Can a 43-year-old male on testosterone replacement therapy (TRT) with hypertestosteronemia present with neurological symptoms such as altered mental status?

Testosterone Supraphysiologic Levels and Neurological Symptoms

While testosterone replacement therapy at therapeutic doses does not directly cause altered mental status, supraphysiologic testosterone levels (twice the upper limit of normal) in a 43-year-old male warrant immediate investigation for serious underlying conditions and potential indirect neurological complications, particularly cardiovascular events that could present with altered mental status.

Direct Neurological Effects of Testosterone

The available evidence does not support testosterone itself causing altered mental status or cognitive impairment, even at therapeutic doses:

• Cognitive function studies show no significant neurological effects: Multiple RCTs including the Cognitive Function Trial (n=493) demonstrated that testosterone treatment had no association with cognitive outcomes across verbal memory, visuospatial memory, language, and executive function domains 1.

• No documented cases of altered mental status from testosterone: The comprehensive American College of Physicians evidence review of 14 trials (n=2,415) examining adverse events did not report altered mental status or acute neurological symptoms as complications of testosterone therapy 1.

• Mood effects are minimal: Testosterone produces only "less-than-small improvements" in depressive symptoms (SMD -0.19) and has no clinically significant effect on cognition or mental status 1.

Critical Indirect Mechanisms to Consider

Cardiovascular Events Presenting as Altered Mental Status

This is the most important consideration in your patient:

• Increased cardiovascular risk with testosterone: Pooled analysis showed a Peto OR of 1.22 (CI 0.66-2.23) for cardiovascular events, with 2.3% incidence in testosterone groups versus 1.5% in placebo 1.

• Cerebrovascular accidents can occur: There is a documented case report of cerebrovascular accident associated with extremely elevated testosterone levels (11,400 ng/dL) after testosterone enanthate injection 2.

• Stroke or TIA must be ruled out: Altered mental status in the context of supraphysiologic testosterone could represent a cerebrovascular event, particularly given the association between testosterone therapy and cardiovascular complications 3, 4.

Erythrocytosis-Related Complications

• Testosterone causes erythrocytosis: This is a well-established adverse effect, with up to 44% risk with injectable testosterone formulations 5.

• Hyperviscosity syndrome: Supraphysiologic testosterone levels causing severe erythrocytosis (hematocrit >54%) could theoretically lead to hyperviscosity, increasing stroke risk and potentially causing altered mental status 5.

• Immediate hematocrit measurement required: The patient needs urgent CBC to assess for dangerous erythrocytosis 5.

Diagnostic Algorithm for This Patient

Immediate Evaluation Required

1. Rule out acute cerebrovascular event: Obtain urgent head CT/MRI, as altered mental status with supraphysiologic testosterone raises concern for stroke or TIA 2, 3.

2. Check hematocrit immediately: Levels >54% require withholding testosterone and considering phlebotomy 5.

3. Assess cardiovascular status: ECG and cardiac biomarkers to exclude myocardial infarction, which can present with altered mental status in some patients 1.

4. Measure actual testosterone level: Confirm the degree of elevation and timing relative to last injection 5.

Secondary Considerations

• Exclude other causes of altered mental status: Hypoglycemia, electrolyte abnormalities, infection, substance use, and other metabolic derangements must be ruled out through standard workup 2.

• Review medication compliance and dosing: Determine if the patient is taking excessive doses (abuse scenario) or if there has been a dosing error 2.

Management Approach

If Cardiovascular Event Confirmed

• Discontinue testosterone immediately: This is an absolute indication to stop therapy 2.

• Standard stroke/MI management protocols: Follow evidence-based acute cardiovascular care guidelines.

If No Acute Event Identified

• Discontinue testosterone until levels normalize: Supraphysiologic levels (2x upper limit) are inappropriate and dangerous 5.

• Investigate cause of excessive levels: Was this intentional abuse, dosing error, or inappropriate prescribing? 2.

• Do not restart without proper evaluation: The patient needs complete reassessment of indication for TRT, as approximately 20-30% of men receiving testosterone lack documented hypogonadism 5.

Critical Clinical Caveat

The altered mental status is almost certainly NOT a direct effect of testosterone on the brain, but rather represents either:

1. A cardiovascular complication (stroke, TIA, MI) precipitated by supraphysiologic testosterone levels
2. An unrelated acute medical condition requiring standard evaluation
3. Hyperviscosity from severe erythrocytosis

The evidence is clear that testosterone does not cause cognitive impairment or altered mental status through direct CNS effects 1, 6. However, the cardiovascular risks associated with testosterone therapy—particularly at supraphysiologic levels—can absolutely cause neurological presentations through cerebrovascular mechanisms 2, 3.