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.