Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.
Level 2 - randomized trial
Extended post-intervention follow-up of two large randomized controlled trials
PubMed 24084921 · doi:10.1001/jama.2013.278040
What was done
Data were integrated from two Women's Health Initiative trials enrolling 27,347 postmenopausal women aged 50 to 79 years across 40 US centers. Women with an intact uterus were randomized to daily conjugated equine estrogens (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) (n=8,506) or placebo (n=8,102) for a median intervention of 5.6 years. Women with prior hysterectomy received CEE alone (0.625 mg/d) (n=5,310) or placebo (n=5,429) for a median intervention of 7.2 years. Both groups were followed for a cumulative median of 13 years to assess coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and total mortality.
What was found
During the intervention phase, CEE plus MPA increased coronary heart disease (196 vs 159 cases; HR 1.18, 95% CI 0.95-1.45) and invasive breast cancer (206 vs 155 cases; HR 1.24, 95% CI 1.01-1.53), as well as stroke, pulmonary embolism, dementia (in women aged >=65), gallbladder disease, and urinary incontinence, while reducing hip fractures, diabetes, and vasomotor symptoms. Breast cancer risk remained elevated during cumulative follow-up (434 vs 323 cases; HR 1.28, 95% CI 1.11-1.48). For CEE alone, intervention-phase coronary heart disease cases were 204 vs 222 (HR 0.94, 95% CI 0.78-1.14) and breast cancer cases were 104 vs 135 (HR 0.79, 95% CI 0.61-1.02); cumulative breast cancer was lower in the CEE group (168 vs 216 cases; HR 0.79, 95% CI 0.65-0.97). Neither regimen altered all-cause mortality overall. Younger women (aged 50-59) taking CEE alone had more favorable trends for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Annual net excess global index cases per 10,000 women on CEE plus MPA ranged from 12 (ages 50-59) to 38 (ages 70-79); on CEE alone, net cases ranged from 19 fewer (ages 50-59) to 51 excess (ages 70-79).
Why it matters
These long-term findings demonstrate that menopausal hormone therapy is not suitable for chronic disease prevention. It remains an option for symptom management, particularly when estrogen alone is initiated in younger postmenopausal women.
Limits
The trials tested only oral CEE and MPA at fixed daily doses, preventing direct generalization to lower doses, other progestins, or transdermal formulations. The study population had an average age substantially older than typical patients beginning treatment at menopause onset.
Cited by
- contradicts Estrogen replacement therapy that is not paired with progesterone increases the risk of stroke and heart attack.