In a 24‑year‑old transgender male who stopped intramuscular testosterone hormone therapy 2–3 months ago and now has an elevated hematocrit of 52% with a low total testosterone of approximately 100 ng/dL, what is the best next step in management?

Management of Elevated Hematocrit in a Transgender Male After Stopping Testosterone

The best next step is to repeat morning testosterone measurements on two separate occasions to confirm persistent hypogonadism, measure LH and FSH to differentiate primary from secondary hypogonadism, and address the elevated hematocrit through smoking cessation counseling (if applicable) and weight optimization before considering testosterone resumption. 1

Understanding the Clinical Situation

This patient presents with two distinct problems that must be addressed separately:

Problem 1: Elevated Hematocrit (52%)

• Hematocrit of 52% represents a critical threshold where intervention is warranted according to multiple guidelines 2
• The American Heart Association suggests that hematocrit >54% warrants immediate intervention including therapeutic phlebotomy, but levels between 50-52% require closer monitoring and risk factor modification 2
• Testosterone-induced erythrocytosis persists for weeks to months after discontinuation because the elevated red blood cell mass has a lifespan of approximately 120 days 3, 4
• The hematocrit increase is most pronounced in the first year of testosterone therapy (rising from 0.39 L/L at baseline to 0.45 L/L after 1 year), and this patient's current level of 52% reflects the cumulative effect of prior testosterone use 3, 4

Problem 2: Low Testosterone (100 ng/dL)

• A single testosterone measurement of 100 ng/dL is insufficient to diagnose hypogonadism 1
• The European Association of Urology requires two separate morning total testosterone measurements (8-10 AM) <300 ng/dL to establish biochemical hypogonadism 1
• After stopping testosterone 2-3 months ago, the hypothalamic-pituitary-gonadal axis may still be recovering, and LH/FSH levels are mandatory to distinguish primary from secondary hypogonadism 1

Immediate Management Algorithm

Step 1: Address the Elevated Hematocrit (Priority)

Before considering testosterone resumption, the hematocrit must be addressed:

• Smoking cessation is the single most important intervention if the patient smokes (OR 2.2 for erythrocytosis in trans men who smoke) 3
• Weight loss if BMI is elevated (OR 3.7 for erythrocytosis in trans men with high BMI) 3
• Monitor hematocrit every 4-6 weeks until it falls below 50% 2
• Therapeutic phlebotomy is NOT recommended at this hematocrit level (52%) unless the patient has high cardiovascular risk factors or symptomatic hyperviscosity 2, 5
  • Evidence supporting phlebotomy efficacy in testosterone-induced erythrocytosis is lacking 5
  • Phlebotomy depletes iron stores and may paradoxically increase thrombotic risk 5

Step 2: Confirm Hypogonadism Diagnosis

The patient requires a complete diagnostic workup:

• Repeat morning total testosterone (8-10 AM) on at least one additional occasion to confirm persistent levels <300 ng/dL 1
• Measure LH and FSH to classify primary vs. secondary hypogonadism 1
  • Elevated LH/FSH with low testosterone = primary (testicular) hypogonadism 1
  • Low or low-normal LH/FSH with low testosterone = secondary (hypothalamic-pituitary) hypogonadism 1
• This distinction is critical because it determines fertility potential and treatment options 1

Step 3: Assess Fertility Desires

Before any testosterone resumption:

• Explicitly confirm whether the patient desires fertility preservation 1
• If fertility is desired, testosterone is absolutely contraindicated and gonadotropin therapy (hCG plus FSH) is mandatory 1
• Testosterone causes prolonged, potentially irreversible azoospermia 1

Treatment Decision Algorithm

If Hematocrit Remains >50% After Risk Factor Modification:

Do NOT restart testosterone until hematocrit falls below 50% 2

• Continue monitoring hematocrit every 4-6 weeks 2
• Consider evaluation for other causes of erythrocytosis (sleep apnea, chronic lung disease, polycythemia vera) 2

If Hematocrit Falls Below 50% AND Hypogonadism is Confirmed:

Choose testosterone formulation based on erythrocytosis risk:

• Transdermal testosterone gel is strongly preferred over injectable testosterone 6, 3

  • Injectable testosterone carries a 43.8% risk of erythrocytosis vs. 15.4% for transdermal preparations 2
  • Trans men receiving testosterone esters had larger increases in hematocrit compared to testosterone undecanoate 4
  • Start with transdermal testosterone gel 1.62% at 40.5 mg daily 1

• If injectable testosterone is necessary due to cost or patient preference:

  • Testosterone undecanoate (long-acting) has lower erythrocytosis risk than testosterone cypionate/enanthate 4, 7
  • However, this patient's history of hematocrit 52% makes transdermal the safest choice 3

Monitoring Requirements After Testosterone Resumption:

Aggressive hematocrit monitoring is mandatory:

• Check hematocrit at 1 month, 3 months, 6 months, then every 6-12 months 2
• Withhold testosterone immediately if hematocrit exceeds 54% 2
• Consider dose reduction or formulation switch if hematocrit exceeds 52% 2
• Target mid-normal testosterone levels (450-600 ng/dL) rather than upper-normal to minimize erythrocytosis risk 1

Critical Pitfalls to Avoid

• Do NOT restart testosterone while hematocrit is 52% – this is a critical threshold requiring intervention 2
• Do NOT diagnose hypogonadism based on a single testosterone measurement – two morning values are required 1
• Do NOT skip LH/FSH testing – the distinction between primary and secondary hypogonadism has critical treatment implications 1
• Do NOT restart testosterone without confirming fertility desires – this causes irreversible suppression of spermatogenesis 1
• Do NOT use injectable testosterone in this patient given the history of elevated hematocrit – transdermal formulations have significantly lower erythrocytosis risk 3, 4
• Do NOT perform therapeutic phlebotomy at hematocrit 52% unless high cardiovascular risk or symptomatic – evidence for efficacy is lacking and may increase thrombotic risk 5

Special Considerations for Transgender Patients

• The largest increase in hematocrit occurs in the first year of testosterone therapy (+4.9% in the first year, with +2.7% in the first 3 months) 4
• Even after the first year, the probability of developing erythrocytosis continues to increase (10% after 1 year, 38% after 10 years) 3
• Developing polycythemia (hematocrit ≥52%) while on testosterone increases the risk of major adverse cardiovascular events and venous thromboembolism (OR 1.35,95% CI 1.13-1.61) in the first year of therapy 8
• Trans men on testosterone undecanoate are less likely to develop hematocrit ≥50% or ≥52% compared to testosterone esters 4