What is the recommended approach for hormone management in transgender females?

Hormone Management for Transgender Females

The recommended approach for hormone management in transgender females involves estradiol therapy combined with an antiandrogen to bring testosterone levels to <50 ng/dL, with dosing individualized based on clinical response and laboratory monitoring. 1

Core Components of Feminizing Hormone Therapy

Estrogen Therapy

• Estradiol is the cornerstone of feminizing hormone therapy, available in oral, transdermal, or injectable forms 1
• Estrogen therapy induces changes in body composition (decreased lean body mass, increased body fat), breast growth, skin softening, decreased body/facial hair, decreased libido, reduced erectile function, and decreased testicular size 1
• Physical changes from estradiol therapy include 3.0-5.5% reduction in lean body mass and significant decreases in hemoglobin levels 1

Anti-Androgen Options

• Anti-androgens are typically added to enable lower doses of estrogen while achieving adequate testosterone suppression 1
• Common anti-androgens include:
  • Spironolactone - most commonly used in many countries 1
  • Cyproterone acetate - effective but with potential health concerns 1
  • GnRH agonists - highly effective but more expensive 1
  • Bicalutamide - peripheral androgen receptor antagonist 1
  • Finasteride - 5α-reductase inhibitor 1

Monitoring and Dosing Considerations

Laboratory Monitoring

• Target testosterone levels <50 ng/dL (female range) 1
• Target estradiol levels in the cisgender female reference range 1
• Recent research questions the standard guideline range of 100-200 pg/mL for estradiol, suggesting optimal feminizing levels may vary 2
• Regular monitoring of hormone levels is essential for individualizing therapy 3

Dosing Approaches

• Oral estradiol: Often requires 4 mg daily or more to achieve adequate feminization and testosterone suppression 3
• Injectable estradiol (cypionate or valerate): Current guidelines may recommend doses that are too high, with starting doses ≤5 mg weekly suggested to avoid supraphysiologic levels 4
• Transdermal estradiol: Patches releasing 50-100 μg/24 hours, changed twice weekly 1

Clinical Effects and Timeline

Expected Physical Changes

• Breast development is a key outcome for many transgender women 1
  • Studies show variable results: 1% with cup size less than A, 9% with A cup, 16% with B cup, and 1% with E cup 1
  • Breast development continues during the first three years of therapy and may extend beyond 1
• Muscle changes include 5% decrease in thigh muscle volume and 4% decrease in quadriceps cross-sectional area 1
• Despite these changes, transgender women may retain greater muscle cross-sectional area than cisgender women 1

Cardiovascular Risk Considerations

• Transgender women have increased risk of venous thromboembolism compared to cisgender men and women 1
• Elevated risk of ischemic stroke and myocardial infarction compared to cisgender women has been observed in population studies 1
• The thrombosis risk persists despite changes in estradiol dosing and preparations over time 1
• For perioperative management, the physical and mental health benefits of continuing estradiol therapy may outweigh thrombosis risk, requiring individualized risk assessment 1

Common Pitfalls and Considerations

• Spironolactone may not enhance testosterone suppression as effectively as expected and might impair achievement of goal estradiol levels 3
• Finasteride has been associated with higher testosterone levels when used alone 3
• Oral estradiol alone may be insufficient for adequate testosterone suppression in many patients 3
• Wide individual variability exists in response to estradiol dosing, highlighting the importance of monitoring hormone levels 3, 2
• Some physical characteristics from male puberty (voice pitch, laryngeal prominence, bone structure) will not change with feminizing hormone therapy 1

Monitoring Algorithm

1. Baseline assessment: Complete blood count, liver function, lipid profile, glucose, and baseline hormone levels 1
2. Initial follow-up: Check estradiol and testosterone levels at 3 months 1
3. Dose adjustments: Titrate estradiol and/or anti-androgen based on hormone levels and clinical response 1
4. Ongoing monitoring: Every 3-6 months during the first year, then annually if stable 1
5. Monitor for adverse effects: Thromboembolism, cardiovascular risk factors, liver function 1