Estrogens normalize the hypothalamic-pituitary-adrenal axis response to stress and increase glucocorticoid receptor immunoreactivity in hippocampus of aging male rats

Aging is associated with a disturbance in the regulation of the hypothalami c-pituitary-adrenal axis (HPA) and reduced levels of glucocorticoid recepto rs (GR) in the hippocampus. To compensate for these effects, we have invest igated whether estrogen therapy normalized the HPA response to stress and G R in hippocampus and paraventricular (PVN) nucleus. Young (3-4 months) and old (20 months) male Sprague-Dawley rats were bled by tail cut in the basal state and following ether stress. While basal and ether-stimulated levels of plasma corticosterone (CORT) were similar in the two groups, old animals presented a delayed termination of the response to ether stress. A dexamet hasone inhibition test carried out in old animals, showed a failure to comp letely block plasma CORT after ether stimulation. Furthermore, in old rats GR-immunoreactive levels were reduced in CA1-CA2 hippocampal subfields and subiculum, while normal levels were obtained in CA3-CA4 and PVN. We observe d that prolonged estrogen treatment (6 weeks) of old rats normalized the te rmination of the stress response, restored dexamethasone inhibition of plas ma CORT, and increased GR immunoreactivity in CA1 and CA2 hippocampal subfi elds and subiculum. The results suggest that estrogen treatment enhanced th e glucocorticoid feedback signal by increasing GR in hippocampus, and corre cted the disturbances in HPA axis regulation. These animal experiments may be important to elucidate the effects of estrogenic on the hippocampal and HPA dysfunction associated with aging and Alzheimer's disease in humans.