Ghrelin and reproduction: a novel signal linking energy status and fertility?

Ghrelin was originally identified in 1999 as the endogenous ligand of the growth hormone (GH) secretagogue receptor (GHS-R). Since then, an ever growing number of publications have reported the potential involvement of this molecule in the regulation of a large array of endocrine and non-endocrine functions, including the control of GH secretion and several other neuroendocrine axes as well as food intake and energy balance. On the basis of its proposed role as indicator of energy insufficiency and the proven reproductive effects of other regulators of energy homeostasis and growth (such as the adipocyte-derived hormone leptin), it is tempting to hypothesize that ghrelin might play a role in the control of reproductive function and fertility. Indeed, although evidences in this area are still fragmentary, we review herein data from different research groups, which have recently substantiated the reproductive facets of this newly identified hormone. Thus, expression of ghrelin has been demonstrated in human and rodent placenta, and ghrelin has been reported to inhibit early embryo development. In addition, ghrelin was shown to suppress luteinizing hormone (LH) secretion in vivo, and to decrease LH responsiveness to LH-releasing hormone (LHRH) in vitro. Moreover, ghrelin was able to inhibit stimulated testicular testosterone secretion, whereas androgens have been proven independent modulators of circulating ghrelin levels. In this context, our group has recently provided extensive evidence for the expression of ghrelin and its putative receptor, the type 1a GHS-R, in rat and human gonads. Testicular expression of ghrelin was highly selective for mature Leydig cells and under the hormonal control of pituitary LH, while in the ovary, expression of ghrelin was demonstrated in steroidogenically active luteal cells and interstitial hilus cells. Likewise, expression of GHS-R type 1a was demonstrated in Sertoli and Leydig cells of the testis and follicular, luteal and interstitial hilus cells in the ovary. In summary, the data so far available indicate that ghrelin may operate at different levels of the reproductive system, including the testis and the ovary, which are potential targets for systemic ghrelin actions. In addition, ghrelin is produced locally within the human and rodent gonads, where the presence of both components (ligand and receptor) of ghrelin signaling system is highly suggestive of a conserved regulatory role for this newly discovered molecule in the regulation of mammalian gonadal function. Overall, it is proposed that ghrelin may cooperate with other regulatory signals, such as leptin, in the integrated control of energy balance and reproduction.