title: Cognitive response to estradiol in postmenopausal women is modified by high cortisol.
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.
authors.affiliation: Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, USA. Ldbaker@uw.edu
authors.forename: Laura D
authors.initials: LD
authors.lastname: Baker
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.forename: Brenna A
authors.initials: BA
authors.lastname: Cholerton
authors.forename: Charles W
authors.initials: CW
authors.lastname: Wilkinson
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.forename: Pattie S
authors.initials: PS
authors.lastname: Green
authors.forename: George R
authors.initials: GR
authors.lastname: Merriam
authors.forename: Mark A
authors.initials: MA
authors.lastname: Fishel
authors.forename: G Stennis
authors.initials: GS
authors.lastname: Watson
authors.forename: Monique M
authors.initials: MM
authors.lastname: Cherrier
authors.forename: Monica L
authors.initials: ML
authors.lastname: Kletke
authors.forename: Pankaj D
authors.initials: PD
authors.lastname: Mehta
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
mesh_terms: D000339:Affect / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage* / Q000097:blood; D004967:Estrogens / Q000008:administration & dosage* / Q000097:blood; D056344:Executive Function / Q000187:drug effects; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D008875:Middle Aged; D009479:Neuropeptides / Q000008:administration & dosage / Q000097:blood; D017698:Postmenopause / Q000187:drug effects*; D011863:Radioimmunoassay; D013997:Time Factors; D057968:Transdermal Patch
chemical_list: D016229:Amyloid beta-Peptides; C105172:CORT protein, human; D004967:Estrogens; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D009479:Neuropeptides; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D006854:Hydrocortisone