11-Oxygenated androgens in health and disease

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.

Fig. 1 ∣. Adrenal androgen synthesis.

The adrenal cortex is structured into three concentric layers, and each layer produces specific steroids: mineralocorticoids are synthesized in the outermost layer (zona glomerulosa); glucocorticoids are produced in the middle layer (zona fasciculata); and androgens are produced in the inner layer (zona reticularis). The enzyme 3β-hydroxysteroid dehydrogenase/Δ^5/4-isomerase type 2 (HSD3B2) catalyses oxidation of the hydroxyl group on carbon 3 of steroids to a keto group and, simultaneously, isomerization of the double bond from the B ring (Δ⁵ steroids) to the A ring (Δ⁴ steroids). Androgens share a 19-carbon structure (C₁₉ steroids), whereas mineralocorticoids and glucocorticoids have a 21-carbon structure (C₂₁ steroids). The most abundant C₁₉ steroids produced by the adrenal glands are dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). The adrenal glands also produce a set of unique androgens, synthesized via the adrenal-specific enzyme, cytochrome P450 11β-hydroxylase (CYP11B1). These steroids are called 11-oxyandrogens, and 11-hydroxyandrostenedione is the most abundant. The relative androgenic potency of tested androgens is depicted based on data from Rege et al. and Storbeck et al.. Testosterone and 11-ketotestosterone are potent androgens. Steroid 5α-reductases (SRD5A) convert testosterone and 11-ketotestosterone to dihydrotestosterone and 11-ketodihydrotestosterone, respectively. Dihydrotestosterone and 11-ketodihydrotestosterone are the most potent androgens. AKR1C3, aldo-keto reductase family 1 member C3 (also known as 17β-hydroxysteroid dehydrogenase type 5); CYB5A, cytochrome b₅ type A; CYP11A1, cytochrome P450 cholesterol side chain cleavage; CYP17A1, cytochrome P450 17A1; OH, hydroxy; StAR, steroidogenic acute regulatory protein; SULT2A1, steroid sulfotransferase type 2A1.

Fig. 2 ∣. Synthesis, circulation and metabolism of 11-oxyandrogens.

19-carbon (C₁₉) steroids are synthesized in the adrenal cortex, including androgen precursors, predominantly dehydroepiandrosterone (DHEA), its sulfate (DHEAS), androstenedione and 11β-hydroxyandrostenedione (11OHA4), and smaller quantities of bioactive androgens, such as testosterone and 11β-hydroxytestosterone (11OHT).The kidney expresses 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), which converts the adrenal-derived 11OHA4 and 11OHT into 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT), respectively. Other target tissues, such as the adipose tissue, prostate, hair follicles and genital skin, are able to convert the adrenal androgen precursors androstenedione, 11OHA4 and 11KA4 into bioactive androgens via 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes and steroid 5α-reductases (SRD5A). The bioactive androgens bind the androgen receptors, located in the cytoplasm, and the hormone-receptor complex translocates to the nucleus, where it activates several androgen-responsive genes. 11KDHT, 11-ketodihydrotestosterone; 11OHDHT, 11β-hydroxydihydrotestosterone; DHT, dihydrotestosterone; OH, hydroxy.

Fig. 3 ∣. Distribution of key C₁₉ steroids across the human female lifespan.

Levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), the major adrenal androgen precursors, begin to increase around age 6 years, peak around the mid-20s and, subsequently, decline gradually. In women during reproductive years, androstenedione and testosterone are produced in similar amounts by both the adrenal glands and the ovaries, and their concentrations decline gradually with ageing. By contrast, levels of 11β-hydroxyandrostenedione (11OHA4) and 11-ketotestosterone (11KT) remain elevated in postmenopausal women. Data obtained from Rege et al. and Nanba et al., and expressed in medians. Total n = 283 girls and women (aged 4–5 years, n = 22; aged 6–8 years, n = 38; aged 9–10 years, n = 23; aged 20–40 years, n = 100; aged 60–80 years, n = 100).