What is the recommended estrogen therapy regimen for transgender women?

Recommended Estrogen Therapy for Transgender Women

Transdermal 17β-estradiol at 50-100 μg/24 hours (via patch) is the recommended first-line estrogen therapy for transgender women, combined with spironolactone 100-300 mg daily as an antiandrogen to achieve testosterone suppression below 50 ng/dL. 1

Estrogen Component

Primary Recommendation: Transdermal Estradiol

• Start with transdermal 17β-estradiol patches releasing 50-100 μg per 24 hours 1, 2
• Transdermal administration is strongly preferred over oral formulations because it avoids first-pass hepatic metabolism, significantly reducing cardiovascular and thrombotic risk 1, 2
• Recent high-quality randomized trial data (2024) demonstrates that transdermal estradiol achieves more rapid testosterone suppression with lower overall estradiol doses compared to sublingual administration 3
• Most transgender women achieve cisgender female testosterone levels within 2 months on 1-2 patches of 0.1 mg/24 hours 3

Alternative Estrogen Routes

• Sublingual 17β-estradiol can be used if transdermal is not tolerated, though it provides no advantage over once-daily dosing and requires higher total doses 3
• Injectable estradiol cypionate or valerate should be started at ≤5 mg weekly (subcutaneous or intramuscular), as current guideline ranges of 2-10 mg weekly often lead to supraphysiologic levels 4
• Vaginal gel (0.5-1 mg daily) is another transdermal option 1

Critical Dosing Principle

• Avoid ethinyl estradiol and conjugated equine estrogens - these carry significantly higher cardiovascular and thrombotic risks compared to bioidentical 17β-estradiol 1

Antiandrogen Component

Spironolactone (First-Line in United States)

• Target dose: 100-300 mg daily, divided into once or twice daily dosing 1
• Start at 50-100 mg daily and titrate based on testosterone suppression 1
• Monitor for hyperkalaemia, acute kidney injury, and hypovolaemia perioperatively 5

Alternative Antiandrogens

• Cyproterone acetate is effective but not available in the United States and carries potential health risks including hepatotoxicity 1, 6
• GnRH agonists provide reliable testosterone suppression but are expensive 5, 6
• Bicalutamide is a peripheral androgen receptor antagonist but may not lower testosterone concentrations 5

Monitoring Protocol

Initial Phase (First Year)

• Check testosterone and estradiol levels after 1-3 months, then every 3-6 months during the first year 1
• Target testosterone <50 ng/dL (cisgender female range) 1
• Traditional estradiol target of 100-200 pg/mL is questioned by recent evidence showing no association with feminizing outcomes 7

Long-Term Monitoring

• Annual physical examination and laboratory monitoring including liver function, lipid profile, and hemoglobin/hematocrit 1
• Screen for cardiovascular risk factors, as transgender women have elevated risk of venous thromboembolism, ischemic stroke, and myocardial infarction compared to cisgender women 5

Important Clinical Considerations

Cardiovascular and Thrombotic Risk

• Venous thromboembolism risk is consistently elevated in transgender women compared to both cisgender men and women, even with modern lower-dose regimens 5
• Risk of ischemic stroke and myocardial infarction is elevated relative to cisgender women 5
• Transdermal estradiol minimizes but does not eliminate these risks 1

Perioperative Management

• There is no evidence supporting routine discontinuation of estradiol before surgery, even for vaginoplasty, and cessation may carry negative psychological consequences 5
• The physical and mental health benefits of estradiol therapy may outweigh thrombosis risk 5
• Use individualized thromboprophylaxis strategies rather than blanket hormone cessation 5

Progesterone: Not Recommended

• Current evidence does not support routine use of progesterone in transgender women 1
• Progesterone may increase risk of breast cancer, thromboembolism, and stroke without proven feminizing benefits 1

Common Pitfalls to Avoid

Dosing Errors

• Never start with high-dose oral estradiol or ethinyl estradiol - these dramatically increase cardiovascular events and thromboembolism without additional feminizing benefit 1
• Do not use injectable estradiol at guideline-recommended starting doses of 5-10 mg weekly - recent data shows this leads to supraphysiologic levels; start at ≤5 mg weekly instead 4

Monitoring Pitfalls

• Do not rely solely on achieving estradiol levels of 100-200 pg/mL as a marker of adequate therapy - this range lacks evidence for optimal feminization 7
• Focus on clinical feminization and testosterone suppression rather than arbitrary estradiol targets 7

Perioperative Errors

• Avoid routine discontinuation of estradiol patches before surgery unless specific high-risk circumstances warrant it 5
• Be aware that topical estradiol patches can increase transdermal uptake with localized heat from patient warming devices or pyrexia 5

Expected Outcomes and Timeline

Feminizing Effects

• Body composition changes with increased fat mass and reduced muscle mass 5
• Breast growth (though often insufficient without augmentation) 5
• Softening of skin and decreased body/facial hair 5
• Decreased libido and erectile function 5
• Decreased testicular size 5

Irreversible Male Characteristics

• Voice pitch, laryngeal prominence, and bone structure do not change with hormone therapy alone and may require surgical intervention 5