Skip to main content
SpringerLink
Log in

Stroke Sex Differences: From Basic Research to Clinical Trials

  • Chapter
  • First Online:
Neuroprotective Therapy for Stroke and Ischemic Disease

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

Sex is shown to affect various aspects of the clinical spectrum of ischaemic stroke, from how an individual patient may present with ischaemic stroke through to how they respond to treatment strategies. In this chapter, we review the evidence for the effect of sex on ischaemic stroke and focus on how the pathological mechanisms of ischaemic stroke, in particular apoptosis, may differ between the sexes. Understanding sex-specific consequences of ischaemic stroke may enable the development of relevant and effective treatment strategies for an individual suffering an ischaemic stroke.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AIF:

Apoptosis-inducing factor

ENOS:

Efficacy of Nitric Oxide in Stroke

NIH:

National Institutes of Health

NOS:

Nitric oxide synthase

PARP:

Poly-ADP ribose polymerase

SITS-ISTR:

Stroke-International Stroke Thrombolysis Register

STAIR:

Stroke Treatment Academic Industry Roundtable

tPA:

Tissue plasminogen activation

References

  1. Gibson CL (2013) Cerebral ischemic stroke: is gender important? J Cereb Blood Flow Metab 33:1355–1361

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rojas JI, Zurru MC, Romano M, Patrucco L, Cristiano E (2007) Acute ischemic stroke and transient ischemic attack in the very old—risk factor profile and stroke subtype between patients older than 80 years and patients aged less than 80 years. Eur J Neurol 14:895–899

    Article  CAS  PubMed  Google Scholar 

  3. Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB et al (2006) The lifetime risk of stroke: estimates from the Framingham study. Stroke 37:345–350

    Article  PubMed  Google Scholar 

  4. Gargano JW, Wehner S, Reeves MJ (2009) Delays among patients with acute stroke. Do presenting symptoms explain sex differences in emergency department? Stroke 40:1114–1120

    Article  PubMed  Google Scholar 

  5. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N et al (2008) Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117:e25–e146

    Article  PubMed  Google Scholar 

  6. Thorvaldsen P, Asplund KM, Kuulasmaa K, Rajakangas AM, Scholl M (1995) Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health organization monitoring trends and determinants in cardiovascular disease. Stroke 26:361–367

    Article  CAS  PubMed  Google Scholar 

  7. Towfighi A, Saver JL, Engelhardt R, Ovbiagele B (2007) A midlife stroke surge among women in the United States. Neurology 69:1898–1904

    Article  PubMed  Google Scholar 

  8. Lofmark U, Hammartstrom A (2007) Evidence for age-dependent education-related differences in men and women with first-ever stroke. Neuroepidemiology 28:135–141

    Article  PubMed  Google Scholar 

  9. Rothwell PM, Coull AJ, Silver LE et al (2005) Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet 366:1970–1975

    Google Scholar 

  10. Jerath NU, Reddy C, Freeman D, Jerath AU, Brown RD (2011) Gender differences in presenting signs and symptoms of acute ischemic stroke: a population-based study. Gend Med 8:312–319

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU (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 

  12. Mandelzweig L, Goldbourt U, Bokyo V, Tanne D (2006) Perceptual, social, and behavioural factors associated with delays in seeking medical care in patient with symptoms of acute stroke. Stroke 37:1248–1253

    Article  PubMed  Google Scholar 

  13. Di Carlo A, Lamassa M, Baldereschi M 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 

  14. Benatru I, Rouaud O, Durier J et al (2006) Stable stroke incidence rates but improved case-fatality 06 in Dijon, France, from 1985 to 2004. Stroke 37:1674–1679

    Article  PubMed  Google Scholar 

  15. Olsen TS, Dehlendorff C, Andersen KK (2007) Sex-related time-dependent variations in post-stroke survival: evidence of a female stroke survival advantage. Neuroepidemiology 29:218–225

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fukuda M, Kanda T, Kamide N, Akutsu T, Sakai F (2009) Gender differences in long-term functional outcome after first-ever ischemic stroke. Intern Med 48:967–973

    Article  PubMed  Google Scholar 

  17. Gray LJ, Sprigg N, Bath PMW, Boysen G, De Deyn PP, Leys D et al (2007) Sex differences in quality of life in stroke survivors. Data from the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST). Stroke 8(11):2960–2964

    Article  Google Scholar 

  18. Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD (1998) Gender-linked brain injury in experimental stroke. Stroke 29:159–166

    Article  CAS  PubMed  Google Scholar 

  19. Toung TJ, Hurn PD, Traystman RJ, Sieber FE (2000) Estrogen decreases infarct size after temporary focal ischemia in a genetic model of type I diabetes mellitus. Stroke 31:2701–2706

    Article  CAS  PubMed  Google Scholar 

  20. Gibson CL, Gray LJ, Murphy SP, Bath PMW (2006) Estrogens and experimental ischemic stroke: a systematic review. J Cereb Blood Flow Metab 26:1103–1113

    Article  CAS  PubMed  Google Scholar 

  21. Gibson CL, Bath PM (2015) Feasibility of progesterone treatment for ischemic stroke. J Cereb Blood Flow Metab 25:431–439

    Article  Google Scholar 

  22. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Makuch R, Horwitz RJ (2001) A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 345:1243–1249

    Article  CAS  PubMed  Google Scholar 

  23. Heyer A, Hasselblatt M, von Ahsen N, Hafner H, Siren AL, Ehrenreich H (2005) In vitro gender differences in neuronal survival on hypoxia in 17B-estradiol-mediated neuroprotection. J Cereb Blood Flow Metab 25:317–321

    Article  Google Scholar 

  24. Li H, Pin S, Zeng Z, Wang MM, Andreasson KA, McCullough LD (2005) Sex differences in cell death. Ann Neurol 58:317–321

    Article  CAS  PubMed  Google Scholar 

  25. Carruth LL, Reisert I, Arnold AP (2002) Sex chromosome genes directly affect brain sexual differentiation. Nat Neurosci 5:933–934

    Article  CAS  PubMed  Google Scholar 

  26. Renolleau S, Fau S, Charriau-Marlangue C (2008) Gender-related differences in apoptotic pathways after neonatal cerebral ischemia. Neuroscientist 14:46–52

    Article  CAS  PubMed  Google Scholar 

  27. Park EM, Cho S, Frys KA, Glickstein SB, Zhou P, Anrather J et al (2006) Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury. J Cereb Blood Flow Metab 26:392–401

    Article  CAS  PubMed  Google Scholar 

  28. Zhu C, Xu F, Wang X, Shibata M, Uchiyama Y, Blomgren K et al (2006) Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischemia. J Neurochem 96:1016–1027

    Article  CAS  PubMed  Google Scholar 

  29. Cordeau P Jr, Lalancette-Herbert M, Weng YC, Krizz J (2008) Live imaging of neuroinflammation reveals sex and estrogen effects on astrocytic response to ischemic injury. Stroke 39:935–942

    Article  CAS  PubMed  Google Scholar 

  30. Sakata A, Mogi M, Iwanami J, Tsukuda K, Min L-J, Fujita T et al (2009) Sex-different effect of angiotensin II type 2 receptor on ischemic brain injury and cognitive function. Brain Res 1300:14–23

    Article  CAS  PubMed  Google Scholar 

  31. Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306:990–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Puyal J, Vaslin A, Mottier V, Clarke PG (2009) Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann Neurol 66:378–389

    Article  CAS  PubMed  Google Scholar 

  33. Towfighi A, Markovic D, Ovbiagele B (2013) Sex differences in revascularization interventions after acute ischemic stroke. J Stroke Cerebrovasc Dis 22:e347–e353

    Article  PubMed  Google Scholar 

  34. Boehme AK, Siegler JE, Mullen MT, Albright KC, Lyerly MJ (2014) Monlezun D, J et al. Racial and gender differences in stroke severity, outcomes, and treatment in patients with acute ischemic stroke. J Stroke Cerebrovasc Dis 23:e255–e261

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kent DM, Price LL, Ringleb P, Hill MD, Selker HP (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 

  36. Kent DM, Buchan AM, Hill MD (2008) The gender effect in stroke thrombolysis: Of CASES, controls and treatment-effect modification. Neurology 71:1080–1083

    Article  CAS  PubMed  Google Scholar 

  37. Lorenzano S, Ahmed N, Falcou A, Mikulik R, Tatlisumak T, Roffe C et al (2013) Does sex influence the response to intravenous thrombolysis in ischemic stroke? Answers from safe implementation of treatments in stroke-international stroke thrombolysis stroke register. Stroke 44:3401–3406

    Article  CAS  PubMed  Google Scholar 

  38. Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM et al (2013) Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44:870–947

    Article  PubMed  Google Scholar 

  39. Group SCotPHSR (1989) Final report on the aspirin component of the ongoing physicians’ health study. Steering committee of the Physicians’ Health Study Research Group. N Engl J Med 321:129–135

    Article  Google Scholar 

  40. Poli D, Antonucci E, Grifoni E, Abbate R, Gensini GF, Prisco D (2009) Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment. Thromb Haemostat 101:938–942

    CAS  Google Scholar 

  41. Bath PMW, Woodhouse L, Scutt P, Krishnan K, Wardlaw JM, Bereczki D et al (2015) Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. Lancet 385(9968):617–628

    Article  CAS  PubMed  Google Scholar 

  42. Woodhouse L, Scutt P, Krishnan K, Berge E, Gommans J, Ntaios G et al (2015) Effect of hyperacute administration (within 6 hours) of transdermal glyceryl trinitrate, a nitric oxide donor, on outcome after stroke: subgroup analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. Stroke 46(11):3194–3201

    Article  CAS  PubMed  Google Scholar 

  43. Bath PMW, Blecic S, Bogousslavsky J, Boysen G, Davis S, Diez-Tejedor E et al (2000) Tirilazad mesylate in acute ischemic stroke - a systematic review. Stroke 31(9):2257–2265

    Article  Google Scholar 

  44. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SA et al (2009) Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40:2244–2250

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li J, McCullough LD (2009) Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab 29:670–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Amiri-Nikpour MR, Nazarbaghi S, Hamdi-Holasou M, Rezaei Y (2015) An open-label evaluator-blinded clinical study of minocycline neuroprotection in ischemic stroke: gender-dependent effect. Acta Neurol Scand 131:45–50

    Article  CAS  PubMed  Google Scholar 

  47. McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD (2005) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 25:502–512

    Article  CAS  PubMed  Google Scholar 

  48. Couturier JY, Ding-Zhou L, Croci N, Plotkine M, Margaill I (2003) 3-Aminobenzamide reduces brain infarction and neutrophil infiltration after transient focal cerebral ischemia in mice. Exp Neurol 184:973–980

    Article  CAS  PubMed  Google Scholar 

  49. Hamby AM, Suh SW, Kauppinen TM, Swanson RA (2007) Use of a poly(ADP-ribose) polymerase inhibitor to suppress inflammation and neuronal death after cerebral ischemia-reperfusion. Stroke 38:632–636

    Article  CAS  PubMed  Google Scholar 

  50. Matsuura S, Egi Y, Yuki S, Horikawa T, Satoh H, Akira T (2011) MP-124, a novel poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor, ameliorates ischemic brain damage in a non-human primate model. Brain Res 1410:122–131

    Article  CAS  PubMed  Google Scholar 

  51. Gibson CL, Gray LJ, Bath PMW, Murphy SM (2008) Progesterone for the treatment of experimental brain injury; a systematic review. Brain 131:318–328

    Article  PubMed  Google Scholar 

  52. Wagner AK, Bayir H, Ren D, Puccio A, Zafonte RD, Kochanek PM (2004) Relationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: the impact of gender, age and hypothermia. J Neurotrauma 21:125–136

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK

    Claire L. Gibson & Raeed Altaee

  2. Stroke, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK

    Philip M. W. Bath

Authors
  1. Claire L. Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip M. W. Bath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raeed Altaee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claire L. Gibson .

Editor information

Editors and Affiliations

  1. Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Paul A. Lapchak

  2. Loma Linda University School of Medicine, Loma Linda, California, USA

    John H. Zhang

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Gibson, C.L., Bath, P.M.W., Altaee, R. (2017). Stroke Sex Differences: From Basic Research to Clinical Trials. In: Lapchak, P., Zhang, J. (eds) Neuroprotective Therapy for Stroke and Ischemic Disease. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-45345-3_30

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-45345-3_30

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-45344-6

  • Online ISBN: 978-3-319-45345-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation