Estrogen and cognitive function
- Fran Grodstein, ScD
Fran Grodstein, ScD
- Professor of Medicine
- Harvard Medical School
- Section Editors
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
The role of estrogen and menopausal hormone therapy (MHT) in cognitive function and Alzheimer disease (the major cause of dementia) has attracted considerable scientific and public interest. Finding a means to delay the onset of dementia is of substantial public health significance because approximately 5 percent of United States women over 60 years of age have dementia; this rises to 12 percent after age 75 years and 28 percent over age 85 years. In addition, the prevalence of dementia will increase markedly in coming years since older adults are the fastest-growing segment of the population.
This topic review will discuss the biologic basis for the hypothesis that estrogen is related to cognitive function and/or Alzheimer disease. Individual areas that will be explored are the role of estrogen in the following:
●Maintenance of cognitive function in nondemented women
●Prevention of Alzheimer disease
●Treatment of women with Alzheimer disease
- Luine VN. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol 1985; 89:484.
- Morley BJ, Rodriguez-Sierra JF, Clough RW. Increase in hypothalamic nicotinic acetylcholine receptors in prepuberal female rats administered estrogen. Brain Res 1983; 278:262.
- Gazzaley AH, Weiland NG, McEwen BS, Morrison JH. Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus. J Neurosci 1996; 16:6830.
- Henderson VW. Estrogen, cognition, and a woman's risk of Alzheimer's disease. Am J Med 1997; 103:11S.
- McEwen BS. Clinical review 108: The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metab 1999; 84:1790.
- Rentz DM, Weiss BK, Jacobs EG, et al. Sex differences in episodic memory in early midlife: impact of reproductive aging. Menopause 2017; 24:400.
- Lui LY, Stone K, Cauley JA, et al. Bone loss predicts subsequent cognitive decline in older women: the study of osteoporotic fractures. J Am Geriatr Soc 2003; 51:38.
- Barrett-Connor E, Goodman-Gruen D. Cognitive function and endogenous sex hormones in older women. J Am Geriatr Soc 1999; 47:1289.
- Geerlings MI, Ruitenberg A, Witteman JC, et al. Reproductive period and risk of dementia in postmenopausal women. JAMA 2001; 285:1475.
- Yaffe K, Haan M, Byers A, et al. Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology 2000; 54:1949.
- Ryan J, Carrière I, Scali J, et al. Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study. Neurology 2009; 73:1729.
- Rice MM, Graves AB, McCurry SM, et al. Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women: The Kame Project. Arch Intern Med 2000; 160:1641.
- Carlson MC, Zandi PP, Plassman BL, et al. Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study. Neurology 2001; 57:2210.
- Kang JH, Weuve J, Grodstein F. Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology 2004; 63:101.
- Kang JH, Grodstein F. Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiol Aging 2012; 33:1129.
- Shaywitz SE, Shaywitz BA, Pugh KR, et al. Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999; 281:1197.
- Resnick SM, Maki PM, Golski S, et al. Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance. Horm Behav 1998; 34:171.
- Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289:2663.
- Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004; 291:2959.
- Viscoli CM, Brass LM, Kernan WN, et al. Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST). Am J Obstet Gynecol 2005; 192:387.
- Almeida OP, Lautenschlager NT, Vasikaran S, et al. A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life. Neurobiol Aging 2006; 27:141.
- Lethaby A, Hogervorst E, Richards M, et al. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev 2008; :CD003122.
- Bagger YZ, Tankó LB, Alexandersen P, et al. Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause 2005; 12:12.
- Espeland MA, Shumaker SA, Leng I, et al. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med 2013; 173:1429.
- Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988; 13:345.
- Kampen DL, Sherwin BB. Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 1994; 83:979.
- Joffe H, Hall JE, Gruber S, et al. Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women. Menopause 2006; 13:411.
- Barrett-Connor E, Kritz-Silverstein D. Estrogen replacement therapy and cognitive function in older women. JAMA 1993; 269:2637.
- Jacobs DM, Tang MX, Stern Y, et al. Cognitive function in nondemented older women who took estrogen after menopause. Neurology 1998; 50:368.
- Szklo M, Cerhan J, Diez-Roux AV, et al. Estrogen replacement therapy and cognitive functioning in the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 1996; 144:1048.
- Resnick SM, Maki PM, Rapp SR, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab 2006; 91:1802.
- Gleason CE, Dowling NM, Wharton W, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med 2015; 12:e1001833; discussion e1001833.
- Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 2016; 87:699.
- Jaffe AB, Toran-Allerand CD, Greengard P, Gandy SE. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem 1994; 269:13065.
- Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998; 279:688.
- LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 2001; 285:1489.
- Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996; 348:429.
- Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 1997; 48:1517.
- Waring SC, Rocca WA, Petersen RC, et al. Postmenopausal estrogen replacement therapy and risk of AD: a population-based study. Neurology 1999; 52:965.
- Baldereschi M, Di Carlo A, Lepore V, et al. Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging. Neurology 1998; 50:996.
- Seshadri S, Zornberg GL, Derby LE, et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease. Arch Neurol 2001; 58:435.
- Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA 2002; 288:2123.
- Roberts RO, Cha RH, Knopman DS, et al. Postmenopausal estrogen therapy and Alzheimer disease: overall negative findings. Alzheimer Dis Assoc Disord 2006; 20:141.
- O'Brien J, Jackson JW, Grodstein F, et al. Postmenopausal hormone therapy is not associated with risk of all-cause dementia and Alzheimer's disease. Epidemiol Rev 2014; 36:83.
- Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol 2011; 69:163.
- Shao H, Breitner JC, Whitmer RA, et al. Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology 2012; 79:1846.
- Henderson VW, Benke KS, Green RC, et al. Postmenopausal hormone therapy and Alzheimer's disease risk: interaction with age. J Neurol Neurosurg Psychiatry 2005; 76:103.
- Petitti DB, Crooks VC, Chiu V, et al. Incidence of dementia in long-term hormone users. Am J Epidemiol 2008; 167:692.
- Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289:2651.
- Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004; 291:2947.
- Coker LH, Hogan PE, Bryan NR, et al. Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study. Neurology 2009; 72:125.
- Resnick SM, Espeland MA, Jaramillo SA, et al. Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study. Neurology 2009; 72:135.
- Kantarci K, Lowe VJ, Lesnick TG, et al. Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. J Alzheimers Dis 2016; 53:547.
- Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 2000; 283:1007.
- Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000; 54:295.
- Hogervorst E, Yaffe K, Richards M, Huppert FA. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst Rev 2009; :CD003799.
- Schneider LS, Farlow M. Combined tacrine and estrogen replacement therapy in patients with Alzheimer's disease. Ann N Y Acad Sci 1997; 826:317.
- ESTROGEN AND COGNITIVE FUNCTION
- Biologic basis
- Epidemiologic evidence
- - Effect of endogenous estrogen
- - Effect of exogenous estrogen
- Clinical trial evidence
- - Younger menopausal women
- ESTROGEN AND DEMENTIA
- Epidemiologic studies
- - Timing of exposure
- Clinical trial data
- - Recently menopausal women
- Treatment of dementia
- SUMMARY AND RECOMMENDATIONS