Women's Heart Health and the Menopausal Transition: Two Faces of the Same Coin.

The beliefs and science surrounding the MT continue to influence every aspect of women’s midlife healthcare today. Attitudes relating to the MT life stage influence women’s symptom profiles, health-seeking behaviours, and importantly, the clinical training and resulting interactions of health professionals and midlife women. However, most women assume that menopause-related changes will happen around the age of 50 years, and only 13% assume changes begin before age 44 years. 17 Although women may be prepared for puberty and childbirth, little to no information and/or education is available about the MT, and women do not know when to attribute symptoms to hormonal changes. 17 Moreover, younger women (age 35-55 years) and clinicians have been taught to assume that women are not at risk for CVDs before menopause. 17 Ironically, the signs and symptoms that are more common in younger women with heart health issues, including chest discomfort, sweating, nausea, shortness of breath, and lightheadedness, are frequently attributed to being “symptoms” of peri-menopause. Sex steroid–associated events, such as early or late menarche, very irregular menstrual cycles at ages 20-35 years, and premature menopause (at age < 40 years) are now recognized as being associated with an increased risk of early CVD, but a gap remains in our understanding of the relationship and/or risks associated with women’s experiences with CVDs throughout the MT. The term CVDs is an inclusive term reflecting a number of vascular conditions, including hypertension, atherosclerosis, cerebrovascular disease, ischemic heart disease, and cardiac failure. Current evidence and a growing knowledge of the patterns of ischemic heart disease (IHD) in younger women suggest that we should be better able to recognize, diagnose, and treat symptomatic women. However, as identified in a 2023 Heart & Stroke Canada report, half the women who experience an MI have their symptoms go unrecognized, and every 16 minutes, a woman in Canada dies as a result of heart disease or stroke. 18 Alarmingly, the number of women under age 65 years with an MI is increasing, especially type II MIs with nonobstructive coronary arteries (MINOCA), which is at least twice as prevalent in women as it is in men. 16 The Heart & Stroke Canada report 18 identifies that the signs and symptoms of IHD for women, such as angina, are more likely to be due to ischemia with nonobstructive coronary arteries (INOCA), which is more common in younger women. Coronary vasomotor disorders, such as coronary artery spasm and coronary microvascular dysfunction, represent a major cause of IHD in middle-aged women. 16 As well, spontaneous coronary artery dissection (SCAD) is a common cause of heart attacks in younger women, with 90% of SCAD patients being women. 19 SCAD has been reported to account for 25% to 30% of all heart attacks in women under age 60 years 16 , 20 —in other words, women in the MT. General estrogenic actions and the benefits and risks of estrogen exposure on vascular physiology and pathophysiology have been determined primarily through cohort and/or registry data for women whose age at menopause was > 45 years, and/or for women with early menopause (at age < 45 years) and women with premature ovarian insufficiency (at age < 45 years) who are on HRT. 14 Consequently, Maas et al. reported that the “possible mechanisms” mediating the CVD benefit of MHT (especially transdermal MHT) include insulin sensitivity, improvements in the lipid profile and body composition, decreases in blood pressure in the case of progestin-containing regimens, and a direct vasodilatory and anti-inflammatory effect. 16 Further, although healthy endothelium is sensitive to the vasodilator properties of estrogens, this sensitivity is reversed when vascular stiffness and atherosclerotic disease develop over time. Evidence indicates that hypoestrogenic environments promote early development of atherosclerosis, impaired endothelial function, and CVD 2 , 16 ; however, although CVD risk increases with menopause, this effect cannot be distinguished from that of aging. 14 Another important point to note is that studies to date have focused on the menopausal experiences of educated white women in the global north, with few if any studies including other populations of women. Augmenting the dearth of evidence on the effects of fluctuations in sex-steroid levels on a women’s vascular system is the reality that MT education and the influence of sex steroids on women’s midlife health is either absent or extremely limited in medical, nursing, and allied health curricula. Content on women’s health—more specifically, women’s heart health—is missing in most cardiovascular textbooks and conferences, or it is relegated to “special interest” sections and/or sessions. This significant gap in our understanding of the interaction of the MTs and women’s heart disease has led to a paradox of sorts, whereby clinicians and women alike attribute the symptoms a woman describes as being related to either the MT and sex steroid–level changes OR female-pattern CVDs. Hodis et al. note that the decline in endothelial function starts in early menopause, even before signs of subclinical atherosclerosis are present. 14 This mechanism, which may be part of the pathophysiology of chest pain and dyspnea of “undetermined” origin, 14 is described by women with lived experience in the Canadian Women’s Heart Health Alliance Atlas, chapter 3, “Stopped at the Gate” and is frequently mistakenly labelled as being a sign of “stress” or as “menopausal symptoms.” 14 , 21 Important to note is that although evidence linking vasomotor symptoms to CVD is limited , hot flashes and/or flushes, cold sweats and night sweats, the classic menopausal symptoms, are linked to CVD risk factors and subclinical CVD, 22 and they may be an important harbinger of female-specific CVD.

A clear finding is that the impact of aging and environmental and/or behavioural risk factors interact with changes in the sex steroids during the MT. Increasing hypoestrogenism is linked to increased adiposity in the absence of weight gain or changes in physical activity, increased total cholesterol, and altered endothelial cell function that leads to increased vascular inflammation and decreased vascular elasticity. 2 Moreover, increase in risk contributed by the diminishment of sex steroids and by age may not be constant and may be influenced by other female-specific risk factors, including complications of pregnancy, and/or endocrine and gynecological conditions, such as polycystic ovarian syndrome and endometriosis. These are risk factors for CVD, and yet women consistently report that the ONLY question they are asked regarding the fundamental influence of sex steroids on women’s health, whether accessing primary or acute care, is “When was your last menstrual period?” It is imperative that all women’s heart health assessments include the collection and documentation of sex-specific risk variables related to hormonal and reproductive status known to be associated with CVD risk. The 2021 consensus document from the European Society of Cardiology entitled “Cardiovascular Health After Menopause Transition, Pregnancy Disorders, and Other Gynaecologic Conditions” succinctly outlines sex-specific risk factors of which the collection is essential to identifying the contributions of sex-specific risk factors in the context of CVD in women (see Fig. 1 ). 16 Figure 1 Female-specific risk factors and strategies for prevention. BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease; HRT, hormone replacement therapy; IHD, ischemic heart disease; MHT, menopausal hormone therapy; OGTT, oral glucose tolerance test. Reproduced with permission from Oxford University Press on behalf of the European Society of Cardiology from Maas AH, et al. 16 ; permission conveyed through Copyright Clearance Center, Inc. Female-specific risk factors and strategies for prevention. BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease; HRT, hormone replacement therapy; IHD, ischemic heart disease; MHT, menopausal hormone therapy; OGTT, oral glucose tolerance test. Reproduced with permission from Oxford University Press on behalf of the European Society of Cardiology from Maas AH, et al. 16 ; permission conveyed through Copyright Clearance Center, Inc. In December 2021, the Society of Obstetricians and Gynaecologists of Canada (SOGC) created a guideline, 23 with the objective of providing strategies for improving the care of perimenopausal and postmenopausal women. The summary statements provide clinical guidance and evidence specific to CVD and women who are in the MT. The summary statements include the following: • Women who initiate menopausal hormone therapy shortly after menopause are, in general, at low risk for events in the next few years (high). Evidence supports aggressive identification and modification of risk factors as the most effective means of reducing cardiovascular risk (high). • Women who initiate menopausal hormone therapy 10 or more years after menopause are at increased risk for adverse cardiac events (high). • With respect to stroke, increased risk has been identified in all age groups using standard formulations of menopausal hormone therapy; however, the incidence in young women is extremely low (low). • Incidence of venous thrombotic events increases with age (> 60 years) and body mass index (BMI), even in otherwise healthy women; menopausal hormone therapy increases the risk (high ). • Menopausal hormone therapy is not indicated for primary or secondary prevention of cardiovascular disease (moderate). • Women with premature or early-onset menopause appear to be at an increased risk of adverse cardiovascular outcomes, and this risk may be prevented by the use of menopausal hormone therapy until the average age of menopause (moderate). • Menopausal hormone therapy increases the risk of venous thromboembolism; oral and combined hormone therapy preparations are more closely associated with risk of venous thromboembolism than either with transdermal preparations or estrogen alone (moderate). • There is a lack of high-quality data to provide guidance on the impact of routes of estrogen administration on the risk of venous thrombotic events or cardiovascular disease (low). • Women who initiate menopausal hormone therapy shortly after menopause are, in general, at low risk for events in the next few years (high). Evidence supports aggressive identification and modification of risk factors as the most effective means of reducing cardiovascular risk (high). • Women who initiate menopausal hormone therapy 10 or more years after menopause are at increased risk for adverse cardiac events (high). • With respect to stroke, increased risk has been identified in all age groups using standard formulations of menopausal hormone therapy; however, the incidence in young women is extremely low (low). • Incidence of venous thrombotic events increases with age (> 60 years) and body mass index (BMI), even in otherwise healthy women; menopausal hormone therapy increases the risk (high ). • Menopausal hormone therapy is not indicated for primary or secondary prevention of cardiovascular disease (moderate). • Women with premature or early-onset menopause appear to be at an increased risk of adverse cardiovascular outcomes, and this risk may be prevented by the use of menopausal hormone therapy until the average age of menopause (moderate). • Menopausal hormone therapy increases the risk of venous thromboembolism; oral and combined hormone therapy preparations are more closely associated with risk of venous thromboembolism than either with transdermal preparations or estrogen alone (moderate). • There is a lack of high-quality data to provide guidance on the impact of routes of estrogen administration on the risk of venous thrombotic events or cardiovascular disease (low). Women who initiate menopausal hormone therapy shortly after menopause are, in general, at low risk for events in the next few years (high). Evidence supports aggressive identification and modification of risk factors as the most effective means of reducing cardiovascular risk (high). Women who initiate menopausal hormone therapy 10 or more years after menopause are at increased risk for adverse cardiac events (high). With respect to stroke, increased risk has been identified in all age groups using standard formulations of menopausal hormone therapy; however, the incidence in young women is extremely low (low). Incidence of venous thrombotic events increases with age (> 60 years) and body mass index (BMI), even in otherwise healthy women; menopausal hormone therapy increases the risk (high ). Menopausal hormone therapy is not indicated for primary or secondary prevention of cardiovascular disease (moderate). Women with premature or early-onset menopause appear to be at an increased risk of adverse cardiovascular outcomes, and this risk may be prevented by the use of menopausal hormone therapy until the average age of menopause (moderate). Menopausal hormone therapy increases the risk of venous thromboembolism; oral and combined hormone therapy preparations are more closely associated with risk of venous thromboembolism than either with transdermal preparations or estrogen alone (moderate). There is a lack of high-quality data to provide guidance on the impact of routes of estrogen administration on the risk of venous thrombotic events or cardiovascular disease (low). More recently, a review in the Canadian Medical Association Journal entitled “A Pragmatic Approach to the Management of Menopause,” reported that, despite early concerns, increasing evidence shows a possible reduction in coronary artery disease with MHT among patients who start MHT before age 60 years or within 10 years of menopause. 24 Furthermore, they note that both RCTs and observational studies consistently show that an association exists between MHT and reductions of coronary artery disease events among women. Lega et al. note that the metabolic benefits of MHT include an improvement in lipid profile (an increase in high-density lipoprotein and a decrease in low-density lipoprotein) and that some studies have suggested an improvement in insulin sensitivity with a reduction in the risk of diabetes. 24 Finally, given the heterogeneity of the progression of women+ (including transgender men and nonbinary people) through the MT, it is important for both clinicians and the women they partner with in healthcare to understand and document ( Fig. 2 ) where they are in the MT. The stages of the MT are normal, and women who are experiencing symptoms are not “ill.” Staging tools, such as the Straw 10+, do scale subtle changes in flow and length of menstrual cycles, vasomotor symptoms— including feelings of heat with flushing, cold sweats, and night sweats—sleep disturbances, and mood/cognition changes—including irritability, tearfulness, insomnia, memory/concentration issues, depression, anxiety, and stress—identified in the Menopause Rating Scale. 25 However, these factors are all suggestive of perimenopause and left untreated may contribute to an increased cardiovascular risk and overall health concerns. Figure 2 The Stages of Reproductive Aging Workshop + 10 staging system for reproductive aging in women. AMH, anti-Mullerian hormone. FMP, final menstrual period; FSH, follicle-stimulating hormone; IU, international units. Reproduced with permission from The North American Menopause Society from Harlow et al. 26 ; permission conveyed through Copyright Clearance Center, Inc. The Stages of Reproductive Aging Workshop + 10 staging system for reproductive aging in women. AMH, anti-Mullerian hormone. FMP, final menstrual period; FSH, follicle-stimulating hormone; IU, international units. Reproduced with permission from The North American Menopause Society from Harlow et al. 26 ; permission conveyed through Copyright Clearance Center, Inc.

The gap in understanding of the relationship between the MT and CVDs in women has meant that women with heart health issues continue to be under-researched, underdiagnosed, undertreated, under-supported, and under-aware. The widespread, consistent assessment and collection of both women’s CVD risk factors as well as MT factors, including menopausal stage and symptoms, is the first step toward understanding women’s heart health that may be applied to determining the most effective way to prevent, diagnose, and/or treat CVDs in women.