An Evolutionary Model for the Ancient Origins of Polycystic Ovary Syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women, characterized by hyperandrogenism, oligo-anovulation and insulin resistance and closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutionary model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are affected by today's contemporary environment through epigenetic events that predispose women to lipotoxicity, with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today's obesogenic environment.

Keywords: adipocyte; adipose stem cells; body fat distribution; evolution; hyperandrogenism; insulin resistance; metabolic adaptation; polycystic ovary syndrome.

Figure 1

Polycystic ovary syndrome as an ancient metabolic-reproductive adaptation that originally enhanced fat storage for survival of humans during ancient times of food deprivation and also favored fewer offspring with a greater likelihood of childhood survival, but now predisposes women to endocrine-reproductive dysfunction in today’s obesogenic environment (16). Ancestral traits resembling PCOS also exist in female rhesus macaques [8,9,10], which share a common ancestor with humans through parallel evolution.

Figure 2

Schematic representation of adipogenesis in subcutaneous abdominal adipose stem cells (ASCs) from normal-weight women with polycystic ovary syndrome. Adipogenesis involves ASC commitment to preadipocytes, followed by an early/late stage preadipocyte differentiation to immature/mature adipocytes [85,86,87]. Dynamic changes in chromatin accessibility of SC abdominal ASCs during adipogenesis activate different transcriptional factors/genes (zinc-finger protein 423 (Zfp423), activator protein-1 (AP-1), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT enhancer binding protein a (CEBPα) and aldo-ketoreductase type 1C3 (AKR1C3), leading to increased free fatty acid (FFA) incorporation/biosynthesis, thus forming triglycerides (TGs) in newly-formed mature adipocytes. In this manner, SC adipose can increase its fat storage through enlargement of mature adipocytes (i.e., hypertrophy) and development of new adipocytes (i.e., hyperplasia) to buffer fatty acid influx as energy intake exceeds its expenditure [88,89].