Metformin, a drug used to treat diabetes and thought to hold great promise at overcoming the infertility associated with polycystic ovary syndrome (PCOS), is less useful for helping women with the condition achieve pregnancy than is the standard treatment with the infertility drug clomiphene, report researchers in an NIH research network.

This study is the largest, most comprehensive effort yet to compare the two drugs in helping women with PCOS achieve successful pregnancy.

The finding appears in the February 8, 2007 issue of the New England Journal of Medicine.

“The results of this study underscore the need to test any new treatment rigorously, no matter how promising it may seem initially,” said Duane Alexander, M.D., Director of the National Institute of Child Health and Human Development, which supported the study, along with the National Center for Research Resources. Both NICHD and NCRR are part of NIH.

Polycystic ovary syndrome (PCOS) affects seven to eight percent of women in the United States and may be the most common cause of female infertility, the study authors wrote. With PCOS, an excess of male hormones interferes with ovulation. The ovaries become enlarged and fill with cysts. In addition to infertility, PCOS symptoms include irregular menstrual periods, excessive body and facial hair, acne, and obesity.

Women with PCOS frequently experience insulin resistance, a prediabetic condition in which higher-than-normal amounts of insulin are required to allow glucose to enter tissues. Earlier studies had shown that drugs such as metformin, which make the body more sensitive to insulin, could increase ovulation in PCOS patients. Similarly, several smaller studies had suggested that metformin, alone or when taken together with the drug clomiphene, could result in greater fertility rates for PCOS patients than could clomiphene taken alone. Clomiphene fosters ovulation by stimulating the release of hormones needed for ovulation to occur.

To conduct the study, the researchers randomly assigned 626 infertile women with PCOS to one of three groups, explained the study’s lead investigator, Richard. S. Legro, M.D., of the Department of Obstetrics and Gynecology at Penn State College of Medicine in Hershey, Pennsylvania. The first group received clomiphene and a placebo, the second group received metformin and a placebo, and the third group received both metformin and clomiphene. The women took the treatments for up to six months. The researchers tested the women’s levels of the hormone progesterone to gauge when the women were ovulating.

The researchers found that fewer women in the metformin only group had given birth than had women in either of the clomiphene groups. In the metformin only group, 15 out of 208 women had given birth, or 7.2 percent. In the clomiphene only group, 47 out of 209 women had given birth, or 22.5 percent. In the combined clomiphene-metformin group, 56 out of 209 women had given birth (26.8 percent). The difference in the number of births between the clomiphene only group and the combined clomiphene-metformin group was not statistically significant. The researchers also found that, compared to the other women in the study, obese women were less likely to conceive during the course of the study and less likely to ovulate in response to metformin.

The researchers noted that women in the combination therapy group ovulated more frequently than did the women in either the clomiphene-alone or the metformin-alone groups. However, the tendency to ovulate more frequently did not translate into a significantly greater number of pregnancies for the combination group.

Dr. Legro said that these findings were consistent with earlier studies that also reported an increase in ovulation from the combined therapy and that these early observations had led to researchers’ initial enthusiasm for metformin as a potential treatment for PCOS. He theorized that although the combination of the two drugs might stimulate more cycles of ovulation than clomiphene alone, these extra cycles might result in a higher number of eggs that are not capable of fertilization or development.

“Our results show that you can’t use ovulation as a surrogate for pregnancy,” Dr. Legro said “An ovulation on clomiphene treatment is twice as likely to result in pregnancy as an ovulation on metformin, thus all ovulations are not alike.”

The researchers also reported that women in the clomiphene groups had more occurrences of multiple pregnancy: 6.4 percent for the clomiphene-only group, 3.3 percent for the combination group and 0 percent for the metformin group. Clomiphene is known to stimulate the release of more than one egg at a time. Dr. Legro noted that the rate of multiple pregnancy seen in the study for women treated with clomphene was less than the multiple pregnancy rate after in vitro fertilization, which averages about 33 percent.

The study authors noted that while metformin alone did not improve the chances for pregnancy, it was useful for lowering the high blood testosterone levels that occur with PCOS.

“In summary, our study supports the use of clomiphene citrate alone as first-line therapy for infertility in women with PCOS,” the study authors wrote.

NCRR provides laboratory scientists and clinical researchers with the environments and tools they need to understand, detect, treat, and prevent a wide range of diseases. With this support, scientists make biomedical discoveries, translate these findings to animal-based studies, and then apply them to patient-oriented research. Ultimately, these advances result in cures and treatments for both common and rare diseases. Through collaborations and networks, NCRR connects researchers with one another, and with patients and communities across the nation. These connections bring together innovative research teams and the power of shared resources, multiplying the opportunities to improve human health. For more information, visit www.ncrr.nih.gov.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.