We identified a novel synthetic steroid, S42, as a promising candidate of selective androgen receptor (AR) modulator. Results of the whole-cell binding assay using COS-7 cells exogenously expressing various steroid receptors indicated that S42 specifically binds to AR and progesterone receptor. When orchiectomized Sprague Dawley rats were administered with S42 for 3 wk, the muscle weight of the levator ani was increased as markedly as that induced by 5 alpha-dihydrotestosterone (DHT), but the weight of the prostate was not elevated at any doses in contrast to DHT. The plasma concentrations of gonadotropin and adiponectin, those down-regulated by DHT, were unaffected by S42. In addition, although the plasma triglyceride level was unaffected by DHT, it was significantly reduced by S42. This effect of S42 was associated with suppression of the SRBP-1c-mediated lipogenic and insulin-desensitizing pathway in the liver and visceral fat. Taken together, S42 works as an AR agonist in muscle and as an AR antagonist in the prostate, pituitary gland, and liver, accompanying beneficial potentials on lipid metabolism. (Endocrinology 150: 5606-5616, 2009)
