What is the risk of developing erythrocytosis (elevated hemoglobin/hematocrit) in men undergoing testosterone replacement therapy?

Risk of Elevated Hemoglobin with Testosterone Replacement Therapy

Erythrocytosis is a common and dose-dependent adverse effect of testosterone replacement therapy, occurring in 2.8% to 43.8% of men depending on formulation and dose, with injectable testosterone carrying the highest risk. 1

Incidence by Formulation

The risk of developing elevated hematocrit (>52%) varies substantially by testosterone formulation:

• Injectable testosterone enanthate: 43.8% of patients develop at least one elevated hematocrit value during treatment 1
• Transdermal nonscrotal patches: 15.4% of patients experience erythrocytosis 1
• Scrotal transdermal patches: 5.5% incidence of erythrocytosis 1
• Transdermal gel preparations: Dose-dependent risk ranging from 2.8% (5 mg/day) to 11.3% (50 mg/day) to 17.9% (100 mg/day) 1

Injectable testosterone formulations produce supraphysiologic peak levels that are strongly associated with erythrocytosis, making transdermal preparations the preferred first-line option for minimizing this risk. 1, 2

Mechanism and Time Course

Testosterone stimulates erythropoiesis through multiple pathways:

• Suppression of hepatic hepcidin transcription, which increases iron availability for red blood cell production 3
• Upregulation of renal erythropoietin production, directly stimulating bone marrow 3
• Increased iron incorporation into red blood cells following testosterone administration 3

The temporal pattern of hematocrit elevation is predictable:

• Most significant increase occurs in the first 3 months of therapy, with hemoglobin and hematocrit rising from subnormal to mid-normal range 1
• Hematocrit rises from baseline 0.39 L/L to 0.45 L/L after 1 year in large cohort studies 4
• Cumulative risk continues to increase over time: 10% probability after 1 year, rising to 38% after 10 years of continuous therapy 4

Age-Related Differences

Older men experience significantly greater increases in hemoglobin and hematocrit compared to younger men receiving identical testosterone doses. 5 This age-related amplification of erythropoietic response makes older patients particularly vulnerable to developing clinically significant erythrocytosis, though the mechanisms remain incompletely understood and appear independent of erythropoietin or soluble transferrin receptor changes 5.

Risk Factors for Developing Erythrocytosis

Specific patient characteristics substantially increase the likelihood of testosterone-induced erythrocytosis:

• Tobacco use: Odds ratio 2.2 (95% CI 1.6-3.3) 4
• Long-acting undecanoate injections: Odds ratio 2.9 (95% CI 1.7-5.0) 4
• Older age at initiation: Odds ratio 5.9 (95% CI 2.8-12.3) 4
• Elevated BMI: Odds ratio 3.7 (95% CI 2.2-6.2) 4
• Pre-existing pulmonary conditions: Odds ratio 2.5 (95% CI 1.4-4.4) 4

Clinical Significance and Thromboembolic Risk

Despite the high incidence of erythrocytosis with testosterone therapy, no testosterone-associated thromboembolic events have been definitively reported in major prospective studies to date. 1 However, this reassuring observation must be interpreted cautiously:

• Elevated hematocrit increases blood viscosity, which theoretically impairs microcirculation and oxygen delivery 6
• Postmarketing reports document venous thromboembolic events including deep vein thrombosis and pulmonary embolism in patients using testosterone products 7
• The FDA label explicitly warns that increases in red blood cell mass may increase the risk of thromboembolic events 7
• Evidence connecting erythrocytosis to major adverse cardiovascular events remains inconclusive 8

The hyperviscosity mechanism can produce serious complications beyond thrombosis, including erythrocytosis-related priapism through impaired penile blood flow dynamics 9.

Monitoring and Management Algorithm

Baseline Assessment

• Document hematocrit or hemoglobin before initiating therapy—hematocrit >54% is an absolute contraindication to starting testosterone 2, 6, 7

Follow-Up Monitoring Schedule

• 2-3 months after treatment initiation 2, 6
• Every 3-6 months during the first year 6
• Annually thereafter if stable 2, 6

Intervention Thresholds

When hematocrit exceeds 54%, testosterone therapy must be withheld immediately. 2, 6, 7 Management options include:

1. Temporarily withhold testosterone until hematocrit decreases to acceptable levels 6, 7
2. Reduce testosterone dosage by 25-50% 2
3. Switch from injectable to transdermal formulation to achieve more stable day-to-day levels 2
4. Therapeutic phlebotomy (remove 500 mL blood every 1-2 weeks until hematocrit <52%) in high-risk patients 2, 6

For hematocrit 52-54%: Reduce dose and consider formulation switch 2

For hematocrit 50-52%: Continue with closer monitoring and consider dose reduction if trending upward 2

Formulation Selection to Minimize Risk

Transdermal testosterone gel is strongly preferred over injectable testosterone for patients at elevated risk of erythrocytosis because it produces more stable testosterone levels and substantially lower rates of erythrocytosis (15.4% vs 43.8%). 1, 2 A typical starting regimen is 1.62% gel at 40.5 mg applied once daily 2.

For patients who develop erythrocytosis on injectable testosterone, switching to transdermal preparations provides more stable day-to-day levels and reduces erythropoietic stimulation. 2

Special Populations Requiring Heightened Vigilance

Elderly patients and those with pre-existing cardiovascular disease face disproportionate risk from elevated blood viscosity, which can aggravate coronary, cerebrovascular, or peripheral vascular disease 2. In these high-risk populations:

• Target mid-normal testosterone levels (450-600 ng/dL) rather than upper-normal range 2
• Use transdermal formulations preferentially over injectables 2
• Monitor more frequently than standard intervals 6

Critical Clinical Pitfalls

• Do not ignore mild erythrocytosis (hematocrit 50-52%) in elderly or cardiovascular patients—even modest elevations increase thrombotic risk 2
• Do not continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy 2, 7
• Do not assume safety based on absence of symptoms—erythrocytosis is often asymptomatic until complications occur 2
• Do not overlook cumulative risk—probability of erythrocytosis continues increasing even after the first year of stable therapy 4