Coronary artery disease after menopause and the role of estrogen replacement therapy

Introduction Cardiovascular disease (CVD) represents the first cause of mortality among women, and in Europe, more women than men are now dying of coronary artery disease (CAD).1 However, premature coronary deaths, that is before the age of 65 and even 75 years, are more common among men.1 This observation implies that, at younger age, women are protected against CAD, and this specific protection is the most likely cause of the overall survival advantage of women over men. No such advantage is being observed for cancer, the second more frequent cause of death for both sexes.2 The most plausible cause of this fact has been considered to be the protective effect of estrogen in premenopausal women.3 Estrogen exerts direct effects on blood vessels as well as systemic effects that may delay the development and progression of atherosclerosis. Its rapid vasodilatory effects are mediated by direct actions on vascular endothelial cells. In addition, estrogen also alters serum lipid concentrations (reduced LDL and increased HDL cholesterol), coagulation and fibrinolytic systems, antioxidant systems, and the production of other vasoactive molecules, such as nitric oxide and prostaglandins, all of which can influence the development of vascular disease.3 In terms of atherosclerosis, disorder data suggest that estrogen has an anti-inflammatory effect on atherosclerotic plaques, resulting in plaque stabilization, whereas plaque erosion, a peculiar substrate for thrombosis in premenopausal women, does not appear to be inhibited by estrogen.4 Studies using intravascular ultrasound (IVUS) have shown less coronary atherosclerosis in women, with respect to men, despite a heavier burden of risk factors.5 Prospective age and sex-matched data from the LADIES Acute Coronary Syndrome (ACS) study confirm that the 10-year advantage of women with regard to the amount of angiographically measurable coronary atherosclerosis persists beyond the 8th decade of age.6 Fertile lifespan, mortality and cardiovascular events This is a complex issue, difficult to address from the methodological point of view, but it represents the basis for the development of goal-directed treatment. This question was addressed by transversal7 as well as longitudinal8,9 studies investigating the relation between age at menopause and all-cause as well as cardiovascular mortality. Some of these studies were specifically investigating cardiovascular health,9 whereas others were longitudinal studies on cancer.7 An important longitudinal study on more than 12 000 women followed up for up to 20 years within a screening project of breast cancer in Utrecht found that any year of delay in menopause was associated with a 2% reduction in the risk of cardiovascular mortality, a benefit that extended for at least 2 decades after menopause. In this study, the benefit was consistent also among women having undergone oophorectomy, whereas in others the association was consistent only for naturally occurring menopause, and not for surgical menopause by bilateral oophorectomy.7,10 Also, some studies have found a significant association between early menopause and mortality only in smokers, which may well be a confounder for cardiovascular mortality.9 In the most recent and complete meta-analysis of 32 studies that included 310 329 women, those who experienced menopause below the age of 45 appeared to have a greater risk of coronary heart disease (CHD), CVD mortality and all-cause mortality, whereas no association was found with stroke risk. By contrast, an age of 45–49 years at onset of menopause, compared with 50 years or older at onset, had no apparent association with adverse outcomes.11 In the LADIES ACS study,6 the frequency of prior myocardial infarction (MI) was identical (15%) among women with menopausal age below or above median (50 years). In patients with no history of MI, the mean age at ACS was 73 ± 10 years both among women below median menopausal age, and among those above the median. The hypothetical link between a longer fertility lifespan and a lower risk of cardiovascular events after menopause might be found in a more favorable risk factor profile as calculated using the Framingham risk score,12 or through a lower risk of subsequent diabetes mellitus.13 An alternative hypothesis considers age at menopause as a biological marker of health and aging: that is, women that are biologically destined to a longer life tend to have also a longer fertile life,7 whereas women with any kind of evident or latent disease tend to experience menopause at a younger age.7,10 Finally, among 695 premenopausal women followed up in the Framingham Heart Study, a significant association was found between an earlier age at menopause and higher premenopausal serum cholesterol and blood pressure,14 leading the Investigators to conclude that ‘heart disease risk determines menopausal age rather than the reverse’. Extent of coronary artery disease in women with more prolonged exposure to estrogen, either physiological or pharmacological As previously mentioned, disorder,4 IVUS5 and angiography6 data have shown less CAD in women as compared with men, an advantage that persists for decades after menopause. This advantage has been plausibly attributed to the effect of estrogen through a number of vascular protective mechanisms.3 Direct consequences of this vision would be that women with ‘early’ menopause should have more extensive CAD and an earlier occurrence of clinically manifest CAD, and the therapeutic administration of estrogen might reduce, or delay, atherosclerosis. This evidence does not exist, and prospective studies to investigate this issue have been scarce so far. The LADIES ACS study was the first to specifically investigate the relation between age at menopause and the extent of CAD.6 The Investigators enrolled 426 women and 249 men (with sampling ratio 2 : 1 of women vs. age-matched men) undergoing coronary angiography due to an ACS. Enrollment was stratified in four age classes from 55 to more than 85 years, with mean age 74 years (interquartile range 65–82 years). The extent of coronary atherosclerosis was assessed in a corelab and classified by using the Gensini score, which considers both critical and subcritical stenoses in a hierarchical order. A specific menopause questionnaire was administered to women during index hospital stay. The mean Gensini score was 60 ± 36 in men vs. 50 ± 32 in women (P < 0.001), being higher in men at any age. The Gensini score in women showed a weak association with age (R2 0.127; P = 0.0129), but not with menopausal age (R2 0.063; P = 0.228). As shown in Fig. 1 also no significant association was found between fertility lifespan (i.e. the time in years between menarche and menopause) and Gensini score.6 A recent metanalysis11 assessed the relation between age at menopause and carotid atherosclerosis (only two studies with these measurements): pooled relative risk [95% confidence interval (CI)] for the risk of carotid atherosclerosis for 3388 participants was 0.74 (0.63–0.87) when comparing women 50 years or older with women younger than 50 years at onset of menopause.Fig. 1: Correlation between Gensini score and fertile lifespan (years), calculated as age at menopause minus age at menarche.Effect of HRT on atherosclerosis and cardiovascular outcomes Post-hoc analyses of prospective cohort studies in the 1980s indicated that postmenopausal HRT was associated with a significantly lower risk of CHD,15 which prompted speculation that such therapy could be used to prevent coronary events. However, subsequent randomized trials failed to show any benefit of HRT with regard to coronary events (Table 1). One explanation is that in observational studies, women were younger (approximately 50 years of age) and closer to menopause (typically within 2 years) when they initiated HRT than were the women included in randomized trials (mean age about 65 years, typically >10 years past menopause). This so-called timing hypothesis suggests that the effects of HRT on atherosclerosis and CHD depend on the timing of the initiation of hormone therapy relative to menopause.Table 1: Studies on HRT and coronary diseaseStudies on the progression of atherosclerosis (carotid and coronary) seem to be, at least in part, in agreement with this hypothesis (Table 1). In fact, the Estrogen in the Prevention of Atherosclerosis Trial of early HRT intervention in healthy postmenopausal women did show some benefit in terms of reduced progression of carotid intima–media thickness,16 whereas the Women's Estrogen–Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial failed to show any benefit of HRT in secondary prevention with regard to coronary lesions.17 Similarly, the Estrogen Replacement and Atherosclerosis trial18 and the Women's Angiographic Vitamin and Estrogen trial19 compared HRT and placebo in postmenopausal women with regard to the angiographic progression of CAD: no effect was observed with treatment in both trials which, however, enrolled women with a mean age of 65 years, and about half had had a prior MI. In the ELITE study,20 643 healthy women were randomly assigned, in a 1 : 1 ratio, to receive oral 17β-estradiol (and progesterone vaginal gel in the case of intact uteri) or matching placebo within strata of early postmenopause (<6 years since menopause) and late postmenopause (≥10 years since menopause). The median age at enrollment was 55 years in the early-postmenopause stratum, and 64 years in the late-postmenopause stratum, and the median time since menopause was 3.5 years in the early-postmenopause stratum and 14 years in the late-postmenopause stratum. HRT significantly reduced the rate of progression of carotid-intimal media thickness (primary endpoint) in the early treatment group, whereas no such effect was observed in the late treatment group (P = 0.03 for interaction between strata). However, no effect at all was observed in both groups with regard to coronary computed tomography data (secondary endpoint). In terms of CAD events, no benefit from HRT was observed in the Heart and Estrogen/progestin Replacement Study (Table 1), again as secondary prevention in women with average age of 67 who had had prior Q wave MI, percutaneous coronary intervention or coronary artery bypass grafting.21 The primary endpoint in the Women's Health Initiative was the rate of CHD (defined as CHD death and total MI rate). Combined estrogen and progestin therapy showed a trend toward an increased risk for CHD after 5 years of follow-up, which persisted through 8.6 years [hazard ratio, 1.22 (CI: 0.99–1.50)].22 For the overall enrolled population, there was no reduction in the risk for CHD with estrogen alone after nearly 8 years of follow-up [hazard ratio, 0.95 (CI: 0.78–1.15)], although subgroup analysis in the unopposed estrogen part of the study of women having undergone hysterectomy did reveal a potential reduction in CHD in women aged 50–59 years [hazard ratio, 0.59 (CI: 0.38–0.90)] but not in women aged 60–69 or 70–79 years, a finding that warrants confirmation in future studies. A study more suitable to prove the timing hypothesis was the Danish Osteoporosis Prevention Study,23 which involved a cohort of women who were, on average, 50 years of age and 7 months past menopause when they were randomly assigned to receive estradiol alone or in combination with sequential norethisterone acetate. This study showed a significantly lower risk of CHD (a composite of death, admission to hospital for heart failure and MI) at 10 years of follow-up among women who received treatment than among women who received no treatment (hazard ratio 0.48, 95% CI: 0.26–0.87; P = 0.015). In this study, no excess risk of any cancer, breast cancer, stroke and venous thrombus embolism was observed in the HRT group. However, as expected from the young women's age at enrollment, the number of events was relatively small to draw any definite conclusion. Current recommendations for HRT As briefly discussed in the present review, experimental evidence of a protective effect of estrogen with regard to coronary atherosclerosis and cardiac events is scarce.24 Angiographic studies neither show a relation between menopausal age and coronary atherosclerosis, nor an effect of HRT on CAD progression. Most studies on HRT have included women who were too old and after too many years of menopause, whereas the better designed study23 was too small to be conclusive. Among the issues not discussed here are the type (of estrogen and progestin) and duration of HRT. Some expert committees and scientific societies, such as the US Preventive Services Task Force,25 the Canadian Task Force on Preventive Healthcare and the American Academy of Family Physicians, have taken a strong position against the postmenopausal use of HRT (either estrogen alone in women without uteri, or combined estrogen and progestin in women with uteri) for the prevention of chronic conditions. Other societies have discouraged the use of HRT for the sole aim of preventing CAD events, though reassuring doctors and patients about the cardiovascular safety of HRT when administered to cure menopausal symptoms. Two important sets of recommendations have been issued recently. The National Institute for Clinical Excellence has the following recommendations26 to assist patients and physicians in decision-making: HRT does not increase CVD risk when started in women aged under 60 years, but does not affect the risk of dying from CVD HRT with estrogen alone is associated with no, or reduced, risk of CHD HRT with estrogen and progestogen is associated with little or no increase in the risk of CHD taking oral (but not transdermal) estrogen is associated with a small increase in the risk of stroke (which, however, is very low in women aged under 60 years). The 2016 Revised Global Consensus Statement on menopausal hormone therapy (MHT)27 has been endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The Asia Pacific Menopause Federation, The International Osteoporosis Foundation and The Federation of Latin American Menopause Societies. With regard to the specific issue of HRT and cardiovascular events, this statement concludes that Randomized controlled trials and observational data as well as meta-analyses provide evidence that standard-dose estrogen-alone MHT may decrease the risk of MI and all-cause mortality when initiated in women younger than 60 years of age and/or within10 years of menopause. Data on estrogen and progestogen MHT initiated in women younger than age 60 years or within 10 years of menopause show a less compelling trend for mortality benefit, and evidence on cardioprotection is less robust with inconsistent results compared with the estrogen-alone group. With the inherent limits described in the present review, these recommendations may assist patients and physicians when deciding for type and duration of HRT in early postmenopausal women to improve quality of life, sexual function and other menopause-related complaints, such as joint and muscle pains, mood changes and sleep disturbances. Acknowledgements Conflicts of interest There are no conflicts of interest.

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