Multiple clinically relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys

Abstract

Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of 4 HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex.

Figure 1

Delayed response (DR) performance is unaffected by hormone treatment. Reacquisition of the DR task at a 1-second delay did not vary across treatment groups. When memory is challenged by increasing the delay between baiting and test, all groups showed an equivalent decline across longer delays. Distraction during a 30-second delay interval impaired memory in all monkeys, an effect that did not interact with treatment condition.

Figure 2

Delayed nonmatching-to-sample (DNMS) performance is unaffected by hormone treatment. Acquisition of the DNMS task at a 10-second delay did not vary across treatment groups. When memory is challenged by increasing the delay between sample and choice, all groups showed an equivalent decline across longer delays. Distraction during a 2-minute delay interval impaired memory in all monkeys, an effect that did not interact with treatment condition.

Figure 3

Object discrimination performance is not improved by hormone treatment. Acquisition of 4 object discrimination training problems did not vary across treatment groups. During a test phase where 8 additional problems were learned, 4 with distraction and 4 without, group E_CONT+P_CYC was significantly impaired relative to vehicle-treated monkeys. This effect is most pronounced in the no-distraction problems, but it did not interact with distraction condition. There was no overall effect of distraction on acquisition of object discrimination problems (although there was an interaction between distraction and block), perhaps because at this point in testing monkeys had become acclimated to distracting events during testing.