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.