References for this review were identified by searches of MEDLINE between 1969 and April 2005 and references of relevant articles. Many articles were also identified through searches of the author's files. The search terms “estrogen”, “hormone replacement therapy”, “oral contraceptive”, “cerebrovascular accident”, “brain ischemia”, “transient ischemic attack”, and “case control” were used. Abstracts and reports from meetings were also included. Only papers published in English were
ReviewOestrogen and stroke in women: assessment of risk
Introduction
Stroke is the third commonest cause of death in women and a major cause of disability. Each year in the USA, 40 000 more women than men have strokes, partly because women tend to live longer. 61% of stroke deaths in the year 2000 were in women.1 As with cardiovascular disease, stroke occurs at later ages in women than in men; high premenopausal oestrogen concentrations in women are thought to protect against stroke and cardiovascular disease. After the menopause oestrogen concentrations are depleted, and oestrogen replacement has been considered as a potential protective agent against both cardiovascular disease and stroke. However, the synthetic oestrogens in early formulations of oral contraceptives were associated with an increased risk of stroke in young women. The debate over oestrogens continues—whether for postmenopausal replacement or for contraception—as the doses and formulations (oral, transdermal, depot, and intrauterine) evolve. Here, I review the observational and randomised studies on oestrogen and stroke in women and discuss the possible mechanisms of risk.
Section snippets
Oral contraceptives and stroke
The association between ischaemic stroke and oral contraceptive use has been widely studied since the first report was published nearly 40 years ago.2 Although the currently prescribed oestrogen doses are much lower than those in the early formulations, most of the case-control studies have shown a significant increased risk of stroke in users of oral contraceptives (table 1).3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 One of the few studies to cast doubt on the risk with oral contraceptives was a
Hormone therapy and stroke
Observational cohort studies have shown that the risk of heart disease is about 50% lower in women who use oestrogen than in non-users, but specific results for stroke have been less clear (table 2)17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 some studies have reported neutral risk,17, 18, 19, 20, 21, 22, 23, 24, 25 some an increased risk,26 and only one study reported a reduction in risk of stroke with hormone therapy.27 Some studies have reported that hormone therapy was
Oestrogen and stroke risk: mechanisms of action
Oestrogen has many recognised mechanisms of action in many different tissues. Elucidation of these mechanisms might help to explain why oestrogen use increases the risk of stroke in some women. In stroke, these mechanisms include those that affect neurons, glial cells, inflammatory processes, endothelial cells and blood flow, and haemostasis (figure).
Oestrogen has been shown to protect neurons, although the evidence has come mainly from studies in animals. For example, several laboratories have
The role of hormone therapy in stroke prevention for women
Whether stroke-prevention therapies can reduce the risk of stroke in women using hormone therapy is uncertain. Various preventative therapies affect endothelial function and atherosclerosis progression. Examples include platelet antiaggregants, statins, and antihypertensive medications. Regarding platelet antiaggregant therapy, the Women's Health Study showed no effect of hormone therapy, which in this setting was not randomised, on the benefit of stroke-risk reduction for women assigned
Conclusions
According to the WHI results, oestrogen in the form of hormone therapy, with or without a progestagen, increased the risk of stroke in healthy women.34, 35 Apart from one epidemiological study,26 most of the evidence is not consistent with the results of the WHI. Women have become increasingly concerned about hormone therapy since the WHI results were announced. Such concerns might be heightened by the lack of clear understanding of the mechanisms by which hormone therapy increases stroke risk.
Search strategy and selection criteria
References (80)
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Cerebral thrombosis and oral contraceptives: a case-control study
Contraception
(1998) - et al.
Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT)
Lancet
(1998) - et al.
Hormone therapy and the risk of stroke after acute myocardial infarction in postmenopausal women
J Am Coll Cardiol
(2001) - et al.
Cardiovascular effects of 6 months of hormone replacement therapy versus placebo: differences associated with years since menopause
Am J Obstet Gynecol
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Does the type of hormone replacement therapy affect lipoprotein (a), homocysteine, and c-reactive protein levels in postmenopausal women?
Metab Clin Exp
(2005) - et al.
Vascular effects of estrogen in type II diabetic postmenopausal women
J Am Coll Cardiol
(2001) - et al.
Effect of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women
Am J Cardiol
(2002) - et al.
Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial
J Am Coll Cardiol
(2000) - et al.
Effects of hormone replacement therapy on blood coagulation and fibrinolysis in hypertensive and normotensive postmenopausal women
Thromb Res
(2005) - et al.
Postmenopausal hormone replacement therapy increases plasmatic thromboxane beta 2
Int J Cardiol
(2005)
Estrogen replacement therapy, thrombophilia, and atherothrombosis
Metabolism
Heart disease and stroke statistics—2003 Update
Investigation of relation between use of oral contraceptives and thromboembolic disease
BMJ
WHO collaborative study of cardiovascular disease and steroid hormone contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study
Lancet
World Health Organization collaborative study of cardiovascular disease and steroid hormone contraception. Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives: result of an international, multicenter, case-control study
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Case-control study of oral contraceptives and risk of thormboembolic stroke: results from international study on oral contraceptives and health of young women
BMJ
Stroke and use of low-dose oral contraceptives in young women: a pooled analysis of two US studies
Stroke
Stroke in users of low-dose oral contraceptives
N Engl J Med
Oral contraception and stroke: evidence from the Royal College of General Practitioners' oral contraception study
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Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study
BMJ
Risk of ischemic stroke among users of the oral contraceptive pill: The Melbourne Risk Factor Study (MERFS) Group
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Ischemic stroke risk with oral contraceptives: a meta-analysis
JAMA
Risk of stroke in women exposed to low-dose oral contraceptives: a critical evaluation of the evidence
Arch Intern Med
Risk of arterial thrombosis in relation to oral contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke
Stroke
Prothrombotic conditions, oral contraceptives and the risk of ischemic stroke
Neurology
Factor V gene mutation is a risk factor for cerebral venous thrombosis
Thromb Haemost
The role of estrogens as a risk factor for stroke in post-menopausal women
West J Med
Hormone replacement therapy and the risk of stroke
Arch Intern Med
Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy
Stroke
Hormone replacement therapy and stroke risk in older women
J Womens Health
Hormone replacement therapy and risk of non-fatal stroke
Lancet
A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease
Ann Intern Med
Hormone replacement therapy and associated risk of stroke in postmenopausal women
Arch Intern Med
Estrogen use and stroke risk in postmenopausal women
Am J Epidemol
Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50
N Engl J Med
Decreased risk of stroke among postmenopausal hormone users: results from a national cohort
Arch Intern Med
Lifestyle factors and risk of cerebrovascular disease in women: the Copenhagen City Heart Study
Stroke
Increased risk of stroke in hypertensive women using hormone therapy
Arch Neurol
Postmenopausal estrogen and progestin use and the risk of cardiovascular disease
N Engl J Med
Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS)
Circulation
Cited by (42)
Sex and stroke risk factors: A review of differences and impact
2024, Journal of Stroke and Cerebrovascular DiseasesContraception in obese older women
2012, MaturitasCitation Excerpt :Risk of stroke rises with both age and obesity in women although the absolute risk is still extremely low in women of reproductive age. A significantly increased risk of ischaemic stroke has been consistently observed in users of oral combined pills compared to non-users [44]. Again, the absolute risk of stroke in CHC users is low with only an additional 4.1 ischaemic strokes per 100,000 non-smoking, normotensive women using low-dose combined pills [45].
Mendelian randomization study and meta-analysis exploring the causality of age at menarche and the risk of intracerebral hemorrhage and ischemic stroke
2023, CNS Neuroscience and TherapeuticsIschemic stroke on hormonal contraceptives: Characteristics, mechanisms and outcome
2021, European Stroke JournalAcute Cerebrovascular Accidents and Gender
2018, Neuroscience and Behavioral PhysiologyThe risk factors and epidemiologic characteristics of stroke in women in the Tyumen Region
2018, Profilakticheskaya Meditsina