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Menopause Matters

Colorectal Cancer

Does Estrogen Play a Protective Role?

Lila E. Nachtigall, MD

In women, colorectal cancer is the third most common non-skin-related cancer (breast cancer is No. 1 and lung cancer is No. 2) and the third leading cause of cancer death (lung cancer is No.1 and breast cancer is No. 2), accounting for approximately 11% of all cancer-related mortality.¹ Although colorectal cancer risk is not associated with menopause per se, it increases as women get older. The incidence of this disease starts to rise between the ages of 40 and 45, and peaks at age 75. The incidence is also higher in persons with a personal or family history of colorectal cancer, adenomatous polyps, or inflammatory bowel disease, and in persons who smoke.

Reducing Risk
Certain lifestyle factors and use of certain pharmacologic agents may be associated with a reduced risk of colorectal cancer. Some evidence indicates that exercise and healthful eating habits (eg, a low-fat, high-fiber diet) have a protective effect.² Use of aspirin or other nonsteroidal anti-inflammatory drugs has also been associated with some reduction in colorectal cancer risk.³ Calcium has shown similar efficacy in this regard.⁴ Further studies are needed, however, before specific recommendations can be made.

Postmenopausal estrogen replacement therapy (ERT) or hormone replacement therapy (HRT; estrogen plus a progestogen) may also play a role in reducing colorectal cancer risk. In a meta-analysis of 18 epidemiologic studies of ERT/HRT use and colorectal cancer, a significant protective effect was found for both colon and rectal cancers in women who had taken hormones as compared with never-users.⁵ Colon cancer risk was reduced by 20%, and rectal cancer risk by 19%. Current users had the greatest reduction in colorectal cancer risk (relative risk [RR], 0.66).

In a similar meta-analysis of 25 studies involving ERT/HRT use and colorectal cancer, ERT/HRT was found to significantly reduce the risk of colon cancer, but not rectal cancer.⁶ Again, current users gained the most protection-a 33% reduction in colon cancer risk. Ever-use of ERT/HRT did not significantly reduce the risk of either colon cancer (RR, 0.92) or rectal cancer (RR, 0.97).

In individual studies, the most compelling data suggest a link between ERT/HRT use and reduced colon cancer risk. In one of the largest case-control studies (815 cases and 1019 controls), a significant decrease in colon cancer risk was observed in postmenopausal women who had ever used ERT/HRT as compared with never-users (RR, 0.82).⁷ Another large case-control study (1400 cases and 1200 controls) showed a marked decrease in colon cancer risk in ERT users (RR, 0.57).⁸ A large observational study conducted by the American Cancer Society on 422,373 postmenopausal women revealed a 29% decrease in colon cancer mortality in hormone users relative to nonusers.9 Data from the Nurses' Health Study indicated that current ERT/HRT use reduced colon cancer risk by 35%,¹⁰ although the benefit was not related to duration of use. Five years after ERT/HRT was discontinued, however, any benefit was lost. None of these studies were randomized or controlled, raising the following question: Could the difference in colon cancer risk between ERT/HRT users and nonusers be explained by factors other than estrogen use? For example, it is possible that women who choose to use ERT/HRT are particularly health-conscious, and are thus more likely to follow a low-fat, high-fiber diet that actually reduces colon cancer risk.

Clinical Implications
For midlife women with risk factors for colon cancer who are considering ERT/HRT, clinicians could inform them of the likely benefit of this therapy in lowering colon cancer risk. Conversely, women should know that ERT/HRT use has not been observed to reduce rectal cancer risk, although no increase in risk has been observed.

Although some evidence supports ERT/HRT for primary prevention of colon cancer, the US Food and Drug Administration has not approved hormone therapy for this indication. Furthermore, no evidence suggests that ERT/HRT is useful as part of a colon cancer treatment regimen. Dissimilarity in the purported prophylactic effects of ERT/HRT against colon cancer versus rectal cancer adds to the conclusion that the pathophysiology, treatment, and prognosis for these two cancers are very different.

In summary, observational evidence suggests that women at risk for colon cancer, but not rectal cancer, could derive some benefit from ERT/HRT. Although ERT/HRT should not be prescribed solely for this effect, women who do take postmenopausal hormone therapy may receive this added chemoprotective benefit.

References

1. American Cancer Society. Cancer Facts & Figures 2000. Atlanta, GA: American Cancer Society; 2000.
   
2. Thune I. Assessments of physical activity and cancer risk. Eur J Cancer Prev. 2000;9:387-393.
   
3. Sjodahl R. Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract: extent, mode, and dose dependence of anticancer effects. Am J Med. 2001;110:66-69.
   
4. The North American Menopause Society. The role of calcium in peri- and postmenopausal women: consensus opinion of The North American Menopause Society. Menopause. 2001;8:84-95.
   
5. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med. 1999;106:574-582.
   
6. Nanda K, Bastian LA, Hasselblad V, Simel DL. Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet Gynecol. 1999; 93:880-888.
   
7. Kampman E, Potter JD, Slattery MI, et al. Hormone replacement therapy reproductive history and colon cancer: a multicenter, case-control study in the United States. Cancer Causes Control. 1997;8:146-158.
   
8. Lauritzen C. Ostrogen substitution in der menopause vor und nach behandelern. In: Lauritzen C, ed. Menopause Hormosubstitution. Basel, Switzerland: Aescupes; 1993:76-88.
   
9. Calle EE, Miracle-McMahill HL, Thun MJ, Heath CW. Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst. 1995;87:517-523.
   
10. Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med. 1998;128: 705-712.

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