Exploring menopausal disparities in cardiovascular risk factors: transitioning from the estrogen to the iron hypothesis

Background Menopause is associated with an increased risk of diabetes, cardiovascular disease (CVD), and mortality. Estrogen deficiency has been suggested as the main cause for this increased, but results are contradictory. An alternative hypothesis would be changes in iron biomarkers. Most previous studies have employed a cross-sectional design to evaluate the association between iron biomarkers and CVD risk factors (CVD-RFs). However, given the natural variability of iron levels, it is essential to incorporate repeated measurements of iron biomarkers for a more comprehensive assessment. Goals We aimed to explore the intra-variability of iron biomarkers over time.2) evaluate the cross-sectional and longitudinal associations between iron biomarkers [serum ferritin, transferrin saturation (TSAT), transferrin] and CVD risk factors (CVD-RFs) among women. Method Data from the prospective CoLaus|PsyCoLaus study, conducted in Switzerland. 10-year prospective (1482 women, mean age 58.83) analysis were conducted using multiple linear regression for the cross-sectional part and multilevel mixed models for the longitudinal part. Intraclass correlation (ICC) was utilized to assess the variability of outcomes and iron markers between surveys in the prospective analysis. Results Different iron biomarkers showed inconsistent associations with CVD-RFs in cross-sectional and prospective analyses. In the cross-sectional analysis, after multivariable adjustment, ferritin levels were positively associated with insulin, while transferrin levels were positively associated with glucose, insulin, total and HDL-cholesterol, and systolic and diastolic blood pressure. No association between TSAT and CVD-RFs was found . In our study all iron biomarkers (serum Iron, serum ferritin, transferrin and TSAT) had a low reliability as defined by the ICC, especially in the transition group (figure 1). To mitigate these challenges, in our study we took advantage of repeated measures of iron biomarkers to correct for this low reliability and improve precision and the ability to capture changes over time In the prospective analysis, and contrary to the cross-sectional analysis, transferrin levels were negatively associated with glucose (β =-0.55, CI= -1.06; -0.04) and diastolic blood pressure (β =-7.14, CI= -15.6; -0.18). Similar findings were obtained after stratification on menopausal status. Conclusion The positive associations between ferritin and CVD-RFs observed in the cross-sectional study were inverted in the prospective study. This discrepancy could be due to the variability of iron biomarkers during lifetime. The substantial longitudinal variation of iron biomarkers suggests that multiple measurements of iron are necessary for longitudinal analyses.