title: The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy.
abstract: BACKGROUND
  The metabolism of estrogen contained within hormone replacement therapy (HRT) is influenced by the route of administration, and this may affect the risk of venous thromboembolism. Thrombin generation, a global coagulation assay, is a marker of hypercoagulability and is of potential use in determining the thrombotic risk associated with particular HRT administration routes.
  
  
  OBJECTIVE
  To determine whether any effect of oral and transdermal HRT on thrombin generation is related to the plasma estrogen profile.
  
  
  METHODS
  We investigated the effects of oral, transdermal and no HRT (controls) in 52, 39 and 52 postmenopausal women, respectively, on thrombin generation, standard markers of thrombophilia, estradiol level and estrone level.
  
  
  RESULTS
  All parameters of thrombin generation were altered in women using oral HRT as compared with controls (P<0.001 for all comparisons). No such differences were found in women using transdermal HRT. Estrone levels correlated with peak thrombin generation (R=0.451, P<0.001) in women using oral HRT, but there was no correlation in women using the transdermal route.
  
  
  CONCLUSIONS
  Thrombin generation is significantly increased in women who use HRT administered by the oral route. This is probably mediated by the hepatic first-pass metabolism of estrone, the main metabolite of oral estradiol, which is avoided by the transdermal route. The effect of estrone on thrombin generation may provide the explanation for the higher thrombotic risk seen in women using oral rather than transdermal HRT.
authors.affiliation: King's Thrombosis Centre, King's College Hospital NHS Foundation Trust, London, UK. catherine.bagot@ggc.scot.nhs.uk
authors.forename: C N
authors.initials: CN
authors.lastname: Bagot
authors.forename: M S
authors.initials: MS
authors.lastname: Marsh
authors.forename: M
authors.initials: M
authors.lastname: Whitehead
authors.forename: R
authors.initials: R
authors.lastname: Sherwood
authors.forename: L
authors.initials: L
authors.lastname: Roberts
authors.forename: R K
authors.initials: RK
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Arya
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D016022:Case-Control Studies; D004958:Estradiol / Q000097:blood; D015914:Estrogen Replacement Therapy / Q000009:adverse effects / Q000379:methods; D004967:Estrogens / Q000378:metabolism; D004970:Estrone / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D015203:Reproducibility of Results; D012306:Risk; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: D004967:Estrogens; D004970:Estrone; D004958:Estradiol; D013917:Thrombin