Selective Androgen Receptor Modulators (SARMs) are nonsteroidal research chemicals that function as either agonists or antagonists when binding to androgen receptors. These compounds were created with the intent of mimicking the tissue-building effects of the male sex hormone, testosterone, without the presence of any unwanted side effects. SARMs have been around for the past two decades but have only recently hit the spotlight in the realm of sports performance. They are especially popular among bodybuilders and fitness buffs because of the supposed anabolic effects they may have on increased lean-body mass. They were originally created with the intent of treating various diseases such as sarcopenia (muscle wasting), osteoporosis, hypogonadism, Alzheimer’s, as well as prostate and breast cancer. Unfortunately, SARMs have had limited human clinical trials due to FDA regulations, but the results we do have are promising. SARMs’ limited side effects and outstanding bioavailability pose them as a potential alternative to traditional injectable testosterone replacement therapy and may very well be the future of human performance.
By Jacob Spann
Decades before SARMs were examined, Selective Estrogen Receptor Modulators or SERMs were being studied for their effects on treating breast cancer. According to a 1998 study, “The successful development of SERMs charted a course for the manipulation of nuclear receptor signaling in both men and women and has been followed by the discovery of SARMs.” Androgen receptors and its endogenous ligands, testosterone and DHT, are part of the steroid hormone receptor group that play a vital role in the physiology and pathology of developing/maintaining muscle, bone, and the development of many different tissues throughout the body. Despite the positive tissue-building benefits, they can potentially elicit some adverse effects on the prostate, heart, and liver as seen in many traditional testosterone replacement therapies. According to a 2020 paper, a few potential complications found in extended uses of synthetic steroid hormones have included “erythrocytosis, prostate hypertrophy, hepatotoxicity, aromatization to estrogen and testicular atrophy.”
SARMs were created to bind to only tissue-building androgen receptors and limit the adverse pathologies associated with androgenic side effects. SARMs are administered either orally or transdermal and once ingested enter the androgen receptor cells via diffusion through the cytoplasm. Androgen receptors are located throughout the body in reproductive and non-reproductive tissues. A 2019 study found that “After translocating to the nucleus, the SARM-AR complex acts as a transcriptional regulator and recruits cofactors and coregulatory proteins, modulating the transcriptional response to binding of the AR complex. While the AR is universally expressed, SARM-AR complexes can have varied effects due to variable cofactor recruitment. These complex configurations, along with tissue-dependent differences in AR expression patterns and regulatory milieu, allow for immense diversity of actions.”
Different types of popular SARMs include Ostarine, one of the most well-known and studied SARMs to date. It is often referred to by a variety of many different names such as Enbosarm, MK-2866 or GTx-024. Ostarine was first developed by GTx Inc. in the late 1990s and has been notable for its effects on increased lean body mass and physical function. This is one of the few SARMs with a history of human clinical trials. One of many studies includes a 12 week, double-blind, placebo-controlled study conducted in 2011 which studied the effects of Ostarine in 120 healthy elderly men and postmenopausal women. The study had 5 different dosing groups including placebo, 0.1 mg, 0.3 mg, 1 mg, 3 mg. The results were dose-dependent but demonstrated an increase in total lean-body mass, physical function, and insulin resistance. Ostarine also showed promising results during a 2009 study conducted in with 120 cancer patients that suffered from cancer induced cachexia (muscle wasting). The average weight loss prior to the trial was 8% and patients were able to continue chemotherapy during the trial. Patients were one of 3 control groups where they received either a placebo, 1 mg, or 3 mg for 16 weeks. Results were measured via Dual Energy X-ray Absorptiometry (DEXA) scan and showed improvements again in both lean body mass and stair-climbing power. Ostarine has repeatedly been shown to have a positive correlation between lean-body mass and increased physical function. It is currently the only SARM to have made it to Phase 3 of clinical trials and could provide a possible remedy to muscle wasting and osteoporosis. LGD-4033 is another SARM developed by Ligand Pharmaceuticals that has shown effects on skeletal muscle and bone in animals but has had very few studies on its impact on humans.
However, there is one study that was performed in 2013 which tested LGD’s safety and tolerability in 76 healthy males between the ages of 21-50. The study lasted 3 weeks and the results showed a slight increase in muscle mass and strength but nothing of practical significance. The main objective of this study was to determine the compound’s safety and tolerability at different doses. Since the study only lasted 3 weeks, a longer study is necessary to observe a significant relationship between increased muscle mass and strength. However, LGD-4033 did influence hormone levels and showed a suppression in total testosterone. But, again, a longer study will be needed to properly address these implications. Another popular SARM renowned for its benefits of decreasing body fat as well as its increased effects on bone density is S4, also known by the name of Anadrine. Although there are few human trials, there are encouraging results from a 2018 study performed on ovariectomized rats. The study consisted of 120 rats studied over 120 days. The results show that S4 was critical in maintaining cortical bone content and bone density. “It was also revealed that S4 provides the unique potential to prevent bone resorption, increase skeletal muscle mass and strength positions and promotes bone anabolism, which makes it a possible new alternative for the treatment of osteoporosis.”
RAD 140, or Testolone, is a newer SARM on the market that is believed to have a 90:1 anabolic to androgenic ratio when compared with that of testosterone. Because of such a high anabolic to androgenic ratio it is thought to offer vast increases in lean- body mass while decreasing body fat percentage. Since it does not interact with the aromatase enzyme nor is it toxic to the liver it is thought to be free of many undesirable side effects. RAD 140 has not been researched in any human clinical trials as it is very new to the market. But preclinical data shows that it could play a pivotal role in the repression of estrogen receptor1 which could inhibit the growth of breast cancer cells.
For a quite some time SARMs had been available via internet and sold as dietary supplements. When labeled as “dietary supplements” companies have been able to find gaps in FDA regulations. Since clinical trials concerning SARMs have been scarce, many individuals have taken it upon themselves to “test” these compounds. According to a 2018 paper, an estimated 2-4 million young people in the U.S. have tried performance-enhancing drugs at some point in their lives. The issue with this is that out of the many products that are being sold as SARMs contain only a fraction of the implied dose. According to a JAMA publication a chemical analysis was performed on 44 different supplements sold as SARMs and only 52% contained actual SARMs and 39% contained other unapproved drugs. This statistic is alarming and could contribute to the movement banning these substances. Since 2008 SARMs have been deemed illegal in sports by the World Anti-Doping Agency because of their increased physical enhancement and anabolic properties. FDA regulatory agencies have made it difficult for SARMS to be approved for use because of precedence set in place by previously approved drugs. In November of last year, the SARMs Control Act of 2019 went into effect which was a bill that amended the controlled substances act. This bill’s intent was to categorize SARMs as a schedule III-controlled substance placing it under the same prohibitions as anabolic steroids.
Due to a lack of approved clinical trials and FDA regulations, the potential impact of SARMs is still untapped. With its advantages including increases in lean-body mass, decreased body fat, and improved physical function, perhaps we may have a better alternative to traditional testosterone replacement therapy modalities. With an increased presence of human clinical trials SARMs may be linked to treatment for a variety of different pathologies and could benefit countless individuals suffering from illness.
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