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 3beta-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.

Figure 1

DHEA-S levels during human development, adrenarche and aging. This figure was modified from Rainey et al [43].

Figure 2

Steroid pathway for DHEA-S production. Production relies on the coordinated expression of StAR, CYP11A, CYP17, and DHEA-sulfotransferase (SULT2A1). Also positively impacting DHEA-S biosynthesis is cytochrome b5 (CYB5), which can enhance the 17,20-lyase activity of CYP17. Negatively impacting the production of DHEA-S is 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2). This figure was modified from Rainey et al [43].

Figure 3

Immunohistochemistry for cytochrome b5 (CYB5), DHEA-sulfotransferase (SULT2A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) in human adrenal cortex. Both SULT2A1 and CYB5 immunoreactivities are strongly detected in the cytoplasm of adrenocortical cells in the reticularis. Immunoreactivity of SULT2A1 is weak in the fasciculata and not detected in the glomerulosa. CYB5 was similarly week in the fasciculata and glomerulosa. On the other hand, reactivity for HSD3B2 was marked in the glomerulosa and fasciculata, but negative in the reticularis. This figure was modified from Rainey et al [43].