What is the appropriate treatment for elevated estrogen levels in men using Anastrazole (generic name: anastrozole)?

Anastrozole for Elevated Estrogen in Men

Direct Recommendation

Anastrozole is NOT FDA-approved for use in men and should only be considered off-label in specific clinical scenarios: men on testosterone therapy with estradiol levels >60 pg/mL (or >40 pg/mL with symptoms) who have undergone mandatory bone density screening and do not have contraindications. 1, 2, 3

FDA-Approved Indications

• Anastrozole is FDA-approved exclusively for postmenopausal women with breast cancer 2
• The drug has no FDA-approved indication for use in males 2
• All use in men represents off-label prescribing 1

Mechanism in Males

Anastrozole blocks aromatase enzyme activity, preventing conversion of testosterone to estradiol in peripheral tissues. 2

• In men, this inhibition reduces circulating estradiol by approximately 50-70% within 24 hours and 80% after 14 days 2
• Unlike postmenopausal women where aromatase is the primary estrogen source, men have more complex hormonal dynamics 2
• The drug causes compensatory increases in testosterone (58% increase), LH, and FSH due to reduced negative feedback 4

Clinical Scenarios Where Use May Be Considered

Men on Testosterone Replacement Therapy

The most evidence-supported use is in men receiving testosterone therapy who develop elevated estradiol levels. 1, 3

• Treat when estradiol >60 pg/mL regardless of symptoms OR >40 pg/mL with symptoms 1, 3
• Approximately 2.6-3% of men on testosterone therapy require aromatase inhibitor treatment 3
• Men on intramuscular testosterone have higher rates of elevated estradiol requiring treatment compared to topical formulations 3

Dosing Regimen

The recommended dose is anastrozole 0.5 mg three times weekly (NOT daily dosing). 1, 3

• This intermittent dosing prevents excessive estradiol suppression while maintaining efficacy 1
• Daily dosing (1 mg/day as used in women) is excessive for men and increases adverse effects 5, 3
• Clinical practice shows significant variability, with some practitioners incorrectly using doses from 1 mg weekly to 1 mg daily 5

Expected Hormonal Changes

• Median estradiol decreases from 65 pg/mL to 22 pg/mL (P <0.001) 3
• Testosterone levels remain stable (616 ng/dL pre-treatment vs 596 ng/dL post-treatment, P=0.926) 3
• Treatment successfully reduces estradiol in approximately 68% of men 3

MANDATORY Pre-Treatment Evaluation

Before prescribing anastrozole to any patient, baseline bone mineral density (BMD) and fracture risk MUST be measured—this is an absolute requirement. 6, 1

Absolute Contraindications

• Severe osteoporosis (T-score <-4) 6, 1
• More than two vertebral fractures 6, 1

Relative Contraindications Requiring Extreme Caution

• Moderate bone mineral density loss requires consideration of concurrent bisphosphonates or RANKL inhibitors 6, 1
• History of osteoporosis should prompt consideration of alternative approaches 6

Required Concurrent Bone Protection

ALL patients on anastrozole must receive: 6, 1

• Calcium supplementation
• Vitamin D supplementation
• Regular weight-bearing exercise
• Annual BMD monitoring if continuing long-term 1

Common Adverse Effects to Counsel Patients About

Joint symptoms are the most common adverse effect and should be explicitly discussed. 6, 1

• Arthralgias and joint stiffness occur very commonly 6, 1
• Vasomotor symptoms including hot flashes 6, 1
• Hypertension and potential cardiovascular effects 1
• Dry eyes and vaginal dryness (though less relevant in males) 6
• Myalgias and fatigue 7

Metabolic Effects in Males

Short-term studies show anastrozole does NOT significantly affect body composition, protein metabolism, or muscle strength in men. 4

• No changes in fat mass, fat-free mass, or body mass index after 10 weeks 4
• No changes in protein synthesis, degradation, or oxidation rates 4
• No changes in muscle strength by isokinetic dynamometry 4
• IGF-1 decreases by 18% despite no change in growth hormone 4

Bone Effects in Males

Short-term data (10 weeks) shows no immediate negative impact on bone turnover markers, but long-term safety is unknown. 4

• Osteocalcin and bone alkaline phosphatase remain unchanged 4
• Kinetically measured bone calcium deposition and resorption rates unchanged 4
• However, in postmenopausal women, anastrozole increases fracture risk during treatment 6, 8
• The long-term bone safety in men remains unstudied and represents a significant knowledge gap 4

Alternative Approach: Optimize Testosterone First

Before adding anastrozole, consider adjusting testosterone dosing to achieve mid-normal range levels (400-600 ng/dL) to minimize aromatization. 1

• This avoids polypharmacy and additional medication risks 1
• Switching from intramuscular to topical testosterone may reduce aromatization 3
• Lower testosterone doses naturally produce less substrate for conversion to estradiol 1

Monitoring Protocol

Regular monitoring is essential to ensure efficacy and safety. 1, 3

• Repeat estradiol and testosterone levels after initiating therapy 3
• Monitor for symptom resolution 3
• Annual bone mineral density if continuing long-term 1
• Assess for musculoskeletal symptoms at each visit 1
• Monitor blood pressure and cardiovascular parameters 1

Critical Practice Gaps and Variability

Current practice shows concerning variability in monitoring and prescribing patterns. 5

• Only 54.7% of practitioners monitor estrogen levels in men on testosterone therapy 5
• Significant variability exists in starting doses and regimens 5
• 14.4% of practitioners prescribe anastrozole prophylactically without elevated levels—this practice lacks evidence support 5

Fertility Considerations

If fertility preservation is a concern, anastrozole may be preferable to testosterone monotherapy alone. 1

• Anastrozole can potentially improve spermatogenesis by increasing endogenous testosterone while reducing estradiol 1
• However, exogenous testosterone itself suppresses spermatogenesis regardless of estradiol management 6
• Men desiring fertility should consider discontinuing testosterone therapy entirely 6

What NOT to Do

• Do not use anastrozole in premenopausal women (ovarian estrogen production cannot be adequately suppressed) 6, 7
• Do not prescribe without baseline bone density assessment 6, 1
• Do not use daily 1 mg dosing in men (this is the female breast cancer dose) 2, 5
• Do not prescribe prophylactically without documented elevated estradiol 5
• Do not continue indefinitely without monitoring bone health 1

Evidence Quality Assessment

The evidence for anastrozole use in men is limited to off-label case series and survey data 5, 3. The highest quality evidence comes from:

• A 2021 retrospective cohort of 1,708 men on testosterone therapy, where only 44 (2.6%) required anastrozole 3
• A 2000 metabolic study in 8 males showing short-term safety but no long-term data 4
• Expert consensus from urology and endocrinology societies supporting cautious off-label use 1

No randomized controlled trials exist comparing anastrozole to placebo or alternative management strategies in men with elevated estradiol. The recommendations are based on physiologic rationale, small observational studies, and extrapolation from female breast cancer data 5, 3, 4.