Keywords

20.1 Vasomotor Symptoms and Metabolic Syndrome

Although the majority of menopausal women suffer from vasomotor symptoms (VMS; hot flushes and night sweats), the underlying etiopathology behind them is not fully identified. However, the decrease in endogenous estrogens and an elevated central sympathetic tone, mediated through alpha-2 adrenergic receptors, have been associated with a narrowed thermoneutral zone in the thermoregulatory center in the brain possibly causing VMS [1]. Menopausal symptoms and their impact on the quality of life are described. Abundant data link metabolic disturbances to the activation of the sympathetic nervous system [2]. This is, in turn, associated with changes in blood pressure (BP) [3], dyslipidemia [4], and the development of insulin resistance [2], which all are components of the MetS. Although both VMS and MetS are linked to sympathetic overactivity, it is unclear whether VMS are an independent risk factor for MetS.

20.1.1 VMS and BP

Cross-sectional data on BP and VMS are mixed. For instance, one study found that in lean and healthy postmenopausal women, the more frequent the VMS, the lower the systolic BP [5]. Data on no association between VMS and BP [6] also exist. In another study both systolic and diastolic BPs were significantly higher in menopausal women with VMS, when compared with asymptomatic women [7]. Of note, women with VMS and increased BP [7] were overweight with a mean BMI between 26 and 29 kg/m2. On the contrary, in studies [6, 7] showing lack of association, the women were lean (mean BMI ≤25 kg/m2).

The Study of Women’s Health across the Nation (SWAN) is a large and ethnically diverse longitudinal study of the menopausal transition with long follow-up and 3302 women enrolled [8]. One of the reports from the SWAN study focuses on the association between VMS and BP [9]. In this study (n = 2839), data on VMS and BP was collected at each annual study visit, and mean follow-up was 8.2 years. Women with ≥6 days with VMS during the preceding 2 weeks had greater increases in diastolic BP over time than did asymptomatic women or those with less symptoms. Symptomatic women were also at an increased risk of developing prehypertension or hypertension during follow-up (hazard ratio of 1.39, 95% CI 1.09–1.79).

20.1.2 VMS and Lipids

As regards lipids, in the SWAN study [10], the presence and frequency of VMS after 8 years was associated with higher lipid and lipoprotein levels. Overall, good quality data on VMS and lipids seems scarce. In a recent pooled analysis [11], data on VMS and lipids consisted of only two studies. A larger number of studies were analyzed for night sweats, and the meta-analysis showed that night sweats were associated with significantly increased levels of total cholesterol (0.17 mmol/L, 95% CI 0.03–0.31) and LDL-cholesterol (mean difference: 0.07 mmol/L, 95% CI 0.01–0.13).

A Korean cross-sectional study on 1906 postmenopausal women with no current HT use addressed specifically the relation between VMS and MetS [12]. The study showed that women with VMS had a higher risk for MetS and that the relationship was stronger for women with a BMI over 25 (OR 2.1, 95% CI 1.3–3.5).

According to a recent systematic review on VMS and metabolic health [13], many studies suffer from high heterogenicity and do not possess the quality to make definite conclusions. However, the majority of data point toward an unbeneficial association between VMS and BP and lipids, to name a few [11], and obesity may well be a factor that modulates these relations [14].

20.1.3 VMS, Obesity, and Insulin Resistance

The prevalence of obesity is increasing steadily in the Western world, and this is in line with the growing incidence of MetS [15]. According to the World Health Organization statistics, the worldwide prevalence of obesity nearly doubled between 1980 and 2008. Excessive body weight and the related MetS are mutually related. Briefly, the hormonal changes in menopause are associated with an increase in total and abdominal adipose tissue [16,17,18], and these changes, together with estrogen deficiency, are well-known risk factors for insulin resistance and type 2 diabetes mellitus, elevated BP, dyslipidemia, and MetS.

Both epidemiologic and longitudinal studies have linked obesity with postmenopausal VMS [19,20,21,22]. The mechanisms are by far not clear, but there is support for the idea that adipose tissue-derived adipokines may be one link between increased adiposity, metabolic disturbances, and VMS. Abdominal obesity is characterized with chronic low-grade inflammation of adipose tissue, which results in impaired adipokine secretion and metabolic dysregulation [23]. Adipokines have been shown to influence the central nervous system, the body temperature [24, 25], as well as sympathetic nerve activity [26]. In the SWAN study, higher odds of VMS in pre- and early perimenopause was related to an adverse adipokine profile [22].

Altered adipokine profile and an increased sympathetic nerve activity have been linked to impaired glucose metabolism as well [26]. However, there are conflicting data on the association between VMS and insulin resistance [14]. In some, but not all studies, elevated BMI explained the positive association between VMS and insulin resistance [27,28,29,30]. However, there is a growing number of data that links increased adiposity, adipokines, metabolic disturbances, and VMS in postmenopausal women.

20.2 Vasomotor Symptoms and Cardiovascular Disease

20.2.1 VMS and Subclinical CVD

Vascular aging, seen as endothelial dysfunction and development of subclinical atherosclerosis, increases the risk of later CVD. Studies on VMS, endothelial dysfunction, and subclinical atherosclerosis, some of them reviewed here, have yielded somewhat conflicting results.

Findings from the SWAN study point toward endothelial dysfunction and subclinical CVD in women with VMS. In a cross-sectional setting of the SWAN study (n = 432–492), women with VMS had poorer endothelial function assessed as brachial flow-mediated dilatation (FMD) [31]. Symptomatic women also had greater aortic calcification and greater carotid intima-media thickness (CIMT) than asymptomatic women [32]. This effect was independent of traditional cardiovascular risk factors, hormone therapy (HT) use, or estradiol levels. Relation between VMS and CIMT was most pronounced in overweight and obese women and in women with persistent VMS. However, no association between symptom status and CIMT progression during a 2-year follow-up was found. A follow-up of the SWAN study [33] shows that long-lasting VMS that begin already in the early menopausal years are associated with a higher CIMT at approximately 59 years of age, when compared with women who traverse through menopause with a low frequency of VMS. Perhaps the longevity of symptoms may be of more significance than just the presence of them?

On the contrary, two studies on recently postmenopausal women with a low CVD risk profile found no adverse effect of VMS on vascular function [34], coronary artery calcification (CAC), or CIMT [35]. Both studies included only lean women; thus, obesity may indeed be a factor that modifies the risk profile associated with vasomotor symptoms. Also, the estrogen-only arm of the WHI trial shows contrasting results as regards CAC [36]. Women with a history of VMS had significantly reduced odds for CAC (OR 0.66, 95% CI 0.45–0.98) compared with women with no VMS. Moreover, estrogen therapy in women with VMS, initiated within 2 years from menopause, resulted in an even lower risk of CAC (OR 0.48, 0.26–0.89), indicating perhaps a more beneficial effect of estrogen therapy in women with VMS. This finding is supported by data from a randomized, placebo-controlled trial, which shows that in women with tolerable VMS or no VMS at all, oral estradiol led to unbeneficial vascular reactivity as assessed by pulse wave analysis and rises in BP. Women with intolerable VMS showed no unbeneficial effects of HT on vascular function, and BP actually decreased during the 6-month intervention [37].

20.2.2 VMS and CVD Outcomes

The exact mechanism by which VMS may affect risk factors for CVD is not known. In addition to risk factors, such as MetS and its components or endothelial dysfunction, researchers have also investigated whether presence of VMS influences clinical outcomes.

An Italian observational study [38] examined whether a history of VMS could affect the outcome of acute coronary syndrome (ACS). A total of 373 consecutive women undergoing coronary angiography due to ACS were followed for 1 year, and data on VMS history was gathered through questionnaires. Women with VMS at menopause were younger at the time of the ACS than asymptomatic women. However, the extent of calcifications at angiography or incidence of cardiovascular events, such as stroke or recurrent ACS at 1 year, did not differ between the groups. Of note, information on VMS was recalled, and the researchers were not able to adjust for possible confounding factors, so these results need to be interpreted cautiously.

A large (n = 11,725) Australian longitudinal population-based study [39] with a 14-year follow-up sought to elucidate whether there could be a difference between hot flushes or night sweats on the risk of incident CHD. The participants were surveyed for VMS and CHD events with repeated self-completed questionnaires at approximately 3-year intervals. Cause of death was confirmed from a national register. Menopause status, type (hot flushes or night sweats), and frequency of VMS and HT use were queried at every survey point. Adjusting for age, menopause status, and lifestyle and chronic disease factors revealed a similarly increased risk for developing CHD for women with frequent hot flushes (OR 1.70, 95% CI 1.16–2.51) or night sweats (OR 1.84, 95% CI 1.24–2.73). Of note, long duration of VMS did not further increase the risk of CHD in this population.

The data on VMS and CVD risk are not unanimous. As regards hard outcomes, an observational study found a decrease in all-cause mortality associated with VMS. The Rancho Bernardo study [40] included white middle- to upper-middle class women, and the researchers distinguished between hot flushes and night sweats instead of overall VMS. During the average 11.5-year follow-up, hot flushes alone were not associated with all-cause mortality, but in women with both hot flushes and night sweats, the risk of all-cause mortality was 28% lower compared with women without VMS. This finding was independent of body mass index, past or current use of estrogen or progestin, physical exercise, and smoking habit. The study included a very selected group of women, and of course, the findings cannot be directly extrapolated to women of other ethnic origins or other social classes.

The longevity of VMS and the cardiovascular effects of estrogen are of interest also when considering the discontinuation of HT. The mean duration of vasomotor symptoms is longer than previously thought, even up to 7–10 years [41]. On the other hand, many current guidelines recommend that HT should be used for the shortest possible time. Both epidemiological [42, 43] and clinical studies have shown an increased risk for overall mortality [44] and CVD outcomes [42, 45] after HT discontinuation. In a Finnish nationwide study, the risk increases were evident during the first post-HT year and significantly higher in women who were younger than 60 years of age at HT discontinuation [42, 43]. Although the mechanisms behind this finding are not known, one interesting possibility is the reoccurrence of VMS in women under 60 years of age at HT discontinuation, and an increased sympathetic activity, which could predispose some women to fatal arrhythmias [46]. Also, withdrawal of the vasodilatory effect of estrogen could lead to vasoconstriction and result in ischemia.

20.2.3 Timing of VMS and CVD Risk

Another piece in the puzzle is the possible impact of the timing of VMS on cardiovascular health. The HERS trial studied women with established CHD. For women with VMS (mean age at baseline 63 years), the risk of CHD events during the first year of HT was ninefold compared to those with no VMS (mean age at baseline 67 years) [47]. The observational arm of the WHI study (WHI-OS) [48], in turn, showed that VMS during menopausal transition did not associate with CVD, whereas women with VMS starting in their sixties or later were at increased risk for CHD, stroke, total CVD, and all-cause mortality, compared with women without a history of VMS. Of note, 44–55% of women in the WHI-OS were current HT users.

Also the Women’s Ischemia Syndrome Evaluation (WISE) addressed the timing of VMS on CVD mortality and nonfatal events [49], and the findings are contradictory to those of HERS and WHI. The WISE study was a four-center prospective cohort study on women (n = 254, mean age 67 years) undergoing coronary angiography due to a suspicion of myocardial ischemia. Nonfatal events were unaffected by the VMS status, but women with early-onset VMS (before age 42) had three times higher CVD mortality risk than women with later-onset VMS (after age 42). Interpretation of the findings is complicated by the fact that also women without VMS had an increased mortality risk when compared with women with later-onset VMS. Women with early-onset VMS had also a lower FMD than women with no or later-onset VMS. Of note, some of the women with early-onset VMS could perhaps suffer from premature ovarian insufficiency, which is an independent CVD risk. Moreover, women with early-onset VMS were obese, whereas women with later-onset VMS were only overweight (p < 0.05). Once again, obesity could play a role here.

20.3 Importance of VMS Measurement

Increasing attention has been given to how VMS are measured, and concerns have been raised that self-reported and recalled VMS may be subject to several biases [50,51,52]. Recent studies have utilized both objective and subjective methods to assess VMS [53, 54]. In two studies that assessed VMS and markers for subclinical CVD, the women (aged 40–60 years) recorded their VMS for 3 days in an electronic hot flush diary and a wrist actigraph and wore a physiologic hot flush monitor for 24 h. The median numbers of physiologically detected and self-reported hot flushes were 12 and 5, respectively, indicating that women do underreport their symptoms. The VMS data were compared to brachial artery FMD (n = 272) and CIMT (n = 295) measurements and controlled for common CVD risk factors. Age bore an impact on the association between physiologically monitored hot flush frequency and brachial FMD. Greater VMS frequency was associated with poorer FMD among women aged 40–53 years, when compared with older women. For this youngest tertile of women, VMS also accounted for the most variance in FMD. In this setting age did not affect CIMT, but women with ≥4 self-reported VMS or with ≥10 physiologically measured VMS had higher CIMT and more carotid plaque than non-flushers. The presence of carotid plaques was positively related to physiologically measured VMS only in women aged 54 or more.

Taken together, women may underreport their symptoms, which may enhance the importance of physiological measurements. Furthermore, different markers for CVD may show different temporal relations to VMS. Whether this in later life translates to clinical CVD, especially with early-onset, long-lasting VMS, needs to be determined.

20.4 Summary

Menopausal VMS are a form of neurovascular dysregulation, and they show a complex interplay with different risk factors for CVD. Current data point toward an increased risk of MetS and CVD in women with VMS. Thus, clinicians should consider screening their patients with VMS for MetS and CVD risk factors.

Majority of the studies are cross-sectional, and the presence and frequency of VMS is often recalled rather than observed. Furthermore, VMS may not have been included in the original study protocol, and the power to detect differences may be low. Thus, we need studies specifically designed to investigate VMS, and future research needs focus on using also objective methods to assess what type of VMS is the most relevant as regards cardiovascular health.

As VMS may negatively affect the quality of life, the use of HT is often needed. Future research should also try to elucidate whether HT possibly reverses any unbeneficial effects of VMS. Some of the questions that still remain open are as follows: (1) if VMS indeed are a risk factor for CVD, should also mild symptoms be treated, and (2) due to the longevity of symptoms, and a possible adverse effect of the discontinuation of HT use in women under 60 years of age, should longer treatments be encouraged?