October 7, 2015

Comparing Treatments for Unexplained Infertility

At a Glance

  • For couples with unexplained infertility, ovarian stimulation therapy with clomiphene proved at least as effective as a potential alternative.
  • The findings support continued use of clomiphene as the first-line therapy for couples with unexplained infertility.
Doctor using laptop and consulting with young couple. Infertility affects about 1 in 10 couples who are trying to have a baby. Even in cases where no obvious cause can be found, treatments can be effective. monkeybusinessimages/iStock/Thinkstock

Many cases of infertility can’t be explained. The woman ovulates normally and has no obvious abnormalities in the reproductive tract, while the man produces adequate numbers of sperm. Treatments for unexplained infertility can vary. The most common approach is to use drugs to stimulate the woman’s ovaries to release an egg (ovarian stimulation). Sperm is then inserted directly into the uterus (intrauterine insemination) for the anticipated ovulation.

Currently, the treatment of choice for ovarian stimulation is either clomiphene or injectable gonadotropins. Clomiphene prevents estrogen from binding to cells, which causes changes in the pituitary gland that ultimately trigger the release of an egg. Gonadotropins augment natural compounds from the pituitary that signal the ovary to release an egg. Treatment with gonadotropins, however, is associated with increased adverse effects and multiple pregnancies, which can raise the risk of pregnancy and birth complications.

A 2014 study found that another drug, letrozole, was more effective than clomiphene for achieving live births in certain women with polycystic ovary syndrome, a leading cause of infertility. Letrozole is a breast cancer drug that suppresses production of estrogen and thus triggers release of the hormones that drive ovulation. Some studies suggested that it might be effective for ovarian stimulation in couples with unexplained infertility.

To investigate, a nationwide research network enrolled 900 couples with unexplained infertility. The women, 18 to 40 years of age, were randomly assigned to treatment with letrozole, clomiphene, or gonadotropins. They received the ovarian stimulation drugs and timed intrauterine inseminations for up to 4 monthly menstrual cycles or until they became pregnant or discontinued treatment. There was no placebo control group, as past studies had already tested gonadotropin and clomiphene against placebo controls, and it was considered inappropriate to do so among couples that had been trying to achieve pregnancy for long periods of time. The research was funded largely by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Results appeared on September 24, 2015, in the New England Journal of Medicine.

Nearly 750 women completed the study. Rates of conception (defined as having a positive pregnancy test) were 47% in the gonadotropin group, 35% in the clomiphene group, and 28% in the letrozole group. There was no significant difference in the time to conception among the 3 groups.

Live births occurred in about 32% of the women in the gonadotropin group, 23% of the clomiphene group, and 19% of the letrozole group. Gonadotropin treatment resulted in multiple pregnancies in 13% of pregnancies compared to 1% for clomiphene and 3% for letrozole. About 30% of the multiple pregnancies in the gonadotropin group involved triplets, whereas all the multiple pregnancies in the clomiphene and letrozole groups were twins. There were no statistical differences among the groups in birth defects or complications with pregnancy or birth.

The findings show that ovarian stimulation therapy with clomiphene is at least as effective as letrozole, with a lower though not statistically significant difference in the frequency of multiple births. “The conclusion for couples with unexplained infertility is that clomiphene still remains the first-line therapy,” concludes first author Dr. Michael P. Diamond of Georgia Regents University.

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Reference: Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Ager J, Huang H, Hansen KR, Baker V, Usadi R, Seungdamrong A, Bates GW, Rosen RM, Haisenleder D, Krawetz SA, Barnhart K, Trussell JC, Ohl D, Jin Y, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. N Engl J Med. 2015 Sep 24;373(13):1230-40. doi: 10.1056/NEJMoa1414827. PMID: 26398071.

Funding: NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR), and National Center for Advancing Translational Sciences (NCATS); and the American Recovery and Reinvestment Act.