Letrozole No Better Than Clomiphene for Unexplained Infertility

Summary and Comment |
September 23, 2015

Letrozole No Better Than Clomiphene for Unexplained Infertility

  1. Robert W. Rebar, MD

Trial results make it difficult to support use of this aromatase inhibitor.

  1. Robert W. Rebar, MD

Women with unexplained infertility are commonly given clomiphene citrate or gonadotropins to stimulate multiple ovulations; however, aromatase inhibitors such as letrozole might reduce multiple gestations while maintaining live birth rates. NIH-funded investigators randomized 900 ovulatory women (age range, 18–40) with unexplained infertility and at least one patent fallopian tube to receive up to four cycles of ovarian stimulation with gonadotropin, clomiphene, or letrozole. The main goal was to determine if letrozole resulted in fewer multiple gestations and a similar live birth rate compared with standard therapy with clomiphene or gonadotropins.

Among ongoing pregnancies, the rate of multiple gestations with letrozole (9 of 67 pregnancies [13%]) did not differ significantly from that with gonadotropin or clomiphene (rate for these two groups combined, 42 of 192 [22%]; P=0.15) or clomiphene (8 of 85 [9%]; P=0.44) but was significantly lower than that with gonadotropin (34 of 107 [32%]; P=0.006). Notably, only twin pregnancies occurred with letrozole or clomiphene, whereas 10 triplet pregnancies occurred with gonadotropin. Live birth rates were similar among women who received letrozole (19%) or clomiphene (23%) but were significantly lower than among women who received gonadotropin (32%). In all groups, frequency of congenital anomalies was within the range expected for spontaneous pregnancies. Time to pregnancy and rates of pregnancy loss and neonatal complications did not differ significantly among groups.


This randomized, controlled trial failed to show superiority of letrozole over clomiphene for treatment of unexplained infertility. Given the years of experience with clomiphene — and the fact that aromatase inhibitors are not approved for ovarian stimulation — it's difficult to support the use of letrozole over clomiphene for women with this condition. Moreover, the occurrence of triplet gestations with gonadotropin should reinforce previous suggestions (Fertil Steril 2010; 94:888) that women with unexplained infertility who do not achieve pregnancy with clomiphene should pursue in vitro fertilization, where the number of embryos transferred can be carefully controlled.

Editor Disclosures at Time of Publication

  • Disclosures for Robert W. Rebar, MD at time of publication Editorial Boards Contraception (Deputy Editor); EndoText (Section Editor) Leadership positions in professional societies American Society for Reproductive Medicine (Member Practice Committee)


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