Injectable Estradiol Use in Transgender and Gender-Diverse Individuals throughout the United States

Context: Guidelines for use of injectable estradiol esters (valerate [EV] and cypionate [EC]) among transgender and gender-diverse (TGD) individuals designated male at birth vary considerably, with many providers noting supraphysiologic serum estradiol concentrations based on current dosing recommendations. Objectives: This work aimed to 1. determine the dose of injectable estradiol (subcutaneous [SC] and intramuscular [IM]) needed to reach guideline-recommended estradiol concentrations for TGD adults using EC/EV; 2. describe the relationship between estradiol concentration relative to timing/dose of last estradiol injection and other covariates; and 3. determine dosing differences between IM/SC EV/EC. Methods: A cross-sectional retrospective study was conducted across 6 US medical centers including TGD adults on same-dose injectable estradiol for more than 75 days, with confirmed timing of estradiol concentration relative to last injection, from January 1, 2019 to December 31, 2023. Descriptive statistics were used to describe patient characteristics and weighted linear mixed models to evaluate relationship between various covariates and estradiol concentration. Results: Data from 562 patients were included. Among those injecting every 7 days who reached the guideline-recommended estradiol concentration (n = 131, 27.5%), the median estradiol dose was 4.0 mg (interquartile range, 3.0-5.0 mg). Among all patients, the majority reached supraphysiologic estradiol concentrations (>200 pg/mL [>734 pmol/L]) while dose and timing in the injection cycle were significant covariates for the estradiol concentration. There were no significant dosing differences between IM/SC EV/EC. Conclusion: Injectable estradiol esters effectively reach guideline-recommended estradiol concentrations but at lower doses than previously recommended. Estradiol concentrations are best interpreted relative to timing of last injection. Route of administration and type of ester do not significantly affect estradiol concentrations.