Does testosterone replacement therapy increase the risk of seizures in adult males with primary or secondary hypogonadism, especially those with pre‑existing seizure risk factors?

Testosterone Does Not Cause Seizures in Hypogonadism Patients

Testosterone replacement therapy (TRT) does not cause seizures in men with hypogonadism; in fact, testosterone and its metabolites may have anticonvulsant properties. 1

Evidence on Testosterone and Seizure Activity

Anticonvulsant Properties of Testosterone Metabolites

• Testosterone metabolism via the 5α-reductase pathway produces ketosteroid metabolites, primarily androsterone and etiocholanolone, which demonstrate the ability to prevent convulsions in the majority of animal studies. 1

• Androsterone has been shown to enhance the antiepileptic activity of phenobarbital, carbamazepine, and gabapentin in animal models of epilepsy. 1

• These neuroactive androgens cross the blood-brain barrier and modify seizure susceptibility, suggesting a protective rather than harmful effect. 1

Testosterone Deficiency and Epilepsy

• Androgen-related disorders, particularly hypogonadism with low free testosterone levels, occur more frequently in epileptic men than in the general male population. 1

• This association suggests that low testosterone may be a consequence of epilepsy or its treatment, rather than testosterone causing seizures. 1

• Antiepileptic drugs, particularly classical ones, can inhibit the activity of the hypothalamic-pituitary-testicular axis and aggravate hypogonadism. 1

Clinical Implications for Hypogonadism Treatment

Safety of Testosterone Replacement

• No major guidelines or safety reviews identify seizures as a recognized adverse effect of testosterone replacement therapy. 2, 3, 4

• The FDA-mandated safety monitoring for testosterone products focuses on cardiovascular events, erythrocytosis, prostate effects, and sleep apnea—not seizures. 2, 4

• Large systematic reviews of testosterone therapy adverse events do not list seizures among serious adverse events or withdrawals due to adverse effects. 2

Recognized Adverse Effects of TRT (Not Including Seizures)

The actual documented risks of testosterone therapy include:

• Erythrocytosis (elevated hematocrit >54%), occurring in up to 44% of patients on injectable testosterone 2, 4
• Potential worsening of benign prostatic hyperplasia 2, 4
• Fluid retention 2, 4
• Testicular atrophy and infertility 2, 4
• Potential worsening of sleep apnea 2, 4
• Acne or oily skin 2, 4

Special Considerations for Patients with Epilepsy

• Men with epilepsy who have documented hypogonadism may actually benefit from testosterone replacement given the anticonvulsant properties of testosterone metabolites. 1

• The primary concern in epileptic patients is the interaction between antiepileptic drugs and testosterone metabolism, not seizure induction by testosterone itself. 1

• Antiepileptic drugs can reduce testosterone bioavailability and worsen pre-existing hypogonadism, creating a rationale for testosterone supplementation rather than avoidance. 1

Clinical Decision Algorithm

For men with hypogonadism considering TRT:

1. Confirm biochemical hypogonadism with two morning testosterone measurements <300 ng/dL 3, 4

2. Document specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction 3, 4

3. Screen for actual contraindications to TRT:

   • Active desire for fertility preservation 3, 4
   • Active or treated male breast cancer 3, 4
   • Hematocrit >54% 3, 4
   • Untreated severe obstructive sleep apnea 2, 3
   • Recent cardiovascular events within 3-6 months 3

4. History of seizures or epilepsy is NOT a contraindication to testosterone therapy 1

5. Initiate treatment with appropriate formulation (transdermal gel preferred as first-line due to stable levels and lower erythrocytosis risk) 3, 4

6. Monitor for recognized adverse effects (hematocrit, PSA, symptom response)—not seizures 3, 4

Common Pitfall to Avoid

Do not withhold testosterone replacement therapy from men with documented hypogonadism based on unfounded concerns about seizure risk. The evidence suggests testosterone metabolites may actually have protective anticonvulsant effects rather than proconvulsant activity. 1 The decision to treat should be based on established contraindications and the balance of proven benefits (improved sexual function, quality of life) versus documented risks (erythrocytosis, prostate effects, cardiovascular considerations in high-risk patients). 2, 3, 4