How to manage elevated estrogen symptoms in men on testosterone replacement therapy (TRT)?

Management of Elevated Estrogen Symptoms in Men on Testosterone Replacement Therapy

Aromatase inhibitors are the first-line treatment for managing elevated estrogen symptoms in men on testosterone replacement therapy, with anastrozole 0.5mg three times weekly being the most effective regimen to reduce estradiol levels while maintaining testosterone levels. 1

Clinical Presentation of Elevated Estrogen in Men on TRT

• Breast tenderness and swelling (gynecomastia) are common symptoms of elevated estradiol levels in men receiving testosterone replacement therapy 2
• Other symptoms may include fluid retention, though this is generally mild and uncommon 2
• Approximately 20.2% of men on testosterone therapy develop high estradiol levels (≥42.6 pg/mL) 3
• Contrary to common belief, high estradiol levels are not associated with higher rates of low libido; in fact, normal or lower estradiol levels are associated with higher rates of documented low libido 3

Diagnostic Approach

• Measure serum estradiol levels in patients who present with breast symptoms or gynecomastia 4
• Consider estradiol testing in all men on testosterone therapy, particularly those using injectable testosterone which has higher rates of estradiol elevation 1
• Elevated estradiol is defined as levels >60 pg/mL regardless of symptoms, or 40-60 pg/mL with subjective symptoms 1
• Monitor total testosterone levels to ensure they remain in the therapeutic range while managing estradiol 2

Treatment Algorithm

First-Line Treatment: Aromatase Inhibitors

• Anastrozole (0.5 mg three times weekly) is the most commonly used and effective aromatase inhibitor for reducing estradiol levels 1
• Aromatase inhibitors work by inhibiting the conversion of testosterone to estradiol by blocking the aromatase enzyme 5
• Treatment with anastrozole can reduce median estradiol levels from 65 pg/mL to 22 pg/mL without significantly affecting total testosterone levels 1

Alternative Approaches

• Selective estrogen receptor modulators (SERMs) may be used to block the effects of estrogen at the receptor level 2
• Human chorionic gonadotropin (hCG) can be considered, particularly in men who wish to maintain fertility 2, 6
• Consider adjusting the testosterone dosage or changing the route of administration, as intramuscular injections are associated with higher rates of estradiol elevation than topical formulations 1

Monitoring During Treatment

• After initiating aromatase inhibitor therapy, follow up within 1-2 months to assess efficacy 2
• Measure estradiol levels to ensure reduction to target range 1
• Monitor testosterone levels to ensure they remain in the therapeutic range 2
• Continue routine monitoring of hematocrit/hemoglobin, as elevated testosterone can lead to erythrocytosis 2
• For men over 40, monitor PSA levels to screen for prostate abnormalities 4

Special Considerations

• For men desiring fertility, aromatase inhibitors may be preferred over adjusting testosterone therapy, as exogenous testosterone can suppress spermatogenesis 6
• Aromatase inhibitors do not affect cortisol or aldosterone secretion, so glucocorticoid or mineralocorticoid replacement therapy is not necessary 5
• Injectable testosterone is associated with higher rates of estradiol elevation compared to topical formulations (38.6% vs 34.1%) 1

Clinical Pitfalls to Avoid

• Do not discontinue testosterone therapy without addressing the underlying cause of elevated estradiol 2
• Avoid excessive reduction of estradiol, as very low levels may negatively impact libido 3
• Do not use compounded testosterone products when commercially manufactured products are available, as they may have inconsistent potency and quality 2
• Remember that elevated endogenous testosterone levels are not generally associated with significant clinical morbidity, suggesting that the target range for testosterone therapy may be broader than traditionally thought 7