Interplay of menopause, coronary artery calcium score and cardiovascular disease risk

Abstract

BACKGROUND

Postmenopausal women face an increased risk of cardiovascular disease (CVD) due to estrogen withdrawal, which exacerbates traditional cardiovascular risk factors such as dyslipidemia, glucose intolerance, and hypertension. Coronary Artery Calcium Score (CACS), a well-established marker of subclinical atherosclerosis, has emerged as a key predictor of adverse cardiovascular events. Despite the recognized association between menopause and heightened CVD risk, there remains a paucity of literature exploring the specific role of menopause in influencing CACS and its implications for cardiovascular morbidity and mortality.

AIM

To examine the interplay between menopause, CACS, and cardiovascular health by synthesizing existing literature.

METHODS

A comprehensive literature search was conducted using PubMed and Google Scholar, focusing on studies that analyzed CACS in postmenopausal women, including the influence of factors such as hormone therapy, Triglyceride-Glucose index, bone mineral density, lipid metabolism, and type-1 diabetes. Data extraction and synthesis emphasized key patterns, metabolic influences, and potential mechanisms driving coronary calcification in menopause.

RESULTS

Findings suggest that menopause contributes to increased CACS through multiple pathways, including altered lipid metabolism, insulin resistance, and arterial stiffness. Additionally, premature menopause is associated with higher CACS and elevated CVD risk. While hormone replacement therapy (HRT) appears to have a protective effect against coronary calcification, further research is needed to clarify its long-term benefits and risks.

CONCLUSION

We introduce a novel framework combining CACS with metabolic and hormonal markers, and discuss estrogen-driven mechanisms and HRT considerations in postmenopausal cardiovascular risk. This review underscores the need for targeted cardiovascular risk assessment in postmenopausal women, integrating CACS with other metabolic markers to improve early detection and prevention of CVD in this high-risk population.

Key Words: Coronary artery calcium score; Menopause; Cardiovascular disease; Coronary artery disease; Coronary calcification; Postmenopausal

Core Tip: Our review critically examines an understudied interplay- menopause, coronary artery calcium score (CACS), and cardiovascular disease (CVD), highlighting estrogen withdrawal’s role in accelerating subclinical atherosclerosis. It analyzes current evidence on the role of metabolic dysregulation, bone mineral density, lipid shifts, insulin resistance, and triglyceride-glucose index as mediators of increased CACS. Given the rising global burden of CVD in aging female populations and the growing use of CACS, this review is especially timely in guiding risk assessment during the menopausal transition. Future research should focus on integrating CACS to traditional risk assessment tools for early CVD detection and prevention.

INTRODUCTION

Postmenopausal women are at an increased risk of cardiovascular disease (CVD), largely attributed to estrogen deficiency, which exacerbates traditional risk factors such as dyslipidemia, glucose intolerance, and hypertension[1]. Menopause is thus recognized as a significant contributor to the development of atherosclerosis and subsequent cardiovascular morbidity and mortality[2,3]. Emerging data also suggest that women who experience premature or early-onset menopause face even greater CVD risks[4].

The Coronary Artery Calcium Score (CACS) is a non-contrast, quantitative computed tomography (CT)-based measure of subclinical atherosclerosis and is well-established as a strong predictor of future cardiovascular events[5]. It offers a reproducible and objective method for assessing coronary atherosclerotic burden, particularly useful in asymptomatic individuals undergoing cardiovascular risk stratification[6]. While the predictive value of CACS for CVD is well documented, the extent to which menopause influences CACS—along with the downstream implications for cardiovascular outcomes—remains inadequately understood. Most of the available literature highlights its role as a CVD risk predictor but its correlation with menopause is relatively understudied

Several studies have begun to explore the interplay between menopause and coronary artery calcification. Estrogen deficiency is believed to influence vascular health through multiple pathways, including altered lipid metabolism, increased insulin resistance, endothelial dysfunction, and arterial stiffness[3,7]. Some evidence also suggests that hormone replacement therapy (HRT), particularly when initiated near the onset of menopause, may confer a protective effect by attenuating coronary calcification[8]. However, the long-term impact of HRT on cardiovascular outcomes remains controversial and requires further investigation.

Despite these insights, there is a lack of comprehensive evaluation of how menopause contributes to increased CACS and the associated risks of cardiovascular morbidity and mortality. This gap is partly due to the relatively recent adoption of CACS as a clinical tool and the limited availability of long-term, menopause-specific data.

This review explores the connection between menopause, CACS, and cardiovascular health by analyzing existing studies. A thorough search of PubMed and Google Scholar was conducted to find research examining CACS in postmenopausal women, considering factors like hormone therapy, the triglyceride-glucose (TyG) index, bone mineral density (BMD), lipid metabolism, and type 1 diabetes (T1DM). The findings focus on patterns, metabolic changes, and potential mechanisms that contribute to coronary calcification in postmenopausal women.

This narrative review aims to synthesize current evidence on the intersection between menopause, CACS, and cardiovascular outcomes. Specifically, it explores potential mechanisms underlying increased coronary calcification in postmenopausal women and evaluates the influence of factors such as hormone therapy, the TyG index, BMD, lipid metabolism, and T1DM.

MATERIALS AND METHODS

Literature search

A thorough literature search was conducted using the openly available databases of PubMed and Google Scholar. Keywords "Coronary", "Calcium", "Score" OR "Scoring", and "Menopause" OR "Post-Menopausal" OR "Menopausal" were used to identify relevant studies that examined the intersection of menopause, CACS, and cardiovascular risk. The search was limited to peer-reviewed studies available in PubMed and Google Scholar. Grey literature, preprints, and clinical trial registries (e.g., ClinicalTrials.gov) were not included, which may introduce a risk of publication bias.

Study selection

The search was restricted to articles published in English language. Studies were included if they provided data on CACS in relation to menopause and cardiovascular outcomes, including the impact of related factors such as hormone therapy, TyG index, BMD, low density lipoprotein (LDL), high density lipoprotein (HDL) metrics, and T1DM.

Data extraction

Data extraction focused on capturing study design, participant characteristics, menopausal status, CACS measurement techniques, and outcomes related to CVD risk. Additionally, information on the impact of factors such as the TyG index, hormone therapy, BMD, T1DM, and LDL, HDL metrics on the relationship between menopausal status, CACS, and CVD was also examined and represented in the tables.

Synthesis of data

The extracted data was reviewed to identify patterns, trends, and gaps in the literature regarding how menopause influences CACS and cardiovascular risk. Particular attention was given to the role of metabolic factors, the effect of hormone therapy, and the influence of comorbid conditions such as Type-1 diabetes on CACS in postmenopausal women.

RESULTS

Relationship between Menopause and CVD

CVD is the leading cause of both morbidity and mortality in adults globally[9]. The cessation of menstruation in females is accompanied by numerous changes in body composition that significantly increase the risk of developing CVD. Premenopausal women exhibit high levels of estrogen, which plays a cardio protective role in the body[9,10]. As women transition to menopause, their estrogen levels decline dramatically, leading to an accelerated onset of cardiovascular abnormalities. Consequently, the peak incidence of CVD in women occurs approximately 10 years later than in men[11]. A study conducted by Freaney et al[12] in 2021 further demonstrated an increased risk of CVD in women experiencing premature menopause, as it is associated with the accelerated development of unstable atherosclerotic lesions with age.

Pre-existing comorbidities, including a high TyG index[13], T1DM[14], hypertension[9], a higher androgenic hormone profile[15], and lower abdominal muscle mass[16], also are significant risk factors for the development of cardiovascular abnormalities in menopausal women. Additionally, disproportionate increases in certain HDL subclasses[17] and the presence of LDL-associated plaques[18], which tend to increase with age, contribute to the steep rise in CVD during menopause. Finally, age-related changes in other well-established cardiovascular risk factors, such as body mass index, body fat distribution, and the structural integrity of blood vessels, also play a role in the heightened incidence of CVD[9].

Role of CACS as a CVD risk marker

The development of CAC is a pathogenic process. It involves ectopic bone formation propelled by inflammatory, developmental, and metabolic factors. Transcription factors like Msx2, Runx2, Osterix, and Sox9 are important regulators and bone morphogenetic proteins are found in calcific arteries. Studies have shown a strong relationship between the presence of CAC and CAD[19].

Based on major single and multi-center studies, CACS has emerged as a reliable and effective method to measure the risk of cardiovascular events in asymptomatic patients. CACS is calculated by CT scans with 1 mm slices and the scans are taken at a specific point in the R-R interval, usually in the mid to late diastole[20] After CT scans, several methods exist to calculate the CACS including the Agaston method, calcium volume score, and relative calcium mass score. Agaston method has been used in multiple population-based studies. Individuals with no risk factors and a CAC of 0 have a very low probability of having significant luminal obstruction. A score greater than 400 correlates with a significantly increased risk of having a major cardiovascular event (MACE) in the future[20-22].

Several large studies including the MESA, CARDIA, and FHS have proven that CAC can reliably predict the risk of cardiovascular events as well as guide preventive therapy. Studies done by Martin et al[23] and Mitchell et al[22] demonstrated that patients with high CAC scores (i.e., ≥ 100) had event rates similar to those with prior CVD, and statins were found to be beneficial, similar to those who use them for secondary prevention. Similarly, studies done by Budoff et al[24] and Peng et al[25] demonstrated that high CAC scores (> 300 to 1000) had MACE rates similar to populations with prior CVD. Uddin et al[26] and Cainzos-Achirica et al[27] showed that CAC scoring helps identify groups that would benefit from aspirin and aggressive anti-hypertension therapy.

Various factors responsible for the interplay of Menopause, CVD, and CACS

TyG index: TyG index, a marker of insulin resistance, has emerged as a strong independent predictor of coronary artery disease and atherosclerotic CVD risk, which may have implications for identifying subclinical atherosclerosis in populations at risk[27], including postmenopausal women

A recent study by Gurbuz and Varis[13] examined the relationship between the TyG index and CACS in postmenopausal women. This study involved 228 women undergoing CT angiography for suspected acute coronary syndrome, with participants grouped by CACS: Under 100, 100-300, and over 300, representing mild, moderate, and severe calcification. The findings showed a significant correlation between TyG and CACS (correlation coefficient: 0.424, P = 0.001). Women with higher TyG values had more coronary calcification, especially those with elevated glucose levels or diabetes. Age, glucose levels, and diabetes were also significant predictors of higher CACS. Notably, the median TyG index was 9.3 in the group with the highest CACS, compared to 8.9 in the lowest group, reinforcing the link between metabolic factors and cardiovascular risk. The authors concluded that TyG, as a marker of insulin resistance, could serve as a non-invasive tool for assessing cardiovascular risk in post-menopausal women, thanks to its strong correlation with CACS. However, the study’s small sample size and short follow-up suggest that further research is needed to confirm its clinical utility alongside CACS for risk assessment. Although most studies demonstrate a positive correlation between TyG and CACS, variations in population size, metabolic comorbidities, and glycemic thresholds may explain inconsistencies across smaller cohort[28].

BMD: Recent research highlights the significant relationship between menopause and BMD. Menopause, particularly early menopause (before age 45), is associated with accelerated bone loss and increased fracture risk. A study by Shieh et al[29] found that each additional year after the final menstrual period is associated with lower postmenopausal lumbar spine (LS) and femoral neck (FN) BMD, and earlier menopause is linked to a higher fracture risk[28].

Changes in body composition during the menopause transition (MT) also play a crucial role. Shieh et al[30] demonstrated that lean mass decreases and fat mass increases during the MT, with lean mass loss being associated with lower BMD and higher fracture risk, while fat mass gain was associated with higher BMD but still increased fracture risk. Additionally, anti-Mullerian hormone (AMH) levels can predict future bone loss. Karlamangla et al[31] showed that lower AMH levels in pre-menopause and early perimenopause are associated with faster declines in BMD at the LS and FN. Furthermore, follicle-stimulating hormone (FSH) levels have been implicated in BMD changes. Park et al[32] found that higher FSH levels during menopause are inversely associated with BMD at the spine and hip, suggesting that both low estradiol and high FSH contribute to bone loss.

In summary, menopause significantly impacts BMD, with earlier menopause, changes in body composition, and hormonal fluctuations (AMH and FSH) being key factors influencing bone health. While lower BMD has consistently been associated with higher cardiovascular risk, some studies fail to find a direct relationship with CACS, possibly due to differences in calcification sites or imaging methods.

LDL: The association between menopause and LDL levels is well-documented in the literature, particularly through the SWAN Heart and HDL Ancillary Studies. The study by El Khoudary et al[18] found that during the MT, women experience significant increases in LDL subclasses, which are associated with greater carotid intima-media thickness (cIMT) and CAC prevalence. Specifically, higher total LDL particles (LDL-P) and apolipoprotein B were linked to greater CAC prevalence and cIMT. These associations were particularly notable during the perimenopause and postmenopausal stages.

Similarly, the study by Qi et al[19] demonstrated that small and medium-sized LDL particles (small-medium LDL-PC) were positively associated with cIMT, CAC, and aortic calcium in unadjusted models. Importantly, menopause status modified the association of small-medium LDL-PC with cIMT, showing a stronger relationship post-menopause.

In summary, these studies indicate that the menopausal transition is associated with increases in LDL subclasses, which are linked to subclinical measures of atherosclerosis, such as cIMT and CAC. This underscores the importance of monitoring lipid profiles in women undergoing menopause to better predict and manage CVD risk. These findings support the use of advanced lipid profiling for refined risk prediction during the menopausal transition.

HDL: HDL cholesterol is generally regarded to be athero-protective however, this effect seems diminished or even reversed in postmenopausal women[32]. The association between HDL cholesterol and increased CVD risk was particularly prominent in women who experienced menopause at an older age and were more than 10 years postmenopausal[33]. El Khoudary et al[34] examined the relationship between HDL metrics and CAC in women transitioning through menopause. While their study primarily focused on CAC, these findings are highly relevant to understanding CACS, as CACS quantifies the extent of CAC. The research highlighted that smaller HDL particles and reduced HDL size were linked to a higher likelihood of CAC presence, especially in late perimenopausal women, which could translate to higher CACS values. Conversely, larger HDL particles were associated with lower CAC density, indicating more stable plaque that may correspond to lower CACS.

These results suggest that traditional markers like HDL-Cholesterol may not fully capture CVD risk during menopause. A more detailed analysis of HDL subclasses and their relationship with CAC could provide deeper insights into CVD risk in post-menopausal women. This aligns with the broader focus on how hormonal and metabolic changes during menopause influence cardiovascular health, which is also reflected in CACS assessments[17].

T1DM: The rising incidence of T1DM and longer life expectancy are resulting in more women with the condition reaching menopause, highlighting the need to evaluate its impact on cardiovascular risk[34].

Research indicates that elevated CAC scores are linked to a higher risk of cardiovascular events in individuals with T1DM[35].

A study, Keshawarz et al[35], 2019, which followed premenopausal women with and without T1DM, for up to 18 years as they transitioned through menopause examined the resulting changes in cardiovascular risk. This study, part of the Coronary Artery Calcification in T1DM initiative, utilized CAC scores along with other cardiovascular risk factors to track these changes over time. The results showed that all women with T1DM had a CAC score greater than 0, regardless of menopausal status, and their baseline CAC volumes were significantly higher than those without diabetes. Moreover, the disparity in CAC volumes between the groups widened as women progressed through menopause. These findings remained significant even after adjusting for other cardiovascular risk factors.

Studies uniformly show elevated CACS in postmenopausal women with T1DM, though progression rates may vary by ethnicity and glycemic control. This consistency highlights T1DM as a high-priority subgroup for early imaging-based risk assessment.

Endogenous sex hormones: At menopause, there is a significant change in the endogenous hormonal milieu, marked by a decrease in estrogen and a relative increase in androgen levels, which can influence a woman's cardiovascular risk. Postmenopausal women with higher androgen levels tend to have an increased burden of CVD risk factors and a more adverse cardiovascular phenotype[36].

A study by Subramanya et al[15] found that a more androgenic hormone profile—characterized by higher levels of free testosterone and lower levels of sex hormone-binding globulin—was associated with greater CAC progression over a 10-year period in a cohort of postmenopausal women free of CVD at baseline. These associations remained significant even after adjusting for traditional CVD risk factors. Notably, the magnitude of these associations was greater in women who were not on HRT and appeared stronger in women aged ≤ 65 years.

One potential explanation is that elevated androgen levels in older women are associated with elevated blood pressure, insulin resistance, and metabolic syndrome. Additionally, beyond its influence on traditional risk factors, estrogen is thought to have a direct inhibitory effect on the coronary calcification process. This effect is mediated through its influence on vascular smooth muscle cells (VSMCs), bone macrophages, and matrix proteins, which are key components of the vessel wall[15]. These findings emphasize the importance of hormone profiling when evaluating cardiovascular risk trajectories in postmenopausal women.

Muscle mass: Muscle mass in women tends to decrease gradually after the 3^rd decade of life and shows an accelerated decline after the 5^th decade[37,38]. A cross-sectional study by Rolland et al[39] demonstrated a decline of 0.6% per year in muscle mass after menopause[38]. Furthermore, a large study of a middle-aged Korean population found that low relative muscle mass was associated with an increased prevalence of subclinical CAD and the degree of CAC in a dose-dependent manner.

Although there are limited studies directly measuring the relationship between muscle mass and CAC in postmenopausal women, a cross-sectional and longitudinal population-based cohort study by Wassel et al[16] reported that each SD greater total muscle area was associated with a 26% reduction in the rate of CAC progression (95%CI: -43% to -4%; P = 0.02) among Filipino postmenopausal women. However, this finding was not replicated in postmenopausal African American or non-Hispanic White women.

These findings suggest that muscle mass may play a critical role in cardiovascular health, particularly in certain ethnic groups, and underscore the need for further investigation into its potential impact on CAC in postmenopausal women[40].

Premature menopause and CACS: Recent research indicates that premature menopause is associated with an increased CACS. The study by Fonseca et al[41] from the ELSA-Brasil cohort found that menopause, particularly when occurring prematurely (before age 40), is independently associated with higher CACS. This association persists even after adjusting for traditional and nontraditional cardiovascular risk factors, suggesting that the hormonal decline associated with menopause may contribute to calcium deposition in coronary arteries. This highlights the importance of monitoring cardiovascular health in women who experience premature menopause[40]. However findings remain inconsistent, for example, Freaney et al[12] in the CARDIA cohort reported no link between premature menopause and CAC, whereas Fonseca et al[41] in ELSA-Brasil found an independent association. Differences in population age, ethnicity, and CACS measurement timing may explain these divergent results.

Hypertension: Blood pressure regulation exhibits notable sex-specific differences, with premenopausal women generally demonstrating lower blood pressure levels compared to men of similar age[41]. This phenomenon is multifactorial and mediated by mechanisms that include increased renin-angiotensin system activation[42,43], a higher prevalence of obesity[44,45], elevated plasma endothelin levels, and a decreased estrogen-to-androgen ratio, which highlights the protective effects of estrogen in premenopausal women[36].

The relationship between blood pressure and CACS in postmenopausal women, however, is complex. In a study by Allison et al[46], involving a subgroup of postmenopausal women from the WHI CEE clinical trial who were 50 to 59 years of age at baseline, an increase in systolic blood pressure (SBP) was associated with both the presence and extent of CAC. Conversely, higher diastolic blood pressure levels were associated with lower odds of CAC, suggesting that pulse pressure (PP) may play a significant role in CAC progression. After adjusting for multiple CVD risk factors, there was a significant trend indicating increased odds for CAC with higher PP levels. Specifically, a PP ≥ 55 mmHg was associated with a 2-fold higher likelihood of the presence of any CAC. In contrast, no significant association was observed between mean arterial pressure and CAC. These findings suggest that SBP and elevated PP may hold clinical relevance for the prevention of CAD in postmenopausal women.

Further evidence of this complexity is provided by another study, which found a positive association between hypertension and CAC in the control group (odds ratio: 2.09, 95%CI: 1.09-4.00). However, this association was not observed in women with primary ovarian insufficiency who experienced early menopause. These findings underscore the importance of considering distinct blood pressure parameters and specific patient subgroups when evaluating CVD risk in postmenopausal women[46,47]. The association between blood pressure and CACS is complex and varies by parameter—systolic, diastolic, or PP—underscoring the need for individualized targets within CACS-guided risk assessment.

DISCUSSION

We propose a conceptual framework where CACS is integrated with emerging hormonal and metabolic markers—such as the TyG index, HDL subclasses, and BMD—into existing risk assessment models. Such integration may enhance the predictive performance of widely used tools like the Framingham Risk Score[48] and the Atherosclerotic Cardiovascular Disease Pooled Cohort Equations[49], especially for midlife women whose traditional risk scores may underestimate risk. At the molecular level, Estrogen deficiency promotes vascular calcification through osteogenic transformation of VSMCs. Without estrogen, VSMCs express bone-related proteins such as Runx2 and BMPs, contributing to calcification[50]. Estrogen also supports inhibitors of mineralization, such as matrix Gla protein, and suppresses inflammatory cytokines like tumor necrosis factor-alpha and interleukin-6, which can enhance VSMC apoptosis and calcific nodule formation[50,51]. These mechanisms underscore estrogen’s protective role and the potential for targeted therapies to address coronary calcification in postmenopausal women. Estrogen-only HRT—commonly prescribed to women with prior hysterectomy—has been associated with a more favorable cardiovascular profile compared to combined estrogen-progestin therapy, which may increase the risk of thromboembolic events and stroke in certain populations[52-54]. The “timing hypothesis” posits that initiating HRT within 10 years of menopause onset or before age 60 may slow the progression of atherosclerosis by preserving endothelial function, whereas delayed initiation may accelerate existing vascular pathology[54,55]. While CACS thresholds such as ≥ 100 or ≥ 300 are widely used, evidence supporting sex-specific cutoffs is limited, and whether lower thresholds should apply to postmenopausal women remains uncertain. The MESA study and others have shown that individuals with CACS ≥100 have event rates similar to secondary-prevention populations, supporting statin use in this group, but data specific to women and HRT guidance remain sparse. Importantly, the heterogeneity in HRT formulations, doses, and patient populations has contributed to variability in outcomes across trials, underscoring the need for individualized clinical decision-making rather than universal recommendations. Integrating clinical insights with molecular understanding may help identify optimal windows for intervention and improve long-term outcomes in this high-risk population (Table 1).

Table 1 Chronological snapshot of 10 studies focusing on the relationship between menopause, coronary artery calcium score, and cardiovascular disease.

Ref.	Title	Year	Country	Objectives	Sample population	Conclusion
Gurbuz et al[13]	Correlation between coronary artery calcium score and triglyceride-glucose index in post-menopausal women	2023	Turkey	To clarify the correlation between CACS and TyG index in post-menopausal women	228	A high correlation was found between the TyG index and CACS (CC: 0.424, P = 0.001) in post-menopausal patients. In addition, patients with increased age, patients with higher glucose levels, and diabetic patients had significantly higher CACS
Cherukuri et al[10]	Coronary artery calcium and bone mineral density by serial CTA: Impact of menopausal hormone therapy	2022	United States	Both osteoporosis and CVD increase in women after menopause. Estrogen deficiency is thought to be an underlying mechanism for both these conditions	374	At baseline 374 women, 40 participants with CAC > 0 had greater decrements in BMD than the 334 participants with CAC = 0 at baseline, The average change in BMD in o-CEE group with CAC was -9.6 ± 13.3 vs -3.1 ± 19.5 in those with zero CAC, P = 0.0018
Chu et al[11]	CAC and atherosclerotic cardiovascular disease risk in women with early menopause: The multi-ethnic study of atherosclerosis	2022	United States	To determine the utility of CAC for atherosclerotic cardiovascular disease risk stratification in women with and without EM	2456	In MESA, > 50% of middle-aged postmenopausal women with EM had CAC = 0, similar to those without EM. Among women with CAC = 0, those with EM had a low to borderline 10-year risk of ASCVD, but the 15-year risk was significantly higher for women with EM vs those without EM. When CAC ≥ 1, the incidence of ASCVD was similar for women with and without EM. These findings support the use of CAC to help improve ASCVD risk stratification in women with EM
Fonseca et al[41]	Menopause and coronary artery calcium score: Results from the ELSA-Brazil study	2022	Brazil	To compare a broad cardio metabolic risk profile of women according to their menopausal status and investigated if menopause per se is associated with presence of CAC in the ELSA-Brasil study	2047	Associations of menopause with CAC, independent of traditional and nontraditional cardiovascular risk factors, suggest that hormonal decline per se may contribute to calcium deposition in coronary arteries
Freaney et al[12]	Association of premature menopause with coronary artery calcium: The CARDIA study	2021	United States	To determine whether premature menopause was associated with higher odds of CAC stratified by race	1785	Premature menopause was not associated with higher odds of any (> 0) or significant (≥ 100) CAC in mid-life compared with women without premature menopause. These findings suggest no difference in subclinical ASCVD as assessed by CAC in mid-life based on menopausal status. It is possible that CAC score alone does not fully capture plaque burden in women, as women may have a higher proportion of mixed and noncalcified plaques not well-identified by quantitative CAC testing
El Khoudary et al[17]	Associations of HDL metrics with CAC score and density in women traversing menopause	2021	United States	To test whether associations of comprehensive HDL metrics with CAC score and density vary by menopause stage or estradiol level in women transitioning through menopause	294	Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation
Nudy et al[55]	The severity of VMS and number of menopausal symptoms in postmenopausal women and select clinical health outcomes in the women's health initiative CaD randomized clinical trial	2020	United States	Evaluate whether VMS severity and number of moderate/severe menopausal symptoms were associated with health outcomes, and whether CaD modified the risks	20050	Severe vasomotor and multiple menopausal symptoms were linked to worse health outcomes; CaD supplementation had no effect
Keshawarz et al[35]	Type 1 diabetes and CAC progression over menopausal transition: The CACTI study	2019	United States	To examine whether risk of CVD changes differentially in women with and those without type 1 diabetes over the transition through menopause	636	Type 1 diabetes was associated with higher CAC volume and accelerated progression of CAC over time. Menopause increased CAC progression more in women with diabetes than in women without diabetes independent of age and other CVD risk factors known to worsen with menopause
Subramanya et al[15]	Endogenous sex hormone levels and CAC progression in post-menopausal women	2018	United States	To study whether sex hormone levels were associated with CAC progression among women in the multi-ethnic study of atherosclerosis	2759	A more androgenic hormone profile of higher free testosterone and lower SHBG is associated with a greater CAC progression up to 10-years in post-menopausal women. Sex hormone levels may help identify women at increased risk for CVD who may benefit from additional risk-reducing strategies
Wassel et al[16]	Abdominal muscle area and CAC change by ethnicity in post-menopausal women	2015	United States	To examine the association of abdominal muscle area with CAC) presence, extent, and progression in a multi-ethnic cohort of older, community-dwelling post-menopausal women	439	There was a significant interaction of ethnicity with baseline oblique muscle area, and marginally significant interactions with baseline total and paraspinal muscle for change in CAC. Among Filipina women, each standard deviation greater total muscle area was associated with a 26% reduced rate of change in CAC; higher paraspinal and oblique muscle area were associated with a 24% and a 37% reduced rate of change in CAC, respectively

CACS: Coronary artery calcium score; TyG index: Triglyceride-glucose index; BMD: Bone mineral density; CTA: Computed tomography angiography; EM: Early menopause; ASCVD: Atherosclerotic cardiovascular disease; CAC: Coronary artery calcium; VMS: Vasomotor symptoms; CaD: Calcium and vitamin D; CVD: Cardiovascular disease; SHBG: Sex hormone-binding globulin.

This review has several limitations. First, heterogeneity in study populations, menopausal definitions, and follow-up durations may affect comparability across studies. Second, variability in CACS measurement methods—such as Agatston, volume, and mass scoring—introduces challenges for cross-study interpretation. For example, a CACS of 100 calculated using the Agatston method may not correspond to the same atherosclerotic burden as a score of 100 derived from volume scoring. This methodological variability complicates threshold-based risk categorization and may partly explain inconsistencies across studies. Finally, most available studies are cross-sectional, involve modest sample sizes, and lack sex-specific subgroup analyses, which limits causal inference and generalizability.

CONCLUSION

Menopause accelerates CVD processes through estrogen withdrawal, contributing to lipid abnormalities, insulin resistance, increased arterial stiffness, and systemic inflammation seen in postmenopausal women. These changes, combined with additional factors such as hypertension, T1DM, and variations in muscle mass, significantly influence CACS and overall cardiovascular health. The association between menopause, CACS, and CVD risk highlights the critical need for improved screening and prevention strategies in postmenopausal women.

CACS has emerged as a reproducible and quantitative marker of subclinical atherosclerosis and can be used as a reliable tool for assessing burden of CVD associated with menopause. Extensive research demonstrating its utility in risk stratification and predicting future cardiovascular events. Large-scale studies such as MESA, and CARDIA have confirmed its predictive value, particularly in populations with high-risk profiles.

Despite significant advancements, gaps remain in understanding the precise mechanisms linking menopause and CACS progression. Future research should focus on longitudinal studies evaluating the interplay between hormone therapy, metabolic factors, and lifestyle interventions to mitigate cardiovascular risk. Addressing these gaps will provide a more comprehensive approach to cardiovascular prevention and management in postmenopausal women, ultimately improving long-term outcomes.