The most common cause of female infertility is polycystic ovary syndrome (PCOS), which occurs in 5% to 10% of reproductive-age women. Clomiphene citrate has been used as a fertility agent for decades and is the current first-line infertility treatment in women with PCOS. However, this selective estrogen-receptor modulator has a number of drawbacks. In addition to its overall poor efficacy, clomiphene is associated with a high multiple-pregnancy rate compared with unassisted conception and an undesirable adverse effect profile, including changes in mood and hot flushes. More effective and safer treatments for infertility are needed. Several studies have shown that aromatase inhibitors, which block estrogen synthesis, increase pregnancy rates. Potential advantages of letrozole and other aromatase inhibitors over clomiphene include a more physiologic stimulation of the endometrium, lower multiple-pregnancy rates, and a better adverse effect profile with fewer vasomotor and mood symptoms. However, a concern for letrozole is its potential for fetal teratogenicity.
The aim of this double-blind, multicenter, randomized trial was to determine whether letrozole is a better fertility agent than clomiphene in women with PCOS and has similar or better safety profile. Subjects were infertile women with PCOS between 18 and 40 years old who wished to become pregnant. A total of 750 women were randomized to receive letrozole or clomiphene for up to 5 treatment cycles. Patient visits determined ovulation and pregnancy and were followed by tracking of pregnancies. Modified Rotterdam criteria were used to diagnose PCOS. All participants had at least 1 patent fallopian tube, a normal uterine cavity, and a male partner with a sperm concentration of at least 14 million per milliliter. The women and their male partners agreed to have regular intercourse. No placebo was used because the 2 drugs were given similarly, with the same duration of treatment and stepwise increase in dose. The primary study outcome was live birth during the treatment period. Data were analyzed by intention to treat.
Women in the letrozole group had more cumulative live births than did those in the clomiphene group (27.5% [103/374] vs 19.1% [72/376]; the rate ratio for live births was 1.44, with a 95% confidence interval of 1.10 to 1.87, P = 0.007. Although there was no difference between groups in overall congenital anomalies, 4 major congenital anomalies were found in the letrozole group versus 1 in the clomiphene group; however, the difference was not significant (P = 0.65). Letrozole was also associated with higher cumulative ovulation rates (61.7% [834 of 1352 treatment cycles] vs 48.3% [688 of 1425 treatment cycles], P < 0.001). No significant between-group differences were found in rates of pregnancy loss after conception (31.8% [49 of 154 pregnancies] in the letrozole group vs 29.1% [30 of 103 pregnancies] in the clomiphene group) or in rates of twin pregnancy (3.4% and 7.4%, respectively). There was a higher incidence of hot flushes in the clomiphene group and a higher incidence of fatigue and dizziness in the letrozole group. Rates of other adverse events in the 2 groups were similar.
These data show that letrozole is a more effective fertility treatment than clomiphene in women with PCOS. Further studies with larger numbers of infants are needed to clarify the safety and teratogenic risks of letrozole.
Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA (R.S.L.); Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX (R.G.B.); 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., S.A.K.); Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA (C.C., K.T.B., P.S.); Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO (W.D.S., R.A., N.S.); 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., Q.Y., H.Z.); Ligand Core Laboratory, University of Virginia Center for Research in Reproduction, Charlottesville, VA (D.J.H.); University of Alabama at Birmingham, Birmingham, AL (G.W.B.); Carolinas Medical Center, Charlotte, NC (R.U.); Virginia Commonwealth University, Richmond, VA (S.L.); Stanford University Medical Center, Stanford, CA (V.B.); State University of New York Upstate Medical University, Onondaga, NY (J.C.T.); and Fertility and Infertility Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD (E.E.)