Type 2 Diabetes, Cardiovascular Disease, and the Evolutionary Paradox of the Polycystic Ovary Syndrome: A Fertility First Hypothesis

Worldwide, the high prevalence of the Polycystic Ovary Syndrome (PCOS), a heritable cause of ovarian infertility, is an evolutionary paradox, which provides insight into the susceptibility of well-fed human populations to cardiovascular disease and diabetes. We propose that PCOS, Type 2 diabetes (T2D) and the Metabolic Syndrome are modern phenotypic expressions of a metabolic genotype attuned to the dietary and energetic conditions of the Pleistocene. This metabolic "Fertility First" rather than "Thrifty" genotype persisted at high prevalence throughout the entire agrarian period - from around 12,000 years ago until 1800 AD - primarily, we contend, because it conferred a fertility advantage in an environment defined by chronic and often severe seasonal food shortage. Conversely, we argue that genetic adaptations to a high carbohydrate, low protein agrarian diet, with increased sensitivity to insulin action, were constrained because these adaptations compromised fertility by raising the lower bound of body weight and energy intake optimal for ovulation and reproduction. After 1800, the progressive attainment of dietary energy sufficiency released human populations from this constraint. This release, through the powerful mechanism of fertility selection, increased, in decades rather than centuries, the prevalence of a genotype better suited to carbohydrate metabolism. This putative mechanism for rapid and recent human evolution can explain the lower susceptibility to T2D of today's Europid populations. This hypothesis predicts that the increasing rates of diabetes and cardiovascular disease, which typically accompany economic development, will be tempered by natural, but particularly fertility, selection against the conserved ancestral genotypes that currently underpin them