Summary
We now understand that estrogens are pleiotropic gonadal steroids that influence plasticity and cell survival of the adult brain. Over the past century, the life span of women has increased from approximately 50 to 80 years of age, but the timing of the menopause remains constant and occurs at approximately 50 years of age. This means that women may now live over one-third of their lives in a hypo-estrogenic, postmenopausal state. The impact of prolonged hypoestrogenicity on the the well-being of women and, in particular, on their brains is a critical health concern since it appears that these older women may suffer an increased risk of cognitive dysfunction and neurodegeneration due to a variety of diseases. Accumulating evidence from both clinical and basic science studies indicates that estrogens may exert critical protective actions against neurodegenerative conditions such as Alzheimer’s disease (AD) and stroke. However, new evidence purports to suggest that, under some circumstances, hormone replacement may not decrease the risk of neurodegenerative diseases and may, in fact, increase risk of cerebrovascular stroke. Here, we review the discoveries that comprise our current understanding of estrogen action against neurodegeneration. These findings carry far-reaching implications for improving the health and quality of life of aging women.
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References
Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hum PD (1998) Gender-linked brain injury in experimental stroke. Stroke 29: 159 - 166
Asthana S, Craft S, Baker LD, Raskind MA, Birnbaum RS, Lofgreen CP, Veith RC, Plymate SR (1999) Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer’s Disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology 24: 657 - 677
Barrett-Connor E, Kritz-Silverstein D (1993) Estrogen replacement therapy and cognitive function in older women. JAMA 269: 2637 - 2641
Birge SJ (1997) The role of estrogen in treatment of Alzheimer’s disease. Neurology 48: S36-S41 Böttner M, Dubai DB, Rau SW, Wise PM (2001) Activin gene expression increases after stroke injury: modulation by estradiol. Soc Neurosci 1165 (Abstract)
Brenner DE, Kukull WA, Stergachis A, van Belle G, Bowen JD, McCormick WC, Teri L, Larson EB (1994) Postmenopausal estrogen replacement therapy and the risk of Alzheimer’s disease: a population-based case-control study. Am J Epidemiol 140: 262 - 267
Dubai DB, Wise PM (2001) Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology 142: 43 - 48
Dubai DB, Kashon ML, Pettigrew LC, Ren JM, Finklestein SP, Rau SW, Wise PM (1998) Estradiol protects against ischemic injury. JCBFM 18: 1253 - 1258
Dubai DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM (1999) Estradiol modulates Bd-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 19: 6385 - 6393
Dubai DB, Wilson ME, Shughrue PJ, Merchenthaler I, Wise PM (2000) Induction of galanin gene expression in estradiol-mediated neuroprotection against cerebral ischemia. Soc Neurosci1449
Dubai DB, Zhu B, Yu B, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM (2001) Estrogen receptor-a, not -(3, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci USA 98: 1952 - 1957
Fillit H (1994) Estrogens in the pathogenesis and treatment of Alzheimer’s disease in postmenopausal women. Ann NY Acad Sci 743: 233 - 239
Fillit H, Weinreb H, Cholst I, Luine V, McEwen B, Amador R, Zabriskie J (1986) Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type. Psychoneuroendocrinology 11: 337 - 345
Hall ED, Pazara KE, Linseman KL (1991) Sex differences in postischemic neuronal necrosis in gerbils. JCBFM 11: 292 - 298
Henderson VW, Paganini-Hill A (1997) Estrogen and Alzheimer’s Disease. J Soc Obstet Gynecol Canada 19: 21 - 28
Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG (1994) Estrogen replacement therapy in older women. Arch Neurol 51: 896 - 900
Henderson VW, Watt L, Buckwalter JG (1996) Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease. Psychoneuroendocrinology 21: 421 - 430
Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, McCleary CA, Klein
RA, Hake AM, Farlow MR (2000) Estrogen for Alzheimer’s disease in women.Randomized, double-blind, placebo-controlled trial. Neurology 54: 295 - 301
Honjo H, Tanaka K, Kashiwagi T, Urabe M, Okada H, Hayashi M, Hayashi K (1995) Senile dementia-Alzheimer’s type and estrogen. Horm Metab Res 27: 204 - 207
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280: 605 - 613
Kampen DL, Sherwin BB (1998) Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 83: 979 - 983
Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, Bacal C, Lingle D, Metter E (1997) A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 48: 1517 - 1521
Marder K, Sano M (2000) Estrogen to treat Alzheimer’s disease: Too little, too late? So what’s a woman to do? Neurology 54: 2035 - 2037
Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Garnst A, Grundman M, Thomas R, Thal LJ (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer’s disease. JAMA 283:
Paganini-Hill A (2001) Hormone replacement therapy and stroke: risk, protection or no effect? Maturitas 38: 243 - 261
Paganini-Hill A, Henderson VW (1994) Estrogen deficiency and risk of Alzheimer’s disease in women. Amer J Epidemiol 140: 256 - 261
Paganini-Hill A, Henderson VW (1996) Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 156: 2213 - 2217
Rau SW, Dubal DB, Wise PM (2001) Immediate early gene regulation by estradiol in ischemic injury. Soc Neurosci p 778 (Abstract)
Robinson D, Friedman L, Marcus R, Tinklenberg J, Yesavage J (1994) Estrogen replacement therapy and memory in older women. J Amer Geriat Soc 42: 919 - 922
Rusa R, Alkayed NJ, Crain BJ, Traystman RJ, Kimes AS, London ED, Klaus JA, Hurn PD (1999) 17beta-estradiol reduces stroke injury in estrogen-deficient female animals. Stroke 30: 1665 - 1670
Schmidt R, Fazekas F, Reinhart B, Kapeller P, Fazekas G, Offenbacher H, Eber B, Schumacher M, Freidl W (1996) Estrogen replacement therapy in older women: a neuropsychological and brain MRI study. J Amer Geriat Soc 44: 1307 - 1313
Shaywitz SE, Shaywitz BA, Pugh KR, Fulbright RK, Skudlarski P, Mend WE, Canstable RT, Naftolin F, Palter SF, Marchione KE, Katz L, Shankweiler DP, Fletcher JM, Lacadie C, Keltz M, Gore JC (1999) Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 281: 1197 - 1202
Sherwin BB (1988) Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13: 345 - 357
Sherwin BB (1994) Estrogenic effects on memory in women. Ann NY Acad Sci 743: 213 - 231
Sherwin BB (1996) Hormones, mood, and cognitive functioning in postmenopausal women. Obstet Gynecol 87: 20S - 26S
Sherwin BB (1997) Estrogen effects on cognition in menopausal women. Neurology 48: S21 - S26
Sherwin BB, Carlson LE (1997) Estrogen and memory in women. J Soc Obstet Gynecol Canada 19: 7 - 13
Simpkins JW, Rajakumar G, Zhang Y-Q, Simpkins CE, Greenwald D, Yu CJ, Bodor N, Day AL (1997) Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg 87: 724 - 730
Tang M-X, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. The Lancet 348: 429 - 432
Toung TJK, Traystman RJ, Hurn PD (1998) Estrogen-mediated neuroprotection after experimental stroke in male rats. Stroke 29: 1666 - 1670
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI (2001) A clinical trial of estrogen-replacement therapy after ischemic stroke. New Engl J Med 345: 1243 - 1249
Wang PN, Liao SQ, Liu RS, Liu CY, Chao HT, Lu SR, Yu HY, Wang SJ, Liu HC (2000) Effects of estrogen on cognition, mood, and cerebral blood flow in AD. A controlled study. Neurology 54: 2061-2066
Are Estrogens Protective or Risk Factors in the Brain? Insights Derived From Animal Models 173
Wang Q, Santizo R, Baughman VL, Pelligrino DA, Iadecola C (1999) Estrogen provides neuroprotection in transient forebrain ischemia through perfusion-independent mechanisms in rats. Stroke 30: 630 - 637
Waring SC, Rocca WA, Petersen RC, O’Brien PC, Tangalos EG, Kokmen E (1999) Postmenopausal estrogen replacement therapy and risk of AD. A population-based study. Neurology 52: 965-970
Wilson ME, Dubai DB, Wise PM (2000) Estradiol protects against injury-induced cell death in cortical explant cultures: a role for estrogen receptors. Brain Res 873: 235 - 242
Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 288: 321 - 333
Yang S-H, Shi J, Day AL, Simpkins JW (2000) Estradiol exerts neuroprotective effects when administered after ischemic insult. Stroke 31: 745 - 750
Zhang Y-Q, Shi J, Rajakumar G, Day AL, Simpkins JW (1998) Effects of gender and estradiol treatment on focal brain ischemia. Brain Res 784: 321 - 324
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Wise, P.M., Dubal, D.B. (2004). Are Estrogens Protective or Risk Factors in the Brain? Insights Derived From Animal Models. In: Chanson, P., Epelbaum, J., Lamberts, S., Christen, Y. (eds) Endocrine Aspects of Successful Aging: Genes, Hormones and Lifestyles. Research and Perspectives in Endocrine Interactions. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-07019-2_11
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DOI: https://doi.org/10.1007/978-3-662-07019-2_11
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