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Positive impact of hormone replacement therapy on the fibrinolytic system: a long‐term randomized controlled study in healthy postmenopausal women

Summary.  Background: The mechanisms by which postmenopausal hormone replacement therapy (HRT) may influence risk of cardiovascular disease are still unclear. Impaired fibrinolytic function is associated with an enhanced risk of cardiovascular disease and therefore the effect of HRT on fibrinolysis may be of importance. Objectives: To investigate the prolonged effect of HRT on the fibrinolytic system and to determine whether two common polymorphisms in the plasminogen activator inhibitor‐1 (PAI‐1) and tissue‐type plasminogen activator (t‐PA) genes modulate this effect. Methods: Healthy postmenopausal women (n = 248) were randomized to HRT (n = 122) or no substitution (n = 126) 5 years prior to investigation. Results: Significantly higher values of t‐PA activity and lower values of PAI‐1 activity and PAI‐1 antigen were found in the HRT group compared with the control group. This effect was independent of smoking and without influence from the two common polymorphisms PAI‐1 −675(4G/5G) and t‐PA intron8ins311. Furthermore, no difference between opposed estrogen (with norethisterone acetate as the gestagen component) and unopposed estrogen therapy was found. Both an intention‐to‐treat and a per‐protocol analysis were performed and similar results were obtained. Conclusions: Long‐term treatment with HRT in healthy postmenopausal women was found to be associated with a beneficial fibrinolytic profile. This effect was found independent of smoking status, opposed and unopposed estrogen therapy had equal effect, and no influence of the two common polymorphisms PAI‐1–675(4G/5G) and t‐PA intron8ins311 was found. This effect of HRT on fibrinolytic capacity may be one of the beneficial effects of HRT in relation to cardiovascular diseases.