Hormone replacement therapy in healthy postmenopausal women: a randomized, placebo-controlled study of effects on coagulation and fibrinolytic factors.

Objectives: To evaluate effects of postmenopausal hormone replacement therapy (HRT) on von Willebrand factor, factor (F)VIII, factor (F)VII, fibrinogen, antithrombin (AT) III, prothrombin fragments 1 and 2, protein C, total and free protein S, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and resistance to activated protein C.

Design: Part 1: double blind randomized trial for 3 months. Part 2: open study for 9 months.

Setting: Department of Endocrinology, University Hospital, Malmö, Sweden.

Subjects: Fifty-one postmenopausal women with a history of amenorrhoea of at least 6 months and body mass index > or = 24 kg m-2 participated in part 1 and 46 participated in part 2.

Intervention: Randomization for placebo (n=24) or HRT (n=27). HRT was given as 2 mg oestradiol valerate for the first 3 months, with the addition of 10 mg medroxyprogesterone for 10 days every third month thereafter.

Measurements: At baseline and after 3 and 12 months.

Results: During 0-3 months in the HRT group, FVII increased (P < 0.01), whereas fibrinogen, AT III and total protein S all decreased (P < 0.001 for all). Changes in variables were expressed as Delta-values. After 3 months Delta-values differed between groups for fibrinogen (P < 0.05), AT III (P < 0.001), total protein S (P < 0.001), and PAI-1 (P < 0.001). During 0-12 months, fibrinogen, total protein S, tPA (P < 0.01 for all) and AT III (P < 0.05) decreased. In the control group, all variables were unchanged during the study, except for increases (P < 0.05) in total protein S after 3 and 12 months, and a decrease (P < 0.01) in FVIII after 12 months. After 12 months Delta-values differed for fibrinogen (P < 0.05), AT III (P < 0.05) and total protein S (P < 0.001).

Conclusions: Unopposed oestrogen substitution was associated with both potentially beneficial effects, such as decreases in fibrinogen, and potentially thrombogenic effects such as decreasing AT III and protein S and increasing FVII. During prolonged follow-up and addition of progesterone, differences between groups concerning FVII were attenuated. These data suggest that effects of HRT upon coagulation are most pronounced early after institution of unopposed treatment.