Estradiol Concentrations for Adequate Gender-Affirming Feminizing Therapy: A Systematic Review

Purpose: Guidelines recommend serum estradiol concentrations of 100-200 pg/mL for transgender women prescribed oral, subcutaneous, or transdermal estradiol with or without adjunct antiandrogen as gender-affirming feminizing hormone therapy (HT). The purpose of this systematic review was to evaluate if the guideline range of 100-200 pg/mL for estradiol concentration is associated with indicators of adequate gender-affirming feminizing HT, specifically feminizing sufficiency, insufficiency, testosterone suppression, or toxicity in transgender women. Methods: The Populations/Intervention/Comparator/Outcome model was applied to the study question, whereby the target population included transgender, gender-diverse, and nonbinary adults using gender-affirming feminizing HT by any route of administration, with or without adjunct antiandrogen use. The comparator was defined as estradiol concentrations within (100-200 pg/mL or 367-734 pM) versus outside (100-200 pg/mL) the guideline range; evaluated outcomes were listed by the same clinical guidelines that recommend using the 100-200 pg/mL range. Embase, MEDLINE, and Web of Science were queried over a 24-year time frame (January 1, 1999-April 20, 2023); the search was restricted to English. The extracted outcomes were categorized as indicators of therapeutic insufficiency, sufficiency, toxicity, or hormone concentration. Results: There were 49 studies that met the inclusion criteria, of which 9, 42, 25, and 5 studies included indicators of therapeutic insufficiency, sufficiency, toxicity, or hormone concentration, respectively. The search did not identify articles demonstrating that the 100-200 pg/mL guideline range provides optimal feminizing outcomes or reduces adverse events. Conclusions: Evidence does not support using the guideline range of 100-200 pg/mL to indicate sufficient feminization in transgender women using gender-affirming feminizing HT.