title: Prevention of preterm birth by progestational agents: what are the molecular mechanisms?
abstract: OBJECTIVE
  Clinically, vaginal progesterone (VP) and 17 alpha-hydroxyprogesterone caproate (17P) have been shown to prevent preterm birth (PTB) in high-risk populations. We hypothesize that treatment with these agents may prevent PTB by altering molecular pathways involved in uterine contractility or cervical remodeling.
  
  
  METHODS
  Using a mouse model, on embryonic day (E)14-E17 CD-1 pregnant mice were treated with: (1) 0.1 mL of 25 mg/mL of 17P subcutaneously; (2) 0.1 mL of castor oil subcutaneously; (3) 0.1 mL of 10 mg/mL of progesterone in a long-lasting Replens (Lil' Drug Store Products, Inc., Cedar Rapids, IA); or (4) 0.1 mL of the same Replens, with 4 dams per treatment group. Mice were sacrificed 6 hours after treatment on E17.5. Cervices and uteri were collected for molecular analysis.
  
  
  RESULTS
  Exposure to VP significantly increased the expression of defensin 1 compared to Replens (P < .01) on E17.5. Neither VP nor 17P altered the expression of uterine contraction-associated proteins, progesterone-mediated regulators of uterine quiescence, microRNA involved in uterine contractility, or pathways involved in cervical remodeling. In addition, neither agent had an effect on immune cell trafficking or collagen content in the cervix.
  
  
  CONCLUSIONS
  Neither VP nor 17P had any effect on the studied pathways known to be involved in uterine contractility or quiescence. In the cervix, neither VP nor 17P altered pathways demonstrated to be involved in cervical remodeling. Administration of VP was noted to increase the expression of the antimicrobial protein defensin 1. Whether this molecular change from VP results in a functional effect and is a key mechanism by which VP prevents PTB requires further study.
authors: Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Christopher.Nold@uphs.upenn.edu
authors: Christopher
authors: C
authors: Nold
authors: Monique
authors: M
authors: Maubert
authors: Lauren
authors: L
authors: Anton
authors: Steven
authors: S
authors: Yellon
authors: Michal A
authors: MA
authors: Elovitz
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D000282:Administration, Intravaginal; D000818:Animals; D002584:Cervix Uteri / Q000187:drug effects* / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006908:Hydroxyprogesterones / Q000008:administration & dosage / Q000627:therapeutic use*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D011374:Progesterone / Q000008:administration & dosage / Q000627:therapeutic use*; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018031:Connexin 43; D018398:Homeodomain Proteins; D006908:Hydroxyprogesterones; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D018045:Receptors, Oxytocin; D050799:STAT5 Transcription Factor; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000077713:17 alpha-Hydroxyprogesterone Caproate; D011374:Progesterone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2