Does testosterone replacement therapy increase the risk of pulmonary embolism?

Does Testosterone Replacement Therapy Increase Risk of Pulmonary Embolism?

Testosterone replacement therapy (TRT) is associated with an increased risk of venous thromboembolism, including pulmonary embolism, particularly within the first 6 months of treatment initiation. 1, 2, 3, 4

Evidence for Increased VTE Risk

Timing and Magnitude of Risk

The risk of venous thromboembolism (VTE), which includes both deep vein thrombosis and pulmonary embolism, follows a specific temporal pattern with TRT:

• The highest risk occurs within the first 6 months of treatment, with a rate ratio of 1.63 (95% CI: 1.12-2.37), corresponding to approximately 10 additional VTE events per 10,000 person-years above the baseline rate. 4

• After 6 months of continuous treatment, the risk returns to baseline (rate ratio 1.00,95% CI: 0.68-1.47), suggesting an adaptation period or selection effect. 4

• The large TRAVERSE trial (5,246 men) demonstrated a higher incidence of pulmonary embolism specifically in the testosterone group compared to placebo, though this was part of broader cardiovascular monitoring. 3

Risk Across Different Populations

The elevated VTE risk appears consistent across patient subgroups:

• Men with pathological hypogonadism: Rate ratio 1.52 (0.94-2.46) in first 6 months 4
• Men without pathological hypogonadism: Rate ratio 1.88 (1.02-3.45) in first 6 months 4
• Men with known VTE risk factors: Rate ratio 1.41 (0.82-2.41) 4
• Men without known VTE risk factors: Rate ratio 1.91 (1.13-3.23) 4

Formulation-Specific Considerations

Intramuscular testosterone injections carry higher thrombotic risk than transdermal preparations due to supraphysiologic testosterone peaks and associated erythrocytosis:

• Erythrocytosis occurs in up to 44% of patients receiving intramuscular injections versus 3-18% with transdermal administration. 1
• Elevated hematocrit is a known risk factor for thrombosis, though the New England Journal of Medicine notes that "no testosterone-associated thromboembolic events have been reported to date" in their 2004 review. 1

Contradictory Evidence and Nuances

Studies Showing No Increased Risk

Some studies have failed to demonstrate increased VTE risk:

• A 2021 meta-analysis of 13 RCTs (n=5,050) found no association between TRT and VTE (RR: 1.03,95% CI: 0.49-2.14), though this was rated as low-quality evidence with wide confidence intervals. 5

• A Veterans Affairs retrospective cohort study of 71,407 men found no significant difference in DVT/PE incidence between treated and untreated groups (0.4-0.5% across all groups). 6

• A 2026 pharmacovigilance study using FDA FAERS data found reporting odds ratios below 1 for both PE (ROR: 0.039) and DVT (ROR: 0.133), indicating no disproportionality signal. 7

Why the Discrepancy?

The conflicting evidence likely reflects:

• Study design differences: Population-based case-control studies 4 capture real-world risk better than RCTs that exclude high-risk patients 5
• Short follow-up in RCTs: Most trials lasted <36 months, potentially missing longer-term effects 5
• Exclusion of high-risk patients: RCTs typically excluded men with recent cardiovascular events, limiting generalizability 8, 3
• Surveillance bias: Pharmacovigilance data may underreport events or reflect selective reporting 7

Clinical Implications and Monitoring

FDA Labeling Requirements

The FDA label for testosterone cypionate does not specifically list VTE or PE as contraindications or warnings, though it requires monitoring of hemoglobin and hematocrit to detect polycythemia. 9

Practical Monitoring Strategy

For patients initiating TRT, implement heightened VTE surveillance during the first 6 months:

• Baseline assessment: Check hematocrit, assess VTE risk factors (obesity, immobility, prior VTE, thrombophilia) 1, 4

• Monitor hematocrit at 3 months and 6 months: If hematocrit exceeds 52%, consider dose reduction, therapeutic phlebotomy, or temporary discontinuation 1

• Patient education: Counsel about leg swelling, chest pain, and dyspnea as warning signs, particularly in months 1-6 4

• Consider transdermal over intramuscular formulations in patients with baseline VTE risk factors to minimize erythrocytosis 1

Common Pitfalls to Avoid

• Don't assume all testosterone formulations carry equal risk: Intramuscular preparations cause more erythrocytosis and potentially higher thrombotic risk 1

• Don't ignore the temporal pattern: The risk is front-loaded in the first 6 months, requiring more vigilant monitoring early 4

• Don't dismiss VTE risk in "low-risk" patients: The increased rate ratio was actually higher in men without traditional VTE risk factors (1.91 vs 1.41) 4