Estrogen Metabolites Are Not Associated with Colorectal Cancer Risk in Postmenopausal Women

Exogenous hormones are linked to colorectal cancer risk reduction (1, 2), yet risks associated with circulating estrogens are elevated (3, 4), or null (5). In normal colonic tissue, ERα enhances cell growth and is expressed at low levels, while the antiproliferative ERβ is abundant (6). In neoplastic colonic tissue, this is reversed. Estradiol binds to both receptors with comparably high affinity, but at least one estrogen metabolite (EM), 17-epiestriol, shows a binding preference for ERβ (7). We speculated that selective binding of EM to ERα or ERβ may influence colon carcinogenesis. Thus, we investigated the association between a panel of EM and colorectal cancer in the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT).

FIT, a randomized trial designed to test alendronate, screened 22,695 postmenopausal women ages 55 to 80 from 1992 to 1993, who provided a bone mineral density (BMD) scan, blood and information on demographic, lifestyle, and reproductive factors through a self-administered questionnaire. B∼FIT comprises 15,595 of the FIT screenees followed for incident cancer through December 2004. An additional questionnaire covering subsequent cancer diagnoses was sent to these participants (8).

Self-reported cancers were confirmed by medical records and/or cancer registries. Additional cases were identified from cancer registries. Vital status was determined by the National Death Index. All participants provided written informed consent, and Institutional Review Board approval was obtained from all clinical sites and the National Cancer Institute.

This analysis was part of a case–cohort study within B∼FIT examining EM in relation to colorectal cancer, breast, endometrial, and ovarian cancer (8). We studied 187 colorectal cancer cases (10 in the subcohort) and 501 subcohort women. Fifteen EM were measured in serum: estrone, estradiol, 2-hydroxyestrone, 2-methoxyestrone, 2-hydroxyestradiol, 2-methoxyestradiol, 2-hydroxyestrone-3-methyl ether, 4-hydroxyestrone, 4-methoxyestrone, 4-methoxyestradiol, 16α-hydroxyestrone, estriol, 17-epiestriol, 16-ketoestradiol, and 16-epiestriol.

EM were examined individually, by pathway (C-2, C-4, or C-16 hydroxylation, with EM in each pathway summed), and by ratios of pathways. Cox proportional hazards regression models with robust variance adjustment were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). For cases not in the subcohort, follow-up began 6 months prior to colorectal cancer diagnosis and ended at diagnosis. For the subcohort, follow-up began at baseline and ended at colorectal cancer diagnosis for cases (n = 10), and death or end of the follow-up for noncases (n = 491). Covariates examined included body mass index (BMI), parity, smoking, postmenopausal hormone use, and ages at menarche, birth of the first child, and menopause. The final model adjusted for clinic site, trial participation status, age at blood collection, and total BMD. No adjustment was made for multiple comparisons.

Descriptive characteristics and HR for lifestyle/reproductive risk factors are presented in Table 1. Compared with the subcohort, cases were older at study entry, followed for fewer years, and had lower BMD at baseline. Current smokers experienced a 40% increased risk, and women with a late age at menopause had >2-fold excess risk, but HR for other factors were not statistically significant.

Women with higher total EM were not at elevated risk compared with those in the lowest quartile (Fig. 1A). HR for estrone and estradiol were not significant, and there was no evidence of dose response. HR and trends were not significant for 2- or 4-pathway metabolites, except for reduced risks for moderately high 2-hydroxyestrone (HR_{Q3 vs. Q1} = 0.54; 95% CI, 0.32–0.90; Fig. 1B) and 4-hydroxyestrone (HR_{Q3 vs. Q1} = 0.53; 95% CI, 0.31–0.91; Fig. 1D). For the 16-pathway, a trend of increasing risk with higher 17-epiestriol was suggested, but results for other metabolites were null (Fig. 1C). HR for quartiles of pathway ratios (2- vs. 4-pathway, 2- vs. 16-pathway, and 4- vs. 16-pathway) showed no association (results not shown).

This first prospective study of EM and colorectal cancer risk found no evidence for associations with these hormones. There was a suggestion of a slight effect for 17-epiestriol, but this may have occurred by chance given the number of comparisons. Our lack of association is consistent with results from one study (5), but not others (3, 4), showing modest elevated risks for estradiol or estrone. Reasons for these disparate findings are not clear. Women in our study were older (mean age 67 vs. 60–64 in prior studies), but all involved postmenopausal women not using menopausal hormones at blood draw. The studies were of comparable size; however, unlike others, BMI was not associated with colorectal cancer in our study. Additionally, immunoassays for estrogens in prior studies may not detect the low levels in postmenopausal women.

Estrogen is not central to the etiology of colorectal cancer, but the change from predominantly ERβ expression in the healthy colon to ERα in neoplastic tissue suggests that it may afford protection in the healthy colon, but promote tumorigenesis once neoplastic changes occur. However, results from observational studies of endogenous and exogenous estrogens are not consistent (1, 2).

In summary, although our apparent lack of association between endogenous estrogens is at odds with findings of reduced risk associated with exogenous hormone use, additional well-powered studies are needed to improve our understanding of the exogenous hormone and colorectal cancer association.

No potential conflicts of interest were disclosed.

Conception and design: R.T. Falk, C.M. Dallal, J.V. Lacey Jr, T.D. Veenstra, L.A. Brinton

Development of methodology: R.T. Falk, J.V. Lacey Jr, T.D. Veenstra, L.A. Brinton

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.V. Lacey Jr, D.S.M. Buist, T.F. Hue, J.A. Tice, X. Xu, L.A. Brinton

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): R.T. Falk, C.M. Dallal, J.V. Lacey Jr, D.C. Bauer, J.A. Tice, R.M. Pfeiffer, T.D. Veenstra, L.A. Brinton

Writing, review, and/or revision of the manuscript: R.T. Falk, C.M. Dallal, J.V. Lacey Jr, D.C. Bauer, D.S.M. Buist, J.A. Cauley, A.Z. LaCroix, J.A. Tice, R.M. Pfeiffer, T.D. Veenstra, L.A. Brinton

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): R.T. Falk, C.M. Dallal, D.C. Bauer, D.S.M. Buist, T.F. Hue, L.A. Brinton

Study supervision: J.V. Lacey Jr, D.S.M. Buist, A.Z. LaCroix

The authors thank Stephanie Litwack-Harrison, MPH, for study management; Eric Boyd and Vicky Chia, PhD, for assistance in data management; and the B∼FIT participants for their contributions to this study.

The original FIT study was supported by Merck Research Laboratories. B∼FIT was supported by the National Cancer Institute (contract # N02-CP; D.C. Bauer and J.A. Tice).