In gender-affirming hormone therapy, estradiol can be administered via oral, transdermal, or parenteral routes.1,2 Antiandrogen medications, such as spironolactone and gonadotropin-releasing hormone (GnRH) agonists, are often used in combination with estradiol to reduce or block the effects of testosterone on secondary sex characteristics.1,2 Estradiol route and antiandrogen choice can vary depending on patient preference, patient age, and stage in puberty. GnRH agonists are more often used for younger patients earlier in puberty, whereas spironolactone is more often used for older patients later in puberty.1,2 Serum hormone profiles among the different routes of estradiol administration are poorly characterized, and there is limited data regarding medical protocols and outcomes.

There are no published data directly comparing the various routes of estradiol administration for the efficacy and consistency in achieving therapeutic serum hormone levels in transgender and gender-diverse (TGD) youth. A few studies have reported data on serum estradiol levels in adolescents and adults on oral, transdermal, intramuscular, or subcutaneous routes of estradiol administration but with little direct comparison of the routes or description of serum estradiol levels at different doses.3, 4, 5, 6

The purpose of this study was to evaluate the serum estradiol levels for TGD youth on subcutaneous, oral, and transdermal estradiol and compare the ability of different estradiol routes in achieving therapeutic serum estradiol levels and suppressing the serum testosterone levels.