Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys

Abstract

Among the identified risks and benefits of hormone-replacement therapy, the effects of treatment on cognitive function in postmenopausal women have proved difficult to define. Here we conducted a controlled, prospective analysis in a nonhuman primate model to test whether surgical menopause and estrogen replacement influence the cognitive outcome of normal aging. Sixteen aged rhesus monkeys were ovariectomized, and throughout the course of subsequent neuropsychological assessment, half received a regimen of low-dose, cyclic estradiol replacement. Hormone treatment substantially reversed the marked age-related impairment vehicle-injected monkeys exhibited on a delayed response test of spatial working memory. Modest improvement was also observed on a delayed nonmatching-to-sample recognition memory task. In contrast, ovariectomy exacerbated age-related deficits in object discrimination learning; the magnitude of this effect was equivalent among vehicle- and estrogen-treated monkeys. Together, these results demonstrate that ovarian hormone status can broadly influence normal cognitive aging in monkeys, affecting capacities mediated by multiple brain regions, including the prefrontal cortex and the medial temporal lobe memory system. The animal model established here should enable progress toward defining the neurobiological mechanisms that mediate the beneficial effects of estrogen on age-related cognitive decline in primates.

Figure 1.

Schematic representation of the neuropsychological test battery. Left, DR; red dot signifies food reward; middle, DNMS; and right, two-choice OD. +, Baited; –, unbaited.

Figure 2.

Mean serum estradiol (E2) levels in aged OVX monkeys 1 d before, and 9 hr, 2 d, and 3 d after vehicle or hormone injection. The results include data from every monkey, but not all time points were evaluated in each subject.

Figure 3.

Neuropsychological performance in aged OVX-veh and OVX-E monkeys. Top, Mean number of trials required to reach the acquisition criterion on the DR task at 0 and 1 sec delays (left), and mean percent correct across delays of 5–60 sec (right). Middle, Mean trials required to learn the DNMS procedure with a 10 sec delay (left), and mean percent correct across retention intervals of 15–600 sec (right). Bottom, Mean percent correct across 10-trial blocks of object discrimination learning (days 1 and 2), and retention after 48 hr (day 3). With the exception of one case in which an OVX-E animal completed only three problems, scores for individual animals were averaged across four discriminations. Error bars indicate SEM.

Figure 4.

Neuropsychological performance in aged OVX-veh and OVX-E monkeys relative to young intact subjects. Top, Delay component of DR; middle, DNMS; bottom, OD, organized as in Figure 3. Error bars indicate SEM.