Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Post-Stopping Phases of the Women’s Health Initiative Randomized Trials

Study Questions:

What are the long-term risks and benefits of menopausal hormone therapy for chronic disease prevention?

Methods:

A total of 27,347 postmenopausal women ages 50-79 years were enrolled at 40 US centers. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8,506) or placebo (n = 8,102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5,310) or placebo (n = 5,429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial, with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.

Results:

The intervention phase of the CEE plus MPA trial ended on July 7, 2002 (after a median of 5.6 years; interquartile range [IQR], 4.8-6.5 years) due to increased breast cancer risk and an unfavorable risk-to-benefit ratio with CEE plus MPA. The intervention phase of the CEE alone trial ended on February 29, 2004 (after a median of 7.2 years [IQR, 6.4-8.1 years]) due to increased stroke incidence that was not offset by lower CHD risk in the hormone therapy group. During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA versus 159 for placebo (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.95-1.45) and 206 versus 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women ages ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated post-intervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs. 323 for placebo; hazard ratio [HR], 1.28; 95% CI, 1.11-1.48). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone versus 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 versus 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 versus 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (ages 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal p < 0.05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.

Conclusions:

The investigators concluded that menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended post-intervention follow-up of the two Women's Health Initiative hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Perspective:

These data allow clinicians and their patients to better understand the long-term risks and benefits of hormonal therapy if such therapy is being considered for use.

Clinical Topics: Vascular Medicine, Sleep Apnea

Keywords: Risk, Myocardial Infarction, Stroke, Follow-Up Studies, Chronic Disease, Pulmonary Embolism, Vascular Diseases, Women's Health, Breast Neoplasms, Coronary Disease, Estrogen Replacement Therapy, Breast, Endometrial Neoplasms, Incidence, Dementia, Colorectal Neoplasms, Risk Assessment, Hormone Replacement Therapy, Diabetes Mellitus


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