Rosenfield Robert L, Ehrmann David A
Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637.
Endocr Rev. 2016 Oct;37(5):467-520. doi: 10.1210/er.2015-1104. Epub 2016 Jul 26.
Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.
1989 - 1995年期间，多囊卵巢综合征（PCOS）被认为是由于雄激素分泌失调导致的功能性卵巢雄激素过多症（FOH）所致。随后的研究支持并扩展了这一假说。当被定义为无法解释的高雄激素性少排卵时，三分之二的PCOS病例具有功能典型的FOH，其特征为17 - 羟孕酮对促性腺激素刺激的高反应性。其余三分之一的PCOS患者在抑制肾上腺雄激素分泌后，可通过睾酮升高检测到FOH。约3%的PCOS患者存在相关的孤立性功能性肾上腺雄激素过多症。其余的PCOS病例症状较轻，缺乏类固醇分泌异常的证据；其中大多数肥胖，我们推测这是导致其非典型PCOS的原因。大约一半有多囊卵巢形态（PCOM）的正常女性存在亚临床FOH相关的类固醇生成缺陷。经典PCOS患者多囊卵巢的卵泡膜细胞在长期培养中存在内在的类固醇生成失调，这可以解释FOH典型的类固醇生成异常。这些细胞过度表达大多数类固醇生成酶，尤其是细胞色素P450c17。通过全基因组关联筛查鉴定出的一种蛋白质，在正常和肿瘤发育中差异表达1A.V2，在正常卵泡膜细胞中的过表达在体外重现了这种PCOS表型。约一半的PCOS患者存在与肥胖相关和/或内在的胰岛素抵抗代谢综合征，代偿性高胰岛素血症具有组织选择性作用，包括加重高雄激素血症。PCOS似乎是一种复杂的性状，由多种遗传和环境因素相互作用导致。遗传因素包括PCOM、高雄激素血症、胰岛素抵抗和胰岛素分泌缺陷。环境因素包括产前雄激素暴露和胎儿生长不良，而获得性肥胖是主要的产后因素。所涉及的多种途径以及缺乏共同线索证明了该综合征的多因素性质和异质性。有必要对该疾病的根本基础进行进一步研究，以最佳地纠正雄激素水平、排卵和代谢稳态。
