Endocrine Abstracts

Kisspeptin, the endogenous ligand of the GPR54 receptor, is a key regulator of reproduction. Inactivating mutations of the GPR54 receptor in mice and humans is associated with a failure of reproductive function. Activating mutations in the GPR54 receptor result in precocious puberty. The endogenous neuropeptide agonist for GPR54, kisspeptin, potently stimulates release of gonadotrophins in rodents and primates.

Objective: We determined the effects of elevating circulating kisspeptin levels on reproductive hormone release in normal male and females.

Method: i) Volunteers (n=6) received an intravenous infusion of kisspeptin-54 (4 pmol/kg per 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.

ii) Volunteers (n=6) attended on six occasions each: twice in each of the follicular, preovulatory and luteal phases. They received a subcutaneous bolus injection of either kisspeptin-54 (0.4 nmol/kg) or 0.9% saline in random order during each phase of the menstrual cycle.

These studies were approved by the local ethics committee.

Results: i) Kisspeptin-54 infusion significantly increased plasma LH, FSH and testosterone concentrations compared to saline infusion (mean LH release: kisspeptin 10.8±1.5 vs saline 4.2±0.5 U/l, P0.001; mean FSH release: kisspeptin 3.9±0.7 vs saline 3.2±0.6 U/l, P0.001; mean testosterone release: kisspeptin 24.9±1.7 vs saline 21.7±2.2 nmol/l, P0.001).

ii) Kisspeptin-54 increased plasma LH compared to saline injection in all phases of the cycle. Sensitivity to kisspeptin was greatest in the preovulatory phase and least in the follicular phase of the cycle (mean increase in LH over baseline (IU/L)±S.E.M: follicular phase: 0.12±0.17; preovulatory phase: 20.64±2.91 (P<0.001 vs follicular phase); luteal phase: 2.17±0.79 (P<0.01 vs follicular phase)).

Conclusion: Elevation of plasma concentrations of kisspeptin in human males and females potently increases reproductive hormone release. Thus kisspeptin may form the basis of a novel therapy for infertility.