Endometrial preparation for frozen embryo transfer: Comparing hormone replacement therapy and natural cycles – Is individualization the Key?

Objective Frozen-thawed embryo transfer has become the predominant mode of embryo transfer in assisted reproductive technology due to widespread vitrification, excellent post thaw survival rate and the advantages of deferred transfers. The success of frozen embryo transfer depends on precise synchronization between embryo development and the endometrium during the window of implantation. This review aims to evaluate whether tailoring endometrial preparation protocols to patient characteristics improves reproductive outcomes. Design Narrative review of randomized controlled trials, systematic reviews, meta analyses, and large observational studies. Subjects Women undergoing frozen–thawed embryo transfer, including patients with recurrent implantation failure, thin endometrium, endometriosis, polycystic ovary syndrome and women with ovulatory cycles. Exposure Conventional hormone replacement therapy cycles and natural cycles along with modified approaches including letrozole stimulated cycles, down regulation and ovulation induction regimens, and adjunctive therapies such as intrauterine platelet rich plasma infusion and immunomodulatory interventions. Main Outcome Measures Endometrial receptivity, live birth rate, clinical pregnancy rate, miscarriage rate, treatment burden, and maternal and neonatal safety outcomes. Results Hormone replacement therapy cycles and natural cycles remain the mainstay of clinical practice, yet both approaches have inherent limitations. Recent advances in reproductive medicine have introduced modified protocols aimed at improving receptivity, enhancing live birth outcomes, and reducing treatment burden. Letrozole stimulated cycles balance physiological corpus luteum function with improved cycle control but evidences are limited and need further validations. Down regulation and ovulation induction regimens seek to optimize receptivity through pituitary suppression followed by individualized luteal support. Adjunctive strategies such as intrauterine platelet rich plasma infusion and immunomodulatory therapies show preliminary benefit in selected populations, particularly women with recurrent implantation failure, thin endometrium, or endometriosis, but the available evidence is limited and heterogeneous. Emerging concepts including endometrial compaction, molecular receptivity profiling, and patient reported outcomes may further refine individualized treatment strategies but needs to be validated by large RCTs. Conclusion The future of endometrial preparation lies in tailoring protocols to patient characteristics and biological signatures while integrating novel strategies judiciously. Robust multi centre randomized trials are urgently needed to validate the efficacy and safety of newer approaches and to assess long term maternal and neonatal outcomes.