GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone.

摘要: Mutations in the GnRH receptor gene (GNRHR) are a cause of idiopathic hypogonadotropic hypogonadism. We describe normosmic female subject with congenital hypogonadism whom treatment pulsatile resulted an unusual response. The not only required increased dose for ovarian follicular development, but LH secretion did increase appropriately, estradiol levels remained low, and she ovulate spontaneously. Sequencing GNRHR coding sequence revealed compound heterozygous mutations leading to amino acid substitutions [N10K+Q11K] P320L. introduction P320L mutation into led failure detectable ligand binding stimulation inositol phosphate production gonadotropin subunit promoter activity response transiently transfected cells. reduced agonist 25% wild-type receptor. In addition, EC(50) value was significantly increased, dose-response curves alpha subunit, LHbeta, FSHbeta transcription by were similarly shifted right. Stimulation more sensitive than LHbeta both receptors, resulting greater loss mutant at any given submaximal concentration. propose that result rightward shift responses unmask differential sensitivities FSH GnRH, low despite appropriate growth.