Pharmacologic Treatment of Polycystic Ovary Syndrome

David A. Ehrmann, M.D.; Daniel Rychlik, M.D.

Disclosures

Semin Reprod Med. 2003;21(3) 

In This Article

Treatment of Associated Metabolic Abnormalities: Insulin Resistance and Glucose Intolerance

As discussed earlier, hyperinsulinemia is a key component in the pathogenesis of PCOS. This realization has provided the basis for advances in treatment strategies for women with the disorder. Weight reduction, when it can be achieved, is still an important component in the treatment of PCOS. However, not all women with PCOS are obese, and because the etiology of obesity in PCOS in not known, there is currently no effective manner to target this problem in PCOS. Pharmacologic reduction in insulin levels appears to offer another therapeutic modality for PCOS and is one that may ameliorate the sequel of both hyperinsulinemia and hyperandrogenemia.

At least five different modalities have been used to lower insulin levels in PCOS. These include weight loss, diazoxide, and more recently metformin, the thiazolidinediones (pioglitazone and rosiglitazone; troglitazone is no longer available for use), and D-chiro-inositol.

Both metformin and the thiazolidinediones effect reductions in insulin levels, but they do so by fundamentally different mechanisms. Metformin is a disubstituted biguanide that, when administered to obese or lean subjects with type 2 diabetes, appears to reduce fasting glucose concentrations as well as improve oral glucose tolerance. This improved glucose tolerance usually occurs with a modest reduction of concomitantly measured plasma insulin levels. Although there is some modest improvement in glucose disposal rate with metformin, the primary mechanism of action appears to be its effect on reducing hepatic glucose output.[52]

The thiazolidinediones are a class of antidiabetic drugs that improve the action of insulin in the liver, skeletal muscle, and adipose tissue. These compounds act primarily as ligands for the nuclear peroxisome proliferator activated receptor γ (PPAR-γ), which, when activated, enhances transcription of a host of factors that promote glucose disposal in fat and muscle. Numerous human studies have demonstrated that thiazolidinediones improve both fasting and postprandial hyperglycemia in subjects with type 2 diabetes. In contrast to the effects observed with metformin, the thiazolidinediones have a major impact on glucose disposal rate, with a modest effect on hepatic glucose output. As such, the thiazolidinediones are most appropriately viewed as true insulin-sensitizing agents.

The first study in which metformin was administered to test the hypothesis that androgen reduction follows from insulin reduction was that of Velazquez et al.[48] In that study, metformin was administered to 26 women with PCOS (500 mg three times daily for 8 weeks) and resulted in a significant reduction in total testosterone, free testosterone, and free androgen index as well as a significant rise in SHBG in comparison with pretreatment levels. These changes were associated with reductions in insulin responses to oral glucose administration and in the "insulogenic index" (defined as the ratio of insulin to glucose response after oral glucose administration). It is important to note that the subjects in this study lost weight, which was a likely contributor to the reduction in insulin secretion on repeated oral glucose tolerance test (OGTT). As a result, the effect of metformin upon insulin secretion could not be clearly separated from that of weight loss.

To circumvent the confounding effects of weight reduction on both insulin secretion and androgen levels, we treated 14 obese, nondiabetic women with PCOS with metformin for a 3-month period during which body weight was maintained and compared their ability to respond to oral and intravenous glucose challenges before and after treatment. In addition, we examined the ovarian steroidogenic response to leuprolide before and after metformin. We found that both the glucose and insulin responses to an oral glucose challenge and the profound insulin resistance of obese women with PCOS were not improved by metformin.[53] These findings were in contrast to those of Nestler and Jakubowicz,[54] who found, in a study of similar design, that the area under the serum insulin curve decreased by 53% after oral glucose administration and was associated with a reduction in both the basal and leuprolide-stimulated serum 17-hydroxyprogesterone concentration. None of these values changed significantly in women who received placebo. A number of additional studies have been published that examine the effects of metformin in women with PCOS as reviewed by Nestler et al.[55]

As discussed previously, metformin has been administered to obese women with PCOS in an attempt to determine whether the ovulatory response to clomiphene would be enhanced by reduction in insulin levels (see earlier). In this study, 61 women with PCOS (one half of whom who had been previously treated with clomiphene without response) were randomly assigned to receive either placebo or metformin (500 mg twice daily) for 1 month. Women who did not ovulate spontaneously, as defined by a serum progesterone above 8 ng/mL, were then given 50 mg of clomiphene daily for 5 days while continuing to take metformin or placebo. Among those who received metformin plus clomiphene, there was a significant (p = 0.03) reduction in the mean area under the serum insulin curve after oral glucose administration from 6745 ± 2021 to 3479 ± 455 µU/mL per minute, which was associated with an ovulatory response rate of 90% compared with an 8% response rate in those who took placebo in concert with clomiphene (p < 0.001). Of note, however, was the lack of reduction in free testosterone in the metformin-treated group. One may infer from these results that metformin could act to enhance ovulation without changing the steroid milieu.

Although fewer studies have been performed using the thiazolidinediones in PCOS, the results of these studies have been highly consistent. Dunaif et al[56] have documented that improvement of insulin resistance by administration of troglitazone, an insulin-sensitizing agent in the thiazolidinedione class of drugs, results in attenuation of hyperinsulinemia and hyperandrogenemia in obese women with PCOS. This improvement in insulin sensitivity was reflected in a reduction of the fasting insulin concentration, 2-hour insulin concentration, and integrated insulin response to a 75-g oral glucose challenge. In addition, there was a significant improvement in the insulin sensitivity index (Si) derived from a rapidly sampled intravenous glucose tolerance test.

We[57] administered troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates the metabolic abnormalities of the syndrome. Before and after treatment with troglitazone, 400 mg daily for 12 weeks, all had a GnRH agonist (leuprolide) test, an OGTT, a frequently sampled intravenous glucose tolerance test (IVGTT), an oscillatory glucose infusion to assess beta cell function, and measures of fibrinolytic capacity, including plasminogen activator inhibitor type 1 (PAI-1). There was no change in body mass index or body fat distribution after treatment. Both the fasting (91 ± 3 versus 103 ± 3 mg/dL; p < 0.001) and 2-hour (146 ± 8 versus 171 ± 6 mg/dL; p < 0.02) plasma glucose concentrations during the OGTT declined significantly. Insulin sensitivity improved significantly. Basal levels of total testosterone and free testosterone declined significantly after troglitazone treatment, as did leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone. Beta cell function also improved as reflected by an enhanced ability to "entrain" insulin secretion in response to an oscillatory glucose infusion. Decreased functional activity of PAI-1 in blood was also observed.

The realization that hyperinsulinemia is a key component in the pathogenesis of PCOS has thus provided the basis for these advances in treatment strategies for women with the disorder. Weight reduction, when it can be achieved, is still an important component in the treatment of PCOS. However, not all women with PCOS are obese, and because the etiology of obesity in PCOS in not known, there is currently no effective manner to target this problem in PCOS. Pharmacologic reduction in insulin levels appears to offer another therapeutic modality for PCOS and is one that may ameliorate the sequel of both hyperinsulinemia and hyperandrogenemia. However, additional studies and long-term follow-up of patients so treated are necessary before these agents can be considered first-line treatment for PCOS.

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