Association Between Increased Estrogen Status and Increased Fibrinolytic Potential in the Framingham Offspring Study

BACKGROUND: Although extensive evidence indicates that estrogen is responsible for the markedly decreased cardiovascular risk of premenopausal women, the mechanism through which estrogen might exert its protective effect has not been adequately explained. Since thrombosis is now recognized to play an important role in the onset of cardiovascular disease, we investigated the relation between estrogen status and fibrinolytic potential, a determinant of thrombotic risk. METHODS AND RESULTS: We determined levels of plasminogen activator inhibitor (PAI-1) antigen and tissue plasminogen activator (TPA) antigen in 1431 subjects from the Framingham Offspring Study. Fibrinolytic potential was compared between subjects with high estrogen status (premenopausal women and postmenopausal women receiving hormone replacement therapy) and low estrogen status (men and postmenopausal women not receiving hormone replacement therapy). In all comparisons, subjects with high estrogen status had greater fibrinolytic potential (lower PAI-1 levels) than subjects with low estrogen status. First, postmenopausal women receiving estrogen replacement therapy had lower levels of PAI-1 than those not receiving therapy (13.0 +/- 0.5 versus 19.5 +/- 1.0 ng/mL, P < .001). Second, premenopausal women had lower levels of PAI-1 than men of a similar age (14.8 +/- 0.6 versus 20.3 +/- 0.8 ng/mL, P < .001); this sex difference diminished when postmenopausal women not receiving hormone replacement therapy were compared with men of a similar age (19.6 +/- 0.7 versus 21.1 +/- 0.7 ng/mL, P = .089). Third, premenopausal women had markedly lower levels of PAI-1 antigen than postmenopausal women not receiving estrogen therapy (14.8 +/- 0.6 versus 19.5 +/- 1.0 ng/mL, P < .001). The between-group differences observed for TPA antigen were similar to those for PAI-1 antigen. CONCLUSIONS: Each of these comparisons indicates that the cardioprotective effect of estrogen may be mediated, in part, by an increase in fibrinolytic potential. These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.