LH and FSH Receptor Mutations and Their Effects on Puberty

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Abstract

Several mutations have been detected in the genes encoding the gonadotrophin receptors, and their phenotypic effects are observed in sexual differentiation, pubertal development and fertility of the affected individuals. Both activating and inactivating mutations are known for the gonadotrophin receptors. These mutations are rare, but they are very elucidating with respect to the details of gonadotrophin action, as well as clarifying the molecular pathogenesis of certain disorders in the development of reproductive functions. Proper diagnosis of these conditions by molecular biological techniques makes it possible to offer specific treatment for patients and proper counselling for patients and their families.

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Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.

R. Kumar, Y Wang, Martin Matzuk … (1997)

Follicle stimulating hormone (FSH) is a member of the glycoprotein hormone family that includes luteinzing hormone (LH), thyroid stimulating hormone, and chorionic gonadotropin. These heterodimeric hormones share a common alpha subunit and differ in their hormone-specific beta subunit. The biological activity is conferred only by the heterodimers. FSH and LH are synthesized in the same cells of the pituitary, the gonadotrophs. FSH receptors are localized to Sertoli cells of the testes and granulosa cells of the ovary. Minimal data has been accumulated so far involving human mutations in the FSH beta, LH beta, or the gonadotropin receptor genes. There are no known mouse strains with mutations in the FSH beta gene. To generate animal models for human diseases involving the gonadotropin signal transduction pathway, we produced mice deficient in the FSH beta subunit and therefore in FSH using ES cell technology. FSH-deficient females are infertile due to a block in folliculogenesis prior to antral follicle formation. Although FSH was predicted to be necessary for spermatogenesis and Sertoli cell growth in males, FSH-deficient males are fertile despite having small testes. Our findings have important implications for male contraceptive development in humans.

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Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure.

Kristiina Aittomäki, JoséLuis Dieguez Lucena, Pirjo Pakarinen … (1995)

Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a heterogeneous condition that in some cases displays Mendelian recessive inheritance. By systematically searching for linkage in multiplex affected families, we mapped a locus for ODG to chromosome 2p. As the previously cloned follicle-stimulating hormone receptor (FSHR) gene had been assigned to 2p, we searched it for mutations. A C566T transition in exon 7 of FSHR predicting an Ala to Val substitution at residue 189 in the extracellular ligand-binding domain segregated perfectly with the disease phenotype. Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor. We conclude that the mutation causes ODG in these families.

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Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility.

Juha S Tapanainen, K Aittomäki, T Vaskivuo … (1997)

Gonadal function is controlled by the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). While LH mainly regulates gonadal steroidogenesis, FSH is considered essential for folliculogenesis in the female and spermatogenesis in the male. We recently discovered that an inactivating point mutation in the FSH receptor (R) gene causes a recessively inherited form of hypergonadotropic ovarian failure in homozygous females. This 566C-->T mutation, predicting an alanine to valine substitution, is located in exon 7 of the FSHR gene, in the region encoding the extracellular domain of the receptor molecule. Functional testing showed a clear-cut reduction in ligand binding and signal transduction by the mutated receptor. Hence, lack of FSH function is incompatible with ovarian follicular maturation and female fertility. In the male, FSH is generally considered essential for the pubertal initiation of spermatogenesis and maintenance of quantitatively normal sperm production in adults. We report here the first characterization of males homozygous for an inactivating FSHR mutation. They have variable degrees of spermatogenic failure, but, surprisingly, do not show azoospermia or absolute infertility. These results question the essential role of FSH for the initiation of spermatogenesis, and demonstrate that FSH is more important for female than for male fertility.

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISBN: 978-3-8055-7429-7

ISBN: 978-3-318-00854-8

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2002

Publication date (Print): 2002

Publication date (Electronic): 17 November 2004

Volume: 57

Issue: Suppl 2

Pages: 35-38

Affiliations

Department of Physiology, University of Turku, Finland, andInstitute of Reproductive Developmental Biology, Imperial College, Faculty of Medicine, London, UK

Article

Publisher ID: 58098 Other ID: Horm Res 2002;57(suppl 2):35–38

DOI: 10.1159/000058098

PubMed ID: 12065924

SO-VID: 680a5f9c-cfbd-4a68-a395-7d887007e068

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