Endocrine Abstracts

The kisspeptins are KiSS-1 gene-derived peptides which signal through the G protein coupled receptor 54 (GPR54), and have recently been shown to be critical regulators of reproduction. Acute intracerebroventricular (ICV) or peripheral administration of kisspeptin to rodents and primates, and peripheral administration to humans, stimulates the hypothalamic-pituitary gonadal (HPG) axis. This effect is thought to be mediated via the hypothalamic gonadotrophin-releasing hormone (GnRH) system. Chronic administration of GnRH agonists paradoxically suppresses the HPG axis following an initial agonistic stimulation. We investigated the effects of chronic kisspeptin administration in adult male rats. Initially we compared the effects of acute subcutaneous administration of equimolar doses of kisspeptin-10, -14 and -54 on the HPG axis. Kisspeptin-54 produced the greatest increase in plasma luteinizing hormone (LH) and total testosterone at 60 mins post injection and was consequently used in the subsequent chronic administration experiment. Kisspeptin-54 at 50 nmol per day was administered subcutaneously to adult male rats using Alzet^® osmotic mini-pumps. Chronic subcutaneous administration of 50 nmol kisspeptin-54 per day for 13 days significantly decreased testicular weight. Histological examination showed degeneration of the seminiferous tubules, with varying degrees of maturation arrest, sloughing and death of germ cells, focally with complete loss of germ cells and degeneration of residual Sertoli cells. There were no measurable differences in Leydig cell morphology. The testicular degeneration was associated with a significant decrease in the circulating levels of the testes-derived hormone, inhibin B. Free and total testosterone were also lower in the kisspeptin-54 treated group, though this change did not reach statistical significance. Chronic administration of GnRH agonists can produce similar testicular effects. These findings indicate that kisspeptin may provide a novel tool for the manipulation of the HPG axis and spermatogenesis.