The role of FSH in castration-induced adipogenesis: Highlighting differences between orchiectomy, GNRH agonists, and antagonists.

e16011 Background: Androgen deprivation therapy (ADT) results in weight gain and development of the metabolic syndrome. Inspired by the observation that adiposity accompanies the incremental increase in serum FSH levels in menopause, we hypothesized that GNRH antagonist which lower FSH levels will associate with reduced adiposity as compared to GNRH analogues and orchiectomy. Methods: 3T3-L1 fibroblasts differentiation into adipocytes and intracellular lipid accumulation were examined in the presence of escalating FSH doses (0-1000 IU/L) in charcoal stripped FCS supplemented medium to simulate castration. Cellular lipogenesis was assessed by image analysis (oil red staining) and by immunoblotting for fatty acid synthase (FAS) expression. In vivo, 6-week old C57Bl/6 male mice (n=30) were divided to receive either: orchiectomy + vehicle, sham procedure + vehicle, orchiectomy + GNRH antagonist (degarelix 50 mg/kg in vehicle), sham + degarelix, orchiectomy + GNRH analogue (enantone 2 mg/kg in vehicle), or sham + enantone. Serum testosterone, LH and FSH levels and differences in animal weight, visceral fat mass (VFm) and liver lipogenesis (oil red staining) were determined following sacrifice at 6 weeks. BMI was measured as weight (gr) divided by the distance between the tail root and the lower incisors (cm2). Results: The mean lowest and highest serum FSH levels were recorded in mice treated with Degarelix vs. orchiectomy (0.43 and 0.935 mIU/mL resp,) and the mean lowest and highest serum testosterone levels were in mice treated with orchiectomy+degarelix vs. sham control (0.12 and 13.1 ng/ml resp). Mice treated with degarelix had a significantly lower BMI compared to enantone (p=0.02). VFm (perirenal fat weight) was significantly lower (p=0.035) in mice castrated by degarelix (mean 0.38gr) as compared to enantone(mean 0.47gr)). Addition of degarelix or enanton to orchiectomy increased the differences in VFm and BMI between the two groups (0.12gr vs. 0.47gr and 3.73 vs. 4.29 gr/cm2 resp.) In vitro, FSH increased lipid accumulation and FAS expression in 3T3-L1 cells. Conclusions: FSH level elevation following castration promotes fat accumulation and weight gain in preclinical models.