Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status - Results from the EPIC cohort

Rudolf Kaaks, Kaja Tikk, Disorn Sookthai, Helena Schock, Theron Johnson, Anne Tjønneland, Anja Olsen, Kim Overvad, Françoise Clavel-Chapelon, Laure Dossus, Laura Baglietto, Sabina Rinaldi, Veronique Chajes, Isabelle Romieu, Heiner Boeing, Madlen Schütze, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Domenico PalliSabina Sieri, Rosario Tumino, Fulvio Ricceri, Amalia Mattiello, Genevieve Buckland, Jose Ramón Quirós, María José Sánchez, Pilar Amiano, Maria Dolores Chirlaque, Aurelio Barricarte, H. Bas Bueno-De-Mesquita, Carla H. Van Gils, Petra H. Peeters, Anne Andersson, Malin Sund, Elisabete Weiderpass, Kay Tee Khaw, Nick Wareham, Timothy J. Key, Ruth C. Travis, Melissa A. Merritt, Marc J. Gunter, Elio Riboli, Annekatrin Lukanova

Research output: Contribution to journalArticlepeer-review


Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1 = 1.56 (95% CI 1.15-2.13), ptrend = 0.02 for testosterone and ORQ4-Q1 = 1.33 (95% CI 0.99-1.79), ptrend = 0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and -negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1 = 1.32 (95% CI 0.87-2.01), ptrend = 0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1 = 0.94 (95% CI 0.60-1.47), ptrend = 0.34, phet = 0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen. What's new? Sex hormones have often been connected with the development of breast cancer, and estrogens have clear pro-proliferative effects on breast cancer cells. In this large prospective study, the authors underscore a direct association of premenopausal levels of testosterone with subsequent breast cancer risk. By contrast, no direct relationship between premenopausal estrogen and progesterone levels with increased breast cancer risk was observed although a weak association between higher estradiol levels and increased risk for tumors diagnosed before age 50 was noted. The authors point to the possibility that a conversion from androgen to estrogen might take place in the breast that may mechanistically explain the increased risk in breast cancer development when androgens are high.

Original languageEnglish
Pages (from-to)1947-1957
Number of pages11
JournalInternational Journal of Cancer
Issue number8
Publication statusPublished - Apr 15 2014


  • breast cancer
  • EPIC
  • estrogen receptor
  • prospective cohort
  • sex hormones

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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