Can phlebotomy (blood draw) reduce testosterone levels in a male patient on testosterone replacement therapy (TRT) with elevated hematocrit levels?

Phlebotomy Does Not Reduce Testosterone Levels

Phlebotomy (blood draw) does not reduce testosterone levels—it only removes red blood cells to lower hematocrit, while testosterone levels remain unchanged or may even trigger compensatory increases in erythropoiesis. This is a critical distinction that is often misunderstood by both patients and providers.

Understanding the Mechanism

Phlebotomy addresses the consequence of testosterone therapy (elevated hematocrit), not the testosterone itself:

• Testosterone stimulates red blood cell production through increased erythropoietin (EPO) and decreased hepcidin, establishing a new EPO/hemoglobin set point 1
• Removing blood via phlebotomy lowers hematocrit temporarily but does not alter circulating testosterone concentrations 2
• The underlying stimulus for erythropoiesis persists as long as testosterone therapy continues, meaning red blood cells will regenerate 1

Critical Evidence on Phlebotomy Effectiveness

Phlebotomy alone is insufficient to maintain safe hematocrit levels in men on testosterone replacement therapy:

• In a study of 39 male blood donors on TRT, 44% had persistently elevated hemoglobin levels (≥180 g/L, equivalent to hematocrit ≥54%) at subsequent donations despite regular blood removal 2
• Repeat blood donation was insufficient to maintain hematocrit below the 54% threshold recommended by guidelines 2
• This raises serious concerns about persistent cardiovascular risk even with regular phlebotomy 2

Guideline-Based Management Approach

When hematocrit exceeds 54%, multiple interventions should be considered 3:

Primary Interventions (in order of preference):

1. Reduce testosterone dosage to decrease erythropoietic stimulus 3
2. Temporarily withhold testosterone therapy until hematocrit normalizes 3
3. Switch to lower-risk formulations: Transdermal preparations (gel, patch, spray) cause less erythrocytosis (15.4%) compared to injectable formulations (43.8%) 3
4. Therapeutic phlebotomy as an adjunct, not standalone treatment 3

Monitoring Requirements:

• Baseline hematocrit before initiating testosterone 3
• Follow-up at 1-2 months, then every 3-6 months during the first year, then annually if stable 3
• More aggressive surveillance for high-risk patients: those using injectables, elderly patients, or those with pre-existing cardiovascular disease 3

Important Clinical Caveats

Phlebotomy may paradoxically increase thrombotic risk through several mechanisms 1:

• Lowers tissue oxygen partial pressure (pO2), triggering compensatory pathways
• Depletes iron stores over time, which can activate prothrombotic mechanisms
• Creates a false sense of security while the underlying erythropoietic stimulus remains active

Increases in hematocrit from baseline are associated with increased risk of major adverse cardiovascular events (MACE) compared to men whose hematocrit remains stable on testosterone therapy 4. This emphasizes that the goal is preventing hematocrit elevation, not just treating it after it occurs.

Practical Algorithm

For hematocrit >54% on testosterone therapy:

1. First-line: Reduce testosterone dose by 25-50% OR switch from injectable to transdermal formulation 3
2. Second-line: Temporarily discontinue testosterone for 4-8 weeks, then restart at lower dose 3
3. Adjunctive: Consider therapeutic phlebotomy (removing 450-500 mL) while implementing dose reduction, but recognize this alone is insufficient 3, 2
4. For patients >70 years or with chronic illness: Use easily titratable formulations (gel, spray, patch) rather than long-acting injectables from the outset 3

The key message: phlebotomy treats the symptom (elevated hematocrit) but not the cause (testosterone-stimulated erythropoiesis), and testosterone levels remain unaffected by blood removal.