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EMAS position statement: Managing menopausal women with a personal or family history of VTE

      Abstract

      Introduction

      Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a serious cardiovascular event whose incidence rises with increasing age.

      Aims

      To formulate a position statement on the management of the menopause in women with a personal or family history of VTE.

      Material and methods

      Literature review and consensus of expert opinion.

      Results and conclusions

      Randomized controlled trials have shown an increased risk of VTE in oral hormone therapy (HT) users. There are no randomized trial data on the effect of transdermal estrogen on VTE. Recent observational studies and meta-analyses suggest that transdermal estrogen does not increase VTE risk. These clinical observations are supported by experimental data showing that transdermal estrogen has a minimal effect on hepatic metabolism of hemostatic proteins as the portal circulation is bypassed. A personal or family history of VTE, especially in individuals with a prothrombotic mutation, is a strong contraindication to oral HT but transdermal estrogen can be considered after careful individual evaluation of the benefits and risks. Transdermal estrogen should be also the first choice in overweight/obese women requiring HT. Observational studies suggest that micronized progesterone and dydrogesterone might have a better risk profile than other progestins with regard to VTE risk. Although these findings should be confirmed by randomized clinical trials, they strongly suggest that both the route of estrogen administration and the type of progestin may be important determinants of the overall benefit-risk profile of HT.

      Keywords

      1. Introduction

      Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a serious event in both men and women. In women, its incidence is uncommon in premenopausal women but rises significantly after the menopause with increasing age [
      • Oger E.
      Incidence of venous thromboembolism: a community-based study in Western France, EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale.
      ,
      • Naess I.A.
      • Christiansen S.C.
      • Romundstad P.
      • et al.
      Incidence and mortality of venous thrombosis: a population-based study.
      ,
      • Deitelzweig S.B.
      • Johnson B.H.
      • Lin J.
      • Schulman K.L.
      Prevalence of clinical venous thromboembolism in the USA: current trends and future projections.
      ]. The absolute risk is small being around 0.5 per 1000 before the age of 50 while it rises after 50 with an absolute risk of 2–3 per 1000 over 60 years in women not taking HT [
      • Oger E.
      Incidence of venous thromboembolism: a community-based study in Western France, EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale.
      ,
      • Naess I.A.
      • Christiansen S.C.
      • Romundstad P.
      • et al.
      Incidence and mortality of venous thrombosis: a population-based study.
      ]. VTE risk factors include genetic [
      • Straczek C.
      • Oger E.
      • Yon de Jonage-Canonico M.B.
      • et al.
      Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration.
      ] and acquired factors [
      • Di Minno G.
      • Mannucci P.
      • Tufano A.
      • et al.
      The first ambulatory screening on thromboembolism: a multicentre, cross-sectional, observational study on risk factors for venous thromboembolism.
      ,
      • Canonico M.
      • Oger E.
      • Conard J.
      • et al.
      Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration, The ESTHER Study.
      ]. Moreover VTE risk varies throughout a woman's life, with hormonal exposure underlying this risk. Several studies have shown that longer exposure to endogenous estrogen is associated with an increased VTE risk [
      • Grady D.
      • Wenger N.
      • Herrington D.
      • et al.
      Postmenopausal hormone therapy increases risk for venous thromboembolic disease, The Heart and Estrogen/progestin Replacement Study.
      ,
      • Simon T.
      • Beau Yon de Jonage-Canonico M.
      • Oger E.
      • et al.
      Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism.
      ]. Also this varying risk may depend on exogenous estrogen use including combined oral contraceptives and postmenopausal hormone therapy (HT).
      Randomized trials have shown that women who were given oral HT had a 2- to 4-fold increase in the risk of VTE as compared to non users with the highest risk occurring in the first year of use [
      • Grady D.
      • Wenger N.
      • Herrington D.
      • et al.
      Postmenopausal hormone therapy increases risk for venous thromboembolic disease, The Heart and Estrogen/progestin Replacement Study.
      ,
      • Hulley S.
      • Furberg C.
      • Barrett-Connor E.
      • et al.
      Noncardiovascular disease outcomes during 6.8 years of hormone therapy: heart and Estrogen/progestin Replacement Study follow-up (HERS II).
      ,
      • Writing Group for the Women's Health Initiative Investigators
      Risk and benefits of estrogen plus progestin in health postmenopausal women.
      ,
      • Cushman M.
      • Kuller L.H.
      • Prentice R.
      • et al.
      Estrogen plus progestin and risk of venous thrombosis.
      ,
      • Anderson G.L.
      • Limacher M.
      • Assaf A.R.
      • et al.
      Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
      ,
      • Rossouw J.E.
      • Prentice R.L.
      • Manson J.E.
      • et al.
      Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
      ]. In the Women's Health Initiative (WHI) study, pulmonary embolism was the main contributor to the burden of cardiovascular disease and accounted for more than 60% of the potentially fatal events due to HT [
      • Writing Group for the Women's Health Initiative Investigators
      Risk and benefits of estrogen plus progestin in health postmenopausal women.
      ,
      • Cushman M.
      • Kuller L.H.
      • Prentice R.
      • et al.
      Estrogen plus progestin and risk of venous thrombosis.
      ,
      • Anderson G.L.
      • Limacher M.
      • Assaf A.R.
      • et al.
      Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
      ,
      • Rossouw J.E.
      • Prentice R.L.
      • Manson J.E.
      • et al.
      Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
      ]. On the other hand, there is growing evidence that the route of estrogen administration significantly affects the VTE risk associated with HT. Recent meta-analyses [
      • Canonico M.
      • Plu-Bureau G.
      • Lowe G.D.
      • Scarabin P.Y.
      Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis.
      ,
      • Olié V.
      • Canonico M.
      • Scarabin P.Y.
      Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women.
      ] suggest that transdermal estrogen does not confer any additional risk of a VTE event in postmenopausal women.
      Hormone therapy is classically contraindicated in women with a personal history of VTE. Nevertheless, recent data suggest that the various types of HT (according to the route of estrogen administration or the type of progestin) have different actions on hemostatic variables. Accordingly, HT might still represent an option in the management of menopause in women with a higher risk for VTE. In any case, such decisions require individual assessment. Moreover, other non-estrogen based options can be used. They have been reviewed in the EMAS position statement on managing the menopause in the context of coronary heart disease [
      • Schenk-Gustafsson K.
      • Brincat M.
      • Erel T.
      • et al.
      EMAS position statement: managing the menopause in the context of coronary hear disease.
      ]. Raloxifene has no effect on climacteric symptoms and is associated with an increased risk of VTE [
      • Ettinger B.
      • Black D.M.
      • Mitlak B.H.
      • et al.
      For the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators, Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized trial.
      ]. Tibolone does not increase VTE risk in women over 60 with osteoporosis [
      • Cummings S.R.
      • Ettinger B.
      • Delmas P.D.
      • et al.
      for the LIFT Trial investigators. The effects of tibolone in older postmenopausal women.
      ]. There are no data regarding tibolone in women with a personal history or at high risk of VTE. There have been no controlled studies regarding the risk of VTE with nutritional supplements that have estrogen-like properties such as phytoestrogens and the risks associated with their use are unknown [
      • Schenk-Gustafsson K.
      • Brincat M.
      • Erel T.
      • et al.
      EMAS position statement: managing the menopause in the context of coronary hear disease.
      ].
      The aim of this position statement is to examine the role of HT on VTE risk in postmenopausal women.

      2. Venous thromboembolism and hormone therapy

      The risk of VTE has been examined in large randomized controlled trials evaluating the efficacy and safety of HT. Oral conjugated equine estrogen (CEE) given in association with medroxyprogesterone acetate (MPA) was the major combination that was evaluated in most of the large trials. The Heart and Estrogen/progestin Replacement Studies (HERS I and II) found an overall 2.1-fold increase in VTE risk over the 6.8 years of follow-up (95% CI, 1.28–3.40) [
      • Grady D.
      • Wenger N.
      • Herrington D.
      • et al.
      Postmenopausal hormone therapy increases risk for venous thromboembolic disease, The Heart and Estrogen/progestin Replacement Study.
      ,
      • Simon T.
      • Beau Yon de Jonage-Canonico M.
      • Oger E.
      • et al.
      Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism.
      ]. In the Women's Health Initiative, a randomized controlled trial of 16,608 postmenopausal women aged 50–79 years, a two-fold risk of VTE with combination HT was confirmed [
      • Writing Group for the Women's Health Initiative Investigators
      Risk and benefits of estrogen plus progestin in health postmenopausal women.
      ,
      • Cushman M.
      • Kuller L.H.
      • Prentice R.
      • et al.
      Estrogen plus progestin and risk of venous thrombosis.
      ,
      • Rossouw J.E.
      • Prentice R.L.
      • Manson J.E.
      • et al.
      Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
      ].
      Review of studies reporting oral CEE-only HT reveal a modest increase of VTE risk of 1.3-fold, but there is large variability in study design with small numbers of patients enrolled. Data from the Women's Health Initiative study concerning the 10,739 women without an uterus indicate that the risk of VTE in women receiving oral CEE given alone is increased during the first 2 years of use (hazard ratio 1.32), but is still less than that with the MPA combination [
      • Anderson G.L.
      • Limacher M.
      • Assaf A.R.
      • et al.
      Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
      ]. There are no data regarding VTE risk and low dose vaginal estradiol or estriol. Since systemic estrogen levels, when recommended dose regimens are used, do not exceed the postmenopausal range and the hepatic first-pass is avoided it is unlikely that vaginal administration confers an extra risk.
      No randomized trial has examined the relationship between transdermal HT and the risk of VTE. However, several large cohort studies and meta-analyses have been published.
      • -
        The first study was the ESTHER study [
        • Scarabin P.
        • Oger E.
        • Plu-Bureau G.
        Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.
        ], a multicenter case–control study of VTE among postmenopausal women aged 45–70. Oral but not transdermal HT was associated with an increased risk of VTE, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users being 3.5 (95% CI 1.8–6.8) and 0.9 (0.5–1.6), respectively.
      • -
        More recently, 4 other large observational studies [
        • Canonico M.
        • Fournier A.
        • Carcaillon L.
        • et al.
        Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.
        ,
        • Schneider C.
        • Jick S.S.
        • Meier C.R.
        Risk of cardiovascular outcomes in users of estradiol/dydrogesterone or other HRT preparations.
        ,
        • Renoux C.
        • Dell’aniello S.
        • Suissa S.
        Hormone replacement therapy and the risk of venous thromboembolism: population-based study.
        ,
        • Ohira T.
        • Folsom A.R.
        • Cushman M.
        • et al.
        Reproductive history, hormone replacement, and incidence of venous thromboembolism: the longitudinal investigation of thromboembolism etiology.
        ] also reported the same results as the ESTHER study. A meta-analysis [
        • Olié V.
        • Canonico M.
        • Scarabin P.Y.
        Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women.
        ] including those latest studies confirms that oral but not transdermal estrogens increased the risk of VTE in postmenopausal women. This analysis therefore suggests that transdermal estrogen might be well tolerated with respect to VTE risk.
      In addition, the risk of VTE was also found to be influenced by the type of progestin. In the ESTHER study, further results suggested that preparations containing norpregnane derivatives were more thrombogenic than those containing micronized progesterone or pregnane derivatives [
      • Canonico M.
      • Oger E.
      • Plu-Bureau G.
      • et al.
      for the Estrogen and Thromboembolism Risk (ESTHER) Study. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.
      ]. In the larger E3N study [
      • Canonico M.
      • Fournier A.
      • Carcaillon L.
      • et al.
      Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.
      ], there was no increase in VTE risk when transdermal estrogen was administered with micronized progesterone or dydrogesterone. Risk estimates were slightly, but not significantly, higher if estrogens were associated with pregnane derivatives or norethisterone acetate. In contrast, a significantly increased VTE risk was found when estrogen was combined with norpregnane derivatives (HR: 1.8; 95% CI 1.2–2.7). In a recent large nested case–control study using the UK general practice research database on women aged 50–79 [
      • Renoux C.
      • Dell’aniello S.
      • Suissa S.
      Hormone replacement therapy and the risk of venous thromboembolism: population-based study.
      ], pregnane derivatives were associated with a slightly higher VTE risk (HR:1.72; 95% CI 1.52–1.94) than nortestosterone derivatives (HR:1.48; 95% CI 1.37–1.60).
      Until recently, there were no data on the relationship between the dose of estrogens and the risk of VTE. However, the data from the observational study using the UK general practice research database suggest that the risk of VTE might be lower when using lower oral estrogen doses as compared to higher ones [
      • Renoux C.
      • Dell’aniello S.
      • Suissa S.
      Hormone replacement therapy and the risk of venous thromboembolism: population-based study.
      ]. In contrast, there was no difference in VTE risk with transdermal estrogen whatever the dose [
      • Scarabin P.
      • Oger E.
      • Plu-Bureau G.
      Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.
      ,
      • Renoux C.
      • Dell’aniello S.
      • Suissa S.
      Hormone replacement therapy and the risk of venous thromboembolism: population-based study.
      ].
      Differential effects of HT on hemostatic variables by route of estrogen administration may explain the difference in VTE risk between oral and transdermal estrogen users. Oral estrogens result in a hepatic first-pass effect which may contribute to impair the biosynthesis and clearance of proteins involved in hemostasis. Randomized trials have consistently shown that oral but not transdermal estrogens activate the coagulation cascade and increase fibrinolytic potential [
      • Lowe G.D.
      • Upton M.N.
      • Rumley A.
      • et al.
      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.
      ,
      • Scarabin P.Y.
      • Alhenc-Gelas M.
      • Plu-Bureau G.
      • et al.
      Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women, A randomized controlled trial.
      ,
      • Oger E.
      • Alhenc-Gelas M.
      • Lacut K.
      • et al.
      Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.
      ]. Oral, not transdermal, estrogen increases plasma concentrations of the prothrombin activation peptide (F1 + 2) [
      • Scarabin P.Y.
      • Alhenc-Gelas M.
      • Plu-Bureau G.
      • et al.
      Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women, A randomized controlled trial.
      ,
      • Oger E.
      • Alhenc-Gelas M.
      • Lacut K.
      • et al.
      Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.
      ]. A lower antithrombin concentration has also been shown in oral but not transdermal estrogen users. Similarly, increased thrombin generation, which is a marker of hypercoagulability has been found in oral, but not transdermal HT users [
      • Oger E.
      • Alhenc-Gelas M.
      • Lacut K.
      • et al.
      Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.
      ]. Furthermore the rise in estrone synthesis by the liver following oral estrogen administration might contribute to this increase in thrombin generation [
      • Bagot C.N.
      • Marsh M.S.
      • Whitehead M.
      • et al.
      The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy.
      ].
      Numerous reports also support for a role of oral estrogen on the protein C system. Activated protein C (APC) is an important natural anticoagulant which reduces the final process of coagulation. APC resistance has been described in patients at high risk for thrombosis and it was initially related to the factor V Leiden mutation. In the absence of factor V Leiden, a reduced response to APC is associated with an increased VTE risk. Acquired APC resistance has been reported in oral contraceptive users [
      • Vandenbroucke J.P.
      • Koster T.
      • Briet E.
      • et al.
      Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation.
      ,
      • Rosing J.
      • Middeldorp S.
      • Curvers J.
      • et al.
      Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study.
      ]. Several randomized trials [
      • Oger E.
      • Alhenc-Gelas M.
      • Lacut K.
      • et al.
      Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.
      ,
      • Hoibraaten E.
      • Mowinckel M.C.
      • de Ronde H.
      • Bertina R.M.
      • Sandset P.M.
      Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial.
      ,
      • Post M.S.
      • Christella M.
      • Thomassen L.G.
      • 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.
      ] have also found that oral but not transdermal estrogen induce APC resistance in postmenopausal women.
      With regard to the type of progestin, two randomized trials have previously shown that micronized progesterone combined with transdermal estrogen did not increase APC resistance or prothrombin activation peptide (F1 + 2) concentrations in contrast to oral estrogen [
      • Scarabin P.Y.
      • Alhenc-Gelas M.
      • Plu-Bureau G.
      • et al.
      Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women, A randomized controlled trial.
      ,
      • Oger E.
      • Alhenc-Gelas M.
      • Lacut K.
      • et al.
      Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.
      ]. On the other hand, a more recent study [
      • Canonico M.
      • Alhenc-Gelas M.
      • Plu-Bureau G.
      • Olie V.
      • Scarabin P.Y.
      Activated protein C resistance among postmenopausal women using transdermal estrogens: importance of progestogen.
      ] shows that norpregnane derivatives (both nomegestrol acetate and promegestone) together with transdermal estrogen induce APC resistance compared to nonusers or users of transdermal estrogens combined with micronized progesterone. In addition, prothrombin activation peptide (F1 + 2) concentrations were higher in users of transdermal estrogens combined with norpregnane derivatives than in nonusers. Therefore, the findings showing that transdermal estrogen together with micronized progesterone is not associated with increased APC resistance is likely to support the epidemiological data suggesting that such combinations may have a safer risk profile than other progestins with regard to VTE risk.

      3. HT and women at high VTE risk

      3.1 Women with personal history of VTE

      HT is contraindicated in women with a personal history of VTE. Several reports have reported an important excess risk in postmenopausal women taking oral HT compared to non users. A recent French study (Menopause, Estrogen and Venous Events (MEVE)) nevertheless suggests that again use of transdermal estrogen may be well tolerated with regard to VTE recurrence [
      • Olie V.
      • Plu-Bureau G.
      • Conard J.
      • et al.
      Hormone therapy and other risk factors for recurrence of venous thromboembolism among postmenopausal women.
      ]. This study included 1023 postmenopausal women with a personal history of VTE who were followed over an average 80 months after stopping anticoagulant therapy. Use of transdermal estrogens was not associated with an increased risk of recurrent VTE (hazard ratio 1.0; 95% CI 0.4–2.4) as compared to non users. In contrast, women using oral estrogens had an increased risk of recurrent VTE (hazard ratio 6.4; 95% CI 1.5–27.3). The difference between both routes of estrogen administration was significant (p = 0.02). Even though these data need further confirmation because of the small numbers of exposed cases in the MEVE study, they are likely to further support transdermal HT as a safer option for women at high risk for VTE.

      3.2 Women with a prothrombotic mutation

      Factor V Leiden and the prothrombin G20210A mutation are the 2 most common genetic defects associated with an increased risk for VTE. A familial history of VTE or a personal history of VTE in the post-partum or with oral contraceptive use usually represent medical conditions which might lead to screening for those thrombogenic mutations.
      The effect of HT on VTE risk in women bearing such mutations was investigated in case-control studies [
      • Herrington D.M.
      • Vittinghoff E.
      • Howard T.D.
      • et al.
      Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease.
      ,
      • Rosendaal F.R.
      • Vessey M.
      • Rumley A.
      • et al.
      Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis.
      ] and both WHI trials. Overall, the presence of the factor V Leiden mutation or prothrombin G20210A mutation increased the risk of VTE by more than 3-fold (pooled odds ratio 3.3, 2.6 to 4.1). The joint effect of thrombogenic mutations and oral estrogen use among postmenopausal women further enhanced the risk of VTE (odds ratio 8.0, 5.4 to 11.9) compared with women without mutations not taking estrogen. In a multicenter case–control study of VTE among postmenopausal women [
      • Straczek C.
      • Oger E.
      • Yon de Jonage-Canonico M.B.
      • et al.
      Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration.
      ], a 25-fold increase in VTE risk was found in those who both carry a prothrombotic mutation and use oral estrogen, compared with nonusers without a mutation. In contrast, current use of transdermal estrogen did not confer additional risk in women who carry a prothrombotic mutation.
      Again, transdermal estrogen administration seems safer than oral estrogen administration with respect to VTE risk, even in women carrying a prothrombotic mutation. These data may have potential implications to minimize the excess risk of VTE among women who require HT. However, the safety of transdermal estrogen has still to be confirmed in randomized trials among carriers of prothrombotic mutations.

      3.3 Obese women

      Obesity is another condition which has been associated with an increased risk of VTE. In the placebo arm of the WHI, obese women had a 2.9 fold increased risk of VTE compared to their lean counterparts. Use of oral HT has been univocally associated with an increased risk of VTE in overweight/obese postmenopausal women. This increased risk ranges from a factor of 4–6 in randomized trials such as the WHI [
      • Cushman M.
      • Kuller L.H.
      • Prentice R.
      • et al.
      Estrogen plus progestin and risk of venous thrombosis.
      ] to a factor of 10–20 in the large E3N observational study [
      • Canonico M.
      • Fournier A.
      • Carcaillon L.
      • et al.
      Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.
      ] in overweight and obese women, respectively. On the other hand, no increased risk with transdermal estrogen was found in observational studies that have specifically examined the relationship between excess weight/obesity and HT use according to the route of estrogen administration [
      • Canonico M.
      • Oger E.
      • Conard J.
      • et al.
      Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration, The ESTHER Study.
      ,
      • Canonico M.
      • Fournier A.
      • Carcaillon L.
      • et al.
      Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.
      ].
      The EMAS position statement in managing obese postmenopausal women can be reviewed in a previous issue of the journal [
      • Lambrinoudaki I.
      • Brincat M.
      • Erel C.T.
      • et al.
      EMAS position statement: management of obese postmenopausal women.
      ]. When HT is required, the lowest estrogen dose using the transdermal estrogen route should be preferred.

      4. Conclusions

      In summary, while HT still remains the most effective therapy to counteract the climacteric symptoms associated with the menopause, VTE is one of the major harmful effects associated with oral HT. Transdermal estrogen appears safer than oral estrogen with regard to VTE risk and should be the first choice in overweight/obese women.
      In most cases, a personal history of VTE represents a contraindication to HT. Screening for a prothrombotic mutation is not recommended in the general postmenopausal population. When HT is required, such screening could be discussed especially, when there is a personal history of VTE in the postpartum or after use of oral contraceptive or a familial history of VTE. Oral HT is contra-indicated in case of thrombogenic mutations and in women at high VTE risk. Transdermal estrogen could be used after an extensive risk-benefit evaluation when any other treatment option is unsatisfactory. There is no evidence that low dose vaginal estradiol or estriol used at the recommended doses are contraindicated. A body of concordant data suggest that micronized progesterone and dydrogesterone have an overall better risk profile than other progestins not only with regard to thrombotic risk but also breast cancer [
      • Fournier A.
      • Berrino F.
      • Clavel-Chapelon F.
      Unequal risks for breast cancer associated with different hormone replacement therapies: results of the E3N cohort study.
      ,
      • Lyytinen H.
      • Pukkala E.
      • Ylikorkala O.
      Breast cancer risk in postmenopausal women using estradiol-progestogen therapy.
      ]. Therefore, in women with an intact uterus, micronized progesterone or dydrogesterone should be preferred in combination with transdermal estrogen [
      • Rexrode K.
      • Manson J.
      Are some types of hormone therapy safer than others?: lessons from the estrogen and thromboembolism risk study.
      ]. Regular follow up by a specialist service is recommended as well as regular re-evaluation of the benefit-risk balance of HT.

      5. Summary recommendations

      • -
        VTE risk rises in postmenopausal women with increasing age.
      • -
        Thrombogenic mutations and excess weight/obesity are additional risk factors in postmenopausal women.
      • -
        There is compelling evidence from randomized controlled trials that use of oral estrogen given either alone or in combination with progestins increases VTE risk in postmenopausal women.
      • -
        Although there is no randomized controlled trial on transdermal estrogens, numerous data (both epidemiological and biological) suggest that transdermal estrogen is safer than oral estrogen with regard to VTE risk.
      • -
        Transdermal HT should be the first choice in overweight/obese postmenopausal women.
      • -
        A personal history of VTE and in some cases, a familial history of VTE (if associated with a prothrombotic mutation) are strong contraindications to oral HT. When HT is required, transdermal estrogen can be considered after careful individual evaluation of the benefits and risks.
      • -
        Micronized progesterone or dydrogesterone are the preferred progestins for non-hysterectomized women.

      Competing interests

      None declared.

      Provenance

      EMAS position statement.

      Acknowledgements

      FT prepared the initial draft which was circulated to all EMAS board members for comment and approval, production was coordinated by MR.

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