Secretion of Gonadotropins in Response to a Novel Kiss-1 Receptor Agonist, RF9 in the Mare: Modulation by Estradiol-17β and Half-Life of RF9 in the Peripheral Circulation

Three experiments were conducted to investigate the effects of the kisspeptin receptor agonist, 1-adamantanecarbonyl-RF-NH2 (RF9) on the secretion of gonadotropins, the role of estradiol-17β in modulating this response, and the metabolic half-life of RF9 in the mare. During the luteal phase of the estrous cycle (experiment 1), light horse mares were treated with sequential I.V. injections of RF9 (0.2 and 0.4 mg/kg) within a 1-hour interval to determine effects on coincident secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Dose-dependent increases (P < .001) in concentrations of both FSH and LH in response to RF9 were observed. In experiment 2, the effect of estradiol-17β (estradiol) pretreatment on responsiveness to RF9 was examined in winter anovulatory mares. Mares received a single intramuscular injection of 5-mg estradiol or corn oil followed by a bolus injection of RF9 18 hours later. Estradiol pretreatment increased (P < .05) peak concentrations of LH in response to RF9. The half-life of RF9 in the circulation of mares following peripheral administration was determined in experiment 3 using liquid chromatography/mass spectrometry. Intravenously injected RF9 was rapidly cleared from the mare's circulatory system, exhibiting a half-life of approximately 40 minutes. Data indicate that RF9 action is likely mediated via the endogenous release of GnRH and controls secretion of both FSH and LH. This effect is modulated by estradiol, putatively by enhanced responsiveness of the pituitary to GnRH and/or upregulation of Kiss-1 receptor in GnRH neurons. Use of RF9 as a pharmacologic agent in the mare may be limited by its short half-life.