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


Pooled data from 30 trials, with 26,708 postmenopausal women followed for a mean duration of 4.5 years, indicate that hormone replacement does not increase total mortality. In the younger group, with mean age 54 years at baseline, HRT was associated with a reduction in total mortality of 39%. In the older group, with mean age 66 years, HRT was not associated with a change in total mortality. A cutoff of 60 years for mean age was chosen, although the results were still robust for cutoffs in the range from 56 to 63 years. Given that there is not one single cutoff but rather a linear relationship between young and old, linear regression analysis was performed that demonstrated a significant trend between increasing mortality OR and increasing age, with a correlation coefficient of 0.98.

These results may help to explain the discrepancies that have been seen between observational studies and randomized trials. The Nurses' Health Study was a 20-year prospective cohort study of 120,000 women under the age of 55 years, and the WHI was a 5-year trial of 16,000 women with mean age 63 years.[2,9] In both studies, HRT was associated with similar increases in breast cancer, stroke, and pulmonary embolism, and similar reductions in colorectal cancer and hip fracture.[48] However, the WHI found an increase in cardiac events without a change in cardiovascular or total mortality, while the Nurses' Health Study found significant reductions in cardiac events as well as cardiovascular and total mortality.

The Nurses' Health Study, after adjusting for potential confounding variables, found that current hormone users, 80% of whom had started treatment within 2 years of menopause, had a total mortality risk of 0.63 (95% CI, 0.56 to 0.70) that of nonusers.[2] This meta-analysis found similar results for total mortality in the younger group (OR, 0.61; 95% CI, 0.39 to 0.95), providing evidence that the mortality benefit seen in the observational studies may be a true effect of HRT when treatment is started shortly after menopause. Beneficial effects of HRT include increases in high-density lipoproteins and reductions in low-density lipoproteins, Lp(a) lipoproteins, homocysteine, fibrinogen, plasminogen activator inhibitor antigen, intrinsic coagulation factors, glucose, weight, insulin levels, and the incidence of new-onset diabetes mellitus, compared to placebo.[29,40,49,50,51,52,53,54,55,56,57,58] In women with diabetes mellitus, HRT reduces central adiposity and improves glycemic control and physical functioning.[59,60] HRT also causes sustained increases in nitric oxide levels and reductions in plasma norepinephrine, plasma renin activity, and endothelin.[61,62,63,64] These endothelial changes have been associated with vasodilation, reduced blood pressure, increased blood flow, and improved cardiac performance.[65,66,67,68,69] It is thought that estrogen has protective properties against cardiovascular disease in premenopausal women, and that the risk for atherosclerosis begins to rise after menopause.[70,71] It is possible that if HRT is started in women in the early postmenopausal period, well before the development of atherosclerosis, primary prevention could be achieved through these improvements in metabolism, hemostasis, and endothelial function. In fact, there is some evidence from clinical trials and animal studies that HRT can halt the progression of atherosclerosis if treatment is started early in the course of the disease.[29,72,73,74,75,76]

No mortality benefit from HRT was seen for women in the WHI trial, most of whom had not taken hormones since the start of menopause at least 10 years earlier.[9] The WHI included women who were under the age of 60 years, but the investigators declined to provide mortality data for those women separately. Of note, a subgroup analysis of cardiac events in the trial found a hazard ratio of 0.89 for those women within 10 years of menopause, 1.22 for those 10 to 15 years from menopause, and 1.71 for those greater than 20 years from menopause.[49] The results demonstrate a nonsignificant, but suggestive, trend toward decreased events in those who initiated treatment shortly after menopause and increased events for those who started treatment many years after menopause. This meta-analysis pooled the results of 13 trials in older women and found no change in total mortality (OR, 1.03; 95% CI, 0.9 to 1.18). Of note, a post-hoc subgroup analysis showed that trials of women with known cardiovascular disease had the same OR for cardiovascular mortality (1.10; 95% CI, 0.86 to 1.41) as those trials of older women without known cardiovascular disease (1.12; 95% CI, 0.79 to 1.58). This indicates that there may be significant progression of atherosclerosis in healthy older women who have been without hormone replacement for many years, so that primary prevention of cardiac disease may not be possible at this stage. The accumulated evidence indicates that once atherosclerosis has already developed, HRT has no effect at reversing the process.[28,46,76,77]

When HRT is started in older women a significant time trend is seen, with increased cardiovascular events in the first year and then decreasing events over the next few years.[9,78] This is thought to be due to a prothrombotic effect of HRT that is greatest within the first year of treatment.[12,79] Estrogen treatment has been shown to increase levels of C-reactive protein and von Willebrand factor antigen, and may promote arterial thrombosis or plaque destabilization in women with established atherosclerosis.[80,81,82] Few trials have followed patients beyond 5 years, so it is not possible say whether long-term treatment is associated with a net cardiovascular benefit or harm in older women.

Hormone replacement has also been shown to affect cancer risk, but its effect on cancer deaths is less clear. In the WHI trial, HRT increased breast cancer incidence by 26% and reduced colon cancers by 27%, without changing the risk for death from each disease.[9,83] This meta-analysis found no change in breast cancer deaths or total cancer deaths. Observational studies have found HRT to be associated with increased mortality for breast cancer and reduced mortality for colon cancer.[84,85]

Hormone replacement has beneficial effects in conditions other than cancer and cardiovascular disease, such as a 35% reduction in the incidence of hip fractures and new-onset diabetes mellitus, and a 60% reduction in recurrent urinary tract infections.[9,30,50,86] In this meta-analysis, hormone replacement decreased the risk of deaths from causes other than cardiovascular disease or cancer. It is possible that this is due, in part, to a reduction in the complications from hip fracture, diabetes mellitus, and sepsis.

This analysis has several limitations, some that are common to most meta-analyses.[87] Standard meta-analytic results are uncertain when the numbers of events per study are small, as is the case with mortality. There was marked heterogeneity in the trials, although no heterogeneity was seen in the results. There was a wide range in study size, medication used, and method of administration. The results for the older group were mainly from a few large high-quality trials, with a majority of the data coming from one trial.[9] The results for the younger group were from many smaller trials, and approximately one half of the deaths were from one trial in ovarian cancer survivors.[25] However, when this trial was excluded from the analysis, there still was a significant reduction in mortality (OR, 0.56; 95% CI, 0.31 to 0.99).

Another limitation of the study is that the age groups were defined according to the mean age of participants in each trial and not based on individual patient's characteristics, allowing for some overlap of ages in the two groups. Most trials did not include mortality as a primary outcome, so it is not clear how ascertainment of deaths was made in each trial. However, all trials reported adverse outcomes that included deaths, and investigators were contacted to get more information about mortality. It is unlikely that the reporting of deaths would be different for the two age groups. It was not possible to assess the absolute mortality rates in this study, as only those trials with at least 1 death could be included in the analysis. The search revealed another 98 trials that were excluded because no deaths were reported. This analysis was based only on published literature and therefore is subject to publication bias. However, funnel plots of effect size versus standard error for the trials in this analysis showed no evidence of bias. Few trials provided data on treatment for longer than 5 years, so it is not possible to assess mortality risk with long-term treatment. Despite these limitations, we believe that this meta-analysis provides valuable evidence concerning the mortality risk associated with HRT in younger and older women.

Treatment decisions concerning hormone replacement must be made on an individual basis, taking into account the age of the woman, the degree of bothersome postmenopausal symptoms, and any associated disease risk factors. The results of this analysis indicate that the benefits of HRT may outweigh the risks if treatment is given to younger women, but the risks may outweigh benefits if treatment is started at a later age. This study could not assess the optimal age at initiation of treatment or the duration of treatment needed in order to maximize benefits while minimizing risks. More large randomized trials of long duration, studying younger women near the start of menopause, would be needed to adequately address these issues.

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