Review: Fetal Programming of Polycystic Ovary Syndrome by Androgen Excess — Evidence from Experimental, Clinical and Genetic Association Studies

Abstract

ObjectivePolycystic ovary syndrome (PCOS) is a common endocrine disorder of premenopausal women, characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance and abdominal obesity as frequent metabolic traits. Although, PCOS manifests clinically during adolescence, emerging data suggest that the natural history of PCOS may originate in intrauterine life. Evidence AcquisitionEvidence from experimental, clinical, and genetic research supporting the hypothesis for the fetal origins of PCOS has been analyzed. Evidence SynthesisFemale primates, exposed in utero to androgen excess, exhibit the phenotypic features of PCOS during adult life. Clinical observations also support a potential fetal origin of PCOS. Women with fetal androgen excess disorders, including congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors, develop features characteristic of PCOS during adulthood despite the normalization of androgen excess after birth. The potential mechanisms of fetal androgen excess leading to a PCOS phenotype in humans are not clearly understood. However, maternal and/or fetal hyperandrogenism can provide a plausible mechanism for fetal programming of PCOS, and this, in part, may be genetically determined. Thus, genetic association studies have indicated that common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgens to target tissues are associated with PCOS and increased androgen levels. These genomic variants may provide the genetic link to prenatal androgenization in human PCOS. ConclusionPrenatal androgenization of the female fetus induced by genetic and environmental factors, or the interaction of both, may program differentiating target tissues toward the development of PCOS phenotype in adult life. ABSTRACT ObjectiveTo perform a review and meta-analysis of the studies evaluating the status of serum inflammatory markers in women with polycystic ovary syndrome (PCOS). DesignSystematic review and meta-analysis of articles published in English before January 2010 and identified using the PubMed search engine. SettingAcademic hospital. Patient(s)Women with PCOS and appropriate controls. Intervention(s)Measurement of serum concentrations of inflammatory markers by high-sensitivity techniques. Main Outcome Measure(s)Meta-analyses of the mean difference in serum C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations among patients with PCOS and appropriate controls, applying random-effects models to limit interstudy variability and using appropriate estimates of evidence dissemination bias. Result(s)Meta-analysis of the 31 articles meeting inclusion criteria showed that circulating CRP was 96% higher in women with PCOS compared to controls (95% confidence interval, 71%-122%; z = 7.32) without evidence of dissemination bias (Egger's regression intercept, 0.45; 95% confidence interval, -2.30 to 3.21). These findings persisted after excluding five studie...

Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters

“…Different animal models have demonstrated that experimentally induced prenatal androgen excess in female fetuses results in changes that, in adulthood, resemble those observed in PCOS women (9,11,37). However, for the mother to provide a potential source of androgen excess to the fetus, the placental androgenmetabolizing capacity has to be exceeded.…”

A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells

“…Exposure to androgen excess can induce a permanent PCOS-like phenotype in adult female mammals [2,3]. Evidence has emerged that ovarian hyperandrogenism can disrupt follicle growth [4].…”

Perinatal Androgenic Exposure and Reproductive Health Effects Female Rat Offspring

“…Exposure to excess androgens during fetal or prepubertal life may induce alterations in the ovary, such as polycystic ovary syndrome (Xita and Tsatsoulis, 2006), increased follicular recruitment (Steckler et al, 2005), and follicular persistence (Manikkam et al, 2006). Sotomayor-Zárate et al (2011) found that exposure to TP at a dose of 1 mg to female rats during the first 12 h of life reduced the number of ovarian follicles, increased cystic follicles, and produced absence of corpora lutea.…”