Twice-Daily Subcutaneous Injection of Kisspeptin-54 Does Not Abolish Menstrual Cyclicity in Healthy Female Volunteers

Background: Kisspeptin is a critical hypothalamic regulator of reproductive function. Chronic kisspeptin administration causes profound tachyphylaxis in male monkeys and in women with functional hypothalamic amenorrhea. The pharmacological effects of chronic kisspeptin exposure in healthy women with normal menstrual cycles have not been studied previously. Aim: Our aim was to determine the effects of follicular-phase kisspeptin-54 treatment on menstrual cyclicity in healthy women. Methods: We performed a prospective, single-blinded, 1-way crossover study. Healthy women received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline during menstrual days 7-14 (n = 5 per treatment arm). Serial assessments of basal reproductive hormones, ultrasound parameters, LH pulsatility, and acute sensitivity to GnRH and kisspeptin-54 injection were performed. Results: Menstrual cyclicity persisted in all women after follicular-phase kisspeptin-54 treatment. Chronic exposure to kisspeptin-54 did not abolish acute stimulation of LH after injection of kisspeptin-54 or GnRH. In addition, kisspeptin-54 treatment was associated with a shorter mean length of the menstrual cycle (mean length of menstrual cycle was 28.6 +/- 1.4 days with saline vs 26.8 +/- 3.1 days with kisspeptin, P<.01), earlier onset of highest recorded serum LH (mean menstrual day of highest LH was 15.2 +/- 1.3 with saline vs 13.0 +/- 1.9 with kisspeptin, P<.05), and earlier onset of the luteal phase (mean menstrual day of progesterone increase was 18.0 +/- 2.1 with saline vs 15.8 +/- 0.9 with kisspeptin, P<.05). Conclusion: Our data suggest that 1 week of exogenous kisspeptin-54 does not abolish menstrual cyclicity in healthy women. Further work is needed to determine whether kisspeptin could be used to treat certain anovulatory disorders.