Why Hormones Protect Against Large Bowel Cancer: Old Ideas, New Evidence

  • Polly A. Newcomb
  • Gaia Pocobelli
  • Victoria Chia
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)

Colorectal cancer (CRC) is second only to lung cancer as the leading cause of cancer mortality in men and women, and remains a significant cause of morbidity. Accumulating evidence from observational, clinical, and laboratory studies indicates that hormones reduce large bowel cancer risk. Recently, questions have arisen regarding which hormones are germane, and in what milieu they are relevant. In this chapter, we consider the genesis of this hypothesis, its studies in humans, and biological pathways that might explain recent and past findings, including new genetic and epigenetic mechanisms. Other perturbations in metabolizing enzymes responsible for estrogen metabolisms and the conversion of progesterone to estrogens may be relevant, although specific polymorphisms contributing to variations in hormone concentrations have not been directly related to CRC risk (1). We also provide some new evidence on the long-term effects of hormones on specific subtypes of large bowel tumors, and on CRC mortality, further supporting putative roles for hormone effects.


Natl Cancer Inst Microsatellite Instability Bile Acid Secretion Proximal Colon Cancer Large Bowel Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Thompson PA, Ambrosone C (2000) Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. J Natl Cancer Inst Monogr 125–34.Google Scholar
  2. 2.
    Surveillance, Epidemiology, and End Results (SEER) Program ( SEER*Stat Database: Incidence – SEER 17 Regs Public-Use, Nov 2005 Sub (1973–2003 varying), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006, based on the November 2005 submission.
  3. 3.
    McMichael AJ, Potter JD (1983) Do intrinsic sex differences in lower alimentary tract physiology influence the sex-specific risks of bowel cancer and other biliary and intestinal diseases? Am J Epidemiol 118: 620–7.PubMedGoogle Scholar
  4. 4.
    Chlebowski R, Wactawski-Wende J, Ritenbaugh C, et al (2004) Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 350: 991–1004.PubMedCrossRefGoogle Scholar
  5. 5.
    Fraumeni JF Jr., Lloyd JW, Smith EM, et al (1969) Cancer mortality among nuns: role of marital status in etiology of neoplastic disease in women. J Natl Cancer Inst 42: 455–68.PubMedGoogle Scholar
  6. 6.
    Potter JD (1999) Colorectal cancer: molecules and populations. J Natl Cancer Inst 91: 916–32.PubMedCrossRefGoogle Scholar
  7. 7.
    Gunter MJ, Leitzmann MF (2006) Obesity and colorectal cancer: epidemiology, mechanisms and candidate genes. J Nutr Biochem 17: 145–56.PubMedCrossRefGoogle Scholar
  8. 8.
    Siiteri PK (1987) Adipose tissue as a source of hormones. Am J Clin Nutr 45: 277–82.PubMedGoogle Scholar
  9. 9.
    Slattery ML, Ballard-Barbash R, Edwards S, et al (2003) Body mass index and colon cancer: an evaluation of the modifying effects of estrogen (United States). Cancer Causes Control 14: 75–84.PubMedCrossRefGoogle Scholar
  10. 10.
    Morimoto LM, Newcomb PA, White E, et al (2005) Insulin-like growth factor polymorphisms and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 14: 1204–11.PubMedCrossRefGoogle Scholar
  11. 11.
    Slattery ML, Edwards SL, Ma KN, et al (1997) Physical activity and colon cancer: a public health perspective. Ann Epidemiol 7: 137–45.PubMedCrossRefGoogle Scholar
  12. 12.
    MacMahon B, Trichopoulos D, Cole P, et al (1982) Cigarette smoking and urinary estrogens. N Engl J Med 307: 1062–5.PubMedGoogle Scholar
  13. 13.
    Newcomb PA, Storer BE, Marcus PM (1995) Cigarette smoking in relation to risk of large bowel cancer in women. Cancer Res 55: 4906–9.PubMedGoogle Scholar
  14. 14.
    Grodstein F, Newcomb PA, Stampfer MJ (1999) Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 106: 574–82.PubMedCrossRefGoogle Scholar
  15. 15.
    La Vecchia C, Gallus S, Fernandez E (2005) Hormone replacement therapy and colorectal cancer: an update. J Br Menopause Soc 11: 166–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Leslie A, Carey FA, Pratt NR, et al (2002) The colorectal adenoma-carcinoma sequence. Br J Surg 89: 845–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Terry MB, Neugut AI, Bostick RM, et al (2002) Risk factors for advanced colorectal adenomas: a pooled analysis. Cancer Epidemiol Biomarkers Prev 11: 622–9.PubMedGoogle Scholar
  18. 18.
    Potter JD, Bostick RM, Grandits GA, et al (1996) Hormone replacement therapy is associated with lower risk of adenomatous polyps of the large bowel: the Minnesota Cancer Prevention Research Unit Case-Control Study. Cancer Epidemiol Biomarkers Prev 5: 779–84.PubMedGoogle Scholar
  19. 19.
    Morimoto LM, Newcomb PA, Ulrich CM, et al (2002) Risk factors for hyperplastic and adenomatous polyps: evidence for malignant potential? Cancer Epidemiol Biomarkers Prev 11: 1012–8.PubMedGoogle Scholar
  20. 20.
    Matthews KA, Kuller LH, Wing RR, et al (1996) Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 143: 971–8.PubMedGoogle Scholar
  21. 21.
    Barrett-Connor E (1991) Postmenopausal estrogen and prevention bias. Ann Intern Med 115: 455–6.PubMedGoogle Scholar
  22. 22.
    Sturgeon SR, Schairer C, Brinton LA, et al (1995) Evidence of a healthy estrogen user survivor effect. Epidemiology 6: 227–31.PubMedGoogle Scholar
  23. 23.
    Rossouw JE, Anderson GL, Prentice RL, et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288: 321–33.PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson GL, Limacher M, Assaf AR, et al (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291: 1701–12.PubMedCrossRefGoogle Scholar
  25. 25.
    Newcomb PA, Storer BE (1995) Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst 87: 1067–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Kampman E, Potter JD, Slattery ML, et al (1997) Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States. Cancer Causes Control 8: 146–58.PubMedCrossRefGoogle Scholar
  27. 27.
    Pischon T, Lahmann PH, Boeing H, et al (2006) Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst 98: 920–31.PubMedCrossRefGoogle Scholar
  28. 28.
    Slattery ML, Potter JD, Curtin K, et al (2001) Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res 61: 126–30.PubMedGoogle Scholar
  29. 29.
    Newcomb PA, Zheng Y, Chia VM, et al (2007) Estrogen plus progestin use and the risk of colorectal cancer in postmenopausal women cancer res 67:7534–9.Google Scholar
  30. 30.
    Chu KC, Tarone RE, Chow WH, et al (1995) Colorectal cancer trends by race and anatomic subsites, 1975–1991. Arch Fam Med 4: 849–56.PubMedCrossRefGoogle Scholar
  31. 31.
    Surveillance, Epidemiology, and End Results (SEER) Program ( Prevalence database: “US Estimated Complete Prevalence Counts on 1/1/2003”. National Cancer Institute, DCCPS, Surveillance Research Program, Statistical Research and Applications Branch, released April 2006, based on the November 2005 SEER data submission.
  32. 32.
    Hersh AL, Stefanick ML, Stafford RS (2004) National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 291: 47–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Slattery ML, Anderson K, Samowitz W, et al (1999) Hormone replacement therapy and improved survival among postmenopausal women diagnosed with colon cancer. Cancer Causes Control 10: 467–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Mandelson MT, Miglioretti D, Newcomb PA, et al (2003) Hormone replacement therapy in relation to survival in women diagnosed with colon cancer. Cancer Causes Control 14: 979–84.PubMedCrossRefGoogle Scholar
  35. 35.
    Murphy TK, Calle EE, Rodriguez C, et al (2000) Body mass index and colon cancer mortality in a large prospective study. Am J Epidemiol 152: 847–54.PubMedCrossRefGoogle Scholar
  36. 36.
    Tamakoshi K, Wakai K, Kojima M, et al (2004) A prospective study of body size and colon cancer mortality in Japan: The JACC Study. Int J Obes Relat Metab Disord 28: 551–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Doria-Rose VP, Newcomb PA, Morimoto LM, et al (2006) Body mass index and the risk of death following the diagnosis of colorectal cancer in postmenopausal women (United States). Cancer Causes Control 17: 63–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Gervaz P, Bouzourene H, Cerottini JP, et al (2001) Dukes B colorectal cancer: distinct genetic categories and clinical outcome based on proximal or distal tumor location. Dis Colon Rectum 44: 364–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Kim H, Jen J, Vogelstein B, et al (1994) Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 145: 148–56.PubMedGoogle Scholar
  40. 40.
    Gryfe R, Kim H, Hsieh ET (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342: 69–77.PubMedCrossRefGoogle Scholar
  41. 41.
    Samowitz WS, Curtin K, Ma KN (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 10: 917–23.PubMedGoogle Scholar
  42. 42.
    Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23: 609–18.PubMedCrossRefGoogle Scholar
  43. 43.
    Foley EF, Jazaeri AA, Shupnik MA, et al (2000) Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60: 245–8.PubMedGoogle Scholar
  44. 44.
    Fearon ER, Vogelstein B (1990) A genetic model of colorectal tumorigenesis. Cell 61: 759–67.PubMedCrossRefGoogle Scholar
  45. 45.
    Morson BC (1974) Evolution of cancer of the colon and rectum. Cancer 34: 845.PubMedCrossRefGoogle Scholar
  46. 46.
    McMichael AJ, Potter JD (1980) Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst 65: 1201–7.PubMedGoogle Scholar
  47. 47.
    Reddy BS, Watanabe K, Weisburger JH, et al (1977) Promoting effect of bile acids in colon carcinogenesis in germ-free and conventional F344 rats. Cancer Res 37: 3238–42.PubMedGoogle Scholar
  48. 48.
    McKeown-Eyssen G (1994) Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol Biomarkers Prev 3: 687–95.PubMedGoogle Scholar
  49. 49.
    Morimoto LM, Newcomb PA, White E, et al (2005) Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: personal and lifestyle factors (United States). Cancer Causes Control 16: 917–27.PubMedCrossRefGoogle Scholar
  50. 50.
    Heald A, Selby PL, White A, et al (2000) Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis. Am J Obstet Gynecol 183: 593–600.PubMedCrossRefGoogle Scholar
  51. 51.
    Renehan AG, Wille-Jorgensen P (2004) Systematic review, Cochrane and Colorectal Disease. Colorectal Dis 6: 73–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Morimoto LM, Newcomb PA, White E, et al (2005) Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: genetic factors. Cancer Epidemiol Biomarkers Prev 14: 1394–401.PubMedCrossRefGoogle Scholar
  53. 53.
    Bardin A, Boulle N, Lazennec G, et al (2004) Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 11: 537–51.PubMedCrossRefGoogle Scholar
  54. 54.
    McDonnell DP, Norris JD (2002) Connections and regulation of the human estrogen receptor. Science 296: 1642–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Konstantinopoulos PA, Kominea A, Vandoros G, et al (2003) Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour’s dedifferentiation. Eur J Cancer 39: 1251–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Potter JD, Cerhan JR, Sellers TA, et al (1995) Progesterone and estrogen receptors and mammary neoplasia in the Iowa Women’s Health Study: how many kinds of breast cancer are there? Cancer Epidemiol Biomarkers Prev 4: 319–26.PubMedGoogle Scholar
  57. 57.
    Poutanen M, Isomaa V, Peltoketo H, et al (1995) Role of 17 beta-hydroxysteroid dehydrogenase type 1 in endocrine and intracrine estradiol biosynthesis. J Steroid Biochem Mol Biol 55: 525–32.PubMedCrossRefGoogle Scholar
  58. 58.
    Schairer C, Lubin J, Troisi R, et al (2000) Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk. JAMA 283: 485–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Peterson CM (2000) Estrogen and progesterone receptors: an overview from the year 2000. J Soc Gynecol Investig 7: S3–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Di Leo A, Messa C, Cavallini A, et al (2001) Estrogens and colorectal cancer. Curr Drug Targets Immune Endocr Metabol Disord 1: 1–12.PubMedCrossRefGoogle Scholar
  61. 61.
    Baylin SB and Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joints genetics. Trends Genet 16: 168–74.PubMedCrossRefGoogle Scholar
  62. 62.
    Issa JP, Ottaviano YL, Celano P (1994) Methylation of the oestrogen receptor CpG island link ageing and neoplasia in human colon. Nature Genet 7: 536–40.PubMedCrossRefGoogle Scholar
  63. 63.
    Potter JD (1995) Hormones and colon cancer. J Natl Cancer Inst 87: 1039–40.PubMedCrossRefGoogle Scholar
  64. 64.
    Hawkins N, Norrie M, Cheong K, et al (2002) CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122: 1376–87.PubMedCrossRefGoogle Scholar
  65. 65.
    Whitehall VL, Wynter CV, Walsh MD, et al (2002) Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res 62: 6011–4.PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Polly A. Newcomb
    • 1
  • Gaia Pocobelli
  • Victoria Chia
  1. 1.Cancer Prevention Public Health ScienceFred Hutchinson Cancer Research CenterSeattleUSA

Personalised recommendations