title: Synthetic gestagens exert differential effects on arterial thrombosis and aortic gene expression in ovariectomized apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Combined hormone replacement therapy with oestrogens plus the synthetic progestin medroxyprogesterone acetate (MPA) is associated with an increased risk of thrombosis. However, the mechanisms of this pro-thrombotic effect are largely unknown. The purpose of this study was to: (i) compare the pro-thrombotic effect of MPA with another synthetic progestin, norethisterone acetate (NET-A), (ii) determine if MPA's pro-thrombotic effect can be antagonized by the progesterone and glucocorticoid receptor antagonist mifepristone and (iii) elucidate underlying mechanisms by comparing aortic gene expression after chronic MPA with that after NET-A treatment.
  
  
  METHODS
  Female apolipoprotein E-deficient mice were ovariectomized and treated with placebo, MPA, a combination of MPA + mifepristone or NET-A for 90 days on a Western-type diet. Arterial thrombosis was measured in vivo in a photothrombosis model. Aortic gene expression was analysed using microarrays; GeneOntology and KEGG pathway analyses were conducted.
  
  
  RESULTS
  MPA's pro-thrombotic effects were prevented by mifepristone, while NET-A did not affect arterial thrombosis. Aortic gene expression analysis showed, for the first time, that gestagens induce similar effects on a set of genes potentially promoting thrombosis. However, in NET-A-treated mice other genes with potentially anti-thrombotic effects were also affected, which might counterbalance the effects of the pro-thrombotic genes.
  
  
  CONCLUSIONS
  The pro-thrombotic effects of synthetic progestins appear to be compound-specific, rather than representing a class effect of gestagens. Furthermore, the different thrombotic responses elicited by MPA and NET-A might be attributed to a more balanced, 'homeostatic' gene expression induced in NET-A- as compared with MPA-treated mice.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Freudenberger
authors.forename: R
authors.initials: R
authors.lastname: Deenen
authors.forename: I
authors.initials: I
authors.lastname: Kretschmer
authors.forename: A
authors.initials: A
authors.lastname: Zimmermann
authors.forename: L F
authors.initials: LF
authors.lastname: Seiler
authors.forename: P
authors.initials: P
authors.lastname: Mayer
authors.forename: H-K
authors.initials: HK
authors.lastname: Heim
authors.forename: K
authors.initials: K
authors.lastname: Köhrer
authors.forename: J W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002341:Carotid Artery Thrombosis / Q000235:genetics*; D002478:Cells, Cultured; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077563:Norethindrone Acetate; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D016133:Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D003271:Contraceptive Agents, Female; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone