Oral contraceptive use by formulation and breast cancer risk by subtype in the Nurses' Health Study II: a prospective cohort study

Published:December 15, 2021DOI:


      Oral contraceptive use has been associated with a higher breast cancer risk; however, evidence for the associations between different oral contraceptive formulations and breast cancer risk, especially by disease subtype, is limited.


      This study aimed to evaluate the associations between oral contraceptive use by formulation and breast cancer risk by disease subtype.

      Study Design

      This prospective cohort study included 113,187 women from the Nurses’ Health Study II with recalled information on oral contraceptive usage from 13 years of age to baseline (1989) and updated data on usage until 2009 collected via biennial questionnaires. A total of 5799 breast cancer cases were identified until the end of 2017. Multivariable Cox proportional hazards models estimated hazard ratios and 95% confidence intervals for the associations between oral contraceptive use and breast cancer risk overall and by estrogen and progesterone receptor and human epidermal growth factor receptor 2 status. Oral contraceptive use was evaluated by status of use (current, former, and never), duration of and time since last use independently and cross-classified, and formulation (ie, estrogen and progestin type).


      Current oral contraceptive use was associated with a higher risk for invasive breast cancer (hazard ratio, 1.31; 95% confidence interval, 1.09–1.58) when compared with never use, with stronger associations observed for longer durations of current use (>5 years: hazard ratio, 1.56; 95% confidence interval, 1.23–1.99; ≤5 years: hazard ratio, 1.19; 95% confidence interval, 0.95–1.49). Among former users with >5 years since cessation, the risk was similar to that of never users (eg, >5 to 10 years since cessation: hazard ratio, 0.99; 95% confidence interval, 0.88–1.11). Associations did not differ significantly by tumor subtype. In analyses by formulation, current use of formulations containing levonorgestrel in triphasic (hazard ratio, 2.83; 95% confidence interval, 1.98–4.03) and extended cycle regimens (hazard ratio, 3.49; 95% confidence interval, 1.28–9.53) and norgestrel in monophasic regimens (hazard ratio, 1.91; 95% confidence interval, 1.19–3.06), all combined with ethinyl estradiol, was associated with a higher breast cancer risk when compared with never oral contraceptive use. No association was observed for current use of the other progestin types evaluated (norethindrone, norethindrone acetate, ethynodiol diacetate, desogestrel, norgestimate, and drospirenone), however, sample sizes were relatively small for some of the subgroups, limiting these analyses.


      Current oral contraceptive use was associated with a higher risk for invasive breast cancer regardless of disease subtype, however, the risk in former users was comparable with never users 5 years after cessation. In analyses by progestin type, associations were observed for select formulations containing levonorgestrel and norgestrel. Assessment of the associations for newer progestin types (desogestrel, norgestimate, drospirenone) was limited by sample size, and further research on more recently introduced progestins is warranted.

      Key words

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        • Daniels K.
        • Daugherty J.
        • Jones J.
        • Mosher W.
        Current contraceptive use and variation by selected characteristics among women aged 15-44: United States, 2011-2013.
        In: Natl Health Stat Report. 2015; 86: 1-14
        • Golobof A.
        • Kiley J.
        The current status of oral contraceptives: progress and recent innovations.
        Semin Reprod Med. 2016; 34: 145-151
      1. United Nations. Department of Economic and Social Affairs. Population division. Contracept Use Method 2019: Data Booklet;2019. Available at: Accessed February 15, 2021.

        • Gierisch J.M.
        • Coeytaux R.R.
        • Urrutia R.P.
        • et al.
        Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review.
        Cancer Epidemiol Biomarkers Prev. 2013; 22: 1931-1943
        • 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.
        Lancet. 1996; 347: 1713-1727
        • Karlsson T.
        • Johansson T.
        • Höglund J.
        • Ek W.E.
        • Johansson Å.
        Time-dependent effects of oral contraceptive use on breast, ovarian, and endometrial cancers.
        Cancer Res. 2021; 81: 1153-1162
        • Hunter D.J.
        • Colditz G.A.
        • Hankinson S.E.
        • et al.
        Oral contraceptive use and breast cancer: a prospective study of young women.
        Cancer Epidemiol Biomarkers Prev. 2010; 19: 2496-2502
        • Mørch L.S.
        • Skovlund C.W.
        • Hannaford P.C.
        • Iversen L.
        • Fielding S.
        • Lidegaard Ø.
        Contemporary hormonal contraception and the risk of breast cancer.
        N Engl J Med. 2017; 377: 2228-2239
        • Millikan R.C.
        • Newman B.
        • Tse C.K.
        • et al.
        Epidemiology of basal-like breast cancer.
        Breast Cancer Res Treat. 2008; 109: 123-139
        • Dolle J.M.
        • Daling J.R.
        • White E.
        • et al.
        Risk factors for triple-negative breast cancer in women under the age of 45 years.
        Cancer Epidemiol Biomarkers Prev. 2009; 18: 1157-1166
        • Kwan M.L.
        • Kushi L.H.
        • Weltzien E.
        • et al.
        Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors.
        Breast Cancer Res. 2009; 11: R31
        • Ma H.
        • Wang Y.
        • Sullivan-Halley J.
        • et al.
        Use of four biomarkers to evaluate the risk of breast cancer subtypes in the Women’s Contraceptive and Reproductive Experiences Study.
        Cancer Res. 2010; 70: 575-587
        • Phipps A.I.
        • Chlebowski R.T.
        • Prentice R.
        • et al.
        Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer.
        J Natl Cancer Inst. 2011; 103: 470-477
        • Work M.E.
        • John E.M.
        • Andrulis I.L.
        • et al.
        Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry.
        Br J Cancer. 2014; 110: 1367-1377
        • Beaber E.F.
        • Malone K.E.
        • Tang M.T.
        • et al.
        Oral contraceptives and breast cancer risk overall and by molecular subtype among young women.
        Cancer Epidemiol Biomarkers Prev. 2014; 23: 755-764
        • Bethea T.N.
        • Rosenberg L.
        • Hong C.C.
        • et al.
        A case-control analysis of oral contraceptive use and breast cancer subtypes in the African American Breast Cancer Epidemiology and Risk Consortium.
        Breast Cancer Res. 2015; 17: 22
        • Ellingjord-Dale M.
        • Vos L.
        • Tretli S.
        • Hofvind S.
        • dos-Santos-Silva I.
        • Ursin G.
        Parity, hormones and breast cancer subtypes - results from a large nested case-control study in a national screening program.
        Breast Cancer Res. 2017; 19: 10
        • Rosenberg L.
        • Boggs D.A.
        • Wise L.A.
        • Adams-Campbell L.L.
        • Palmer J.R.
        Oral contraceptive use and estrogen/progesterone receptor–negative breast cancer among African American women.
        Cancer Epidemiol Biomarkers Prev. 2010; 19: 2073-2079
        • Ritte R.
        • Tikk K.
        • Lukanova A.
        • et al.
        Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study.
        BMC Cancer. 2013; 13: 584
        • Busund M.
        • Bugge N.S.
        • Braaten T.
        • Waaseth M.
        • Rylander C.
        • Lund E.
        Progestin-only and combined oral contraceptives and receptor-defined premenopausal breast cancer risk: the Norwegian Women and Cancer Study.
        Int J Cancer. 2018; 142: 2293-2302
        • Colditz G.A.
        • Hankinson S.E.
        The Nurses’ Health Study: lifestyle and health among women.
        Nat Rev Cancer. 2005; 5: 388-396
        • Bao Y.
        • Bertoia M.L.
        • Lenart E.B.
        • et al.
        Origin, methods, and evolution of the three Nurses’ Health Studies.
        Am J Public Health. 2016; 106: 1573-1581
        • Burchardt N.A.
        • Shafrir A.L.
        • Kaaks R.
        • Tworoger S.S.
        • Fortner R.T.
        Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947-1964: The Nurses’ Health Study II, a prospective cohort study.
        Eur J Epidemiol. 2021; 36: 827-839
        • Shafrir A.L.
        • Schock H.
        • Poole E.M.
        • et al.
        A prospective cohort study of oral contraceptive use and ovarian cancer among women in the United States born from 1947 to 1964.
        Cancer Causes Control. 2017; 28: 371-383
        • Hunter D.J.
        • Manson J.E.
        • Colditz G.A.
        • et al.
        Reproducibility of oral contraceptive histories and validity of hormone composition reported in a cohort of US women.
        Contraception. 1997; 56: 373-378
        • Rosner B.
        • Colditz G.A.
        Nurses’ health Study: log-incidence mathematical model of breast cancer incidence.
        J Natl Cancer Inst. 1996; 88: 359-364
        • Colditz G.A.
        • Rosner B.
        Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study.
        Am J Epidemiol. 2000; 152: 950-964
        • Petitti D.B.
        Clinical practice. Combination estrogen-progestin oral contraceptives.
        N Engl J Med. 2003; 349: 1443-1450
        • Wang M.
        • Spiegelman D.
        • Kuchiba A.
        • et al.
        Statistical methods for studying disease subtype heterogeneity.
        Stat Med. 2016; 35: 782-800
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Iversen L.
        • Sivasubramaniam S.
        • Lee A.
        • Fielding S.
        • Hannaford P.
        Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ oral contraception Study.
        Am J Obstet Gynecol. 2017; 216: 580.e1-580.e9
        • Kumle M.
        • Weiderpass E.
        • Braaten T.
        • Persson I.
        • Adami H.O.
        • Lund E.
        Use of oral contraceptives and breast cancer risk: the Norwegian-Swedish Women’s Lifestyle and Health Cohort Study.
        Cancer Epidemiol Biomarkers Prev. 2002; 11: 1375-1381
        • Sitruk-Ware R.
        Pharmacological profile of progestins.
        Maturitas. 2004; 47: 277-283
        • Davtyan C.
        Four generations of progestins in oral contraceptives.
        (Available at:) (Accessed May 28, 2021)
        • Collins D.C.
        Sex hormone receptor binding, progestin selectivity, and the new oral contraceptives.
        Am J Obstet Gynecol. 1994; 170: 1508-1513
        • Rowlands S.
        Newer progestogens.
        J Fam Plann Reprod Health Care. 2003; 29: 13-16
        • Schindler A.E.
        • Campagnoli C.
        • Druckmann R.
        • et al.
        Classification and pharmacology of progestins.
        Maturitas. 2003; 46: S7-S16
        • Kuenen-Boumeester V.
        • Van der Kwast T.H.
        • van Putten W.L.
        • Claassen C.
        • van Ooijen B.
        • Henzen-Logmans S.C.
        Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer.
        Int J Cancer. 1992; 52: 581-584
        • Hall R.E.
        • Clements J.A.
        • Birrell S.N.
        • Tilley W.D.
        Prostate-specific antigen and gross cystic disease fluid protein-15 are co-expressed in androgen receptor-positive breast tumours.
        Br J Cancer. 1998; 78: 360-365
        • Moinfar F.
        • Okcu M.
        • Tsybrovskyy O.
        • et al.
        Androgen receptors frequently are expressed in breast carcinomas: potential relevance to new therapeutic strategies.
        Cancer. 2003; 98: 703-711
        • Han L.
        • Jensen J.T.
        Does the progestogen used in combined hormonal contraception affect venous thrombosis risk?.
        Obstet Gynecol Clin North Am. 2015; 42: 683-698

      Supplemental References

        • Burchardt N.A.
        • Shafrir A.L.
        • Kaaks R.
        • Tworoger S.S.
        • Fortner R.T.
        Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947-1964: The Nurses’ Health Study II, a prospective cohort study.
        Eur J Epidemiol. 2021; 36: 827-839
        • Davtyan C.
        Four generations of progestins in oral contraceptives.
        (Available at:) (Accessed May 20, 2021)
        • Collins L.C.
        • Marotti J.D.
        • Baer H.J.
        • Tamimi R.M.
        Comparison of estrogen receptor results from pathology reports with results from central laboratory testing.
        J Natl Cancer Inst. 2008; 100: 218-221
        • Tamimi R.M.
        • Baer H.J.
        • Marotti J.
        • et al.
        Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer.
        Breast Cancer Res. 2008; 10: R67