Regulation of the adrenal androgen biosynthesis

Abstract

The human adrenal reticularis produces the so-called adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S). As opposed to the cortisol and aldosterone little is known regarding the mechanisms that regulate the production of the adrenal androgens. Several recent studies have shown that type II 3β-hydroxysteroid dehydrogenase (HSD3B2), cytochrome b5 (CYB5), and steroid sulfotransferase (SULT2A1) play an important role in the regulation of adrenal androgen production. Specifically, adrenal production of DHEA-S is correlated with reticularis expression of SULT2A1 and CYB5. In contrast, HSD3B2 has an inverse correlation with adrenal androgen production likely due to its unique ability to remove precursors from the pathway leading to DHEA. Therefore, its expression is limited to the adrenal glomerulosa/fasciculata but not in reticularis. The differential expression of these three proteins appears to be critical for reticularis function. In this review, we focus on studies that have begun to define the mechanisms regulating the transcription of these genes. Understanding the mechanisms controlling differential expression of these proteins should provide novel information about the human adrenal reticularis and its production of DHEA and DHEA-S. KeywordsAdrenal; Androgen; Cytochrome b5; DHEA-sulfotransferase; 3β-hydroxysteroid dehydrogenase II. Background & SignificanceThe fetal adrenal produces large amounts of dehydroepiandrosterone (DHEA) and DHEAsulfate (DHEAS) during fetal development (Fig. 1). DHEA-S concentrations are also high in the newborn (Fig. 1) [1]. However, by age 1, the specialized fetal zone is lost and replaced by the definitive adrenal cortex, which initially synthesizes little DHEA-S (Fig. 1). Hence, DHEA-S production declines precipitously during the first months of life and remains low until adrenarche commences at about age 6-8 [2]. This rise in the circulating concentrations of DHEA and DHEA-S is the biochemical hallmark of adrenarche [3]. Importantly, the rise in DHEA-S occurs prior to the increase of either estrogens or androgens associated with puberty [4]. Circulating DHEA-S concentrations continue to rise and peak during the second decade of life, with levels being higher in males than in females (Fig. 1) [3,5]. While circulating concentrations of DHEA and DHEA-S rise progressively in adrenarche, cortisol and ACTH concentrations do not change significantly in this period, indicating that adrenarche is not simply a global activation of the pituitary-adrenal axis.Correspondence and reprint requests addressed to: William E Rainey, Ph.D. Department of Physiology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912,, Email: E-mail: wrainey@mcg.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its f...

Novel mechanisms for DHEA action

“…The physiological role of circulation DHEA and DHEA-S as sources of bulk androgen cannot be overlooked (Rainey et al 2004, Rainey & Nakamura 2008, Rege & Rainey 2012, because a source of androgen is required to rapidly produce the sex-related hormones during adrenarche and parturition. Our studies of DHEA metabolism and the biological action of DHEA and its metabolites on hepatic metabolism have provided evidence that induction of the enzymes normally involved in foreign compound metabolism by DHEA is common to those induced by drugs and chemical toxicants (Webb et al 2006).…”

“…DHEA synthesis mainly occurs in the adrenal zona reticularis: the inner zone of the adrenal cortex (Parker Jr 1999;Rainey & Nakamura 2008). All steroid hormones are derived from cholesterol with the first enzymatic reaction occurring in the mitochondria.…”

“…DHEA is modified at the 3βʹ-hydroxyl group to generate DHEA sulfate (DHEA-S). DHEA and DHEA-S synthesis are developmentally and hormonally regulated (reviewed in Rainey & Nakamura 2008). Regeneration of active DHEA occurs in tissues via the action of steroid sulfatase, and this is an important biological function of adipose in postmenopausal women in whom the major source of estradiol is from adrenal DHEA-S conversion to estrogens in fat tissue (Labrie et al 2007).…”

Effects of tris(2,3-dibromopropyl) isocyanurate on steroidogenesis in H295R cells

“…If TBC inhibited cortisol and aldosterone synthesis, it could possibly disturb cortical hormone balance and may cause health problems related with glycometabolism (Løvås and Husebye 2007). 3bHSD2 play a vital role in the adrenal biosynthesis of mineralocorticoids (aldosterone) and glucocorticoids (cortisol), but its expression is oppositely correlated with adrenal androgens synthesis such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione (Rainey and Nakamura 2008). CYP17 is a dual-functional enzyme that catalyzes the synthesis of both cortisol and androgens.…”

Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography–tandem mass spectrometry

“…In men, androgens are produced by testes and adrenals in different amounts (6,7,8). Serum TS levels derive mostly from testes, as well as progesterone (P), androstenedione (AS), and 17-hydroxyprogesterone (17OHP) (∆4 pathway).…”