Cardiovascular disease (CVD) is the overall leading cause of death in women. More women die from CVD than from cancer, chronic lower respiratory diseases, and Alzheimer’s disease combined. A report on heart disease and stroke statistics from the American Heart Association cited that CVD caused about one death per minute among females as early as 2008 [1]. Differences in the incidence of cardiovascular disease between men and women have been assumed to be age-related, with menopause believed to be a key turning point for women. Compared with a group of age-matched men, premenopausal women have been shown to have significantly less morbidity and mortality from cardiovascular diseases, and cardiovascular disease events such as myocardial infarction [2]. After menopause however, the risk of cardiovascular disease including coronary heart disease in women increases. Declining ovarian function that results in estrogen deficiency and increasingly adverse lipid profiles has been observed as a contributing factor [3]. As a general trend, the prevalence of CVD has been demonstrated to be virtually the same for men and women by the age of 40, and by 60 years of age, women have a higher prevalence of CVD than men[4]. Since the mid-1980’s, a greater number of women died annually in the U.S. from CVD than men [1].
Hormone replacement therapy (HRT) is often prescribed by clinicians to restore the levels of estrogen, progesterone, and other hormones in postmenopausal women. Some clinicians prescribe HRT to alleviate symptoms of menopause such as hot flashes and vaginal atrophy, while others less commonly prescribe HRT for prevention of chronic diseases such as CVD and osteoporosis. The landscape for HRT is dynamic, and the rationale for HRT utilization is varied. While the relationships between age and the development of heart disease are well-documented in men and women, the role that estrogen plays in CVD has not yet been fully understood. Large authoritative studies from the 1980s and ’90s affirmed that estrogen is beneficial for a woman’s cardiovascular system while more recent results from the Women’s Health Initiative (WHI) clinical trials suggested just the opposite. Further complicating matters, re-analysis of the WHI data suggested that women may benefit from estrogen replacement as long as they do not take it for too many years or begin its use too many years after menopause onset. This article reviews and highlights the largest clinical studies on hormone replacement therapy and also provides a fresh perspective on the increased prevalence of CVD in postmenopausal women.
Women’s Health Initiative
The Women’s Health Initiative (WHI) was comprised of multiple clinical trials which together involved 161,808 generally healthy, postmenopausal women. The studies were designed to test the effects of postmenopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer. The hormone component was made up of two studies: a study of estrogen-plus-progestin in women with a uterus and a study of estrogen-alone in women without a uterus. In both hormone therapy studies, women were randomly assigned to either the hormone medication being studied or to placebo.
The WHI study of estrogen-progestin combination therapy was published in the Journal of the American Medical Association (JAMA) in 2002 and was comprised of 8,506 healthy postmenopausal women aged 50 to 79 with intact uteri at baseline [5]. The treatment group received 0.625 mg/day of conjugated equine estrogen (CEE) and 2.5 mg/day of medroxyprogesterone acetate (MPA). The WHI study of estrogen monotherapy was published in JAMA in 2004 and was comprised of 5,310 postmenopausal women aged 50 to 79 with prior hysterectomy [6]. The treatment group received 0.625 mg/day CEE. Both of these studies were stopped early because risks were deemed to exceed the benefits of treatment. Higher risks of stroke and thromboembolic events were observed in the HRT groups of both WHI studies. A meta-analysis of 28 clinical trials involving almost 40,000 postmenopausal women corroborated these findings, showing that women taking HRT had 29% increased ischemic stroke risk and overall worse stroke outcome than control subjects [7]. In the case of CEE and MPA combination therapy, there was an increased risk of breast cancer as well.
A follow-up analysis of both abovementioned WHI studies was published in JAMA in 2007. A key finding of the follow-up analysis was that women who initiated HRT sooner after menopause had reduced risk of coronary heart disease (CHD) than those who started HRT later after the onset of menopause. For women who started HRT—either estrogen monotherapy or estrogen-progestin combination therapy—less than 10 years after the onset of menopause, there was no apparent increase in risk of CHD (see Table 1) relative to no-treatment in each study. In contrast, for women who initiated HRT 20 years or more after the onset of menopause, a higher risk of CHD was clearly observed [8]. No subgroup in WHI observed a statistically significant reduction in overall CHD risk, and the risk of stroke was higher among women taking HRT regardless of years since menopause. Authors of the re-analysis stressed that HRT is effective for short-term treatment of vasomotor symptoms during menopause but not for long-term prevention of CVD.
Nurses’ Health Study: What Doses of HRT Should Be Used?
The Nurses’ Health Study (NHS), a large prospective observational cohort study, followed 48,470 post-menopausal women aged 30 to 63 years old for up to 10 years (337,854 person-years). Most of these women, 71.5%, reported using CEE [9]. Among these users, at the first follow-up visit two years after study enrollment, 35.9% took 1.2 mg/day, 36.3% took 0.6 mg/day, and the rest took lower doses [10]. The NHS found that postmenopausal estrogen users had about one-half the risk of major CHD or fatal CVD and no increase in the risk of stroke when compared with women who had never taken estrogen. The NHS investigators concluded that the cardiovascular benefits of postmenopausal estrogen therapy outweighed the risks, separate from the alleviation of systems. Additionally, the study found increased benefit for women taking HRT closer to the onset of menopause.
Importantly, HRT dosing was observed to play a role: the incidence of CHD among women taking more than 1.25 mg per day of CEE was higher than women never taking estrogen, however CHD was significantly lower for women taking lower doses than women never taking estrogen [9].
A follow-up analysis of NHS (see Table 2), published in 2006, confirmed the cardiovascular benefit of HRT as well as the importance of initiating HRT quickly after menopause. The researchers used similar analytic techniques, inclusion criteria, and adjustments for cardiovascular risk factors as those used in the Women’s Health Initiative studies [11]. Compared with those never taking HRT, women starting estrogen monotherapy near menopause had 38% lower relative risk of developing CHD (relative risk of 0.62, 95% CI: 0.52-0.76). Although not statistically significant, women starting the same therapy 10 years or more after menopause had 13% lower relative risk of CHD (relative risk of 0.87, 95% CI: 0.69-1.10). Furthermore, the follow-up analysis reported a relative risk for CHD of 0.71 (95% CI, 0.56-0.89) and 0.90 (95% CI, 0.62-1.29) for women taking combination estrogen-progestin therapy near menopause and 10 years or more after menopause, respectively. This difference was also statistically insignificant.
Overall, the results suggest that women who start hormone replacement closer to the onset of menopause are at a lower risk of CHD while women who start HRT long after onset of menopause are at increased risk [11]. These results held true regardless of the type of HRT. Authors of the re-analysis noted that a definitive conclusion could not be made from the comparisons of the WHI and NHS. Few women in the WHI trials were enrolled shortly after onset of menopause; moreover, only small numbers of women in the NHS cohort and the other observational studies began HRT long after menopause. Although younger postmenopausal women are better candidates for HRT, randomized trials and observational studies suggest against its long-term use for chronic disease prevention due to increased risk of stroke and pulmonary embolism.
Framingham Study: HRT
A smaller clinical study of HRT was published in 1985 as part of the Framingham Study, involving 1,234 postmenopausal women aged 50 to 79 with prior hysterectomy. The Framingham Study reported that women receiving HRT had an elevated risk of cardiovascular morbidity and greater than twice the incidence of cerebrovascular disease. A higher dose of 1.25 mg per day CEE was commonly in use at the time of this study and may explain why the study found an increased risk of CHD in postmenopausal women taking hormones [9]. A follow-up analysis of the Framingham Study data found a cardioprotective effect of estrogen in younger women when cases of angina pectoris were omitted [12]. The follow-up analysis excluded angina as an endpoint for CHD because of changes in current medical practice—understanding that women with apparently normal coronary arteries, indicated by coronary arteriograms, can experience chest pains [13, 14].
Conflicting Results of Major Trials
Inconsistent results seen between these large studies may be due to a variety of factors such as age, pre existing conditions, time of HRT initiation, hormone types, and dosage. Women in the WHI studies were older on average, with only 10% of subjects between 50 and 54 and 70% between 60 and 79 years of age [15]. These older women were more likely to have previously developed atherosclerotic plaques which received potential harm or no benefit by the administration of estrogen after a postmenopausal homeostasis, one with minimal endogenous hormones, had already been reached [16]. Increased inflammation leading to plaque rupture or bleeding into the plaque causing coronary blockage were cited as potential mechanisms for this elevated risk in older women receiving HRT. Additionally, it has been reported that about 70% of these women were overweight, 50% were either past or current cigarette smokers, and more than 35% had been treated for high blood pressure [15]. These women were not excluded from the study. Interestingly, estrogen replacement in younger postmenopausal women with less advanced atherosclerosis provided notable benefits, lower LDL levels and increased vasodilation [16] . A more recent re-analysis of both WHI study arms, seen in Table 3, attempts to reconcile differences from the NHS by establishing the effect of hormone therapy on coronary heart disease risk at different durations from onset of menopause [8].
In comparison with the other major clinical studies on HRT, the Nurses’ Health Study enrolled younger patients who were more likely to have initiated HRT closer to onset of menopause when estrogen levels had not yet fully dropped off. These women were more likely to receive estrogen’s beneficial effect of reducing low-density lipoprotein cholesterol (LDL-C) and increasing high-density lipoprotein cholesterol (HDL-C), thus proving favorable cardiovascular outcomes [17]. Also, younger women were less likely to have progressed atherosclerotic plaques or lesions at enrollment.
A review article published by JAMA in 1991 looked at previous studies of HRT in postmenopausal women and found that most but not all of the clinical studies demonstrated approximately 50% risk reduction for coronary events in women using oral estrogen without progestin [18]. Additionally, Stampfer and Colditz from Harvard Medical School looked at 16 prospective studies and all but one, the Framingham Study [19], showed decreased relative risks of CHD in women taking estrogens [20].
Few studies evaluated the effects of duration and dose of estrogen therapy on cardiovascular risk. Stampfer et al. and Henderson et al. both found no effect of duration nor dose of estrogen use on cardiovascular outcomes in the observational Nurses’ Health Study [9, 21]. Additionally, disparities were seen in age of menopause onset and type of menopause (ie. surgical or natural) [20]. It is also possible that hormones administered transdermally may have may yield better clinical outcomes because they more closely reflect normal metabolism and physiology of endogenous sex hormones [5].
In spite of widespread recognition among physicians that HRT alleviates menopausal symptoms, a 2012 guideline warned against the use of such treatments in postmenopausal women for prevention of chronic conditions such as osteoporosis, dementia, and cardiovascular disease [22]. Researchers at Oregon Health and Science University published a meta-analysis of 9 other studies, relying heavily on 11 years of follow-up data from the WHI studies. This report served as an official 2012 update for the U.S. Preventive Services Task Force (USPSTF), acting as the cornerstone for recommendations by the USPSTF against the use of HRT for preventing chronic conditions. Perhaps most significant of these analyses, researchers found that both HRT regimens increased risk of stroke and thromboembolic events.
Bio-Identical Hormone Replacement Therapy (BHRT) vs. Traditional HRT
For decades now, placebo-controlled studies have observed elevated CHD risks in women taking oral contraceptives which are chemically similar to HRT (usually ethinyl estradiol plus a progestin). These results were ignored by many practitioners until the WHI highlighted potential cardiovascular risks with CEE monotherapy or combination CEE-MPA in postmenopausal women. However the results were of no surprise to those who had realized that “hormone replacement means replacement of exactly identical hormones following Nature’s ‘original blueprints’ for types, quantities, timing, and methods of use” [23].
One review paper commented that older oral contraceptives contain higher doses of synthetic estrogen (ethinylestradiol) and progestins which are six to seven times more potent than natural estrogens such as estradiol, and estrone [24]. The argument for natural estrogens is both strong and nuanced. Natural estrogens produced by the body have been shown to decrease LDL-cholesterol, decrease Lp(a) and triglycerides, and increase HDL. The cardioprotective effects of estrogen on lipids are coupled with greater arterial dilation (lowering blood pressure), the inhibition of atherosclerotic plaque growth, and the reduction of coagulation factors, all of which contribute to heart attacks and stroke [25]. Furthermore, estrogen acts to influence arterial endothelial cells in the release of nitric oxide, which in turn reduces blood pressure and inhibits platelet activation and subsequent coagulation and thrombosis. In fact, estrogen deficiency has been shown to cause endothelial dysfunction, a major risk factor for atherosclerosis and hypertension [25]. In contrast with the well-established cardioprotective effects of endogenous estrogens , the increased cardiovascular risks found in large HRT clinical trials are likely attributable to their use of conjugated equine estrogens, derived from horse urine, and medroxyprogesterone acetate, a synthetic analog of human progesterone.
A study of 58 postmenopausal women on different HRT regimens assessed HDL-cholesterol as a marker of coronary artery disease health [26]. The study reported that women taking estradiol with synthetic progestins had significantly lower HDL levels when compared with previous treatment using estradiol alone. There was no reported reduction of HDL levels for women who had switched from estradiol monotherapy over to estradiol and oral micronized progesterone (a naturally occurring hormone). This study was important because of its direct comparison of natural and synthetic hormone therapy and demonstrated synthetic progestins can increase CVD risk while natural progesterone did not.
The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, funded by NIH and published in JAMA in 1996, was a double-blind, placebo-controlled study involving 875 healthy postmenopausal women [27]. Patients were randomized into 4 arms: placebo, CEE monotherapy, combination CEE+MPA, and CEE plus oral micronized progesterone. The study reported after 3 years that CEE use resulted in elevated HDL levels, a result which was all but diminished when MPA was added. Patients’ HDL levels remained elevated when natural progesterone was administered together with CEE.
Another randomized, double-blind study of postmenopausal women with coronary artery disease observed similarly beneficial effects of natural progesterone in comparison with MPA [28]. This clinical trial reported that administration of estradiol in stress-induced myocardial ischemia improved vasodilation but medroxyprogesterone acetate (MPA) did not. Separately, a 65% increase in the risk of venous thromboembolism (VTE) was observed with CEE use, and CEE+MPA combination therapy increased VTE risk an additional 60%, relative to control populations [29]. Use of estradiol, however, decreased VTE risk by about 8% in this clinical study.
“Menopausal symptoms, as well as heart disease, osteoporosis, and other long-term consequences of menopause, are largely a result of deficiencies in the production of ovarian estrogens and progesterone, not of horse hormones or pseudohormone patent medicines.”
“Although the requisite large-scale, double-blind, placebo-controlled trials proving the cardiovascular safety and efficacy of BHRT are yet to be done, decades of other research and clinical experience convincingly argue that bio-identical hormones, when used at physiologic doses and administered via a route and on a schedule that closely mimics Mother Nature’s design, carry all the cardiovascular benefits of the naturally-secreted ovarian hormones and none of the risks of their patented alien molecular cousins.”
“Bio-identical hormones are able to “facilitate the dilation and constriction of coronary arteries in response to normal stimuli so that the heart muscle gets the blood it needs when it needs it.”
“The reactivity of coronary arteries is partially under the control of estrogen and progesterone, which relax arterial smooth muscle so that blood flow to heart muscle tissue increases. It should come as no surprise by now that bio-identical estrogen and progesterone promote healthy vasodilation and coronary blood flow in postmenopausal women.” [23]
Framingham Study: CHD
In a separate article of the Framingham Study published earlier in 1978, among a cohort of 2,873 women followed for up to 24 years, no premenopausal women who did not smoke or take oral contraceptives developed myocardial infarction or died of CHD [32]. This remarkable observation begs the question: Do the cessations of menses themselves, rather than hormone or iron levels, contribute causatively to increased risk of CHD in adult women? The Framingham Study found that women who had a hysterectomy prior to menopause had 2.7 higher relative odds of new-onset CHD than premenopausal women the same age (P < 0.01), regardless of ovary removal [33].
Hemodynamic Perspective on Blood Loss
Why does periodic blood loss in premenopausal women with intact uteri result in lower risk for cardiovascular diseases? A study authored by Marina Kameneva et al. from the University of Pittsburgh highlighted the differences in concentration and age distribution of red blood cells (RBCs) in the blood, suggesting they are responsible for pivotal increases in CHD for postmenopausal women [34]. A large number of clinical investigations attribute high packed red cell volume as a primary risk factor in CVD. During menstruation, typically between 50-100 mL of blood or more is lost, enough to account for significantly reduced hematocrit and approximately 80% more new RBCs than seen in men and 85% fewer old RBCs than in men[34]. After menopause and cessation of menses, the hematocrit and rheologic properties of erythrocytes in women generally approaches that of men, who are themselves unable to achieve periodic blood loss naturally.
A study of 821 women aged 25-74 demonstrated that postmenopausal women have higher blood viscosity, hematocrit, plasma viscosity, and fibrinogen levels than premenopausal women [35]. Also, mortalities of men from CHD and myocardial infarction are much higher than that of women during their reproductive years [2]. Despite beliefs that higher iron stores in men may contribute to this increased mortality, several clinical studies have shown negative or no association between CHD and body iron levels [36]. While hematocrit is typically 15-20% lower in women during their reproductive years than men, renewal of RBCs after periodic blood loss results in about 80% more young RBCs and 85% fewer old RBCs than blood in males [34]. These newer blood cells are more flexible and less likely to aggregate and impede blood flow, resulting in decreased blood viscosity. Because adult males do not naturally undergo periodic blood loss, their old RBCs are devoured by the body at the spleen, releasing free hemoglobin which can inhibit the vasodilating effects of nitric oxide, resulting in vasoconstriction. Decreased nitric oxide levels have been correlated with hypertension and atherosclerosis.
Monthly blood loss and the subsequent renewal of RBCs have been established to have a significant rheological impact. Increased RBC aggregation and rigidity are well-documented CHD risk factors [37] Both high-shear blood viscosity and low shear blood viscosity are reduced and improved as a result of hematocrit declines as well as the improved deformability of newer, younger RBCs. Normal RBCs usually have a lifespan of 100-120 days, at which point they become engulfed and inhibit nitric oxide’s cardioprotective effects [34]. Menses in premenopausal women (and regular blood donation as an analog in men) can be said to rejuvenate the blood, reducing blood viscosity and improving blood flow and tissue perfusion. A large prospective clinical study showed that among 2,682 middle aged-men followed for a mean of 5 years, heart attack risk was reduced by 86 percent for blood donors [38]. Perhaps more surprising, another large study of about 4,000 people found non-smoking men who had given blood in the previous three years showed about half the risk of myocardial infarction or stroke as those men who had never given blood [39]. While not naturally occurring, blood donation or therapeutic phlebotomy may be able to serve as an analog intervention for men, providing them with the same rheologic benefits seen in premenopausal women with periodic blood loss. Improved blood viscosity as a result of regular blood loss may improve oxygen delivery throughout the body and minimize biophysical stress to the vasculature preventing the development of CVD.
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