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Mariana Ramirez, MD




Grad Student




Medical Science and Clinical Investigation


Mariana Ramirez, MD; Michael Honigberg, MD, MPP; Dongyu Wang, MPH; Jennifer E. Ho MD*; Emily S. Lau, MD, MPH*

Principal Investigator

Jennifer E. Ho MD & Emily S. Lau, MD, MPH


Protein Biomarkers of Early Menopause and Incident Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of death among women globally. Sex differences in CVD pathogenesis are well established, and female-specific risk factors, including adverse pregnancy outcomes, are increasingly recognized as CV risk factors. Premature/early menopause is an important risk factor for CVD development in women, but mechanistic insights underlying its association with CVD are limited. This knowledge gap has important clinical implications, considering that up to 10% of women undergo early menopause. In this context, we sought to investigate potential biologic pathways that may contribute to CVD development in women with premature/early menopause.


Emerging data support an association between premature and early menopause with increased risk of future cardiovascular disease (CVD). This observation has been acknowledged by practice guidelines that recognize premature menopause as a risk-enhancing factor for women at intermediate risk for atherosclerotic cardiovascular disease (ASCVD). However, mechanisms underlying the link between age at menopause with CVD remain poorly characterized.



We sought to identify protein biomarkers associated with early menopause (menopause before age 45 years) among postmenopausal women enrolled in the Framingham Heart Study (FHS).



We measured 71 circulating CVD protein biomarkers in 1578 postmenopausal women enrolled in the FHS. We examined the association of early menopause with biomarkers testing whether early menopause modified the association of biomarkers with incident CV outcomes (heart failure, hard CVD, and all-cause death) using multivariable regression and Cox models, respectively.



Among 1578 postmenopausal women included (mean age 62 years), 404 (26%) had a history of early menopause. Of 71 biomarkers examined, we identified 13 biomarkers that were significantly associated with early menopause, of which 8 with higher in women with early menopause (including resistin and adrenomedullin [ADM]) and 5 were higher in women with reference menopause (including IGF-1 and CNTN1; false discovery rate q<0.1 for all). Early menopause also modified the association of specific biomarkers with incident CV outcomes, including ADM and APOA1 (pint <0.05).



Early menopause influences circulating levels of CVD protein biomarkers and modifies the association between select biomarkers and incident CV outcomes. Identified biomarkers highlight distinct biological pathways, including inflammation, adiposity, and neurohormonal regulation. Further investigation of these pathways may provide mechanistic insights into the pathogenesis of early menopause-associated CVD.

Research Context