SARMs, Selective Androgen Receptor Modulators, are a relatively new class of research chemicals that have selective androgenic activity in a given area of the body.[1] The specific activity is determined by which androgen receptors are activated and in what tissue.[1] The clinical capability of SARMs is expected to be more broad and diverse than anabolic/androgenic steroids like testosterone, which are almost never a first choice for treatment.[1] Testosterone and its ilk are considered unsuitable because their androgenic activity is systemic, meaning that undesirable side effects such as virilization in women, left ventricular hypertrophy in patients receiving doses exceeding a certain level, and various other effects that are difficult to prevent are commonplace
In addition to the specific targeted nature of the first-generation SARMs, they offer a major advantage in practical applied treatment over the androgens: they can be dosed orally without liver toxicity, which means that applied treatments require less training of subjects and in the future, use of the research chemicals may be possible for a larger group where injection or oral toxicity of anabolic steroids previously prevented indication by practitioners.[1]
Ke and Wang speculate that in elderly men with osteoporosis, or at risk of osteoporosis, could benefit from SARM therapy that (unlike testosterone and its derivatives) does not have any activity on the testes or prostate.[2]
While future SARMs may be developed with zero androgenic effect in target tissue at all, which would provide benefits such as (for example) anabolism of bone or muscle tissue with zero side effects, current SARMs all have some degree of androgenic effect in tissue, though still less than testosterone. The anabolic/androgenic ratio of SARMs currently available is between 3:1 and 10:1, whereas testosterone is 1:1.[3]
S-4 is an experimental or investigation-stage proprietary SARM research chemical developed by GTx Inc for treatment of benign prostatic hypertrophy, muscle wasting, and osteoporosis.[4] S-4 is considered a partial agonist of the androgen receptors in target tissue.[3] S-4 has less pronounced anabolic and androgenic compared to other SARMs. In trials treating BPH induced in animal models, S-4 reduced prostate weight as effectively as finasteride and without producing any reduction in muscle mass or other side effects common with androgen receptor binding compounds.[5] Gao et al suggest that by binding to androgen receptors, S-4 prevents DHT from binding and activating, but bypasses the expected anti-androgenic effects that would occur from occupying androgen receptors due to the fact that S-4 itself is a partial agonist of androgen receptors.[6] S-4 has also been shown to prevent bone loss, reduce body fat, and improve muscle strength and body composition in orchidectomized and ovariectomized rats.[7,8]
1] Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD. Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. Journal of Medicinal Chemistry 52 (12): 3597–617. 2009.
[2] Ke HZ, Wang XN, O'Malley J, Lefker B, Thompson DD. Selective androgen receptor modulators--prospects for emerging therapy in osteoporosis? J Musculoskelet Neuronal Interact 5 (4): 355. 2005.
[3]Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT. Pharmacodynamics of selective androgen receptor modulators. Journal of Pharmacology and Experimental Therapeutics. 2003 Mar;304(3):1334-40.
[4]Hanada K, Furuya K, Yamamoto N, Nejishima H, Ichikawa K, Nakamura T, Miyakawa M, Amano S, Sumita Y, Oguro N. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol. Pharm. Bull. 26 (11): 1563–9. 2003.
[5] Gao W, Kearbey JD, Nair VA, Chung K, Parlow AF, Miller DD, Dalton JT. Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5alpha-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia. Endocrinology. 2004 Dec;145(12):5420-8.
[6] Gao W, Kim J, Dalton JT. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. Pharmaceutical Research. 2006 Aug;23(8):1641-58.
[7] Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT. Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharm Res. 2007 Feb;24(2):328-35.
[8] Gao W, Reiser PJ, Coss CC, Phelps MA, Kearbey JD, Miller DD, Dalton JT. 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.
