Abstract 596: Androgen Deprivation Therapy--Induced Weight Gain and Atherosclerosis in Prostate Cancer: Differences Between Orchiectomy, GnRH Agonist and Antagonist

Cardiovascular disease (CVD) is one of the most common causes of mortality in prostate cancer patients. In prostate cancer treatment androgen deprivation therapy (ADT) is associated with weight gain and development of the metabolic syndrome. However, different modes of ADT can achieve castration. A post-hoc analysis of phase III trials suggests that GnRH antagonists are associated with less cardiac events in men with pre-existing CVD during the first year of ADT. We investigated the effects of bilateral orchiectomy, GnRH agonists and GnRH antagonists on the development of CVD in a mouse model. We hypothesize that GnRH antagonists will associate with reduced adiposity and development of atherosclerosis compared to GnRH analogues and orchiectomy. We used LDL receptor knockout mice (n=12/group) as models for CVD to investigate and compare the effects of orchiectomy, sham surgery, sham surgery plus GnRH antagonist (degarelix) and sham surgery plus GnRH agonist (leuprolide). Longitudinal weight gain (4 months), visceral fat accumulation (CT measurements), fasting blood glucose, glucose tolerance, serum triglycerides, and testosterone levels were studied along with characteristics of aortic atherosclerotic plaques. Leuprolide-treated mice gained significantly more weight and visceral fat compared to mice treated with degarelix. Significantly lower levels of serum triglycerides and better response to glucose loading were recorded in mice treated with degarelix. The atherosclerotic plaque area in the aortic sinus in leuprolide-treated and orchiectomized mice was significantly larger than in control mice, but not significantly different from control in degarelix-treated mice. The necrotic plaque area with degarelix was significantly smaller compared to leuprolide-treated and orchiectomized mice. In a preclinical mouse model, the use of GnRH antagonists attenuates weight gain and development of atherosclerosis.