Reduced Metabolites Mediate Neuroprotective Effects of Progesterone in the Adult Rat Hippocampus. The Synthetic Progestin Medroxyprogesterone Acetate (Provera) Is Not Neuroprotective

The study investigated the neuroprotective effects of progesterone and its metabolites in the hippocampus of ovariectomized rats subjected to kainic acid-induced excitotoxicity. Progesterone was found to increase levels of its metabolites, 5α-dihydroprogesterone (DHP) and 3α,5α-tetrahydroprogesterone (THP), in both plasma and hippocampus, which prevented neuronal loss. In contrast, the synthetic progestin medroxyprogesterone acetate (MPA, Provera) did not increase these metabolite levels and failed to prevent neuronal loss. The use of finasteride, a 5α-reductase inhibitor, blocked the increase of DHP and THP and negated progesterone's neuroprotective effects, while indomethacin, a 3α-hydroxysteroid dehydrogenase inhibitor, blocked the neuroprotective effects of DHP and THP. These findings suggested that the metabolism of progesterone to DHP and THP was essential for its neuroprotective effects, whereas MPA did not share these benefits.