Does Postmenopausal Estrogen Use Confer Neuroprotection?

ABSTRACT

Sex steroids modulate brain function at all developmental stages of life. This article focuses on the role of sex steroids after menopause with the intent of addressing the question whether or to what extent sex steroids, particularly estrogenic agents, are neuroprotective for the aging brain of women. The rationale for delving into this complicated topic is that the information and perspective so acquired will aid physicians in counseling surgically and naturally menopausal women about their therapeutic options. Whereas we review and synthesize relevant data from monkey, other animal, cellular, and molecular studies, the emphasis is on human studies and reconciling the disparate evidence. Although the knowledge gaps are considerable, available evidence suggests that extended use of non-oral estradiol is a reasonable course of action if the woman to be treated has a relatively low risk for cardiovascular disease and venous thromboembolism or a high concern about developing dementia. It is important to emphasize that estradiol may negatively impact an already unhealthy individual and yet synergize other health-promoting behaviors such as good nutrition, exercise, and stress reduction in a relatively healthy individual.

KEYWORDS

Menopause - hormones - estradiol - neuroprotection

REFERENCES

• 1 Morrison J H, Brinton R D, Schmidt P J, Gore A C. Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women.  J Neurosci. 2006;  26 10332-10348
• 2 Cahill L. His brain, her brain.  Sci Am. 2005;  292 40-47
• 3 Nuñez J L, McCarthy M M. Evidence for an extended duration of GABA-mediated excitation in the developing male versus female hippocampus.  Dev Neurobiol. 2007;  67 1879-1890
• 4 Gao S, Hendrie H C, Hall K S, Hui S. The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis.  Arch Gen Psychiatry. 1998;  55 809-815
• 5 Plassman B L, Langa K M, Fisher G G et al.. Prevalence of dementia in the united States: the aging, demographics, and memory study.  Neuroepidemiology. 2007;  29 125-132
• 6 Feldman H, Levy A R, Hsiung G Y et al.. A Canadian cohort study of cognitive impairment and related dementias (ACCORD): study methods and baseline results.  Neuroepidemiology. 2003;  22 265-274
• 7 Langa K M, Foster N L, Larson E B. Mixed dementia: emerging concepts and therapeutic implications.  JAMA. 2004;  292 2901-2908
• 8 Zhu C W, Scarmeas N, Torgan R et al.. Longitudinal study of effects of patient characteristics on direct costs in Alzheimer disease.  Neurology. 2006;  67 998-1005
• 9 National Center for Health Statistics. 2004 Current Resident Tables, Diagnoses, Medications, and Vaccinations: Tables 34 and 38, National Nursing Home Survey (NNHS). June 2008. Available at: http://www.cdc.gov/nchs/about/major/nnhsd/ResidentTables_Estimates.htm#Diagnoses Accessed November 24, 2008
• 10 Ellison J M. A 60-year-old woman with mild memory impairment: review of mild cognitive impairment.  JAMA. 2008;  300 1566-1574
• 11 Feldman H H, Jacova D, Robillard A et al.. Diagnosis and treatment of dementia: 2. diagnosis.  Can Med Assoc J. 2008;  178 825-836
• 12 Grodstein F, Manson J E, Stampfer M J, Rexrode K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy.  Arch Intern Med. 2008;  168 861-866
• 13 Pazol K, Wilson M E, Wallen K. Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques.  J Clin Endocrinol Metab. 2004;  89 2998-3006
• 14 Zandi P P, Carlson M C, Plassman B L et al.. Hormone replacement therapy and incidence of Alzheimer disease in older women.  JAMA. 2002;  288 2123-2129
• 15 Rocca W A, Bower J H, Maraganore D M et al.. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.  Neurology. 2007;  69 1074-1083
• 16 Rocca W A, Grossardt B R, Geda Y E et al.. Long-term risk of depressive and anxiety symptoms after early bilateral oophorectomy.  Menopause. 2008;  15 1050-1059
• 17 Schmidt P J. Mood, depression, and reproductive hormones in the menopausal transition.  Am J Med. 2005;  118(Suppl 12B) 54-58
• 18 Hao J, Janssen W G, Tang Y et al.. Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and old female rhesus monkeys.  J Comp Neurol. 2003;  465 540-550
• 19 Hao J, Rapp P R, Leffler A E et al.. Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys.  J Neurosci. 2006;  26 2571-2578
• 20 Tang Y, Janssen W G, Hao J et al.. Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys.  Cereb Cortex. 2004;  14 215-223
• 21 Raichle M E. The brain's dark energy.  Science. 2006;  314 1249-1250
• 22 Lobo R A. Menopause and stroke and the effects of hormone therapy.  Climacteric. 2007;  10(S2) 27-31
• 23 Writing Group for the Women's Health Initiative Investigators . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.  JAMA. 2002;  288 321-333
• 24 Anderson G L, Limacher M, Assaf A R et al.. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.  JAMA. 2004;  291 1701-1712
• 25 Seeman T E, McEwen B S, Singer B H, Albert M S, Rowe J W. Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging.  J Clin Endocrinol Metab. 1997;  82 2458-2465
• 26 Dubal D B, Zhu H, Yu J et al.. Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury.  Proc Natl Acad Sci U S A. 2001;  98 1952-1957
• 27 McEwen B S. The molecular and neuroanatomical basis for estrogen effects in the central nervous system.  J Clin Endocrinol Metab. 1999;  84 1790-1797
• 28 McEwen B S. Estrogen actions throughout the brain.  Recent Prog Horm Res. 2002;  57 357-384
• 29 Wang L, Andersson S, Warner M, Gustafsson J A. Estrogen actions in the brain. Science's STKE.  2002;  Available at: http://www.stke.org/cgl/content/full/sigtrans;2002/138/p.pe29
• 30 Stadberg E, Mattson L A, Milsom I. The prevalence and severity of climacteric symptoms and the use of different treatment regimens in a Swedish population.  Acta Ob Gyn Scand. 1997;  76 442-448
• 31 Hollander L E, Freeman E W, Sammel M D, Berlin J A, Grisso J A, Battistini M. Sleep quality, estradiol levels, and behavioral factors in late reproductive age women.  Obstet Gynecol. 2001;  98 391-397
• 32 Barrett-Connor E, Young R, Notelovitz M et al.. A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles.  J Reprod Med. 1999;  44 1012-1020
• 33 Castelo-Branco C, Vicente J J, Figueras F et al.. Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern, and sexuality in postmenopausal women.  Maturitas. 2000;  34 161-168
• 34 Graham C A, Janssen E, Sanders S A. Effects of fragrance on female sexual arousal and mood across the menstrual cycle.  Psychophysiology. 2000;  37 76-84
• 35 Insel T R, Young L, Wang Z. Central oxytocin and reproductive behaviors.  Rev Reprod. 1997;  2 28-37
• 36 Matteo S, Rissman E F. Increased sexual activity during the midcycle portion of the human menstrual cycle.  Horm Behav. 1984;  18 249-255
• 37 Pfaff D W. Hormones, genes, and behavior.  Proc Natl Acad Sci U S A. 1997;  94 14213-14216
• 38 Savic I, Berglund H, Gulyas B, Roland P. Smelling of odorous sex hormone-like compounds causes sex-differentiated hypothalamic activations in humans.  Neuron. 2001;  31 661-668
• 39 Warner P, Bancroft J. Mood, sexuality, oral contraceptives, and the menstrual cycle.  J Psychosom Res. 1988;  32 417-427
• 40 Finkelstein J W, Susman E J, Chinchilli V M et al.. Estrogen or testosterone increases self-reported aggressive behaviors in hypogonadal adolescents.  J Clin Endocrinol Metab. 1997;  82 2433-2438
• 41 Finkelstein J W, Susman E J, Chinchilli V M et al.. Effects of estrogen or testosterone on self-reported sexual responses and behaviors in hypogonadal adolescents.  J Clin Endocrinol Metab. 1998;  83 2281-2285
• 42 Birge S J. HRT and cognitive function: what are we to believe?.  Menopause. 2002;  9 221-223
• 43 Duka T, Tasker R, McGowan J F. The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females.  Psychopharmacology (Berl). 2000;  149 129-139
• 44 Hogervost E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis.  Neuroscience. 2000;  101 485-512
• 45 LeBlanc E S, Janowsky J, Chan B KS, Nelson H D. Hormone replacement therapy and cognition.  JAMA. 2001;  285 1489-1499
• 46 Resnick S M, Maki P M. Effects of hormone replacement therapy on cognitive and brain aging.  Ann N Y Acad Sci. 2001;  949 203-214
• 47 Wolf O T, Kudielka B M, Hellhammer D H, Torber S, McEwen B S, Kirschbaum C. 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
• 48 Irwin R W, Yao J, Hamilton R T, Cadenas E, Brinton R D, Nilsen J. Progesterone and estrogen regulate oxidative metabolism in brain mitochondria.  Endocrinology. 2008;  149 3167-3175
• 49 Smith Y R, Zubieta J K. Neuroimaging of aging and estrogen effects on central nervous system physiology.  Fertil Steril. 2001;  76 651-659
• 50 Gibbs R B. Basal forebrain cholinergic neurons are necessary for estrogen to enhance acquisition of a delayed matching-to-position T-maze task.  Horm Behav. 2002;  42 245-257
• 51 Moses E L, Drevets W C, Smith G et al.. Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET study.  Biol Psychiatry. 2000;  48 854-860
• 52 Maki P M, Resnick S M. Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition.  Neurobiol Aging. 2000;  21 373-383
• 53 Kugaya A, Epperson C N, Zoghbi S et al.. Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women.  Am J Psychiatry. 2003;  160 1522-1524
• 54 Rasgon N L, Silverman D, Siddarth P et al.. Estrogen use and brain metabolic change in postmenopausal women.  Neurobiol Aging. 2005;  26 229-235
• 55 Smith Y R, Minoshima S, Kuhl D E, Zubieta J K. Effects of long-term hormone therapy on cholinergic synaptic concentrations in healthy postmenopausal women.  J Clin Endocrinol Metab. 2001;  86 679-684
• 56 Moses-Kolko E L, Berga S L, Greer P J, Smith G, Cidis Meltzer C, Drevets W C. Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women.  Fertil Steril. 2003;  80 554-559
• 57 Shaywitz S E, Naftolin F, Zelterman D et al.. Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen.  Menopause. 2003;  10 420-426
• 58 Joffe H, Hall J E, 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;  13 411-422
• 59 Persad C C, Zubieta J K, Love T, Wang H, Tkaczyk A, Smith Y R. Enhanced neuroactivation during verbal memory processing in postmenopausal women receiving short-term hormone therapy.  Fertil Steril. 2008 August;  8 , (Epub ahead of print)
• 60 Helwick C. Estrogen may be neuroprotective after all. Medscape Medical News, June 18, 2009. Study authors: Geist C, Silverman D. http://Available at: www.medscape.com/viewarticle/576259 Accessed March 31, 2009
• 61 Bender C M, Sereika S M, Berga S L et al.. Cognitive impairment associated with adjuvant therapy in breast cancer.  Psychooncology. 2006;  15 422-430
• 62 Bender C M, Sereika S M, Brufsky A M et al.. Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer.  Menopause. 2007;  14 995-998
• 63 Jenkins V A, Ambroisine L M, Atkins L, Cuzick J, Howell A, Fallowfield L J. The effects of anastrozole on cognitive performance in postmenopausal women participating in a randomized double blind chemoprevention trial (IBIS II).  Lancet Oncol. 2008;  9 753-761
• 64 Berga S L. Anastrozole: brain draining or sparing?.  Lancet Oncol. 2008;  9 913-914
• 65 Mook D, Felger J, Graves F, Wallen K, Wilson M E. Tamoxifen fails to affect central serotonergic tone but increases indices of anxiety in female rhesus macaques.  Psychoneuroendocrinology. 2005;  30 273-283
• 66 Breuer B, Anderson R. The relationship of tamoxifen with dementia, depression, and dependence in activities of daily living in elderly nursing home residents.  Women Health. 2000;  31 71-85
• 67 Wilson M E, Mook D, Graves F C, Gleger J, Bielsky I R, Wallen K. Tamoxifen is an estrogen antagonist on gonadotropin secretion and responsiveness of the hypothalamic-pituitary-adrenal axis in female monkeys.  Endocrine. 2003;  22 305-315
• 68 Lacreuse A, Wilson M E, Herndon J G. Estradiol, but not raloxifene, improves aspects of spatial working memory in aged ovariectomized rhesus monkeys.  Neurobiol Aging. 2002;  23 589-600
• 69 Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K. Hormone replacement therapy for cognitive function in postmenopausal women.  Cochrane Database Syst Rev. 2008;  (1) CD003122
• 70 Rocca W A, Grossardt B R, de Andrade M, Malkasian G D, Melton III L J. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study.  Lancet Oncol. 2006;  7 821-828
• 71 Rocca W A, Bower J H, Maraganore D M et al.. Increased risk of parkinsonism in women who underwent oophorectomy before menopause.  Neurology. 2008;  70 200-209
• 72 Benedetti M D, Maraganore D M, Bower J H et al.. Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case-control study.  Mov Disord. 2001;  16 830-837
• 73 Marchbanks P A, McDonald J A, Wilson H G et al.. Oral contraceptives and the risk of breast cancer.  N Engl J Med. 2002;  346 2025-2032
• 74 Shumaker S A, Legault C, Rapp S R 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 2651-2662
• 75 Shumaker S A, Legault C, Kuller L et al.. Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study.  JAMA. 2004;  291 2947-2958
• 76 Neiss M B, Carello P E, Samuels M H, Janowsky J S. LeBlancES . Hot flashes and estrogen therapy do not influence cognition in early menopausal women.  Menopause. 2007;  14 191-200
• 77 Hlatky M A, Boothroyd D, Vittinghoff E, Sharp P, Whooley M A. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy.  JAMA. 2002;  287 591-597
• 78 Berga S L. Does estrogen use support cognition in postmenopausal women?.  Menopause. 2007;  14 163-165
• 79 Whooley M A, Grady D, Cauley J A. Postmenopausal estrogen therapy and depressive symptoms in older women.  J Gen Intern Med. 2000;  15 535-541
• 80 Yaffe K, Liu L Y, Grady D, Cauley J, Kramer J, Cummings S R. Cognitive decline in relation to non-protein-bound oestradiol concentrations.  Lancet. 2000;  356 708-712
• 81 Canonico M, Oger E, Plu-Bureau G et al.. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.  Circulation. 2007;  115 840-845
• 82 Post M S, Christella M, Thomassen L G et al.. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women.  Arterioscler Thromb Vasc Biol. 2003;  23 1116-1121
• 83 Scarabin P Y, Oger E, Plu-Bureau G. EStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.  Lancet. 2003;  362 428-432
• 84 Straczek C, Oger E, Yon de Jonage-Canonico M B et al.. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of administration.  Circulation. 2005;  112 3495-3500 S
• 85 Gleason C E, Schmitz T W, Hess T et al.. Hormone effects on fMRI and cognitive measures of encoding: importance of hormone preparation.  Neurology. 2006;  67 2039-2041
• 86 Mulnard R A, Cotman C W, Kawas C et al.. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized, clinical trial. Alzheimer's Disease Cooperative Study.  JAMA. 2000;  283 1007-1015
• 87 MacLennan A H, Henderson V W, Paine B J et al.. Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study.  Menopause. 2006;  13 28-36
• 88 Weuve J, Kang J H, Manson J E, Breteler M M, Ware J H, Grodstein F. Physical activity, including walking, and cognitive function in older women.  JAMA. 2004;  292 1454-1461
• 89 Lautenschlager N T, Cox K L, Flicker L et al.. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial.  JAMA. 2008;  300 1027-1037