Will adding Testosterone Replacement Therapy (TRT) improve estradiol levels in patients with low testosterone levels?

Will TRT Improve Estradiol Levels?

Yes, testosterone replacement therapy (TRT) will increase estradiol levels in men with low testosterone, as testosterone is aromatized to estradiol in peripheral tissues, particularly adipose tissue. 1

Mechanism of Estradiol Increase on TRT

• Aromatization is the primary mechanism: Testosterone administered during TRT is converted to estradiol by the enzyme aromatase, which is particularly abundant in adipose tissue 1, 2
• FDA-labeled pharmacokinetics confirm this: The official testosterone gel prescribing information explicitly states that "mean estradiol and DHT concentration profiles paralleled the changes observed in testosterone" during treatment 3
• The AUA guideline acknowledges this phenomenon: It is "not uncommon for estradiol levels to increase while patients are on testosterone therapy as total testosterone increases" 1

Clinical Significance and Monitoring

When to Measure Estradiol

• Measure baseline estradiol only in specific circumstances: The AUA recommends measuring serum estradiol in testosterone deficient patients who present with breast symptoms or gynecomastia prior to commencing testosterone therapy 1
• Routine monitoring is not recommended: There is no guideline recommendation for routine estradiol monitoring in asymptomatic men on TRT 1

Prevalence of Elevated Estradiol on TRT

• Elevated estradiol occurs in approximately 20% of men on TRT: In a large cohort of 34,016 men screened at Low T Centers, 7,215 (20.2%) developed high estradiol levels (defined as ≥42.6 pg/ml) after injectable testosterone therapy 4
• Age affects risk: Men aged 45-65 years had the highest rates of hyperestrogenism (22.1%), while those under 25 had the lowest rates (3.3%) 4

Clinical Consequences

• Symptomatic gynecomastia is uncommon: Despite estradiol increases, the AUA notes that symptomatic gynecomastia or other breast symptoms are uncommon on TRT 1
• High estradiol may not correlate with symptoms: Interestingly, one study found that high estradiol levels were not associated with higher rates of low libido; in fact, men with normal or lower estradiol levels had higher documented rates of low libido 4
• Cardiovascular considerations: The Princeton III Consensus found associations between high estradiol levels and cardiovascular disease in cross-sectional studies, though causality remains unclear 1

Management of Elevated Estradiol on TRT

When to Intervene

• Treat based on symptoms, not just numbers: Men who develop breast pain, breast tenderness, or nipple tenderness on TRT should be monitored, as symptoms sometimes abate without intervention 1
• Refer elevated baseline levels: Men with elevated baseline estradiol measurements should be referred to an endocrinologist before starting TRT 1

Treatment Options if Needed

• Aromatase inhibitors are effective: Anastrozole 0.5 mg three times weekly can reduce estradiol levels in men on TRT with levels >60 pg/mL or 40-60 pg/mL with symptoms 5
• Documented efficacy: In men treated with anastrozole, median estradiol decreased from 65 pg/mL to 22 pg/mL (p<0.001) while maintaining testosterone levels 5
• Only 2.6% require treatment: In a large cohort, only 44 of 1,708 men (2.6%) on TRT required aromatase inhibitor therapy for elevated estradiol 5

Important Caveats

• Obesity increases aromatization: Men with obesity have higher rates of testosterone-to-estradiol conversion due to increased adipose tissue aromatase activity 1, 2
• Laboratory variability is significant: There is no single standard for estradiol measurement, and results vary considerably between laboratories; serial measurements should be performed at the same laboratory 2
• TRT formulation matters: Injectable testosterone may result in higher estradiol levels compared to topical formulations, with 38.6% of men requiring aromatase inhibitors using intramuscular TRT versus 34.1% using topical 5