Developmental origin of polycystic ovary syndrome - a hypothesis

Abstract

Polycystic ovary syndrome (PCOS) is a common but complex endocrine disorder and is a major cause of anovulation and consequent subfertility. It is also associated with a metabolic disturbance, characterized by hyperinsulinaemia and insulin resistance that carries an increased risk of type 2 diabetes in later life. Despite its prevalence little is known about its aetiology, but there is increasing evidence for an important genetic involvement. On the basis of experimental observations in the prenatally androgenized sheep and rhesus monkey, and supported by data from human studies, we propose that the clinical and biochemical features of PCOS can arise as a consequence of genetically determined hypersecretion of androgens by the ovary during, or very likely long before, puberty. The resulting hyperandrogenism results in 'programming' of the hypothalamic-pituitary unit to favour excess LH secretion, and encourages preferential abdominal adiposity that predisposes to insulin resistance. The severity of hyperinsulinaemia and insulin resistance (which has a profound influence on the phenotype of PCOS) is further influenced by both genetic factors (such as polymorphism in the insulin gene regulatory region) and environmental factors, notably obesity. This hypothesis therefore suggests a unifying, 'linear' model to explain the aetiology of the heterogeneous phenotype.

FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women

“…Again, a relevant environmental component (diet, exercise, etc.) contributes to PCOS pathogenesis [17], and PCOS is likely to result from the interaction of genetic with environmental (and maybe prevalent) factors.…”

Polycystic ovary syndrome in adolescents

“…We have proposed that PCOS is a genetically determined ovarian disorder characterized by excessive androgen production and that the heterogeneity of PCOS can be explained by the interaction of this disorder with environmental factors, notably dietary. 14,15 The basis of this hypothesis resides in the observations of Abbott and colleagues regarding the results of prenatal exposure of excess androgen in female Rhesus monkeys. These animals, exposed to high concentrations of testosterone in utero, develop, as adults, many of the typical features of PCOS such as hypersecretion of LH, ovarian hyperandrogenism, anovulation in relation to increased body weight and insulin resistance.…”

“…21 However, even if the foetal ovary does not produce significant amounts of androgen, the postulate is that the ovary is genetically predisposed to hyperscrete androgen when the hypothalamic-pituitary axis is activated physiologically, either in early post-natal life or at puberty (or indeed both). The consequences of this increased exposure to androgen include abnormalities of LH secretion, 22 and insulin secretion and action, 14,15 which manifest themselves during adolescence ( Figure 1). The idea that the genesis of PCOS is pre-pubertal is supported by the observations that polycystic ovarian morphology 23 and even clinical manifestations of androgen excess have been reported in pre-pubertal girls.…”

“…Insulin resistance is a common, but by no means invariable, feature of PCOS and although it is our contention that, in most cases of PCOS, there is an underlying, primary ovarian abnormality, there is clearly an important interaction of insulin resistance/hyperinsulinaemia with the ovarian disorder. 14 The clinical and biochemical abnormalities are amplified by overweight and obesity. 2,3 In a series of nearly 300 women with PCOS presenting to a single reproductive endocrine clinic, we found that the prevalence of hirsutism and of ovulatory dysfunction was significantly greater in overweight and obese women than in lean subjects.…”

The 2nd–4th digit ratio (2D:4D) and neck circumference: implications for risk factors in coronary heart disease

“…Thus, the WHR in women is positively correlated with serum levels of testosterone and negatively with women's 2D:4D 6 and the WHR of mothers is negatively related to the 2D:4D of their children. 9 WHR in female subjects appears to be directly linked to health and fertility as it has been shown to be an accurate predictor of risk for various diseases (e.g., Singh 10 and Abbott et al 11 ). In men, studies have shown that aging is accompanied by decreasing testosterone levels, which in turn decrease lean body mass and increase abdominal fat deposition.…”