Drugs for Unexplained Infertility: Comparing the Results

Posted on November 19, 2015 by Inception Fertility

Funded in part by the U.S. National Institutes of Health, a multicenter, randomized clinical trial has found that a breast cancer drug called letrozole (Femara) has similar but no better effectiveness than standard fertility drugs in treating women between the ages of 18 and 40 with unexplained infertility.1


To get more clarity about outcomes for couples with unexplained infertility, researchers conducted a head-to-head comparison of the three drugs at 12 locations throughout the U.S. Findings from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial were published in the September 24 issue of the New England Journal of Medicine.

More on the results of the study, but first a little background.

Treatment for unexplained infertility. Inexplicably, couples with unexplained infertility have trouble conceiving, even though the woman ovulates normally and has no serious reproductive tract problems, and the man produces healthy, motile sperm. With enough tries, many couples with unexplained infertility are really sub-fertile and will eventually become pregnant over time. For those wanting to increase the odds of conception, however, the first step is often to stimulate the woman’s ovaries with fertility medications and then to insert the man’s sperm directly into the uterus (intrauterine insemination).

This treatment may work by increasing the number of eggs that are ovulated and by producing hormonal changes in the lining of the uterus (endometrium). In vitro fertilization (IVF) is less commonly used as a first line of treatment due to cost, especially since health insurance plans don’t typically cover it for unexplained infertility.3

How the drugs work. The three drugs stimulate the ovary in slightly different ways:

  • Clomiphene prevents the brain from seeing there is estrogen circulating and in response, the hypothalamus induces the pituitary to put out more of the hormone FSH which induces the ovary to mature an egg or eggs.
  • Letrozole temporarily halts production of estrogen, which influences the hypothalamus and pituitary to produce more FSH.
  • Gonadotropin hormones (FSH and LH) are produced by the pituitary and cause the ovary to mature and release an egg. Commercially available gonadotropin drugs contain either FSH alone or FSH and LH. 3

Pregnancy success. During the present study, 900 women were randomly selected to undergo ovarian stimulation with clomiphene, letrozole, or gonadropins for up to 4 treatment cycles. Clomiphene and letrozole were taken as coated tablets; women received gonadotropins by daily injections under the skin.

Thirty-two percent of the women using gonadropins gave birth; 23.3 percent of women on clomiphene gave birth; and 18.7 percent of those on letrozole gave birth. These were cumulative birth rates over the 4 cycles of treatment.

Why did letrozole perform better in previous trials for women with polycystic ovarian syndrome than in the current study with unexplained infertility? The authors aren’t sure, but suspect it may have something to do with hormonal changes affecting the development of the endometrium in women with unexplained infertility. Another possible explanation is that the drug produces differing levels of androgens in these two different types of infertility.

Chances of multiples. Although gonadotropins produced a higher birth rate, it also raised the chances of multiples, which increase risks such as preterm birth. Of those on gonadotropins, 8.3 percent had twins (25 women) and 2 percent (6 women) had triplets. By contrast, only 1.3 percent (4 women) on clomiphene and 2.7 percent (8 women) on letrozole had twins. Neither clomiphene or letrozole produced triplets.

Safety and side effects. Overall, the rates of adverse events were quite similar between the three treatment groups. However, cumulative serious adverse events were more common with gonadotropins. Also, women in this group tended to have their treatment cycles cancelled more often due to concerns about ovarian hyperstimulation syndrome – a potentially dangerous over-reaction to the gonadotropin stimulation.

No clear winner? In this study, letrozole produced the lowest pregnancy rates and gonadotropins the most multiples. Although not a decisive winner, clomiphene may still strike the best balance for stimulating ovulation in women with unexplained infertility.


  1. Diamond MP et al. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med. 2015;373:1230–1240.
  2. Legro RS et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371:119–129.
  3. MedicalXpress: Standard treatment better than proposed alternative for unexplained infertility.

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