What is the recommended estrogen therapy regimen for a male to female transgender woman?

Male-to-Female Estrogen Therapy

For transgender women, initiate feminizing hormone therapy with estradiol (oral, transdermal, or injectable) combined with an anti-androgen, targeting estradiol levels in the cisgender female reference range and testosterone suppression to <50 ng/dL. 1

Core Medication Regimen

Estradiol Options

• Oral estradiol: Standard formulation available in multiple doses 1
• Transdermal estradiol: Patches or gel formulations with lower VTE risk than oral preparations 2, 1
• Injectable estradiol: Valerate or cypionate preparations, though current guidelines recommend starting doses that are likely too high 3
  • Start injectable estradiol cypionate or valerate at ≤5 mg weekly (subcutaneous or intramuscular) to avoid supraphysiologic levels 3
  • Traditional guideline recommendations of 2-10 mg weekly or 5-30 mg every 2 weeks lead to excessive levels across the injection cycle 3

Anti-Androgen Selection

Anti-androgens enable lower estrogen doses while achieving adequate testosterone suppression 1:

• Spironolactone: Most commonly used in many countries, starting at 50-200 mg daily (not the conservative 25 mg dose) 1

  • Functions as aldosterone receptor antagonist with anti-androgen activity by decreasing testosterone production and competitively inhibiting androgen receptor binding 1
  • Common side effects include diuresis (29%), menstrual irregularities (22%), breast tenderness (17%) 1
  • Routine potassium monitoring unnecessary in young healthy individuals at typical doses 1

• GnRH analogues: Directly suppress FSH and LH production, halting testosterone at its source 1

• Bicalutamide and finasteride: Act peripherally as androgen receptor antagonists 1

Target Hormone Levels

• Testosterone: <50 ng/dL 1
• Estradiol: Within cisgender female reference range 1
• Monitor hormone levels every 3-6 months during the first year, then annually if stable 1

Expected Physical Changes

• Decreased lean body mass (3.0-5.5% reduction) 1
• Significant decreases in hemoglobin levels 1
• Breast development (variable results: 1% <A cup, 9% A cup, 16% B cup, 1% E cup) 1
• Skin softening and decreased body/facial hair 1
• 5% decrease in thigh muscle volume and 4% decrease in quadriceps cross-sectional area 1
• Body composition changes with increases in total body fat 1

Critical Cardiovascular Risk Management

Transgender women have significantly elevated thrombotic and cardiovascular risks compared to cisgender individuals:

• Venous thromboembolism (VTE): Increased risk compared to both cisgender men and women, with risk persisting despite changes in estradiol dosing and preparations 1
• Ischemic stroke: Higher incidence in transfeminine people using gender-affirming hormone therapy 2
  • Cohort study of 2,842 transfeminine people showed elevated ischemic stroke incidence 2
• Myocardial infarction: Elevated risk independent of hormone therapy formulation 1
• Cardiovascular death: Three-fold increase compared to cisgender women, with dose-dependent VTE risk 1

Risk Mitigation Strategies

• Evaluate and modify cardiovascular risk factors before and during therapy 2
• Consider transdermal estradiol formulations, which have lower VTE risk than oral preparations 2, 1
• Avoid ethinyl estradiol, which increases VTE risk more than other estrogen formulations 1
• Implement thromboprophylaxis strategies, particularly peri-operatively 1
• Individualized thrombosis risk assessment required for surgical decisions regarding continuation or cessation of estradiol 1

Monitoring Protocol

Baseline Assessment

• Complete blood count 1
• Liver function tests 1
• Lipid profile 1
• Glucose 1
• Baseline hormone levels (testosterone and estradiol) 1

Follow-Up Schedule

• 3 months: Check estradiol and testosterone levels, adjust doses based on response 1
• Every 3-6 months during first year: Monitor hormone levels and clinical response 1
• Annually thereafter: If stable on therapy 1

Ongoing Monitoring Parameters

• Blood pressure (testosterone may increase) 1
• Lipid profiles regularly 1
• Hemoglobin levels 1

Special Populations and Considerations

Patients with Liver Disease

• Transgender women with prostate cancer who have undergone orchiectomy do not require systemic GnRH agonist/antagonist therapy 2
• Coordinate with hepatologist during transition for patients with liver disease 2
• Testosterone replacement may cause transient elevations in liver enzymes 2

Anatomical Considerations

• Document accurate organ inventory in medical record to guide local and systemic therapy options 2
• Transgender women who retain gonads and prostate require hormone therapy analogous to cisgender men for prostate cancer 2
• Those who have undergone orchiectomy do not need gonadotropin-releasing hormone agonists for hormone-dependent cancers 2

Common Pitfalls to Avoid

• Excessive injectable estradiol dosing: Current guideline-recommended starting doses (2-10 mg weekly) are too high and lead to supraphysiologic levels 3
• Inadequate BMI consideration: Increased BMI associated with lower estrogen dose requirements in transgender women 4
• Ignoring cardiovascular risk stratification: Failure to evaluate baseline cardiovascular risk before initiating therapy 2, 1
• Using ethinyl estradiol: This formulation has higher VTE risk than other estrogen preparations 1

Laboratory Value Interpretation

• For transgender individuals on hormone therapy >1 year, interpret laboratory values based on affirmed gender 5
• Consider cystatin C over creatinine for kidney function evaluation, as it is less dependent on muscle mass 5