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(Circulation. 2001;104:2826.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Sex Steroids Used in Hormonal Treatment Increase Vascular Procoagulant Activity by Inducing Thrombin Receptor (PAR-1) Expression

Role of the Glucocorticoid Receptor

Olaf Herkert, PhD; Herbert Kuhl, PhD; Jurgen Sandow, PhD; Rudi Busse, MD, PhD; Valérie B. Schini-Kerth, PhD

From the Institut für Kardiovaskuläre Physiologie (O.H., R.B., V.B.S.-K.), Zentrum der Frauenheilkunde und Geburtshilfe (O.H., H.K.), and Zentrum der Pharmakologie (J.S.), Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.

Correspondence to V.B. Schini-Kerth, PhD, Pharmacologie et Physicochimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Faculté de Pharmacie, 74, route du Rhin BP 24, F-67401 Illkirch, France. E-mail schini{at}aspirine.u-strasbg.fr

Background— The use of sex steroids in oral contraception or hormonal replacement therapy is associated with an increased risk of cardiovascular thromboembolic complications. Although both the estrogen and the progestin components have been involved, the underlying mechanisms responsible are unclear.

Methods and Results— This study examined whether sex steroids promote hemostasis indirectly by increasing the procoagulant activity of blood vessels. Treatment of vascular smooth muscle cells with several progestins (progesterone, 3-keto-desogestel, gestodene, and medroxyprogesterone acetate) upregulated proteolytically activatable thrombin receptor (PAR-1) expression, resulting in a potentiated thrombin-induced tissue factor expression and surface procoagulant activity. In contrast, neither the progestins levonorgestrel, norethisterone, and norgestimate nor the synthetic estrogen 17-ethinylestradiol had such effects. The effect of the stimulatory progestins, which induce glucocorticoid-like effects in several cell systems, was mimicked by dexamethasone and inhibited by the progesterone and glucocorticoid receptor antagonist RU-38486. In addition, long-term administration of progesterone, 3-keto-desogestrel, or medroxyprogesterone acetate to ovariectomized rats increased PAR-1 protein level in the arterial wall, resulting in an increased responsiveness of isolated aortic rings to thrombin.

Conclusions— These data demonstrate that several progestins markedly potentiate the vascular procoagulant effects of thrombin by increasing the availability of membrane thrombin receptors in the smooth muscle, an effect that is most likely due to their glucocorticoid-like activity.

Key Words: thrombin • tissue factor • thrombosis • muscle, smooth • progestin

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