Biosynthesis of adrenal androgens

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Dehydroepiandrosterone (DHEA) is synthesized in the zona reticularis of the adrenal gland partly in response to serum levels of the pituitary, adreno-corticotropic hormone (ACTH). DHEA is sulfated in the adrenal gland via the enzyme sulfo-transferase into DHEA-sulfate (DHEA-S), which is thought to be the storage form of DHEA. However, this concept has recently been challenged and thus so has the idea of DHEA-S reflecting the bioavailabil-ity of DHEA in the tissues. The current thinking has been that there is free interconversion between DHEA and DHEA-S, but recently the reverse conversion of DHEA-S to DHEA has been shown not to occur, at least in liver cells, although the study has been challenged on methodologic grounds [266,267].

DHEA and DHEA-S production follow an age-dependent pattern: high levels after birth due to increased synthesis by the fetal adrenal gland, a second surge at the time of adrenarche (between the sixth and tenth years of life), maximum levels during the third decade of life, and a gradual decline to about 10-20% of maximum values by the seventh or eighth decade of life [268,269]. While serum DHEA-S concentration does not vary throughout the day, DHEA secretion follows a diurnal pattern similar to that of cortisol [270,271].

Figure 18.6 depicts the synthesis and metabolism of DHEA. DHEA itself is synthesized from 17-OH pregnenolone via conversion by the 17-20 lyase portion of the enzyme P450c17. Subsequently, DHEA is converted to androstenedione by the enzyme 3P-hydroxysteroid dehydrogenase (3P-HSD). Finally, androstenedione is converted to T by the enzyme 17P-OH hydroxysteroid dehydrogenase (17P-HSD), and subsequently to estrogen by the enzyme aro-matase [233-235,270-272]. An important requirement for DHEA action is the ability of DHEA and DHEA-S to continuously interconvert, via the enzyme sulfotransferase, as only unsulfated DHEA can undergo downstream conversion to the biochemically-active hormone testosterone [270,272].

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