Recent experimental and clinical studies suggest that estrogen may be an important factor influencing neuronal function during normal and pathological aging. Using different behavioral paradigms in rodents, estrogen replacement was shown to enhance learning and memory as well as attenuate learning deficits associated with cholinergic impairment. The goal of this study was to determine whether cognitive sensitivity to estrogen manipulations (short-term ovariectomy and chronic estrogen replacement) is affected by aging. Middle-aged and old female Fischer-344 rats were used to estimate the effects of estrogen manipulations at two different stages of reproductive aging. At middle age, when the females underwent an initial stage of reproductive aging (irregular cyclicity), ovariectomy did not significantly affect the acquisition of the T-maze active avoidance as compared with Sham rats, while estrogen replacement decreased behavioral vulnerability to scopolamine. However, when tested at more advanced stage of aging (consistent diestrus), old ovariectomized rats were more sensitive to scopolamine as compared with the control rats. Moreover, estrogen treatment at this age did not produce any protective effect against scopolamine. Contrasting findings of the effects of estrogen replacement in middle-aged and old rats suggest that the ability of estrogen to enhance the basal forebrain cholinergic function declines with age. These data indicate that aging processes may substantially modulate the mechanisms of estrogen action. A "time window" during which hormone replacement must be initiated in order to be effective could be determined in terms of the stages of reproductive senescence. This study is the first to clearly demonstrate that the cognitive effects of estrogen replacement are still preserved during the initial stages of reproductive aging (irregular cyclicity) and dramatically limited as aging progresses (cessation of proestrus).