|Selective androgen receptor modulator|
|Biological target||Androgen receptor|
|Chemical class||Steroidal; nonsteroidal|
Selective androgen receptor modulators (SARMs) are a class of androgen receptor ligands that were developed with the intention of maintaining some of the desirable effects of androgens, such as improving bone density and increasing lean body mass, with a much lower risk of androgenic side effects than alternative therapies such as testosterone.
Anabolic androgenic steroids (AAS) are potentially useful for a variety of medical conditions, but their use is limited by side effects. In the late 1990s, researchers discovered a new class of non-steroidal compounds chemically similar to the antiandrogens bicalutamide and hydroxyflutamide. These non-steroidal SARMs have a high anabolic activity in skeletal muscles, but have little or no androgenic activity in other tissues.
SARMs have been investigated in human studies for the treatment of osteoporosis, cachexia, benign prostatic hyperplasia, stress urinary incontinence, prostate cancer, and breast cancer and have also been considered for the treatment of Alzheimer’s disease, Duchenne muscular dystrophy, hypogonadism. and as a male contraceptive. As of 2020[update], there are no SARMs which have been approved for therapeutic use by the U.S. Food and Drug Administration; however, in 2022 the FDA granted fast track designation to ostarine in some types of metastatic breast cancer. Although adverse effects in clinical studies have been infrequent and mild, SARMs can cause elevated liver enzymes, reduction of HDL cholesterol levels, and hypothalamic–pituitary–gonadal axis (HPG axis) suppression.
Since the early twenty-first century, SARMs have been used in doping; they were banned by the World Anti-Doping Agency in 2008. SARMs are readily available on internet-based gray markets and are commonly used recreationally to stimulate muscle growth.
Anabolic androgenic steroids (AAS), including those produced endogenously such as testosterone and dihydrotestosterone (DHT), bind to and activate the androgen receptor (AR) to produce their effects. AAS effects can be separated into androgenic (the development and maintenance of male sexual characteristics) and anabolic (increasing bone density, muscle mass and strength). AAS also affect hematopoiesis, coagulation, metabolism, and cognition. Anti-androgens such as bicalutamide, flutamide, and nilutamide are non-steroidal AR antagonists that work by binding to the AR to prevent androgenic action; this class of chemicals dates to the 1970s. Interest in non-steroidal AR agonists increased after the therapeutic uses of selective estrogen receptor modulators (SERMs) became evident. The discovery of aryl propionamides, which share structural similarity with bicalutamide and hydroxyflutamide, suggested a way to make compounds that attach to the AR and produce both anabolic and anti-androgenic effects. Selective androgen receptor modulators (SARMs) were developed out of a desire to maintain the anabolic effects of androgens on muscle and bone, while avoiding side effects on other tissues such as the prostate and cardiovascular system.
The first SARMs to be discovered in the 1940s were steroidal and formed by modifications to the testosterone molecule that change its binding affinity to the AR. Non-steroidal SARMs were invented in 1998 independently by two research groups, one at the University of Tennessee that created an aryl propionamide SARM and Ligand Pharmaceuticals that made a SARM with a quinolone. The name was adopted by analogy with SERMs. Other SARMs include tetrahydroquinolines, tricyclics, bridged tricyclics, aniline, diaryl aniline, bicylclic hydantoins, benzimidazole, imidazolopyrazole, indole, and pyrazoline derivatives. SARMs can be agonists, antagonists, or partial agonists of the AR depending on the tissue, which can enable targeting specific medical conditions while minimizing side effects. Those that have advanced to human trials show stronger effects in bone and muscle tissue and weaker effects in the prostate. SARMs are orally bioavailable and largely eliminated via hepatic metabolism and metabolized through amide hydrolysis and A-ring nitro reduction.
The mechanism of action of SARMs' tissue-specific effects continues to be debated as of 2020[update]. SARMs are not a substrate for 5a-reductase enzyme that converts testosterone to DHT, a highly androgenic compound. Other researchers argue that the differences in how SARMs attach to the androgen receptor compared to AAS account for the differences in their effect. In vitro testing of the SARMs ostarine and YK-11 showed that they bound to the AR, but unlike true AR agonists, blocked the amine and carboxy terminal. SARMs interact with transcription coregulators that are present in specific tissues as well as transcription factors, which plays a role in their selective effects.
|Ostarine (Enobosarm)||Arylpropionamide||GTx||Breast cancer, cachexia, stress urinary incontinence|
|Andarine (S-4)||Arylpropionamide||GTx||Hepatocellular carcinoma|
|Ligandrol (LGD-4033)||Pyrrolidinebenzonitrile||Ligand Pharmaceuticals||Osteoporosis|
|OPK-88004||Indole||OPKO||Benign prostatic hyperplasia, quality of life in prostate cancer patients|
|RAD140||Phenyloxadiazole||Radius Health||Breast cancer|
Research and possible therapeutic applications
Due to their tissue selectivity, SARMs have the potential to treat a wide variety of conditions, including debilitating diseases. They have been investigated in human studies for the treatment of osteoporosis, cachexia, benign prostatic hyperplasia, stress urinary incontinence, prostate cancer, and breast cancer and have also been considered for the treatment of Alzheimer’s disease, Duchenne muscular dystrophy, hypogonadism and as a male contraceptive. As of 2020[update], there are no SARMs which have been approved for therapeutic use by the U.S. Food and Drug Administration.
Most SARMs have been tested in vitro or on rodents, while limited clinical trials in humans have been carried out. Initial research focused on muscle wasting. Ostarine is the most well-studied SARM; according to its manufacturer, GTx Incorporated, 25 studies have been carried out on more than 1,700 humans as of 2020[update] involving doses from 1 to 18 mg each day. As of 2020[update], there is little research distinguishing different SARMs from each other. Much of the research on SARMs has been conducted by corporations and has not been made publicly available.
Benign prostatic hyperplasia
In rat models of BPH, SARMs reduced prostatic weight. OPK-88004 advanced to a phase II trial in humans, but it was terminated due to difficulty in measuring prostate size, the trial's primary endpoint.
SARMs may help treat AR and estrogen receptor (ER) positive breast cancer, which comprise the majority of breast cancers. AAS were historically used successfully to treat AR positive breast cancer, but were phased out after the development of anti-estrogen therapies, due to androgenic side effects and concerns about aromatization to estrogen (which does not occur with SARMs). Although a trial on AR positive triple negative breast cancer (which is ER-) was ended early due to lack of efficacy, ostarine showed benefits in some patients with ER+, AR+ breast cancer in a phase II study. In patients with more than 40 percent AR positivity as determined by immunohistochemistry, the clinical benefit rate (CBR) was 80 percent and the objective response rate (ORR) was 48 percent—which was considered promising given that the patients had advanced disease and had been heavily pretreated. In 2022, the FDA granted fast track designation to ostarine for AR+, ER+, HER2- metastatic breast cancer.
Bone and muscle wasting
As of 2020[update], there are no drugs approved to treat muscle wasting in people with chronic diseases, and there is therefore an unmet need for anabolic drugs with few side effects. One aspect hindering drug approval for treatments for cachexia and sarcopenia is disagreement in endpoints. Several clinical trials have found that SARMs improve lean mass in humans, but it is not clear whether strength and physical function are also improved. After promising results in a phase II trial, a phase III trial of ostarine was proven to increase lean body mass but did not show significant improvement in function. It and other drugs have been refused regulatory approval due to a lack of evidence that they increased physical performance; preventing decline in functionality was not considered an acceptable endpoint by the Food and Drug Administration. It is not known how SARMs interact with dietary protein intake and resistance training in people with muscle wasting.
Phase II trials of ostarine for stress urinary incontinence—considered promising, given that the levator ani muscle involved has a high androgen receptor density—did not meet their endpoint and were abandoned.
Unlike other treatments for osteoporosis, which work by decreasing bone loss, SARMs have shown potential to promote growth in bone tissue. LY305 showed promising results in a phase I trial in humans.
In contrast to AAS and testosterone replacement, which have many side effects that have curtailed their medical use, SARMs are well tolerated and have no increase in adverse events compared to placebo reported by patients in randomized controlled trials. SARMs are not virilizing and cannot be aromatized to estrogen, thus causing no estrogenic side effects. Unlike current versions of testosterone replacement, SARMs can be administered orally and do not have many drug interactions.
Mild and infrequent side effects in the form of altered biomarkers have been reported, mainly elevated liver enzymes and reduction in HDL cholesterol. Transdermal administration may reduce these effects. Although elevated liver enzymes caused by SARMs might indicate hepatocellular injury, it is not known if SARMs cause a significant risk of hepatoxicity. Several case reports have associated SARMs with drug-induced liver injury when used recreationally. Whether SARMs increase the risk of cardiovascular events is unknown. SARMs have less effect on blood lipid profiles than testosterone replacement; it is not known whether androgen-induced HDL reductions increase cardiovascular risk; and SARMs increase insulin sensitivity and lower triglycerides.
Although they cause less suppression of the hypothalamic–pituitary–gonadal axis (HPG axis) than testosterone, studies have found that gonadotropins, free and total testosterone, and SHBG can be reduced in a compound- and dose-dependent fashion in men from SARM usage. Typically SHBG is reduced along with total testosterone and total cholesterol while hematocrit is increased. Most studies have found that follicle-stimulating hormone (FSH), lutenizing hormone (LH), prostate-specific antigen, estradiol, and DHT levels are not altered. Of SARMs that have been investigated, ostarine is one of the least suppressive of gonadotropins, even in doses much higher than used in clinical trials. How the HPG axis is affected in women using SARMs is unknown. SARMs' effect in suppressing the gonadotropins FSH and LH is what makes SARMs potentially useful as a male contraceptive.
Outside of pharmaceutical research, SARMs are a gray market substance produced by small laboratories and often marketed as a research chemical supposedly not for human consumption. Although SARMs are readily available for purchase on the internet, one study found that a majority of products advertised as SARMs online were mislabeled. Anecdotes and guides on usage can also be found online and on social media. Some compounds are commonly marketed for recreational use as SARMs despite having a different mechanism of action, including MK-677 / Ibutamoren (a growth hormone secretagogue), GW501516 / cardarine (an agonist of the PPARß/δ), and SR9009 / Stenabolic (an agonist of the Rev-Erb).
SARMs are used by bodybuilders and competitive athletes due to their anabolic and lack of androgenic effects, particularly in the United States, Europe, and other western countries. Some individuals using SARMs recreationally combine multiple SARMs or take a SARM along with other compounds, although there is no research on combining SARMs. The doses used often exceed those from clinical trials; nevertheless, the fat-free mass gained from SARMs is generally lower than what is obtained with moderate doses of testosterone derivatives. According to one study of SARM users, more than 90 percent were satisfied with their usage and 64.2 percent would take SARMS again even though a majority experienced adverse effects.
SARMs were banned by the World Anti-Doping Agency (WADA) in 2008. SARMs can be detected in urine and hair after consumption. WADA reported its first adverse analytical finding for SARMs in 2010 and the number of positive tests has increased since then; the most commonly detected SARMs are ostarine and ligandrol. Athletes competing in the NFL, NBA, UFC, NCAA, and the Olympics have tested positive.
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