Hormones and Cancer

, Volume 9, Issue 2, pp 117–127 | Cite as

Circulating Hormones and Mammographic Density in Premenopausal Women

  • Kimberly A. Bertrand
  • A. Heather Eliassen
  • Susan E. Hankinson
  • Bernard A. Rosner
  • Rulla M. Tamimi
Original Paper


Prior research suggests that several endogenous hormones in premenopausal women are associated with breast cancer risk; however, few studies have evaluated associations of endogenous hormones with mammographic density (MD) in premenopausal women. We conducted a cross-sectional study of plasma hormone levels in relation to MD among 634 cancer-free premenopausal women in the Nurses’ Health Study II. We measured percent MD from screening mammograms using a computer-assisted method. We assayed estradiol, estrone, and estrone sulfate in blood samples timed in early follicular and mid-luteal phases of the menstrual cycle as well as testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, sex hormone–binding globulin (SHBG), and anti-Müllerian hormone in luteal or untimed samples. We used multivariable linear regression to quantify the association of %MD with quartiles of each hormone, adjusting for age, body mass index, and breast cancer risk factors. Women in the highest quartile of follicular estradiol levels had significantly greater %MD compared to those in the lowest quartile [difference, 6.7 percentage points; 95% confidence interval (CI) 2.2, 11.3; p-trend < 0.001]. Similar associations were observed for follicular free estradiol but not luteal-phase estradiol. Also, women in the top (vs. bottom) quartile of free testosterone had significantly lower %MD (difference, − 4.7; 95% CI − 8.7, − 0.8; p-trend = 0.04). Higher SHBG was significantly associated with higher percent MD (difference, 4.8; 95% CI 1.1, 8.6; p-trend = 0.002). Percent MD was not strongly associated with other measured hormones. Results were similar in analyses that excluded women with anovulatory cycles. Our findings suggest that follicular estradiol and SHBG may play an important role in premenopausal percent MD.





Dehydroepiandrosterone sulfate


Sex hormone–binding globulin


Anti-Müllerian hormone


Nurses’ Health Study II


Mammographic density


Body mass index


Odds ratio


Confidence interval



This work was supported by the Breast Cancer Research Foundation and the National Cancer Institute (CA124865, CA67262, CA176726, and CA168504). K.A.B. was supported by the Nutritional Epidemiology of Cancer Education and Career Development Program (R25 CA098566) and the Simeon J. Fortin Charitable Foundation, Bank of America, Co-Trustee, N.A. We would like to thank the participants and staff of the Nurses’ Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. We also thank Kristina Astone for technical help. The authors assume full responsibility for analyses and interpretation of these data.

Supplementary material

12672_2017_321_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 20 kb)


  1. 1.
    Endogenous H, Breast Cancer Collaborative G, Key TJ, Appleby PN, Reeves GK, Travis RC, Alberg AJ, Barricarte A, Berrino F, Krogh V et al (2013) Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 14(10):1009–1019CrossRefGoogle Scholar
  2. 2.
    Kaaks R, Tikk K, Sookthai D, Schock H, Johnson T, Tjønneland A, Olsen A, Overvad K, Clavel-Chapelon F, Dossus L, Baglietto L, Rinaldi S, Chajes V, Romieu I, Boeing H, Schütze M, Trichopoulou A, Lagiou P, Trichopoulos D, Palli D, Sieri S, Tumino R, Ricceri F, Mattiello A, Buckland G, Ramón Quirós J, Sánchez MJ, Amiano P, Chirlaque MD, Barricarte A, Bas Bueno-de-Mesquita H, van Gils CH, Peeters PH, Andersson A, Sund M, Weiderpass E, Khaw KT, Wareham N, Key TJ, Travis RC, Merritt MA, Gunter MJ, Riboli E, Lukanova A (2014) Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status—results from the EPIC cohort. Int J Cancer 134(8):1947–1957. CrossRefPubMedGoogle Scholar
  3. 3.
    Fortner RT, Eliassen AH, Spiegelman D, Willett WC, Barbieri RL, Hankinson SE (2013) Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses’ Health Study II. Breast Cancer Res 15(2):R19. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    McCormack VA, dos Santos Silva I (2006) Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomark Prev 15(6):1159–1169. CrossRefGoogle Scholar
  5. 5.
    Martin LJ, Boyd NF (2008) Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res 10(1):201. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M, Hammond G, Minkin S (2002) The association of breast mitogens with mammographic densities. Br J Cancer 87(8):876–882. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Aiello EJ, Tworoger SS, Yasui Y, Stanczyk FZ, Potter J, Ulrich CM, Irwin M, McTiernan A (2005) Associations among circulating sex hormones, insulin-like growth factor, lipids, and mammographic density in postmenopausal women. Cancer Epidemiol Biomark Prev 14(6):1411–1417. CrossRefGoogle Scholar
  8. 8.
    Tamimi RM, Hankinson SE, Colditz GA, Byrne C (2005) Endogenous sex hormone levels and mammographic density among postmenopausal women. Cancer Epidemiol Biomark Prev 14(11 Pt 1):2641–2647. CrossRefGoogle Scholar
  9. 9.
    Greendale GA, Palla SL, Ursin G, Laughlin GA, Crandall C, Pike MC, Reboussin BA (2005) The association of endogenous sex steroids and sex steroid binding proteins with mammographic density: results from the postmenopausal estrogen/progestin interventions mammographic density study. Am J Epidemiol 162(9):826–834. CrossRefPubMedGoogle Scholar
  10. 10.
    Warren R, Skinner J, Sala E, Denton E, Dowsett M, Folkerd E, Healey CS, Dunning A, Doody D, Ponder B et al (2006) Associations among mammographic density, circulating sex hormones, and polymorphisms in sex hormone metabolism genes in postmenopausal women. Cancer Epidemiol Biomark Prev 15(8):1502–1508. CrossRefGoogle Scholar
  11. 11.
    Bertrand KA, Eliassen AH, Hankinson SE, Gierach GL, Xu X, Rosner B, Ziegler RG, Tamimi RM (2012) Urinary estrogens and estrogen metabolites and mammographic density in premenopausal women. Breast Cancer Res Treat 136(1):277–287. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gierach GL, Patel DA, Falk RT, Pfeiffer RM, Geller BM, Vacek PM, Weaver DL, Chicoine RE, Shepherd JA, Mahmoudzadeh AP, Wang J, Fan B, Herschorn SD, Xu X, Veenstra T, Fuhrman B, Sherman ME, Brinton LA (2015) Relationship of serum estrogens and metabolites with area and volume mammographic densities. Horm Cancer 6(2–3):107–119. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Walker K, Fletcher O, Johnson N, Coupland B, McCormack VA, Folkerd E, Gibson L, Hillier SG, Holly JM, Moss S, Dowsett M, Peto J, dos Santos Silva I (2009) Premenopausal mammographic density in relation to cyclic variations in endogenous sex hormone levels, prolactin, and insulin-like growth factors. Cancer Res 69(16):6490–6499. CrossRefPubMedGoogle Scholar
  14. 14.
    Jung S, Stanczyk FZ, Egleston BL, Snetselaar LG, Stevens VJ, Shepherd JA, Van Horn L, LeBlanc ES, Paris K, Klifa C, Dorgan JF (2015) Endogenous sex hormones and breast density in young women. Cancer Epidemiol Biomark Prev 24(2):369–378. CrossRefGoogle Scholar
  15. 15.
    Yong M, Atkinson C, Newton KM, Aiello Bowles EJ, Stanczyk FZ, Westerlind KC, Holt VL, Schwartz SM, Leisenring WM, Lampe JW (2009) Associations between endogenous sex hormone levels and mammographic and bone densities in premenopausal women. Cancer Causes Control 20(7):1039–1053. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Iversen A, Frydenberg H, Furberg AS, Flote VG, Finstad SE, McTiernan A, Ursin G, Wilsgaard T, Ellison PT, Jasienska G, Thune I (2016) Cyclic endogenous estrogen and progesterone vary by mammographic density phenotypes in premenopausal women. Eur J Cancer Prev 25(1):9–18. CrossRefPubMedGoogle Scholar
  17. 17.
    Noh JJ, Maskarinec G, Pagano I, Cheung LW, Stanczyk FZ (2006) Mammographic densities and circulating hormones: a cross-sectional study in premenopausal women. Breast 15(1):20–28. CrossRefPubMedGoogle Scholar
  18. 18.
    Borugian MJ, Spinelli JJ, Gordon PB, Abanto Z, Brooks-Wilson A, Pollak MN, Warren LJ, Hislop TG, Gallagher RP (2014) Fasting insulin and endogenous hormones in relation to premenopausal breast density (Canada). Cancer Causes Control 25(3):385–394. CrossRefPubMedGoogle Scholar
  19. 19.
    Jung S, Egleston BL, Chandler DW, Van Horn L, Hylton NM, Klifa CC, Lasser NL, LeBlanc ES, Paris K, Shepherd JA, Snetselaar LG, Stanczyk FZ, Stevens VJ, Dorgan JF (2015) Adolescent endogenous sex hormones and breast density in early adulthood. Breast Cancer Res 17(1):77. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Bertrand KA, Baer HJ, Orav EJ, Klifa C, Kumar A, Hylton NM, LeBlanc ES, Snetselaar LG, Van Horn L, Dorgan JF (2016) Early life body fatness, serum anti-Mullerian hormone, and breast density in young adult women. Cancer Epidemiol Biomark Prev 25(7):1151–1157. CrossRefGoogle Scholar
  21. 21.
    Dorgan JF, Stanczyk FZ, Egleston BL, Kahle LL, Shaw CM, Spittle CS, Godwin AK, Brinton LA (2009) Prospective case–control study of serum Mullerian inhibiting substance and breast cancer risk. J Natl Cancer Inst 101(21):1501–1509. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nichols HB, Baird DD, Stanczyk FZ, Steiner AZ, Troester MA, Whitworth KW, Sandler DP (2015) Anti-Müllerian hormone concentrations in premenopausal women and breast cancer risk. Cancer Prev Res (Phila) 8(6):528–534. CrossRefGoogle Scholar
  23. 23.
    Eliassen AH, Zeleniuch-Jacquotte A, Rosner B, Hankinson SE (2016) Plasma anti-Mullerian hormone concentrations and risk of breast cancer among premenopausal women in the Nurses’ health studies. Cancer Epidemiol Biomark Prev 25(5):854–860. CrossRefGoogle Scholar
  24. 24.
    Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, Dowsett M, Hankinson SE (2006) Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 98(19):1406–1415. CrossRefPubMedGoogle Scholar
  25. 25.
    Tworoger SS, Sluss P, Hankinson SE (2006) Association between plasma prolactin concentrations and risk of breast cancer among predominately premenopausal women. Cancer Res 66(4):2476–2482. CrossRefPubMedGoogle Scholar
  26. 26.
    Tworoger SS, Missmer SA, Eliassen AH, Spiegelman D, Folkerd E, Dowsett M, Barbieri RL, Hankinson SE (2006) The association of plasma DHEA and DHEA sulfate with breast cancer risk in predominantly premenopausal women. Cancer Epidemiol Biomark Prev 15(5):967–971. CrossRefGoogle Scholar
  27. 27.
    Byng JW, Boyd NF, Little L, Lockwood G, Fishell E, Jong RA, Yaffe MJ (1996) Symmetry of projection in the quantitative analysis of mammographic images. Eur J Cancer Prev 5(5):319–327. CrossRefPubMedGoogle Scholar
  28. 28.
    Pettersson A, Hankinson SE, Willett WC, Lagiou P, Trichopoulos D, Tamimi RM (2011) Nondense mammographic area and risk of breast cancer. Breast Cancer Res 13(5):R100. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rosner B, Cook N, Portman R, Daniels S, Falkner B (2008) Determination of blood pressure percentiles in normal-weight children: some methodological issues. Am J Epidemiol 167(6):653–666. CrossRefPubMedGoogle Scholar
  30. 30.
    Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE (2000) Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res 60(14):3744–3748PubMedGoogle Scholar
  31. 31.
    Stone J, Ding J, Warren RM, Duffy SW, Hopper JL (2010) Using mammographic density to predict breast cancer risk: dense area or percentage dense area. Breast Cancer Res 12(6):R97. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lokate M, Peeters PH, Peelen LM, Haars G, Veldhuis WB, van Gils CH (2011) Mammographic density and breast cancer risk: the role of the fat surrounding the fibroglandular tissue. Breast Cancer Res 13(5):R103. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Pettersson A, Graff RE, Ursin G, Santos Silva ID, McCormack V, Baglietto L, Vachon C, Bakker MF, Giles GG, Chia KS et al (2014) Mammographic density phenotypes and risk of breast cancer: a meta-analysis. J Natl Cancer InstGoogle Scholar
  34. 34.
    Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90(17):1292–1299. CrossRefPubMedGoogle Scholar
  35. 35.
    Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE (2004) Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 96(24):1856–1865. CrossRefPubMedGoogle Scholar
  36. 36.
    Hirko KA, Spiegelman D, Willett WC, Hankinson SE, Eliassen AH (2014) Alcohol consumption in relation to plasma sex hormones, prolactin, and sex hormone-binding globulin in premenopausal women. Cancer Epidemiol Biomark Prev 23(12):2943–2953. CrossRefGoogle Scholar
  37. 37.
    Södergård R, Bäckström T, Shanbhag V, Carstensen H (1982) Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem 16(6):801–810. CrossRefPubMedGoogle Scholar
  38. 38.
    Missmer SA, Spiegelman D, Bertone-Johnson ER, Barbieri RL, Pollak MN, Hankinson SE (2006) Reproducibility of plasma steroid hormones, prolactin, and insulin-like growth factor levels among premenopausal women over a 2- to 3-year period. Cancer Epidemiol Biomark Prev 15(5):972–978. CrossRefGoogle Scholar
  39. 39.
    Vachon CM, Kuni CC, Anderson K, Anderson VE, Sellers TA (2000) Association of mammographically defined percent breast density with epidemiologic risk factors for breast cancer (United States). Cancer Causes Control 11(7):653–662. CrossRefPubMedGoogle Scholar
  40. 40.
    Boyd NF, Lockwood GA, Byng JW, Little LE, Yaffe MJ, Tritchler DL (1998) The relationship of anthropometric measures to radiological features of the breast in premenopausal women. Br J Cancer 78(9):1233–1238. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Samimi G, Colditz GA, Baer HJ, Tamimi RM (2008) Measures of energy balance and mammographic density in the Nurses’ Health Study. Breast Cancer Res Treat 109(1):113–122. CrossRefPubMedGoogle Scholar
  42. 42.
    Durrleman S, Simon R (1989) Flexible regression models with cubic splines. Stat Med 8(5):551–561. CrossRefPubMedGoogle Scholar
  43. 43.
    Linton L, Taylor M, Dunn S, Martin L, Chavez S, Stanitz G, Huszti E, Minkin S, Boyd N (2016) Associations of serum levels of sex hormones in follicular and luteal phases of the menstrual cycle with breast tissue characteristics in young women. PLoS One 11(10):e0163865. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Somboonporn W, Davis SR, National H, Medical Research C (2004) Testosterone effects on the breast: implications for testosterone therapy for women. Endocr Rev 25(3):374–388. CrossRefPubMedGoogle Scholar
  45. 45.
    Pasquali R, Vicennati V, Bertazzo D, Casimirri F, Pascal G, Tortelli O, Labate AM (1997) Determinants of sex hormone-binding globulin blood concentrations in premenopausal and postmenopausal women with different estrogen status. Virgilio-menopause-health group. Metabolism 46(1):5–9. CrossRefPubMedGoogle Scholar
  46. 46.
    Dupont J, Le Roith D (2001) Insulin-like growth factor 1 and oestradiol promote cell proliferation of MCF-7 breast cancer cells: new insights into their synergistic effects. Mol Pathol 54(3):149–154. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hamelers IH, Steenbergh PH (2003) Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. Endocr Relat Cancer 10(2):331–345. CrossRefPubMedGoogle Scholar
  48. 48.
    Frydenberg H, Flote VG, Iversen A, Finstad SE, Furberg AS, Torjesen PA, Wilsgaard T, Schlichting E, Ellison PT, Ursin G, Thune I (2014) Insulin-like growth factor-1, growth hormone, and daily cycling estrogen are associated with mammographic density in premenopausal women. Cancer Causes Control 25(7):891–903. CrossRefPubMedGoogle Scholar
  49. 49.
    Schernhammer ES, Tworoger SS, Eliassen AH, Missmer SA, Holly JM, Pollak MN, Hankinson SE (2007) Body shape throughout life and correlations with IGFs and GH. Endocr Relat Cancer 14(3):721–732. CrossRefPubMedGoogle Scholar
  50. 50.
    Rice MS, Tamimi RM, Connolly JL, Collins LC, Shen D, Pollak MN, Rosner B, Hankinson SE, Tworoger SS (2012) Insulin-like growth factor-1, insulin-like growth factor binding protein-3 and lobule type in the Nurses’ Health Study II. Breast Cancer Res 14(2):R44. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Graham SJ, Stanchev PL, Lloyd-Smith JO, Bronskill MJ, Plewes DB (1995) Changes in fibroglandular volume and water content of breast tissue during the menstrual cycle observed by MR imaging at 1.5 T. J Magn Reson Imaging 5(6):695–701. CrossRefPubMedGoogle Scholar
  52. 52.
    White E, Velentgas P, Mandelson MT, Lehman CD, Elmore JG, Porter P, Yasui Y, Taplin SH (1998) Variation in mammographic breast density by time in menstrual cycle among women aged 40-49 years. J Natl Cancer Inst 90(12):906–910. CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Kimberly A. Bertrand
    • 1
  • A. Heather Eliassen
    • 2
    • 3
  • Susan E. Hankinson
    • 2
    • 3
    • 4
  • Bernard A. Rosner
    • 2
    • 5
  • Rulla M. Tamimi
    • 2
    • 3
  1. 1.Slone Epidemiology Center at Boston UniversityBostonUSA
  2. 2.Channing Division of Network MedicineHarvard Medical School and Brigham and Women’s HospitalBostonUSA
  3. 3.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  4. 4.Department of Biostatistics and Epidemiology, School of Public Health and Health SciencesUniversity of Massachusetts AmherstAmherstUSA
  5. 5.Department of BiostatisticsHarvard T.H. Chan School of Public HealthBostonUSA

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