Menopausal Hormone Therapy and Long-Term Mortality Risk

Study Questions:

Is hormonal therapy associated with risk of death among postmenopausal women?


Data from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials were used for the present analysis. Women ages 50-79 years of age, all postmenopausal and residing in the United States, were enrolled between 1993 and 1998 and followed through December 31, 2014. Women were randomized to conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8,506) versus placebo (n = 8,102) for 5.6 years (median) at the time of intervention completion (2002) if they had a uterus, and to CEE alone (n = 5,310) versus placebo (n = 5,429) for 7.2 years (median) at the time of trial completion (2004) if they had had a hysterectomy. At completion of the intervention phase, assignment was unblended; <4% of the population reported post-trial hormonal therapy use. The primary outcomes for this analysis were all-cause mortality and cause-specific mortality.


A total of 27,347 women (baseline mean age 63.4 years, 80.6% white) were included, of which 7,489 deaths occurred during the cumulative 18-year follow-up. A total of 1,088 deaths occurred during the intervention phase and 6,401 deaths occurred during post-intervention follow-up. All-cause mortality was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.94-1.03) in the overall pooled cohort.

For women randomized to CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08) compared to placebo. For women randomized to CEE alone, the HR was 0.94 (95% CI, 0.88-1.01) compared to placebo. For cardiovascular mortality, there was no difference observed between the hormonal therapy group and the placebo group for the overall pooled cohort (HR, 1.00 [95% CI, 0.92-1.08] or 8.9% with hormone therapy vs. 9.0% with placebo). A similar pattern was noted for total cancer mortality (HR, 1.03 [95% CI, 0.95-1.12] or 8.2% with hormone therapy vs. 8.0% with placebo). The results did not differ between trials (CEE plus MPA or CEE alone). When examined by 10-year age groups comparing younger women (ages 50-59 years) to older women (ages 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.


The authors concluded that among postmenopausal women, hormone therapy with CEE plus 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 during a cumulative follow-up of 18 years.


These data suggest that 5-7 years of hormonal therapy is not associated with increased risk for long-term cardiovascular or all-cause mortality, in particular for women under the age of 60 years.

Clinical Topics: Prevention

Keywords: Estrogens, Estrogens, Conjugated (USP), Female, Hormone Replacement Therapy, Hysterectomy, Medroxyprogesterone, Medroxyprogesterone Acetate, Mortality, Neoplasms, Postmenopause, Progestins, Primary Prevention, Risk, Women

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