Roles of kisspeptins in the control of hypothalamic-gonadotropic function: focus on sexual differentiation and puberty onset.

Kisspeptins, a family of peptides encoded by the Kiss1 gene that act via the G protein-coupled receptor 54 (GPR54 or Kiss1R), were initially catalogued as metastasis suppressors, but have recently emerged as pivotal gatekeepers of puberty onset and reproductive function. Indeed, since the seminal observations (in late 2003) that inactivating mutations of GPR54 are coupled to absence of puberty and hypogonadotropic hypogonadism in human and mice, a large number of experimental studies, conducted in different species, including humans, have substantiated the roles of kisspeptins and GPR54 as essential elements in the physiologic regulation of key aspects of reproductive maturation and function. These appear to include, among others, the process of brain sexual differentiation during critical (early) periods of maturation and the timing of puberty onset. Recent exciting developments in these particular areas will be comprehensively reviewed herein. These functions, together with the proven roles of kisspeptins in the control of GnRH neurons and the transmission ofthe regulatory actions of key signals, such as sex steroids, metabolic hormones and environmental cues, point out that the Kiss1 system is an indispensable player of the reproductive brain, whose discovery is now considered as (one of) the most important findings in reproductive physiology in the last decades.