What are the concerns and management strategies for a patient with elevated red blood cell (RBC) count, hemoglobin, and hematocrit levels due to topical testosterone (testosterone) therapy?

Management of Testosterone-Induced Erythrocytosis

You Should Be Very Concerned About These Laboratory Values

Your patient has developed significant erythrocytosis with a hematocrit of 56% (hemoglobin 189 g/L), which exceeds the critical intervention threshold of 54% and requires immediate action beyond simple dose reduction. 1, 2, 3

The elevated hematocrit increases blood viscosity, which can aggravate vascular disease in coronary, cerebrovascular, and peripheral circulation—a particularly dangerous situation that has been associated with strokes and transient ischemic attacks in patients with hematocrit ≥48%. 4

Your Current Plan Is Insufficient

Simply reducing testosterone to once daily will likely not adequately address this degree of erythrocytosis. Research demonstrates that repeat blood donation was insufficient to maintain hematocrit below 54% in 44% of patients on testosterone replacement therapy, and many continued to have persistently elevated hemoglobin levels despite regular phlebotomy. 5

The FDA label for testosterone explicitly states: "If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration." 3

Immediate Management Algorithm

Step 1: Temporarily Discontinue Testosterone

• Stop all testosterone therapy immediately until hematocrit decreases below 54%. 1, 2, 3
• The FDA drug label specifically recommends discontinuation rather than dose reduction when hematocrit becomes elevated. 3

Step 2: Therapeutic Phlebotomy

• Arrange urgent therapeutic phlebotomy to reduce red blood cell mass and decrease thrombotic risk. 1, 2
• Blood donation alone may be insufficient—therapeutic phlebotomy provides more controlled volume removal. 5

Step 3: Monitor Hematocrit Weekly

• Check hematocrit weekly until it falls below 50%, then every 2 weeks until stable below 48%. 2
• Hemoglobin is more accurate than hematocrit for monitoring as it remains stable with blood sample storage. 2

Step 4: Restart at Lower Dose with Different Formulation

• Once hematocrit normalizes, consider switching from topical scrotal application to a lower-risk formulation. 1
• Injectable testosterone carries 43.8% risk of elevated hematocrit, transdermal patches 15.4%, and low-dose testosterone gel only 2.8-11.3%. 6, 1
• Target testosterone levels in the middle tertile of normal range (450-600 ng/dL) rather than higher levels. 1

Thrombotic Risk Assessment

Stroke and Blood Clot Concerns Are Legitimate

• The FDA has issued warnings about venous thromboembolic events including deep vein thrombosis and pulmonary embolism in patients using testosterone products. 3
• In one study, 2 patients with hematocrit ≥48% suffered strokes after stopping testosterone therapy, and 1 had transient ischemic attacks while on therapy. 4
• The increased blood viscosity from erythrocytosis paradoxically worsens tissue oxygenation despite higher hemoglobin levels. 6

Evaluate for Additional Risk Factors

• Assess for smoking (increases erythrocytosis risk 2.2-fold), elevated BMI (increases risk 3.7-fold), and chronic obstructive pulmonary disease. 1
• Check for cardiovascular risk factors including age, diabetes, hypertension, and pre-existing vascular disease, which compound the thrombotic risk. 2

Monitoring After Restart

Intensive Surveillance Protocol

• Measure hematocrit at 1 month after restarting testosterone, then every 3 months for the first year, then annually if stable. 2, 3
• Most hematocrit changes occur in the first 3 months of therapy. 2
• The FDA recommends checking hematocrit 3-6 months after starting treatment as standard practice. 3

Intervention Thresholds Going Forward

• If hematocrit exceeds 54% again: immediately stop testosterone, perform therapeutic phlebotomy, and reassess the risk-benefit ratio of continuing therapy. 1, 2
• If hematocrit reaches 50-54%: reduce dose by 25-50% and recheck in 2-4 weeks. 1

Critical Pitfalls to Avoid

• Do not simply reduce the dose without stopping therapy first—the current hematocrit of 56% requires complete cessation per FDA guidelines. 3
• Do not rely on blood donation alone—research shows this is often insufficient to maintain safe hematocrit levels in testosterone users. 5
• Do not restart at the same dose or formulation—scrotal application may have higher systemic absorption; consider switching to lower-risk gel formulation. 1
• Do not ignore the testosterone level of 48.5 nmol/L (approximately 1400 ng/dL)—this is supraphysiologic and explains the erythrocytosis; target levels should be 450-600 ng/dL. 1

Mechanism Explanation

Testosterone stimulates erythropoiesis through multiple pathways: it increases erythropoietin production, suppresses hepcidin (allowing increased iron availability), and directly stimulates red blood cell production. 7, 8, 9 The elevated hemoglobin creates a new erythropoietin set point, meaning EPO levels remain inappropriately normal despite polycythemia, perpetuating the erythrocytosis even after testosterone levels normalize. 9