• Justine Hugon-Rodin, Keisuke Yoshii, Najiba Lahlou, Jennifer Flandrin, Anne Gompel, and Nicolas de Roux.
• Paris Descartes University, Gynecology Endocrinology Unit, Port-Royal Teaching Hospital, AP-HP, Paris, France.
• J. Clin. Endocrinol. Metab. 2018 Dec 1; 103 (12): 4482-4490.

ContextMutations in the kisspeptin receptor (KISS1R) gene have been reported in a few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110).ObjectivesTo describe a female patient with nCHH and a novel homozygous KISS1R mutation and to assess the role of kisspeptin pathway to induce an ovulation by GnRH pulse therapy.Design, Setting, And InterventionObservational study of a patient including genetic and kisspeptin receptor functions and treatment efficiency using a GnRH pump.Main Outcome MeasureResponse to pulsatile GnRH therapy.ResultsA partial isolated gonadotropic deficiency was diagnosed in a 28-year-old woman with primary amenorrhea and no breast development. A novel homozygous c.953T>C variant was identified in KISS1R. This mutation led to substitution of leucine 318 for proline (p.Leu318Pro) in the seventh transmembrane domain of KISS1R. Signaling via the mutated receptor was profoundly impaired in HEK293-transfected cells. The mutated receptor was not detected on the membrane of HEK293-transfected cells. After several pulsatile GnRH therapy cycles, an LH surge with ovulation and pregnancy was obtained.ConclusionGnRH pulsatile therapy can induce an LH surge in a woman with a mutated KISS1R, which was previously thought to be completely inactivated in vivo.

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