BOSTON – Letrozole is superior to clomiphene for stimulating ovulation and should be considered the new standard of care for treating anovulatory infertility in women with the polycystic ovary syndrome, investigators said at the conjoint meeting of the International Federation of Fertility Societies and the American Society for Reproductive Medicine.
In a randomized prospective study, 27.5% of women with polycystic ovary syndrome (PCOS) who received letrozole (Femara) had a live birth, compared with 19.5% of women treated with clomipheme. The rate ratio for live births, the primary endpoint, was 1.44 in favor of letrozole (P =.011), said Dr. Richard S. Legro, professor of obstetrics and gynecology at the Pennsylvania State University in Hershey.
"We think that this is going to be a pivotal trial that changes practice," he said.
Neil Osterweil/IMNG Medical Media
Dr. Richard S. Legro
The Pregnancy in Polycystic Ovary Syndrome (PPCOS I) trial, published in 2007, showed that clomiphene, a selective estrogen receptor modulator (SERM), was superior to the insulin sensitizer metformin for treatment of infertility in women with PCOS, but at the cost of higher-risk multiple births, Dr. Legro noted (N. Engl. J. Med. 2007;356:551-66).
In addition, clomiphene resistance was common in that study: 25% of participants never ovulated once in up to six treatment cycles, and 78% of patients treated with clomiphene were not able to conceive.
The rationale behind the use of letrozole, an aromatase inhibitor normally prescribed as an adjuvant therapy in women with hormone-responsive breast cancer, is that it interferes with inappropriate estrogen feedback at the hypothalamus, causing a corresponding rise in the secretion of follicle-stimulating hormone.
Letrozole also has a shorter half-life than clomiphene, meaning that there is a lower risk of fetal exposure to the drug in early pregnancy. In addition, Dr. Legro said that aromatase inhibitors were shown in a systematic review to induce more monofollicular ovulation and have more favorable endometrial effects than SERMs (J. Clin. Endocrinol. Metab. 2006;91:760-71).
For the current study, the investigators enrolled 750 infertile women with a diagnosis of PCOS according to modified Rotterdam criteria: ovulatory dysfunction with either hyperandrogenism or polycystic ovaries. The women, aged of 18-39 years, were in good health and did not have other potentially confounding endocrinopathies. There were no body mass index (BMI) limits in the study, but patients with high BMIs were counseled about the effects of excess weight on fertility.
A total of 376 patients were assigned to receive clomiphene 50 mg/day and 374 were assigned to receive letrozole 2.5 mg/day in doses escalating to 7.5 mg/day for a total of 5 days per cycle for up to five cycles. The drugs were provided in identical capsules over the same schedule.
Apart from the cumulative incidence of live births, there were no significant differences between the two drug groups in pregnancy duration, infant birth weight, proportion of male infants (including twins), or twin live births.
Ovulation rates with letrozole were significantly superior to clomiphene beginning at the second cycle and continuing through the fifth and final cycle (P less than .01).
Fecundity also was better with letrozole, with rate ratios compared with clomiphene of 1.31 for conception, 1.31 for singleton pregnancy, and 1.29 for singleton live birth.
There were four major congenital abnormalities in the children of women who took letrozole, including cerebral palsy with arrested hydrocephalus with polycythemia and neutropenia, imperforate anus with perineal fistula and spina bifida with a tethered spinal cord, right hemimegancephaly and dysgenesis of the left frontal and temporal lobes without hydrocephalus, and a large cardiac ventricular septal defect that required surgical repair.
There was only one major abnormality in the clomiphene group – an atrial ventricular septal cardiac defect with pulmonary stenosis.
There was one minor birth defect – ankyloglossia – in the letrozole group. There were two intrauterine fetal or neonatal deaths in the letrozole group and three in the clomiphene group.
In the question-and-response session following the presentation, Dr. Frederick Licciardi, director of the oocyte donation program at NYU Fertility Center in New York City, questioned the need for a randomized trial, noting that previous studies have shown that letrozole is superior to clomiphene in this population.
"I think the studies were too small, and didn’t focus on live birth. It takes a study like this to detect this sort of advantage," Dr. Legro replied.
The study was funded by the National Institutes of Health. Dr. Legro reported receiving consulting fees from GlaxoSmithKline, Ferring, and Abbott; lecture fees from Serono; and grant support from Pfizer.