Wednesday, July 9, 2014 - The drug letrozole appears to be more effective than the standard drug clomiphene for helping women with polycystic ovary syndrome (PCOS) to achieve pregnancy, according to a large study from a research network supported by the National Institutes of Health.

PCOS affects from 5 to 10 percent of reproductive age women and may be the most common cause of female infertility, the study authors wrote. With PCOS, the ovaries are enlarged and contain multiple small cyst-like structures (immature ovarian follicles). Women with PCOS may produce an excess of male hormones, which interferes with ovulation. In addition to infertility, PCOS symptoms include irregular menstrual periods, excessive body and facial hair, acne, and obesity. Women with PCOS also may experience insulin resistance, a prediabetic condition in which higher-than-normal amounts of insulin are produced to maintain normal blood glucose levels.

The researchers found that that women treated with letrozole not only were more likely to ovulate than were women treated with the standard drug, clomiphene, but were also more likely to have a live birth.

"This study showed conclusively that for this group of patients, treatment with letrozole resulted in proportionately more live births than did treatment with clomiphene," said Louis V. De Paolo, chief of NICHD's Fertility and Infertility Branch.

The study's first author is Richard S. Legro, M.D., from the Department of Obstetrics and Gynecology at Penn State College of Medicine in Hershey, PA. The study, appearing in the New England Journal of Medicine, was conducted by the Reproductive Medicine Network of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) In addition to funding from NICHD, funding was also provided by the NIH's National Center for Advancing Translational Sciences.

"We are extremely encouraged that letrozole could provide a new, oral, first line therapy for this common disorder," Dr. Legro said. "A letrozole-based treatment potentially could provide a less invasive, less expensive therapy, with a much lower risk of multiple pregnancy."

The study enrolled 750 infertile women with PCOS who were between 18 and 40 years of age, from February 2009 through January 2012 The women were assigned at random to receive either clomiphene or letrozole for 5 days, beginning on the third day of their menstrual cycle, for up to 5 monthly cycles If the women failed to ovulate or if their test results indicated that they produced insufficient progesterone following ovulation, the researchers increased the dose of the drug the women were being treated with during the next monthly cycle Women with test results indicating conception had occurred were followed until an ultrasound exam could confirm that a pregnancy had been established and throughout pregnancy until delivery.

Of the 374 women who received letrozole, 103 (27.5 percent) eventually had a live birth Of the 376 women who received clomiphene, 72 (19.1 percent) experienced a live birth The cumulative ovulation rate was higher for the letrozole group, with ovulation occurring 834 times in 1352 cycles, or 61.7 percent of the time The women in the clomiphene group ovulated 688 times out of a total of 1425 cycles, or 48.3 percent of the time.

There were no statistically significant differences between the groups for:

Multiple pregnancy, with twin pregnancies occurring in 3.4 percent among the letrozole group and 7.4 percent of the clomiphene group

Pregnancy loss (31.8 percent of the letrozole group and 29.1 percent of the clomiphene group

Infants born with birth defects (3.9 percent with letrozole and 1.4 percent with clomiphene)

Women treated with letrozole had significantly fewer hot flashes than those treated with clomiphene, but more dizziness and fatigue.

Letrozole, currently used as a treatment for breast cancer in women who have gone through menopause, inhibits the production of estrogen, which influences the action of the brain's hypothalamus and pituitary on the functioning of the ovaries Clomiphene prevents estrogen from binding to its target on the cell and so acts on the pituitary to cause the ovary to release the egg cell The study authors noted that one prior study suggested that letrozole might increase the risk of birth defects, but added that their study results do not support the earlier study's findings Although their study did not uncover an increased risk of birth defects, the authors concluded that additional studies are needed to rule out whether letrozole could pose a similar or greater risk of birth defects than do other infertility treatments.