title: GnRH antagonist associates with less adiposity and reduced characteristics of metabolic syndrome and atherosclerosis compared with orchiectomy and GnRH agonist in a preclinical mouse model.
abstract: OBJECTIVE
  Observational studies relate androgen deprivation therapy (ADT) to metabolic syndrome (MS) and cardiovascular disease, an association potentially subject to uncontrollable confounding factors, especially diet and genetic/metabolic risk factors. In the absence of prospective randomized clinical trials, causality remains unproven. We comparatively investigated the effects of different ADT modalities on the development of MS and atherosclerosis in a mouse model.
  
  
  METHODS
  Low-density lipoprotein receptor knockout mice underwent orchiectomy plus vehicle (2.5% mannitol), sham surgery plus vehicle (control), sham surgery plus gonadotropin-releasing hormone (GnRH) antagonist (degarelix), or sham surgery plus GnRH agonist (leuprolide) (n = 9-13/group) and were followed for 4 months. Visceral fat accumulation, lean body mass, adipocyte size, fasting blood glucose, glucose tolerance, serum levels of leptin, follicle-stimulating hormone, luteinizing hormone, and testosterone, along with atherosclerotic plaque size and characteristics were measured.
  
  
  RESULTS
  All 3 modes of ADT decreased circulating testosterone levels in mice, although leuprolide treatment reached nadir levels of testosterone later. Orchiectomized and leuprolide-treated mice gained significantly more visceral fat compared with degarelix-treated mice. Improved glucose tolerance tests were recorded in degarelix-treated mice. The aortic atherosclerotic plaque area in leuprolide-treated and orchiectomized mice was larger than in control mice (P<0.005 and P = 0.002, respectively), but it was not significantly different from control in degarelix-treated mice. The necrotic core area in degarelix-treated mice was smaller compared with leuprolide-treated and orchiectomized mice (P = 0.011 and P = 0.002, respectively).
  
  
  CONCLUSIONS
  Our results suggest that ADT induced MS and atherosclerosis in a preclinical mouse model to a mode-specific extent. GnRH antagonist generated the least atherosclerosis and characteristics of MS compared with orchiectomy and GnRH agonist.
authors.affiliation: Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Hopmans
authors.affiliation: Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Wilhelmina C M
authors.initials: WC
authors.lastname: Duivenvoorden
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Geoff H
authors.initials: GH
authors.lastname: Werstuck
authors.affiliation: Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laurence
authors.initials: L
authors.lastname: Klotz
authors.affiliation: Department of Surgery, McMaster University, Hamilton, Ontario, Canada. Electronic address: jehonathan.pinthus@jcc.hhsc.ca.
authors.forename: Jehonathan H
authors.initials: JH
authors.lastname: Pinthus
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D050154:Adiposity; D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects; D050197:Atherosclerosis / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D016729:Leuprolide / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects; D009919:Orchiectomy / Q000009:adverse effects / Q000379:methods; D011897:Random Allocation; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D009842:Oligopeptides; D011973:Receptors, LDL; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D007987:Gonadotropin-Releasing Hormone; D016729:Leuprolide
keywords: Androgen deprivation therapy; Cardiovascular disease; Degarelix; Leuprolide; Metabolic syndrome; Orchiectomy