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Abstract

HRT, consisting of estrogens alone, or in combination with a progestogen, is widely used for the relief of symptoms in postmenopausal women. Early observational studies have suggested that HRT might be associated with a reduced risk of cardio- and cerebro-vascular events. These encouraging results prompted randomized controlled trials assessing the risks and benefits of HRT in primary and secondary prevention of arterial vascular events. However, these clinical trials and further observational studies did not confirm the protective effect of HRT; it is now established that HRT increases the risk of stroke. This increased risk is mainly related to an increased risk of ischemic stroke. Oral estrogen alone and combined with progestogen are associated with a similar increased risk, which may be dose dependent. Conversely, a low dose of transdermal estrogens with or without a progestogen does not seem to be associated with such an increased risk of stroke, whereas the impact of tibolone, a synthetic steroid, remains uncertain. In summary, there is now a large amount of evidence demonstrating that HRT is associated with increased risk of stroke, in particular, ischemic subtype.

Keywords

cardiovascular disease drug safety estrogen therapy menopause

HRT, involving giving sex steroid hormones such as estrogen alone or with a progestogen, is widely used in postmenopausal women [1]. HRT helps to relieve menopausal symptoms and has also been shown to prevent osteoporosis. The observation that the incidence of stroke is lower in women than in men and that the incidence of stroke steadily increases after menopause was believed to be, at least in part, related to a protective effect of endogenous estrogens. This hypothesis was corroborated by biological studies showing that estrogens may play a role in vascular protection, although it later appeared that their effect on the vascular bed was more complex than previously believed [2,3].

These initial observations rapidly prompted research into the potential benefit of HRT for primary and secondary prevention of cardio- and cerebro-vascular diseases in postmenopausal women. The earliest observational studies were especially encouraging, showing in general a substantial reduction or no effect in the risk of both types of events. These results logically led to randomized controlled trials (RCTs) assessing the efficacy of HRT in the primary and secondary prevention of arterial vascular events, including stroke, with the well-known negative results that followed. Not only was no benefit demonstrated, but HRT was actually found to be associated with an increased risk of stroke.

In this article we will discuss the relationship between HRT and the risk of stroke, including the effect on subtypes of stroke, the variation in risk associated with the different types of HRT, estrogens and estrogen doses.

HRT & the risk of stroke

The risk of stroke associated with the use of HRT has been examined in several observational studies and RCTs. The earliest observational studies reported either no association between HRT use and stroke or a decreased risk in postmenopausal women taking HRT compared with nonusers [4 –20]. One exception was the Framingham cohort study, which reported a twofold increased risk of cerebro-vascular events (stroke or transient ischemic attack) among HRT users after adjustment for other risk factors. The study reported that postmenopausal estrogen users were 2.3-times more likely to suffer a stroke [21]. Later, the Nurses' Health Study, another large prospective cohort with 16 years of follow-up, reported no association between current use of HRT and the risk of stroke. However, when ischemic stroke was analyzed separately, an increased risk of ischemic stoke was found in current users of HRT [22]: the relative risk (RR; note that RR is also used generically throughout the paper to refer to the rate ratio and the hazard ratio) of ischemic stroke was 1.63 (95% CI: 1.10–2.39) for current users of estrogen alone and 1.42 (95% CI: 0.73–2.75) for current users of estrogen combined with progestin.

Following these initial observations that the risk of stroke may actually differ from that of cardiovascular events, more attention was paid specifically to the risk of stroke. Most of the earlier observational studies did not differentiate between ischemic and hemorrhagic stroke, two entities with different physiopathology, and therefore potentially differently affected by HRT. The definition of HRT exposure varied between studies as well as by the type of HRT assessed. This may have partly explained the discrepancies between earlier studies.

A reanalysis of the Nurses' Health Study cohort after up to 20 years of follow-up, including 70,533 women, showed an increased risk of ischemic stroke in current users of HRT compared with never-users (RR: 1.26; 95% CI: 1.00–1.61) [23]. Using the UK's General Practice Research Database (GPRD), Arana and colleagues showed that recent HRT use was associated with an increased risk of transient ischemic attack and ischemic stroke, although the results were not statistically significant for stroke [24].

Few RCTs have specifically examined stroke outcome associated with taking HRT in primary or secondary prevention based on the premise of earlier observational studies showing a potential benefit of HRT in preventing cardio- and cerebro-vascular events.

Two RTCs found no effect of HRT on the risk of stroke in women with previous coronary artery disease [25,26]. In the Heart and Estrogen/Progestin Replacement Study (HERS), HRT was associated with a RR of stroke of 1.23 (95% CI: 0.89–1.70) [26]. Fatal stroke occurred more often in women taking HRT, and the results were not statistically significant. However, stroke was a secondary outcome and the number of events was small. The open-label follow-up of the HERS study confirmed the absence of effect of HRT on the risk of stroke (mean follow-up: 2.7 years after the completion of the initial RCT) [27]. Another RCT, the Women's Estrogen for Stroke Trial (WEST) specifically assessed the role of estrogen for secondary prevention of stroke in women who recently had a transient ischemic attack or an ischemic stroke [28]. The primary end point was death from any cause or nonfatal stroke. Women were randomly assigned to 17-β estradiol or placebo. Estrogen therapy did not reduce mortality (RR: 1.2; 95% CI: 0.8–1.8) or the risk of nonfatal stroke (RR: 1.0; 95% CI: 0.7–1.4), but was associated with a numerically higher risk of fatal stroke (RR: 2.9; 95% CI: 0.9–9.0). Nonfatal strokes were associated with slightly worse neurologic and functional deficits.

Finally, the Women's Health Initiative (WHI) study was a large, randomized, double-blind, placebo-controlled trial designed to test the effects of the most commonly used postmenopausal hormone therapy preparation in the USA, namely conjugated equine estrogen and medroxyprogesterone [29]. The estrogen–progestogen trial was stopped 3 years before its planned termination date because of an observed increased risk of breast cancer and vascular events, including stroke [30]. The study included 16,608 postmenopausal women followed on average for 5.6 years. Stroke occurred in 151 women taking HRT and 107 women taking placebo, approximately 80% being ischemic stroke. Women taking HRT had a 31% increased of stroke (hazard ratio: 1.31; 95% CI: 1.02–1.68). This increase translates to a number needed to treat of 181 women over 7 years to produce one additional stroke. The estrogen-alone component of the trial enrolled 10,739 postmenopausal women with prior hysterectomy to receive either 0.625 mg of conjugated equine estrogens or placebo and was also closed prematurely after a mean follow-up of 6.8 years [31,32]. Overall, 295 women experienced a stroke during an average follow-up of 7 years (80% ischemic stroke), 168 taking estrogen and 127 taking the placebo; those women taking estrogen had an increased risk of stroke (hazard ratio 1.37; 95% CI: 1.09–1.73) [32]. An analysis by subtypes of stroke showed that the excess stroke risk was driven by an excess risk of ischemic stroke (RR: 1.55; 95% CI: 1.19–2.01) without an increase in the risk of hemorrhagic stroke (RR: 0.64; 95% CI: 0.35–1.18).

Recent meta-analyses have confirmed the hypothesis that the increased risk of stroke is driven by the excess of ischemic strokes. A meta-analysis of observational studies found an overall increased stroke risk (RR: 1.12; 95% CI: 1.01–1.23), but a 20% increased risk of ischemic stroke when analyzed separately (RR: 1.20; 95% CI: 1.01–1.40) [33]. A recent meta-analysis of RCTs confirmed that HRT was associated with a 30% increased risk of stroke (RR: 1.29; 95% CI: 1.13–1.47). This excess risk was related to an increased risk of ischemic stroke (RR: 1.29; 95% CI: 1.06–1.56), whereas there was no evidence of an excess risk of hemorrhagic stroke (RR: 1.07; 95% CI: 0.65–1.75) [34]. Taking HRT was also associated with a worse stroke outcome, defined as death or disability (RR: 1.56; 95% CI: 1.11–2.20). The increased stroke severity with use of HRT was confirmed in a subsequent meta-analysis using ordinal data analyses (RR: 1.31; 95% CI: 1.12–1.54) [35]. Overall, there is no convincing evidence to suggest that HRT affects the risk of hemorrhagic stroke and the increased risk of stroke appears to be essentially related to ischemic stroke. However, these estimates are usually based on a small number of cases as the proportion of hemorrhagic strokes represents only 15–20% of all strokes. Thus, even the nonstatistical significance of the pooled rate ratio of hemorrhagic stroke (RR: 1.07) cannot exclude rate ratios of 1.75, the upper 95% confidence limit.

HRT & the risk of stroke by hormone type

Most of the earlier observational studies involved the use of estrogens alone, with few examining the risk of stroke with both regimens, estrogen alone or combined with a progestogen. As mentioned previously, these studies found no increased risk of stroke and no differences between the effects of estrogen alone or in combination with progestogen [5,13,15]. For instance, in a large case–control study from the Danish national patient register, odds ratios of ischemic stroke were 1.16 (95% CI: 0.86–1.58) for current use of estrogen alone and 1.17 (95% CI: 0.92–1.47) for estrogen combined with progestogen [13]. From the large Nurses' Health Cohort study, it was shown that both estrogen alone or combined with a progestogen increased the risk of ischemic stroke with rate ratios being 1.63 (95% CI: 1.10–2.39) and 1.42 (95% CI: 0.73–2.75), respectively [22]. In the longer follow-up from the same cohort, estrogen with progestogen was associated with an increased risk of stroke (RR: 1.45; 95% CI: 1.10–1.92), but not conjugated estrogen alone (RR: 1.18; 95% CI: 0.95–1.46), although no analyses examined the risk of ischemic stroke separately [23]. In addition, using the UK's GPRD, a 30% increase in transient ischemic attacks was found, irrespective of the type of regimen used [24]. A recent observational study which also used the GPRD and was sufficiently large to study the outcome of stroke, confirmed an increased risk of stroke with both regimens [36]. Current use of oral estrogens alone increased the risk of stroke by 35% (RR: 1.35; 95% CI: 1.16–1.58) and current use of oral estrogens plus progestogen by 24% (RR: 1.24; 95% CI: 1.08–1.41).

Recent meta-analyses combining results from RCTs found no evidence of differences in the risk of stroke associated with type of HRT. Bath and colleagues found that estrogen alone was associated with a 21% increased risk of stroke (RR: 1.21; 95% CI: 0.87–1.67) and estrogen with progestogen was associated with a 32% increased risk (RR: 1.32; 95% CI: 1.09–1.60) with no significant heterogeneity between types of HRT [34]. This was confirmed in a subsequent meta-analysis, finding a 30% increased risk of stroke with both types of HRT: estrogen alone (RR: 1.30; 95% CI: 1.07–1.57) and combined regimens (RR: 1.29; 95% CI: 1.06–1.56) [37]. Data were insufficient to separately analyze ischemic and hemorrhagic strokes.

HRT & the risk of stroke by estrogen & progestogen type

Most large observational studies or RCTs have been based on the use of conjugated equine estrogens that are commonly used in the USA. In Europe, other forms of estrogen, such as estradiol are also used, but studies generally did not present separate results according to the estrogen form. Consequently, information on the potentially different risk of stroke according to the use of conjugated estrogens or estradiol is limited. In a recent meta-analysis of RCTs, subgroup analyses by estrogen type did not show any difference between both types [35].

Similarly, variation in the risk of stroke according to the type of progestogen used is uncertain. Different progestogens are used, medroxyprogesterone in North America and various types in Europe, such as 19-nortestosteron derivatives. No RCT assessed the risk of stroke according to the type of progestogen used and most trials have used medroxyprogesterone. In the WHI study, the addition of medroxyprogesterone did not seem to increase the risk of stroke. One observational study has found that the addition of progestogen increased the risk compared with the use of estrogen alone [38]. In this study, however, the estrogen was not conjugated equine estrogen, but 17-β estradiol. Therefore, the influence of progestogen type cannot be disentangled from the influence of the estrogen type.

HRT & the risk of stroke by estrogen dose

Few studies have specifically addressed the issue of estrogen dose and the risk of stroke. The earliest studies that examined this aspect did not show any difference according to the estrogen dosage, although they were also not able to identify the increased risk of stroke that was subsequently confirmed [12,39].

A dose–response relationship was found in the Nurses' Health Study with an increased risk of stroke with current use of higher doses of oral conjugated estrogens [22,23]. The risk of stroke was increased among women taking 0.625 mg oral conjugated estrogens (RR: 1.35; 95% CI: 1.08–1.68) and among those taking 1.25 mg or more (RR: 1.63; 95% CI: 1.18–2.26) [23]. This dose–response relationship became even more pronounced when specifically examining the risk of ischemic stroke with RRs of 1.44 (95% CI: 1.07–1.93) and 2.00 (95% CI: 1.32–3.05), respectively. The risk of hemorrhagic stroke was less consistent and based on too few cases to draw any meaningful conclusion. Arana and colleagues also found an estrogen dose-dependent increased risk of transient ischemic attacks [24]. In a population-based observational study using a nested case–control analysis to assess the risk of stroke associated with high or low estrogen doses of transdermal and oral formulation using the same GPRD database, low-dose patches did not increase the risk (RR: 0.81; 95% CI: 0.62–1.05) compared with no use, whereas the risk was increased with high-dose patches (RR: 1.89; 95% CI: 1.15–3.11). The increased risk of stroke associated with the current use of oral formulations was virtually the same with low dose (RR: 1.25; 95% CI: 1.12–1.40) and high dose (RR: 1.48; 95% CI: 1.16–1.90) compared with no use, although the point estimate was higher with a higher dosage of estrogen (>0.625 mg of equine estrogen or >2 mg of estradiol) [36].

HRT & the risk of stroke associated with route of administration

Data on the risk of stroke according to the route of administration are scarce. Clinical trials evaluated oral HRTs and did not explore other routes of administration. Most observational studies exclusively assessed the oral route of administration or did not differentiate between oral and transdermal routes of administration. An observational study suggested a lower risk of transient ischemic attack with transdermal estrogen use compared with oral estrogen, but the risk of stroke could not be estimated because of the small number of cases [24]. Using the UK GPRD, a recent large population-based observational study showed that the use of low-dose transdermal estrogen replacement therapy (≤50 μg) with or without progestogen was not associated with an increased risk of stroke (RR: 0.81; 95% CI: 0.62–1.05) compared with no use, whereas the risk was increased with high-dose patches (RR: 1.89; 95% CI: 1.15–3.11) as well as with oral HRT [36]. Direct comparison of transdermal HRT with oral therapy showed that the risk of stroke was lower among transdermal users (RR: 0.74; 95% CI: 0.58–0.95).

Transdermal estrogen preparations are as effective as oral estrogens in the treatment of postmenopausal symptoms and several studies have suggested that the transdermal route exerts a different biological impact by avoidance of the first pass effect in the liver [40]. Oral but not transdermal estrogens induces hepatic protein synthesis of clotting factors and various inflammation markers [41 –43]. These differences have been attributed to the high concentration of estrogens in the portal circulation after oral administration and their subsequent first-pass metabolism in the liver, whereas the transdermal route avoids this first pass effect in the liver [41]. Thus, different routes of administration of HRT may be associated with a different risk of stroke.

HRT & the risk of stroke associated with timing of initiation of HRT

Regarding the effect of timing of HRT treatment and the risk of stroke, there are no data to date indicating that women taking HRT early after menopause would have a different risk than women taking HRT later. Recent observational studies addressing this particular question did not find any evidence for a different effect of HRT according to age or time since menopause and initiation of HRT. Using the GPRD, Weiner and colleagues found that the relative risk of stroke was 1.52 (95% CI: 1.11–2.08) for women younger than 55 years of age and 1.23 (95% CI: 0.99–1.52) for women over 55 years of age at the start of HRT [44]. Similarly, in the Nurses' Health Cohort study, no differences were observed in the increased risk of stroke according to initiation of HRT at young ages or near menopause and at older ages or even more than 10 years after menopause [45]. Only short-term users (<5 years) initiating HRT at younger ages had no clear increased risk of stroke; however, this result was based on a small number of cases leading to wide confidence intervals precluding any firm conclusion.

The WHI study, the main RCT that investigated the risks and benefits of HRT in the primary prevention of stroke, included women aged 50–79 years, with approximately 30% in the 50–59 years age group at inclusion [30,32]. The risk of stroke appeared similar whether women initiated HRT at a younger or older age, but although a large number of women were included, the number of stroke cases was low, particularly in this lowest age group, as expected. The authors acknowledged that the numbers of events in the subgroups in the individual trials were too small to provide definitive answers regarding the effect of age or time since menopause at initiation of HRT. A secondary analysis of the combined trials performed to increase power showed an increased risk of stroke, with no statistically significant variation by age or time since menopause [46].

Other

Tibolone is a selective tissue estrogenic activity regulator used in more than 90 countries for the treatment of menopausal symptoms, but not in the USA [47]. Its unique profile could indicate a different cardiovascular effect, but clinical studies on the cerebrovascular effect of tibolone are lacking. In a case–control study nested within the UK's GPRD and designed to examine the risk of stroke associated with the use of tibolone, the rate ratio of stroke associated with current use of tibolone relative to nonuse of HRT was 1.08 (95% CI: 0.82–1.44) [48]. The rate ratios with current use of estrogens alone and estrogen plus progestogen were 1.26 (95% CI: 1.10–1.45) and 1.19 (95% CI: 1.05–1.36), respectively. Although there was no evidence of an elevated risk of stroke associated with the use of tibolone, the low number of subjects using tibolone in the study does not permit ruling out a risk of the same magnitude as that associated with estrogen or estrogen–progestogen therapy, as indicated by the upper 95% confidence limit. The results of the Long-Term Intervention on Fractures with Tibolone (LIFT) study showed a twofold increased rate of stroke with the use of tibolone [49]. This RCT, which was primarily designed to test the effect of tibolone in reducing the risk of vertebral fracture, provides the highest level of evidence of an increased risk of stroke using this drug in older women.

Conclusion

An increased risk of stroke associated with HRT use has been consistently found among most recent observational studies and RCTs published to date (Table 1). This excess risk is mainly driven by an increase in the risk of ischemic stroke. Oral forms of estrogens, alone or in combination with a progestogen, appear to be associated with identical increased risks of stroke, although the conjugated equine estrogens alone or combined with medroxyprogesterone acetate were more frequently studied than other estrogens or progestogens. By contrast, a large population-based study showed that low doses of transdermal estrogens were not found to be associated with an excess risk. Stroke risk associated with different routes of administration has not been assessed in a RCT. Uncertainties remain regarding whether other treatments for menopausal symptoms, such as tibolone, have a similar risk profile.

Table 1.

Summary of meta-analyses of observational studies and randomized trials on the risk of stroke associated with the use of HRT, by type of stroke and type of therapy.

	Studies (n)	Patients (n)	Rate ratio (95% CI)	Ref.
Observational studies
Overall stroke	9	NR	1.12 (1.01–1.23)	[33]
Ischemic stroke	4	NR	1.20 (1.01–1.40)
Subarachnoid	3	NR	0.80 (0.57–1.04)
Intracerebral	4	NR	0.71 (0.25–1.29)
Randomized trials
Overall stroke	28	39,769	1.29 (1.13–1.47)	[34]
Ischemic stroke	16	23,426	1.29 (1.06–1.56)
Hemorrhagic stroke	17	23,690	1.07 (0.65–1.75)
Randomized trials
Estrogen only	12	14,256	1.21 (0.87–1.67)	[34]
Estrogen only	3	76,855†	1.30 (1.07–1.57)	[37]
Estrogen + progestin	16	25,513	1.32 (1.09–1.60)	[34]
Estrogen + progestin	3	105,330†	1.29 (1.06–1.56)	[37]

†

Patient-years. NR: Not reported.

Future perspective

It is evident that women undergoing menopause will continue to require and request treatment for its vexing symptoms. While new treatments will be tested in RCTs to evaluate their effectiveness at reducing these symptoms, observational studies will be needed to assess unintended effects. The methodological flaws of the earlier observational studies that suggested a benefit of HRT on cardiovascular outcomes are now well known and should not be repeated in the future. The newer observational studies investigating the risks of HRT that used more accurate methods, have led to results that are more consistent with those of randomized trials. The future should see the application of such proper epidemiological methods in forthcoming studies, along with existing healthcare databases and computerized medical records, in order to quickly provide essential data on the safety of new treatments for menopause. As for existing treatments for menopause, uncertainties still remain regarding, for instance, the exact effects of different types and doses of progestogens, as well as variations in the risk in women with different vascular risk factors. This essential knowledge will not only enable physicians to prescribe HRT more accurately, balancing benefits and risks, but will also indirectly increase our understanding of mechanisms of action of sex steroids hormones on the vascular system.

Executive summary

HRT, consisting of estrogens alone, or in combination with a progestogen, was believed to reduce cardiovascular risk.

New studies show that HRT is associated with an increased risk of ischemic stroke, but not hemorrhagic stroke.

The increased risk is of the same magnitude with oral estrogens alone and combined with progestogens.

Low-dose transdermal estrogens with or without a progestogen are not associated with an increased risk of stroke.

The risk with tibolone, a synthetic steroid, remains uncertain.

Footnotes

Samy Suissa has received research grants and honoraria from three pharmaceutical companies that make HRT, Organon, Bayer and Wyeth. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Hormone Therapy Administration in Postmenopausal Women and Risk of Stroke

Abstract

Keywords

HRT & the risk of stroke

HRT & the risk of stroke by hormone type

HRT & the risk of stroke by estrogen & progestogen type

HRT & the risk of stroke by estrogen dose

HRT & the risk of stroke associated with route of administration

HRT & the risk of stroke associated with timing of initiation of HRT

Other

Conclusion

Future perspective

Footnotes

References