title: Effects of dydrogesterone and of its stable metabolite, 20-alpha-dihydrodydrogesterone, on nitric oxide synthesis in human endothelial cells.
abstract: OBJECTIVE
  To investigate the effects of P, medroxyprogesterone acetate (MPA), and dydrogesterone (DYD) and its metabolite, 20-alpha-dihydrodydrogesterone (DHD) on endothelial synthesis of nitric oxide (NO) and characterize the signaling events recruited by these compounds. The Women's Health Initiative trial reports an excess of heart disease in postmenopausal women receiving MPA.
  
  
  METHODS
  Cell culture.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Human endothelial cells from umbilical vein.
  
  
  METHODS
  Treatments with P, MPA, DYD, or DHD.
  
  
  METHODS
  Measure of NO release, endothelial nitric oxide synthase (eNOS) activity and expression, and activation of ERK 1/2 and Akt.
  
  
  RESULTS
  The administration of DYD alone or in combination with estrogen to endothelial cells results in neutral effects on NO synthesis and on the activity and expression of eNOS. In parallel, the stable metabolite DHD acts similarly to natural P, enhancing the expression of eNOS and inducing rapid activation of the enzyme through the regulation of the ERK 1/2 mitogen-activated protein kinase cascade. 20-Alpha-dihydrodydrogesterone and P also potentiate eNOS induction by E2. On the contrary, MPA does not trigger eNOS enzymatic activation and decreases the extent of eNOS induction by E2.
  
  
  CONCLUSIONS
  These findings support the concept that synthetic progestins act differently on vascular cells and that hormonal preparations may differ as to their cardiovascular effects.
authors.affiliation: Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy. t.simoncini@obgyn.med.unipi.it
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.forename: Antonella
authors.initials: A
authors.lastname: Caruso
authors.forename: Maria Silvia
authors.initials: MS
authors.lastname: Giretti
authors.forename: Camila
authors.initials: C
authors.lastname: Scorticati
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Fu
authors.forename: Silvia
authors.initials: S
authors.lastname: Garibaldi
authors.forename: Chiara
authors.initials: C
authors.lastname: Baldacci
authors.forename: Paolo
authors.initials: P
authors.lastname: Mannella
authors.forename: Letizia
authors.initials: L
authors.lastname: Fornari
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Genazzani
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004394:Dydrogesterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C514239:20-alpha-dihydrodydrogesterone; D011372:Progestins; D009569:Nitric Oxide; D011374:Progesterone; D004958:Estradiol; D004394:Dydrogesterone; D017258:Medroxyprogesterone Acetate; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases