Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, USA,
Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, USA,
Front Horm Res. 2019;53:1-17. doi: 10.1159/000494899. Epub 2019 Sep 9.
In utero androgen excess reliably induces polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in female monkeys, sheep, rats, and mice. In humans, however, substantial technical and ethical constraints on fetal sampling have curtailed safe, pathogenic exploration during gestation. Evidence consistent with in utero origins for PCOS in humans has thus been slow to amass, but the balance now leans toward developmental fetal origins. Given that PCOS is familial and highly heritable, difficulties encountered in discerning genetic contributions to PCOS pathogenesis are puzzling and, to date, accounts for <10% of PCOS presentations. Unaccounted heritability notwithstanding, molecular commonality in pathogenic mechanisms is emerging, suggested by co-occurrence at the same gene loci of (1) PCOS genetic variants (PCOS women), (2) epigenetic alterations in DNA methylation (PCOS women), and (3) bioinformatics, gene networks-identified, epigenetic alterations in DNA methylation (female rhesus monkeys exposed to testosterone (T) in utero). In addition, naturally occurring hyperandrogenism in female monkeys singles out individuals with PCOS-like reproductive and metabolic traits accompanied by somatic biomarkers of in utero T exposure. Such phenotypic and molecular convergence between highly related species suggests not only dual genetic and epigenetic contributions to a developmental origin of PCOS but also common molecular pathogenesis extending beyond humans.
在子宫内雄激素过多可可靠地诱导雌性猴子、绵羊、大鼠和小鼠出现多囊卵巢综合征（PCOS）样的生殖和代谢特征。然而，在人类中，对胎儿采样的实质性技术和伦理限制限制了在妊娠期间进行安全的、发病机制的探索。因此，与人类 PCOS 宫内起源相一致的证据积累缓慢，但目前的平衡倾向于发育性胎儿起源。鉴于 PCOS 是家族性的且高度可遗传，如果在辨别 PCOS 发病机制中的遗传贡献方面遇到困难，这令人费解，迄今为止，这仅占 PCOS 表现的<10%。尽管存在未被解释的遗传力，但致病机制中的分子共性正在出现，这表现在（1）PCOS 遗传变异（PCOS 女性）、（2）DNA 甲基化的表观遗传改变（PCOS 女性）和（3）生物信息学、基因网络鉴定的 DNA 甲基化的表观遗传改变（在子宫内暴露于睾酮（T）的雌性恒河猴）在相同的基因座中共同出现。此外，在雌性猴子中自然发生的雄激素过多症会挑选出具有 PCOS 样生殖和代谢特征的个体，同时伴有宫内 T 暴露的躯体生物标志物。这些高度相关物种之间的表型和分子趋同不仅表明 PCOS 的发育起源既有遗传又有表观遗传的双重贡献，而且还存在超出人类范围的共同分子发病机制。
