What are the long-term health effects of targeting upper normal testosterone levels with testosterone replacement therapy (TRT)?

Long-Term Health Effects of Targeting Upper Normal Testosterone Levels with TRT

Targeting the upper end of normal testosterone levels with TRT is not recommended due to increased risks of erythrocytosis, fluid retention, and potential cardiovascular complications without clear additional benefits to morbidity, mortality, or quality of life. 1

Potential Risks of Upper-Range TRT Targeting

Cardiovascular Effects

• While evidence on cardiovascular risk is mixed, targeting higher testosterone levels increases the likelihood of adverse effects
• The New England Journal of Medicine notes that fluid retention, while generally mild, can be problematic for patients with congestive heart failure or renal insufficiency 1
• Low-certainty evidence from 14 trials showed a possible small increase in adverse cardiovascular events with testosterone treatment (Peto odds ratio, 1.22) 1

Hematologic Effects

• Erythrocytosis is a significant dose-dependent risk:
  • Occurs in 3-18% with transdermal administration
  • Occurs in up to 44% with injection therapy 1
  • Higher testosterone levels correlate with greater risk of elevated hematocrit
  • May increase blood viscosity, potentially aggravating vascular disease in coronary, cerebrovascular, or peripheral circulation 1

Other Physiological Effects

• Fluid retention (uncommon but clinically significant at higher doses)
• Potential worsening of benign prostatic hyperplasia symptoms in older men 2
• Possible worsening of sleep apnea (particularly with higher testosterone levels) 1
• Testicular atrophy and potential infertility through feedback inhibition of the hypothalamic-pituitary-testicular axis 2

Efficacy Considerations

The benefits of targeting upper-normal testosterone levels versus mid-normal levels are not well established:

• Clinical guidelines note: "There is no universal agreement regarding target levels of replacement therapy, although many experienced clinicians aim for the mid- to upper-normal range in order to optimize the response to treatment." 1
• However, the same guidelines explicitly state: "Treatment to raise levels above the physiologic range is discouraged." 1
• The American College of Physicians found that testosterone treatment produced only small improvements in sexual function and quality of life, with little to no benefit for physical function, cognition, and other outcomes 1

Monitoring Recommendations

If TRT is used, careful monitoring is essential, especially when targeting higher testosterone levels:

1. Baseline assessment:

   • PSA and digital rectal examination
   • Hematocrit or hemoglobin level
   • Lipid evaluation (optional)
   • Assessment of voiding symptoms and sleep apnea history 1

2. Follow-up schedule:

   • First follow-up: 1-2 months after initiation
   • Subsequent visits: Every 3-6 months for the first year, then yearly
   • Monitor: Symptomatic response, voiding symptoms, sleep apnea, digital rectal examination, serum testosterone, PSA, hematocrit/hemoglobin 1

3. Dose adjustment protocol:

   • If hematocrit rises above reference range: Consider temporarily withholding TRT, reducing dosage, or performing phlebotomy 1
   • If adequate clinical response is achieved even with low-normal testosterone levels, no dosage adjustment is needed 1

Evidence Quality and Limitations

• Long-term safety data on testosterone therapy targeting upper-normal levels is lacking 1
• Most studies excluded men with recent cardiovascular disease, limiting generalizability 1
• The FDA has required manufacturers to conduct controlled clinical trials to evaluate cardiovascular outcomes of testosterone therapy 1
• The TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) is following participants for up to 5 years for cardiovascular and prostate safety 1

Clinical Recommendation

Based on the available evidence, a more conservative approach targeting mid-normal testosterone levels appears to offer the best balance of benefits and risks:

1. Target mid-normal testosterone range rather than upper-normal to minimize risk of adverse effects
2. Adjust based on symptom response rather than solely on testosterone levels
3. Monitor closely for erythrocytosis, cardiovascular effects, and prostate health
4. Consider individual risk factors - particularly avoid targeting upper-normal levels in men with cardiovascular disease, sleep apnea, or BPH

The primary goal should be symptom management rather than achieving specific testosterone levels, as improvements in quality of life and sexual function can occur even with modest increases in testosterone 3.