Circulating Biomarkers Mediate Obesity–Endometrial Cancer Link, With Distinct Pathways in Pre- and Postmenopausal Women
核心洞察
Obesity (搜索) was associated with a more than threefold increased endometrial cancer (搜索) risk in both premenopausal (OR=3.24) and postmenopausal (OR=3.34) women in a nested case-control study within the EPIC cohort.
Circulating biomarkers of inflammation, insulin resistance, and sex hormones jointly mediated approximately 50% of the obesity (搜索)–endometrial cancer (搜索) association in both menopausal groups.
In postmenopausal women, estrone was the dominant mediator (proportion mediated=15%), while interleukin-6 emerged as the key mediator in premenopausal women (proportion mediated=24%).
Obesity (搜索) is associated with a more than threefold increase in endometrial cancer (搜索) risk, and roughly half of this excess risk may be explained by circulating biomarkers of inflammation, insulin resistance, and sex hormones, according to a new analysis from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study further reveals that the mediating pathways differ by menopausal status, with sex hormones predominating after menopause and inflammatory markers playing a more prominent role in premenopausal women.
The findings, drawn from prediagnostic blood measurements in 337 matched postmenopausal case-control pairs and 196 premenopausal pairs, provide mechanistic insight into how excess adiposity drives endometrial carcinogenesis across the reproductive lifespan.
Joint mediation accounts for half of excess risk
Using a nested case-control design, researchers estimated the natural indirect effect (NIE) of obesity (搜索)—defined as body mass index ≥30 kg/m² versus <25 kg/m²—on endometrial cancer (搜索) risk through a panel of circulating biomarkers. The adjusted odds ratio (OR) for the total effect of obesity on endometrial cancer was 3.34 (95% CI = 1.97 to 5.65) in the postmenopausal analysis and 3.24 (95% CI = 1.43 to 7.36) in the premenopausal analysis.
When all biomarkers were considered jointly, the OR through the indirect pathway (OR_NIE) was 1.82 (95% CI = 1.21 to 2.74) in postmenopausal women, corresponding to a proportion mediated (PM) of 50%. In premenopausal women, the joint OR_NIE was 1.79 (95% CI = 0.97 to 3.29), with a PM of 49%.
Estrone dominates in postmenopausal women
Sequential mediation analysis, which accounted for upstream biomarkers based on a prespecified causal sequence, identified estrone as the key mediator in the postmenopausal setting. The OR_NIE for estrone beyond upstream biomarkers was 1.20 (95% CI = 1.02 to 1.41), with a proportion mediated of 15%. This finding underscores the central role of sex hormone pathways in obesity (搜索)-driven endometrial cancer (搜索) risk after menopause, when ovarian estrogen production ceases and adiposity becomes the primary source of endogenous estrogens.
Interleukin-6 emerges as key mediator in premenopausal women
In contrast, among premenopausal women, interleukin-6 (IL-6) remained a significant mediator after accounting for upstream biomarkers, with an OR_NIE of 1.35 (95% CI = 1.03 to 1.78) and a proportion mediated of 24%. This result highlights the importance of chronic inflammation in mediating the obesity (搜索)–endometrial cancer (搜索) relationship earlier in reproductive life, when circulating sex hormone levels are still largely governed by ovarian function.
Distinct biological pathways by menopausal status
The study, which measured biomarkers spanning inflammation, insulin resistance, and sex hormones, found some overlap in mediating pathways across menopausal groups but also clear distinctions. The authors concluded that "sex hormones were the most prominent mediators in postmenopausal obesity (搜索), whereas biomarkers for inflammation may play an important role in premenopausal obesity."
These results align with the broader understanding that obesity (搜索) promotes endometrial cancer (搜索) through multiple interconnected mechanisms, including aromatase-driven conversion of androgens to estrogens in adipose tissue, chronic low-grade inflammation, and hyperinsulinemia. The differential prominence of these pathways by menopausal status may inform future risk-prediction models and targeted preventive interventions.
The study's nested case-control design within the large, prospective EPIC cohort strengthens the validity of the findings by using prediagnostic biomarker measurements, thereby reducing the risk of reverse causation. However, the authors acknowledge that mediation analyses rely on assumptions about causal ordering that cannot be fully verified in observational data.