Hormones and Cancer

, Volume 9, Issue 4, pp 240–253 | Cite as

The Impact of Hormonal Contraceptives on Breast Cancer Pathology

  • Jesse A. Dorchak
  • Sifat Maria
  • Joseph L. Guarinoni
  • Anette Duensing
  • Stella Somiari
  • Jane Cavanaugh
  • Brenda Deyarmin
  • Hai Hu
  • Joji Iida
  • Craig D. Shriver
  • Paula A. Witt-EnderbyEmail author
Original Paper


This retrospective case series study, using data obtained through questionnaires and histopathological diagnoses from 656 patients enrolled in the Department of Defense (DoD) Clinical Breast Care Project (CBCP), evaluated associations between hormonal contraceptive use and breast cancer pathology including benign breast pathologies. Three combination hormonal contraceptive agents (COCs) Lo Ovral (LO), Ortho Novum (ON), and Ortho Tri-Cyclen (OTC) were evaluated as they represented the most commonly used hormonal contraceptives in our cohort. The results of this study suggest that the ever use of LO + ON + OTC does not influence the overall incidence of benign breast condition or malignant disease compared to other COCs; however, patients that have used OTC had an association with a diagnosis of benign or luminal A pathologies whereas ON was associated with a diagnosis of benign and DCIS; LO showed no association with any diagnosis—benign or malignant. Patients that have used LO or ON were more likely to be diagnosed with breast cancer at age ≥ 40 years whereas patients that had ever used OTC were likely to be diagnosed before the age of 40. Caucasians were less likely to have used OTC and more likely to have used ON; however, use of either hormonal agent positively correlated with premenopausal status at diagnosis and having a benign condition. Age at diagnosis, ethnicity, BMI, family history, menstruation status, and duration of use were all independent predictors of different histopathological subtypes. We conclude that patient-specific variables should be considered when deciding on which type of hormonal contraceptive to use to minimize the risk of developing breast cancer or a breast-related pathology.



We thank all patients for their participation in the CBCP. We thank Jianfang Liu, Nicholas Costantino, and Brad Mosteller for their guidance on statistical analysis and Deepika Rao and Khalid Kamal especially for their help on the multivariate analyses.

Author Contributions

Designed and researched topic, drafted IRB requests at Duquesne, evaluated and extracted data from CBCP query searches, and analyzed data: JAD, JLG. Drafted and wrote the manuscript: JAD, JLG, and PAW-E. Contributed to statistical analysis, specifically multinomial logistical regression: SM. Participated in CBCP query searches: BD. Marc Purazo: preliminary statistics. Critically reviewed the manuscript and provided input: SS, JI, HH, PAW-E, JC, CDS, AD. Supervisors for this study: SS, PAW-E.

Compliance with Ethical Standards

Appropriate IRB approval was obtained for the Clinical Breast Care Project (CBCP) from the study sites at the Walter Reed National Military Medical Center and Windber Research Institute/Windber Medical Center. IRB approval was also obtained from Duquesne University School of Pharmacy and Division of Pharmaceutical, Administrative and Social Sciences.


The identification of specific products, scientific instrumentation, or organization is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the authors, Department of Defense, or any component agency. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or US Government.


  1. 1.
    American Cancer Society. Cancer facts & figures 2016. 2016. Journal.
  2. 2.
    Centers for Disease Control and Prevention: Cancer among women. 2015. Journal .
  3. 3.
    Amadou A, Fabre A, Torres-Mejía G, Ortega-Olvera C, Angeles-Llerenas A, McKenzie F, Biessy C, Hainaut P, Romieu I (2013) Hormonal therapy and risk of breast cancer in Mexican women. PLoS One 8(11):e79695CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Boyd NF, Melnichouk O, Martin LJ, Hislop G, Chiarelli AM, Yaffe MJ, Minkin S (2011) Mammographic density, response to hormones, and breast cancer risk. J Clin Oncol 29(22):2985–2992CrossRefPubMedGoogle Scholar
  5. 5.
    Brynhildsen (2014) Combined hormonal contraceptives: prescribing patterns, compliance, and benefits versus risks. Therapeutic advances in drug safety 5(5):201–213CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bui KT, Wakefield CE, Kasparian NA, Tyler J, Abbott J, Tucker K (2013) Oral contraceptive use in women at increased risk of breast/ovarian cancer: knowledge and attitudes. Psycho-Oncology 22(1):228–232CrossRefPubMedGoogle Scholar
  7. 7.
    Dorgan JF, Klifa C, Deshmukh S, Egleston BL, Shepherd JA, Kwiterovich PO, van Horn L, Snetselaar LG, Stevens VJ, Robson AM, Lasser NL, Hylton NM (2013) Menstrual and reproductive characteristics and breast density in young women. Cancer Causes Control 24(11):1973–1983CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Imkampe A-K, Bates T (2012) Correlation of age at oral contraceptive pill start with age at breast cancer diagnosis. Breast J 18(1):35–40CrossRefPubMedGoogle Scholar
  9. 9.
    Lu, Yani, Ma, Huiyan, Malone, Kathleen E, Norman, Sandra A, et al. (2011) Oral contraceptive use and survival in women with invasive breast cancer. Cancer Epidemiology and Prevention BiomarkersGoogle Scholar
  10. 10.
    Moorman PG, Havrilesky LJ, Gierisch JM, Coeytaux RR, Lowery WJ, Peragallo Urrutia R, Dinan M, McBroom AJ, Hasselblad V, Sanders GD, Myers ER (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(33):4188–4198CrossRefPubMedGoogle Scholar
  11. 11.
    Assi HA, Khoury KE, Dbouk H, Khalil LE et al (2013) Epidemiology and prognosis of breast cancer in young women. Journal of thoracic disease 5(Suppl 1):S2PubMedPubMedCentralGoogle Scholar
  12. 12.
    Thorbjarnardottir T, Olafsdottir EJ, Valdimarsdottir UA, Olafsson O, Tryggvadottir L (2014) Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort study of 16 928 women 48 years and older. Acta Oncol 53(6):752–758CrossRefPubMedGoogle Scholar
  13. 13.
    Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø (2017) Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med 377(23):2228–2239CrossRefPubMedGoogle Scholar
  14. 14.
    World contraceptive patterns 2013. New York: United Nations, Department of Economic and Social Affairs Journal .(
  15. 15.
    Current contraceptive status among women aged 15–44: United States, 2011–2013. 2014. Journal (Issue)Google Scholar
  16. 16.
    Schindler AE (2013) Non-contraceptive benefits of oral hormonal contraceptives. International journal of endocrinology and metabolism 11(1):41–47PubMedGoogle Scholar
  17. 17.
    Christopher LA, Miller L (2007) Women in war: operational issues of menstruation and unintended pregnancy. Mil Med 172(1):9–16CrossRefPubMedGoogle Scholar
  18. 18.
    Evans G, Sutton EL (2015) Oral contraception. Medical Clinics 99(3):479–503PubMedGoogle Scholar
  19. 19.
    Gambacciani M, Levancini M (2014) Hormone replacement therapy and the prevention of postmenopausal osteoporosis. Przeglad menopauzalny = Menopause review 13(4):213–220CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Powell-Dunford NC, Cuda AS, Moore JL, Crago MS, Kelly AM, Deuster PA (2011) Menstrual suppression for combat operations: advantages of oral contraceptive pills. Womens Health Issues 21(1):86–91CrossRefPubMedGoogle Scholar
  21. 21.
    Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JAV, Santen RJ (2015) Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism 100(11):3975–4011CrossRefGoogle Scholar
  22. 22.
    Hoften V, Carlijn B, Huibert P, Petra HM, Grobbee DE et al (2000) Long-term oral contraceptive use increases breast cancer risk in women over 55 years of age: the DOM cohort. Int J Cancer 87(4):591–594CrossRefPubMedGoogle Scholar
  23. 23.
    Marchbanks PA, Curtis KM, Mandel MG, Wilson HG, Jeng G, Folger SG, McDonald JA, Daling JR, Bernstein L, Malone KE, Wingo PA, Simon MS, Norman SA, Strom BL, Ursin G, Weiss LK, Burkman RT, Spirtas R (2012) Oral contraceptive formulation and risk of breast cancer. Contraception 85(4):342–350CrossRefPubMedGoogle Scholar
  24. 24.
    Kumle M, Weiderpass E, Braaten T, Persson I et al (2002) Use of oral contraceptives and breast cancer risk. Cancer Epidemiology and Prevention Biomarkers 11(11):1375–1381Google Scholar
  25. 25.
    Althuis MD, Brogan DD, Coates RJ, Daling JR, Gammon MD, Malone KE, Schoenberg JB, Brinton LA (2003) Breast cancers among very young premenopausal women (United States). Cancer Causes Control 14(2):151–160CrossRefPubMedGoogle Scholar
  26. 26.
    Dumeaux V, Alsaker E, Lund E (2003) Breast cancer and specific types of oral contraceptives: a large Norwegian cohort study. Int J Cancer 105(6):844–850CrossRefPubMedGoogle Scholar
  27. 27.
    Dumeaux V, Fournier A, Lund E, Clavel-Chapelon F (2005) Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women. Cancer Causes Control 16(5):537–544CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lee SY, Kim MT, Kim SW, Song MS, Yoon SJ (2003) Effect of lifetime lactation on breast cancer risk: a Korean women's cohort study. Int J Cancer 105(3):390–393CrossRefPubMedGoogle Scholar
  29. 29.
    Wu M-H, Chou Y-C, Yu J-C, Yu C-P, Wu CC, Chu CM, Yang T, Lai CH, Hsieh CY, You SL, Chen CJ, Sun CA (2006) Hormonal and body-size factors in relation to breast cancer risk: a prospective study of 11,889 women in a low-incidence area. Ann Epidemiol 16(3):223–229CrossRefPubMedGoogle Scholar
  30. 30.
    Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ (2007) Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner’s oral contraception study. BMJ 335(7621):651CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Shantakumar S, Terry MB, Paykin A, Teitelbaum SL, Britton JA, Moorman PG, Kritchevsky SB, Neugut AI, Gammon MD (2007) Age and menopausal effects of hormonal birth control and hormone replacement therapy in relation to breast cancer risk. Am J Epidemiol 165(10):1187–1198CrossRefPubMedGoogle Scholar
  32. 32.
    Dorjgochoo T, Shu X-O, Li H-L, Qian H-Z, Yang G, Cai H, Gao Y-T, Zheng W (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(10):2442–2449CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rosenberg L, Zhang Y, Coogan PF, Strom BL, Palmer JR (2008) A case-control study of oral contraceptive use and incident breast cancer. Am J Epidemiol 169(4):473–479CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Beaber EF, Buist DSM, Barlow WE, Malone KE, Reed SD, Li CI (2014) Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age. Cancer Res 74(15):4078–4089CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hunter, David J, Colditz, Graham A, Hankinson, Susan E, Malspeis, Susan, et al., 2010, Oral contraceptive use and breast cancer: a prospective study of young women. Cancer Epidemiology and Prevention Biomarkers: p. cebp. 0747.2010Google Scholar
  36. 36.
    Kawai M, Minami Y, Kuriyama S, Kakizaki M, Kakugawa Y, Nishino Y, Ishida T, Fukao A, Tsuji I, Ohuchi N (2010) Reproductive factors, exogenous female hormone use and breast cancer risk in Japanese: the Miyagi cohort study. Cancer Causes Control 21(1):135–145CrossRefPubMedGoogle Scholar
  37. 37.
    Vessey M, Yeates D (2013) Oral contraceptive use and cancer: final report from the Oxford–Family Planning Association contraceptive study. Contraception 88(6):678–683CrossRefPubMedGoogle Scholar
  38. 38.
    Lanfranchi, Angela (2014) Normal breast physiology: the reasons hormonal contraceptives and induced abortion increase breast-cancer risk. Issues L. & Med. 29: p. 135Google Scholar
  39. 39.
    North American Menopause Society: The 2012 hormone therapy position statement of the North American Menopause Society. 2012. Journal. 19: p. 257Google Scholar
  40. 40.
    Pup D, Lino B, Massimiliano DF, Raffaele C, Carla, et al. (2014) Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk. Anti-Cancer Drugs 25(7):745–750Google Scholar
  41. 41.
    Chlebowski RT, Anderson GL (2012) Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Inst 104(7):517–527CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Anderson GL, Women’s Health Initiative steering committee (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712CrossRefPubMedGoogle Scholar
  43. 43.
    Fournier A, Bernio F, Clavel-Chapelon F (2008) Unequal risks for BC associated with different hormone replacement therapies: results from the E3N cohort study. BC Res Treat 107(1):101–111Google Scholar
  44. 44.
    Lyytinen H, Pukkala E, Ylikorkala O (2009) Breast cancer risk in postmenopausal women using estradiol–progestogen therapy. Obstet Gynecol 113(1):65–73CrossRefPubMedGoogle Scholar
  45. 45.
    Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, Lessin L, Chlebowski RT (2006) Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295(14):1647–1657CrossRefPubMedGoogle Scholar
  46. 46.
    Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Mark Cline J (2007) Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat 101(2):125–134CrossRefPubMedGoogle Scholar
  47. 47.
    Beaber, Elisabeth F, Malone, Kathleen E, Tang, Mei-Tzu Chen, Barlow, William E, et al. (2014) Oral contraceptives and breast cancer risk overall and by molecular subtype among young women. Cancer Epidemiology and Prevention BiomarkersGoogle Scholar
  48. 48.
    Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, Malone KE (2009) Risk factors for triple-negative breast cancer in women under the age of 45 years. Cancer Epidemiology and Prevention Biomarkers. 18(4):1157–1166CrossRefGoogle Scholar
  49. 49.
    Elebro K, Butt S, Dorkhan M, Jernström H, Borgquist S (2014) Age at first childbirth and oral contraceptive use are associated with risk of androgen receptor-negative breast cancer: the Malmö diet and cancer cohort. Cancer Causes Control 25(8):945–957CrossRefPubMedGoogle Scholar
  50. 50.
    Phipps AI, Chlebowski RT, Prentice R, McTiernan A, Wactawski-Wende J, Kuller LH, Adams-Campbell LL, Lane D, Stefanick ML, Vitolins M, Kabat GC, Rohan TE, Li CI (2011) Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst 103(6):470–477CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ritte R, Tikk K, Lukanova A, Tjønneland A, Olsen A, Overvad K, Dossus L, Fournier A, Clavel-Chapelon F, Grote V, Boeing H, Aleksandrova K, Trichopoulou A, Lagiou P, Trichopoulos D, Palli D, Berrino F, Mattiello A, Tumino R, Sacerdote C, Quirós JR, Buckland G, Molina-Montes E, Chirlaque MD, Ardanaz E, Amiano P, Bueno-de-Mesquita HB, van Gils CH, Peeters PHM, Wareham N, Khaw KT, Key TJ, Travis RC, Weiderpass E, Dumeaux V, Lund E, Sund M, Andersson A, Romieu I, Rinaldi S, Vineis P, Merritt MA, Riboli E, Kaaks R (2013) Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study. BMC Cancer 13(1):584CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Work ME, John EM, Andrulis IL, Knight JA, Liao Y, Mulligan AM, Southey MC, Giles GG, Dite GS, Apicella C, Hibshoosh H, Hopper JL, Terry MB (2014) Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry. Br J Cancer 110(5):1367–1377CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn H-J, Panel members (2011) Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22(8):1736–1747CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Lancet (1996) Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. 347: p. 1713–27Google Scholar
  55. 55.
    Jernström H, Loman N, Johannsson OT, Borg Å, Olsson H (2005) Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing. Eur J Cancer 41(15):2312–2320CrossRefPubMedGoogle Scholar
  56. 56.
    Kotsopoulos J, Lubinski J, Moller P, Lynch HT et al (2014) Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers. Breast Cancer Res Treat 143(3):579–586CrossRefPubMedGoogle Scholar
  57. 57.
    Janssen Pharmaceutical, Inc, 2015, Ortho Novum and Modicon (norethindrone and ethinyl estradiol) package insertGoogle Scholar
  58. 58.
    Africander D, Verhoog N, Hapgood J (2011) Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 76:636–652CrossRefPubMedGoogle Scholar
  59. 59.
    Stanczyk F (2003) All progestins are not created equal. Steroids 68:879–890CrossRefPubMedGoogle Scholar
  60. 60.
    Huang WY, Newman B, Millikan RC, Schell MJ, Hulka BS, Moorman PG (2000) Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am J Epidemiol 151:703–714CrossRefPubMedGoogle Scholar
  61. 61.
    Sweeney C, Giuliano AR, Baumgartner KB, Byers T, Herrick JS, Edwards SL, Slattery ML (2007) Oral, injected and implanted contraceptives and breast cancer risk among U.S. Hispanic and non-Hispanic white women. Int J Cancer 121:2517–2523CrossRefPubMedGoogle Scholar
  62. 62.
    Ma H, Wang Y, Sullivan-Halley J, Weiss L, Marchbanks PA, Spirtas R, Ursin G, Burkman RT, Simon MS, Malone KE, Strom BL, McDonald JA, Press MF, Bernstein L (2010) Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women’s contraceptive and reproductive experiences study. Cancer Res 70:575–587CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jesse A. Dorchak
    • 1
    • 2
  • Sifat Maria
    • 2
  • Joseph L. Guarinoni
    • 2
  • Anette Duensing
    • 3
  • Stella Somiari
    • 1
  • Jane Cavanaugh
    • 2
  • Brenda Deyarmin
    • 1
  • Hai Hu
    • 1
  • Joji Iida
    • 1
  • Craig D. Shriver
    • 4
  • Paula A. Witt-Enderby
    • 2
    Email author
  1. 1.Chan Soon-Shiong Institute of Molecular Medicine at WindberWindberUSA
  2. 2.Division of Pharmaceutical, Administrative and Social SciencesDuquesne University School of PharmacyPittsburghUSA
  3. 3.Department of Pathology, UPMC Hillman Cancer Center, Cancer Therapeutics ProgramUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of SurgeryWalter Reed National Military Medical CenterBethesdaUSA

Personalised recommendations