{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:14:30Z","timestamp":1789168470195,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2014,9,5]],"date-time":"2014-09-05T00:00:00Z","timestamp":1409875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Bundesinstitut f\u00ef\u00bf\u00bdr Arzneimittel und Medizinprodukte, Bonn, Germany"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Combined hormone replacement therapy with oestrogens plus the synthetic progestin medroxyprogesterone acetate (<jats:styled-content style=\"fixed-case\">MPA<\/jats:styled-content>) is associated with an increased risk of thrombosis. However, the mechanisms of this pro\u2010thrombotic effect are largely unknown. The purpose of this study was to: (i) compare the pro\u2010thrombotic effect of MPA with another synthetic progestin, norethisterone acetate (<jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>), (ii) determine if MPA's pro\u2010thrombotic effect can be antagonized by the progesterone and glucocorticoid receptor antagonist mifepristone and (iii) elucidate underlying mechanisms by comparing aortic gene expression after chronic <jats:styled-content style=\"fixed-case\">MPA<\/jats:styled-content> with that after <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content> treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Female apolipoprotein E\u2010deficient mice were ovariectomized and treated with placebo, <jats:styled-content style=\"fixed-case\">MPA<\/jats:styled-content>, a combination of <jats:styled-content style=\"fixed-case\">MPA<\/jats:styled-content> + mifepristone or <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content> for 90\u2009days on a Western\u2010type diet. Arterial thrombosis was measured <jats:italic>in vivo<\/jats:italic> in a photothrombosis model. Aortic gene expression was analysed using microarrays; GeneOntology and <jats:styled-content style=\"fixed-case\">KEGG<\/jats:styled-content> pathway analyses were conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>MPA's pro\u2010thrombotic effects were prevented by mifepristone, while <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content> 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 <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>\u2010treated mice other genes with potentially anti\u2010thrombotic effects were also affected, which might counterbalance the effects of the pro\u2010thrombotic genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The pro\u2010thrombotic effects of synthetic progestins appear to be compound\u2010specific, rather than representing a class effect of gestagens. Furthermore, the different thrombotic responses elicited by <jats:styled-content style=\"fixed-case\">MPA<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content> might be attributed to a more balanced, \u2018homeostatic\u2019 gene expression induced in <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>\u2010 as compared with <jats:styled-content style=\"fixed-case\">MPA<\/jats:styled-content>\u2010treated mice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12814","type":"journal-article","created":{"date-parts":[[2014,6,13]],"date-time":"2014-06-13T07:05:08Z","timestamp":1402643108000},"page":"5032-5048","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Synthetic gestagens exert differential effects on arterial thrombosis and aortic gene expression in ovariectomized apolipoprotein <scp>E<\/scp>\u2010deficient mice"],"prefix":"10.1111","volume":"171","author":[{"given":"T","family":"Freudenberger","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Pharmakologie und Klinische Pharmakologie Universit\u00e4tsklinikum D\u00fcsseldorf Heinrich\u2010Heine\u2010Universit\u00e4t D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Deenen","sequence":"additional","affiliation":[{"name":"Biologisch\u2010Medizinisches Forschungszentrum (BMFZ) Universit\u00e4tsklinikum D\u00fcsseldorf Heinrich\u2010Heine\u2010Universit\u00e4t D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Kretschmer","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmakologie und Klinische Pharmakologie Universit\u00e4tsklinikum D\u00fcsseldorf 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