What is a typical MTF (Male-To-Female) Hormone Replacement Therapy (HRT) protocol?

MTF Hormone Replacement Therapy Protocol

Core Feminizing Hormone Regimen

For male-to-female gender-affirming hormone therapy, initiate 17β-estradiol at 1-2 mg daily (oral) or 50-100 mcg daily (transdermal), combined with an antiandrogen, and add micronized progesterone 100-200 mg daily after 12-24 months of estrogen therapy. 1, 2, 3

Estrogen Component

• Transdermal 17β-estradiol is the preferred route at 50-100 mcg daily, as it avoids hepatic first-pass metabolism, minimizes thrombotic risk, and provides more physiologic serum levels compared to oral formulations 1
• Oral 17β-estradiol 1-2 mg daily is an acceptable alternative if transdermal is not tolerated or available 1, 3
• Start at the lower end of the dosing range and titrate upward based on clinical response and serum estradiol levels 3
• Avoid ethinyl estradiol-based preparations (like birth control pills) as they carry higher cardiovascular and thrombotic risks 1

Antiandrogen Component

• Spironolactone 100-200 mg daily (divided doses) is the most commonly used antiandrogen in the United States
• Alternatives include cyproterone acetate 10-50 mg daily (not available in US) or GnRH agonists for complete testosterone suppression
• Finasteride 5 mg daily can be added for additional androgen blockade, particularly for scalp hair preservation

Progesterone Addition

• Add micronized progesterone 100-200 mg daily orally after 12-24 months of estrogen therapy to support breast development and overall feminization 2
• Micronized progesterone is strongly preferred over synthetic progestins due to superior cardiovascular and metabolic safety profile 1, 2
• Administer at bedtime as it may cause sedation
• Avoid medroxyprogesterone acetate (MPA) in this population due to unfavorable effects on lipids, vasomotion, and cardiovascular risk 1

Monitoring Protocol

Baseline Assessment (Before Initiating HRT)

• Complete blood count, comprehensive metabolic panel, lipid panel 4, 5
• Liver function tests (transaminases, bilirubin) 4
• Serum testosterone and estradiol levels 1
• Prolactin level (baseline for future monitoring)
• Fasting glucose or HbA1c
• Consider bone density (DEXA) if risk factors present 1

Follow-Up Monitoring Schedule

• At 3 months: Serum estradiol (target 100-200 pg/mL), testosterone (target <50 ng/dL), liver enzymes, electrolytes (if on spironolactone) 3, 4
• At 6 months: Repeat hormone levels, lipid panel, prolactin 4, 5
• Annually thereafter: Complete metabolic panel, lipid panel, hormone levels, prolactin, clinical assessment 3, 4
• Every 3-6 months: Clinical reassessment of feminization progress, side effects, and treatment goals 3

Critical Safety Considerations

Absolute Contraindications

• History of estrogen-sensitive malignancy (breast, endometrial) 6
• Active or recent (within 1 year) venous thromboembolism 1, 7
• Active liver disease or significantly elevated transaminases 1
• Uncontrolled cardiovascular disease 1, 7

Common Pitfalls to Avoid

• Do not use conjugated equine estrogens or ethinyl estradiol - these carry higher thrombotic risk than bioidentical 17β-estradiol 1
• Do not add progestin in the first year - allow estrogen monotherapy to establish baseline feminization first 2
• Do not use synthetic progestins (MPA, norethindrone) when micronized progesterone is available due to inferior safety profile 1, 2
• Do not prescribe without baseline and ongoing monitoring - hormone levels guide dose adjustments and detect complications early 3, 4

Managing Common Side Effects

• Venous thromboembolism risk: Transdermal estradiol significantly reduces this risk compared to oral; consider this route for anyone with VTE risk factors 1, 7
• Elevated liver enzymes: Switch from oral to transdermal estradiol; if persistent, reduce dose or discontinue 1
• Hyperkalemia (with spironolactone): Monitor potassium at 1 month, then periodically; avoid potassium supplements and ACE inhibitors 1
• Inadequate feminization: Check compliance first, then verify serum estradiol levels are in target range (100-200 pg/mL) before increasing dose 3

Duration and Long-Term Management

• Continue therapy indefinitely as discontinuation will result in reversal of feminizing effects and return of masculine characteristics 3, 7
• After orchiectomy, antiandrogen can be discontinued but estrogen must be continued lifelong to prevent osteoporosis 1, 3
• Reassess risks and benefits every 3-6 months initially, then annually once stable 3, 5
• Bone density monitoring every 2 years if risk factors present or after orchiectomy 1