Hormone replacement therapy and stroke: risk, protection or no effect?

Maturitas 38 (2001) 243– 261 www.elsevier.com/locate/maturitas

Invited Review

Hormone replacement therapy and stroke: risk, protection or no effect? Annlia Paganini-Hill * Department of Pre6enti6e Medicine, Keck School of Medicine of the Uni6ersity of Southern California, Los Angeles, CA 90089 -9175, USA Received 14 November 2000; accepted 18 January 2001

Abstract Despite declining death rates due to stroke over the last several decades, stroke remains the third leading killer (after heart disease and cancer) of women in most developed countries. Because stroke not only kills but also leaves many survivors mentally and physically impaired, control of the disease must be through primary prevention. Several observations lead to the speculation that estrogen may reduce stroke risk. This paper reviews the epidemiologic studies that have evaluated the association of hormone replacement therapy (HRT) and stroke. In the past 25 years, 29 studies have produced no conclusive evidence of a beneficial effect. The lack of consistency in stroke endpoints, definition of HRT user, estrogen preparation, and influence of combined regimen might account in part for the unclear relationship. Nonetheless, the preponderance of evidence suggests that HRT does not increase stroke risk. Some data indicate that estrogen users have a moderately reduced risk of fatal stroke, but details about the optimal dose, duration and type of estrogen are insufficient. The apparent difference in the findings of studies of fatal and non-fatal stroke suggests that estrogen may prevent the most lethal form of stroke or may improve survival. Additional data from ongoing randomized clinical trials in the coming years may help resolve the question of the effect of HRT on stroke morbidity and mortality. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hormone replacement therapy; Stroke; Risk; Protection; Estrogen replacement therapy

1. Introduction

* Corresponding author. Present address: 842 Manzanita Drive, Laguna Beach, CA 92651-1960, USA. Tel.: +1-9493761842; fax: + 1-949-6231222, ext. 7767. E-mail address: [email protected] (A. Paganini-Hill).

One of six American women will die from stroke [1,2]. Despite declining death rates due to stroke over the last several decades, stroke remains the third leading killer (after heart disease and cancer) of women in the USA and most developed countries. Because the size of the el-

0378-5122/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0378-5122(01)00167-0

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derly population is growing and stroke incidence doubles every 10 years after age 55 [3], the absolute number of strokes and deaths from stroke in women increases each year. Not only does stroke kill, it leaves many survivors (over half of them female [4]) mentally and physically impaired. Stroke is the major cause of serious, long-term disability [4]. It is the second leading cause of dementia (after Alzheimer’s disease), but it ranks first in very old women [5]. In addition, more than 30% of stroke patients suffer from depression, with an increased risk in women [6,7]. Millions of postmenopausal women use hormone replacement therapy (HRT) — either unopposed estrogen replacement therapy (ERT) or combined estrogen+progestin therapy (CHRT) [8]. In a recent national sample in the USA, nearly 40% of postmenopausal women aged 50– 74 years were current HRT users [9]. Although ERT has been available for 50 years, the indications for use have gradually widened from relief of current menopausal symptoms to prevention of future osteoporotic fractures or coronary heart disease (CHD). Several observations lead to the speculation that estrogen may reduce stroke risk: “ Stroke and CHD share many risk factors, and CHD itself doubles risk of stroke [10,11]. “ Surgical removal of the ovaries may increase risk of both CHD and cerebrovascular disease [12]. “ Men suffer heart attacks and strokes an average of 10 years earlier in life than women do, but as women approach menopause, their risk begins to rise and the ratio of stroke rates between men and women grows smaller with age and disappears among older (\80 years) adults [3,4,10]. “ In epidemiological studies, ERT users have a 35% reduction in risk of CHD [13,14]. Together, these findings suggest that estrogen may reduce stroke risk through modification of intervening risk factors in the same way as it lowers risk of CHD. Since stroke is a significant cause of morbidity and mortality in postmenopausal women, any association between HRT and stroke risk would

greatly affect the public’s health. The present paper reviews new knowledge of the potential effects of HRT on stroke risk factors and on incidence and mortality from stroke in postmenopausal women.

2. Stroke subtypes Stroke is a heterogeneous group of diseases which can be classified by their pathology as ischemic (70%), hemorrhagic (27%), or other etiologies (3%) [15]. The mechanism of ischemia and the site of the vascular lesion can differentiate ischemic infarction as large vessel atherothrombotic (10% of all strokes), lacunar (19%), cardioembolic (14%), or undetermined origin (28%). Hemorrhagic strokes can be divided about equally into subarachnoid hemorrhage (SAH) and intracerebral hemorrhage, depending on the site and origin of the blood.

3. HRT and stroke risk factors The three major stroke risk factors — hypertension, diabetes and smoking — are shared by men and women [16–20]. Estrogen may affect or be affected by these conditions so they are particularly relevant to postmenopausal women. Hypertension is the dominant stroke risk factor for all stroke subtypes in both men and women [16–20]. However, while a greater percentage of men younger than 60 years have high blood pressure, after age 60 more women than men are affected [21]. Nonetheless, in both sexes, the benefit of lowering blood pressure for primary stroke prevention is overwhelming [22,23]. Until recently, HRT was considered contraindicated for postmenopausal women with hypertension. However, the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial found no evidence that HRT (either unopposed estrogen or estrogen+ progestin) increases blood pressure in postmenopausal women [24]. Diabetes is an independent risk factor for ischemic stroke, increasing risk two to four times [10,17,25,26]. However, diabetes is both more

A. Paganini-Hill / Maturitas 38 (2001) 243–261

prevalent and a stronger risk factor in women than men [4,26]. If women have diabetes before menopause, it destroys their lower risk advantage compared with men [4]. Stroke risk also increases with worsening glucose intolerance category (mildly elevated blood sugar, asymptomatic hyperglycemia, diabetes) [27] and with increased insulin resistance/hyperinsulinemia among subjects with normal glucose status [28]. In the PEPI Trial, postmenopausal women taking oral ERT or CHRT had increased 2-h glucose levels compared with placebo group [24]. Fasting insulin and glucose levels were lower in women assigned active treatment in this and other trials [29,30] as were fasting insulin levels in women treated with transdermal estrogen [30]. The beneficial effect of HRT on fasting insulin (a marker for insulin resistance) and carbohydrate metabolism might decrease risk of ischemic stroke. Cigarette smoking nearly doubles risk of ischemic stroke and triples risk of SAH, with a higher risk among women than men [19,31]. Risk increases with increasing number of cigarettes smoked, and smoking cessation leads to a reduction in stroke risk. Women who smoke have an earlier age at natural menopause [32,33] and lower estrone and estradiol levels after receiving ERT than nonsmokers [33]. Serum cholesterol may be another risk factor for stroke although the relationship is unclear and data on women scant. A meta-analysis of 45 prospective epidemiologic studies [34] and a pooled analysis of 11 cholesterol-lowering trials [35] found no effect on stroke. However, some observational studies and clinical trials in men suggest a protective effect of lower cholesterol levels on ischemic stroke [35– 37] and an increased risk of hemorrhagic stroke [17,18,37]. Several randomized clinical trials have shown that oral administration of estrogen (with or without progestin) reduces LDL and total cholesterol levels and increases HDL, principally HDL2, cholesterol levels in postmenopausal women [24,29,38,39]. Transdermal estrogen, however, has little effect on lipoprotein levels [38]. Thus the beneficial action of oral estrogens on lipids, and subsequently on atherosclerosis, may reduce risk of ischemic stroke.

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4. HRT and stroke The relationship between HRT and stroke risk has been of longstanding interest. In the past 25 years, 29 observational studies (in 42 articles) have evaluated the effect of HRT on stroke risk in postmenopausal women. Earlier summaries of the literature on estrogen and stroke concluded there was little if any association [14,40]. Grady et al. [14] derived a summary relative risk (RR) of stroke in ERT users of 0.96 (95% CI, 0.82 to 1.13), but pointed out evidence of statistical heterogeneity among the 15 studies. Three study designs have been used: (1) casecontrol studies comparing estrogen use among women with stroke to those without stroke [41– 48]; (2) uncontrolled cohort studies comparing the stroke rate in estrogen users to that in the general population [49–55]; and (3) internally controlled cohort studies comparing the stroke rate among estrogen users to that of nonusers in the same sample [56–80]. Tables 1–3 summarize the articles on HRT and stroke risk and are grouped by study design. The tables describe for each study the population examined, the definition of stroke used, the number of stroke cases, the number of controls or size of the cohort, the frequency of HRT in the controls or cohort, and the RR estimates for ever use (or if not reported, current use) of HRT. These studies reveal no clear and consistent association between HRT and stroke. All five case-control studies examining the relationship of HRT and risk of all stroke or ischemic stroke reported essentially null effects, with relative risks ranging from 1.0 to 1.2 [42,43,45,47,48]. The four uncontrolled cohort studies [50,51,53,55] found a 20–50% reduced risk of stroke among estrogen users, which was statistically significant in two [53,55]. Ten [56,58,60,61,63,65,68,76– 78] of the 16 internally controlled cohort studies found a 30% or greater reduction in stroke risk among estrogen users, which was significant in five [56,61,63,65,68]. Another found a moderate but significant 20% lower risk [80]. One found a statistically significant increased risk [59], and another four no overall effect of estrogen [70,71,75,79]. The relative risks for total stroke (principally

246

Table 1 Case-control studies of HRT and stroke Relative risk

210

430-8 F+NF

1.12

1245 736 42 147 73

257 152 9 29 16

430-8 F+NF Non-embolic infarction Embolic infarction Hemorrhagic infarction TIA

0.97 1.13 0.49 0.86 2.79

18a

396

198

Occlusive cerebrovascular disease hospital discharge

1.16

SAH F

0.64c

Population

% HRT in controls

No. of controls

1. Pfeffer (1976) [41]

CA retirement community

27

1034

29

Pfeffer (1978) [42]

No. of cases

2. Rosenberg (1980) [43]

CA HMO

3. Adam (1981) [44]

England and Wales deaths

7

45

23

4. Thompson (1989) [45]

England GP groups

14

488

244

Stroke F+NF

1.20

5. Longstreth (1994) [46]

WA county

37 20a

206

103

SAH F+NF

0.47* 0.38*

6. Pedersen (1997) [47]

Denmark

7 ERTa/ 14 CHRTa

3171

1422 160 95 846 435

7. Petitti (1998) [48]

a

CA HMO

29a

349

349

430-6 NF 430 SAH 431 Intracerebral hemorrhage 432-4,436 Thromboemobolic 435 TIA

0.52/1.22 0.15/1.17 1.16/1.17 2.11*/1.25

Ischemic stroke NF Hemorrhagic stroke NF

1.03 0.33*

Current use Numbers refer to International Classification of Diseases: 430, SAH; 431, intracerebral hemorrhage; 432, other and unspecified intracranial hemorrhage; 433, occlusion and stenosis of precerebral arteries; 434, occlusion of cerebral arteries; 435, transient cerebral ischemia; 436, acute but ill-defined cerebrovascular disease; 437, other and ill-defined cerebrovascular disease; 437.0, cerebral atherosclerosis; 437.1, other generalized ischemic cerebrovascular disease; 438, late effects of cerebrovascular disease; 290.4, arteriosclerotic dementia; 344, other paralytic syndromes. F, fatal, NF, non-fatal. c RR calculated from data presented in paper. * PB0.05. b

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Case definitionb

First author (date) [Ref.]

Table 2 Uncontrolled cohort studies of HRT and stroke Population

% HRT

Size of cohort

1. Burch (1974) [49] Byrd (1977) [50]

TN: hysterectomized patients

100

737 1016

2. MacMahon (1978) [51]

KT: private patients

100

3. Hunt (1987) [52] Hunt (1990) [53]

UK: menopause clinics

100 (1 year+)

4. Falkeborn (1993) [54]

Sweden: Uppsala Health Care Region

100

No. of strokes

Case definition

Relative risk

8 8

Cerebrovascular accident F Cerebrovascular accident F

0.89a 0.53a

1891

?

Stroke F

0.80

4544 4544

14 23

430-8, 290.4 F 430-8, 290.4 F

0.65 0.54*

23 088

361 42 27

430-8, 344 hospital admit 430 SAH 431 Intracerebral hemorrhage 432-5 Thromboembolic stroke 431-6 Acute stroke 430-8, 344 F

0.90* 1.19 0.68*

121

Schairer (1997) [55]

23 246

256 172

0.91 0.85* 0.79*

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First author (date) [Ref.]

a

RR calculated from data presented in paper. * PB0.05.

247

248

Table 3 Internally controlled cohort studies of HRT and stroke First author (date) [Ref.]

Population

1. Hammond (1979) [56]

NC: Duke University Ob/Gyn 49 (5 years+) Dept

2. Petitti (1979) [57]

CA: Walnut Creek Contraceptive Drug Study (case/control analysis)

28a 38a 44

MA: Framingham Heart Study

24

Petitti (1987) [58] 3. Wilson (1985) [59]

% HRT in controls

Size of cohort

No. of strokes

Case definition

Relative risk

17

Stroke syndromes incidence

0.22b,*

16 759 6093

11 23 9

430 SAH F+NF 431-6 other stroke F+NF 430-8 F

1.6 0.9 0.6

1234

45

Stroke/TIA F+NF

2.27*

21

Atherothrombotic brain infarct

2.60*

430-7 F

0.40

431-4, 436, 437.0-1 F+NF Stroke F

0.69 0.37*

430-6 Cerebral infarcts, intracerebral hematomas, unspecifed strokes, TIAs, retinal artery occlusion F+NF First stroke/TIA F+NF

0.89b

Cerebrovascular accident NF Cerebrovascular accident NF

0 0*

Stroke F

0.53*

436 F 436 F 430-8 Hospitalization 430-2 Hemorrhagic stroke 433-4 Occlusive stroke

0.63 0.60* 1.05 1.03 0.90

4. Bush (1987) [60]

North America: Lipid Research Clinics Program

26a

2270

8

5. Finucane (1993) [61]

USA: NHANES I

21

1910

250 64

6. Boysen (1988) [62]

Denmark: Copenhagen City Heart Study

22

5602

87

22

4716

238

49 52

124 157

1 4

8. Paganini-Hill (1988) [66] CA: Leisure World Cohort Study Henderson (1991) [67] Paganini-Hill (1994) [68] Paganini-Hill (2001) [69]

56

8807

63

56 56 57

8853 8851 8508

92 134 1207 105 505

9. Sturgeon (1995) [70]

USA: Breast Cancer Demonstration Project

52

49 017

116

430-8 F

1.0

10. Folsom (1995) [71]

IA: Iowa Women’s Health Study

11a

41 837

90

430-8 F

1.31

Lindenstrøm (1993) [63] 7. Lafferty (1985) [64] Lafferty (1994) [65]

OH: private practice

0.28* (in smokers)

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610

Table 3 (Continued) Population

% HRT in controls

11. Stampfer (1991) [72]

USA: Nurses’ Health Study

22a

48 470

25a

59 337

(case/control analysis)

25a 33a

1837 70 533

MO: Mid America Heart Institute coronary angioplasty patients USA: Study of Osteoporotic Fractures

41

Grodstein (1996) [73]

Grodstein (1997) [74] Grodstein (2000) [75]

12. O’Keefe (1997) [76]

13. Cauley (1997) [77]

Size of cohort

337

No. of strokes

Case definition

Relative risk

Total stroke F+NF Ischemic stroke F+NF SAH F+NF Total stroke F+NF Ischemic stroke F+NF SAH F+NF 430-8 F Stroke F+NF Ischemic stroke F+NF Hemorrhagic stroke F+NF Stroke F

0.97 1.46 0.53 1.03 1.40* 0.90 0.68 1.13 1.26* 0.93 0.81

Stroke NF

0.45b

6

Stroke F

0.29b

430-8 F

0.47

430-8 incidence 430-8 F

0.86 0.16

Stroke F

0.92

430-8 F

0.81

224 113 36 552 281 144 167 767 432 174 119 17

14a

8947

73

14. Sourander (1998) [78]

Finland: mammography screening in Turku

12a

7944

111 51

15. Fung (1999) [79]

CA: Rancho Bernardo

72

1031

37

290 827

2390

16. Rodriguez (2001) [80]

USA: Cancer Prevention Study 12 II

a

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First author (date) [Ref.]

a

Current use RR calculated from data presented in paper. * PB0.05. b

249

250

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ischemic stroke) from all studies ranged from 0 to 2.3. Clearly, the studies of estrogen and stroke are not as uniform as those of estrogen and CHD, where nearly all studies show significant protection. The studies of HRT and stroke are, however, fraught with difficulties. The definitions of stroke were often crude and varied among the studies. Although stroke is a heterogeneous collection of diseases, most epidemiological studies grouped together all stroke subtypes. If HRT affects the risks of subtypes differently, combining them might mask the effects. Another problem is that often the only comparison made was between ever and never users of estrogen. If current estrogen users enjoy greater protection or risk against stroke than past users, combining current and past into ever use will produce a misleading risk estimate. In addition, since the proportion of current users differs among studies, results for ever use will vary. Other estrogen-use patterns undoubtedly differed among the studies, including doses, durations, recency, and types of estrogen. Some of the conflicting results on estrogen and stroke may be due to grouping all estrogen users together regardless of these parameters. As the addition of progestin to the hormone regimen in women with a uterus (to reduce the excess risk of endometrial cancer associated with unopposed estrogen) is a relatively recent practice, progestin use was uncommon during the period when most of these epidemiologic studies were conducted. Thus only a few studies have reported the effects of CHRT separately from those of ERT. Eleven studies have looked at specific stroke subtypes, particularly ischemic stroke or SAH. Some of these have included more detailed information on HRT than ever/never use. Below we review the findings of these studies by stroke subtype to see if the inconsistent findings among the HRT and stroke studies can be explained.

4.1. HRT and ischemic stroke Eight studies looked at ischemic (or as variously defined occlusive, atherothrombotic, or thromboembolic) stroke [42,43,47,48,54,59,69,75]

finding RRs of 0.9 to 2.6. Three studies found essentially no effect of e6er use of HRT [42,54,69]. The Framingham Heart Study found a significantly increased risk (RR= 2.6) in users [59]. This study also showed an elevated risk of CHD (unlike most prospective studies) and adjusted for a number of potential confounders including HDL cholesterol levels, which may reflect a potential pathway for stroke development. Unfortunately, detailed information on estrogen and ischemic stroke risk is limited [43,47,48,54,55,69,75]. Five studies looked at current users separately from past users [43,47,48,69,75] (Fig. 1A). Three [43,47,48] found essentially no effect of current use on stroke risk (RRs ranging from 1.0 to 1.2). The Nurses’ Health Study showed a significantly increased risk in current users (RR= 1.3) but not past users (RR = 1.0) [75]. The Leisure World Study found risk of occlusive stroke decreased with increasing recency of use (for trend, PB 0.05); women who had used ERT within one-year of study enrollment had the lowest risk (RR= 0.7, P B 0.05)) [69]. Petitti et al. [48] found no clear trend of increasing or decreasing risk of ischemic stroke in relation to duration of current hormone use (primarily conjugated equine estrogen with or without medroxyprogesterone acetate) (Fig. 1B). Neither did the Nurses’ Health Study [75]. However, in the Leisure World Study, risk of hospitalization for occlusive stroke decreased with increasing years of ERT (for trend, pB 0.05) [69]. Data on the effect of estrogen dose is scant (Fig. 1C). In Leisure World, risk of occlusive stroke did not differ by the dose of the longest used oral conjugated estrogen (RR= 0.9 for both low ( 5 0.625 mg) and high (] 1.25 mg) dose) [69]. In the Nurses’ Health Study, risk of ischemic stroke was increased significantly among women who took 0.625 mg of oral conjugated estrogen daily (RR= 1.4) and among those who took 1.25 mg or more daily (RR= 2.0) but not among those who took 0.3 mg daily (RR= 0.4) [75]. Only three studies reported on the relationship of stroke to CHRT separately from ERT [47,48,54] (Fig. 1D). Pederson found no association between thromboembolic infarction and cur-

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Fig. 1. Relative risk estimates and confidence intervals for studies of HRT and ischemic stroke.

251

252

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Fig. 1. (Continued)

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rent use of either CHRT or ERT (RR = 1.2) [47]. Petitti and colleagues found risk of ischemic stroke to be 1.0 for current use of estrogen alone and 0.6 for current use of estrogen+ progestin compared to never use [48]. In Sweden, Falkenborn and co-workers classified estrogens by potency and found that for thromboembolic stroke, potent estrogens (estradiol and conjugated estrogens) and combined therapy (estradiol valerate and levonorgestrel) were associated with a 30% or greater reduction, but weak estrogens (primarily estriol) were not [54]. However, all three confidence intervals were wide and included one. The Nurses’ Health Study found little association between all stroke and current use of oral conjugated estrogen alone (RR= 1.2), but a 45% significantly higher risk among women taking combined estrogen+ progestin compared to those who had never taken hormone therapy [75].

253

In the two largest case-control studies of SAH, more detailed information on hormone use was provided. In Washington, USA, longer duration and more recent use were associated with lower risk (for trend, PB 0.002 for both) [46] (Fig. 2B). In Denmark, risk was 0.5 in current ERT users, 1.2 in current CHRT users, and 0.8 in past ERT/ CHRT users relative never users; none of the risks was statistically significant [47] (Fig. 2C). Three other studies looked at all hemorrhagic strokes combined. Two found no effect of ERT [42,69] and one a significantly reduced risk in current users (RR= 0.3) [48]. In a study which classified intracerebral hemorrhagic strokes separately, weak estrogens were not associated with risk (RR= 0.8), but a marked and significant reduction in risk was seen for potent estrogens (RR = 0.6) [54].

4.3. HRT and fatal stroke 4.2. HRT and hemorrhagic stroke The seven reports of effect of HRT on SAH are also discrepant [44,46,47,54,55,57,73]. Two casecontrol studies [44,46] found a 35– 50% reduced risk among e6er users of estrogen (significant in one [46]). One uncontrolled cohort study found HRT was associated with a non-significantly elevated risk of incident SAH (RR= 1.2) [54]. In the same population risk of fatal SAH ranged from 1.7 in women prescribed weak estrogens to 0.5 in those prescribed CHRT, but with wide and overlapping confidence intervals [55]. Risk of SAH among current HRT users also differed widely among studies (Fig. 2A). A relatively large case-control study found that current HRT users had significantly reduced risk of SAH (RR = 0.38), but the effect was observed only in smokers [46]. In an internally controlled cohort study, current estrogen therapy was associated with a 1.6 risk of SAH, but the study had only 11 cases and the risk was not significant [57]. Analysis of the Nurses’ Health Study found no effect of current (RR = 0.9) or past (RR= 0.8) HRT on risk of SAH [73]. In all SAH studies, the number of cases was small (11– 160). The low incidence makes the study of SAH difficult, especially in cohort studies.

The most consistent evidence for an effect of HRT on stroke is found for fatal stroke [50,51,53,55,58,60,61,68,70,71,75–80] (Fig. 3A). All four uncontrolled cohort studies reported a 20-50% reduced risk in HRT users [50,51,53,55], which was significant in two [53,55]. Nine internally controlled cohort studies found risk reduced 20–80% [58,60,61,68,75–78,80], which was significant in three [61,68,80]. Two found essentially no effect with risks of 0.9 and 1.0 [70,79]. One found a non-significantly increased risk (RR=1.3) [71]. Few studies reported details of HRT (duration, dose, recency and type of estrogen) and fatal stroke. All but two [71,79] of nine studies [60,68,70,71,75,77– 80] found at least a 20% reduced risk in current users (Fig. 3B). In the Leisure World Cohort, risk decreased significantly with increasing recency of use: 0.70, 0.66, 0.36 for 15+ , 2–14, and 0–1 years since last use [68]. Risk also decreased with increasing duration of ERT in the Leisure World Study [68] and the Osteoporotic Fracture Study [77], but not in the Iowa Women’s Health Study [71] (Fig. 3C). In Leisure World, both low (5 0.625 mg) and high (] 1.25 mg) doses of oral conjugated estrogen were associated with significantly reduced risk of fatal stroke (RR= 0.4) [68]. In the Nurses’ Health

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254

Study, the risks for these doses were 1.0 and 1.2 [75]. In this same study, risk for fatal stroke was 0.81 among current users of estrogen alone and 1.2 among users of CHRT; both risks were nonsignificant [75]. In Sweden, weak estrogens, potent estrogens and combined treatment reduced risk 10, 30 and 40% [55]. The reduced risk was statistically significant for potent estrogens.

ondary analysis of one clinical trial of aspirin in patients with transient ischemic attacks found that women who used estrogens had a reduced risk of stroke, retinal infarction and death (RR= 0.20, P= 0.06) [81]. In contrast, a reanalysis of another clinical trial of aspirin found a higher rate of ischemic stroke among ERT users (RR= 3.2, P= 0.007) [82].

4.4. HRT in women with stroke

4.5. Randomized clinical trials of HRT and stroke

Few studies have evaluated the risk of recurrent stroke in women using HRT (Table 4). A sec-

All the epidemiological studies examining the

Fig. 2. Relative risk estimates and confidence intervals for studies of HRT and subarachnoid hemorrhage.

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Fig. 3. Relative risk estimates and confidence intervals for studies of HRT and fatal stroke.

255

256

First author (date) [Ref.]

Population

% HRT

Internally controlled studies in women with pre6ious TIA (Transient ischemic attack) American–Canadian USA, Canada: Persantine Aspirin Trial 11% Co-operative (1986) [81] Hart (1999) [82] Stroke Prevention in Atrial Fibrillation 33%a III Trial Randomized clinical trial Hulley (1998) [39]

a

Current use * PB0.05.

HERS Trial: women with coronary disease

50%a

Size of trial

No. of strokes

293

36

274

15

2763

204

Case definition

Relative risk

Stroke, retinal infarction F+NF Ischemic stroke F+NF

0.23

Stroke/TIA

3.2*

1.3

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Table 4 Other studies of HRT and stroke

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association of estrogen use and stroke discussed above are non-experimental investigations without random assignment of subjects to estrogen or placebo. This leads to the possibility of recall bias, selection bias, and confounding. A major concern in such studies is the ‘‘healthy user effect’’ (self-selection of HRT by women with health-promoting habits and fewer risk factors) and the differential interaction with the medical care system between users and nonusers. Although many investigators adjusted for potential confounders, women who use HRT may differ from nonusers in some unquantified but confounding way. A clinical trial randomly assigning women to estrogen and placebo groups would ensure that the estrogen and not some characteristic of estrogen users accounts for any observed benefits. The only randomized clinical trial of HRT with published results on stroke endpoints is the HERS trial [39] (Table 4). A total of 2763 postmenopausal women with CHD were randomized to receive 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate or placebo daily. With average follow-up of 4.1 years, treated women exhibited no difference in incidence of stroke/transient ischemic attack compared with controls (RR=1.13, 95% CI 0.85– 1.48). The study, however, did not examine unopposed estrogen or other estrogen and progestin regimens. It also did not study the use of HRT in postmenopausal women without CHD. Although only one-third of the 9-year treatment period of the Women’s Health Initiative (WHI) is complete, investigators recently issued a press release and wrote letters to participants about early findings [83]. WHI randomized 27000 women without CHD to receive estrogen + progestin or placebo if they have a uterus or to receive estrogen or placebo if they do not. The investigators ‘observed a small increase in the number of heart attacks, strokes, and blood clots’ among hormone-treated women compared to placebo-treated women in the first 2 years of the trial. They noted that overtime these differences seemed to get smaller and may disappear.

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Table 5 Estrogen effects on the vascular system Impro6es lipoprotein concentrations Decreases LDL cholesterol Increases HDL, especially HDL2, cholesterol Decreases lipoprotein(a) Inhibits LDL oxidation Affects 6ascular inflammation fa6orably Inhibits expression of cellular adhesion molecules Inhibits proliferation of vascular smooth-muscle cells Accelerates growth of endothelial cells Enhances fibrinolysis Decreases fibrinogen Decreases plasminogen-activator inhibitor-1 Decreases tissue plasminogen activator antigen Impro6es 6asodilation and 6asomotor reacti6ity Promotes flow of potassium, sodium and calcium ions in vascular smooth-muscle cells Enhances activity of the endothelium-derived relaxing factor nitric oxide Increases prostacylin production Increases cerebral blood flow Exerts neuroprotecti6e effects Reduces lesion size in experimental ischemia Attenuates neuronal death

4.6. Potential biologic mechanisms: effects of estrogen on 6ascular system Estrogen therapy may reduce the risk of vascular disease and stroke via several mechanisms (Table 5) [84]. Estrogen improves serum cholesterol levels, inhibits low density lipoprotein oxidation, favorably affects vascular inflammation, and thus may reduce atherosclerotic plaque formation. The effects of estrogen on tissue plasminogen activator and plasminogen activator inhibitor-1 enhances fibronolysis. Effects on ion-channel function, nitric oxide, and vasodilatory enzymes improve vasodilation and vasomotor reactivity and help maintain cerebral blood flow. Animal studies show that estrogen exerts neuroprotective effects in the setting of cerebral ischemia. Estrogen treatment dramatically reduced mortality by one-half in animal models of ischemia including middle cerebral artery occlusion and common carotid artery occlusion [85]. Both a reduction in lesion size and attenuation of neuronal death

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[85,86] may improve stroke outcome and explain the observed beneficial effect of estrogen against fatal stroke in postmenopausal women.

in the coming years may clarify the effects of HRT on the cardiovascular system. These additional data may help resolve the question of whether HRT increases risk, offers protection or has no effect on stroke morbidity and mortality.

5. Conclusion As women approach menopause, their risk of stroke begins to rise and increases steadily with age. Each year stroke claims the lives of more females than males and leaves many others with severe disability. Because stroke is often fatal and the impact of treatment on prognosis limited, control of the disease must be through primary prevention. Although several observations suggest that HRT might protect women from stroke, 29 studies in the past 25 years have produced no conclusive evidence of a beneficial effect. The lack of consistency in stroke endpoints, definition of HRT user (ever versus current), estrogen preparation (conjugated equine estrogen, estradiol versus other estrogens), and influence of combined regimen might account in part for the unclear association between HRT and risk of stroke. The results raise the interesting question of why estrogens have no consistent effect on stroke but appear to be so protective of CHD in observational studies with the same designs and often in the same cohorts. Nonetheless, the preponderance of evidence suggests that HRT does not increase stroke risk, although data on the impact of hormone therapy in the initial months of use is sparse. Some data indicate that estrogen users have a moderately reduced risk of fatal stroke, but details about the optimal dose, duration and type of estrogen are insufficient. The apparent difference in the findings of studies of fatal and non-fatal stroke suggests that estrogen may prevent the most lethal form of stroke or may improve stroke survival. Animal studies showing that estrogen decreases lesion size and neuronal death in experimental cerebral ischemia as well as reduces mortality provide biologic mechanisms for the observed beneficial effect of estrogen against fatal stroke in postmenopausal women. Completion of ongoing randomized clinical trials (WHI and Women’s Estrogen for Stroke Trial)

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