Reconsidering the Polycystic Ovary Syndrome (PCOS)

Abstract

Though likely the most common clinical diagnosis in reproductive medicine, the Polycystic Ovary Syndrome (PCOS) is still only poorly understood. Based on previously published research, and here newly presented supportive evidence, we propose to replace the four current phenotypes of PCOS with only two entities-a hyperandrogenic phenotype (H-PCOS) including current phenotypes A, B, and C, and a hyper-/hypoandrogenic phenotype (HH-PCOS), representing the current phenotype D under the Rotterdam criteria. Reclassifying PCOS in this way likely establishes two distinct genomic entities, H-PCOS, primarily characterized by metabolic abnormalities (i.e., metabolic syndrome) and a hyperandrogenic with advancing age becoming a hypoandrogenic phenotype (HH-PCOS), in approximately 85% characterized by a hyperactive immune system mostly due to autoimmunity and inflammation. We furthermore suggest that because of hypoandrogenism usually developing after age 35, HH-PCOS at that age becomes relatively treatment resistant to in vitro fertilization (IVF) and offer in a case-controlled study evidence that androgen supplementation overcomes this resistance. In view of highly distinct clinical presentations of H-PCOS and HH-PCOS, polygenic risk scores should be able to differentiate between these 2 PCOS phenotypes. At least one clustering analysis in the literature is supportive of this concept.

Keywords: Polycystic Ovary Syndrome (PCOS); androgens; hyperactive immune system; infertility; on vitro fertilization (IVF); phenotype D.

Figure 1

Schematic of androgen decline with advancing age in PCOS and non-PCOS women. The figure demonstrates androgen levels in phenotypes A, B, and C until menopause remain high in comparison to androgens in non-PCOS patients. Phenotype D, however, over approximately 10 years between ages 25–35, goes from hyper- to hypoandrogenism, at which point this phenotype becomes relatively resistant to infertility treatments, a resistance that, as shown in this manuscript, can be reversed through androgen supplementation.