Menopause Live - IMS Updates

Date of release: 24 May, 2010

Various HRT regimens and risk of venous thromboembolism

In a recently published paper by Renoux and colleagues [1], the risk of venous thromboembolism (VTE) is evaluated for a number of different hormone replacement therapies (HRT) for postmenopausal women. The analysis was made in the United Kingdom’s General Practice Research database using a nested case–control approach. The cohort of 955,582 postmenopausal women aged 50–79 years included 23,505 cases of VTE (2.46%). The analysis highlighted use of non-oral estrogen and tibolone for which 365 (transdermal) and 148 (tibolone) cases of VTE were present.


The increased risk of VTE for users of oral estrogens and oral estrogen–progestogen preparations (2006 cases; adjusted rate ratio (RR) 1.52; 95% confidence interval (CI) 1.44–1.61) was confirmed. This risk with oral formulations was particularly elevated during the first year of use and disappeared 4 months after discontinuation. A stepwise increase in risk was observed with increasing dosages of the estrogen component. There was no increased risk of VTE for transdermal preparations with estrogens or estrogen–progestogen combinations (RR 1.00; 95% CI 0.89–1.12)) and tibolone (RR 0.92; 95% CI 0.77–1.10).


Among the effects of HRT on the risk of cancer, osteoporosis and cardiovascular diseases, it is important to know that the risk of VTE appears to be different for different preparations. The present study adds significant substance to the data that there is no increased VTE risk for transdermal, estrogen-containing preparations and tibolone. The study also showed that there is a reduced VTE risk for oral preparations with lower dosages.
These results help in the decision of which medication to select in personalized medicine. It should be noted that, for estrogens, the difference in VTE risk for oral and non-oral administration is specific for 17β-estradiol when used for replacement therapy, and this difference is not found for ethinylestradiol when used for contraception.
The absence of significant risk associated with the use of transdermal preparations in the present case–control study conforms with a previous case–control study with a slightly lower, but comparable number of cases [2]. In the latter study, the absence of increased VTE risk in carriers of the prothrombotic mutations in factor V and prothrombin provides strong supportive evidence for the absence of increased VTE risk associated with transdermal estrogen preparations [3]. 
The issue of selection of progestogens is not yet fully clarified. The observation of an increased VTE risk with transdermal estrogen preparations combined with norpregnanes requires explanation, perhaps a prescription bias of these products for hyperestrogenic women [2].
The occurrence of the absence of increased risk of VTE with tibolone was suggested by observations in randomized studies with groups of 1500–2200 subjects [4–6]. The present study with a case–control design (148 vs. 1651 subjects) adds strongly to this evidence.
The plausibility for the absence of increased risk of VTE for both transdermal preparations and tibolone may be found in the analysis of changes in hemostatic variables induced by the treatments. This approach is not validated, but the difference in effects between tibolone and transdermal estrogens, on the one hand, and oral estrogen, on the other hand, provides a possible validation of hemostatic changes versus risk of VTE. It is tempting to suggest that the collective weakening in coagulation inhibition, caused by the joint changes in antithrombin, protein S, free tissue factor pathway inhibitor and activated protein C resistance induced by oral estrogens, is the culprit that is plausibly related to venous thromboembolism and this collective weakening is absent for transdermal estrogens and tibolone.


Cornelis Kluft
Centre for Human Drug Research, Leiden, The Netherlands


  1. Renoux C, Dellaniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: population-based study. J Thromb Haemost 2010 Mar 4. Epub ahead of print.

  2. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840-5.

  3. Straczek C, Oger E, Yon de Jonage-Canonico MB, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation 2005;112:3495-500.

  4. Archer DF, Hendrix S, Gallagher JC, et al. Endometrial effects of tibolone. J Clin Endocrinol Metab 2007;92:911-18

  5. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708.

  6. Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol 2009;10:135-46.