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A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer

¹ Albert Einstein College of Medicine and ² Montefiore Medical Center, New York, New York; ³ Rutgers University, New Brunswick, New Jersey; ⁴ Yale University School of Medicine, New Haven, Connecticut; ⁵ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁶ McGill University, Montreal, Quebec, Canada; ⁷ Fred Hutchinson Cancer Research Center, Seattle, Washington; and ⁸ MedStar Research Institute, Hyattsville, Maryland

Requests for reprints: Marc Gunter, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, NY 10461. Phone: 718-430-3089; Fax: 718-430-8780. E-mail: mgunter{at}aecom.yu.edu

Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HR_q4-q1), 2.33; 95% confidence interval (95% CI), 1.13-4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HR_q4-q1, 0.53; 95% CI, 0.31-0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HR_q4-q1, 4.30; 95% CI, 1.62-11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data. (Cancer Epidemiol Biomarkers Prev 2008;17(4):921–9)