Elsevier

Vitamins & Hormones

Volume 77, 2007, Pages 285-300
Vitamins & Hormones

Ghrelin and Reproduction: Ghrelin as Novel Regulator of the Gonadotropic Axis

https://doi.org/10.1016/S0083-6729(06)77012-1Get rights and content

Abstract

Identification of ghrelin in late 1999, as the endogenous ligand of the growth hormone secretagogue receptor (GHSR), opened up a new era in our understanding of the regulatory mechanisms of several neuroendocrine systems, including growth and energy homeostasis. Based on similarities with other endocrine integrators and its proposed role as signal for energy insufficiency, it appeared tempting to hypothesize that ghrelin might also operate as regulator of reproductive function. Yet, contrary to other of its biological actions the reproductive “dimension” of ghrelin has remained largely unexplored. Nonetheless, experimental evidence, coming mostly from animal studies, have been gathered during the last years suggesting that ghrelin may actually function as a metabolic modulator of the gonadotropic axis, with predominant inhibitory effects in line with its role as signal of energy deficit. These effects likely include inhibition of luteinizing hormone (LH) secretion (which has been reported in different species and developmental stages), as well as partial suppression of normal puberty onset. In addition, expression and/or direct gonadal actions of ghrelin have been reported in the human, rat, and chicken. Altogether, those findings document a novel reproductive facet of ghrelin, which may cooperate with other neuroendocrine integrators, as leptin, in the joint control of energy balance and reproduction.

Section snippets

Introduction: Ghrelin Is a Multifunctional Regulator with Key Roles in Energy Balance

Identification of ghrelin by reverse pharmacology in late 1999 was the endpoint of the long search for the endogenous natural ligand of the growth hormone secretagogue (GHS) receptor (GHSR) (Kojima et al., 1999), and a major breakthrough in contemporary neuroendocrinology. As direct proof of the extraordinary interest drawn by this molecule, more than 1850 research articles have been published on this topic over the last 7 years. The major structural and functional features of ghrelin have been

Neuroendocrine Control of Reproduction: The Gonadotropic Axis

Reproductive capacity, defined by the ability to generate fertilizable gametes and to sustain pregnancy and lactation, critically depends on a concerted series of developmental events and the coordinated function of different endocrine elements which compose the so-called hypothalamic-pituitary-gonadal (HPG) or gonadotropic axis. Three major groups of hormonal factors can be identified in this system: the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH), the pituitary

Reproduction and the Energy Status Are Functionally Linked

The capacities to maintain the state of energy reserves and to reproduce are pivotal factors for the survival of individuals and species. Accordingly, these functions are under the precise control of different regulatory networks, which are partially overlapping. Indeed, on the basis of intuitive knowledge, the contention that reproduction is metabolically gated, especially in the female, had been well settled since old ages. Thus, fecundity was often symbolized by states of energy abundance

Ghrelin as Putative Regulator of the Gonadotropic Axis

Following the prototypic case of leptin, different research groups, including ours (Fernandez-Fernandez et al., 2006), have searched for potential neuroendocrine integrators involved in the joint control of energy homeostasis and reproduction. Initial characterization of the biological profile of ghrelin made it a suitable candidate for such a function. Thus, ghrelin appeared to be involved not only in the regulation of growth but also energy homeostasis; ghrelin being an orexigenic signal

Role of Ghrelin in the Control of Gonadotropin Secretion

Among its potential actions on the reproductive axis, the effects of ghrelin on gonadotropin secretion have been now explored in different species. Overall, the studies so far conducted on the rat, rhesus monkey, and sheep have demonstrated that central administration of ghrelin is able to suppress different aspects of pulsatile LH secretion (Fernandez-Fernandez 2004, Furuta 2001, Iqbal 2006, Vulliémoz 2004). Thus, central injection of ghrelin reduced LH pulse frequency, without major changes

Putative Roles of Ghrelin in Puberty Onset

Other facet of ghrelin actions on the gonadotropic system that has been experimentally explored is its ability to modulate the activation of the HPG axis at puberty. In this sense, it is well known that puberty is exquisitely sensitive to the state of energy reserves, situations of energy insufficiency being associated to the delay or absence of puberty (Fernandez-Fernandez et al., 2006). Based on the proposed role of ghrelin as signal of energy insufficiency, involved the long-term control of

Molecular Diversity of Ghrelin: Reproductive Effects of UAG and Obestatin

One of the most intriguing facets of ghrelin physiology is related with the molecular diversity of the elements of this signaling system, which applies both to the ligand and its receptor. Concerning the ligands, processing of ghrelin precursor results in the generation of acylated and unacylated (UAG) forms of ghrelin (Gualillo et al., 2006; see also Section I); UAG being far more abundant in the circulation than the acylated molecule. In addition, the differential posttranslational processing

Expression and Direct Actions of Ghrelin in the Gonads

Besides central actions on the reproductive axis, several lines of evidence indicate that ghrelin is also expressed and conducts specific biological effects directly at the gonadal level; a phenomenon which illustrates the multifaceted mode of action of ghrelin in the control of the gonadotropic axis. Detailed description of those facets of ghrelin physiology can be found elsewhere (Barreiro 2004, Tena-Sempere 2005). For the purpose of the present chapter, it is important to stress that

Futures Perspectives and Conclusions

Since its cloning 7 years ago, ghrelin has evolved from the endogenous counterpart of synthetic GH secretagogues into a fundamental pleiotropic regulator of different biological functions, including food intake and energy homeostasis. Based on its biological profile, as signal of energy insufficiency whose circulating levels negative correlate with body mass index, and following the prototypic example of leptin, it was hypothesized that ghrelin could operate also as modulator of some facets of

Acknowledgments

The author is indebted with E. Aguilar and L. Pinilla (University of Cordoba, Spain), and with C. Dieguez and F. F. Casanueva (University of Santiago de Compostela, Spain) for continuous support and helpful discussions during preparation of this chapter. The experimental work conducted in the author's laboratory was supported by grants BFI 2002-00176 and BFI 2005-07446 from Ministerio de Educacion y Ciencia (Spain), funds from Instituto de Salud Carlos III (Project PI042082 and CIBER-03

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