The Women's Health Initiative: evolving insights over 15 years

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In 2002, the first publication from the Women's Health Initiative (WHI) trial was released, reporting an increased risk of coronary heart disease (CHD) and invasive breast cancer for women using combined estrogen plus progestin (E+P).1 The CHD findings were unexpected because numerous, large observational studies had suggested lower risks of cardiovascular disease (CVD) among women taking menopausal hormone therapy (MHT), including reductions in both CVD incidence and all-cause mortality.2-6 For the past 15 years, researchers have culled data from the WHI to further understand these initial findings and to try to clarify the complex relationship between menopause, hormones, and health. The impact of age and years since menopause on the relationship between MHT initiation and health outcomes, also known as the timing hypothesis, has been identified as one of the important factors explaining the complex, and sometimes discrepant, findings. Specifically, it has been found that women who were less than 10 years from menopause or aged between 50 and 59 years at baseline when MHT was started had lower hazard ratios for CHD than women initiating hormone therapy (HT) at an older age.7-10
The relationship between vasomotor symptom presence and CVD risk is another topic that has been evaluated in detail since the initial WHI publication. Among women aged between 50 and 59 years, MHT had similar effects on CVD risk in women with and without vasomotor symptoms.10 Among women initiating MHT further from menopause, however, the presence of vasomotor symptoms magnified their CVD risk,10,11 raising the concern that vasomotor symptom presence may be associated with elevated CVD risk. This is an important hypothesis to study because a majority of women experience vasomotor symptoms during the peri- or postmenopausal period and many continue MHT for a decade or more; it is clinically relevant to know which symptomatic women will be at increased CVD risk. Numerous studies have suggested that vasomotor symptoms may be associated with increased CVD risk based on surrogate markers, such as carotid intima-media thickness and markers of inflammation and hemostasis such as tissue plasminogen activator antigen, interleukin (IL)-6 and IL-8.12-17 However, other studies have demonstrated favorable associations between vasomotor symptoms and various CVD parameters, such as endothelial vasodilation, or clinical outcomes, especially in younger peri- and postmenopausal women experiencing vasomotor symptoms.18-21
In an effort to further clarify this relationship, the study reported by Harrington et al22 in this issue of Menopause examined the cross-sectional associations of vasomotor symptom presence and severity with multiple hemostatic parameters (antithrombin, plasminogen activator inhibitor-1, protein C antigen, total and free protein S antigen, total and free tissue factor pathway inhibitor, D-dimer, normalized activated protein C sensitivity ratio thrombin generation) in the WHI Cardiovascular Disease (CVD) Biomarker Case-Control Study. In contrast to several other studies evaluating markers of hemostasis, Harrington et al found no significant evidence that vasomotor symptom presence or severity was associated with the hemostatic parameters evaluated. Although women with vasomotor symptoms had lower normalized activated protein C sensitivity ratio values than those without these symptoms, the finding was attenuated after multivariable adjustment.
Differences between the WHI population studied by Harrington et al (postmenopausal, with menopause occurring more than 20 years earlier for many) and the Study of Women's Health Across the Nation (pre- and early perimenopausal) evaluated in the earlier hemostasis studies may contribute to the differences in results for associations between hemostatic parameters and CVD risk.

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