Can men with hyperestrogenism (high estrogen levels) on testosterone therapy use anastrazole (generic name: anastrazole) to reduce estrogen production?

Anastrozole Use in Men on Testosterone Therapy with Elevated Estrogen

Anastrozole can be used off-label in men with elevated estrogen on testosterone therapy, though this represents use outside FDA-approved indications, which are exclusively for postmenopausal women with breast cancer. 1

Evidence for Use in Men on Testosterone Therapy

The most relevant clinical data comes from a 2021 study demonstrating that anastrozole 0.5 mg three times weekly effectively reduces estradiol levels in men on testosterone therapy from a median of 65 pg/mL to 22 pg/mL (P < 0.001) while maintaining stable testosterone levels (616 ng/dL pre-treatment vs 596 ng/dL post-treatment). 2 This study treated men with estradiol >60 pg/mL or >40 pg/mL with symptoms, finding that 68% achieved adequate estradiol reduction. 2

Mechanism and Hormonal Effects

Aromatase inhibitors like anastrozole block the conversion of testosterone to estradiol by inhibiting cytochrome P450 enzymes, which can increase endogenous testosterone production while decreasing estrogen. 3 In men on testosterone replacement, this prevents excessive aromatization of exogenous testosterone to estradiol. 1

Critical Safety Considerations Before Prescribing

Mandatory Bone Health Assessment

Before initiating anastrozole, you must measure baseline bone mineral density and assess fracture risk, as this is an absolute requirement regardless of the indication. 3, 1, 4

• Severe osteoporosis (T-score < -4 or >2 vertebral fractures) is an absolute contraindication to anastrozole use. 3, 1, 4
• Moderate bone density loss requires extreme caution and consideration of concurrent bone-protective agents like bisphosphonates or RANKL inhibitors. 3, 1
• All patients on anastrozole require calcium and vitamin D supplementation plus regular weight-bearing exercise. 3, 1, 4

Bone Metabolism Effects in Men

The evidence on bone effects in men is mixed. A 2005 study in elderly hypogonadal men showed that anastrozole 1 mg daily for 12 weeks decreased estradiol from 26 pg/mL to 17 pg/mL while increasing testosterone from 99 ng/dL to 207 ng/dL, but did not increase bone resorption markers or decrease bone mineral density over this short period. 5 However, a 2001 study in eugonadal older men found that anastrozole 2 mg daily increased bone resorption markers (C-telopeptide increased 33% by 9 weeks) and decreased bone formation markers despite only a 29% reduction in estradiol. 6

The conflicting data suggests that bone effects may depend on baseline testosterone levels and degree of estradiol suppression, but caution is warranted given the established bone toxicity in postmenopausal women. 3, 5, 6

Expected Adverse Effects

Patients must be counseled about common side effects:

• Joint stiffness and arthralgias (very common). 3, 1, 4
• Vasomotor symptoms including hot flashes. 3, 1, 4
• Hypertension and potential cardiovascular effects. 3, 1, 4
• Dry eyes and potential mood changes. 3, 4

Dosing Recommendations

The most commonly studied regimen in men on testosterone therapy is anastrozole 0.5 mg three times weekly, which appears safer than daily dosing by limiting excessive estradiol suppression. 2 Daily dosing of 1 mg (the FDA-approved dose for postmenopausal women) may suppress estradiol too aggressively in men. 3

Alternative Approach: Optimize Testosterone Dosing First

Before adding anastrozole, consider adjusting testosterone dosing to achieve mid-normal range levels (400-600 ng/dL) to minimize aromatization, as this avoids polypharmacy and additional risks. 1 Men on intramuscular testosterone may have higher rates of estradiol elevation compared to topical formulations. 2

Monitoring Protocol

• Measure estradiol and testosterone levels 4-6 weeks after initiating anastrozole to ensure adequate estradiol reduction without excessive suppression. 2
• Target estradiol levels of 20-40 pg/mL (avoiding both excessive elevation and over-suppression below 10-15 pg/mL). 2
• Repeat bone mineral density annually if continuing long-term therapy. 3, 1
• Monitor for musculoskeletal symptoms and cardiovascular parameters. 3, 1

Fertility Considerations

If fertility preservation is a concern, anastrozole may be preferable to continuing exogenous testosterone alone, as it can improve spermatogenesis. 3 A 2021 study in hypogonadal subfertile men with BMI ≥25 kg/m² showed that anastrozole 1 mg daily increased sperm concentration from 7.8 to 14.2 million/mL and achieved a 46.6% clinical pregnancy rate. 7 The AUA guidelines note that aromatase inhibitors can be used in men desiring fertility as an alternative to exogenous testosterone. 3

Key Clinical Pitfall

The most critical error is prescribing anastrozole without baseline bone density assessment and ongoing bone health monitoring, as this exposes patients to fracture risk without appropriate surveillance. 3, 1, 4