The Effects of Transdermal Estradiol and Oral Conjugated Estrogens on Haemostasis Variables

Summary

The effects of oral and transdermal administration of estrogen replacement therapy (ERT) have been fairly well investigated regarding lipoprotein and carbohydrate metabolism, while the effects of different modes of estrogen administration on the haemostatic system have been less well studied.

To delineate and compare the effects of perorally administered conjugated estrogens (CE) and transdermally administered estradiol (E₂) in doses needed for hormone replacement therapy (HRT) on haemostasis parameters, 23 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (0.625 mg CE and 50 μg E₂/24h) are the lowest which, with few exceptions, eliminate climacteric symptoms. Both CE and E₂ increased factor VII:C, factor VII:Ag, and the prothrombin fragment₁₊₂. The increase in factor VII:Ag, however, was significantly higher after treatment with CE. These changes were all towards a state of hypercoagulability. Furthermore, CE decreased plasminogen activator inhibitor (PAI) and the thrombin-antithrombin complexes (TAT), as well as antithrombin (ATIII).

• References

• 1 Stampfer MJ, Colditz GA, Willet WC, Manson JAE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease - Ten-year follow-up from the Nurses’ Health Study. New Engl J Med 1991; 756-62
• 2 Ross RK, Paganini-Hill A, Mack TM, Arthur M, Henderson BE. Menopausal oestrogen therapy and protection from death from ischaemic heart disease. Lancet 1981; 1: 858-60
• 3 Bush TC, Barret-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchiudran CM, Tyroler HA, Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987; 75: 1102-9
• 4 De Lignieres B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, Thanh-Tham G, Mairon N, Corvol P, Guy-Grand B, Mauvais-Jarvis P, Sitruk-Ware R. Biological effects of estradiol 17-β in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metabol 1986; 62: 536-41
• 5 Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Herschman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biologic effects of transdermal estradiol. N Engl J Med 1986; 314: 1615-20
• 6 Hardisty RM, Macpherson JC. A one-stage factor VIII (antihaemophilic globulin) assay and its use on venous and capillary plasma. Thromb Diath Haemorrh 1962; 7: 215-29
• 7 Denson KW. The specific assay of Prower-Stuart factor VII. Acta Haematol 1961; 25: 105-20
• 8 Nilsson JM, Olow B. Determination of fibrinogen and fibrino-genolytic activity. Thromb Diath Haemorrh 1962; 8: 297-310
• 9 Lindberg UB, Crona N, Stigendal L, Teger-Nilsson AC, Siifverstolpe G. A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis variables. Thromb Haemostas 1989; 61 (01) 65-69
• 10 Aylward M. Coagulation factors in opposed and unopposed oestrogen treatment at the climacteric. Postgrad Med J 1978; 54 (suppl 2) 31-7
• 11 Meade TW. Factor VII and ischaemic heart disease: Epidemiological evidence. Haemostasis 1983; 13: 178-85
• 12 Dalaker K, Hjermann J, Prydz H. A novel form of factor VII in plasma from men at risk for cardiovascular disease. Br J Haemat 1985; 61: 315-22
• 13 Carvalho de Sousa J, Azevedo J, Soria C, Barros F, Ribiero C, Parreira F, Caen JP. Factor VII hyperactivity in acute myocardial thrombosis. A relation to the coagulation activation. Thromb Res 1988; 51: 165-73
• 14 Sabra A, Bonnar J. Haemostatic system changes induced by 50 pg and 30 μg estrogen/progestogen oral contraceptives. Modification of estrogen effects by levonorgestrel. J Reprod Med 1983; 28: 85-91
• 15 Bonnar J. Coagulation effects of oral contraceptives. Am J Obstet Gynecol 1987; 157: 1042-8
• 16 Conard J, Samama M, Basdevant A, Guy-Grand B, De Lignieres B. Differential ATIII-response to oral and parenteral ad-ministration of 17β- estradiol. Thromb Haemostas 1983; 49: 245
• 17 Hamsten A, Wiman B, De Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 25: 1557-63
• 18 Nilsson IM, Ljungnér H, Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J 1985; 290: 1453-6
• 19 Siegbahn A, Ruusuvaara L. Age dependence of blood fibrinolytic components and the effects of low dose oral contraceptives on coagulation and fibrinolysis in teenagers. Thromb Haemostas 1988; 60 (03) 361-4
• 20 Jespersen J, Kluft C. Inhibition of tissue-type plasminogen activator in plasma of women using oral contraceptives and in normal women during a menstrual cycle. Thromb Haemostas 1986; 55: 388-9
• 21 Aro J, Haapiainen R, Rasi V, Rannikko S, Alfthan O. The effect of parenteral estrogen versus orchiectomy on blood coagulation and fibrinolysis in prostatic cancer patients. Eur Urol 1990; 17: 161-5
• 22 Caine YG, Bauer KA, Barzegar S, Cate HT, Sacks FM, Walsh BW, Schiff I, Rosenberg RD. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemostas 1992; 68 (04) 392-5
• 23 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: Insights gained from studies using markers of haemostatic system activation. Blood 1987; 70 (02) 343-50