A marker for heart disease risk considerably worsens as women transition through menopause, according to a new analysis from the largest and longest running study of women’s health in midlife, the Study of Women’s Health Across the Nation (SWAN).
Black women experience this accelerated decline earlier in menopause than their white counterparts.
According to the research team, led by scientists at the University of Pittsburgh Graduate School of Public Health, the findings add to growing evidence that menopause is a critical time for changes in cardiovascular health and underscore the importance of women and their doctors focusing on heart health during the menopausal transition.
The results are reported online and will appear in the March issue of Arteriosclerosis, Thrombosis, and Vascular Biology, a journal of the American Heart Association.
“Midlife is not just a period where women have hot flashes and experience other menopausal symptoms,” said senior author Samar R. El Khoudary, Ph.D., M.P.H., associate professor of epidemiology at Pitt Public Health.
“It’s a time when their cardiovascular disease risk is increasing as we see significant changes in multiple clinical measures of their physical health.”
El Khoudary and her team used a subset of data from SWAN Heart, an ancillary study that enrolled women from Pittsburgh and Chicago between 2001 and 2003 and included two examinations of early markers of cardiovascular health over time. Ultimately, 339 women were included in this study, 36% black and the rest white.
The study focused on how arterial stiffness changes as women transition through menopause. Arterial stiffness refers to the elasticity of arteries and is measured by looking at how fast blood flows through arteries.
Stiffer arteries can lead to dysfunction in how well the heart pumps and moves blood, and damage to the heart, kidneys and other organs.
The researchers tracked the women through SWAN for up to 12.5 years, or until they reached menopause, allowing them to confidently anchor the arterial stiffness measure to the menopausal transition.
On average, as women went through menopause, their arterial stiffness increased by about 0.9% up to one year before their last menstrual period to about 7.5% within one year before and after their last period, a considerable acceleration.
The black women in the study experienced greater increases in arterial stiffness earlier in the transition than white women, more than a year before menopause.
The findings held after adjusting for numerous factors that could affect heart health, including waist circumference, blood pressure, lipids, smoking status, physical activity levels and financial stress.
“SWAN is a unique source of data on changes in women’s health over several decades, and this is the latest in a long line of research by our team and others that indicates the menopausal transition is a very important time for heart health,” said lead author Saad Samargandy, M.P.H., a Ph.D. student at Pitt Public Health.
“While there are limitations to our study, including that a sizeable minority of the women had their arterial stiffness measured at only one time point, we were still able to see that major changes to cardiovascular disease risk happen around menopause.”
This study follows several others that link the menopausal transition to the accumulation of heart fat, changes in cholesterol, inflammation and coronary artery calcification, among other heart disease risk factors.
“Our study is not able to tell us why we’re seeing these changes during the menopausal transition,” El Khoudary said.
“But we speculate that the dramatic hormonal changes accompanying menopause might play a role by increasing inflammation and affecting vascular fat deposition, a hypothesis that we would like to test in future studies.”
Clinical trials will be needed to test if lifestyle interventions, such as changes to diet or physical activity; medications, such as statins or hormone replacement therapy; or even increased screening and tracking of measures of heart health could be beneficial as women go through menopause, she said.
“But we can say, right now, that women should be made aware that their cardiovascular health is likely to worsen as they go through menopause,” El Khoudary said. “Therefore, frequent monitoring of cardiovascular risk factors may be prudent, particularly in black women who are at even greater risk earlier in the menopausal transition.”
Cardiovascular disease (CVD) is the leading cause of death in men and women from Western countries, with 17.5 million deaths worldwide in 2012, representing 31% of all global deaths.1
Approximately 7.4 million of these were due to coronary heart disease (CHD). CHD risk increases in women after the age of 50 years, leading to suggestions that menopause may be a contributing factor.2–4
A recent meta-analysis suggested that women who had early menopause (before age 45 years) are at 50% higher CHD risk compared with those with later menopause.5 However, that analysis was not able to include 9 studies out of the 14 studies they found examining the association between age at menopause and CHD, nor was it able to examine whether there is a (non-)linear dose–response relationship or threshold effect or whether type of menopause (surgical or natural) was associated with CHD risk.
The biological mechanisms through which menopause might influence CHD risk are postulated to include reductions in oestrogen levels, but rises in conventional cardiovascular risk factors (e.g. major lipids and blood pressure) around the time of menopause may also play a role.6–8
However, the extent to which the association between menopausal characteristics and CHD can be explained by such factors remains unclear.
We conducted a large pan-European prospective case–cohort study (EPIC-CVD) with an average of 11 years of follow-up to quantify the associations of menopausal status, age at menopause and type of menopause with risk of CHD; we also examined the shape of the relationship between age at menopause (as a continuous exposure) and risk of CHD; and we assessed the extent to which the associations of menopausal characteristics with risk of CHD could be explained by established cardiovascular risk factors.
Menopausal status, timing and type of menopause
Menopause was assessed by questionnaire at baseline. Women were categorized as pre-menopausal if they had experienced menses over the past 12 months before recruitment and by design, for women with missing or incomplete questionnaires, if they were 54 years or younger at recruitment.
The pre-menopausal group also includes the peri-menopausal women, since numbers were too small to analyse them as a separate group.
Women were categorized as post-menopausal if they had experienced no menses for 12 months or longer due to natural or surgical menopause and by design, for women with missing or incomplete questionnaire data, if they were 55 years or older at recruitment.12
Post-menopausal women were classified as having had a natural or surgical menopause, where surgical menopause was defined as having had a hysterectomy, unilateral or bilateral oophorectomy, only when age at surgery preceded or was equal to age at menopause.
In the Malmö centre, since the age at removal of a woman’s womb and/or one or both ovaries was not recorded, women were classified as having had a surgical menopause regardless of age at surgery and age at menopause was then imputed (see below).
For naturally post-menopausal women, age at menopause was defined as the age at which they had their last menstruation. For surgically post-menopausal women, their age at surgery was used instead.
Since most other studies compare early menopause with late menopause, we present risk associations for decreases (rather than increases) in age at menopause, by multiplying age at menopause by –1
Discussion
Our study has shown that age at menopause has an inverse dose–response relationship with risk of CHD. Surgical menopause is also associated with an increased CHD risk, even once the earlier age at menopause is accounted for.
A proportion of the risk appears to be explained by cardiovascular risk factors that have been postulated to mediate the associations of menopausal characteristics with risk of CHD.
Our finding that the higher risk of CHD in post-menopausal women attenuated upon adjustment for conventional cardiovascular risk factors and reproductive factors is in line with a previous meta-analysis29 that also found an increased risk for post-menopausal women.
These analyses could be challenging, since one might expect both pre- and post-menopausal women to have their events around the same age in their post-menopausal period. However, the age at event in our study was 56.4 ± 7.1 years for pre-menopausal women and 69.8 ± 7.0 years for post-menopausal women, indicating enough dispersion to show a robust effect.
Similarly, our finding that earlier menopause is associated with a higher CHD risk is also consistent with a recent meta-analysis5 that showed a higher CHD risk for women with an age at menopause before 45 years.
However, our access to individual participant data (rather than literature-based summary results) meant that we were able to amplify previous findings by showing that the relationship is continuous and approximately linear across the range in age at menopause.
Hence, there is no clear age threshold below which early menopause appears to be of intrinsic concern, within the approximate mean ages of the earliest (34 years) and latest (56 years) categories of menopausal age.
Age at menopause might be harder to recall when women used HT, but the results of the sensitivity analysis excluding women using HT barely changed, indicating that this did not influence our results.
We identified BMI as an effect modifier and the stratified results appeared similar to the findings of a smaller study,18 which suggested that age at menopause has a stronger association with CHD in obese women compared with non-obese women.
Previous evidence on the associations of surgical and natural menopause with CHD is conflicting.2,3,24,30,31
Comparison of these studies is difficult, since the definition of surgical menopause and inclusion of women using HT differs by study. Notably, none of the studies on surgical menopause adjusted for age at menopause in their analysis, notwithstanding the fact that a surgical menopause occurs consistently earlier than a natural menopause.
Our study shows that the association between surgical menopause and CHD risk is largely explained by the earlier age at menopause, but residual risk remains. Excluding women using HT only slightly altered the results.
However, when we defined surgical menopause as bilateral oophorectomy only, the results attenuated towards the null, suggesting that the effect of surgical menopause might be smaller than previously thought.
As conventional cardiovascular risk factors such as blood pressure, lipids and C-reactive protein (CRP) rise around the age of menopause, we specifically examined the extent to which these potential mediators explained the associations we observed in Model 4.
Our analyses suggested that these factors can explain part of the association between menopausal characteristics and higher risk of CHD, because the greatest difference in the percentage of proportion explained was found between Model 3 and Model 4 in each association.
This concurs with the findings of several other studies, which showed the greatest changes in lipid levels around the time of menopausal transition.7,8,32–36
Our results should be interpreted with caution, as measurement error might exist in the mediators that could distort the adjustment.37
Furthermore, as EPIC-CVD has only a single measure of these risk factors at baseline (i.e. after the menopause in post-menopausal women), it is not possible to reliably distinguish whether the attenuations seen are due to mediation or confounding.38
Our study has several strengths. We used data from a large prospective study encompassing diverse European populations with a long duration of follow-up and a substantial number of validated incident CHD events.
The availability of a wide range of cardiovascular and reproductive risk factors allowed us to systematically examine the effects of accounting for these factors. We were also able to examine the impact of HT use, which has not been possible in many previous studies.
Potential limitations include missing or incomplete menopause data, which may have led to non-differential misclassification resulting in under-estimation of the true associations39; self-reported menopausal characteristics, although studies show that the validity is rather good for menopausal status and age and varies for surgical menopause40–42; the possibility of residual confounding; and measurement error in the intermediates. As EPIC-CVD did not have measures of sex hormones, we were not able to evaluate the contribution of oestrogen.
The fact that there are HT users among pre-menopausal women can be explained by the inclusion of peri-menopausal women in this category. Finally, a substantial number of the pre-menopausal women would likely have become post-menopausal during the follow-up period. Therefore, our associations may have been slightly underestimated.
In conclusion, earlier age at menopause and surgical menopause are both associated with higher risk of CHD, which might suggest that these women need close monitoring in clinical practice.
The excess risk is, in part, explained by conventional cardiovascular risk factors. Therefore, these risk factors should play an important role in the monitoring of these women. However, there is still a residual association between menopausal characteristics and CHD, of which the mechanism is not fully understood and which merits further research.
More information: Saad Samargandy et al, Arterial Stiffness Accelerates Within 1 Year of the Final Menstrual Period, Arteriosclerosis, Thrombosis, and Vascular Biology (2020). DOI: 10.1161/ATVBAHA.119.313622
