Effect of gonadotropin-inhibitory hormone on luteinizing hormone secretion in humans

BackgroundGonadotropin-inhibitory hormone (GnIH, human homologue of RFRP-3) suppresses gonadotropin secretion in animal models, but its effects have not been studied in the human. ObjectiveWe tested the hypotheses that exogenous GnIH inhibits LH secretion (i) in postmenopausal women and (ii) in men concurrently administered exogenous kisspeptin. DesignFollowing in vitro and in vivo preclinical studies to functionally characterize the GnIH peptide, a dose-finding study (human GnIH: 15-150 g/kg/h, iv for 3 h) was undertaken, and 50 g/kg/h selected for further evaluation. Five postmenopausal women were administered 50 g/kg/h iv infusion for 3 h or vehicle on two separate days. Four men were administered kisspeptin-10 (03 g/kg iv bolus) with simultaneous infusion of GnIH (50 g/kg/h, iv for 3 h) or vehicle. ParticipantsHealthy postmenopausal women (mean age 58 2 years, LH: 308 29 IU/l, FSH: 787 64 IU/l, oestradiol: <50 pmol/l) and men (398 +/- 21 years, mean total testosterone 121 +/- 18 nmol/l, LH 22 +/- 02 IU/l). Primary outcomeChange in area under curve (AUC) of LH during GnIHvs vehicle. ResultsDuring GnIH administration in postmenopausal women, LH secretion decreased (AUC: -99 +/- 18 IU/3 h) vs vehicle (AUC: -05 +/- 17 IU/3 h; P = 002). Kisspeptin-10-stimulated LH responses in men were not affected by GnIH co-administration (60-min AUC of LH 62 +/- 08 IU/h with kisspeptin-10 alone, 63 +/- 10 IU/h, kisspeptin-10 with GnIH, P = 072). Exogenous GnIH was well tolerated, with no adverse events reported. ConclusionsGonadotropin-inhibitory hormone decreased LH secretion in postmenopausal women in this first-in-human study. Kisspeptin-stimulated LH secretion in men was not inhibited during concomitant administration of GnIH.