Background: Kisspeptin is a critical regulator of normal reproductive function. In humans inactivating mutations of the kisspeptin receptor GPR54 cause hypogonadotrophic hypogonadism and pubertal failure. Activating mutations of GPR54 cause precocious puberty. Hypothalamic amenorrhoea (HA) accounts for over 30% of cases of amenorrhoea in women of reproductive age. Current treatments have limited success rates and side effects. In rodent models of HA hypothalamic KISS1 expression is reduced, and kisspeptin administration restores reproductive function. We recently demonstrated that subcutaneous (s.c.) kisspeptin injection (6.4 nmol/kg) stimulates reproductive hormone release in human females with normal menstrual cycles. The effects of kisspeptin administration in patients with infertility have not been investigated previously.
Aim: To determine the effects of kisspeptin administration on gonadotrophin release in infertile women with HA.
Methods: We performed an ethically approved prospective, randomised, double-blinded study. Patients with HA received a sc bolus injection of either kisspeptin-54 (6.4 nmol/kg) or 0.9% saline (n=5 per group). Blood was sampled at regular intervals for 4 h post-injection for measurement of plasma gonadotrophins.
Results: Kisspeptin potently increased mean luteinising hormone (LH) 48-fold and follicle stimulating hormone (FSH) 16-fold when compared to saline injection (mean change over 4 h post-injection compared to baseline: LH (IU/l); saline 0.5±0.6, kisspeptin 24.0±3.5, (P<0.001). FSH (IU/l); saline 0.6±0.7, kisspeptin 10.2±3.5, (P<0.001). Subjects with HA were over 4-fold more responsive to kisspeptin injection than previously studied healthy females in the follicular phase of the menstrual cycle (mean area under curve LH increase: HA 40.2 h iU, healthy females in follicular phase 9.8 h iU, P<0.01).
Conclusion: In this first study of kisspeptin administration within a human model of infertility, we demonstrate that exogenous administration of kisspeptin in women with HA potently stimulates LH and FSH release. Our data shows that kisspeptin is a potential novel therapy for human infertility.