Endocrine Abstracts

The ligand-receptor kisspeptin/GPR54 system was originally identified in the context of tumor biology. Thus, KiSS-1 was cataloged as metastasis suppressor gene, which encodes a number of related peptides, termed kisspeptins, with ability to activate the previously ‘orphan’ receptor GPR54. Interestingly, the known biological actions of kisspeptins were apparently limited to their ability to inhibit tumor progression and, likely, to control trophoblast invasion. However, by late 2003, the putative role of kisspeptin/GPR54 system in the neuroendocrine control of the reproductive axis was disclosed by the observation that loss-of-function mutations and deletions of the GPR54 gene were associated with absence of puberty onset and hypogonadotropic hypogonadism both in humans and rodents. These observations drew an immediate attention on the previously unsuspected, reproductive facet of kisspeptins, which was thoroughly analyzed thereafter. Indeed, in the last year, the extraordinary potency of kisspeptins in inducing gonadotropin release has been documented in a number of species, such as the rat, mouse, sheep, monkey and, very recently, the human. Such a gonadotropin-releasing action is believed to derive primarily from a direct stimulatory effect upon the hypothalamic GnRH system, as activation of GnRH neurons and GnRH release by kisspeptins has been very recently demonstrated. In addition, hypothalamic expression of KiSS-1 gene, and to a lower extent of GPR54, appeared to be developmentally (maximum at puberty) and hormonally (by sex steroids) regulated, and functional studies have provided solid evidence for a relevant role of KiSS-1 signaling in timing of puberty onset in rodent and primate species. Altogether, these experimental observations qualify the KiSS-1/GPR54 system is a novel, essential gatekeeper of the GnRH/gonadotropin axis and, hence, of the reproductive function in mammals.