ABSTRACT: The development of menopausal symptoms and related disorders, which lead women to seek prescriptions for postmenopausal estrogen therapy and hormone therapy, is a common reason for a patient to visit her gynecologist, but these therapies are associated with an increased risk of venous thromboembolism. The relative risk seems to be even greater if the treated population has preexisting risk factors for venous thromboembolism, such as obesity, immobilization, and fracture. Recent studies suggest that orally administered estrogen may exert a prothrombotic effect, whereas transdermally administered estrogen has little or no effect in elevating prothrombotic substances and may have beneficial effects on proinflammatory markers. When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy. As part of the shared decision-making process, the gynecologist should weigh the risks against the benefits when prescribing combination estrogen plus progestin hormone therapy or estrogen therapy and counsel the patient accordingly.
The purpose of this Committee Opinion is to review evidence on the safety of postmenopausal estrogen therapy. Noting that the gynecologist may prescribe either synthetic progestins or natural progesterone in conjunction with estrogen, this Committee Opinion will address estrogen-related risks only. The absolute risk of venous thromboembolism is age dependent. The incidence is estimated to be approximately 54/100,000 per year in women in their 40s, increasing to 62–122/100,000 per year in women in their 50s, and is approximately 300–400/100,000 per year in women aged 70–80 years. For women in their 80s, the estimated annual risk is approximately 700/100,000 (1–4). Combination estrogen plus progestin hormone therapy (HT) or estrogen therapy (ET) for the management of menopausal symptoms and related disorders is associated with an increased risk of venous thromboembolism. Commonly, a relative increase in risk of twofold to fivefold is cited for HT users (5–9). There is adequate evidence in the medical literature that natural progesterone is not associated with an increased risk of venous thromboembolism (10). Conversely, there is evidence that by comparison, synthetic progestins (eg, medroxyprogesterone acetate) do increase the risk of venous thromboembolism (10–12). The use of estrogen alone has been associated with a 1.2–1.5-fold relative risk compared with that of nonusers (13–18).
The relative risk of venous thromboembolism in women who take ET seems to be even greater if the treated population has preexisting risk factors for venous thromboembolism, such as obesity, immobilization, and fracture. As observed in the Heart and Estrogen/progestin Replacement Study, increased age and underlying coronary vascular disease are also risk factors for venous thromboembolism (16). Women with prothrombotic mutations, such as Leiden factor V, G20210A prothrombin mutation, protein C and protein S deficiencies, and other congenital thrombophilic disorders, are also especially at risk, as are women with acquired thrombophilic conditions (17). A number of substances, such as factor VII, factor VIIIc, factor IX, protein C, and C-reactive protein, are linked to an increased risk of venous thromboembolism (16, 17).
In most investigations of the relationship of venous thromboembolism and menopausal HT, the route of hormone administration has been primarily oral. It has been proposed that orally administered estrogen may exert a prothrombotic effect through the hepatic induction of some of these substances (18–23). The prothrombotic effect is possibly related to high concentrations of estrogen in the liver due to the “first-pass” effect. Studies that compared oral and transdermal ET have demonstrated that transdermally administered estrogen has little or no effect in elevating prothrombotic substances and may have beneficial effects on proinflammatory markers, including C-reactive protein, prothrombin activation peptide, and antithrombin activity. Also, in contrast to oral ET, transdermal ET also may have a suppressive effect on tissue plasminogen activator antigen and plasminogen activator inhibitor activity (23–29).
The Estrogen and Thromboembolism Risk study, a multicenter case–control study of thromboembolism among postmenopausal women aged 45–70 years, demonstrated an odds ratio for venous thromboembolism in users of oral and transdermal estrogen to be 4.2 (95% CI, 1.5–11.6) and 0.9 (95% CI,0.4–2.1), respectively, when compared with nonusers (10). Transdermal estrogen had no increased risk compared with nonusers. Similar results were reported elsewhere (30–35) and of particular importance, in women who were stratified for weight (36) and the presence of prothrombotic mutations (37).
Several nonoral delivery systems presently are available for the administration of estradiol. These include transdermal estradiol patches, ethanolic estradiol-containing gels and sprays, and the vaginal (ring) delivery system. Topical vaginal creams and tablets prescribed for treatment of local urogenital atrophic changes have low levels of systemic absorption but have no detectable effect on coagulation proteins or incidence of venous thromboembolism. Both transdermal (patches or gels) and vaginal (ring) delivery bypass the gastrointestinal conversion of estradiol to estrone with less increase of triglyceride levels, clotting factors, and globulins (38). The vaginal ring containing estradiol acetate for systemic treatment, shown to be effective in the management of vasomotor symptoms, is not associated with an increased risk of venous thromboembolism (38–40). The practicing gynecologist should be aware that other less mainstream estrogen delivery methods, including transbuccal lozenges and troches, are widely used throughout the United States. These alternatives, which are meant to dissolve in the mouth and bypass the enterohepatic circulation, are available as single agents or in combination with other hormones and are fashioned by compounding pharmacies. Data on the safety and efficacy of compounded troches and lozenges are limited. Although widely prescribed, these less mainstream estrogen delivery methods have not been subjected to significant scientific scrutiny.
The development of menopausal symptoms and related disorders, which lead women to seek prescriptions for postmenopausal ET and HT, is a very common reason for a patient to visit her gynecologist. In healthy women with a negative risk history, the probability of venous thromboembolism is generally low. This risk increases with age and the presence of additional risk factors, including the presence of cardiovascular disease, obesity, fracture, renal disease, and both congenital and acquired thrombophilic disorders. These risk factors are not rare. Therefore, it is prudent for the prescriber to carefully assess the personal and family history of patients before prescribing HT or ET. When prescribing ET, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of ET. As part of the shared decision-making process, the gynecologist should weigh the risks against the benefits when prescribing HT or ET, and counsel the patient accordingly.
- Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933–8. [PubMed] ⇦
- Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585–93. [PubMed] [Full Text] ⇦
- White RH. The epidemiology of venous thromboembolism. Circulation 2003;107:I4–8. [PubMed] [Full Text] ⇦
- Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002;162:1182–9. [PubMed] [Full Text] ⇦
- Grady D, Hulley SB, Furberg C. Venous thromboembolic events associated with hormone replacement therapy. JAMA 1997;278:477. [PubMed] ⇦
- Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977–80. [PubMed] [Full Text] ⇦
- Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983–7. [PubMed] [Full Text] ⇦
- Perez Gutthann S, Garcia Rodriguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997;314:796–800. [PubMed] [Full Text] ⇦
- Prentice RL, Manson JE, Langer RD, Anderson GL, Pettinger M, Jackson RD, et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12–23. [PubMed] [Full Text] ⇦
- Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Circulation 2007;115:840–5. [PubMed] [Full Text] ⇦
- Casanova G, Spritzer PM. Effects of micronized progesterone added to non-oral estradiol on lipids and cardiovascular risk factors in early postmenopause: a clinical trial. Lipids Health Dis 2012;11:133. [PubMed] [Full Text] ⇦
- Battaglioli T, Martinelli I. Hormone therapy and thromboembolic disease. Curr Opin Hematol 2007;14:488–93. [PubMed] ⇦
- Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. Women’s Health Initiative Steering Committee. JAMA 2004;291:1701–12. [PubMed] [Full Text] ⇦
- Curb JD, Prentice RL, Bray PF, Langer RD, Van Horn L, Barnabei VM, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006;166:772–80. [PubMed] [Full Text] ⇦
- Douketis JD, Julian JA, Kearon C, Anderson DR, Crowther MA, Bates SM, et al. Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study. J Thromb Haemost 2005;3:943–8. [PubMed] [Full Text] ⇦
- Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000;132:689–96. [PubMed] [Full Text] ⇦
- 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 [published erratum appears in Ann Intern Med 2003;138:360]. Ann Intern Med 2002;136:680–90. [PubMed] [Full Text] ⇦
- Randomised comparison of oestrogen versus oestrogen plus progestogen hormone replacement therapy in women with hysterectomy. Medical Research Council’s General Practice Research Framework. BMJ 1996;312:473–8. [PubMed] [Full Text] ⇦
- Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med 1993;328:1069–75. [PubMed] [Full Text] ⇦
- Meilahn EN, Kuller LH, Matthews KA, Kiss JE. Hemostatic factors according to menopausal status and use of hormone replacement therapy. Ann Epidemiol 1992;2:445–55. [PubMed] ⇦
- Kraaijenhagen RA, in’t Anker PS, Koopman MM, Reitsma PH, Prins MH, van den Ende A, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000;83:5–9. [PubMed] ⇦
- Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343:457–62. [PubMed] [Full Text] ⇦
- Lowe GD, Upton MN, Rumley A, McConnachie A, O’Reilly DS, Watt GC. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein--a cross-sectional population survey. Thromb Haemost 2001;86:550–6. [PubMed] ⇦
- Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997;17:3071–8. [PubMed] [Full Text] ⇦
- Post MS, Christella M, Thomassen LG, van der Mooren MJ, van Baal WM, Rosing J, et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol 2003;23:1116–21. [PubMed] [Full Text] ⇦
- Oger E, Alhenc-Gelas M, Lacut K, Blouch MT, Roudaut N, Kerlan V, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. SARAH Investigators. Arterioscler Thromb Vasc Biol 2003;23:1671–6. [PubMed] [Full Text] ⇦
- Folsom AR, Lutsey PL, Astor BC, Cushman M. C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thromb Haemost 2009;102:615–9. [PubMed] [Full Text] ⇦
- Margarido PF, Bagnoli VR, Maggio da Fonseca A, Maciel GA, Soares JM Jr, D’Amico EA, et al. Transdermal estrogen therapy effects on fibrinogen levels in women with a past history of venous thromboembolism: a pilot study. Clin Exp Obstet Gynecol 2011;38:232–5. [PubMed] ⇦
- Eilertsen AL, Hoibraaten E, Os I, Andersen TO, Sandvik L, Sandset PM. The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis. Maturitas 2005;52:111–8. [PubMed] [Full Text] ⇦
- Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. WHI Investigators. JAMA 2003;289:2673–84. [PubMed] [Full Text] ⇦
- Minkin MJ. Considerations in the choice of oral vs. transdermal hormone therapy: a review. J Reprod Med 2004;49:311–20. [PubMed] ⇦
- Laliberte F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause 2011;18:1052–9. [PubMed] ⇦
- Olie V, Canonico M, Scarabin PY. Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol 2010;17:457–63. [PubMed] ⇦
- Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ 2010;340:c2519. [PubMed] [Full Text] ⇦
- Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. EStrogen and THromboEmbolism Risk Study Group. Lancet 2003;362:428–32. [PubMed] [Full Text] ⇦
- Canonico M, Oger E, Conard J, Meyer G, Levesque H, Trillot N, et al. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. EStrogen and THromboEmbolism Risk (ESTHER) Study Group. J Thromb Haemost 2006;4:1259–65. [PubMed] [Full Text] ⇦
- Straczek C, Oger E, Yon de Jonage-Canonico MB, Plu-Bureau G, Conard J, Meyer G, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Circulation 2005;112:3495–500. [PubMed] [Full Text] ⇦
- Ballagh SA. Vaginal hormone therapy for urogenital and menopausal symptoms. Semin Reprod Med 2005;23:126–40. [PubMed] [Full Text] ⇦
- Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms. Obstet Gynecol 2003;102:823–34. [PubMed] [Obstetrics & Gynecology] ⇦
- Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol 1996;174:85–92. [PubMed] [Full Text] ⇦