What are the risks of elevated testosterone levels in a patient undergoing testosterone supplementation?

Risks of Elevated Testosterone Levels During Supplementation

The most critical risk of testosterone levels above normal range is erythrocytosis leading to increased blood viscosity, which can have grave cardiovascular consequences including aggravation of coronary, cerebrovascular, and peripheral vascular disease—particularly dangerous in elderly patients. 1

Primary Dose-Limiting Risk: Erythrocytosis

Erythrocytosis is the most common dose-limiting adverse effect of testosterone therapy, with risk directly proportional to formulation type and supraphysiologic dosing. 2

Formulation-Specific Risk Stratification:

• Injectable testosterone: 43.8% incidence of elevated hematocrit (>52%) 1, 2
• Transdermal patches: 15.4% incidence 1, 2
• Testosterone gel (low dose): 2.8-11.3% incidence 2
• Testosterone gel (high dose): 17.9% incidence with dose-dependent relationship 1, 3

Mechanism and Cardiovascular Consequences:

Supraphysiologic testosterone levels stimulate erythropoiesis, causing hemoglobin to increase 15-20% above baseline. 1 When hematocrit rises above normal range, increased blood viscosity impairs microcirculation and oxygen delivery, creating particular danger in patients with pre-existing vascular disease. 1, 3

The risk is compounded in patients with:

• Chronic obstructive pulmonary disease 1, 3
• Advanced age 1
• Pre-existing cardiovascular disease 1

Critical Intervention Thresholds:

Hematocrit >54% mandates immediate intervention including: 2, 3

• Temporary discontinuation of testosterone therapy 2, 3
• Therapeutic phlebotomy or blood donation 1, 2, 3
• Dose reduction upon resumption 1, 2

Most hematocrit changes occur within the first 3 months of therapy, requiring intensive early monitoring. 2, 3

Cardiovascular Risk Profile

Current evidence shows that the relationship between testosterone therapy and cardiovascular events (myocardial infarction, stroke, cardiovascular death) remains uncertain and controversial. 1 The 2018 AUA guideline explicitly states that it cannot be definitively stated whether testosterone therapy increases or decreases cardiovascular risk. 1

Key Considerations:

• Some post-marketing studies suggest increased risk of myocardial infarction and stroke with testosterone use 4
• Injectable formulations may carry higher cardiovascular risk than transdermal preparations, possibly due to greater time spent in supraphysiologic and subtherapeutic ranges 1
• Testosterone therapy should not be commenced for 3-6 months following any cardiovascular event 1

Venous Thromboembolism:

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, has been reported in patients using testosterone products. 4 However, observational studies since the 2014 FDA warning have not confirmed an association between testosterone therapy and increased VTE risk. 1 Reassuringly, no testosterone-associated thromboembolic events were documented in major clinical trials despite erythrocytosis occurrence. 1, 3

Prostate-Related Risks

Benign Prostatic Hyperplasia:

Patients with pre-existing BPH require monitoring for worsening symptoms, though benign prostatic hyperplasia complications are rare with physiologic testosterone dosing. 1, 4

Prostate Cancer:

There is no compelling evidence that testosterone has a causative role in prostate cancer. 1 Prospective studies examining serum androgen levels and subsequent prostate cancer development have failed to show significant associations. 1 Notably, prostate cancer becomes more prevalent precisely when testosterone levels decline with aging. 1

However, known or suspected prostate carcinoma remains an absolute contraindication to testosterone therapy. 4

Reproductive Consequences

Exogenous testosterone therapy interrupts normal spermatogenesis, leading to oligospermia or azoospermia, and should never be prescribed to men actively trying to conceive. 1 This effect may be irreversible in some cases. 4 Testicular atrophy and infertility are common with testosterone supplementation. 1, 4

Additional Risks with Supraphysiologic Levels

Metabolic Effects:

• Fluid retention and edema, potentially precipitating congestive heart failure in patients with pre-existing cardiac, renal, or hepatic disease 4
• Testosterone has neutral effects on lipid profiles when maintained within physiologic range 1

Sleep Disorders:

Sleep apnea may occur or worsen in patients with risk factors. 4

Dermatologic:

• Acne 1
• Local skin reactions with topical preparations 1

Gynecomastia:

Can occur due to aromatization of excess testosterone to estradiol. 1

Critical Monitoring Algorithm to Prevent Supraphysiologic Levels

The 2018 AUA guideline recommends adjusting testosterone dosing to achieve total testosterone levels in the middle tertile of normal range (450-600 ng/dL), not higher. 1

Monitoring Schedule:

• Baseline: Hemoglobin/hematocrit, PSA, testosterone level 1, 3
• 1-2 months: Testosterone level, hemoglobin/hematocrit 1, 3
• Every 3-6 months during first year: Complete monitoring panel 1, 3
• Annually thereafter if stable: Ongoing surveillance 3

Timing of Testosterone Measurements by Formulation:

• Injectable testosterone: Measure midway between injections, targeting mid-normal value (500-600 ng/dL) 1
• Transdermal preparations: Can measure anytime, though peak occurs 6-8 hours post-application 1
• Testosterone gel: Levels vary substantially; consider measuring at both +2 hours (peak) and +23 hours (trough) to ensure adequate coverage without supraphysiologic peaks 5

Red Flags Requiring Immediate Action:

• Hematocrit >54% 2, 3
• Baseline hematocrit >50% (investigate before initiating therapy) 3
• Cardiovascular symptoms (chest pain, shortness of breath, dizziness) 1
• PSA >4.0 ng/mL or rapid PSA rise 1

Common Pitfalls to Avoid

The most critical error is using excessive dosing that drives testosterone levels above the normal physiologic range. Use minimal dosing necessary to achieve mid-normal testosterone levels (450-600 ng/dL), not maximal levels. 1

Injectable formulations carry substantially higher risk of erythrocytosis and supraphysiologic peaks—consider transdermal preparations as first-line to minimize these risks. 1, 2

Never prescribe 17-alpha-alkylated oral testosterone due to hepatotoxicity risk. 1

Patients with additional risk factors (smoking, elevated BMI, COPD) require more intensive monitoring, as these independently increase erythrocytosis risk. 2, 3