Abstract:
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.
摘要:
从1965年到2015年,人们在理解常见雄激素过量疾病的潜在机制方面取得了巨大进展。肾上腺过早和多囊卵巢综合征(PCOS)。作者从调查这些疾病的角度回顾了这个时代的重要发现,从他早期发现性早熟的血浆雄激素的独特模式和大多数多毛妇女血浆游离睾酮浓度指数的升高开始。分子遗传学基础,虽然不是发育的生物学基础,现在已知肾上腺素和11-氧睾酮显示为主要的生物活性肾上腺雄激素。PCOS发病机理的研究路线的演变是历史上的:神经内分泌学领域的研究里程碑;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,复杂的遗传学。大规模的全基因组关联研究导致2014年发现了一种意外的类固醇生成调节因子DENND1A(在正常和肿瘤发育中差异表达)。剪接变体DENND1A。V2在长期培养的PCOS卵泡膜细胞中组成性过表达,并解释了它们的PCOS样表型。遗传学很复杂,然而:DENND1A内含子变体拷贝数与表型严重程度有关,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有关。肥胖通过胰岛素抵抗和促炎细胞因子过量加剧PCOS表现;过量的脂肪组织也形成睾酮。1/4明显正常女性的多囊卵巢位于PCOS功能谱上。还有很多需要学习。