How to manage a male patient with hyperestradiolism on anastrozole with normal testosterone levels?

Management of Male Hyperestradiolism on Anastrozole with Normal Testosterone

Immediate Assessment and Verification

For a male patient with elevated estradiol on anastrozole who is not on testosterone therapy, the first priority is to discontinue anastrozole immediately and investigate the underlying cause of hyperestradiolism, as anastrozole is not indicated for this condition in men with normal testosterone levels. 1, 2

The European Association of Urology explicitly recommends against using aromatase inhibitors in eugonadal men (those with normal testosterone levels), even for metabolic concerns, as there is no evidence of benefit and potential for harm 2. Anastrozole works by blocking the conversion of testosterone to estradiol, but in men not on testosterone therapy, its use can paradoxically worsen the hormonal imbalance by triggering compensatory increases in gonadotropins 3.

Diagnostic Workup Required

Confirm the Diagnosis

• Repeat morning total testosterone (8-10 AM) on two separate occasions to verify truly normal levels (>300 ng/dL) 1, 2
• Measure free testosterone by equilibrium dialysis if total testosterone is borderline, as SHBG alterations can mask true hypogonadism 1, 2
• Repeat estradiol measurement after discontinuing anastrozole for 2-4 weeks to establish true baseline levels 4

Identify the Etiology of Elevated Estradiol

• Measure LH and FSH levels to distinguish primary from secondary causes 1
• Check serum prolactin if LH/FSH are low or low-normal, as hyperprolactinemia can cause hormonal imbalances 1
• Obtain sex hormone-binding globulin (SHBG) to assess for functional abnormalities 2
• Assess for obesity and metabolic syndrome, as excessive aromatization in adipose tissue is the most common cause of elevated estradiol in eugonadal men 2, 5

Rule Out Serious Pathology

• Men with elevated baseline estradiol measurements should be referred to an endocrinologist to exclude estrogen-secreting tumors, testicular tumors, or other endocrine disorders 1
• If testosterone is <150 ng/dL with low/normal LH, obtain pituitary MRI to exclude non-secreting adenomas 1

Treatment Algorithm

If Obesity is Present (BMI ≥25 kg/m²)

First-line intervention is weight loss through calorie-restricted diets and regular exercise, as this addresses the root cause of excessive aromatization in adipose tissue and can normalize the testosterone-to-estradiol ratio without medication 2, 5. Studies demonstrate that weight loss improves hormonal profiles in men with obesity-associated hormonal imbalances 5.

If True Hypogonadism is Confirmed (Testosterone <300 ng/dL)

• Anastrozole 1 mg daily can be considered as monotherapy to increase endogenous testosterone production while lowering estradiol 5, 6
• Expected outcomes include increases in testosterone (mean increase 52% from 271 to 412 ng/dL), decreases in estradiol (mean decrease from 32 to 16 pg/mL), and improvement in testosterone-to-estradiol ratio (from 9 to 26.5) after 5 months 5
• Monitor hormonal response at 6-8 weeks: measure testosterone, estradiol, LH, and FSH 5, 6
• If fertility is desired, anastrozole is preferred over testosterone replacement, as it preserves spermatogenesis 1, 5

If Testosterone Remains Normal After Workup

Do not restart anastrozole. The European Association of Urology strongly recommends against aromatase inhibitor therapy in eugonadal men 2. Instead:

• Address underlying causes: optimize metabolic health, treat sleep apnea if present, discontinue medications that may increase estradiol (e.g., certain antipsychotics, chronic opioids) 2
• If gynecomastia or breast symptoms are present, anastrozole may provide symptomatic relief (resolution of tenderness within 4 weeks in most cases), but breast tissue reduction is limited and surgery remains the definitive treatment 7
• Refer to endocrinology for persistent unexplained hyperestradiolism despite normal testosterone 1

Critical Pitfalls to Avoid

• Never continue anastrozole in a eugonadal man without a clear indication, as this violates evidence-based guidelines and may cause harm through excessive estradiol suppression 2
• Never assume elevated estradiol alone justifies treatment without confirming symptoms (gynecomastia, breast tenderness) or underlying hypogonadism 1, 7
• Never diagnose hypogonadism based on a single testosterone measurement due to assay variability and diurnal fluctuation 1, 2
• Never overlook obesity as the primary driver of hormonal imbalance, as weight loss is more effective and safer than pharmacologic intervention 2, 5

Monitoring If Anastrozole is Continued (Only in Hypogonadal Men)

• Measure testosterone, estradiol, LH, and FSH at 6-8 weeks, then every 3-6 months 5, 6
• Target testosterone-to-estradiol ratio >10 for optimal hormonal balance 5
• Discontinue if no improvement in symptoms or hormonal parameters after 6 months 7, 5
• Monitor for adverse effects: acne, testicular enlargement, and changes in bone density with long-term use 4, 7