Endometriosis and Early-Onset Cardiovascular Disease Across Levels of Systemic Inflammation: A Cross-Sectional Study of NHANES 1999–2006

Background: Endometriosis is a chronic gynecologic condition which has been linked with higher cardiovascular disease (CVD) risk. Although systemic inflammation is central to endometriosis and CVD pathophysiology, it remains unclear whether endometriosis is associated specifically with early-onset CVD and whether systemic inflammation modifies this association. Methods: This was a cross-sectional study of 5,345 women aged 20-54 years from the National Health and Nutrition Examination Survey (1999-2006). Endometriosis and early-onset CVD were self-reported. Early-onset CVD was defined as a composite measure of coronary heart disease, angina/angina pectoris, heart attack, congestive heart failure, or stroke. Systemic inflammation was measured using C-reactive protein [CRP; low/moderate (≤3 mg/L) and high (>3mg/L)] and the systemic immune-inflammation index (SII; tertiles). Survey-weighted logistic regression was used to assess associations and heterogeneity by systemic inflammation, with stabilized inverse probability weighting (IPW) to adjust for confounding. Results: Of the 5,435 women, 370 (6.9%) reported an endometriosis diagnosis and 162 (3.0%) early-onset CVD. After IPW adjustment for age, body mass index, smoking status, education, age at menarche, physical activity and race/ethnicity, endometriosis was associated with higher odds of early-onset CVD (prevalence odds ratio [POR] = 1.91, 95% CI: 1.23-2.97). This association was strongest among women with high CRP (POR= 2.33, 95% CI: 1.49-3.66), but not among those with low/moderate CRP levels (p-interaction= 0.086). Across SII strata, the strongest association was observed among women in the medium SII tertile (POR = 2.92, 95% CI: 1.47-5.78), with no associations in the low or high tertiles (p-interaction = 0.288). Conclusion: Endometriosis was associated with higher odds of early-onset CVD in this nationally representative sample of U.S. women. Although the strength of the association varied across CRP and SII strata, formal tests for interaction were not statistically significant. These findings should be understood as exploratory and require further investigation in prospective studies.