The use of combined hormone replacement therapy with estrogen plus progestin among postmenopausal women was associated with an increased risk of breast cancer, according to the results of a long-term analysis published in the Journal of the National Cancer Institute.

Hormone replacement therapy (HRT) is often prescribed for women during menopause, which is a natural phase of the female lifecycle during which the ovaries produce significantly less estrogen, ovulation ceases, and menstruation ends. For many women, menopause has uncomfortable side effects such as hot flashes, sleep disturbances, depression, mood swings, and anxiety. Additionally, menopause may also be accompanied by increased urinary tract infections, incontinence, vaginal discomfort due to a lack of estrogen-based lubrication, and decreased bone density.

Although HRT has been widely prescribed for menopausal women, it has come under scrutiny because some studies have indicated that it may be associated with an increased risk of certain types of cancer and other health problems. Combined HRT has been linked with an increased risk of breast cancer, lung cancer, heart disease, stroke, and blood clots, but a decreased risk of colorectal cancer and fractures. Data is conflicting. The Women’s Health Initiative (WHI) randomized trial found that estrogen plus progestin increased both breast cancer incidence and mortality; however, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers.

The WHI study included several randomized clinical trials and also an observational study that enrolled 93,000 women who were not eligible or were not willing to participate in the trials. In the current analysis, researchers identified 41,449 women from the observational study with no prior hysterectomy and a negative mammogram within two years. Of these women,16,121 were users of combined HRT, while 25,328 were nonusers.

After a mean follow-up of 11.3 years, there were 2,236 breast cancers. The researchers found that the annualized rate of breast cancer was higher among hormone users (0.60%) compared with nonusers (0.42%). Women who initiated HRT closer to menopause had higher breast cancer risk, but this risk decreased as time from menopause increased. The association between combined HRT and breast cancer was stronger among women with ongoing use, with an annual rate of 0.75% compared with 0.41% in the overall population. Survival after the diagnosis of breast cancer was comparable in HRT users and nonusers.

The researchers concluded that women taking estrogen-plus-progestin HRT after menopause have an increased risk of invasive breast cancer. Research will likely be ongoing in order to determine the influence of duration of HRT or current use at the time of diagnosis on the type or prognosis of the tumors.


Chlebowski RT, Manson JE, Anderson GL, et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. Journal of the National Cancer Institute. 2013; 105 (8): 526-535.

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