Can individuals with a history of seizures safely take testosterone (hormone replacement therapy)?

Testosterone Therapy in Individuals with Seizure Disorders

Testosterone replacement therapy can be safely used in individuals with a history of seizures, with appropriate monitoring and precautions. 1

Safety of Testosterone in Seizure Disorders

The 2024 American Heart Association/American Stroke Association guideline provides the most recent and highest quality evidence regarding testosterone use in individuals with medical conditions. It states that for men aged 45-80 with confirmed hypogonadism, "initiation or continuation of testosterone replacement therapy is reasonable and does not increase the risk of stroke" 1. This recommendation is based on high-quality evidence from the TRAVERSE study, a large randomized controlled trial.

While seizures have been observed in the context of SSRI use, requiring cautious use in patients with seizure disorders 1, there is no similar high-level evidence suggesting testosterone therapy increases seizure risk.

Physiological Considerations

Testosterone's effects on seizure threshold involve complex mechanisms:

• Testosterone itself has mixed effects on brain excitability 2
• Testosterone metabolizes along two pathways:
  1. Conversion to estradiol (via aromatase), which may increase brain excitability and potentially worsen seizures 2
  2. Conversion to 5α-dihydrotestosterone (DHT) and subsequently to 3α-androstanediol, which decreases brain excitability through GABA-A receptor modulation and has anticonvulsant properties 2

Recommendations for Testosterone Use in Seizure Disorders

1. Confirm hypogonadism diagnosis before initiating therapy:

   • Symptoms of hypogonadism
   • Two separate morning testosterone measurements <300 ng/dL 3

2. Dosing and monitoring:

   • Target testosterone levels in the mid-normal range (450-600 ng/dL) 3
   • Check testosterone levels 4-6 weeks after initiation and every 3-6 months thereafter 3
   • Monitor for seizure frequency changes, particularly during dose adjustments

3. Consider formulation carefully:

   • Transdermal preparations may be preferred over intramuscular injections, as they provide more stable hormone levels and lower risk of erythrocytosis (5.5-15.4% vs 43.8%) 3
   • Subcutaneous administration shows lower post-therapy hematocrit and estradiol levels compared to intramuscular testosterone cypionate 3

4. Special considerations:

   • Avoid testosterone therapy in men trying to conceive, as it suppresses spermatogenesis 1
   • For men with seizures wanting to maintain fertility, consider alternative therapies such as aromatase inhibitors, human chorionic gonadotropin, or selective estrogen receptor modulators 1, 4, 5

Potential Benefits for Seizure Control

Some evidence suggests that manipulating testosterone metabolism might actually benefit seizure control:

• Aromatase inhibitors (which block testosterone conversion to estradiol) have shown potential benefit for seizure control in small studies 4, 5
• These medications may help by:
  1. Decreasing estradiol levels (potentially reducing excitatory effects)
  2. Increasing testosterone levels within normal range
  3. Potentially shifting metabolism toward the anticonvulsant 3α-androstanediol pathway 4

Monitoring and Safety Precautions

1. Regular seizure monitoring:

   • Document baseline seizure frequency before starting therapy
   • Monitor for changes in seizure pattern, particularly during initiation and dose adjustments

2. Standard testosterone therapy monitoring:

   • Hematocrit/hemoglobin every 3-6 months (discontinue if hematocrit exceeds 54%) 3
   • PSA and digital rectal exam in men over 40 years
   • Blood pressure monitoring

3. Medication interactions:

   • Review concomitant medications, particularly antiepileptic drugs
   • Some antiepileptic drugs may affect testosterone metabolism

Conclusion

Testosterone replacement therapy can be safely used in individuals with seizure disorders when appropriately indicated and monitored. The most recent high-quality evidence suggests no increased risk of serious adverse events. In some cases, proper management of testosterone levels might even contribute to improved seizure control through its metabolic pathways, though more research is needed in this area.