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Kisspeptin-54 Stimulates Gonadotropin Release Most Potently during the Preovulatory Phase of the Menstrual Cycle in Women

Department of Metabolic Medicine (W.S.D., O.B.C., E.L.T., K.G.M., M.P., R.R., G.K.N., V.A., A.K., M.A.G., S.R.B.), Imperial College London, Hammersmith Hospital, and Division of Clinical Chemistry (R.R., G.K.N., V.A., M.D.), Hammersmith Hospitals National Health Service Trust, London W12 0NN, United Kingdom

Address all correspondence and requests for reprints to: Professor S. R. Bloom, Department of Metabolic Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.

Context: Kisspeptin, the endogenous ligand of the G protein-coupled receptor 54, is a key regulator of the hypothalamo-pituitary-gonadal (HPG) axis. GPR54-null mice exhibit reproductive dysfunction, and exogenous kisspeptin potently stimulates the HPG axis in rodents, primates, and human males. The effects of kisspeptin administration to human females are unknown.

Objective: Our objective was to investigate the effects of kisspeptin on LH release during the menstrual cycle in female volunteers.

Design: Bolus sc kisspeptin-54 was administered to female volunteers, and plasma gonadotropins were measured.

Setting: The study took place at a hospital clinical research facility.

Volunteers: Subjects were healthy female volunteers with regular menstrual cycles.

Intervention: 1) Volunteers received a sc bolus injection of kisspeptin-54 (0, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 nmol/kg; n = 3–4 per dose) in the follicular phase; and 2) volunteers (n = 8) received a sc bolus injection of either kisspeptin-54 (0.4 nmol/kg) or saline in random order during each phase of the menstrual cycle.

Main Outcome Measures: Plasma gonadotropins were measured.

Results: 1) Kisspeptin-54 caused a dose-dependent increase in mean LH over time at doses from 0.2–6.4 nmol/kg. 2) Kisspeptin-54 increased plasma LH compared with saline injection in all phases of the cycle. The effect of kisspeptin was greatest in the preovulatory phase and least in the follicular phase of the cycle [mean increase in LH over baseline (IU/liter) ± SEM for follicular phase was 0.12 ± 0.17; preovulatory phase, 20.64 ± 2.91 (P < 0.001 vs. follicular phase); luteal phase, 2.17 ± 0.79 (P < 0.01 vs. follicular phase)].

Conclusion: Elevation of plasma kisspeptin in human females potently stimulates LH release in the preovulatory phase and provides a novel mechanism for manipulation of the HPG axis in women.

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