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Resistance of Hypogonadic Patients with Mutated GnRH Receptor Genes to Pulsatile GnRH Administration

Service d’Endocrinologie et Maladies Métaboliques (P.C., A.B.), CHU Rangueil, 31403 Toulouse; Endocrinologie Cellulaire et Moléculaire de la Reproduction (S.C., R.C., M.-L.K.), URA Centre Nationale de la Recherche Scientifique 7080, Université Pierre and Marie Curie, 75006 Paris; Service d’Endocrinologie et des Maladies de la Reproduction (S.C.-M., P.B., M.-L.K.), Hôpital Saint-Antoine, 75012 Paris; INSERM U342 (N.L., M.-L.K.), Hôpital Saint-Vincent-de-Paul, 75014 Paris; Service de Biochimie Médicale (M.-L.K.), Hôpital Pitiè-Salpetrière, 75013 Paris, France

Address all correspondence and requests for reprints to: Philippe Caron, M.D., Service d’Endocrinologie, CHU Rangueil, 1 Avenue J. Poulhès, 31403 Toulouse Cedex, France.

We have studied a kindred with three siblings with isolated hypogonadotropic hypogonadism caused by compound heterozygote mutations in the GnRH receptor gene. The disorder was transmitted as an autosomal recessive trait. The R262Q mutation in intracellular loop 3 of the receptor was associated with a mutation in the third transmembrane domain of the receptor, A129D, that has never been described before. This A129D mutation results in a complete loss of function, indicated by the lack of inositol triphosphate (TP3) 3 production by transfected Chinese hamster ovary (CHO) cells after GnRH stimulation. The two brothers had microphallus and bilateral cryptorchidism and were referred for lack of puberty, whereas their sister had primary amenorrhea and a complete lack of puberty. Their basal gonadotropin concentrations were below the reference range, and their endogenous LH secretory patterns were abnormal, with a low-normal frequency of small pulses or no apparent LH pulse. Pulsatile GnRH administration (10 µg/pulse every 90 min for 40 h) resulted in increased mean LH without any significant changes in testosterone levels in the two brothers, whereas the LH secretory profile of their sister remained apulsatile. Larger pulses of exogenous GnRH (20 µg every 90 min for 24 h) caused the sister to produce recognizable low amplitude LH pulses. The concentrations of free -subunit significantly increased in all patients during the pulsatile GnRH administration. Thus, these hypogonadal patients are partially resistant to pulsatile GnRH administration, suggesting that they should be treated with gonadotropins to induce spermatogenesis or ovulation rather than with pulsatile GnRH.

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