Extending letrozole treatment duration effective in inducing ovulation in women with PCOS

The commonly used LE regimen for ovulation induction inwomen with PCOS is 2.5 mg daily for 5 days. If the initial dose fails toinitiate follicular development, it often is increased to 5 mg in the nextcycle after a progesterone-induced withdrawal period, and a maximum daily doseof 7.5 mg will be used in the subsequent cycle if still anovulatory.

In accordance with the theory that the ''FSH window'' is asimportant as the ''FSH threshold'' during the selection of dominant follicles,we hypothesized that longer treatment with LE could extend the ''FSH window'',thereby inducing follicle growth in patients who initially do not respond toroutine treatment.

In Xiuxian Zhu and Yonglun Fu's study, considering the riskof ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies, the FSHwindow was widened in a stepwise manner by extending the LE treatment durationstep by step. They defined LE resistance as failure of ovulation after a 5-dayregimen of 5 mg of LE per day for at least 1 cycle. For women with PCOS and LEresistance, a 7-day regimen of 5 mg LE daily was prescribed in the firstovulation induction cycle, and if ovulation did not occur, a 10-day regimen wasprescribed in the subsequent cycle. Such a method of extending LE treatmentduration was named as a ''2-step extended LE regimen'' in the present study.Herein, they reported the ovulation rates and clinical pregnancy outcomes inwomen with PCOS and LE resistance who underwent ovulation induction using the2-step extended LE regimen.

This retrospective study was conducted at Shanghai FirstMaternity and Infant Hospital. Records of women with PCOS and LE resistance whounderwent ovulation induction using the 2-step extended LE regimen betweenOctober 2019 and December 2021 were screened. A total of 69 women with PCOS andLE resistance were included. Ovulation rate was the primary outcome. Clinicalpregnancy rate, live birth rate, spontaneous ovulation rate, and ovarianhyperstimulation syndrome rate were the secondary outcomes. Study resultsdemonstrated that extending LE treatment duration is a feasible method forinducing ovulation in women with PCOS and LE resistance.

Of the 69 patients, 48 ovulated after the 7-day and 16 afterthe 10-day regimen. Overall, the cumulative ovulation rate reached 92.75%(64/69) after the 2-step extended LE regimen, with a cumulative clinicalpregnancy rate of 31.88% (22/69) and a cumulative live birth rate of 24.63%(17/69). All patients ovulated spontaneously without exogenous trigger agentsand none experienced ovarian hyperstimulation syndrome.

Of the 69 women with PCOS and LE resistance, 48 achievedovulation after LE treatment duration was increased to 7 days, among whom 17became pregnant and 14 achieved a live birth.

For the other 21 women, LE treatment duration was increasedto 10 days; among whom 16 achieved adequate follicular growth, 5 becamepregnant, and 3 achieved a live birth.

Overall, the cumulative ovulation rate reached 92.75%, thecumulative CPR was 31.88%, and the cumulative live birth rate was 24.64%. Studyresults demonstrated that extending LE treatment duration is a feasible methodfor inducing ovulation in women with PCOS and LE resistance.

Adding exogenous human chorionic gonadotropin orgonadotropin-releasing hormone agonist when at least 1 follicle has a diameterof >18 mm is a routine procedure in the management of women with ovulatorydysfunction. From authors' perspective, the administration of exogenous triggerdrugs is unnecessary. Because of the short half-life of LE (approximately 45hours), serum E2 values could gradually rise after LE treatment isdiscontinued. Thus, one can just wait for the spontaneous LH surge and thesubsequent rupture of dominant follicles. There are concerns about thepotential risk of ovulation failure of larger follicles, as follicles >22 mmwere related to a higher incidence of unruptured follicles in a previous study.In this study, follicles >25 mm were observed in 11 patients. All of themspontaneously ovulated without the addition of exogenous human chorionic gonadotropinor gonadotropin-releasing hormone.

During the ovulation induction cycle using the 2-stepextended LE regimen, the endometrium was thin at the early follicular phaseowing to the daily administration of LE at a dose of 5 mg, which could decreasethe E2 levels by 97%– 99%. Once circulating E2 levels increased, endometrialdevelopment accelerated. The strategy of waiting for spontaneous ovulationensured that there was sufficient time for patients to achieve adequateendometrial thickness before ovulation. The mean endometrial thickness beforeovulation was 10.58 ± 2.63 mm in the 7-day regimen recipients and 10.8 ±2.74 mm in the 10-day regimen recipients. These values were not less than themean endometrial thickness values in those who underwent a 5-day regimen of LE,2.5 or 5 mg daily. A duration-dependent reduction in the endometrial thicknesswas not observed in study.

In conclusion, study findings demonstrated that extending LEtreatment duration is a feasible method for inducing ovulation in women withPCOS and LE resistance. Whether extending LE duration for a longer time will beeffective in patients who do not respond to a 10-day regimen of 5 mg LE dailyremains our further explorations. Large-scale prospective studies are needed tovalidate our findings and provide evidence for the individual usage of LE inthe ovulation induction of women with PCOS.

Source: XiuxianZhu and Yonglun Fu; Fertility and Sterility

https://doi.org/10.1016/j.fertnstert.2022.09.018