ABSTRACT: The increase in frozen embryo transfers (FETs) is a consequence of advances in embryo vitrification and the implementation of genetic screening of embryos. There is debate over the best progesterone administration route in substituted cycles and the relationship between progesterone levels on embryo transfer (ET) day and reproductive outcomes. This trial aimed to compare the clinical results of different progesterone supplementation schedules before ET and assess the relationship between plasmatic progesterone levels on transfer day and clinical outcomes. In a prospective, randomized, controlled study, 500 patients were randomly divided into two groups based on the progesterone administration route (oral or vaginal) before ET. Progesterone levels were measured on ET day (PP1) and B-HCG determination (PP2). The primary endpoint was the live birth rate according to different progesterone schedules and levels on transfer day. Despite higher plasmatic progesterone levels with oral administration compared to the vaginal route, there were no significant differences in clinical pregnancy (50.20 vs 47.37%), live birth (43.67 vs 40.89%) or miscarriage rates (13.01 vs 13.68%). Progesterone levels on transfer day were significantly higher among ongoing pregnancies (24.96 ± 1.00 ng/mL) compared to non-ongoing pregnancies (19.39 ± 1.47 ng/mL) and non-pregnancies (17.56 ± 0.99 ng/mL) (P = 0.0001). LAY SUMMARY: The use of FET for the treatment of infertility is increasing. There are two key ongoing debates. First, consensus still needs to be reached regarding the most effective method for preparing the endometrial lining regarding maternal and neonatal outcomes. Second, the optimal progesterone level on the day of ET remains unclear. While how progesterone is administered affects its concentration, no significant differences in clinical outcomes have been observed. However, successful pregnancies tend to have higher progesterone levels than others. Given that the way progesterone is administered does not affect pregnancy rates, patient preferences should guide protocol choices, and further research is needed to explore the association between low progesterone levels on the day of ET and poorer reproductive outcomes. TRIAL REGISTRATION NUMBER: EUDRACT: 2022-000382-41. The clinical trial was approved by the AEMPS (Agencia Española de Productos Sanitarios y Medicamentos
Spanish Agency for Medicines and Health Products) and the local Drugs Research Ethics Committee (CEIm-E). The Institutional Review Board approved the trial. TRIAL REGISTRATION DATE: 24 August 2022. Date of first patient's enrolment: 10 September 2022.