title: Certain progestins prevent the enhancing effect of 17beta-estradiol on NO-mediated inhibition of platelet aggregation by endothelial cells.
abstract: OBJECTIVE
  Estro-progestin treatments have been associated with an increased risk of thromboembolic events in postmenopausal women. This study examined whether progestins affect the stimulatory effect of estrogens on the endothelial formation of nitric oxide (NO), a potent antithrombotic factor.
  
  
  RESULTS
  Experiments were performed with human endothelial cells. Endothelial NO synthase (eNOS) and GTP cyclohydrolase I (GTPCH I) mRNA expression was assessed by RT-PCR, eNOS protein by Western blotting, NO formation by electron spin resonance spectroscopy, and platelet aggregation by an aggregometer. Medroxyprogesterone acetate (MPA), progesterone, levonorgestrel, and nomegestrol acetate prevented the 17beta-estradiol (17beta-E)-induced expression of eNOS mRNA and protein. MPA and progesterone reduced the 17beta-E-induced formation of NO and potentiation of the inhibitory effect of endothelial cells on platelet aggregation whereas levonorgestrel and nomegestrol acetate were without effect. Moreover, MPA and progesterone prevented the 17beta-E-induced expression of GTPCH I mRNA. Mifepristone, a glucocorticoid and progesterone receptor antagonist, and L-sepiapterin prevented the inhibitory effect of MPA and progesterone on platelet aggregation.
  
  
  CONCLUSIONS
  Certain progestins, including MPA, attenuate the 17beta-E-induced NO-mediated inhibition of platelet aggregation by endothelial cells through preventing both eNOS and GTPCH I expression most likely via activation of glucocorticoid receptors.
authors.affiliation: Département de Pharmacologie et Physico-Chimie, Institut Gilbert Laustriat, Université Louis Pasteur Strasbourg I, Illkirch, France.
authors.forename: Murielle
authors.initials: M
authors.lastname: Zerr-Fouineau
authors.forename: Marie
authors.initials: M
authors.lastname: Jourdain
authors.forename: Caroline
authors.initials: C
authors.lastname: Boesch
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.forename: Christian
authors.initials: C
authors.lastname: Bronner
authors.forename: Valérie B
authors.initials: VB
authors.lastname: Schini-Kerth
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D006136:GTP Cyclohydrolase / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D016912:Levonorgestrel / Q000494:pharmacology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008535:Megestrol / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009649:Norpregnadienes / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011374:Progesterone / Q000378:metabolism*; D045167:Progesterone Congeners / Q000009:adverse effects / Q000494:pharmacology*; D011622:Pterins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism; D013997:Time Factors
chemical_list: D006727:Hormone Antagonists; D009649:Norpregnadienes; D045167:Progesterone Congeners; D011622:Pterins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D009569:Nitric Oxide; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D016912:Levonorgestrel; C038501:nomegestrol acetate; D017258:Medroxyprogesterone Acetate; C016727:sepiapterin; D008535:Megestrol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase