The role of KiSS-1 in the regulation of puberty in higher primates

Puberty in higher primates is triggered by resurgence in the pulsatile secretion of hypothalamic GnRH after a hiatus in the robust release of this hypophysiotropic signal during childhood and juvenile development. Interestingly, the prepubertal decline in GnRH release is not associated with a marked reduction in the expression of either the gene that codes for GnRH (GnRH-1) or the decapeptide itself, and the network of GnRH neurons in the hypothalamus of the juvenile may by activated prematurely and with surprising ease by intermittent neurochemical stimulation with N-methyl-d-aspartate (NMDA), a glutamate receptor agonist. KiSS-1, a gene that encodes for kisspeptin-121, which is proteolytically cleaved to a 54 amino acid peptide, metastin, was initially studied in the context of tumor suppression. In 2003, however, inactivating mutations in the metastin receptor, GPR54, were reported to be associated with hypogonadotropic hypogonadism and absent puberty in man. Subsequent studies in the rhesus monkey have shown that GPR54 and KiSS-1 are expressed in the mediobasal hypothalamus (MBH), KiSS-1 expression in the MBH increases at the time of the pubertal resurgence in GnRH release and pulsatile, but not continuous, i.v. administration of metastin 45-54 in the juvenile male monkey elicits sustained GnRH release precociously. The significance of these findings in the context of the initiation of the onset of puberty is discussed.