Effects of Ghrelin upon Gonadotropin-Releasing Hormone and Gonadotropin Secretion in Adult Female Rats: In vivo and in vitro Studies

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Abstract

A reproductive facet of ghrelin, a stomach-derived orexigenic peptide involved in energy homeostasis, has been recently suggested, and predominantly inhibitory effects of ghrelin upon luteinizing hormone (LH) secretion have been demonstrated in rat models. Yet, the modulatory actions of ghrelin on the gonadotropic axis remain scarcely evaluated. We report herein a detailed analysis of the effects of ghrelin upon LH and follicle-stimulating hormone (FSH) secretion in the female rat, using a combination of in vivo and in vitro approaches. Intracerebroventricular administration of ghrelin (3 nmol/rat) evoked a significant inhibition of LH secretion in cyclic female rats throughout the estrous cycle (proestrus afternoon, estrus, metestrus), as well as in ovariectomized females. In good agreement, gonadotropin-releasing hormone (GnRH) secretion by hypothalamic fragments from ovariectomized females was significantly inhibited by ghrelin. In contrast, ghrelin dose-dependently stimulated basal LH and FSH secretion by pituitary tissue in vitro; a phenomenon that was proven dependent on the phase of estrous cycle, as it was neither detected at estrus nor observed after ovariectomy. Conversely, GnRH-stimulated LH secretion in vitro was persistently inhibited by ghrelin regardless of the stage of the cycle, whereas stimulated FSH secretion was only inhibited by ghrelin at estrus. In addition, cyclic fluctuations in mRNA levels of growth hormone secretagogue receptor (GHS-R)1a, i.e. the functional ghrelin receptor, were observed in the pituitary, with low values at estrus and metestrus. GHS-R1a mRNA levels, however, remained unchanged after ovariectomy. In summary, our data illustrate a complex mode of action of ghrelin upon the gonadotropic axis, with predominant inhibitory effects at central (hypothalamic) levels and upon GnRH-induced gonadotropin secretion, but direct stimulatory actions on basal LH and FSH secretion. Overall, our results further document the reproductive role of ghrelin, which might be relevant for the integrated control of energy balance and reproduction.

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Leptin regulation of neuroendocrine systems.

Barbara Elmquist, Clifford B. Saper, J Flier … (2000)

The discovery of leptin has enhanced understanding of the interrelationship between adipose energy stores and neuronal circuits in the brain involved in energy balance and regulation of the neuroendocrine axis. Leptin levels are dependent on the status of fat stores as well as changes in energy balance as a result of fasting and overfeeding. Although leptin was initially thought to serve mainly as an anti-satiety hormone, recent studies have shown that it mediates the adaptation to fasting. Furthermore, leptin has been implicated in the regulation of the reproductive, thyroid, growth hormone, and adrenal axes, independent of its role in energy balance. Although it is widely known that leptin acts on hypothalamic neuronal targets to regulate energy balance and neuroendocrine function, the specific neuronal populations mediating leptin action on feeding behavior and autonomic and neuroendocrine function are not well understood. In this review, we have discussed how leptin engages arcuate hypothalamic neurons expressing putative orexigenic peptides, e.g., neuropeptide Y and agouti-regulated peptide, and anorexigenic peptides, e.g., pro-opiomelanocortin (precursor of alpha-melanocyte-stimulating hormone) and cocaine- and amphetamine-regulated transcript. We show that leptin's effects on energy balance and the neuroendocrine axis are mediated by projections to other hypothalamic nuclei, e.g., paraventricular, lateral, and perifornical areas, as well as other sites in the brainstem, spinal cord, and cortical and subcortical regions. Copyright 2000 Academic Press.

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Ghrelin--a hormone with multiple functions.

Robert B. Grossman, Anthony Goldstone, Márta Korbonits … (2004)

Ghrelin is brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach mucosa but it is also expressed widely in different tissues and therefore may have both endocrine and paracrine effects. Ghrelin is the endogenous ligand of the G protein-coupled growth hormone secretagogue receptor. In the current review we comprehensively summarize (i) the data available regarding the structure, expression pattern and regulation of ghrelin and its receptor; (ii) the available information regarding the effect of ghrelin on the pituitary hormone axis, appetite regulation, cardiac and gastrointestinal function, carbohydrate metabolism, adipose and reproductive tissue, cell proliferation and behavioral effects; (iii) experimental and clinical data regarding circulating ghrelin levels observed in various physiological and pathological conditions; and (iv) data on gene variations of ghrelin and its receptor. It is apparent that ghrelin is involved in many more processes than originally envisaged, and in particular appears to have relatively less relevance to growth hormone physiology and more to the regulation of energy fluxes in the organism. Increasing data link ghrelin to the overall control of energy use and flow in situations where there is a limitation of energy sources and ghrelin appears to play a pivotal role in energy homeostasis. Copyright 2004 Elsevier Inc.

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Leptin in male reproduction: the testis paradigm.

M Tena-Sempere, M.L. Barreiro (2002)

Leptin, the adipocyte-derived hormone that plays a key role in body weight homeostasis, has recently emerged as a relevant neuroendocrine mediator in different systems, including the reproductive axis. Thus, compelling evidence points out a major role of leptin in the regulation of female pubertal development and fertility, both in humans and experimental animals. The contribution of leptin to the proper functioning of the male reproductive system has been less clear. However, data gathered in recent years, from independent groups and through a variety of experimental approaches, strongly suggest that leptin is able to act at different levels of the hypothalamic-pituitary-testicular axis. Herein, we review the biological effects and potential mechanisms of action of leptin upon rodent testis. Leptin appears to act as a direct inhibitory signal for testicular steroidogenesis, which may be relevant to explain the link between decreased testosterone secretion and hyperleptinaemia in obese men. Analysis of the molecular basis for leptin-induced inhibition of testosterone secretion revealed the potential involvement of decreased gene expression of several up-stream factors (e.g. SF-1, StAR and P450scc) in the steroidogenic pathway. In this context, testicular expression of leptin receptor (Ob-R) gene shows a complex pattern of alternative splicing with generation of multiple variants, including the functional leptin receptor type-b (Ob-Rb) and several short isoforms. Moreover, Ob-R mRNA expression in rat testis was regulated by homologous (leptin) as well as heterologous (gonadotropins) signals. Overall, the current data indicate that the testis is a direct target for leptin actions. Furthermore, the available evidence is suggestive of a tightly regulated, complex mode of action of leptin at different levels of the male gonadal axis that involves not only stimulatory but also inhibitory effects.

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Author and article information

Journal

Journal ID (publisher-id): NEN

Journal ID (nlm-ta): Neuroendocrinology

Journal ID (doi): 10.1159/issn.0028-3835

Title: Neuroendocrinology

Publisher: S. Karger AG

ISSN (Print): 0028-3835

ISSN (Electronic): 1423-0194

Publication date Subscription-year: 2005

Publication date (Print): May 2006

Publication date (Electronic): 31 May 2006

Volume: 82

Issue: 5-6

Pages: 245-255

Affiliations

Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain

Article

Publisher ID: 92753 Other ID: Neuroendocrinology 2005;82:245–255

DOI: 10.1159/000092753

PubMed ID: 16721030

SO-VID: 6832eb7f-f574-45b9-b920-90a645602463

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 01 December 2005

Date accepted : 14 February 2006

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Figures: 5, Tables: 1, References: 56, Pages: 11

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Effects of Ghrelin upon Gonadotropin-Releasing Hormone and Gonadotropin Secretion in Adult Female Rats: In vivo and in vitro Studies

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Most cited references 33

Leptin regulation of neuroendocrine systems.

Ghrelin--a hormone with multiple functions.

Leptin in male reproduction: the testis paradigm.

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