One difference between the WHI hormone trials and the observational studies is that women enrolled in the WHI were an average of 63 years of age at menopausal hormone treatment initiation, approximately 12 years postmenopausal on average.14,19–21
In sharp contrast, enrollees in the observational studies tended to start menopausal hormone treatment at or near menopause, at an average age of 51 years.22
Thus, women in the WHI also were older and longer postmenopausal than is usual for initiation of menopausal hormone treatment in clinical practice.23
Because atherosclerotic lesions accumulate long before a first clinical event occurs,24,25
the older women in the WHI trials may have harbored significant subclinical coronary heart disease, and thus would not have been good candidates for a treatment such as menopausal hormone treatment, which seems to be more effective in primary rather than secondary prevention of atherosclerosis. The idea that differences in age or time since menopause when menopausal hormone treatment is initiated may account for differences in coronary heart disease outcomes, and even opposite effects of menopausal hormone treatment on coronary heart disease have become known as the “timing hypothesis.”24,26–28
Evidence for the timing hypothesis comes from varied sources. In an experimental model with surgically menopausal monkeys that develop typical atherosclerosis when fed a high saturated fat diet, estrogen treatment reduces coronary atherosclerosis by 50% to 70% if begun immediately after ovariectomy.29–31
In contrast, estrogen treatment has no beneficial effect when delayed by 2 years, which is the equivalent of approximately 6 years delay in humans. 32
This finding is consistent with the lack of secondary coronary heart disease prevention by menopausal hormone treatment observed in trials in women with a clinical history of heart disease.33–35
In the Nurses’ Health Study, women initiating menopausal hormone treatment at or near menopause were observed to experience significant coronary heart disease protection (hazard ratio [HR] = 0.66, 95% confidence interval [CI], 0.54–0.80 for EA; HR = 0.72, 95% CI, 0.56–0.92 for E+P), whereas the few who started menopausal hormone treatment 10+ years after menopause were not (HR = 0.87, 95% CI, 0.69–1.10 for EA; HR = 0.90, 95% CI, 0.62–1.29 for E+P).36
Subgroup analyses of WHI data also support the timing hypothesis. For example, as shown in , in the E+P trial a nonsignificant trend toward protection (HR = 0.89; 95% zCI, 0.5–1.5) was seen in women who were less than 10 years post-menopausal, whereas significant excess risk occurred in women more than 20 years postmenopausal (HR = 1.71; 95% CI, 1.1–2.5).20
Similarly, as shown in , in the EA trial19,37
there was a trend for coronary heart disease protection in women 50 to 59 years of age (HR = 0.63; 95% CI, 0.36–1.08), but a trend toward increased risk in women aged more than 70 years (HR = 1.11; 95% CI, 0.82–1.52). Similar trends were seen when data from both E+P and EA trials were pooled.38
Also, conjugated equine estrogen-treated women, who were 50 to 59 years old at randomization into the EA trial, showed a significantly lower mean coronary calcium burden compared with those treated with placebo when studied 8.7 (mean) years after randomization.39
Figure 1 HRs and 95% CIs for coronary heart disease in WHI hormone trials. A, By time since menopause in the E+P study (redrawn from Manson et al20). B, By age group in EA study (redrawn from Anderson et al19 and Hsia et al37). CHD = coronary heart disease.
Finally, a large meta-analysis of randomized clinical trials comparing coronary heart disease outcomes after menopausal hormone treatment started in younger versus older women reported reduced coronary heart disease only in the younger women.40
In a complementary cost– benefit analysis, Salpeter et al41
found that quality adjusted life-years for menopausal hormone treatment are immediately positive in younger women, but, apropos of the duration effects discussed next, shift from negative to positive only after a significant delay in older women.
In contrast with those findings, a recent post hoc analysis that pooled observational data from WHI participants who initiated menopausal hormone treatment on their own when recently menopausal (but whose duration of treatment was unknown) with data from women randomized to study drug within 5 years of menopause failed to detect a timing effect. 42
This finding may reflect the fact that duration of treatment was not considered in the analysis.
The “timing hypothesis” has been discussed widely and is included in the conclusions of a consensus scientific statement recently published by the Endocrine Society, which states in part that “Subgroup analyses suggest that the lack of benefit or increase in coronary heart disease risk observed in the overall analysis of the WHI resulted from harmful effects of menopausal hormone treatment in older women starting therapy many years after onset of menopause.” 43
However, this hypothesis awaits rigorous testing. Two currently ongoing randomized clinical trials of menopausal hormone treatment address the timing hypothesis, the Kronos Early Estrogen Prevention Study,44
which compares 2 hormone regimens (oral conjugated equine estrogen vs transdermal estradiol, both with cyclic oral progesterone) with placebo in women less than 3 years postmenopausal, and the Early Versus Late Intervention Trial With Estradiol (Howard Hodis, Principal Investigator), which examines effects of oral estradiol in recently and more remotely menopausal women. Both trials monitor the development or progression of atherosclerosis as detected by noninvasive cardiovascular imaging. Neither is powered for clinical event outcomes.