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Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. A total of 27,347 postmenopausal women aged 50–79 years were enrolled at 40 US centers to the Women’s Health Initiative trial [1]. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/day) plus medroxyprogesterone acetate (MPA; 2.5 mg/day) ([i]n[/i] = 8506) or placebo ([i]n[/i] = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/day) ([i]n[/i] = 5310) or placebo ([i]n[/i] = 5429). The intervention lasted a median of 5.6 years in CEE + MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. During the CEE + MPA intervention phase, the numbers of coronary heart disease (CHD) cases were 196 for CEE + MPA vs. 159 for placebo (hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.95–1.45) and 206 vs. 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 aged ≥ 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 + MPA vs. 323 for placebo; 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 vs. 222 cases for placebo (HR 0.94; 95% CI 0.78–1.14) and 104 vs. 135, respectively, for invasive breast cancer (HR 0.79; 95% CI 0.61–1.02); cumulatively, there were 168 vs. 216, respectively, cases of breast cancer diagnosed (HR 0.79; 95% CI 0.65–0.97). Results for other outcomes were similar to CEE + MPA. Neither regimen affected all-cause mortality. For CEE-alone, younger women (aged 50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index. Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE + 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. In conclusion, findings from the intervention and extended post-intervention follow-up of the two WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.



  1. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Womens Health Initiative Randomized Trials. JAMA 2013;310:1353-68.
  2. Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. 1. Comparison of therapeutic efficacy. J Am Geriatr Soc 2013;61:1005-10.
  3. Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. 2. Comparative risks. J Am Geriatr Soc 2013;61:1011-18.
  4. SchierbeckLL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409.
  5. Sarrel PM, Njike VY, Vinante V, et al. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 5059 years. Am J Public Health 2013;103:1583-8
  6. Kindig DA, Cheng ER. Even as mortality fell in most US counties, female mortality nonetheless rose in 42.8% of counties from 1992 to 2006. Health Affairs 2013;32:451-8.
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