Abstract
Hormone replacement therapy is now the standard of care for amelioration of the symptoms of menopause and prevention of osteoporosis. More recently, it has been appreciated that hormone replacement may also have beneficial effects on the brain. This review will contrast the biologic data showing that estrogen has significant neuroprotectant effects on the brain, with data from cross-sectional and epidemiologic studies of women showing that hormone replacement may have beneficial effects for cognition in aging. Together, studies suggest that the temporal pattern of hormone replacement may be critical for maintaining cognitive health in aging.
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References and Recommended Reading
Payami H, Zareparsi S, Montee K, et al.: Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet 1996, 58:803–811.
Howieson D, Holm L, Kaye J, et al.: Neurologic function in the optimally healthy oldest old: neuropsychologic evaluation. Neurology 1993, 43:1882–1886.
Kaye J, Swihart T, Howieson D, et al.: Volume loss of the hippocampus and temporal lobe in healthy elderly persons destined to develop dementia. Neurology 1997, 48:1297–1304.
Hyman B, Van Hoesen G, Damasio A: Memory-related neural systems in Alzheimer’s disease: an anatomic study. Neurology 1990, 40:1721–1730.
Samuel W, Masliah E, Hill L, et al.: Hippocampal connectivity and Alzheimer’s dementia: effects of synapse loss and tangle frequency in a two-component model. Neurology 1994, 44:2081–2088.
Kelly M, Lagrange A, Wagner E, Ronnekleiv O: Rapid effects of estrogen to modulate G protein-coupled receptors via activation of protein kinase A and protein kinase C pathways. Steroids 1999, 64:64–75.
McEwen B: The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metab 1999, 84:1790–1797.
Simerly R: Hormonal regulation of limbic and hypothalamic pathways. In Neurobiological Effects of Sex Steroid Hormones. Edited by Micevych P, Hamoer R. New York: Cambridge University Press; 1995:85–114.
Heiman M, Ben-Jonathan N: Dopaminergic receptors in the rat anterior pituitary change during the estrous cycle. Endocrinology 1982, 111:37–41.
McEwen B, Krey L, Luine V: Steroid hormone action in the neuroendocrine system: when is the genome involved? In The Hypothalamus. Edited by Reichlin R, Baldessarini R, Martin J. New York: Raven Press; 1978:255–268.
Wade C, Robinson S, Shapiro R, Dorsa D: Estrogen receptor (ER)-alpha and ER-beta exhibit unique pharmacologic properties when coupled to activation of the mitogen-activated protein kinase pathway. Endocrinology 2001, 142:2336–2342.
Delville Y: Progesterone-facilitated sexual receptivity: A review of arguments supporting a nongenomic mechanism. Neurosci Biobehav Rev 1991, 15:407–414.
Brubaker K, Gay C: Evidence for plasma membrane-mediated effects of estrogen. Calcif Tissue Int 1999, 64:459–462.
McEwen B, Alves S: Estrogen actions in the central nervous system. Endocrine Rev 1999, 20:279–307. Review of estrogen’s effects on the brain.
Cross E, Roselli C: 17b-Estradiol rapidly facilitates chemoinvestigation and mounting in castrated male rats. Am J Physiol 1999, 276:R1346-R1350.
Becker JB, Beer ME: The influence of estrogen on nigrostriatal dopamine activity: behavioral and neurochemical evidence for both pre- and postsynaptic components. Behav Brain Res 1986, 19:27–33.
Castner SA, Xiao L, Becker JB: Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies. Brain Res 1993, 610:127–134.
McDermott JL, Kreutzberg JD, Liu B, Dluzen DE: Effects of estrogen treatment on sensorimotor task performance and brain dopamine concentrations in gonadectomized male and female CD-1 mice. Horm Behav 1994, 28:16–28.
Roselli C, Klosterman S, Resko J: Anatomic relationships between aromatase and androgen receptor mRNA expression in the hypothalamus and amygdala of adult male cynomolgus monkeys. J Comp Neurol 2001, 439:208–223.
Roselli C, Stadelman H, Horton L, Resko J: Regulation of androgen metabolism and luteinizing hormone-releasing hormone content in discrete hypothalamic and limbic areas of male rhesus macaques. Endocrinology 1987, 120:97–106.
Chambers K, Thornton J, Roselli CE: Age-related deficits in brain androgen binding and metabolism, testosterone, and sexual behavior of male rats. Neurobiol Aging 1991, 12:123–130.
Roselli C, Thornton J, Chambers K: Age-related deficits in brain estrogen receptors and sexual behavior of male rats. Behav Neurosci 1993, 107:202–209.
Dubal D, Zhu H, Yu J, et al.: Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A 2001, 98:1952–1957.
Wise P, Dubal D, Wilson M, et al.: Mini review: neuroprotective effects of estrogen-new insights into mechanisms of action. Endocrinology 2001, 142:969–973. Review of the neuroprotectant effects of estrogen.
Shughrue P, Lane M, Merchenthaler I: Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 1997, 388:507–525.
Register T, Shively C, Lewis C: Expression of estrogen receptor a and b transcripts in female monkey hippocampus and hypothalamus. Brain Res 1998, 788:320–322.
Kuiper G, Shughrue P, Merchenthaler I, Gustafsson JA: The estrogen receptor b subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroencodrinol 1998, 19:253–286.
Murphy D, Cole N, Greenberger V, Segal M: Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons. J Neurosci 1998, 18:2550–2559.
Woolley C, McEwan B: Estradiol mediates fluctuations in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 1992, 12:2549–2554.
Woolley C, McEwen B: Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 1993, 336:293–306. Landmark paper showing effects of estrogen on memory-related neural processes.
Wallis C, Luttge W: Influence of estrogen and progesterone on glutamic acid decarboxylase activity in discrete regions of rat brain. J Neurochem 1980, 34:609–613.
Gee K: Steroid modulation of the GABA/benzodiazepine receptor-linked chloride ionopore. Mol Neurobiol 1988, 2:291–317.
Sumner B, Fink G: Estrogen increases the density of 5-hydroxytryptamine2A receptors in cerebral cortex and nucleus accumbens in the female rat. J Steroid Biochem Mol Biol 1995, 54:15–20.
Williams C: Short-term but not long-term estradiol replacement improves radial-arm maze performance in young and aging rats. Soc Neurosci Abstracts 1996, 459:5.
Sandstrom N, Williams C: Memory retention is modulated by acute estradiol and progesterone replacement. Behav Neurosci 2001, 115:384–393. Study showing memory effects of estrogen and its modification by progesterone.
Ettinger B: Optimal use of postmenopausal hormone replacement. Obstet Gynecol 1988, 72:31S-36S.
Greendale, G., & Judd, H: Menopause: Health implications and clinical management. J Am Geriatr Soc 1993, 41:426–436.
Korenman S: Menopausal endocrinology and management. Arch Intern Med 1982, 142:1131–1136.
Lufkin E, Carpenter P, Ory S, et al.: Estrogen replacement therapy: current recommendations. Mayo Clin Proc 1998, 63:453–460.
Judd H, Judd G, Lucas W, Yen S: Endocrine function of the postmenopausal ovary: Concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 1974, 39:1020–1024.
Gordon H, Lee P: No difference in cognitive performance between phases of the menstrual cycle. Psychoneuroendocrinology 1993, 18:521–531.
Hampson E, Kimura D: Reciprocal effects of hormonal fluctuations on human motor and perceptual-spatial skills. Behav Neurosci 1988, 102:456–459.
Hampson E, Kimura D: Sex differences and hormonal influences on cognitive function in humans. In Behavioral Endocrinology. Edited by Becker J, Breedlove S, Crews D. Hillsdale: Lawrence Erlbaum; 1992:357–398.
Halpern D: Sex differences in cognitive abilities. Hillsdale: Lawrence Erlbaum; 1986.
Hampson E: Estrogen-related variations in human spatial and articulatory-motor skills. Psychoneuroendocrinology 1990, 15:97–111.
Sandstrom N, Kaufman J, Huettel S: Males and females use different distal cues in a virtual environment navigation task. Cogn Brain Res 1998, 6:351–360.
Chiarello C, McMahon M, Schaefer K: Visual cerebral lateralization over phases of the menstrual cycle: a preliminary investigation. Brain Cogn 1989, 11:18–36.
Postma A, Winkel J, Tuiten A, van Honk J: Sex differences and menstrual cycle effects in human spatial memory. Psychoneuroendocrinology 1999, 24:175–192.
Davis S: Androgen replacement in women: A commentary. J Clin Endocrinol Metab 1999, 84:1886–1891.
LeBlanc E, Janowsky J, Chan B, Nelson H: Hormone replacement therapy and cognition: Systematic review and meta-analysis. JAMA 2001, 285:1489–1499. Formal meta-analysis of data on the cognitive effects of hormone replacement.
Hogervorst E, Boshuisen M, Riedel W, et al.: The effect of hormone replacement therapy on cognitive function in elderly women. Psychoneuroendocrinology 1999, 24:43–68.
Kampen D, Sherwin B: Estradiol is related to visual memory in healthy young men. Behav Neurosci 1996, 110:613–617.
Sherwin B: Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988, 13:345–357.
Sherwin B, Tulandi T: "Add-back" estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. J Clin Endocrinol Metab 1996, 81:2545–2549.
Polo-Kantola P, Portin R, Polo O, et al.: The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women. Obstet Gynecol 1998, 91:459–466.
Kimura D: Sex, sexual orientation and sex hormones influence human cognitive function. Curr Opin Neurobiol 1996, 6:259–263.
Janowsky JS, Carello P, Orwoll E: Progesterone reverses estrogen’s enhancement of verbal memory. Soc Neurosci Abstracts 1999, 24:1062.
Maki P, Zonderman A, Resnick S: Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy. Am J Psychiatry 2001, 158:227–233.
Resnick SM, Maki PM, Golski S, et al.: Effencts of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance. Horm Behav 1998, 34:171–182.
Maki P, Resnick S: Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiol Aging 2000, 21:373–383.
Schmidt R, Fazekas F, Reinhart B, et al.: Estrogen replacement therapy in older women: a neuropsychological and brain MRI study. J Am Geriatr Soc 1996, 44:1307–1313.
Berman K, Schmidt P, Rubinow D, et al.: Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc Natl Acad Sci U S A 1997, 94:8836–8841.
Rice M, Graves A, McCurry S, 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, 160:1641–1649.
Natale V, Albertazzi P, Zini M, Di Micco R: Exploration of cyclical changes in memory and mood in postmenopausal women taking sequential combined estrogen and progestogen preparations. BJOG 2001, 108:286–290.
Barrett-Connor E, Kritz-Silverstein D: Estrogen replacement therapy and cognitive function in older women. JAMA 1993, 269:2637–2641.
Barrett-Connor E, Kritz-Silverstein D: Gender differences in cognitive function withe age: the Rancho Bernardo Study. J Am Geriatr Soc 1999, 47:159–164.
Brenner D: Postmenopausal estrogen replacement therapy and the risk of Alzheimer’s Disease: a population-based case control study. Am J Epidemiol 1994, 104:262–267.
Henderson B, Paganini-Hill A, Ross, R: Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991, 151:75–78.
Matthews K, Cauley J, Yaffe K, Zmuda J: Estrogen replacement therapy and cognitive decline in older community women. JAGS 1999, 47:518–523.
Inestrosa N, Marzolo MP, Bonnefont A: Cellular and molecular basis of estrogen’s neuroprotection. Mol Neurobiol 1998, 17:86.
Tang MX, Jacobs DM, Stern Y, et al.: Effect of estrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996, 348:429–432.
Jacobs DM, Tang MX, Stern Y, et al.: Cognitive function in nondemented older women who took estrogen after menopause. Neurology 1998, 50:368–373.
Steffens DC, Norton MC, Plassman BL, et al.: Enhanced cognitive performance with estrogen use in nondemented community-dwelling older women. JAGS 1999, 47:1171–1175.
Wolf O, Kudielka B, Hellhammer D, et al.: Two weeks of transdermal estradiol treatment in postmenopausal elderly women and its effect on memory and mood: Verbal memory changes are associated with the treatment induced estradiol levels. Psychoneuroendocrinology 1999, 24:727–741.
Henderson V, Paganini-Hill A, Miller B, et al.: Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000, 54:295–301.
Mulnard R, Cotman C, 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, 283:1007–1015. Study showing no effect of estrogen replacement on the course of Alzheimer’s disease.
Wang P, Liao S, Liu R, et al.: Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study [see comments]. Neurology 2000, 54:2061–2066.
Asthana S, Baker L, Craft S, et al.: High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 2001, 57:605–612.
Wolf O, Kudielka B, Hellhammer D, et al.: Two weeks of transdermal estadiol treatment in postmenopausal elderly women and its effect on memory and mood: Verbal memory changes are associated with the treatment induced estradiol levels. Psychoneuroendocrinology 1999, 24:727–741.
Geerlings M, Ruitenberg A, Witteman J, et al.: Reproductive period and risk of dementia in postmenopausal women. JAMA 2001, 285:1475–1481.
Writing Group for the Women’s Health Initiative: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002, 288:321–333.
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Janowsky, J.S. The role of ovarian hormones in preserving cognition in aging. Curr Psychiatry Rep 4, 467–473 (2002). https://doi.org/10.1007/s11920-002-0075-9
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DOI: https://doi.org/10.1007/s11920-002-0075-9