What is the recommended approach for initiating gender-affirming hormone therapy in patients seeking male-to-female or female-to-male transition, considering their medical history and overall well-being?

Gender-Affirming Hormone Therapy

Gender-affirming hormone therapy should be initiated after confirming persistent gender dysphoria/incongruence and obtaining informed consent, using estradiol plus anti-androgens for male-to-female transition and testosterone for female-to-male transition, with both regimens demonstrably improving quality of life and reducing psychological distress. 1, 2, 3

Pre-Treatment Assessment

Before initiating hormone therapy, complete the following baseline evaluation:

• Confirm persistent gender dysphoria or gender incongruence through appropriate diagnostic assessment 4
• Obtain baseline laboratory studies: complete blood count, liver function tests, lipid profile, glucose, and baseline hormone levels (testosterone, estradiol) 2, 5
• Provide mandatory fertility preservation counseling, as hormone therapy may permanently affect fertility 2, 5
• Screen for cardiovascular risk factors including history of thromboembolism, stroke, myocardial infarction, and assess baseline blood pressure 2, 5
• Assess bone health with baseline bone mineral density if risk factors present 6

Male-to-Female (Feminizing) Hormone Therapy

Core Regimen

Initiate estradiol as the cornerstone medication combined with an anti-androgen to achieve feminization while suppressing testosterone production 1, 2:

Estradiol options:

• Oral: 2-6 mg daily 2
• Transdermal patches: 0.1-0.4 mg/day 2
• Injectable (estradiol valerate or cypionate): 5-20 mg IM every 1-2 weeks 2
• Avoid ethinyl estradiol due to higher thrombotic risk 2, 5

Anti-androgen options:

• Spironolactone 100-300 mg daily (most commonly used) 2, 5
• Cyproterone acetate 1, 2
• GnRH agonists (puberty blockers) 2, 5
• Bicalutamide 1, 2
• Finasteride 1, 2

Target Hormone Levels

• Testosterone: <50 ng/dL 2, 5
• Estradiol: within cisgender female reference range 2, 5

Expected Physical Changes

• Breast development (variable, ranging from A to E cup in studies) 5
• Decreased muscle mass (3.0-5.5% reduction in lean body mass) 2, 5
• Softening of skin 1, 2
• Decreased body and facial hair growth 1, 2
• Decreased libido and reduced erectile function 1, 2
• Decreased hemoglobin levels to female reference range 2, 5

Critical Risks and Monitoring

Cardiovascular and thrombotic risks are the primary concerns:

• Increased risk of venous thromboembolism compared to cisgender men and women 1, 2, 5
• Elevated risk of ischemic stroke and myocardial infarction 2, 5
• Weight gain 1, 2
• Potential compromised bone structure 1, 2

Female-to-Male (Masculinizing) Hormone Therapy

Core Regimen

Initiate testosterone therapy targeting serum concentrations of 300-1,000 ng/dL in the typical cisgender male reference range 1, 3:

Testosterone options:

• Intramuscular or subcutaneous testosterone cypionate or enanthate (most common) 3
• Transdermal gel (1.62%): 40.5 mg daily for needle-phobic patients 3
• Testosterone patches: 50-100 μg/24 hours 3
• Avoid testosterone undecanoate due to pulmonary oil microembolism and anaphylaxis risk 3

Adjunct therapy:

• Progestin may be co-administered to halt menstruation 1

Target Hormone Levels

• Testosterone: 300-1,000 ng/dL (mid-normal male range preferred) 3
• Hemoglobin will increase to male reference range within 3 months 1, 3

Expected Physical Changes

• Deepening of voice (irreversible) 1, 3
• Facial and body hair growth (irreversible) 1, 3
• Menstrual suppression 1, 3
• Clitoral growth 1, 3
• Increased muscle mass and decreased fat mass 1, 3
• Increased libido 1, 3

Critical Risks and Monitoring

Hematologic complications are the primary concern:

• Polycythemia/erythrocytosis (particularly with injectable formulations; consider switching to transdermal if develops) 1, 3
• Reduced HDL cholesterol 1, 3
• Potential increased risk of myocardial infarction 1, 3
• Androgenic alopecia and acne 1, 3
• Gynecological effects: pelvic pain and genital dryness 1, 3
• Blood pressure elevation 3

Monitoring Algorithm

Initial Phase (First Year)

1. Baseline assessment (as detailed above) 2, 5
2. 3-month follow-up: Check estradiol and testosterone levels, adjust dosing as needed 2, 5
3. Every 3-6 months during first year: Monitor hormone levels, complete blood count (especially for testosterone patients), lipid profile, liver function, blood pressure 2, 3, 5

Maintenance Phase (After First Year)

• Annual monitoring once hormone levels stable 2, 5
• Continue monitoring for cardiovascular risk factors, bone health, and metabolic indices 7, 6
• For testosterone patients: monitor hematocrit regularly; if rises above normal male reference range, temporarily withhold therapy, reduce dose, or perform phlebotomy 3

Common Pitfalls to Avoid

• Failing to provide comprehensive baseline assessment and fertility preservation counseling before initiating therapy 2
• Not monitoring hormone levels regularly, especially during the first year 2, 5
• Overlooking cardiovascular risk factors that may be exacerbated by hormone therapy, particularly thromboembolism risk with estrogen 2, 5
• Using supraphysiologic testosterone dosing, which increases adverse effects without additional benefit 3
• Prescribing ethinyl estradiol, which carries higher thrombotic risk than other estrogen formulations 2
• Neglecting mental health support during transition, despite strong evidence that hormone therapy improves quality of life and reduces gender dysphoria 1, 3, 8
• Inadequate testosterone dosing in female-to-male patients, which can negatively impact bone density 3

Perioperative Considerations

• Testosterone therapy should generally be continued perioperatively 1
• For estradiol therapy, there is no evidence supporting routine discontinuation before surgery, even for major procedures like vaginoplasty, though individualized thrombosis risk assessment is essential 1
• Discontinuing estradiol may carry negative psychological consequences 1

Laboratory Interpretation

After more than 1 year on hormone therapy, interpret laboratory values based on affirmed gender rather than sex assigned at birth 2