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A New Compound Heterozygous Mutation of the Gonadotropin-Releasing Hormone Receptor (L314X, Q106R) in a Woman with Complete Hypogonadotropic Hypogonadism: Chronic Estrogen Administration Amplifies the Gonadotropin Defect¹

Endocrinologie Cellulaire et Moléculaire de la Reproduction, Centre National de la Recherche Scientifique, Université Paris VI (M.L.K., S.C., R.C.), 75005 Paris, France; Laboratoire de Biologie Hormonale, Hôpital Saint Vincent de Paul (N.L.), 75014 Paris, France; Department of Endocrinology, Hemel Hempstead General Hospital (C.E.H., C.J.J., N.R.F.), Watford, Hertfordshire HP2 4AD, United Kingdom; Service d’Endocrinologie, Hôpital Saint Antoine (P.B.), 75012 Paris, France; and Unité de Génétique Moléculaire, Service de Biochimie Médicale, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (M.L.K., J.P.L.), 75013 Paris, France

Address all correspondence and requests for reprints to: Dr. Marie-Laure Kottler, Department of Génétique et Reproduction, Hôpital Clémenceau, Centre Hospitalo Universitaire, 14033 CAEN Cedex, France. E-mail: mlkottle{at}snv.jussieu.fr

We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the GnRH receptor (GnRHR) gene. A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described. L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO-K1 cells compared to the wild-type receptor. The disease is transmitted as an autosomal recessive trait, as shown by pedigree analysis. Heterozygous patients with GnRHR mutations had normal pubertal development and fertility.

The present study shows an absence of LH and FSH response to pulsatile GnRH administration (20 µg/pulse, sc, every 90 min). However, GnRH triggered free -subunit (FAS) pulses of small amplitude, demonstrating partial resistance to pharmacological doses of GnRH. FSH, LH, and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of GnRH. Not only were plasma FSH, LH, and FAS concentrations decreased, but FAS responsiveness was reduced.

This new case emphasizes the implication of the GnRH receptor mutations in the etiology of idiopathic hypogonadotropic hypogonadism. We also have evidence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level, dependent on the GnRHR signaling pathway.

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