Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial

Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1671-6. doi: 10.1161/01.ATV.0000087141.05044.1F. Epub 2003 Jul 17.


Objective: Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen.

Methods and results: We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17beta-estradiol orally (n=63) or 50 microg 17beta-estradiol transdermally per day (n=68), both associated with 100 mg progesterone daily or placebo (n=65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (P=0.006) and transdermal ERT (P<0.001), but there was no significant effect of transdermal ERT compared with placebo (P=0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1+2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio.

Conclusions: Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Administration, Oral
  • Estrogens / administration & dosage*
  • Estrogens / therapeutic use
  • Female
  • Humans
  • Postmenopause / physiology*
  • Progesterone / administration & dosage*
  • Progesterone / therapeutic use
  • Protein C / metabolism*


  • Estrogens
  • Protein C
  • Progesterone