title: A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer.
abstract: 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.
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA. mgunter@aecom.yu.edu
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Gunter
authors.forename: Donald R
authors.initials: DR
authors.lastname: Hoover
authors.forename: Herbert
authors.initials: H
authors.lastname: Yu
authors.forename: Sylvia
authors.initials: S
authors.lastname: Wassertheil-Smoller
authors.forename: Joann E
authors.initials: JE
authors.lastname: Manson
authors.forename: Jixin
authors.initials: J
authors.lastname: Li
authors.forename: Tiffany G
authors.initials: TG
authors.lastname: Harris
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Rohan
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Xue
authors.forename: Gloria Y F
authors.initials: GY
authors.lastname: Ho
authors.forename: Mark H
authors.initials: MH
authors.lastname: Einstein
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kaplan
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
authors.forename: Judith
authors.initials: J
authors.lastname: Wylie-Rosett
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.forename: Garnet
authors.initials: G
authors.lastname: Anderson
authors.forename: Barbara V
authors.initials: BV
authors.lastname: Howard
authors.forename: Howard D
authors.initials: HD
authors.lastname: Strickler
mesh_terms: D000368:Aged; D015992:Body Mass Index; D018269:Carcinoma, Endometrioid / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood*; D007328:Insulin / Q000097:blood*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009765:Obesity / Q000150:complications; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D004958:Estradiol