Cardiovascular Risk Associated with Menopause and Menopause Hormone Therapy: A Review and Contemporary Approach to Risk Assessment

Abstract

Purpose of Review

Discuss the effects of menopause and menopause hormone therapy (MHT) on cardiovascular risk, and propose a structured, person-centered framework for cardiovascular risk assessment when initiating MHT.

Recent Findings

The risk of atherosclerotic heart disease accelerates during the menopause transition due to hormonal, metabolic, and vascular changes. Both menopause and MHT affect cardiovascular risk factors (i.e. blood pressure, lipids, insulin resistance) and cardiovascular events (i.e. myocardial infarction and stroke). Early clinical trial evidence demonstrated that oral synthetic MHT, including conjugated equine estrogen (CEE) with medroxyprogesterone acetate (MPA), is associated with increased coronary heart disease and stroke risk, particularly in older, postmenopausal women. Contemporary formulations such as low-dose transdermal estrogen and micronized progesterone have lower cardiovascular risk. A personalized assessment when initiating MHT should consider age, time since menopause, baseline cardiovascular (CV) risk, and choice of MHT formulation. Assessment of baseline CV risk should include a comprehensive review of traditional CV risk factors and consideration of risk-enhancing factors (including female-specific risk factors) and imaging for subclinical atherosclerosis (i.e. coronary artery calcium scoring) to provide a person-centered risk assessment.

Summary

Menopause is an important period to implement prevention strategies to reduce future incidence CVD. A structured, individualized approach that accounts for the timing, formulation and delivery of MHT can optimize cardiovascular safety. This review provides a framework for personalized decision-making and highlights the need for further research to clarify MHT’s impact on long-term CV outcomes.

Graphical Abstract

Visual Model of Cardiovascular Risk Factors Influencing Menopausal Hormone Therapy Decisions. This conceptual figure displays the intersection of cardiovascular and reproductive health during menopause. Radiating outward are key cardiovascular risk factors influenced by both menopause and menopausalhormone therapy (MHT), including blood pressure, lipid profile changes, insulin resistance, adiposity, coronary artery calcium (CAC), carotid atherosclerosis, Lp(a), and lifestyle behaviors. This visually integrated model highlights the need for individualized, risk-stratified assessment when considering MHT, with attention to as many of these factors as possible. Created in BioRender. D’Costa, Z. (2025)

Introduction

Cardiovascular disease (CVD) is the leading cause of death in women [1, 2]. Many women develop coronary artery disease (CAD) later than men, typically during midlife, with 60% of women nationally seeking care for cardiac conditions at this stage [2, 3]. Menopause represents a pivotal physiologic transition, commonly accompanied by symptoms that prompt a significant number of people to seek clinical care. These encounters offer a critical window for comprehensive cardiovascular risk assessment and preventive interventions to mitigate long-term risk. Menopause induces a constellation of hormonal, psychosocial, and physiologic changes – including vasomotor symptoms, sleep disturbances, mood changes, and metabolic shifts – that can negatively impact quality of life and accelerate risk for future CVD [4, 5]. Worsening cardiovascular (CV) risk factors inherent to the menopause transition promote vascular vulnerability and likely accelerate atherosclerosis [4]. Therefore, the menopause transition is an important window of opportunity for implementing strategies to prevent cardiovascular disease.

Historically, menopause hormone therapy (MHT) has been used to alleviate menopause symptoms, though its oral synthetic formulations were associated with increased CV events, including coronary heart disease (CHD) and stroke, in older postmenopausal women [6]. Contemporary data on transdermal estrogen and micronized progesterone MHT formulations have been shown to have lower cardiovascular risks than oral and synthetic formulations, particularly in younger women [7]. This review aims to discuss the accelerated atherosclerotic risk seen during the menopause transition, highlight the key trial findings on the impact of MHT on cardiovascular disease, and propose a comprehensive, person-centered approach for evaluating cardiovascular risk when initiating MHT. This framework integrates evaluation of both modifiable and non-modifiable CVD risk factors, including universal screening for elevated lipoprotein(a) [Lp(a)] levels, recognition of female-specific CVD risk-enhancers, and leveraging vascular imaging to screen for subclinical vascular disease to support an individualized risk stratification.

Menopause and MHT Effects on Cardiovascular Risk

While the risk for atherosclerotic cardiovascular disease (i.e. myocardial infarction and stroke) increases with aging, there is an accelerated increase in the incidence of CVD after menopause [8, 9]. The use of MHT for managing menopausal symptoms has a complex relationship with several risk factors for atherosclerosis. Key risk factors and MHT effects include (Table 1):

Table 1.

Effects of menopause and menopausal hormone therapy on cardiovascular risk factors: A summary of clinical and metabolic changes

Risk Factor	Effect of Menopause	Effect of MHT
Blood Pressure (BP)	- Systolic BP ↑ 4–7 mm Hg - Diastolic ↑ 3–5 mm Hg - Accelerated age-related BP ↑	- Oral estrogen ↓ SBP by 1–6 mm Hg - Combined therapy ↑ SBP - Transdermal estrogen ↓ DBP by up to 5 mm Hg
Weight, Adiposity, and BMI	- ↑ Visceral and pericardial fat - ↑ BMI and waist circumference linked to CHD and mortality	- Modest ↓ visceral fat - ↓ BMI (~ 1 kg/m²) - Preserves lean tissue mass
Insulin Resistance	- ↑ Insulin resistance (OR 1.40–1.59) - ↑ HbA1c by ~ 5%	- ↑ Insulin sensitivity - ↓ HbA1c by up to 0.6% - ↓ Fasting glucose by ~ 20 mg/dL
Lipid Profile Changes (HLD)	- ↑ total cholesterol (10–14%) - ↑ LDL (10–20 mg/dL) - ↑ApoB (8–15%) - ↑ Initially, then ↓ HDL	- ↓ LDL (9–18 mg/dL) - ↑ HDL - Transdermal estrogen is more favorable for triglycerides (less elevation than oral) - No overall CVD risk ↓
Lipoprotein(a) [Lp(a)]	- ↑ by ~ 25% during menopause - ↑ ASCVD risk with Lp(a) > 50 mg/dL - ↑↑ ASCVD risk with Lp(a) > 100 mg/dL (doubled)	- ↓ Lp(a) by 20–30%, oral > other forms - Does not ↓ CVD events
Coronary Artery Calcification (CAC)	- ↑ CAC scores (OR 2.37) Mean CAC = 53	- Oral estrogen ↓ CAC - Transdermal may↑ CAC
Carotid Atherosclerosis	- ↑ CIMT progression - Independent predictor of stroke and CHD	- Early initiation may slow CIMT - No benefit with lower dose or delayed start
Physical Activity, Smoking, and Diet	- ↓ Physical activity - ↓ Dietary quality - No change in smoking status	- No direct effect on physical activity, diet, or smoking habits
Myocardial Infarction (MI) Risk	- ↑ MI risk (accumulation of other CV risk factors)	- CEE + MPA formulation ↑ MI risk (HR 1.29) - Transdermal formulation is safer
Stroke Risk	- ↑ Ischemic stroke risk (HR 1.1–2.0) - ↑↑ in early-onset menopause	- Oral estrogen ↑ stroke risk (~ 40%) - Transdermal < 50 mcg is safer - Risk unaffected by initiation timing

Table 1. Summary of Cardiovascular Risk Factors Affected by Menopause and Menopausal Hormone Therapy (MHT). This table outlines key clinical, laboratory, and imaging-based risk factors associated with menopause, along with the corresponding effects of MHT. Menopause contributes to worsening of blood pressure, central adiposity, insulin resistance, lipid profiles, and subclinical atherosclerosis as measured by CAC and CIMT. MHT demonstrates variable effects depending on formulation and timing, with oral estrogen often improving lipid profiles and Lp(a) levels, but without a clear reduction in cardiovascular events. Transdermal formulations tend to have more favorable effects on blood pressure and metabolic risk, though stroke and thrombotic risks remain formulation- and dose-dependent.

Vital Signs

• Blood Pressure (BP): Blood pressure tends to increase during menopause. Systolic BP (SBP) increases by 4–7 mm Hg and diastolic BP (DBP) increases by 3–5 mm Hg on average during menopause [10–15]. High blood pressure is the leading preventable risk factor for stroke and myocardial infarction [10–15]. Age-related rises in blood pressure accelerate during menopause [16]. Oral estrogen therapy can lead to minor reductions in SBP by about 1–6 mm Hg [17–20]. However, when combined with progesterone, it leads to small increases in SBP. Transdermal therapy can have neutral or beneficial effects by decreasing DBP up to 5 mm Hg [21, 22].

• Weight, Adiposity, and Body Mass Index (BMI): While increased weight and BMI are not independently linked to menopause, accelerated visceral adipose tissue and pericardial fat deposition are associated with the loss of ovarian function during menopause [12, 23–25]. Many women in the age range for menopause have an age-adjusted elevated prevalence of obesity compared to younger women. Post-menopausal women with elevated BMI (≥ 40), waist circumference of greater than 115.5 cm (compared with < 108.4 cm), and central adiposity have increased CHD, heart failure, and mortality [26–28]. Several studies have shown that MHT causes minimal weight gain and is associated with a modest reduction in total and visceral adiposity, smaller waist circumference increases, and lower BMI (approximately 1 kg/m²) compared to no therapy [29–32]. Additionally, MHT preserves lean soft tissue mass that can attenuate the shift toward central adiposity seen after menopause [2].

Laboratory Values

• Insulin Resistance: Menopause often coincides with worsening cardiometabolic health, including insulin resistance and new-onset diabetes, contributing to heightened cardiovascular risk. One study found that post-menopausal women had higher fasting hemoglobin A1c levels by 5% compared to premenopausal women [33]. In one Japanese study, the effects of natural and surgical menopause on insulin resistance were investigated, and the odds ratios (OR) were 1.40 and 1.59, respectively, compared with premenopausal women [34]. MHT can reduce insulin resistance in postmenopausal women when initiated within the early onset of menopause but it depends on the dose and formulation [2, 35, 36]. Meta-analyses have shown that MHT reduces HbA1c (up to 0.6%) and fasting glucose (about 20 mg/dL), as well as improves glucose regulation in women with type 2 diabetes [37].

• Lipid Profile Changes and Hyperlipidemia (HLD): Menopause independently leads to adverse changes in lipid profiles, including elevating total Cholesterol by 10–14%, low-density lipoprotein (LDL) Cholesterol by 10–20 mg/dL or 14–19%, and apolipoprotein B (Apo(B)) levels by 8–15% rather than as a result of aging alone [12, 38–43]. High-density lipoprotein cholesterol (HDL) peaks during peri- and early menopause before declining later in life [38–47]. High HDL in menopause appears to correlate with increased carotid atherosclerosis, the inverse impact seen in the pre-menopause state [5, 48]. It is postulated that the HDL particle’s intrinsic antioxidant and antiatherogenic function weakens during menopause [48, 49]. Overall, menopause is associated with the development of a more atherogenic lipid profile. Oral MHT reduces LDL (by 9–18 mg/dL) and raises HDL, but can raise triglycerides [32, 50, 51]. Transdermal estrogen formulation MHT have less of an effect on triglycerides and LDL [50]. Despite the benefits of MHT on LDL, MHT does not translate to reduced overall CVD risk.

  • Lipoprotein(a): Lp(a) is six times more atherogenic than LDL on a per-particle basis. Elevated Lp(a) (> 50 mg/dL) is associated with an increased 10-year atherosclerotic cardiovascular disease (ASCVD) risk, and the cardiovascular risk of Lp(a) is directly correlated with the degree of Lp(a) elevation [52, 53]. Lp(a) levels are 5–10% higher in women than in men [54]. Across the lifespan, Lp(a) levels are relatively stable in men, while women have an increase in Lp(a) during menopause by approximately 25% [55, 56]. Approximately 90% of Lp(a) levels are determined by genetic factors, but they can also be influenced by diet and hormones [55]. Estrogen use for menopause (both oral and transdermal formulations) has been shown to lower Lp(a) by 20–30%, though this decrease in Lp(a) does not translate to decreased CVD risk [31, 57–59]. This paradox is poorly understood, and further research on the cardio-prognostic effects of Lp(a) lowering is warranted.

Imaging

• Coronary Artery Calcification (CAC): Increased CAC scores indicate subclinical atherosclerosis and predict future CV events [60, 61]. CAC scores are computed by noninvasive imaging with coronary CT to quantify calcified atherosclerosis burden in the coronary arteries. It can provide robust short- and long-term risk stratification. It can be useful for to further refine ASCVD risk estimation when deciding whether to initiate primary prevention statin therapy. A higher CAC score indicates higher CVD risk in both men and women. A calcium score of zero has a strong negative predictive value for short-term ASCVD events [62]. For context, CAC scores of 1–99 Agatston units carry a 10-year ASCVD risk that varies by age (3.8% for ages 45–54, 6.5% for ages 55–64, and 8.3% for ages 65–74), suggesting moderately increased atherosclerosis risk that can be addressed in an individualized manner [63]. However, CAC scores greater than or equal to 100 Agatston units have a higher 10-year ASCVD risk of more than 7.5%, the widely accepted threshold for initiating statin therapy, regardless of demographic subset, due to a more significant atherosclerosis burden [63]. Additionally, the American College of Radiology (ACR) Guidelines indicate that the estimated 5-year number needed to treat (NNT) for statin therapy to prevent an coronary event is 549 in patients with zero CAC versus 42 in patients with nonzero CAC [64]. Furthermore, those with a CAC score ≥ 100 and elevated Lp(a) appear to be at higher ASCVD risk than those with a similar CAC score (≥ 100) but normal Lp(a). This data supports that CAC scoring can further define ASCVD risk in those with elevated Lp(a) and help guide primary prevention strategies [65]. Menopause is associated with an elevated CAC ≥ 0, with an OR of 2.37 [66]. According to the Healthy Women Study, a mean CAC score of 53 was reported in post-menopausal women [67, 68]. The degree of CAC has been shown to increase significantly around the menopause transition and indicate subclinical atherosclerosis and CVD risk. For example, women with Type 1 diabetes have been shown to have an approximately 75% increase in CAC volume after menopause, compared to premenopausal values [69]. Therefore, CAC testing should be considered when assessing CV risk in women during menopause. There has been conflicting data on the overall effect of MHT on CAC. In the Women’s Health Initiative (WHI) study, it was found that oral estrogen lowered CAC compared with placebo [70–72]. However, in the Kronos Early Estrogen Prevention Study (KEEPS) study, different types of MHT formulations were tested, and found that synthetic or conjugated equine estrogen (CEE) improved epicardial adipose tissue progression, which is linked to CAC deposition, but that transdermal MHT was linked to increasing CAC progression [73].

• Carotid Atherosclerosis: Carotid intima-media thickness (CIMT) is a marker of subclinical atherosclerosis. CIMT is measured using ultrasonography, and elevated CIMT is an independent risk factor for stroke and coronary artery disease [74]. For example, the Atherosclerosis Risk in Communities (ARIC) trial found that increased CIMT (≥ 1.0 mm) had a higher risk of MI and CHD (HR 2.62 in women and 1.20 in men) [75]. CIMT increases at an accelerated rate during late perimenopause [60]. Therefore, CIMT testing can be used to assess patients’ CVD and stroke risk during menopause. While some data suggest benefit of MHT on CIMT progression when initiated early within the perimenopausal period (within 6 years of onset), this effect is not consistently seen in clinical trials [2, 76].

Lifestyle

• Physical Activity, Cigarette Smoking, and Healthy Diet: These factors are all important components of cardiovascular health for women in the menopausal transition. Data from the Study of Women’s Health Across the Nation (SWAN), a prospective, observational study of women during midlife, found that a healthy lifestyle (including abstinence from smoking, healthy diet, and engagement in regular physical activity) during the menopause transition was associated with less subclinical atherosclerosis later in life [77]. These data emphasize the importance of encouraging a healthy diet, regular physical activity, and avoiding smoking during the menopause transition [78–80].

Overall CV Risk

• Myocardial Infarction (MI) Risk: Menopause increases the risk of MI due to the accumulation of CV risk factors already discussed. MHT, particularly with synthetic formulations of estrogen and progesterone, increases the risk for MI in the general population but may decrease risk when initiated closer to the onset of menopause (before the age of 60 and within 10 years of menopause onset) (HR 1.29, 95% CI 1.02–1.63) [2, 6, 72]. Natural MHT (i.e. estradiol and micronized progesterone) and transdermal estrogen formulations have been shown to have a lower risk of MI than synthetic formulations.

• Stroke Risk: Menopause increases the risk of stroke, especially when menopause occurs early (before the age of 45), with a hazard ratio of 1.1 to 2.0 [2, 81, 82]. Both oral estrogen-only and combined MHT increase ischemic stroke risk as demonstrated by the WHI trial. Transdermal estrogen, especially at doses < 50 mcg, appears to have lower stroke risk based on observational data. The risk of stroke remains elevated no matter the timing of initiation of oral MHT [6, 81, 83].

Types of MHT, Delivery Methods, and CVD Risk

MHT is a tool that providers may use to address some of the symptoms of menopause that may negatively impact patients’ quality of life. The formulation and delivery of MHT significantly influence its risk profile for CVD, including venous thromboembolism, stroke, and CAD. There is significant literature, including large, randomized controlled data, that assesses the vascular risks of oral MHT formulation. Most literature on transdermal MHT formulation is based on an observational study.

• Systemic Estrogen and Progesterone: Combined MHT (estrogen and progesterone) carries a higher CVD risk than estrogen-only MHT [70], suggesting that progesterone plays a role in adverse outcomes, including elevated stroke and venous thromboembolism risk with elevation of very low density lipoprotein (VLDL) and C-reactive protein (CRP) [84]. Medroxyprogesterone acetate (MPA) has been shown to attenuate the beneficial LDL-lowering effects of estrogen [85]. A seminal study discussed later in this review, the WHI, also found that CEE and MPA, both synthetic forms of estrogen and progesterone, respectively, demonstrate elevated CVD risk in older postmenopausal women, though prescription of synthetic hormones has fallen significantly out of favor due to their overall increased CVD risk [6, 70, 71, 86]. Women who possess a uterus require progesterone to mitigate the risk of endometrial hyperplasia with unopposed estrogen. Oral estrogen has been found to decrease LDL by 15–19%, increase HDL by 16–18%, and increase triglycerides by 24–42% [87]. Additionally, oral estrogen has favorable effects on insulin resistance and blood pressure [85]. Estrogen has been shown to lower CAC progression (OR 0.78, 0.74, and 0.69 for CAC scores of 0, 10 or more, and 100 or more, respectively) [71]. However, despite these benefits on individual risk factors, estrogen has not been shown to have an overall reduction in cardiovascular events and has been shown to have significant thrombotic risks [85].

  • Timing of Initiation: Women who are initiated on systemic MHT closer to the onset of menopause have been found to have less CHD risk than those more than 10 years from menopause [85].

• Dose Dependent Relationship: Lower dose estrogen dosing (0.5 mg oral estradiol) compared with conventional or high dose estrogen (1–2 mg oral estradiol) has lower cardiovascular risk [88].

• Natural vs. Synthetic Estrogen: There appear to be higher risks of venous thromboembolism (VTE) and possible MI with synthetic estrogen (CEE, ethinyl estradiol) compared with natural estrogen (estradiol) use [88–90].

• Natural vs. Synthetic Progesterone: Older synthetic progesterone formulations (MPA, Norethindrone acetate, levonorgestrel, drospirenone), as used in the WHI and Heart and Estrogen/Progestin Replacement Study (HERS) studies, can lower HDL by 8–18%. Natural progesterone (micronized progesterone), in contrast, has a neutral impact on HDL. Natural progestin also had a lower VTE risk compared with synthetic progestin [85, 89, 91].

• Bioidenticals (Natural): Bioidentical hormones are derived from plant extracts and are modified to be structurally identical to endogenous estrogen (such as estradiol and micronized progesterone). In society, when referencing bioidentical hormones, people may be referring to custom-compounded, multi-hormone regimens that are dose-adjusted based on serial hormone levels. Compounded bioidentical hormone therapy (cBHT) has variability in quality, consistency, and relatable dosing. CBHT also lacks rigorous quality control, which can affect potency, purity, and absorption, leading to inconsistent therapeutic effects and possible safety concerns. Similarly, no significant clinical data support the efficacy or long-term safety of cBHT [92]. Therefore, the Menopause Society, American College of Obstetricians and Gynecologists, and Endocrine Society advise against cBHT. Furthermore, pellet formulations are not advised due to unpredictable bioavailability [92].

• Transdermal Estrogen: Transdermal formulations are associated with lower thrombotic and stroke risks compared to oral estrogen, making them a preferred option for patients with dyslipidemia or hypertriglyceridemia, but have no direct effect on coronary atherosclerosis [89]. However, these findings are based on smaller observational studies because, to date, no direct randomized control trial (RCT) compares oral and transdermal therapy to stroke/VTE risk. There is a dose-dependent relationship in transdermal estrogen prescription as well, and lower dose formulations should be pursued to minimize CVD risk.

• Vaginal Estrogen Therapy: While oral and transdermal MHT address vasomotor symptoms given systemic effects, vaginal estrogen therapy addresses genitourinary symptoms including vulvovaginal atrophy, painful intercourse, and frequent urinary tract infections. Low-dose vaginal estrogen therapy is most effective for these symptoms which typically increase as patient’s increase with age after menopause. Vaginal estrogen therapy has minimal systemic absorption and therefore is not associated with heightened cardiovascular risk, and as a result may be useful for patients with contraindications for systemic MHT [90–93].

Clinical Trials and Evidence on MHT and CVD

The trials below represent the key literature in understanding the history of MHT on cardiovascular risk.

• Women’s Health Initiative (WHI): WHI studied the primary prevention of MHT and found increased CVD events in older women randomized to MHT [70]. This study was a large-scale, multi-center, RCT that enrolled 161,808 postmenopausal women aged 50–79 from 1993 to 1998 across 40 centers in the USA and tested MHT on 27,347 patients. This was an older, postmenopausal population, with a mean of 63 years, with the majority enrolled greater than 10 years since menopause, and did not have vasomotor symptoms [94]. The two main hormonal interventions included (1) oral CEE (0.625 mg/day) + MPA (2.5 mg/day) vs. placebo, and (2) oral CEE (0.625 mg/day) alone in women who had undergone prior hysterectomy vs. placebo. Primary outcomes were coronary heart disease and invasive breast cancer, with secondary outcomes including stroke, pulmonary embolism (PE), colorectal cancer, endometrial cancer, hip fracture, and death from other causes. Notably, in those treated with CEE + MPA, there was an increased risk of CHD (HR 1.29, 95% CI 1.02–1.63) and stroke (HR 1.41, 95% CI 1.07–1.85). Further subgroup analysis also demonstrated who with higher LDL had higher CHD risk while on CEE + MPA. Subgroup analysis of the CEE + MPA groups showed that the increased CHD risk was seen primarily in those who were older and further from the menopause transition (≥ 10 years from menopause). Stroke risk similarly increased with age in those treated in CEE + MPA, however, the stroke risk remained elevated across age groups, including those near menopause [72, 95]. In contrast to those treated with CEE + MPA, those treated with CEE alone did not have increased CHD risk (HR 0.94, 95% CI 0.78–1.14), but increased stroke risk was seen (1.39, 95% CI 1.10–1.77) [6]. Given the difference in CHD outcomes between the CEE + MPA and CEE-alone groups, the MPA was believed to contribute to the increased CHD risk. Subgroup analyses of both groups found that CAC and Lp(a) were reduced with estrogen therapy, but that stroke risk was increased [6, 71, 72, 86, 96, 97]. Hazard ratio findings are detailed in Table 2.

Table 2.

Relative risk of major health outcomes in the women’s health initiative: comparison of conjugated equine Estrogen plus Medroxyprogesterone acetate (CEE + MPA) vs. Estrogen alone (CEE)

Outcome	CEE + MPA (HR, 95% CI)	CEE Alone (HR, 95% CI)
Coronary Heart Disease	1.29 (1.02–1.63)	0.94 (0.78–1.14)
Invasive Breast Cancer	1.26 (1.00-1.59)	0.79 (0.61–1.02)
Stroke	1.41 (1.07–1.85)	1.39 (1.10–1.77)
PE	2.13 (1.39–3.25)	1.34 (0.87–2.06)
Colorectal Cancer	0.63 (0.43–0.92)	1.08 (0.75–1.55)
Endometrial Cancer	0.83 (0.47–1.47)	Not applicable (hysterectomy)
Hip Fracture	0.66 (0.45–0.98)	0.61 (0.41–0.91)
Death from Other Causes	0.98 (0.82–1.18)	1.04 (0.88–1.22)

Table 2. Clinical Outcomes Associated with Menopausal Hormone Therapy in the Women’s Health Initiative (WHI). This table summarizes hazard ratios (HR) with 95% confidence intervals for key clinical outcomes in postmenopausal women randomized to conjugated equine estrogen plus medroxyprogesterone acetate (CEE + MPA) versus estrogen alone (CEE) in the WHI trial. CEE + MPA was associated with increased risk of coronary heart disease, invasive breast cancer, stroke, and pulmonary embolism, while reducing the risk of hip and colorectal cancers. Estrogen-only therapy showed a neutral effect on coronary heart disease and was not associated with increased breast cancer risk, but it similarly increased stroke risk. Endometrial cancer data were not applicable in the estrogen-only arm due to prior hysterectomy. These results underscore the importance of individualized risk assessment when considering hormone therapy.

• Heart and Estrogen/Progestin Replacement Study (HERS): HERS I and HERS II were secondary prevention trials for women who already had known heart disease (CAD confirmed by angiography, MI history, coronary artery bypass graft (CABG)) [98, 99]. The study enrolled 2763 postmenopausal women, on average 67 years old, with CVD from 20 centers across the nation. Participants were randomly assigned to receive synthetic CEE (0.625 mg/day) + MPA (2.5 mg/day) vs. placebo. HERS I was randomized, double blind, and placebo-controlled, followed over 4.1 years, while HERS II was an open-label extension with an additional 2.7 years after HERS I [98]. The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. HERS I reported increased CHD events in the first year of MHT (HR 1.52, 95% CI 1.01–2.29), while HERS II found no sustained benefit in CHD risk reduction over time up to 6.8 years (HR 0.99, 95% CI 0.84–1.17), with continued increased VTE risk (HR 2.89, 95% CI 1.50–5.58) [100]. A subgroup analysis of this trial found that the increased CHD risk during the first year of MHT use in those with established CHD was not seen in those on statin therapy [77].

• The Early versus Late Intervention Trial with Estradiol (ELITE) Trial and Kronos Early Estrogen Prevention Study (KEEPS): The ELITE and KEEPS Trials examined the “timing/endothelium hypothesis,” which posits that the effect of MHT on the endothelium differ depending on the timing of initiation relative to the onset of menopause. MHT may have cardioprotective effects on a healthy endothelium; however, MHT may have detrimental effects on a diseased endothelium with established atherosclerotic plaques [101]. The ELITE trial demonstrated that oral estradiol reduced the progression of CIMT if initiated less than 6 years after menopause (p = 0.008) [102]. The population was 643 healthy postmenopausal women without diabetes or CVD who were stratified into early (< 6 years) or late (> 10 years) post-menopause. They were randomized to receive either oral 17β-estradiol (1 mg/day) vs. placebo if the patients had no uterus and vaginal micronized progesterone (45 mg/day for 10 days each month) was added vs. placebo for patients with a uterus. In contrast, the KEEPS trial similarly studied the timing of initiation of MHT but studied synthetic oral estrogen and transdermal estrogen [76]. This population was 727 healthy women within 3 years of initiating menopause who were randomized to receive oral synthetic estrogen (CEE 0.45 mg/day) + micronized progesterone (200 mg/day for 12 days each month), or transdermal 17β-estradiol (t-E2, 50 µg/day) + micronized progesterone (200 mg/day for 12 days each month), vs. placebo. The primary outcome studied was the progression of CIMT, but no significant effect of either intervention was shown. An additional outcome studied was a trend for reduced CAC with CEE, but this was not statistically significant. Overall, research findings on the potential CV protective benefits of early MHT initiation are conflicting, and further research evaluating the timing, dose, and formulation effects on CV health during the menopause transition is needed [2].

In summary, MHT is not recommended for the primary or secondary prevention of cardiovascular disease [103]. The HERS trials of MHT in postmenopausal women with established CVD did not find MHT to be cardio-protective, and in HERS showed a signal of harm in the first year of initiation. The findings from WHI demonstrated that MHT (in the form of CEE + MPA) does not confer protection for the primary prevention of CHD and may increase the risk of CHD when initiated in older postmenopausal women, especially during the first year after the initiation of hormone use. Furthermore, in WHI, CEE, and MPA, increased stroke risk, regardless of age or years since menopause. CEE alone does not appear to increase CHD risk in the population, but does increase stroke risk regardless of years from menopause onset, and these risks heighten with age. Notably, WHI was a study of older, post-menopausal women who were not experiencing significant menopause symptoms. Today, most patients who are being considered for MHT to alleviate symptoms are near the menopause transition and often 10–15 years younger than most of the population studied in WHI. Evidence suggests that women in early menopause who are in good cardiovascular health are at low risk of adverse cardiovascular outcomes and should be considered candidates for the use of MHT for relief of menopausal symptoms [103]. Therefore, when initiating MHT, it is important to consider the patient’s age, years from the onset of menopause, and risks for cardiovascular events to appropriately counsel the patient on the potential CV risks of MHT.

Comprehensive Approach To CV Risk Assessment when Initiating MHT Assessment

Multiple recent algorithms are available when assessing CV risk and initiating MHT. The fundamental steps include: (1) perform a person-centered CV risk assessment, including the presence of known MHT contraindications, age and time since menopause, and severity of menopause symptoms, (2) provide a recommendation for MHT use and formulation based on CV risk category, (3) ensure to reassess risks versus benefits of MHT at follow-up [104, 105]. This proposed algorithm incorporates universal Lp(a) screening and consider the presence of subclinical atherosclerosis in risk assessment. Additionally, this framework highlights the consideration of MHT formulation and CV risk prevention strategies while on MHT. In the proposed algorithm (Fig. 1), menopausal women are stratified into four risk categories—low, intermediate, high, and very high—based on their ASCVD risk score, presence of CV risk factors, and evidence of subclinical or clinical atherosclerosis .

Fig. 1.

Risk-Based Algorithm for Guiding Menopausal Hormone Therapy Using ASCVD Score, Subclinical Atherosclerosis, and Lp(a) Stratification. Cardiovascular Risk Stratification for Menopausal Hormone Therapy (MHT). This clinical decision tool integrates traditional ASCVD risk scoring, presence of cardiovascular disease (CVD) risk factors, and subclinical atherosclerosis to guide MHT use. Patients are stratified into low, intermediate, high, or very high risk based on ASCVD estimates, comorbidities, imaging findings (CAC, carotid ultrasound), and history of thrombotic disease. MHT is generally considered appropriate for low- and select intermediate-risk individuals. Caution is advised in high-risk patients, and MHT should be avoided in very high-risk patients, including those with clinical ASCVD and CAC ≥ 100 AU. Statin and aspirin therapy may be considered based on ASCVD risk score, Lp(a) levels, and imaging results. This framework supports individualized, risk-informed decision-making in midlife women. Created in MSVisio. Spertus, E. (2025)

1. Perform Comprehensive Person-Centered CV Risk Assessment

   • ASCVD Risk Score: The ASCVD risk score is a tool to estimate an individual’s 10-year risk of developing cardiovascular events like MI and stroke, incorporating several factors such as age, sex, race, total cholesterol, HDL cholesterol, systolic blood pressure, diabetes, and smoking status to predict risk [106]. The ASCVD risk score is used to determine who may benefit from statin therapy for the primary prevention of ASCVD [107]. Furthermore, a patient’s ASCVD risk assessment can be considered to assess their atherosclerotic risk and potential risk for atherosclerotic complications from MHT [108].
   • ASCVD Risk Enhancing Factors: Many risk factors for CV disease are not included in the ASCVD risk score calculation. Examples include family history of premature ASCVD, chronic auto-inflammatory conditions (i.e. lupus, rheumatoid arthritis, human immunodeficiency virus), and several biomarkers, including elevated high-sensitivity C-reactive protein, elevated Lp(a), and elevated Apolipoprotein (B) [107]. Furthermore, there are several female-specific risk factors for ASCVD, including a history of premature menopause, polycystic ovarian syndrome, and hypertensive disorders of pregnancy. As discussed above, evaluation of subclinical atherosclerosis (CAC scoring, carotid ultrasound) can be used to further refine a patient’s atherosclerotic risk estimation and should be considered when assessing risk prior to starting MHT. Therefore, when estimating ASCVD risk for the initiation of MHT, it is important to consider that these risk-enhancing factors should be incorporated into the risk assessment [109].
   • Thromboembolic Risk Enhancing Factors: The presence of hypercoagulable disorders (i.e. Factor V Leiden) or a personal history of VTE or PE should be considered when assessing thrombotic risks associated with MHT use.
2. Provide a Recommendation for MHT Use and Formulation Based on CV Risk Category

   • Low Risk: Women with low risk for CV events related to MHT include women who are less than 60 and within 10 years of menopause, who have a low estimated ASCVD risk (< 5%), and one or fewer CV risk factors, and can be considered for MHT prescription. All patients, regardless of risk, should be counseled on a heart-healthy lifestyle given the accelerated CV risk seen with menopause. Those with elevated Lp(a) (≥ 50 mg/dL or ≥ 125 nmol/L) should be considered for statin and aspirin therapy while on MHT to lower CV risk. While there are currently no approved medications approved for the indication to lower Lp(a), the current recommended management for elevated Lp(a) is optimization of LDL levels (including lifestyle and statin therapy), and other modifiable CV risk factors (i.e., hypertension, diabetes). The degree of Lp(a) should be considered when initiation primary prevention treatment. An Lp(a) level ≥ 180 mg/dL is an extreme elevation and carries an increased lifetime risk of ASCVD similar to those with heterozygous familial hyperlipidemia. Aspirin, which reduces platelet activation, may help offset the prothrombotic properties of Lp(a) [110, 111]. Several recent studies have suggested that aspirin may be beneficial for the primary prevention of CV events in those with elevated Lp(a) [111, 112]. Per the 2019 ACC/AHA Primary Prevention Guidelines, aspirin 81 mg may be considered for the primary prevention of ASCVD in select adults aged 40 to 70 who are at increased risk of ASCVD but not increased risk of bleeding [107]. CAC scoring and carotid ultrasound can help guide whether to initiate a statin or aspirin in patients with elevated Lp(a) while on MHT.
   • Intermediate Risk: Intermediate risk includes women with 5–10% ASCVD risk or the presence of one to two well-controlled CV risk factors. Similarly, these patients are considered lower risk with MHT, but statin and aspirin use may be considered in the population, particularly if risk-enhancing factors are present, like elevated Lp(a). Furthermore, an intermediate risk patient should consider transdermal estrogen formulation and micronized progesterone, given the more favorable CV risk compared to oral estrogen and synthetic progesterone.
   • High Risk: High risk encompasses those with estimated high (> 10%) ASCVD risk, uncontrolled high-risk CVD risk factors, evidence of subclinical atherosclerosis (such as CAC 1–99 or asymptomatic carotid plaques), and older postmenopausal women (≥ 60 years old or ≥ 10 years from menopause). This higher-risk population should be counseled to be cautious with MHT and consider non-MHT therapy. Their cardiovascular risk factors should be treated, and they may potentially transition to a lower risk category with treatment. However, MHT is not contraindicated in this group and may be considered to alleviate menopause symptoms after thorough shared decision making with the patient and their provider. Favored MHT formulation for this group includes a low-dose transdermal estrogen formulation and micronized progesterone.
   • Very High Risk: Very high risk is defined by the presence of clinical ASCVD (e.g., prior MI, stroke, or PAD), CAC > 100, or high-clot risk (like prior VTE or certain hypercoagulable disorders). In this group, we advise patients to avoid systemic MHT, but non-MHT therapies for menopause symptoms should be explored. These patients should still be considered for vaginal estrogen therapy given limited systemic effects. Patients with a history of spontaneous coronary artery dissection (SCAD) should avoid MHT, given that estrogen plays a key role in the risk of dissection [113, 114]. Those with fibromuscular dysplasia (FMD) should be counseled on the potential vascular risk of MHT and should explore non-MHT treatment for menopause symptoms [115].

• 3)Reassess Risks of MHT at Follow-up.

After initiating MHT, it is important to repeat the CV risk assessment at regular follow-up. As patients age, and their cardiovascular risks increase, it is important to consider when to discontinue MHT based on ongoing risk and benefit conversations.

Conclusions and Future Directions

In summary, the menopause transition is a critical window for care and individual cardiovascular assessment due to the rise of risk factors for CVD inherent during this time. Though many interventions of MHT can alleviate the uncomfortable symptoms of menopause they may also augment cardiovascular risk. Therefore, personalized assessment of ASCVD risk and benefit analysis prior to initiation of MHT is necessary during this time. While there are many benefits of utilizing this approach, it is important to note some of the limitations of the aggregate data. For one, much of the data referenced is from older clinical trials (e.g., WHI, HERS) and references older postmenopausal women (> 63 years) who were not initiating MHT for vasomotor symptoms. This review applies these findings to younger women closer to menopause for limited time courses. Additionally, while contemporary data shows that transdermal estrogen and micronized progesterone MHT formulations have lower cardiovascular risks than oral and synthetic formulations, the supporting evidence is predominantly observational without significant randomized control data. Therefore, MHT formulation should be chosen carefully prior to initiation. Similarly, there is limited data on the risks of initiating MHT in smaller high-risk populations such as those with SCAD or FMD, and this risk is based on pathophysiological rationale and small cohort data. While several national and international cardiology societal guidelines support universal screening for elevated Lp(a), this is not yet implemented routinely in preventative screening assessments. While observational data and secondary analysis from primary prevention aspirin randomized trials support the potential benefit of aspirin in those with elevated Lp(a), randomized clinical trials evaluating the use of aspirin for the primary prevention of cardiovascular disease are needed to better understand the benefit of aspirin while balancing bleeding risks [116].

This review presents a comprehensive, person-centered risk approach for evaluating cardiovascular risk in the context of MHT. This framework integrates evaluation of both modifiable and non-modifiable CVD risk factors, including universal screening for elevated lipoprotein(a) (Lp(a)) levels, recognition of female-specific CVD risk-enhancers, and leveraging vascular imaging to screen for subclinical vascular disease to support an individualized risk stratification. The tool proposed builds on existing risk assessment design (such as the ASCVD risk assessment) to estimate ASCVD risk and guide prevention strategies specifically for initiating MHT, while historical tools were not developed or validated for this precise purpose. This tool incorporates specific cardiac markers such as routine Lp(a) measurement at menopause, and assessment for subclinical atherosclerosis (i.e. CAC scoring, carotid ultrasound) to help guide individualized provider-patient shared decision making. Menopausal management draws upon the specialties of Obstetrics/Gynecology, Endocrinology, Cardiology, and Primary Care, and a thorough multidisciplinary approach is warranted in decision making. There has been significant research on MHT and cardiovascular risk, but questions remain for new therapies. Novel therapies such as Lp(a)-targeted therapies may address these specific risk factors, marking a new frontier in managing menopausal cardiovascular health.

Key References

• Sobel TH, Shen W. Transdermal estrogen therapy in menopausal women at increased risk for thrombotic events: a scoping review. Menopause. 2022;29(4):483–490. 10.1097/GME.0000000000001938.

  • This scoping review highlights the safety of transdermal estrogen as a preferred formulation for women with thrombotic risk, informing personalized MHT strategies.
• Ferreira Campos L, de Andrade Costa G, Domingues Feitosa M, et al. Effect of hormone therapy on blood pressure and hypertension in postmenopausal women: a systematic review and meta-analysis. Menopause. 2024;31(6):556–562. 10.1097/GME.0000000000002359.

  • This meta-analysis provides updated evidence on how MHT influences blood pressure, critical for cardiovascular risk assessment.
• Jiang X, Aragaki AK, Nudy M, et al. The association of hormone therapy with blood pressure control in postmenopausal women with hypertension: a secondary analysis of the Women’s Health Initiative. Menopause. 2023;30(1):28–36. 10.1097/GME.0000000000002086.

  • Supports the nuanced effect of MHT on hypertension depending on formulation and timing.
• Speksnijder EM, Ten Noever de Brauw GV, Malekzadeh A, et al. Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis. Diabetes Care. 2023;46(10):1866–1875. 10.2337/dc23-0451.

  • This meta-analysis demonstrates the glycemic benefits of MHT, particularly relevant for women with diabetes.
• Torosyan N, Visrodia P, Torbati T, et al. Dyslipidemia in midlife women: Approach and considerations during the menopausal transition. Maturitas. 2022;166:14–20. 10.1016/j.maturitas.2022.08.001.

  • A key article summarizing lipid changes during menopause and guiding dyslipidemia management in this population.
• Nie G, Yang X, Wang Y, et al. The Effects of Menopause Hormone Therapy on Lipid Profile in Postmenopausal Women: A Systematic Review and Meta-Analysis. Front Pharmacol. 2022;13:850815. 10.3389/fphar.2022.850815.

  • Provides detailed evidence of the favorable effects of MHT on LDL and HDL levels.
• Björnson E, Adiels M, Taskinen MR, et al. Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis. J Am Coll Cardiol. 2024;83(3):385–395. 10.1016/j.jacc.2023.10.039.

  • Establishes the high atherogenicity of Lp(a), reinforcing its importance in menopausal CV risk assessment.
• Volgman AS, Koschinsky ML, Mehta A, Rosenson RS. Genetics and Pathophysiological Mechanisms of Lipoprotein(a)-Associated Cardiovascular Risk. J Am Heart Assoc. 2024;13(12):e033654. 10.1161/JAHA.123.033654.

  • Explains how genetic and hormonal factors, including menopause, contribute to Lp(a)-mediated cardiovascular risk.
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  • Shows Lp(a)'s independent contribution to coronary artery calcification, a pivotal imaging marker in midlife risk assessment.
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  • Essential guideline outlining stroke prevention approaches, including sex-specific recommendations relevant to MHT.
• Cho L, Kaunitz AM, Faubion SS, et al. Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long? Circulation. 2023;147(7):597–610. 10.1161/CIRCULATIONAHA.122.061559.

  • A high-impact summary of how modern evidence should reshape individualized MHT use in clinical practice.
• Nudy M, Aragaki AK, Jiang X, et al. Long-Term Changes to Cardiovascular Biomarkers After Hormone Therapy in the WHI. Obstet Gynecol. 2025;145(4):357–367. 10.1097/AOG.0000000000005862.

  • Evaluates the durable biomarker changes post-MHT, supporting a deeper understanding of long-term cardiovascular risk.
• Hirsch H, Manson JE. Menopausal symptom management in women with cardiovascular disease or vascular risk factors. Maturitas. 2022;161:1–6. doi:10.1016/j.maturitas.2022.01.016

  • Provides a summary of best practices when treating menopausal symptoms in women with pre-existing CVD, including addressing risks, formulation, dosing and route of delivery of MHT.

Author Contributions

L.J. had the idea for this article and critically reviewed this work. Z.D. performed the literature search, data analysis, manuscript creation, table (Tables 1 and 2) and figure creation (Figure a). E.S. performed figure creation (Figure 1). S.H., R.J., T.H, M.CP., J.S., and K.W. contributed and critically revised the work.

Funding

The authors did not receive support from any organization for the submitted work.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval

This is a review. There was no formal ethics approval needed in the creation of this manuscript.

Statements and Disclosures

Our team has no statements or disclosures.

Consent to Publish

No consent was needed in the creation of this manuscript as it is a review of existing data as opposed to original research. However, consent was obtained in the original studies cited in this review.

Human and Animal Rights and Informed Consent

No animal or human subjects by the authors were used in this study.

Competing interests

The authors declare no competing interests.