We All Remember Our First Kiss: Kisspeptin and the Male Gonadal Axis

Abstract

The year 2003 was witness to a friendly collision between the fields of cancer and reproduction when a little known G protein-coupled receptor (GPR54) was pushed into the limelight. GPR54 was first cloned from rat brain in 1999 (1), but was an orphan receptor until 2001, when several groups discovered a high affinity ligand (2)(3)(4). This ligand, metastin, is derived from the proteolytic processing of a parent protein called kisspeptin-1 (metastin 1-54 ϭ kisspeptin-1 68 -121). Metastin's name was so coined because of its role as a metastasis suppressor (5, 6). However, until 2003, there were few direct clues that the metastin/GPR54 pathway played a pivotal role in the reproductive cascade.Meanwhile, on a backdrop of several decades of neurobiological research into the mechanisms of the onset of puberty, investigators in the 1990s began using genetic approaches to find novel neuromodulators of GnRH secretion using patients with idiopathic hypogonadotropic hypogonadism, a condition characterized by an absence of sexual development and low gonadotropin and sex steroid levels. Although these investigations uncovered genes whose protein products are involved in GnRH neuronal migration (KAL1, FGFR1) (7-9), gonadotrope sensitivity to GnRH (GNRHR, NROB1) (10, 11), and integrative signaling regarding peripheral energy stores (LEP, LEPR) (12-14), searches continued to find genes more directly involved in the triggering or inhibition of GnRH secretion.In 2003, two groups independently discovered loss-of-function mutations in the gene encoding the G protein-coupled receptor GPR54 in patients with idiopathic hypogonadotropic hypogonadism (15,16). Targeted deletion of Gpr54 in mice was also found to give rise to a phenocopy syndrome of delayed sexual development and hypogonadotropism (16). Suddenly, this receptor, and its ligand metastin, were pulled from their previous niches in cancer biology and thrust directly into longstanding questions within reproductive biology.With the human genetic discoveries surrounding GPR54 creating unique opportunities for both basic investigators and animal physiologists, studies were published with lightening speed that further raised the possibility for compelling roles for metastin and GPR54 in reproduction. Expression levels of KISS1 mRNA were found to rise significantly across the pubertal transition in female and agonadal male monkeys (17). In vivo, the administration of metastin raises LH in adult male mice (18), adult male rats (19 -22), immature female rats (23), juvenile agonadal male monkeys (17), and mature, ovariectomized, estradiol-treated sheep (24). The effects of metastin on LH secretion can be observed with every method of administration including intracerebroventricular, iv, ip, and sc. Moreover, metastin appears to play an important role in normal pubertal development. Chronic central administration of metastin to sexually immature female rats induces early vaginal opening (23). In rat models of leptin insufficiency, metastin can also induce LH secretion (23).Although the s...

Seasonality in sperm parameters in normal men and dyspermic patients on medical intervention

“…This peptide has been credited with a regulatory role for the seasonal secretion of GnRH, possibly kisspeptin and gonadotrophins (Reiter, 1998;Seminara, 2005). Additionally, this hormone may exert a direct gonadal effect as indicated by the presence of its receptors in Leydig cells and seminiferous tubules (Karasek et al, 1990;Luboshitzky et al, 1995).…”

Direct and indirect effects of kisspeptin on liver oxidant and antioxidant systems in young male rats

“…Kisspeptin/GPR54 complex plays a critical role in the central regulation of the hypothalamo-pituitary gonadal axis on both male and female. 9,10 Exogenously administered kisspeptin evokes a stimulatory effect on gonadotropin secretion. 4 It is now well documented that peripheral and central (intracerebroventricular, ICV) administration of kisspeptin stimulates a dose-dependent rise in serum levels of gonadotropin in adult male rats.…”

Distribution and regulation of gonadotropin-releasing hormone, kisspeptin, RF-amide related peptide-3, and dynorphin in the bovine hypothalamus

“…It has been shown that kisspeptin neurons are located upstream of GnRH neurons to stimulate LH release ( Seminara, 2005 ). Because the excitatory effect of kisspeptin on gonadotropin secretion is inhibited by GnRH antagonists ( Navarro et al, 2005 ), and as kisspeptin administration to hypothalamo-pituitary disconnected ewe models could not change LH concentration ( Smith et al, 2008b ), it has been concluded that kisspeptin acts at the hypothalamic level, not the pituitary, to stimulate GnRH release.…”