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29 October 2010

In 2002, the Women's Health Initiative (WHI) randomized trial of placebo vs hormone therapy with estrogen and progestin was stopped early because of evidence of harm.1 Sales of combined estrogen-progestin plummeted 32% between the period immediately before the study's release and the analogous period 1 year later, as the WHI trial had shown that hormone therapy increased a woman's risk of breast cancer and myocardial infarction.2 The finding contradicted decades of case-control and observational cohort studies that had suggested that hormone therapy was associated with strong protective effects on the cardiovascular system. The WHI results also undermined a long and successful campaign by hormone replacement advocates to present hormone therapy as a panacea against heart disease, loss of femininity, and other perils of aging. In addition, the WHI documented numerous other negative effects of hormone therapy, including an increased risk of stroke and pulmonary embolism,1 which are not strongly associated with the timing of hormone therapy initiation. Ultimately, the only long-term benefit of hormone therapy that the US Food and Drug Administration (FDA) allows the manufacturer to claim is reduction of risk of osteoporotic fractures.3

That breast cancer rates in the WHI increased among women receiving hormone therapy was not surprising. Epidemiological and biological studies had anticipated the effect,4 although the magnitude of risk was not known until the WHI, which showed that the effect of hormone therapy on breast cancer risk was about the same as the deleterious effect on cardiovascular health. Several years after use of hormone therapy plummeted in the United States, breast cancer incidence also declined.5

Chlebowski et al6 report results of an 11-year follow-up of WHI estrogen-progestin trial participants that address many of these questions. The authors found that hormone therapy increases the frequency of breast cancer and that the breast cancers are on average more advanced and may be larger. The authors found no evidence that the cancers had favourable prognostic features, such as more frequently being estrogen receptor positive or lacking HER2 /neu gene amplification. If anything, the results suggest a trend in the direction of less favourable cancers. In addition, the authors found strong evidence that the rate of breast cancer death is increased by hormone therapy. It is also probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study and that with longer follow-up, the deleterious effect will appear larger. This suggestion is based on several observations: the mortality curves appear to still be separating at the end of the current follow-up (Figure 4A in the article); the difference in cumulative breast cancer incidence between women in the hormone therapy and placebo groups is widening (Figure 2 in the article), which will ultimately lead to more deaths; and the breast cancers diagnosed among women who received hormone therapy are associated with a poorer prognosis.

Based on present data, the authors project that approximately 1.3 additional deaths from breast cancer per 10 000 person-years of follow-up have already occurred among the women who received hormone therapy in the study. Since this number is relatively small, clinicians might conclude that a brief period of hormone therapy for relief of menopausal symptoms is safe. Such a view would be consistent with some professional guidelines7 and with the FDA-approved label for combined estrogen-progestin therapy.3 However, the study by Chlebowski et al6 does not address the effect of short periods of hormone therapy on breast cancer risk (or other disease risk), and the current estimate of the deleterious effects of hormone therapy may be underestimated.

Therefore, the available data dictate caution in the current approach to use of hormone therapy, particularly because one of the lessons from the WHI is that physicians are ill-equipped to anticipate the effect of hormone therapy on long-term health. Clinicians who prescribe brief courses of hormone therapy for relief of menopausal symptoms should be aware that this approach has not been proven in rigorous clinical trials and that the downstream negative consequences for their patients are of uncertain magnitude. Given the substantial population of women who seek relief from menopausal symptoms and the large potential burden of disease that could be created if medications given to alleviate symptoms today cause cancer and other deaths tomorrow, it seems that additional randomized trials are needed specifically to determine whether lower doses or shorter durations of hormone therapy could alleviate menopausal symptoms without increasing cancer risk.


  1. Rossouw JE, Anderson GL, Prentice RL; et al, Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
  2. Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women's Health Initiative. JAMA. 2004;292(16):1983-1988.
  3. US Food and Drug Administration. Prempro prescribing information. 2009.
  4. Key TJA, Pike MC. The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol. 1988;24(1):29-43.
  5. Chlebowski RT, Kuller LH, Prentice RL; et al, WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573-587.
  6. Chlebowski RT, Anderson GL, Gass M; et al, WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA.2010;304(15):1684-1692.
  7. US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the US Preventive Services Task Force. Ann Intern Med. 2005;142(10):855-860.

Edited by Hanifullah Khan from  Bach PB. Postmenopausal Hormone Therapy and Breast Cancer: An Uncertain Trade-off. JAMA  2010;304(15):1719-1720. doi:10.1001/jama.2010.1528

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