Does hypogonadism (low testosterone levels) play a role in nonepileptic seizures?

Role of Low Testosterone in Nonepileptic Seizures

Low testosterone levels may play a role in nonepileptic seizures through neuroendocrine mechanisms, though the direct evidence is limited. While hypogonadism has been more extensively studied in epilepsy, emerging research suggests hormonal imbalances could contribute to vulnerability for psychogenic nonepileptic seizures (PNES).

Neuroendocrine Factors in Nonepileptic Seizures

Testosterone and Brain Excitability

• Testosterone and its metabolites have complex effects on brain excitability:
  • Estradiol (a testosterone metabolite) increases brain excitability
  • 3alpha-androstanediol (another testosterone metabolite) decreases brain excitability through GABA-A receptor action 1
  • These opposing effects may influence seizure threshold in both epileptic and nonepileptic conditions

Stress Hormones and PNES

• Research has shown that PNES patients with sexual abuse history have lower neuropeptide Y (NPY) levels 2
• NPY is associated with stress resilience, and low levels may increase vulnerability to PNES symptoms
• This suggests neuroendocrine factors, including sex hormones, could influence susceptibility to nonepileptic seizures

Hypogonadism and Seizure Disorders

Prevalence in Seizure Disorders

• Hypogonadotropic hypogonadism (low testosterone with disturbed pituitary gonadotropin secretion) has been found in 12% of patients with temporal lobe epilepsy compared to only 1.5% in the general population 3
• Androgen-related disorders occur more frequently in epileptic men than in the general male population, often presenting as hypogonadism with low free testosterone levels 4

Bidirectional Relationship

• The relationship between hormones and seizures is bidirectional:
  • Hormonal changes can affect seizure threshold
  • Seizures and seizure-like events can disrupt hypothalamic-pituitary function
  • This creates a potential cycle where hormonal imbalances and seizure events reinforce each other 5

Clinical Implications

Assessment Considerations

• For patients with nonepileptic seizures who present with symptoms of hypogonadism:
  • Measure morning total and free testosterone levels
  • Check luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels
  • Evaluate estradiol levels 6
  • Interpret hormone levels in the context of clinical symptoms

Treatment Approaches

• If low testosterone is identified in patients with nonepileptic seizures:
  • Consider testosterone replacement therapy (TRT) with target levels of 450-600 ng/dL 6
  • Monitor hematocrit (should remain below 54%) and PSA regularly during treatment
  • Evaluate for symptom improvement in both seizure frequency and hormonal symptoms

Potential Therapeutic Considerations

• Aromatase inhibitors may be beneficial in some cases by:
  • Preventing conversion of testosterone to estradiol (which increases brain excitability)
  • Potentially enhancing the 3alpha-androstanediol pathway (which decreases brain excitability) 1
  • Helping restore normal testosterone levels in men with low testosterone

Caveats and Limitations

• Most research on hormones and seizures focuses on epileptic rather than nonepileptic seizures
• The specific mechanisms linking testosterone levels to nonepileptic seizures remain poorly understood
• Multiple factors beyond hormones contribute to nonepileptic seizures, including psychological stressors and trauma
• Treatment decisions should consider the complex interplay between hormones, stress, and psychological factors

While the direct evidence linking low testosterone specifically to nonepileptic seizures is limited, the broader neuroendocrine connections suggest that addressing hormonal imbalances may be a valuable component of comprehensive treatment for some patients with PNES.