plos one
Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility
N Engl J Med 2015; 373:1230-1240September 24, 2015DOI: 10.1056
Michael P. Diamond, M.D., Richard S. Legro, M.D., Christos Coutifaris, M.D., Ph.D, Ruben Alvero, M.D., Randal D. Robinson, M.D., Peter Casson, M.D., Gregory M. Christman, M.D., Joel Ager, Ph.D., Hao Huang, M.D., M.P.H., Karl R. Hansen, M.D., Ph.D., Valerie Baker, M.D., Rebecca Usadi, M.D., Aimee Seungdamrong, M.D., G. Wright Bates, M.D., R. Mitchell Rosen, M.D., Daniel Haisenleder, Ph.D., Stephen A. Krawetz, Ph.D., Kurt Barnhart, M.D., J.C. Trussell, M.D., Dana Ohl, M.D., Yufeng Jin, M.S., Nanette Santoro, M.D., Esther Eisenberg, M.D., M.P.H., and Heping Zhang, Ph.D
Author(s) affiliation:
NICHD Reproductive Medicine Network


Short description:
Therapeutic options for couples with unexplained infertility include assisted reproductive technologies, such as in vitro fertilization (IVF) and embryo transfer, and empirical ovarian stimulation combined with intrauterine insemination. The high cost and limited insurance coverage of IVF in all but a few locales in the United States make it an unattainable option for most infertile couples.1 Empirical ovarian stimulation has been thought to promote childbearing by increasing the number of ova ovulated, as well as possibly by enhancing implantation, placentation, or both through hormonal effects on the endometrium.2-4 However, empirical ovarian stimulation (with clomiphene or particularly with gonadotropin) is frequently complicated by the ovarian hyperstimulation syndrome and by multiple gestations, with an increased risk of preterm birth and associated neonatal morbidity and costs.

Aromatase inhibitors have been used successfully to induce ovulation in women with the polycystic ovary syndrome.11 In addition, multiple reports suggest that aromatase inhibitors may be effective alternative agents for ovarian stimulation in couples with unexplained infertility. Their administration is reported to be associated with monofollicular development in most cases,3,17 which may result in enhanced fertility and a reduced risk of ovarian hyperstimulation and multiple births,12,13,20 as compared with current standard therapies such as gonadotropin and clomiphene. Use of an aromatase inhibitor to promote conception has not been associated with a significantly increased risk of congenital anomalies.11,21 We designed the present randomized trial to assess whether ovarian stimulation with letrozole, an aromatase inhibitor, as compared with clomiphene or gonadotropin, would result in a lower rate of multiple gestation without lowering the likelihood of pregnancy.
Link to the journal


Abstract taken from PubMed

The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates.
We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies.
After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P less than 0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications.
In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; number, NCT01044862.)
Link to the paper on PubMed
Comment in:
Fewer live births occur with letrozole than standard therapy for unexplained infertility, study shows. [BMJ. 2015] endeavors to ensure that the information in this article is accurate,reliable and up to date. However, the information is provided "as is" without warranty of any kind. IVF-Worldwide does not accept any responsibility or liability for the accuracy,content, completeness, legality, or reliability of the information contained in this article. is not responsible for the content of other websites linked to or referenced from this website. The website does not endorse the information, content,presentation or accuracy of such other websites and does not make any warranty,express or implied, regarding them.