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, one 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 yrs) received 0.10 mg/d of transdermal 17β-estradiol (E2) or placebo for eight weeks. During the last four days of the trial, subjects also received 90 mg/d (30 mg TID) of oral hydrocortisone (CORT) to induce stress-level elevations in cortisol, or a matched placebo. The four 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 four 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 co-administration. Our findings indicate that cognitive and physiological responses to estradiol are adversely affected by elevated stress hormone levels of cortisol in healthy postmenopausal women.

Actions and interactions of estradiol and glucocorticoids in cognition and the brain: Implications for aging women

“…This dichotomy is highlighted in reports of E2 treatment on cognition in post-menopausal women, with some reporting negative effects (Espeland et al, 2004; Mulnard et al, 2000; Rapp et al, 2003; Resnick et al, 2006; Shumaker et al, 2003) and others reporting benefits (Baker et al, 2012; Duff and Hampson, 2000; Maki et al, 2001; Miller et al, 2002; Smith et al, 2001; Wolf and Kirschbaum, 2002; Wolf et al, 1999), which receive support from basic science reports of estrogenic fortification of the central nervous system (Brinton et al, 2000; Chen et al, 2006; Hosoda et al, 2001; Pike, 1999). To reconcile these mixed reports, Brinton (2005) proposed a healthy cell bias of estrogen action, stating that E2 would be advantageous to a population of healthy cells, but detrimental to a population of declining or already injured cells.…”

“…Women randomly assigned to transdermal hormone replacement experienced improved performance on the Stroop task, spatial working memory (Baker et al, 2012; Krug et al, 2006), digit ordering (Krug et al, 2006), and delayed recall (Baker et al, 2012). Similarly, women already using hormone replacement also made fewer errors on non-spatial working memory (sequential memory of an unfamiliar story, digit ordering and digit span backward) and spatial working memory tasks (Duff and Hampson, 2000), performed better on measures of verbal fluency and working memory (Miller et al, 2002), and displayed better performance on a non-verbal memory task (Smith et al, 2001) compared with women not taking any hormone supplements (See Table 2 for effects on working memory).…”

“…In contrast, estradiol promotes neural growth and protection (Brinton et al, 2000; Chen et al, 2006; Gerstner et al, 2007; Hao, 2006; Saravia et al, 2007) and improvement of cognitive function (Baker et al, 2012; Krug et al, 2006; Shaywitz et al, 2003; Velázquez-Zamora et al, 2012; Wolf et al, 1999) 1 .…”

Stress, Inflammation, and Aging

“…Whether normal or excess psychological stress in aging interacts with estradiol status to produce negative effects on cognitive function is unclear, although recent experimental studies suggest a direct interaction between stress hormones and the effects of sex steroids. 25 In the face of acute psychosocial stress, the effects of exogenous estradiol in postmenopausal women may be negative on both mood and cognition 26, 27 ; however, the interaction with chronic stress or mood disorders is less well defined. 28 The effects of psychosocial stress and/or elevated cortisol on brain circuits necessary for cognitive performance and mood regulation remain to be more clearly defined.…”

Hormonal Changes in Response to Extreme Environment Factors

“…Кроме того, предполагают, что эстрогены способны ингибировать процессы апоптоза нервных клеток при стрессе, тем самым сохраняя их количество в условиях массовой гибели под воздействием повреждающих факторов [74]. Наконец, наличие или отсутствие этих гормонов вносит вклад в непрерывную регуляцию нейрогенеза в течение всей жизни, замедляя процессы старения мозга [75].…”