Editors: Norris, John W.; Hachinski, Vladimir
Title: Stroke Prevention, 1st Edition
Copyright 2001 Oxford University Press
> Table of Contents > I - Primary Prevention > 8 - Hormones and Stroke Prevention
function show_scrollbar() {}
8
Hormones and Stroke Prevention
Diana B. Petitti
The belief that use of estrogenic hormones by postmenopausal women prevents coronary artery disease is widespread. It is often assumed that if hormone replacement therapy prevents coronary disease, it will prevent stroke.
Sex differences in stroke incidence and mortality, studies of estrogen experimental stroke in animals, and studies of the effects exogenous hormones on the mediators of stroke provide information pertinent to this issue. Data on these topics, as well data from randomized trials and observational epidemiology, are reviewed in this chapter. Although epidemiologic studies show that use of combined estrogen/progestin oral contraceptives does not prevent stroke and probably increases the risk of ischemic and hemorrhagic stroke in some women, the chapter also reviews recent information on this topic.
Stroke Incidence and Mortality in Men and Women
The incidence of stroke is higher in men than women.1,2 Figure 8.1, which summarizes data on stroke incidence from the WHO MONICA study, 1 shows that this is true throughout the world. Table 8.1 shows that stroke mortality is also higher in men than women, at least up to age 85. While the data this table are from the United States, they consistent with data other settings.
FIGURE 8.1. Age-standardized stroke incidence rates in men and women by country, WHO Monica Project. Source: Thorvaldsen et al. Stroke incidence, case fatality, and mortality in the WHO Monica Project. Stroke 1995;26:361 367 . Rates from multiple sites in one country were averaged |
P.138
Higher rates of cigarette smoking or diabetes, more poorly controlled blood pressure, or other lifestyle factors could explain the difference in stroke incidence and mortality between men and women. However, the fact that relationship between male sex and a higher stroke risk (or female lower stroke risk) holds in so many different geographic settings suggests that sex differences endogenous hormones may be responsible for at least some of the difference.
TABLE 8.1. Stroke Mortality Rate/100,000 for Men and Women in the United States by Race and Age | |||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
P.139
Animal Studies of Estrogen and Stroke Outcome
Young adult female rats and gerbils have lower mortality less cerebral ischemia than males after experimental occlusion of the cerebral arteries that produces stroke. 3,4 The protection against experimental ischemic brain injury disappears after reproductive senescence in middle-aged female rats. 5 Ovariectomy young female rats increases infarct size after experimental cerebral occlusion, 6 and administration of exogenous estradiol decreases ischemic injury in both old and young animals, 5,6,7 with a therapeutic window of three hours. 7 The mechanism of protection from injury was found to be independent blood flow in two different experiments.5,7 This line of research raises the tantalizing possibility that exogenous estrogen might prevent death and disability after stroke, even if estrogen does not decrease the incidence of stroke.
Effects of Exogenous Estrogen and Estrogen/Progestin Combinations on the Mediators of Stroke
The mechanisms of stroke are not completely understood. Glucose metabolism, blood pressure, coagulation and fibrinolysis, the interaction of platelets the endothelium, and the renin-angiotensin-aldosterone system all may play a role in the development of stroke. Some these factors may also modify extent of damage following stroke. Lipid levels may affect stroke risk directly or indirectly through their effects on coagulability and platelet function.
For both stroke and coronary disease, the distinctions between atherogenesis and thrombosis are being replaced by integrated models of vascular function. The complexity of the mechanisms stroke and the incompleteness our understanding of stroke pathogenesis complicate the interpretation information on the effect of exogenous hormones on factors that mediate stroke.
Estrogen and Estrogen/Progestin Combinations in Postmenopausal Women
The literature on the effect of exogenous estrogen and estrogen/progestin combinations on potential mediators of stroke in postmenopausal women is vast. Table 8.2 summarizes five recent particularly well-conducted studies of this topic.8,9,10,11,12
Postmenopausal estrogen and estrogen/progestin combinations decrease fasting serum glucose and insulin levels do not affect blood pressure. Studies are consistent in showing a favorable effect of the combined estrogen/progestin therapies currently in widespread use on levels of total cholesterol and highdensity and low-density lipoprotein cholesterol levels, but they increase triglycerides. The effect of combined therapy on lipids is generally less than that estrogen alone. That is, the combination therapies are generally more lipid neutral than estrogen alone.
TABLE 8.2. Effects of Postmenopausal Estrogen and Estrogen/Progestin Combinations on Proven and Possible Mediators of Stroke Risk | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
P.140
The effects of postmenopausal estrogen and estrogen/progestin combinations on factors that affect coagulation and measures of fibrinolysis are complex. Summarizing the data, estrogens, and probably also postmenopausal estrogen/progestin combinations, enhance both coagulability and fibrinolysis.
Considering these effects, postmenopausal estrogen and estrogen/progestin combinations might be predicted to increase, decrease, or have no effect on the occurrence of stroke. The net effect of estrogens and estrogen/progestin combinations might be different for ischemic than for hemorrhagic stroke. That is, the data on the effects of postmenopausal hormones mediators stroke are compatible with any observed effect on stroke incidence, and they are compatible with effects on the incidence of hemorrhagic stroke that are different from those on ischemic stroke.
Estrogen/Progestin Combinations as Oral Contraceptives
The literature on the effects of oral contraceptives potential mediators of stroke risk in postmenopausal women is also vast. Table 8.3 summarizes the conclusions
P.141
TABLE 8.3. Effects of Combined Low Estrogen Dose (<50 Micrograms) Oral Contraceptives on Proven and Possible Mediators of Stroke Risk Whether the Type of Progestin Modifies the Effect (adapted from refs. 13,14,15) | ||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
For oral contraceptives, much attention has been paid to their effects on factors that predispose to venous thromboembolic disease. These data are also difficult to interpret, although there is an emerging consensus that combined estrogen/progestin oral contraceptives may cause thromboembolism in women with resistance to activated protein C, a hereditary thrombophilia, and perhaps in women with other inherited thrombophilias. Winkler15 discusses in detail the data on thrombophilia and oral contraceptives the many theories about why they increase the risk of venous thrombosis.
Hormone Replacement and Carotid Thickness
The Cardiovascular Health Study11 reported on the results of a cross-sectional analysis of ultrasound assessment carotid artery thickness and percent stenosis in relation to postmenopausal hormone use. The study involved 2955 women 65 or more years of age at the time the ultrasound assessment at entry to study. Of these women, 356 were current users of estrogen or estrogen/progestin
P.142
TABLE 8.4. Ultrasound Assessment of Carotid Intimal-Medial Thickness and Percent Carotid Stenosis in Estrogen Users and Nonusers in the Cardiovascular Health Study (ref 11) | |||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Table 8.4 summarizes the results of this cross-sectional analysis. Common and internal carotid thicknesses were both statistically significantly less in current hormone users than in noncurrent users. The percentage of current hormone users with 50% or more stenosis of the carotid artery (1.8%) was significantly less than in noncurrent users (5.6%). The association of current estrogen use with a thinner common carotid wall persisted after adjustment for age, hysterectomy, race, income, smoking, fasting glucose, factor VII, and use of lipid-lowering medication. The association of current estrogen use with a thinner carotid artery wall was attenuated by further adjustment for high-density and low-density lipopro-tein cholesterol levels. The authors interpreted this as evidence that the benefits of hormone replacement act through their effects on lipid levels.
Randomized Trials of Postmenopausal Hormone Replacement Therapy
The Hormone Estrogen/Progestin Replacement Study (HERS) was a randomized, blinded, placebo-controlled study that involved 2763 postmenopausal women with coronary disease that was specifically designed to assess the effect of hormone replacement therapy on cardiovascular disease endpoints. 16 Women were assigned to placebo or to 0.625 milligrams of conjugated equine estrogen plus 2.5 milligrams of medroxyprogesterone acetate as a continuous combined regimen. After an average of 4.1 years follow-up, 108 of the 1380 women assigned to estrogen/progestin therapy and 96 of the 1383 women assigned placebo had a stroke or transient ischemic attack (TIA). The relative risk of ischemic stroke plus TIA in women assigned to hormone use was 1.13 (95% CI 0.85 1.48).
P.143
Hemminki and McPherson17 extracted data on cardiovascular disease from 22 published randomized trials of postmenopausal estrogen replacement therapy that were conducted to assess outcomes other than cardiovascular disease and did a meta-analysis of these data. The 22 trials identified for the meta-analysis involved more than 4000 women who had been assigned to hormone replacement or to placebo and to no treatment or vitamins minerals. The odds ratio for all cardiovascular disease in women assigned to hormone therapy was 1.39 (95% CI 0.48 3.95). The meta-analysis did not present data on the rate or risk of stroke in hormone users.
Hemminki and McPherson's meta-analysis excluded a large randomized trial (1265 subjects) reported by Speroff et al.18 that compared estradiol alone, estradiol plus norethindrone acetate as continuous combined therapy, or placebo alone. No data on stroke were presented in the only publication from this study.
The Women's Health Initiative is an on-going randomized trial that was also designed specifically to address the effect of postmenopausal estrogen only and estrogen/progestin therapy on cardiovascular endpoints. 19 Data stroke inci-dence and mortality are not yet available.
Observational Studies of Hormone Replacement Therapy
A number of observational epidemiologic studies have been performed specifically to assess the effect of postmenopausal hormone replacement therapy and the risk of stroke. Other studies provide data on the stroke but were not done specifically to address this topic. Table 8.5 describes the overall designs of the studies that provide data on postmenopausal hormone replacement therapy and the risk of stroke.20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44
The observational studies that provide data on hormone replacement therapy and stroke varied in the degree to which they used rigorous definitions of and included review to confirm cases. Some prospective studies ascertained hormone use only at entry to the study, and the results thus pertain ever having used of hormone replacement therapy, an exposure variable that is difficult to interpret. Some cohort studies included women with a past history of stroke at entry. Some studies did not control for potential confounders, the most important being hypertension, diabetes, and cigarette smoking, which are known to differ between hormone users and nonusers are also strong risk factors for stroke. Some studies can be inferred to pertain only use of estrogen alone because of the era in which they were conducted, and some present estimates of the risk of stroke separately in users of estrogen and estrogen/progestin combination. However, for many studies, the exact hormone regimen used by women in the study cannot be determined. The data in the next tables should interpreted recognizing these limitations.
TABLE 8.5. Summary of Studies that Provide Estimates of the Relative Risk of Stroke in Users of Postmenopausal Hormone Replacement Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
P.144
P.145
Table 8.6 shows the results of the eight studies that provided an estimate risk for all fatal and nonfatal stroke in users of hormone replacement therapy. Three studies provided an estimate of the risk of stroke separately in current and past hormone users. All three studies were rigorous, had clear case definitions, and controlled for hypertension, diabetes, and smoking. The relative risk estimates from these studies were all very close to 1.0 in current hormone users. The studies showed that an effect of hormone use, if there is an effect, does not persist after cessation of use.
Table 8.7 shows the results of the nine studies that provided an estimate risk of ischemic stroke only in users hormone replacement therapy. Six studies provided an estimate of the risk of ischemic stroke separately in current hormone users and three provided an estimate in past users. All six studies that provided risk estimates in current users had clear case definitions and case review, were limited to first-ever stroke, and controlled for hypertension, diabetes, and smoking. In four of the six studies, the relative risk of ischemic stroke was higher in current users of hormone replacement therapy than nonusers. The four largest studies included more than 1500 women with ischemic stroke. All four studies reported relative risk estimates for ischemic stroke that were greater than 1.0, although the 95% CIs included 1.0 in all studies except Nurses' Health Study. The estimated relative risks of ischemic stroke in past users of hormone replacement therapy were close to 1.0 in all three studies that estimated risk in past hormone users.
Table 8.8 shows the results of the seven studies that provided an estimate the risk of hemorrhagic stroke only in users of hormone replacement therapy. Four studies were limited to subarachnoid hemorrhage. Five studies provided an estimate of the risk of hemorrhagic stroke separately in current hormone users and two provided an estimate in past users. The results of these studies were extremely heterogenous. Risk estimates for hemorrhagic stroke in current users of replacement hormone therapy ranged from 0.33 to 1.6. Even the three largest studies, all well-conducted, were contradictory, with risk estimates for hemorrhagic stroke in current users of hormone replacement therapy 0.38, 0.90, and 1.00. No conclusion about the effect of current use of hormone replacement therapy on the risk of hemorrhagic stroke can be drawn.
Table 8.9 shows the results of the nine studies that provided an estimate risk of fatal stroke in users hormone replacement therapy. Data on are of particular interest because of the findings in animal studies. Four studies provided an estimate of the risk of fatal stroke separately in current hormone users and three provided an estimate in past users. Unfortunately, these studies often did not include clear definitions of what qualified as a fatal stroke and did not include case review. The results were heterogenous. estimated relative risks of fatal stroke in current users hormone replacement therapy ranged from 0.16 to 0.95. On the other hand, the risk estimates for current use were all less
P.146
P.147
P.148
P.149
P.150
TABLE 8.6. All Stroke: Estimated Relative Risk in Users of Postmenopausal Hormone Replacement Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
TABLE 8.7. Ischemic Stroke: Estimated Relative Risk in Users of Postmenopausal Hormone Replacement Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
TABLE 8.8. Hemorrhagic Stroke: Estimated Relative Risk in Users of Postmenopausal Hormone Replacement Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
TABLE 8.9. Fatal Stroke: Estimated Relative Risk in Users of Postmenopausal Hormone Replacement Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Randomized Trials of Exogenous Estrogen and Stroke in Men
The Coronary Drug Project was a.large, randomized trial of lipid-lowering drugs in men with coronary disease that included two estrogen treatment arms, conjugated equine estrogen, at two doses, 2.5 and 5.0 milligrams. Data on the incidence of fatal stroke were presented in the publication about the results from 2.5 milligram treatment arm.45 Data on estrogen and fatal stroke also were presented in a publication about the results of randomized trials the Veterans Administration (VA) Cooperative Prostate Cancer Treatment trial.46
Table 8.10 shows that in the Coronary Drug Project the rate of fatal stroke was slightly lower in men treated with 2.5 milligrams of estrogen. In contrast, the VA Cooperative Study, the rate of fatal stroke in men treated with 5.0 milligrams of diethylstilbestrol was elevated substantially. The number of fatal strokes small in both studies. The dose of estrogen used the VA trial was very large. The studies do not provide evidence that estrogen prevents fatal stroke, but they do not out rule out this possibility.
Combined Estrogen/Progestin Oral Contraceptives and Stroke
Since oral contraceptives were first marketed in the early 1960's, the dose of both estrogen and progestin has decreased markedly. Early studies of stroke oral contraceptive use are consistent in finding an increased risk of ischemic stroke in current oral contraceptive users, but these studies are not relevant to oral contraceptive formulations now in widespread use.
Early studies on the relationship between oral contraceptives and hemorrhagic stroke are inconsistent. The unavailability and infrequency of use of radiologic tests (CT and MRI scans) that would distinguish between ischemic and hemorrhagic stroke makes these early studies difficult to interpret, and elevations in the risk of hemorrhagic stroke might be due to misclassification ischemic stroke as hemorrhagic because of presentation with headache.
Table 8.11 summarizes the results of four recent large studies stroke and oral contraceptive use in which a high percentage of cases had CT or MRI scan to define the type of stroke.47,48,49,50,51 Importantly, these studies also assessed smoking and hypertension as possible confounders and effect modifiers.
The two studies done in the United States47,48 found no overall increase risk of ischemic stroke in current oral contraceptive users. Both the WHO study49,50
P.151
P.152
TABLE 8.10. Effect of Estrogen on Fatal Stroke in Randomized Trials in Men | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
TABLE 8.11. Summary of Four Studies of Stroke Risk in Current Users of Combination Oral Contraceptives | |||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
The U.S. studies found either no increase in the risk of hemorrhagic stroke current oral contraceptive users or only a small increase.47,48 The WHO study reported a relative risk of hemorrhagic stroke in current oral contraceptive users of 1.8 (95% CI 1.3 2.3) in developing countries and 1.4 0.8 2.3) European countries. 50
The WHO study had a sufficiently large number of subjects to assess in detail the degree to which hypertension, smoking, age, and estrogen dose modified the effect of current oral contraceptive use for stroke. Table 8.12 shows estimates the relative risk of ischemic and hemorrhagic stroke in current oral contraceptive users according to hypertension, smoking, age, and estrogen dose from the WHO study. The relative risks of both ischemic and hemorrhagic stroke were dramatically higher in current oral contraceptive users with hypertension than current oral contraceptives without hypertension. The relative risks of both ischemic and hemorrhagic stroke were also higher in current oral contraceptive users who smoked than in current users who did not smoke, but the magnitude of the difference in the risk of stroke between the current users who smoked and did not smoke was less than for women with and without hypertension.
In the European centers of the WHO study, higher estrogen dose oral contraceptives were associated with a higher risk of ischemic, but not hemorrhagic, stroke. The relative risks of hemorrhagic stroke in current oral contraceptive users who did not have hypertension, in non-smokers, and in women less than 35 years of age all were 1.1 1.4. In the European centers, the relative risk of ischemic stroke in current users of low-estrogen oral contraceptives was 1.36. The latter risks from the WHO study are about same as the overall relative risks of hemorrhagic stroke and ischemic stroke in current oral contraceptive users the two U.S. studies. In both U.S. studies, current use of oral contraceptives in women with hypertension and in women more than 35 years of age was rare, and the
P.153
P.154
TABLE 8.12. Estimated Relative Risk of Stroke in Current Oral Contraceptives Users by Presence or Absence of Hypertension, Smoking, Age >35, and Estrogen Dose: WHO Collaborative Study | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Summary and Conclusions
Stroke incidence and mortality are higher in men than women, suggesting that hormonal factors may influence the development of stroke or its outcome. Studies in rats show that endogenous and exogenous estrogen affect the extent of ischemic injury after experimental occlusive stroke, suggesting a possible effect of estrogen in preventing death and disability following stroke.
Exogenous estrogen and estrogen/progestin combinations affect a number of factors that may mediate the occurrence of stroke in postmenopausal women. The net effect of the complex changes on stroke risk in the whole animal cannot be predicted. The possibility that the net effect might be to decrease risk of stroke cannot be ruled out.
The only randomized trial that has provided data on the effect of postmenopausal hormones on the risk of stroke in women showed no effect of combined estrogen/progestin therapy on the risk of a combined endpoint of ischemic stroke plus TIA. Observational studies of postmenopausal hormones and stroke, taken as a whole, show no decrease in the risk of ischemic stroke current users. Observational studies on the effect of hormone replacement therapy hemorrhagic stroke are inconsistent, and no firm conclusion can be drawn from them. Epidemiologic studies confined to fatal stroke do not rule out the possibility that estrogen might decrease the risk of death following stroke, as suggested by animal studies.
The body of evidence on low-estrogen and combined estrogen/progestin oral contraceptives and stroke shows that current oral contraceptive use does not increase the risk of stroke in young women who do not have hypertension and do not smoke.
References
1. Thorvaldsen P, Asplund K, Kuulasmaa et al. Stroke incidence, case fatality, and mortality in the WHO MONICA project. Stroke 1995;26:361 367.
2. Alter M, Shang ZX, Sobel E, et al. Standardized incidence ratios of stroke: A worldwide review. Neuroepidemiology 1986;5:148 158.
3. Alkayed NH, Harukuni I, Kimes AS, et al. Gender-linked brain injury in experimental stroke. Stroke 1998;29:159 165.
P.155
4. Hum PD, Alkayed NJ, Tong TJK. Female vs. male: Injury in experimental stroke. In: Crieglstein J, ed. Pharmacology of Cerebral Ischemia. Stuttgart, Germany: Medpharm Scientific Publishers, 1998.
5. Alkayed NJ, Murphy SJ, Traystman RJ, et al. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 2000;31:161 168.
6. Fukuda K, Yao H, Ibayashi S, et al. Ovariectomy exacerbates and estrogen replacement attenuates photothrombotic focal ischemic brain injury in rats. Stroke 2000;31: 155 160.
7. Yang SH, Shi J, Day AL, et al. Estradiol exerts neuroprotective effects when administered after ischemic insult. Stroke 2000;31:745 749.
8. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199 208.
9. Nabulsi AA, Folsom AR, White A, et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993;328:1069 1075.
10. Koh KK, Mincemoyer R, Bui MN, et al. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997;336:683 690.
11. Manolio TA, Furberg CD, Shemanski L, et al. Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. Circulation 1993;88:2163 2171.
12. Caine YG, Bauer KA, Barzegar S, et al. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992;68:392 395.
13. Crook D, Godsland I. Safety evaluation of modern oral contraceptives. Effects on lipoprotein and carbohydrate metabolism. Contraception 1998;57:189 201.
14. Winkler U. Blood coagulation and oral contraceptives. Contraception 1998;57:203 209.
15. WHO Scientific Group. Cardiovascular disease and steroid hormone contraception: Report of a WHO scientific group. WHO technical report series 877. Geneva, Switzerland, 1997.
16. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605 613.
17. Hemminki E, McPherson K. Impact of postmenopausal hormone therapy on cardiovascular events and cancer: Pooled data from clinical trials. BMJ 1997;315:149 153.
18. Speroff L, Rowan J, Symons et al. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART Study). JAMA 1996;276:1397 1403.
19. The Women's Health Initiative Study Group. Design of the Initiative clinical trial and observational study. Controlled Clin Trials 1998;19:61 109.
20. Pfeffer RI, Van Den Noort S. Estrogen use and stroke risk in postmenopausal women. Am J Epidemiol 1976;103:445 456.
21. Rosenberg SH, Fausone V, Clark R. The role of estrogens as a risk factor for stroke in postmenopausal women. West J Med 1980;133:292 296.
22. Adam S, Williams V, Vessey MP. Cardiovascular disease and hormone replacement treatment: A pilot case-control study. BMJ 1981;282:1277 1278.
23. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50: The Framingham Study. N Engl J Med 1985;313:1038 1043.
P.156
24. Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: Results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987;75:1102 1109.
25. Petitti DB, Wingerd J, Pellegrin F, et al. Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150 1154.
26. Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: Longterm follow-up of women in the Walnut Creek Study. Obstet Gynecol 1987;70:289 293.
27. Boysen G, Nyboe J, Appleyard M, et al. Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Stroke 1988;19:1345 1353.
28. Lindenstrom E, Boysen G, Nyboe J. Lifestyle factors and risk of cerebrovascular disease in women: The Copenhagen City Heart Study. Stroke 1993;24:1468 1472.
29. Hunt K, Vessey M, McPherson et al. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynaecol 1987;94:620 635.
30. Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users hormone replacement therapy: An updated analysis. Br J Obstet Gynaecol 1990;97:1080 1086.
31. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: A prospective study. BMJ 1988;297:519 522.
32. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991;151:75 78.
33. Wolf PH, Madans JH, Finucane FF, et al. Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: Evidence from a national cohort. Am J Obstet Gynecol 1991;164:489 494.
34. Finucane FF, Madans JH, Bush TL, et al. Decreased risk of stroke among postmenopausal hormone users: Results from a national cohort. Arch Intern Med 1993; 153:73 79.
35. Longstreth WT, Nelson LM, Koepsell TD, et al. Subarachnoid hemorrhage and hormonal factors in women: A population-based case-control study. Ann Intern Med 1994;121:168 173.
36. Folsom AR, Mink PJ, Sellers TA, et al. Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am J Public Health 1995;85:1128 1132.
37. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453 61.
38. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. EnglJ Med 1997;336:1769 1775.
39. Pedersen AT, Lidegaard O, Kreiner S, et al. Hormone replacement therapy and risk of non-fatal stroke. Lancet 1997;350:1277 1283.
40. Petitti DB, Sidney S, Quesenberry CP Jr, et al. Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy. Stroke 1998;29:23 28.
41. Sourander L, Rajala T, Raiha I, et al. Cardiovascular and cancer morbidity mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 1998;352:1965 1969.
42. Fung MM, Barrett-Connor E, Bettencourt RR. Hormone replacement therapy and stroke risk in older women. J Womens Health 1999;8:359 364.
P.157
43. Falkeborn M, Persson I, Terent A, et al. Hormone replacement therapy and the risk of stroke: Follow-up of a population-based cohort in Sweden. Arch Intern Med 1993;153:1201 1209.
44. Grodstein F, Stampfer MJ, Falkeborn M, et al. Postmenopausal hormone therapy and risk of cardiovascular disease and hip fracture in a cohort Swedish women. Epidemiology 1999; 10:476 480.
45. The Coronary Drug Project Research Group. The Project: Findings leading to discontinuation of the 2.5-mg day estrogen group. JAMA 1973;226:652 657.
46. The Veterans Administration Co-operative Urological Research Group. Treatment and survival of patients with cancer the prostate. Surg Gynecol Obstet 1967;124:1011 1017.
47. Petitti DB, Sidney S, Bernstein A, et al. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996;335:8 15.
48. Schwartz SM, Siscovick DS, Longstreth WT Jr., et al. Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med 1997;127:596 603.
49. 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 1996;348:498 505.
50. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: Results of an international, multicentre, case-control study. Lancet 1996;348:505 510.
51. Heinemann LAJ, Lewis MA, Thorogood M, et al. Oral contraceptives and risk of thromboembolic stroke: Results for the Transnational Study on Oral Contraceptives and the Health of Young Women. BMJ 1997;315:1502 1504.