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GNRHR Mutations in a Woman with Idiopathic Hypogonadotropic Hypogonadism Highlight the Differential Sensitivity of Luteinizing Hormone and Follicle-Stimulating Hormone to Gonadotropin-Releasing Hormone

Reproductive Endocrine Unit (A.U.M., J.S.A., K.A.M., S.B.S., J.E.H., W.F.C.) and Harvard-Wide Reproductive Endocrine Sciences Center (A.U.M., H.K., G.Y.B., J.S.A., K.A.M., S.B.S., J.E.H., W.F.C., U.B.K.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology, Diabetes and Hypertension (H.K., G.Y.B., U.B.K.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and Oregon National Primate Research Center and Department of Physiology and Pharmacology (P.M.C.), Oregon Health and Science University, Beaverton, Oregon 97006

Address all correspondence and requests for reprints to: Dr. Astrid Meysing, Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: ameysing{at}partners.org.

Mutations in the GnRH receptor gene (GNRHR) are a cause of idiopathic hypogonadotropic hypogonadism. We describe a normosmic female subject with congenital idiopathic hypogonadotropic hypogonadism in whom treatment with pulsatile GnRH resulted in an unusual response. The subject not only required an increased dose of pulsatile GnRH for ovarian follicular development, but LH secretion did not increase appropriately, estradiol levels remained low, and she did not ovulate spontaneously.

Sequencing of the GNRHR coding sequence revealed compound heterozygous mutations leading to amino acid substitutions [N10K+Q11K] and P320L. The introduction of the P320L mutation into the GnRH receptor led to failure of detectable ligand binding and failure of stimulation of inositol phosphate production and gonadotropin subunit gene promoter activity in response to GnRH in transiently transfected cells. The [N10K+Q11K] mutation resulted in reduced binding of a GnRH agonist to 25% of the wild-type receptor. In addition, the EC₅₀ value for GnRH stimulation of inositol phosphate production was significantly increased, and the dose-response curves for stimulation of gonadotropin subunit, LHß, and FSHß gene transcription by GnRH were similarly shifted to the right. Stimulation of FSHß gene transcription was more sensitive to GnRH than LHß for both wild-type and [N10K+Q11K] GnRH receptors, resulting in a greater loss of LHß stimulation than FSHß by the [N10K+Q11K] mutant at any given submaximal GnRH concentration.

We propose that the mutations in the GnRH receptor result in a rightward shift of the dose-response curves of gonadotropin responses to pulsatile GnRH in the subject and unmask the differential sensitivities of LH and FSH to GnRH, resulting in low LH and estradiol levels despite appropriate FSH secretion and follicular growth.

This work was supported in part by the National Institute of Child Health and Human Development/National Institutes of Health through Cooperative Agreement U54 HD28138 as part of the Specialized Cooperative Centers Program in Reproduction Research (to W.F.C. and U.B.K.) and by National Institutes of Health Grant HD19899 (to P.M.C.), the Deutsche Forschungsgemeinschaft (to A.U.M.), and the Lalor Foundation (to G.Y.B.).

A.U.M. and H.K. contributed equally to this work.

Abbreviations: GnRHR, GnRH receptor; GSU, gonadotropin subunit; HA, hemagglutinin; hCG, human chorionic gonadotropin; hGnRHR, human GnRHR; IHH, idiopathic hypogonadotropic hypogonadism; IP, inositol phosphate.

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