Nonhuman primates as models for human adrenal androgen production: Function and dysfunction |
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Authors: | D H Abbott I M Bird |
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Institution: | (1) Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA;(2) Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, USA |
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Abstract: | The origin of circulating DHEA and adrenal-derived androgens in humans and nonhuman primates is largely distinct from other
mammalian species. In humans and many Old world primates, the fetal adrenal gland and adult zona reticularis (ZR) are known
to be the source for production of DHEA (and DHEAS) in mg quantities. In spite of similarities there are also some differences.
Herein, we take a comparative endocrine approach to the diversity of adrenal androgen biosynthesis and its developmental timing
in three primate species to illustrate how understanding such differences may provide unique insight into mechanisms underlying
adrenal androgen regulation and its pathophysiology in humans. We contrast the conventional developmental onset of adrenal
DHEA biosynthesis at adrenarche in humans with (1) an earlier, peri-partutrition onset of adrenal DHEA synthesis in rhesus
macaques (Old World primate) and (2) a more dynamic and reversible onset of adrenal DHEA biosynthesis in female marmosets
(New World primate), and further consider these events in terms of the corresponding developmental changes in expression of
CYP17, HSD3B2 and CYB5 in the ZR. We also integrate these observations with recently described biochemical characterization
of CYP17 cDNA cloned from each of these nonhuman primate species and the corresponding effects of phosphorylation versus CYB5
coexpression on 17,20 lyase versus 17-hydroxylase activity in each case. In addition, female rhesus macaques exposed in utero
to exogenous androgen excess, exhibit symptoms of adrenal hyperandrogenism in adult females in a manner reminiscent of that
seen in the human condition of PCOS. The possible mechanisms underlying such adrenal hyperandrogenism are further considered
in terms of the effects of altered relative expression of CYP17, HSD3B2 and CYB5 as well as the altered signaling responses
of various kinases including protein kinase A, or the insulin sensitive PI3-kinase/AKT signaling pathway which may impact
on 17,20 lyase activity. We conclude that while the triggers for the onset of ZR function in all three species show clear
differences (age, stage of development, social status, gender), there are still common mechanisms driving an increase in DHEA
biosynthesis in each case. A full understanding of the mechanisms that control 17,20 lyase function and dysfunction in humans
may best be achieved by comparative studies of the endocrine mechanisms controlling adrenal ZR function and dysfunction in
these nonhuman primate species. |
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Keywords: | DHEA Adrenal Human Rhesus Marmoset Adrenarche PCOS CYP17 HSD3B2 CYB5 Phosphorylation 17 20 lyase |
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