Abstract
Estradiol has potent favorable effects on brain function and behavior in animals while in human trials, the results are inconsistent. A number of potential mediating variables influencing response to estradiol have been proposed to account for this variability, 1 of which includes stress. We conducted a placebo-controlled study to examine joint and independent effects of estradiol and elevated levels of the stress hormone cortisol on cognition and biomarkers of aging and neurodegenerative disease. Thirty-nine healthy postmenopausal women (56-84 years) received 0.10 mg/dL of transdermal 17β-estradiol (E2) or placebo for 8 weeks. During the last 4 days of the trial, subjects also received 90 mg/day (30 mg 3×/day) of oral hydrocortisone (CORT) to induce stress-level elevations in cortisol, or a matched placebo. The 4 groups thus included placebo (placebo patch/placebo pill), CORT-alone (placebo patch/hydrocortisone), E2-alone (estradiol patch/placebo pill), and E2+CORT (estradiol patch/hydrocortisone). Eight weeks of E2 increased plasma estradiol by 167%, and 4 days of CORT increased plasma cortisol by 119%. Overall, E2 had favorable effects on verbal memory (p = 0.03), working memory (p = 0.02), and selective attention (p = 0.04), and the magnitude of these effects was attenuated for E2+CORT. E2-alone and E2+CORT had opposing effects on plasma levels of the amyloid-β (Aβ) biomarker (Aβ40/42 ratio, p < 0.05), with the more favorable response observed for E2-alone. CORT-induced increases in insulin-like growth factor-1 were blunted by E2 coadministration. Our findings indicate that cognitive and physiological responses to estradiol are adversely affected by elevated stress hormone levels of cortisol in healthy postmenopausal women.