A Randomized Double-Blind Comparison of the Effects of Clomiphene Citrate and the Aromatase Inhibitor Letrozole on Ovulatory Function in Normal Women

Abstract

Clomiphene citrate is an effective inducer of ovulation, but pregnancy rates per cycle remain comparatively low, possibly because of an antiestrogenic effect on the endometrium. Letrozole, a potent, orally active aromatase inhibitor, suppresses the production of estrone from androstenedione and has markedly increased gonadotropin levels in animal studies. A possible role of letrozole in ovulation induction was explored in a randomized, double-blind, pilot study enrolling 19 ovulatory women ranging in age from 18 to 35 years. After a natural cycle, the women received either 2.5 mg of letrozole or 50 mg of clomiphene citrate daily on days 5 to 9 after menstruation. Ovarian follicle formation was monitored by transvaginal ultrasonography. The major measure of outcome was the number of mature follicles measuring at least 18 mm at the time of the LH surge. In the 16 women completing both study cycles, a comparable increase in the number of mature follicles at the LH surge was noted in both treatment groups. The mean number was 2.2 with clomiphene therapy and 1.7 in women given letrozole. Midcycle endometrial thickness averaged 10.1 mm in the clomiphene group and 10.6 mm in the letrozole group during the treatment cycle, not a significant difference. All letrozole-treated women but fewer than 60% of those given clomiphene citrate had trilaminar pattern endometrium at midcycle in the natural cycle. The numbers did not drop significantly in either group during the treatment cycle. Follicular gonadotropin profiles were comparable in the two groups in both natural and medicated cycles. Estradiol levels in treatment cycles were higher with clomiphene and lower than those in natural cycles when letrozole was administered. Letrozole seems to be equivalent to clomiphene citrate for stimulating follicle growth in normally ovulating women. This agent may make women more sensitive to FSH, enhance endometrial development (compared with clomiphene), and increase implantation rates through more physiological estradiol levels. Letrozole should be a useful alternative to clomiphene citrate for ovarian hyperstimulation in both intrauterine insemination and in vitro fertilization.