Premenopausal and postmenopausal obesity and endometrial cancer risk: circulating biomarkers of inflammation, insulin resistance, and sex hormones as mediators

BACKGROUND: Obesity may increase endometrial cancer risk through pathways involving chronic inflammation, insulin resistance, and altered sex hormone levels. METHODS: Within the European Prospective Investigation into Cancer and Nutrition cohort, we investigated these mediating pathways using pre-diagnostic circulating biomarkers measured in 337 matched case-control pairs with postmenopausal measurements and 196 pairs with premenopausal measurements. We estimated the natural indirect effect (NIE) of obesity [body mass index (BMI) ≥30 kg/m2 vs < 25 kg/m2] on endometrial cancer risk: (1) for each biomarker separately, (2) for all biomarkers jointly, and (3) sequentially, accounting for upstream biomarkers based on an assumed causal sequence specified a priori. RESULTS: The adjusted odds ratio (OR) between obesity and endometrial cancer risk was 3.34 [95% confidence interval (CI) 1.97 to 5.65] in the postmenopausal analysis, and 3.24 (1.43 to 7.36) in the premenopausal analysis. Jointly, the ORNIE through all biomarkers was 1.82 [CI 1.21 to 2.74; proportion mediated (P.M.)=50%] in the postmenopausal analysis and 1.79 (0.97 to 3.29; 49%) in the premenopausal analysis. In sequential mediation analysis, estrone [ORNIE =1.20 (CI 1.02 to 1.41); P.M. = 15%] remained a key mediator beyond upstream biomarkers in the postmenopausal analysis and interleukin-6 (IL-6) [1.35 (1.03 to 1.78); 24%] remained a key mediator in the premenopausal analysis. CONCLUSIONS: Circulating biomarkers for inflammation, insulin resistance, and sex hormones may mediate the effect of obesity on endometrial cancer risk, with some overlaps in mediating pathways. Sex hormones were the most prominent mediators in postmenopausal obesity, whereas biomarkers for inflammation may play an important role in premenopausal obesity.

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Journal
JNCI Journal of the National Cancer Institute
Published
2026-04-17
DOI
https://doi.org/10.1093/jnci/djag119
Primary Topic
Endometrial and Cervical Cancer Treatments
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article
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article

Premenopausal and postmenopausal obesity and endometrial cancer risk: circulating biomarkers of inflammation, insulin resistance, and sex hormones as mediators

James Yarmolinsky, Amaia Aizpurua, Carine Biessy, Sabina Rinaldi et al.
JNCI Journal of the National Cancer Institute
Endometrial and Cervical Cancer Treatments
article

Premenopausal and postmenopausal obesity and endometrial cancer risk: circulating biomarkers of inflammation, insulin resistance, and sex hormones as mediators

James Yarmolinsky, Amaia Aizpurua, Carine Biessy, Sabina Rinaldi, Marianne Canonico, Ruth C. Travis, A. Fournier, ­Rosario ­Tumino, Holly Baker‐Rand, Pekka Keski‐Rahkonen, Charlotte Le Cornet, Giovanna Masala, Renée T. Fortner, Vivian Viallon, Sabine Naudin, Marcela Guevara, Sabrina E. Wang, Marta Crous‐Bou, Camilla Panico, Marı́a Teresa Giraudo, Natalia Cabrera Castro, Matthias Schulze, Emma J Crosbie, Maria-Jose Sánchez, Laura Burney Ellis, Tracy O'Mara, Maria Kyrgiou, Laure Dossus, Marc J Gunter, Mattias Johansson, S Ghazaleh Dashti
article en

Abstract

BACKGROUND: Obesity may increase endometrial cancer risk through pathways involving chronic inflammation, insulin resistance, and altered sex hormone levels. METHODS: Within the European Prospective Investigation into Cancer and Nutrition cohort, we investigated these mediating pathways using pre-diagnostic circulating biomarkers measured in 337 matched case-control pairs with postmenopausal measurements and 196 pairs with premenopausal measurements. We estimated the natural indirect effect (NIE) of obesity [body mass index (BMI) ≥30 kg/m2 vs < 25 kg/m2] on endometrial cancer risk: (1) for each biomarker separately, (2) for all biomarkers jointly, and (3) sequentially, accounting for upstream biomarkers based on an assumed causal sequence specified a priori. RESULTS: The adjusted odds ratio (OR) between obesity and endometrial cancer risk was 3.34 [95% confidence interval (CI) 1.97 to 5.65] in the postmenopausal analysis, and 3.24 (1.43 to 7.36) in the premenopausal analysis. Jointly, the ORNIE through all biomarkers was 1.82 [CI 1.21 to 2.74; proportion mediated (P.M.)=50%] in the postmenopausal analysis and 1.79 (0.97 to 3.29; 49%) in the premenopausal analysis. In sequential mediation analysis, estrone [ORNIE =1.20 (CI 1.02 to 1.41); P.M. = 15%] remained a key mediator beyond upstream biomarkers in the postmenopausal analysis and interleukin-6 (IL-6) [1.35 (1.03 to 1.78); 24%] remained a key mediator in the premenopausal analysis. CONCLUSIONS: Circulating biomarkers for inflammation, insulin resistance, and sex hormones may mediate the effect of obesity on endometrial cancer risk, with some overlaps in mediating pathways. Sex hormones were the most prominent mediators in postmenopausal obesity, whereas biomarkers for inflammation may play an important role in premenopausal obesity.

JNCI Journal of the National Cancer Institute
Royal Children's Hospital (AU), Norwegian Institute of Public Health (NO), Harvard University (US), Imperial College Healthcare NHS Trust (GB), Inserm (FR), The University of Melbourne (AU), German Cancer Research Center (DE), Université de Versailles Saint-Quentin-en-Yvelines (FR), QIMR Berghofer Medical Research Institute (AU), Heidelberg University (DE), Université Paris-Saclay (FR), Manchester Academic Health Science Centre (GB), Basque Government (ES), Cancer Research UK (GB), Prevention Institute (US), Institut Gustave Roussy (FR), Agostino Gemelli University Polyclinic (IT), University of Manchester (GB), University of Oxford (GB), Instituto de Salud Pública de Navarra (ES), Institut d'Investigació Biomédica de Bellvitge (ES), St Mary's Hospital (GB), London Cancer (GB), Manchester University NHS Foundation Trust (GB), University of Ragusa (IT), Biogipuzkoa Health Research Institute (ES), Cancer Research And Biostatistics (US), Centre de recherche en Epidémiologie et Santé des Populations (FR), Navarre Institute of Health Research (ES), Instituto de Investigación Biosanitaria de Granada (ES), Cancer Clinic (US), Department of Medical Sciences (BY), Cancer Registry of Norway (NO), Murdoch Children's Research Institute (AU), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Department of Public Health (US), German Institute of Human Nutrition (DE), Centre international de recherche sur le cancer (FR), Imperial College London (GB), University of Turin (IT), Andalusian School of Public Health (ES), Universidad de Murcia (ES)
Good health and well-being
Openalex Percentile: Top 16%
Endometrial and Cervical Cancer Treatments
DOISourceOpenAlex
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