Mortality Associated with Hormone Replacement Therapy in Younger and Older Women

Shelley R. Salpeter, MD; Judith M.E. Walsh, MD, MPH; Elizabeth Greyber, MD; Thomas M. Ormiston, MD; Edwin E. Salpeter, PhD


J Gen Intern Med. 2004;19(7) 

In This Article

Abstract and Introduction

Objective: To assess mortality associated with hormone replacement in younger and older postmenopausal women.
Design: A comprehensive search of medline, cinahl, and embase databases was performed to identify randomized controlled trials of hormone replacement therapy from 1966 to September 2002. The search was augmented by scanning selected journals through April 2003 and references of identified articles. Randomized trials of greater than 6 months' duration were included if they compared hormone replacement with placebo or no treatment, and reported at least 1 death.
Measurements: Outcomes measured were total deaths and deaths due to cardiovascular disease, cancer, or other causes. Odds ratios (OR) for total and cause-specific mortality were reported separately for trials with mean age of participants less than and greater than 60 years at baseline.
Main Results: Pooled data from 30 trials with 26,708 participants showed that the OR for total mortality associated with hormone replacement was 0.98 (95% confidence interval [CI], 0.87 to 1.12). Hormone replacement reduced mortality in the younger age group (OR, 0.61; CI, 0.39 to 0.95), but not in the older age group (OR, 1.03; CI, 0.90 to 1.18). For all ages combined, treatment did not significantly affect the risk for cardiovascular or cancer mortality, but reduced mortality from other causes (OR, 0.67; CI, 0.51 to 0.88).
Conclusions: Hormone replacement therapy reduced total mortality in trials with mean age of participants under 60 years. No change in mortality was seen in trials with mean age over 60 years.

In the assessment of risks and benefits of hormone replacement therapy (HRT), observational studies and clinical trials have yielded apparently conflicting results. Large prospective cohort studies have shown that women who used HRT, most of whom started treatment shortly after menopause, had significant reductions in total and cardiovascular mortality compared to nonusers.[1,2,3,4,5,6,7,8] The results remained significant after adjusting for cardiovascular risk factors such as age, smoking, and blood pressure. The largest randomized trial of HRT, the Women's Health Initiative (WHI), evaluated women with mean age 63 years and found that HRT increased the risk of cardiovascular events, without changing total or cardiovascular mortality.[9]

It is possible that the mortality reduction seen in observational studies was due to a confounding variable that was not adequately adjusted for, such as general health status or access to health care.[10,11,12] Another explanation is that when HRT is started in younger women, a true mortality benefit is seen. Mortality is a relatively rare outcome, even in large trials. For example, the WHI had approximately 5 deaths per 1,000 patient-years.[9] A more precise estimate of the impact of HRT on mortality can be made by pooling the results of many trials. The objective of this study was to assess the effect of age on total and cause-specific mortality associated with HRT by performing a meta-analysis of randomized controlled trials.


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