Examining the Evidence
Q. Which is best for PCOS-related infertility: clomiphene or metformin?
A. Clomiphene is superior to metformin in achieving live births in infertile women with polycystic ovary syndrome (PCOS), but carries a higher risk of multiple gestation.
Frontline therapy for ovulation induction in women with PCOS has evolved from clomiphene to metformin, particularly since Palomba and colleagues1 noted comparable ovulation rates and improved conception rates when metformin was given. This new report by Legro and colleagues from the Cooperative Multicenter Reproductive Medicine Network resoundingly contradicts that more limited report and reasserts the primacy of clomiphene in ovulation induction for PCOS. It is reminiscent of the Women’s Health Initiative, in that a well-designed large clinical trial has yielded findings opposite those theorized by investigators.
Legro and colleagues also report a reassuringly low multiple-pregnancy rate in the treatment groups that included clomiphene citrate, and no multiples in the metformin-only group. In addition, they demonstrate a clear, deleterious effect of extreme obesity (body mass index [BMI] greater than 35) on the efficacy of clomiphene and metformin individually and of the 2 agents combined.
Distinctive features of this trial
It is worth noting that the trial by Legro and colleagues contrasts the study by Palomba and associates in 2 critical design characteristics. First, Palomba and associates included only women with a BMI less than 30, whereas Legro and colleagues included a range of body sizes: Only 30% of participants were less than obese and nearly half were massively obese.
Second, the Palomba study was conducted in Italy, presumably in a more homogeneous population than the multiethnic, multicenter trial by Legro and colleagues. However, in the latter trial, even the subgroup analysis for the 179 subjects with a BMI less than 30 demonstrated the same relative proportions of ovulation and conception as the overall trial, albeit with higher rates than in heavier women.
The 2 studies also used slightly different criteria to document ovulation, and the study by Legro and colleagues used the more robust outcome of live birth rate as a primary endpoint—a much more clinically useful measure.
Nonetheless, these differences are insufficient to explain the striking contrast between the data from Legro and colleagues and virtually all of the limited recent work in this area, calling into question the recent move toward metformin as primary frontline therapy. The size, design, and multicenter nature of this trial demand that we consider it the primary source for level I evidence on the subject.
The greater the obesity, the lower the fertility
Perhaps an equally important finding of this study is the diminished response to metformin, clomiphene, or both in women with a BMI of 35 or above. This suggests that aggressive therapy up front may be warranted in these patients in addition to a coordinated plan of dietary and exercise therapy.
Bottom line: Use clomiphene first
This study points us back to the long-standing practice of using clomiphene citrate as frontline therapy for ovulation induction in women with PCOS, with the additional caveat that body size is a critical modifier of this therapy. However, the cumulative ovulation rate of about 40% and cumulative conception rate of about 20% in women with a BMI less than 35 taking metformin make that drug a reasonable frontline option for couples very concerned about multiple gestation or significant side effects with clomiphene.
1. Palomba S, Orio F, Jr, Falbo A, 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.