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Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility

Diamond, Michael P.; Legro, Richard S.; Coutifaris, Christos; Alvero, Ruben; Robinson, Randal D.; Casson, Peter; Christman, Gregory M.; Ager, Joel; Huang, Hao; Hansen, Karl R.; Baker, Valerie; Usadi, Rebecca; Seungdamrong, Aimee; Wright Bates, G.; Rosen, R. Mitchell; Haisenleder, Daniel; Krawetz, Stephen A.; Barnhart, Kurt; Trussell, J. C.; Ohl, Dana; Jin, Yufeng; Santoro, Nanette; Eisenberg, Esther; Zhang, Hepingfor the NICHD Reproductive Medicine Network

Obstetrical & Gynecological Survey: December 2015 - Volume 70 - Issue 12 - p 757–758
doi: 10.1097/OGX.0000000000000275
GYNECOLOGY: INFERTILITY/REPRODUCTIVE TECHNOLOGIES
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ABSTRACT Empirical ovarian stimulation with gonadotropin or clomiphene is the standard therapy for women with unexplained infertility. Use of these agents, however, is often complicated by the ovarian hyperstimulation syndrome, multiple gestations, an increased risk of preterm birth, and associated neonatal morbidity. A number of studies have reported that an aromatase inhibitor, letrozole, may be an effective alternative for ovarian stimulation in couples with unexplained infertility. This agent has been used successfully to induce ovulation in women with the polycystic ovary syndrome, a leading cause of infertility. There have been reports of a similar or improved pregnancy rate with letrozole as compared with gonadotropin or clomiphene. Letrozole has been associated with monofollicular development in most patients, which may result in enhanced fertility, a reduced risk of ovarian hyperstimulation, and multiple births compared with gonadotropin and clomiphene. Moreover, its administration has not been associated with a significantly increased risk of congenital anomalies.

This multicenter randomized trial assessed whether ovarian stimulation with letrozole would result in a lower rate of multiple gestation while maintaining live birth rates as compared with clomiphene or gonadotropin. The study was conducted at 12 clinical sites throughout the United States. Study subjects were 900 couples with unexplained infertility. Women were between 18 and 40 years of age with regular menses, had a normal uterine cavity with at least 1 patent fallopian tube, and had a male partner with semen that met the intrauterine insemination threshold for normal sperm counts.

Women were randomly assigned to ovarian stimulation (up to 4 cycles) with gonadotropin (n = 301) clomiphene (n = 300), or letrozole (n = 299). Gonadotropin was administered by subcutaneous injection, and clomiphene or letrozole was administered orally as coated tablets. The primary outcome, multiple gestation among women with pregnancies, was compared first between the letrozole group and the overall standard-therapy group (clomiphene and gonadotropin groups combined) and then among the 3 groups. A placebo control group was not used.

Treatment with gonadotropin, clomiphene, or letrozole resulted in clinical pregnancies 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 gonadotropin or clomiphene (P = 0.003) or gonadotropin alone (P < 0.001) but not with clomiphene alone (P = 0.10). The multiple gestation rate with letrozole among ongoing pregnancies with fetal heart activity (13% [9/67 pregnancies]) did not differ significantly from the rate with gonadotropin or clomiphene (22% [42/192]; P = 0.15) or clomiphene alone (9.4% [8/85]; P = 0.44) but was lower than the rate with gonadotropin alone (32% [34/107]; P = 0.006). All multiple gestations in the clomiphene and letrozole groups were twins; gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among the 3 groups in the frequencies of congenital anomalies or major fetal and neonatal complications.

Ovarian stimulation with letrozole in women with unexplained infertility results in a significantly lower frequency of multiple gestation but a lower frequency of live birth, as compared with gonadotropin but not clomiphene. These data support continued use of clomiphene as first-line therapy for couples with unexplained infertility.

Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA (M.P.D.); Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI (M.P.D., J.A., S.A.K.); Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey (R.S.L.); and Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia (C.C., K.B.), PA; Department of Obstetrics and Gynecology, University of Colorado, Denver, CO (R.A., N.S.); Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX (R.D.R.); Department of Obstetrics and Gynecology, University of Vermont, Burlington, VT (P.C.); Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI (G.M.C., D.O.); Department of Biostatistics, Yale University School of Public Health, New Haven, CT (H.H., Y.J., H.Z.); Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine, Oklahoma City, OK (K.R.H.); Stanford University Medical Center, Stanford, CA (V.B.); Carolinas Medical Center, Charlotte, NC (R.U.); University of Medicine and Dentistry of New Jersey, Newark, NJ (A.S.); University of Alabama at Birmingham, Birmingham, AL (G.W.B.); Department of Reproductive Endocrinology and Infertility, University of California, San Francisco, CA (R.M.R.); Ligand Core Laboratory, University of Virginia Center for Research in Reproduction, Charlottesville, VA (D.H.); Upstate University Hospital, Syracuse, NY (J.C.T.); and Fertility and Infertility Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD (E.E.)

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