Abstract 9970: Androgen Deprivation Therapy by Surgical Castration, Gonadotropin Releasing Hormone Receptor Agonists or Antagonists and the Development of Atherosclerosis in Apoe-deficient Mice

Abstract

Introduction: Adjuvant treatment of prostate cancer often involves androgen deprivation therapy (ADT) by orchiectomy (Orx), gonadotropin releasing hormone (GnRH) receptor agonists or GnRH receptor antagonists. Clinical studies of men with preexisting atherosclerotic disease, have indicated that cardiovascular event rates differs between different types of ADT, suggesting that not only testosterone deficiency, but also direct effects of ADT on processes in the atherosclerotic plaque may be involved. Immune cell GnRH receptors have been implicated as potential mediators. In the present study, we compared the effects of common types of ADT on de-novo atherosclerosis in mice. Methods: Chow-fed Apoe-deficient mice (n=121) were allocated to Orx and/or monthly injections with the GnRH receptor agonist leuprolide (0.5 mg s.c.), the GnRH receptor antagonist degarelix (0.5 mg s.c.) or saline starting from 8 weeks of age (n=19-21 in each group). At 26 weeks of age, the burden of atherosclerosis was quantified by en face analysis of the Oil red O-stained aortic arch and in histological sections of the aortic root. Bone marrow-derived macrophages and splenocytes were incubated in the presence of leuprolide (10 -6 mol/L) or degarelix (10 -6 mol/L). Data is shown as mean ± sem, *p<0.05, **p<0.01. Results: All types of ADT augmented hypercholesterolemia and atherosclerosis with no significant differences in the size of the effect (Figure A-B). In Orx mice, the addition of leuprolide, but not degarelix, led to further increases in plasma total cholesterol and in atherosclerosis in the aortic root (D), but not the aortic arch (C). Plaque necrosis was unaffected by ADT. No effects of the drugs on macrophage cytokine secretion or splenocyte proliferation were observed. Conclusions: ADT did not exert differential effects on the development of atherosclerosis in the Apoe-deficient mice. A pro-atherogenic, possibly cholesterol-mediated, effect of leuprolide was seen in Orx mice.