Kisspeptin is the peptide product of the KiSS-1 gene and endogenous agonist for the GPR54 receptor. The kisspeptin/GPR54 system has recently been suggested as a key regulator of the reproductive system. GPR54 deficient mice have abnormal sexual development and low circulating gonadotrophins and in humans, GPR54 mutations have been shown to cause hypogonadotrophic hypogonadism. Thus, GPR54 appears to be essential for normal gonadotrophin secretion and the regulation of puberty. To further investigate the role of kisspeptin in the hypothalamic-pituitary-gonadal (HPG) axis, we examined the effect of intracerebroventricular (i.c.v.) and peripheral administration of the active kisspeptin fragment, kisspeptin-10, on circulating gonadotrophins and total testosterone levels in adult male rats. The effect of kisspeptin-10 in vitro on the release of hypothalamic peptides from hypothalamic explants and gonadotrophins from anterior pituitary fragments was also determined. The i.c.v. administration of kisspeptin-10 dose-dependently increased plasma luteinizing hormone (LH) and increased plasma follicle stimulating hormone (FSH) and total testosterone at 60 minutes post-injection. In a separate investigation into the time course of this response, i.c.v. administered kisspeptin-10 (3 nanomoles) significantly increased plasma LH at 10, 20 and 60 minutes, FSH at 60 minutes and total testosterone at 20 and 60 minutes post-injection. Kisspeptin-10 stimulated the release of luteinizing hormone-releasing hormone (LHRH) from in vitro hypothalamic explants. Peripheral administration of kisspeptin-10 increased plasma LH, FSH and total testosterone. However, doses of 100-1000 nanomolar kisspeptin-10 had no effect on LH or FSH release from pituitary fragments. These results demonstrate that kisspeptin potently stimulates the HPG axis, and these effects are likely to be mediated via the hypothalamic LHRH system.
*These authors contributed equally to these studies