title: Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women.
abstract: Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Women's Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)(q4-q1), 1.73; 95% confidence interval (CI), 1.16-2.57; P(trend) = 0.005], waist circumference (HR(q4-q1), 1.82; 95% CI, 1.22-2.70; P(trend) = 0.001), and free IGF-I (HR(q4-q1), 1.35; 95% CI, 0.92-1.98; P(trend) = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05-2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I.
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 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: Thomas E
authors.initials: TE
authors.lastname: Rohan
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.forename: Barbara V
authors.initials: BV
authors.lastname: Howard
authors.forename: Judith
authors.initials: J
authors.lastname: Wylie-Rosett
authors.forename: Garnet L
authors.initials: GL
authors.lastname: Anderson
authors.forename: Gloria Y F
authors.initials: GY
authors.lastname: Ho
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kaplan
authors.forename: Jixin
authors.initials: J
authors.lastname: Li
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Xue
authors.forename: Tiffany G
authors.initials: TG
authors.lastname: Harris
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
authors.forename: Howard D
authors.initials: HD
authors.lastname: Strickler
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology*; D004958:Estradiol / Q000097:blood*; D005260:Female; D006801:Humans; D015994:Incidence; D007328:Insulin / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D008875:Middle Aged; D017698:Postmenopause; D012307:Risk Factors
chemical_list: D007328:Insulin; D004958:Estradiol; D007334:Insulin-Like Growth Factor I