Expert Commentary

Does menopausal estrogen therapy increase the risk of benign proliferative breast disease?

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Yes Use of unopposed estrogen (as 0.625 mg of conjugated equine estrogen daily) more than doubled the risk of benign proliferative breast disease, according to the findings of this randomized controlled trial. It’s unclear whether this finding ultimately translates to a greater risk of breast cancer.


Benign proliferative breast disease (BPBD) is a relatively common condition that is diagnosed by biopsy. It is important because of the economic and psychological burdens of biopsy and because BPBD may be a precursor to breast cancer. Some experts believe that the earliest phase of a continuum leading to invasive cancer is BPBD without atypia, followed by BPBD with atypia, in situ cancer, and then invasive disease.

Population was derived from WHI study

In this report, the risk of incident BPBD was compared among hysterectomized women 50 to 79 years old who participated in the Women’s Health Initiative (WHI). These women were randomized to conjugated equine estrogen (CEE) or placebo and monitored for, on average, 6.9 years of follow-up. They underwent baseline and annual clinical breast examination and mammography.

Overall, 232 new cases of BPBD were diagnosed among 10,739 women—approximately two thirds of them in the group randomized to CEE. Compared with women randomized to placebo, women taking CEE had twice the risk of being diagnosed with BPBD without atypia (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.71–3.20). For the subgroup of women with BPBD in whom histopathology was moderately extensive or florid (but lacking atypia), risk was similarly elevated (HR, 2.22).

Use of CEE was not associated with a substantially increased risk of atypical hyperplasia.

Limitations of the study

This trial tested only one estrogen regimen and dosage. It also was terminated earlier than expected, which may have rendered the risk estimates less precise. In addition, a significant number of participants stopped taking CEE during the trial.


This study found a significantly heightened risk of BPBD with use of unopposed estrogen, raising concerns about the potential for subsequent breast cancer. However, the same WHI estrogen-only trial from which this study1 derives, as well as the Nurses Health Study,2 found no increased risk of invasive breast cancer with estrogen therapy.

The authors of this WHI report suggest that longer follow-up of participants may help resolve this contradiction. In the meantime, some clinicians may choose to advise women who are beginning unopposed estrogen therapy that they face an elevated risk of breast biopsy for benign breast disease.—ANDREW M. KAUNITZ, MD

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