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Ghrelin as a pleotrophic modulator of gonadal function and reproduction

Abstract

Reproductive maturation and function are under the influence of a wide variety of regulatory signals, which include nutritional and metabolic cues, as well as hormones that control energy homeostasis. Evidence is mounting that the gut hormone ghrelin—a putative signal of energy insufficiency and a functional antagonist of leptin—operates as a pleotrophic modulator of gonadal function and reproduction. This Review aims to summarize our current knowledge of the possible reproductive functions of ghrelin, such as the ability to modulate gonadotropin secretion, to influence puberty onset, and to directly regulate gonadal physiology. Notably, most of the actions of ghrelin upon the reproductive axis reported to date are inhibitory. This observation suggests that ghrelin might mediate at least part of the well-known suppressive effect of energy deficit on the onset of puberty, gonadal function and fertility. The reproductive actions of ghrelin have been described in a range of species, including humans, and expression of ghrelin and its canonical receptor has been detected in the gonads. As a consequence, it is tempting to speculate that ghrelin is an integral player in the dynamic regulation of gonadal function, and that through a multifaceted mode of action this hormone contributes to the integration of energy balance and reproduction.

Key Points

  • Acting centrally, ghrelin inhibits luteinizing hormone secretion in a range of species (including humans) and at different developmental stages

  • Ghrelin acts as a negative modifier of puberty onset (rat) and its circulating levels decline as puberty progresses (human)

  • Ghrelin is expressed in the placenta and might act as a negative modulator of early embryonic development

  • Ghrelin is expressed in the testis (human and rat) and modulates key aspects of testicular maturation (Leydig cell proliferation) and function (steroidogenesis and Sertoli cell gene expression)

  • Ghrelin is expressed in the ovary (mammals and nonmammalian species) and modulates ovarian cell proliferation and/or function (e.g. steroidogenesis)

  • Altered secretion of ghrelin has been described in polycystic ovary syndrome

  • Ghrelin acts as a pleotrophic regulator of the reproductive axis, and potentially contributes to the coupling of energy homeostasis and gonadal function

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Figure 1: Schematic representation of the major peptide products of the ghrelin gene.
Figure 2: Pleotrophic actions of ghrelin on the hypothalamic–pituitary–gonadal axis.

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Acknowledgements

M Tena-Sempere acknowledges the contributions of members of the Physiology Section of the University of Córdoba and the Department of Physiology of the University of Santiago, especially L Pinilla, E Aguilar, F Gaytan and C Dieguez, who have worked on the reproductive actions of ghrelin described in this Review. The research of M Tena-Sempere is supported by grants BFI 2002-00176 and BFU 2005-07446 from the Ministerio de Educación y Ciencia, funds from the Instituto de Salud Carlos III (Project PI042082 and CIBER Fisiopatología de la Obesidad y Nutrición), and EU research contract EDEN QLK4-CT-2002-00603.

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Tena-Sempere, M. Ghrelin as a pleotrophic modulator of gonadal function and reproduction. Nat Rev Endocrinol 4, 666–674 (2008). https://doi.org/10.1038/ncpendmet1003

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