Effect of gonadotropin inhibitory hormone (GnIH) on luteinizing hormone secretion in humans

Abstract

Gonadotropin inhibitory hormone (GnIH, human homologue of RFRP-3) suppresses gonadotropin secretion in animal models, but its effects have not been studied in the human.

Objective

We tested the hypotheses that exogenous GnIH inhibits LH secretion a) in postmenopausal women, and b) in men concurrently administered exogenous kisspeptin.

Design

Following in vitro and in vivo pre-clinical studies to functionally characterize the GnIH peptide, a dose-finding study (human GnIH 1.5 to 150 μg/kg/h, iv for 3h) was undertaken, and 50 μg/kg/h selected for further evaluation.

Five postmenopausal women were administered 50 μg/kg/h iv infusion for 3h or vehicle on two separate days.

Four men were administered kisspeptin-10 (0.3 μg/kg iv bolus) with simultaneous infusion of GnIH (50 μg/kg/h, iv for 3h) or vehicle.

Participants

Healthy postmenopausal women (mean age 58±2 years, LH: 30.8±2.9 IU/L, FSH: 78.7±6.4 IU/L, estradiol: <50 pmol/L) and men (39.8±2.1 years, mean total testosterone 12.1±1.8 nmol/L, LH 2.2±0.2 IU/L).

Primary Outcome

Change in area-under-curve of LH during GnIH vs. vehicle.

Results

During GnIH administration in postmenopausal women, LH secretion decreased (Δ AUC -9.9±1.8 IU/3h) vs. vehicle (Δ AUC -0.5±1.7 IU/3h) (P= 0.02). Kisspeptin-10 stimulated LH responses in men was not affected by GnIH co-administration (60-min AUC of LH 6.2±0.8 IU/h with kisspeptin-10 alone, 6.3±1.0 IU/h, kisspeptin-10 with GnIH, P = 0.72).

Exogenous GnIH was well tolerated, with no adverse events reported.

Conclusions

GnIH 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.

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