From 1965 to 2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology, insulin resistance, hyperinsulinism, type 2 diabetes mellitus, folliculogenesis, androgen secretion, obesity, phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large-scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicate that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and proinflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in 40 percent of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.

中文翻译：

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寻找常见高雄激素血症的原因，1965 年至 2015 年左右。


从 1965 年到 2015 年，人们在了解常见雄激素过多性疾病、肾上腺功能早现和多囊卵巢综合征 (PCOS) 的机制方面取得了巨大进步。作者从他研究这些疾病的角度回顾了这个时代的重要发现，首先是他早期发现肾上腺初现过早的血浆雄激素的独特模式，以及大多数多毛女性血浆游离睾酮浓度指数的升高。肾上腺初现的分子遗传学基础（尽管不是发育生物学基础）现已已知，并且 11-氧睾酮已被证明是主要的生物活性肾上腺雄激素。 PCOS 发病机制研究路线的演变是历史性的：在神经内分泌学、胰岛素抵抗、高胰岛素血症、2 型糖尿病、卵泡发生、雄激素分泌、肥胖、表型、产前雄激素化、表观遗传学等领域引用了研究里程碑。和复杂的遗传学。大规模全基因组关联研究导致 2014 年发现了一种未被怀疑的类固醇生成调节因子 DENND1A（在正常和肿瘤发育中存在差异表达）。剪接变体 DENND1A.V2 在长期培养的 PCOS 卵泡膜细胞中组成型过表达，并解释了其 PCOS 样表型。然而，遗传学很复杂：DENND1A 内含子变异拷贝数与表型严重程度相关，最近的数据表明 DENND1A 调控网络和其他基因中的罕见变异与 PCOS 相关。肥胖通过胰岛素抵抗和促炎细胞因子过量加剧多囊卵巢综合征的表现；多余的脂肪组织也会形成睾酮。 40% 表面正常的女性患有多囊卵巢，属于 PCOS 功能谱。还有很多东西有待学习。