What are the risks and considerations for prescribing testosterone therapy to a male patient with hypogonadism (low sex hormone) and a history of pulmonary embolism (blockage of an artery in the lungs) or risk factors for thromboembolic events (blood clots)?

Testosterone Therapy and Pulmonary Embolism Risk

In a male patient with hypogonadism and a history of pulmonary embolism, testosterone therapy should generally be avoided or used with extreme caution, as the FDA explicitly warns that venous thromboembolic events including pulmonary embolism have been reported in postmarketing surveillance, and if a VTE is suspected, testosterone should be discontinued immediately. 1

Critical FDA Safety Warning

The FDA drug label contains a black-box level warning specifically addressing this scenario:

• Postmarketing reports have documented venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products 1
• If a venous thromboembolic event is suspected, discontinue treatment with testosterone gel and initiate appropriate workup and management 1
• Patients must be evaluated immediately if they report signs and symptoms of pain, edema, warmth and erythema in the lower extremity for DVT or acute shortness of breath for PE 1

Mechanism of Thrombotic Risk

Testosterone increases thrombotic risk through multiple pathways:

• Testosterone causes polycythemia (elevated hematocrit) by increasing red blood cell mass, which directly increases blood viscosity and thromboembolic risk 1
• The FDA mandates checking hematocrit before initiating treatment, re-evaluating at 3-6 months (when most increases occur), then annually 1
• If hematocrit becomes elevated, therapy must be stopped until it decreases to an acceptable concentration 1
• Intramuscular testosterone injections carry higher risk of erythrocytosis (43.8% of patients) compared to transdermal preparations (15.4%), with risk directly related to supraphysiologic testosterone and estradiol levels 2

Evidence on VTE Risk in Hypogonadal Men

The evidence presents a concerning picture despite some reassuring guideline statements:

Observational Data Shows Increased Risk:

• A 2020 case-crossover study of 39,622 men found testosterone therapy was associated with more than doubled short-term VTE risk in both men with hypogonadism (OR 2.32,95% CI 1.97-2.74) and without hypogonadism (OR 2.02,95% CI 1.47-2.77) 3
• The risk was particularly pronounced in younger men under 65 years (OR 2.99,95% CI 1.91-4.68) 3

Case Series Demonstrate Recurrent Events Despite Anticoagulation:

• A 2016 study of 67 patients with thrombotic events after starting testosterone found 47 had DVT-PE, occurring at a median of 6 months after initiation 4
• Critically, 11 patients had a second thrombotic event despite adequate anticoagulation while continuing testosterone, and 6 had a third event 4
• Thrombophilia was common: 24% had Factor V Leiden heterozygosity and 14% had lupus anticoagulant 4

RCT Data Shows Reassuring but Limited Evidence:

• The 2020 American College of Physicians guideline review of 14 RCTs (n=2,415) found no significant increase in cardiovascular events (Peto OR 1.22, CI 0.66-2.23), but this was low-certainty evidence 2
• Most RCTs excluded men with recent cardiovascular disease, limiting generalizability to patients with prior PE 2
• Few venous thromboembolism events were reported in trials (0.6% testosterone vs 0.5% placebo), but no trials were powered to detect VTE differences 2
• Most trials lasted less than 1 year, providing no data on long-term safety 2

Clinical Decision Algorithm for Patients with Prior PE

Step 1: Assess Absolute Necessity

• Confirm true hypogonadism with two morning testosterone levels <300 ng/dL before considering any therapy 5
• Evaluate whether symptoms are truly attributable to low testosterone versus other causes (depression, sleep disorders, obesity, medications) 2

Step 2: Risk Stratification

High-risk features that strongly argue against testosterone use:

• Recent PE (within 6-12 months) 6
• Recurrent VTE history 4, 7
• Known thrombophilia (Factor V Leiden, lupus anticoagulant, prothrombin mutation) 4
• Active malignancy 3
• Immobility or recent surgery 3
• Concurrent cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, atrial fibrillation) 6, 5

Step 3: Consider Safer Alternatives First

• Lifestyle modifications including weight loss and increased physical activity should be prioritized, as these can independently improve testosterone levels and symptoms without cardiovascular risks 6, 5
• For secondary hypogonadism, clomiphene citrate may be safer as it stimulates endogenous production rather than providing exogenous hormone, though safety data in PE survivors is lacking 5

Step 4: If Testosterone is Considered Despite PE History

This decision requires explicit informed consent discussion including:

• The theoretical small benefits (modest improvements in sexual function and quality of life per ACP guidelines) 2
• The potential for catastrophic outcomes (recurrent PE, death) 6, 5
• The fact that thrombosis may recur despite adequate anticoagulation if testosterone is continued 4, 7

Mandatory monitoring protocol if initiated:

• Baseline hematocrit, then recheck at 1-2 months (not 3-6 months as FDA suggests for general population) given high-risk status 6
• Hematocrit >54% mandates dose reduction or temporary discontinuation 6
• Continue therapeutic anticoagulation indefinitely if patient was already anticoagulated for prior PE 4, 7
• Consider thrombophilia screening before initiation to identify patients at highest risk 4

Patient must immediately report:

• Chest pain, shortness of breath, leg pain, swelling, warmth, or erythema 1
• Any neurological symptoms 6

Critical Pitfalls to Avoid

• Do not prescribe testosterone to men with recent PE (<6-12 months) under any circumstances 6, 1
• Do not continue testosterone if VTE occurs—the FDA explicitly states to discontinue immediately 1
• Do not assume anticoagulation provides adequate protection—case series show recurrent events despite therapeutic anticoagulation when testosterone is continued 4, 7
• Do not extrapolate safety data from healthy trial participants to high-risk patients with prior PE—trials systematically excluded such patients 2
• Do not use intramuscular formulations in high-risk patients—they carry the highest erythrocytosis risk (43.8%) 2
• Do not delay hematocrit monitoring—most increases occur within the first 3 months 2, 1

The Bottom Line

For most men with prior pulmonary embolism, the risk-benefit ratio strongly favors avoiding testosterone therapy entirely. The combination of FDA postmarketing warnings, case series showing recurrent events despite anticoagulation, and observational data showing doubled VTE risk outweighs the modest symptomatic benefits demonstrated in RCTs. 1, 4, 7, 3 If therapy is absolutely necessary after exhausting alternatives, it requires indefinite anticoagulation, intensive monitoring, immediate availability for urgent evaluation, and explicit patient understanding that recurrent PE may occur and could be fatal. 6, 1