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This version published online on August 11, 2005
Endocrinology, doi:10.1210/en.2005-0572
A more recent version of this article appeared on November 1, 2005
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Submitted on May 11, 2005
Accepted on August 2, 2005

Selective Androgen Receptor Modulator (SARM) Treatment Improves Muscle Strength and Body Composition, and Prevents Bone Loss in Orchidectomized Rats

Wenqing Gao, Peter J. Reiser, Christopher C. Coss, Mitch A. Phelps, Jeffrey D. Kearbey, Duane D. Miller, and James T. Dalton*

Division of Pharmaceutics, College of Pharmacy, Department of Oral Biology, College of Dentistry, The Ohio State University, Columbus, OH 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163

* To whom correspondence should be addressed. E-mail: Dalton.1{at}osu.edu.

The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in our previous study (Endocrinology 145(12):5420-28, 2004). 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 weeks. 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 (3 mg/kg) treated animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights over 2-fold greater than that observed in intact controls, while S-4 (3 mg/kg) returned these androgenic organs to only 16% and 17%, respectively, of the control levels. S-4 (3, 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 (BMD) 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.
Key words: Selective androgen receptor modulator • Muscle wasting • Osteoporosis




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