17alpha-Ethinylestradiol rapidly alters transcript levels of murine coagulation genes via estrogen receptor alpha.

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Cleuren AC, Van der Linden IK, De Visser YP, Wagenaar GT, Reitsma PH, Van Vlijmen BJ

17alpha-Ethinylestradiol rapidly alters transcript levels of murine coagulation genes via estrogen receptor alpha.

J Thromb Haemost. 2010 Aug;8(8):1838-46. doi: 10.1111/j.1538-7836.2010.03930.x. Epub 2010 May 27.

PubMed ID

20524981 [ View in PubMed

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Abstract

BACKGROUND: Oral estrogen use is associated with changes in plasma levels of many coagulation proteins. OBJECTIVE: To gain more insight into the underlying mechanism of estrogen-induced changes in coagulation. METHODS: Ovariectomized female mice were used to study the impact of oral 17alpha-ethinylestradiol (EE) on plasma coagulation, hepatic coagulation gene transcript levels, and dependence on estrogen receptor (ER) alpha and ERbeta. RESULTS: Ten days of oral EE treatment resulted in significantly reduced plasma activity levels of factor (F)VIII, FXII, combined FII/FVII/FX and antithrombin, whereas FIX activity significantly increased. Regarding hepatic transcript levels, oral EE caused significant decreases in fibrinogen-gamma, FII, FV, FVII, FX, FXII, antithrombin, protein C, protein Z, protein Z inhibitor and heparin cofactor II mRNA levels, whereas FXI levels significantly increased and transcript levels of FVIII, FIX, protein S and alpha(2) -antiplasmin remained unaffected. All EE-induced coagulation-related changes were neutralized by coadministration of the non-specific ER antagonist ICI182780. In addition, ERalpha-deficient mice lacked the EE-induced changes in plasma coagulation and hepatic transcript profile, whereas ERbeta-deficient mice responded similarly to non-deficient littermate controls. A crucial role for the ER was further demonstrated by its rapid effects on transcription, within 2.5-5 h after EE administration, suggesting a short chain of events leading to its final effects. CONCLUSIONS: Oral EE administration has a broad impact on the mouse coagulation profile at the level of both plasma and hepatic mRNA levels. The effects on transcription are rapidly induced, mostly downregulatory, and principally mediated by ERalpha.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Mestranol	Estrogen receptor alpha	Protein	Humans	Yes	Agonist	Details