Among postmenopausal women, hormone therapy with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality, according to a study published in JAMA.

JoAnn E. Manson, MD, DrPH, from the Division of Preventive Medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues used observational follow-up data from the 2 Women’s Health Initiative hormone therapy trials. The study included 27,347 postmenopausal women between 50 and 79 years of age who were enrolled between 1993 and 1998 and followed through 2014.

In the first trial, 16,608 women with a uterus were randomly assigned to receive CEE 0.625 mg/d plus MPA 2.5 mg/d or placebo. In the second trial, 10,739 women with a hysterectomy were randomly assigned to receive daily oral CEE 0.625 mg alone or placebo.

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After 18 years of follow-up, the all-cause mortality in the overall pooled cohort was 27.1% in women receiving hormone therapy vs 27.6% in the placebo group (hazard ratio [HR], 0.99). Additionally, all-cause mortality was 26.4% in women receiving CEE plus MPA vs 26.0% for placebo (HR, 1.02). For women receiving CEE alone, the all-cause mortality was 28.3% vs 30.0% for placebo (HR, 0.94).

The cardiovascular mortality rate in the pooled cohort was 8.9% in the hormone therapy group vs 9.0% in the placebo group (HR, 1.00), and the cancer mortality rate was 8.2% in the hormone therapy group vs 9.0% in the placebo group (HR, 1.03). Mortality for other causes was 10.0% in the hormone group vs 10.7% in the placebo group (HR, 0.95). The researchers note that the results did not differ significantly between the trials.

When the investigators compared mortality in younger women (50 to 59 years) with mortality in older women (70 to 79 years), the ratio of nominal HRs for all-cause mortality was 0.61 during the intervention phase and 0.87 during the 18-year follow-up.

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“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate-to-severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” the study authors noted.

“Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment,” they added. “In clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”

In an accompanying editorial, Melissa McNeil, MD, MPH, University of Pittsburgh, notes that the effect of hormone therapy on cancer mortality, especially breast cancer mortality, has caused concern for patients and clinicians and has resulted in a reluctance to prescribe hormone therapy for troubling menopausal symptoms. However, the results of the trial should provide reassurance, given that the mortality rates were similar between hormone users and nonusers.

“This information will be helpful in counseling women considering whether to start hormone therapy and hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” Dr McNeil concluded.


  1. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials. JAMA. 2017;318(10):927-938. doi:10.1001/jama.2017.11217
  2. McNeil M. Menopausal hormone therapy: Understanding long-term risks and benefits. JAMA. 2017;318(10):911-913. doi:10.1001/jama.2017.11462