Extending letrozole treatment beyond 5 days induces ovulation in certain PCOS patients

For women with polycystic ovary syndrome (PCOS), if a 5-day letrozole regimen for ovulation induction does not work, extending the duration of treatment may do the job, as shown in a study.

In a cohort of 69 women with PCOS who have failed a 5-day letrozole regimen, ovulation occurred after treatment duration was increased to 7 days for 48 women, of whom 17 achieved pregnancy and 14 delivered successfully. [Fertil Steril 2022;doi:10.1016/j.fertnstert.2022.09.018]

Among the other 21 women, 16 achieved adequate follicular growth after extending letrozole treatment to 10 days, with five becoming pregnant and three having a live birth.

The cumulative ovulation rate reached 92.75 percent, the cumulative clinical pregnancy rate was 31.88 percent, and the cumulative live birth rate was 24.64 percent.

All patients ovulated spontaneously without exogenous trigger agents and experienced neither ovarian hyperstimulation syndrome nor triple or higher-order pregnancies, according to the investigators.

“These findings may be attributed to the stepwise method used in this study for extending letrozole treatment duration. For women who failed to ovulate after a 5-day regimen, a 7-day regimen was used. If dominant follicles still did not develop, a 10-day regimen was prescribed,” they said.

“Thereby a severe subgroup of PCOS women with poor ovarian response were selected gradually, and in this way, the safety of ovulation induction was warranted,” they added.

Endometrial thickness

One important observation is that the endometrium was thin at the early follicular phase due to the daily administration of letrozole at a dose of 5 mg, which has been shown to reduce the oestradiol levels by up to 99 percent. [Glob J Health Sci 2015;8:244-252]

However, the strategy of waiting for spontaneous ovulation as opposed to the administration of exogenous trigger drugs ensured that there was sufficient time for patients to achieve adequate endometrial thickness before ovulation, the investigators explained.

“Because of the short half-life of letrozole (approximately 45 hours), serum oestradiol values could gradually rise after treatment is discontinued… Once circulating oestradiol levels increased, endometrial development accelerated,” they said. [Fertil Steril 2006;85:277-284]

The mean age of the women included in the study was 30.48 years, while the mean body mass index was 24.8 kg/m². Most of these women were young and nulliparous, with a short duration of infertility. All of them had menstrual dysfunction, with 58 (84.06 percent) having oligomenorrhea and 11 (15.94 percent) having amenorrhea.

Amenorrhea showed an association with the absence of ovulation in logistic regression analysis. This, according to the investigators, indicated that the severity of menstrual dysfunction had the potential to predict the sensitivity of the ovaries to letrozole.

“Thus, menstrual history may help determine the initiation and duration of LE treatment and reduce the rates of nonresponse among women with PCOS,” the investigators said.

However, they acknowledged that it is still unclear whether extending treatment duration will effectively induce ovulation in women who do not respond to a 10-day regimen of 5 mg letrozole daily.

The investigators called for large-scale prospective studies to validate the present findings, as well as to elucidate the mechanisms underlying ovarian sensitivity and to identify the biomarkers of ovarian response to letrozole, which should provide guidance regarding the use of letrozole during ovulation induction in women with PCOS.