Injectable Estradiol Dosing and Pharmacokinetics in Transgender and Gender-Diverse Adults
Overview
This multicenter retrospective study of 562 transgender and gender-diverse adults demonstrated that injectable estradiol esters (cypionate and valerate) effectively achieve guideline-recommended estradiol concentrations at lower doses than previously suggested. Estradiol concentrations were significantly influenced by dose and timing relative to the last injection, while the route of administration (intramuscular vs subcutaneous) and type of ester did not significantly affect serum levels.
Background
Estrogen therapy, primarily via bioidentical 17β-estradiol, is central to gender-affirming hormone therapy (GAHT) for transgender and gender-diverse individuals designated male at birth. Injectable estradiol esters, estradiol cypionate (EC) and estradiol valerate (EV), are increasingly used parenterally either intramuscularly (IM) or subcutaneously (SC). Current dosing guidelines vary widely, and providers have reported supraphysiologic estradiol concentrations with standard dosing, raising safety concerns. There is limited evidence comparing dosing and pharmacokinetics between EC and EV or between IM and SC administration routes.
Data Highlights
Parameter
Value
Number of patients
562
Patients injecting every 7 days reaching guideline estradiol levels
131 (27.5%)
Median estradiol dose for those reaching guideline levels
4.0 mg (IQR 3.0-5.0 mg)
Majority estradiol concentrations
Supraphysiologic (>200 pg/mL)
Significant covariates for estradiol concentration
Dose and timing of last injection
Dosing differences between IM/SC EV/EC
None significant
Key Findings
Among patients injecting estradiol every 7 days, only 27.5% reached guideline-recommended estradiol concentrations, with a median dose of 4.0 mg.
The majority of patients exhibited supraphysiologic estradiol concentrations (>200 pg/mL), indicating doses may often exceed physiological targets.
Estradiol serum concentration is significantly influenced by both the dose administered and the timing of measurement relative to the last injection.
No significant differences in estradiol concentrations or dosing were observed between intramuscular and subcutaneous routes or between estradiol cypionate and valerate esters.
Current dosing recommendations may be higher than necessary to achieve target estradiol levels in transgender and gender-diverse adults.
Clinical Implications
Clinicians should consider that lower doses of injectable estradiol than traditionally recommended may be sufficient to achieve target serum estradiol concentrations in transgender and gender-diverse patients. Interpretation of estradiol levels should account for timing relative to the last injection to avoid misclassification of hormone status. Both intramuscular and subcutaneous administration routes, as well as estradiol valerate and cypionate esters, can be used interchangeably without significant impact on serum estradiol levels.
Conclusion
Injectable estradiol esters effectively achieve guideline-recommended estradiol concentrations at lower doses than previously recommended, with dose and timing being key determinants of serum levels. Route of administration and ester type do not significantly affect estradiol pharmacokinetics in transgender and gender-diverse adults.
References
Endocrine Society Guidelines 2017 -- Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons
World Professional Association for Transgender Health (WPATH) Standards of Care, Version 8
Hembree et al. 2017 -- Endocrine Treatment of Transgender Adults: An Endocrine Society Clinical Practice Guideline
by Aaron L Misakian, Carly E Kelley, Erika A Sullivan, Julia J Chang, Gagandeep Singh, Sarah Kokosa, Jonathan Avila, Holly Cooper, Jane W Liang, Bren Botzheim, Meg Quint, Athavi Jeevananthan, Ellenor Chi, Madison Harmer, Laurel Hiatt, Michaela Kowalewski, Benjamin Steinberg, Telisha Tausinga, Hannah Tanner, Tiffany F Ho, Bayarmaa Mark, Brian Zenger, Sophia Hu, Amanuail Gebregzabheir, Justin M Penny, Danielle F Loeb, Tyler Strickland, Sean J Iwamoto, Micol S Rothman, Ole-Petter R Hamnvik, Danit Ariel
