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

Gottsäter A, Rendell M, Hulthén UL, Berntorp E, Mattiasson I (University of Lund, University Hospital, Malmö, Sweden). Hormone replacement therapy in healthy postmenopausal women: a randomized, placebo‐controlled study of effects on coagulation and fibrinolytic factors. J Intern Med 2001; 249: 237–246. 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 ≥ 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 Δ‐values. After 3 months Δ‐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 Δ‐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.