AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Association of Early Menarche and Early Menopause with Cardiovascular-Kidney-Metabolic Syndrome Stage Progression
By Hoshi R, Gibson H, Li C et al.
Background: The prevalence of Cardiovascular-Kidney-Metabolic syndrome (CKMS) is increasing among women, and the associated all-cause mortality is higher in women than men across all CKM stages. Understanding the contribution of female-specific risk factors, such as hormonal exposure, to CKMS may help elucidate sex-related mechanisms underlying long-term cardiovascular and cardiometabolic health. Results can inform targeted prevention strategies for women. Hypothesis: Early female reproductive milestones, i.e., menarche and menopause, are associated with CKMS severity and faster worsening, identifying women with an unfavorable hormonal exposure trajectory. Moreover, the occurrence of both reproductive factors can have an additive effect. Methods: We examined associations of early menarche (< 10y), early menopause (< 45y), and combined conditions with CKMS among women in the VITamin D and OmegA-3 TriaL (VITAL, NCT01169259). First, ordinal logistic regression models adjusted for age, race/ethnicity, postmenopausal hormone therapy, and smoking were used to evaluate associations with baseline CKMS stage. Then, restricting to women with at least one follow-up, time-to-event analyses for stage worsening were examined using Cox proportional hazards regression. Stage worsening was the highest observed CKM stage relative to baseline across follow-up visits (years 1, 2, and 4). The predictors were early menarche, early menopause, or both (exploratorily). Follow-up time was defined as the interval from baseline to the worst progression event or to the last available CKM assessment. Because CKMS was assessed only at discrete study visits, event times were interval-coarsened. Models were adjusted for age, race/ethnicity, postmenopausal hormone therapy use, smoking, baseline CKM stage, and trial randomization treatment. Results: 11,963 VITAL women (mean age [SD] 68.7 ± 6.7; 27% non-White) were classified into a CKM stage at baseline. Ordinal logistic regression models showed that early menarche (3.4%) and early menopause (20.5%) were independently associated with higher baseline CKM stages compared with women without these exposures (OR: 1.42, 95%CI: 1.17 - 1.74 and OR: 1.39, 95%CI: 1.27 - 1.53, respectively; both p<0.001; Fig 1A). An additive effect (OR: 1.62, 95%CI: 1.15 - 2.28, p = 0.005) was also observed for joint conditions (1.2%). In the adjusted Cox proportional hazards models, early menopause was associated with an increased risk of CKM progression (HR: 1.17, 95%CI: 1.03 - 1.32, p = 0.012; Fig 1B). Early menarche and exploratory analysis of joint conditions showed a non-significant increase in risk. Conclusions: Early menopause and early menarche were independently and additively associated with greater CKMS severity in cross-sectional analyses. Only early menopause showed a significant increased risk of faster worsening CKM stage during a follow-up time of 4 years.