Metformin for PCOS symptoms: 5 challenging cases
This inexpensive and versatile drug broadens the choices for treating polycystic ovary syndrome. An expert describes its efficacy for common manifestations of PCOS.
The combination of clomiphene and metformin was superior to clomiphene alone in inducing ovulation in women with PCOS, in 3 randomized clinical trials.26-28 In 1 trial, 56 infertile women with PCOS, oligoovulation, and resistance to clomiphene monotherapy received either metformin 850 mg twice daily or placebo for 1 month.28 The average BMI of the subjects was about 31. Metformin treatment was associated with a significant decrease in serum LH and testosterone concentration.
In the first month of the trial, 1 woman in the metformin group became pregnant. After the initial month, clomiphene citrate 100 mg daily for cycle days 4 to 7 was administered to both groups. In the metformin plus clomiphene group, 21 women (78%) ovulated, compared with 4 women (14%) in the placebo plus clomiphene group.
Early evidence suggests higher pregnancy rates. Data about the impact of metformin plus clomiphene on pregnancy and delivery rates in women with PCOS are limited. In 1 study, investigators reported that the pregnancy rate was 55% in women treated with metformin plus clomiphene compared with 7% in women treated with placebo plus clomiphene.26 In this study, women with PCOS who did not ovulate when treated with clomiphene (150 mg daily for 5 days) received either metformin (1,500 mg daily) or placebo for 7 weeks. During the initial 7-week treatment period, 1 of the 12 women in the metformin group and none of the 15 women in the placebo group ovulated.
After this initial treatment period, all women received clomiphene citrate, beginning at a dose of 50 mg daily for 5 days, with dosage escalation in the absence of ovulation. Nine of the 12 women in the metformin plus clomiphene group ovulated, compared with 4 of the 15 women in the placebo plus clomiphene group. Of the women who completed the clinical trial, 6 of 11 in the metformin plus clomiphene group became pregnant, compared with 1 of 14 in the placebo plus clomiphene group.
Another clinical trial demonstrated the merit of a trial of clomiphene plus metformin when ovulation does not occur with clomiphene alone, before advancing to a resource-intensive regimen such as gonadotropin therapy. Women were given either clomiphene plus metformin or gonadotropin injections.29 Pregnancy rates after both treatments were similar. However, the cost of treatment for the clomiphene plus metformin therapy was 25% that of gonadotropin therapy.
TABLE 2
Treatment of anovulatory infertility associated with PCOS: A stepwise approach
| STEP | INTERVENTION | COST | RISK OF MULTIPLE GESTATION |
|---|---|---|---|
| 1 | Weight loss (if baseline weight is elevated) | Low cost | Not increased |
| 2 | Clomiphene | Low cost | Modest increase (7% risk of twins, 0.5% risk of triplets) |
| 3 | Metformin alone | Low cost | Not increased |
| 4 | Clomiphene plus metformin | Low cost | Modest increase |
| 5 | Clomiphene plus glucocorticoid | Low cost | Modest increase |
| 6 | FSH injections | Resource-intensive | Significantly increased (20% risk of twins, 5% risk of triplets) |
| 7 | Ovarian surgery | Resource-intensive | Not increased |
| 8 | In vitro fertilization | Resource-intensive | Markedly increased (30% risk of twins, 4% risk of triplets; risk dependent on number of embryos transferred) |
| FSH = follicle-stimulating hormone | |||
Clinical courseRecommend alternatives to in vitro fertilization
At this point in her care, this patient should not be offered IVF treatment. IVF is a resource-intensive treatment that is associated with a high rate of multiple gestation. This patient could instead be directed to any of the low-resource options that she has not yet tried: weight loss, metformin monotherapy, or clomiphene plus a glucocorticoid or clomiphene plus metformin.30 Even though this patient is only slightly overweight (her BMI of 27.8 is near normal), losing weight sometimes restores ovulatory menses in women with PCOS.31- 35
Several clinical trials have reported that, in women with PCOS with a serum DHEAS higher than 2 μg/mL, clomiphene plus a glucocorticoid is more effective than clomiphene alone for inducing ovulation.36
Metformin plus clomiphene. In this case, you decide it would be helpful to give the patient metformin. The drug is initiated at a dose of 500 mg daily, to be taken with dinner. The metformin dose is increased over a period of weeks to a target dose of 500 mg 3 times daily (850 mg twice daily is another option). After 2 months of metformin therapy, you prescribe clomiphene 100 mg daily (50 mg daily is sometimes prescribed) for cycle days 5 to 9. The patient ovulates and becomes pregnant.
CASE 4
Treating PCOS during pregnancy
A 35-year-old woman with PCOS began taking metformin 500 mg 3 times a day for amenorrhea and infertility. She also started a diet and exercise plan, losing 45 lb during the first 6 months. She began to menstruate monthly and became pregnant. She asks if she should continue metformin during pregnancy.
Weigh risk versus benefit
Metformin is a category B drug and is not approved by the US Food and Drug Administration for use in pregnancy. Some clinicians who use metformin to treat diabetes continue the agent during pregnancy.37 However, many authorities recommend insulin as first-line therapy when medication is necessary during pregnancy, while others recommend using an agent that does not cross the placenta, such as glyburide.38
