What are the guidelines for testosterone treatment in individuals with erythrocytosis (excessive red blood cell production), specifically for female-to-male (FTM) patients?

Management of Testosterone Therapy in FTM Patients with Erythrocytosis

When erythrocytosis develops in FTM patients on testosterone therapy, switch from injectable to transdermal formulations, reduce dosing to achieve mid-normal testosterone levels (450-600 ng/dL), and implement therapeutic phlebotomy or temporary discontinuation if hematocrit exceeds 54%. 1

Understanding the Risk Profile

Erythrocytosis is the most common dose-limiting adverse effect of testosterone therapy, occurring with significantly different frequencies based on formulation 1:

• Injectable testosterone: 43.8% develop elevated hematocrit (>52%) 1
• Transdermal patches: 15.4% develop elevated hematocrit 1
• Testosterone gel (low dose): 2.8-11.3% develop erythrocytosis 1

In FTM-specific populations, severe erythrocytosis (hematocrit >54%) occurs in only 0.5-0.6% of patients, with hematocrit >50% occurring in approximately 11-12.6% 2, 3. The largest hematocrit increase occurs in the first year of therapy (from 0.39 to 0.45 L/L), though risk continues to accumulate over time 3.

Critical Thresholds and Cardiovascular Risk

Elevation of hematocrit above normal range may have grave consequences, particularly since increased blood viscosity can aggravate vascular disease in coronary, cerebrovascular, or peripheral circulation. 1 The risk is compounded in patients with pre-existing conditions like chronic obstructive pulmonary disease 1.

The mechanism involves hyperviscosity impairing normal blood flow dynamics, where blood viscosity becomes the limiting factor in oxygen delivery to tissues, paradoxically worsening tissue oxygenation despite higher hemoglobin levels 4.

Specific Management Algorithm

Step 1: Immediate Intervention Based on Hematocrit Level

When hematocrit exceeds 54%, intervention is mandatory 1, 4:

• Temporarily discontinue testosterone therapy 1
• Perform therapeutic phlebotomy or blood donation 1
• Consider dose reduction as alternative 1

For hematocrit 50-54%, consider intervention based on individual cardiovascular risk factors 1.

Step 2: Formulation Switch

Transition from injectable to transdermal testosterone is the single most effective strategy to reduce erythrocytosis risk 1, 3:

• Injectable testosterone enanthate carries 2.9 times higher odds of erythrocytosis compared to transdermal 3
• Long-acting undecanoate injections have even higher risk 3
• Transdermal preparations maintain therapeutic testosterone levels with substantially lower erythrocytosis rates 1

Step 3: Dose Optimization

Adjust dosing to achieve total testosterone levels in the middle tertile of normal range (450-600 ng/dL) 1:

• Use minimal dosing necessary to maintain physiologic levels 1
• Higher doses show direct correlation with erythrocytosis incidence 1
• Supraphysiologic testosterone and estradiol levels are associated with increased erythrocytosis 1

Step 4: Address Modifiable Risk Factors

Tobacco cessation is critical, as smoking increases erythrocytosis risk 2.2-fold 3:

• Advise immediate smoking cessation 3
• Weight loss if BMI is elevated (3.7-fold increased risk with high BMI) 3
• Older age at testosterone initiation carries 5.9-fold higher risk 3

Monitoring Strategy

Measure hemoglobin/hematocrit at baseline and monitor during therapy, with most intensive surveillance in the first year 1:

• Most hematocrit changes occur in first 3 months 1
• Baseline hematocrit >50% warrants investigation before initiating therapy 1
• Severe erythrocytosis (>54%) is rare in FTM patients, occurring in <1% 2, 3

Special Considerations

The evidence connecting testosterone-induced erythrocytosis to major adverse cardiovascular events (MACE) remains limited 5. No testosterone-associated thromboembolic events have been definitively reported to date 1. However, the theoretical risk from hyperviscosity, particularly in patients with pre-existing cardiovascular disease, justifies aggressive management 1.

Dihydrotestosterone (DHT) levels may play a role in erythrocytosis development 6. Patients with higher post-treatment DHT levels (605 vs 436 ng/dL) show greater hematocrit increases 6. Consider 5α-reductase inhibitors in refractory cases, as their use is associated with lower erythrocytosis rates 6.

Common Pitfalls to Avoid

• Do not continue injectable testosterone at current doses when erythrocytosis develops - the formulation itself is the primary driver 1
• Do not ignore hematocrit 50-54% - intervention may be warranted based on cardiovascular risk profile 1
• Do not assume erythrocytosis risk plateaus after first year - cumulative probability continues increasing (38% by 10 years) 3
• Do not overlook pulmonary conditions - these carry 2.5-fold increased risk and compound hemoconcentration danger 1, 3