Optimizing estradiol duration to reduce progesterone-related cancellation in hormone replacement therapy frozen embryo transfer cycles: toward a patient-tailored approach

Objective To study whether the duration of estradiol exposure in hormone replacement therapy (HRT) cycles for frozen embryo transfer (FET) is associated with progesterone-related cycle cancellation and reproductive outcomes. Materials and methods This retrospective cohort study included 2, 001 HRT–FET cycles following a freeze-all strategy performed between January 2020 and June 2025. Patients were stratified according to estradiol exposure duration into short (8–9 days; n = 980), intermediate (10–11 days; n = 746), and prolonged (12–14 days; n = 275) exposure groups. Serum progesterone levels were assessed on the day of progesterone initiation. The primary outcome was cycle cancellation due to progesterone elevation (progesterone ≥1.5 ng/mL on the day of progesterone initiation). Secondary outcomes included implantation, clinical pregnancy, miscarriage, and live birth rates. Results The overall cycle cancellation rate was 3.3% (66/2, 001) and increased significantly with longer estradiol exposure, occurring in 2.1%, 3.9%, and 5.8% of cycles in the short, intermediate, and prolonged groups, respectively (OR 1.69 per category, 95% CI 1.22-2.34, p = 0.002). Live birth rates per transfer were similar across groups (47.2%, 52.3%, and 49.4%, respectively; p = 0.122). In multivariable analysis, prolonged estradiol exposure (OR 3.68, 95% CI 1.76–7.71, p < 0.001), intermediate exposure (OR 2.08, 95% CI 1.13–3.81, p = 0.019), age >37 years (OR 2.58, 95% CI 1.36–4.90, p = 0.004), and diminished ovarian reserve (OR 5.13, 95% CI 2.87–9.16, p < 0.001) were independent predictors of cycle cancellation, whereas polycystic ovary syndrome (OR 0.23, 95% CI 0.08–0.69, p = 0.009) was independently associated with a lower likelihood of cancellation. In the multivariable model restricted to transferred cycles, neither intermediate nor prolonged estradiol exposure was independently associated with live birth compared with short estradiol exposure (intermediate: OR 1.25, 95% CI 0.88–1.78, p = 0.204; prolonged: OR 0.93, 95% CI 0.57–1.51, p = 0.775). Conclusions Prolonged estradiol exposure in HRT–FET cycles is associated with increased progesterone-related cycle cancellation without improving reproductive outcomes. A patient-tailored approach based on ovarian reserve status and age may help reduce avoidable cancellations.