Is menopause a driver of cardiovascular disease?

Menopause is clinically determined by a single moment in time defined as the lack of menstrual periods for 12 consecutive months. However, the process starts years before with a peri-menopausal time period followed by a post-menopausal phase that extends for decades. The peri-menopausal transition (MT) is part of normal physiology and not a disease; it is rather a condition dominated by symptoms and quality of life issues for some women. Because women typically develop cardiovascular disease (CVD) several years later than men, this observation led to the hypothesis that the MT contributes to increased CVD.¹ Women represent 51% of the world population and all will undergo menopause, yet critical gaps remain in our fundamental understanding of the menopause process related to CVD (and other diseases) which limits clinical practice and therapeutic interventions for women.

MT and menopause therapy include menopause hormone therapy (MHT) used predominantly for signs and symptoms of the MT. The leadership of the Food and Drug Administration, together with that of the Department of Health and Human Services recently approved November 10, 2025 drug labeling changes to six MHT products to clarify risk considerations for these drugs. Specifically, risk statements related to CVD, breast cancer and probable dementia were removed from the “black-box warning,” the agency’s most prominent safety-related warning.² This policy change signals a major shift in safety messaging for MHT and is expected to increase MHT use.³ A recent contemporary comprehensive systematic Cochrane review of available evidence indicated weak evidence as to MHT benefits and risk. Specifically, it concluded that “estrogen-only hormone therapy probably makes little to no difference to coronary events, probably increases the risk of stroke and gallbladder disease, makes little to no difference in the risk of breast cancer, and probably reduces the risk of all fractures, while combined hormone therapy may increase the risk of thromboembolism and probably increases the risk of breast cancer”.⁴ Many women and clinicians are now challenged to make decisions with this weak evidence regarding risks and benefits of MHT use.

Accordingly, investigation of the MT and cardiovascular health (CVH) is welcome. Zhi and colleagues⁵ investigated MT related to disadvantaged sociodemographic backgrounds or residence in disadvantaged neighborhoods which have been associated with greater CVD burden in women. In a cohort of women enrolled during pregnancy and followed through midlife, those with social determinants of health (SDH) of lower income, lower education, or identifying as Non-Hispanic Black exhibited poor CVH across follow-up. Independent of individual SDH, residence in vulnerable neighborhoods, measured by a Social Vulnerability Index (SVI) at enrollment or over time was also associated with lower CVH across follow-up. The SVI was also associated with an accelerated CVH decline during premenopause, but not during the peri- or post menopause time.

The current study also found that when adverse SDH and high SVI identified at baseline was persistent it was related to persistently poor CVH at follow up.⁵ This is not surprising - adverse social conditions would be expected to be relevant at all ages. Hurricane Katrina is a real-world example. Among the roughly 66,000 students who were evacuated from New Orleans, research suggests those evacuees who returned the New Orleans metro area had much lower test score growth from 2005 to 2009 compared to those who did not return.⁶ Accordingly, the current study conclusions that future studies examine interventions to increase access to social and economic resources in order to promote more favorable CVH trajectories among women during midlife are good next steps. However, given the authors’ premenopause findings, we might edit the conclusion to ‘during premenopausal years.’

Notably, the current study reported adverse SVI was associated with an accelerated CVH decline only in the premenopause, not in the peri- or post menopause time periods.⁵ Further, the overall pattern of CVH scores in the peri- and post menopause demonstrated decline slopes that did not appear to change over time, e.g. did not accelerate (Central Figure A). This resembles the long-standing age-specific plot of female CVD mortality as a function of age (Central Figure B)⁷ demonstrating no acceleration through the peri- and post menopause time periods. Additionally, a contemporary analysis demonstrates systolic blood pressure age-related acceleration begins in the second decade of women’s lives rather than during the MT or menopause ages (Central Figure C)⁸. These constellation of these findings are most consistent with menopause having no discernible effect on the exponential increment in CVD death with age, unlike the abrupt midlife decline in the age-related slope for breast cancer related to the declining endogenous estrogen levels in the menopause (Central Figure B). Accordingly, if menopause is not a driver of CVD in women, what could be driving the relatively constant decline in CVH following the younger premenopausal years? The answer likely is the well-accepted CVD major risk factor – age! Indeed, a contemporary CVD study in carefully phenotyped women failed to distinguish menopause from age.⁹

Central Figure. Findings consistent with menopause having no discernible effect on the exponential increment in CVD death with age.

(A) Comparison of overall CVH score relative to time to last report of menopause status(with permission)⁵

(B) US women, semilogarithmic plots of age-specific heart disease and breast cancer deaths rates vs age (with permission)⁷

(C) Life course trajectories of BP elevation indicating that BP elevation in women begins earlier and progresses more rapidly in women than in men over the life course (with permission).⁸

CVH=cardiovascular health; SBP=systolic blood pressure; SVI=social vulnerability index

Due to limited investigation and therefore limited understanding of reproductive health relations to CVD in women leaves us with many knowledge gaps. The current 2020 AHA consensus paper on menopause and CVD noted that the 2011 American Heart Association guidelines for CVD prevention in women did not include information about the contribution of the MT to increased CVD in women.¹ Summarizing work over the past 20 years including longitudinal studies of women transitioning through menopause has implicated MT with adverse cardio-metabolic CVD risk and rising CVD mortality rates in women. The recommendations that future studies make a conscious effort to include and focus on women who are undergoing the MT, especially those related to MHT are appropriately strongly endorsed. However, it is important to remember that CVD mortality rates have risen comparably in women and men since 2010 along with cardio-metabolic worsening in both sexes due to rising rates of obesity and diabetes, with the most evident CVD mortality increases in younger premenopausal women.¹⁰ Accordingly, these data do not support the conclusion that the MT contributes to the rising CVD mortality in women, nor the expressed concern that current rising rates of CVD in women are due to decline in MHT use following the Women’s Health Initiative¹ and FDA black box warning.²

MT and menopause do not appear to be drivers of CVD in women. There is not a clear signal of contribution of MT to worsening of CVH independent of age. Women are now asking should they be treated with MHT? Clinicians are asking is the lifting of the FDA black box warning of MHT with regard to CVD appropriate?³ Investigators are asking should an expert panel of those experienced in the areas of MT, MHT and CVD be convened?³ What additional investigations are needed to answer the important MT and menopause questions, relevant to 51% female representatives of the world population? We need menopausal research that spans basic, translational, and clinical studies in order to provide the much-needed scientific evidence to enable effective, safe reassurance and when appropriate evidence-based interventions for MT and menopause. While we ponder these questions, we also need to do a better job of preventing CVD in women with our evidence-based risk assessment and proven risk factor modification strategies at all ages, including during the premenopause well before before the MT and menopause.