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The estrogen paradox

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 496–497 (2007)Cite this article

A randomized controlled trial published in 2006 demonstrated that postmenopausal women who underwent hormone therapy with estrogen alone for a mean of 7.1 years unexpectedly had a decreased risk of breast cancer.1 High doses of estrogen also cause regression of hormone-dependent breast cancers.2 By contrast, a large observational study reported an increased breast cancer risk in women treated with estrogen alone for ≥20 years.3 We have adopted the term 'estrogen paradox' to highlight the seemingly incongruous nature of these results. In this Viewpoint, we discuss our hypothesis and describe possible mechanisms to account for the observed effects.

The initial publication of the Women's Health Initiative (WHI) reported a 23% decrease in invasive breast cancer (IBC) incidence in patients who received estrogen alone, a finding that narrowly missed statistical significance (hazard ratio [HR] 0.77, 95% CI 0.59–1.01).4 An exploratory analysis of the updated results from the WHI reported a 33% reduction in IBC incidence in patients who strictly adhered to their estrogen therapy (HR 0.67, 95% CI 0.47–0.97).1 In addition, a 31% lower incidence of localized breast cancer (HR 0.69, 95% CI 0.51–0.95) and a 29% reduction in ductal cancers (HR 0.71, 95% CI 0.52–0.99) were reported among women who used estrogen alone. The decreased breast cancer risk was limited to women who had not used hormone therapy previously.1 Concurrent observational data from the Nurses Health Study (NHS) suggested a 26% decrease in breast cancer risk in obese women (HR 0.74, 95% CI 0.55−1.00), and a non-significant 10% decrease in all study participants who took estrogen alone for 5–9 years.3 Overall, these results are highly suggestive of a beneficial effect of estrogen on breast cancer risk; however, they must be considered provisional until rigorous confirmation in additional randomized controlled trials.

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References

  1. Stefanick ML et al. (2006) Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295: 1647–1657

    Article  CAS  Google Scholar 

  2. Ingle JN et al. (1981) Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med 304: 16–21

    Article  CAS  Google Scholar 

  3. Chen WY et al. (2006) Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 166: 1027–1032

    Article  CAS  Google Scholar 

  4. Anderson GL et al. (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291: 1701–1712

    Article  CAS  Google Scholar 

  5. Greiser CM et al. (2005) Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials. Hum Reprod Update 11: 561–573

    Article  CAS  Google Scholar 

  6. Welch HG and Black WC (1997) Using autopsy series to estimate the disease 'reservoir' for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 127: 1023–1028

    Article  CAS  Google Scholar 

  7. Ryan JA and Coady CJ (1962) Intraductal epithelial proliferation in the human breast—a comparative study. Can J Surg 5: 12–19

    CAS  PubMed  Google Scholar 

  8. Song RX et al. (2001) Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17 beta-estradiol. J Natl Cancer Inst 93: 1714–1723

    Article  CAS  Google Scholar 

  9. Lewis JS et al. (2005) Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation. J Natl Cancer Inst 97: 1746–1759

    Article  CAS  Google Scholar 

  10. Cavalieri E et al. (2006) Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta 1766: 63–78

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. RJ Santen is a Professor of Medicine in the Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center, Charlottesville, VA, USA,

    Richard J Santen

  2. DC Allred is a Professor and Director of Breast Pathology in the Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.,

    D Craig Allred

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  1. Richard J Santen
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  2. D Craig Allred
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Correspondence to Richard J Santen.

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Santen, R., Allred, D. The estrogen paradox. Nat Rev Endocrinol 3, 496–497 (2007). https://doi.org/10.1038/ncpendmet0535

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