Abbott D H, Bird I M
Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA.
Rev Endocr Metab Disord. 2009 Mar;10(1):33-42. doi: 10.1007/s11154-008-9099-8.
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.
人类和非人类灵长类动物体内循环的脱氢表雄酮（DHEA）及肾上腺源性雄激素的来源，在很大程度上有别于其他哺乳动物物种。在人类和许多旧世界灵长类动物中，已知胎儿肾上腺和成年肾上腺网状带（ZR）是毫克级DHEA（及硫酸脱氢表雄酮）的产生来源。尽管存在相似之处，但也有一些差异。在此，我们采用比较内分泌学方法，研究三种灵长类动物肾上腺雄激素生物合成的多样性及其发育时间，以说明了解这些差异如何能为人类肾上腺雄激素调节及其病理生理学的潜在机制提供独特见解。我们将人类肾上腺初情期肾上腺DHEA生物合成的传统发育起始，与（1）恒河猴（旧世界灵长类动物）更早的围产期肾上腺DHEA合成起始，以及（2）雌性狨猴（新世界灵长类动物）更具动态性且可逆的肾上腺DHEA生物合成起始进行对比，并根据ZR中CYP17、HSD3B2和CYB5表达的相应发育变化来进一步考量这些事件。我们还将这些观察结果与最近描述的从这些非人类灵长类动物物种中克隆的CYP17 cDNA的生化特性，以及每种情况下磷酸化与CYB5共表达对17,20 -裂解酶与17 -羟化酶活性的相应影响相结合。此外，在子宫内暴露于外源性雄激素过量的雌性恒河猴，成年雌性会出现肾上腺雄激素过多症状，其表现方式让人联想到人类多囊卵巢综合征（PCOS）的情况。从CYP17、HSD3B2和CYB5相对表达改变的影响，以及包括蛋白激酶A在内的各种激酶或胰岛素敏感的PI3 -激酶/AKT信号通路的改变信号反应（可能影响17,20 -裂解酶活性）方面，进一步考量这种肾上腺雄激素过多的潜在机制。我们得出结论，虽然所有这三个物种中ZR功能起始的触发因素存在明显差异（年龄、发育阶段、社会地位、性别），但在每种情况下仍有驱动DHEA生物合成增加的共同机制。通过对控制这些非人类灵长类动物物种肾上腺ZR功能及功能障碍的内分泌机制进行比较研究，或许能最好地全面理解控制人类17,20 -裂解酶功能及功能障碍的机制。
