STATE-OF-THE-ART PAPER
Hormone Replacement Therapy and the Cardiovascular System
Lessons Learned and Unanswered Questions
Pamela Ouyang, MB, BS, FACC*,a,*,
Erin D. Michos, MD* and
Richard H. Karas, MD, PhD, FACC ,b
* Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Molecular Cardiology Research Center and the Division of Cardiology, Tufts-New England Medical Center, Boston, Massachusetts
Manuscript received October 5, 2005;
accepted October 21, 2005.
* Reprint requests and correspondence: Dr. Pamela Ouyang, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, A1 East, Baltimore, Maryland 21224 (Email: pouyang{at}jhmi.edu).
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Abstract
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Cardiovascular disease is the leading cause of death among women in the U.S., exceeding breast cancer mortality in women of all ages. Women present with cardiovascular disease a decade after men, and this has been attributed to the protective effect of female ovarian sex hormones that is lost after menopause. Animal and observational studies have shown beneficial effects of hormone therapy when it is initiated early in the perimenopausal period or before the development of significant atherosclerosis. However, randomized, placebo-controlled trials in older women have not shown any benefit in either primary prevention or secondary prevention of cardiovascular events, with a concerning trend toward harm. This review outlines the lessons learned from the basic science, animal, observational, and randomized trials, and then summarizes yet-unanswered questions of hormone therapy and cardiovascular risk.
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Abbreviations and Acronyms
| | CHD = coronary heart disease | | CI = confidence interval | | CRP = C-reactive protein | | HDLC = high-density lipoprotein cholesterol | | HT = hormone therapy | | IMT = intima-medial thickness | | LDLC = low-density lipoprotein cholesterol | | MI = myocardial infarction | | MPA = medroxyprogesterone acetate |
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Cardiovascular disease is the leading cause of death among women in the U.S., accounting for more than 500,000 deaths annually (1). Mortality attributable to coronary heart disease (CHD) exceeds breast cancer mortality in women at all ages (2). The vast majority of these cardiovascular events occur in postmenopausal women. Heart disease develops in women on average 10 years later in life compared with men, and this lag has been attributed to the protective effects of female sex hormones, particularly estrogens, before menopause (3).
Initially, data from animal studies and observational studies such as the Nurses’ Health Study (4) strongly supported a protective cardiovascular benefit of hormone therapy (HT) after menopause, an effect not supported by randomized placebo-controlled trials in both secondary prevention (5) and primary prevention (6), which instead showed a concerning trend toward harm. However, many unanswered questions remain.
This review outlines lessons learned from basic science of estrogen action and animal studies and from observational and randomized trials, followed by a discussion of as-yet-unanswered questions about HT and cardiovascular risk.
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Molecular and cellular basis of estrogen in vascular biology
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Estrogen can have both positive and negative effects on the cardiovascular system (7) (Fig. 1). On the positive side, estrogen has potentially beneficial effects on lipid parameters, such as reducing low-density lipoprotein cholesterol (LDLC) and increasing high-density lipoprotein cholesterol (HDLC), facilitating nitric oxide-mediated vasodilation, and inhibiting the response of blood vessels to injury and the development of atherosclerosis (8). On the negative side, estrogens increase triglycerides (9,10) and inflammatory markers such as C-reactive protein (CRP) (11,12). Estrogen also has many prothrombotic effects, such as increasing circulating levels of prothrombin and decreasing antithrombin III (13,14), contributing to an increased risk of venous thromboembolic events. Importantly, many of these effects of estrogen are mediated by first-pass effects on the liver, and thus result from oral but not transdermal administration of HT. For example, increased levels of CRP seem to occur only with oral estrogen administration. The extent to which this is associated with an increase in cardiovascular disease risk is uncertain (15,16). These observations underscore the potential importance of the mode of administration on the overall effects of HT on CHD risk as discussed below.
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Figure 1 Estrogen: beneficial and thrombogenic effects. CAM = cell adhesion molecule; Cox-2 = cyclooxygenase 2; ER = estrogen receptor; HRT = hormone replacement therapy; LDL = low-density lipoprotein; MCP = monocyte chemoattractant protein; MMP = matrix metalloproteinase; TNF = tumor necrosis factor; VSMC = vascular smooth muscle cell. Reprinted, with permission, from Mendelsohn and Karas (7).
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Mechanisms of estrogen action
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As our understanding of the mechanisms by which estrogens affect the cardiovascular system has increased, it has become clear that the complexity of the biological effects of estrogens are reflective of quite complex mechanisms of action (7,8). As noted above, estrogens regulate a variety of systemic or circulating factors, including lipids, inflammatory factors, and members of the coagulation/fibrinolytic cascades. Estrogens can also act directly on the heart and the vasculature. The effects of estrogen are mediated by estrogen receptors, of which two are known, ER and ERß, and both are expressed in cardiovascular cells and tissues (7,8). Estrogen receptors are classically thought of as ligand-activated transcription factors that reside in the cell nucleus and regulate gene expression in response to hormone binding. This mechanism, often referred to as the genomic pathway, likely underlies the longer-term effects of estrogen, such as those on circulating levels of lipids and coagulation factors. More recently it has become clear that estrogen receptors also transduce the rapid effects of estrogen that occur within minutes (17) and are referred to as non-genomic because they do not depend on changes in gene expression. These rapid effects of estrogen are mediated by a subpopulation of estrogen receptors localized to cell membrane signaling domains called caveolae. The best-studied example of this non-genomic pathway for estrogen action in the cardiovascular system is the activation of endothelial cell nitric oxide synthase that results in arterial vasodilation in response to acute administration of estrogen.
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Impact of disease state on the cardiovascular effects of estrogen
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There is growing evidence showing that the effects of estrogen on the vasculature depend in part on the extent to which atherosclerosis has become established. For example, estrogen receptor expression is markedly diminished in atherosclerotic arteries (18,19), and thus, to the extent that direct, receptor-dependent effects on the vasculature contribute to the potential for anti-atherosclerotic effects, this will be diminished or absent in diseased arteries. In addition, the effects of estrogen on a given pathway may have different consequences depending on the state of health of the underlying vessel. For example, estrogen up-regulates specific members of the matrix metalloproteinase (MMP) family such as MMP-9 (20). The MMPs degrade the extracellular matrix with the arterial wall. Thus, in a non-diseased artery, an estrogen-induced increase in MMP-9 may have little or no consequences, whereas in an atherosclerotic artery, where MMP-9 is expressed in the shoulder region of an atherosclerotic plaque, an increase in MMP-9 activity could conceivably be associated with an increased risk of plaque rupture and thus acute coronary syndromes. The Fitzgerald laboratory has recently shown that estrogen-mediated up-regulation of cyclooxygenase-2 plays an important role in retarding atherosclerosis in a hypercholesterolemic mouse model (21). This suggests that atherosclerotic arteries with impaired cyclooxygenase-2 responses may also lose this potentially beneficial effect of hormone treatment.
More direct support for the hypothesis that the effects of estrogen on cardiovascular risk depend on the timing of initiation of therapy in relation to the extent of underlying atherosclerosis comes from the Clarkson laboratory. Using a well-established monkey model of atherosclerosis, Clarkson and colleagues have shown that the antiatherosclerotic effects of oral conjugated equine estrogens (CEE) are apparent only in monkeys with minimal underlying atherosclerosis at the time that therapy is initiated, as reviewed in Karas and Clarkson (20), a finding also supported by rodent and rabbit studies (22,23).
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Cardiovascular disease and menopause
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Interest in the role estrogen plays in cardiovascular disease was stimulated by the observed increase in cardiovascular events after menopause. In 1976 the Framingham investigators reported a 2.6-fold higher incidence of cardiovascular events in age-matched postmenopausal women compared with premenopausal women (24). The excess CHD risk associated with surgical menopause was 2.7-fold higher compared with premenopausal women of the same age (p < 0.01) (25) and 2.2-fold higher compared with women with a natural menopause. This excess risk seemed to be prevented by estrogen replacement therapy (26). Plasma lipoproteins were thought to play a role in the increased CHD risk that menopause confers because total cholesterol, LDL cholesterol, and triglyceride levels all increase in women after menopause (27), and HT seemed to counter these unfavorable effects of lipids, although the cardioprotective HDL cholesterol levels also decreased (28). In addition, there is an age-associated increase in the incidence of cardiovascular disease for both premenopausal and postmenopausal women independent of the effects of HT. Overall, however, data indicate that withdrawal of estrogen during menopause is associated with an increased risk of heart disease above that seen for premenopausal women. This led to interest in the potential cardiovascular benefit from postmenopausal estrogen replacement therapy.
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Animal studies of hormone replacement
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In animal studies, estrogens exert vasodilator (29), anti-inflammatory (30), and antiatherosclerotic (31) properties, as well as favorably affecting lipid profiles. In a study of randomized ovariectomized hypercholesterolemic rabbits, estradiol significantly reduced atherosclerosis progression compared with levonorgestrel or no hormones (32). A series of studies have also shown that estradiol significantly lessens the response to vascular injury in mice and further implicate ER as the specific estrogen receptor that mediates this vasculoprotective effect (33–36). Similarly in ovariectomized monkeys, 17ß-estradiol or CEE reduced coronary artery atherosclerosis compared with control animals by 50% (p  0.05) (37) to 72% (p < 0.04) (38). Although the role of estrogen replacement seemed promising in the animal studies, the data regarding progesterone were more conflicting (39).
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Observational trials of hormone replacement
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Overall, the animal studies suggested a promising role of estrogen replacement after menopause. Simultaneously, a series of observational and case-control trials also suggested benefit (reviewed in Table 1). The majority of the smaller case-control studies (40–45) showed nonsignificant trends toward reduction in CHD events with overall odds ratios ranging from 0.69 to 0.9. However, a large case-control study did show a significant association with HT and reduced incidence of first myocardial infarction (MI) (46). Longer duration of use seemed to confer even more cardiovascular benefit (47).
In addition to reducing CHD events, cross-sectional data suggested less subclinical atherosclerosis in HT users (48). In an observational analysis of the Cardiovascular Health Study of women >65 years of age, estrogen users had lower levels of subclinical disease as measured by a variety of surrogate end points (49). Even more promising, the much larger observational Nurses’ Health Study of 70,000 asymptomatic women showed a lower incidence of CHD events and all-cause mortality in HT users compared with nonusers (4,50,51). It is important to note that most women in the Nurses’ Health Study likely started taking HT in the perimenopausal period and were free of known CHD at the start of the study.
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Randomized trials of hormone replacement therapy
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The animal and observational studies were followed by a series of randomized, placebo-controlled trials of HT in both primary and secondary prevention, and with both surrogate and cardiovascular event outcomes, which failed to confirm cardiovascular benefit (reviewed in Table 2). Although two smaller randomized trials using the surrogate end points of carotid intima-medial thickness (IMT) (52) and brachial reactivity (53) favored estrogen, three other randomized trials looking at atherosclerotic progression by coronary angiography showed no benefit (54–56). In women who already had coronary disease (57) or increased subclinical atherosclerosis on carotid IMT assessment (58,59), HT had no impact on disease progression. Also in a study of postmenopausal women presenting with unstable angina, acute HT started in the hospital setting had no effect on reducing further ischemic events evaluated by ambulatory electrocardiographic monitoring (60). Similarly, HT given to women with recent acute stroke did not reduce subsequent stroke or mortality (61).
The Heart and Estrogen/Progestin Replacement Study (HERS) was the first published secondary prevention trial in 2,763 women with known CHD followed up for the primary outcome of the cardiovascular events of nonfatal MI or CHD death. At a mean of 4.1 years, there was no significant difference in the HT arm versus the placebo arm (hazard ratio of 0.99, 95% confidence interval [CI] 0.80 to 1.22) (5). There seemed to be a trend toward benefit at longer durations of therapy, but this was not supported with the longer follow-up period of seven years (hazard ratio of 0.99, 95% CI 0.81 to 1.22) (62).
The largest randomized clinical trial is the Women’s Health Initiative (WHI), which included 16,608 women with an intact uterus randomized to CEE and medroxyprogesterone acetate (MPA) or placebo with a 5.6-year mean follow-up (6). This was stopped early because of an increase in breast cancer among HT users with no cardiovascular benefit. An additional 10,739 women with hysterectomy were randomized to CEE alone or placebo, and that trial also showed no cardiovascular benefit (63). The findings for the combined CEE-MPA arm suggested that for 10,000 person-years there would be seven more CHD events, eight more strokes, eight more pulmonary embolisms, and eight more invasive breast cancers. For the CEE alone group, there would be an absolute excess of 12 strokes per 10,000 people despite a risk reduction of 6 fewer hip fractures. The WISDOM trial (64), based in the United Kingdom with a design similar to the WHI trial, was discontinued in 2002 after the results of the WHI trial were published.
Randomized placebo-controlled trials reduce many of the biases inherent in observational studies but have other limitations. The WHI trial is a very important study that has changed the national view of HT. Although primarily a primary prevention trial, a small number of patients did have established disease, including a history of MI (1.6%), history of angina (2.8%), history of coronary bypass surgery/percutaneous coronary intervention (1.1%), history of stroke (0.7%), and/or CHD risk factors of diabetes (4.4%), hypertension on therapy (35.7%), and hyperlipidemia on therapy (12.5%). The mean age of 63 years puts the majority of these women at least 10 years after menopause at the time of initiation of HT. There was also significant crossover between the two arms. Of consideration, only one drug regimen, CEE 0.625/MPA 2.5 mg orally per day, was tested, so these findings may or may not apply to lower dosages of these drugs, other formulations, or other routes of delivery.
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Questions to be answered
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Given the findings of the HERS and of WHI trials, is the HT discussion ended for good? Hardly. The conflicting results from animal/observational studies compared with the randomized controlled trials raise many unanswered questions. These include whether some of the discrepancy is related to the age of the women in the studies, the timing of initiation (perimenopausal or postmenopausal), the amount of atherosclerosis at the time of initiation (primary vs. secondary prevention), the dosage, and the preparation form (transdermal, oral, or intravenous with or without progesterone), and whether there are genetic aspects to benefit or harm from HT.
Recently, Prentice et al. (65) reanalyzed the data from the observational trials adjusting for time from estrogen-plus-progestin initiation and confounding variables, and found that the readjusted hazard ratio estimates between the observational and experimental trials became much more similar for outcomes of CHD and thromboembolism, although less so for stroke (65). These analyses suggest that the apparent discrepancies between clinical trial and observational study findings may be substantially explained by classical confounding and differences in distributions of time of initiation.
Timing of initiation.
Because atherosclerosis accelerates after estrogen deficiency, it would seem logical that estrogen replacement would have the most benefit when starting early in perimenopausal women. Most women in the observational trials such as the Nurses’ Health Study, which suggested a protective effect of estrogen, started HT during the perimenopausal transition (66), whereas the WHI trial contained too few women in the perimenopausal period to evaluate whether any cardiac protection was seen. In the WHI trial the average age was 10 years after menopause, an age at which subclinical atherosclerosis has developed in many women (67).
In support of the notion that timing of initiation is critical, animal studies also showed no benefit of estrogen in animals that already had artery damage, either from balloon injury or from atherosclerotic diet, before initiation of HT (68). These animal studies are consistent with the findings of the secondary prevention (i.e., HERS) trials. In postmenopausal women in the Cardiovascular Health Study, estrogen replacement only caused vasodilation of the brachial artery in younger women without clinical or subclinical cardiovascular disease, suggesting that the favorable effects of estrogen may be limited to only those in whom atherosclerotic vascular disease has not yet developed (69).
The Kronos Early Estrogen Prevention Study (KEEPS) is a multicenter randomized placebo-controlled clinical trial that will evaluate the effectiveness of 0.45 mg CEE or 50 µg transdermal estradiol (in combination with 200 mg progesterone) in preventing the progression of carotid IMT or coronary calcium in women who are within 36 months of their final menstrual period (70). It is hoped that the KEEPS trial will provide some answers to the important question of whether HT will have a beneficial role if started early, although a relatively small sample size and the use of a surrogate end point represent limitations of this study. Hodis et al. (71) have recently launched the Early vs. Late Intervention Trial with Estrogen (ELITE), which is also focused on examining the potential importance of time since menopause on the cardiovascular effects of HT. In the ELITE study, the effects of oral 17ß-estradiol on carotid IMT will be compared directly in perimenopausal women versus those >6 years after menopause.
Dose.
Although 0.625 mg CEE clearly showed no cardiovascular benefit in the HERS and WHI trials, the observational Nurses’ Health Study found the protective effect of CEE only in the lower doses of 0.3 mg and 0.625 mg, whereas 1.25 mg and higher doses were not protective. In a small randomized, double-blind crossover trial by Koh et al. (13) of 57 postmenopausal women on progesterone, lower-dose CEE 0.3 mg compared with 0.625 mg had similar favorable effects on HDL, triglycerides, and brachial reactivity, but had fewer prothrombotic effects and a smaller increase in CRP. In postmenopausal diabetic women without a recent MI among the Kaiser Permanente database, low-dose or medium-dose estrogen (<0.625 mg) decreased the risk of MI, which was not seen with a higher dose (72). Whether a lower dose of estrogen such as 0.3 mg CEE would provide cardioprotection without increasing thromboembolism remains to be seen.
Route of delivery.
The formulation of estrogen used in the large clinical trials and in the majority of the smaller studies was CEE with or without MPA. There are extremely limited randomized trial data for other preparations of HT. Transdermal estrogen delivery provides sustained release of estrogens and more constant blood levels than oral administration. When estrogen is given orally, it has first-pass effects on the liver. Transdermal preparations avoid the first-pass effects on the liver and have less effect on the lipoprotein profile (73). Estradiol-to-estrone conversion is slower in parental administration, but transdermal delivery more commonly facilitates an estradiol-estrone ratio of about 1, which is similar to the physiological ratio in the pre-menopausal state.
Other differences that favor the transdermal approach include a neutral effect on CRP, a decrease in factor VII and fibrinogen, and a reduction in blood pressure (74). Because the first pass through the liver is avoided, there may be less induction of a prothrombotic state with the transdermal preparation. The Estrogen and Thromboembolism Risk study Group (ESTHER) case-controlled trial found that oral estrogen but not a transdermal formulation increased the risk of venothromboembolism in postmenopausal women on HT compared with control subjects (75).
In a case-controlled study, transdermal users seemed to have similar level of cardioprotective effects as those receiving oral preparations (46). These effects are not significant, but this may be attributable to small sample size. However, an animal study using transdermal estradiol did not find inhibition of aortic atherosclerosis (76).
Overall, the benefits of a transdermal estrogen preparation over an oral one seem encouraging, but further randomized trials are warranted (77). It is hoped that the KEEPS trial (70), which will randomize healthy perimenopausal women to oral versus transdermal hormone replacement, will provide information on this important question.
Genetics.
It is possible that genetically determined subgroups of women may benefit by or be harmed from HT. Studies have shown that the cardiovascular effects of HT differ in individuals with specific genetic variants of certain genes such as apolipoprotein E4 (–) and myeloperoxidase (78,79). Recent work has also shown that genetic variation in the estrogen receptor itself may modulate the cardiovascular effects of HT, and also alter the underlying risk of CHD. The Herrington laboratory recently showed that a specific genetic variant of ER is associated with an enhanced HDL-increasing effect of HT (80). Quite surprisingly, this same genetic variant of ER was also recently shown to be associated with an approximately three-fold increased risk of MI in men in the Framingham heart study (81).
Statin use.
Perhaps concomitant statin use may attenuate the negative cardiovascular effects of HT. Subgroup analysis of the HERS trial showed that the increased cardiovascular risks of HT in this population of women with established CHD did not occur in women taking statin therapy; however, there was no incremental risk reduction for cardiovascular events in women on both statin and HT compared with statin alone (82).
Summary.
In conclusion, the HT controversy has not yet been laid to rest. Current randomized clinical trial data support the American Heart Association/American College of Cardiology guidelines that HT should not be prescribed for prevention of cardiovascular disease (83,84). However, it remains possible that some formulations and doses of HT may have favorable cardiovascular benefits when initiated earlier in the pre-menopausal or perimenopausal period in women without pre-existing atherosclerotic disease. We await the KEEPS and ELITE trial results, among others, to further answer this important issue.
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Footnotes
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a Dr. Ouyang was supported by grants M01RR02719 and R01HL074406 from the National Institutes of Health. 
b Dr. Karas is an Established Investigator for the American Heart Association.
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Abstract
Molecular and cellular basis...