Clinical Question: Does unopposed estrogen therapy in postmenopausal women with hysterectomy increase the risk of breast cancer?

Setting: Outpatient (any)

Study Design: Randomized controlled trial (double-blinded)

Allocation: Concealed

Synopsis: Hormone therapy with estrogen and progesterone increases the risk of invasive breast cancer. The risk in postmenopausal women with hysterectomy who have been treated with estrogen alone is uncertain. As part of the Women’s Health Initiative, investigators randomized (concealed allocation assignment) 10,739 postmenopausal women, 50 to 79 years of age, who had undergone hysterectomy. The women received 0.625 mg per day of conjugated equine estrogen or placebo. Persons assessing outcomes remained blinded to treatment group assignment. Follow-up occurred for nearly 95 percent of the participants for a mean of 7.1 years.

Using intention-to-treat analysis, investigators observed nonsignificant reductions in invasive breast cancer and total breast cancer in women receiving conjugated equine estrogen. Significantly more women in this group had questionably abnormal mammography results (36.2 versus 28.1 percent in the placebo group over seven years), requiring further short-term evaluation.

Bottom Line: Estrogen therapy alone does not increase the risk of breast cancer in postmenopausal women who have had a hysterectomy. Women receiving estrogen are more likely to require further testing because of questionably abnormal mammography results, which could lead to heightened anxiety and a reduced quality of life. The decision to use estrogen in postmenopausal women after hysterectomy should be individualized based on overall potential risks and benefits. Women most likely to benefit from estrogen therapy include those with disabling hot flashes and an increased risk of osteoporotic fractures. Treatment should be limited, whenever possible, to within the first five years after menopause. (Level of Evidence: 1b)