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Stroke and the female brain

Nature Clinical Practice Neurology volume 4, pages 22–33 (2008)Cite this article

Abstract

Stroke is a major public health problem. The female population carries a higher stroke burden than the male population, both because females have a longer life expectancy and because most stroke deaths occur in women. Differences between the sexes in relation to stroke are increasingly being recognized; for example, among stroke survivors, women tend to have worse outcomes than men, as indicated by more-severe disability and an increased likelihood of institutionalization in women. Women and men with stroke also differ in their risk factor profiles, and they respond differently to primary-prevention and acute stroke treatment. Women experience variations in endogenous estrogens throughout their life cycle and might also be exposed to exogenous estrogens, both of which markedly affect the brain. An understanding of the effects of endogenous and exogenous estrogens on cerebral hemodynamics could guide research into explaining how hormone therapy increases the risk of stroke in postmenopausal women. This Review summarizes the sex differences related to stroke, and the effect of endogenous and exogenous hormones on the cerebrovasculature of the female brain. It also proposes potential research approaches, the results of which could fill in gaps in our knowledge regarding the mechanism of action of estrogen in the brain.

Key Points

  • Women account for the majority of stroke deaths, and women who survive stroke have worse disability and a higher likelihood of institutionalization than do male stroke survivors

  • Women have unique risk factors for stroke that relate to events that change endogenous hormone levels throughout their life cycle, such as pregnancy and menopause

  • Exogenous estrogens can increase the risk of stroke, as shown in multiple studies of oral contraceptive use and postmenopausal hormone therapy

  • Research efforts need to focus on understanding sex differences in stroke treatment and outcomes at the levels of cerebrovascular physiology and the neurovascular unit

  • Additional areas for research include attempting to explain why hormone therapy use in relatively healthy women increases the risk of stroke

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References

  1. Thom T et al. (2006) Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113: e85–e151

    PubMed  Google Scholar 

  2. Seshadri S et al. (2006) The lifetime risk of stroke: estimates from the Framingham Study. Stroke 37: 345–350

    Article  PubMed  Google Scholar 

  3. Towfighi A et al. (2007) A midlife stroke surge among women in the United States. Neurology [10.1212/1201.wnl.0000268491.0000289956.c0000268492]

  4. Matthews KA et al. (2001) Changes in cardiovascular risk factors during the perimenopause and postmenopause and carotid artery atherosclerosis in healthy women. Stroke 32: 1104–1111

    Article  CAS  PubMed  Google Scholar 

  5. Di Carlo A et al. (2003) Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe: data from a Multicenter Multinational Hospital-Based Registry. Stroke 34: 1114–1119

    Article  PubMed  Google Scholar 

  6. Holroyd-Leduc JM et al. (2000) Sex differences and similarities in the management and outcome of stroke patients. Stroke 31: 1833–1837

    Article  CAS  PubMed  Google Scholar 

  7. Roquer J et al. (2003) Sex differences in first-ever acute stroke. Stroke 34: 1581–1585

    Article  PubMed  Google Scholar 

  8. Kapral MK et al. (2005) Sex differences in stroke care and outcomes: results from the registry of the Canadian Stroke Network. Stroke 36: 809–814

    Article  PubMed  Google Scholar 

  9. Dallongeville J et al. (2004) The association of metabolic disorders with the metabolic syndrome is different in men and women. Ann Nutr Metab 48: 43–50

    Article  CAS  PubMed  Google Scholar 

  10. Hanefeld M et al. (2007) Impact of the individual components of the metabolic syndrome and their different combinations on the prevalence of atherosclerotic vascular disease in type 2 diabetes: the Diabetes in Germany (DIG) study. Cardiovasc Diabetol 6: e13

    Article  CAS  Google Scholar 

  11. Iglseder B et al. (2005) The metabolic syndrome is a stronger risk factor for early carotid atherosclerosis in women than in men. Stroke 36: 1212–1217

    Article  PubMed  Google Scholar 

  12. Howard G et al. for the ARIC Investigators (1993) Carotid artery intimal–medial thickness distribution in general populations as evaluated by B-mode ultrasound. Stroke 24: 1297–1304

    Article  CAS  PubMed  Google Scholar 

  13. Marini C et al. (2005) Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 36: 1115–1119

    Article  PubMed  Google Scholar 

  14. Hart RG et al. (1999) Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. Stroke 30: 1223–1229

    Article  CAS  PubMed  Google Scholar 

  15. Humphries K et al. (2001) New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome. Circulation 103: 2365–2370

    Article  CAS  PubMed  Google Scholar 

  16. Lin H-J et al. (1996) Stroke severity in atrial fibrillation: the Framingham study. Stroke 27: 1760–1764

    Article  CAS  PubMed  Google Scholar 

  17. Antithrombotic Trialists' Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: 71–86

  18. Antiplatelet Trialists' Collaboration (1994) Collaborative overview of randomised trials of antiplatelet therapy—I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 308: 81–106

  19. Berger J et al. (2006) Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 295: 306–313

    Article  CAS  PubMed  Google Scholar 

  20. Williams J et al. (2007) Gender differences in outcomes among patients with symptomatic intracranial arterial stenosis. Stroke 38: 2055–2062

    Article  PubMed  Google Scholar 

  21. Kent DM et al. (2005) Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke 36: 62–65

    Article  CAS  PubMed  Google Scholar 

  22. Hill MD et al. (2006) Sex-based differences in the effect of intra-arterial treatment of stroke: analysis of the PROACT-2 study. Stroke 37: 2322–2325

    Article  CAS  PubMed  Google Scholar 

  23. Saposnik G et al. (2005) Predictors of major neurologic improvement after thrombolysis in acute stroke. Neurology 65: 1169–1174

    Article  PubMed  Google Scholar 

  24. Elkind M et al. (2007) Sex as a predictor of outcomes in patients treated with thrombolysis for acute stroke. Neurology 68: 842–848

    Article  CAS  PubMed  Google Scholar 

  25. Shah S et al. (2006) Influence of gender on outcomes after intra-arterial thrombolysis for acute ischemic stroke. Neurology 66: 1745–1746

    Article  CAS  PubMed  Google Scholar 

  26. Kelly-Hayes M et al. (2003) The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Diseases 12: 119–126

    Article  Google Scholar 

  27. Glader EL et al. for the Riks-Stroke Collaboration (2003) Sex differences in management and outcome after stroke: a Swedish national perspective. Stroke 34: 1970–1975

    Article  PubMed  Google Scholar 

  28. Wyller T et al. (1997) Are there gender differences in functional outcome after stroke? Clin Rehabil 11: 171–179

    Article  CAS  PubMed  Google Scholar 

  29. Paradiso S and Robinson R (1998) Gender differences in poststroke depression. J Neuropsychiatry Clin Neurosci 10: 41–47

    Article  CAS  PubMed  Google Scholar 

  30. Qureshi A et al. (2006) African American women have poor long-term survival following ischemic stroke. Neurology 67: 1623–1629

    Article  PubMed  Google Scholar 

  31. Smith MA et al. (2005) Gender comparisons of diagnostic evaluation for ischemic stroke patients. Neurology 65: 855–858

    Article  PubMed  Google Scholar 

  32. Shaywitz BA et al. (1995) Sex differences in the functional organization of the brain for language. Nature 373: 607–609

    Article  CAS  PubMed  Google Scholar 

  33. Hier D et al. (1994) Gender and aphasia in the Stroke Data Bank. Brain Lang 47: 155–167

    Article  CAS  PubMed  Google Scholar 

  34. Müller M and Schimrigk K (1996) Vasomotor reactivity and pattern of collateral blood flow in severe occlusive carotid artery disease Stroke 27: 296–299

    Article  PubMed  Google Scholar 

  35. Matteis M et al. (1998) Age and sex differences in cerebral hemodynamics: a transcranial Doppler study. Stroke 29: 963–967

    Article  CAS  PubMed  Google Scholar 

  36. Bushnell CD et al. (2006) Advancing the Study of Stroke in Women: summary and recommendations for future research from an NINDS-sponsored multidisciplinary working group. Stroke 37: 2387–2399

    Article  PubMed  Google Scholar 

  37. Yang S et al. (2005) Estrogens as protectants of the neurovascular unit against ischemic stroke. Curr Drug Targets CNS Neurol Disord 4: 169–177

    Article  CAS  PubMed  Google Scholar 

  38. Hashimoto M et al. (1995) Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation 92: 3431–3435

    Article  CAS  PubMed  Google Scholar 

  39. Diomedi M et al. (2001) Influence of physiologic oscillation of estrogens on cerebral hemodynamics. J Neurol Sci 185: 49–53

    Article  CAS  PubMed  Google Scholar 

  40. Shamma FN et al. (1992) Middle cerebral artery blood velocity during controlled ovarian hyperstimulation. Fertil Steril 57: 1022–1025

    Article  CAS  PubMed  Google Scholar 

  41. Kittner SJ et al. (1996) Pregnancy and the risk of stroke. N Engl J Med 335: 768–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ros HS et al. (2001) Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 12: 456–460

    Article  Google Scholar 

  43. Bateman B et al. (2006) Intracerebral hemorrhage in pregnancy: frequency, risk factors, and outcome. Neurology 67: 424–429

    Article  CAS  PubMed  Google Scholar 

  44. Sharshar T et al. for the Stroke in Pregnancy Study Group (1995) Incidence and causes of strokes associated with pregnancy and puerperium: a study in public hospitals of Île de France. Stroke 26: 930–936

    Article  CAS  PubMed  Google Scholar 

  45. James A et al. (2005) Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 106: 509–516

    Article  PubMed  Google Scholar 

  46. Singhal AB (2004) Postpartum angiopathy with reversible posterior leukoencephalopathy. Arch Neurol 61: 411–416

    Article  PubMed  Google Scholar 

  47. Zunker P et al. (1995) Cerebral hemodynamics in pre-eclampsia/eclampsia syndrome. Ultrasound Obstet Gynecol 6: 411–415

    Article  CAS  PubMed  Google Scholar 

  48. Elvan-Taspinar A et al. (2004) Central hemodynamics of hypertensive disorders in pregnancy. Am J Hypertens 17: 941–946

    Article  PubMed  Google Scholar 

  49. Ronnback M et al. (2005) Pulse wave reflection in currently and previously preeclamptic women. Hypertens Pregnancy 24: 171–180

    Article  PubMed  Google Scholar 

  50. Demarin V et al. (1997) Maternal cerebral circulation in normal and abnormal pregnancies. Acta Obstet Gynecol Scand 76: 619–624

    Article  CAS  PubMed  Google Scholar 

  51. Chireau MV et al. (2005) Pregnancy complications are associated with stroke risk later in life. Ann Neurol 58: S41

    Article  Google Scholar 

  52. Ray J et al. (2005) Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 366: 1797–1803

    Article  PubMed  Google Scholar 

  53. Wilson BJ et al. (2003) Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 326: 845–852

    Article  PubMed  PubMed Central  Google Scholar 

  54. Brown DW et al. (2006) Preeclampsia and the risk of ischemic stroke among young women: results from the Stroke Prevention in Young Women Study. Stroke 37: 1055–1059

    Article  PubMed  Google Scholar 

  55. Smith GC et al. (2001) Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 357: 2002–2006

    Article  CAS  PubMed  Google Scholar 

  56. Liu Y et al. (2001) Relative androgen excess and increased cardiovascular risk after menopause: a hypothesized relation. Am J Epidemiol 154: 489–494

    Article  CAS  PubMed  Google Scholar 

  57. Krause D et al. (2006) The influence of sex steroid hormones on cerebrovascular function. J Appl Physiol 101: 1252–1261

    Article  CAS  PubMed  Google Scholar 

  58. The Writing Group for the PEPI Trial (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 273: 199–208

  59. Haines C et al. (1996) Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. Arch Intern Med 156: 866–872

    Article  CAS  PubMed  Google Scholar 

  60. Spencer C et al. (1997) Is there a menopausal metabolic syndrome? Gynecol Endocrinol 11: 341–355

    Article  CAS  PubMed  Google Scholar 

  61. Sutton-Tyrrell K et al. (1998) Carotid atherosclerosis in premenopausal and postmenopausal women and its association with risk factors measured after menopause. Stroke 29: 1116–1121

    Article  CAS  PubMed  Google Scholar 

  62. Lidegaard O (1987) Cerebrovascular deaths before and after the appearance of oral contraceptives. Acta Neurol Scand 75: 427–433

    Article  CAS  PubMed  Google Scholar 

  63. Gillum LA et al. (2000) Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA 284: 72–78

    Article  CAS  PubMed  Google Scholar 

  64. Chan W-S et al. (2004) Risk of stroke in women exposed to low-dose oral contraceptives: a critical evaluation of the evidence. Arch Intern Med 164: 741–747

    Article  PubMed  Google Scholar 

  65. Baillargeon J-P et al. (2005) Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis. J Clin Endocrinol Metab 90: 3863–3870

    Article  CAS  PubMed  Google Scholar 

  66. Keating N et al. (1999) Use of hormone replacement therapy by postmenopausal women in the United States. Ann Intern Med 130: 545–553

    Article  CAS  PubMed  Google Scholar 

  67. Grady D et al. (1992) Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Internal Med 117: 1016–1037

    Article  CAS  Google Scholar 

  68. Hulley S et al. for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280: 605–613

    Article  CAS  PubMed  Google Scholar 

  69. Simon JA et al. (2001) Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS). Circulation 103: 638–642

    Article  CAS  PubMed  Google Scholar 

  70. Viscoli CM et al. (2001) A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 345: 1243–1249

    Article  CAS  PubMed  Google Scholar 

  71. Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288: 321–333

  72. The Women's Health Initiative Steering Committee (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 291: 1701–1712

  73. Rapp SR et al. (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 289: 2663–2672

    Article  CAS  PubMed  Google Scholar 

  74. Hersh AL et al. (2004) National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 291: 47–53

    Article  CAS  PubMed  Google Scholar 

  75. Barrett-Connor E et al. (2005) The rise and fall of menopausal hormone therapy. Annu Rev Public Health 26: 115–140

    Article  PubMed  Google Scholar 

  76. Hendrix SL et al. (2006) Effects of conjugated equine estrogen on stroke in the Women's Health Initiative. Circulation 113: 2425–2434

    Article  CAS  PubMed  Google Scholar 

  77. Wassertheil-Smoller S et al. (2003) Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA 289: 2673–2684

    Article  CAS  PubMed  Google Scholar 

  78. Klaiber EL et al. (2005) A critique of the Women's Health Initiative hormone therapy study. Fertil Steril 84: 1589–1601

    Article  CAS  PubMed  Google Scholar 

  79. Roussouw J et al. (2007) Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297: 1465–1477

    Google Scholar 

  80. Manson JE et al. (2007) Estrogen therapy and coronary-artery calcification. N Engl J Med 356: 2591–2602

    Article  CAS  PubMed  Google Scholar 

  81. Brott T et al. (1989) Measurements of acute cerebral infarction: a clinical examination scale. Stroke 20: 864–870

    Article  CAS  PubMed  Google Scholar 

  82. Colton C et al. (2005) Sex steroids, APOE genotype and the innate immune system. Neurobiol Aging 26: 363–371

    Article  CAS  PubMed  Google Scholar 

  83. Vegeto E et al. (2001) Estrogen prevents the LPS-induced inflammatory response in microglia. J Neurosci 21: 1809–1818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Brown C et al. (2007) The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol. Neurobiol Aging [10.1016/j.neurobiolaging.2007.04.018]

  85. Yaffe K et al. (2000) Estrogen use, APOE and cognitive decline: evidence of gene-environment interaction. Neurology 54: 1949–1954

    Article  CAS  PubMed  Google Scholar 

  86. Schott L et al. (2004) Segment-specific effects of cardiovascular risk factors on carotid artery intima–medial thickness in women at midlife. Arterioscler Thromb Vasc Biol 24: 1951–1956

    Article  CAS  PubMed  Google Scholar 

  87. Carandang R et al. (2006) Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. JAMA 296: 2939–2946

    Article  CAS  PubMed  Google Scholar 

  88. Kolominsky-Rabas P et al. (2001) Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 32: 2735–2740

    Article  CAS  PubMed  Google Scholar 

  89. Jaigobin C and Silver FL (2000) Stroke and pregnancy. Stroke 31: 2948–2951

    Article  CAS  PubMed  Google Scholar 

  90. Lanska DJ and Kryscio RJ (1998) Stroke and intracranial venous thrombosis during pregnancy and puerperium. Neurology 51: 1622–1628

    Article  CAS  PubMed  Google Scholar 

  91. Lanska DJ and Kryscio RJ (2000) Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis. Stroke 31: 1274–1282

    Article  CAS  PubMed  Google Scholar 

  92. Jeng J-S et al. (2004) Stroke in women of reproductive age: comparison between stroke related and unrelated to pregnancy. J Neurol Sci 221: 25–29

    Article  PubMed  Google Scholar 

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  1. Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA cbushnel@wfubmc.edu

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  1. CD Bushnell is an Associate Professor at Wake Forest University Health Sciences, Winston-Salem, NC, USA.,

    Cheryl D Bushnell

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Bushnell, C. Stroke and the female brain. Nat Rev Neurol 4, 22–33 (2008). https://doi.org/10.1038/ncpneuro0686

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