Aromatase inhibitors as add-on treatment for men with epilepsy.

Manipulation of neurosteroids to treat epilepsy has been an area of active research. The effect of testosterone on brain excitability and seizure threshold has been mixed; the estradiol metabolite of testosterone increases brain excitability, while the reduced metabolite of testosterone, 3alpha-androstanediol, decreases brain excitability, likely through an action at the gamma-amino butyric acid A receptor. Therefore, the metabolites of testosterone produce opposite effects on brain excitability in seizure models. Aromatase is the enzyme for the conversion of testosterone to 17beta-estradiol. Aromatase inhibitors could decrease brain excitability by decreasing local estradiol levels and therefore, could be beneficial for the treatment of epilepsy. Aromatase inhibitors are US Food and Drug Administration-approved and have a long history of safe use in menopausal women with breast cancer. This review presents the results of using anastrazole in an open-label, add-on manner in a small group of men with epilepsy in order to improve seizures. The results suggested some effect on reduction of seizures and no side effects. Testosterone levels did increase, but not to above the normal range. Letrozole used in a single case was also beneficial for seizures. It was concluded that aromatase inhibitors may be a useful adjunct to the treatment of epilepsy, but habituation to the treatment may be limiting. Many men with epilepsy have low testosterone, and aromatase inhibition may be helpful in restoring levels to normal. Modulation of reproductive hormones by aromatase inhibition as well as enhancement of the 3alpha-androstanediol pathway may be an avenue of epilepsy treatment that would not produce sedative side effects, which is often a limiting factor with standard antiseizure medications. A further interesting result is that elevated follicle stimulating hormone and luteal stimulating hormone levels were associated with seizure reduction, suggesting that they may be a biomarker for a beneficial effect of aromatase inhibition on brain excitability.