J Endocrinol Invest. 1998 Oct;21(9):589-601
Polycystic ovary syndrome and insulin resistance: thrifty genes struggling with over-feeding and sedentary life style?
Department of Obstetrics and Gynaecology, Uppsala University, Akademiska Hospital, Sweden.
Almost two decades of research have greatly increased our knowledge in the complex field of metabolic aberrations in polycystic ovary syndrome, but still many problems remain unsolved. The statistical association between insulin levels and androgens originally put the focus on possible direct cause-and-effect relationships between these factors. Indeed there is evidence that insulin may affect ovarian functions in multiple ways, presumably in some cases causing anovulation and hyperandrogenism. Clearly, insulin may increase biologically active testosterone through reducing SHBG levels. Conversely, major increases in androgen levels may induce muscular changes leading to reduced insulin-mediated glucose uptake. There are suggestions of increased steroidogenesis in both ovarian and adrenal pathways, with the net result of increased androgen production. There are also findings supporting increased corticosteroid production, which could contribute to insulin resistance directly or through promoting accumulation of abdominal fat, a typical feature of over-weight women with PCOS. Free fatty acids, released in great amounts from abdominal fat, may induce insulin resistance. Insulin resistance may also be due to a primary aberration in the insulin receptor. Putatively increased serine phosphorylation may cause both impairment of the insulin signal and increased 17,20 lyase activity, thus suggesting a common cause for insulin resistance and increased androgen production. There are also findings supporting a high prevalence of beta-cell dysfunction in PCOS, ranging from increased insulin secretion, not explained by insulin resistance or BMI, to failing beta-cell function, mainly in obese women during progress to glucose intolerance and NIDDM. Recent genetic findings also support a multifactorial genesis to PCOS, notably with positive findings both in genes regulating steroidogenesis and insulin secretion. It is suggested that PCOS is the result of “thrifty” genes, providing advantages in times of shortage of nutrition such as muscular strength, moderate abdominal fatness and decreased insulin sensitivity, i.e. an anabolic, energy saving constitution. However, when this constitution is exposed to unlimited food supplies and modern sedentary life style a full-blown PCOS with insulin resistance and infertility is triggered, presumably via several mechanisms, which follow a logical amplification system between two basic anabolic hormones, insulin and testosterone.