Our results showing an overall reduction in risk of all-cause and IHD mortality with HT use are consistent with those from previous observational studies, but not with those from clinical trials. However, our results for all-cause mortality with HT use by age group were generally comparable to those from the WHI trial 10
which found decreased risk in women randomized at age 50–59 (RR=0.70; 95% CI 0.51–0.96) and increased risk in women randomized at age 70–79 (RR=1.14; 95% CI 0.94–1.37). That is, age appears to modify the relationship between HT and mortality both in our study and in the WHI randomized trial, with both studies showing a similar trend of HRs increasing with increasing age. It has been argued that increased risk of CHD among HT users in the WHI clinical trial is likely related to the age (or time duration since menopause) at first use of HT11,12
. Another explanation is that it is a woman’s current age rather than her age at first use that modifies the effect of HT. Due to the relatively short follow-up period and more confined age range for the WHI trial, that study could not differentiate age at randomization from age at current use. In contrast, we were able to estimate the influence of these two age periods separately as modifying variables. Assuming that self-reported baseline HT use reflected a women’s usage pattern over the follow-up period; (and our data from 2000–2001 indicate that the majority (79 percent) of current users of HT at baseline remained current users at that time), our results suggest that it is age at current use that is the important determinant. We found that age at baseline was a more significant modifier of the relationship between HT use at baseline and both all-cause mortality and IHD mortality than was age at, or years since menopause and first use. We interpret this finding as evidence that current age, rather than age at first use, is relevant to the reduced hazards of all-cause and IHD mortality. Therefore, the implications of our findings are similar for older women who are current HT users of long duration, as well as for older women who might be currently considering whether to begin using HT for the first time.
Several potential biases, including selection bias, compliance bias, follow-up bias, and inadequate control of confounding may account for the protective effects of HT use on mortality that have been seen in observational studies. Our study may be subject to the previously described “healthy woman effect,” whereby women taking HT have more education and are of higher social class, and are more compliant, healthier, and with a more favorable lifestyle than nonusers 1
. Education and social class are strongly inversely associated with risk factors for CHD 18
. However, since participants in our study were all public school teachers or administrators in California, our sample is homogeneous in some characteristics; and more uniform with respect to education and socioeconomic status than some other cohorts. It may be, therefore, less likely that education or social class were confounders of the relationship between HT use and risk of death from IHD in our study. The follow-up period for the current analysis includes a span of approximately 2.5 years subsequent to the widely publicized WHI results 9
(mid-2002 to the end of 2004). Based on other studies showing a profound impact of the WHI results on HT use in the general population 19–21
, many CTS participants who reported current HT use at baseline would have ceased using HT by the end of the follow-up period. It seems unlikely however that cessation of hormone use or any of the aforementioned biases caused the modifying effect of age at baseline observed in this cohort.
An additional concern is that we may have missed short term increases in the risk of mortality occurring shortly after the beginning of HT therapy, due to left truncation of women who die or are otherwise less likely to participate shortly after a disease event. Hernan et al 13
found increased risk of CHD incidence in the two years after start of HT therapy in the data from the Nurses’ Health Study, by examining a series of nested “non-randomized trials” of CHD disease incidence in HT initiators and non-initiators, over a total of 8 contact/recontact cycles, while using time of HT initiation rather than time of questionnaire as the start of observation in these “trials”. We are not able to replicate these analyses since we do not obtain CHD incidence for the teachers, and are reliant upon mortality data. While missing such short term events could have led to biased estimates of the overall effect of HT on mortality (‘initiation bias’), we find it unlikely that this would have lead to the distinct age × HT interactions that are seen so strongly here. Nor would this issue appear to negate the implications of our findings for older women who started HT close to close to menopause about whether or not they now benefit from continued HT use. Our study of the relative importance of the two time-related variables, age at start of HT vs. age at baseline, implies that they do not.
A strength of this analysis is the high proportion of CTS participants, even those at a relatively advanced age, who reported current HT use on the baseline questionnaire. This provided considerable statistical power to estimate the effects of use over a wide age range. Furthermore, the broad age distribution of women in the CTS and the wide diversity in ages at first HT use allowed us to address questions about the modifying effects of current age, as distinct from the modifying effect of age at first use. In summary, our study suggests that the health consequences of HT vary primarily by age of current use, with age at first use being of negligible independent importance. We found an association between current use at baseline and reduced risk for all-cause mortality in younger, but not older, postmenopausal women in the CTS. Our results add to the growing evidence that hormone use may have beneficial effect in younger women, but have little cardiovascular benefit in older women, and has direct implications regarding the lack of potential benefits of continued use of HT therapy for older women who began HT close to menopause.