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Comparison to testosterone
Currently used androgens for male hormone replacement therapy are typically injectable or skin delivery formulations of testosterone or testosterone esters. Injectable forms of testosterone esters (such as testosterone enanthate, propionate, or cypionate) produce undesirable fluctuations in testosterone blood levels, with overly high levels shortly after injection and overly low afterwards. Skin patches do provide a better blood level profile of testosterone, but skin irritation and daily application still limit their usefulness. Oral androgens are not currently used due to concerns about liver toxicity.
SARMs provide the opportunity to design molecules that can be delivered orally, but that selectively target the androgen receptors in different tissues differently. The goal of research in this area is to allow a customized response: tissues that are the target of the therapy will respond as they would to testosterone; other tissues where undesirable side effects are produced will not.
None of the SARMs yet developed are truely selective for anabolic effects in muscle or bone tissues without producing any androgenic effects in tissues such as the prostate gland, however the compounds tested so far show a ratio of anabolic to androgenic effects of at least 3:1 and even up to as much as 10:1, whereas all known anabolic steroids have a ratio of around 1:1.123
This suggests that while SARMs are likely to show some virilizing effects when used at high doses (e.g. recreational abuse by bodybuilders), at lower therapeutic doses they may well be effectively selective for anabolic effects, which will be important if SARMs are to have clinical application in the treatment of osteoporosis in women. One substantial advantage of even the first-generation SARMs developed to date is that they are all orally active without causing liver damage, whereas most anabolic steroids are not active orally and must be injected, and those anabolic steroids which are orally active tend to cause dose-dependent liver damage which can become life-threatening with excessive use. Research is continuing into more potent and selective SARMs, as well as optimising characteristics such as oral bioavailability and increased half-life in vivo, and seeing as the first tissue-selective SARMs were only demonstrated in 2003, the compounds tested so far represent only the first generation of SARMs and future development is likely to produce greatly superior agents compared to those available at present.
Selectivity in men
For example, if the target is bone growth in elderly men with osteopenia or osteoporosis, but with no overt signs of hypogonadism, a SARM targeting bone and muscle tissue, but with lesser activity on the prostate or testes would be more desirable.4
Selectivity in women
A SARM for women would ideally stimulate bone retention, or libido and other sexual function that androgens can influence, without negative side effects such as development of male gender characteristics (virilization), increased LDL/HDL ratios, liver disfunction, and so forth.5
Examples
- Andarine ("S-1") - partial agonist, intended mainly for treatment of benign prostatic hypertrophy
- BMS-564,929 - mainly affects muscle growth, intended as general treatment for symptoms of andropause
- LGD-2226 - affects both muscle and bone
- Ostarine ("S-4")7 - affects both muscle and bone, intended mainly for osteoporosis but also general treatment for andropause
- S-40503 - selective for bone tissue, particularly low virilization, intended for osteoporosis and may be suitable for use in women
See also
References
- ^ 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. PMID 12604714
- ^ 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. Biological and Pharmaceutical Bulletin. 2003 Nov;26(11):1563-9. PMID 14600402
- ^ Ostrowski J, Kuhns JE, Lupisella JA, Manfredi MC, Beehler BC, Krystek SR Jr, Bi Y, Sun C, Seethala R, Golla R, Sleph PG, Fura A, An Y, Kish KF, Sack JS, Mookhtiar KA, Grover GJ, Hamann LG. Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats. Endocrinology. 2007 Jan;148(1):4-12. PMID 17008401
- ^ Ke HZ, Wang XN, O'Malley J, Lefker B, Thompson DD (2005). "Selective androgen receptor modulators--prospects for emerging therapy in osteoporosis?". J Musculoskelet Neuronal Interact 5 (4): 355. PMID 16340136, http://www.ismni.org/jmni/pdf/22/23THOMPSON.pdf.
- ^ Negro-Vilar A (1999). "Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium". J. Clin. Endocrinol. Metab. 84 (10): 3459–62. doi:. PMID 10522980.
- ^ Allan GF, Tannenbaum P, Sbriscia T, et al (2007). "A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats". Endocrine 32 (1): 41–51. doi:. PMID 17992601.
- ^ Kearbey JD, Gao W, Narayanan R, et al (2007). "Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats". Pharm. Res. 24 (2): 328–35. doi:. PMID 17063395.
