ORCID Profile
0000-0002-4741-5567
Current Organisations
Universidad de Córdoba Facultad de Medicina y Enfermería
,
Instituto Maimónides de Investigación Biomédica de Córdoba
,
Centro de Investigación Biomédica en Red
,
Department of Higher Education
,
Universidad de Córdoba - Facultad de Medicina
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Publications
Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al.
Publisher: Oxford University Press (OUP)
Date: 12-2013
DOI: 10.1530/EJE-13-0763
Comparative Analysis of the Effects of Ghrelin and Unacylated Ghrelin on Luteinizing Hormone Secretion in Male Rats
Publisher: The Endocrine Society
Date: 05-2006
DOI: 10.1210/EN.2005-1422
Abstract: Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of erse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.
Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrichet al.
Publisher: Wiley
Date: 24-10-2013
Expression of Growth Hormone Secretagogue Receptor Type 1a, the Functional Ghrelin Receptor, in Human Ovarian Surface Epithelium, Mullerian Duct Derivatives, and Ovarian Tumors
Publisher: The Endocrine Society
Date: 03-2005
DOI: 10.1210/JC.2004-1532
Abstract: Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R), is a newly identified, ubiquitously expressed molecule that has been involved in a wide array of endocrine and nonendocrine functions, including cell proliferation. In this context, our group recently reported the expression of ghrelin and its functional receptor, the GHS-R type 1a, in the human ovary and testis as well as several testicular tumors. Ovarian malignancies, however, remain unexplored. Notably, a vast majority of ovarian tumors derive from the surface epithelium, which originates from the celomic epithelium. Considering the proven expression of ghrelin in the human ovary, and its reported effects in the proliferative activity of different cancer cell lines, we aimed at evaluating whether the ovarian surface epithelium as well as related reproductive structures and tumors are potential targets of ghrelin. To this end, expression of GHS-R1a was analyzed by immunohistochemistry in a panel of normal, metaplastic, and neoplastic tissues. Uniform GHS-R1a immunostaining was detected throughout the ovarian surface epithelium. Likewise, ciliated cells within the fallopian tube epithelium showed strong GHS-R1a expression. In contrast, other celomic derivatives, such as endometrium and endocervix, were negative for GHS-R1a immunoreactivity. In keeping with data from normal tissues, inclusion cysts from the surface epithelium expressed GHS-R1a. Similarly, benign serous tumors resembling fallopian tube epithelium were also positive, whereas serous cystadenocarcinomas showed GHS-R1a expression only in highly differentiated specimens. In contrast, other neoplasms, such as mucinous cystadenomas and cystadenocarcinomas, endometrioid tumors, clear cell carcinomas, and Brenner tumors, did not express GHS-R1a. In conclusion, our results demonstrate that the ovarian surface epithelium and related tumors are potential targets for systemic or locally produced ghrelin because they express the functional type 1a GHS-R. Considering the relevant role of the ovarian surface epithelium in key physiological events (such as ovulation) and neoplastic transformation of the ovary, the potential actions of ghrelin in those phenomena merit further investigation.
Policy Decisions on Endocrine Disruptors Should Be Based on Science Across Disciplines: A Response to Dietrich et al.
Publisher: The Endocrine Society
Date: 11-2013
DOI: 10.1210/EN.2013-1854
Selective loss of kisspeptin signaling in oocytes causes progressive premature ovulatory failure
Publisher: Oxford University Press (OUP)
Date: 17-01-2022
Abstract: Does direct kisspeptin signaling in the oocyte have a role in the control of follicular dynamics and ovulation? Kisspeptin signaling in the oocyte plays a relevant physiological role in the direct control of ovulation oocyte-specific ablation of kisspeptin receptor, Gpr54, induces a state of premature ovulatory failure in mice that recapitulates some features of premature ovarian insufficiency (POI). Kisspeptins, encoded by the Kiss1 gene, are essential for the control of ovulation and fertility, acting primarily on hypothalamic GnRH neurons to stimulate gonadotropin secretion. However, kisspeptins and their receptor, Gpr54, are also expressed in the ovary of different mammalian species, including humans, where their physiological roles remain contentious and poorly characterized. A novel mouse line with conditional ablation of Gpr54 in oocytes, named OoGpr54−/−, was generated and studied in terms of follicular and ovulatory dynamics at different age-points of postnatal maturation. A total of 59 OoGpr54−/− mice and 47 corresponding controls were analyzed. In addition, direct RNA sequencing was applied to ovarian s les from 8 OoGpr54−/− and 7 control mice at 6 months of age, and gonadotropin priming for ovulatory induction was conducted in mice (N = 7) from both genotypes. Oocyte-selective ablation of Gpr54 in the oocyte was achieved in vivo by crossing a Gdf9-driven Cre-expressing transgenic mouse line with a Gpr54 LoxP mouse line. The resulting OoGpr54−/− mouse line was subjected to phenotypic, histological, hormonal and molecular analyses at different age-points of postnatal maturation (Day 45, and 2, 4, 6 and 10–11 months of age), in order to characterize the timing of puberty, ovarian follicular dynamics and ovulation, with particular attention to identification of features reminiscent of POI. The molecular signature of ovaries from OoGpr54−/− mice was defined by direct RNA sequencing. Ovulatory responses to gonadotropin priming were also assessed in OoGpr54−/− mice. Oocyte-specific ablation of Gpr54 caused premature ovulatory failure, with some POI-like features. OoGpr54−/− mice had preserved puberty onset, without signs of hypogonadism. However, already at 2 months of age, 40% of OoGpr54−/− females showed histological features reminiscent of ovarian failure and anovulation. Penetrance of the phenotype progressed with age, with & % and 100% of OoGpr54−/− females displaying complete ovulatory failure by 6- and 10 months, respectively. This occurred despite unaltered hypothalamic Gpr54 expression and gonadotropin levels. Yet, OoGpr54−/− mice had decreased sex steroid levels. While the RNA signature of OoGpr54−/− ovaries was dominated by the anovulatory state, oocyte-specific ablation of Gpr54 significantly up- or downregulated of a set of 21 genes, including those encoding pituitary adenylate cyclase-activating polypeptide, Wnt-10B, matrix-metalloprotease-12, vitamin A-related factors and calcium-activated chloride channel-2, which might contribute to the POI-like state. Notably, the anovulatory state of young OoGpr54−/− mice could be rescued by gonadotropin priming. N/A. Conditional ablation of Gpr54 in oocytes unambiguously caused premature ovulatory failure in mice yet, the ultimate molecular mechanisms for such state of POI can be only inferred on the basis of RNAseq data and need further elucidation, since some of the molecular changes observed in OoGpr54−/− ovaries were secondary to the anovulatory state. Direct translation of mouse findings to human disease should be made with caution since, despite the conserved expression of Kiss1/kisspeptin and Gpr54 in rodents and humans, our mouse model does not recapitulate all features of common forms of POI. Deregulation of kisspeptin signaling in the oocyte might be an underlying, and previously unnoticed, cause for some forms of POI in women. This work was primarily supported by a grant to M.P. and M.T.-S. from the FiDiPro (Finnish Distinguished Professor) Program of the Academy of Finland. Additional financial support came from grant BFU2017-83934-P (M.T.-S. Ministerio de Economía y Competitividad, Spain co-funded with EU funds/FEDER Program), research funds from the IVIRMA International Award in Reproductive Medicine (M.T.-S.), and EFSD Albert Renold Fellowship Programme (S.T.R.). The authors have no conflicts of interest to declare in relation to the contents of this work. N/A.
Kisspeptins and the control of gonadotropin secretion in male and female rodents
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.
Reprint of: Policy decisions on endocrine disruptors should be based on science across disciplines: A response to Dietrich, et al.
Publisher: Elsevier BV
Date: 2014
Expression of Ghrelin and Its Functional Receptor, the Type 1a Growth Hormone Secretagogue Receptor, in Normal Human Testis and Testicular Tumors
Publisher: The Endocrine Society
Date: 2004
Abstract: Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHS-R), has been primarily linked to the central neuroendocrine regulation of GH secretion and food intake, although additional peripheral actions of ghrelin have also been reported. In this context, the expression of ghrelin and its cognate receptor has been recently demonstrated in rat testis, suggesting a role for this molecule in the direct control of male gonadal function. However, whether this signaling system is present in human testis remains largely unexplored. In this study we report the expression and cellular location of ghrelin and its functional receptor, the type 1a GHS-R, in adult human testis. In addition, evaluation of ghrelin and GHS-R1a immunoreactivity in testicular tumors and dysgenetic tissue is presented. The expression of the mRNAs encoding ghrelin and GHS-R1a was demonstrated in human testis specimens by RT-PCR, followed by direct sequencing. In normal testis, ghrelin immunostaining was demonstrated in interstitial Leydig cells and, at lower intensity, in Sertoli cells within the seminiferous tubules. In contrast, ghrelin was not detected in germ cells at any stage of spermatogenesis. The cognate ghrelin receptor showed a wider pattern of cellular distribution, with detectable GHS-R1a protein in germ cells, mainly in pachytene spermatocytes, as well as in somatic Sertoli and Leydig cells. Ghrelin immunoreactivity was absent in poorly differentiated Leydig cell tumor, which retained the expression of GHS-R1a peptide. In contrast, highly differentiated Leydig cell tumors expressed both the ligand and the receptor. The expression of ghrelin and GHS-R1a was also detected in dysgenetic Sertoli cell-only seminiferous tubules, whereas germ cell tumors (seminoma and embryonal carcinoma) were negative for ghrelin and were weakly positive for GHS-R1a. In conclusion, our results demonstrate that ghrelin and the type 1a GHS-R are expressed in adult human testis and testicular tumors. Overall, the expression of ghrelin and its functional receptor in human and rat testis, with roughly similar patterns of cellular distribution, is highly suggestive of a conserved role for this newly discovered molecule in the regulation of mammalian testicular function.
Reprint of: Policy decisions on endocrine disruptors should be based on science across disciplines: A response to Dietrich et al.
Publisher: Elsevier BV
Date: 02-2014
Immunolocalization of Ghrelin and Its Functional Receptor, the Type 1a Growth Hormone Secretagogue Receptor, in the Cyclic Human Ovary
Publisher: The Endocrine Society
Date: 02-2003
Abstract: Ghrelin is a novel 28-amino acid peptide identified as the endogenous ligand for the GH secretagogue receptor (GHS-R). Besides its hallmark central neuroendocrine effects in the control of GH secretion and food intake, an unexpected reproductive facet of ghrelin has recently emerged because expression of this molecule and its cognate receptor has been demonstrated in rat testis. However, whether this signaling system is present in human gonads remains to be evaluated. In this study, we have assessed the presence and cellular location of ghrelin and its functional receptor, namely the type 1a GHS-R, in the cyclic human ovary by means of immunohistochemistry using specific polyclonal antibodies. Strong ghrelin immunostaining was demonstrated in ovarian hilus interstitial cells. In contrast, ghrelin signal was not detected in ovarian follicles at any developmental stage, nor was it present in newly formed corpora lutea (CL) at very early development. However, specific ghrelin immunoreactivity was clearly observed in young and mature CL, whereas expression of the peptide disappeared in regressing luteal tissue. Concerning the cognate receptor, ovarian expression of GHS-R1a protein showed a wider pattern of tissue distribution, with detectable specific signal in oocytes as well as somatic follicular cells luteal cells from young, mature, old, and regressing CL and interstitial hilus cells. Of particular note, follicular GHS-R1a peptide expression paralleled follicle development with stronger immunostaining in granulosa and theca layers of healthy antral follicles. In conclusion, our results are the first to demonstrate that ghrelin and its functional type 1a receptor are expressed in the cyclic human ovary with distinct patterns of cellular location. The presence of both components (ligand and receptor) of the ghrelin signaling system within the human ovary opens up the possibility of a potential regulatory role of this novel molecule in ovarian function under physiological and pathophysiological conditions.
Discovery of Potent Kisspeptin Antagonists Delineate Physiological Mechanisms of Gonadotropin Regulation
Publisher: Society for Neuroscience
Date: 25-03-2009
DOI: 10.1523/JNEUROSCI.5740-08.2009
Abstract: Neurons that produce gonadotropin-releasing hormone (GnRH) are the final common pathway by which the brain regulates reproduction. GnRH neurons are regulated by an afferent network of kisspeptin-producing neurons. Kisspeptin binds to its cognate receptor on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion, thus gating down-stream events supporting reproduction. We have developed kisspeptin antagonists to facilitate the direct determination of the role of kisspeptin neurons in the neuroendocrine regulation of reproduction. In vitro and in vivo studies of analogues of kisspeptin-10 with amino substitutions have identified several potent and specific antagonists. A selected antagonist was shown to inhibit the firing of GnRH neurons in the brain of the mouse and to reduce pulsatile GnRH secretion in female pubertal monkeys the later supporting a key role of kisspeptin in puberty onset. This analog also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the postcastration rise in LH in sheep, rats, and mice, suggesting that kisspeptin neurons mediate the negative feedback effect of sex steroids on gonadotropin secretion in mammals. The development of kisspeptin antagonists provides a valuable tool for investigating the physiological and pathophysiological roles of kisspeptin in the regulation of reproduction and could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer.
Policy Decisions on Endocrine Disruptors Should Be Based on Science across Disciplines: A Response to Dietrich et al.
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000355668
Hypothalamic Expression of Human Growth Hormone Induces Post‐Pubertal Hypergonadotrophism in Male Transgenic Growth Retarded Rats
Publisher: Wiley
Date: 31-07-2006
DOI: 10.1111/J.1365-2826.2006.01467.X
Abstract: Growth hormone (GH) is known to regulate peripheral components of the hypothalamo-pituitary gonadal (HPG) axis, but it remains unclear whether GH exerts a significant influence on the activity of the hypothalamo-pituitary components of the HPG axis. In this study, we investigated the development of HPG axis function in the male transgenic growth retarded (Tgr) rat, a model of moderate systemic GH deficiency caused by hypothalamic expression of human (h)GH. Impaired postnatal somatotroph expansion and moderate GH deficiency in male Tgr rats were accompanied by a two- to three-fold increase in pituitary gonadotrophin content, but without a significant change in the pituitary gonadotroph population. A three- to nine-fold elevation in basal circulating luteinising hormone concentration was seen in postpubertal Tgr rats, with a smaller increase in follicle-stimulating hormone. Despite this hypergonadotrophism, there was no corresponding increase in steroidogenic (circulating testosterone and seminal vesicle weights) or gametogenic (spermatozoa counts in seminiferous tubules) activity in the postpubertal Tgr testis. Following puberty, the plasma leptin concentration also became progressively elevated in Tgr males. Circulating gonadotrophin and leptin levels were normalised in Tgr rats by peripheral physiological replacement of rat GH, but plasma testosterone concentration was unaffected. These results confirm that hGH exerts a positive influence on the central control of gonadotrophin secretion in the Tgr rat, but the absence of a corresponding elevation in the steroidogenic or gametogenic function of the Tgr testis implies that the peripheral GH/insulin-like growth factor I axis may also exert a permissive influence on testicular function. The relative contribution of somatogenic and lactogenic mechanisms and the potential influence of elevated leptin and decreased sensitivity to androgen feedback to the development of postpubertal hypergonadotrophism in Tgr males remain to be determined.
Related Organisations
Universidad De Córdoba Facultad De Medicina Y Enfermería
Location: Spain
Instituto Maimónides De Investigación Biomédica De Córdoba
Location: Spain
Related Funding Activities
No related grants have been discovered for Manuel Tena-Sempere.