For Polycystic Ovary Syndrome, Clomiphene Bests Metformin for Pregnancy

HERSHEY, Pa., Feb.7 -- For women with polycystic ovary syndrome the fertility drug clomiphene proved superior to metformin, a diabetes drug, in achieving a live birth, researchers found in a head-to-head study.

A multicenter randomized trial showed that the live-birthrate among women given clomiphene, the standard treatment, was three times the rate of those treated with metformin, Richard Legro, M.D., of Pennsylvania State University here, and colleagues, reported in the Feb 8 issue of the New England Journal of Medicine.

Multiple births were a minor complication, occurring among the women given clomiphene but not among those treated with metformin, they said.

The standard infertility drug clomiphene is an antiestrogenic agent that promotes the release of follicle-stimulating hormone, stimulating the development of ovarian follicles and ovulation. Researchers have hoped that metformin, an insulin sensitizer used to treat diabetes, might help overcome infertility in polycystic ovary syndrome.

The researchers randomly assigned 626 infertile women with polycystic ovary syndrome to receive clomiphene plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to six months. Medication was discontinued when pregnancy was confirmed, and the participants were followed until delivery.

The live-birth rate was 22.5% (47 of 209) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P

It is possible, Dr. Legro said, that although the combined treatment might stimulate more cycles of ovulation than clomiphene alone, these extra cycles might result in a higher number of eggs incapable of fertilization or development.

With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group, the researchers said.

The pregnancy rates in this trial were lower than those reported by others, the researchers said, perhaps reflecting the inclusion of obese women and the fact that many subjects had a long-standing history of infertility. These factors may also have contributed to pregnancy complications, they added.

"Our study demonstrated the limitations of relying on ovulation rates as a surrogate for live-birth rates," the researchers said. Although the study found that pregnancy was approximately twice as likely when ovulation was induced by clomiphene as when it was induced by metformin, the study did not address the mechanisms for improved fecundity per ovulation with each of the drugs, the researchers said.

This study also could not address the effects of continuing metformin throughout pregnancy, although these findings raise concerns and highlight the need for randomized trials for this indication, the investigators wrote.

Also, they noted that the women in the study received extended-release metformin, and this form of the drug may be less efficacious in women with polycystic ovary syndrome than is immediate-release metformin.

In summary, Dr. Legro's team wrote, "our study supports the use of clomiphene citrate alone as first-line therapy for infertility in women with the polycystic ovary syndrome.

"We did not find a significant benefit of combination therapy with clomiphene and metformin over clomiphene alone with respect

to the live-birth rate. In addition, the results of our study underscore the limitations of the use of ovulation as a surrogate marker for live birth in infertility trials," they concluded.

In an accompanying editorial, David Guzick, M.D., Ph.D., of the University of Rochester (N.Y.) wrote, "It is increasingly recognized that women with the polycystic ovary syndrome are at increased risk for the metabolic syndrome and associated health risks and that metformin may well be important in treating these metabolic disturbances."

However, he said, this study "provides strong evidence that the metabolic benefits of metformin do not translate into live-birth rates that are as high as those with the old-fashioned standard, clomiphene citrate.

"Aside from the low but ever-present risk of multiple pregnancy, the use of clomiphene citrate to treat infertility in women with the polycystic ovary syndrome is simple, inexpensive, generally safe, and -- as demonstrated by Legro et al -- more efficacious than the use of metformin," he concluded.

Dr. Legro reported receiving consulting fees from GlaxoSmithKline, Ferring, and Abbott, lecture fees from Serono, and grant support from Pfizer. Co-authors Huiman Barnhart, Ph.D., reported consulting fees from TAP and grant support from Ortho Biotech; William Schlaff, M.D., reported grant support from Organon and Wyeth; Michael Diamond, M.D., received consulting fees from TAP and Serono and grant support from Serono, TAP, GlaxoSmithKline, and Merck; Peter McGovern, M.D., reported grant support from Ferring and Serono; Nicholas Cataldo, M.D., reported consulting fees from Organon. John Nestler, M.D., reported holding an equity interest in Bristol- Myers Squibb. Phyllis Leppert, M.D., Ph.D., received grant support from TAP; and Evan Myers, M.D., reported consulting fees from Merck and TAP and grant support from Merck.

Dr. Guzick, the editorial writer, reported no potential conflict of interest relevant to this article.