Conjugated equine estrogen, with medroxyprogesterone acetate, enhances formation of 5alpha-reduced progestogens and reduces anxiety-like behavior of middle-aged rats.

The mechanisms by which progestogens influence affective behaviors in females are poorly understood despite clear changes in mood/affect that are associated with their decline during menopause. Conjugated equine estrogens (CEE), with or without medroxyprogesterone acetate (MPA), are commonly prescribed hormone-replacement, but there is heterogeneity in responses to these pharmacotherapies. One way in which these compounds differ is in their capacity to potentiate metabolism of progesterone to its 5alpha-reduced products, dihydroprogesterone and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). This study investigated whether responses to CEE and MPA may be related to the capacity to metabolize progesterone. Middle-aged female rats that had maintained reproductive status, or those that had a decline, were administered vehicle, CEE and/or MPA. Effects on anxiety-like (open field, elevated plus maze) and social behaviors (social interaction test), and plasma and hippocampus steroid levels were determined. We hypothesized that CEE, but not MPA, would decrease anxiety-like behavior coincident with increased hippocampal metabolism of progesterone. CEE, or CEE+MPA, increased central entries in the open field and time spent on the open arms of the plus maze, but did not alter social interaction of rats that had maintained reproductive status. CEE and/or CEE+MPA increased E2 and 3alpha,5alpha-THP in plasma and/or hippocampus of rats, but MPA increased levels of dihydroprogesterone in the hippocampus of rats with declining reproductive status. Simple regressions showed that hippocampus 3alpha,5alpha-THP levels accounted for a significant proportion of the variance in anxiety-like behavior. Therefore, effects of CEE to reduce anxiety-like behavior of middle-aged rats may be owing, in part, to its capacity to enhance levels of 3alpha,5alpha-THP in the hippocampus.