title: Expression of estrogen receptor alpha and beta is decreased in hypospadias.
abstract: OBJECTIVE
  Estrogenic endocrine disruptors acting via estrogen receptors α and β have been implicated in the etiology of hypospadias. However, the expression and distribution of estrogen receptors α and β in normal and hypospadiac human foreskins is unknown. We characterized the location and expression of estrogen receptors α and β in normal and hypospadiac foreskins.
  
  
  METHODS
  We prospectively collected excess foreskin from 35 patients undergoing hypospadias repair and 15 patients undergoing elective circumcision. Hypospadias was classified as severe in 18 patients and mild in 17 based on the ectopic position of the meatus. mRNA expression levels in estrogen receptors α and β were quantified using reverse transcriptase polymerase chain reaction. Receptor location was characterized by immunohistochemical analysis. Additionally immunohistochemical analysis was performed in 4 archived human fetal penises.
  
  
  RESULTS
  Mean ± SD ages were similar for the circumcision (9.5±3 months) and hypospadias repair groups (9±3 months, p=0.75). mRNA expression levels in estrogen receptors α and β were significantly decreased in hypospadiac foreskin cases compared to controls (p<0.001), while no statistically significant differences were seen between foreskins with severe and mild hypospadias. Estrogen receptor β immunostaining was strong in normal foreskin but weak in hypospadiac foreskin. Estrogen receptor β immunoreactivity was most intense in the stratum basale and stratum spinosum. Estrogen receptor α immunostaining was weak in normal and mild hypospadias foreskin, and undetectable in severe hypospadias. Fetal penises expressed strong estrogen receptor β immunopositivity in the urethral plate epithelium, corpus spongiosum, corpora cavernosa and penile skin, while estrogen receptor α immunostaining was not detected.
  
  
  CONCLUSIONS
  These data demonstrate a difference in estrogen receptor α and β expression and location in the foreskin of patients with hypospadias compared to controls. These findings are consistent with aberrant estrogenic effects having a role in the etiology of hypospadias.
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco Children's Hospital, San Francisco, California 94143, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Qiao
authors.forename: Esequiel
authors.initials: E
authors.lastname: Rodriguez
authors.forename: Dana A
authors.initials: DA
authors.lastname: Weiss
authors.forename: Max
authors.initials: M
authors.lastname: Ferretti
authors.forename: Gail
authors.initials: G
authors.lastname: Risbridger
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Baskin
mesh_terms: D047628:Estrogen Receptor alpha / Q000032:analysis* / Q000096:biosynthesis*; D047629:Estrogen Receptor beta / Q000032:analysis* / Q000096:biosynthesis*; D052816:Foreskin / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D007021:Hypospadias / Q000378:metabolism* / Q000473:pathology; D007223:Infant; D008297:Male; D011446:Prospective Studies
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta