Study: Clomiphene Best On PCOS Infertility

Researchers Say Clomiphene More Effective Than Metformin for Treatment of Polycystic Ovary Syndrome

(WebMD)  One of the oldest treatments for a common cause of infertility is still the best treatment, according to findings from a study that experts say will have a major impact on clinical practice.

The ovulation-stimulating drug clomiphene — used in the U.S. to treat infertility for the past four decades — was found to be more effective than the diabetes drug metformin for the treatment of polycystic ovary syndrome (PCOS)-related infertility.

Metformin has become the leading treatment for PCOS, despite the fact that it has not been approved for this purpose and had not been rigorously studied in infertile patients with the disorder until now.

One brand name of metformin is Glucophage; researchers in the study used Glucophage XR — an extended release form of the drug.

Experts agree that the large, government-funded study proves that clomiphene is the best first-line treatment for PCOS-related infertility.

The study appears in the Feb. 8 issue of the New England Journal of Medicine.

"The findings are unequivocal," National Institute of Child Health and Human Development program director Tracy Rankin tells WebMD. "Metformin has been used off-label for years in the treatment of these patients, based largely on anecdotal evidence that it works."

Polycystic ovary syndrome is a leading cause of infertility. Some studies suggest that it is the most common cause of female infertility. PCOS is a hormonal disorder, which can interfere with ovulation when the ovary releases an egg. Ovaries can become enlarged and develop cysts. Women with the disorder may also experience irregular menstrual periods and excessive body and facial hair growth.

Obesity is also common among women with PCOS, as is the prediabetic condition known as insulin resistance.

The thinking has been that drugs which help sensitize the body to insulin, like metformin, increase ovulation in women with PCOS, and, in turn, help these women achieve viable pregnancies.

Some small studies suggested that metformin worked better than clomiphene, which promotes ovulation by stimulating the release of specific hormones.

The newly published study included 626 infertile women with PCOS, randomly assigned to treatment with metformin, clomiphene, or a combination of the two drugs for up to six months. The women didn't know which exact treatment they were getting. Women who became pregnant were followed until delivery or pregnancy loss.

The live birth rate among the women in the study who took only metformin was only 7 percent. Roughly 22 percent of the women who took only clomiphene gave birth, as did 27 percent of women who took both drugs.

The improvement in outcomes with the combination treatment did not reach statistical significance—compared to clomiphene alone—says researcher Richard S. Legro, M.D.

"The message that this study sends is that metformin isn't as good as we thought it was and it should definitely not be used as a first-line, single therapy for infertility," Legro tells WebMD.

The researchers write that there were more multiple births among the clomiphene groups (one set of triplets and four sets of twins) than the "metformin alone" group, which had none.

Women treated with both metformin and clomiphene had higher ovulation rates than women who took either single treatment, but they did not achieve higher pregnancy or live-birth rates.

This seeming paradox shows, Legro says, that not all ovulations are created equal.
"It appears that some ovulations are better than others," he says. "Clearly, ovulation rates do not tell the whole story. Now the question becomes, 'What is it about a clomiphene ovulation that makes it better than a metformin ovulation?' I don't have an answer, but it certainly deserves more study."

Even though the decades-old infertility drug was proven more effective than the diabetes drug, Legro points out that neither treatment was particularly effective, with just over one in five women in the study giving birth.

"PCOS is a major cause of infertility, and we need new treatments that work better than the ones we have," he says.

David S. Guzick, M.D., Ph.D., of the University of Rochester School of Medicine, tells WebMD that many infertility specialists who have abandoned clomiphene in recent years will be surprised by the new findings.

"Clomiphene has been viewed by many as passé for the treatment of PCOS-related infertility, while metformin has increasingly been seen as the drug of choice," he says. "But this study shows that the tried-and-true treatment works better."

SOURCES: Legro, R.S. The New England Journal of Medicine, Feb. 8, 2007; Vol. 356: pp. 551-566. Richard S. Legro, M.D., department of obstetrics and gynecology, Penn State College of Medicine, Hershey, Pa. Tracy Rankin, program director, National Institutes of Child Health and Human Development, National Institutes of Health. David S. Guzick, M.D., Ph.D., dean, University of Rochester School of Medicine and Dentistry, Rochester, N.Y.