Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats

Endocrinology. 2005 Nov;146(11):4887-97. doi: 10.1210/en.2005-0572. Epub 2005 Aug 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetamides / pharmacology*
  • Aminophenols / pharmacology*
  • Anabolic Agents / pharmacology*
  • Animals
  • Body Composition / drug effects*
  • Bone Density / drug effects
  • Bone Diseases, Metabolic / etiology*
  • Bone Diseases, Metabolic / prevention & control*
  • In Vitro Techniques
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Muscle Contraction / drug effects
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiology
  • Myosin Heavy Chains / metabolism
  • Orchiectomy / adverse effects*
  • Osteocalcin / blood
  • Papillary Muscles / metabolism
  • Protein Isoforms / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / metabolism*


  • Acetamides
  • Aminophenols
  • Anabolic Agents
  • Protein Isoforms
  • Receptors, Androgen
  • Osteocalcin
  • Insulin-Like Growth Factor I
  • andarine
  • Myosin Heavy Chains