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 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.

Figure 1.

Hypothetical maternal and fetal contributions to in utero female androgen excess reprogramming for a hyperandrogenic female offspring.

Figure 2.

Hypothetical target sites for androgen receptor mediated in utero androgen excess female fetal reprogramming for reproductive and metabolic PCOS-like traits.