Minimal Dose Paradigm in IUI Stimulation for Unexplained Infertility: Letrozole-Initiated Late Gonadotropin Protocol

Background: Optimizing pregnancy outcomes while minimizing gonadotropin exposure and treatment burden remains a major goal in ovulation induction for intrauterine insemination (IUI), particularly for patients with polycystic ovary syndrome (PCOS) or high ovarian reserve. Sequential protocols combining early letrozole with late-onset recombinant FSH (rFSH) have been proposed to enhance efficiency while reducing medication requirements. However, real-world comparative data adjusting for baseline differences are limited. Methods: This retrospective comparative cohort study included 764 IUI cycles performed between January 2022 and October 2025. Cycles were stimulated either with conventional rFSH (n = 372) or letrozole plus late-onset rFSH (n = 392). The primary outcome was pregnancy per cycle, defined by a positive serum β-hCG. Secondary outcomes included clinical pregnancy, total gonadotropin dose, endometrial thickness, cycle cancelation, and obstetric outcomes. Confounding was addressed using multivariable logistic regression, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and doubly robust estimation. Results: The crude pregnancy rate was higher in the letrozole plus late rFSH group compared with conventional rFSH (14.8% vs. 9.9%, p = 0.042). Women in the sequential stimulation group had higher AMH levels, higher antral follicle counts, and a higher prevalence of PCOS (32.4% vs. 16.3%, p = 0.001). After adjustment for age, ovarian reserve, and other baseline characteristics using regression, PSM, and IPTW, the stimulation protocol was not independently associated with pregnancy (adjusted OR 1.09, 95% CI 0.68–1.74; p = 0.657). Female age remained the strongest predictor of pregnancy (adjusted OR 0.70 per year increase; p < 0.001). The sequential protocol required a significantly lower total gonadotropin dose (median 375 IU vs. 750 IU; p < 0.001) while maintaining comparable cycle cancellation and safety outcomes. Conclusions: Sequential stimulation with letrozole plus late-onset rFSH achieves pregnancy outcomes comparable to conventional rFSH stimulation while significantly reducing gonadotropin requirements. After adjustment for PCOS status and ovarian reserve, the protocol itself did not independently influence pregnancy, suggesting that crude differences reflected baseline imbalances rather than true treatment effects. This approach represents a clinically efficient, gonadotropin-sparing option for IUI, particularly in patients at risk for excessive ovarian response.