Evaluating the effectiveness and adverse effects of oral versus transdermal estradiol for endometrial preparation in frozen-thawed embryo transfer: a randomized controlled trial

Endometrial preparation significantly influences the success of embryo transfer procedures. Although both oral and transdermal estradiol are common methods for endometrial priming, their efficacy and potential side effects remain uncertain. This randomized controlled trial aims to compare the effectiveness of oral and transdermal estradiol in endometrial preparation, while also evaluating their respective side effects in patients undergoing assisted reproduction treatments. This randomized clinical trial (ISRCTN15301227) was conducted at Hung Vuong Hospital between July 2020 and March 2022. Among 550 eligible patients undergoing frozen embryo transfer cycles, we included 380 patients for the study. The study protocol and all materials received approval from the Ethics Committee of Hung Vuong Hospital (1315/CN-HĐĐĐ). Participants were randomly assigned to one of two groups: Group A (n =190) received oral estradiol at an initial dose of 4 mg per day for 7 days, with the dose increased according to clinical response. Group B (n =190) received transdermal estradiol at an initial dose of 2 measures of 2.5 g estradiol gel per day for 7 days, with the dose similarly increased according to clinical response. Treatment in both groups began on days 2–3 of the menstrual cycle, with the maximum duration of estradiol administration being 27 days. We compared estradiol levels on the day of progesterone administration, duration of treatment, total estradiol dose, endometrial thickness, pregnancy outcomes, and any observed side effects between the two groups. Group A exhibited significantly higher estradiol levels on the day of progesterone administration compared to Group B (270.5 pg/ml versus 186.5 pg/ml, p < 0.001). However, the comparison revealed no significant difference in endometrial thickness between the two groups (10.5 mm versus 10.6 mm, p = 0.85). Furthermore, pregnancy rates including positive human chorionic gonadotropin, clinical pregnancy, ongoing pregnancy, live birth, and pregnancy failure were also found to be similar between the two groups. Notably, a greater proportion of patients in Group A experienced mild side effects compared to those in Group B (20.3% versus 10.1%, respectively; n =37 versus n =18), and this discrepancy was found to be statistically significant (p = 0.007). Transdermal estradiol offers comparable endometrial thickness and pregnancy outcomes, along with improved patient compliance and fewer side effects compared to oral estradiol.