Skip to main content

Advertisement

Log in

The Effects of Estrogen in Ischemic Stroke

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Stroke is a leading cause of death and the most common cause of long-term disability in the USA. Women have a lower incidence of stroke compared with men throughout most of the lifespan which has been ascribed to protective effects of gonadal steroids, most notably estrogen. Due to the lower stroke incidence observed in pre-menopausal women and robust preclinical evidence of neuroprotective and anti-inflammatory properties of estrogen, researchers have focused on the potential benefits of hormones to reduce ischemic brain injury. However, as women age, they are disproportionately affected by stroke, coincident with the loss of estrogen with menopause. The risk of stroke in elderly women exceeds that of men and it is clear that in some settings estrogen can have pro-inflammatory effects. This review will focus on estrogen and inflammation and its interaction with aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2–220. doi:10.1161/CIR.0b013e31823ac046.

    PubMed  Google Scholar 

  2. Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke. 1997;28(3):491–9.

    PubMed  CAS  Google Scholar 

  3. Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K. Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab. 2004;24(4):458–66. doi:10.1097/00004647-200404000-00011.

    PubMed  Google Scholar 

  4. Yu SW, Wang H, Dawson TM, Dawson VL. Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity. Neurobiol Dis. 2003;14(3):303–17.

    PubMed  CAS  Google Scholar 

  5. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581–7. doi:10.1056/NEJM199512143332401.

    Google Scholar 

  6. Adams Jr HP, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38(5):1655–711. doi:10.1161/STROKEAHA.107.181486.

    PubMed  Google Scholar 

  7. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40(8):2761–8. doi:10.1161/STROKEAHA.108.544957.

    Google Scholar 

  8. California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology. 2005;64(4):654–9. doi:10.1212/01.WNL.0000151850.39648.51.

    Google Scholar 

  9. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002;297(5579):259–63. doi:10.1126/science.1072221297/5579/259.

    PubMed  CAS  Google Scholar 

  10. Eliasson MJ, Huang Z, Ferrante RJ, Sasamata M, Molliver ME, Snyder SH, et al. Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage. J Neurosci. 1999;19(14):5910–8.

    PubMed  CAS  Google Scholar 

  11. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997;3(10):1089–95.

    PubMed  CAS  Google Scholar 

  12. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994;265(5180):1883–5.

    PubMed  CAS  Google Scholar 

  13. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A. 1991;88(14):6368–71.

    PubMed  CAS  Google Scholar 

  14. Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, et al. Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem. 2004;279(37):38563–70. doi:10.1074/jbc.M405461200M405461200.

    PubMed  CAS  Google Scholar 

  15. Turtzo LC, McCullough LD. Sex-specific responses to stroke. Future Neurol. 2010;5(1):47–59. doi:10.2217/fnl.09.66.

    PubMed  Google Scholar 

  16. Li H, Pin S, Zeng Z, Wang MM, Andreasson KA, McCullough LD. Sex differences in cell death. Ann Neurol. 2005;58(2):317–21. doi:10.1002/ana.20538.

    PubMed  CAS  Google Scholar 

  17. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7(10):915–26. doi:10.1016/S1474-4422(08)70193-5.

    PubMed  Google Scholar 

  18. Liu F, Li Z, Li J, Siegel C, Yuan R, McCullough LD. Sex differences in caspase activation after stroke. Stroke. 2009;40(5):1842–8. doi:10.1161/STROKEAHA.108.538686.

    PubMed  CAS  Google Scholar 

  19. Lang JT, McCullough LD. Pathways to ischemic neuronal cell death: are sex differences relevant? J Transl Med. 2008;6:33. doi:10.1186/1479-5876-6-33.

    PubMed  Google Scholar 

  20. Renolleau S, Fau S, Charriaut-Marlangue C. Gender-related differences in apoptotic pathways after neonatal cerebral ischemia. Neuroscientist. 2008;14(1):46–52. doi:10.1177/1073858407308889.

    PubMed  CAS  Google Scholar 

  21. Zhang L, Nair A, Krady K, Corpe C, Bonneau RH, Simpson IA, et al. Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice. J Clin Invest. 2004;113(1):85–95. doi:10.1172/JCI18336.

    PubMed  CAS  Google Scholar 

  22. Harry GJ, Kraft AD. Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology. 2012;33(2):191–206. doi:10.1016/j.neuro.2012.01.012.

    PubMed  Google Scholar 

  23. Sheffield LG, Berman NE. Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging. 1998;19(1):47–55.

    PubMed  CAS  Google Scholar 

  24. Liu F, Yuan R, Benashski SE, McCullough LD. Changes in experimental stroke outcome across the life span. J Cereb Blood Flow Metab. 2009;29(4):792–802. doi:10.1038/jcbfm.2009.5.

    PubMed  CAS  Google Scholar 

  25. Liu F, McCullough LD. Interactions between age, sex, and hormones in experimental ischemic stroke. Neurochem Int. 2012. doi:10.1016/j.neuint.2012.10.003.

  26. Appelros P, Stegmayr B, Terent A. Sex differences in stroke epidemiology: a systematic review. Stroke. 2009;40(4):1082–90. doi:10.1161/STROKEAHA.108.540781.

    PubMed  Google Scholar 

  27. Armstrong-Wells J, Johnston SC, Wu YW, Sidney S, Fullerton HJ. Prevalence and predictors of perinatal hemorrhagic stroke: results from the kaiser pediatric stroke study. Pediatrics. 2009;123(3):823–8. doi:10.1542/peds.2008-0874.

    PubMed  Google Scholar 

  28. Raju TN, Nelson KB, Ferriero D, Lynch JK. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics. 2007;120(3):609–16. doi:10.1542/peds.2007-0336.

    PubMed  Google Scholar 

  29. Golomb MR, Dick PT, MacGregor DL, Curtis R, Sofronas M, de Veber GA. Neonatal arterial ischemic stroke and cerebral sinovenous thrombosis are more commonly diagnosed in boys. J Child Neurol. 2004;19(7):493–7.

    PubMed  Google Scholar 

  30. Golomb MR, Fullerton HJ, Nowak-Gottl U, Deveber G. Male predominance in childhood ischemic stroke: findings from the international pediatric stroke study. Stroke. 2009;40(1):52–7. doi:10.1161/STROKEAHA.108.521203.

    PubMed  Google Scholar 

  31. Salih MA, Abdel-Gader AG, Al-Jarallah AA, Kentab AY, Alorainy IA, Hassan HH, et al. Stroke in Saudi children. Epidemiology, clinical features and risk factors. Saudi Med J. 2006;27 Suppl 1:S12–20.

    PubMed  Google Scholar 

  32. Bonduel M, Sciuccati G, Hepner M, Pieroni G, Torres AF, Frontroth JP, et al. Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry. Acta Haematol. 2006;115(3–4):180–5. doi:10.1159/000090932.

    PubMed  Google Scholar 

  33. Ingemarsson I. Gender aspects of preterm birth. BJOG. 2003;110 Suppl 20:34–8.

    PubMed  Google Scholar 

  34. Hintz SR, Kendrick DE, Vohr BR, Kenneth Poole W, Higgins RD. Gender differences in neurodevelopmental outcomes among extremely preterm, extremely-low-birthweight infants. Acta Paediatr. 2006;95(10):1239–48. doi:10.1080/08035250600599727.

    PubMed  Google Scholar 

  35. Sheiner E, Levy A, Katz M, Hershkovitz R, Leron E, Mazor M. Gender does matter in perinatal medicine. Fetal Diagn Ther. 2004;19(4):366–9. doi:10.1159/00007796777967.

    PubMed  Google Scholar 

  36. Di Renzo GC, Rosati A, Sarti RD, Cruciani L, Cutuli AM. Does fetal sex affect pregnancy outcome? Gend Med. 2007;4(1):19–30.

    PubMed  Google Scholar 

  37. Johnston MV, Hagberg H. Sex and the pathogenesis of cerebral palsy. Dev Med Child Neurol. 2007;49(1):74–8. doi:10.1111/j.1469-8749.2007.0199a.x.

    PubMed  Google Scholar 

  38. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham heart study. Stroke. 2009;40(4):1032–7. doi:10.1161/STROKEAHA.108.542894.

    PubMed  Google Scholar 

  39. Niewada M, Kobayashi A, Sandercock PA, Kaminski B, Czlonkowska A. Influence of gender on baseline features and clinical outcomes among 17,370 patients with confirmed ischaemic stroke in the international stroke trial. Neuroepidemiology. 2005;24(3):123–8. doi:10.1159/000082999.

    PubMed  Google Scholar 

  40. Roquer J, Campello AR, Gomis M. Sex differences in first-ever acute stroke. Stroke. 2003;34(7):1581–5. doi:10.1161/01.STR.0000078562.82918.

    PubMed  Google Scholar 

  41. Fukuda M, Kanda T, Kamide N, Akutsu T, Sakai F. Gender differences in long-term functional outcome after first-ever ischemic stroke. Intern Med. 2009;48(12):967–73.

    PubMed  Google Scholar 

  42. Arnold M, Halpern M, Meier N, Fischer U, Haefeli T, Kappeler L, et al. Age-dependent differences in demographics, risk factors, co-morbidity, etiology, management, and clinical outcome of acute ischemic stroke. J Neurol. 2008;255(10):1503–7. doi:10.1007/s00415-008-0949-9.

    PubMed  CAS  Google Scholar 

  43. Bhatnagar P, Sinha D, Parker RA, Guyler P, O’Brien A. Intravenous thrombolysis in acute ischaemic stroke: a systematic review and meta-analysis to aid decision making in patients over 80 years of age. J Neurol Neurosurg Psychiatry. 2011;82(7):712–7. doi:10.1136/jnnp.2010.223149.

    PubMed  Google Scholar 

  44. Engelter ST, Reichhart M, Sekoranja L, Georgiadis D, Baumann A, Weder B, et al. Thrombolysis in stroke patients aged 80 years and older: Swiss survey of IV thrombolysis. Neurology. 2005;65(11):1795–8. doi:10.1212/01.wnl.0000183702.04080.27.

    PubMed  CAS  Google Scholar 

  45. Zeevi N, Kuchel GA, Lee NS, Staff I, McCullough LD. Interventional stroke therapies in the elderly: are we helping? AJNR Am J Neuroradiol. 2012;33(4):638–42. doi:10.3174/ajnr.A2845.

    PubMed  CAS  Google Scholar 

  46. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med. 1995;155(5):469–73.

    PubMed  CAS  Google Scholar 

  47. Lane DA, Lip GY. Female gender is a risk factor for stroke and thromboembolism in atrial fibrillation patients. Thromb Haemost. 2009;101(5):802–5.

    PubMed  CAS  Google Scholar 

  48. Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD. Gender-linked brain injury in experimental stroke. Stroke. 1998;29(1):159–65. discussion 66.

    PubMed  CAS  Google Scholar 

  49. Hart RG, Eikelboom JW, Pearce LA. Sex, Stroke, and Atrial Fibrillation. Arch Neurol. 2012:1–3. doi:10.1001/archneurol.2012.26911362172

  50. Avgil Tsadok M, Jackevicius CA, Rahme E, Humphries KH, Behlouli H, Pilote L. Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation. JAMA. 2012;307(18):1952–8. doi:10.1001/jama.2012.3490.

    PubMed  Google Scholar 

  51. Sullivan RM, Zhang J, Zamba G, Lip GY, Olshansky B. Relation of Gender-Specific Risk of Ischemic Stroke in Patients With Atrial Fibrillation to Differences in Warfarin Anticoagulation Control (from AFFIRM). Am J Cardiol. 2012. doi:10.1016/j.amjcard.2012.08.014.

  52. Forster A, Gass A, Kern R, Wolf ME, Ottomeyer C, Zohsel K, et al. Gender differences in acute ischemic stroke: etiology, stroke patterns and response to thrombolysis. Stroke. 2009;40(7):2428–32. doi:10.1161/STROKEAHA.109.548750.

    PubMed  Google Scholar 

  53. Hall ED, Pazara KE, Linseman KL. Sex differences in postischemic neuronal necrosis in gerbils. J Cereb Blood Flow Metab. 1991;11(2):292–8. doi:10.1038/jcbfm.1991.61.

    PubMed  CAS  Google Scholar 

  54. Herson PS, Koerner IP, Hurn PD. Sex, sex steroids, and brain injury. Semin Reprod Med. 2009;27(3):229–39. doi:10.1055/s-0029-1216276.

    PubMed  CAS  Google Scholar 

  55. Hurn PD, Vannucci SJ, Hagberg H. Adult or perinatal brain injury: does sex matter? Stroke. 2005;36(2):193–5. doi:10.1161/01.STR.0000153064.41332.f6.

    PubMed  Google Scholar 

  56. Lewis DK, Thomas KT, Selvamani A, Sohrabji F. Age-related severity of focal ischemia in female rats is associated with impaired astrocyte function. Neurobiol Aging. 2012;33(6):1123 e1–16. doi:10.1016/j.neurobiolaging.2011.11.007.

    Google Scholar 

  57. Dinapoli VA, Benkovic SA, Li X, Kelly KA, Miller DB, Rosen CL, et al. Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat. Neuroscience. 2010;170(2):633–44. doi:10.1016/j.neuroscience.2010.07.011.

    PubMed  CAS  Google Scholar 

  58. Turtzo LC, McCullough LD. Sex differences in stroke. Cerebrovasc Dis. 2008;26(5):462–74. doi:10.1159/000155983.

    PubMed  Google Scholar 

  59. Manwani B, McCullough LD. Estrogen in ischaemic stroke: the debate continues. Eur J Neurol. 2012;19(10):1276–7. doi:10.1111/j.1468-1331.2012.03746.x.

    PubMed  CAS  Google Scholar 

  60. Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab. 2000;20(4):631–52. doi:10.1097/00004647-200004000-00001.

    PubMed  CAS  Google Scholar 

  61. Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, et al. Strategies and methods for research on sex differences in brain and behavior. Endocrinology. 2005;146(4):1650–73. doi:10.1210/en.2004-1142.

    PubMed  CAS  Google Scholar 

  62. Arnold AP. Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues. J Neuroendocrinol. 2009;21(4):377–86. doi:10.1111/j.1365-2826.2009.01831.x.

    PubMed  CAS  Google Scholar 

  63. Arnold AP, Chen X. What does the "four core genotypes" mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol. 2009;30(1):1–9. doi:10.1016/j.yfrne.2008.11.001.

    PubMed  Google Scholar 

  64. Cohen-Bendahan CC, van de Beek C, Berenbaum SA. Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings. Neurosci Biobehav Rev. 2005;29(2):353–84. doi:10.1016/j.neubiorev.2004.11.004.

    PubMed  CAS  Google Scholar 

  65. Bakker J, De Mees C, Douhard Q, Balthazart J, Gabant P, Szpirer J, et al. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci. 2006;9(2):220–6. doi:10.1038/nn1624.

    PubMed  CAS  Google Scholar 

  66. Arnold AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav. 2009;55(5):570–8. doi:10.1016/j.yhbeh.2009.03.011.

    PubMed  CAS  Google Scholar 

  67. McCullough LD, Hurn PD. Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab. 2003;14(5):228–35.

    PubMed  CAS  Google Scholar 

  68. Persky RW, Liu F, Xu Y, Weston G, Levy S, Roselli CE, et al. Neonatal testosterone exposure protects adult male rats from stroke. Neuroendocrinology. 2012. doi:10.1159/000343804.

  69. Siegel C, Li J, Liu F, Benashski SE, McCullough LD. miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. Proc Natl Acad Sci U S A. 2011;108(28):11662–7. doi:10.1073/pnas.1102635108.

    PubMed  CAS  Google Scholar 

  70. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis. 2010;10(5):338–49. doi:10.1016/S1473-3099(10)70049-9.

    PubMed  Google Scholar 

  71. Chrousos GP. Stress and sex versus immunity and inflammation. Sci Signal. 2010;3(143). doi:10.1126/scisignal.3143pe36. pe36.

  72. Tian Y, Stamova B, Jickling GC, Liu D, Ander BP, Bushnell C, et al. Effects of gender on gene expression in the blood of ischemic stroke patients. J Cereb Blood Flow Metab. 2012;32(5):780–91. doi:10.1038/jcbfm.2011.179.

    PubMed  CAS  Google Scholar 

  73. Stamova B, Tian Y, Jickling G, Bushnell C, Zhan X, Liu D, et al. The X-chromosome has a different pattern of gene expression in women compared with men with ischemic stroke. Stroke. 2012;43(2):326–34. doi:10.1161/STROKEAHA.111.629337.

    PubMed  Google Scholar 

  74. Tian Y, Stamova B, Jickling GC, Xu H, Liu D, Ander BP, et al. Y chromosome gene expression in the blood of male patients with ischemic stroke compared with male controls. Gend Med. 2012;9(2):68–75 e3. doi:10.1016/j.genm.2012.01.005.

    PubMed  Google Scholar 

  75. Sampson AK, Jennings GL, Chin-Dusting JP. Y are males so difficult to understand?: a case where "X" does not mark the spot. Hypertension. 2012;59(3):525–31. doi:10.1161/HYPERTENSIONAHA.111.187880.

    PubMed  CAS  Google Scholar 

  76. Manwani B, McCullough LD. Sexual dimorphism in ischemic stroke: lessons from the laboratory. Womens Health (Lond Engl). 2011;7(3):319–39. doi:10.2217/whe.11.22.

    Google Scholar 

  77. Turtzo LC, Siegel C, McCullough LD. X chromosome dosage and the response to cerebral ischemia. J Neurosci. 2011;31(37):13255–9.

    PubMed  CAS  Google Scholar 

  78. Qureshi IA, Mehler MF. The emerging role of epigenetics in stroke: III. Neural stem cell biology and regenerative medicine. Arch Neurol. 2011;68(3):294–302. doi:10.1001/archneurol.2011.6.

    PubMed  Google Scholar 

  79. Qureshi IA, Mehler MF. The emerging role of epigenetics in stroke: II. RNA regulatory circuitry. Arch Neurol. 2010;67(12):1435–41. doi:10.1001/archneurol.2010.300.

    PubMed  Google Scholar 

  80. Qureshi IA, Mehler MF. Emerging role of epigenetics in stroke: part 1: DNA methylation and chromatin modifications. Arch Neurol. 2010;67(11):1316–22. doi:10.1001/archneurol.2010.275.

    PubMed  Google Scholar 

  81. Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol. 2008;8(1):25–32. doi:10.1016/j.coph.2007.09.001.

    PubMed  CAS  Google Scholar 

  82. MacDonald JF, Xiong ZG, Jackson MF. Paradox of Ca2+ signaling, cell death and stroke. Trends Neurosci. 2006;29(2):75–81. doi:10.1016/j.tins.2005.12.001.

    PubMed  CAS  Google Scholar 

  83. Beckman JS, Crow JP. Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem Soc Trans. 1993;21(2):330–4.

    PubMed  CAS  Google Scholar 

  84. Crow JP, Beckman JS. Reactions between nitric oxide, superoxide, and peroxynitrite: footprints of peroxynitrite in vivo. Adv Pharmacol. 1995;34:17–43.

    PubMed  CAS  Google Scholar 

  85. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, et al. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A. 2006;103(48):18308–13. doi:10.1073/pnas.0606526103.

    PubMed  CAS  Google Scholar 

  86. Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A. 2006;103(48):18314–9. doi:10.1073/pnas.0606528103.

    PubMed  CAS  Google Scholar 

  87. Yuan M, Siegel C, Zeng Z, Li J, Liu F, McCullough LD. Sex differences in the response to activation of the poly(ADP-ribose) polymerase pathway after experimental stroke. Exp Neurol. 2009;217(1):210–8. doi:10.1016/j.expneurol.2009.02.012.

    PubMed  CAS  Google Scholar 

  88. Reubold TF, Eschenburg S. A molecular view on signal transduction by the apoptosome. Cell Signal. 2012;24(7):1420–5. doi:10.1016/j.cellsig.2012.03.007.

    PubMed  CAS  Google Scholar 

  89. Bushnell CD. Stroke and the female brain. Nat Clin Pract Neurol. 2008;4(1):22–33. doi:10.1038/ncpneuro0686.

    PubMed  Google Scholar 

  90. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293–304. doi:10.1056/NEJMoa050613.

    PubMed  CAS  Google Scholar 

  91. Ment LR, Vohr BR, Makuch RW, Westerveld M, Katz KH, Schneider KC, et al. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr. 2004;145(6):832–4. doi:10.1016/j.jpeds.2004.07.035.

    PubMed  CAS  Google Scholar 

  92. Ohlsson A, Roberts RS, Schmidt B, Davis P, Moddeman D, Saigal S, et al. Male/female differences in indomethacin effects in preterm infants. J Pediatr. 2005;147(6):860–2. doi:10.1016/j.jpeds.2005.07.032.

    PubMed  CAS  Google Scholar 

  93. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345(17):1243–9. doi:10.1056/NEJMoa010534.

    PubMed  CAS  Google Scholar 

  94. Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA. 2003;289(20):2673–84. doi:10.1001/jama.289.20.2673289/20/2673.

    PubMed  CAS  Google Scholar 

  95. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7. doi:10.1002/14651858.CD004143.pub4.

  96. Gaskins AJ, Wilchesky M, Mumford SL, Whitcomb BW, Browne RW, Wactawski-Wende J, et al. Endogenous reproductive hormones and C-reactive protein across the menstrual cycle: the BioCycle Study. Am J Epidemiol. 2012;175(5):423–31. doi:10.1093/aje/kwr343.

    PubMed  Google Scholar 

  97. Carcaillon L, Garcia-Garcia FJ, Tresguerres JA, Gutierrez Avila G, Kireev R, Rodriguez-Manas L. Higher levels of endogenous estradiol are associated with frailty in postmenopausal women from the toledo study for healthy aging. J Clin Endocrinol Metab. 2012;97(8):2898–906. doi:10.1210/jc.2012-1271jc.2012-1271.

    PubMed  CAS  Google Scholar 

  98. Lakoski SG, Herrington DM. Effects of hormone therapy on C-reactive protein and IL-6 in postmenopausal women: a review article. Climacteric. 2005;8(4):317–26. doi:10.1080/13697130500345109.

    PubMed  CAS  Google Scholar 

  99. Wander K, Brindle E, O’Connor KA. C-reactive protein across the menstrual cycle. Am J Phys Anthropol. 2008;136(2):138–46. doi:10.1002/ajpa.20785.

    PubMed  Google Scholar 

  100. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345:e6409. doi:10.1136/bmj.e6409bmj.e6409.

    PubMed  Google Scholar 

  101. Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc Natl Acad Sci U S A. 2007;104(14):6013–8. doi:10.1073/pnas.0610394104.

    PubMed  CAS  Google Scholar 

  102. Liu F, Benashski SE, Xu Y, Siegel M, McCullough LD. Effects of chronic and acute oestrogen replacement therapy in aged animals after experimental stroke. J Neuroendocrinol. 2012;24(2):319–30. doi:10.1111/j.1365-2826.2011.02248.x.

    PubMed  CAS  Google Scholar 

  103. Lakshman R, Forouhi NG, Sharp SJ, Luben R, Bingham SA, Khaw KT, et al. Early age at menarche associated with cardiovascular disease and mortality. J Clin Endocrinol Metab. 2009;94(12):4953–60. doi:10.1210/jc.2009-1789.

    PubMed  CAS  Google Scholar 

  104. Meseguer A, Puche C, Cabero A. Sex steroid biosynthesis in white adipose tissue. Horm Metab Res. 2002;34(11–12):731–6. doi:10.1055/s-2002-38249.

    PubMed  CAS  Google Scholar 

  105. Bulun SE, Simpson ER. Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab. 1994;78(2):428–32.

    PubMed  CAS  Google Scholar 

  106. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366(24):2257–66. doi:10.1056/NEJMoa1111840.

    PubMed  CAS  Google Scholar 

  107. Zakharova MY, Meyer RM, Brandy KR, Datta YH, Joseph MS, Schreiner PJ, et al. Risk factors for heart attack, stroke, and venous thrombosis associated with hormonal contraceptive use. Clin Appl Thromb Hemost. 2011;17(4):323–31. doi:10.1177/1076029610368670.

    PubMed  CAS  Google Scholar 

  108. Kittner SJ, Stern BJ, Feeser BR, Hebel R, Nagey DA, Buchholz DW, et al. Pregnancy and the risk of stroke. N Engl J Med. 1996;335(11):768–74. doi:10.1056/NEJM199609123351102.

    PubMed  CAS  Google Scholar 

  109. Tettenborn B. Stroke and pregnancy. Neurol Clin. 2012;30(3):913–24. doi:10.1016/j.ncl.2012.06.002.

    PubMed  Google Scholar 

  110. Das A, Smith JA, Gibson C, Varma AK, Ray SK, Banik NL. Estrogen receptor agonists and estrogen attenuate TNF-alpha-induced apoptosis in VSC4.1 motoneurons. J Endocrinol. 2011;208(2):171–82. doi:10.1677/JOE-10-0338.

    PubMed  CAS  Google Scholar 

  111. Tenenbaum M, Azab AN, Kaplanski J. Effects of estrogen against LPS-induced inflammation and toxicity in primary rat glial and neuronal cultures. J Endotoxin Res. 2007;13(3):158–66. doi:10.1177/0968051907080428..

    PubMed  CAS  Google Scholar 

  112. Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol. 2009;30(2):201–11. doi:10.1016/j.yfrne.2009.04.007.

    PubMed  CAS  Google Scholar 

  113. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 2012;7(1):42–59. doi:10.1007/s11481-011-9287-2.

    PubMed  Google Scholar 

  114. Kamada M, Irahara M, Maegawa M, Ohmoto Y, Takeji T, Yasui T, et al. Postmenopausal changes in serum cytokine levels and hormone replacement therapy. Am J Obstet Gynecol. 2001;184(3):309–14. doi:10.1067/mob.2001.109940.

    PubMed  CAS  Google Scholar 

  115. Dziewulska D, Mossakowski MJ. Cellular expression of tumor necrosis factor a and its receptors in human ischemic stroke. Clin Neuropathol. 2003;22(1):35–40.

    PubMed  CAS  Google Scholar 

  116. Figiel I, Dzwonek K. TNFalpha and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin. Brain Res. 2007;1131(1):17–28. doi:10.1016/j.brainres.2006.10.095.

    PubMed  CAS  Google Scholar 

  117. Dopp JM, Mackenzie-Graham A, Otero GC, Merrill JE. Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia. J Neuroimmunol. 1997;75(1–2):104–12.

    PubMed  CAS  Google Scholar 

  118. Bebo Jr BF, Linthicum DS. Expression of mRNA for 55-kDa and 75-kDa tumor necrosis factor (TNF) receptors in mouse cerebrovascular endothelium: effects of interleukin-1 beta, interferon-gamma and TNF-alpha on cultured cells. J Neuroimmunol. 1995;62(2):161–7.

    PubMed  CAS  Google Scholar 

  119. Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, Depuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs. 2012. doi:10.1007/s40263-012-0013-2.

  120. Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab. 2012;32(9):1677–98. doi:10.1038/jcbfm.2012.88jcbfm201288.

    PubMed  CAS  Google Scholar 

  121. Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87(1):10–20. doi:10.1016/j.brainresbull.2011.10.004.

    PubMed  CAS  Google Scholar 

  122. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke. 1994;25(7):1481–8.

    PubMed  CAS  Google Scholar 

  123. Maddahi A, Kruse LS, Chen QW, Edvinsson L. The role of tumor necrosis factor-alpha and TNF-alpha receptors in cerebral arteries following cerebral ischemia in rat. J Neuroinflammation. 2011;8:107. doi:10.1186/1742-2094-8-107.

    PubMed  CAS  Google Scholar 

  124. Cui G, Wang H, Li R, Zhang L, Li Z, Wang Y, et al. Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke. J Neuroinflammation. 2012;9(1):235. doi:10.1186/1742-2094-9-235.

    PubMed  CAS  Google Scholar 

  125. Liao SL, Chen WY, Chen CJ. Estrogen attenuates tumor necrosis factor-alpha expression to provide ischemic neuroprotection in female rats. Neurosci Lett. 2002;330(2):159–62.

    PubMed  CAS  Google Scholar 

  126. Calippe B, Douin-Echinard V, Laffargue M, Laurell H, Rana-Poussine V, Pipy B, et al. Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3-kinase pathway. J Immunol. 2008;180(12):7980–8.

    PubMed  CAS  Google Scholar 

  127. Sumbria RK, Boado RJ, Pardridge WM. Brain protection from stroke with intravenous TNFalpha decoy receptor-Trojan horse fusion protein. J Cereb Blood Flow Metab. 2012. doi:10.1038/jcbfm.2012.97jcbfm201297.

  128. Matthews JR, Hay RT. Regulation of the DNA binding activity of NF-kappa B. Int J Biochem Cell Biol. 1995;27(9):865–79.

    PubMed  CAS  Google Scholar 

  129. Emmanouil M, Taoufik E, Tseveleki V, Vamvakas SS, Probert L. A role for neuronal NF-kappaB in suppressing neuroinflammation and promoting neuroprotection in the CNS. Adv Exp Med Biol. 2011;691:575–81. doi:10.1007/978-1-4419-6612-4_60.

    PubMed  CAS  Google Scholar 

  130. Rupec RA, Baeuerle PA. The genomic response of tumor cells to hypoxia and reoxygenation. Differential activation of transcription factors AP-1 and NF-kappa B. Eur J Biochem. 1995;234(2):632–40.

    PubMed  CAS  Google Scholar 

  131. Dudek EJ, Shang F, Taylor A. H(2)O(2)-mediated oxidative stress activates NF-kappa B in lens epithelial cells. Free Radic Biol Med. 2001;31(5):651–8.

    PubMed  CAS  Google Scholar 

  132. Hoffmann A, Levchenko A, Scott ML, Baltimore D. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science. 2002;298(5596):1241–5. doi:10.1126/science.1071914298/5596/1241.

    PubMed  CAS  Google Scholar 

  133. Carroll JE, Howard EF, Hess DC, Wakade CG, Chen Q, Cheng C. Nuclear factor-kappa B activation during cerebral reperfusion: effect of attenuation with N-acetylcysteine treatment. Brain Res Mol Brain Res. 1998;56(1–2):186–91.

    PubMed  CAS  Google Scholar 

  134. Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M. NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med. 1999;5(5):554–9. doi:10.1038/8432.

    PubMed  CAS  Google Scholar 

  135. Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, et al. Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke. 2004;35(4):987–91. doi:10.1161/01.STR.0000120732.45951.26.

    PubMed  Google Scholar 

  136. Culmsee C, Siewe J, Junker V, Retiounskaia M, Schwarz S, Camandola S, et al. Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons. J Neurosci. 2003;23(24):8586–95.

    PubMed  CAS  Google Scholar 

  137. Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q, et al. The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain Res Bull. 2001;55(3):375–86.

    PubMed  CAS  Google Scholar 

  138. Foehr ED, Lin X, O’Mahony A, Geleziunas R, Bradshaw RA, Greene WC. NF-kappa B signaling promotes both cell survival and neurite process formation in nerve growth factor-stimulated PC12 cells. J Neurosci. 2000;20(20):7556–63.

    PubMed  CAS  Google Scholar 

  139. Duckworth EA, Butler T, Collier L, Collier S, Pennypacker KR. NF-kappaB protects neurons from ischemic injury after middle cerebral artery occlusion in mice. Brain Res. 2006;1088(1):167–75. doi:10.1016/j.brainres.2006.02.103.

    PubMed  CAS  Google Scholar 

  140. Sarnico I, Lanzillotta A, Benarese M, Alghisi M, Baiguera C, Battistin L, et al. NF-kappaB dimers in the regulation of neuronal survival. Int Rev Neurobiol. 2009;85:351–62. doi:10.1016/S0074-7742(09)85024-1.

    PubMed  CAS  Google Scholar 

  141. Ridder DA, Schwaninger M. NF-kappaB signaling in cerebral ischemia. Neuroscience. 2009;158(3):995–1006. doi:10.1016/j.neuroscience.2008.07.007.

    PubMed  CAS  Google Scholar 

  142. Xing D, Oparil S, Yu H, Gong K, Feng W, Black J, et al. Estrogen modulates NFkappaB signaling by enhancing IkappaBalpha levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-beta. PLoS One. 2012;7(6):e36890. doi:10.1371/journal.pone.0036890PONE-D-11-18299.

    PubMed  CAS  Google Scholar 

  143. Lian H, Shim DJ, Gaddam SS, Rodriguez-Rivera J, Bitner BR, Pautler RG, et al. IkappaBalpha deficiency in brain leads to elevated basal neuroinflammation and attenuated response following traumatic brain injury: implications for functional recovery. Mol Neurodegener. 2012;7(1):47. doi:10.1186/1750-1326-7-47.

    PubMed  CAS  Google Scholar 

  144. Hoffmann A, Baltimore D. Circuitry of nuclear factor kappaB signaling. Immunol Rev. 2006;210:171–86. doi:10.1111/j.0105-2896.2006.00375.x.

    PubMed  Google Scholar 

  145. Liu F, Lang J, Li J, Benashski SE, Siegel M, Xu Y, et al. Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke. Stroke. 2011;42(4):1090–6. doi:10.1161/STROKEAHA.110.594861.

    PubMed  CAS  Google Scholar 

  146. Hoda MN, Li W, Ahmad A, Ogbi S, Zemskova MA, Johnson MH, et al. Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke. Exp Transl Stroke Med. 2011;3(1):16. doi:10.1186/2040-7378-3-16.

    PubMed  CAS  Google Scholar 

  147. Li J, McCullough LD. Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab. 2009;29(4):670–4. doi:10.1038/jcbfm.2009.3.

    PubMed  CAS  Google Scholar 

  148. McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25(4):502–12. doi:10.1038/sj.jcbfm.9600059.

    PubMed  CAS  Google Scholar 

  149. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002;419(6905):367–74. doi:10.1038/nature01034nature01034.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the NINDS RO1 NS055215-06 to Dr. McCullough.

Conflict of Interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Louise D. McCullough.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koellhoffer, E.C., McCullough, L.D. The Effects of Estrogen in Ischemic Stroke. Transl. Stroke Res. 4, 390–401 (2013). https://doi.org/10.1007/s12975-012-0230-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-012-0230-5

Keywords

Navigation