How to manage hyperestrogenism (elevated estrogen levels) in men undergoing testosterone therapy?

Management of Hyperestrogenism in Men on Testosterone Therapy

Aromatase inhibitors are the most effective treatment for managing elevated estrogen levels in men on testosterone therapy, with anastrozole being the most commonly prescribed medication at a typical starting dose of 0.5 mg three times weekly. 1

Pathophysiology and Prevalence

• Testosterone therapy can lead to elevated estradiol levels due to peripheral aromatization of testosterone to estrogen, particularly in adipose tissue 2
• Approximately 3% of men on testosterone therapy develop elevated estradiol levels requiring intervention 1
• Higher rates of elevated estradiol are seen with injectable testosterone formulations (38.6%) compared to topical preparations (34.1%) 1
• Men between 45-65 years have the highest prevalence (22.1%) of hyperestrogenism during testosterone therapy 2

Clinical Presentation and Diagnosis

• Measure serum estradiol in men on testosterone therapy who present with:

  • Gynecomastia or breast symptoms (pain, tenderness) 3
  • Sexual dysfunction (particularly orgasmic function impairment) 4
  • Erectile dysfunction (hyperestrogenism is associated with more severe ED) 4

• Normal estradiol range for men: <42.6 pg/mL 2

• Consider intervention when:

  • Estradiol levels >60 pg/mL regardless of symptoms 1
  • Estradiol levels 40-60 pg/mL with symptoms 1

Treatment Options

First-Line Treatment: Aromatase Inhibitors

• Anastrozole is the most commonly prescribed medication (62.3% of cases) for symptomatic hyperestrogenism 5
• Typical starting dose: 0.5 mg three times weekly 1
• Goal: Reduce estradiol to normal range (below 42.6 pg/mL) while maintaining therapeutic testosterone levels 1
• Median pre-treatment estradiol levels of 65 pg/mL can be reduced to 22 pg/mL with appropriate aromatase inhibitor therapy 1

Alternative Options

• Selective estrogen receptor modulators (SERMs) may be used as an alternative to aromatase inhibitors 3
• Consider adjusting testosterone therapy:
  • Switching from injectable to topical formulations may reduce estradiol levels 1
  • Reducing testosterone dosage to achieve levels in the mid-normal range (450-600 ng/dL) rather than high-normal range 3

Monitoring and Follow-up

• Measure estradiol levels 4-6 weeks after initiating treatment 1
• Continue monitoring testosterone levels every 6-12 months while on therapy 3
• Assess for symptom improvement (breast symptoms, sexual function) 3
• Monitor for potential side effects of aromatase inhibitors:
  • Bone mineral density changes (long-term use)
  • Joint pain
  • Fatigue

Important Considerations and Cautions

• Contrary to common belief, high estradiol levels were not associated with higher rates of low libido in a large study of 34,016 men 2
• Commercially manufactured products should be prescribed rather than compounded formulations 3
• Avoid alkylated oral testosterone due to risk of liver toxicity 3
• Consider discontinuing testosterone therapy if target levels are achieved but symptoms do not improve after 3-6 months 3
• Monitor hemoglobin/hematocrit, as testosterone therapy increases risk of erythrocytosis, particularly with injectable formulations 3

Special Populations

• For men with fertility concerns, avoid exogenous testosterone therapy as it suppresses spermatogenesis 3
• In men with fertility concerns who need treatment for testosterone deficiency, consider human chorionic gonadotropin (hCG) as it is the only FDA-approved agent among fertility-preserving options 3, 6