Adding Metformin to Clomiphene

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: Metformin improves pregnancy rates in women with insulin resistance.

Source: Moll E, et al. Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? Hum Reprod 2008;23:1830-1834.

Moll and colleagues from Amsterdam performed a subgroup analysis within their randomized clinical trial of women with polycystic ovary syndrome comparing metformin plus clomiphene treatment with clomiphene alone.1 The overall results of their trial detected no differences in ovulation rates, pregnancy rates, or spontaneous abortion rates achieved by adding metformin to clomiphene treatment.2 This reanalysis of the data, derived from a total of 225 patients, indicated no differences based on BMI, testosterone levels, or glucose levels. However, there was a significant increase in pregnancy rates when metformin was combined with clomiphene in women older than age 28 who were centrally obese as measured by a waist:hip ratio of 0.85 or greater.

Commentary

The trend to use metformin either alone or with clomiphene began around the year 2000, based on a few small studies.3,4 Since then, randomized trials in the United States and Canada, plus the above trial in the Netherlands, concluded that metformin did not improve the infertility treatment of women with polycystic ovary syndrome.2,5,6 In other words, pregnancy rates were similar comparing metformin alone, clomiphene alone, or both drugs in combination. Thus, we returned to the decades-old position that first-line treatment should be clomiphene.

One other study has performed a subgroup analysis, a randomized trial comparing metformin to placebo in only 23 women.7 Nevertheless the Italian authors concluded that metformin improved ovulation rates in patients with hyperinsulinemia. Unfortunately, the Amsterdam trial did not measure insulin levels. However, the fact that the Dutch subgroup analysis found higher pregnancy rates associated with metformin in older, obese women (who are more likely to be hyperinsulinemic) argues that adding metformin to women with insulin resistance does make sense. This is reinforced by the Dutch finding of a benefit in women with an increased waist:hip ratio, the surrogate marker recognized to be most strongly associated with insulin resistance. Even though this was a relatively large clinical trial, the number of women in the subgroups was relatively small (10-30) making it difficult to achieve statistical power and produce strong conclusions regarding associations with testosterone levels and BMI.

Only a randomized trial comparing different treatment protocols among adequately powered subgroups can provide us with better data. Until then, it seems reasonable to add metformin when women with insulin resistance are unable to achieve pregnancy with multiple cycles of clomiphene treatment. It is also reasonable to assume that older women with central obesity are very, very likely to be hyperinsulinemic, and sometimes it is more cost effective to use metformin empirically.

The clinical trials comparing clomiphene and metformin have documented an increase in gestational diabetes and preeclampsia in the clomiphene-treated groups. It is worth considering metformin treatment of patients throughout pregnancy in overweight women with insulin resistance. Studies have indicated a reduction in pregnancy complications, including the incidence and treatment of gestational diabetes, with metformin administration and no adverse fetal affects with exposure in the first trimester of pregnancy.8-11

In addition, we should not forget that metformin treatment improves insulin sensitivity and lowers androgen levels in women with polycystic ovaries and anovulation. These are important and beneficial results in terms of reducing the risks of the long-term consequences of diabetes mellitus and cardiovascular disease.

References

  1. Moll E, et al. Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? Hum Reprod 2008;23:1830-1834.
  2. 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;332:1485.
  3. Nestler JE, et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876-1880.
  4. 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.
  5. Legro RS, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551-566.
  6. 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.
  7. Moghetti P, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139-146.
  8. Vanky E, et al. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: Results of a randomized study. Hum Reprod 2004;19:1734-1740.
  9. Tertti K, et al. Comparison of metformin and insulin in the treatment of gestational diabetes: A retrospective, case-control study. Rev Diabet Stud 2008;5:95-101.
  10. Rowan JA, et al; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-2015.
  11. Bolton S, et al. Continuation of metformin in the first trimester of women with polycystic ovary syndrome is not associated with increased perinatal morbidity. Eur J Pediatr 2008 May 7; Epub ahead of print.