Background: Androgen deprivation therapy (ADT) is associated with weight gain and development of the metabolic syndrome (MS). Different modes of ADT can achieve castration but with different affects on serum FSH levels. Inspired by the observation that adiposity accompanies the incremental increase in serum follicle stimulating hormone (FSH) levels in menopause, we hypothesized that gonadotrophin-releasing hormone (GnRH) antagonists which maximally inhibit FSH levels will associate with reduced adiposity and MS development compared to GNRH analogues and orchiectomy. Methods: In-vitro models of adipocyte differentiations were used to investigate FSH effects on lipid accumulation and expression of the rate limiting enzyme in this process-FAS. In-vivo models for adipogenesis and MS (LDL receptor KO mice) were used to investigate and compare the effects of orchiectomy (n=12), sham surgery (control, n=12), sham surgery plus GNRH antagonist (Degarelix, n=12) and sham surgery plus GNRH agonist (Enanton, n=12). Mice were also manipulated by two nutritional conditions (normal/high fat diet). Longitudinal weight gain (four month), visceral fat accumulation (CT measurements), fasting blood glucose, two hours glucose tolerance tests, serum triglycerides, FSH, LH, and testosterone levels were studied along with number and characteristics of aortic atherosclerotic plaques. Results: The lowest and highest serum FSH levels were recorded in mice treated with degarelix versus orchiectomy and significantly lower levels of FSH and LH in mice treated with degarelix versus enanthon were recorded. Mice treated with enantone gained significantly more weight and visceral fat compared to mice treated with degarelix. Significant lower levels of serum triglycerides and better response to glucose loading were recorded in mice treated with degarelix. Data on atherosclerotic plaques is currently processed and will be discussed, but preliminary analysis reveal lower plauque size in mice treated with degarelix. Conclusions: Usage of GNRH antagonists as ADT attenuates weight gain and development of the MS in preclinical models.