(021) Route of Estradiol and Progesterone Use and Risk of Mortality and Adverse Events in Transfeminine Individuals

Abstract Introduction Hormone therapy is central to transfeminine care, yet short-term cardiovascular and mortality data are limited. While the Women’s Health Initiative demonstrated route- and regimen-dependent mortality differences in cisgender women, comparable evidence in transfeminine populations is lacking. Objective To evaluate all-cause mortality and adverse clinical outcomes occurring ≥90 days after estradiol initiation, comparing (1) transdermal vs non-transdermal routes and (2) estradiol alone vs estradiol + progesterone. Methods We conducted a retrospective cohort study using the TriNetX Research Network, including transfeminine adults with gender dysphoria (F64.0, F64.8, F64.9) initiating estradiol (2003–2025). Exposures were route (transdermal vs non-transdermal: injectable or oral) and progesterone co-use (estradiol alone vs estradiol + progesterone; ≥1 prescription within 90 days). Outcomes were assessed beginning 90 days after hormone initiation and included all-cause mortality (primary), major adverse cardiovascular events (MACE), venous thromboembolism (VTE), hormone-responsive cancers (breast, colon, rectosigmoid junction, and rectum), dementia, and fractures. Covariates for propensity-score matching included age, calendar year, cardiometabolic comorbidities, smoking, HIV, and medication use. Incidence was expressed as risk differences (95 % CIs) by age (18–39, 40–59, ≥60). Kaplan–Meier curves began 90 days post-initiation; group differences used log-rank tests. Median time-to-event was estimated when ≥50 % experienced the outcome, and comparisons between exposure groups were performed using log-rank tests. Baseline characteristics were compared between groups to identify prescribing patterns and confounding structure. Results Among 4089 transfeminine individuals initiating estradiol, 2926 received transdermal and 1163 received non-transdermal formulations. Event rates occurring after 90 days of hormone initiation were low overall. There were no significant differences in all-cause mortality or major adverse cardiovascular events (MACE) between transdermal and non-transdermal groups across age groups (Table1). A non-significant trend toward higher MACE rates was observed in patients ≥60 years receiving transdermal estrogen (8.6% vs 5.2%; p = 0.089). When comparing estradiol alone (n = 4545) vs estradiol + progesterone (n = 1412), all-cause mortality after 90 days was lower in the estrogen and progesterone group among those aged 18–39 (0.26% vs 0.57%; p = 0.023), with no significant differences in MACE or VTE across age groups (Table 2). Median time-to-event was not reached for any outcome because fewer than 50 % experienced the event during follow-up. Kaplan–Meier analysis showed no significant difference in time-to-event between groups (Table 1, 2). Baseline characteristics differed significantly between exposure groups with patients receiving transdermal estrogen and those prescribed progesterone in addition to any route of estrogen having higher prevalence of hypertension, hyperlipidemia, and cardiometabolic medication use (Table 3). Conclusions In this multicenter, database-driven study, mortality and cardiovascular event rates following feminizing hormone therapy were low, with no significant differences by estrogen route. Progesterone co-prescription was associated with lower mortality in younger individuals without increased thromboembolic or cardiovascular risk. Although median time-to-event data were not reached, longitudinal analyses showed no significant differences in event timing between groups. Baseline comorbidity differences suggest prescribing patterns are tailored to patient risk. These findings provide early safety evidence supporting transdermal estrogen and combination therapy in transfeminine care and highlight the need for long-term prospective studies to confirm these trends. Disclosure No.