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Curr Treat Options Cardiovasc Med. 2009 June ; 11(3): 241–250.

Hormone Therapy and Stroke: Is It All About Timing?
Cheryl Bushnell, MD, MHS

Opinion statement
Although women have a lower incidence of stroke than men in most age groups, women have an overall increased lifetime risk of stroke. Women also have unique risk factors for stroke, including the menopausal transition, the existence of debilitating vasomotor symptoms for some women, and the issues related to hormonal treatment for those symptoms. Although the initial studies of hormone therapy (HT) use in postmenopausal women suggested significant protection against heart disease, there was no obvious protection against stroke. Randomized trials of HT for secondary prevention showed a lack of benefit for both heart disease and stroke, and the suggestion of some early risk after initiation. However, the Women’s Health Initiative (WHI), a primary prevention study of the impact of HT on women aged 50 to 79 years, showed an increased risk of stroke, whether the HT was estrogen alone or estrogen combined with progestin. Therefore, HT is not recommended for stroke prevention, and it appears to cause harm. The reason for this increased stroke risk is not understood, but some have suggested that the initiation of HT closest to the time of menopausal transition should decrease the risk. Although there was a lower risk of heart disease when HT was initiated earlier, the risk appeared to be the same for stroke regardless of the timing. This was shown in both the WHI and the Nurses’ Health Study cohorts. Therefore, more research is needed to understand the mechanisms for the increased stroke risk and to identify those who may be at risk because of HT for vasomotor symptoms, atrophic vaginitis, or osteoporosis, the three remaining indications for HT use in women. Trials are under way to assess the intermediate outcomes of HT on subclinical vascular disease in perimenopausal/early postmenopausal women.

Introduction
STROKE IN WOMEN Compared with men, women have a lower incidence of stroke until about the age of 85 years or older [1]. However, because women live longer, their lifetime risk of stroke is actually higher (1 in 5 chance) than men’s (1 in 6) [2]. In general, the incidence of ischemic stroke in women in the United States is 3 in 1000 between ages 55 and 65, 5.6 in 1000 from 65 to 74 years, 12.5 in 1000 from 75 to 84 years, and 20 in 1000 over age 85 [1] (also see systematic review for more epidemiologic data [3•]). IS MENOPAUSE A RISK FACTOR FOR STROKE? The risk of stroke in women nearly doubles between age 55 and 65 years [1], corresponding to at least 10 years after the average age for menopause. During the menopausal transition period, estradiol levels decline by about 60% [4]. After menopause, estradiol levels continue
Copyright © 2009 by Current Medicine Group LLC Corresponding author, Cheryl Bushnell, MD, MHS, Women’s Health Center of Excellence for Research, Leadership, and Education, Wake Forest Health Sciences University, Medical Center Boulevard, Winston-Salem, NC 27157, USA. cbushnel@wfubmc.edu. Disclosure No potential conflict of interest relevant to this article was reported.

and postmenopause [5]. most importantly endothelial nitric oxide synthase. A study from Norway focused on stroke mortality in 3561 women over a 37-year follow-up period. 0. A systematic review of these studies showed a strong and generally consistent association between HT use and an approximate 50% reduction in coronary heart events [12]. Other significant variables in the logistic regression model included hypertension. In contrast to the rapid decline in estradiol. then this early exposure could be deleterious [10•]. was not clearly demonstrated [12]. 1. 95% CI. and racial/ethnic differences in menstrual histories. This combination leads to a relative androgen excess during the menopausal transition [6]. Only a few studies have examined the relationship between age at menopause and stroke [9. whereas obesity was protective (OR. however. geographic. The investigators found no significant relationship between age at menopause and stroke mortality. if menarche begins before age 13. 0. menarche begins at age 13 and menopause at age 47). stroke risk is increased when lifetime exposure to endogenous estrogens is less than 34 years (eg. The results of this study may be interpreted in multiple ways. low-density lipoprotein.95) [10•].51. an analysis of the Nurses’ Health Study (NHS) found no relationship between age at menopause and stroke incidence (is chemic or hemorrhagic types) [11]. Author manuscript. circulating testosterone levels decrease more gradually during this period [6]. Conversely. The menopausal shifts in hormonal levels and ratios of estrogens to androgens are important because these sex steroids appear to have opposite effects on vascular risk. therefore. investigators interviewed postmenopausal women regarding their age at menarche and age at menopause. Using standardized questionnaires. This occurs in part because estrogen facilitates production and sensitivity to vasodilatory factors. the age at menopause was not significant. The number of years between these two events was defined as the lifetime exposure to estrogens.56–0.Bushnell Page 2 to decline but then plateau after 1 to 3 years. or the duration of ovarian activity [10•].11]. regardless of age at menopause. The researchers examined this variable in cases (postmenopausal women with stroke or transient ischemic attack [TIA]) and age-matched controls.03) and age at menarche less than 13 years (OR. androgens have a detrimental effect on cerebral blood vessels by increasing arterial tone. including improving vasodilation and arterial compliance [7] by decreasing cerebral vascular tone and increasing cerebral blood flow [8]. menopause was defined as the cessation of menstrual bleeding. diabetes. and there may be regional. Estrogens have multiple beneficial effects on the cardiovascular system. A similar protection against stroke. It is important to note that women with cardioembolic stroke were excluded. First.92) were independently associated with an increased risk of ischemic stroke [10•]. 95% CI. estradiol levels decrease by seven.73. and hyperlipidemia. 1.49. 95% CI. Similarly. .10•.13–2. regardless of ischemic or hemorrhagic stroke type [9]. available in PMC 2011 April 12. However. The reasons for the discrepancy between stroke and heart disease are still poorly understood but could be related to the heterogeneity of Curr Treat Options Cardiovasc Med. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript A study from Spain examined the lifetime exposure to estrogen rather than just the age at menopause. Consistent with other studies. 1. Hormone therapy and stroke Observational studies • The first investigations into the possible benefits of hormone therapy (HT) for cardiovascular disease prevention were performed with epidemiologic cohort studies. Overall. They also lead to a proatherogenic profile in women by decreasing high-density lipoprotein and increasing triglycerides. 1.15–1. They found that estrogen exposure less than 34 years (odds ratio [OR].to 10-fold between pre. This finding supports the evidence that endogenous estrogens likely protect against stroke. and total cholesterol [6]. these results may not be generalizable beyond the region in which the data were collected.

1.56) [29]. This cohort maintains a follow-up greater than 90%. postmenopausal HT use. and the small number of cases (45 with cerebrovascular disease and 21 with ischemic stroke). the NHS demonstrated a risk of stroke that was of a similar magnitude to the Women’s Health Initiative (WHI. Randomization eliminates much of the bias associated with observational studies. discussed later).74 and estrogen plus progestin: RR. Combining these two stroke types may have confounded the effect in some studies. and physical activity.001) [29]. 0.91). . 1.39) [29].14••]. 1. with more than 485. and continuous medroxyprogesterone acetate • Curr Treat Options Cardiovasc Med.18–1. but there was no association with estrogen plus progestin users (RR.987 person-years of follow-up for women who never used HT and 409. Despite the general sentiment at the time that HT provides multiple vascular benefits. 95% CI. 1. 95% CI. We now know that HT seems to be associated with ischemic but not hemorrhagic stroke [13. cardiovascular risks.05) [20].43. There also was a 50% increase in risk of cardiovascular morbidity. A summary of observational cohort studies reporting the relationship between hormone replacement therapy and stroke is given in Table 1 [15–28].3 mg. the recent analysis also showed a positive correlation between increasing dose of estrogen and increasing stroke risk (RR. 95% CI. 0. 95% CI. 121. diet. Overall. P for trend < 0. the most significant risk was shown for ischemic stroke (estrogen alone: RR. 0.39.625 mg. The attributable risk for HT was approximately an additional two cases of stroke per 10. Author manuscript. RR.55–1.95). and RR.63 and estrogen plus progestin: RR.93 for 0. the dosage or duration of use. however. and HT were contrary to most of the other observational studies published in the same era (Table 1).625 mg. this report was an early warning of things to come nearly 15 years later. • The Framingham Study is worth highlighting because the results of its analysis of postmenopausal women. The first randomized trial of HT for secondary prevention of coronary heart disease (CHD) was the Heart Estrogen–Progestin Replacement Study (HERS).62 for 1.27. Women with a documented history of CHD were randomly assigned to receive conjugated equine estrogen (CEE).04–1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript • Randomized trials of hormone therapy • Because of the generally positive results of observational cohorts in favor of HT’s protection against heart disease. The analysis. estrogen use was associated only with an increased incidence of stroke (P < 0. although these trials also have important limitations. With regard to stroke subtype. There was a trend toward an increased risk for hemorrhagic stroke in users of estrogen alone (RR. 0.17–1. randomized trials were performed to test this hypothesis. Another important cohort to highlight is the NHS because it has provided some of the most detailed epidemiologic data related to stroke type and estrogen dose. Notable studies are described individually in the following text.629 person-years of follow-up among current HT users [29]. cardiovascular disease.37. One of the more recent analyses included follow-up questionnaires through June 2004.98–1. This study showed that cerebrovascular disease events and ischemic stroke in particular were increased more than twofold among HT users [20].53. available in PMC 2011 April 12. but among nonsmokers. 1. 1. 1.25 mg.54 for 0.700 female nurses aged 30 to 55 years completed mail questionnaires regarding their medical histories. 1. 1.000 women per year taking hormones [29]. 95% CI. Similar to previous analyses of this cohort [25]. 1. There was a significantly increased risk of stroke in current users compared with never-users (estrogen alone: relative risk [RR].87.21– 1.Bushnell Page 3 stroke types and etiologies. 95% CI. Since 1976. 0. 1. was limited by a lack of details regarding continuation of HT after specific examination dates.

95% CI. and when used. and if this was documented by transvaginal ultrasound.4). • The next randomized trial of HT and stroke was designed to determine whether 17estradiol.03).3. 0. 0. Author manuscript. 2. there also was a trend toward a higher risk of fatal strokes in women using estrogen (RR. Multiple secondary outcomes were reported. progesterone was used only if necessary.5 mg. the hazard ratio (HR) for African NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript • • Curr Treat Options Cardiovasc Med. the primary end point. 2. P = 0. including TIAs and fatal and nonfatal ischemic and hemorrhagic strokes. Stroke was included in the overall global index for the earliest events occurring during the follow-up period [32]. Women were excluded if they had a history of acute MI.8–1. this was one of the few trials to use the formulation of estradiol that is physiologically relevant. The primary outcome was the earliest CHD event (nonfatal myocardial infarction [MI] and CHD death). 95% CI. women with a uterus could also take a 12-day course of MPA. 1.1–5. between the two groups (RR.2 years. There were no overall differences in the rates of any of these stroke types. when stroke risk was adjusted for adherence in the estrogen-alone trial. an endometrial biopsy was performed. Over a mean follow-up period of 2. However. and the primary adverse outcome was invasive breast cancer. this group was older and at higher risk than the women who typically would be prescribed HT. 2. . It is important to point out that the average age of the study participants was 71 years. 95% CI. 95% CI. 1. Women without a significant cardiovascular disease history were randomly assigned to receive CEE. The first study to evaluate whether HT is an effective strategy for preventing vascular disease in healthy women was the WHI. 1.0) [31]. Women without a uterus were monitored for endometrial hyperplasia. Several subgroup analyses have been performed to determine whether women with certain risk factors or characteristics would be at increased risk of ischemic stroke with CEE alone or CEE/MPA. Therefore.63) and a 40% increased risk of stroke (RR. post hoc analysis showed a twofold increased risk of fatal or nonfatal stroke in the estradiol group during the first 6 months after randomization (RR.Bushnell Page 4 (MPA). 5 mg. 2.85) in the CEE/MPA group [32].9. As an alternative to transvaginal ultrasound.29. daily or placebo. The Women’s Estrogen for Stroke Trial (WEST) randomly assigned 664 women with a recent history of stroke or TIA to 1 mg of 17estradiol daily versus placebo [31]. there was no significant difference in rates of stroke or death. There have been no characteristics identifying women at increased or decreased risk of stroke based on these analyses and no significant trends based on age by decade [13. there was a 30% increased risk of CHD events (RR. it was given cyclically. WEST reinforced the HERS results.02–1.41. This trial was stopped early because of this increase in cardiovascular events as well as an increase in the rates of breast cancer among treated women.8 years. 0. available in PMC 2011 April 12. Overall. stroke.9–9. A more detailed analysis of the stroke events showed that the risk was primarily for ischemic and not hemorrhagic stroke and that there was no significant difference in most of the relevant stroke outcomes between groups [13]. and about 75% of the women had hypertension at baseline.07–1. annually. or TIA in the previous 6 months. but there were relatively few of these events. and MPA. 95% CI.1. However.14••]. However.0. After a mean of 5. the physiologic form of estrogen.5 mg.625 mg. continuously versus placebo. suggesting that estrogen does not protect women from recurrent strokes or death and that there may be an early risk of stroke following initiation of treatment. thereby limiting the statistical power to detect a difference (Table 2) [30]. 1. 1. 1. is efficacious for secondary prevention of stroke. The WHI included an observational study as well as randomized trials with multiple end points important for women’s health.

The women in the CEE group were more likely to suffer an ischemic stroke (HR.80) whereas the risk for Caucasians was relatively unchanged (HR. a randomized. but tamoxifen alone was not [38]. and 8 per 10. and although the statistical power was limited. reported no significant effect on the incidence of CHD events or nonfatal stroke [39]. Very few events occurred during follow-up. there was an increase in venous thromboembolism and fatal strokes with raloxifene.19–2. 95% CI. Studies to determine the risk of stroke with tamoxifen have been conflicting. Author manuscript.24. 1.85–1.48 (95% CI. Selective estrogen receptor modulators (SERMs). but there was an increased risk for stroke with CEE (RR. • The other important result of the WHI estrogen-alone arm was a divergence in the risk for different types of cardiovascular events. Despite this very dramatic response to one clinical trial.Bushnell Page 5 American women increased to 3. The Estonian trial of postmenopausal HT consisted of two arms: a blinded HT group with a corresponding blinded placebo group. it is important to remember that the absolute risk for stroke in the WHI was low. and as such they have been used as adjuvant or preventive treatment for breast cancer. A meta-analysis of breast cancer prevention and treatment trials showed an increased risk of ischemic stroke but not all strokes [37]. .000 women per year of use. 95% CI. A detailed post hoc analysis of fatal stroke events showed that this risk was evident only after 3 years of follow-up. For example. Table 2) [33]. 95% CI.37.61.77. Another clinical trial of CEE/MPA and health outcomes in women was conducted in Estonia.50) [14••].73). 1. 1.18). 95% CI.12–10. 1.67. 1. The Raloxifene Use for the Heart (RUTH) trial.09–1. a magnitude similar to that seen in the CEE/MPA arm of the trial [14••]. many women stopped taking HT on their own. Despite the large number of women in the study overall. 95% CI.01) than hemorrhagic stroke (HR.000 women for the combination [14••]. the smaller numbers of stroke cases in these subgroups limited the power to detect any significant relationships with HT use. the combined blind and nonblind HT groups showed a nonsignificant increase in cerebrovascular disease (HR. HT prescriptions fell dramatically in the year following the WHI’s publication in 2002 [34]. there was no difference in CHD events between the CEE and placebo groups. 0. although they were not well informed about the study’s findings [35. and a nonblinded HT group with a corresponding control group [33]. also similar to the study’s other arm [14••].36]. A large case-control study of the Kaiser Permanente Southern California database of women with breast cancer showed that chemotherapy was associated with stroke. The stroke outcomes were based on International Classification of Disease (ICD)-10 codes for stroke (cerebrovascular diseases). placebocontrolled trial of 60 mg of raloxifene.38–6.12–2. 1. Raloxifene also has been studied prospectively for its impact on cardiovascular events. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript • • • • Curr Treat Options Cardiovasc Med. such as tamoxifen and raloxifene. are nonsteroidal drugs that are antiestrogenic in mammary tissue. 0.64. 1. and no specific characteristics were associated with the risk of fatal stroke [40]. 1. Few studies have led to the major shift in clinical practice brought about by the WHI. 95% CI.82) and stroke only (HR. and these were further categorized into stroke only.55.35–1. The reason for the lack of increase in CHD events with treatment is uncertain but suggests that ischemic stroke risk is related to estrogen rather than to progestin [14••]. However. the risk was 13 strokes per 10. amid the media frenzy surrounding the WHI. 0. 1. 0. In addition. available in PMC 2011 April 12. In the estrogen-alone arm.

14–4. The possibility of time since menopause as a risk factor for events was studied in the WHI through a secondary analysis of events in women grouped by years since menopause began. at least one of the pitfalls of the WHI was the lack of measurement of subclinical vascular disease at the start of the trial. however. Another possible explanation. In addition. 0.93. 1.74.19. and an increased risk in women at 20 years or more since menopause onset (HR. 0. However.23. available in PMC 2011 April 12.50–1. but after menopause or in the setting of early-onset atherosclerosis.58. 0.02) [45]. there was no change in the risk based on years since menopause began or on age. 95% CI. versus placebo [42•]. if women are known to have significantly increased carotid artery intimal medial thickness (a • • • Curr Treat Options Cardiovasc Med. The Long-term Intervention on Fractures with Tibolone (LIFT) study was a randomized. P = 0. 0. P = 0. estrogen is harmful because of its effects on accelerating atherosclerosis and an increased risk of thrombosis.58–0.25 mg daily. Data from multiple sources highlight the fact that the risk projections of coronary disease cannot be applied universally to stroke in women.84–1. 95% CI. 1. Author manuscript. 0. the trial was stopped prematurely because the tibolone group had an increased risk of stroke (relative hazard.28.41– 0. although there was no significant risk of CHD or venous thromboembolism [42•]. whereas the heart disease protection was robust. P value for trend. 95% CI.03–1. This evidence was shown in a monkey model of atherosclerosis and estrogen treatment [43]. The trial showed that the drug significantly reduced the risk of vertebral (relative hazard. 0. neither the unified hypothesis nor the timing hypothesis appears to accurately reflect the pattern of stroke risk with HT based on observational and randomized trial data.45). The NHS also reported no association between the timing of initiation of HT and the risk of stroke [29].10.16). This was true with the observational studies that did not show protection against stroke with postmenopausal HT use. no significant effect in women at 10 to 19 years (HR.01).02). double-blind. 1. However.Bushnell Page 6 • The Study of Tamoxifen and Raloxifene (STAR) trial was designed to compare these two SERMs in the prevention of invasive breast cancer and for other cardiovascular events. for stroke. progestogenic. 1. The leading hypothesis has been the timing hypothesis. 1. that estrogen is protective against cardiovascular disease when women are younger and the vessels are healthy. 0. 95% CI. is used to treat menopausal symptoms as well as osteoporosis in more than 90 countries. This hypothesis.55. was formulated only for the possible mechanism of CHD risk. a drug with metabolites that have estrogenic. that is. the unified hypothesis. 2. Also. There was a decreased risk of CHD in women at less than 10 years (HR. despite the investigators’ claim of enrolling primarily healthy women. 0. 95% CI. and not stroke. the timing of initiation in relation to menopause has no relevance for stroke risk. placebo-controlled clinical trial of tibolone. Tibolone.74) and nonvertebral fractures (relative hazard. Regardless of the timing. proposes that combination HT increases the risk of plaque erosion/rupture with early exposure but that there is a long-term reduction in plaque formation and antagonism of the vasculoprotective effects of estrogens by progesterone [44]. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript • How does hormone therapy increase the risk of stroke in postmenopausal women? • The mechanism(s) by which exogenous estrogens lead to an increased risk of stroke is not known despite multiple secondary analyses of the WHI cohort and ancillary studies. 95% CI. For example. .76. and androgenic activities. whereas it may for CHD risk. This study reported no difference in stroke events between these two treatments [41].

which can then be correlated with endogenous hormones and the vascular measures (clinicaltrials. and the American Heart Association’s 2007 update of its guidelines for cardiovascular disease prevention in women [48] all recommend against menopausal HT and SERMs for primary or secondary prevention of cardiovascular disease (class III. The Early Versus Late Intervention Trial With Estradiol (ELITE) is enrolling women less than 6 years and more than 10 years post menopause. These risk markers may be different for stroke than for coronary disease. Another ongoing study. available in PMC 2011 April 12. the North American Menopause Society [46]. level A). then these women have more advanced atherosclerosis. . Without the subclinical information. Therefore. and to identify women who are at low or high risk for cardiovascular disease although they appear healthy. especially if they are more than 5 years past menopause. based on the differences in risk with years from menopause onset.45 mg) and transdermal estradiol (50 µg). men are age matched to an equal number of pre-/perimenopausal and postmenopausal women. which is still estrogen replacement. The Kronos Early Estrogen Protection Study (KEEPS) is a randomized trial of low-dose CEE (0.Bushnell Page 7 risk factor for future cardiovascular disease) or evidence of coronary artery calcium. is being conducted in middle-aged women and men to specifically determine the impact of endogenous hormones on subclinical vascular disease. This study also will measure biomarkers that reflect endothelial activation. the designation of “healthy” may not be accurate. In the SAVVY study. KEEPS began enrollment in 2005 and anticipates completion in 2010.edu/medicine/aru) [50]. Sex Aging and Variation in Vascular Functionality (SAVVY). there are many unanswered questions. the American College of Obstetrics and Gynecology Hormone Therapy Task Force [47].gov. • • • • Curr Treat Options Cardiovasc Med. At least two ongoing studies of early initiation of HT in women who are perimenopausal or early postmenopausal will help address some of the unanswered questions raised by the WHI. The primary outcomes are progression of carotid intimal medial thickness and accrual of coronary artery calcium [49]. Women with debilitating vasomotor symptoms will continue to seek the most effective therapy. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript New directions for hormone therapy research • Although the WHI has provided a vast amount of information on health outcomes in women. measured with carotid intimal medial thickness. which might put them at higher risk of stroke with estrogen exposure. there is still a need to find better risk markers that could identify women at risk before initiating HT. • To put the risk into clinical perspective. measured with brachial artery flow–mediated dilation. Although HT clearly is not recommended for stroke prevention because of the increased risk. ELITE is designed to test the hypothesis of timing of initiation of estrogen therapy to prevent progression of subclinical atherosclerosis but is also assessing for cognitive decline (www. both in combination with cyclic oral micronized progesterone (200 mg) for 12 days of each month. and thrombosis. there are multiple gaps in knowledge that need to be filled to understand the mechanism of harm and the divergence in risk between stroke and heart disease related to timing of initiation and influence of progestins. HT regimens that have not yet been studied for cardiovascular disease [49]. Similar to KEEPS. Author manuscript. and on endothelial function.usc. inflammation. NCT00681681).

[PubMed: 14568807] 16. Am J Epidemiol. Rannevik G. et al. 2001. Johnell O. 7:915–926. et al. Jeppsson S. 2008. 21:103–113.Bushnell Page 8 References and Recommended Reading Papers of particular interest. Estimates from the Framingham Study. Circulation. [PubMed: 12771114] 14. [PubMed: 16702472] This study represents a comprehensive analysis of all stroke events in the randomized trial cohort of the WHI. 352:1965–1969. Ann Intern Med. McKinlay SM. 1997. Rajkumar C. Jacobsen B. Maturitas. Howard G. Liu Y. Bush T. Wassertheil-Smoller S. Neurology. 30:350–356. Risk of ischemic stroke and lifetime estrogen exposure. Rajala T. 2007. 2005. a lifetime estrogen exposure of less than 34 years in a large cohort of women in Spain was associated with a higher risk of ischemic stroke. Flegal K. Petitti DB. Sex differences in stroke: epidemiology. Artini P. 68:33–38. Ultrasound Obstet Gynecol. Lokkegaard E. 1992. Author manuscript. 29:23–28. 159:1061–1066. Age at natural menopause and stroke mortality. JAMA. Hendrix SL. Hu F. 154:489–494. and combines the estrogenalone and CEE/MPA groups. Beiser AS. [PubMed: 9872245] Curr Treat Options Cardiovasc Med. Petitti DB. 2008. 2003. The normal menopause transition: an overview. Egido J. 1995. J Am Coll Cardiol. Sourander L. clinical presentation. [PubMed: 18722812] This is a comprehensive and up-to-date systematic review of sex differences in stroke. Limacher M. 289:2673–2684. 113:2425–2434. [PubMed: 10335682] 12. [PubMed: 16397184] 3. et al. and outcomes. Jovanovic Z. et al. 15. 2003. 23:137–145. et al. [PubMed: 16184506] 9. et al. Hormonal therapy increases arterial compliance in postmenopausal women. [PubMed: 15178828] 10. Hormone therapy to prevent disease and prolong life in postmenopausal women. Stroke. The lifetime risk of stroke. have been highlighted as: NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript • Of importance •• Of major importance 1. [PubMed: 1443971] 13. 117:e25–e146. 2006. Age at natural menopause and risk of cardiovascular disease. 35:1548–1551. Persico N. et al. published recently. Reeves M. 117:1016–1037. Quesenberry CP Jr. Bushnell C. 2004. Heart disease and stroke statistics–2008 update: a report from the American Heart Association Committee and Stroke Statistics Subcommittee. 26:546–551. [PubMed: 11549553] 7. Cohort study with 3561 stroke deaths during 37-year follow-up. [PubMed: 7752947] 5. SHBG and bone mineral density. Arch Intern Med. Rosamond W. Mancini F. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. 37:345–350. Cameron JD. Transdermal HRT and Doppler findings in normotensive and hypertensive postmenopausal patients. et al. et al. Grady D. Bernstein A. Hendrix SL. Kingwell BA. 1996. Effect of estrogen plus progestin on stroke in postmenopausal women. de Lecinana M. [PubMed: 9247504] 8. Ding J. Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy. [PubMed: 8735352] 6. 1998. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones. Heitmann BL. Wassertheil-Smoller S. Stroke. Circulation. 60:1379–1384. [PubMed: 18086926] 2. et al. Arch Neurol. Raiha I. Lancet. Grodstein F. Stroke. available in PMC 2011 April 12. Heuch I. Relative androgen excess and increased cardiovascular risk after menopause: a hypothesized relation. [PubMed: 9445323] 17. . [PubMed: 17200489] Although this study did not measure endogenous hormones. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Furie K. Sidney S. Kvale G. 2006. et al. whereas age at natural menopause was not. Johnson KC. 4. 11. Kelly-Hayes M. Seshadri S. Hennekens C. Rubin SM. medical care. et al. 1998. The Women’s Health Initiative: a randomized trial. et al. Increased risk of stroke in hypertensive women using hormone therapy. Fernandez C. 1999. Maturitas. Lancet Neurol. et al.

Cauley JA. Boysen G. Kreiner S. Tosteson AN. Principal results from the Women’s Health Initiative randomized controlled trial. et al. Postmenopausal hormone therapy and stroke. 2004. 133:922–941. et al. Geiger AM. Wilson PW. A clinical trial of estrogen-replacement therapy after ischemic stroke. The hormone therapy dilemma: women respond. 2003. J Am Med Womens Assoc. N Eng J Med. 1999. Persson I. [PubMed: 7347044] 24. Hsia J. Clark R. 1993. Ettinger B. Angeja BG. Postmenopausal hormone therapy and risk of stroke. available in PMC 2011 April 12. 63:1230–1233. [PubMed: 2995808] 21. Am J Epidemiol. Madans JH. Bernstein L. Stampfer M. 24:1468–1472. [PubMed: 1274949] 19. Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757]. Mosca L. Psaty BM. Circulation. [PubMed: 16504428] 34. Fischer K. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy post-menopausal women. Bushnell CD. [PubMed: 9357407] 20. Viscoli CM. Annual trends and response to recent evidence. Neurology. [PubMed: 11680444] 32. Brass LM. 2008. Risk of ischemic stroke with tamoxifen treatment for breast cancer: a meta-analysis. Doner L. cigarette smoking. . Bettencourt RR. Ottesen B. Arch Intern Med. observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. 2006. [PubMed: 8422201] 27. Rosenberg SH. 1980. Stefanick ML. JAMA. 1985. 1997. 288:321–333. Ann Intern Med. N Engl J Med. 355:125–137. et al. et al. J Womens Health. Manson J. 1993. Stroke. [PubMed: 15477543] 38. Pfeffer R. Hersh AL. Terent A. The Heart and Estrogen-progestin Replacement Study (HERS). 153:1201–1209. 153:73–79. Manson JE. Colditz GA. 133:292–296. [PubMed: 8388207] 23. Effect of the Women’s Health Initiative on women’s decisions to discontinue postmenopausal hormone therapy. Bush TL. Falkeborn M. Arch Intern Med. Fischberg GM. Lidegaard O. Rexrode K. [PubMed: 14662208] 37. 313:1038–1043. [PubMed: 8378948] 28. 350:1277–1283. et al. Chen W. et al. Nyboe J. Grodstein F. Collins P. Barrett-Connor E. 2004. 291:47–53. A prospective. [PubMed: 11156873] 31. [PubMed: 12117397] 33. Grady D. 2002. Estrogen use and stroke risk in postmenopausal women. 103:638–642. 38:1297–1301. Davis WW. Maturitas. Hormone replacement therapy and the risk of stroke. Barrett-Connor E. N Engl J Med. [PubMed: 12553641] 36. Finucane F. Van Den Noort S. Simon JA. J Am Coll Cardiol. Obstet Gynecol. Stroke risk and tamoxifen therapy for breast cancer. [PubMed: 10326990] 22. 162:1954–1960. and cardiovascular morbidity in women over 50. 2001. Goldstein LB. 168:861–866. [PubMed: 12230417] 25. 55:162–173. 2003. Go AS. Role of time since menopause and age at initiation of hormone therapy. 2006. JAMA. [PubMed: 15494603] 39. Hormone replacement therapy and stroke risk in older women. Lifestyle factors and risk of cerebrovascular disease in women: the Copenhagen City Heart Study. Postmenopausal estrogen use.Bushnell Page 9 18. [PubMed: 18443262] 30. The role of estrogens as a risk factor for stroke in postmenopausal women. Arch Intern Med. National use of postmenopausal hormone therapy. Fung MM. Hormone replacement therapy and risk of nonfatal stroke. Author manuscript. 8:359–364. Decreased risk of stroke among postmenopausal hormone users: results from a national cohort. 2002. Garrison RJ. 1976. 103:445–456. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. J Natl Cancer Inst. Veerus P. et al. Heckbert SR. Hormone therapy and the risk of stroke after acute myocardial infarction in postmenopausal women. Fausone V. 58:33–43. Hovi S-L. et al. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Curr Treat Options Cardiovasc Med. Lemaitre RN. Lindenstrom E. [PubMed: 11691498] 29. 2001. et al. [PubMed: 14709575] 35. 345:1243–1249. Kernan WN. 96:1528–1536. 2000. 2004. Grodstein F. Stafford RS. Pederson AT. et al. Lancet. 2001. 26. Arch Intern Med. Castelli WP. 1993. Hormone replacement therapy and associated risk of stroke in postmenopausal women. Shlipak MG. West J Med. Breslau ES. 102:1225–1232. et al.

Fertil Steril. Delmas P. [PubMed: 15804727] 50. Rossouw J. Grady D. 2005. [PubMed: 16754727] 42. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Harman S.Bushnell Page 10 40. 295:2727–2741. 2004. Brinton E. Utian WH. Barrett-Connor E. 2007. 2009. et al. Banka C. Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Clarkson T. Estrogen replacement therapy. 8:3–12. Mikkola T. Obstet Gynecol. Costantino JP. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. 53:605–619. et al. Cardiovasc Res. Archer DF. 2006. Hodis H. [PubMed: 15749481] 45. Langer R. 115:1481–1501. 2008. Mosca L. JAMA. ACOG Task Force for Hormone Therapy American College of Obstetricians and Gynecologists Women’s Health Care Physicians: Summary of balancing risks and benefits. et al. [PubMed: 17309915] 49. et al. Vogel V. 2005. Prentice R. 104:128S–129S. Mosca L. Mack W. et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. raloxifene on the risk of developing invasive breast cancer and other disease outcomes. 2007. 15:584–602. Effects of tamoxifen vs. 297:1465–1477. et al. 2007. Postmenopausal hormone therapy in clinical perspective. Wickerham DL. 83:558–566. [PubMed: 17353803] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Curr Treat Options Cardiovasc Med. Bachmann GA. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Cedars M. Benjamin E. [PubMed: 17405972] 46. The effects of tibolone in older postmenopausal women. [PubMed: 18580541] 47. Menopause. 43. et al. JAMA. N Engl J Med. Climacteric. and vascular function. Menopause. Stroke. [PubMed: 11861031] 44. Phillips L. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. [PubMed: 18948611] 41. atherosclerosis. Ettinger B. . 14:944–957. [PubMed: 18703472] Tibolone is approved for treatment of vasomotor symptoms and osteoporosis in Europe. [PubMed: 15458943] 48. Cummings S. 359:697–708. 2002. making it unlikely it will be approved for use in the United States. 2008. 40:147–155. Author manuscript. Manson J. but this randomized trial showed that treatment with this drug increased the risk of stroke. available in PMC 2011 April 12. KEEPS: The Kronos Early Estrogen Prevention Study. Circulation.

68. [19] Wilson et al.01. Estrogen. Sweden Cohort Rosenberg et al.03 Cohort 13. 2525 controls Nonusers. 3.27 2. 1.66 y Estrogen users.86 Case-control 349 cases. HT/ nonsmoker. [20] Fung et al.7 y.12 Cohort 7944 total.91–1. nonusers. 0. 278 HT users Total cohort = 2.63 Study design Patients. 0. ICH.97 1.16 0.08. 1– 7. HT users. 3. 1.98. Author manuscript. [21] Falkeborn et al. CA Cohort 1031 total.00.75–1.8% of controls ? ? Estrogen users.53 National Health and Nutrition Examination Survey Copenhagen City Heart Study Cohort Cohort HT Any stroke (fatal and nonfatal) Nonfatal stroke.76 y. Finland CA retirement community Case-control 1278 total Use > 12 mo in 46% of cases.42–1.03 0.70 0. 0. 349 controls Cases. 1.34–2.02.65 0.14 y Case-control 1234 total. 1513 nonusers) 4716 total (238 stroke events) ? ? Controls.57.65–1.2 y.179. 1. 44.6 Nonfatal. HT.088 HT users 198 cases.75 0.1 y Estrogen users. 396 controls 726 cases.Table 1 Risk of stroke in observational studies of hormone therapy Cohort Danish Nurse Study Northern CA Kaiser Turku. 1.76–1. n HT type Stroke type RR 95% CI 0.629 person-years 1910 total (397 HT users. [15] Petitti et al. [25] Finucane et al.7 y Estrogen (alone or combined) Nonfatal IS 1. 0. 1.37 1. 8.78.55–1.92 0. 485. 3. [26] Lindenstrom et al.70–13.47–0.69–1.21–1. 0.43. 0.79–1.987 person-years. [27] NIH-PA Author Manuscript Bushnell 0.09 0. median 3.17–1.27. WA Case-control Northern CA Kaiser Case-control Estrogen (alone or combined) Estrogen (alone or combined) Estrogen (alone or combined) IS (fatal and nonfatal) IS (fatal and nonfatal) IS (fatal and nonfatal) Lemaitre et al. controls. 409.59–1. 0.91 1.98–2.01 Grodstein et al.49 0.3 y. 988 HT users ? Estrogen Nonfatal IS 0.174 personyears. 0–43 y) Estrogen (alone or combined) IS (fatal and nonfatal) 1.74.24. [17] Pfeffer and Van Den Noort [18] Danish National Patient Register Framingham Heart Study Rancho Bernardo. 8.77 0. total of 23. 0. fatal.5 y Estrogen (alone or combined) Estrogen (alone or combined) Estrogen (alone or combined) Estrogen (alone or combined) IS (fatal and nonfatal) Cerebrovascular disease and IS Stroke (fatal and nonfatal) IS (fatal and nonfatal) All estrogens Any stroke 1.17–1. available in PMC 2011 April 12.13. Seattle. IS. [23] Group Health. 0.122 total.62 NA 0. 7. fatal stroke.95 0. 1.29–1. 3674 HT users 6 y (range. [16] Sourander et al.84 NIH-PA Author Manuscript Page 11 NIH-PA Author Manuscript . [22] Uppsala. 302 HT users Case-control 4593 total Pederson et al. 3. 8. 2.57 Duration of exposure Study Lokkegaard et al. [24] Nurses’ Health Study Cohort Curr Treat Options Cardiovasc Med.41 ? HT Any stroke HT/smoker.00–1.70.

Study National Registry of MI Cohort 114. available in PMC 2011 April 12. [28] HT—hormone therapy. NA—not available. NIH-PA Author Manuscript Page 12 NIH-PA Author Manuscript NIH-PA Author Manuscript Curr Treat Options Cardiovasc Med. RR—relative risk.89 0. n HT type Stroke type RR 95% CI Duration of exposure Bushnell Angeja et al.371 nonusers) ? HT IS (fatal and nonfatal) 0. ICH—intracerebral hemorrhage.724 total (7353 HT users.18 Cohort Study design Patients. IS—ischemic stroke. 107. Author manuscript.66–1. .

Author manuscript.83–1. HT—hormone therapy. [30] Viscoli et al. WHI—Women’s Health Initiative.00 1.90 4.70–1.38–6.90–20. 8102 CEE. 494. 327 2.55 HT.1 Ischemic 2–5* Stroke only CEE/MPA Cerebrovascular diseases (ICD-10 I60–I69) CEE All HT. RR—relative risk.80–1.85–1.90–9.67 Patients.58–2. 5310. Curr Treat Options Cardiovasc Med. [33] Estonian Trial Blind HT.83–1.09–1. 10th revision. available in PMC 2011 April 12. 1383 4.90 0.20 1.2 0.73–3.82 0. 373 * Median follow-up was not given.50 1. placebo. 507.40 1.73 1.66 1. MPA— medroxyprogesterone acetate.18 0.61 2. HERS—Heart Estrogen–Progestin Replacement Study.09–1. placebo. placebo. control. 8506.61 1.77 0.24 1.01 0. 1380. [14••] WHI Veerus et al.38–6.10 0.4 1.44 1.Table 2 Bushnell Risk of stroke in randomized controlled trials of hormone therapy Cohort HERS Fatal Nonfatal WEST Nonfatal Ischemic Fatal WHI Fatal 7. open HT.61 0. CEE—conjugated equine estrogen. 5429 5. NIH-PA Author Manuscript Page 13 NIH-PA Author Manuscript NIH-PA Author Manuscript .18 0.40 0. n Average follow-up.19–2. [31] Wassertheil-Smoller et al.1 CEE/MPA Ischemic 1. 404. placebo.8 17 -estradiol Stroke or death 1. y HT type Stroke type RR 95% CI Study Simon et al. [13] Hendrix et al. WEST—Women’s Estrogen for Stroke Trial.00 0. placebo. 337.37 1.55 1. ICD-10—International Classification of Diseases.6 CEE/MPA Ischemic 1.77 Estrogen.