TRT has become a widely discussed treatment for men experiencing symptoms of low testosterone, often referred to as hypogonadism. This therapy involves administering exogenous testosterone to restore hormone levels, which can lead to improvements in energy, muscle mass, and libido. A concern associated with TRT is the potential for blood clot formation, known medically as thrombosis. Clots form when blood thickens inside a blood vessel, obstructing circulation. When these clots form in deep veins, typically in the legs, it is called deep vein thrombosis (DVT). If a DVT breaks off and travels to the lungs, it results in a life-threatening pulmonary embolism (PE).
How Testosterone Affects Blood Composition
Testosterone influences the blood system primarily by stimulating red blood cell production, a process called erythropoiesis. The hormone stimulates bone marrow to produce more red blood cells, increasing the proportion of red blood cells in the total blood volume, measured as hematocrit. This rise in red blood cell count causes the blood to become thicker, a condition known as polycythemia, which increases blood viscosity. Higher blood viscosity means the blood flows less smoothly through the vessels, contributing to a pro-thrombotic state and elevating the risk of clotting.
Testosterone stimulates erythropoiesis partly by increasing erythropoietin (EPO) levels, which signals the bone marrow to produce red blood cells. It may also affect iron regulation by suppressing hepcidin, a protein that controls iron availability, allowing more iron to be utilized for red blood cell synthesis. The increased concentration of red blood cells is considered the primary biological mechanism linking testosterone therapy to an increased risk of venous thromboembolism (VTE). Testosterone may also alter the balance of clotting proteins, potentially encouraging clot formation, though evidence for this mechanism is less definitive.
The Clinical Evidence Linking Testosterone and Clots
The clinical data linking testosterone therapy and blood clot risk is complex, involving findings from large observational studies and regulatory warnings. Some large retrospective studies found an association between starting TRT and an elevated risk of venous thromboembolism (VTE), especially within the first six months of therapy. For example, some research suggested the VTE risk may double in men using TRT compared to non-users immediately following treatment initiation.
These findings prompted the U.S. Food and Drug Administration (FDA) to require manufacturers to add a warning about VTE risk to the labels of all approved testosterone products. This regulatory action was based on post-market reports of blood clots. The required warning addressed VTE cases related and unrelated to treatment-caused polycythemia, suggesting a broader concern than just blood thickening.
The evidence is not entirely consistent, however, as some large-scale studies and meta-analyses based on randomized controlled trials (RCTs) have not detected a statistically significant increase in VTE risk with TRT. This difference often stems from study design; observational studies include a wider population than the carefully selected participants in RCTs. Despite conflicting data, VTE remains a recognized adverse event. Clinicians agree that while TRT offers benefits, the potential for a VTE event requires patient awareness and careful monitoring.
Identifying Patients at Elevated Risk
The risk of developing a blood clot while on TRT is not uniform and is heightened in individuals with specific pre-existing conditions. A personal history of a previous venous thromboembolism (DVT or PE) places a patient at a higher susceptibility for recurrence. Individuals with known thrombophilias—inherited or acquired disorders that increase the tendency to clot—also require cautious consideration before initiating TRT.
Treatment variables also influence a patient’s risk profile. The method of testosterone administration impacts the likelihood of developing polycythemia, the primary driver of clot risk. Intramuscular injections are associated with a significantly higher risk of elevated hematocrit compared to transdermal gels or patches. This is because injections often lead to peaks in testosterone levels that stimulate erythropoiesis more aggressively than the stable levels achieved with topical formulations.
Patients who start therapy with a baseline hematocrit already in the upper normal range (typically above 50%) face a greater risk of developing concerning polycythemia. Co-morbidities that naturally increase the red blood cell count, such as severe sleep apnea, chronic obstructive pulmonary disease, or heavy smoking, can compound the effects of testosterone and raise the risk of hyperviscosity. These factors necessitate a comprehensive assessment of a patient’s health to mitigate potential clotting risks.
Safety Measures and Monitoring During Therapy
Monitoring is essential during TRT to mitigate the risk of adverse events, especially blood clot formation. Before initiating TRT, a patient’s hematocrit and hemoglobin levels must be measured to establish a baseline. If the baseline hematocrit is high (over 50%), the underlying cause should be investigated before starting treatment.
Regular blood tests are necessary once therapy begins to track the red blood cell count and detect polycythemia. The recommended monitoring schedule involves rechecking hematocrit and hemoglobin at one to two months after starting treatment, then every three to six months during the first year, and annually thereafter if levels remain stable. If a patient’s hematocrit rises above 54%, the testosterone dose should be reduced or the therapy temporarily stopped until levels normalize.
Patients should be aware of the warning signs of a potential DVT or PE to seek immediate medical attention. Symptoms of a DVT include sudden swelling, pain, tenderness, or warmth in one leg, often in the calf or thigh. A pulmonary embolism is a medical emergency presenting with sudden shortness of breath, chest pain that worsens with a deep breath, or a rapid heart rate. If dose adjustment or switching formulations is insufficient to control high hematocrit, therapeutic phlebotomy—drawing blood to reduce the red blood cell mass—may be considered.