title: Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice.
abstract: BACKGROUND
  Treatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin-releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested that not all means of ADT carry the same risk, raising the possibility of non-testosterone-mediated effects of different forms of ADT on atherosclerosis. Here we compared effects of ADT on atherosclerosis in intact and orchiectomized Apoe-deficient mice.
  
  
  RESULTS
  Chow-fed Apoe-deficient mice were allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe-deficient mice, all types of ADT reduced testosterone production to castration levels. Although hypercholesterolemia was accentuated in leuprolide-treated mice, the amount and composition of atherosclerosis was not different between the different types of ADT. In orchiectomized Apoe-deficient mice, leuprolide, but not degarelix, augmented hypercholesterolemia, changed body, thymus, and spleen weights, and increased atherosclerosis in the aortic root. No direct effects of the drugs were detectable on cytokine secretion from murine bone marrow-derived macrophages or on splenocyte proliferation.
  
  
  CONCLUSIONS
  No differences in the development of atherosclerosis were detected among groups of intact Apoe-deficient mice treated with different types of ADT. A pro-atherogenic, possibly cholesterol-mediated, effect of leuprolide was seen in orchiectomized mice that might be relevant for understanding the potential cardiovascular risk associated with GnRH agonist-based ADT.
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Christian Bo
authors.initials: CB
authors.lastname: Poulsen
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Martin Bødtker
authors.initials: MB
authors.lastname: Mortensen
authors.affiliation: Non-Clinical Development, Ferring Pharmaceuticals A/S, Copenhagen, Denmark.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koechling
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Charlotte Brandt
authors.initials: CB
authors.lastname: Sørensen
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain jben@clin.au.dk.
authors.forename: Jacob Fog
authors.initials: JF
authors.lastname: Bentzon
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D016729:Leuprolide / Q000633:toxicity*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000633:toxicity*; D009919:Orchiectomy; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000726:Androgen Antagonists; D001057:Apolipoproteins E; D009842:Oligopeptides; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D016729:Leuprolide
keywords: androgen deprivation therapy; atherosclerosis; inflammation; testosterone