocrine in the classical sense. Thus for ex le local estrogen biosynthesis in the bones of men plays a hitherto unsuspected role in the maintenance of bone mineralization and in epiphyseal fusion and in the testes, estrogen is essential for male germ cell development. On the other hand, in postmenopausal women, the mesenchymal cells of the breast are the major source of estrogen responsible for breast cancer development. This realization points to the importance of circulating C19 precursors in the maintenance of adequate estrogen biosynthesis in extragonadal sites and suggests the possibility of new therapies to block estrogen synthesis in a tissue-specific fashion.
Publisher: Wiley
Date: 21-01-2010
DOI: 10.1002/ART.27330
Abstract: A number of experimental observations have associated elevated estrogen levels with amelioration of inflammation. The involvement of estrogen and estrogen receptor (ER) isotypes in the regulation of inflammation in males is not well understood. In this study, we used specific ERalpha and ERbeta agonists in male mice deficient in estrogen because of a deletion of aromatase (aromatase-knockout [ArKO] mice) to investigate ER isotype utilization in estrogen regulation of inflammation. Lipopolysaccharide (LPS)-induced cytokine expression and antigen-induced arthritis (AIA) were investigated in male ArKO and WT littermate mice, as well as in response to selective agonists of ERalpha (16alpha-LE2) and ERbeta (8beta-VE2). The therapeutic effect of selective ER agonists was also examined in mice with collagen-induced arthritis (CIA). Estrogen deficiency in ArKO mice was associated with significant increases in LPS-induced serum interleukin-6 (IL-6), tumor necrosis factor, monocyte chemotactic protein 1, and interferon-gamma levels, which were significantly abrogated by administration of 16alpha-LE2, but not 8beta-VE2. In contrast, both 16alpha-LE2 and 8beta-VE2 significantly increased LPS-induced IL-10 levels. Estrogen deficiency was also associated with significant exacerbation of AIA and antigen-specific T cell proliferation, which was reversed by administration of either 16alpha-LE2 or 8beta-VE2. ArKO mice showed increased antigen-specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16alpha-LE2, but not 8beta-VE2, significantly reduced the severity of CIA, which was associated with inhibition of anti-CII-specific IgG. These data indicate that endogenous estrogen plays an essential inhibitory role in inflammation in male mice and that ERalpha is the dominant receptor that mediates these effects.
Publisher: Elsevier BV
Date: 05-2005
Publisher: Proceedings of the National Academy of Sciences
Date: 06-07-1999
Abstract: It is well established that spermatogenesis is controlled by gonadotrophins and testosterone. However, a role for estrogens in male reproduction recently was suggested in adult mice deficient in estrogen receptor α. These mice became infertile primarily because of an interruption of fluid reabsorption by the efferent ductules of the epididymis, thus leading to a disruption of the seminiferous epithelium [Hess, R. A., Bunick, D., Lee, K. H., Bahr, J., Taylor, J. A., Korach, K. S., and Lubahn, D. B. (1997) Nature (London) 390, 509–512]. Despite the demonstration of the aromatase enzyme, which converts androgens to estrogens, and estrogen receptors within the rodent seminiferous epithelium, the role of aromatase and estrogen in germ cell development is unknown. We have investigated spermatogenesis in mice that lack aromatase because of the targeted disruption of the cyp19 gene (ArKO). Male mice deficient in aromatase were initially fertile but developed progressive infertility, until their ability to sire pups was severely impaired. The mice deficient in aromatase developed disruptions to spermatogenesis between 4.5 months and 1 year, despite no decreases in gonadotrophins or androgens. Spermatogenesis primarily was arrested at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and there was a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells. In addition, Leydig cell hyperplasia/hypertrophy was evident, presumably as a consequence of increased circulating luteinizing hormone. Our findings indicate that local expression of aromatase is essential for spermatogenesis and provide evidence for a direct action of estrogen on male germ cell development and thus fertility.
Publisher: Elsevier BV
Date: 04-1999
Publisher: Elsevier BV
Date: 09-2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2003
DOI: 10.1097/00001756-200310270-00020
Abstract: Previous studies indicate an important role for estrogen in memory and learning. Aromatase-knockout (ArKO) mice are unable to produce estrogen because they lack a functional Cyp 19 gene that encodes for aromatase, the enzyme that converts testosterone into estrogen. Using a Y-maze test for short-term spatial reference memory, we found that both male and female ArKO mice performed significantly worse than wildtype controls. Gonadectomy reduced Y-maze responses in male and female wildtype controls, but had no effect in ArKO mice. After gonadectomy, there was no significant difference between wildtype and ArKO mice. For the first time using ArKO mice, our findings confirm the importance of estrogen in memory in both males and females.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-05-2006
Publisher: The Endocrine Society
Date: 04-2003
Abstract: Estrogen deficiency in the aromatase knockout (ArKO) mouse leads to the development of obesity by as early as 3 months of age, which is characterized by a marked increase in the weights of gonadal and infrarenal fat pads. Humans with natural mutations of the aromatase gene also develop a metabolic syndrome. In the present study cellular and molecular parameters were investigated in gonadal adipose tissue from 10-wk-old wild-type (WT) and ArKO female mice treated with 17beta-estradiol or placebo to identify the basis for the increase in intraabdominal obesity. Stereological examination revealed that adipocytes isolated from ArKO mice were significantly larger and more abundant than adipocytes isolated from WT mice. Upon treatment with estrogen, the volume of these adipocytes was greatly reduced, whereas the reduction in the number of adipocytes was much less pronounced. Transcriptional analysis using real-time PCR revealed concomitant changes with adipocyte volume in the levels of transcripts encoding leptin and lipoprotein lipase, whereas peroxisome proliferator-activated receptor gamma levels followed a pattern closer to that of adipocyte number. Little change was observed in levels of transcripts for factors involved in de novo fatty acid synthesis, beta-oxidation, and lipolysis, suggesting that changes in the uptake of lipids from the circulation are the main mechanisms by which estrogen regulates lipid metabolism in these mice.
Publisher: Oxford University Press (OUP)
Date: 05-2004
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.BRAINRES.2005.10.018
Abstract: Defects in serotonergic transmission, including serotonin transporter (SERT) function, have been implicated in depression, anxiety disorders and some aspects of schizophrenia. The sex steroid hormone estrogen is known to modulate functional SERT activity, but whether it is up- or down-regulated is unclear. The aim of the present study was to examine the effect of a low estrogen state in mice on the behavioral effect of drugs acting through the SERT, serotonin uptake kinetics and SERT density in the hippoc us. We compared control mice, ovariectomized (OVX) C57BL/6J mice and aromatase knockout (ArKO) mice that are unable to produce estrogen. Fluoxetine treatment, but not fenfluramine treatment, significantly increased prepulse inhibition (PPI), a measure of sensorimotor gating, in C57BL/6J mice. The effect of fluoxetine was greater in OVX compared to sham-operated mice. In ArKO and J129 wild-type mice, fluoxetine increased PPI to the same extent while fenfluramine increased PPI more in ArKO mice compared to controls. Measurement of the time-course for diffusion and reuptake of exogenous serotonin in the CA3 region of the hippoc us showed that, in OVX mice, the fluoxetine-induced slowing of signal decay after application of serotonin was enhanced when compared to sham-operated controls. Similarly, in ArKO mice, the effect of fluoxetine was enhanced, suggesting that SERT function was greater than in J129 wild-type controls. Measurement of SERT density by [3H]-citalopram autoradiography, revealed an 18% decrease in hippoc us of OVX mice compared to intact controls. SERT density was also significantly reduced in nucleus accumbens (26%) but not in other regions, such as the raphe nuclei. Together, these results suggest that a low estrogen state increases SERT activity in the hippoc us despite an apparent reduction in SERT density. The behavioral consequences of these changes depend on the model of estrogen state used.
Publisher: Proceedings of the National Academy of Sciences
Date: 16-08-2004
Abstract: Sjögren's syndrome (SS) is an incurable, autoimmune exocrinopathy that predominantly affects females and whose pathogenesis remains unknown. Like rheumatoid arthritis, its severity increases after menopause, and estrogen deficiency has been implicated. We have reported that estrogen receptor-α and -β-knockout mice develop autoimmune nephritis and myeloid leukemia, respectively, but neither develops SS. One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse. In these animals, there is elevated B lymphopoiesis in bone marrow. We now report that ArKO mice develop severe autoimmune exocrinopathy resembling SS. By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney. Also, as is typically found in human SS, there were proteolytic fragments of α-fodrin in the salivary glands and anti-α-fodrin antibodies in the serum of both female and male ArKO mice. When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice. In age-matched WT mice fed a diet containing normal levels of phytoestrogen, there were no autoimmune lesions. These results reveal that estrogen deficiency results in a lymphoproliferative autoimmune disease resembling SS and suggest that estrogen might have clinical value in the prevention or treatment of this disease.
Publisher: Wiley
Date: 08-05-2003
DOI: 10.1002/PROS.10230
Abstract: Red clover (RC)-derived dietary isoflavones have been implicated as potential preventative agents for the development and prevalence of non-malignant prostate diseases. This study investigated whether dietary isoflavones inhibit prostate growth in vivo in the aromatase knock-out (ArKO) mouse that exhibits lifelong elevation of androgens leading to prostate enlargement. Adult (11-week-old) wild-type (WT) and ArKO mice were fed on protein matched isoflavones free (IF) and RC (isoflavone rich) diets for 28 days. In idual prostate lobes and testes were weighed and collected for histological analysis and serum androgens were measured. Responses were compared to castration and estrogen administration to ArKO mice to determine the mechanism of action. ArKO mice fed on IF diet exhibited enlarged prostate lobes and elevated serum androgens compared to WT mice. Following 28 days of RC diet, ArKO VP, AP, and SV weights were reduced to WT weights, although testis and body weights remained unaltered. Stereological analysis of VPs revealed a reduction in all components of the tissue, particularly the lumen. The RC diet reduced ArKO serum testosterone and dihydrotestosterone to WT levels. In comparison to castration and estrogen administration, the dietary isoflavones were shown to be anti-androgenic rather than weakly estrogenic, mimicking responses observed in the castrated ArKO, rather than estrogen treated ArKOs. This study demonstrates that RC-derived isoflavones have a significant effect on prostatic growth, and are capable of reducing the enlarged non-malignant prostate phenotype of the adult ArKO mouse, by acting as anti-androgenic agents rather than weak estrogenic substances.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-02-2004
DOI: 10.1161/01.CIR.0000109699.45186.30
Abstract: Background— Altered proliferation and death of vascular smooth muscle cells (VSMCs) are important mechanisms in vascular growth and remodeling. This study examined the effect of endogenous estrogens on VSMC proliferation. Methods and Results— An estrogen-deficient animal model, the aromatase-knockout (ArKO) mouse, was used. Primary cultures of VSMCs were established from aortas of 11-week-old male and female ArKO and wild-type (WT) mice. In ArKO cells, the absence of aromatase cytochrome P450 mRNA expression was demonstrated by reverse transcription–polymerase chain reaction Western blotting showed normal expression of estrogen receptor protein. Proliferative responses to serum or platelet-derived growth factor-BB were lower in ArKO than WT cells 17β-estradiol (E 2 , 10 nmol/L) enhanced the response to platelet-derived growth factor-BB in ArKO cells but inhibited the response in WT cells. E 2 inhibited activity of mitogen-activated protein kinase ERK1/2 in WT but not ArKO cells. Apoptosis-related death caused by tumor necrosis factor-α was greater in ArKO than in WT cells this effect in ArKO was attenuated by E 2 . Differences in VSMC proliferation between ArKO and WT occurred in both sexes. Morphological studies in aortas derived from male mice at 1 year of age demonstrated that medial smooth muscle area was ≈10% less in ArKO than WT mice at this age. Conclusions— Deficiency of endogenous estrogens reduces proliferation and enhances apoptosis-related death in VSMCs exogenous E 2 corrects these abnormalities.
Publisher: Elsevier BV
Date: 05-2002
DOI: 10.1016/S0303-7207(02)00052-7
Abstract: The steroidogenic pathway within the ovary gives rise to progestins, androgens and oestrogens, all of which act via specific nuclear receptors to regulate reproductive function and maintain fertility. The precise role of oestrogen in the ovary remains to be elucidated, hence the data presented here which arises from studies designed to resolve this issue. Oestrogens signal via two receptor subtypes ERalpha and ERbeta, both of which are present in the ovary. ERbeta, the most abundant mRNA, is primarily expressed by GC where it transduces signals from ovarian-derived and exogenous oestrogens. Specific roles for each of the ERs in the ovary have yet to be established, despite ER knockout studies indicating both are required for normal function. The ArKO mouse is a model of oestrogen insufficiency. These mice are infertile as a result of arrested folliculogenesis (at the antral stage) and a failure to ovulate. Trans/re-differentiation of somatic cells in the ovary gives rise to Sertoli cell-like and Leydig cell-like cells within abnormal follicular structures. Disruption to the balance of sex steroids in the ovary is likely to facilitate this phenotype. Future studies will focus on the regulation of somatic cell differentiation, assigning roles to in idual ERs and establishing definitive targets of oestrogen action in the ovary.
Publisher: The Endocrine Society
Date: 09-2003
DOI: 10.1210/EN.2003-0244
Abstract: The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to disruption of the Cyp19 gene. We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia. In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets. Our results show a sexually dimorphic response to estrogen deficiency in terms of cholesterol homeostasis in the liver. ArKO females presented with elevated serum cholesterol conversely, ArKO males had elevated hepatic cholesterol levels. In response to dietary cholesterol, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase transcript levels were significantly reduced in females, whereas males showed more modest changes. Neither low density lipoprotein nor sterol regulatory element-binding protein expression levels were significantly altered by diet or genotype. The expression of Cyp7a, which encodes cholesterol 7α-hydroxylase, was significantly reduced in ArKO females compared with wild-type females and was increased by cholesterol feeding. Cyp7a expression was significantly elevated in the wild-type males on the high cholesterol diet, although no difference was seen between genotypes on the control diet. The ATP-binding cassette G5 and ATP-binding cassette G8 transporters do not appear to be regulated by estrogen. The expression of acyl-coenzyme A:cholesterol acyltransferase 2 showed a sexually dimorphic response, where estrogen appeared to have a stimulatory effect in females, but not males. This study reveals a sexually dimorphic difference in mouse hepatic cholesterol homeostasis and roles for estrogen in the regulation of cholesterol uptake, biosynthesis, and catabolism in the female, but not in the male.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0960-0760(01)00136-4
Abstract: Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.
Publisher: The Endocrine Society
Date: 02-2004
DOI: 10.1210/EN.2003-0646
Abstract: Available data on the influence of estradiol (E2) on GH levels remains controversial. A factor contributing to this uncertainty is a lack of knowledge of both E2 action on somatotropes as well as the molecular mechanisms involved. In this study we investigated gene expression implicated in GH secretion in somatotropes derived from female aromatase knockout (ArKO) mice. In these mice E2 production is blocked due to disruption of the Cyp19 gene encoding aromatase, the enzyme responsible for estrogen biosynthesis. The effect of E2 replacement was also studied by in vivo treatment of mice with E2 for 3 wk. It was demonstrated that somatotropes from ArKO mice had a low expression of GH, GH secretagogue receptor, GHRH receptor (GHRH-R), and pituitary-specific transcription factor (Pit-1). On the other hand, the somatotropes exhibited elevated expression of somatostatin receptors (sst1–5). Overall, these effects resulted in a reduction in GH secretion. E2 replacement increased GHRH-R, Pit-1, and GH mRNA levels to 185%, 193%, and 157% and reduced the levels of sst1, sst2, sst4, and sst5 mRNA expression in ArKO mice, respectively. E2 replacement did not affect the levels of pituitary estrogen (α and β) and androgen receptor mRNA expression. It is concluded that the expression of important genes involved in GH synthesis in somatotropes of the female ArKO mouse are functionally down-regulated, and such a down-regulation is reversed to normal levels by E2 replacement. The levels of GH secretagogue receptor, GHRH-R, and Pit-1 mRNA expression were also reduced, and sst1 and sst3 mRNA expression enhanced in aging ArKO and wild-type mice, resulting in a decrease in GH mRNA expression. It is suggested that aging is another important impact factor for the pituitary expression and regulation of GH mRNA in female mice.
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.JSBMB.2016.05.013
Abstract: We investigated the effects of estrogens on glucose homeostasis using the Aromatase Knockout (ArKO) mouse, which is unable to convert androgens into estrogens. The ArKO mouse is a model of total estrogen ablation which develops symptoms of metabolic syndrome. To determine the development and progression of whole body state of insulin resistance of ArKO mice, comprehensive whole body tolerance tests were performed on WT, ArKO and estrogen administrated mice at 3 and 12 months of age. The absence of estrogens in the male ArKO mice leads to hepatic insulin resistance, glucose and pyruvate intolerance from 3 to 12 months with consistent improvement upon estrogen treatment. Estrogen absence in the female ArKO mice leads to glucose intolerance without pyruvate intolerance or insulin resistance. The replacement of estrogens in the female WT and ArKO mice exhibited both insulin sensitizing and resistance effects depending on age and dosage. In conclusion, this study presents information on the sexually dimorphic roles of estrogens on glucose homeostasis regulation.
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.TEM.2006.01.004
Abstract: We are rapidly becoming aware of the importance of estrogen in maintaining virtually all facets of male health. In order for estrogens to be synthesized endogenously, the enzyme responsible for their synthesis from androgens, aromatase, must be functional. The seven known men in whom aromatase is nonfunctional all have a mutation in either exon V or IX of the CYP19 gene, which encodes aromatase. Collectively, these men are reported to have undetectable estrogen normal to high levels of testosterone and gonadotropins tall stature with delayed skeletal maturation and epiphyseal closure osteoporosis impaired lipid and insulin metabolism and impaired reproductive function. The aromatase knockout mouse presents with a phenotype that is similar in many aspects and provides a valuable tool with which to examine and manipulate the actions of estrogen. By studying the naturally occurring aromatase-deficient humans, together with studies of the aromatase-knockout mouse, we are expanding our understanding of the essential role of estrogen in male physiology.
Publisher: Elsevier BV
Date: 05-2000
DOI: 10.1016/S0303-7207(99)00243-9
Abstract: The hypothesis that activin and inhibin are autocrine aracrine mediators of ovarian folliculogenesis has a solid basis. In mouse and rat models, granulosa cells (GC) of committed follicles express mRNA and protein for the activin/inhibin subunits and mRNA for the activin receptors (type I and II). Dimeric inhibin-A and -B are produced by postnatal ovarian cell dispersates and (GC) in culture. Similar levels of inhibin-A and -B are produced by postnatal ovarian cells, but thereafter as the ovary develops, inhibin-A becomes the predominant form. Activin was more effective than transforming growth factor-beta (TGF-beta) in enhancing follicle stimulating hormone (FSH)-stimulated inhibin production by ovarian cells. Evidence for a local regulatory role of estrogen in the ovary is also accumulating. Murine models of estrogen receptor (ERalpha or ERbeta) disruption produce mice with abnormal ovarian phenotypes. Female mice, which lack the capacity to produce estrogen (ArKO mice), have arrested folliculogenesis, no corpora lutea, elevated levels of luteinising hormone (LH), FSH and testosterone and are infertile. These data are consistent with autocrine aracrine actions of activin in the early growth of committed follicles and estrogen in follicular maturation.
Publisher: Wiley
Date: 09-2002
Publisher: Public Library of Science (PLoS)
Date: 10-02-2014
Publisher: Springer Science and Business Media LLC
Date: 1995
DOI: 10.1038/BJC.1995.6
Abstract: An explant culture technique was used to culture normal urothelium from patients with muscle-invasive bladder cancer (transitional cell carcinoma, TCC) (n = 11) and from non-tumour-bearing patients (n = 60). Cell cultures were examined for expression of p53 using the monoclonal antibody p53-240. There was a statistically significant increase in p53 expression in normal urothelial cell cultures from patients with TCC (P < 0.0005). Normal urothelial cultures from patients with TCC also showed more rapid proliferation in vitro when compared with non-tumour-bearing patients (P 5% of cells expressing p53. p53 expression in this subgroup was found to correlate with cell proliferation in vitro (r2 = 0.766). None of these urothelial specimens was observed to express p53 when paraffin-embedded preparations were stained with p53-D07 antibody prior to culture. The rate of cellular proliferation in this subgroup did not differ from that of normal urothelium from TCC patients. Twenty-two paraffin-embedded, muscle-invasive TCC specimens were also evaluated for p53 expression using p53-D07. The expression of p53 in these tumours did not differ from that observed in normal urothelial cell cultures from patients with TCC (P = 0.26). This study identifies an overexpression of p53 in normal urothelial cells from patients with TCC and in proliferating cultures from a significant subgroup of patients without malignant disease. Increased p53 expression in normal cultured urothelial cells from patients with bladder cancer implies a global change in the mechanisms controlling urothelial cell ision. This may represent an early step in the pathway to carcinogenesis.
Publisher: Proceedings of the National Academy of Sciences
Date: 07-11-2000
Abstract: The aromatase-knockout (ArKO) mouse provides a useful model to examine the role that estrogens play in development and homeostasis in mammals. Lacking a functional Cyp19 gene, which encodes aromatase, the ArKO mouse cannot synthesize endogenous estrogens. We examined the adipose depots of male and female ArKO mice, observing that these animals progressively accumulate significantly more intraabdominal adipose tissue than their wild-type (WT) littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared with WT controls, as were elevated insulin levels, although blood glucose levels were unchanged. Associated with these changes, a striking accumulation of lipid droplets was observed in the livers of ArKO animals. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.
Publisher: Wiley
Date: 21-03-2003
DOI: 10.1034/J.1601-183X.2003.00014.X
Abstract: Estrogen has been suggested to play a neuromodulatory and neuroprotective role on the brain dopamine system. We used aromatase knockout (ArKO) mice that lack a functional aromatase enzyme and are unable to convert testosterone into estrogen, and assessed prepulse inhibition of acoustic startle, locomotor hyperactivity to hetamine treatment and rotarod performance. Mice were tested at either 1 month, 4-5 months or 12-18 months of age. In male, but not female ArKO mice, there was an age-related reduction of prepulse inhibition. The 12-18 months old male ArKO mice also showed significantly greater hetamine-induced hyperactivity. Mice heterozygous for the mutation showed no deficits or were in-between wildtype mice and ArKO mice. We postulate that these data indicate a neuroprotective role of estrogen, particularly in male mice, on ageing of brain mechanisms involved in pre-pulse inhibition and locomotor activity regulation. It is likely that these brain mechanisms are or include dopaminergic activity.
Publisher: Annual Reviews
Date: 03-2002
DOI: 10.1146/ANNUREV.PHYSIOL.64.081601.142703
Abstract: ▪ Abstract There is growing awareness that androgens and estrogens have general metabolic roles that are not directly involved in reproductive processes. These include actions on vascular function, lipid and carbohydrate metabolism, as well as bone mineralization and epiphyseal closure in both sexes. In postmenopausal women, as in men, estrogen is no longer solely an endocrine factor but instead is produced in a number of extragonadal sites and acts locally at these sites in a paracrine and intracrine fashion. These sites include breast, bone, vasculature, and brain. Within these sites, aromatase action can generate high levels of estradiol locally without significantly affecting circulating levels. Circulating C 19 steroid precursors are essential substrates for extragonadal estrogen synthesis. The levels of these androgenic precursors decline markedly with advancing age in women, possible from the mid-to-late reproductive years. This may be a fundamental reason why women are at increased risk for bone mineral loss and fracture, and possibly decline of cognitive function, compared with men. Aromatase expression in these various sites is under the control of tissue-specific promotors regulated by different cohorts of transcription factors. Thus in principle, it should be possible to develop selective aromatase modulators (SAMs) that block aromatase expression, for ex le, in breast, but allow unimpaired estrogen synthesis in other tissues such as bone.
Publisher: Bioscientifica
Date: 24-06-2011
DOI: 10.1530/JOE-10-0462
Abstract: Male aromatase knockout mice (ArKO an estrogen-deficient model) present with male-specific hepatic steatosis that is reversible upon 17β-estradiol replacement. This study aims to elucidate which estrogen receptor (ER) subtype, ERα or ERβ, is involved in the regulation of triglyceride (TG) homeostasis in the liver. Nine-month-old male ArKO mice were treated with vehicle, ERα- or ERβ-specific agonists via s.c. injection, daily for 6 weeks. Male ArKO mice treated with ERα agonist had normal liver histology and TG contents compared with vehicle-treated ArKO omental (gonadal) and infra-renal (visceral) fat pad weights were normalized to those of vehicle-treated wild-type (WT). In contrast, ERβ agonist treatment did not result in the similar reversal of these ArKO phenotypes. In vehicle-treated ArKO mice, hepatic transcript expression of fatty acid synthase ( Fasn ) and stearoyl-coenzyme A desaturase 1 (key enzymes in de novo FA synthesis) were significantly elevated compared with vehicle-treated WT, but only Fasn expression was lowered to WT level after ERα agonist treatment. There were no significant changes in the transcript levels of carnitine palmitoyl transferase 1 (required for transfer of FA residues into the mitochondria for β-oxidation) and sterol regulatory element-binding factor 1c (the upstream regulator of de novo FA synthesis). We also confirmed by RT-PCR that only ERα is expressed in the mouse liver. There were no changes in hepatic androgen receptor transcript level across all treatment groups. Our data suggest that estrogens act via ERα to regulate TG homeostasis in the ArKO liver. Since the liver, adipose tissue and arcuate nucleus express mainly ERα, estrogens could regulate hepatic functions via peripheral and central pathways.
Publisher: Elsevier BV
Date: 05-1995
Abstract: The proteasome plays a central role in ubiquitin-dependent and -independent proteolysis in eukaryotic cells. The hawkmoth proteasome was purified from larval body wall and characterized with respect to substrate specificity, sensitivity to protease inhibitors, and cross-reactivity with monoclonal antibodies (mAbs) raised against human placenta proteasome. Leupeptin selectively inhibited the trypsin-like activity (T-L) and N-ethylmaleimide inhibited both T-L and chymotrypsin-like activities, whereas 0.02% sodium dodecyl sulfate stimulated the peptidylglutamyl peptide hydrolase, branched-chain amino acid preferring, and caseinolytic activities 20-, 18-, and 3.8-fold, respectively. All four peptidase activities were inhibited by 3,4-dichloroisocoumarin. One-dimensional immunoblot analysis showed that the level and subunit composition of the proteasome varied between tissues. The relative levels of proteasome were high in intersegmental muscle and ovary, lower in Malpighian tubule, male accessory gland, and ventral nerve cord, and lowest in flight muscle and fat body. The tissues differed in the relative amount of a 41-kDa doublet a 22-kDa subunit was present only in the male accessory gland. Two-dimensional polyacrylamide gel electrophoresis showed that the hawkmoth proteasome contained at least 26 subunits, compared with 28 subunits in lobster. Immunological analysis using four subunit-specific mAbs identified the putative homologs of the human zeta, C2, C3, and C8 alpha-type subunits in the hawkmoth and lobster enzymes. Two of the four mAbs reacted with three or more of the hawkmoth subunits and three of the mAbs reacted with two or more of the lobster subunits. In addition, two other mAbs that recognize epitopes shared by a number of alpha-type subunits indicated that at least 15 (lobster) or 16 (hawkmoth) subunits were alpha-type. These results suggest that much of the subunit complexity of the arthropod proteasomes is a consequence of extensive post-translational modifications.
Publisher: The Endocrine Society
Date: 12-2006
DOI: 10.1210/EN.2006-0879
Abstract: Menopause is associated with an accumulation of visceral fat. An emerging concept suggests that relatively elevated levels of circulating androgens, compared with estrogens in postmenopausal women, underlie this shift in body fat distribution. In this study we administered dihydrotestosterone (DHT) to ovariectomized mice to examine the effect of relative androgen excess on adipose tissue distribution and function in estrogen-deficient mice. Compared with controls, DHT-treated mice exhibited increased body weight and visceral fat mass associated with triglyceride accumulation. Phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase was significantly decreased by DHT in visceral fat. In 3T3-L1 cells, DHT decreased phosphorylation of AMPK in a dose-dependent manner. In addition, DHT increased the expression of lipogenic genes (fatty acid synthase, sterol regulatory element binding protein-2, and lipoprotein lipase) in visceral fat. These data provide the first in vivo evidence that an increased androgen to estrogen ratio can promote visceral fat accumulation by inhibiting AMPK activation and stimulating lipogenesis.
Publisher: The Endocrine Society
Date: 04-2004
DOI: 10.1210/EN.2003-1369
Abstract: The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to a disruption to the Cyp19 gene. Previously we have shown both male and female ArKO mice have an age progressive obese phenotype and a sexually dimorphic disruption to hepatic cholesterol and triglyceride homeostasis. Only ArKO males have elevated hepatic triglyceride levels leading to hepatic steatosis partly due to an increase in expression of enzymes involved in de novo lipogenesis and transporters involved in fatty acid uptake. In this study ArKO males were treated with 17β-estradiol (3 μg/ kg·d) at 18 wk old for 6 wk. Wild-type controls were not treated, and ArKO controls received vehicle oil injections. Estrogen replacement reverses the previously reported obese and fatty liver phenotypes this was achieved by reductions in gonadal, visceral, and brown adipose tissue weights and significantly decreased hepatic triglyceride levels. Estrogen deficiency led to a significant up-regulation of hepatic fatty acid synthase expression, which was reduced with 17β-estradiol replacement, although not quite reaching significance. Acetyl Coenzyme A carboxylase α mRNA expression showed no significant changes. Expression of transcripts encoding adipocyte differentiated regulatory protein, a fatty acid transporter, was significantly elevated in estrogen-deficient males, and 17β-estradiol replacement significantly reduced these levels. Scavenger receptor class b type 1 showed no significantly changes. This study reveals that the previously reported disruption to triglyceride homeostasis in estrogen-deficient males can be reversed with 17β-estradiol treatment, indicating an important role for estrogen in maintaining triglyceride and fatty acid homeostasis in males.
Publisher: Springer Science and Business Media LLC
Date: 05-2007
Abstract: Aromatase deficiency is rare in humans. Affected in iduals cannot synthesize endogenous estrogens. Aromatase is the enzyme that catalyzes conversion of androgens into estrogens, and if aromatase is nonfunctional because of an inactivating mutation, estrogen synthesis cannot occur. If the fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, so is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother the maternal indicators resolve following delivery. To date, only seven males and seven females with aromatase deficiency have been reported. Affected females are typically diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotrophic hypogonadism. Affected males, on the other hand, do not present with obvious defects at birth, so are diagnosed much later in life, presenting with clinical symptoms, which include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess adiposity. Estrogen replacement therapy reverses the symptoms in male and female patients.
Publisher: Elsevier BV
Date: 07-2002
DOI: 10.1016/S0303-7207(02)00090-4
Abstract: Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is present in the mouse gonads, brain, adipose tissue and bone. Depletion of endogenous estrogens in the aromatase deficient mouse (ArKO) caused by the targeted disruption of the Cyp19 gene resulted in an impairment of sexual behaviour and an age-dependent disruption of spermatogenesis. This disruption occurred during early spermiogenesis, due possibly to increased number of apoptotic round spermatids. Development of obesity was associated with ageing, decrease in lean mass, hypercholesterolemia, hyperleptinemia, and insulin resistance and hepatic steatosis. However, it was not correlated with hyperphagia but to decreased physically-active behaviour. ArKO mice also developed osteoporosis. Thus, studies using the ArKO mice model has led to several insights into the multiple roles played by estrogens in the development and maintenance of fertility, sexual behaviour, lipid metabolism and bone remodelling.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.JSBMB.2007.05.029
Abstract: Estrogen has an important role to play in energy homeostasis in both men and mice. Lack of estrogen results in the development of a metabolic syndrome in humans and rodents, including excess adiposity, hepatic steatosis (in male but not female aromatase knockout (ArKO) mice) and insulin resistance. Estrogen replacement results in a prompt reversal of the energy imbalance symptoms associated with estrogen deficiency. A corollary to the perturbed energy balance observed in the ArKO mouse is the death by apoptosis of dopaminergic neurons in the hypothalamic arcuate nucleus of male ArKO mice, an area of the brain pivotal to the regulation of energy uptake, storage, and mobilisation. An extension of our work exploring the relationship between estrogen and adiposity has been to examine the role played by androgens in energy balance. We have demonstrated that an increased androgen to estrogen ratio can promote visceral fat accumulation in the rodent by inhibiting AMPK activation and stimulating lipogenesis. Therefore, understanding the regulation of energy homeostasis is becoming an increasingly fascinating challenge, as the number of contributors, their communications, and the complexity of their interactions, involved in the preservation of this equilibrium continues to increase. Models of aromatase deficiency, both naturally occurring and engineered, will continue to provide valuable insights into energy homeostasis.
Publisher: The Endocrine Society
Date: 06-2001
DOI: 10.1210/ER.22.3.289
Publisher: Springer Science and Business Media LLC
Date: 14-07-2009
DOI: 10.1007/S00213-009-1604-6
Abstract: The aim of the present study was to investigate the possible role of oestrogen in schizophrenia by comparing aromatase knockout (ArKO) mice, which are unable to produce oestrogen, with wild-type controls using two behavioural animal models with relevance to the illness, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition (PPI). Baseline PPI was not different between ArKO and controls. Treatment with apomorphine, MK-801 and hetamine caused disruption of PPI in all groups. However, in female but not male ArKO mice, the effect of both apomorphine and hetamine was reduced. In female ArKO mice, hetamine-induced hyperlocomotion was markedly reduced, but in male mice, the genotype difference was far smaller. Female but not male ArKO mice also showed a reduction of phencyclidine-induced locomotor hyperactivity. The density of dopamine transporters, but not D1 and D2 receptors, was significantly increased in the caudate putamen of male but not female ArKO mice compared to wild-type mice. This could represent a compensatory dopaminergic upregulation in male ArKO mice. Because of their lack of oestrogen production, it was anticipated that ArKO mice would display enhanced effects of hetamine on locomotor activity and PPI. Instead, in these animals, aromatase knockout appeared to be 'protective'. This may represent limitations in the ability to model a complex illness such as schizophrenia in a constitutive knockout model, such as ArKO mice. Moreover, the current results may point at the involvement of other sex steroids, which are also altered in ArKO mice, in dopaminergic control of behaviour.
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.MOLBRAINRES.2005.07.004
Abstract: The aromatase knockout (ArKO) mouse is estrogen deficient. Using reverse-transcription and real-time PCR, we showed that transcript levels of the N-methyl-d-aspartate (NMDA) receptor subunit NR2B are significantly higher in the hippoc us of female ArKO mice compared to wild-type (WT) littermates. Expression levels of NR1, NR2A, but not NR2C, also tended to be higher in ArKO mice. In the Morris watermaze test for spatial memory, both genotypes displayed equal significant improvement in the latency in locating the invisible platform over the 5-day training period. These findings show that selective loss of estrogen synthesis is associated with changes in NMDA receptor subunit expression in the hippoc us but little change in spatial learning ability.
Location: United States of America
No related grants have been discovered for Margaret Jones.