Transdermal Estrogen Safe With Respect to Venous Thromboembolism?

Oral estrogen shows increased risk of VTE, but transdermal does not in a French prospective cohort. (1)

     Several studies have suggested that route of estrogen administration can affect risk of venous thromboembolism (VTE) in women using postmenopausal hormone replacement therapy (HRT).  The authors reviewed data from a prospective cohort of French teachers born between years 1925 and 1950 who completed biennial self-administered questionnaires on a range of health issues.  In those who self-reported a thromoboembolic event, follow-up questions as well as a query of the subject’s physician(s) futher populated the data on such events.  Death certificates were reviewed for deceased subjects and revealed 68 additional events (all PE). Thromboembolic events (deep vein thrombosis (DVT) or pulmonary embolism (PE)) were included if they were diagnosed by an imaging procedure.  Exclusion criteria for events included superficial vein thromboses, upper-extremity DVT, central retinal vein obstruction and recurrent events.  Subject exclusion criteria were history of cancer, VTE prior to study period, recurrent VTE, or nonidopathic VTE. 

     A total of 549 incidents of VTE (415 DVT, 134 PE) were identified in 80,308 women who met inclusion criteria out of the total study enrollment of 98,995.  Of those 549 women with a VTE during the study perior, 181 were never users, 66 were past users, and 255 were current users of HRT.  An additional 47 women were using “other” or “unknown” treatments.  Progestagens were used in all but 26 of the women using HRT (micronized progesterone – 47, pregnane deriviatives – 91, norpregnane derivatives – 69, nortestosterone derivatives – 22).

     Mean age at the start of follow-up period was 54, with women followed over an average of 10.1 years.  The hazard ratio for VTE with oral estrogen use was 1.7 (95% CI: 1.1-2.8) and with transdermal estrogens was 1.1 (95% CI: 0.8-1.8).  Use of a norpregnane derivative was independently associated with an increased risk of VTE (HR 1.8, 95% CI: 1.2-2.7), while other progestagens were not. 

Comments:


     The investigators have obtained results consistent with prior studies (ESTHER) that suggest transdermal estrogens with or without a non-norpregnane progestagen may be safe with respect to VTE.  The current study has a number of limitations; it was a self-reporting survey with a non-trivial exclusion of almost one-fifth of respondents.  While 9.9% of respondents reported tobacco use (a known risk factor for VTE in HRT), the authors did not report prevalence of smokers in each arm of the study.  Since this was simply an observational cohort study, patients at higher risk of VTE based on their individual physician’s clinical impression may have guided the use of HRT type and route or may have prevented the use of HRT all together.  Lastly the study was funded by the manufacturer of a transdermal estrogen product. Nevertheless this study is yet another in a growing series of investigations which suggest that estrogen route and progestagen type can impact VTE risk.  While these results can not be generalized to transgender populations, they are suggestive and are helpful for guiding future research.  

     It is possible that there may be a skewing towards a higher incidence of VTE as the investigators did not separate out users of 17-beta estradiol vs. conjugated equine estrogens (Premarin).

References:

1) Canonico M, Fournier A, Carcaillon L, Olié V, Plu-Bureau G, Oger E, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism. Arteriosclerosis, thrombosis, and vascular biology. 2010;30(2):340–5