What is the upper acceptable level for hematocrit (blood cell percentage) in a male on testosterone replacement therapy?

Hematocrit Monitoring in Males on Testosterone Replacement Therapy

The upper acceptable level for hematocrit in a male on testosterone replacement therapy is 54%, above which therapy should be discontinued and therapeutic phlebotomy considered to minimize the risk of thrombotic events. 1

Monitoring Guidelines and Thresholds

Testosterone replacement therapy (TRT) commonly causes erythrocytosis (increased red blood cell production), which is the most significant hematological side effect of treatment. The risk varies by administration route:

• Injectable testosterone: Highest risk (up to 43.8%)
• Gel preparations: Intermediate risk (11.3-17.9%)
• Transdermal patches: Lowest risk (2.8-5.5%) 1

Monitoring Schedule

• Baseline measurement before starting TRT
• 3-6 months after initiation
• Annually thereafter if stable 1

Action Thresholds

The European Association of Urology (EAU) 2025 guidelines specifically state that treatment adjustments are required for hematocrit >54%, which may include withdrawal of testosterone and phlebotomy in high-risk cases 2.

Clinical Implications of Elevated Hematocrit

Recent evidence demonstrates that developing polycythemia (hematocrit ≥52%) while on TRT is an independent risk factor for major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE) in the first year of therapy 3. Patients with polycythemia had a 35% higher risk of MACE/VTE compared to those with normal hematocrit while on TRT (OR 1.35,95% CI 1.13-1.61) 3.

Risk Factors for Developing Erythrocytosis

Several factors increase the likelihood of developing erythrocytosis on TRT:

• Tobacco use (OR 2.2)
• Long-acting testosterone undecanoate injections (OR 2.9)
• Older age at initiation of hormone therapy (OR 5.9)
• Higher BMI (OR 3.7)
• Pre-existing pulmonary conditions (OR 2.5) 4

Management of Elevated Hematocrit

When hematocrit exceeds 54%, the following interventions should be considered:

1. Discontinue testosterone therapy temporarily 2, 1
2. Perform therapeutic phlebotomy in high-risk cases 2, 1
3. Consider modifying administration route - switching from injectable to transdermal forms may reduce risk 4, 5
4. Address modifiable risk factors:
   • Smoking cessation
   • Weight loss if BMI is elevated 4

Important Caveats and Pitfalls

1. Regular blood donation may be insufficient: Research shows that repeat blood donation alone is often insufficient to maintain hematocrit below 54% in patients on TRT 6.

2. Hematocrit increases most in the first year: The largest increase typically occurs within the first year of therapy (from approximately 0.39 L/L at baseline to 0.45 L/L after one year), but the probability of developing erythrocytosis continues to increase with duration of therapy (10% after 1 year, 38% after 10 years) 4.

3. Patients with history of clotting concerns: These individuals require particularly vigilant hematocrit monitoring, and more conservative thresholds may be warranted in those with underlying thrombophilia 1.

4. Administration route matters: Intramuscular testosterone undecanoate leads to significantly higher rates of elevated hematocrit compared to transdermal gel formulations 5.

By adhering to these monitoring guidelines and intervention thresholds, the risk of adverse events associated with TRT-induced erythrocytosis can be minimized while maintaining the benefits of therapy.