Its main side effects are gastrointestinal upset and diarrhea. Lactic acidosis has been reported in patients who have renal or liver disease. Of the many studies of metformin use in women with PCOS, most7-16 but not all17-20 have demonstrated that a dose of 500 mg 3 times daily lowers circulating androgen levels, reduces weight, improves insulin resistance, or induces ovulation in women with PCOS.
If a patient achieves a 5% to 10% weight loss, I may stop treatment to see if she ovulates without the drug. I use menstrual history to assess efficacy.
In none of the trials was ovulation induced successfully in all women receiving metformin. In other words, certain subpopulations may be metformin-resistant. Nevertheless, metformin’s efficacy in improving insulin resistance and enhancing ovulation is overwhelming in nonmorbidly obese and lean women with PCOS. However, this agent may not be efficacious in women who are morbidly obese.19
As a first-line therapy, I use metformin in PCOS patients who do not wish to become pregnant and clomiphene citrate if the patient is trying to conceive (FIGURE).
Thiazolidinediones also are insulin-sensi-tizing agents, but work primarily in muscle and adipose tissue. These compounds stimulate peroxisome proliferator-activated receptor-γ, triggering the production of glucose transporter proteins.20
Of the 2 currently marketed thiazolidine-diones—pioglitazone and rosiglitazone—only the latter has been evaluated for treatment of women with PCOS.21,22 Preliminary reports suggest that rosiglitazone may improve insulin sensitivity, reduce serum androgen levels, and induce ovulation in women with PCOS.
Although my experience is limited, I give rosiglitazone when metformin fails to regulate menses or when the patient cannot tolerate metformin’s gastrointestinal side effects.
The primary side effect of the thiazolidinediones is liver toxicity. One agent, troglitazone, was removed from the market for this effect.
Extended use of insulin-sensitizing agents. There are no data on the long-term effects of insulin-sensitizing agents in women with PCOS. I reevaluate the patient 1 month after beginning therapy (to assess side effects and tolerability), 6 months later, and then annually.
If a patient achieves a 5% to 10% weight loss, I may stop treatment to see if she ovulates without the drug. I use menstrual history to assess efficacy.
If the patient’s baseline testosterone levels are elevated, I may also measure serum testosterone after 5 to 6 weeks of therapy to see if the levels are decreasing. Although another drug may come on the market at any time, I tend to think of metformin therapy as lasting at least until menopause.
TABLE 1
Insulin-sensitizing agents
| AGENT | DOSE | NOTABLE SIDEEFFECTS | MECHANISM OFACTION | PREGNANCY CATEGORY |
|---|---|---|---|---|
| Metformin | 1,500-2,000 mg/d | Gastrointestinal distress | Reduces glucose production in the liver | B |
| Thiazolidinediones | ||||
| Pioglitazone | 30-45 mg/d | Liver toxicity | Increases insulin sensitivity via peroxisome proliferator-activated receptor-γ (PPAR-γ) | C |
| Rosiglitazone | 4-8 mg/d | |||
2. Facilitate ovulation
Even women who do not desire fertility stand to gain by ending chronic anovulation, which increases the risk of endometrial cancer. Fortunately, a number of avenues are available.
Weight loss. Up to 70% of women with PCOS are obese and thus at increased risk for diabetes, hypertension, and cardiac disease. Numerous studies have shown that weight loss can lower circulating androgen levels and induce resumption of regular menstrual cycles. Surprisingly, only a modest weight loss—as little as 5% of initial weight—can produce these changes.23
Therefore, all obese women with PCOS should be advised to lose weight—not only to improve their chance for spontaneous ovulation, but for the multiple health benefits associated with weight loss itself.
Clomiphene citrate. Even improvements in insulin resistance not accompanied by weight loss can improve ovulation. For decades, clomiphene has been used as first-line therapy to induce ovulation in women with PCOS. It is a selective estrogen receptor modulator, exerting its effects at the level of the hypothalamus and pituitary gland, where it acts as an antagonist to the estrogen receptor. Blocking the negative feedback of estrogen in the hypothalamus and pituitary gland increases the production and release of follicle-stimulating hormone. This increase stimulates the development of secondary ovarian follicles and ultimately results in ovulation.
Clomiphene is not effective in hypoestrogenic women or those who lack a functionally normal hypothalamus and pituitary gland.
For women hoping to conceive, initiate clomiphene treatment in the early follicular phase and continue for 5 days. The starting dose is one 50-mg tablet per day. If ovulation does not occur, increase the dose by 50 mg in the next cycle, to 100 mg/d. If ovulation has not occurred by the time a daily dose of 150 mg is reached, response to higher concentrations is unlikely and the condition should be considered clomiphene-resistant.24 Approximately 15% of women with PCOS have clomiphene-resistant anovulation.25