Disturbances in insulin secretion and sensitivity in women with the polycystic ovary syndrome.

Insulin resistance, defined as a diminished effect of a given dose of insulin on glucose homeostasis, is a highly prevalent feature of women with PCOS. Insulin resistance in PCOS is closely associated with an increase in truncal-abdominal fat mass, elevated free fatty acid levels, increased androgens, particularly free testosterone through reduced SHBG levels, and anovulation. The causes for insulin resistance in PCOS are still unknown. One line of evidence suggests that an increase in truncal-abdominal fat mass and subsequently increased free fatty acid levels induce insulin resistance in women with PCOS. Increased effects of corticosteroids and a relative reduction in oestrogen and progesterone seem to be involved in the aberrant body fat distribution. Conversely, there are also results supporting primary, genetic target cell defects as a cause of insulin resistance in PCOS. An explanation for these seemingly contradictory results could be that the group of women with PCOS is heterogeneous with respect to the primary event in carbohydrate/insulin disturbances. Also insulin secretion in PCOS is characterized by heterogeneity. At one end of the spectrum is a large subgroup of mainly obese women with reduced insulin secretion, which appears to result from failure of the beta cells to compensate for insulin resistance in susceptible women, resulting in glucose intolerance and NIDDM. In the insulin-resistant patients with normal glucose tolerance, most of the hyperinsulinaemia is probably due to secondarily increased insulin secretion and decreased insulin degradation. However, a component of the increased first-phase insulin release is not due to measurable insulin resistance. Notably, this is also found in lean women with normal insulin sensitivity, and is not reversed after weight reduction, in contrast to the findings for insulin resistance. The implications of this enhanced insulin release are not fully clear, but it may tentatively be associated with carbohydrate craving and subsequently increased risks for development of obesity and insulin resistance. It may represent a primary disturbance of insulin secretion in PCOS or may be associated with the perturbed steroid balance in anovulation. The insulin-androgen connection in PCOS appears to be amplified by several different mechanisms, notably in both directions, the initiating event probably varying between individuals. Thus insulin increases the biological availability of potent steroids, primarily testosterone, through the suppression of SHBG synthesis. Insulin is also involved as a progonadotrophin in ovarian steroidogenesis, with the possible net result of interfering with ovulation and/or increasing ovarian androgen production in states of hyperinsulinaemia. Conversely, testosterone may indirectly contribute to insulin resistance through facilitating free fatty acid release from abdominal fat, but perhaps also through direct muscular effects at higher serum levels. It seems likely that this constitution, presumably genetic, would provide evolutionary advantages in times of limited nutrition, given the energy-saving effects of insulin resistance. Hypothetically, hyperinsulinaemia (primary) could provide a stimulus to ensure intake of nourishment, but unlimited food supplies could in some cases initiate a vicious 'anabolic' circle, in which several of the proposed amplifying mechanisms between insulin and androgens--in both directions--could take part.