Effects of endogenous and exogenous estrogen exposures in midlife and late-life women on episodic memory and executive functions.

Cognitive aging affects episodic memory and executive functions, and these vulnerable domains are postulated to be modulated by endogenous and exogenous estrogen exposures. In midlife and late-life women without dementia, estrogen effects on cognition can be examined through associations with concentrations of serum estrone and estradiol and through clinical trials of estrogen-containing hormone therapy. To this end, we reviewed published studies including at least 100 women (larger studies are less prone to publication bias) addressing associations between estrogen levels and performance on neuropsychological tests of episodic memory or executive functions (including working memory; seven studies), or that reported results of placebo-controlled clinical trials of hormone therapy with objective measures within these cognitive domains (eight studies). Results were considered separately for midlife and late-life (age≥65 years) women. There were no consistent associations between endogenous serum estrogen concentrations and episodic memory or executive functions in naturally menopausal midlife women or in older postmenopausal women. Clinical trial findings suggested no substantial impact of exogenous estrogens on episodic memory or executive functions over time frames of up to several years. A quantitative synthesis of clinical trial results supported the inference of absence of effect. This overall conclusion of no substantial effect on episodic memory or executive functions might reassure women concerned by potential adverse cognitive consequences of menopause or of relatively short-term midlife hormone therapy. There was no apparent window of opportunity during which exogenous hormones might benefit near-term cognition, but included studies provided limited power to identify such a window. Conclusions are tempered by small numbers of studies, imprecise estimates of long-term estrogen exposures, and narrow range of neuropsychological tests. Long-term (late-life) cognitive consequence of midlife estrogen exposures are poorly addressed by current data, as are cognitive consequences of surgical menopause and cognitive consequences of exogenous estrogens during the menopause transition. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.