How to manage elevated hemoglobin (high red blood cell count) in patients undergoing testosterone (male hormone) therapy?

Management of Elevated Hemoglobin in Patients on Testosterone Therapy

When hematocrit exceeds 54%, you must intervene by either temporarily discontinuing testosterone, reducing the dose, or performing therapeutic phlebotomy to reduce cardiovascular and thromboembolic risk. 1, 2

Baseline Monitoring Requirements

Before initiating testosterone therapy:

• Measure baseline hemoglobin/hematocrit in all patients 1, 2
• If baseline hematocrit exceeds 50%, withhold testosterone therapy until the underlying cause is investigated 1, 2
• This prevents treating patients with pre-existing polycythemia who may have other serious conditions 1

Follow-Up Monitoring Schedule

The monitoring frequency should be:

• 1-2 months after starting therapy 2
• Every 3-6 months during the first year 2
• Annually thereafter if stable 2
• More frequent monitoring for patients on injectable testosterone (43.8% risk of elevated hematocrit vs. 15.4% with transdermal) 1, 2

Intervention Thresholds and Actions

Hematocrit >54%: Mandatory Intervention

You must take action when hematocrit exceeds 54% through one or more of these approaches: 1, 2

1. Therapeutic phlebotomy - First-line intervention to directly remove excess red blood cells 2
2. Temporarily discontinue testosterone therapy - Stops the erythropoietic stimulus 1, 2
3. Reduce testosterone dosage - Decreases stimulation of red blood cell production 1, 2

The rationale: Elevation above normal range increases blood viscosity, which can aggravate coronary, cerebrovascular, or peripheral vascular disease, particularly in elderly patients. 1

Critical Caveat About Blood Donation

Regular blood donation alone is often insufficient to maintain hematocrit below 54%. 3 In a study of men on testosterone therapy who donated blood regularly, 44% had persistently elevated hemoglobin levels (≥180 g/L, equivalent to hematocrit ≥54%) at subsequent donations, and 25% of all clinic visits showed elevated levels despite ongoing donation. 3 This creates a false sense of security for both patients and providers. 3

Formulation-Specific Risk Stratification

Injectable testosterone carries significantly higher risk of erythrocytosis than transdermal preparations:

• Injectable testosterone enanthate: 43.8% incidence of hematocrit >52% 1, 2
• Transdermal patches: 15.4% incidence 1, 2
• Testosterone gel: dose-dependent risk (2.8% to 17.9%) 2

Consider switching from injectable to transdermal formulations in patients who develop erythrocytosis. 1

High-Risk Patients Requiring Closer Monitoring

Patients with these conditions need more frequent hematocrit checks: 1, 2

• Chronic obstructive pulmonary disease (COPD already increases hematocrit independently) 1, 2
• Pre-existing cardiovascular disease 1
• Advanced age (elderly have greater risk from increased blood viscosity) 1
• Concurrent conditions causing elevated hematocrit 2

Dosing Strategy to Minimize Risk

Target testosterone levels in the middle tertile of normal range (450-600 ng/dL) using minimal effective dosing. 1 Supraphysiologic testosterone levels are associated with higher rates of erythrocytosis, particularly with injectable formulations. 1 Most hemoglobin/hematocrit increases occur within the first three months of therapy. 1

Mechanism and Timeline

Testosterone stimulates erythropoiesis by increasing erythropoietin (EPO) levels and suppressing hepcidin, which increases iron availability for red blood cell production. 4 The 7-10% increase in hemoglobin/hematocrit occurs primarily in the first 1-3 months, with EPO levels eventually returning toward baseline but at a new "set point" despite continued therapy. 4

FDA Labeling Requirements

The FDA mandates that hemoglobin and hematocrit levels be checked periodically in patients receiving long-term androgen administration to detect polycythemia. 5 Patients should be instructed to report symptoms such as changes in skin color or ankle swelling. 5

Cardiovascular Risk Context

While increased hematocrit theoretically increases cardiovascular risk through elevated blood viscosity, no direct testosterone-associated thromboembolic events have been reported in major studies despite the increased erythrocytosis risk. 2 However, the lack of reported events does not eliminate the theoretical risk, particularly in high-risk populations. 1