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Menopausal symptoms and cardiovascular disease mortality in the Women's Ischemia Syndrome Evaluation (WISE)
Abstract
Objective:
Studies have linked vasomotor symptoms (VMS) to markers of cardiovascular disease (CVD) risk, yet few have considered clinical cardiovascular events. Data suggest that associations may depend upon the age that symptoms occur. We examined associations between VMS and cardiovascular events and endothelial function, considering age of symptom onset.
Methods:
The Women's Ischemia Syndrome Evaluation enrolled women referred for coronary angiography for suspected myocardial ischemia. A total of 254 women aged more than 50 years, postmenopausal, with both ovaries, not taking hormone therapy underwent a baseline evaluation, were followed annually (median?=?6.0 y), and the National Death Index was searched to ascertain CVD mortality (median?=?9.3 y). A subset of participants underwent brachial artery ultrasound for flow-mediated dilation (FMD). Receiver-operating curve analysis was used to determine vasomotor symptom groups (symptoms beginning?<?age 42 [early onset], beginning ?42 [later onset], never) which were examined in relation to cardiovascular events and FMD in Cox proportional hazard and linear regression models.
Results:
Women reporting early onset VMS (HR?=?3.35, 95% CI?=?1.23-7.86, P?=?0.005) and women who never had VMS (HR?=?2.17, 95% CI?=?1.02-4.62, P?=?0.05) had higher CVD mortality than women with later onset symptoms (multivariable models). Women with early onset VMS had lower FMD than women with later onset symptoms (b?=?-4.31, SE?=?2.10, P?=?0.04, multivariable).
Conclusions:
Women with signs and symptoms of ischemia who had VMS beginning early in midlife had higher CVD mortality and reduced endothelial function relative to women with later onset symptoms. Future research should evaluate the vascular phenotype of women with early midlife VMS.
... Our data on homogenously Asian female population, which is likely to have different genetic and environmental liabilities from other ethnic/racial groups, add to the previous work. The early-occurring VMSs may have important implications in women's cardiovascular health, as timing of the VMSs onset may have substantial impact on CVD-related prognosis 19 . Women with early-onset VMSs had poorer endothelial function, which was characterized by the higher intima media thickness, a well-known subclinical CVD marker for www.nature.com/scientificreports/ ...
... Women with early-onset VMSs had poorer endothelial function, which was characterized by the higher intima media thickness, a well-known subclinical CVD marker for www.nature.com/scientificreports/ future CVD event, as well as higher CVD mortality compared to those with consistently low VMSs throughout menopausal transition 19,20 . Although other cholesterols did not show significant relationship with VMSs, we carefully suggested that elevated LDL levels may serve as an indicator that identifies premenopausal women at high risk of VMSs. ...
... The mechanism underlying the association between increased LDL cholesterol and risk of VMSs is poorly understood. According to the recent findings, VMSs, including hot flashes and night sweats, in middle-aged women are reflective of CVD risk and are associated with various markers of endothelial dysfunction 6,19,20 . Endothelial dysfunction is considered a major initiating event in the development of atherosclerosis and subsequent CVD development 23 , and there is evidence that chronic elevation of plasma LDL cholesterol is a major determinant of endothelial dysfunction 17 . ...
We investigated the associations between serum lipid profiles and risk of early-onset vasomotor symptoms (VMSs) in premenopausal women. This cohort study comprised 2,540 premenopausal women aged 42–52 years without VMSs at baseline (median follow-up: 4.4 years). VMSs, including hot flashes and night sweats, were assessed using the Menopause-Specific Quality of Life questionnaire (Korean version). Early-onset VMSs were defined as VMSs that occurred premenopause; moderate/severe VMSs were defined as a score of ≥ 3 points (range: 0 to 6, 6 being most bothersome). Cox proportional hazard regression models were used to estimate hazard ratios with 95% confidence intervals (CI) for the development of VMSs across the lipid levels. Higher low-density lipoprotein (LDL) cholesterol levels were positively associated with increased risk of early-onset VMSs. Compared to the < 100 mg/dL LDL group, the multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for incident VMSs were 1.19 (1.03–1.37) and 1.20 (1.03–1.40) in participants with LDL cholesterol levels of 100–129 mg/dL and ≥ 130 mg/dL, respectively ( P for trend = 0.027). The multivariable-adjusted HR for incident moderate/severe VMSs was 1.37 (95% CI: 1.08–1.73) in participants with LDL ≥ 130 mg/dL, compared to those with LDL < 100 mg/dL. Meanwhile, triglycerides and total and high-density lipoprotein cholesterol levels were not significantly associated with early-onset VMSs risk in premenopausal women. Premenopausal women with high serum LDL cholesterol concentrations had a higher risk of incident early-onset VMSs. Further studies should confirm our findings and examine whether LDL-lowering interventions reduce the risk of early-onset VMSs among women during menopause transition.
... 3,7 Similarly, menopausal symptoms, specifically vasomotor symptoms (VMS) associated with the menopausal transition, are linked with markers of cardiovascular risk, [11][12][13][14][15] subclinical CVD, 2,16-18 and adverse cardiovascular outcomes. 19 As with HDP, the underlying pathophysiology linking VMS and CVD risk remains unclear, although it is likely that VMS are also a marker of risk rather than being causative or disease generating. 20 Despite the recognition of HDP and VMS as femalespecific risk factors for CVD, the association between HDP and VMS has not been well studied, with the exception of a single study from a cardiology clinic that reported greater VMS in women with a history of HDP. ...
... [40][41][42] Certain trajectories of VMS have been linked to cardiovascular risk, with women experiencing VMS early in the menopausal transition demonstrating the highest risk of subclinical disease as measured by carotid intima media thickness in the Study of Women's Health Across the Nation 18 and greater CVD mortality in the Women's Ischemia Syndrome Evaluation. 19 However, the Women's Health Initiative Observational Study identified women with later onset VMS to have greater risk for coronary heart disease and all-cause mortality. 41 As with HDP, emerging data suggest that VMS may be associated with accelerated aging, independent of their effect on sleep. ...
... 44,45 Despite identification of these CVD risk factors, prediction of which women will go on to develop symptomatic disease remains difficult, 46,47 and a uniform approach to follow-up of women with a history of an HDP is lacking. 7,48 Similarly, it has yet to be definitively established which specific patterns or trajectories of VMS predispose women to be at greatest risk for future CVD, 18,19,41 and whether the presence of an HDP in combination with bothersome VMS at the time of menopause is associated with even greater future risk for an individual woman. It is also unclear if the presence of an HDP earlier in life can help identify women may experience more bothersome menopause symptoms, and whether proactive education on management may improve the menopause experience. ...
Objective:
Hypertensive disorders of pregnancy and menopausal symptoms, specifically vasomotor symptoms, have both been associated with cardiovascular disease risk in women. However, data are sparse on the association between these two female-specific cardiovascular risk factors. This study was conducted to investigate the association between a history of a hypertensive disorder of pregnancy and menopausal symptoms.
Methods:
This was a cross-sectional study of women aged 40 to 65 years seen for specialty consultation in women's health clinics at Mayo Clinic Rochester, MN and Scottsdale, AZ, between May, 2015 and September, 2019. A self-reported history of hypertensive disorders of pregnancy served as the independent variable, and menopause symptoms as assessed by the Menopause Rating Scale were the primary outcome measure.
Results:
Of 2,684 women included in the analysis, 180 had a self-reported history of a hypertensive disorder of pregnancy. The total menopausal symptom scores as well as somatic and psychological domain scores were higher in women with a history of a hypertensive disorder of pregnancy compared to women without a history of a hypertensive disorder of pregnancy or to women without a pregnancy. On multivariable analysis, women with a hypertensive disorder of pregnancy using hormone therapy had significantly higher total menopause symptom scores than women with no such history.
Conclusions:
In this large cross-sectional study, a history of hypertensive disorders of pregnancy was associated with more bothersome menopausal symptoms. Additional study is needed to determine the strength of this association, underlying mechanisms of the association, and clinical implications for cardiovascular risk prediction in women.
... Nearly 80% of women experience vasomotor symptoms (VMS) during the menopausal transition, [6][7][8][9] and recent data suggest a potential relationship between VMS and indicators of cardiovascular disease. 10,11 VMS have been correlated with cardiovascular disease risk factors, [12][13][14][15][16][17] subclinical measures of cardiovascular disease progression, 18 such as carotid intima-media thickness, [19][20][21] coronary artery calcium, 22 aortic calcification, 23 endothelial dysfunction, 24,25 and cardiovascular clinical events, [25][26][27] albeit with conflicting results. Early VMS have been linked to unfavorable outcomes in women with stable coronary artery disease, 25 but the independent contribution of VMS in predicting clinical endpoints in postmenopausal women after an acute coronary syndrome (ACS) has never been explored. ...
... Nearly 80% of women experience vasomotor symptoms (VMS) during the menopausal transition, [6][7][8][9] and recent data suggest a potential relationship between VMS and indicators of cardiovascular disease. 10,11 VMS have been correlated with cardiovascular disease risk factors, [12][13][14][15][16][17] subclinical measures of cardiovascular disease progression, 18 such as carotid intima-media thickness, [19][20][21] coronary artery calcium, 22 aortic calcification, 23 endothelial dysfunction, 24,25 and cardiovascular clinical events, [25][26][27] albeit with conflicting results. Early VMS have been linked to unfavorable outcomes in women with stable coronary artery disease, 25 but the independent contribution of VMS in predicting clinical endpoints in postmenopausal women after an acute coronary syndrome (ACS) has never been explored. ...
... 10,11 VMS have been correlated with cardiovascular disease risk factors, [12][13][14][15][16][17] subclinical measures of cardiovascular disease progression, 18 such as carotid intima-media thickness, [19][20][21] coronary artery calcium, 22 aortic calcification, 23 endothelial dysfunction, 24,25 and cardiovascular clinical events, [25][26][27] albeit with conflicting results. Early VMS have been linked to unfavorable outcomes in women with stable coronary artery disease, 25 but the independent contribution of VMS in predicting clinical endpoints in postmenopausal women after an acute coronary syndrome (ACS) has never been explored. ...
Objective:
Vasomotor symptoms (VMS) during menopausal transition have been linked to a higher burden of cardiovascular risk factors, subclinical vascular disease, and subsequent vascular events. We aim to investigate the association of VMS with the extent of coronary disease and their prognostic role after an acute coronary syndrome.
Methods:
The Ladies Acute Coronary Syndrome study enrolled consecutive women with an acute coronary syndrome undergoing coronary angiography. A menopause questionnaire was administered during admission. Angiographic data underwent corelab analysis. Six out of 10 enrolling centers participated in 1-year follow-up. Outcome data included the composite endpoint of all-cause mortality, recurrent myocardial infarction, stroke, and rehospitalization for cardiovascular causes within 1 year.
Results:
Of the 415 women with available angiographic corelab analysis, 373 (90%) had complete 1-year follow-up. Among them, 202 women had had VMS during menopausal transition. These women had the same mean age at menopause as those without VMS (50 years in both groups), but were younger at presentation (median age 71 vs 76 years; P < 0.001), despite a more favorable cardiovascular risk profile (chronic kidney dysfunction 4.5% vs 15.9%; P = 0.001; prior cerebrovascular disease 4.5 vs 12.2%; P = 0.018). Extent of coronary disease at angiography was similar between groups (mean Gensini score 49 vs 51; P = 0.6; mean SYNTAX score 14 vs 16; P = 0.3). Overall cardiovascular events at 1 year did not differ between groups (19% vs 22%; P = 0.5).
Conclusions:
In postmenopausal women with an acute coronary syndrome, a history of VMS was associated with younger age at presentation, despite a lower vascular disease burden and similar angiographically defined coronary disease as compared with women without VMS. No difference could be found in terms of overall clinical outcomes. These results should be interpreted cautiously as all analyses were unadjusted and did not account for risk factor differences between women with and without a history of VMS.
... 4,5 Changes in the sex hormone levels occurring around the menopause onset have been associated with metabolic changes, resulting in slower lipid metabolism, impairment of glucose tolerance and increased body weight, 6 leading to higher cardiovascular morbidity and mortality in ageing women. [7][8][9][10] Further, menopausal symptoms have been associated with increased cardiovascular risk factors, increased risk of coronary heart disease, and increased allcause and cardiovascular disease (CVD) mortality. 8,10,11 Thus, menopause has been suggested as a risk factor for developing cardiometabolic diseases (CVD, metabolic syndrome and type 2 diabetes). ...
... [7][8][9][10] Further, menopausal symptoms have been associated with increased cardiovascular risk factors, increased risk of coronary heart disease, and increased allcause and cardiovascular disease (CVD) mortality. 8,10,11 Thus, menopause has been suggested as a risk factor for developing cardiometabolic diseases (CVD, metabolic syndrome and type 2 diabetes). [12][13][14] Indeed, the incidence of CVD is increased in the postmenopausal period, thus, consensus statements from leading experts have made this a priority for cardiovascular prevention in women's health. ...
Context:
Menopause has been associated with adverse cardiovascular disease (CVD) risk profile, yet it is unclear whether the changes in CVD risk factors differ by reproductive stage independently of underlying aging trajectories.
Design:
The CoLaus study is a prospective population-based cohort study in Lausanne, Switzerland.
Patients:
We used data from women at baseline and follow-up (mean 5.6 ±0.5 years) from 2003 to 2012 who did not use hormone therapy. We classified women into (i) premenopausal, (ii) menopausal transition, (iii) early (≤ 5 years), and (iv) late (> 5 years) postmenopausal by comparing their menstruation status at baseline and follow-up.
Measurements:
We measured fasting lipids, glucose, and cardiovascular inflammatory markers. We used repeated measures (linear mixed models) for longitudinal analysis, using premenopausal women as a reference category. We adjusted analyses for age, medications, and lifestyle factors.
Results:
We used the data from 1,710 women aged 35-75 years. Longitudinal analysis showed that the changes in CVD risk factors were not different in the other three menopausal categories compared to premenopausal women. When age was used as a predictor variable and adjusted for menopause status, most CVD risk factors increased, while interleukin 6 and interleukin 1β decreased with advancing age.
Conclusion:
The current study suggests that women have a worsening cardiovascular risk profile as they age, and although menopausal women may have higher levels of cardiovascular risk factors compared to premenopausal women at any given time, the five-year changes in cardiovascular risk factors may not depend on reproductive stage. This article is protected by copyright. All rights reserved.
... Our data on homogenously Asian female population, which is likely to have different genetic and environmental liabilities from other ethnic/racial groups, add to the previous work. The early-occurring VMSs may have important implications in women's cardiovascular health, as timing of the VMSs onset may have substantial impact on CVD-related prognosis 19 . Women with early-onset VMSs had poorer endothelial function, which was characterized by the higher intima media thickness, a well-known subclinical CVD marker for future CVD event, as well as higher CVD mortality compared to those with consistently low VMSs throughout menopausal transition 19,20 .Although other cholesterols did not show signi cant relationship with VMSs, we carefully suggested that elevated LDL levels may serve as an indicator that identi es premenopausal women at high risk of VMSs. ...
... The early-occurring VMSs may have important implications in women's cardiovascular health, as timing of the VMSs onset may have substantial impact on CVD-related prognosis 19 . Women with early-onset VMSs had poorer endothelial function, which was characterized by the higher intima media thickness, a well-known subclinical CVD marker for future CVD event, as well as higher CVD mortality compared to those with consistently low VMSs throughout menopausal transition 19,20 .Although other cholesterols did not show signi cant relationship with VMSs, we carefully suggested that elevated LDL levels may serve as an indicator that identi es premenopausal women at high risk of VMSs. It might allow for early intervention to reduce the risk of VMS and the future CVD events. ...
Objectives: We investigated the associations between serum lipid profiles and risk of early-onset vasomotor symptoms (VMSs) in premenopausal women.
Study design: This cohort study comprised 2,540 premenopausal women aged 42–52 years without VMSs at baseline (median follow-up: 4.4 years).
Main outcome measures: VMSs, including hot flashes and night sweats, were assessed using the Menopause-Specific Quality of Life questionnaire (Korean version). Early-onset VMSs were defined as VMSs that occurred premenopause; moderate/severe VMSs were defined as a score of ≥ 3 points (range: 0 to 6, 6 being most bothersome). Parametric proportional hazard models were used to determine whether lipid levels affected VMS onset during the follow-up period.
Results: Higher low-density lipoprotein (LDL) cholesterol levels were positively associated with increased risk of early-onset VMSs. Compared to the < 100 mg/dL LDL group, the multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for incident VMSs were 1.19 (1.03–1.37) and 1.22 (1.04–1.42) in participants with LDL cholesterol levels of 100-129 mg/dL and ≥ 130 mg/dL, respectively (P for trend = 0.015). The multivariable-adjusted HR for incident moderate/severe VMSs was 1.40 (95% CI: 1.11–1.77) in participants with LDL ≥ 130 mg/dL, compared to those with LDL < 100 mg/dL. Meanwhile, triglycerides and total and high-density lipoprotein cholesterol levels were not significantly associated with early-onset VMSs risk in premenopausal women.
Conclusions: Premenopausal women with high serum LDL cholesterol concentrations had a higher risk of incident early-onset VMSs. Further studies should confirm our findings and examine whether LDL-lowering interventions reduce the risk of early-onset VMSs among women during menopause transition.
... 4,5 Changes in the sex hormone levels occurring around the menopause onset have been associated with metabolic changes, resulting in slower lipid metabolism, impairment of glucose tolerance and increased body weight, 6 leading to higher cardiovascular morbidity and mortality in ageing women. [7][8][9][10] Further, menopausal symptoms have been associated with increased cardiovascular risk factors, increased risk of coronary heart disease, and increased allcause and cardiovascular disease (CVD) mortality. 8,10,11 Thus, menopause has been suggested as a risk factor for developing cardiometabolic diseases (CVD, metabolic syndrome and type 2 diabetes). ...
... [7][8][9][10] Further, menopausal symptoms have been associated with increased cardiovascular risk factors, increased risk of coronary heart disease, and increased allcause and cardiovascular disease (CVD) mortality. 8,10,11 Thus, menopause has been suggested as a risk factor for developing cardiometabolic diseases (CVD, metabolic syndrome and type 2 diabetes). [12][13][14] Indeed, the incidence of CVD is increased in the postmenopausal period, thus, consensus statements from leading experts have made this a priority for cardiovascular prevention in women's health. ...
Introduction
Menopause has been associated with adverse cardiovascular disease (CVD) risk profile, yet it is unclear whether the changes in CVD risk factors differ by reproductive stage independently of underlying aging trajectories. We examined whether reproductive stages are differently associated with changes in cardiovascular risk factors.
Methods
This is a prospective population-based cohort study. We used data from women at baseline and follow-up (mean 5.5 years). We classified women into (i) premenopausal, (ii) menopausal transition, (iii) early (≤5 years), and (iv) late (>5 years) postmenopausal by comparing their menstruation status at baseline and follow-up. In the cross-sectional analysis, we compared CVD risk factors at baseline across different reproductive stages using multivariable linear regression models. In the longitudinal analysis, we used multivariable linear mixed models. We used premenopausal women as a reference category and adjusted our analyses for age, medications, hormone replacement therapy, lifestyle, body mass index (BMI) at baseline and follow-up.
Results
We used the data from 2,558 women aged 35–75 years. At baseline, compared to premenopausal women, (i) transition and early postmenopausal groups had higher HDL, (ii) early- and late postmenopausal women had higher BMI, total cholesterol, adiponectin, and interleukin-6 levels, and (iii) all other women groups had higher diastolic blood pressure and glucose levels, while no differences were observed in the other CVD risk factors. At follow-up, women across the four reproductive categories showed an increase in BMI, total cholesterol, triglycerides, and fasting glucose compared to baseline. However, linear mixed models showed that, the changes in CVD risk factors were not significantly different in the other three menopausal categories compared to premenopausal women. When using age as a predictor variable and adjusting for menopause status, most of the CVD risk factors increased, while interleukin 6 and interleukin 1b decreased with advancing age. The estimates did not change when the analyses were restricted to women who did not report hormone therapy-use.
Conclusion
The current study suggests that women have a worsening of cardiovascular risk profile as they age, and although menopausal women may have higher levels of cardiovascular risk factors compared to premenopausal women at any given time, the five year changes in cardiovascular risk factors may not depend on menopausal status per se. More studies are still needed to disentangle the contribution of age and menopause in postmenopausal CVD risk, and other pathways not explored in this study.
FUNDunding Acknowledgement
Type of funding sources: Other. Main funding source(s): COLAUS was supported by a research grants from GlaxoSmithKline and the Swiss National Science Foundation and
... Notably, VMS are a dynamic symptom for which the time course varies widely across women. Furthermore, in many studies, VMS are recalled from years or decades prior, 25,26 and thereby are limited by the pronounced recall biases characteristic of symptom reports. One longitudinal Australian study reported that VMS were associated with subsequent coronary heart disease, 27 yet key risk factors (eg, lipids and blood pressure [BP]) were not measured, and findings were based on a low disease event rate. ...
... The WHI (Women's Health Initiative) Study showed that late-occurring VMS were associated with incident coronary heart disease, 26 whereas a report from the WISE (Women's Ischemia Syndrome Evaluation) Study found that VMS occurring early in midlife were associated with greater subsequent CVD mortality. 25 In both of these studies, VMS reports were assessed at a single time point and relied on recalled information from many years earlier. With its repeated prospective assessments of VMS over 16 visits and 22 years and prospective collection of CVD events, the present study provides among the strongest evidence to date that frequent VMS experienced either early in the menopause transition or persistently over the course of the transition are associated with incident CVD. ...
Background
Cardiovascular disease (CVD) in women has unique features, including associations with reproductive factors that are incompletely understood. Vasomotor symptoms (VMS), the classic menopausal symptom, are linked to CVD risk factors and subclinical CVD. Evidence linking VMS to CVD events is limited. We tested whether frequent and/or persistent VMS were associated with increased risk for fatal and nonfatal CVD events in SWAN (Study of Women’s Health Across the Nation).
Methods and Results
A total of 3083 women, aged 42 to 52 years at baseline, underwent up to 16 in‐person visits over 22 years. Assessments included questionnaires on VMS frequency (0, 1–5, or ≥6 days/2 weeks), physical measures, phlebotomy, and reported CVD events (myocardial infarction, stroke, heart failure, and revascularization). A subset of events was adjudicated via medical record. Death certificates were obtained. Relationships between baseline VMS or persistent VMS over the follow‐up (proportion of visits with frequent VMS) with combined incident nonfatal and fatal CVD were tested in Cox proportional hazards models adjusted for demographics, medication use, and CVD risk factors. Participants experienced 231 CVD events over the follow‐up. Women with frequent baseline VMS had an elevated risk of subsequent CVD events (relative to no VMS; ≥6 days: hazard ratio [HR] [95% CI], 1.51 [1.05–2.17], P =0.03; 1–5 days: HR [95% CI], 1.02 [0.75–1.39], P =0.89, multivariable). Women with frequent VMS that persisted over time also had an increased CVD event risk (>33% versus ≤33% of visits: HR [95% CI], 1.77 [1.33–2.35], P <0.0001, multivariable).
Conclusions
Frequent and persistent VMS were associated with increased risk of later CVD events. VMS may represent a novel female‐specific CVD risk factor.
... It was found that women with VMS <42 years had lower FMD (flow-mediated dilation), reduced endothelial function, and higher CVD mortality relative to women with later onset symptoms. [8] Estrogen has pleiotropic effects. It has both nuclear, slow response through regulating transcription factor and rapid nonnuclear effects through membrane-associated estrogen receptor (ER). ...
... In the wise study, the incidence of obstructive coronary artery disease in women with angina increases dramatically after the age of 50, with a prevalence of 48% in the 55-64 age group and 79% for women >75 years of age. [8] In population-based LifeLines Cohort Study, 63,466 women, aged between 18 and 65 years, were grouped into premenopausal, perimenopausal, naturally postmenopausal, and surgically postmenopausal. Postmenopausal women aged 45 years had higher TC and low-density lipoprotein cholesterol (LDL-c) and systolic and diastolic blood pressure than in postmenopausal women aged 50. ...
... These studies gave mixed results, since some of them found a higher risk of subsequent cardiovascular events among women with a history of VMS [23,24], whereas others [25,26] did not. The relation between timing of VMS and cardiovascular events in menopause has also been investigated, with mixed results: whereas the WISE study of women with stable coronary artery disease found elevated risk among women reporting VMS during early midlife (below the age of 42 years in that particular study) [27], an increased risk of clinical cardiovascular events and all-cause mortality was found in the Women's Health Initiative Observational Study (WHI-OS) among women reporting late-onset VMS (defined as VMS after menopause) [26]. ...
... The two potential mechanisms are not mutually exclusive, particularly with regard to endothelial dysfunction, which may be considered an early stage of atherosclerosis. Endothelial dysfunction must be investigated using specific methods, such as brachial artery flow-mediated dilation (FMD) [27,31,32]. Coronary microvascular dysfunction, which should be considered as an etiology for ischemic heart disease with signs and symptoms of myocardial ischemia, but no obstructive coronary disease, should be either investigated using coronary vasoreactivity testing as the gold standard [16,18,19], or taken for granted in the case of documented myocardial ischemia with no or nonocclusive coronary artery disease. ...
Myocardial infarction (MI) is rare in pre-menopausal women, and in most cases has a gender-specific pathogenesis. After menopause, MI incidence increases gradually to equalize men’s rate in the eighth decade of age, with similar pathogenesis. This epidemiological observation has raised a number of hypotheses on the protective effect of estrogen against atherosclerosis and its related diseases. However, MI has a multifactorial pathogenesis with variable contributions of inflammation, eroded or ruptured atherosclerotic plaques, vasoconstriction and thrombosis. Whether perimenopausal vasomotor symptoms are associated with a better, worse or neutral effect on the risk of myocardial infarction has long been disputed. The recent finding of the LADIES ACS study that women reporting transitional vasomotor symptoms have earlier onset myocardial infarction, as compared to women without symptoms, despite similar risk factors and extent of coronary angiographic disease, supports the hypothesis that endothelial dysfunction, or other vasoconstrictive mechanisms, may play a key role in precipitating an acute coronary syndrome at an earlier age. These factors, rather than other atherosclerotic markers, should be specifically investigated in order to elucidate the so far elusive link between vasomotor symptoms and risk of MI.
... Menopause decreases women quality of life and de- clines their health status [4]. The most common symptoms associated with me- nopause are hot flushes [5], genitourinary problems [6] [7], sexual problems [8], mood changes [9], heart [10] and bone [11] problems. ...
... The age of natural menopause generally clusters around 44 and 55 years of age, for women worldwide [5]. The average age at menopause in developed countries is about 51 years [1]. ...
... 11 Identifying OSA is important because it is associated with significantly increased risk for coronary heart disease, hypertension, stroke, atrial fibrillation, carotid atherosclerosis, depression, and death. [20][21][22][23][24][25][26][27] Although OSA and VMS have both been independently associated with menopause and with cardiovascular risk, the association between VMS and OSA in midlife women is unclear (Fig. 1). 28 The purpose of this study was to explore the relationship between self-reported VMS and OSA risk in midlife women using commonly available questionnaires in the clinical setting. ...
... 20 In the Women's Ischemia Syndrome Evaluation (WISE) study, women with early onset VMS (first occurring before the age of 42 y) had lower flowmediated dilatation and higher cardiovascular mortality than those who experienced later onset VMS. 21 Overall, the aggregate data support an association between VMS and CHD risk, 39,40 with a suggestion that night sweats more than daytime hot flashes may be associated with increases in blood pressure. 41,42 The STOP-BANG self-report was used in the present study to assess OSA risk. ...
Objective:
The aim of the study was to determine the association between self-reported vasomotor symptoms (VMS) and obstructive sleep apnea (OSA) risk.
Methods:
The STOP-BANG to evaluate OSA and Menopause Rating Scale (MRS) were administered to 2,935 women seen in the Women's Health Clinic at Mayo Clinic in Rochester, MN, between May 2015 and December 2016. Of these, 1,691 women were included in the analysis. Total MRS and VMS ratings were compared using logistic regression, with age, smoking, and body mass index (BMI) included as covariates between women at intermediate/high risk versus low risk for OSA.
Results:
Total MRS scores were significantly higher in women with intermediate/high-risk OSA scores versus those with low-risk scores [mean (SD): 16.8 (8.0) vs 12.9 (7.0), P < 0.001]. Women at intermediate/high OSA risk were older, had more education, self-reported hypertension, BMI >35 kg/m, and were less likely to be married or employed. Self-reported severe/very severe VMS were significantly associated with intermediate/high risk versus low risk for OSA (26.6% vs 15.0%; P < 0.001). After adjusting for age, BMI, smoking status, and self-reported hypertension, the odds of having intermediate/high risk for OSA were 1.87 times higher for those with severe/very severe VMS compared with those with none/mild/moderate VMS (95% CI, 1.29-2.71, P < 0.001). This association persisted upon subgroup analysis based on BMI <25 kg/m (odds ratio 2.15; 95% CI, 1.12-4.16, P = 0.022).
Conclusions:
Self-reported severe/very severe VMS were associated with intermediate/high risk for OSA in midlife women, even in women with BMI <25 kg/m. Given the limitations of the STOP-BANG tool, OSA risk may, however, have been overestimated.
... The rate of cardiovascular events is sharply increasing after the age of 50 years in women, which coincides with the time of the natural menopausal transition [1,2]. The hormonal milieu related to the cessation of ovarian function is linked with significant metabolic derangement, including abdominal adiposity features, pro-atherogenic dyslipidaemia, insulin resistance and new-onset hypertension [3]. ...
Purpose
The increase in cardiovascular risk after the menopausal transition remains partly explained until today. Further research is needed to identify risk factors potentially modifiable by primary prevention practices. This cross-sectional study, part of a larger prospective project, aims to investigate possible associations between dietary patterns and indices of vascular structure and function among healthy postmenopausal women.
Methods
Postmenopausal women (n = 310) without clinically overt cardiovascular disease were recruited consecutively from a University Menopause Clinic over three years. Dietary intake was assessed by a validated food frequency questionnaire and the MedDietScore. In addition, we assessed anthropometric/biochemical parameters, including the Triglyceride-glucose index (TyG-Index), body fat distribution [triceps skinfold (TSF), mid-upper arm circumference (MUAC)] and physical activity. The vascular assessment included carotid-femoral pulse wave velocity (PWV), carotid and femoral-artery intima-media thickness (IMT) and atheromatous plaques presence.
Results
Consumption of non-refined cereals was associated with carotid-bulb IMT (R² = 5.5% b-coefficient = −0.142; p = 0.011), adjusting for age, physical activity, lipids, systolic blood pressure, smoking, body mass index, insulin resistance, and daily energy intake. PWV was associated with the intake of total dairy products (R² = 27.3%, b-coefficient = −0.117; p = 0.017). Higher red meat consumption was related to a greater TyG-index (Model 1, R² = 14.3%, b-coefficient=0.121; p = 0.048), an association mediated by total daily energy intake. Higher consumption of alcohol, as well as the MedDietScore, were inversely associated with TSF measurements, significant after Bonferroni correction.
Conclusion
Dietary patterns are associated with metabolic indices and subclinical atherosclerosis in postmenopausal women independently of traditional cardiovascular risk factors, total energy intake or physical activity.
... However, recent studies suggest that VMSs can occur far earlier than previously reported, even during the premenopausal or early menopausal transition stages, and that they can persist for longer than 10 years after the final menstrual period [7,8]. Since early-onset and long-lasting VMSs are more likely to be related to psychological symptoms [9] and other adverse health outcomes, such as subclinical and cardiovascular events [10,11], there has been growing attention on identifying the risk factors for early-onset VMSs and their distinct pathophysiology. ...
The role of nonalcoholic fatty liver disease (NAFLD) in vasomotor symptom (VMS) risk in premenopausal women is unknown. We examined the prevalence of early-onset VMSs according to NAFLD status in lean and overweight premenopausal women. This cross-sectional study included 4242 premenopausal Korean women (mean age 45.4 years). VMSs (hot flashes and night sweats) were assessed using the Korean version of the Menopause-Specific Quality of Life questionnaire. Hepatic steatosis was determined using liver ultrasound; lean was defined as a body mass index of <23 kg/m2. Participants were categorized into four groups: NAFLD-free lean (reference), NAFLD-free overweight, lean NAFLD, and overweight NAFLD. Compared with the reference, the multivariable-adjusted prevalence ratios (PRs) (95% confidence intervals (CIs)) for VMSs in NAFLD-free overweight, lean NAFLD, and overweight NAFLD were 1.22 (1.06–1.41), 1.38 (1.06–1.79), and 1.49 (1.28–1.73), respectively. For moderate-to-severe VMSs, the multivariable-adjusted PRs (95% CIs) comparing NAFLD-free overweight, lean NAFLD, and overweight NAFLD to the reference were 1.38 (1.10–1.74), 1.73 (1.16–2.57), and 1.74 (1.37–2.21), respectively. NAFLD, even lean NAFLD, was significantly associated with an increased risk of prevalent early-onset VMSs and their severe forms among premenopausal women. Further studies are needed to determine the longitudinal association between NAFLD and VMS risk.
... Most women begin experiencing menopausal symptoms in their 40s and peak at age 50 (Thurston et al., 2017). The climacterium is irresistible and a terrible picture for most women. ...
This study discusses the management of climacteric obstetrics and menopause. Menopause is the final feminine cycle or when the final monthly cycle happens, one of the mental viewpoints of changing self-concept amid menopause is unquestionably menopausal ladies ended up on edge around their bodies and frame self-concept approximately how their bodies are. The side effects experienced by ladies some time recently menopause cause the mother to be ill-equipped approximately physical and mental changes. To decrease this, ladies must get ready themselves both physically and mentally for menopause. Ladies who are going through menopause go through the primary stages counting premenopause, perimenopause, menopause, and postmenopause, and menopause for the most part happens in ladies matured 45-50 a long time.
... In MsHeart and other studies, more frequent self-reported and physiologically assessed VMS have been associated with greater carotid atherosclerosis (intima media thickness and plaque) (58)(59)(60). Other work suggests that reported VMS may also be associated with increased risk of future clinical CVD events (e.g., myocardial infarction, heart failure, stroke) and CVD mortality, which may depend on the timing of the VMS (61,62). These associations between VMS and CVD risk generally are not explained by endogenous estradiol levels when these measurements are available. ...
Most studies of menopause and brain aging have focused on the role of the sex steroid hormone, estradiol, as a key mechanisms contributing to cognitive and brain aging in women. An emerging literature demonstrates that beyond endogenous estradiol levels, menopausal symptoms, particularly vasomotor symptoms (VMS), are also key determinants of menopause-related changes in cognition and brain function. Critically, that literature shows the importance of using objective techniques to identify associations of VMS with memory performance, brain structure, and brain function. While self-report measures are important patient-centered outcomes in women's health research, objective measures of VMS typically relate more strongly to indices of cognitive and brain health. Currently, it is premature to make a causal claim about VMS and memory dysfunction, but initial findings raise the possibility that women with VMS might experience an improvement in cognition with VMS treatment. More generally, these findings underscore the utility of investigating female-specific risk factors for cognitive decline.
... Endogenous Estrogen WISE women with early onset vasomotor symptoms have higher CVD mortality and lower flowmediated dilation than those with later onset symptoms [29]. Hypothalamic hypoestrogenism (HHE) results from inadequate ovarian stimulation by the hypothalamus in premenopausal women, resulting in low estrogen levels. ...
Purpose of review:
For over 20 years, the Women's Ischemia Syndrome Evaluation (WISE), a program sponsored by the National Heart, Lung, and Blood Institute, has explored diverse and important aspects of ischemic heart disease in women.
Recent findings:
Women with symptoms and signs of ischemia but no significant epicardial obstructive coronary artery disease (INOCA) were documented to be at elevated risk for recurrent angina hospitalization, major adverse cardiac events, death, and health resource consumption rivaling those with obstructive coronary disease. WISE investigators have advanced our understanding of cardiovascular outcomes, systemic manifestations, psychological variables, socioeconomic factors, genetic contributions, hormonal status, advanced imaging, coronary functional findings, biomarkers, patient-reported outcomes, and treatments pertaining to women with this disease entity. This review delves into the WISE findings subsequent to a prior review1, postulates directions for future research, and asks are we "Even 'WISE-R?'".
... arrhythmias, Raynaud's disease, menopausal hot flushes, hypertension, hypertension of pregnancy, and pulmonary hypertension), vascular remodelling associated with atherosclerosis, or spontaneous coronary artery dissection and heart failure. [5][6][7][8][9][10] Using data from global databases/registries and clinical trials, the recently published study by Motiejuanaite et al. 11 further substantiates sex differences (by self-report as a man or woman) in biological parameters associated with hospital admissions for acute heart failure. The international GREAT registry that included patients from Finland, France, Italy, Spain, Switzerland, Czech Republic, Lithuania, the USA, Canada, China, Japan, and South Korea identified physiological differences at admission between men and women including age, body mass index, systolic blood pressure, left ventricular ejection fraction, estimated glomerular filtration rate, obstructive pulmonary disease, acute coronary syndrome, and acute arrhythmias. ...
... Our finding parallels prior WHI findings that late-occurring VMS are associated with CVD risk (8). However, this pattern is not universally observed (9,(29)(30)(31). The reasons for this diverse set of observations regarding VMS timing and their associations with health outcomes is not entirely clear; however, the nature of the outcome (e.g., subclinical CVD or CVD risk factors versus clinical CVD), the study design (e.g., cross sectional, longitudinal), and the method of VMS assessment (retrospective reports, prospective reports, physiologic assessments) are likely important. ...
Purpose
The hallmark menopausal symptom, vasomotor symptoms (VMS), has been linked to adverse health indicators. However, the relationship between VMS and biological aging has not been tested. We examined associations between menopausal VMS and biological aging as assessed by two DNA methylation-based epigenetic aging indicators previously linked to poor health outcomes.
Methods
Participants were members of the Women’s Health Initiative Observational Study (WHI-OS) integrative genomics sub-study (N = 1,206) who had both ovaries and were not taking hormone therapy. Relationships between VMS at enrollment (presence, severity) or VMS timing groups (no VMS: not at menopause onset nor at study enrollment; early VMS: at menopause onset but not at enrollment; persistent VMS: at menopause onset and study enrollment; and late VMS: at enrollment but not at menopause onset) and epigenetic clock indicators predictive of physical aging and early death (DNAm PhenoAge, DNAm GrimAge) were tested in linear regression models adjusting for age, race/ethnicity, hysterectomy, education, body mass index, smoking, and in additional models, sleep disturbance.
Results
Women were on average 65 years of age at enrollment. Severe hot flashes at enrollment were associated with higher DNAm PhenoAge [relative to no hot flashes: B(SE)=2.79(1.27), p=.028, multivariable]. Further, late-occurring VMS were associated with both higher DNAm PhenoAge [B(SE)=2.15 (.84), p=.011] and DNAm GrimAge [B(SE)=1.09 (.42), p=.010, multivariable] relative to no VMS.
Main Conclusions
Among postmenopausal women, severe or late-occurring VMS was associated with accelerated epigenetic age, controlling for chronological age. Postmenopausal women with severe or late-occurring VMS may have greater underlying epigenetic aging.
... [7][8][9] Lack of estrogen in postmenopausal women can increase the risks of cardiovascular disease, obesity, and osteoporosis, with the feedback-mediated increase in the level of FSH level in the blood. [10][11][12] Compensation therapy with estrogen injection has been used as an antiaging strategy. 13,14 However, this therapy has negative consequences concerning the occurrence of cancer. ...
Background:
Follicle-stimulating hormone (FSH) has multiple biological functions. It is currently considered that FSH can inhibit cervical cancer, and our aim was to explore the underlying molecular mechanisms.
Materials and methods:
An in vivo experiment using nude mice injected with HeLa cells was performed. Flow cytometry, western blotting, and real-time quantitative PCR analyses were done.
Results:
Twenty one days after injection of HeLa cells, the subcutaneous tumor mass was significantly lower (P<0.01) in mice treated with 20 mIU/mL FSH, but did not disappear. In vitro observations indicated that FSH might inhibit cell proliferation and activate cell apoptosis to induce the reduction of HeLa cells. The mRNA and protein levels of Cyclin D1, Cyclin E1, and Caspase 3 changed accordingly as expected in vivo and in vitro. Moreover, FSH inactivated the nuclear factor-kappa B (NF-κB) pathway in subcutaneous tumors; the NF-κB(p65) activity in HeLa cells was significantly decreased using 20 mIU/mL FSH and was increased when FSH was administered along with lipopolysaccharide, accompanied by the same change of cell number. Further, FSH accelerated protein kinase A (PKA) activity, but inactivated glycogen synthase kinase 3 beta (GSK-3β) activity. Specific inhibition of PKA and/or GSK-3β provided in vitro evidence that directly supported the FSH-mediated inhibition of GSK-3β to inactivate NF-κB via the promotion of PKA activity.
Conclusion:
Our data are the first description of the molecular regulatory mechanisms of FSH-mediated inhibition of the development of cervical cancer by decreasing the cell cycle and activating cell apoptosis via the PKA/GSK-3β/NF-κB pathway.
... Исследователями представлены убедительные данные о взаимосвязи вазомоторных симптомов менопаузы с заболеваниями сердечно-сосудистой системы (ССЗ), в частности с артериальной гипертензией, а также нейроэндокринными заболеваниями [32][33][34]. Есть данные об ассоциации приливов с метаболическими нарушениями [35], в том числе с инсулинорезистентностью [36], гиперхолестеринемией и гипертриглицеридемией [37]. Однако степень риска при этом варьирует в зависимости от многих факторов, в том числе от тяжести и вида нейровегетативной симптоматики, а также времени и причины наступления менопаузы [38,39]. ...
... Commonly known as hot flushes or night sweats (VMS) are experienced by about 60-80% of postmenopausal women during the perimenopausal phase [46][47][48]. Most importantly, VMS severely affect women's sense of wellbeing and quality of life [49,50]. According to a Cochrane review, there was a significant reduction in the frequency and severity of hot flushes with HRT as compared to placebo [51,52]. ...
BACKGROUND: Throughout history, menopause has been regarded as a transition in a woman's life. With the increase in life expectancy, women now spend more than a third of their lives in menopause. During these years, women may experience intolerable symptoms both physically and mentally, leading them to seek clinical advice. It is imperative for healthcare providers to improve the quality of life by reducing bothersome menopausal symptoms and preventing disorders such as osteoporosis and atherosclerosis. The current treatment in the form of hormone replacement therapy (HRT) is sometimes inadequate with several limitations and adverse effects. Objective and rationale: The current review aims to discuss the need, efficacy, and limitations of current HRT; the role of other ovarian hormones, and where we stand in comparison with ovary-in situ; and finally, explore towards the preparation of an HRT model by regeneration of ovaries tissues through stem cells which can replicate a functional ovary.
... This may ultimately contribute to better management of menopausal symptoms, improved quality of life, and potential mitigation of cardiovascular risk in menopausal women. [36][37][38] ...
Objective:
Response to menopausal hormone therapy (MHT) shows individual variation. SLCO1B1 encodes the OATP1B1 transporter expressed in the liver that transports many endogenous substances, including estrone sulfate, from the blood into hepatocytes. This study evaluated the relationship between genetic variation in SLCO1B1 and response to MHT in women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic, Rochester, MN.
Methods:
KEEPS participants were randomized to oral conjugated equine estrogen (n = 33, oCEE), transdermal 17β-estradiol (n = 33, tE2), or placebo (n = 34) for 48 months. Menopausal symptoms (hot flashes, night sweats, insomnia, palpitations) were self-reported before treatment and at 48 months. Estrone (E1), E2, and sulfated conjugates (E1S, E2S) were measured using high-performance liquid chromatography-tandem mass spectrometry. SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) was genotyped using a TaqMan assay.
Results:
After adjusting for treatment, there was a significant association between the SLCO1B1 rs4149056 TT genotype (encoding normal function transporter) and lower E1S, E1S/E1, and E2S (P = 0.032, 0.010, and 0.008, respectively) compared with women who were heterozygous (TC) or homozygous (CC) for the reduced function allele. The interactions between genotype, treatment, and E2S concentration were stronger in women assigned to tE2 (P = 0.013) than the women taking oCEE (P = 0.056). Among women assigned to active treatment, women with the CT genotype showed a significantly greater decrease in night sweats (P = 0.041) than those with the TT genotype.
Conclusions:
Individual variation in sulfated estrogens is explained, in part, by genetic variation in SLCO1B1. Bioavailability of sulfated estrogens may contribute to relief of night sweats.
... [21][22][23] In general, the severity of vasomotor symptoms is also associated with an increased risk of cardiovascular disease including endothelial dysfunction, development of carotid intima media thickness, coronary artery calcification, cardiac microvascular disease, and adverse cardiac events. [24][25][26][27] However, the risk may vary with both the age of onset of menopause and the severity and type of the vasomotor disturbance (daytime hot flashes, night sweats, or both.) 1,12,13,20,[28][29][30] Several genetic variants for enzymes involved with estrogen metabolism and for estrogen receptors are associated with onset of menopause and with the presence and severity of vasomotor instability. ...
Hot flashes have typically been classified as "symptoms of menopause" that should be tolerated or treated until they resolve. However, mounting evidence points to hot flashes as a manifestation of one or several underlying pathophysiological processes. Associations exist between the presence, timing of onset, severity, and duration of hot flashes, and the risk of several neurological (affecting sleep, mood, and cognition) and cardiovascular conditions. In addition, four consistent patterns of vasomotor disturbances have been identified across different countries, making it unlikely that these patterns are solely explained by socioeconomic or cultural factors. The changing hormonal environment of menopause may unmask differences in the autonomic neurovascular control mechanisms that put an individual woman at risk for chronic conditions of aging. These differences may have a genetic basis or may be acquired across the life span and are consistent with the variability of the clinical manifestations of aging observed in women after bilateral oophorectomy. It is time to investigate the pathophysiological mechanisms underlying the four patterns of vasomotor symptoms more closely, and to shift from describing hot flashes as symptoms to be tolerated to manifestations of an underlying autonomic neurovascular dysregulation that need to be addressed.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.
... Similarly, contrasting findings regarding the role of VMS timing have also been found in studies with CVDrelated endpoints, the reasons for which remain unclear. 14,29,30 Our results also suggest that night sweats or their effects may be largely responsible for the association between VMS overall and diabetes. Examinations of the influence of reported hot flashes and night sweats separately on the risk of cardiovascular and metabolic outcomes are scarce. ...
Objective:
Vasomotor symptoms (VMS), encompassing hot flashes and night sweats, may be associated with diabetes, but evidence is limited. We sought to estimate these associations.
Methods:
Among 150,007 postmenopausal Women's Health Initiative participants from 1993 to 2014, we prospectively examined associations of incident diabetes with VMS characteristics at enrollment: any VMS, severity (mild/ moderate/severe), type (hot flashes/night sweats), timing (early [premenopausal or perimenopausal]/late [postmenopausal]), and duration. Cox proportional-hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs).
Results:
Mean duration of follow-up was 13.1 years. VMS prevalence was 33%. Reporting any VMS was associated with 18% increased diabetes risk (95% CI 1.14, 1.22), which increased with severity (mild: HR 1.13, 95% CI 1.08, 1.17; moderate: HR 1.29, 95% CI 1.22, 1.36; severe: HR 1.48, 95% CI 1.34, 1.62) and duration (4% per 5 years, 95% CI 1.03, 1.05), independent of obesity. Diabetes risk was more pronounced for women reporting any night sweats (night sweats only: HR 1.20, 95% CI 1.13, 1.26; night sweats and hot flashes: HR 1.22, 95% CI 1.17, 1.27) than only hot flashes (HR 1.08, 95% CI 1.02, 1.15) and was restricted to late VMS (late: HR 1.12, 95% CI 1.07, 1.18; early and late: HR 1.16, 95% CI 1.11, 1.22; early: HR 0.99, 95% CI 0.95, 1.04).
Conclusions:
VMS are associated with elevated diabetes risk, particularly for women reporting night sweats and postmenopausal symptoms. The menopause transition may be an optimal window for clinicians to discuss long-term cardiovascular/metabolic risk with patients and leverage the bother of existing symptoms for behavior change to improve VMS and reduce diabetes risk.
... However, controversy exists as to whether this increased risk is due to the effect of aging alone or as a consequence of the cardiometabolic and vascular changes that occur during menopause [4,5]. Therefore, it is critical to better understand the mechanisms contributing to the rapid and adverse changes in CVD risk that occur as women reach menopause [6,7] as they may guide new practical preventive and treatment approaches in this at-risk population. ...
Background:
Premenopausal women have fewer cardiovascular disease (CVD) events than postmenopausal women and age-matched men, but the reasons are not fully understood. Coronary endothelial function (CEF), a barometer of coronary vascular health, promises important insights into age and sex differences in atherosclerotic CVD risk, but has not been well characterized in healthy individuals because of the invasive nature of conventional CEF measurements. Recently developed magnetic resonance imaging (MRI) methods were used to quantify CEF (coronary area and flow changes in response to isometric handgrip exercise (IHE), an endothelial-dependent stressor) to test the hypothesis that healthy women have better CEF compared to men particularly at a younger age.
Methods:
The study participants were 50 healthy women and men with no history of coronary artery disease (CAD) or traditional CV risk factors and Agatston coronary calcium score (on prior CT) <10 for those ≥ 50 years. Coronary cross-sectional area (CSA) measurements and flow-velocity encoded images (CBF) were obtained at baseline and during continuous IHE using 3T breath-hold cine MRI-IHE. CEF (%change in CSA and CBF with IHE) comparisons were made according to age and sex, and all women ≥50 years were post-menopausal.
Results:
In the overall population, there were no differences in CEF between men and women. However, when stratified by age and sex the mean changes in CSA and CBF during IHE were higher in younger premenopausal women than older postmenopausal women (%CSA: 15.2±10.6% vs. 7.0±6.8%, p = 0.03 and %CBF: 59.0±37.0% vs. 30.5±24.5% p = 0.02). CBF change was also nearly two-fold better in premenopausal women than age-matched men (59.0±37.0% vs. 33.6±12.3%, p = 0.03).
Conclusions:
Premenopausal women have nearly two-fold better mean CEF compared to postmenopausal women. CEF, measured by CBF change is also better in premenopausal women than age-matched men but there are no sex differences in CEF after menopause. Fundamental age and sex differences in CEF exist and may contribute to differences in the development and clinical manifestations of atherosclerotic CVD, and guide future trials targeting sex-specific mechanisms of atherogenesis.
... It is an opportunity to assess the risk of diseases highly prevalent in postmenopausal women, to review preventive strategies, and to provide counseling and education to women with the goal of reducing the burden of chronic diseases of aging, especially cardiovascular disease [4]. Evidence is accumulating related to sex-specific differences in cardiovascular disease risk and the associations between factors such as polycystic ovary syndrome, diseases of pregnancy (eg, gestational diabetes and preeclampsia), natural and iatrogenic premature menopause, and the timing of the onset and persistence of vasomotor symptoms (VMSs) and future cardiovascular disease [5][6][7][8][9][10][11]. ...
The Women’s Health Clinic (WHC) at Mayo Clinic in Rochester, Minnesota, has provided consultative care to women with menopausal and sexual health concerns since 2005. Clinical information on the 8,688 women seen in the WHC through May 2017 who gave consent for the use of their medical records in research is contained in the Data Registry on Experiences of Aging, Menopause, and Sexuality (DREAMS). Initially, DREAMS was created to improve the clinical care of women, but it has become a valuable research tool. About 25% of the DREAMS women have been seen in the WHC 2 or more times, allowing for passive longitudinal follow-up. Additionally, about 25% of the DREAMS women live in the 27-county region included in the expanded Rochester Epidemiology Project medical records linkage system, providing additional information on those women. The cohort has been used to investigate associations between: caffeine intake and vasomotor symptom bother; recent abuse (physical, sexual, verbal, and emotional) and menopausal symptoms; specific menopausal symptoms and self-reported view of menopause; and obstructive sleep apnea risk and vasomotor symptom severity and the experience of vasomotor symptoms in women older than 60 years. A study nearing completion describes a clinical series of over 3,500 women presenting for sexual health consultation by sexual function domain and by decade of life. Other studies under way are determining correlates with sexual health and dysfunction. Planned studies will investigate associations between the experience with menopause and the risk of disease.
Introduction:
Vasomotor symptoms (VMS) are the symptoms most frequently experienced by women transitioning to menopause and are a primary indication for menopausal hormone therapy. A growing body of evidence has associated the presence of VMS with future risk for cardiovascular disease (CVD) events. This study aimed to systematically evaluate, qualitatively and quantitatively, the possible association between VMS and the risk for incident CVD.
Methods:
This systematic review and meta-analysis included 11 studies evaluating peri- and postmenopausal women in a prospective design. The association between VMS (hot flashes and/or night sweats) and the incidence of major adverse cardiovascular events, including coronary heart disease (CHD) and stroke, was explored. Associations are expressed as relative risks (RR) with 95 % confidence intervals (CI).
Results:
The risk for incident CVD events in women with and without VMS differed according to the age of participants. Women with VSM younger than 60 years at baseline had a higher risk of an incident CVD event than women without VSM of the same age (RR 1.12, 95 % CI 1.05-1.19, I2 0%). Conversely, the incidence of CVD events was not different between women with and without VMS in the age group >60 years (RR 0.96, 95 % CI 0.92-1.01, I2 55%).
Conclusion:
The association between VMS and incident CVD events differs with age. VMS increases the incidence of CVD only in women under 60 years of age at baseline. The findings of this study are limited by the high heterogeneity among studies, pertaining mainly to different population characteristics, definitions of menopausal symptoms and recall bias.
Objective:
Vasomotor symptoms (VMS), the most frequently reported symptoms during the menopausal transition, have been associated with inflammation. Whether inflammation is a risk factor for or a consequence of VMS remains unclear. The objectives of these analyses were to determine if elevated proinflammatory marker levels were associated with increased incident VMS in women without VMS at baseline and whether these associations varied by menopause transition stage or race/ethnicity.
Methods:
We used longitudinal data on incident VMS, high-sensitivity C-reactive protein (hs-CRP; n = 1,922) and interleukin-6 (IL-6; n = 203) from 13 follow-up visits in the Study of Women's Health Across the Nation, which included five racial/ethnic groups of midlife women. We performed multivariable discrete-time survival analyses to determine adjusted hazard ratios (aHRs) for the association of these proinflammatory markers with incident VMS in women without VMS at baseline.
Results:
We found no significant associations of incident VMS with dichotomized hs-CRP (>3 vs ≤3 mg/L) at baseline, concurrent or prior visit (aHRs, 1.04-2.03) or IL-6 (>1.44 vs ≤1.44 pg/mL) at visit 1, concurrent or prior visit (aHRs, 0.67-1.62), or continuous hs-CRP or IL-6 values over 13 follow-up visits (with nonsignificant adjusted increased hazards ranging from 0% to 2%).
Conclusions:
Our results showed no significant association of the proinflammatory biomarkers, hs-CRP or IL-6, either concurrently or with subsequent incident VMS, indicating that inflammation was unlikely to be a risk factor for VMS. Thus, clinical treatments directed at reducing inflammation would be unlikely to reduce the occurrence of VMS.
Objective:
This study evaluated whether vasomotor symptom (VMS) severity and number of moderate/severe menopausal symptoms (nMS) were associated with health outcomes, and whether calcium and vitamin D (CaD) modified the risks.
Methods:
The Women's Health Initiative CaD study was a double blind, randomized, placebo-controlled trial, which tested 400 IU of 25-hydroxyvitamin-D and 1,000 mg of calcium per day in women aged 50 to 79 years. This study included 20,050 women (median follow-up of 7 y). The outcomes included hip fracture, colorectal cancer, invasive breast cancer, all-cause mortality, coronary heart disease, stroke, cardiovascular death, and total cardiovascular disease (CVD). MS included: hot flashes, night sweats, dizziness, heart racing, tremors, feeling restless, feeling tired, difficulty concentrating, forgetfulness, mood swings, vaginal dryness, breast tenderness, migraine, and waking up several times at night. Associations between VMS severity and nMS with outcomes were tested.
Results:
No association between VMS severity and any outcome were found. In contrast, nMS was associated with higher stroke (hazard ratio [HR] 1.40 95% confidence interval [CI] 1.04-1.89 for ≥ 2 MS vs none; HR 1.20 95% CI 0.89-1.63 for 1 MS vs none, P trend = 0.03) and total CVD (HR 1.35, 95% CI, 1.18-1.54 for ≥ 2 MS vs none; HR 0.99, 95% CI, 0.87-1.14 for 1 MS vs none P trend < 0.001). CaD did not modify any association.
Conclusion:
Severity of VMS was not associated with any outcome. Having ≥2 moderate or severe MS was associated with an increased risk for CVD. The number of moderate/severe MS may be a marker for higher CVD risk. : Video Summary:http://links.lww.com/MENO/A669.
Background
Menopausal vasomotor symptoms (VMS, i.e., hot flushes and night sweats) have been associated with unfavorable risk factors and surrogate markers of cardiovascular disease (CVD), but their association with clinical CVD events is unclear. We aimed to examine the associations between different component of VMS and timing of VMS and risk of CVD.
Study Design
We harmonized and pooled individual-level data from 23 365 women in six prospective studies which contributed to the InterLACE consortium. Women who experienced CVD events before baseline were excluded. The associations between frequency (never, rarely, sometimes and often), severity (never, mild, moderate and severe), and timing (before or after age of menopause, i.e., early or late onset) of VMS and incident CVD were analysed. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI).
Results
In the adjusted model, no evidence of association was found between frequency of hot flushes and incident CVD, while women who reported night sweats “sometimes” (HR 1.22, 95% CI 1.02-1.45) or “often” (1.29, 1.05-1.58) had higher risk of CVD. Increased severity of either hot flushes or night sweats was associated with higher risk of CVD. The hazards ratios of CVD in women with severe hot flushes, night sweats and any VMS were 1.83 (1.22, 2.73), 1.59 (1.07, 2.37) and 2.11 (1.62, 2.76) respectively. Women who reported severity for both hot flushes and night sweats had a higher risk of CVD (1.55, 1.24-1.94) than those with hot flushes alone (1.33, 0.94-1.88) and night sweats alone (1.32, 0.84-2.07). Women with either early onset (1.38, 1.10-1.75) or late onset (1.69, 1.32-2.16) VMS had an increased risk of incident CVD, compared with women who did not experience VMS.
Conclusion
Severity rather than frequency of VMS (hot flushes and night sweats) was associated with increased risk of CVD. VMS with onset before or after menopause were also associated with increased risk of CVD.
As longevity expands, women are spending a third of their existence in menopause and beyond. The vast majority suffer from symptoms that negatively impact their quality of life. Systemic vasomotor symptoms (VMS) are the classic cluster affecting 80% of peri- and post-menopausal women. Once thought to be relatively brief, they sometimes persist more than 10 years. Compelling, yet enigmatic, is the recent finding that women with bothersome and long VMS compared with age-matched peers often have worst underlying preclinical markers of cardiovascular disease (CVD).
Objective:
To ascertain the association between vasomotor menopausal symptoms (VSM), hot flushes and night sweats, and cardiovascular disease, coronary heart disease and cerebrovascular disease.
Study design:
The study sample comprised 8881 women (aged 45-50 years) with available hospital separation data from the 1946-51 cohort (1996-2016) of the ongoing Australian Longitudinal Study on Women's Health, a national prospective cohort study.
Main outcome measures:
First fatal or non-fatal cardiovascular disease, coronary heart disease, and cerebrovascular disease events were obtained through linkage with hospital admission data, the National Death Index, and Medicare Benefits Schedule. Hot flushes and night sweats were assessed via questionnaires at each main survey. Additionally, we calculated the duration of symptoms based on whether or not women reported vasomotor menopausal symptoms in each survey.
Results:
There were 925 cardiovascular disease, 484 coronary heart disease and 154 cerebrovascular disease events. There was no consistent evidence of any association with vasomotor menopausal symptoms, hot flushes and night sweats. We did find marginally statistically significant associations between presence of night sweats and cardiovascular disease (Hazard Ratio = 1.18, 95 % Confidence Interval: 1.01-1.38), and between the duration of vasomotor menopausal symptoms [years] and coronary heart disease (Hazard Ratioper year = 1.03, 95 % Confidence Interval: 1.00-1.05). However, given the number of associations tested, these findings could very well have arisen by chance.
Conclusion:
In this large longitudinal study with 20 years of follow-up and clinical outcomes we did not find a convincing association between vasomotor menopausal symptoms, hot flushes, night sweats and cardiovascular disease, coronary heart disease and cerebrovascular disease.
Vasomotor symptoms (VMS), such as hot flushes and night sweats, are common during the menopausal transition. Although the underlying etiopathology behind vasomotor symptoms is not fully identified, they have been associated with an overdrive of the sympathetic nervous system, which in turn may result in altered vascular function, changes in blood pressure (BP) and lipids, and the development of insulin resistance. Metabolic syndrome (MetS) is a cluster of closely related risk factors for cardiovascular disease (CVD): elevated BP, dyslipidemia, hyperglycemia, and central obesity. Thus, VMS and MetS share a common nominator, sympathetic overactivity. As of lately, due to these associations, the presence of VMS has gained interest as a possible risk factor for CVD. However, the results are mixed, and interpretation of findings is further complicated by the fact that some researchers distinguish between hot flushes and night sweats and others do not. In this chapter we present the most recent data on the possible relations between menopausal vasomotor symptoms, the components of metabolic syndrome, and cardiovascular disease.
The drastic reduction in the circulating levels of estrogens along the menopausal transition triggers a list of symptoms, where hot flashes (HF) constitute a frequently reported episode. Women describe hot flashes as a sudden feeling of heat affecting the upper body, trunk, head, and neck and spreading upwards or, less frequently, downwards. The whole phenomenon is described as a heat wave, which is accompanied by sweating and reddening of the skin, and that persists for short intervals, of minutes or even seconds. HF present during day and night and, when intense enough, affect the quality of sleep and provoke frequent waking-up episodes.
Purpose:
Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose.
Patients and methods:
We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ.
Results:
Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 v 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; P = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three v 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; P = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen (P = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo.
Conclusion:
Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.
The menopause transition (MT) is a critical period of women's lives marked by several physiologic changes and menopause-related symptoms that have implications for health. Risk for cardiovascular disease, the leading cause of death in women, increases after menopause, suggesting a contribution of the MT to its development. This article focuses on the relationship between 2 main features of the MT and women's cardiovascular health: (1) dynamic alterations of sex hormones, particularly endogenous estradiol and follicle-stimulating hormone, and (2) vasomotor symptoms, the cardinal symptom of the menopause. Limitations and future directions are discussed.
Objective:
Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations.
Methods:
Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol.
Results:
In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol.
Conclusions:
Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.
Purpose of review:
Sex-specific differences in pathophysiology, prevalence, and impact of cardiovascular disease (CVD) risk factors may explain the high cardiovascular mortality rates in women.
Recent findings:
We review the sex differences in traditional risk factors (dyslipidemia, hypertension, diabetes, and smoking) and nontraditional risk factors (menopause and hormones, pregnancy, inflammation and autoimmune diseases, anemia, depression, and migraines) and their prognostic and therapeutic implications.
Summary:
Recent research indicates that with respect to traditional risk factors such as dyslipidemia, hypertension, diabetes, and smoking, women appear to have a similar risk of CVD when compared to men. The risk is accelerated after menopause, possibly because of vascular and lipid profile changes. Pregnancy offers a unique opportunity and window to screen otherwise healthy women who may be at an increased risk of CVD in the future. Clinicians should be aware of other novel risk factors including inflammation, anemia, migraines, and depression, and further studies are warranted in order to identify therapeutic implications for these conditions and CVD risk.
Objective:
The menopausal transition is associated with somatic symptoms and increased rates of depression, which can impair quality of life (QOL) and increase cardiovascular disease (CVD) risk. This period is also associated with accelerated vascular aging (arterial stiffening and endothelial dysfunction), an antecedent to CVD. This secondary analysis sought to explore associations between depression, menopausal symptoms and QOL, and vascular aging across menopause stages.
Methods:
Arterial stiffness (carotid artery compliance), endothelial function (brachial artery flow-mediated dilation [FMD]), menopausal symptoms (Menopausal Symptom List [MSL]), depression (Center for Epidemiologic Studies Depression Scale [CES-D]), and QOL (Utian QOL Scale [UQOL]) were measured in 138 women (19-70 years) classified as premenopausal (n = 41, 34 ± 8 years; mean ± SD), early (n = 25, 49 ± 3 years), or late perimenopausal (n = 26, 50 ± 4 years), or early (n = 22, 55 ± 4 years) or late postmenopausal (n = 24, 61 ± 5 years). Differences across menopause stages were determined using one-way analysis of variance; associations between vascular measures and MSL, CES-D, and UQOL were tested using Pearson's correlation analyses.
Results:
Menopausal symptoms, depression, and QOL worsened across menopause stages, particularly in late perimenopausal women. Vasosomatic symptom frequency, and general somatic symptom frequency and severity were inversely correlated with carotid artery compliance and FMD (r = -0.27 to -0.18, all P < 0.05). Only correlations with general somatic symptoms were significant after adjusting for multiple comparisons. Total QOL was positively correlated with carotid artery compliance (r = 0.23, P = 0.01). CES-D scores were not correlated with carotid artery compliance or FMD (r = -0.08, -0.03, P = 0.35).
Conclusions:
Vascular dysfunction across the stages of menopause was associated with greater frequency and severity of menopausal symptoms, and lower QOL, but not depression. Mechanisms underlying these associations (eg, inflammation, oxidative stress) should be explored.
Cardiovascular disease is the leading cause of death in women. There is a dramatic rise in risk factors for cardiovascular disease during the menopausal transition that is independent of aging. Endothelial dysfunction is an early hallmark of developing cardiovascular disease and has been shown to increase across the stages of menopause. Exercise is considered one of the most effective lifestyle therapies to maintain and improve endothelial function. However, accumulating evidence suggests that exercise does not have the same benefit on endothelial function in menopausal women as it does in other populations, and factors associated with menopause likely influence the endothelial responsiveness to exercise. This review will detail the current available evidence on endothelial dysfunction, exercise, and menopause, including mechanisms that may mediate the accumulating endothelial dysfunction in women with menopause, the impact of exercise on endothelial function in women, and whether regular exercise is an effective therapeutic and prevention strategy to maintain endothelial function with menopause. We conclude that the effect of exercise on endothelial function differs according to menopausal stage and cardiovascular disease risk burden. Finally, we will address critical gaps in the literature with the goal of identifying future research directions to improve healthy aging in women.
Purpose of review:
Drugs have been extensively prescribed for the treatment of psychotic symptoms in schizophrenia and related disorders, as well as for the management of psychotic features in delirium, dementia and affective disorders. The aim of this narrative review is to focus on the recent literature on drug treatment in women with psychosis at the transition to menopause and subsequently.
Recent findings:
The recent literature emphasizes the following points: the efficacy of antipsychotic medication in psychosis is largely confined to the alleviation of delusions and hallucinations; menopause and ageing alter the kinetics and dynamics of drug action; drugs other than antipsychotics are currently being tested to address the cognitive, affective and negative symptoms of psychotic illnesses; menopausal symptoms add to comorbidities and require simultaneous treatment, raising the probability of deleterious drug interactions; antipsychotic drugs have many side effects and contribute to high mortality rates in the older psychosis population.
Summary:
A major implication for research is that antipsychotic drugs with a wider range of action and with fewer side effects are urgently needed. The clinical implications of the pharmacotherapy of psychotic illness are: older women's needs must be assessed through a comprehensive history and review of systems and physical and mental examination. To avoid adverse effects, drug dosages are best kept low and polypharmacy avoided wherever possible. It is important to frequently reassess older patients, as their pharmacotherapy requirements change with age and with comorbidity.
Ischemic heart disease remains the leading cause of death in the United States for both men and women. Since the 1980s medical advancements in prevention and management of ischemic heart disease have dramatically reduced morbidity and mortality. Unfortunately improvements in care have not affected men and women equitably and there remain significant disparities in outcomes post acute myocardial infarction (AMI) when gender is considered. Women have worse outcomes from AMI as compared to men, with younger women experiencing comparatively higher mortality rates. As our knowledge of cardiovascular health continues to develop, we have come to recognize that there are gender differences in AMI presentation, pathophysiology and eventual management. The basis for this can be attributed to both biological differences in pathophysiological mechanisms and also to unequal delivery of care. Women with AMI remain under-recognized and under-treated by the current health care system, despite increasing awareness and advancement in women’s cardiovascular health. This chapter will discuss known and emerging gender differences in pathophysiology, risk factors, clinical presentation, diagnosis, and management of AMI, with aim to educate healthcare providers about ongoing significant disparities. Additional efforts and research are imperative to improving outcomes for women with AMI.
Vasomotor symptoms (VMS), or hot flushes and night sweats, are the classic symptom of menopause. Recent years have brought key advances in the knowledge about VMS. VMS last longer than previously thought, on average 7–10 years for frequent or moderate to severe VMS. Although VMS have long been understood to be important to women’s quality of life, research has also linked VMS to indicators of cardiovascular disease (CVD) risk, such as an adverse CVD risk factor profile, greater subclinical CVD and, in emerging work, CVD events. Relations between VMS and CVD are not typically accounted for by CVD risk factors. In newer work, VMS–CVD risk relations are demonstrated with state-of-the-art subjective and objective measures of VMS. Some research indicates that VMS–CVD risk relations may be sensitive to the timing or duration of VMS. Thus, research collectively supports relations between VMS and CVD risk independent of known CVD risk factors. Next steps include identifying the mechanisms linking VMS and CVD risk indicators, understanding any timing effects, and clarifying the precise nature of relations between VMS and CVD risk. Clinical implications are discussed.
Menopausal symptoms have a substantial effect on the quality of life of women and on performance at the workplace; increased awareness of symptoms and acquisition of coping strategies might help
Certain menopausal symptoms might serve as markers for future health; severe vasomotor symptoms and sleep disorders might increase cardiovascular risk, whereas severe vasomotor symptoms and depression might affect cognitive function
The nature of menopausal symptoms is common to all women; however, geographical location and ethnicity influence the prevalence of certain symptoms
Individual factors such as personal history, current health status (particularly obesity) and socioeconomic status considerably worsen a woman's experience of menopause
Health-care providers should offer education to women on improving modifiable lifestyle factors to reduce the risk of future illness
Menopause seems to accelerate the ageing process; therefore, the manifestation of menopausal symptoms might be in part due to ageing
Cardiovascular disease is a leading cause of death worldwide. Sex differences in risk and presentation of cardiovascular disease reflect interactions of genetic differences dictated by sex chromosomes, genetic polymorphisms, sex-steroidal modulation of gene expression, and epigenetic modulation by environmental factors. Differences by gender in disease perception and diagnostic and treatment strategies also affect prognosis. We focus on sex differences in the areas of syndromes leading to myocardial ischemia, heart failure, and arrhythmias. Our goal is to provide the background for students and researchers interested in understanding sex differences in these areas and to highlight research gaps to encourage future work.
Objective:
Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations.
Methods:
Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol.
Results:
In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol.
Conclusions:
Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.
Endothelial dysfunction is a key feature of preeclampsia and may contribute to increased cardiovascular disease risk years after pregnancy. Flow-mediated dilation (FMD) is a non-invasive endothelial function test that predicts cardiovascular event risk. New protocols allow researchers to measure three components of the FMD response: FMD, low flow-mediated constriction, and shear stimulus. This review encourages researchers to think beyond "low FMD" by examining how these three components may provide additional insights into the mechanisms and location of vascular dysfunction. The review then examines what FMD studies reveal about vascular dysfunction in preeclampsia while highlighting opportunities to gain greater mechanistic insight from new protocols. Studies using traditional protocols show that FMD is low in mid-pregnancy prior to preeclampsia, at diagnosis, and for 3 years post-partum. However, FMD returns to normal by 10 years post-partum. Studies using new protocols are needed to gain more mechanistic insight.
Limited brachial artery (BA) flow-mediated dilation during brachial artery reactivity testing (BART) has been linked to increased cardiovascular risk. We report on the phenomenon of BA constriction (BAC) following hyperemia.
To determine whether BAC predicts adverse CV outcomes and/or mortality in the women's ischemic Syndrome Evaluation Study (WISE). Further, as a secondary objective we sought to determine the risk factors associated with BAC.
We performed BART on 377 women with chest pain referred for coronary angiography and followed for a median of 9.5 years. Forearm ischemia was induced with 4 minutes occlusion by a cuff placed distal to the BA and inflated to 40mm Hg > systolic pressure. BAC was defined as >4.8% artery constriction following release of the cuff. The main outcome was major adverse events (MACE) including all-cause mortality, non-fatal MI, non-fatal stroke, or hospitalization for heart failure.
BA diameter change ranged from -20.6% to +44.9%, and 41 (11%) women experienced BAC. Obstructive CAD and traditional CAD risk factors were not predictive of BAC. Overall, 39% of women with BAC experienced MACE vs. 22% without BAC (p=0.004). In multivariate Cox proportional hazards regression, BAC was a significant independent predictor of MACE (p=0.018) when adjusting for obstructive CAD and traditional risk factors.
BAC predicts almost double the risk for major adverse events compared to patients without BAC. This risk was not accounted for by CAD or traditional risk factors. The novel risk marker of BAC requires further investigation in women.
Context:
Emerging research suggests links between menopausal hot flashes and cardiovascular disease risk. The mechanisms underlying these associations are unclear, due to the incomplete understanding of the physiology of hot flashes. OBJECTIVE AND MAIN OUTCOME MEASURES: We examined the associations between hot flashes/night sweats and glucose and insulin resistance over 8 yr, controlling for cardiovascular risk factors and reproductive hormones.
Design, setting, and participants:
Participants in the Study of Women's Health Across the Nation (SWAN) (n=3075), a longitudinal cohort study, were ages 42-52 yr at entry. Women completed questionnaires (hot flashes, night sweats: none, 1-5 d, ≥6 d, past 2 wk), physical measures (blood pressure, height, weight), and a fasting blood draw [serum glucose, insulin, estradiol (E2), FSH] annually for 8 yr. Hot flashes/night sweats were examined in relation to glucose and the homeostasis model assessment (HOMA) in mixed models, adjusting for demographics, cardiovascular risk factors, medications, and E2/FSH.
Results:
Compared to no flashes, hot flashes were associated with a higher HOMAlog index [vs. none; hot flashes, 1-5 d: % difference (95% confidence interval), 2.37 (0.36-4.43), P=0.02; and ≥6 d: 5.91 (3.17-8.72), P<0.0001] in multivariable models that included body mass index. Findings persisted adjusting for E2 or FSH, and were similar for night sweats. Findings were statistically significant, yet modest in magnitude, for the outcome glucose.
Conclusions:
Hot flashes were associated with a higher HOMA index, an estimate of insulin resistance, and to a lesser extent higher glucose. Metabolic factors may be relevant to understanding the link between hot flashes and cardiovascular disease risk.
The aim of this study was to examine changes in health-related quality of life (HRQL) during the menopausal transition, controlling for chronological aging, symptoms, and other covariates.
This was a prospective, longitudinal study of women aged 42 to 52 years at baseline recruited at seven US sites (N = 3,302) in the multiethnic Study of Women's Health Across the Nation. Women eligible for the cohort had an intact uterus, had at least one ovary, were not currently using exogenous hormones, were either premenopausal or early perimenopausal, and were self-identified as one of the study's designated racial/ethnic groups. Data from the baseline interview and six annual follow-up visits are reported. HRQL was assessed with five subscales from the Medical Outcomes Study Short-Form Health Survey, with reduced functioning defined as being in the lowest 25% on a subscale. Covariates included symptoms, medical conditions, sociodemographics variables, physical activity, and psychological factors.
With adjustment for baseline age, chronological aging, and relevant covariates, the odds of reduced role-physical functioning were significantly greater at late perimenopause (odds ratio, 1.46; 95% CI, 1.08-1.99) and postmenopause (odds ratio, 1.49; 95% CI, 1.09-2.04) compared with premenopause. Menopause status was unrelated to bodily pain, vitality, role-emotional, or social functioning. Hormone therapy users were more likely to report reduced functioning. Other variables significantly related to HRQL across all domains included vasomotor symptoms, urine leakage, poor sleep, arthritis, depressed mood, perceived stress, and stressful life events.
The menopausal transition showed little impact on HRQL when adjusted for symptoms, medical conditions, and stress.
A community-based survey was conducted during 1995-1997 of factors related to menopausal and other symptoms in a multi-racial/ethnic sample of 16,065 women aged 40-55 years. Each of seven sites comprising the Study of Women's Health across the Nation (SWAN) surveyed one of four minority populations and a Caucasian population. The largest adjusted prevalence odds ratios for all symptoms, particularly hot flashes or night sweats (odds ratios = 2.06-4.32), were for women who were peri- or postmenopausal. Most symptoms were reported least frequently by Japanese and Chinese (odds ratios = 0.47-0.67 compared with Caucasian) women. African-American women reported vasomotor symptoms and vaginal dryness more (odds ratios = 1.17-1.63) but urine leakage and difficulty sleeping less (odds ratios = 0.64-0.72) than Caucasians. Hispanic women reported urine leakage, vaginal dryness, heart pounding, and forgetfulness more (odds ratios = 1.22-1.85). Hot flashes or night sweats, urine leakage, and stiffness or soreness were associated with a high body mass index (odds ratios = 1.15-2.18 for women with a body mass index > or =27 vs. 19-26.9 kg/m2). Most symptoms were reported most frequently among women who had difficulty paying for basics (odds ratios = 1.15-2.05), who smoked (odds ratios = 1.21-1.78), and who rated themselves less physically active than other women their age (odds ratios = 1.24-2.33). These results suggest that lifestyle, menstrual status, race/ethnicity, and socioeconomic status affect symptoms in this age group.
To further our understanding of the relation between mood and menopause, the authors examined 1) the association between persistent mood symptoms and menopausal status and 2) factors that increase a woman's vulnerability to an overall dysphoric mood during the early perimenopausal period. The sample consisted of an ethnically diverse community cohort of 3,302 pre- and early perimenopausal women aged 42-52 years who were participants in the Study of Women's Health Across the Nation, an ongoing US multisite longitudinal study of menopause and aging. At study entry (1995-1997), women reported information on recent menstrual regularity and premenstrual symptoms, as well as on sociodemographic, symptom, health, sleep, psychosocial, and lifestyle variables. Rates of persistent mood symptoms were higher among early perimenopausal women (14.9%-18.4%) than among premenopausal women (8%-12%). In analyses adjusting for major covariates and confounders, early perimenopausal women had higher odds of irritability, nervousness, and frequent mood changes but not of feeling "blue." The effect of being early perimenopausal on overall dysphoric mood was greatest among women with an educational level of less than high school graduation. These findings suggest that persistent mood symptoms and overall dysphoric mood are associated with the early perimenopause, particularly among women with lower educational attainment.
The timing of initiation of hormone therapy may influence its effect on cardiovascular disease.
To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began.
Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10,739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16,608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998.
Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials.
In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [corrected] cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10,000 person-years; for women 10 to 19 years since menopause began, 4 per 10,000 person-years; and for women 20 or more years from menopause onset, 17 per 10,000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was -2 per 10,000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and -1 per 10,000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10,000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06).
Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms.
clinicaltrials.gov Identifier: NCT00000611.
It has been hypothesized that women with vasomotor symptoms differ from those without with respect to cardiovascular risk factors or responses to exogenous hormone therapy. We studied whether the presence and extent of menopausal complaints are associated with cardiovascular risk profile. Data were used from a population-based sample of 5523 women, aged 46 to 57 years, enrolled between 1994 and 1995. Data on menopausal complaints and potential confounders were collected by questionnaires. Total cholesterol, systolic and diastolic blood pressures, and body mass index were measured. Linear and logistic regression analyses were used to analyze the data. Night sweats were reported by 38% and flushing by 39% of women. After multivariate adjustment, women with complaints of flushing had a 0.27-mmol/L (95% CI: 0.15 to 0.39) higher cholesterol level, a 0.60-kg/m(2) (95% CI: 0.35 to 0.84) higher BMI, a 1.59-mm Hg (95% CI: 0.52 to 2.67) higher systolic blood pressure, and a 1.09-mm Hg (95% CI: 0.48 to 1.69) higher diastolic blood pressure compared with asymptomatic women. Flushing was also associated with hypercholesterolemia (odds ratio: 1.52; 95% CI: 1.25 to 1.84) and hypertension (OR: 1.20; 95% CI: 1.07 to 1.34). Results were similar for complaints of night sweating. The findings support the view that menopausal complaints are associated with a less favorable cardiovascular risk profile. These findings substantiate the view that differences in the presence of menopausal symptoms as a reason for using hormone therapy could explain discrepant findings between observational research and trials.
ABSTRACT Observational studies have demonstrated a lower risk of coronary heart disease (CHD) events in postmenopausal women taking hormone therapy, but, in contrast, clinical trials have shown no benefit and in some instances suggest an increased risk of CHD. This discrepancy may in part result from the timing of initial hormone therapy in relation to age and the interval since the onset of menopause. This report is a secondary analysis of Women’s Health Initiative studies—all randomized controlled trials—in which 10,739 postmenopausal women with a history of hysterectomy were assigned to receive 0.625 mg daily of conjugated equine estrogens (CEE) or placebo, and another 16,608 not having hysterectomy received either CEE plus 2.5 mg of medroxyprogesterone acetate (MPA) or placebo. Hormone therapy did not lower the overall risk of CHD. After adjusting for risk factors, the hazard ratio (HR) for CHD was lower in women taking CEE alone than in those given both CEE and MPA. The overall risk of stroke was increased, with no apparent difference between individual trials. Although events became more numerous with advancing age, there was no significant added effect of hormone therapy by age for any outcome in the combined trials. The HR for CHD was 0.76 in women within 10 years of menopause, 1.10 for those 10 to 20 years after menopause, and 1.28 for those more than 20 years after menopause. Findings were similar for women with and those without previous cardiovascular disease. The effect of hormone therapy on the risk of stroke was not influenced by years since menopause. Estimated absolute excess risk figures associated with hormone therapy became progressively larger with increasing age starting at age 60 years. Age and years since menopause correlated with one another at a high level. There were no significant trends for hormone therapy by years since last treatment, and no significant interactions were noted between either previous hormone use or oophorectomy status on the one hand and, on the other, in-trial hormonal effects by age or years since menopause. These findings offer some reassurance that hormone therapy still is a reasonable option for the management of menopausal symptoms over the short term, but they do not imply that prolonged hormone use is safe. The investigators agree that hormone therapy is appropriate for the short-term relief of moderate or severe vasomotor symptoms—but not over the long-term to prevent cardiovascular disease.
Objective
Diurnal salivary cortisol patterns in healthy adults are well established but have not been studied in midlife women with hot flashes. We hypothesized that frequent hot flashes areassociated with aberrant cortisol patterns similar to sleep-deficient individuals. DesignCross-sectional. ParticipantsA total of 306 women, ages 40-62, randomized to a behavioural intervention for hot flashes. MeasurementsBaseline comparisons of cortisol geometric means (nmol/l) from four daily time points averaged over two consecutive days plus other calculated cortisol measures were made between groups defined by baseline: (i) mean daily hot flash frequency tertile (55, N=103; >55-88, N=103; >88, N=100) and (ii) selected characteristics. Repeated-measures linear regression models of log-transformed cortisol evaluated group differences, adjusting for covariates. ResultsWomen were 67% White and 24% African American, with 76 (SD 39) hot flashes per day. Salivary cortisol geometric means (nmol/l) among all women were as follows: 750 (SD 448) total, 86 (SD 56) wake, 100 (SD 75) wake +30min, 37 (SD 33) early afternoon and 16 (SD 18) bedtime. Wake+30-minute values showed an 18% median rise from wake values (interquartile range -24 to 96%), and means varied by hot flash frequency tertile, from lowest to highest: 114(SD 73), 103 (SD 65) and 86 (SD 78), respectively, P=0003. Beside the early afternoon value (P=002), cortisol values did not vary by hot flash frequency. Conclusion
Taken together, these findings suggest that high frequency of moderate-to-severe hot flashes may be associated with subtle abnormalities in cortisol concentrations - a pattern consistent with chronic sleep disturbance.
Background and purpose:
Emerging work has linked menopausal vasomotor symptoms (VMS) to subclinical cardiovascular disease (CVD) among women. However, VMS are dynamic over time. No studies have considered how temporal patterns of VMS may relate to subclinical CVD. We tested how temporal patterns of VMS assessed over 13 years were related to carotid intima media thickness (IMT) among midlife women.
Methods:
The Study of Women's Health Across the Nation is a longitudinal cohort study of midlife women. Eight hundred and eleven white, black, Hispanic, and Chinese participants with a well-characterized final menstrual period completed measures of VMS, a blood draw, and physical measures approximately annually for 13 years. Women underwent a carotid artery ultrasound at study visit 12.
Results:
Four trajectories of VMS were identified by trajectory analysis (consistently high, early-onset, late-onset, persistently low VMS) and tested in relation to carotid indices in linear regression models. Results indicated that women with early-onset VMS had both greater mean IMT (beta, b [standard error, SE]=0.03 [0.01], P=0.03) and greater maximal IMT (b [SE]=0.04 [0.01], P=0.008) than women with consistently low VMS, adjusting for demographics and CVD risk factors.
Conclusions:
This is the first study to test trajectories of VMS in relation to subclinical CVD. Women with VMS early in the menopause transition had higher mean IMT and maximal IMT than those with consistently low VMS across the transition. Associations were not accounted for by demographic factors nor by CVD risk factors. Results can signal to women in need of early CVD risk reduction.
This article examines published evidence from longitudinal studies of the menopausal transition that address the following questions: (1) Which symptoms do women report during the perimenopause, and how prevalent are these symptoms as women traverse the menopausal transition? (2) How severe are symptoms and for how long do they persist? (3) To what do women attribute their symptoms, and do their attributions match findings from epidemiologic studies of community-based populations? (4) How significant are these symptoms in women’s lives? Data from published longitudinal studies were examined for evidence bearing on each of these questions. Only vasomotor symptoms, vaginal dryness, and sleep disturbance symptoms varied in prevalence significantly across menopausal transition stages and the postmenopause in ≥1 population studied. A minority of women report severe symptoms. Given the limited follow-up data available, it is unclear how long symptoms persist after the menopause. Women attribute their symptoms to a variety of factors (biological and psychosocial), and their attributions correspond well to those correlates identified in epidemiologic studies of community-based populations. The significance of symptoms for women’s lives remains uncertain. The impact of symptoms during the perimenopause on well-being, role performance, adaptation to demands of daily living, and quality of life warrants additional study. The appraisal of the consequences of perimenopausal symptoms by women from different ethnic groups will be enhanced significantly as a result of the Study of Women’s Health Across the Nation (SWAN) and other investigations in progress.
Rapid, nongenomic vascular cell and tissue responses to estrogen have been demonstrated for more than a decade. Although the pendulum continues to swing, accumulating evidence, both clinical and pre-clinical, support favorable effects of ovarian steroid hormones in the vascular system. These effects are mediated both by classical steroid hormone receptor-mediated transcriptional modulation, and largely by endothelial plasma membrane-associated estrogen receptor (ER) α, which when engaged triggers a signaling cascade resulting in release of cardioprotective nitric oxide (NO). In addition to full-length ERα (ER66), an N-terminus truncated ERα isoform, ER46, plays a key role in these rapid endothelial responses to 17β-estradiol (E2). We have recently determined that ER46 can be a Type I integral transmembrane molecule. In this review, we discuss ER isoforms, rapid E2-stimulated signaling in the endothelium, the importance of the ER46 transmembrane orientation, and the clinical context of this rapid endothelial signaling.
Women presenting with signs and symptoms of myocardial ischemia frequently have no or nonobstructive coronary artery disease (CAD).
This study aimed to investigate the associations between angiographic measures and longer-term clinical outcomes among women with signs and symptoms of ischemia referred for coronary angiography.
A prospective cohort analysis of women referred for coronary angiography and enrolled in the National Heart, Lung, and Blood Institute-sponsored WISE was performed. An angiographic severity score was prospectively developed, assigning points for any stenosis weighted by stenosis severity, location, and collaterals and was then tested for prediction for adverse outcome in 917 women, over a median of 9.3 years.
The study was conducted in referral centers.
Women with signs and/or symptoms of myocardial ischemia referred for coronary angiography were consecutively consented and enrolled in a prospective study.
Main outcomes included first occurrence of cardiovascular death or nonfatal myocardial infarction. Hospitalization for angina was a secondary outcome.
Cardiovascular death or myocardial infarction at 10 years occurred in 6.7%, 12.8%, and 25.9% of women with no, nonobstructive, and obstructive CAD (P < .0001), respectively. Cumulative 10-year cardiovascular death or myocardial infarction rates showed progressive, near-linear increases for each WISE CAD severity score range of 5, 5.1 to 10, 10.1 to 20, 20.1 to 50, and >50. The optimal threshold in the WISE severity score classifications for predicting cardiovascular mortality was >10 (eg, 5.0-10 vs 10.1-89), with both a sensitivity and specificity of 0.64 and an area under the curve of 0.64 (P = .02, 95% CI 0.59-0.68).
Among women with signs and symptoms of ischemia, nonobstructive CAD is common and associated with adverse outcomes over the longer term. The new WISE angiographic score appears to be useful for risk prediction in this population.
This work aims to review preclinical/clinical cardiovascular studies that led to randomized trials of the risks and benefits of postmenopausal hormone therapy (HT), the pathobiological basis for the timing hypothesis, and subset analyses of randomized trials that tend to support the timing hypothesis; to elaborate experimental data that might inform the results of recent trials; and to summarize evidence regarding how early is early enough for the initiation of HT.
This work used interpretive literature review.
Preclinical and large observational studies provided what was considered at the time to be convincing evidence that HT provided protection against progressing coronary artery atherosclerosis. Those findings prompted three randomized, placebo-controlled, prospective trials to determine the risks and benefits of HT. None provided any evidence that HT had any beneficial effects on preexisting coronary artery atherosclerosis. Monkey studies provided clear evidence that HT was effective in slowing the progression of coronary artery atherosclerosis only when administered soon after surgical menopause and that benefit was lost if estrogen therapy was delayed until the plaques had become complicated. The phenomenon was referred to as the "timing hypothesis," and evidence for its translation into postmenopausal women was sought in subset analyses of data from the Women's Health Initiative and from newly planned prospective trials.
Current data are both supportive and not supportive of the timing hypothesis. However, evidence indicating that estrogens administered in the perimenopausal transition or early in menopause are not harmful to the cardiovascular system and, when given for a few years for the treatment of menopausal symptoms, may slow the progression of atherosclerosis and reduce the postmenopausal cardiovascular disease burden seems convincing.
To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol, and follicle-stimulating hormone.
Study of Women's Health Across the Nation participants (N=3,201), aged 42-52 years at entry, completed interviews on frequency of hot flushes and night sweats (none, 1-5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoprotein A-1, apolipoprotein B, lipoprotein[a], triglycerides, serum estradiol, follicle-stimulating hormone) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones.
Compared with no flushes, experiencing hot flushes was associated with significantly higher LDL (1-5 days: β [standard error]=1.48 [0.47], P<.01; 6 days or more: β [standard error]=2.13 [0.62], P<.001), HDL (1-5 days: β [standard error]=0.30 [0.18]; 6 days or more: β [standard error]=0.77 [0.24], P<.01), apolipoprotein A-1 (1-5 days: β [standard error]=0.92 [0.47], P<.10; 6 days or more: β [standard error]=1.97 [0.62], P<.01), apolipoprotein B (1-5 days: β [standard error]=1.41 [0.41], P<.001; 6 days or more: β [standard error]=2.51 [0.54], P<.001), and triglycerides (1-5 days: percent change [95% confidence interval]=2.91 [1.41-4.43], P<.001; 6 days or more: percent change [95% confidence interval[=5.90 [3.86-7.97], P<.001) in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences in lipid levels between hot flushes 6 days or more compared with no days ranged from less than 1 (for HDL) to 10 mg/dL (for triglycerides). Night sweats were similar. Associations were strongest for lean women.
Vasomotor symptoms were associated with higher LDL, HDL, apolipoprotein A-1, apolipoprotein B, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk.
II.
To estimate the duration of moderate-to-severe menopausal hot flushes and identify potential risk factors for hot flush duration.
The Penn Ovarian Aging Study cohort was monitored for 13 years. Hot flushes were evaluated at 9-month to 12-month intervals through in-person interviews. The primary outcome was the duration of moderate-to-severe hot flushes estimated by survival analysis (n=259). Potential risk factors included menopausal stage, age, race, reproductive hormone levels, body mass index (BMI), and current smoking. A secondary analysis included women who reported any hot flushes (n=349).
The median duration of moderate-to-severe hot flushes was 10.2 years and was strongly associated with menopausal stage at onset. Hot flushes that started near entry into the menopause transition had a median duration greater than 11.57 years; onset in the early transition stage had a median duration of 7.35 years (95% confidence interval [CI] 4.94-8.89; P<.001); and onset in the late transition to postmenopausal stages had a median duration of 3.84 years (95% CI 1.77-5.52; P<.001). The most common ages at onset of moderate-to-severe hot flushes were 45-49 years (median duration, 8.1 years; 95% CI 5.12-9.28). African American women had a longer duration of hot flushes than white women in adjusted analysis.
The median duration of hot flushes considerably exceeded the timeframe that is generally accepted in clinical practice. The identified risk factors, particularly menopausal stage, race, and BMI, are important to consider in individualizing treatment and evaluating the risk-to-benefit ratio of hormones and other therapies.
Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS).
We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N = 60,027): (1) no VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]), (2) VMS at menopause onset but not at WHI-OS enrollment (early VMS), (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]), and (4) VMS at WHI-OS enrollment but not at menopause onset (late VMS).
For women with early VMS (n = 24,753), compared with no VMS (n = 18,799), hazard ratios (95% CIs) in fully adjusted models were as follows: major coronary heart disease (CHD), 0.94 (0.84-1.06); stroke, 0.83 (0.72-0.96); total CVD, 0.89 (0.81-0.97); and all-cause mortality, 0.92 (0.85-0.99). For women with persistent VMS (n = 15,084), there was no significant association with clinical events. For women with late VMS (n = 1,391), compared with no VMS, hazard ratios (95% CIs) were as follows: major CHD, 1.32 (1.01-1.71); stroke, 1.14 (0.82-1.59); total CVD, 1.23 (1.00-1.52); and all-cause mortality, 1.29 (1.08-1.54).
Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with the onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from the classic perimenopausal VMS.
Emerging evidence suggests associations between menopausal hot flashes and cardiovascular risk. However, whether hot flashes are associated with intima media thickness (IMT) or IMT changes over time is unknown. We hypothesized that reported hot flashes would be associated with greater IMT cross-sectionally and with greater IMT progression over 2 years.
Participants were 432 women aged 45 to 58 years at baseline participating in the Study of Women's Health Across the Nation (SWAN) Heart, an ancillary study to the SWAN. Measures at the SWAN Heart baseline and follow-up visit 2 years later included a carotid artery ultrasound, reported hot flashes (past 2 weeks: none, 1-5 d, ≥6 d), and a blood sample for measurement of estradiol.
Women reporting hot flashes for 6 days or more in the prior 2 weeks had significantly higher IMT than did women without hot flashes at the baseline (mean [SE] difference, 0.02 [0.01] mm; P=0.03) and follow-up (mean [SE] difference, 0.02 [0.01] mm; P=0.04) visits, controlling for demographic factors and cardiovascular risk factors. Reporting hot flashes at both study visits was associated with higher follow-up IMT relative to reporting hot flashes at neither visit (mean [SE] difference, 0.03 [0.01] mm; P=0.03). Associations between hot flashes and IMT largely remained after adjusting for estradiol. An interaction between hot flashes and obesity status was observed (P=0.05) such that relations between hot flashes and IMT were observed principally among overweight/obese women. Hot flashes were not associated with IMT progression.
These findings provide some indication that women reporting hot flashes for 6 days or more in the prior 2 weeks may have higher IMT than do women without hot flashes, particularly for women who are overweight or obese. Further work should determine whether hot flashes mark adverse underlying vascular changes.
Estrogens, and in particular 17β-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes including the cardiovascular system. Although epidemiological studies and Nurses' Health Study suggested, and all animal models of early atheroma clearly demonstrated a vasculoprotective action of both endogenous and exogenous estrogens, the Women's Health Initiative did not confirm the preventive action of estrogens against coronary heart disease (CHD). However, women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with increased CHD risk among women more distant from menopause. Thus, it is now mandatory to try to understand the mechanisms that could have influenced the actions of estrogens at various stages of atherosclerosis and/or of life. In this current review, we will summarize our understanding of the potential cellular targets and mechanisms of the vasculoprotective actions of estrogens, as well as of the lack of action of estrogens when administered after a period of hormonal deprivation. The mechanisms of the aggravating role of progestogens such as medroxyprogesterone acetate will be considered. Finally, we will analyze the possibilities to uncouple some beneficial from other undesirable actions following the partial/selective activation of estrogen receptors.
Emerging evidence suggests that women with vasomotor menopausal symptoms (VMS) may have an adverse cardiovascular disease (CVD) risk profile. We investigated whether VMS are related to an increased risk of future coronary heart disease (CHD) and whether possible associations can be explained by CVD risk factors.
Data used were from a Dutch and Swedish population-based sample of 10,787 women enrolled between 1995 and 2000, aged 46 to 64 years, and free of CVD at baseline. Data on VMS were collected by questionnaires. Body mass index and blood pressure were measured in all women, and total cholesterol levels were measured in a subgroup of the population. Multivariable Cox regression models were used to analyze the data.
After a mean ± SD follow-up period of 10.3 ± 2.1 years, 303 women were diagnosed with CHD. Symptoms of flushing were not associated with risk of CHD. However, the presence of night sweats was associated with a significantly modest increased risk of CHD, with a multivariable-adjusted hazard ratio of 1.33 (95% CI, 1.05-1.69). This association was attenuated but not eliminated after correction for body mass index, blood pressure, and total cholesterol (hazard ratio, 1.25; 95% CI, 0.99-1.58).
Women with menopausal symptoms of night sweats have a significantly moderately increased risk of CHD, which cannot be totally explained by the levels of CVD risk factors.
Context:
The effect of early menopause on indices of vascular function has been little studied.
Objective:
The objective of the study was to investigate the effect of early menopause on indices of subclinical atherosclerosis and identify predictors of those indices in early menopausal women.
Design, setting, and participants:
This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women.
Main outcome measures:
Brachial artery flow-mediated dilation (FMD) and common carotid intima-media thickness (IMT) were studied. Estrogen receptor (ER)-alpha (rs2234693 T-->C and rs9340799 A-->G) and ERbeta (rs4986938 A-->G) polymorphisms were studied in menopausal women.
Results:
FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters.
Conclusions:
Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected. Severity of hot flushes is the main determinant of endothelial dysfunction in early menopausal women. The studied ER polymorphisms do not offer important information on vascular health in early menopause.
The purpose of this study was to examine the associations of vasomotor symptoms with risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in community-dwelling older women, with a mean age of 69 years.
This prospective population-based study included 867 postmenopausal women who provided lifestyle and menopause-related history at the 1984 to 1987 visit of the Rancho Bernardo Study and answered a 1989 mailed questionnaire on menopause and vasomotor symptoms. Ninety-eight percent were followed for vital status through July 2004.
Overall, 73% reported hot flashes, of whom 39% also reported night sweats. During the 11.5-year average follow-up, there were 405 deaths, of which 194 were attributed to CVD and 71 to CHD. Hot flashes alone were not associated with all-cause mortality, but women who, in addition to hot flashes, also had night sweats had an almost 30% (hazard ratio [HR], 0.72; 95% CI, 0.55-0.94) lower all-cause mortality risk compared with women without this symptom, independent of body mass index, past or current use of estrogen or progestin, physical exercise, and smoking habit. There was a similar lower risk of CVD and CHD mortality in women with night sweats when adjusted for past or current use of estrogen or progestin (HR, 0.62; 95% CI, 0.42-0.92 and HR, 0.51; 95% CI, 0.26-0.99, respectively). These associations were independent of hormone use but were no longer significant after adjusting for body mass index, physical exercise, and smoking.
Reported night sweats at menopause are associated with reduced risk of death over the following 20 years, independent of multiple risk factors including past or current use of postmenopausal estrogen therapy.
The aim of this study was to examine interactions between hot flushes, estrogen plus progestogen therapy (EPT), and coronary heart disease (CHD) events in postmenopausal women with CHD.
We analyzed data from the Heart and Estrogen/Progestin Replacement Study, a randomized, placebo-controlled trial of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate in 2,763 postmenopausal women with CHD. Hot flushes were assessed at baseline using self-administered questionnaires; women reporting bothersome hot flushes "some" to "all" of the time were considered to have clinically significant flushing. Cox regression models were used to examine the effect of EPT on risk of CHD events among women with and without significant flushing at baseline.
The mean age of participants was 66.7 +/- 6.8 years, and 89% (n = 2,448) were white. Sixteen percent (n = 434) of participants reported clinically significant hot flushes at baseline. Among women with baseline flushing, EPT increased risk of CHD events nine-fold in the first year compared with placebo (hazard ratio = 9.01; 95% CI, 1.15-70.35); among women without baseline flushing, treatment did not significantly affect CHD event risk in the first year (hazard ratio = 1.32; 95% CI, 0.86-2.03; P = 0.07 for interaction of hot flushes with treatment). The trend toward differential effects of EPT on risk for CHD among women with and without baseline flushing did not persist after the first year of treatment.
Among older postmenopausal women with CHD, EPT may increase risk of CHD events substantially in the first year of treatment among women with clinically significant hot flushes but not among those without hot flushes.
Background:
Although evidence suggests adverse vascular changes among women with hot flashes, it is unknown whether hot flashes are associated with subclinical cardiovascular disease. The aim of this study was to examine relations between menopausal hot flashes and indices of subclinical cardiovascular disease. We hypothesized that women with hot flashes would show reduced flow-mediated dilation and greater coronary artery and aortic calcification compared with women without hot flashes.
Methods and results:
The Study of Women's Health Across the Nation Heart Study (2001 to 2003) is an ancillary study to the Study of Women's Health Across the Nation, a community-based cohort study. Participants were 492 women (35% black, 65% white) 45 to 58 years of age who were free of clinical cardiovascular disease and had a uterus and at least 1 ovary. Measures included a brachial artery ultrasound to assess flow-mediated dilation, electron beam tomography to assess coronary artery and aortic calcification, reported hot flashes (any/none, previous 2 weeks), and a blood sample for measurement of estradiol concentrations. Cross-sectional associations were evaluated with linear regression and partial proportional odds models. Hot flashes were associated with significantly lower flow-mediated dilation (beta=-1.01; SE, 0.41; P=0.01) and greater coronary artery (odds ratio, 1.48; 95% confidence interval, 1.04 to 2.12) and aortic (odds ratio, 1.55; 95% confidence interval, 1.10 to 2.19) calcification in age- and race-adjusted models. Significant associations between hot flashes and flow-mediated dilation (beta=-0.97; SE, 0.44; P=0.03) and aortic calcification (odds ratio, 1.63; 95% confidence interval, 1.07 to 2.49) remained in models adjusted for cardiovascular disease risk factors and estradiol.
Conclusions:
Women with hot flashes had reduced flow-mediated dilation and greater aortic calcification. Hot flashes may mark adverse underlying vascular changes among midlife women.
A simple method is described for the simultaneous radioligand assay of four delta5-3beta-hydroxysteroids adjacent to one another on the biosynthetic pathway (pregnenolone [1], 17alpha-hydroxypregnenolone, dehydroepiandrosterone and 5-androsterone-3beta, 17beta-diol), and their four delta4-3keto products (progesterone, 17alpha-hydroxyprogesterone, 4-androstene-3, 17-dione and testosterone). Two plasma aliquots are extracted and fractionated each for four steroids and individual corrections are made for losses. For fractionation, maximum use is made of the high resolution and reproducibility of celite minicolumns, using propylene glycol as stationary phase, and a discontinuous gradient of ethyl acetate in iso-octane as mobile phase. The fractions are then assayed in the appropriate radioligand end-assay system. Each assay was finally validated by demonstrating coincidence of peaks of immuno- and radioactive steroid in extracts of female plasma. Results in pre-pubertal girls and women in the follicular phase of the menstrual cycle suggest that the major change in adrenal steroid production at puberty may be an increase in 17, 20-desmolase activity. There appears to be little reversal of this change in adrenal function after ovariectomy.
The Women's Ischemia Syndrome Evaluation (WISE) is a National Heart, Lung and Blood Institute-sponsored, four-center study designed to: 1) optimize symptom evaluation and diagnostic testing for ischemic heart disease; 2) explore mechanisms for symptoms and myocardial ischemia in the absence of epicardial coronary artery stenoses, and 3) evaluate the influence of reproductive hormones on symptoms and diagnostic test response.
Accurate diagnosis of ischemic heart disease in women is a major challenge to physicians, and the role reproductive hormones play in this diagnostic uncertainty is unexplored. Moreover, the significance and pathophysiology of ischemia in the absence of significant epicardial coronary stenoses is unknown.
The WISE common core data include demographic and clinical data, symptom and psychosocial variables, coronary angiographic and ventriculographic data, brachial artery reactivity testing, resting/ambulatory electrocardiographic monitoring and a variety of blood determinations. Site-specific complementary methods include physiologic and functional cardiovascular assessments of myocardial perfusion and metabolism, ventriculography, endothelial vascular function and coronary angiography. Women are followed for at least 1 year to assess clinical events and symptom status.
In Phase I (1996-1997), a pilot phase, 256 women were studied. These data indicate that the WISE protocol is safe and feasible for identifying symptomatic women with and without significant epicardial coronary artery stenoses.
The WISE study will define contemporary diagnostic testing to evaluate women with suspected ischemic heart disease. Phase II (1997-1999) is ongoing and will study an additional 680 women, for a total WISE enrollment of 936 women. Phase III (2000) will include patient follow-up, data analysis and a National Institutes of Health WISE workshop.
To identify symptoms experienced in a cohort of healthy women in the late reproductive years; to compare symptom reports between African American and Caucasian women; and to determine the extent to which other factors in reproductive health, mood and behavior, lifestyle, and demographic background are associated with the reported symptoms.
A cohort of women aged 35 to 47 years (mean age, 41 years) was identified through random digit dialing. This study is a cross-sectional analysis of data collected at enrollment from a subset of 308 women who completed daily symptom reports (DSR) for one menstrual cycle. Data were obtained in structured interviews and self-administered standard questionnaires. The associations of the study variables with symptoms as assessed by the DSR were examined using analysis of variance and general linear models.
The African American women were significantly more likely to report in interview that they experienced menopausal symptoms (46% vs. 30%; p < 0.001) and had significantly higher ratings on the physiological symptom factor of the DSR, which included hot flashes, dizziness, poor coordination/clumsiness, urine leaks, and vaginal dryness. The DSR yielded two other factors of psychological and somatic symptoms. Race was associated only with the physiological symptom factor in the multivariable analyses. Neither race nor age were associated with psychological symptoms, which were predicted by current or past mood problems.
Symptoms commonly associated with the menopause are experienced in the late reproductive years before observable changes in menstrual cycles. African American women reported more physiological symptoms than white women. These data provide an essential baseline for longitudinal study of symptoms associated with the ovarian decline in the perimenopausal years.
The purpose of this study is to provide a contemporary qualitative and quantitative analysis of coronary angiograms from a large series of women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study who had suspected ischemic chest pain. Previous studies have suggested that women with chest pain have a lower prevalence of significant coronary artery disease (CAD) compared with men. Detailed analyses of angiographic findings relative to risk factors and outcomes are not available. All coronary angiograms were reviewed in a central core laboratory. Quantitative measurement of percent stenosis was used to assess the presence and severity of disease. Of the 323 women enrolled in the pilot phase, 34% had no detectable, 23% had measurable but minimal, and 43% had significant ( > 50% diameter stenosis) CAD. Of those with significant CAD, most had multivessel disease. Features suggesting complex plaque were identified in < 10%. Age, hypertension, diabetes mellitus, prior myocardial infarction (MI), current hormone replacement therapy, and unstable angina were all significant, independent predictors of presence of significant disease (p < 0.05). Subsequent hospitalization for a cardiac cause occurred more frequently in those women with minimal and significant disease compared with no disease (p = 0.001). The common findings of no and extensive CAD among symptomatic women at coronary angiography highlight the need for better clinical noninvasive evaluations for ischemia. Women with minimal CAD have intermediate rates of rehospitalization and cardiovascular events, and thus should not be considered low risk.
Noninvasive methods are needed for the identification of women at highest risk for coronary artery disease (CAD) who might benefit most from aggressive preventive therapy. Identification of brachial artery atherosclerosis, which correlates with coronary artery atherosclerosis, may be useful to estimate or stratify CAD risk. Because atherosclerosis disrupts the arterial architecture that regulates vessel size, we hypothesized that noninvasively measured large brachial artery diameter is a manifestation of atherosclerosis that is associated with angiographic CAD in women with chest pain.
We examined 376 women (mean age, 57.1 years) with chest pain in the National Heart, Lung, and Blood Institute's Women's Ischemia Syndrome Evaluation study who underwent B-mode ultrasound scan measurement of brachial artery diameter at rest and during hyperemic stress (to quantify flow-mediated dilation), quantitative coronary angiography, and risk factor assessment.
Large resting brachial artery diameter was associated with significant angiographic CAD (3.90 +/- 0.79 mm vs 3.52 +/- 0.59 mm in women with CAD vs no CAD; P <.001). Impaired flow-mediated dilation, which correlated with resting diameter (r = -0.17; P =.001), was weakly associated with significant CAD (2.74% +/- 7.11% vs 4.48% +/- 9.52% in CAD vs no CAD; P =.046). After adjustment for age, body size, and CAD risk factors, women with large resting brachial artery diameters (>4.1 mm) had 3.6-fold increased odds (95% confidence interval, 1.8 to 7.1; P <.001) of significant angiographic CAD compared with those with small brachial arteries (</=3.6 mm).
Large resting brachial artery diameter is an independent predictor of significant CAD in women with chest pain. Therefore, a simple ultrasonographic technique may be useful in the identification of women with chest pain who are at increased risk for CAD.