Menopausal Hormone Therapy and Risk of All-Cause Mortality

Hormone therapy written on a paper on a clipboard
Hormone therapy written on a paper on a clipboard
No other randomized clinical trial of hormone therapy has been large enough to assess a potential modifying effect of age on all-cause mortality, and most previous trials of chronic disease outcomes have focused on older women.

Postmenopausal women receiving hormone therapy with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for 5.6 years or 7.2 years of CEE alone may not have a risk of all-cause cardiovascular or cancer mortality when compared with woman receiving placebo, according to a study published in JAMA.

Researchers retrospectively reviewed data from 2 randomized clinical trials (the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials; identifier: NCT00000611) that occurred between 1993 and 1998, in addition to post trial follow-up data through 2014. Investigators identified 27,347 postmenopausal women aged 50 to 79 years, and randomly assigned women with a uterus (n=16,608) to receive either daily oral CEE plus MPA (n=8506) or placebo (n=8102) for 5.6 years, and women who had undergone a hysterectomy (n=10,739) to receive either oral CEE alone (n=5310) or placebo (n=5429) for 7.2 years. The primary outcome observed was all-cause mortality; cause-specific mortality was also an observed outcome.

Study results revealed 7849 deaths; 1088 occurred during the intervention phase, and 6401 deaths occurred during the 18-year follow-up. The primary outcome of all-cause mortality in the hormone therapy and placebo groups was 27.1% and 27.6%, respectively (hazard ratio, 0.99; 95% CI, 0.94-1.03). Hazard ratios of women treated with CEE plus MPA and women treated with CEE alone were 1.02 (95% CI, 0.96-1.08) and 0.94 (95% CI, 0.88-1.01), respectively.

Limitations of this study include only 1 dose, formulation, and route of hormone therapy studied, thereby limiting the generalizability of the study findings. In addition, 80.6% of participants were racially identified as “white,” limiting the generalizability of the findings in other racial populations.

Researchers concluded that during a cumulative 18-year follow-up of these 2 hormone therapy clinical trials, hormone therapy with CEE plus MPA for 5.6 years and CEE alone for 7.2 years in postmenopausal women “was not associated with risk of all-cause, cardiovascular, or cancer mortality” when compared with placebo.

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Based on these results, clinicians can discuss multiple hormone therapy treatment options with postmenopausal women without concern for higher all-cause mortality in any group.


Manson JE, Aragaki AK, Rossouw JE, et al; WHI Investigators. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the women’s health initiative randomized trials. JAMA. 2017;318:927-938.