Between 40 and 70 percent of women with polycystic ovary syndrome (PCOS) have functional adrenal hyperandrogenism (FAH) caused by hyper-responsiveness to adrenocorticotropic hormone (ACTH). Insulin has been suggested as the chemical responsible for ovarian and adrenal dysregulation, resulting in hyperandrogenism. Insulin-sensitizing agents, such as metformin, decrease insulin levels and reduce ovarian hyperandrogenism in women with PCOS. Obese adolescents with PCOS are at high risk for developing type 2 diabetes mellitus because of severe insulin resistance and high circulating levels of insulin; however, metformin can reduce insulinemia and decrease FAH. Arslanian and associates studied the effect of three months of metformin treatment on glucose tolerance, insulin sensitivity and concentrations, and ACTH-stimulated adrenal androgen activity.

Fifteen obese adolescents with PCOS and impaired glucose tolerance who were being evaluated for either irregular menses or hirsutism and acne were given metformin in a dosage of 850 mg per day for one to two weeks, after which the dosage was increased to 850 mg twice daily. Data on clinical characteristics, body composition, and metabolic and hormonal tests were collected before and after intervention.

After three months of treatment with metformin, body mass index (BMI) improved because of an increase in height among subjects and, to a lesser degree, a decrease in weight. Abdominal adipose tissue decreased slightly and significantly. Side effects, when present, were mild and transient. Results of oral glucose tolerance tests improved significantly and normalized in eight of the 15 subjects. Insulin concentrations dropped significantly, with evidence of improved hepatic insulin sensitivity. No significant change occurred in any lipid parameter. Total and free testosterone levels decreased significantly, and six patients reported improvement in menstrual cyclicity. Hormone response to ACTH stimulation was significantly reduced after treatment.

The authors conclude that in obese adolescents with PCOS and impaired glucose tolerance, metformin can improve glucose tolerance and insulin sensitivity, reduce insulinemia, and lower elevated androgen levels. The drop in the exaggerated adrenal response to ACTH stimulation with treatment may correct FAH. The side effects of three months of metformin treatment are minimal and easily tolerated. Further blinded, placebo-controlled studies are needed to confirm these effects of metformin.

editor's note: The hyperandrogenism and chronic anovulation of PCOS make this condition a common cause of infertility that affects up to 6 percent of women of reproductive age. Because regular menses and ovulation resume with metformin therapy, Heard and associates studied pregnancy outcomes in anovulatory infertile women with PCOS who were treated with metformin. This study included some women who reported previous treatment with clomiphene citrate and some who did not. Forty-eight patients began taking metformin at a dosage of 500 mg twice daily for six weeks, and the dosage was increased to 500 mg three times daily if there was no ovulatory response. After six weeks on the highest dosage of metformin with no response, 50 mg per day of clomiphene citrate was added to the metformin regimen for a maximum of six cycles. An ovulatory response (based on midcycle monitoring of luteinizing hormone) occurred in 40 percent of patients with metformin alone, and 60 percent responded after the addition of low-dose clomiphene. After three months of treatment, 20 women conceived. Side effects of metformin were self-limiting, but 10 percent of patients had to reduce the dosage. Further studies are needed to evaluate the role of metformin as a fertility drug.—r.s.