JAMA 2013 Oct 01;310(13)1353-1368, JE Manson, RT Chlebowski, ML Stefanick, AK Aragaki, JE Rossouw, RL Prentice, G Anderson, BV Howard, CA Thomson, AZ Lacroix, J Wactawski-Wende, RD Jackson, M Limacher, KL Margolis, S Wassertheil-Smoller, SA Beresford, JA Cauley, CB Eaton, M Gass, J Hsia, KC Johnson, C Kooperberg, LH Kuller, CE Lewis, S Liu, LW Martin, JK Ockene, MJ O’Sullivan, LH Powell, MS Simon, L Van Horn, MZ Vitolins, RB Wallace
TAKE-HOME MESSAGE
- Is menopausal hormone therapy effective for chronic disease prevention?
- Data from the two Women’s Health Initiative (WHI) hormone therapy trials were analyzed. Measured outcomes were coronary heart disease and invasive breast cancer. Cumulative follow-up was 13 years.
- Menopausal hormone therapy was found to be appropriate for symptom management in some women; however, results of the two WHI hormone therapy trials do not support its use for chronic disease prevention.
Commentary By
The risks and benefits of hormone replacement therapy (HRT) can be quite complex. This report by Manson et al provides a comprehensive review of the two Women’s Health Initiative trials and the post-intervention follow-up (an average of 13 years), which assists in understanding the risks that may persist long after the therapy has ended.
Health-related outcomes associated with HRT include coronary heart disease (CHD), breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. In the intervention group in one of the trials, women with an intact uterus received conjugated equine estrogens (CEE) 0.625 mg/day plus medroxyprogesterone acetate (MPA) 2.5 mg/day. In the other trial, women with previous hysterectomy received CEE 0.625 mg/day only. The intervention phases of both trials were stopped after a few years due to recognition of certain adverse health outcomes, including increased risk of breast cancer with the CEE plus MPA regimen and increased risk of stroke with CEE only.
In the CEE plus MPA trial post-intervention and follow-up, the increased breast cancer risk persisted, along with other chronic disease risks. In the CEE only trial, younger women (aged 50–59 years) had a more favorable risk-to-benefit ratio than older women, indicating the impact of age on health outcomes with HRT; however, increased risk of certain chronic conditions, such as stroke continued to be a concern. In older women, a higher risk of CHD was also demonstrated. Both regimens were associated with an increased risk of stroke, venous thrombosis, and gallbladder disease. These results further confirm that HRT should not be used for chronic disease prevention.
As primary care physicians counseling our patients, a discussion of all the inherent risks associated with HRT is very important. Although HRT may effectively treat menopausal vasomotor symptoms, such as hot flashes, we must weigh the chronic disease risks and strongly consider alternative therapies for symptomatic treatment.
ABSTRACT
Importance: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
Objective: To report a comprehensive, integrated overview of findings from the 2 Women’s Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.
Design, Setting, and Participants: A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.
Interventions: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). 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.
Main Outcomes and Measures: 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: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% 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 postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus 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 plus 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 (nominal P < .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 and Relevance: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 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.
Journal Abstract: http://jama.jamanetwork.com/article.aspx?articleid=1745676