- Women with PCOS and insulin resistance are at increased risk for impaired glucose tolerance or diabetes. Hypoglycemic agents can reduce circulating androgen levels, increase sex hormone binding globulin, facilitate weight loss, and induce ovulation.
- Take steps to enhance or induce ovulation. Even women who do not desire fertility stand to gain, because chronic anovulation increases the risk of endometrial cancer.
- Address hirsutism and other hyperandrogenic effects. Treatment of hirsutism is best approached with a combination of medical and mechanical means. Counsel patients that response is likely to be slow and subtle.
Managing PCOS has always been a complex process, due to the wide range of troubles experienced by patients with this disorder. An effective treatment strategy should address the 3 clinical challenges typical of the syndrome:
- insulin resistance,
- menstrual irregularities associated with anovulation, and
- hyperandrogenic symptoms such as hirsutism.
Here, I review recent findings—including new data on the use of insulinsensitizing agents for hyperinsulinemia—and offer a practical guide, complete with algorithm (FIGURE), for managing women with PCOS.
PCOS: A diagnosis of exclusion
PCOS clearly is a common cause of hirsutism and anovulation and is associated with intrinsic insulin resistance in many women. This disorder affects up to 6% of reproductiveage women and tends to develop shortly after menarche.
Although there is considerable disagreement about diagnostic criteria, most clinicians rely on the 1990 National Institutes of Health (NIH) Consensus Conference guidelines.1 These include clinical or biochemical evidence of hyperandrogenism and ovulatory dysfunction, and the absence of other causes. Thus, at present, PCOS is a diagnosis of exclusion.
Surprisingly, ultrasound visualization of “polycystic” ovaries is not one of the diagnostic criteria for PCOS. That is because women who have polycystic ovaries are not necessarily anovulatory. Conversely, the ovaries of women who meet the NIH criteria for PCOS may not appear to be polycystic.
1. Treat insulin resistance
Insulin exerts its primary effects in the liver, signaling the organ to reduce glycogenolysis and gluconeogenesis. Insulin also affects muscle, adipose tissue, and other organs, where it increases glucose uptake.
Insulin resistance—a reduction in the tissue response to insulin—affects one third to one half of all women with PCOS and leads to compensatory hyperinsulinemia.2 Although the obesity associated with PCOS may exacerbate insulin resistance, even lean PCOS patients can be affected.3
Insulin augments the stimulating effect of luteinizing hormone on the growth and androgen secretion of ovarian theca cells and inhibits the production of sex hormone binding globulin. For this reason, women with PCOS and insulin resistance are at increased risk for betacell dysfunction and subsequent impaired glucose tolerance or diabetes. Thus, it is not surprising that oral hypoglycemic agents have been used to treat these patients. In fact, numerous studies have demonstrated that oral hypoglycemic agents can reduce circulating androgen levels, increase sex hormone binding globulin, facilitate weight loss, and induce ovulation in these women.
Measure tissue response. The “gold standard” for assessing insulin sensitivity is the hyperinsulinemic-euglycemic clamp. Unfortunately, because it requires a constant intravenous infusion of insulin, this technique is not clinically practical.
Fortunately, many other methods are available to assess insulin sensitivity, including the insulin tolerance, oral glucose tolerance, and fasting insulin tests. One method that has gained popularity is the fasting glucose:insulin ratio.4 However, there are clear ethnic and racial differences in the normal values for this test. Since these values are not available for all subpopulations, the usefulness of this study is limited.2
Nevertheless, assessing a woman’s fasting plasma glucose helps determine whether she has impaired glucose tolerance. The National Diabetes Association defines diabetes as a fasting plasma glucose level of 126 mg or more per deciliter on 2 separate occasions; impaired glucose tolerance is defined as a fasting plasma glucose level between 110 mg and 126 mg per deciliter. Since impaired glucose tolerance is a risk factor for the development of diabetes, this test is useful in populations at risk.
Metformin’s efficacy in improving insulin resistance and enhancing ovulation is overwhelming in nonmorbidly obese and lean women with PCOS.
I use fasting plasma glucose to assess glucose tolerance and screen for diabetes mellitus. However, as neither serum insulin levels nor impaired glucose tolerance are predictive of response to insulinsensitizing agents, I do not use the results to determine who should receive these drugs.
Choose the appropriate agent. Oral hypoglycemic agents are classified by type, each of which affects a different area in the glucose metabolism scheme.
- Sulfonylureas, which have been available since the 1950s, reduce glucose levels by stimulating the release of insulin.5 Sulfonylureas may cause hypoglycemia and have not been studied in women with PCOS.
- α-glucosidase inhibitors slow or block the breakdown of starches and sugars in the gastrointestinal tract, thereby reducing the absorption of glucose.
- Insulin-sensitizing agents work through various mechanisms (TABLE 1). Like the α-glucosidase inhibitors, they rarely cause hypoglycemia. Since insulin resistance is likely to lead to impaired glucose tolerance and subsequent type 2 diabetes, insulin-sensitizing agents make good clinical sense.