Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Abstract

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 females1. 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 adults2–5. 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Aittomäki, K. et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82, 959–968 (1995).

    Article  Google Scholar 

  2. Matsumoto, A.M., Karpas, A.E. & Bremner, W.J. Chronic human chorionic gonadotropin administration in normal men: evidence that follicle-stimulating hormone is necessary for the maintenance of quantitatively normal spermatogenesis in man. J Clin. Endocr. Metab. 62, 1184–1192 (1986).

    Article  CAS  Google Scholar 

  3. Steinberger, E. Hormonal control of mammalian spermatogenesis. Physiol. Rev. 51, 1–22 (1991).

    Article  Google Scholar 

  4. Sharpe, R.M. Regulation of spermatogenesis. in The Physiology of Reproduction, Second Edn. (Eds Knobil, E. & Neill, J.D.) 1363–1434 (Raven Press, New York, 1994).

  5. Zirkin, B.R., Awonyi, C., Griswold, M.D., Russell, L.D. & Sharpe, R.M. Is FSH required for adult spermatogenesis? J. Androl. 15, 273–276 (1994).

    CAS  PubMed  Google Scholar 

  6. Aittomäki, K. The genetics of XX gonadal dysgenesis. Am. J. Hum. Genet. 54, 844–51 (1994).

    PubMed  PubMed Central  Google Scholar 

  7. Aittomäki, K. et al. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J. Clin. Endocr. Metab. 81, 3722–3726 (1996).

    PubMed  Google Scholar 

  8. Bremner, W.R., Matsumoto, A.M., Sussman, A.M. & Paulsen, C.A. Follicle-stimulating hormone and human spermatogenesis. J. Clin. Invest. 68, 1044–1052 (1981).

    Article  CAS  Google Scholar 

  9. Orth, J.M., Gunsalus, G.M. & Lamperti, A.A. Evidence from Sertoli Cell-depleted rats indicates that spermatid number in adults depends on Sertoli Cells produced during perinatal development. Endocrinology 122, 787–794 (1988).

    Article  CAS  Google Scholar 

  10. Hess, R.A., Cooke, P.S., Bunick, D. & Kirby, J.D. Adult testicular enlargement induced by neonatal hypothyroidism is accompanied by increased Sertoli and germ Cell numbers. Endocrinology 132, 2607–2613 (1993).

    Article  CAS  Google Scholar 

  11. Zeleznik, A.J. Dynamics of primate follicular growth. A physiologic perspective. In The Ovary (Eds Adashi, E.Y. & Leung, P.C.K.) 41–55 (Raven Press, New York, 1993).

  12. Kumar, T.R., Wang, Y., Lu, N. & Matzuk, M.M. Follicle stimulating hormone is required for ovarian follicle maturation but not for spermatogenesis. Nature Genet. 15, 201–204 (1997).

    Article  CAS  Google Scholar 

  13. Gromoll, J., Simoni, M. & Nieschlag, E. An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin. Endocr. Metab. 81, 1367–1370 (1996).

    CAS  PubMed  Google Scholar 

  14. Weinbauer, G.F., Behre, H.M., Fingscheidt, U. & Nieschlag, E. Human follicle-stimulating hormone exerts a stimulatory effect on spermatogenesis, testicular size and serum inhibin levels in the gonadotropin-releasing hormone antagonist-treated, non human primate (Macaca fascicularis). Endocrinology 129, 1831–1839 (1991).

    Article  CAS  Google Scholar 

  15. Minegishi, T., Nakamura, K., Takakura, Y., Ibuki, Y. & Igarashi, M. Cloning and sequencing of human FSH receptor cDNA. Biochem. Biophys. Res. Commun. 175, 1125–1130 (1991).

    Article  CAS  Google Scholar 

  16. Kelton, C.A. et al. The cloning of the human follicle stimulating hormone receptor and its expression in COS-7, CHO, and Y-1 Cells. Mol. Cell. Endocrinol. 89, 141–151 (1992).

    Article  CAS  Google Scholar 

  17. World Health Organization. Laboratory manual for the examination of human semen and semen-cervical mucus interaction. (Cambridge University Press, Cambridge, 1992).

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tapanainen, J., Aittomäki, K., Min, J. et al. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nat Genet 15, 205–206 (1997). https://doi.org/10.1038/ng0297-205

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0297-205

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing