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Adrenal Androgens and Androgen Precursors—Definition, Synthesis, Regulation and Physiologic Actions

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Abstract

The human adrenal produces more 19 carbon (C19) steroids, by mass, than either glucocorticoids or mineralocorticoids. However, the mechanisms regulating adrenal C19 steroid biosynthesis continue to represent one of the most intriguing mysteries of endocrine physiology. This review will discuss the C19 steroids synthesized by the human adrenal and the features within the adrenal that allow production of these steroids. Finally, we consider the effects of these steroids in normal physiology and disorders of adrenal C19 steroid excess. © 2014 American Physiological Society. Compr Physiol 4:1369‐1381, 2014.

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Figure 1. Figure 1. Adrenal C19 steroid biosynthetic pathways. The steroid secreted from the human adrenal at the highest levels have larger font. The more abundant steroids are graphically overemphasized. Abbreviations: DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; StAR, steroidogenic acute regulatory protein; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2; CYB5A, cytochrome b5; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 5; SULT2A1, steroid sulfotransferase type 2A1, CYP11B1, 11β‐hydroxylase.
Figure 2. Figure 2. Adrenal steroidogenic enzymes and associated proteins that impact C19 steroid production with their human adrenal zonal expression pattern. Abbreviations: ZG, zona glomerulosa; ZF, zona fasciculata; ZR, zona reticularis; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; CYP17, 17α‐hydroxylase/17,20‐lyase; CYB5, cytochrome b5; SULT2A1, steroid sulfotransferase type 2A1; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 3; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2.
Figure 3. Figure 3. Adrenal‐derived C19 steroids act as precursors for the production of more potent androgens in peripheral tissues, including hair follicles, genital skin, and prostate. The classical pathway for bioactive androgen synthesis, as well as a proposed alternative pathway using 11β‐hydroxyandrostenedione (11OHA) is shown. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHT, 11β‐hydroxytestosterone;11OHDHT, 11β‐hydroxyDHT; STS, sulfatase; HSD3B, 3β‐hydroxysteroid dehydrogenases; HSD17, 17β‐hydroxysteroid dehydrogenases; SRD5A, 5α‐reductase type A.
Figure 4. Figure 4. Pathways of steroid hormone synthesis in 21‐hydroxylase deficiency. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHA, 11β‐hydroxyandrostenedione; 11OHT, 11β‐hydroxytestosterone; SRDA1/2, 5α‐reductase types 1 or 2; AKR1C2/4, 3α‐hydroxysteroid dehydrogenases types 2 or 4; CYP17A1, 17α‐hydroxylase/17,20‐lyase; HSD17B3/6, 17β‐hydroxysteroid dehydrogenase types 3 or 6; AKR1C3, 17β‐hydroxysteroid dehydrogenase types 5.


Figure 1. Adrenal C19 steroid biosynthetic pathways. The steroid secreted from the human adrenal at the highest levels have larger font. The more abundant steroids are graphically overemphasized. Abbreviations: DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; StAR, steroidogenic acute regulatory protein; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2; CYB5A, cytochrome b5; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 5; SULT2A1, steroid sulfotransferase type 2A1, CYP11B1, 11β‐hydroxylase.


Figure 2. Adrenal steroidogenic enzymes and associated proteins that impact C19 steroid production with their human adrenal zonal expression pattern. Abbreviations: ZG, zona glomerulosa; ZF, zona fasciculata; ZR, zona reticularis; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; CYP17, 17α‐hydroxylase/17,20‐lyase; CYB5, cytochrome b5; SULT2A1, steroid sulfotransferase type 2A1; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 3; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2.


Figure 3. Adrenal‐derived C19 steroids act as precursors for the production of more potent androgens in peripheral tissues, including hair follicles, genital skin, and prostate. The classical pathway for bioactive androgen synthesis, as well as a proposed alternative pathway using 11β‐hydroxyandrostenedione (11OHA) is shown. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHT, 11β‐hydroxytestosterone;11OHDHT, 11β‐hydroxyDHT; STS, sulfatase; HSD3B, 3β‐hydroxysteroid dehydrogenases; HSD17, 17β‐hydroxysteroid dehydrogenases; SRD5A, 5α‐reductase type A.


Figure 4. Pathways of steroid hormone synthesis in 21‐hydroxylase deficiency. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHA, 11β‐hydroxyandrostenedione; 11OHT, 11β‐hydroxytestosterone; SRDA1/2, 5α‐reductase types 1 or 2; AKR1C2/4, 3α‐hydroxysteroid dehydrogenases types 2 or 4; CYP17A1, 17α‐hydroxylase/17,20‐lyase; HSD17B3/6, 17β‐hydroxysteroid dehydrogenase types 3 or 6; AKR1C3, 17β‐hydroxysteroid dehydrogenase types 5.
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Adina Turcu, Joshua M. Smith, Richard Auchus, William E. Rainey. Adrenal Androgens and Androgen Precursors—Definition, Synthesis, Regulation and Physiologic Actions. Compr Physiol 2014, 4: 1369-1381. doi: 10.1002/cphy.c140006