Nonhuman primates as models for human adrenal androgen production: function and dysfunction.
Nonhuman primates as models for human adrenal androgen production: function and dysfunction.
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DOI：
10.1007/s11154-008-9099-8
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发表时间：
2009-03
影响因子：
8.2
通讯作者：
Bird, I. M.
中科院分区：
文献类型：
--
作者：
Abbott, D. H.;Bird, I. M.
人类和非人类灵长类动物体内循环中的脱氢表雄酮和肾上腺来源的雄激素的来源在很大程度上不同于其他哺乳动物物种。在人类和许多东半球灵长类动物中，胎儿的肾上腺和成年的网状带(ZR)被认为是产生镁含量DHEA(和DHEAS)的来源。尽管有相似之处，但也有一些不同之处。在这里，我们采用比较内分泌的方法来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机，以说明了解这种差异如何为人类肾上腺雄激素调节及其病理生理提供独特的见解。我们将人类肾上腺始期肾上腺DHEA生物合成的常规发育期与(1)恒河猴(东半球灵长类)较早的围产期肾上腺DHEA合成的发育期和(2)雌性恒河猴(新大陆灵长类)肾上腺DHEA生物合成的更动态和可逆的发育期进行比较，并进一步根据ZR中CYP17、HSD3B2和CYB5表达的相应发育变化来考虑这些事件。我们还将这些观察结果与最近从这些非人类灵长类物种中克隆的CYP17基因的生化特征以及磷酸化与CyB5共表达对17，20裂解酶与17-羟基酶活性的相应影响结合在一起。此外，雌性恒河猴在子宫内暴露于外源性雄激素过量时，成年雌性猕猴会出现肾上腺雄激素过高的症状，这与人类患有多囊卵巢综合征时的症状相似。从细胞色素P17、HSD3B2和细胞色素B5相对表达的改变，以及蛋白激酶A或胰岛素敏感的PI3-K/AKT信号通路对17，20裂解酶活性的影响，进一步探讨了肾上腺高雄激素血症的可能机制。我们的结论是，虽然三个物种启动ZR功能的触发因素都有明显的差异(年龄、发育阶段、社会地位、性别)，但每种情况下DHEA生物合成的增加仍然有共同的机制。通过对这些非人类灵长类物种控制肾上腺ZR功能和功能障碍的内分泌机制的比较研究，可以充分理解人类控制17，20裂解酶功能和功能障碍的机制。
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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影响因子：
3.6
作者：
Dharia, S;Slane, A;Parker, CR
通讯作者：
Parker, CR
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2.1
作者：
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作者：
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作者：
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通讯作者：
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