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Examining the Evidence

Q Does unopposed estrogen increase the risk of breast cancer?

September 2006 · Vol. 18, No. 9

<huc>A</huc> Not over the short term. Postmenopausal, hysterectomized women who use estrogen for less than 5 years do not appear to increase their risk of breast cancer—and may actually reduce it. The precise level of risk associated with longer periods of use remains unclear, but appears to be elevated.

Expert Commentary

Although the US Food and Drug Administration requires drug treatment trials to include evidence of both benefit and risk, most clinical trials study adverse effects only over the short term, typically less than 2 years, with notable exceptions such as breast cancer adjuvant treatment trials.1 The assessment of long-term effects has largely fallen to the field of pharmacoepidemiology, and the most common research tool has been the observational cohort study.

Details of the studies

The WHI offered a unique opportunity to determine long-term benefits and risks from the 2 most commonly prescribed hormone regimens in the United States at the time the study began.2,3 In the estrogen-only arm, hysterectomized women were randomized to 0.625 mg daily of conjugated equine estrogen (CEE) or placebo, and were to be followed for 8 to 12 years to observe any major diseases that occurred, including breast cancer.

In 2004, the trial was stopped early after a mean 6.8 years of follow-up, because of a persistent elevated risk for stroke and no evidence of protection against coronary disease in the women randomized to estrogen.

Stefanick et al. In their closer look at WHI breast cancer data for the estrogen-only arm, Stefanick and colleagues found that women taking CEE had a nonstatistically significant 20% reduced risk of developing invasive breast cancer after a mean 7.1 years of follow-up. Examination over time did not suggest an increasing risk of breast cancer with CEE for up to 9 years of follow-up; rather, risk in CEE-treated women remained diminished, compared with placebo, throughout follow-up. Among women who had used estrogen alone for 5 or more years prior to enrollment in the WHI trial, the risk of invasive breast cancer increased nonsignificantly by 28% in CEE-treated women compared with placebo.

Chen et al. In their reanalysis of Nurses’ Health Study data from 28,835 postmenopausal women without a uterus, Chen et al observed comparable results after 5 to 9.9 years of CEE use—ie, a non-significant 13% reduced risk of breast cancer. However, among women who used CEE for 15 to 19.9 years, a nonstatistically significant 19% increase in the risk of invasive breast cancer was observed, and among women who used CEE for 20 or more years, a statistically significant 41% increased risk was seen.

Findings agree with earlier data

These 2 studies are in accord with previous observational studies of exogenous estrogen and the risk of breast cancer.4 A combined dataset representing more than 52,000 breast cancer cases and more than twice as many controls found that current or recent (past 1–4 years) use of a daily dose of unopposed CEE of 0.625 mg or less, for less than 5 years, was associated with a 23% reduced risk of breast cancer, compared with nonusers.4 Use of this formulation for 5 or more years was associated with a 64% increase in risk.

Similarly, the UK-based Million Women Study found that use of unopposed estrogen for less than 1 year reduced the risk for breast cancer by 19%, compared with never-users, but longer use increased risk by 25% to 37%.5

Bottom line: No heightened risk in the short term

Women choosing to take unopposed estrogen to control menopausal symptoms do not appear to face an increased risk of breast cancer if they use it for less than 5 years. Observational studies suggest they may increase their risk of breast cancer by using estrogen for 5 or more years, but no data from clinical trials are available past 7 years of follow-up.

The lower risk of breast cancer for women using unopposed estrogen for only short periods of time, seen in both the WHI clinical trial and the large observational studies, remains unexplained.

Dr. McTiernan is a consultant to Novartis Canada, Procter & Gamble, and Zymogenetics.


1. Mamounas EP. NSABP breast cancer clinical trials: recent results and future directions. Clin Med Res. 2003;1:309-326.

2. Anderson GL, Limacher M, Assaf AR, et al, for 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;291:1701-1712.

3. Prentice R, Rossouw JR, Johnson SR, Freedman LS, McTiernan A. The role of randomized controlled trial in assessing the benefits and risks of long-term hormone replacement therapy: example of the Women’s Health Initiative. Menopause. 1996;3:71-76.

4. 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;350:1047-1059.

5. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419-427.

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