KiSS-1 system and reproduction: Comparative aspects and roles in the control of female gonadotropic axis in mammals

In late 2003, inactivating mutations of the G protein-coupled receptor GPR54 were found in patients suffering hypogonadotropic hypogonadism. This observation led to the proposal that this receptor and its putative ligands (kisspeptins, encoded by the KiSS-1 gene) are essential in the control of reproduction; a contention that has been now substantiated by an ever growing number of experimental studies. However, most (if not all) of this work has been carried out in mammals (human, sheep and laboratory rodents). Moreover, characterization of gonadotropin responses to kisspeptin was conducted in males, whereas its actions on the female gonadotropic axis initially received much less attention. Notwithstanding, recent experimental data have unveiled very prominent roles of the KiSS-1 system in the control of key aspects of female reproduction, which include not only the timing puberty onset and its modulation by metabolic factors, but also the dynamic regulation of the gonadotropic axis in adulthood. On the latter, the KiSS-1 neuron has been proposed as key intermediary element for the negative and positive feedback effects of sex steroids on gonadotropin secretion. Moreover, expression of KiSS-1 (mRNA and peptide) and its receptor have been recently reported in the ovary, adding further complexity to the potential actions of this system in the female. In sum, compelling experimental evidence, obtained in mammals, has recently defined the pivotal role of the KiSS-1/GPR54 system in the control of essential aspects of female reproduction, from puberty to ovulation. While characterization of its role in non-mammalian species remains largely unexplored, the presence of GPR54 in GnRH neurons and the changes in its expression during pubertal development, reported recently in fish species, are suggestive of a conserved function of the KiSS-1/GPR54 system in the control of reproduction during evolution.