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Clomiphene is still the first choice to treat infertility and the gold standard for women with PCOS, argues this expert. He critiques research that suggests metformin is superior and discusses the reason two key trials yielded such starkly different results.
Until recently, conventional wisdom had it that metformin was useful for treating infertility among women with polycystic ovary syndrome (PCOS), whether as a primary or adjuvant agent. But then along came randomized trials examining the effects of clomiphene and metformin on infertility among women with PCOS to challenge that assumption. We know that conclusive data from properly designed clinical trials often rock the hypothetical boat. In this case, though, the data from these trials have sunk the boat promoting metformin for treating infertility in women with PCOS.
THE THREE TRIALS in Table 1 are all randomized, double-blind, multicenter trials that used metformin and clomiphene to treat infertility in women with PCOS. All three trials enrolled participants for up to six cycles, involved no adjuvant medications such as hCG to trigger ovulation, and conception was by timed intercourse without inseminations. Each, however, had a unique design and endpoint. Only the Pregnancy in Polycystic Ovary Syndrome (PPCOS) trial of the Reproductive Medicine Network (RMN) conducted by myself and colleagues was designed and powered to detect a difference in live birth rates between the treatment groups.3,5 The two largest trials (those of Moll and colleagues and the PPCOS-RMN trial) are internally consistent.2,3 Put another way, both found no benefit on live birth from the combination of metformin and clomiphene. The trials most at loggerheads with each other are the trial of Palomba and colleagues, which found that metformin was significantly better than clomiphene in achieving live birth, and the PPCOS-RMN trial, which found the opposite.1,3
Why then the discrepant results between these two trials? Palomba and colleagues critiqued the PPCOS-RMN trial, citing three reasons for the discrepancy6 :
1. the PPCOS-RMN trial included couples with other infertility factors,
2. the PPCOS-RMN trial included obese women (cutoff for the Palomba trial and the Moll trial was a BMI <30 kg/m2 ), and
3. the PPCOS-RMN trial allowed women previously exposed to metformin and clomiphene to participate (Palomba and colleagues did not).
COUPLES WITH OTHER INFERTILITY FACTORS. The first criticism doesn't hold water because the PPCOS-RMN study thoroughly screened subjects with PCOS and the couple for other infertility factors. Our study required: