Background: Kisspeptin is a novel hypothalamic hormone with powerful stimulatory effects on the hypothalamo-pituitarygonadal (HPG) axis. Inactivating mutations in the kisspeptin receptor lead to pubertal failure. We have previously demonstrated that injection of kisspeptin-54 stimulates LH release in healthy men and women. Recent studies in animals suggest that endogenous kisspeptin may be involved in stimulating the GnRH pulse generator. Determining whether exogenous administration of kisspeptin can stimulate the human GnRH pulse generator, has important therapeutic implications.
Aim: To determine if kisspeptin-54 administration can stimulate the GnRH pulse generator in healthy female volunteers.
Methods: Six healthy female volunteers underwent frequent blood sampling for serum LH measurement every 10 min for 8 h (as a surrogate marker of the GnRH pulse generator) during the follicular phase of menstrual cycle. A s.c. injection of saline or kisspeptin-54 (0.30.6 nmol/kg) was administered 4 h after commencing the study. LH pulsatility within each subject was compared between the 4 h pre-injection and 4 h post-injection.
Results: No significant differences in number of LH pulses and LH pulse amplitude were observed before and after saline injection. A 6-fold increase in mean number of LH pulses was observed following kisspeptin-54 injection when compared the pre-injection period (mean number of LH pulses during 4 h: 0.50±0.48, pre-injection; 3.00±0.69, post-injection, P<0.05 versus pre-injection). The LH pulse amplitude was nearly 2-fold higher after kisspeptin-54 injection when compared with the pre-injection period (mean pulse amplitude in IU/l during 4 h: 1.31±0.09, pre-injection; 2.31±0.25, post-injection, P<0.05 versus pre-injection).
Conclusions: We have demonstrated for the first time that kisspeptin-54 stimulates activity of the GnRH pulse generator in humans. A single injection of kisspeptin-54 injection increases LH pulse frequency and LH pulse amplitude in healthy women. This data has important therapeutic implications for the future development of kisspeptin to treat patients with disorders of reproduction.