Standard treatment better than proposed alternative for unexplained infertility

Treatment with clomiphene, a standard therapy for couples with unexplained infertility, results in more live births than treatment with a potential alternative, letrozole, according to a landmark study of more than 900 couples conducted by a National Institutes of Health research network, which included the University of Alabama at Birmingham School of Medicine’s Division of Reproductive Endocrinology and Infertility.

The study authors undertook the comparison because earlier findings suggested that letrozole might achieve as many live births as other treatments, but result in fewer multiple pregnancies. Moreover, a 2014 study by the same network found that letrozole was more effective than clomiphene for achieving pregnancy in women with another infertility disorder, polycystic ovary syndrome. The study appears in the New England Journal of Medicine.

“Letrozole treatment offered no advantages over clomiphene treatment,” said study author Esther Eisenberg, M.D., of the Fertility and Infertility Branch of the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, which supports the research network. “Women in the letrozole treatment group had fewer live births, but four times as many multiple pregnancies as women in the clomiphene group.”

“We were very fortunate here at UAB to be a crucial part of this trial,” said G. Wright Bates, M.D., professor of Reproductive Endocrinology in the Department of Obstetrics and Gynecology and principal investigator for the UAB site, one of 12 locations around the country. “We were the only medical center in the Southeast that participated, enrolled patients and contributed data through our association with the Reproductive Medicine Network. It is very satisfying that we can contribute to landmark research that can benefit patients the world over, not just here at home in Alabama.”

Unexplained infertility is said to occur when a couple cannot conceive, even though the woman ovulates normally, has no obvious abnormalities in the reproductive tract, and the man is producing an adequate number of motile sperm. The most common treatment involves using drugs to stimulate the woman’s ovaries to release an egg, and inserting her partner’s sperm directly into the uterus (intrauterine insemination). In vitro fertilization is an option, the study authors write, but is less commonly offered as the procedure is expensive and many health insurance plans do not provide coverage for it.

UAB’s Division of Reproductive Endocrinology and Infertility is available to address any reproductive concerns for patients interested in expanding their family. Patients who are older than 35 and have not been able to conceive on their own for six months, and those under 35 who have tried unsuccessfully for a year without contraception are encouraged to call 205-934-3130. Likewise, if someone is experiencing pelvic pain or not having regular menstrual cycles and wants to get pregnant, do not wait — call today.

Both letrozole and clomiphene stimulate the ovary to release eggs, but by slightly different means. Clomiphene prevents estrogen from binding to cells and triggers the pituitary to signal the release of the egg. Letrozole prevents estrogen from being produced, thereby influencing the brain’s hypothalamus and the pituitary to trigger an egg’s release. Many fertility specialists also offer treatment with gonadotropins, substances produced by the pituitary which cause the ovary to release an egg. Treatment with gonadotropins has declined in recent years, Eisenberg says, because of concerns that their use could lead to an increased risk for multiple pregnancies. Multiple pregnancy increases the chance that the infants will need to be delivered by cesarean section, and that the infants will be born prematurely, which is a risk factor for infant death and disability.

“The take-home message from the trial — which will change how OB/GYNs and fertility doctors practice — is if you’re already ovulating, clomiphene is a better drug,” Bates said. “And if you’re going to use fertility injections, you must do a very careful assessment to decide if it’s worth the risk of having multiples.”

The Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial was conducted at 12 locations throughout the United States by researchers in the NICHD Cooperative Reproductive Medicine Network. 

The 900 women who took part in the study were randomly assigned to three groups of approximately 300 each for treatment with either letrozole, clomiphene or gonadotropins. All women were between 18 and 40 years of age. The women received the drugs for up to four monthly menstrual cycles or until they became pregnant or discontinued treatment.

Conception occurred in slightly less than 46.8 percent of cycles in the gonadotropin group, 35.7 percent in the clomiphene group and 28.4 percent of the letrozole group. Live births occurred in approximately 32.2 percent of the women receiving gonadotropin, 23.3 percent of the clomiphene group and 18.7 percent of the letrozole group. The clomiphene group had the fewest multiple pregnancies, at 1.3 percent, followed by 2.7 percent in the letrozole group and 13.4 percent in the group receiving gonadotropins. For the clomiphene and letrozole groups, all multiple pregnancies were twins. For the women receiving gonadotropins, 24 multiple pregnancies involved twins and 10 involved triplets.

Because gonadotropins resulted in the most multiple pregnancies of the three treatments, and letrozole resulted in the fewest conceptions and lowest pregnancy rates, the study authors concluded that clomiphene citrate is the most appropriate means to stimulate ovulation in unexplained infertility treated with intrauterine insemination. Among the three groups, there were no statistical differences in birth defects or complications with pregnancy or birth.

“UAB’s participation in these two landmark trials through the Reproductive Medicine Network really highlights the fact that we are on the cutting edge of the treatment for infertility,” Bates said. “Fertility treatment should be individualized, as not every patient will benefit from the same therapy. UAB offers the latest evidence-based fertility treatments in a compassionate setting. This approach dramatically increases a couple’s chance of success and taking home a healthy baby.”

For more, including how to schedule an appointment, visit UAB Medicine.