What are the risks and management strategies for pulmonary embolism in patients with a history of thromboembolic events or risk factors undergoing testosterone replacement therapy (TRT)?

Testosterone Therapy and Pulmonary Embolism Risk

Testosterone replacement therapy (TRT) carries a documented risk of venous thromboembolism (VTE) including pulmonary embolism, particularly in patients with underlying thrombophilia or pre-existing VTE risk factors, and the FDA requires warnings about this risk on all testosterone product labels. 1

FDA-Mandated Warning on Venous Thromboembolism

The FDA drug label explicitly states that postmarketing reports have documented venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products. 1 Patients who report signs and symptoms of pain, edema, warmth and erythema in the lower extremity should be evaluated for DVT, and those presenting with acute shortness of breath should be evaluated for PE. 1 If a venous thromboembolic event is suspected, testosterone therapy must be discontinued immediately and appropriate workup and management initiated. 1

Risk Stratification Before Initiating TRT

Absolute Contraindications

• Active or recent history of VTE (DVT/PE) within the past 3-6 months 2
• Known thrombophilia or hypercoagulable state 3, 4
• Active cancer (particularly with ongoing chemotherapy or immobilization) 2

High-Risk Conditions Requiring Thrombophilia Screening

Before initiating TRT, screen for thrombophilia in patients with: 3, 4

• Personal history of unprovoked VTE (even if remote)
• Family history of VTE in first-degree relatives before age 50
• Recurrent thrombotic events
• Thrombosis at unusual sites (cerebral, mesenteric, portal vein)

Specific thrombophilia testing should include: 3, 4

• Factor V Leiden mutation (present in 24% of patients who developed thrombosis on TRT vs 12% controls)
• Lupus anticoagulant (present in 14% of TRT-associated thrombosis cases vs 4% controls)
• Prothrombin G20210A mutation
• Antithrombin III, Protein C, Protein S deficiencies
• Elevated Factor VIII and Factor XI levels
• Plasminogen activator inhibitor-1 (PAI-1) 4G4G homozygosity
• Anticardiolipin antibodies and anti-β2-glycoprotein-1 antibodies
• Homocysteine levels

Evidence on TRT-Associated Thrombosis

Case Series Data

Research demonstrates that thrombotic events occur at a median of 6-11 months after initiating TRT in patients with previously undiagnosed thrombophilia. 3, 4 In one series of 67 patients who developed thrombosis after starting TRT, 70% had deep venous thrombosis-pulmonary embolism, 24% had osteonecrosis, and 6% had ocular thrombosis. 4

Critical finding: Among patients who continued TRT after a first thrombotic event, 11 experienced a second event despite adequate anticoagulation, and 6 of these had a third thrombosis while still anticoagulated. 4 This demonstrates that TRT should be permanently discontinued after any thrombotic event, regardless of anticoagulation status.

Mechanism of Thrombosis

Exogenous testosterone undergoes aromatization to estradiol (E2), and when elevated E2-induced thrombophilia is superimposed on underlying thrombophilia-hypofibrinolysis, thrombosis occurs. 3 In one study, 33% of men on testosterone had elevated estradiol levels (>42.6 pg/mL). 3

Polycythemia as Additional Risk Factor

The FDA label warns that increases in hematocrit, reflective of increases in red blood cell mass, may increase the risk of thromboembolic events. 1 Hematocrit must be checked prior to initiating treatment, re-evaluated at 3-6 months after starting treatment, and then annually. 1 If hematocrit becomes elevated, therapy must be stopped until hematocrit decreases to an acceptable concentration. 1

Management of Patients With Prior VTE History

Patients With Prior Provoked VTE

For patients whose prior VTE was provoked by a major transient/reversible risk factor (surgery with general anesthesia >30 minutes, hospitalization ≥3 days with acute illness, trauma with fractures), the long-term recurrence risk is low (<3% per year) after completing 3-6 months of anticoagulation. 2 However, initiating TRT would convert this to a persistent risk factor scenario, requiring indefinite anticoagulation if TRT is pursued. 2

Patients With Prior Unprovoked VTE

Patients with unprovoked VTE have a high recurrence risk (>8% per year) after stopping anticoagulation. 2 TRT is contraindicated in this population as it would add an additional persistent thrombotic stimulus requiring indefinite anticoagulation, and case series show recurrent thrombosis despite therapeutic anticoagulation when TRT is continued. 4

Patients With Antiphospholipid Antibody Syndrome

Indefinite anticoagulation with a vitamin K antagonist (VKA) is mandatory for patients with antiphospholipid antibody syndrome and prior VTE. 2 TRT should be avoided entirely in this population given the 14% prevalence of lupus anticoagulant in TRT-associated thrombosis cases. 4

Monitoring Strategy If TRT Is Initiated

For patients deemed appropriate candidates after thorough risk assessment: 1

Baseline (before starting TRT):

• Complete blood count with hematocrit
• Comprehensive thrombophilia panel (as outlined above)
• Baseline estradiol level

At 3-6 months:

• Hematocrit (stop if elevated)
• Estradiol level (consider aromatase inhibitor if >42.6 pg/mL)
• Clinical assessment for VTE symptoms

Annually thereafter:

• Hematocrit
• Clinical assessment for VTE symptoms

Anticoagulation Management If VTE Occurs on TRT

Immediate actions: 1

1. Discontinue testosterone therapy immediately and permanently
2. Initiate therapeutic anticoagulation per standard VTE guidelines
3. Complete diagnostic workup for extent of thrombosis

Duration of anticoagulation: 2

• Minimum 3 months of therapeutic anticoagulation
• Extended (indefinite) anticoagulation should be considered given that TRT represents a persistent risk factor that was present at the time of the index event 2
• Even after TRT discontinuation, underlying thrombophilia identified during workup may warrant extended anticoagulation

Choice of anticoagulant: 2

• Direct oral anticoagulants (DOACs) are preferred: apixaban, rivaroxaban, edoxaban, or dabigatran
• VKA (warfarin) is required for antiphospholipid antibody syndrome
• After 6 months, reduced-dose apixaban (2.5 mg twice daily) or rivaroxaban (10 mg daily) should be considered for extended therapy 2

Key Clinical Pitfalls

Do not restart TRT after a thrombotic event, even with therapeutic anticoagulation. Case series demonstrate recurrent thrombosis in 11 patients who continued TRT despite adequate anticoagulation, with 6 experiencing a third event. 4

Do not assume normal baseline thrombophilia testing eliminates risk. One patient in a case series developed thrombosis despite no identifiable clotting abnormalities. 3

Do not overlook elevated estradiol levels. Monitor and consider aromatase inhibitors if estradiol exceeds 42.6 pg/mL, as this contributes to the thrombotic mechanism. 3

Do not use intramuscular testosterone formulations in high-risk patients. Intramuscular injections are associated with higher rates of erythrocytosis (43.8%) compared to transdermal preparations (15.4%), increasing thrombotic risk. 2