ANXIOLYTIC METABOLITES OF PROGESTERONE - CORRELATION WITH MOOD AND PERFORMANCE-MEASURES FOLLOWING ORAL PROGESTERONE ADMINISTRATION TO HEALTHY FEMALE VOLUNTEERS

Progesterone is readily reduced in humans to its A-ring metabolites, a llopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one) and pregnanol one (3 alpha-hydroxy-5 beta-pregnan-20-one) The latter have been repor ted to have anxiolytic, hypnotic and anesthetic actions when administe red to laboratory animals and (or) humans. Consequently, we measured a llopregnanolone and pregnanolone in 18 healthy females, ages 18-25, at the time of peak plasma progesterone following an oral dose of micron ized progesterone (1,200 mg) in a double-blind, placebo-controlled stu dy. The plasma levels of the parent steroid and metabolites were compa red with changes in mood, cognition, and motor performance following p rogesterone administration. We observed good correlations between plas ma progesterone and plasma allopregnanolone (r = 0.85), plasma pregnan olone (r = 0.81) and the combined metabolites (r = 0.92). Plasma allop regnanolone was significantly correlated with measures of fatigue, con fusion and immediate recall, and these correlation coefficients were s omewhat greater than those for plasma progesterone and these same beha vioral measures. Significant changes in fatigue, delayed verbal recall and symbol copying were experienced by subjects who achieved high lev els (greater than or equal to 95.55 nmol/l) of these anxiolytic metabo lites, while those with lower metabolite levels reported no negative e ffects. These data suggest that allopregnanolone and pregnanolone may contribute to or mediate the observed behavioral effects of progestero ne.