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Multicenter Study
. 2015 Aug 1;107(10):djv210.
doi: 10.1093/jnci/djv210. Print 2015 Oct.

A Prospective Evaluation of Endogenous Sex Hormone Levels and Colorectal Cancer Risk in Postmenopausal Women

Neil Murphy  1 , Howard D Strickler  2 , Frank Z Stanczyk  2 , Xiaonan Xue  2 , Sylvia Wassertheil-Smoller  2 , Thomas E Rohan  2 , Gloria Y F Ho  2 , Garnet L Anderson  2 , John D Potter  2 , Marc J Gunter  2
Affiliations
Multicenter Study

A Prospective Evaluation of Endogenous Sex Hormone Levels and Colorectal Cancer Risk in Postmenopausal Women

Neil Murphy et al. J Natl Cancer Inst. .

Abstract

Background: Postmenopausal hormone therapy use has been associated with lower colorectal cancer risk in observational studies. However, the role of endogenous sex hormones in colorectal cancer development in postmenopausal women is uncertain.

Methods: The relation of colorectal cancer risk with circulating levels of estradiol, estrone, free (bioactive) estradiol, progesterone and sex hormone-binding globulin (SHBG) was determined in a nested case-control study of 1203 postmenopausal women (401 case patients and 802 age and race/ethnicity-matched control patients) enrolled in the Women's Health Initiative Clinical Trial (WHI-CT) who were not assigned to the estrogen-alone or combined estrogen plus progestin intervention groups. We used multivariable-adjusted conditional logistic regression models that included established colorectal cancer risk factors. All statistical tests were two-sided.

Results: Comparing extreme quartiles, estrone (odds ratio [OR]q4-q1 = 0.44, 95% confidence interval [CI] = 0.28 to 0.68, P trend = .001), free estradiol (ORq4-q1 = 0.43, 95% CI = 0.27 to 0.69, P trend ≤ .0001), and total estradiol (ORq4-q1 = 0.58, 95% CI = 0.38 to 0.90, P trend = .08) were inversely associated with colorectal cancer risk. SHBG levels were positively associated with colorectal cancer development (OR[q4-q1] = 2.30, 95% CI = 1.51 to 3.51, P trend ≤ .0001); this association strengthened after further adjustment for estradiol and estrone (ORq4-q1 = 2.50, 95% CI = 1.59 to 3.92, P trend < .0001). Progesterone was not associated with colorectal cancer risk.

Conclusion: Endogenous estrogen levels were inversely, and SHBG levels positively, associated with colorectal cancer risk, even after control for several colorectal cancer risk factors. These results suggest that endogenous estrogens may confer protection against colorectal tumorigenesis among postmenopausal women.

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Figures

Figure 1.
Figure 1.
Association between circulating (A) estradiol, (B) estrone, (C) free estradiol, and (D) sex hormone–binding globulin (SHBG) with colorectal cancer allowing for nonlinear effects (restricted cubic spline). Solid lines indicate the odds ratio, and shaded gray areas indicate the 95% confidence intervals. Multivariable models only—adjusted for waist circumference, alcohol consumption, family history of colorectal cancer, physical activity, smoking status, and NSAID use. Estradiol and estrone models additionally adjusted for insulin, insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP), and SHBG. Free estradiol model additionally adjusted for insulin, IGF-1, and CRP. SHBG model additionally adjusted for insulin, IGF-1, CRP, estradiol, and estrone. The references for these restricted cubic spline plots (with five knots placed at the 10th, 25th, 50th, 75th, and 95th percentiles) were estradiol 7 pg/mL, estrone 32.4 pg/mL, free estradiol 0.17 pg/mL, and SHBG 22 nmol/L.
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