title: Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats.
abstract: The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights more than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy and Department of Oral Biology, The Ohio State University, 500 West 12th Avenue, L. M. Parks Hall, Room 242, Columbus, Ohio 43210, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Gao
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Reiser
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Coss
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kearbey
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000627:Aminophenols / Q000494:pharmacology*; D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D001823:Body Composition / Q000187:drug effects*; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000209:etiology* / Q000517:prevention & control*; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009919:Orchiectomy / Q000009:adverse effects*; D015675:Osteocalcin / Q000097:blood; D010210:Papillary Muscles / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000081:Acetamides; D000627:Aminophenols; D045930:Anabolic Agents; D020033:Protein Isoforms; D011944:Receptors, Androgen; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; C492992:andarine; D018995:Myosin Heavy Chains