The effects of kisspeptin administration on the menstrual cycle in healthy women

Abstract

BackgroundKisspeptin (encoded by the KISS1 gene) is a crucial regulator of normal reproductive function. In human beings, KISS1 deletion results in a failure to go through puberty whereas activating mutations result in central precocious puberty. Administration of kisspeptin induces ovulation in rodents and sheep, but whether exogenous kisspeptin can alter the menstrual cycle in healthy women is not known. This study aimed to determine the effects of kisspeptin administration on the menstrual cycle in healthy women. MethodsA prospective, single-blinded, one-way crossover study at Imperial College, London, was performed. Five healthy female volunteers aged 24–37 years were recruited through adverts in the local press. They each received twice-daily subcutaneous injections of kisspeptin-54 or saline for 7 days during days 7 to 14 of their menstrual cycle. All women underwent serial assessments of basal reproductive hormones, ultrasound measurements, and luteinising hormone (LH) pulsatility, as well assessment of acute sensitivity to gonadotrophin-releasing hormone (GnRH) and kisspeptin injection. Because of the intensive protocol, women attended for assessments every 2–3 days throughout the cycle, rather than daily, to minimise stress and enhance compliance. Ethics approval was granted by the Hammersmith and Queen Charlotte's and Chelsea Hospitals Research Ethics Committee (registration number 05/Q0406/142). FindingsKisspeptin-54 treatment shortened the menstrual cycle (mean length of menstrual cycle: saline 28·6 days [SE 3·1] vs kisspeptin 26·8 [3·1], p=0·0043), advanced the onset of highest recorded serum LH (mean menstrual day of highest recorded LH 15·2 [SE 2·9] vs 13·0 [4·1], p=0·0372), and advanced the onset of the luteal phase of the menstrual cycle (mean menstrual day of progesterone increase 18·0 [SE 2·1] vs 15·8 [2·0], p=0·0402). On menstrual day 15, the largest ovarian follicle had a significantly higher diameter after kisspeptin-54 than after saline (mean diameter of largest follicle saline 10·0 mm [SE 4·4] vs kisspeptin 15·5 mm [2·2], p=0·04). LH pulsatility was maintained during kisspeptin-54 treatment. Sensitivity to exogenous kisspeptin-54 and exogenous GnRH was maintained during twice-daily kisspeptin-54 administration. InterpretationWe have shown, for the first time to our knowledge using biochemical and radiological data, that exogenous kisspeptin-54 advances the menstrual cycle in healthy women. These data have important therapeutic implications for the use of kisspeptin in the treatment of women with reproductive disorders. Even though participants attended every 2–3 days rather than daily, statistical significance in key parameters was still achieved, confirming the strength of the data. In addition, use of both biochemical and radiological data allowed detailed analysis of the underlying physiological processes. FundingWellcome Trust, National Institute for Health Research, UK Medical Research Council.