Background: Genetic deficiency of the hypothalamic hormone kisspeptin, lead to pubertal failure and infertility. Kisspeptin is therefore a critical hypothalamic activator of reproduction. Kisspeptin-10 stimulates gonadotrophin release in both male and female rodents. However few studies have investigated the effects of kisspeptin-10 on gonadotrophin release in humans, and none have investigated its effects in women. If kisspeptin is to be useful for treating reproductive disease, its effects in both men and women must be evaluated.
Aim: To compare the effects of kisspeptin-10 administration on gonadotrophin release in healthy men and women.
Methods: We performed an ethics-approved prospective, randomised, double-blinded study. Intravenous bolus (IVB) kisspeptin-10 was administered to men and women (n=45/group). Subcutaneous bolus and iv infusion of kisspeptin-10 was also administered to women (n=45/group). Blood was sampled at regular intervals for 4 hours post-injection for measurement of area under curve (AUC) plasma luteinising hormone (LH).
Results: In healthy men, IVB kisspeptin-10 (0.3 nmol/kg) stimulated significant LH secretion, and maximal stimulation was observed following 10 nmol/kg kisspeptin-10 (mean AUC LH increase: 6.1±1.3 h.iU/L, P<0.001 vs. saline). In healthy women during the follicular phase of menstrual cycle, no increases in LH were observed following IVB, sc bolus or 90-min iv infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg and 720 pmol/kg/min, respectively. By contrast, LH was stimulated potently following 10 nmol/kg IVB kisspeptin-10 (mean AUC increase: 30.3±7.7 h.iU/l, P<0.05 vs. saline). The plasma half-lives of kisspeptin-10 were similar in all three subject groups (3.8±0.3 min; men; 4.1±0.4min, follicular women; 4.1±0.4 min, preovulatory women; P=0.91).
Conclusion: We reveal for the first time, striking sexual dimorphism in the effects of the hypothalamic hormone kisspeptin-10 in humans. Kisspeptin-10 stimulates gonadotrophin release in men and pre-ovulatory women, but fails to stimulate gonadotrophin release in follicular phase women. These data have important clinical implications for the potential of kisspeptin-10 to treat disorders of reproduction.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: The section of Investigative medicine is funded by grants from the Medical Research Council (MRC) Biotechnology and Biological Sciences Research Council, National Institute of Health Research (NIHR), an Integrative Mammalian Biology Capacity Building Award, and an FP7-Health-2009-241592 EurO CHIP Grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. This work was also supported by an MRC project grant. C.N.J. is supported but and NIHR Clinical Lectureship, Early Career Grant, and Wellcome Starter Grant for Clinical Lecturers. G.M.K.N. is supported by a Wellcome Clinical Training Fellowship. A.N.C. is supported by a charity award. W.S.D. is supported by an NIHR Career Development Fellowship.