Is testosterone therapy concerning in an adult patient with a history of hemorrhagic stroke and aneurysm?

Testosterone Therapy in Patients with History of Hemorrhagic Stroke and Aneurysm

Testosterone therapy should be avoided or used with extreme caution in patients with a history of hemorrhagic stroke and aneurysm, as the FDA warns that postmarketing studies have shown increased risk of stroke associated with testosterone replacement therapy, and most safety studies specifically excluded patients with recent cerebrovascular disease. 1

Critical Safety Concerns

FDA Warning and Contraindications

• The FDA drug label explicitly states that "some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy." 1
• Testosterone products carry warnings about venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, which could theoretically increase thrombotic risk. 1

Evidence Limitations in High-Risk Populations

• The 2024 AHA/ASA Stroke Prevention Guidelines note that the TRAVERSE study (the highest quality evidence available) specifically enrolled men with cerebrovascular disease, but this referred to ischemic cerebrovascular disease, not hemorrhagic stroke. 2
• The American College of Physicians' 2020 guideline emphasizes that "participants were typically aged 60 years or older; white; and without recent cardiovascular events, history of prostate cancer, or elevated levels of prostate-specific antigen," which limits generalizability to patients with prior hemorrhagic stroke. 2
• Most testosterone safety trials excluded patients with recent cardiovascular or cerebrovascular events, meaning there is essentially no direct evidence for safety in hemorrhagic stroke survivors. 2, 3

Hemorrhagic vs. Ischemic Stroke: A Critical Distinction

Why Hemorrhagic Stroke History Changes the Risk-Benefit Calculation

• While the 2024 AHA/ASA guidelines state that "initiation or continuation of testosterone replacement therapy is reasonable and does not increase the risk of stroke" in men 45-80 years with confirmed hypogonadism, this recommendation is based on the TRAVERSE study which found no increased risk of nonfatal stroke (primarily ischemic). 2
• Hemorrhagic stroke has fundamentally different pathophysiology than ischemic stroke—it involves vessel rupture rather than thrombosis, and the presence of an aneurysm indicates structural vascular weakness. 2
• Testosterone's effects on blood pressure, hematocrit, and potential prothrombotic effects could theoretically increase risk of aneurysm rupture or recurrent hemorrhage, though this has not been studied. 1

Hematocrit Elevation Risk

• Testosterone therapy commonly increases hematocrit, with FDA labeling requiring monitoring as "hematocrit >54% warrants dose reduction or temporary discontinuation." 3, 1
• Elevated hematocrit increases blood viscosity, which could theoretically increase pressure on weakened vessel walls or unruptured aneurysms. 3

Clinical Decision Framework

When Testosterone Should Be Avoided

• In patients with history of hemorrhagic stroke and known aneurysm (ruptured or unruptured), the theoretical benefits of testosterone therapy (small improvements in sexual function and quality of life per the American College of Physicians) are vastly outweighed by the potential for catastrophic outcomes including recurrent hemorrhage or aneurysm rupture. 2, 3
• The presence of other cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) significantly increases recurrent stroke risk and further tips the balance against testosterone use. 3

If Testosterone Is Considered Despite These Risks

• Patients must undergo comprehensive counseling about the unknown risks, as "most studies excluded men with recent cardiovascular disease, limiting the generalizability of safety data to patients with prior stroke." 3
• Ensure optimal management of all modifiable risk factors, particularly blood pressure control, which is critical in patients with aneurysms. 3
• Implement intensive monitoring with first follow-up at 1-2 months, checking hemoglobin/hematocrit (increases occur rapidly within 3 months), blood pressure, and neurological symptoms. 3
• Patients must be counseled to immediately report cardiovascular symptoms including chest pain, shortness of breath, dizziness, or any new neurological symptoms. 3

Alternative Management Strategies

Prioritize Non-Pharmacologic Approaches

• Lifestyle modifications including weight loss and increased physical activity should be the first-line approach, as these can independently improve testosterone levels and symptoms without the cardiovascular risks. 2, 3
• The AUA guideline states that "lifestyle modifications, such as losing weight, or maintaining weight within the recommended range, along with increasing physical activity, has the potential to increase total testosterone levels and/or reduce signs and symptoms associated with testosterone deficiency." 2

Consider Clomiphene Citrate as Alternative

• For men with secondary hypogonadism who desire treatment, clomiphene citrate may be a safer alternative as it stimulates endogenous testosterone production rather than providing exogenous hormone. 4
• However, even clomiphene safety data in hemorrhagic stroke survivors is lacking, and the American College of Physicians notes that safety studies excluded high-risk cardiovascular patients. 4

Common Pitfalls to Avoid

• Do not extrapolate safety data from ischemic stroke studies to hemorrhagic stroke patients—these are fundamentally different disease processes. 2, 3
• Do not initiate testosterone without confirming true hypogonadism with two morning testosterone levels <300 ng/dL, as the AUA guideline requires. 2
• Do not overlook the aneurysm status—unruptured aneurysms require ongoing surveillance and blood pressure control, which could be compromised by testosterone therapy. 3
• Do not minimize the severity of potential adverse outcomes—the theoretical small improvements in quality of life must be weighed against risk of death or severe disability from recurrent hemorrhage. 2, 3