regimen in particular—may have caused an increase in heart attack and stroke, there is no evidence that it actually led to an increase in overall death rates. Instead, the overall mortality rate was similar among women who were given the hormones and those who were not. For example, when the data from the Women’s Health Initiative were analyzed, the risk of death among womenS who were given estrogen–progestin HT was actually 2 percent less than for women who were given the placebo, although the difference was not statistically significant (Writing Group for the Women’s Health Initiative Investigators, 2002). A meta-analysis of the data from other randomized controlled trials pointed to a similar conclusion (Salpeter et al., 2004).

The second reason is that it now appears that the findings from the Women’s Health Initiative were likely to have been related to the timing of HT initiation in the trial. In the earlier studies based on observation of women receiving HT prescribed by their physicians, most of the women received treatment starting in early menopause. For example, 80 percent of the participants in the Nurses’ Health Study began HT within 2 to 3 years after beginning menopause (Manson and Bassuk, 2007). Since women in the United States begin menopause, on average, at age 51 (Manson et al., 2007), a large majority of the women in that study would have started HT by the time they were 53 or 54. By contrast, the average age of the women starting HT in the Women’s Health Initiative was 63, and most of the women in the study had begun menopause at least a decade before joining the study (Grodstein et al., 2006). However, these older women may have been more representative of the age group for which HT was being prescribed in later years to prevent fracture and cardiovascular disease.

One possible explanation for the different effects of HT at different ages is that estrogen supplements may have varying effects on the heart depending on the stage of atherosclerosis. Some researchers have hypothesized that in the early stages of atherosclerosis, estrogen may have a beneficial effect because it improves lipid and endothelial function, but in the later stages, when the arteries have developed more serious lesions, the estrogen may cause clotting or a rupturing of the plaque in the arteries (Manson and Bassuk, 2007). If so, the timing of the HT becomes critical.

Since the release of the Women’s Health Initiative findings, a number of studies have examined this possibility. In general, these studies have reanalyzed the data from previous reports by looking at the differences in how HT affected women at different ages, specifically those who started the treatment around the time of menopause versus those who started much later. Most of these reanalyses suggest that while women who begin HT well after menopause may have an increased risk of heart disease and stroke, those who start around the time of menopause do not, and for them the HT does appear to protect somewhat against heart disease (Goldman, 2010b).

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