Nonhuman primates as models for human adrenal androgen production: function and dysfunction

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.

Figure 1. Relationship between relative expression levels of CYP17, HSD3BII and CYB5 in the adrenal zona fasciculata and ZR as suggested by histologic studies of human and nonhuman primate adrenals, and the resulting predominant direction of pregnenolone metabolism

In the Zona fasciculata (Panel A) the higher affinity of CYP17 17-hydroxylase activity (17-OHase) for pregnenolone directs pregneolone metabolism first to 17-hydroxypregnenolone (17-OHP5), and subsequent abundant levels of 3BHSDII then directs further conversion to 17-hydroxyprogesterone (17-OHP4). In the absence of any significant CYP17 delta 4 lyase activity, the highly efficient CYP21 enzyme also present in the same membranes can then undertake 21-hydroxylation (21-Ohase) to make deoxycortisol and so commit to cortisol production. However, in the ZR (Panel B) where CYP17 is still highly expressed but 3BHSDII is expressed at a lower level or absent, high levels of CYB5 unique to this zone bind CYP17 and (together with CYP17 phosphorylation?) enhance the relative 17–20 lyase activity. In the presence of CYB5 and the relative absence of 3BHSDII, the net direction of pregnenolone metabolism is now 17-OHase activity to 17-hydroxypregnenolone and then 17–20 lyase conversion to DHEA. In the presence of low levels of 3BHSDII, some additional conversion to androstenedione (A4) is possible. Other abbreviations: Progesterone, P4.

Figure 1. Relationship between relative expression levels of CYP17, HSD3BII and CYB5 in the adrenal zona fasciculata and ZR as suggested by histologic studies of human and nonhuman primate adrenals, and the resulting predominant direction of pregnenolone metabolism

In the Zona fasciculata (Panel A) the higher affinity of CYP17 17-hydroxylase activity (17-OHase) for pregnenolone directs pregneolone metabolism first to 17-hydroxypregnenolone (17-OHP5), and subsequent abundant levels of 3BHSDII then directs further conversion to 17-hydroxyprogesterone (17-OHP4). In the absence of any significant CYP17 delta 4 lyase activity, the highly efficient CYP21 enzyme also present in the same membranes can then undertake 21-hydroxylation (21-Ohase) to make deoxycortisol and so commit to cortisol production. However, in the ZR (Panel B) where CYP17 is still highly expressed but 3BHSDII is expressed at a lower level or absent, high levels of CYB5 unique to this zone bind CYP17 and (together with CYP17 phosphorylation?) enhance the relative 17–20 lyase activity. In the presence of CYB5 and the relative absence of 3BHSDII, the net direction of pregnenolone metabolism is now 17-OHase activity to 17-hydroxypregnenolone and then 17–20 lyase conversion to DHEA. In the presence of low levels of 3BHSDII, some additional conversion to androstenedione (A4) is possible. Other abbreviations: Progesterone, P4.