Published: Jul 9, 2014
By Sarah Wickline, Staff Writer, MedPage Today

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Letrozole (Femara) used off-label to treat infertility outperformed first-line treatment clomiphene, with higher rates of live births in women with polycystic ovary syndrome, researchers reported.

In a double-blind, randomized, multicenter trial with 750 women, ages 18 to 40,diagnosed with polycystic ovary syndrome, 27.5% of women treated with 2.5 mg letrozole daily carried a baby to term compared with 19.1% of women treated with 50 mg clomiphene daily (odds ratio 1.44, 95% CI, 1.10 to 1.87, P=0.007),Richard S. Legro, MD, of Penn State College of Medicine, and colleagues reported in The New England Journal of Medicine.

“I think it’s [letrozole] a very effective treatment for women with anovulation due to polycystic ovarian syndrome. I feel very comfortable using it, and certainly after reviewing this study I feel the same,” Rebecca Flyckt, MD, a fertility specialist at the Cleveland Clinic, told MedPage Today in an interview.

Flyckt clarified that the research supports the use of letrozole for infertility treatments in women with polycystic ovarian syndrome, but not necessarily for other underlying causes of infertility.

Letrozole is an aromatase inhibitor, which is marketed under the brand name Femara. It is approved to treat hormonally-responsive breast cancer. The FDA has not approved letrozole as a fertility aid, but specialists have been using it off-label for hormone-related conditions for more than a decade.

Clomiphene, brand names Serophene and Clomid, is a selective estrogen receptor modulator (SERM), and it is the first-line of treatment for infertility in women with polycystic ovary syndrome.

For the trial, doses were given in a 1:1 ratio in permuted blocks of two, four, or six, starting on the third day of the cycle for 5 days for up to five menstrual cycles.

For nonresponsive women, defined as experiencing less than a 3 ng per milliliter increase in progesterone in the midluteal phase, the doses were increased in both groups.

Maximum daily doses of letrozole were 7.5 mg, and 150 mg of clomiphene, for 5 days. Poor ovulation response occurred in 2% of all of the combined 2,777 treatment cycles. Menstrual bleeding was induced in 24.6% of anovulatory cycles, which was deemed acceptable by the study parameters.

Live birth rates with regard to treatment cycle, and miscarriage rates were similar between groups.

Compared with letrozole, women treated with clomiphene showed improvements in biochemical hyperandrogenemia, and hirsutism. But, women treated with letrozole had a sharper decrease in antral follicle count, a slighter increase in endometrial thickness, and lower estradiol levels during the midluteal phase.

In a 2007 study by the same authors, clomiphene’s drawbacks included poor efficacy with a 22% rate of live births within six cycles of therapy, a 3% to 8% multiple pregnancy rate, and a complete failure to induce ovulation in 25% of cases.

Both clomiphene and letrozole have a risk of serious side effects, and carry an FDA pregnancy category X categorization.

“Letrozole does have some side effects, and Clomid does as well. I think that’s true of any medication we prescribe. But, actually, I find that side effects with letrozole are generally fewer,” Flyckt said.

Serious adverse events related to ovarian cyst formations occurred in three participants, two of whom were in the letrozole arm.

Patients who took clomiphene were more likely to report hot flashes compared with patients taking letrozole (33% versus 20.3%). Patients who took letrozole were more likely to report fatigue (21.7% versus 14.9%), and dizziness (12.3% versus 7.6%) than patients who took clomiphene.

Flyckt said that roughly 10% of her patients experience moodiness, hot flashes, headaches, and ovarian cysts with clomiphene.

“A relatively small percentage of my patients with letrozole experience side effects,” Flyckt said, citing headaches and acne among chief complaints.

Ectopic pregnancy occurred in 3.2% of the clomiphene group, and 2.7% of the letrozole group.

Common side effects among women who became pregnant in both groups included gestational diabetes, preeclampsia or eclampsia, preterm labor, and premature rupture of membranes.

Neonatal complications were similar between groups, and they included jaundice, respiratory distress syndrome, and intrauterine growth restriction.

Neonatal death occurred in 3.0% of births in the clomiphene group, and 1.0% of births in the letrozole group.

Major congenital abnormalities occurred in four infants from the letrozole arm, and one infant from the clomiphene arm. Although, the difference in birth defect rates between groups did not reach significance (P=0.65). “[T]his difference was not significant but given the group size, we cannot rule out a potential difference,” the authors wrote.

As the anomalies seen in both treatment arms were diverse in nature, the authors wrote they did not see common mechanisms between the two drugs.

Drop out and study removal rates were similar among groups with 22.6% in the clomiphene arm, and 19.5% in the letrozole arm leaving before the end of treatment (P=0.30).

The authors noted that women who conceive without the help of fertility treatments have a rate of 5.8% for congenital abnormalities.

“Further study with larger numbers of infants is needed to clarify the safety and teratogenic risks with letrozole relative to those with other infertility therapies,” the authors wrote.