Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3alpha-androstanediol and 17beta-estradiol

Testosterone modulates seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, testosterone modulation of seizure susceptibility is hypothesized to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17beta-estradiol. Reduction of testosterone by 5alpha-reductase generates 5alpha-dihydrotestosterone (DHT), which is then converted to 3alpha-androstanediol (3alpha-Diol), a powerful GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Systemic doses of testosterone decreased seizure threshold in rats and increased the incidence and severity of pentylenetetrazol (PTZ)-induced seizures in mice. These proconvulsant effects of testosterone were associated with increases in plasma 17beta-estradiol and 3alpha-Diol concentrations. Pretreatment with letrozole, an aromatase inhibitor that blocks the conversion of testosterone to 17beta-estradiol, significantly inhibited testosterone-induced exacerbation of seizures. The 5alpha-reductase inhibitor finasteride significantly reduced 3alpha-Diol levels and also blocked letrozole's ability to inhibit the proconvulsant effects of testosterone. The 5alpha-reduced metabolites of testosterone, DHT and 3alpha-Diol, had powerful anticonvulsant activity in the PTZ test. Letrozole or finasteride had no effect on seizure protection by DHT and 3alpha-Diol, but indomethacin partially reversed DHT actions. 3alpha-Diol but not 3beta-androstanediol, a GABA(A) receptor-inactive stereoisomer, suppressed 4-aminopyridine-induced spontaneous epileptiform bursting in rat hippocampal slices. Thus, testosterone-derived neurosteroids 3alpha-Diol and 17beta-estradiol could contribute to the net cellular actions of testosterone on neural excitability and seizure susceptibility.