Is it safe for women to take spironolactone while undergoing Hormone Replacement Therapy (HRT) with testosterone?

Spironolactone Use During Testosterone HRT for Transgender Women

Spironolactone is safe and effective to use during testosterone-suppressing hormone therapy for transgender women, as it is one of the most commonly recommended anti-androgens specifically for this purpose. 1

Clinical Rationale and Mechanism

Spironolactone serves as a cornerstone anti-androgen in feminizing hormone therapy by:

• Decreasing testosterone production directly 2
• Competitively blocking testosterone and dihydrotestosterone binding to androgen receptors in target tissues 2
• Enabling lower estrogen doses while achieving adequate testosterone suppression 1

The Endocrine Society specifically identifies spironolactone as the most commonly used anti-androgen in many countries for transgender women undergoing feminizing hormone therapy. 1

Dosing and Target Levels

Standard spironolactone dosing ranges from 100-200 mg daily when combined with estradiol therapy. 3, 4

• Target testosterone levels should be <50 ng/dL (female reference range) 1
• Target estradiol levels should be in the cisgender female reference range 1
• One study using spironolactone 100 mg/day with estradiol achieved female-range testosterone in only 19% of participants, while higher doses (200-600 mg/day) successfully lowered testosterone to female range in most subjects 3, 4

Monitoring Requirements

Initial monitoring should occur every 3 months during the first year, then annually if stable. 1

Baseline assessment must include:

• Complete blood count, liver function, lipid profile, glucose 1
• Baseline testosterone and estradiol levels 1
• Blood pressure measurement 2, 5
• Serum potassium and renal function 6

Safety Profile and Side Effects

Hyperkalemia risk is minimal in young, healthy individuals with normal renal, hepatic, and adrenal function. 2, 5

• In women aged 18-45 taking spironolactone 50-200 mg daily, only 0.75% of potassium measurements exceeded 5.0 mmol/L, and six of 13 abnormal tests normalized on repeat testing 2
• Routine potassium monitoring is not required unless specific risk factors exist (chronic kidney disease, diabetes, baseline potassium >5.0 mEq/L) 5, 6

Common dose-related side effects include:

• Diuresis (29%) 2
• Menstrual irregularities (22%) - not applicable to transgender women 2
• Breast tenderness (17%) and enlargement 2
• Fatigue, headache, dizziness 2

Clinical Effectiveness

Spironolactone combined with estradiol produces excellent feminization results in most transgender women. 4

A 12-month study of 50 transgender women using spironolactone (200-600 mg/day) with physiologic estrogen doses demonstrated:

• Testosterone decreased from 642 ng/dL to 49 ng/dL 4
• Excellent clinical response including decreased male-pattern hair, breast development, feminization, and decreased erections 4
• Systolic blood pressure decreased from 128 to 121 mm Hg 4

Important Caveat: Comparative Efficacy

Cyproterone acetate demonstrates superior testosterone suppression compared to spironolactone (90% vs 19% achieving target testosterone <50 ng/dL at equivalent estrogen doses), but carries risks of drug-induced liver injury and hyperprolactinemia. 3 This makes spironolactone the preferred first-line option in countries where it is available, with dose escalation as needed to achieve target testosterone levels.

Contraindications

Avoid spironolactone in patients with:

• Significant renal impairment 2
• Cardiovascular disease requiring ACE inhibitors 2
• Baseline hyperkalemia 6
• Severe hepatic dysfunction 2