Role of menopause in the development of cardiovascular disease in women

Abstract

Cardiovascular disease (CVD) is the most common cause of death in women. Early identification of CVD risk factors in women is often overlooked by physicians leading to delays in diagnosis and treatment of CVD with subsequent morbidity and mortality. There may be a correlation between declining hormone levels during menopause and the prevalence of CVD during midlife. Alterations in the CVD risk profile of women throughout the menopause transition (MT) are multifactorial and include changes to arterial stiffness, endothelial function, lipid metabolism, insulin resistance and adipose fat distribution. Menopausal Hormonal Therapy (THM) is a potential therapy to reduce CVD risk, though clinical trials have shown conflicting results, with some trials reporting an increase in CVD events with THM. A holistic approach to care for women going through the MT could be beneficial to improve their CVD risk profile and quality of life. This would include early identification of risk factors in individual patients and raising public and professional awareness of CVD risk burden in this patient population. Improving the knowledge of healthcare professionals and the public that women going through the MT are at an increased risk of CVD is a key target area to improve cardiovascular health in women. Current risk assessment scores for CVD do not include sex-specific risk factors. Guidelines and National Health Systems are beginning to recognise the importance of reproductive history in women’s cardiovascular health. In this review, we aim to discuss traditional and sex specific risk factors for CVD in menopausal women, current guidelines on THM, gaps in knowledge and strategies to reduce CVD in women.

Introduction

Cardiovascular disease (CVD) is the most common cause of death among women worldwide.¹ Despite improvements in the diagnosis and treatment of CVD over the last few decades, there continues to be gender imbalance in accessing healthcare for CVD. These inequities particularly affect women from ethnic minorities and/or poorer countries, and those facing social deprivation.¹ Menopause is the period in a woman’s life where they undergo permanent cessation of menstruation and ovarian function. The average age of onset of the menopause is 51 years of age with a range of between 40 and 60 years.² There are sex differences in the incidence of CVD with lower rates seen in premenopausal women thought to be largely related to the protective effects of oestrogen.³ The role of oestrogen in the regulation of blood pressure, vascular function and cardiac function is well established.^{4 5} The decline in oestrogen throughout the menopause transition (MT) is associated with adverse cardiovascular outcomes. In addition, declining oestrogen levels can have a deleterious effect on cognitive function and the risk of developing Alzheimer’s disease.⁶

The Lancet Women and Cardiovascular Disease Commission highlighted the need to reduce the global burden of CVD in women by 2030.⁷ The commission highlighted gaps in access to care for women, knowledge related to CVD prevention and on-going research. The American Heart Association and American College of Cardiology (AHA/ACC) guidelines recognise that premature ovarian insufficiency (POI) (which is ovarian insufficiency under 40 years) increases CVD risk but this has not been fully supported by the European guidelines.^{8 9} In the UK, there has been recognition by the National Health Service (NHS) that menopause questions should be incorporated into NHS health checks, raising awareness and helping women to be directed to appropriate services, information and treatment options for symptom relief.¹⁰ This review examines the impact of menopause on cardiovascular risk, the underlying mechanisms, clinical implications and prevention strategies.

CVD in women

Data from over 15 years ago suggested women present up to 10 years later with CVD than men.¹¹ More recent data from the Coronary Artery Risk Development in Young Adults study investigated this. The study concluded that at 35 years old, sex differences emerge in CVD risk. Moreover, it found that there was a 2% cumulative incidence of men developing coronary heart disease (CHD) 10 years earlier than women, which is in accordance with previous data.¹² In a study of young patients aged 35–54 years presenting with acute myocardial infarction (AMI), hospitalisations with AMI were more common among women and women were less likely to receive guideline based therapies.¹³ A large study reported by Zhu and colleagues showed an association between age at menopause and the incidence of CVD. There was a higher cardiovascular risk in women presenting with menopause before 50 years of age and a significantly reduced cardiovascular risk in women reaching menopause after 51 years of age. The association was strongest in POI and early menopausal women (menopause at 44 years or younger) up to 60 years of age, with no significant association seen once the women reached 70 years of age.¹⁴ These findings reinforce the need to raise awareness of CVD in young women and incorporate female-specific variables in assessing risk. A recent study investigated acute coronary syndromes (ACS) in premenopausal women and highlighted a major challenge in correctly diagnosing and treating young women with CVD, resulting in frequent misdiagnosis and mistreatment in this patient group. Furthermore, the study argued that risk assessment in young women should involve components such as pregnancy history, lipoprotein(a) and history of familial hypercholesterolaemia as well as traditional CVD risk factors. This study highlighted some future directions for the management of premenopausal women with ACS, such as establishing sex-specific reference values for intracoronary imaging, implementing strategies to increase female participation in trials and policies to address social determinants of health that affect CVD risk.¹⁵ Shin et al reported an association between POI (<40 years) and the incidence of heart failure and atrial fibrillation.¹⁶ These studies highlight the importance of assessing a woman’s reproductive history as well as traditional risk factors when assessing cardiovascular risk.

Epidemiology

POI is a clinically distinct condition from early menopause and affects 1% of women under the age of 40. It is defined as the loss of normal ovarian function before the age of 40, and is characterised by infrequent or absent menstrual periods as well as elevated gonadotrophins and low estradiol.^{17 18} In contrast, early menopause is defined as the permanent cessation of ovarian function between the ages of 40 and 44 years. POI puts women at an increased risk of ischaemic heart disease (IHD), myocardial infarction (MI) and stroke.^{18 19} The increase in CVD risk is attributed to a lack of endogenous oestrogen and worsening of cardiovascular risk factors such as endothelial dysfunction and adverse lipid profiles.¹⁹ Menopausal Hormonal Therapy (THM) is strongly recommended for the prevention of CVD in women with POI when initiated promptly at the time of diagnosis and maintained until the average age of natural menopause.^{19 20} THM works to restore the normal serum oestrogen concentration. In addition to THM, patients should be educated on the importance of lifestyle modification to further prevent CVD.²⁰

POI and early menopause are associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) due to earlier development of cardiometabolic syndrome.⁹ In a study of 46 238 women with a mean age of 62.1 years, CVD was higher in women with POI and early menopause compared with those who reached menopause between 50 and 52 years.²¹ A meta-analysis reported a 1.7-fold increase in fatal or non-fatal IHD risk in POI patients.²² A recent prospective study has shown that women with POI face a 40% higher lifetime risk of CHD (fatal and non-fatal MI).²³

Surgical menopause is when both ovaries are removed prior to natural menopause. It is performed for the treatment of benign or malignant conditions, such as endometriosis or to reduce the risk of breast and ovarian cancer. In surgical menopause, sex hormone levels fall drastically as opposed to natural menopause, where they decline more gradually. Surgical menopause is associated with a higher risk of developing CVD. The InterLACE consortium reported pooled data on 203 767 postmenopausal women and found that surgical menopause was associated with a higher risk of CVD than natural menopause.²⁴ This observation was also confirmed in a UK Biobank cohort study of 144 260 women who had undergone surgical menopause or POI.²⁵ This observation was not seen in a study of prophylactic bilateral oophorectomy patients for ovarian cancer who underwent CT coronary artery calcium (CAC) to evaluate CVD risk.²⁶ Oophorectomy is often performed as part of a hysterectomy procedure for benign conditions such as uterine fibroids or endometriosis. These conditions are found to coexist with other metabolic conditions that increase CVD risk and can be associated with changes in lipid metabolism.^{27 28}

Pathophysiological mechanisms

There are many pathophysiological mechanisms that contribute to a change in the CVD risk profile of women undergoing the menopause (figure 1). These include changes to arterial stiffness, endothelial dysfunction, lipid metabolism, insulin resistance and adipose fat distribution. A recent mouse model study has shown that asprosin levels (a glucogenic adipokine secreted by white adipose tissue) were higher in mice with long-term ovariectomy. Asprosin was found to potentiate vasoconstriction and lead to arterial stiffness.²⁹ As oestrogen levels reduce during menopause, the vasodilating part of the renin-angiotensin-aldosterone system (RAAS) may decrease, and the vasoconstrictive arm may increase in activity. Those alterations in the RAAS are found throughout many tissues, including brain, heart, adipose tissue and kidney.³⁰ RAAS also impacts thrombosis (through tissue factor VIIa) and inflammation (mainly by interleukin (IL)-6), which contribute to CVD.³¹ IL-6 can also increase the fibrinogen level to enhance thrombosis.^{32 33} Women tend to have higher fibrinogen levels than men, including in the setting of premature coronary artery disease (CAD), although the reasons for this difference are not fully understood. Importantly, higher fibrinogen levels are associated with more extensive coronary atherosclerosis in women with CAD.³⁴ Ageing leads to arterial stiffness but what remains unclear is the role of menopause in the progression of arterial stiffness. A cross-sectional study including 52 891 women from the UK Biobank assessed the arterial stiffness index changes over the MT. The investigators found that menopausal women had a higher arterial stiffness index as compared with premenopausal women. The study concluded that menopause is associated with increased arterial stiffness independent of traditional risk factors.³⁵ In addition, one study showed that the incidence of CVD is similar in both perimenopausal and postmenopausal women, whereas follicle-stimulating hormone, luteinising hormone, estradiol, total cholesterol (TC) and low density lipoprotein (LDL) are significantly different in different age groups. It indicated that increasing age was associated with a higher risk of CVD.³⁶ During menopause there are changes in endothelial function which may have a direct effect on vasodilatation of smooth muscle cells by the reduced synthesis of nitric oxide and increased synthesis of endothelin 1, leading to vasoconstriction.³⁷ Endothelial dysfunction occurs across the stages of the menopause. In a cross-sectional study of 132 women, flow mediated dilatation (FMD) was assessed across different stages of menopause. The study found that declining endothelial function was seen in the early stages of menopause and worsened after loss of ovarian function and prolonged oestrogen deficiency.^{38 39} Declining ovarian function is associated with increased proinflammatory cytokines, such as IL-1, IL-6 and tissue necrosis factor alpha. The Women’s Ischaemia Syndrome Evaluation study demonstrated higher serologic T helper type 1 cytokines in premenopausal women with premature obstructive CAD.^{9 40}

Figure 1. Pathophysiological mechanisms. IL-1, interleukin 1; IL-6, interleukin-6; RAAS, renin angiotensin aldosterone system; TNF, tumour necrosis factor.

In addition to ageing and endothelial dysfunction, there are some genetic determinants that impact CAD in women. Although many susceptibility loci are shared between men and women, their phenotypic expression may differ according to sex.^{41 42} The distinction may be particularly relevant in female premature CAD, where genetic predisposition may interact with female-specific exposures, including hormonal changes during pregnancy and the MT.⁴³ This may reflect sex-specific biological mechanisms, potentially involving mitochondrial DNA variation or genes located on the X chromosome.⁴⁴

Incorporating menopause specific cardiovascular risk factors into routine cardiovascular practice

Clinical assessment including reproductive history

An important strategy for clinicians to improve cardiovascular outcomes in women is recognising menopause as a sex-specific period during which cardiovascular risk accelerates. Clinicians should incorporate a comprehensive reproductive history into a standard cardiovascular risk assessment. This would include recording the age of onset of menopause and determining if this was POI or early menopause both of which increase the risk of a woman developing CHD. They should also determine the type of menopause, whether this was natural or a surgical menopause. The latter causes a sudden cessation of estradiol which can lead to increased cardiovascular risk. Other important questions during the clinical assessment should include a history of adverse pregnancy associated outcomes (APOs) and details on current or previous hormone therapy. Collation of this data into electronic patient record can provide important information relevant to cardiovascular risk assessment.

APOs including gestational diabetes, preterm birth, placental abruption, small for gestational age and hypertensive disorders of pregnancy are increasingly recognised as female specific cardiovascular risk factors.⁴⁵ Women with APOs are at greater risk of CAD, stroke, heart failure, type 2 diabetes mellitus (T2DM) and hypertension.⁴⁶ The prevalence of APOs in women is almost 30%.⁴⁷ The AHA recognises the importance of identifying these APOs in the risk assessment of CVD, so as to identify women who may require more aggressive primary prevention for CVD.⁴⁵ APOs can have a long-lasting effect on CVD risk. The Swedish National Cohort Study found that women who experienced an APO had an increased risk of IHD up to 46 years after delivery.⁴⁸ This highlights the importance of regular follow-up and monitoring of CVD risk profile in this group.

Menopause-associated cardiometabolic changes for monitoring

Metabolic syndrome

Women who are in the MT should be monitored for changes in their cardiometabolic profile. Declining estradiol levels can lead to changes in the metabolic and vascular profile in women increasing CVD risk. Menopause has not been found to be independently linked to hypertension and increases in insulin or glucose beyond natural ageing. However, the prevalence of metabolic syndrome has been found to increase with the MT beyond the scope of natural ageing.⁸ A study of 32 959 women of which 5210 were postmenopausal concluded that postmenopausal women with metabolic syndrome had significantly higher risks of CVD. Women at early menopause or with elevated fasting glucose had the highest risk. The study highlighted the importance of early detection of metabolic syndrome in postmenopausal women.⁴⁹ The features of metabolic syndrome, such as increased glucose and insulin levels, central intra-abdominal body fat and changes in lipid profile, may be a direct result of ovarian failure or may be a consequence of central fat redistribution with a decline in oestrogen.⁵⁰

Dyslipidaemia

During the MT, there are many changes seen in lipid metabolism, namely a reduction in high density lipoprotein (HDL), an increase in LDL and an increase in TC and triglycerides. These lipid changes have a causal relationship with declining estradiol levels and age and are largely mediated by changes in lipid metabolism during the MT. The pathogenetic mechanisms include alterations of HDL cardioprotective properties, increases in proprotein convertase subtilisin/kexin type 9, LDL and lipoprotein A levels.⁵¹ These lipid changes, in turn, could be a risk enhancer for ASCVD. The Study of Women’s Health Across the Nation (SWAN) investigated metabolic changes in the HDL pathway using the cholesterol efflux capacity (CEC) as a surrogate marker. A high CEC would normally be cardiovascular protective in premenopausal women; however, during the MT a high level did not indicate cardiovascular protective properties. This would indicate HDL may be dysfunctional during the MT.⁵²

The role of lipid lowering medication in menopausal women has been evaluated in hyperlipidaemic postmenopausal women. The Beyond Endorsed Lipid Lowering with Electron-beam tomography Scanning study investigated intensive versus moderate statin therapy and evaluated CAC using electron-beam tomography. The study showed a greater reduction in LDL cholesterol levels with higher statin therapy but did not relate to CAC score.⁵³ Lipid lowering therapy is recommended to women who meet specific criteria for high cardiovascular risk or with familial hypercholesterolaemia. Despite these recommendations to implement lipid lowering therapy, women are less likely to be offered this treatment than men.⁵⁴

Hypertension

Blood pressure should be routinely monitored during the MT. The prevalence of hypertension increases during MT.⁵⁵ With vascular ageing, changes occur in endothelial function, arterial stiffness and activation of the RAAS.⁵⁶ Systolic blood pressure is lower in women than in men at younger ages, however the rate of increase in systolic blood pressure among women is much more rapid than in men as age increases.⁵⁷ This is likely due to overactivation of the RAAS. However, it remains unclear whether the menopause independently contributes to hypertension or if chronological ageing and adverse changes in body composition are primarily responsible.⁵⁸ The AHA Scientific Statement from 2020 on Menopause Transition and Cardiovascular Disease Risk highlights that hypertension is the most significant and modifiable CVD risk factor in women.⁸ Women often receive suboptimal management of their hypertension and therefore frequent monitoring of blood pressure during the MT may help to reduce the incidence of stroke and CVD.⁵⁹

Insulin resistance and diabetes

Changes in body shape are frequently seen in women during the MT with a more central distribution of body fat. Visceral fat is less sensitive to insulin and women going through the MT need assessment of their glycaemic control. Women with T2DM have a 25–50% greater risk of CVD compared with men with T2DM.⁵⁷ Insulin resistance is a risk factor for the development of T2DM and CVD. Metabolic syndrome, which has insulin resistance as one of its components, has been found to be linked to the MT and the development of CVD. Biological sex differences, mainly driven by female sex hormones such as oestrogen, have a protective effect on developing cardiometabolic disorders.⁶⁰ Oestrogen has a protective effect by maintaining the insulin sensitivity of the tissues. Insulin resistance is due to the inability to regulate the uptake of glucose by tissues. The European Prospective Investigation into Cancer and Nutrition InterAct study found that earlier age at menopause was associated with an increased risk of T2DM. The hazard of T2DM was 32% higher in menopause before the age of 40 than menopause at 50–54 years. This may be attributable to a shortened exposure to oestrogen.⁶¹

Weight gain

Weight gain is a well-established risk factor for the development of CVD. The MT is often associated with adverse changes in body composition and weight gain, with adipose tissue accumulating in the central and visceral areas of the body, and a reduction in lean muscle mass.^{62 63} The pathophysiology behind this change is uncertain; however, it has been hypothesised that normal ageing, a decline in oestrogen and behavioural factors all contribute to this.⁶⁴ The Framingham Heart Study found that an earlier age of menopause was associated with increased body mass index (BMI), waist circumference and overall obesity.⁶⁵ However, this was not replicated in the SWAN study which concluded that the MT does affect BMI, but other variables such as ethnicity and physical inactivity, may be more important factors.⁶⁶ A study of 3876 women found that women who had reached the menopause had 6% increased odds of central obesity compared with women who had not reached the menopause. The study concluded that menopause changes the central fat distribution in women.⁶⁷ The SWAN cardiovascular fat ancillary study found that late peri and postmenopausal women had more total heart adipose tissue than premenopausal and early perimenopausal women independent of other covariates.⁶⁸ These studies have confirmed that during the MT, there are changes in adipose fat tissue distribution, namely being more central and affecting the visceral organs.

Vasomotor symptoms

Vasomotor symptoms (VMS) are the most common symptom experienced by women throughout the MT. The British Menopause Society estimate that 70–80% of midlife women experience VMS.⁶⁹ It is important for clinicians to incorporate questions about VMS during cardiovascular risk assessment as they are a cardiovascular risk enhancer in women going through the MT. VMS consist of hot flushes and night sweats experienced primarily around the head, neck, chest and upper back.⁷⁰ The cause of VMS is not fully understood and is likely to be due to multiple factors. Reproductive hormones play an important role in the development of VMS.⁷¹ VMS are associated with risk factors predisposing to CVD such as hypertension, dyslipidaemia and diabetes. Certain risk factors such as obesity and smoking can predispose women to develop more frequent or severe VMS.⁷² Furthermore, subclinical CVD such as carotid intima media thickness, brachial artery FMD and aortic calcification have been linked to frequent and severe VMS.^{73 74} The SWAN study found that frequent and or persistent VMS increased the risk of fatal and non-fatal CVD events. The study evaluated 3083 women aged 42–52 years at baseline and found an association of frequent and persistent VMS with CVD events.⁷⁵ This provides further evidence that VMS are a sex specific cardiovascular risk factor in menopausal women. VMS develop due to overstimulation of the neurones involved in the thermoregulatory pathway during estradiol withdrawal. VMS have also been shown to affect autonomic nervous system cardiac control, alterations in the hypothalamic pituitary adrenal axis and changes to procoagulant profiles⁷⁶ (figure 2).

Figure 2. Cardiovascular risk factors during the menopausal transition. CVD, cardiovascular disease; HDL, high density lipoprotein; LDL, low density lipoprotein; MT, menopause transition; T2DM, type 2 diabetes mellitus.

Estradiol therapy is a longstanding treatment used for the management of VMS.⁷⁷ Although THM remains an effective treatment for VMS, it is not suitable for all women and non-hormonal therapies can play an important role in the management of VMS in this patient group. Among these, selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) are prescribed for the management of VMS. Currently, low dose paroxetine is the only US Food and Drug Administration (FDA) approved SSRI for the management of VMS. Other SSRIs and SNRIs can be prescribed off label for the same purpose.⁷⁷ Non-hormonal therapies proved a potential way to manage VMS in patients who are unable to or do not want to take hormonal treatment options.

The National Institute for Health and Care Excellence (NICE) guidelines recommend the use of fezolinetant 45 mg once daily as a non-hormonal treatment option for moderate-to-severe VMS when THM is unsuitable.⁷⁸ Fezolinetant is a neurokinin-3 antagonist and works via targeting hypothalamic neurokinin receptors that modulate thermoregulatory pathways.⁷⁷ Two major randomised control trials provided the evidence for the NICE recommendation, they concluded that fezolinetant was effective in reducing the frequency and severity of VMS compared with the placebo group.^79–81

Recent trials have investigated the use of a specific non-hormonal therapy, elinzanetant, to manage VMS. Elinzanetant is a dual neurokinin-1,3 receptor antagonist which works by targeting hypothalamic pathways responsible for thermoregulation.⁸² The OASIS 1 and 2 randomised control trials investigated the efficacy and safety of elinzanetant. They concluded that elinzanetant had a favourable safety profile and was effective in reducing VMS frequency and severity.⁸³ In July 2025 the Medicines and Healthcare products Regulatory Agency was the first regulator worldwide to approve the use of elinzanetant for moderate-to-severe VMS.⁸⁴ Since July 2025 elinzanetant has been approved in various areas worldwide. A recent review carried out an indirect comparison of elinzanetant to other non-hormonal treatments for the management of VMS and concluded that elinzanetant had favourable properties to other non-hormonal therapies such as paroxetine, fezolinetant, desvenlafaxine and gabapentin.⁸⁵ VMS are a risk enhancer for CVD and therefore non-hormonal therapies may be a potential therapeutic option to control this.

Hormone therapy for menopause and CVD

Current guidelines indicate a holistic approach and the use of THM to improve symptoms of the menopause.^{86 87} The Women’s Health Initiative (WHI) randomised control trial did not report a reduction in cardiovascular events with the use of THM but an increase in stroke and venous thromboembolism as well as breast cancer.^{88 89} These risks were associated with the use of conjugated equine oestrogen (CEE) with medroxyprogesterone acetate (MPA) in an older population, further from menopause than is typical for current THM initiation.^{90 91} Therefore, the results of the WHI should not be generalised to all THM regimes. This trial has caused uncertainty among clinicians in prescribing THM in the past despite current evidence indicating the valuable use of THM in certain patient groups.⁹⁰ THM replaces sex hormones that decline during the MT. The loss of oestrogen and progesterone hormones are associated with adverse vascular and myocardial changes.⁹² The timing of initiation of THM in relation to the onset of the MT is arguably crucial to its effectiveness in reducing CVD risk. The timing hypothesis is built on the theory that when oestrogen acts on a normal healthy blood vessel endothelium, commonly seen in younger women, it encourages the dilatation of the blood vessel via the production of nitric oxide and reduces inflammation. These positive effects are not necessarily seen when oestrogen therapy is used in older women. In women with advanced atherosclerosis the protective effects of oestrogen may be absent, instead there may be an increased risk of atherosclerotic plaque rupture and thrombotic event.⁹³ It has now been established that THM commenced within 10 years of onset of perimenopause has many health benefits without affecting CVD risk in patients under 60.⁶³ The 2015 Cochrane Review concluded that patients who started THM within 10 years of menopause had a lower mortality rate, lower CHD risk but an increased risk of venous thromboembolism (VTE) than others. In comparison patients who began THM more than 10 years post menopause had no change in mortality or CHD rate but an increased risk of stroke.⁹⁴ In a secondary analysis of the WHI, Rossouw et al concluded that in women aged 50–59 years of age, both CEE and CEE with MPA treatments were effective in reducing VMS without affecting ASCVD risk. However, this was not replicated in over 70 year old patients whose risk of ASCVD was increased.⁹⁵ These findings are in accordance with current guideline recommendations for the hormonal treatment of VMS.⁹⁶ The Early versus Late Postmenopausal Treatment with Estradiol randomised control trial which evaluated early versus late postmenopausal treatment with estradiol, involved 643 women and found that oral estradiol therapy commenced within 6 years of menopause was associated with less subclinical atherosclerosis than women randomised to the placebo arm. These results were not observed in women given THM 10 years post menopause.⁹⁷ In contrast, the Kronos Early Oestrogen Prevention Study randomised control trial, which investigated the use of THM among postmenopausal women, only found improvements in mood, hot flushes, sleep and bone mineral density. There was no signal to indicate a reduction in carotid intima medial thickness but interpretation of this study needs to be cautious as the populations were different in the two studies.⁹⁸ The Heart and Oestrogen/progestin Replacement Study included 2763 postmenopausal women and found that THM did not affect the primary outcome of non-fatal MI or CHD death.⁹⁹ THM has also been shown to reduce the risk of CVD in surgical menopause under the age of 50 years. In a pooled cohort of patients from the InterLACE study, women undergoing surgical menopause before the age of 50 who were taking HRT had a lower risk of CVD than women who were not using HRT.²⁴

The route of administration of sex hormone is important and can also influence CVD risk. Estradiol can be administered in two major forms, orally or transdermally. Oral estradiol has been associated with an increased risk of stroke or thrombotic event due to oral estradiol undergoing first-pass hepatic metabolism and activating the coagulation pathway. Transdermal estradiol avoids the hepatic first-pass metabolism therefore avoiding unwanted coagulation activation.^{100 101} Transdermal estradiol does not elevate a woman’s risk of VTE or stroke. Transdermal estradiol is recommended as first choice in women at risk of CVD or thrombotic event.¹⁰⁰ An important point to acknowledge and to consider when prescribing THM is use of systemic oral estradiol has been found to be associated with an increased risk of VTE.⁸⁸ A WHI Observational Prospective Cohort Study evaluated different types of estradiol and routes of administration. Oral estradiol was associated with a lower risk of stroke and transdermal estradiol was associated with a lower risk of CHD, but statistical power was limited in this study¹⁰² (table 1).

Table 1. Summary of THM trials.

Trial name	Sample size	Population	Type of THM	Comparator	Study design	Primary outcome	Follow-up	Main results
WHI Oestrogen plus Progestin89	16 608	Postmenopausal women with intact uterus, aged 50–79 years old	0.625 mg oral CEE plus 2.5 mg MPA	Placebo	Randomised controlled primary prevention trial	CHD (non-fatal MI and CHD death). Invasive breast cancer primary adverse outcome. Global index of risks.	Mean 5.2 years (trial terminated early due to safety concerns)	Health risks exceeded benefits. Oestrogen plus progestin should not be used for primary prevention of CHD, due to persistent adverse effects in CVD.
HERS99	2763	Postmenopausal women with intact uterus with established coronary disease, <80 years old. Mean age: 66.7 years	0.625 mg o-CEE plus 2.5 mg of MPA in one tablet daily	Placebo	Randomised, blinded, placebo-controlled secondary prevention trial	Non-fatal MI or CHD death.	Mean 4.1 years	No significant difference in non-fatal MI or CHD death between groups. No significant differences in secondary CVD outcomes.
KEEPS98	727	Healthy recently postmenopausal women (within 6 months to 3 years of natural menopause) Aged 42–58 years 80% non-Hispanic white	0.45 mg o-CEE or 50 µg t-E2. Both groups 200 mg micronised progesterone for first 12 days of each month.	Placebo	Randomised, double blinded, placebo-controlled trial	CIMT progression.	4 years	No significant difference in CIMT progression in either group. Oral oestrogen (p=0.43). Transdermal oestrogen (p=0.64).
ELITE97	643	Healthy postmenopausal women classified into <6 years (early post menopause) or >10 years (late post menopause)	Oral 17β-estradiol 1 mg per day plus 45 mg progesterone vaginal gel administered sequentially	Placebo	Randomised double blinded placebo-controlled trial	CIMT progression.	Median 5 years	Less CIMT progression in early post menopause group (p=0.008), no significant change to CIMT in late post menopause group (p=0.29)
WHI Estrogen-alone102	10 739	Postmenopausal women with prior hysterectomy, aged 50–79 23% minority race/ethnicity	0.625 mg CEE	Placebo	Randomised double-blinded, placebo-controlled disease prevention trial	CHD incidence (non-fatal MI or CHD death). Invasive breast cancer primary safety outcome. Global index of risks.	6.8 years (intervention phase of trial ended early)	Use of CEE increases risk of stroke, does not influence CHD incidence among this patient group.

CEE, conjugated equine oestrogen; CHD, coronary heart disease; CIMT, Carotid-Artery Intima-Media Thickness; CVD, cardiovascular disease; ELITE, Early versus Late Post Menopausal Treatment with Estradiol; HERS, Heart Estrogen/Progestin Replacement Study; KEEPS, Kronos Early Estrogen Prevention Study; MI, myocardial infarction; MPA, medroxyprogesterone acetate; o-CEE, oral conjugated equine estrogens; t-E2, transdermal 17β-estradiol; THM, Menopausal Hormonal Therapy; WHI, Women’s Health Initiative.

In addition, the choice of progestin influences cardiovascular risk. Micronised progesterone is often recommended and preferred in Europe due to the improved safety profile with regards to breast cancer, thrombotic disease and CVD risk compared with other forms of progestin. The choice of regime of THM should be tailored to the individual, taking into account CVD and breast cancer risk to formulate the safest approach for the patient.¹⁰³

A major development in THM was the FDA’s decision to remove black box labelling on THM products in 2025. Black box labelling was introduced in response to findings from the WHI and led to risk averse prescribing of THM due to concerns of complications such as breast cancer, thromboembolism, dementia and CVD.^{89 90} The decision to remove these labels was due to the information on the box labelling no longer being in line with current evidence on THM.⁹⁰ It has now been established that THM commenced within 10 years of onset of perimenopause has many health benefits without affecting CVD risk in patients under 60.^{90 104} The removal of the FDA box labelling has important future implications. It promotes a shift towards patient centred, individualised medicine that is influenced by factors such as type of hormone preparation, age and time since the MT.⁹⁰

The European Society of Cardiology Consensus Document has summarised potential benefits and risks for women on THM in relation to CVD following an extensive review of the literature.⁶³ These benefits included THM use in women under 60 years of age and within 10 years of menopause may reduce the risk of CVD; furthermore, the earlier the commencement of THM, the greater the benefit for cardiovascular health. Potential risks have been noted such as a slight increased risk of VTE with oral estradiol compared with transdermal. The risk of stroke is slightly elevated with oral estradiol therapy and THM is not recommended to women after a prior CVD event or women at high cardiovascular risk.

Clinical implications

Members of the public and healthcare professionals do not routinely acknowledge the importance of menopause on CVD. In this review, we have discussed the importance of detailing the reproductive history during cardiovascular risk assessment and potential modifiable risk enhancers for clinicians to monitor and treat appropriately. There is a movement to change this by NHS England with the recent addition of menopause-related questions to the NHS health check. This will provide an important risk assessment during the MT in addition to evaluating traditional risk factors for CVD. This approach aims to provide a window for early intervention and lifestyle modification to improve the health of menopausal women.

Regular physical activity, a balanced nutritional diet, smoking cessation, good blood pressure control and maintaining a healthy weight are key strategies to reduce the incidence of CVD. Recent research has shown that lifestyle modification can also have an impact on the development of CVD in sex-specific populations, such as women affected by menopause. The New South Wales prospective study involving 46 238 women aged 45 years or over found that lifestyle modification was associated with a consistent reduction in CVD.²¹ Furthermore, the SWAN study developed a Healthy Lifestyle Score (HLS) derived from self-reported data on smoking, diet and physical activity.¹⁰⁵ In a subsequent study, the SWAN investigators reported an association of the HLS and the development of subclinical ASCVD in menopausal women.¹⁰⁶ In addition, the WHI investigated the association of a Healthy Lifestyle Index (HLI) with CVD; those in higher HLI quintiles had a lower risk of CVD.¹⁰⁷ These studies highlight that in sex-specific conditions such as the menopause, there is a clear association between healthy lifestyle and the development of CVD. This underpins the need to raise awareness about risk factor modification in the public and healthcare professional domains.

Screening for CVD disease

Breast arterial calcification (BAC) assessment may provide a novel way of screening for patients at risk of CVD.⁵⁷ Currently, the NHS invites women for breast screening from the age of 50–53 years, and thereafter every 3 years up until the age of 71 years. BAC is commonly seen on mammograms but is not routinely reported to be an adverse clinical indicator. A single centre retrospective study involving 18 092 women quantified BAC using artificial intelligence and found that BAC was independently associated with mortality and CVD.¹⁰⁸ A cohort study of 5059 women also found that BAC was associated with an increased risk of ASCVD.¹⁰⁹ This work is hypothesis generating and could be a potential screening target to identify women at increased risk of CVD.

Gaps in knowledge and future directions

Risk stratification for menopausal women may be a mechanism for identifying women at risk of CVD. Analysis of the WHI randomised control trial concluded that CVD risk scores can be more effective in identifying postmenopausal women at higher risk of CVD than age or time since menopause. The clinical risk scores used in this study were the AHA/ACC and the Framingham Heart Study Risk Scores.¹¹⁰

Due to the lack of consensus from clinical trials and observational studies in reducing CVD risk with THM, it is currently not recommended for primary or secondary prevention of CVD. It is important to evaluate the pre-existing CVD risk in all women who are being considered for THM. One tool that is used to assess ASCVD risk is the 2013 ACC/AHA pooled cohort risk equation. This assesses the risk over 10 years of developing ASCVD in patients between the age of 40 and 79 years.¹¹¹ Patients who are considered intermediate risk or higher following the evaluation with the risk calculator may be advised to avoid THM.¹¹²

Risk prediction for ASCVD could include the assessment of factors such as family history of premature ASCVD, primary hypercholesterolaemia, high risk race/ethnicity, metabolic syndrome, abnormalities in lipid profile as well as other factors defined in 2019 AHA/ACC guideline on the prevention of CVD.¹¹³

A multidisciplinary team (MDT) approach can be used to provide specialist input for women at risk of CVD throughout the MT. This model of care is well established in chronic disease management and can help reduce disease-specific morbidity and mortality. A good example of the success of multidisciplinary care is a heart team approach to managing heart disease in pregnancy.¹¹⁴ A holistic approach of multidisciplinary care could involve various specialists such as cardiologists, gynaecologists, general practitioners, endocrinologists, physiotherapists, nurses and dieticians to help in the risk assessment, screening, identification and treatment of CVD in middle-aged women throughout their midlife course. The MDT team would acknowledge the importance of risk factor reduction and sex-specific differences in CVD risk and presentation.

The Journal of the American College of Cardiology expert panel has proposed a clinical practice model for screening and management of CVD among menopausal women. The four steps involve: (1) initial evaluation and menopause questionnaires; (2) ASCVD risk stratification and THM candidacy; (3) additional risk stratification for intermediate/high risk patients such as measurement of lipoprotein(a) levels and CAC scoring, and (4) defining high risk patients for THM.¹¹⁵ The expert panel also proposed more didactic and experiential menopause training for healthcare professionals involved in the management of women in the MT.

There are sex differences in the quality of care for patients with CVD. An example of this is that women are less likely to receive primary and secondary preventative therapy for CVD than men.^{116 117} To promote change and allow greater access to treatment and services to reduce CVD risk for women, there needs to be increased representation in the enrolment of women in cardiovascular research. This will help provide the evidence required to guide clinicians and other healthcare professionals in managing women at risk of CVD and reduce the burden of disease. Approaches such as broadening recruitment populations, creating accessible platforms and community recruitment can help to achieve this goal. A review of global burden of CVD in women highlighted the unmet need for clinical trials testing treatments in sex predominant CVD.¹

Conclusion

We propose that menopause specific cardiovascular risk factors are incorporated into the assessment of cardiovascular risk for women. The association of CVD and the MT is complex and multifactorial. As circulating oestrogen levels fall during the menopause, this leads to changes in the metabolic profile of women, lipid abnormalities, arterial stiffness, endothelial dysfunction and an increase in central obesity, which are risk factors for developing CVD. The role of THM in reducing CVD risk is not clear and therefore has not been adopted into current guidelines. It is clear that women going through menopause require close monitoring and risk assessment. Treatment strategies should include tight control of cardiovascular risk factors to prevent ASCVD. A focus on menopausal women in clinical trials can help address this and promote active investigation, diagnosis and treatment of cardiovascular risk factors ultimately reducing the CVD burden. Clinician and patient awareness of menopause specific risk factors during risk assessment is vital for the identification of women at risk of CVD. This approach is fundamental to reducing CVD in women.

Resources

This review has a particular focus on cardiovascular risk factors, hormone replacement therapy and clinical implications. A literature search was conducted using PubMed, Google Scholar and major cardiovascular journals. Searches contained combinations of key words and phrases.

Data availability statement

No data are available.