The Effects of Menopausal Hormone Therapy on Breast Cancer: Evidence from the Women’s Health Initiative Randomized Placebo-Controlled Trials



Within the past decade, comprehensive evidence about the risks and benefits of menopausal hormone therapy (MHT), formerly referred to as hormone replacement therapy (HRT), has been published from the National Institutes of Health (NIH)-funded Women’s Health Initiative (WHI) randomized placebo-controlled trials of combined estrogen plus progestin therapy and estrogen-only therapy. Current, widely accepted practice, which arose after two 1975 landmark studies reported increased endometrial cancer risk in women who were using “unopposed” estrogen, i.e., estrogen-only, is to administer estrogen to women who have undergone prior hysterectomy (with either surgical or natural menopause) and to use a combination of estrogen and progesterone (E plus P) in women with an intact uterus. Progesterone is added in these women to prevent endometrial hyperplasia, which is known to be increased by unopposed estrogen, and is believed to prevent endometrial carcinoma, the risk of which increases substantially with long duration estrogen-only use and remains elevated for several years after discontinuation of hormone therapy. Understanding results of these trials is extremely helpful as many women have used various forms of hormone replacement and are often concerned about the associated cancer risk. In addition, healthy women without breast cancer histories will often inquire about the use of hormone replacement and the potential impact on breast cancer risk.


Breast Cancer Risk Menopausal Hormone Therapy Conjugate Equine Estrogen Endometrial Cancer Risk Combine Estrogen 
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  1. 1.
    The Writing Group for the Women’s Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative. JAMA. 2002;288:321–33.CrossRefGoogle Scholar
  2. 2.
    The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701–12.CrossRefGoogle Scholar
  3. 3.
    Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med. 1975;293:1164–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med. 1975;293:1167–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA. 1996;275:370–5.CrossRefGoogle Scholar
  6. 6.
    Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85:304–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52, 705 women with breast cancer and 108, 411 women without breast cancer. Lancet. 1997;350(9089):1047–59.Google Scholar
  8. 8.
    Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen plus progestin replacement therapy and breast cancer risk. JAMA. 2000;283:485–91.PubMedCrossRefGoogle Scholar
  9. 9.
    Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92:328–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Million Women Study Collaborators. Breast cancer and hormone replacement therapy in Million Women Study. Lancet. 2003;362:419–42.CrossRefGoogle Scholar
  11. 11.
    Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA. 2003;289:3243–53.PubMedCrossRefGoogle Scholar
  12. 12.
    Chlebowski RT, Anderson G, Pettinger M, Lane D, Langer RD, Gilligan MA, et al. Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy. Arch Intern Med. 2008;168:370–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett E, et al. Effects of conjugated equine estrogens on breast cancer and mammography in postmenopausal women with hysterectomy: the Women’s Health Initiative Randomized Trial. JAMA. 2006;295:1647–57.PubMedCrossRefGoogle Scholar
  14. 14.
    Hersh AL, Stefanick ML, Stafford RS. National use of post-menopausal hormone therapy: annual trends and response to recent evidence, 1995-2003. JAMA. 2004;291:47–53.PubMedCrossRefGoogle Scholar
  15. 15.
    Ravdin PM, Cronin K, Howlander N, et al. A sharp decrease in breast cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SAA, Brzyski R, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036–45.PubMedCrossRefGoogle Scholar
  17. 17.
    Chlebowski R, Kuller L, Prentice R, Stefanick ML, Manson J, Gass M, et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009; 360:573–87.PubMedCrossRefGoogle Scholar
  18. 18.
    Prentice RL, Chlebowski RT, Stefanick ML, Manson JE, Langer RD, Pettinger M, et al. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiology. 2008;167:1207–16.CrossRefGoogle Scholar
  19. 19.
    Prentice RL, Chlebowski RT, Stefanick ML, Manson JE, Langer RD, Pettinger M, et al. Conjugated equine estrogens and breast cancer risk in the Women’s Health Initiative Clinical Trial and Observational Study. Am J Epidemiol. 2008;167:1407–15.PubMedCrossRefGoogle Scholar

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© Springer New York 2010

Authors and Affiliations

  1. 1.Stanford Prevention Research CenterStanford UniversityStanfordUSA

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