Current concepts of polycystic ovary syndrome pathogenesis

This review provides a model for understanding polycystic ovary syndrome (PCOS) pathophysiology and updates the evidence on which it is based. Then, it highlights complimentary molecular genetic and epigenetic advances in understanding PCOS cause.

Important studies into PCOS cause built on the 2014 discovery of a novel regulatory protein variant that underlies the typical PCOS steroidogenic abnormalities: DENND1A.V2 (differentially expressed in normal and neoplastic development, isoform 1A, variant 2). Over 30 DENND1A gene variants have been found, the vast majority upstream of the coding sequence and potentially regulatory. These variants are individually uncommon but collectively plausibly cause 50% of PCOS. Anti-Müllerian hormone (AMH)/AMH receptor variants with decreased function possibly cause 6.7% of PCOS. DENNND1A was recently reported to belong to a signaling network that upregulates luteinizing hormone receptor expression and insulin mitogenic signaling. Prenatal androgen administration has proven to be a potent epigenetic regulator that causes transgenerational epigenomic changes in a mouse PCOS model with similarities to those in human PCOS and PCOS daughters.

In addition to finding how gene variants contribute to PCOS pathogenesis, better understanding of androgen epigenetic mechanisms of action in diverse tissues can be expected to expand our understanding of PCOS pathogenesis.