Gender-Affirming Hormone Therapy: Recommended Medications and Treatment Plans
For transgender women (male-to-female), initiate estradiol combined with an anti-androgen; for transgender men (female-to-male), initiate testosterone monotherapy targeting physiologic male ranges. These recommendations are based on the Endocrine Society 2017 guidelines and subsequent updates. 1, 2
Pre-Treatment Requirements and Assessment
Before initiating gender-affirming hormone therapy (GAHT), patients must meet specific criteria and undergo comprehensive evaluation:
Eligibility Criteria
- Confirmed persistence of gender dysphoria or gender incongruence by an appropriately trained mental health professional (required for adolescents, recommended for adults) 3, 4
- Capacity to provide informed consent to partially irreversible treatment, typically achieved by age 16 years 3, 5
- No absolute contraindications to hormone therapy based on medical assessment 2, 6
Baseline Laboratory Assessment
Obtain the following tests before initiating therapy: 2, 6
- Complete blood count (CBC)
- Comprehensive metabolic panel including liver function tests
- Lipid profile
- Fasting glucose or HbA1c
- Baseline hormone levels: estradiol and testosterone
Mental Health Considerations
Screen for psychiatric comorbidities, as transgender individuals have significantly elevated rates of anxiety, depression, bipolar disorder, obsessive-compulsive disorder, ADHD, schizophrenia, and autism compared to cisgender populations. 1 These conditions require specific peri-operative and ongoing management considerations.
Fertility Preservation Counseling
All patients seeking gender-affirming medical treatment must receive information and counseling for fertility preservation before starting hormone therapy, as both feminizing and masculinizing treatments may permanently affect fertility. 1, 2, 6
Feminizing Hormone Therapy (Male-to-Female)
Core Medication Regimen
Estradiol is the cornerstone of feminizing therapy, available in multiple formulations: 2, 7
- Oral estradiol: Standard formulation (avoid ethinyl estradiol due to increased VTE risk) 7
- Transdermal estradiol: Patches or gel
- Injectable estradiol: Valerate or cypionate
Anti-androgens are typically added to enable lower estrogen doses while achieving adequate testosterone suppression. 2, 7 Common options include:
Anti-Androgen Options and Mechanisms
- Spironolactone (most commonly used in many countries): Functions as aldosterone receptor antagonist with anti-androgen activity by decreasing testosterone production and competitively inhibiting androgen receptor binding; typical doses 50-200 mg daily 7, 3
- Cyproterone acetate: Progestational anti-androgen (not available in US) 2
- GnRH agonists: Directly suppress FSH and LH production at hypothalamic-pituitary axis, halting testosterone production at its source 7
- Bicalutamide: Peripheral androgen receptor antagonist 2, 7
- Finasteride: 5-alpha-reductase inhibitor 2
Target Hormone Levels
Maintain testosterone <50 ng/dL and estradiol in the cisgender female reference range (typically 100-200 pg/mL). 2, 7, 6
Expected Physical Changes
Anticipated feminizing effects include: 2, 6
- Breast development (variable results: 1% <A cup, 9% A cup, 16% B cup, 1% E cup) 7
- Decreased lean body mass (3.0-5.5% reduction) 7
- Decreased muscle mass (5% decrease in thigh muscle volume, 4% decrease in quadriceps cross-sectional area) 7
- Softening of skin 2
- Decreased body and facial hair 2
- Decreased libido and reduced erectile function 2
- Hemoglobin decrease to female reference range 6
Cardiovascular Risk Management
Transgender women have significantly elevated cardiovascular risks compared to cisgender individuals: 7
- Three-fold increased risk of venous thromboembolism (VTE) compared to cisgender men and women 7
- Elevated risk of ischemic stroke and myocardial infarction 7
- Three-fold increase in cardiovascular death compared to cisgender women 7
These risks are dose-dependent and persist despite changes in estradiol formulations over time, requiring individualized thrombosis risk assessment, particularly peri-operatively. 7
Monitoring Protocol for Feminizing Therapy
Follow this structured monitoring schedule: 2, 7, 6
- 3 months: Check estradiol and testosterone levels, adjust doses based on response
- Every 3-6 months during first year: Monitor hormone levels, CBC, liver function, lipids
- Annually once stable: Hormone levels, comprehensive metabolic panel, lipid profile, cardiovascular risk assessment
Additional Risks and Side Effects
- Weight gain
- Potential compromised bone structure (if testosterone suppressed without adequate estrogen)
- Elevated prolactin (rare)
Spironolactone-Specific Monitoring
At typical doses (50-200 mg daily), routine potassium monitoring is unnecessary in young healthy individuals, as only 0.75% of young women taking these doses had potassium >5.0 mmol/L. 7 Consider potassium monitoring if:
- Dose increases significantly
- Taking ACE inhibitors, ARBs, NSAIDs, or digoxin 7
Common spironolactone side effects: Diuresis (29%), menstrual irregularities (22% in those with intact ovaries), breast tenderness (17%), breast enlargement, fatigue, headache, dizziness. 7
Masculinizing Hormone Therapy (Female-to-Male)
Core Medication Regimen
Testosterone monotherapy is used to induce virilization and suppress feminizing characteristics. 2, 6 Available formulations include:
- Intramuscular testosterone: Cypionate or enanthate (most common)
- Transdermal testosterone: Gel or patches
- Subcutaneous testosterone: Newer formulation
Target Hormone Levels
Maintain serum testosterone concentrations in the typical cisgender male reference range (300-1,000 ng/dL). 2, 6
Expected Physical Changes
Anticipated masculinizing effects include: 2, 6
- Increased muscle mass
- Decreased fat mass
- Deepening of voice (due to thicker vocal cords)
- Body and facial hair growth
- Menstrual suppression (typically within 3-6 months)
- Increased libido
- Clitoral growth
- Hemoglobin increase to male reference range within 3 months 6
Monitoring Protocol for Masculinizing Therapy
Follow this structured monitoring schedule: 2, 6
- 3 months: Check testosterone levels, CBC (monitor hematocrit for erythrocytosis), liver function
- Every 3-6 months during first year: Testosterone levels, CBC, lipid profile, blood pressure
- Annually once stable: Testosterone levels, CBC, comprehensive metabolic panel, lipid profile, cardiovascular risk assessment
Risks and Side Effects
Monitor for and counsel patients about: 2, 6
- Erythrocytosis (most common significant risk; monitor hematocrit regularly) 2
- Increased blood pressure 6
- Elevated triglycerides and LDL cholesterol 6
- Decreased HDL cholesterol 6
- Acne 6
- Androgenic alopecia (male pattern baldness) 6
- Pelvic pain 6
Transgender men on testosterone therapy have increased cardiovascular and atherosclerotic risk and hematocrit in keeping with the natal male population, which should be considered in clinical assessment. 1
Laboratory Value Interpretation During GAHT
A critical but often overlooked aspect of transgender care is proper interpretation of laboratory values:
General Principles
- For individuals on GAHT ≥12 months: Interpret lab values within reference range for affirmed gender 6
- For individuals on GAHT <12 months: Interpret values in context of type, dose, and duration of GAHT 6
Specific Laboratory Considerations
Red blood cell indices, liver enzymes, electrolytes, and creatinine are significantly influenced by GAHT. 6
Important exceptions:
- Cardiac troponin: Use reference ranges from sex assigned at birth, as troponin depends on heart size 1, 6
- PSA in transgender women: Lower the upper limit of normal to 1.0 ng/mL for those with low testosterone, as prostatic volume and PSA decrease with feminizing therapy 1
- Creatinine: Consider using cystatin C for evaluating kidney function in transgender individuals on hormone therapy, as creatinine is influenced by muscle mass changes 2
Chemotherapy Dosing Considerations
For chemotherapy agents relying on body weight calculations, calculate both male and female doses and choose the most appropriate based on clinical expertise, particularly for individuals on GAHT ≥6 months. 1
Adolescent-Specific Considerations
Pubertal Suppression
For gender-dysphoric adolescents who have entered puberty at Tanner Stage G2/B2, treat with GnRH agonists (puberty blockers) to suppress endogenous sex hormone production. 3, 5 This allows time for further exploration of gender identity while preventing irreversible pubertal changes.
Puberty blockers have been shown to reduce suicidality and improve psychological function in adolescents. 6
Timing of Gender-Affirming Hormones
Gender-affirming hormones (estradiol or testosterone) are usually initiated at age 16 years after a multidisciplinary team confirms persistence of gender dysphoria and sufficient mental capacity for informed consent. 3, 5 Compelling reasons may justify initiation prior to age 16 years, although minimal published experience exists for treatment before 13.5-14 years of age. 3
Cancer Screening Considerations
Breast Cancer Screening in Transgender Women
Starting at age 50 years, transgender women who have received 5 years of feminizing hormone treatment should undergo screening mammography. 1 Recommendations vary slightly:
- Fenway Health: Annual screening 1
- UCSF Center of Excellence: Biennial screening 1
- Endocrine Society: Screen similar to cisgender women 1
Breast cancer incidence in transgender women is 4.1 per 100,000 person-years, significantly lower than cisgender women (155 per 100,000) but higher than cisgender men (1.28 per 100,000). 1
Organ-Based Screening
Cancer screening should be based on risk factors, organ inventory, and standard screening guidelines. 8 For example:
- Transgender women who retain prostate tissue require prostate cancer screening
- Transgender men who retain breast tissue after top surgery may require breast imaging
- Cervical cancer screening for those with intact cervix regardless of gender identity
Special Clinical Situations
Pregnancy in Transgender Men
Transgender men and non-binary patients who become pregnant require specialized antenatal care. 1 Key considerations:
- Refer all transgender patients booking for antenatal care for anaesthetic assessment to inform decision-making before birth 1
- Testosterone therapy must cease during pregnancy to allow for egg retrieval or pregnancy, which can worsen dysphoria 1
- Epidural analgesia may help prevent exacerbation of gender dysphoria by reducing sensation from vaginal examinations during labor 1
- Care should be led by senior anaesthetist and obstetrician 1
Peri-Operative Management
The decision to continue or temporarily cease hormone therapy before surgery requires individualized thrombosis risk assessment, particularly for transgender women on estrogen given elevated VTE risk. 7 Thromboprophylaxis strategies are essential peri-operatively. 7