Cardiovascular Risk

Estrogen deficiency associated with the menopausal transition leads to many distressing symptoms, including vasomotor symptoms, sexual disorders and, in the long term, hormonal depletion results in changes in the risk of metabolic syndrome and increases in diabetes and cardiovascular disease. All these symptoms negatively impact on quality of life. Attention should focus on the estrogens’ fundamental functions on cardiovascular system and metabolic balance.

Estrogens and Cardiovascular Risk

Estrogens and the other sex hormones regulate fundamental cardiovascular functions including blood pressure, blood flow, vasodilatation and vasoconstriction, vascular inflammation and remodelling, atherosclerosis [8]. These actions of endogenous estrogens on the cardiovascular system can be mediated directly on the vessels or indirectly through the modulation of cardiovascular risk factors. Estrogen exerts pleiotropic functions on the cardiovascular system through both genomic and non-genomic effects [9, 10]. Traditionally, estrogen receptors (ERs) work via the regulation of transcriptional processes, involving nuclear translocation and binding on specific response elements, thus leading to regulation of target gene expression (ERE). The non-transcriptional mechanisms of signal transduction, called ‘non-genomic’ effects, are independent by gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or of cell membrane-bound regulatory proteins. Relevant biological actions of steroids have been associated with this signalling in different tissues. Ubiquitary regulatory cascades such as mitogen-activated protein kinases (MAPK), the phosphatidylinositol 3-OH kinase (PI3 K) and tyrosine kinases are modulated through non-transcriptional mechanisms by steroid hormones. Furthermore, steroid hormone receptors’ modulation of cell membrane-associated molecules such as ion channels and G-protein-coupled receptors has been shown in diverse tissues. The vascular wall is a site where non-genomic steroid hormones’ actions are particularly prominent. For instance, estrogens and glucocorticoids trigger rapid vasodilatation due to rapid induction of nitric oxide (NO) synthesis in endothelial cells via the estrogen receptor-dependent activation of MAPK and PI3 K, leading to relevant pathophysiological consequences, in vitro and in vivo. Estrogen triggers rapid vasodilatation, exerts anti-inflammatory effects, regulates vascular cell growth and migration, leading to a protective action on vessels [11]. Recent advancements in the characterization of the molecular basis of estrogen’s actions help us to understand the biological functions of estrogen and would be beneficial in elucidating current controversies on estrogen’s clinical efficacy in the cardiovascular system [12–14].

Endothelium represents an elective cellular target for estrogens. It is well established that estrogen improves vascular function, maintaining and repairing endothelium, reduces atherosclerosis. ERs are expressed in endothelial cells and have an athero-protective effect. Through the recruitment of ERs, estradiol increases endothelial NO and prostacyclin synthesis, thus slowing early atheroma formation. Estradiol also decreases synthesis of pro-inflammatory cytokines by circulating or resident immune cells. In addition, estradiol facilitates endothelial vascular healing and neoangiogenesis. Emerging evidence suggests that protective effects exerted by estrogens on endothelium include multiple cellular mechanisms. Estrogen has been demonstrated to activate calcium-dependent potassium channels and induce a rapid increase in NO release [15]. These non-genomic effects of estrogens on NO production are paralleled by their genomic actions exerted by activation of endothelial NO synthase (eNOS) through a receptor-mediated system [16]. Estrogen has antioxidant and anti-inflammatory properties, acting through multiple effects. Among them, estrogen may upregulate prostacyclin synthase and the expression of vascular endothelial growth factor. Conversely, it inhibits endothelin-1 release, and modulates adhesion-molecule and tumour necrosis factor α (TNF-α) expression and endothelial cell apoptosis [17, 18]. Moreover, estrogen can act by upregulating superoxide dismutase in the vascular district, which contributes to increased superoxide ion clearance [19]. Estrogen may also influence the redox balance through modulation of mitochondrial enzyme activity: these antioxidant effects are a main mechanism by which hormones protect women during their fertile life. In fact, oxidative stress is generally higher in men compared to premenopausal women. After menopause, when hormonal levels markedly fall, the risk of cardiovascular events rapidly rise in women, in parallel to a rapid increase of oxidative stress biomarker levels [20].

ERα is important in reducing endothelial dysfunction after ischemia and reperfusion [21]. The overall protection afforded by estrogen is likely mediated by effects on both myocytes and endothelial cells, and possibly other tissues such as inflammatory cells and endothelial progenitor cells (EPCs). Estrogen promotes EPCs’ survival and plays an important role in cardiac repair by bone marrow–derived endothelial progenitor cells after infarction [22]. Estrogen increases survival of cardiomyocytes after myocardial infarction, and females have increased activity of the antiapoptotic kinase Akt, which may contribute to the protection observed in females. The inflammatory response and inflammatory cytokines are also regulated by estrogen [23], and this could influence the ischemia-reperfusion injury and remodelling. EPCs repair endothelial structure and enhance activity of eNOS, restoring the functional status of the endothelium. Contrary to mature endothelial cells which have limited regenerative capacity, EPCs home in the endothelial injury and ischemia sites proliferating and integrating into the endothelium. In addition, they produce vascular growth factors [24]. EPCs are higher in fertile women than men; their numbers fall after menopause. It seems that EPCs are a better predictive factor for vascular health than conventional risk factors, such as lipid profile, hypertension and diabetes [25] (Figure 15.1).

Figure 15.1 Estrogen effects and cardiovascular system.

Management of Cardiovascular Risk Factors in Women

Screening for CVD at regular intervals after menopause is extremely important. This includes measurement of blood pressure, lipids and perhaps inflammatory markers, BMI and ascertainment of lifestyle factors such as activity level and smoking status. In addition, a family history of heart disease and stroke is important. Risk assessment tools allow the calculation of a 10-year risk of myocardial infarction based on gender and race for individuals aged 40–79 years [29]. The main risk calculators used are the Framingham model [32] and a new one from the American Heart Association [33]. The latter is also used as part of the algorithm to decide about initiating statin therapy. The main components of these risk models are age, sex, race, total cholesterol, HDL cholesterol, systolic blood pressure, treatment for high blood pressure, diabetes and smoking status. Interventions to reduce the risk of CVD after menopause include smoking cessation, weight control through diet and exercise, aggressive treatment of elevated blood pressure, and therapies directed at elevated cholesterol and thrombosis risks. The American Heart Association has outlined diet and lifestyle recommendations to reduce CVD, resulting in better population health. The prevailing belief is that statins reduce CHD events and all-cause mortality under primary and secondary prevention conditions in women and men. However, careful examination and meta-analyses of randomized controlled trial (RCT) data do not provide clear evidence that statins reduce CHD events or all-cause mortality in women under primary prevention conditions. The sex-specific effects are similar for aspirin. In meta-analyses of primary CHD prevention trials, aspirin significantly reduced myocardial infarction (MI) by approximately 32 per cent, with a null effect on stroke in men, whereas in women, aspirin had a null effect on MI but significantly reduced ischemic stroke by approximately 17 per cent [34]. The primary CHD prevention trials and sex-specific meta-analyses of primary prevention trials shows no evidence that aspirin therapy relative to placebo reduces CHD events or all-cause mortality in women.

The Role of Hormone Replacement Therapy

MHT has been subject of discussion and debate. In the early 1990s, the effects of MHT were thought to be beneficial because of a reduction of 30–50 per cent in risk of cardiovascular disease and osteoporosis. These effects were confirmed by a large number of observational studies, thus in 1992 the American College of Physicians published guidelines strongly advising a preventative use of MHT [35]. In those years an escalation in the use of MHT was registered across the world. However, in the late 1990s, the protective role and the safety of MHT was questioned. RCTs overturned the previous hypothesis about the advantage of MHT showing evidence of no cardiovascular benefit from MHT, rather indeed a negative effect on women’s health: the Women’s Health Initiative (WHI) trial had a great impact on it. Over 16 000 menopausal women between the ages of 50 and 79 (mean age 63 years) were enrolled. After a mean of 5.2 years of follow-up the study was stopped because of increased risk of cancer and adverse effects on cardiovascular system. The principal findings from the WHI were associated with a substantial decline in MHT use by postmenopausal women. Nevertheless, more recent subgroup analyses suggested that the lack of benefit or increase in CVR observed in the WHI resulted from the harmful effect of MHT in older women further from menopause [36]. It is clear that the characteristics of women selected for RCTs were different from those of women studied from the general population or from which the estrogen cardioprotective hypothesis was generated. There is strong evidence that estrogen therapy may be cardioprotective if started around the time of menopause (often referred to as the ‘window of opportunity’ or ‘timing’ hypothesis). These hypotheses could have biological basis: around the time of menopause, women still have healthy arteries, allowing a ‘window’ for MHT to produce cardiovascular benefit [37]. However, with aging, arteries become less responsive to the beneficial effects of estrogens. Indeed, menopause is associated with endothelial dysfunction, decreased NO-dependent relaxation and intimal thickening; moreover, age-related changes in ER-amount, distribution or affinity may also contribute to cardiovascular risk. It is well established that estrogen may have different and controversial effects on the atherosclerotic process depending on its stage. In more than 15 years of follow-up of women in the WHI, the cumulative data in the 50- to 59-year-old age group showed a reduction of CHD [38]. Meta-analyses of RCTs, including data from the WHI, have shown a significant reduction in CHD as well as mortality in women treated with estrogen under the age of 60. In the most recent Cochrane analysis, women using MHT within 10 years of menopause had a reduction of all-cause mortality of 0.70 (95 per cent CI 0.52–0.95) and of cardiovascular mortality of 0.52 (95 per cent CI 0.29–0.96) [39].

Not only the timing, but also the role of the type, dose and route of MHT should be analysed. These hypotheses have encouraged different recent prospective trials using MHT with CHD as the endpoint: the Kronos Early Estrogen Prevention Study (KEEPS) [40], the Early versus Late Intervention Trial with Estradiol (ELITE) [41]. KEEPS is a randomized clinical, double-blinded, placebo-controlled trial to test the hypothesis that initiation of MHT (oral conjugated equine estrogens [CEE 0.45 mg] or transdermal estradiol (0.05 mg) with oral micronized progesterone (MP) for 12 days of each month) in healthy, recently postmenopausal women (n = 727) would reduce the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT). KEEPS was designed to understand the effects of timely menopausal MHT on cardiovascular health. KEEPS did not show a difference between CEE 0.45 mg, transdermal estradiol 0.05 mg and placebo in terms of carotid artery intima-media thickness and coronary calcium. After 4 years, the MHT did not affect the rate of increase in CIMT and there was a trend for reduced accumulation of coronary artery calcium with CEE [42]. The ELITE trial studied the effects of oral estradiol 1 mg and placebo in two groups of women, one <6 years from menopause and the other >10 years from menopause, and showed that initiation of MHT in elderly women (<60 years old) or those who are more than 10 years postmenopause may be associated with increased risk for coronary events [41]. Venous thromboembolism (VTE) and stroke could increase with initiation of oral MHT in the older age groups, but concomitant use of statins may mitigate the risk of VTE events following initiation of MHT in women over age 60. In a study published in the British Medical Journal, Schierbeck and colleagues report the long-term follow-up of a cohort of postmenopausal women originally enrolled in the Danish Osteoporosis Prevention Study (DOPS). The study enrolled 1006 patients aged 45–58 who were recently menopausal or had perimenopausal symptoms between 1990 and 1993 and they prospectively received standard doses of estradiol and norethisterone in an open-label fashion, or no treatment for 10 years, and had 16 years of follow-up [43]. The main result is that women receiving MHT had a significantly lower incidence of CHD without an increased risk of stroke, VTE or breast cancer. There are at least two main differences between these studies and the WHI trial: the age of the women enrolled and the characteristic of therapy. In fact, additional variables also may alter the cardiovascular effects of MHT, including the choice of progestin. The WHI trial employed just one route of administration (oral), one formulation of estrogen (CEE, 0.625 mg), and only one progestogen (medroxyprogesterone acetate [MPA], 2.5 mg). Synthetic MPA is vasoconstrictive, whereas natural progesterone has vaso-relaxation effects and a neutral or slightly salutary effect on blood pressure. The KEEP trial, for example, studied healthy postmenopausal women aged 42–58 years who received oral CEE 0.45 mg/day or transdermal estradiol patch 50 mg/week, each with cyclic oral MP 200 mg for 12 days/month, and it found no effect on CIMT progression. MPA is associated with higher risk of CVD as compared to estrogen-only therapies. In contrast to most synthetic progestins, progesterone causes little or no reduction in HDL cholesterol levels and has compared favourably in its effects on LDL cholesterol, low-density lipoprotein phospholipids and very low-density lipoprotein triglycerides. Oral micronized progesterone has been demonstrated to provide endometrial protection from estrogen stimulation and to protect against endometrial hyperplasia and carcinoma, it may be used in lieu of synthetic progestins [44].

Nevertheless, after nearly 20 years the never-ending contradiction between studies showing the ‘benefit of MHT’ and guidelines stating that ‘MHT should not be used to prevent chronic disorders’ still exists.

In conclusion, CHD events and all-cause mortality benefits occur when MHT is initiated in younger women (<60 years old) in close proximity to menopause (<10 years since menopause) and a null and possible adverse effect occurs when initiated in older women (≥60 years old) remote from menopause (>20 years since menopause). The cumulative MHT randomized trial data initiated in younger women contrast to lipid-lowering and aspirin therapy in the primary prevention of CHD and, most importantly, in the reduction of all-cause mortality in women under primary prevention conditions. As with men, hypertension in women is the single most important treatable risk factor for stroke. With reduction of blood pressure, the risk of stroke is reduced by between 30 and 40 per cent, MI risk is reduced by 20–25 per cent and heart failure is reduced by 50 per cent. The use of statins therapy in women in the primary prevention of stroke is less clear than that in men. According to recent cross-sectional studies, there is no convincing evidence that rises in BP will occur in otherwise normotensive menopausal women due to MHT containing estrogens, or that BP will increase further due to MHT in menopausal hypertensive women. Moreover, MHT is not contraindicated in women with hypertension, and women with hypertension may be prescribed MHT as long as BP levels can be controlled by antihypertensive medication [45].

The most recent Position Statement of the North American Menopause Society on MHT published in 2017 [46] clarifies the existing data and provides easy recommendations for menopause management, suggesting that ‘for healthy, and chronologically young perimenopausal women within 10 years of the onset of menopause, the lower dose regimens of MHT (estrogen alone or with a progestogen) offers benefits that outweigh risks, with fewer CVD events in younger versus older women’ (Figure 15.2).

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