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  • Review Article
  • Published:

Genetics of androgen metabolism in women with infertility and hypoandrogenism

Nature Reviews Endocrinology volume 11, pages 429–441 (2015)Cite this article

Subjects

Key Points

  • Testosterone activity, via the androgen receptor, on granulosa cells is increasingly recognized as essential for the early stages of folliculogenesis

  • Dehydroepiandrosterone (DHEA) supplementation of women with low functional ovarian reserve (LFOR) is a popular treatment for infertility, as these women almost universally have lower levels of testosterone than healthy women

  • DHEA supplementation has remained controversial primarily due to a lack of adequately powered clinical trials demonstrating its efficacy, but also owing to considerable variability in the metabolism of DHEA to testosterone

  • Approximately 10–15% of women who respond poorly to DHEA supplementation have insufficiently increased levels of testosterone—a major product of DHEA metabolism

  • Abnormally poor metabolism of DHEA to testosterone can be caused by a number of known genetic variants, as well as by endocrine and immune conditions

  • Hormonal responses to DHEA supplementation in women with LFOR can indicate genetic variants associated with poor metabolism of DHEA to testosterone and, thereby, suggest new personalized treatment options for these patients

Abstract

Hypoandrogenism in women with low functional ovarian reserve (LFOR, defined as an abnormally low number of small growing follicles) adversely affects fertility. The androgen precursor dehydroepiandrosterone (DHEA) is increasingly used to supplement treatment protocols in women with LFOR undergoing in vitro fertilization. Due to differences in androgen metabolism, however, responses to DHEA supplementation vary between patients. In addition to overall declines in steroidogenic capacity with advancing age, genetic factors, which result in altered expression or enzymatic function of key steroidogenic proteins or their upstream regulators, might further exacerbate variations in the conversion of DHEA to testosterone. In this Review, we discuss in vitro studies and animal models of polymorphisms and gene mutations that affect the conversion of DHEA to testosterone and attempt to elucidate how these variations affect female hormone profiles. We also discuss treatment options that modulate levels of testosterone by targeting the expression of steroidogenic genes. Common variants in genes encoding DHEA sulphotransferase, aromatase, steroid 5α-reductase, androgen receptor, sex-hormone binding globulin, fragile X mental retardation protein and breast cancer type 1 susceptibility protein have been implicated in androgen metabolism and, therefore, can affect levels of androgens in women. Short of screening for all potential genetic variants, hormonal assessments of patients with low testosterone levels after DHEA supplementation facilitate identification of underlying genetic defects. The genetic predisposition of patients can then be used to design individualized fertility treatments.

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Figure 1: Metabolism of exogenously administered DHEA.

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Acknowledgements

The authors acknowledge R. Tal for critically reviewing the manuscript.

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Authors and Affiliations

  1. Center for Human Reproduction, 21 E. 69th Street, New York, 10021, NY, USA

    Aya Shohat-Tal, David H. Barad, Vitaly Kushnir & Norbert Gleicher

  2. Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, 14642, NY, USA

    Aritro Sen

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Contributions

A.S.-T. and N.G. researched data for the article, provided substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission. A.S., D.H.B and V.K. reviewed and/or edited the manuscript before submission.

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Correspondence to Aya Shohat-Tal.

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Competing interests

N.G. and D.H.B. are listed as co-inventors on four awarded US patents, which claim therapeutic benefits of DHEA and other androgens in women with low functional ovarian reserve (US 7615544: 'Method of improving cumulative embryo score and quantity of fertilized oocytes, increasing euploidy rate and of normalizing ovarian function using an androgen such as dehydroepiandrosterone'; US 8067400: 'Androgen treatment in females'; US 8501719: 'Androgen treatment in females'; US 8501718: 'Androgen treatment in females'). N.G. and D.H.B. are also listed as co-inventors on two awarded US patents, which are not related to the subject of this Review (US 8629120: 'Method of treatment related to the FMR1 gene'; and US 8951724: 'Detection of infertility risk and premature ovarian aging, addressing various claimed effects and diagnostic functions of the FMR1 gene on ovaries and female fertility'). N.G. owns shares in Fertility Nutraceuticals, a company that sells DHEA products, and both N.G. and D.H.B. receive patent royalties from this company. N.G. is also the owner of The Center for Human Reproduction, New York, NY, USA. A.S. T., A.S. and V.K. declare no competing interests.

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Shohat-Tal, A., Sen, A., Barad, D. et al. Genetics of androgen metabolism in women with infertility and hypoandrogenism. Nat Rev Endocrinol 11, 429–441 (2015). https://doi.org/10.1038/nrendo.2015.64

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