“With this study, my colleagues and I recommend and support the use of clomiphene alone and not in combination with metformin as a first-line therapy for infertility in women with PCOS,” said Christos Coutifaris, MD, PhD, Director of the Division of Reproductive Endocrinology and Infertility and the principal investigator from Penn. “These results emphasize the need to test any new application rigorously, no matter how promising it may seem initially.”

According to the study authors, women who took metformin ovulated more that the women who were given the standard treatment. Similarly, women in the combination therapy group ovulated more frequently than did the women in either the clomiphene-alone or the metformin-alone groups. However, as the current study revealed, an increase in ovulation did not result in more successful pregnancies and deliveries for either the metformin alone, or combination group.

The researchers theorize 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.

“The bottom line here is that ovulation does not necessarily result in a successful pregnancy,” said Coutifaris. “The results suggest that an ovulation due to clomiphene is two times as likely to result in pregnancy compared to an ovulation caused by metformin.”

PCOS affects seven to eight percent of women in the United States and may be the most common cause of female infertility. With PCOS, an excess of male hormones interfere with ovulation and cause the ovaries to enlarge and fill with cysts.

Women with PCOS frequently experience insulin resistance, a pre-diabetic 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 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. 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 medication 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 study authors also 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.

This study was funded by the National Institute of Child Health and Human Development and the National Center for Research Resources.

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