Effect of age on synthesis of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one in rat cortex in vitro.

Progesterone 5-alpha-reductase activity and 3-alpha-hydroxysteroid dehydrogenase activity were determined in the cortex of male and female rats in vitro. Age effects were investigated. The age of the male rats was 3-23 months, and that of the female rats 4-23 months. On addition, we investigated the enzyme 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase in rat cortex in order to estimate the local synthesis of progesterone from pregnenolone. We found age-related increases in progesterone 5-alpha-reductase activity in the female rats (r = 0.64, p < 0.01, n = 6) and in the male rats (r = 0.5, p < 0.05, n = 18). 3-alpha-HSDH activity remained constant with age in female and male rats. The ratio of 3-alpha-hydroxysteroid dehydrogenase activity to 5-alpha-reductase activity tended to decrease with age (not significantly) in both male rats (r = -0.45, p = 0.06, n = 19) and the female rats (r = -0.36, p = 0.17, n = 16). We could not detect significant metabolism of pregnenolone to progesterone in rat cortex in vitro. The sensitivity of the assays of 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase was calculated from the mean of the blank values + 3SD; the sensitivity of the assay was calculated as 0.103 fmol/mg protein/min. No significant metabolism of pregnenolone could be detected in cortex pooled from several male rats. The mean metabolism of progesterone was 1,200 times higher than the detection threshold of the assay for 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase. We conclude that modifications of the inhibitory effects of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one via altered progesterone metabolism in rat cortex are possible with aging. A connection with the age-related increase in incidence of epileptic attacks, and with age-related changes in the effects of anticonvulsant and GABAA-active drugs, appears possible.