TITLE: HORMONE REPLACEMENT THERAPY
AUTHORS:    MARIE M. BUDEV, DO -- Department of Pulmonary and Critical
Care Medicine
HOLLY L. THACKER, MD -- Director, Women's Health Center at The Gault Women's Health and Breast Pavillion
PUBLISHED: DECEMBER 10, 2003
     

Exogenous hormones are used worldwide by more than 100 million women yearly as hormonal contraception or postmenopausal hormonal therapy (HT). Because they are given in healthy women, the issue of exogenous hormone safety has received considerable attention.1 We review the risks and pathophysiology of thrombosis associated with exogenous hormone administration, including hormonal contraceptive preparations, postmenopausal HT, and selected estrogen receptor modulator therapy (SERM), and we link to the chapter on Venous Thromboembolism (VTE), which covers pathophysiology, diagnosis, treatment, and outcomes. Both retrospective and prospective nonexperimental epidemiologic studies have shown a twofold to fourfold increase in the relative risk of VTE with the use of either hormonal contraception or postmenopausal HT. Prospective, randomized, controlled trials have shown an increase in VTE with the use of HT. Yet clinical thrombotic events are rare in the general population, and overall they are more a side effect than the main effect of exogenous hormone use and should not be a contraindication to the initiation of therapy.

Whether to administer exogenous hormonal contraception or postmenopausal HT depends on the net benefit for the woman after any additive risk factors are taken into account. Risk factors include differences in the thrombotic potential of various preparations, a family and especially personal history of VTE, and the presence of additive environmental factors such as immobility and surgery that may increase the risk of VTE.2

HORMONAL CONTRACEPTION
The introduction of the hormonal contraceptive pill in 1959 was a major medical achievement that changed the way women could control reproduction and thereby achieve a greater life expectancy and better health status. The Centers for Disease Control and Prevention has listed hormonal contraception as one of the top 10 advances in medicine in the last century.3 It currently is the most popular form of reversible, nonsurgical contraception worldwide.1
DEFINITION

The term "hormonal contraception" for many patients is synonymous with the oral contraceptive pill. More than 60 million women rely on "The Pill" as their contraceptive method of choice. The Food and Drug Administration (FDA) has reported that no other medication in the history of medical science has been studied more extensively than the oral contraceptive pill.4

Most oral contraceptives are a combination of estrogen in the form of ethinyl estradiol (EE) and an androgen-derived progestin. Recently, hormonal contraception has expanded to include injectable forms of medroxyprogesterone and estradiol (MPA/E2C; Lunelle); dermal patch combinations (Ortho Evra); and hormonal vaginal contraceptive rings (NuvaRing). Also available are progestin-only agents, including the progestin-only pill ("mini-pill" including Micronor, or Ovrette), injectable medroxyprogesterone (Depo-Provera Contraceptive Injection), and levonorgestrel releasing Mirena intrauterine system. Relatively few thrombotic occurrences have been reported for progestin-only hormonal contraception, and progestin-only therapy it is generally presumed to be safe with respect to VTE.
CONTRACEPTIVE PREPARATIONS
AND THE RISK OF VTE
The first case of thrombosis associated with hormonal contraception occurred in 1961 when a nurse taking a high-dose estrogen pill developed a pulmonary embolism.5 Myocardial infarction and stroke were reported in pill users during the following years. These early reports seemed to suggest that the thrombotic potential of the oral contraceptive pill was related to its relatively high estrogen content of 50 ug or higher. By the 1970s, the low-dose oral contraceptive pill was introduced, containing 35 µg EE. Twenty years later, the third-generation progestins (desogestrel, gestodene, and norgestimate) were developed, containing even lower formulations of EE (20 µg EE). The third-generation progestins had fewer androgenic effects than the traditional progestins. Yet, the third-generation oral contraceptive pill was found, in a number of European epidemiologic studies, to actually be associated with an increase in VTE compared with the older contraceptive preparations despite the lower overall estrogen content.6
HORMONAL CONTRACEPTION
AND THE RISK OF VTE

Clinical trials designed to study the thrombogenic potential of hormonal contraceptives have lacked a strong study design and methodology. Since large crossover randomized trials are not possible for ethical reasons, hormonal contraceptives have mainly been studied using a series of case-control studies followed by a series of cohort analytic studies. The first case-control study, in 1967 by the Royal College of General Practitioners, reported that users of oral contraceptives had a threefold increased risk of venous thrombosis compared with nonusers.7 A large, prospective trial in 1970 and a series of small studies over the next two decades seemed to confirm this same threefold increase in the risk of VTE in hormonal contraceptive users.8 Most of these studies indicated that the risk was immediate, in the early phases of use, and did not increase with a longer duration of use.

But many of those early trials used a clinical "bedside" diagnosis of VTE and not objective testing, thus probably misinterpreting the true prevalence of VTE and underestimating its risk.5 More recent studies have found a twofold to sixfold increased risk for venous thrombosis for oral contraceptive users. In the landmark Leiden Thrombophilia Study, the absolute risk for VTE was estimated at 0.8 per 10,000 per year among nonusers and 3.0 per 10,000 per year among hormonal contraceptive users.9 Another British study similarly found an annual risk in hormonal contraceptive users of 2.0 per 10,000 users.10 Overall, these numbers seem to indicate a low absolute risk, translating into thousands of women [needing] to abstain from hormonal contraceptive use in order to prevent one case of thrombosis a year.

The most recent evidence regarding the risk of VTE and HT came from the terminated estrogen/progestin arm of the Women's Health Intitiative (WHI). Although the development of VTE was not one of the primary outcomes of this large, randomized, multicenter trial in late postmenopausal women utilizing postmenopausal HT for preventive purposes, the risk of VTE factored heavily into the negative net risk/benefit global index that lead to the premature termination of this are of the estrogen-progestin ARM of the WHI. The use of HT increased the risk of VTE to a relative risk of 2.11 which means a '211% increased risk overall'. Translated into absolute risk of VTE in a postmenopausal hormonal therapy user means 34 VTE events annually per 10,000 women treated with HT versus 16 VTE events per 10,000 women who are non-HT users. The risk of VTE with HT persisted throught the 5 year study.11,12

The ESTER study group-EStrogen and THromboEmbolism Risk group13 is a case controlled study in France found that oral but NOT trandermal estrogen was associated with increased risk of VTE in postmenopausal women. Their data suggest but do not confirm that transdermal estrogen may be safer than oral estrogen with respect to thrombotic risk.

Of note, the original publication from the WHI11 which quoted an increased risk for cardiovascular disease in HT users was published in full detail14 and did not find, after central adjudication, any significant increased risk for cardiovascular disease in HT users RR 1.24 (95% confidence interval included unity 1.0-1.54).

It is important to recognize that although hormonal contraception may be associated with a significant portion of VTE events in young women, it does not account of all VTE events. Many other risk factors need to be considered in deciding whether some women have a higher risk of thrombosis when using hormonal contraception including obesity, age, a personal or family history of a VTE event, or the presence of a familial hypercoagulable state (including factor V Leiden, prothrombin 20210A, or deficiencies of protein C, protein S, or antithrombin). With the familial thrombophilic states, including protein C, protein S, and antithrombin deficiencies, the risk of first thrombosis is significantly increased.15 In addition, reports of mild hyperhomocysteinemia (homocysteine >18.5 µmol/L) is a common but mild risk factor for venous thrombosis.16 A history of a VTE event is the strongest indicator for recurrence in the future.8

Factor V Leiden Mutation
Of all the inherited thrombophilias, the factor V Leiden mutation is thought to be the most common cause of congenital hypercoagulability states today and may be responsible for about half of all cases of familial venous thrombosis.17 Women who are heterozygotic or homozygotic for the factor V Leiden mutation have a greater thrombotic risk when using hormonal contraceptive preparations.9 In women who carry the factor V Leiden mutation, the frequency of puerperal death from pulmonary embolism ranges from 1 in 2,000 women to 1 in 15, 000 women.18 Carriers of the factor V Leiden mutation had an eightfold increased risk of VTE in the Leiden Thrombophilia Study.9 The study also suggested that the incidence of VTE in a heterozygotic carrier of factor V Leiden who was also an oral contraceptive user was increased multiplicatively with RR 34.7-fold versus 3.7-fold in a woman not carrying the mutation. Similar relative risks were found in smaller studies. Even higher risks were reported for an individual homozygous for the factor V Leiden mutation, with an almost 100-fold increase in those homozygous carriers on hormonal contraceptives compared with non-carrier who were not users. Schambeck and colleagues found that the thrombotic risk of oral contraceptives in factor V Leiden carriers is generally unpredictable temporally.19 Recent investigations, including the Bavarian Thromboembolic Risk cohort study (BATER), confirmed the increased relative risk of idiopathic VTE for users of hormonal contraceptives who are also factor V Leiden carriers.20 However, the overall true risk for factor V Leiden carriers was found to be less than that shown by previous data from the Leiden Thrombophilia Study. The BATER study,20 using adjusted risk estimates, suggested that the VTE risk for women with the factor V Leiden mutation is likely to be increased twofold to fourfold rather than sevenfold. The adjusted risk estimate for a heterozygotic factor V Leiden carrier on hormonal contraceptives was increased to 10-fold to 15-fold rather than 30-fold to 50-fold. Girolami and colleagues also suggested that the factor V Leiden defect did not seem to be a significant factor for withholding hormonal contraception from carriers of the mutation who had not themselves experienced a VTE.21

Benefits of Hormonal Contraception
Hormonal contraceptives, especially the birth control pill, enjoy a great deal of popularity worldwide. The general advice holds that using hormonal contraception increases the risk for VTE to an unacceptable degree. But dispensing with hormonal therapy may actually lead to an increase in the rate of unintended pregnancies, which themselves increase the rate of VTE compared with the nonpregnant state.8 Hormonal contraceptives have an excellent risk-benefit balance compared with other contraceptive methods currently available.22 They are one of the most effective reversible means of preventing pregnancy.23 Discouraging the use of such an effective means of contraception could result in an unwanted and unplanned pregnancies, leading to a greater risk of VTE or possibly contributing to the development of pre-eclampsia, abruptio placentae, fetal growth retardation, stillbirth, and miscarriages.24

Hormonal contraception also has noncontraceptive benefits, including decreased dysfunctional uterine bleeding, reduction of dysmenorrhea, and the treatment of endometriosis, acne, and functional ovarian cysts.25 Hormonal contraception also provides significant protection from ovarian and endometrial cancer.22 Hormonal contraceptive use in the carriers of the BRCA1 and BRCA2 mutations has also shown reductions in ovarian cancer incidence. The incidence and mortality associated with ovarian cancer (lifetime risk 1 in 57) is greater than the attributable risk of developing VTE disease in a woman with factor V Leiden mutation and using hormonal contraception (risk 1 in 9,259 women).26 Denying these carriers hormonal contraception may not actually help women.
PATHOPHYSIOLOGY

The factors and mechanism by which female hormones lead to a prothrombotic state is complex and not fully understood. Procoagulant factors include modest increases in the levels of factor VII, factor VIII, factor X, prothrombin, and fibrinogen with associated decreases in the anticoagulant proteins including antithrombin, and protein S. Using a thrombin generation assay, it has been noted that women taking hormonal contraceptives actually develop activated protein C-resistance, which may provide an explanation for the increased thrombotic risk associated with hormonal contraceptive users who are carriers of factor V Leiden mutation.25
POSTMENOPAUSAL HORMONE
THERAPY AND THROMBOSIS
DEFINITION

The primary role for HT is relief of postmenopausal symptoms including vasomotor instability, genitourinary and quality-of-life issues, and bone protection.30 Although the thrombogenicity of hormonal contraception has been recognized for more than 40 years, convincing evidence for the thrombogenic potential of postmenopausal HT has emerged only in the last 7 years.31

Most HT preparations contain an estrogen and a progestin to avoid endometrial hyperplasia or stimulation (in women who have a uterus progestin therapy is included with estrogen). Estrogen-only therapy is used in women without a uterus. The most common combined, continuous hormone preparations in North America include conjugated estrogens plus medroxyprogesterone. Micronized estradiol is also available in transdermal patch form, gel form, and vaginal tablets, and transdermal lotion as used in vaginal rings.

The estrogen formulations used in the postmenopausal state are at a much lower dose than those used in hormonal contraception and are considered to have significantly lower biologic potency than systemic forms of HT or the SERMs raloxifene and tamoxifen. All are thought to generally increase the rate of VTE 2-3 fold.
POSTMENOPAUSAL THERAPY
AND THE RISK OF VTE

As the postmenopausal female population increases, the use of postmenopausal HT is also increasing.

Early studies of postmenopausal estrogen therapy showed a slight increase in the risk of venous thrombosis,30 but subsequent studies did not repeat those findings.9 Only in the last decade has a series of studies demonstrated that HT users have a twofold to fourfold increased risk of venous thrombosis,32 and that HT, regardless of duration of use, increases thrombosis risk. As with hormonal contraception, a number of studies have shown that the risk of thrombosis is highest during the first year of use.33

Rosendaal and colleagues investigated whether the increased risk of thrombosis posed by HT is affected by the factor V Leiden mutation or prothrombin 20210A mutation (the two most common prothrombotic mutations) in women aged 45 to 64 years.29 Among women with a first deep vein thrombosis, more than 50% were receiving HT at the time of thrombosis compared with 24% of those with VTE who were not receiving HT. Among the women with VTE, 23% had a prothrombotic either factor V Leiden or prothrombin 20210A, versus 7% among control groups.

It has been calculated that women on HT who have factor V Leiden mutations have a 15-fold increase in the risk of thrombosis compared with women who did not have the mutation and did not use HT, suggesting that HT and factor V Leiden risk is more than additive. The Heart and Estrogen/Progestin Replacement Study17,34 and the Estrogen Replacement and Atherosclerosis trial,35 two randomized controled trials that looked at HT and secondary cardiovascular outcomes, found a 1.7% and 2.6% respective increase in VTE in women on HT. Further investigation, through genotyping of blood samples, found that 16.7% of women with VTE carried the factor V Leiden mutation versus 6.3% of controls. The EVTET random controlled trial of the use of HT in women with a previous deep vein thrombosis was prematurely terminated because of the high rate of recurrence of 8.5% per year in the treatment group versus only 1.1% in the placebo group.36
PATHOPHYSIOLOGY
The estrogens in HT are similar in their hemostatic effects to those of hormonal contraceptives. All estrogens (given either orally or transdermally) seem to increase the levels of procoagulant factors VII, X, CII, and XIII and conversely decrease anticoagulant factors such as protein S and antithrombin, leading to a more procoagulant state not balanced by fibrinolytic activity.5
SELECTIVE ESTROGEN
RECEPTOR MODULATORS
Tamoxifen (Nolvadex), raloxifene (Evista), and other SERMs have apparent antiestrogenic effects on the breast and variable effects on the endometrial tissue. Tamoxifen is used for breast cancer treatment and prevention, and raloxifene is approved by the FDA only for the prevention and treatment of osteoporosis. But there is an estrogenic effect on blood clotting by these agents, and they confer the same risks of VTE as does HT. In a controlled trial of tamoxifen versus placebo, an increase was observed in the relative risk of deep vein thrombosis (RR 1.6) in women with breast cancer.37 The MORE trial, has not reported any increased risk of arterial thrombotic events or early cardiovascular harm, but has a reported a twofold or greater risk of VTE in the raloxifene-treated group.38
PRACTICAL RECOMMENDATIONS
Any women with a personal or family history of VTE who is contemplating starting hormonal contraception, HT, or SERMs should be screened for a possible hereditary thrombophilia; however, screening of the general population without a personal or family history of VTE before starting exogenous hormones is not recommended. The most challenging subset of women are those with known thrombophilia who have pressing indications for hormonal contraception, HT, or SERM therapy. Aromatase inhibitors (Arimidex, Femara) are favored in women with breast cancer who have a history of VTE as there has been no reported increased risk of VTE with these agents. There are other options for osteoporosis treatment, including bisphosphonates (Actonal or Fosamax), and other methods of nonhormonal contraception therapies, such as barrier contraception, available for women at high risk.
SUMMARY

The benefit of knowing that a woman has a hereditary thrombophilia does not necessarily lie in the reduction of the number of fatality cases, but allowing carriers of the mutation to be aware of the increased thrombotic risk they face with the use of any exogenous HT. Educating women on the additive effect posed by various risk factors including age, obesity, family history, and the multiplicative risk in women with a known thrombophilia and/or an unexplained VTE is of even greater importance. As with any other medication that we prescribe, the risk/benefit ratio should be assessed with the individual woman based on her combined risk factors and her indication for hormonal therapy.
REFERENCES
  1. Carter CJ. Oral contraceptives and thrombosis. Curr Opin Pulm Med. 2000;6:296-300.

  2. Douketis JD, Ginsberg JS, Holbrook A, Crowther M, Duku EK, Burrows RF. A reevaluation of the risk for venous thromboembolism with the use of oral contraceptives and hormone replacement therapy. Arch Intern Med. 1997;157:1522-1530.

  3. Available at http://www.cdc.gov/od/
    nvpo/pubs/arttop10.htm. Accessed September 2003.

  4. Available at http://www.fda.gov/bbs/topics/
    CONSUMER/CON00027.html. Accessed September 2003.

  5. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol.2002;22:201-210.

  6. Jick H, Jick SS, Gurewich V, et al. Risk of idopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differenct progestogen compounds. Lancet. 1995:346:1589-1593.

  7. Oral contraception and thrombo-embolic disease. J R Coll Gen Pract. 1967;13:267-279.

  8. Koster T, Small RA, Rosendaal FR, Helmerhorst FM. Oral contraceptives and venous thromboembolism: a quantitative discussion of the uncertainties. J Intern Med. 1995;238:31-37.

  9. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of Factor V Leiden mutation. Lancet. 1994;344:1453-1457.

  10. Jick H, Kaye JA, Vasilakis-Scaramozza C, Jick SS. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis. BMJ. 2000;321:1190-1195.

  11. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

  12. North American Menopause Society. Amended report from the NAMS Advisory Panel on Postmenopausal Hormone Therapy. Menopause. 2003;10:6-12.

  13. Scarabin PY, Oger E, Plu-Bureau G; EStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428-32.

  14. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-34.

  15. Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999;81:198-202.

  16. Rosing J, Curvers J, Tans G. Oral contraceptives, thrombosis and haemostasis. Eur J Obstet Gynecol Reprod Biol. 2001;95:193-197.

  17. Herrington DM, Vittinghoff E, Howard TD, et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol. 2002;22:1012-1017.

  18. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997;127:895-903.

  19. Schambeck CM, Schwender S, Haubitz I, Geisen UE, Grossman RE, Keller F. Selective screening for the Factor V Leiden mutation: is it advisable prior to the prescription of oral contraceptives? Thromb Haemost. 1997;78:1480-1483.

  20. Spannagl M, Heinemann LA, Schramm W. Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism? Eur J Contracept Reprod Health Care. 2000;5:105-112.

  21. Girolami A, Simioni P, Tormene D. APC resistance, oral contraceptive therapy and deep vein thrombosis: settled and unsettled problems. Haematologica. 2000;85:225-226.

  22. Budev M, Thacker HL. Women's hormonal health issues. In: Stoller JK, Ahmad M, Longworth DL, eds. The Cleveland Clinic Intensive Review of Internal Medicine, 3rd ed. Baltimore: Lippincott Williams & Wilkins, 2002:14-30.

  23. Skegg DC. Oral contraception and health. Br Med J. 1999;318:69-70.

  24. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;340:9-13; erratum 1999;341:384.

  25. Speroff L. Oral contraceptives and arterial and venous thrombosis: a clinician's formulation. Am J Obstet Gynecol. 1998;179:S25-S36.

  26. Creinin MD, Lisman R, Strickler RC. Screening for factor V Leiden mutation before prescribing combination oral contraceptives. Fertil Steril. 1999;72:646-651.

  27. Bauer KA. Hormone replacement therapy and the factor V Leiden mutation. Arterioscler Thromb Vasc Biol. 2002;22:879-880.

  28. Elder J, Thacker HL. Women's Health: Menopause. Cleveland Clinic Foundation Electronic Textbook of Medicine. Available at: http://www.clevelandclinicmeded.com/
    diseasemanagement/women/
    menopause/menopause.htm    . Accessed February 2003.

  29. Rosendaal FR, Vessey M, Rumley A, et al. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis. Br J Haematol. 2002;116:851-854.

  30. Surgically confirmed gallbladder disease, venous thromboembolism, and breast tumors in relation to postmenopausal estrogen therapy. A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. N Engl J Med. 1974;290:15-19.

  31. Petitti DB, Wingerd J, Pellegrin F, Ramcharan S. Risk of vascular disease in women. Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA. 1979;242:1150-1154.

  32. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2000;132:689-696.

  33. Perez Gutthann S, Garcia Rodriguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. Br Med J. 1997;314:796-800.

  34. Herrington DM. The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 1999;131:463-466.

  35. Herrington DM, Reboussin DM, Brosnihan KB. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N Engl J Med. 2000;343:522-529.

  36. Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy-results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost. 2000;84:961-967.

  37. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.

  38. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002;287:847-857.
    39.

This information is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition.

In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this web site.
Copyright 2003 The Cleveland Clinic Foundation