Besides a diversity of gynecological symptoms, 50–70% of Caucasian women experience vasomotor symptoms (VMS) during menopause transition, consisting of hot flushes, night sweats, palpitations, sleeping disturbances, concentration problems, headaches etc. These symptoms may also be related to oxidative stress and an adverse CVD risk profile [20], although the literature is mixed regarding relations between hot flashes and CVD. Severe VMS in women have been associated with hypertension, elevated total cholesterol levels and increased CVD events [21–23]. Several studies have suggested that subclinical atherosclerosis is more prevalent in women with VMS compared to women without these symptoms [24, 25]. Menopausal vasomotor symptoms are associated with increased sympathetic and decreased parasympathetic function that may enhance the risk of cardiovascular events [17, 26–28]. Vasomotor symptoms are also exacerbated by an increase in insulin resistance and inflammatory factors derived from visceral adipose tissue, which has an increased activity after menopause [29]. In the Women’s Health Initiative Observational Study (WHI-OS) it was found that early VMS (before/around cessation of menstruation) are associated with a lower CVD risk (HR 0.89, 95% CI 0.81–0.97), while VMS in late menopause indicate an elevated CVD risk profile (HR 1.23, 95% CI 1.00–1.52) [30]. The mechanisms of VMS may therefore be different within separate stages of menopause transition and may vary over time. It is assumed that early VMS are associated with estrogen-dependent lowering of the thermo-neutral zone in the brain, whereas late VMS (age 55+) are more related to a higher sympathetic nervous system activity after menopause [19, 31]. Women at increased CVD risk, such as after previous hypertensive pregnancy disorders (HPD), have a higher sympathetic nerve activity and more disabling VMS compared to women after normotensive pregnancies [32, 33].

Primary ovarian insufficiency (POI), formerly known as premature ovarian failure (POF), is characterized by secondary amenorrhea for at least 4 months accompanied by an elevated FSH above 40 IU/L, occurring prior to age of 40 years [34, 35]. The incidence of POI is reported to be 1–2%. Earlier menopausal age than normal is associated with an increased incidence of CVD [36–38]. In a systematic review of 32 studies, including more than 310.000 women, it was found that women who experienced a menopause younger than 45 years have a relative risk of 1.19 (CI 1.08–1.31) for CVD mortality [39]. Other epidemiological data have led to a calculated 2% decrease of CVD mortality risk for each year that menopause is delayed [40]. Women who have recently been diagnosed with POI have a slightly unfavorable serum lipid profile compared to healthy controls with a normal ovarian function [41]. Early menopause is also a predictor of recurrent angina symptoms after myocardial infarction [42]. In a case-control study of 83 respectively 266 women >45 years, women with POI exhibited an unfavorable cardiovascular risk profile, including higher abdominal fat, elevated chronic inflammatory factors, and a trend towards increased blood pressure, and an impaired kidney function compared to controls, but no difference in subclinical signs of atherosclerosis was found [43]. Despite the association of premature cessation of ovarian function and short term health problems such as decreased fertility and climacteric symptoms, current available data indicate that POI is only a modest risk factor for IHD and overall CVD risk but not for stroke [44]. Age at onset of menopause is (partly) heritable with a link to DNA repair and immune mediator pathways [45].

BRCA1/2 mutation carriers are at high risk of breast and ovarian cancer. To reduce the risk of ovarian cancer a risk-reducing salpingo-oophorectomy (RRSO) is advised to all BRCA1/2 mutation carriers at age 35–40 years (BRCA1) and at age 40–45 years (BRCA2) [46]. In women without previous breast cancer, hormone therapy may be considered until natural age at menopause after premature surgical menopause [47]. As BRCA genes play an important role in DNA damage repair, they may also interfere with the pathophysiology of atherosclerosis. This hypothesis is supported by finding that BRCA1/2 deficient cells are more sensitive to oxidative stress [48, 49]. The potential increased intrinsic and extrinsic susceptibility of BRCA1/2 mutation carriers to CVD needs further research.

In the Nurses’ Health Study it was found that that a bilateral ovariectomy after hysterectomy is associated with a two times higher risk for CVD, especially when performed before 50 years of age [50]. In the Women’s Health Initiative (WHI) Observational Study this disadvantage was found to be importantly associated with a lower socio-economic status (SES) and a more adverse CVD risk profile in women undergoing a hysterectomy [51]. Large population-based data from Sweden however confirmed a positive association between hysterectomy with/without oophorectomy and CVD in women <50 years, but not at older age [52].

In many cases the indication for a hysterectomy is related to endometriosis, which promotes inflammation, oxidative stress and an adverse lipid profile [53]. It is therefore warranted that gynecologists and cardiovascular specialists seek collaboration to optimize CVD prevention in these patients.

Postmenopausal women have over a threefold greater risk of atherosclerosis when compared to premenopausal women, however after adjustment for age and other potential confounders it is controversial whether menopause is associated with increased risk independent of aging [13]. The decline in endothelial function appears to start in early menopause before signs of subclinical atherosclerosis are present [54, 55]. This could provoke undetermined symptoms of chest pain and dyspnea which is often labeled as “stress” or complaints secondary to menopause. However, women who are diagnosed with ‘undetermined’ chest pain syndromes have a twofold increased risk to develop a IHD event in the next 5–7 years and improvement of lifestyle factors and risk factor modification is therefore crucial [56, 57].

Smoking induces premature endothelial dysfunction in premenopausal women by downregulation of the estrogen receptors in the vascular wall, activation of inflammation and the thrombotic system and promoting LDL cholesterol oxidation [58].

The ability to detect endothelial dysfunction, as a first sign of vascular ageing, may be important in assessing cardiovascular risk in women more accurately, although the variability of response limits the application in clinical practice [59]. This can be done non-invasively by peripheral techniques such as ultrasound of the brachial artery (FMD: flow mediated dilatation) or digital arterial tonometry (endoPAT) [60]. With measurements of pulse wave velocity (PWV) the degree of arterial stiffness can be established, functioning as a predictor of future CVD events [61, 62]. The gold standard of assessing coronary endothelial function invasively involves the responses of both the epicardial arteries and the microcirculation to an endothelium dependent vasodilator such as acetylcholine [63]. Measurements of peripheral endothelial function correlates modestly with coronary artery endothelial function and predicts future cardiovascular events in population studies [64]. A potential disadvantage is that functional tests are time-consuming, have day-to-day variability similar to blood pressure that requires repeated testing and are importantly dependent on the expertise of the vascular laboratory [65]. An advantage of these techniques is that functional vascular abnormalities can be noticed before any signs of subclinical atherosclerosis are seen, as is the case with carotid intima media thickness measurements (CIMT) or a coronary artery calcium score with CT angiography (CCTA).

Hypertension is a critically important risk factor that affects women in the early postmenopausal years and elevated blood pressure is often poorly treated [66, 67]. There is anecdotal concern that when a man has an elevated blood pressure we call it ‘hypertension’, but when it affects a woman we call it ‘stress’. This may be one reason why women with elevated blood pressure are treated differently than men in primary care [68]. About 30–50% of women develop hypertension (RR >140/90 mmHg) before the age of 60 and the onset of hypertension can cause a variety of symptoms that are often attributed to menopause [69, 70]. Detection and control of elevated blood pressure in the perimenopause is crucial for the prevention of future hypertension [71]. There are more missed opportunities for treating hypertension adequately in women at middle-age than in similarly aged men [72]. Also, in normotensive women, higher normal blood pressures are associated with greater cardiovascular risk compared to lower blood pressures even when in the normal range [73]. The socalled “white-coat” hypertension at the doctor’s office occurs more often in women and may progress over time to sustained hypertension [74, 75]. Systolic blood pressure is the best predictor of CV risk and increases more with the white coat response than does diastolic blood pressure. As blood pressure is characterized by a considerable variability over time additional ambulatory monitoring is recommended in these patients. Self-monitoring with modern eHealth applications is getting more popular and may improve quality of blood pressure monitoring and adherence to medical therapy [76, 77]. In the 2014 AHA guidelines hypertension in adults treatment goals are stricter for patients <60 years than in elderly [78]. However, this was before publication of the Systolic Blood Pressure Intervention Trial (SPRINT) trial that found evidence of cardiovascular benefit with more intensive lowering of systolic blood pressure (goal <120 mmHg) compared with the currently recommended goal (<140 mmHg) in older patients (>75 years) with cardiovascular risk but without diabetes or stroke [79]. This has led to an ongoing debate to which extent blood pressure should be lowered in men/women, within various age-categories and different levels of CVD risk [80, 81]. Publication already suggests lowering the threshold for normal systolic blood pressure to 130 mmHg in upcoming guidelines with a particular emphasis on women [80, 82].

The rise in systolic blood pressure with ageing is caused by an increase in vascular stiffness of the great arteries in combination with atherosclerotic changes in the vessel wall. Systolic blood pressure is considered to be the most important arbiter of risk with ageing, and rises more steeply in women compared to men [83–85]. This is also related to the additional effects of hormonal changes during menopause [69, 86–88]. Several other sex-hormone related factors and weight gain have an additive effect on the rise in blood pressure during menopausal transition (Table 5.1) [89–92]. Also, sodium sensitivity increases during menopausal transition, frequently leading to intermittent fluid retention (edema legs, hands, lower eyelids) [93–96]. Physicians should intensify the detection of hypertension in middle-aged women after previous hypertensive pregnancy disorders and preeclampsia [97, 98]. Women develop more vascular and myocardial stiffness than men with ageing [99–101]. This is closely associated with their higher prevalence of diabetes, obesity and hypertension, resulting in more strokes, left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) [102–104].

Whereas hypertension may be asymptomatic in elderly patients with stiffened and atherosclerotic arteries, it can induce many diverse symptoms in younger patients [105]. Higher blood pressure causes shear stress on the arterial wall promoting endothelial dysfunction that may translate into symptoms of chest pain [106, 107]. This often responds well to short acting nitrates causing vasodilatation and lowering blood pressure. In the WISE study hypertension was prevalent in 55% of females, mean age 58 years, who were referred for coronary angiography for chest pain syndromes [13, 108]. Many frequently occurring complaints at middle-age can be related to a higher blood pressure, such as an oppressive chest pain or continuous band sensation at rest, with or without radiation to the shoulder blades, jaws and left (or both) arm(s). Many hypertensive women report that they prefer “to take off their bra” when being at home (patient A). Other symptoms such as sleep disturbances, palpitations, paroxysmal atrial fibrillation (AF), headaches, dizzyness, fluid retention, dyspnea, extreme tiredness and lack of energy are also frequently mentioned. Symptoms may vary over time (days/weeks/months) and increase during stressful situations and exercise. Many women experience symptoms of dyspnea while climbing the stairs or running to a bus and interchange their bike into an electric bike to catch up with their husbands. In Table 5.2 frequently reported symptoms related to elevated blood pressure in middle-aged women are described. In women having severe VMS mean 24-h blood pressure is 10 mmHg higher than in asymptomatic women, while treatment of hypertension reduces these symptoms [109, 110]. Drospirenone, a progestin with anti-mineralocorticoid properties, combined with 17-beta estradiol at various doses, lowers blood pressure in hypertensive subjects with moderate hypertension, whilst effectively alleviating VMS [111]. Patient A and B are common examples of middle-aged women with symptomatic hypertension. These kind of patients often visit outpatient clinics where a traditional cardiac work-up is done to rule out obstructive CAD, ending up without a diagnosis, treatment and plausible explanation for their symptoms. The choice for the most appropriate type of anti-hypertensive medication should be importantly based on the predominant symptoms that patients have, their resting heart rate and tolerance of various medications.

Elevated blood pressure may induce extrasystoles, paroxysmal supraventricular tachycardia or AF with variable strain-related ST-T changes on the resting ECG. The latter may be caused by shear stress on the myocardium, often in combination with endothelial dysfunction and/or subendocardial ischemia in the smaller coronary arteries. In the Women’s Health initiative study it was found that non-specific repolarisation abnormalities are associated with an increased long-term cardiovascular risk [112]. Dynamic ECG changes are frequently present during high peak systolic blood pressures at the emergency department and dissolve well with nitrates. In younger women at low chance of having obstructive CAD this often lead to unnecessary and repeated coronary angiograms.

Thus far, the currently used newer generations of oral contraceptives (OC) have not been associated with an increased risk for hypertension or IHD, but with a persistent increased risk of venous thrombo-embolism (VTE) [113–116]. In the MEGA-study, women who were current smokers and used OC had an 8.8-fold higher risk (OR 8.79, CI 95 5.73–13.49) for VTE than nonsmoking women who did not use oral contraceptives [117]. The higher risk of ACS in young women on OC has been predominantly attributed to the combined deleterious effects of smoking [118]. Smoking acts synergistically with OC use and counteracts the protective vasodilating effects of endogenous estrogens in women before menopause. Prolonged OC use for many years lowers the risk of ovarian, endometrium and colon cancer [119]. Long-term OC use has not been found to be associated with a higher coronary atherosclerosis burden as measured by quantitative coronary angiography [120]. Recent data derived from almost five million French women indicate that that levonorgestrel-containing pills should be the first choice when prescribing a combined OC [121]. However, these are still contraindicated in women after an ischemic cardiac or neurologic event and in women after VTE/pulmonary embolism [116, 122]. Also, in women >35 years with multiple CVD risk factors OC are not recommended [123]. In women receiving therapeutic anticoagulation with vitamin K antagonists or novel oral anticoagulants (NOACs) the risk for a recurrent VTE is not increased [124]. The elevated risk for abnormal uterine bleeding (AUB) in high risk premenopausal women, induced by the use of (dual) platelet therapy, NOACs or vitamin K antagonists, may demand specific individual gynaecological advise such as for the levonorgestrel releasing intra uterine system (LNG-IUS) or endometrial ablation [125]. Concomitant long-term use of a NOAC with acetylsalicylicacid or other antiplatelet drugs (clopidogrel, ticagrelor, prasugrel) should be avoided, because combination therapy increases the risk of AUB and does not improve efficacy for stroke or VTE prevention [126, 127].

The apparent vasoprotective effects of estrogens during the fertile years of life have been the basis for the assumption that hormone therapy (HT) may protect against CVD [128]. This “estrogen-hypothesis” was initially supported by large observational studies, such as the Nurses’ Health Study, in which it was found that the prevalence of CVD was lower in HRT users that in non-users [129]. Despite, in the large randomized HT trials, such as the Women’s Health Initiative (WHI) studies, a CVD protective effect of HT could not be demonstrated and in contrast even more harm was seen in elderly (>60 years) women at elevated CVD risk [130]. In a meta-analysis of randomized-controlled trials a significantly lower risk of IHD and death from any cause (HR 0.72, CI 0.62–0.82) was found in HT users younger than 60 years who were less than 10 years since menopause [131]. The Danish Osteoporosis Prevention Study (DOPS), included women on average 50 years and 7 months past menopause, to HT with estradiol alone or in combination with a progesterone and showed a significantly lower risk of IHD at 10 and 16 years of follow-up among HT users compared to non-users [132]. The effects of HT on CVD are therefore importantly dependent on the timing of therapy initiation relative to menopause [12, 133]. Moreover, the type of HT, the dose and the route of administration should be also considered. In the Kronos Early Estrogen Prevention Study (KEEPS), low-dose treatment with oral conjugated estrogens or combined estradiol patch with oral progesterone among young women (42–58 years) at low risk for CVD showed no significant effect on CIMT progression compared to placebo after 2 years of treatment [134]. Conversely, in the Early versus Late Intervention Trial with Estradiol (ELITE) HT was associated with less progression of subclinical atherosclerosis (measured as CIMT) compared to placebo when therapy was initiated within 6 years after menopause but not when it was started after 10 or more years after menopause [135]. The risk of VTE risk is higher in users of systemic combined estrogen–progestogen treatment than in users of estrogen only [136]. Several studies have shown that transdermal estrogen and vaginal estrogen do not appear to increase the risk of VTE [136, 137]. Hormone therapy improvement in cognitive function has not been supported [138], and longer term trials demonstrate increased dementia and mild cognitive impairment with HT compared to placebo [139, 140].

For women with premature menopause it is advised that HT should be administered at least until the median age of natural menopause which is 51 years [141, 142]. Longer duration of treatment can be considered when severe menopausal VMS are present. After the publications of the WHI results there had been a 80% decline in the prescription of HT, leaving many patients and doctors in confusion [143]. This has led to an overuse of untested potentially harmful alternative treatments. Although HT is not recommended for the primary or secondary prevention of IHD in postmenopausal women, its (temporary) use can be relatively safe in the hands of well-trained physicians, weighing risks and benefits with the patient. Women with known IHD or with many coronary risk factors seeking HT because of troublesome climacteric symptoms should be properly counselled for their individual baseline risk of developing breast cancer, VTE and CVD (recurrence) (see Table 5.3).

Appropriate counselling and treatment of VMS and CVD risk factors is essential for women during midlife, also because the impact of menopausal symptoms on work ability is high [144, 145]. In 2015 the European menopause and andropause society (EMAS) has released a clinical guide for postmenopausal health, emphasizing the need for an individual patient approach with appropriate choice of HT and route of administration [146]. This is also the starting point of the NICE guidelines on menopause management that were released in November 2015 (https://​www.​nice.​org.​uk/​guidance/​NG23) and the revised global consensus statement on menopausal hormone therapy [147]. For the possibilities of non-hormonal management of VMS the EMAS has recently provided a separate position statement [148].