Extended versus conventional letrozole regimen in patients with polycystic ovary syndrome undergoing their first ovulation induction cycle: a prospective randomized controlled trial

Can an extended letrozole regimen result in a higher ovulatory rate than a conventional regimen in patients with polycystic ovary syndrome (PCOS) undergoing their first ovulation induction cycle? There was no statistical difference in ovulation rate between patients with PCOS using the extended letrozole regimen and those using the conventional letrozole regimen. Letrozole has become the first-line agent for ovulation induction. However, there is still a proportion of non-responsive cycles in patients with PCOS undergoing ovulation induction therapy with letrozole alone, and the extended letrozole regimen has been demonstrated to be a feasible method for inducing ovulation in these non-responders. Nevertheless, whether the extended regimen could be applied to all patients with PCOS as a first choice for the induction of ovulation remains to be explored. This was a prospective randomized controlled trial that included 148 female patients with PCOS who underwent their first ovulation induction cycle with letrozole from January 2021 to October 2022. Participants were randomly assigned to receive an extended (5 mg letrozole daily for 7 days) or conventional regimen (5 mg letrozole daily for 5 days) for one treatment cycle. The ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, and the rate of multiple pregnancies. The ovulation rate among patients receiving an extended letrozole regimen was slightly higher than the rate with a conventional letrozole regimen, but the difference did not reach statistical significance in either the intention-to-treat analysis (90.54% [67/74] vs 79.73% [59/74], P = 0.065; relative risk [95% confidence interval]: 0.881 [0.768-1.009]) or per-protocol analysis (90.54% [67/74] vs 84.29% [59/70], P = 0.257; relative risk [95% confidence interval]: 0.931 [0.821-1.055]). The number of preovulatory follicles was nearly identical in the two groups (1.39±0.62 vs 1.37±0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. With regards to the endometrial parameters, the mean endometrium thickness was slightly thicker with the conventional LE regimen compared to that with the extended LE regimen, though with no statistical difference (9.27±1.72mm vs 9.57±2.28mm, P = 0.792). In the per-protocol analysis, the rates of clinical pregnancy (20.27% [15/74] vs 14.29% [10/70], P = 0.343; relative risk [95% confidence interval]: 0.705 [0.34-1.463]) and live birth (13.51% [10/74] vs 11.43% [8/70], P = 0.705; relative risk [95% confidence interval]: 0.846 [0.354-2.019]) did not differ significantly between treatment groups. Moreover, all conceptions were singletons without neonatal defects. The major concerns regarding this study are its single-centre and open-label nature. Additionally, the limited number of lean patients with PCOS with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restricted the generalizability of our findings. A change from the standard strategy of ovulation induction in patients with PCOS is not advisable, because a statistically superior effect of the extended LE regimen over a conventional regimen was not detected. The extended LE regimen could be applied with caution in a specific population who failed to respond to a conventional regimen rather than all the patients with PCOS during ovulation induction. Additional prospective trials with larger sample sizes and different PCOS subgroups are needed to assess the ovulatory effects of various letrozole treatment durations. This study was funded by the Shanghai First Maternity and Infant Hospital, affiliated with Tongji University School of Medicine (grant numbers: 2023B03 to Y.F., 2023B18 to X.Z., and 2020RC02 to Y.F.). The authors report no conflicts of interest. Chinese Clinical Trial Registry (ChiCTR2100042082). January 13, 2021. January 21, 2021.