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  • Review Article
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11-Oxygenated androgens in health and disease

Nature Reviews Endocrinology volume 16, pages 284–296 (2020)Cite this article

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Abstract

The adrenal gland is a source of sex steroid precursors, and its activity is particularly relevant during fetal development and adrenarche. Following puberty, the synthesis of androgens by the adrenal gland has been considered of little physiologic importance. Dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are the major adrenal androgen precursors, but they are biologically inactive. The second most abundant unconjugated androgen produced by the human adrenals is 11β-hydroxyandrostenedione (11OHA4). 11-Ketotestosterone, a downstream metabolite of 11OHA4 (which is mostly produced in peripheral tissues), and its 5α-reduced product, 11-ketodihydrotestosterone, are bioactive androgens, with potencies equivalent to those of testosterone and dihydrotestosterone. These adrenal-derived androgens all share an oxygen atom on carbon 11, so we have collectively termed them 11-oxyandrogens. Over the past decade, these androgens have emerged as major components of several disorders of androgen excess, such as congenital adrenal hyperplasia, premature adrenarche and polycystic ovary syndrome, as well as in androgen-dependent tumours, such as castration-resistant prostate cancer. Moreover, in contrast to the more extensively studied, traditional androgens, circulating concentrations of 11-oxyandrogens do not demonstrate an age-dependent decline. This Review focuses on the rapidly expanding knowledge regarding the implications of 11-oxyandrogens in human physiology and disease.

Key points

  • Dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are the most abundant adrenal androgen precursors, but they are biologically inactive as androgens.

  • The adrenal gland is the primary source of a set of 11-oxygenated 19-carbon steroids, also termed 11-oxyandrogens, which have several roles in human physiology and disease.

  • 11-Ketotestosterone is a bioactive 11-oxyandrogen, with a potency similar to that of testosterone, and its concentrations exceed those of testosterone in prepubertal children and in postmenopausal women.

  • Concentrations of 11-oxyandrogens are elevated in several disorders of androgen excess, including premature adrenarche, congenital adrenal hyperplasia and polycystic ovary syndrome, and they can contribute to the progression of castration-resistant prostate cancer.

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Fig. 1: Adrenal androgen synthesis.
Fig. 2: Synthesis, circulation and metabolism of 11-oxyandrogens.
Fig. 3: Distribution of key C19 steroids across the human female lifespan.

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Acknowledgements

The authors acknowledge the support of grants from the NIH (1K08DK109116 to A.F.T., R01DK069950 and R01DK43140 to W.E.R., R01GM086596 to R.J.A.) and the University of Michigan (MCubed U064177 to A.F.T. and W.E.R.).

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Authors and Affiliations

  1. Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA

    Adina F. Turcu, Richard J. Auchus & William E. Rainey

  2. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Juilee Rege & William E. Rainey

  3. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

    Richard J. Auchus

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  1. Adina F. Turcu
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Contributions

A.F.T. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. J.R. contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. R.J.A. and W.E.R. contributed to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Adina F. Turcu.

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Nature Reviews Endocrinology thanks V. Papadopoulos, S. Wudy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Adrenarche

An early stage in sexual maturation specific to humans and other primates that is caused by androgen synthesis from the adrenal glands and is associated with the development of pubic hair, body odour, skin oiliness and acne.

Steroidogenesis

The process of steroid synthesis.

Tropic

Related to hormones that stimulate the growth and activity of target glands.

Second messengers

Small intracellular molecules that mediate the effects of first messengers, that is, neurotransmitters and hormones.

Pubarche

The first appearance of pubic hair at puberty.

Sulfonation

The transfer of a sulfonate group (SO3−1) from the universal sulfonate donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to an appropriate acceptor molecule.

Glucuronidation

A process of steroid metabolism that consists of transfer of the glucuronic acid component of uridine diphosphate glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase.

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Turcu, A.F., Rege, J., Auchus, R.J. et al. 11-Oxygenated androgens in health and disease. Nat Rev Endocrinol 16, 284–296 (2020). https://doi.org/10.1038/s41574-020-0336-x

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