Effects of long-term treatment with estrogen and medroxyprogesterone acetate on synapse number in the medial prefrontal cortex of aged female rats

Objective: The present study investigated the effects of long-term hormone treatment, including the most commonly prescribed progestin, medroxyprogesterone acetate, during aging on synaptophysin-labeled boutons, a marker of synapses, in the medial prefrontal cortex (mPFC) of rats. Methods: Female Long Evans hooded rats were ovariectomized at middle age (12-13 mo) and were placed in one of four groups: no replacement (n = 5), 17 beta-estradiol alone (n = 6), estradiol and progesterone (n = 7), or estradiol and medroxyprogesterone acetate (n = 4). Estradiol was administered in the drinking water and progestogens were administered via subcutaneous pellets that were replaced every 90 days. After 7 months of hormone replacement, the animals were euthanized, and the brains were stained for synaptophysin, a membrane component of synaptic vesicles. The density of synaptophysin-labeled boutons was quantified in the mPFC using unbiased stereology and multiplied by the volume of the mPFC to obtain the total number. Results: Animals receiving estradiol and medroxyprogesterone acetate had significantly more synaptophysin-labeled boutons in the mPFC than did animals not receiving replacement (P < 0.03) and those receiving estradiol and progesterone (P < 0.02). In addition, there was a nonsignificant trend for animals receiving estradiol alone to have more synapses than those receiving estradiol and progesterone. Conclusions: This study is the first to examine the effects of estradiol and medroxyprogesterone acetate during rat aging on cortical synaptic number. Estradiol with medroxyprogesterone acetate, but not progesterone, resulted in a greater number of synapses in the mPFC during aging than did no replacement.