What is the recommended approach for female testosterone replacement therapy?

Female Testosterone Replacement Therapy

Testosterone therapy in women should be reserved exclusively for carefully selected postmenopausal women with hypoactive sexual desire disorder (HSDD) who have failed other interventions, using low-dose transdermal formulations with testosterone levels targeted to the upper portion of the normal female reference range. 1, 2, 3

FDA Approval Status and Off-Label Use

• No testosterone preparation is FDA-approved for use in women in the United States, though testosterone therapy has been used off-label for over 40 years to treat low libido and sexual dysfunction 2, 3
• The only FDA-approved androgen for women is intravaginal DHEA (dehydroepiandrosterone) for genitourinary syndrome of menopause, not systemic testosterone replacement 3
• Testosterone enanthate injection is FDA-approved only for metastatic mammary cancer in postmenopausal women (1-5 years post-menopause), not for sexual dysfunction or general hormone replacement 4

Specific Indications for Testosterone Therapy

Primary indication:

• Postmenopausal women with HSDD who are adequately estrogenized and have failed to respond to addressing other contributors to sexual dysfunction (relationship issues, medications, depression, other medical conditions) 2, 3

Clinical presentation requiring consideration:

• Absent or greatly diminished sexual motivation/desire (libido) 2
• Persistent unexplainable fatigue or lack of energy 2
• Lack of sense of well-being 2
• History of bilateral oophorectomy (surgical menopause creates more profound androgen deficiency than natural menopause) 5, 2

Formulation Selection and Dosing Strategy

Preferred formulation:

• Transdermal testosterone (gels or patches) is the only acceptable route for female testosterone replacement 1
• Oral testosterone preparations are absolutely contraindicated due to hepatotoxicity and adverse lipid effects 6, 1
• Injectable testosterone is not recommended for women due to difficulty with dose titration and risk of supraphysiologic levels 7

Target testosterone levels:

• Aim for serum testosterone levels at the upper portion of the normal reference range for reproductive-aged women, or slightly above 1
• Mid-range dosing (avoiding high-normal levels) minimizes adverse effects while maintaining efficacy 7
• Use the lowest effective dose 6

Baseline Assessment Requirements

Before initiating therapy, obtain:

• Complete lipid profile (oral testosterone adversely affects lipids; transdermal does not) 1
• Baseline hematocrit/hemoglobin (testosterone can cause erythrocytosis) 6, 7
• Liver function tests if any hepatic concerns 6
• Cardiovascular risk assessment 1
• Breast examination and mammography per age-appropriate guidelines 6
• Endometrial assessment if uterus present and not on adequate progestogen 1

Clinical history must exclude:

• Active breast cancer or history of breast cancer 4
• Cardiovascular disease (relative contraindication requiring careful risk-benefit analysis) 1
• Liver disease 6
• Polycythemia or conditions predisposing to hyperviscosity 7

Monitoring Protocol During Therapy

First follow-up visit at 1-2 months:

• Assess symptomatic response (sexual function, energy, well-being) 6
• Measure serum testosterone level 6
• Check hematocrit/hemoglobin 6, 7
• Evaluate for virilizing side effects (acne, hirsutism, voice changes) 1

Subsequent monitoring every 3-6 months for first year, then annually:

• Serum testosterone levels 6
• Hematocrit/hemoglobin (erythrocytosis occurs in 3-18% with transdermal formulations) 7
• Lipid profile 6
• Clinical assessment of sexual function and quality of life 6
• Skin examination for local reactions (erythema/pruritus occurs in up to 66% with patches, 5% with gels) 6
• Breast examination and age-appropriate mammography 6
• Cardiovascular assessment 1

Efficacy Evidence

• Controlled trials up to 2 years demonstrate that testosterone added to estrogen significantly improves multiple facets of sexual function including libido, desire, arousal, frequency, and satisfaction in postmenopausal women 2
• Short-term studies show no increased risk of hepatotoxicity, endometrial hyperplasia, or behavioral hostility when testosterone levels are maintained at appropriate ranges 1
• Women tolerate low-dose testosterone therapy well with no serious side effects in trials up to 2 years 2

Safety Considerations and Side Effects

Common, reversible side effects:

• Mild acne and hirsutism (dose-dependent and reversible) 1
• Skin reactions at application site (more common with patches than gels) 6

Serious potential risks requiring monitoring:

• Erythrocytosis/polycythemia (can lead to hyperviscosity and thrombotic risk) 7
• Lipid profile changes with oral formulations only (transdermal does not adversely affect lipids) 1
• Theoretical breast cancer risk (data mixed; some studies suggest testosterone may decrease estrogen-induced breast proliferation) 1

No evidence of increased risk for:

• Cardiovascular events (no adverse effects on blood pressure, blood viscosity, arterial reactivity, or hypercoagulable states in short-term studies) 1
• Endometrial hyperplasia or cancer 1, 5

Critical Pitfalls to Avoid

• Never use oral testosterone preparations due to hepatotoxicity and neoplasia risk 6
• Never prescribe testosterone without concurrent adequate estrogen replacement in postmenopausal women (testosterone therapy requires adequate estrogenization) 2
• Never allow supraphysiologic testosterone levels (increases risk of virilization and other adverse effects) 3
• Never ignore rising hematocrit (if hematocrit rises above reference range, temporarily withhold therapy, reduce dose, or perform phlebotomy) 6, 7
• Never prescribe long-acting injectable formulations to women (impossible to titrate and reverse if adverse effects occur) 7
• Never continue therapy without documented clinical benefit (if no improvement in sexual function after adequate trial, discontinue) 6

Duration of Therapy

• Continue therapy only as long as clinical benefit persists and patient desires treatment 3
• Long-term safety beyond 2 years is unknown - patients must be counseled about this limitation 1, 3
• Reassess need for continuation at each monitoring visit 6
• Consider discontinuation trial periodically to determine if ongoing therapy remains necessary 3

Contraindications

Absolute contraindications:

• Active or history of breast cancer 4
• Pregnancy 4
• Active liver disease 6

Relative contraindications requiring careful assessment:

• Cardiovascular disease 1
• Polycythemia or conditions causing hyperviscosity 7
• Severe acne or hirsutism 1

Patient Counseling Requirements

Patients must understand:

• Testosterone therapy is not FDA-approved for sexual dysfunction in women 2, 3
• Long-term safety data (>2 years) are lacking, particularly regarding cardiovascular risk and breast cancer 1, 3
• Virilizing effects (voice deepening, clitoral enlargement) may be irreversible if they occur 1
• Therapy requires ongoing monitoring with regular blood tests and clinical assessments 6
• Alternative treatments for sexual dysfunction should be exhausted first 3