Nonlinear reduction in risk for colorectal cancer by oral contraceptive use: a meta-analysis of epidemiological studies

Abstract

Purpose

Although the relationship between oral contraceptive (OC) use and colorectal cancer (CRC) risk has been studied extensively, the results of epidemiological studies are controversial. Therefore, we carried out a meta-analysis of epidemiological studies to summarize the available evidence and to quantify the potential dose–response relation.

Methods

We searched PubMed database for studies of OC use and CRC risk that were published until the end of March 2014. Random- and fixed-effects models were applied to estimate summary relative risks (RRs) and 95 % confidence intervals (CIs).

Results

Twelve cohorts and seventeen case–control studies with a total of 15,790 CRC cases were included in the final analysis. The summary RR for the ever versus never category of OC use was 0.82 (95 % CI 0.76–0.88). Similar result was observed when we compared the longest duration of OC use with the shortest duration (RR = 0.86, 95 % CI 0.76–0.96). Furthermore, the results of stratified analysis were comparable to those of overall meta-analysis. In dose–response analysis, significant inverse associations emerged in nonlinear models for the duration of OC use and CRC (P nonlinearity = 0.001). The greatest risk reduction was observed when the duration of OC use was approximately 42 months. There was moderate heterogeneity in the analysis, and no evidence of small-study bias was observed.

Conclusions

Based on the findings of this meta-analysis, ever use of OC is associated with lower risk of CRC. Additionally, there is a statistically significant nonlinear inverse association between the duration of OC use and CRC risk.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Ferlay J, Soerjomataram I, Ervik M et al (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, Accessed on 1/April/2014

  2. 2.

    Lin JH, Giovannucci E (2010) Sex hormones and colorectal cancer: what have we learned so far? J Natl Cancer Inst 102:1746–1747

    PubMed Central  PubMed  Article  Google Scholar 

  3. 3.

    McMichael AJ, Potter JD (1980) Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst 65:1201–1207

    CAS  PubMed  Google Scholar 

  4. 4.

    Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y et al (1999) Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 91:620–625

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Weissberger AJ, Ho KK, Lazarus L (1991) Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 72:374–381

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Campagnoli C, Abba C, Ambroggio S, Peris C (2003) Differential effects of progestins on the circulating IGF-I system. Maturitas 46(Suppl 1):S39–S44

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE et al (2008) Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res 68:329–337

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. 8.

    Narisawa T, Magadia NE, Weisburger JH, Wynder EL (1974) Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of N-methyl-N′-nitro-N-nitrosoguanidine in rats. J Natl Cancer Inst 53:1093–1097

    CAS  PubMed  Google Scholar 

  9. 9.

    Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J et al (2004) Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 350:991–1004

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Ritenbaugh C, Stanford JL, Wu L, Shikany JM, Schoen RE et al (2008) Conjugated equine estrogens and colorectal cancer incidence and survival: the Women’s Health Initiative randomized clinical trial. Cancer Epidemiol Biomarkers Prev 17:2609–2618

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  11. 11.

    Bosetti C, Bravi F, Negri E, La Vecchia C (2009) Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis. Hum Reprod Update 15:489–498

    PubMed  Article  Google Scholar 

  12. 12.

    Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC et al (2010) Hormonal contraception and risk of cancer. Hum Reprod Update 16:631–650

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Fernandez E, La Vecchia C, Balducci A, Chatenoud L, Franceschi S et al (2001) Oral contraceptives and colorectal cancer risk: a meta-analysis. Br J Cancer 84:722–727

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  14. 14.

    Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG et al (2013) Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev 22:1931–1943

    PubMed  Article  Google Scholar 

  15. 15.

    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535

    PubMed Central  PubMed  Article  Google Scholar 

  16. 16.

    Zervoudakis A, Strickler HD, Park Y, Xue X, Hollenbeck A et al (2011) Reproductive history and risk of colorectal cancer in postmenopausal women. J Natl Cancer Inst 103:826–834

    PubMed Central  PubMed  Article  Google Scholar 

  17. 17.

    Tsilidis KK, Allen NE, Key TJ, Bakken K, Lund E et al (2010) Oral contraceptives, reproductive history and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 103:1755–1759

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. 18.

    Kabat GC, Miller AB, Rohan TE (2008) Oral contraceptive use, hormone replacement therapy, reproductive history and risk of colorectal cancer in women. Int J Cancer 122:643–646

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L et al (2007) Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner’s oral contraception study. BMJ 335:651

    PubMed Central  PubMed  Article  Google Scholar 

  20. 20.

    Lin J, Zhang SM, Cook NR, Manson JE, Buring JE et al (2007) Oral contraceptives, reproductive factors, and risk of colorectal cancer among women in a prospective cohort study. Am J Epidemiol 165:794–801

    PubMed  Article  Google Scholar 

  21. 21.

    Rosenblatt KA, Gao DL, Ray RM, Nelson ZC, Thomas DB (2004) Contraceptive methods and induced abortions and their association with the risk of colon cancer in Shanghai, China. Eur J Cancer 40:590–593

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Vessey M, Painter R, Yeates D (2003) Mortality in relation to oral contraceptive use and cigarette smoking. Lancet 362:185–191

    PubMed  Article  Google Scholar 

  23. 23.

    van Wayenburg CA, van der Schouw YT, van Noord PA, Peeters PH (2000) Age at menopause, body mass index, and the risk of colorectal cancer mortality in the Dutch Diagnostisch Onderzoek Mammacarcinoom (DOM) cohort. Epidemiology 11:304–308

    PubMed  Article  Google Scholar 

  24. 24.

    Troisi R, Schairer C, Chow WH, Schatzkin A, Brinton LA et al (1997) Reproductive factors, oral contraceptive use, and risk of colorectal cancer. Epidemiology 8:75–79

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Martinez ME, Grodstein F, Giovannucci E, Colditz GA, Speizer FE et al (1997) A prospective study of reproductive factors, oral contraceptive use, and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 6:1–5

    CAS  PubMed  Google Scholar 

  26. 26.

    Bostick RM, Potter JD, Kushi LH, Sellers TA, Steinmetz KA et al (1994) Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States). Cancer Causes Control 5:38–52

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Rudolph A, Toth C, Hoffmeister M, Roth W, Herpel E et al (2013) Colorectal cancer risk associated with hormone use varies by expression of estrogen receptor-beta. Cancer Res 73:3306–3315

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Lo AC, Soliman AS, Khaled HM, Aboelyazid A, Greenson JK (2010) Lifestyle, occupational, and reproductive factors and risk of colorectal cancer. Dis Colon Rectum 53:830–837

    PubMed Central  PubMed  Article  Google Scholar 

  29. 29.

    Long MD, Martin CF, Galanko JA, Sandler RS (2010) Hormone replacement therapy, oral contraceptive use, and distal large bowel cancer: a population-based case–control study. Am J Gastroenterol 105:1843–1850

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  30. 30.

    Campbell PT, Newcomb P, Gallinger S, Cotterchio M, McLaughlin JR (2007) Exogenous hormones and colorectal cancer risk in Canada: associations stratified by clinically defined familial risk of cancer. Cancer Causes Control 18:723–733

    PubMed  Article  Google Scholar 

  31. 31.

    Nichols HB, Trentham-Dietz A, Hampton JM, Newcomb PA (2005) Oral contraceptive use, reproductive factors, and colorectal cancer risk: findings from Wisconsin. Cancer Epidemiol Biomarkers Prev 14:1212–1218

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Levi F, Pasche C, Lucchini F, La Vecchia C (2003) Oral contraceptives and colorectal cancer. Dig Liver Dis 35:85–87

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Fernandez E, La Vecchia C, Franceschi S, Braga C, Talamini R et al (1998) Oral contraceptive use and risk of colorectal cancer. Epidemiology 9:295–300

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Kampman E, Potter JD, Slattery ML, Caan BJ, Edwards S (1997) Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case–control study in the United States. Cancer Causes Control 8:146–158

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Jacobs EJ, White E, Weiss NS (1994) Exogenous hormones, reproductive history, and colon cancer (Seattle, Washington, USA). Cancer Causes Control 5:359–366

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Kampman E, Bijl AJ, Kok C, Van’T VP (1994) Reproductive and hormonal factors in male and female colon cancer. Eur J Cancer Prev 3:329–336

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Peters RK, Pike MC, Chang WW, Mack TM (1990) Reproductive factors and colon cancers. Br J Cancer 61:741–748

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  38. 38.

    Kune GA, Kune S, Watson LF (1990) Oral contraceptive use does not protect against large bowel cancer. Contraception 41:19–25

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Furner SE, Davis FG, Nelson RL, Haenszel W (1989) A case–control study of large bowel cancer and hormone exposure in women. Cancer Res 49:4936–4940

    CAS  PubMed  Google Scholar 

  40. 40.

    Potter JD, McMichael AJ (1983) Large bowel cancer in women in relation to reproductive and hormonal factors: a case–control study. J Natl Cancer Inst 71:703–709

    CAS  PubMed  Google Scholar 

  41. 41.

    Weiss NS, Daling JR, Chow WH (1981) Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors. J Natl Cancer Inst 67:57–60

    CAS  PubMed  Google Scholar 

  42. 42.

    Wu-Williams AH, Lee M, Whittemore AS, Gallagher RP, Jiao DA et al (1991) Reproductive factors and colorectal cancer risk among Chinese females. Cancer Res 51:2307–2311

    CAS  PubMed  Google Scholar 

  43. 43.

    Dorjgochoo T, Shu XO, Li HL, Qian HZ, Yang G et al (2009) Use of oral contraceptives, intrauterine devices and tubal sterilization and cancer risk in a large prospective study, from 1996 to 2006. Int J Cancer 124:2442–2449

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  44. 44.

    Luan NN, Wu QJ, Gong TT, Vogtmann E, Wang YL et al (2013) Breastfeeding and ovarian cancer risk: a meta-analysis of epidemiologic studies. Am J Clin Nutr 98:1020–1031

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  45. 45.

    Guan HB, Wu QJ, Gong TT (2013) Parity and kidney cancer risk: evidence from epidemiologic studies. Cancer Epidemiol Biomarkers Prev 22:2345–2353

    PubMed  Article  Google Scholar 

  46. 46.

    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    PubMed  Article  Google Scholar 

  47. 47.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Hamling J, Lee P, Weitkunat R, Ambuhl M (2008) Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med 27:954–970

    PubMed  Article  Google Scholar 

  49. 49.

    Greenland S, Longnecker MP (1992) Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol 135:1301–1309

    CAS  PubMed  Google Scholar 

  50. 50.

    Orsini N, Li R, Wolk A, Khudyakov P, Spiegelman D (2012) Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software. Am J Epidemiol 175:66–73

    PubMed Central  PubMed  Article  Google Scholar 

  51. 51.

    Royston P (2000) A strategy for modelling the effect of a continuous covariate in medicine and epidemiology. Stat Med 19:1831–1847

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Bagnardi V, Zambon A, Quatto P, Corrao G (2004) Flexible meta-regression functions for modeling aggregate dose-response data, with an application to alcohol and mortality. Am J Epidemiol 159:1077–1086

    PubMed  Article  Google Scholar 

  53. 53.

    Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  54. 54.

    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V et al (2010) Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study. BMJ 340:927

    Article  Google Scholar 

  56. 56.

    Aune D, Lau R, Chan DS, Vieira R, Greenwood DC et al (2011) Nonlinear reduction in risk for colorectal cancer by fruit and vegetable intake based on meta-analysis of prospective studies. Gastroenterology 141:106–118

    PubMed  Article  Google Scholar 

  57. 57.

    Everson GT, McKinley C, Kern FJ (1991) Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Invest 87:237–246

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  58. 58.

    McMichael AJ, Potter JD (1985) Host factors in carcinogenesis: certain bile-acid metabolic profiles that selectively increase the risk of proximal colon cancer. J Natl Cancer Inst 75:185–191

    CAS  PubMed  Google Scholar 

  59. 59.

    Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE et al (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7:536–540

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Qiu Y, Waters CE, Lewis AE, Langman MJ, Eggo MC (2002) Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor beta. J Endocrinol 174:369–377

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Campbell-Thompson M, Lynch IJ, Bhardwaj B (2001) Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Res 61:632–640

    CAS  PubMed  Google Scholar 

  62. 62.

    Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B et al (2003) Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol 41:1358–1363

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer MJ et al (2000) A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev 9:345–349

    CAS  PubMed  Google Scholar 

  64. 64.

    Sutton-Tyrrell K, Wildman RP, Matthews KA, Chae C, Lasley BL et al (2005) Sex-hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN). Circulation 111:1242–1249

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Chang CK, Ulrich CM (2003) Hyperinsulinaemia and hyperglycaemia: possible risk factors of colorectal cancer among diabetic patients. Diabetologia 46:595–607

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Moorman PG, Havrilesky LJ, Gierisch JM, Coeytaux RR, Lowery WJ et al (2013) Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. J Clin Oncol 31:4188–4198

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

This study was supported by The National Natural Science Foundation of China (Grants 81072118, 81172491, and 81101527 for Bei Lin); the PhD Programs Foundation of Ministry of Education of China (Grants 20112104110016 and 20112104120019 for Bei Lin); the Shengjing Free Researcher Project (Grant 200807 for Bei Lin); the Younger research fund of Shengjing Hospital (Grant 2014sj09 for Qi-Jun Wu).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Qi-Jun Wu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10552_2014_483_MOESM1_ESM.tif

Forest plot (fixed-effects model) of ever use of oral contraceptive and colon cancer risk. Squares indicate study-specific relative risks (size of the square reflects the study-specific statistical weight); horizontal lines indicate 95% CIs; diamond indicates the summary relative risk estimate with its 95% CI. CI: confidence interval; RR: relative risk (TIFF 2486 kb)

10552_2014_483_MOESM2_ESM.tif

Forest plot (fixed-effects model) of ever use of oral contraceptive and rectal cancer risk. Squares indicate study-specific relative risks (size of the square reflects the study-specific statistical weight); horizontal lines indicate 95% CIs; diamond indicates the summary relative risk estimate with its 95% CI. CI: confidence interval; RR: relative risk (TIFF 1926 kb)

10552_2014_483_MOESM3_ESM.tif

Forest plot (random-effects model) of the duration of oral contraceptive use and colon cancer risk. Squares indicate study-specific relative risks (size of the square reflects the study-specific statistical weight); horizontal lines indicate 95% CIs; diamond indicates the summary relative risk estimate with its 95% CI. CI: confidence interval; RR: relative risk (TIFF 2142 kb)

10552_2014_483_MOESM4_ESM.tif

Forest plot (fixed-effects model) of the duration of oral contraceptive and rectal cancer risk. Squares indicate study-specific relative risks (size of the square reflects the study-specific statistical weight); horizontal lines indicate 95% CIs; diamond indicates the summary relative risk estimate with its 95% CI. CI: confidence interval; RR: relative risk (TIFF 2015 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Luan, NN., Wu, L., Gong, TT. et al. Nonlinear reduction in risk for colorectal cancer by oral contraceptive use: a meta-analysis of epidemiological studies. Cancer Causes Control 26, 65–78 (2015). https://doi.org/10.1007/s10552-014-0483-2

Download citation

Keywords

  • Reproduction
  • Epidemiology
  • Colorectal neoplasms
  • Cancer prevention
  • Women