Exploring the role of ghrelin as novel regulator of gonadal function

In mammals, proper gonadal function critically relies on a complex regulatory network of systemic (endocrine) and locally-produced (paracrine and autocrine) signals. Among others, a number of factors primarily involved in the control of energy balance and metabolism have been proven as putative modulators of the gonadal axis, thus providing the basis for the well-known link between energy homeostasis and fertility. Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R), has been recently demonstrated as a pleiotropic regulator involved in a large array of endocrine and non-endocrine functions, including food intake and energy balance. However, the potential reproductive role of this newly discovered molecule has remained largely neglected. Yet, we review herein several lines of evidence which strongly suggest the involvement of ghrelin in the control of some aspects of gonadal function. Thus, expression of ghrelin has been demonstrated in mature Leydig cells of rat and human testis, as well as in steroidogenically active luteal and interstitial hilus cells of the ovary. In addition, expression of the functional ghrelin receptor, the GHS-R type 1a, has been shown in Sertoli and Leydig cells of the testis, and in follicular, luteal, surface epithelial and interstitial hilus cells of the ovary. In terms of function, ghrelin has been proven to dose-dependently inhibit testicular testosterone secretion in vitro, and to modulate Leydig cell proliferation in vivo, as well as the expression of relevant testicular genes, such as that encoding stem cell factor. Moreover, extragonadal actions of ghrelin upon the reproductive axis have been also reported, as ghrelin was able to suppress LH secretion in vivo and to decrease LH responsiveness to GnRH in vitro. In summary, the data so far available strongly suggest that, through local and/or systemic actions, ghrelin operates as a novel regulator of gonadal function that may contribute to the integrated control of energy balance and reproduction.