Resistance and the Polycystic Ovary Syndrome
The polycystic ovary syndrome (PCOS) is a prevalent disorder
affecting ~6-10% of women of reproductive age (i.e., between 3.5-5.0
million women in the U.S.), and is characterized by chronic
anovulation and hyperandrogenism. A frequent feature of women with
PCOS is insulin resistance accompanied by compensatory
hyperinsulinemia, and increasing evidence suggests that
hyperinsulinemia plays an important role in the pathogenesis of PCOS.
Hyperinsulinemia produces hyperandrogenism in women with PCOS via
two distinct and independent mechanisms: 1) by stimulating ovarian
androgen production, and 2) by directly and independently reducing
serum SHBG levels. The net result of these actions is to increase
circulating free testosterone concentrations. An inherent (genetically
determined) ovarian defect likely is present in women with PCOS,
which makes the ovary either susceptible to or more sensitive to
insulin's stimulation of androgen production. Limited evidence
suggests that hyperinsulinemia might also promote ovarian androgen
production by influencing pituitary release of gonadotropins, but
this has not been critically evaluated.
In addition to promoting hyperandrogenism, recent evidence indicates
that hyperinsulinemia contributes to the anovulation of PCOS.
Hyperinsulinemia could adversely affect folliculogenesis and impede
ovulation by increasing intra ovarian androgen production, altering
gonadoropin secretion, or directly affecting follicular development.
The relationship of hyperinsulinemia to PCOS is important from a
clinical standpoint, because: 1) it dictates that women with PCOS
need to be evaluated for other disorders associated with insulin
resistance (type 2 diabetes mellitus, hypertension, dyslipidemia,
atherosclerosis), and 2) it suggests that medications that reduce
circulating insulin might prove to be effective therapies for PCOS.
Indeed, several studies have demonstrated that 30-50% of obese women
with PCOS will develop either IGT or Type 2 diabetes by the age of
30. Conversely, in a recent study of the Diabetes Clinic at Virginia
Commonwealth University, we found that 28% of premenopausal women
with Type 2 diabetes had PCOS, with a quarter of them being
undiagnosed. Studies have also documented early (premature) plaques
in the coronary arteries of 35-40 year-old women with PCOS.
Confirming the important role of hyperinsulinemic insulin resistance
in the pathogenesis of PCOS, insulin reduction, whether achieved by
inhibition of pancreatic insulin release (diazoxide or octreotide)
or improvement in peripheral insulin sensitivity (metformin,
troglitazone or D-chiro-inositol), is associated with a reduction
in circulating androgens in women with PCOS, an improvement in
ovulatory function, and enhanced fertility.
Limited evidence also suggests that agents that improve insulin
sensitivity might also favorably affect those complications of PCOS
that may be attributable to insulin resistance – for example, such
treatments may reduce blood pressure, serum triglycerides and
circulating PAI-1 concentrations. The recent results of the
NIH-sponsored Diabetes Prevention Project, which showed that either
intensive lifestyle modification (diet and exercise) or treatment
with the insulin sensitizing drug metformin decreased the
development of Type 2 diabetes in individuals at high risk, lends
further credence to the idea that treatment of women with PCOS with
insulin sensitizing drugs may have long-term salutary effects on
Thus, in the past 16 years, progress in characterizing the
relationship between insulin and PCOS has been substantial, pointing
the way to new and novel therapy of PCOS. While many questions
remain, clearly sufficient evidence has accumulated to justify
clinical use of insulin- sensitizing agents in the management of
women with PCOS.