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Hormonal replacement therapy and thrombosis
(Portuguese PDF version)

Maria Elisabeth Rennó de Castro Santos^*

^* Assistant doctor, Hospital Santa Casa de Belo Horizonte; Professor, School of Medicine of the State of Minas Gerais.

Correspondence:
Dra. Maria Elisabeth Rennó de Castro Santos
Rua Capelinha, 500
CEP 30220-300 - Belo Horizonte - MG
Tel.: +55 (31) 3241.2023 / +55 (31) 3223.5734
Fax: +55 (31) 3241.5440
E-mail: beth.renno@globo.com

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ABSTRACT

Hormonal replacement therapy (HRT) has been increasingly indicated to women during and after menopause with the aim of alleviating symptoms and preventing osteoporosis and coronary heart disease. Despite the well-known association between the use of estrogens and the higher incidence of thromboembolic events, controlled trials, with a significant number of patients, to evaluate the true risk / benefit of this therapy, had not been conducted until recently. The aim of the present article is to present the major results of these studies.

Key words: hormone replacement therapy, thrombosis, menopause.
Palavras-chave: terapia de reposição hormonal, trombose, menopausa.

J Vasc Br 2003;2(1):17-22

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INTRODUCTION

The use of estrogen has been associated with the increased incidence of thromboembolic events since the 1960s. Hormone replacement therapy with low estrogen doses, associated or not with progestin, has been increasingly indicated to women during and after menopause, with the aim of relieving symptoms, reducing fracture risks due to osteoporosis and decreasing the incidence of coronary heart disease. Controlled trials with a significant number of patients, to evaluate the true risk/benefit of this therapy, had not been carried out until recently, showing controversial results about the benefits, but confirming the risks, such as the higher incidence of thromboembolic events.

HORMONE REPLACEMENT THERAPY

Types and composition

Most preparations currently used in hormone replacement therapy (HRT) combine the use of estrogen and progestin. In this case, the estrogen may be natural (e.g.: estradiol), synthetic (e.g.: ethynyl estradiol) or conjugated equine estrogens. Estrogens used in oral preparations are often associated with a structurally related progestin or with progesterone or testosterone; in this case, medroxyprogesterone acetate is the most frequently used. The single use of estrogen increases the incidence of endometrial cancer, and is therefore only recommended for women submitted to hysterectomy.¹

The route of administration may be oral, transdermal (patches), percutaneous (gel), subcutaneous (pellets) or nasal.
The pharmacokinetics and power of these compounds vary according to the type and route of administration, resulting in different clinical effects.^2,3 A pending question is whether synthetic estrogens or equine conjugates and medroxyprogesterone acetate used in HRT have the same effects observed with 17-beta-estradiol and natural human progesterone.^4-6

Mechanism of action

One of the mechanisms of action of estrogen and progesterone lies in the interaction with specific receptors- alpha and beta estrogen receptors and A and B progesterone receptors, which belong to a superfamily of proteins that mediate the effects of steroid hormones.^7-9 The interaction between estrogen and estrogen receptors found in endothelial cells accounts for several regulatory actions at the vascular wall components.¹⁰ There is some special interest in the effects of this interaction with actions on lipid metabolism,^11,12 vasomotor tone,¹³ response of smooth muscle cell to injury,⁷ reduction of homocysteine levels14 and reduction of cell adhesion molecules12 on the inflammatory response, coagulation factors and coagulation inhibitors (Table 1).

Table 1 - Probable mechanisms of action of estrogen at the vascular level

	Effect
Lipid metabolism	Increase of total cholesterol Increase of HDL cholesterol Reduction of LDL cholesterol Reduction of Lipoprotein Lp (a) Increase of triglyceride levels
Reduction of vasomotor tone	Increase of nitric oxide production Reduced production of endothelin
Smooth muscle cells	Reduction of cellular proliferation after injury
Reduction of atherosclerotic plaque	Reduction of vessel wall thickness Reduction of atherosclerotic plaque
Additional effects	Reduced insulin resistance Reduction of homocysteine Increase of C-reactive protein Reduction of cell adhesion molecules
Effects on hemostasis	Increase of venous thrombosis Reduction of endogenous anticoagulants Increased activation of coagulation Increase of fibrinolysis (reduced PAI-1)

 

The true mechanism through which estrogens act and activate coagulation has not been clearly established yet. Some actions on coagulation factors, coagulation inhibitors and fibrinolysis have been observed. Estrogens increase thrombin and fibrin (as shown by the high levels of fragments 1+2, of thrombin-antithrombin complexes and of fibrinopeptide A),^15,16 fibrinogen reduction, reduction of coagulation inhibitors such as antithrombin, protein C and tissue factor inhibitor, in addition to actions on fibrinolysis, such as the reduction of plasminogen activator inhibitor-1 (PAI-1).^2,16-18

Selective modulators of estrogen receptors, such as tamoxifen and raloxifene, have antiestrogen effects on endometrial and mammary tissues and are used for the treatment of breast cancer. However, these compounds have estrogenic effects on coagulation and therefore increase the risk of venous thromboembolism.^17,19

Patients with thrombophilia, both hereditary (factor V Leiden, mutation of prothrombin 20210A) and acquired (anticardiolipin antibody), submitted to HRT, show a higher incidence of arterial and venous thromboses. While factor V Leiden elevates the risk of venous thrombosis by approximately four times and HRT elevates this risk three times, the association of factor V Leiden with HRT allows a 15-fold increase, thus suggesting the existence of a synergistic mechanism between these two factors (Table 2).^17-21

Table 2 - Association of factor V Leiden, HRT and relative risk of venous thrombosis

Factor V Leiden	HRT	Relative risk	95%CI
-	-	1
-	+	3.2	1.7 to 6.0
+	-	3.9	1.3 to 11.2
+	+	15.5	3.1 to 76.7

 

THROMBOEMBOLISM RISK

Since 1996, clinical studies have confirmed a twofold to fourfold risk of venous thrombosis in HRT patients,^22-27 which goes against the initial idea that HRT with low doses would not increase the incidence of thromboembolic events, differently from contraceptive drugs, which contain elevated estrogen levels.

The risk of thrombosis is higher during the first year of treatment,^24,27-29 probably due to thrombophilic disorders observed in some women submitted to HRT.¹⁷

Both the use of oral estrogens and transdermal patches is associated with the increase of thrombosis risk,²⁴ which is quite similar to what occurs with the use of conjugate estrogens and estradiol.²⁷

The effects of estrogens, especially on lipid metabolism, vasomotor tone and atherosclerotic plaque, associated with the lower incidence of coronary heart disease in premenopausal women, led to the hypothesis of a probable vasoprotective effect with regard to atherosclerotic coronary disease, and cerebral and peripheral ischemia. HRT was therefore also recommended for the primary and secondary prevention of these diseases. Clinical studies with a large number of patients were conducted, but terminated earlier than expected due to the high level of complications observed. The conclusion is that coagulation disorders caused by estrogens, with the increased incidence of arterial and venous thrombosis, outnumber the supposedly beneficial effects at the coronary and cerebral level.^12,30

RECENT CLINICAL STUDIES

The Estrogen in Venous Thromboembolism Trial (EVTET), which included women with previous history of deep venous thrombosis submitted to HRT, revealed high incidence of recurrent thrombosis (8.5% a year in treated patients as against 1.1% in the placebo-controlled group).³¹ On account of this, the study was concluded earlier.

Data from the Heart and Estrogen/Progestin Replacement Study (HERS) confirm the twofold to threefold increase of relative risk for thromboembolism. In HERS, thromboembolic events occurred in 34 women under HRT (6.3/1,000 women/year) and in 12 women in the control group (2.2/1,000 women/year), which may mean a relative risk of 2.89 for the group under HRT.^19,32

The Women's Health Initiative Hormone Program (WHI), which included 16,608 postmenopausal women, aged between 50 and 79 years, randomized into a group treated with estrogen and progestin or into a placebo-controlled group, also confirmed the increase in the incidence of thromboembolic events - 34 cases in the treated group against 16 cases in the control group, with a relative risk of 2.11 (95%CI: 1.26 to 3.55). The study, expected to last eight years and six months, was canceled in June 2002, after five years, due to the fact that risks exceeded benefits, with increased incidence of deep venous thrombosis and pulmonary embolism, in addition to elevated incidence of acute myocardial infarction, cerebral ischemia and breast cancer.^33,34

The Women's International Study of Long Duration Oestrogen after Menopause (WISDOM), implemented in 1999 in the United Kingdom, Australia and New Zealand, with the target inclusion of 22,000 patients and expected to last until 2012, suspended the inclusion of new cases in July 2002 due to the results presented by the American WHI study. In October 2002, the British Medical Research Council withdrew financial support by alleging that the data obtained from the WHI study were ample evidence that the study should not continue.

The U.S Preventive Services Task Force (USPSTF), based on extant scientific evidence, recommended, in October 2002, that HRT be not used for primary prevention of chronic diseases, since risks exceeded benefits. The highest risk for venous thromboembolism was based on 12 larger studies, with relative risk of 2.14 (95%CI: 1.64 to 2.81).^35-37 Some benefits were observed as to the increase of bone density, reduction of fracture risk and colorectal cancer. The detected risks relate to the increased incidence of breast cancer, venous thromboembolism, coronary heart disease, stroke, and cholecystitis. The evidence regarding the risk/benefit in terms of cognitive disorders, ovarian cancer, death from breast cancer, cardiovascular disease and general mortality is still insufficient (Table 3).

Table 3 - Risks and benefits of HRT

Variable	Results	Assessment of USPSTF
Symptoms	70 to 80% of improvement
Osteoporosis	Reduction in the total number of fractures: 5 in 10,000 women/year under HRT - WHI reduction of 27% in the total of fractures (meta - analysis)	There is scientific evidence that HRT increases bone mineral density and reduces fracture risk
Colorectal cancer	20% reduction of colon cancer and 19% reduction of rectal cancer (WHI and HERS)	There is scientific evidence that HRT reduces the incidence of colorectal cancer
Loss of memory and dementia		Studies with large methodological limitations
Breast cancer	Increase in incidence RR 1.26 (95%CI 1.00 - 1.59) - WHI RR 1.27 (95%CI 0.84 - 1.94) - HERS	There is scientific evidence that HRT increases the incidence of breast cancer. Effects on mortality are still uncertain
Stroke	RR 1.41 (95%CI 0.86 - 2.31) WHI	There is some scientific evidence that HRT increases the incidence of strokes
Venous thromboembolism	RR 2.11 (95%CI 1.26 - 3.55) WHI Higher incidence in the first year of treatment: RR 3.49 (95%CI 2.33 - 5.59) AHRQ	There is scientific evidence that HRT increases the incidence of venous thromboembolism
Endometrial cancer	Higher risk with the single use of estrogen RR 2.3 (95%CI 2.1- 2.5), with elevated levels for over 5 years after HRT with estrogen + progestin, does not increase the risk	There is scientific evidence that HRT with the use of single estrogen in non-hysterectomized women increases the incidence of endometrial cancer
Cholecystitis	Higher risk RR 1.8 (95%CI 1.6 - 2.0) NHS	There is some scientific evidence that HRT increases the incidence of cholecystitis
Coronary heart disease	Increased risk RR 1.29 (95%CI 1.02 - 1.63) WHI Incidence is 50% higher in the first year of treatment, with later reduction in HERS	HRT does not reduce, and could actually increase the incidence of coronary heart disease. Effects on mortality are still uncertain

 

CONCLUSION

The initial expectations about HRT, formerly recommended with the aim of relieving the symptoms of menopause and preventing chronic diseases that affect postmenopausal women, were not confirmed. Scientific evidence points to an increase in the number of arterial and venous thromboses, and there seems to be a group at higher risk concerning thrombophilic disorders. Moreover, only the benefits of symptom improvement and prevention of osteoporosis were confirmed.

Nevertheless, several aspects of HRT still remain unclear: its mechanism of action in coagulation, the different effects between the several types of estrogens and progestins, doses and routes of administration, groups at higher risk, and the risk/benefit ratio in some pathologies and in general mortality. The use of HRT should be carefully evaluated and the potential risks and benefits should be discussed in each specific case. Other efficient methods for the prevention of chronic diseases should also be considered.

 

REFERENCES

1.Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Int Med 1992;117:1016-37.

2. Rosendaal FR, Helmerhost FM, Vandenbroucke JP. Oral contraceptives, hormone replacement therapy and thrombosis. Thromb Haemost 2001;86:112-23.

3. Anderson F. Kinetics and pharmacology of estrogen in pre and postmenopausal women. Int J Fert 2000;38:55-64.

4. Barton M. Postmenopausal estrogen replacement therapy and atherosclerosis: can current compounds provide cardiovascular protection? Expert Opin Investig Drugs 2001;10:789-809.

5. Dubey RK, Jackson EK. Cardiovascular protective effects of 17ß - estradiol metabolites. J Appl Physiol 2001;91:1868-83.

6. Barton M, Dubey RK Clinical practice. Postmenopausal hormone - replacement therapy. N Engl J Med 2001;345(1):34-40.

7. Baysal K, Losordo D. Estrogen receptors and cardiovascular disease. Clin Exp Pharmacol Physiol 1996;23:537-48.

8. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801-11.

9. Mendelsohn ME. Genomic and nongenomic effects of estrogen in the vasculature. Am J Cardiol 2002;90(1A):3F-6F.

10. Cid MC, Schnaper HW, Kleinnan HK. Estrogens and the vascular endothelium. Am J Cardiol 2002;90(1A):11F-16F.

11. Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein and apolipoprotein (a) concentrations: analysis of studies published from 1974 - 2000. Fert Steril 2001;75:898-915.

12. Teede HJ. Hormone replacement therapy and the prevention of cardiovascular disease. Hum Reprod Update 2002;3:201-15.

13. Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Up regulation of nitric oxide synthetase by estradiol in human aortic endothelial cells. FEBS Lett 1995;360:291-3.

14. Van Baal WM, Kooistra T, Stehouwer CD. Cardiovascular disease risk and hormone replacement therapy: a review based on randomized controlled studies in postmenopausal women. Curr Med Chem 2000;7:499-517.

15. Koh KK, Home MKI, Csako G, Waclawiw MA, Cannon RO. Relation of fibrinolytic potentiation by estrogen to coagulation pathway activation in postmenopausal women. Am J Cardiol 1999;83:466-69.

16. Herrington DM, Klein KP. Genome and hormones: gender differences in physiology. Invited review: pharmacogenetics of estrogen replacement therapy. J Appl Physiol 2001;91:2776-2784.

17. Rosendaal FR, Helmerhost FM, Vanderbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002;22:201-10.

18. Hoibraaten E, Qvigstad E, Anderesen TO, Mowinckel MC, Sandset PM. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism - results from a randomized, double - blind, clinical trial. Thromb Haemost 2001;85:775-781.

19. Konkle BA. Thrombophilic states in women - special concerns. Hematology (Am Soc Hematol Educ Program) 2001;325-30.

20. Rosendaal FR, Vessey M, Rumley A, et al. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis. Br J Haematol 2002;116:851-4.

21. Herrington DM, Vittinghoff E, Howard TD, et al. Factor V Leiden, hormone replacement therapy and risk of thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol 2002;22:1012-17.

22. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983-987.

23. Daly E, Vessey MP, Painter R, Hawkins MM. Case-control study of venous thromboembolism risk in users of hormone replacement therapy. Lancet 1996;348:1027.

24. Varas Lourenzo C, Garcia Rodrigues LA, Cattaruzzi C, Troncon MG, Agostinis L, Perez Gutthann S. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population - based study in southern Europe. Am J Epidemiol 1998;147:387-90.

25. Grady D, Furberg C. Venous thromboembolic events associated with hormone replacement therapy. JAMA 1997;278:477.

26. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Int Med 2000;132:689-96.

27. Hoibraaten E, Abdelnoor M, Sandset PM. Hormone replacement therapy with estradiol and risk of venous thromboembolism: a population- based case - control study. Thromb Haemost 1999;82:1218-21.

28. Daly E, Vessey MP, Hawkins MW, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80.

29. Rivas Yépez JA, Freire CMV, Almeida MCC, Souza PMT. Trombose venosa, fenômenos tromboembólicos e terapêutica de reposição hormonal. Cir Vasc Angiol 1998;14:33-37.

30. Araújo JD. A terapêutica de reposição hormonal e o tromboembolismo venoso. Revista Socesp 1999;9:6.

31. Hoibraaten E, Qvigstad E, Arnensen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent thromboembolism during hormone replacement therapy: results of the randomized, double-blind, placebo - controlled estrogen in venous thromboembolism (EVTET). Thromb Haemost 2000;84:961-7.

32. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/ Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.

33. Women's Health Initiative (WHI) Data and Safety Monitoring Board (DSMB) Statement reported in WHI HRT Update June 2002. Available at: www.whi.org/update/2002update.

34. Writing Group for The Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women's health initiative randomized controlled trial. JAMA 2002;288:321-33.

35. Miller J, Chan BK, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136:680-90.

36. Miller J, Chan BK, Nelson HD. Hormone replacement therapy and risk for thromboembolism. Systematic evidence review n. 11(prepared by Oregon Health and Science Evidence - based Practice Center) Rockville MD: Agency for Healthcare Research and Quality, 2002. Available at: http://www.ahrq.gov/clinic/serfiles.htm.

37. U.S. Preventive Services Task Force. Hormone Replacement Therapy for Primary Prevention of Chronic Conditions: Recommendations and Rationale. October 2002. Agency for Health Care Research and Quality, Rockville, MD. Available at: www.ahrq.gov/clinic/3rduspstf/hrt/hrtr.htm.