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

Background: Optimizing intrauterine insemination (IUI) outcomes while minimizing gonadotropin exposure, treatment cost, and the risk of ovarian hyperstimulation syndrome (OHSS) remains a central challenge in ovulation induction, particularly among women with polycystic ovary syndrome (PCOS) or high antral follicle counts (AFC). Sequential stimulation protocols incorporating early letrozole followed by delayed recombinant follicle-stimulating hormone (rFSH) have been proposed as a strategy to improve clinical efficiency while preserving safety and pregnancy outcomes. Objective To compare pregnancy outcomes, gonadotropin consumption, and safety profiles of a letrozole plus late-onset rFSH protocol versus conventional rFSH stimulation in IUI cycles, with particular emphasis on patients with PCOS and high ovarian reserve. Methods: This retrospective comparative cohort study included 764 IUI cycles performed between January 2022 and December 2025 at a tertiary assisted reproductive technologies center. Cycles were stimulated either with early letrozole followed by late-onset rFSH (n = 392) or with conventional rFSH alone (n = 372). The primary outcome was pregnancy per cycle, defined by a positive serum β-hCG test. Secondary outcomes included total gonadotropin dose, endometrial thickness, cycle cancellation, OHSS incidence, and obstetric outcomes. Multivariable logistic regression, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), mediation analysis, and doubly robust methods were applied to account for baseline imbalances and confounding. Results: In unadjusted analyses, different stimulation protocols influenced pregnancy rates, but the letrozole plus late-rFSH group used significantly lower gonadotropin doses. After accounting for factors like female age and ovarian reserve, stimulation protocol did not independently predict pregnancy outcomes; female age was the main predictor. The rates of cycle cancellation and OHSS were low and similar across protocols, including in women with PCOS and high AFC. Propensity score analyses verified that the letrozole-based protocol produced pregnancy outcomes comparable to standard rFSH stimulation while decreasing gonadotropin use. Conclusions: Sequential stimulation with letrozole plus late-onset rFSH provides pregnancy outcomes comparable to conventional rFSH stimulation while significantly reducing gonadotropin requirements and maintaining favorable safety profiles, even in high-risk populations such as PCOS and high AFC patients. These findings support individualized ovarian stimulation strategies that prioritize both clinical effectiveness and treatment efficiency in IUI cycles.