Frontline treatments show best results for unexplained infertility

A breast cancer drug with promise for improving the chance that couples with unexplained infertility can have a baby without increasing their risk of multiple births apparently does not deliver, according to a comparative study.

“The question was could we reduce the risk of twins and triplets without negatively impacting the total number of women who can conceive?” said Dr. Michael P. Diamond, reproductive endocrinologist and Chairman of the Department of Obstetrics and Gynecology at the Medical College of Georgia at Georgia Regents University.

In a study published in the New England Journal of Medicine, researchers showed pregnancy rates and live birth rates were significantly lower in women treated with letrozole, an aromatase inhibitor that enables ovulation, than those receiving the frontline drugs gonadotropin or clomiphene. As an example, live birth rates were 32.3 percent in women taking gonadotropin and 18.7 percent with letrozole.

The cancer drug has been used off-label for infertility for several years because of anecdotal reports that it could help women conceive with less risk of multiple births. Diamond participated in another study published last summer, also in NEJM, that showed letrozole was better than clomiphene at improving rates of ovulation, conception, pregnancy and live birth in women with polycystic ovary syndrome. PCOS affects 5-10 percent of reproductive-age women whose major infertility problem is that they don’t ovulate.

But letrozole’s success in women with PCOS does not hold up when the cause of infertility is unclear. While patients with unexplained infertility taking letrozole did have a significantly lower number of multiple births than those taking gonadotropins, those rates were comparable to clomiphene, said Diamond, the new study’s corresponding author. Letrozole therapy did result in a significantly reduced number of multiple births compared with gonadotropin, but its rates were two-and-a-half times higher than clomiphene’s.

“The conclusion for couples with unexplained infertility is that clomiphene probably still remains the first-line therapy,” Diamond said of the widely used drug that enables production of more eggs and the hormones that support them.

Women taking gonadotropin, which is given by shot rather than by tablet like the other two drugs, had the highest rate of pregnancy and live births, but it also had the highest multiple birth rate, Diamond noted. Gonadotropin therapy resulted in 24 sets of twins and 10 sets of triples. Letrozole and clomiphene therapy produced only twins, which generally result in fewer complications during pregnancy and after birth than triplets. There were no significant differences among the three treatment arms in resulting birth defects or newborn complications.

The study looked at 900 women age 18 to 40 with unexplained infertility at 12 centers across the nation through the Cooperative Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

A third of patients were randomly assigned to receive up to four cycles of ovarian stimulation with gonadotropin, clomiphene or letrozole; there was no placebo group. Researchers obtained an investigational new drug application with the Food and Drug Administration for the study since letrozole is currently only approved for breast cancer treatment.

Like clomiphene, letrozole actually tricks the body into making more estrogen. Clomiphene, which is a selective estrogen receptor modulator, binds to estrogen receptors when estrogen levels are high so the brain gets the message to make even more, Diamond said. The pituitary gland gets stimulated by the hypothalamus, and patients make follicle stimulation hormone, which enables the eggs to mature, and more luteinizing hormone, which stimulates ovulation, enabling the mature egg to be released for fertilization. Letrozole produces similar results by blocking estrogen production, Diamond said.

“In a typical monthly cycle, there is usually one follicle and one egg that develop to the point of ovulation,” Diamond said. “What happens with the fertility drugs, you are overriding the mechanisms which usually only lead to development of one dominant follicle and release of one egg.”

Women are diagnosed with unexplained infertility if they have been trying for a year to get pregnant and there are no obvious problems such as lack of ovulation, an abnormal uterus or evidence of inflammation, such as endometriosis. Some of the women may have already had a previous child.

Yale University provided data coordination for the study. Diamond is also GRU’s senior vice president for research.