Injectable Estradiol Use in Transgender and Gender-Diverse Individuals in the U.S.: A Multicenter Retrospective Study

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

doi:10.1210/clinem/dgaf015

Injectable Estradiol Use in Transgender and Gender-Diverse Individuals in the U.S.: A Multicenter Retrospective Study

J Clin Endocrinol Metab. 2025 Jan 11:dgaf015. doi: 10.1210/clinem/dgaf015. Online ahead of print.

Authors

Aaron L Misakian¹, Carly E Kelley², Erika A Sullivan³, Julia J Chang⁴, Gagandeep Singh⁵, Sarah Kokosa², Jonathan Avila⁶, Holly Cooper¹, Jane W Liang⁷, Bren Botzheim⁷, Meg Quint^{7

8}, Athavi Jeevananthan², Ellenor Chi⁹, Madison Harmer⁹, Laurel Hiatt¹⁰, Michaela Kowalewski⁹, Benjamin Steinberg⁹, Telisha Tausinga⁹, Hannah Tanner⁹, Tiffany F Ho³, Bayarmaa Mark⁹, Brian Zenger⁹, Sophia Hu¹¹, Amanuail Gebregzabheir^{12

13}, Justin M Penny⁵, Danielle F Loeb^{12

13

14}, Tyler Strickland^{12

13}, Sean J Iwamoto^{12

13

15}, Micol S Rothman^{12

13}, Ole-Petter R Hamnvik¹⁶, Danit Ariel⁴

Affiliations

¹ Division of Pediatric Endocrinology and Diabetes, Stanford University School of Medicine, Stanford, CA.
² Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC.
³ Department of Family and Preventive Medicine, University of Utah, School of Medicine, Salt Lake City, UT.
⁴ Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford, CA.
⁵ Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, MN.
⁶ Division of Adolescent Medicine, Stanford University School of Medicine, Stanford, CA.
⁷ Stanford University School of Medicine, Stanford, CA.
⁸ Department of Epidemiology, University of Michigan, Ann Arbor, MI.
⁹ University of Utah, School of Medicine, Salt Lake City, UT.
¹⁰ Department of Human Genetics, University of Utah, School of Medicine, Salt Lake City, UT.
¹¹ Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
¹² Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO.
¹³ University of Colorado School of Medicine Gender Diversity Programs: UCHealth Integrated Transgender Program, Aurora, CO.
¹⁴ Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, NY, NY.
¹⁵ Endocrine Section, Medicine Service, Rocky Mountain Regional VA Medical Center, Aurora, CO.
¹⁶ Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

PMID: 39797602
DOI: 10.1210/clinem/dgaf015

Abstract

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: 1. Determine dose of injectable estradiol (subcutaneous [SC] and intramuscular [IM]) needed to reach guideline-recommended estradiol concentrations for TGD adults using EC/EV. 2. Describe relationship between estradiol concentration relative to timing/dose of last estradiol injection and other covariates. 3. Determine dosing differences between IM/SC EV/EC.

Methods: Cross-sectional retrospective study across six United States medical centers including TGD adults on same-dose injectable estradiol for >75 days, with confirmed timing of estradiol concentration relative to last injection, from 1/1/2019---12/31/2023. 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 seven 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 impact estradiol concentrations.

Keywords: Estradiol injections; estradiol cypionate; estradiol valerate; gender-affirming hormone therapy; transgender.

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