In utero Androgen Excess: A Developmental Commonality Preceding Polycystic Ovary Syndrome?

Abstract

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 towards developmental fetal origins. Given that PCOS is familial and highly heritable, difficulty in discerning genetic contributions to PCOS pathogenesis is puzzling and, to date, accounts for <10% of PCOS presentations. Unaccounted heritability notwithstanding, molecular commonality in pathogenic mechanism is emerging, suggested by co-occurrence of replicated PCOS genetic variants and epigenetic alterations in DNA methylation at the same replicated, PCOS risk loci with bioinformatics-identified gene loci within monkey epigenetic alterations in DNA methylation array-determined gene networks from females exposed to testosterone (T) in utero. In addition, naturally occurring female hyperandrogenism in monkeys singles out females 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 PCOS, as well as a developmental origin, but also common molecular pathogenesis extending beyond humans.