Background: Obesity is a major risk factor for endometrial cancer; a relationship thought to be largely explained by high estrogen levels in obese women. Obesity is also associated with high levels of insulin, which has mitogenic activity. However, no prospective studies have assessed whether insulin and/or insulin-like growth factor-I (IGF-I) are associated with endometrial cancer independent of endogenous estrogen levels. Materials and Methods: We conducted a case-cohort study of incident endometrial cancer among subjects enrolled in the Women's Health Initiative, a prospective cohort of 93,676 postmenopausal women. The study involved 250 incident cases, and a random subcohort of 465 subjects. Total IGF-I, free IGF-I, IGF binding protein-3, insulin, glucose and estradiol levels were measured in fasting baseline serum samples. Multivariate Cox models were used to estimate associations with incident endometrial cancer - in particular, associations with endometrioid adenocarcinomas (EA), the main histologic type (N=205). Results: Insulin levels were associated with increased risk of EA (hazard ratio for highest versus lowest quartile [HRq4-q1] =2.33, 95% confidence interval [CI], 1.13-4.82), among women not using hormone therapy (HT), after adjustment for age and estradiol levels, and following separate adjustment for age and body mass index (BMI) (HRq4-q1=2.44, 95% confidence interval [CI], 1.09-5.45) Free IGF-I was inversely associated with EA (HRq4-q1 =0.53, 95% CI, 0.31-0.90), after adjustment for age, and HT use/estradiol levels. Both of these associations were stronger among women with BMI ≥25Kg/M2, especially the association between insulin and EA (HRq4-q1 = 4.30, 95% CI, 1.62-11.43), adjusted for age, HT use/estradiol levels, and free IGF-I. Conclusions: These data provide the first prospective evidence that hyperinsulinemia may be a risk factor for EA independent of endogenous estrogen levels. Free IGF-I levels were inversely associated with EA, consistent with prior cross-sectional data.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]