title: Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones.
abstract: OBJECTIVE
  To determine the effect of GnRH analogues (GnRH-a) leuprolide acetate (LA) and cetrorelix acetate on gonadal hormone-regulated expression of extracellular matrix in uterine leiomyoma three-dimensional (3D) cultures.
  
  
  METHODS
  Laboratory study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Women undergoing hysterectomy for symptomatic leiomyomas.
  
  
  METHODS
  The 3D cell cultures, protein analysis, Western blot, immunohistochemistry.
  
  
  METHODS
  Expression of extracellular matrix proteins, collagen 1, fibronectin, and versican in leiomyoma cells 3D cultures exposed to E2, P, LA, cetrorelix acetate, and combinations for 24- and 72-hour time points.
  
  
  RESULTS
  The 3D leiomyoma cultures exposed to E2 for 24 hours demonstrated an increased expression of collagen-1 and fibronectin, which was maintained for up to 72 hours, a time point at which versican was up-regulated significantly. Although P up-regulated collagen-1 protein (1.29 ± 0.04) within 24 hours of exposure, significant increase in all extracellular matrix (ECM) proteins was observed when the gonadal hormones were used concomitantly. Significant decrease in the amount of ECM proteins was observed on use of GnRH-a, LA and cetrorelix, with 24-hour exposure. Both the compounds also significantly decreased ECM protein concentration despite the presence of E2 or both gonadal hormones.
  
  
  CONCLUSIONS
  This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy.
authors.affiliation: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Minnie
authors.initials: M
authors.lastname: Malik
authors.affiliation: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Joy
authors.initials: J
authors.lastname: Britten
authors.affiliation: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jeris
authors.initials: J
authors.lastname: Cox
authors.affiliation: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Amrita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Electronic address: william.catherino@usuhs.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Catherino
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016729:Leuprolide / Q000494:pharmacology*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D013997:Time Factors; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053675:Versicans / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D024042:Collagen Type I; D005353:Fibronectins; C508322:VCAN protein, human; D053675:Versicans; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D016729:Leuprolide; C062876:cetrorelix
keywords: Uterine leiomyoma 3D culture; cetrorelix acetate; extracellular matrix; gonadal hormones; leuprolide acetate