ORALLY-ADMINISTERED PROGESTERONE ENHANCES SENSITIVITY TO TRIAZOLAM INPOSTMENOPAUSAL WOMEN

An endogenously formed metabolite of progesterone, 3 alpha-hydroxy-5 a lpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP) modulates the gamma- aminobutyric acid receptor complex and plays a physiologic role in bra in excitability regulation. On the basis of in vitro observations of 3 alpha-OH-5 alpha-DHP-enhanced [H-3]flunitrazepam binding, we investig ated the potential clinical effect of coadministering oral progesteron e and triazolam. Sixteen postmenopausal women were randomly assigned t o receive either intravenous triazolam plus oral progesterone 300 mg ( TRZPROG) or intravenous triazolam plus oral placebo (TRZ). Triazolam w as infused until 0.5 mg was given or until a predetermined maximal res ponse was attained. Pharmacodynamic evaluation included DSST, continuo us performance test, hand-eye coordination, short-term memory, and sed ation, Effect ratios were calculated as the ratio of area under the ef fect-time curve to area under the curve (AUC). Variants of the sigmoid E(max), model were fit to the data from the three psycho-motor perfor mance tests. A triazolam dose of less than 0.5 mg was administered to seven of eight subjects in the TRZPROG and five of eight subjects in t he TRZ group, resulting in lower triazolam AUC values for the TRZPROG than for the TRZ group (p = 0.0275). There was clear evidence for a ph armacodynamic interaction. Mean effect ratios for all tests were great er in the TRZPROG group than in the TRZ group (DSST, p = 0.0097; conti nuous performance test, p = 0.0338; hand-eye coordination, p = 0.0041) , The TRZPROG group had lower EC(50) values than the TRZ group (DSST, p = 0.0435; continuous performance test, p = 0.0381; hand-eye coordina tion, p = 0.0154). These results confirm our hypothesis that the concu rrent administration of progesterone enhances the effects of triazolam . This is new evidence that documents the effect of progesterone on ph armacodynamic response to benzodiazepines in humans. This study provid es evidence that in vitro receptor binding observations qualitatively predict pharmacodynamic response to benzodiazepines.