EFFECTS OF ESTRADIOL AND RALOXIFENE ON COGNITION IN AGED OVARIECTOMIZED MONKEYS: PRELIMINARY FINDINGS





A. Lacreuse*, A.V. Raghavan, A.L. Reid, M.E. Wilson, J.G. Herndon.

Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30322




Because estrogens help to maintain a wide range of physiological systems, their decline at menopause can give rise to numerous health problems, including cognitive impairment. A role for estrogen in cognition is further suggested by findings that estrogen replacement therapy (ERT) may protect against age-related cognitive decline and Alzheimer's disease. Since ERT increases the risk of developing uterine and breast cancers, however, a new class of non-carcinogenic compounds, deemed selective estrogen receptor modulators (SERMs) is being considered as a desirable alternative to ERT. Clearly, the influence of SERMs upon cognition must be evaluated to determine whether they confer the same advantages as conventional ERT upon cognitive function.
We used a rhesus monkey model of human menopause to examine the effects of ERT and the SERM raloxifene on cognition. We tested 5 aged female rhesus monkeys (21-24 years old) that had been ovariectomized for many years (10-16 years) on a battery of cognitive tests sensitive to aging and tapping several cognitive domains, including the Delayed Response (DR), the Delayed Non Matching-to-Sample with a 10 minute delay (DNMS-10 min) and the spatial-Delayed Recognition Span Test (DRST). Monkeys were tested 5 days a week on each task, 1 task per week, for 4 consecutive months, while undergoing monthly treatments with placebo, ethinyl estradiol (EE2), and raloxifene in a within-subject design. We found that EE2 treatment enhanced performance on the spatial-DRST, a task of spatial memory, but did not affect performance on the other tasks of the battery. Further, the improvement was restricted to working memory, as opposed to reference memory. Raloxifene had no effect on cognitive performance for any tasks. These findings show that estradiol is able to enhance spatial working memory in aged monkeys despite many years of estrogenic deprivation. Supported by NIH grants AG18998 and RR00165.




Key words: Estrogen; cognition; ovariectomy; aging; monkey







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