Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males

WS Dhillo; OB Chaudhri; M Patterson; EL Thompson; KG Murphy; MK Badman; BM McGowan; V Amber; S Patel; MA Ghatei; SR Bloom

Mutation of the GPR54 receptor is associated with a failure of reproductive function. The endogenous neuropeptide agonist for GPR54, kisspeptin, potently stimulates the hypothalamic-pituitary-gonadal (HPG) axis in rodents and primates.

Objective: The present study was designed to determine the effects of elevating circulating kisspeptin levels on LH, FSH and testosterone in male volunteers.

Method: Study (i) Volunteers were infused with a 90 minute infusion of kisspeptin-54 (0.125, 0.25, 0.5, 1, 2, 4, 8, 12, 18, 27 or 40 pmol/kg/min, n=3 per dose). Blood was sampled for LH. Study (ii) Volunteers (n=6) received a 90 minute intravenous infusion of kisspeptin-54 (4 pmol/kg/min) and a control infusion of saline (0.9%) at least 3 days apart in random order. Blood was sampled for kisspeptin, LH, FSH and testosterone measurements. This study was approved by the local Ethical Committee.

Results: (i) There was a dose-dependent increase in mean LH over time from an infusion rate of 0.25 pmol.kg⁻¹.min⁻¹ up to 4 pmol/kg/min. The latter dose of kisspeptin-54 was chosen for study (ii) as it was the lowest infusion dose which maximally increased LH levels in male volunteers.

(ii) Kisspeptin-54 infusion significantly increased plasma LH, FSH and testosterone concentrations compared to saline infusion (mean 90 minute LH: kisspeptin 10.8±1.5 vs saline 4.2±0.5 U/l, P<0.001; mean 90 minute FSH: kisspeptin 3.9±0.7 vs saline 3.2±0.6 U/l, P<0.001; mean 180 minute testosterone: kisspeptin 24.9±1.7 vs saline 21.7±2.2 nmol/l, P<0.001). The plasma half-life of kisspeptin-54 was calculated to be 27.6±1.1 min. The mean metabolic clearance rate (MCR) was 3.2±0.2 ml/kg/min and the volume of distribution (VD) was 128.9±12.5 ml/kg.

Conclusion: Elevation of plasma concentrations of kisspeptin in human males significantly increases circulating LH, FSH and testosterone levels. Kisspeptin infusion provides a novel mechanism for HPG axis manipulation in disorders of the reproductive system.

Endocrine Abstracts

P681