# Select Androgen Receptor Modulators (SARMS): The Future of Side Effect Free Anabolic Drugs



## Stacked (Oct 3, 2011)

*Select Androgen Receptor Modulators (SARMS): The Future of Side Effect Free Anabolic Drugs*

*SARMS: The Future of Side Effect Free Anabolic Drugs

*Steve Rogers was a scrawny fine arts student whom attempted to enlist in the army only to be turned away due to his poor physical status. A U.S. officer offered Rogers an alternative way to serve his country by being a test subject for an experimental drug project called "Operation Rebirth."   The experiment was a top secret defense research project designed to create physically superior soldiers. He was given injections of the formula dubbed the "Super Soldier Serum."  The serum was free of side effects and successfully altered his physiology from its frail state to a superhero with enhanced strength and muscle mass.  Rogers was given a costume modeled after the American flag, a bulletproof shield, and the codename Captain America.   Just like in the comics, scientists have been searching for decades for a side effect free drug to enhance muscle mass.  The search for a "Super Soldier Formula" actually began during the cold war.  Anabolic steroids were the first original "Super Soldier Formula" and was actually first used in humans by Adolph Hitler, as he gave German soldiers steroids to increase their size, strength and aggressiveness, however unlike the comic book hero Captain America formula they were full of undesired side effects.  For example, in this month's British Journal of Sports Medicine, cardiovascular function measured by Doppler echocardiography was compared from 45 bodybuilders whom abused anabolic steroids (anabolic steroids abused were metenolone, nandrolone, and esters of testosterone.  Oral anabolics were fluoxymesterone, mesterolone, metenolone, metandione, oxandrolone, and oxymetholone) for at least 5 years.  The anabolic steroid users were compared to natural bodybuilders whom had never taken anabolic steroids.  After cardiac imaging, after several years of steroid abuse, bodybuilders showed a sub-clinical impairment of both systolic (heart emptying of blood) and diastolic (heart filling of blood) heart functioning, the impairment in cardiac functioning was associated with dosage and time of duration of steroid abuse2.   The use of anabolic steroids is a double edge sword for most bodybuilders, giving high increases in muscle growth and fat loss at the cost of undesired side effects.

*Testosterone: The Double Edged Sword
*
Recent interest is using testosterone as an anabolic agent for muscle wasting diseases as cancer, HIV, and age related testosterone suppression has been slowed because of widespread concerns of testosterone related side effects on prostate, serum lipids, and the cardiovascular system8. Testosterone has an effect on increasing blood viscosity by increasing hematocrit levels. In one study, testosterone treated men are 4-times more likely to experience a greater hematocrit level greater than 50% compared to placebo treated men.  Hematocrit increase is the most frequent adverse event associated with testosterone administration is dose related3.   Anabolic steroids is associated with various side effects; therefore, illicit use of megadoses of anabolics for the purpose of bodybuilding and enhancement of athletic performance can lead to serious and irreversible organ damage34 Additionally, anabolic steroid use can lead to kidney and liver damage, hypertension, suppression of testosterone, and gynecomastia3, 8.   It should be mentioned that serious side effects as liver damage have not been observed when testosterone is administered transdermally or by injections10 as most liver toxicity is from oral anabolics.  Injectable forms of testosterone (testosterone enanthate, propionate, or cypionate) are not ideal for medical use because they produce undesirable fluctuations in testosterone blood levels, with supraphysiological concentrations early, and then subnormal levels toward the end of the cycle before the next injection, providing an unsatisfactory profile and in some cases undesired side effects24.   Researchers are pushing for anabolic agents that are anabolic in muscle and bone yet have minimal side effects.

*The Problem with Today's Steroids...Increased Prostate Risk and Not Muscle Tissue Specific*

The two major androgens, testosterone and dihydrotestosterone (DHT), mediate protein anabolism and affect metabolism through the activation of the androgen receptor.  Several recent studies have shown that testosterone dose dependently increases muscle hypertrophy and decreases adipose tissue 32, 33.  Testosterone is converted to both active metabolites DHT and estrogen.  Approximately 0.3% of testosterone is converted to estradiol via the action of aromatase, and enzyme expressed in the brain, liver, and adipose tissue4.  Estrogen plays a major role in relating metabolic processes, mood and cognition, cardiovascular disease, sexual functioning including libido, and bone turnover in men.  Additionally, approximately 6 to 8% of testosterone is converted to DHT through the actions of 5a-reductase, an enzyme highly expressed in the male reproductive tract (prostate), hair follicles, and genital skin.  Conversion of DHT amplifies the actions of testosterone by 3-5 fold, owing to the greater affinity of DHT to the androgen receptor5.  Testosterone is a weaker androgen for binding to the androgen receptor than DHT; it requires approximately 10-fold higher levels of testosterone to activate the androgen receptor compared to DHT26.   Both DHT and testosterone can increase muscle mass but DHT is associated with a host of side effects, specifically the prostate.  The development and growth of prostate cancer depends on the androgen receptor and its high-affinity binding of DHT, which derives from testosterone. Most prostate tumors regress after therapy to prevent testosterone production by the testes.  Approximately 10% of men over 50 will be diagnosed with prostate cancer9. Multiple lines of evidence suggest the importance of androgens, especially DHT, in the development of benign prostate hyperplasia (BPH).  For instance, BPH does not develop in males that have genetic mutations of 5a-reductase (cannot convert testosterone to DHT) or in males whom have low levels of testosterone6.    Moreover, clinical treatment of BPH either by chemical or surgical castration, or with a 5a-reductase inhibitor (drug that prevents testosterone from converting to DHT) will significantly decrease of the size of the prostate7.   Good news for bodybuilders is that a revolutionary new class of drugs called Select Androgen Receptor Modulators (SARMS) may hold promise of the future of side effect free anabolic drugs.  SARMS seems to be especially beneficial for reducing the incidence of prostate problems in men without losing muscle mass.  The usual treatment from men with prostate problems is a chemical castration cocktail that lowers testosterone but decreases prostate growth at the cost of losing muscle mass.  As reported by Gao et al.23 SARMS may be used as a potential treatment for BPH as one class of SARMS selectively decreased prostate weight with similar efficiency to the 5a-reductase inhibitor finasteride without decreases in lean muscle mass or altering plasma hormone levels of testosterone and leutinizing hormone which are suppressed by finasteride treatment. Additionally, SARMS are highly selective for muscle than the prostate.

*Selective Androgen Receptor Modulators (SARMS): Every Bodybuilders Wet Dream Come True*

The biological actions of androgens are primarily mediated by the androgen receptor.  The androgen receptor is expressed in target tissues as the prostate, skeletal muscle, liver, central nervous system, with the highest expression being produced in the prostate and adrenal gland38.  Men with rare mutations of the androgen receptor have lower lean mass and higher bodyfat than normal men37.  The physiological importance of the androgen receptor has been demonstrated as animal studies that administer androgen receptor antagonist (drugs that block the actions of androgens binding to its receptor) during muscle overload have suppressed muscle hypertrophy29. This suggests that the androgen pathway has a significant effect in exercise-induced muscle hypertrophy and emphasizes the importance of the increase in the number of androgen receptors in exercised muscle. Additionally, when scientists administered the androgen antagonist flutamide, to rats undergoing puberty resulted in a suppressed muscle growth30.  Researchers have developed the new non-steroidal drug SARMS which would minimize the side effects of testosterone by promoting full anabolic activity in muscle and bone, while minimizing the undesirable side effects on prostate, hair, skin, and without affecting sperm production and sex-drive.  So how the hell are they going to accomplish that?  The beauty of SARMS is that they lack estrogenic activity and do not convert to estrogen..Say goodbye to bitch tits! SARMS also do not under 5a-reduction, which means low binding affinity for the prostate and hair follicles.   In addition, SARMS have full anabolic activity in muscle and bone, yet have minimal effect the on prostate.  SARMS are highly specific to the androgen receptor as they have a 1000-fold less binding affinity for any other receptor27.  Researchers have been searching for years for a highly orally active anabolic agent that has minimal effects on the liver.  SARMS are also orally available and so far seem to have minimal effect on the liver15.  Sounds like every bodybuilder's wet dream, but these drugs are in clinical trials right now and the animal research is extremely promising.  In this month's journal of Endocrinology, researchers reported that the SARM drug LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rats. Interestingly, LGD2226 also increased sex-behavior in male rats. _SARMS_ is an orally available, non- aromatizable androgen which mediates a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogens27. So where the hell can you get these drugs?  Unfortunately, these drugs are still in the experimental phase of animal research but SARMS well may replace testosterone as it has a greater binding capacity to the androgen receptor yet minimal side effects on the prostate.  So maybe you can put some whiskers on and put on a furry suit and disguise yourself as a 280 pound muscle bound rat and get these drugs before everyone else.  On second thought, hold off on that because the first things researchers do to rats to eliminate the confounding activity of different testosterone levels in rats is to cut off their balls!!  So unless you want to give up bodybuilding and become an opera singer your gonna have to wait a little longer.

*SARMS: Anabolic Activity in Muscle and Bone with Minimal Effect on the Prostate.*

Testosterone induced increase in muscle mass is associated with hypertrophy of both type I and type II fibers and increased satellite cell activation13, 14.   The effect of testosterone is thought to be mediated by the androgen receptor as muscle growth factors in vitro (in test tubes) are blocked by the androgen antagonist bicalutamide (blocks the actions of testosterone from binding to the androgen receptor), indicating that the effects of testosterone are mediated thru the androgen receptor pathway13.   Lee et al.36 has reported that androgen receptor signaling pathway enhances the expression of myogenin (Myogenin is an important mediator of muscle growth) and accelerates the expression of muscle growth factors.  AR expression is widespread throughout the body and androgens play a desirable role in promoting bone strength, increasing muscle mass, decreasing fat tissue, and increasing muscle strength.   A study in the Journal of Steroid Biochemistry and Molecular Biology reported that when resistance trained men had muscle biopsies taken the greatest predictor of males 1-RM strength was not testosterone but the androgen receptor content in the thigh muscle35. SARMS are muscle specific compared to testosterone.  For example, one study reported that oral dosaging of SARMS exhibited a >50-fold selectivity for muscle over the prostate.  Testosterone propionate had only a 2-fold selectivity for muscle versus prostate16.  Other studies have reported that SARMS activity of a drug called S-4 (oh it's easy to remember…the chemical name for s-4 is: S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) produced greater anabolic activity in muscle than testosterone propionate but had less androgenic activity on the prostate25.  Additionally, a new study published this month in the journal of Endocrinology reported that when SARMS were just as anabolic in muscle compared to testosterone cypionate but less androgenic.  In that study, testosterone cypionate increased prostate weight and muscle growth in a dose dependent manner, meaning the more testosterone they used the more muscle hypertrophy was experienced but with similar increases in prostate growth.  SARMS showed more anabolic activity in muscle with minimal stimulation of the prostate.  Compared with testosterone cypionate, SARMS was more than 200 times more potent in stimulation of muscle and 80 times more selective for muscle versus prostate. Additionally, both testosterone cypionate and SARMS decreased adipose tissue in a dose dependent manner28. The study demonstrated that SARMS has the potential to provide a greater safety delivery than testosterone, mainly with low stimulation of the prostate, yet hyperanabolic effects on muscle tissue.  SARMS has also been shown to increase skeletal muscle strength.  SARMS was administered to rats that were castrated and compared to the anabolic effects of DHT.  For example, SARMS restored the castrated-induced losses in lean muscle mass and increased muscle strength.  DHT also demonstrated similar increases in muscle size and strength, but DHT increased prostate growth significantly, but SARMS treatment only increased prostate growth by 16%18.  Another interesting note in that SARMS treatment tends to increase IGF-I expression in animals, whereas treatment with DHT significantly decreased IGF-I expression in these animals, providing another example for possible differential regulation of gene expression by SARMS and DHT, which could contribute to the tissue-specific pharmacological activities of these AR18. Hopefully, with SARMS bodybuilders can throw out their Saw Palmetto supplementation.

SARMS has been shown to prevent bone loss as well19.  The direct action of testosterone in bone via the AR-mediated pathway is essential for its anabolic effects in bone. Nevertheless, conversion of testosterone to DHT by 5a-reductase is not required for the process because finasteride (a 5a-reductase inhibitor) treatment did not affect bone mass density in rats or humans21, 22.  Animal experiments with one SARM called LGD2226, revealed that it prevented bone loss and exerted anabolic activity in rats that were made testosterone deficient by snipping their nads off.  Of particular note, the SARMS drug demonstrated highly anabolic activity than testosterone propionate in the levator ani muscle (levator ani muscle: A muscle in the pelvis that is highly responsive to testosterone concentrations due to its rich concentrations of androgen receptors.  It has been widely used as an assay for the anabolic activity of steroids.)  yet it had minimal effects on prostate growth. In contrast, when the rats were treated with testosterone propionate, had growth of the levator ani muscle but also had increases in prostate growth as well17.


*Things to Consider….*
It should be noted that testosterone increases muscle mass thru multiple pathways: increasing protein synthesis, increasing GH secretion, increasing IGF-1 levels, increasing satellite cell activation, and increasing androgen receptor concentration in muscle.  The androgen receptor binding affinity of steroids is only partly responsible for the androgen receptor mediated effects of both physiological and synthetic steroids.  For example, it is well known that some steroids are potent anabolic agents, yet bind to the androgen receptor weakly31.  Another interesting fact is that testosterone can increase lean body mass and reduce fat mass in androgen-deficient men37.  The skeletal muscle androgen receptor may exert both receptor dependent (testosterone, DHT) and independent actions (intramuscular IGF-1) in the functionally overloaded muscle, which may be related to growth factor signaling.  The androgen receptor in muscle is decreased during aging which may be an important contributing factor to the age related decrease in muscle mass that occurs with aging. The development of SARMS for clinical use is promising based on preclinical data owing to their selective high anabolic activity in muscle.  SARMS could be useful for the prevention of many muscle wasting diseases and age related decreases in muscle mass without unwanted side effects associated with testosterone.  In addition, SARMS may be prevent or treat prostate enlargement as SARMS is a partial agonist on the prostate.  SARMS also lack estrogenic activity and do not under go 5a-reduction so it can't be concerted to DHT.  The International Olympic Committee is already preparing for the use of SARMS with Olympic athletes.  The IOC is already designing doping procedures to detect athletes abusing SARMS in the urine20.  SARMS looks like the next big thing for increasing muscle mass and strength in athletes.  Soon bodybuilders may be able to get a truly oral anabolic drug that is muscle specific and with minimal side effects…so hold on to your ass this one's going to be big!!  You might also want to get out your blue spandex and find a shield; SARMS may be the "Super Soldier Formula" of the future.

By: Robbie Durand, MA

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3.Modlinski R, Fields KB. The effect of anabolic steroids on the gastrointestinal system, kidneys, and adrenal glands. Curr Sports Med Rep. 2006 Apr;5(2):104-9. Review. 
4.Heinlein CA, Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol. 2002 Oct;16(10):2181-7. Review. 
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6.Andriole G, Bruchovsky N, Chung LW, Matsumoto AM, Rittmaster R, Roehrborn C, Russell D, Tindall D. Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol. 2004 Oct;172(4 Pt 1):1399-403. Review.


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