title: Effect of estrogen on pseudomonas mucoidy and exacerbations in cystic fibrosis.
abstract: BACKGROUND
  Women with cystic fibrosis are at increased risk for mucoid conversion of Pseudomonas aeruginosa, which contributes to a sexual dichotomy in disease severity.
  
  
  METHODS
  We evaluated the effects of estradiol and its metabolite estriol on P. aeruginosa in vitro and in vivo and determined the effect of estradiol on disease exacerbations in women with cystic fibrosis.
  
  
  RESULTS
  Estradiol and estriol induced alginate production in P. aeruginosa strain 01 and in clinical isolates obtained from patients with and those without cystic fibrosis. After prolonged exposure to estradiol, P. aeruginosa adopted early mucoid morphology, whereas short-term exposure inhibited bacterial catalase activity and increased levels of hydrogen peroxide, which is potentially damaging to DNA. Consequently, a frameshift mutation was identified in mucA, a key regulator of alginate biosynthesis in P. aeruginosa. In vivo levels of estradiol correlated with infective exacerbations in women with cystic fibrosis, with the majority occurring during the follicular phase (P<0.05). A review of the Cystic Fibrosis Registry of Ireland revealed that the use of oral contraceptives was associated with a decreased need for antibiotics. Predominantly nonmucoid P. aeruginosa was isolated from sputum during exacerbations in the luteal phase (low estradiol). Increased proportions of mucoid bacteria were isolated during exacerbations occurring in the follicular phase (high estradiol), with a variable P. aeruginosa phenotype evident in vivo during the course of the menstrual cycle corresponding to fluctuating estradiol levels.
  
  
  CONCLUSIONS
  Estradiol and estriol induced mucoid conversion of P. aeruginosa in women with cystic fibrosis through a mutation of mucA in vitro and were associated with selectivity for mucoid isolation, increased exacerbations, and mucoid conversion in vivo. (Funded by the Molecular Medicine Ireland Clinician-Scientist Fellowship Programme.).
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Sanjay H
authors.initials: SH
authors.lastname: Chotirmall
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Smith
authors.forename: Cedric
authors.initials: C
authors.lastname: Gunaratnam
authors.forename: Sonya
authors.initials: S
authors.lastname: Cosgrove
authors.forename: Borislav D
authors.initials: BD
authors.lastname: Dimitrov
authors.forename: Shane J
authors.initials: SJ
authors.lastname: O'Neill
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Harvey
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Greene
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
mesh_terms: D000464:Alginates; D003550:Cystic Fibrosis / Q000382:microbiology; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D004964:Estriol / Q000494:pharmacology*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D020723:Glucuronic Acid / Q000096:biosynthesis / Q000235:genetics; D006603:Hexuronic Acids; D006801:Humans; D007494:Ireland; D010641:Phenotype; D011135:Polysaccharides, Bacterial / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012042:Registries
chemical_list: D000464:Alginates; D006603:Hexuronic Acids; D011135:Polysaccharides, Bacterial; D004958:Estradiol; D020723:Glucuronic Acid; D004964:Estriol