Clomiphene, Metformin, or Both
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but clomiphene should be first-line treatment.
Source: Legro RS, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. New Engl J Med. 2007;356:551-566.
Legro and colleagues, reporting for the Cooperative Multicenter Reproductive Medicine Network, presented the results of a multicenter, randomized trial indicating that clomiphene is superior to metformin in achieving live births in women with the polycystic ovary (PCO) syndrome.1 Two hundred and nine women with PCO were randomized to clomiphene (50 to 150 mg per day for 5 days), 208 women received the extended-release form of metformin (2000 mg per day), and 209 women were given both drugs; the treatment limit was 6 cycles.
| Clomiphene | Metformin | Both | |
| Live-birth rate | 22.5% | 7.2% | 26.8% |
| Multiple pregnancies | 6.0% | 0% | 3.1% |
| Conception rate | 29.7% | 12.0% | 38.3% |
| Average BMI | 36.0 | 35.6 | 34.2 |
Commentary
Small studies previously concluded that metformin administration to women with PCO who are resistant to clomiphene yielded an increase in pregnancy rates.2, 3 A randomized trial of 100 women with PCO in Italy observed similar ovulation rates comparing metformin with clomiphene treatment, but a greater live-birth rate was recorded in the metformin group because of a higher spontaneous abortion rate associated with clomiphene.4 The Italian study was noteworthy in that the subjects were not obese and likely had a low prevalence of insulin resistance, making the outcome even harder to explain when comparing it with the American trial.
In the American trial, the subjects were considerably overweight, and the rate of live births progressively decreased with increasing body weight. Nevertheless, the superiority of clomiphene treatment was observed in all weight groups. Of the metformin group, 45% failed to achieve a single ovulation compared with 24.9% in the clomiphene group. Although the average fasting insulin levels were elevated, the standard deviations were very high, consistent with the known variability in this measurement. More importantly, the calculated insulin resistance was similar in the 3 groups. Metformin treatment caused a small loss of weight and improved insulin sensitivity, but despite this beneficial change, there was no advantage in live births.
A possible explanation for the better outcome with clomiphene is that clomiphene treatment is associated with multiple follicle development as evidenced by the increase in multiple pregnancies. There still may be a role for metformin; an increased rate of pregnancy complications in the clomiphene group, especially gestational diabetes and preeclampsia, suggests a role for metformin treatment throughout pregnancy in overweight women with insulin resistance.
Two other recent randomized trials agree with the American results. A 6-month, multicenter study of 228 women in the Netherlands compared the effect of adding metformin or placebo to clomiphene treatment.5 There were no differences in ovulation rates, ongoing pregnancy rates, or spontaneous abortion rates; in other words, metformin did not improve the response to clomiphene. A Canadian study of 154 women reported higher ovulation rates with first-line metformin treatment, but the pregnancy rates were similar comparing metformin-alone, clomiphene-alone, and both drugs in combination.6
Two small randomized trials, only 21 women in Turkey and 26 women in the U.K., also did not find any improvement in ovulation and pregnancy rates when metformin was added to clomiphene treatment.7, 8
The bottom line is that metformin treatment improves insulin sensitivity and lowers androgen levels, important achievements in terms of reducing the risk of the long-term consequences of diabetes mellitus and cardiovascular disease in anovulatory women with insulin resistance. But the evidence from recent clinical trials of respectable size fails to demonstrate any live-birth advantage of metformin treatment for infertility. It seems to me that it remains reasonable to add metformin when women with insulin resistance are unable to achieve pregnancy with multiple cycles of clomiphene treatment. Based on the new evidence, first-line treatment should be clomiphene.
References
- Legro RS, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. New Engl J Med.2007;356:551-566.
- Nestler JE, et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New Engl J Med. 1998;338:1876-1880.
- Vandermolen DT, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310-315.
- Palomba S, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068-4074.
- Moll E, et al. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006;332:1461-1462.
- Neveu N, et al. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril. 2007;87:113-120.
- Sahin Y, et al. The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2004;15:214-220.
- Sturrock ND, et al. Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice. Br J Clin Pharmacol. 2002;53:469-473.
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