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Delayed Puberty and Primary Amenorrhea Associated with a Novel Mutation of the Human Follicle-Stimulating Hormone Receptor: Clinical, Histological, and Molecular Studies

INSERM E120 (O.L., A.D., I.B., M.M.) and Laboratoire d’Hormonologie et Biologie Moléculaire (G.M., M.M.), Hôpital Bicêtre, 94275 Le Kremlin Bicêtre, France; and Service d’Endocrinologie et Maladies de la Reproduction (P.T., F.K.), Hôpital Necker; 75015 Paris; Service d’Anatomopathologie (M.C. V.L.), Hôpital Cochin, 75014 Paris, France

Address all correspondence and requests for reprints to: Prof. Micheline Misrahi, INSERM E120, Bat. Gregory Pincus Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre, France. E-mail: micheline.misrahi{at}bct.ap-hop-paris.fr.

Inactivating mutations of the FSH receptor have been described in rare cases of premature ovarian failure. Only one mutation was associated with a complete phenotype, including delayed puberty, primary amenorrhea, and small ovaries. We describe here a new patient presenting a similar complete phenotype of premature ovarian failure, with high plasma FSH levels associated with very low estrogen and inhibin B levels. No biological response to high doses of recombinant FSH was detected. A novel homozygous Pro⁵¹⁹Thr mutation was found in this patient. This mutation is located in the second extracellular loop of the FSH receptor, within a motif highly conserved in gonadotropin and TSH receptors. The mutation totally impairs adenylate cyclase stimulation in vitro. FSH binding experiments and confocal microscopy showed that this mutation alters the cell surface targeting of the mutated receptor, which remains trapped intracellularly. Histological studies of the ovaries of the patient showed an increase in the density of small follicles compared with age-matched normal women. A complete block in follicular maturation after the primary stage was also observed. Immunocytochemical studies allowed detection of the expression of c-Kit and proliferation cellular nuclear antigen, whereas no apoptosis was shown by the 3'-end-labeling method. This observation supports the concept that in humans FSH seems mandatory for the initiation of follicular growth only after the primary stage. In our patient complete FSH resistance yields infertility, which is remarkably associated with the persistence of a high number of small follicles.

This work was supported by INSERM, the University Paris XI, and the Fondation pour le Recherche Médicale Française.

G.M. and P.T. contributed equally to this work.

Abbreviations: FSHR, FSH receptor; P450_arom, aromatase cytochrome P450; P450_c17, 17-hydroxylase cytochrome P450; P450_scc, side-chain cleavage; PCNA, proliferation cellular nuclear antigen; POF, premature ovarian failure; SF1, steroidogenic factor 1; TUNEL, terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling.

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