Cardiometabolic changes in the menopause transition

Cardiovascular disease (CVD) remains the leading cause of death in women. Midlife cardiometabolic changes are a key contributor to this risk. Women experience an increase in cardiovascular (CV) risk beginning in the fifth decade of life, approximately 10 years later than men, which temporally aligns with the menopause transition. Many cardiometabolic alterations during perimenopause are not solely attributable to chronologic aging but are instead linked to ovarian aging. Recognizing menopause-related cardiometabolic changes provides clinicians with an opportunity to identify CV risk early and implement targeted prevention strategies. DOES THE TIMING AND TYPE OF MENOPAUSE AFFECT CARDIOVASCULAR DISEASE RISK? Natural menopause occurs at a mean age of 52 years; however, menopause occurring early (ages 40-45 y) or prematurely (before age 40 y) is consistently associated with higher rates of coronary heart disease, stroke, heart failure, and CV mortality. In a large, pooled analysis, there was a graded increase in CVD risk with earlier age at natural menopause compared with menopause at ages 50 to 51 years. Hazard ratios for incident CVD were 1.55 for premature (<40 y), 1.30 for early (40-44 y), and 1.12 for relatively early (45-49 y) menopause.1 Type of menopause also influences CVD risk. Surgical menopause, defined as bilateral oophorectomy before the age of natural menopause, is associated with greater CV risk than natural menopause.2 The abrupt loss of ovarian hormones, notably estrogen, is associated with accelerated adverse and metabolic changes, especially in eligible women who do not receive hormone therapy (HT; estrogen-alone if hysterectomy; combined therapy if bilateral salpingo-oophorectomy alone). These findings underscore the importance of integrating both the timing and type of menopause into routine cardiometabolic risk assessment and management. DOES BLOOD PRESSURE CHANGE IN RELATION TO MENOPAUSE? Blood pressure increases during midlife, with up to 70% of women having hypertension after the age of 60 years. Lower estrogen levels are associated with increased angiotensin type 1 receptor expression, higher angiotensin-converting enzyme activity and plasma renin levels, greater vasoconstrictor and sympathetic activity, and increased salt sensitivity, all of which contribute to higher blood pressure.3 Earlier longitudinal analyses from the Study of Women’s Health Across the Nation (SWAN) and the UK Biobank suggested that blood pressure changes across the menopause transition largely reflect chronologic aging, with linear increases in systolic blood pressure (SBP) and little change or declines in diastolic blood pressure. However, newer SWAN analyses identified three distinct SBP trajectories over long-term follow-up, characterized by lower-, moderate-, and higher-baseline SBP. Notably, the lower-baseline SBP trajectory demonstrated an accelerated rise beginning about 1 year after menopause, consistent with a menopause-specific effect. In contrast, the moderate- and higher-baseline SBP trajectories increased up to menopause and then either continued at a similar rate or plateaued thereafter, suggesting predominantly age-related patterns.4 Younger age at menopause was associated with the low-accelerated rise in blood pressure trajectory, whereas increasing vasomotor symptoms were linked to higher blood pressure levels over time. Clinically, perimenopause represents a critical window for intensified blood pressure monitoring and intervention. HOW DOES LIPID METABOLISM CHANGE DURING PERIMENOPAUSE? During the menopause transition, unfavorable lipid changes occur independent of aging. Total cholesterol, low-density lipoprotein cholesterol, and triglycerides increase most rapidly several years before and after the final menstrual period.5 Emerging evidence from SWAN suggests that high-density lipoprotein cholesterol (HDL-C) function becomes impaired during perimenopause, rendering HDL-C less cardioprotective. Dysfunctional HDL-C may lose its anti-inflammatory and reverse cholesterol transport properties, potentially explaining the paradoxical associations between higher HDL-C levels and increased atherosclerotic burden in postmenopausal women.6 WHAT CHANGES OCCUR REGARDING INSULIN RESISTANCE, METABOLIC SYNDROME, AND BODY COMPOSITION AT MIDLIFE? Insulin resistance increases during midlife and contributes to progression toward type 2 diabetes mellitus and CVD. Although glucose dysregulation appears largely driven by aging, the prevalence and severity of metabolic syndrome increase during perimenopause independent of age.5 Metabolic syndrome, characterized by central obesity, dyslipidemia, hypertension, and insulin resistance, worsens most rapidly during perimenopause. Clinicians should recognize the menopause transition as a period of heightened vulnerability to clustering of metabolic risk factors and manage according to established clinical guidelines. Changes in body composition are a hallmark of ovarian aging, whereas weight gain is more associated with chronologic aging. Women experience increases in total fat mass, particularly visceral and ectopic adiposity around the heart, liver, and muscle, along with relative loss of lean mass. Previous studies demonstrated that beginning approximately 2 years before the final menstrual period, the rate of fat mass gain doubles while lean mass declines, changes that continue through the early postmenopausal period and are independent of chronologic aging. Visceral fat accumulation accelerates during perimenopause and is strongly associated with insulin resistance, inflammation, and atherosclerosis. Increases in epicardial and paracardial fat deposition have also been observed during perimenopause and are independently associated with CV risk. These changes often occur despite minimal changes in body weight, underscoring the importance of assessing waist circumference and metabolic health rather than relying on body mass index alone.7 HOW DO SLEEP DISTURBANCES DURING THE MENOPAUSE TRANSITION INFLUENCE MIDLIFE CARDIOMETABOLIC HEALTH? Sleep disturbances, including insomnia and obstructive sleep apnea, become more prevalent during the menopause transition. Sleep apnea risk increases in up to 11% of women after menopause, particularly after surgical menopause. Poor sleep quality and sleep-disordered breathing worsen hypertension, insulin resistance, systemic inflammation, and overall CV risk. Shorter sleep duration and poorer sleep quality are linked to worse CV health, specifically in postmenopausal women, highlighting a menopause-specific vulnerability. Therefore, screening for sleep disorders should be incorporated into cardiometabolic risk assessment in midlife women. IS THERE A ROLE FOR HORMONE THERAPY IN PRESERVING CARDIOVASCULAR HEALTH? Hormone therapy is not recommended for the primary or secondary prevention of CVD, yet remains an effective treatment for menopause symptoms in appropriately selected women.8 When HT is initiated later (>10 y since menopause), there may be an increase in CV risk. Since the results of the Women’s Health Initiative, two smaller randomized placebo-controlled trials (the Kronos Early Estrogen Prevention Study [KEEPS] and the Early versus Late Intervention Trial with Estradiol [ELITE]) evaluated whether HT compared with placebo could prevent CV disease by examining surrogate markers of coronary heart disease.9,10 Both studies found that HT initiated close to menopause (within 3-6 y) did not increase CV risk. KEEPS demonstrated neutral effects of low-dose estrogen on surrogate markers of coronary heart disease—carotid intima-media thickness (cIMT) and coronary artery calcium (CAC), whereas ELITE showed that estrogen initiated close to menopause significantly slowed cIMT progression without changes in CAC. These findings applied to normal arteries, which does not translate into clinically significant reductions in CV events and does not support the use of HT for CVD prevention. KEY SUMMARY POINTS The menopause transition represents a critical window for cardiometabolic risk identification and prevention. Cardiometabolic changes during the menopause transition contribute significantly to the rise in cardiovascular disease observed in midlife women. Early recognition and targeted intervention during this transition offer a unique opportunity to mitigate long-term cardiovascular risk and improve health outcomes for women. Lifestyle interventions remain foundational. CLINICAL RECOMMENDATIONS Incorporate menopause-specific factors into routine cardiovascular risk assessment, including age and type of menopause, blood pressure, lipid profile, glucose metabolism, body composition, and sleep quality. Consider menopause as a risk-enhancing factor when determining the intensity of preventive therapies. Use the American Heart Association’s Life’s Essential 8 to address lifestyle measures and modifiable risk factors (blood pressure, blood glucose, blood cholesterol, and sleep) that may improve long-term cardiovascular outcomes in women. Coming next in theStep-by-Stepseries: Jessica Caldwell, PhD, director of the Women’s Alzheimer’s Movement Prevention and Research Center at the Cleveland Clinic, reviews the physiologic basis for the cognitive complaints of menopausal women and offers strategies to share with patients to protect brain health.This article is part of the ongoing series Menopause Step-by-Step, a monthly Menopause education feature.11 The Editors of this series are Dr. Cynthia Stuenkel, Dr. Cheryl Cox Kinney, and Dr. Isaac Schiff.