Venous thrombosis/thromboembolism risk and menopausal treatments

Key points

  • The risk of DVT in most women is low.
  • Take note of risk factors predisposing women to VTE prior to commencing MHT.
  • Individualise all treatment based on the patient, her clinical features, her needs and her risk assessment.
  • If MHT is to be used in a woman assessed to be at high risk of developing a DVT, a transdermal preparation should be used.

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Menopausal hormone therapy (MHT) containing oestrogens in tablet form increase the risk of deep vein thrombosis (DVT) and pulmonary embolus (PE) (1, 2). The thrombotic effects of MHT containing oral oestrogen are associated with a slightly increased risk of stroke and venous thrombo-embolism (VTE) but not of coronary heart disease (3).

What causes the increased risk?

Oral oestrogens have a prothrombotic effect via effects on the extrinsic pathway of the coagulation cascade with altered production of hepatic coagulation proteins thought to be secondary to the effect of the first pass through the hepatic circulation. Changes include increased activated protein C resistance, increased thrombin activation, decreased anti-thrombin III activity, decreased protein S levels, decreased Factor VII levels and decreased tissue factor pathway inhibitor (4, 5). Different effects are observed with oral combined MHT versus oestrogen alone (6, 7). The increased risk of a thrombotic event is greater within the first year of starting treatment, persists throughout the time of taking oral MHT and returns to baseline on cessation of MHT (8).

By comparison, transdermal MHT has little or no effect on coagulation factors or risk of VTE.

How great is the risk?


VTE events – no of women per 1,000 per year


WHI oral E+MPA study

WHI oral E only study





E only

50-59 years





60-69 years





70-79 years






Body mass Index kg/m2

















How to minimise the risk

Risk of recurrence of VTE

The risk of recurrence of VTE in a woman with previous VTE depends on the setting in which that VTE has occurred. VTEs occurring after surgery have a very low risk of recurrence. Those with non-surgical trigger factors, such as immobilisation, fracture, plaster cast, COCP, have an 8% risk of recurrence at 2 years, compared with 20% in patients with unprovoked VTE. 

There is no additional significant association between recurrent VTE and use of transdermal oestrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4) (15).

Likewise, thrombophilias increase the risk of a first VTE but, unlike oral MHT, transdermal MHT is not associated with an additional increase in risk (16).

Recommended reading

  1. Archer DF, Oger E. Estrogen and progestogen effect on venous thromboembolism in menopausal women. Climacteric. 2012;15:235– 40.
  2. Scarabin PY. Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis. Climacteric. 2018:23


  1. Anderson FA, Jr., Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I9-16.
  2. Canonico M, Plu-Bureau G, Lowe GDO, Scarabin P-Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336(7655):1227-31.
  3. Boardman HM, Hartley L, Eisinga A, Main C, Roque I Figuls M, Bonfill Cosp X, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2015;3:CD002229.
  4. Levi M, Middeldorp S, Buller HR. Oral contraceptives and hormonal replacement therapy cause an imbalance in coagulation and fibrinolysis which may explain the increased risk of venous thromboembolism. Cardiovasc Res. 1999;41(1):21-4.
  5. Scarabin P-Y, Hemker HC, Clement C, Soisson V, Alhenc-Gelas M. Increased thrombin generation among postmenopausal women using hormone therapy: importance of the route of estrogen administration and progestogens. Menopause. 2011;18(8):873-9.
  6. Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292(13):1573-80.
  7. 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(7):772-80.
  8. Eisenberger A, Westhoff C. Hormone replacement therapy and venous thromboembolism. J Steroid Biochem Mol Biol. 2014;142:76-82.
  9. Scarabin PY. Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis. Climacteric. 2018:23.
  10. Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, et al. The effects of tibolone in older postmenopausal women. N Engl J Med. 2008;359:697-708.
  11. Canonico M, Plu-Bureau G, Scarabin P-Y. Progestogens and venous thromboembolism among postmenopausal women using hormone therapy. Maturitas. 2011;70(4):354-60.
  12. Scarabin PY. Hormones and venous thromboembolism among postmenopausal women. Climacteric. 2014;17 Suppl 2:34-7.
  13. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e195S-e226S.
  14. 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. Circulation. 2007;115(7):840-5.
  15. Olie V, Plu-Bureau G, Conard J, Horellou M-H, Canonico M, Scarabin P-Y. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause. 2011;18(5):488-93.
  16. 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. Circulation. 2005;112(22):3495-500.

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Content created July 2018