There is a well-recognized association between hyperinsulinemia (insulin resistance) and anovulatory hyperandrogenemia (PCO), especially in obese women. Metformin, an oral agent used to treat diabetes mellitus, decreases hepatic glucose production and improves insulin sensitivity. Treatment with metformin reduces hyperinsulinemia, LH levels and free testosterone concentrations in overweight women with PCO. Non-obese women with hyperinsulinemia may also show a clinical response when treated with metformin, and anovulatory patients may ovulate or improve their response to clomiphene.

Pretreatment Laboratory Tests
Tests include fasting glucose and insulin; creatinine and LFTs; prolactin, LH, FSH and TSH if not already done. A fasting glucose to insulin ratio of less than 4:1 may be a useful indicator for metformin use.

Dosage and Administration
The optimal dosage of PCOs has not been established for ovulation induction purposes. Nestler (NEJM 338:1876, 1998) suggests 1500 mg per day in divided doses. During the first week, take one pill (500 mg) with dinner. During the second week, add a second pill with breakfast. During the third week, add a third pill with lunch.

If, after eight weeks, there is no significant weight loss (less than four pounds) or no resumption of normal menstrual periods, the dose of metformin can be increased to 850 mg. After an additional six to eight weeks, induce withdrawal bleeding with 10 mg of Provera per day for 10 days. On the fifth day of withdrawal bleeding, start Clomiphene at 100 mg per day for five days, and measure serum progesterone on days 21 and 28 after the initiation of withdrawal bleeding. If there is no ovulatory response, discontinue the Metformin treatment.

Side Effects and Safety
No safe dosages have been established for healthy young women. Metformin is classified as pregnancy Category B. Some physicians use metformin during pregnancy to decrease the risk of miscarriage, but there is no data showing the effectiveness of this approach.
GI side effects are correlated with the dosage. Nausea and/or loose stools are common with dosages above 1,000 mg per day. These subside within one month in most, but not all, women.


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