Selective androgen receptor modulator
Drug class
Enobosarm (ostarine), anonsteroidalSARM under investigation for potential medical use.
Class identifiers
Synonyms	Nonsteroidal androgen (although not all SARMs are nonsteroidal)[1]
Use	Investigational
Biological target	Androgen receptor
Chemical class	Mostlynonsteroidal
Legal status
Legal status	AU: S4 (Prescription only)[2]
In Wikidata

Selective androgen receptor modulators (SARMs) are a class of drugs thatselectively activate theandrogen receptor in specifictissues, promotingmuscle andbone growth while having less effect onmale reproductive tissues like theprostate gland.

Non-selectivesteroidal drugs, calledanabolic androgenic steroids (AAS), have been used for various medical purposes, but their side effects limit their use. In 1998, researchers discovered a new class of non-steroidal compounds, the SARMs. These compounds selectively stimulate the androgen receptor, offering potent effects on bone and muscle to increase bone density and lean body mass while having minimal impact on reproductive tissues.

SARMs have been investigated in human studies for the treatment ofosteoporosis,cachexia (wasting syndrome),benign prostatic hyperplasia,stress urinary incontinence, andbreast cancer. As of 2023^[update], there are no SARMs which have been approved by the United StatesFood and Drug Administration or theEuropean Medicines Agency. Although adverse effects in clinical studies have been infrequent and mild, SARMs can causeelevated liver enzymes, reduction ofHDL cholesterol levels, andhypothalamic–pituitary–gonadal axis (HPG axis) suppression, among other side effects.

Since the early twenty-first century, SARMs have been used indoping; they were banned by theWorld Anti-Doping Agency in 2008. SARMs are readily available on internet-basedgray markets and are commonly used recreationally to stimulate muscle growth.

Anabolic androgenic steroids (AAS) are used to treat a variety of medical conditions, but their side effects have fueled a search for a new class of drugs, with a better separation between desirable anabolic and undesirable androgenic effects. The first clinically used AAS wastestosterone which was discovered in 1935 and first approved for medical use in 1939.^[5] AAS including those producedendogenously such astestosterone anddihydrotestosterone (DHT), bind to and activate theandrogen receptor (AR) to produce their effects. AAS effects can be separated into androgenic (the development and maintenance of malesexual characteristics) and anabolic (increasingbone density, muscle mass and strength). AAS also affecthematopoiesis,coagulation,metabolism, and cognition.^[6][7] For most medical applications, an AAS with potent anabolic and minimal androgenic and cardiovascular effects would be an advantage.

In the 1930s,17α-alkylated anabolic steroids were discovered. These have increased metabolic stability and are orally active, but are not tissue selective.^[8] These alkylated anabolic steroids still have significant androgenic effects, and are alsohepatotoxic.^[9][10] In 1950,nandrolone (19-nortestosterone) was first synthesized, which is sometimes considered a SARM due to greatertissue selectivity than testosterone.^[8][10][11] In addition, 7α-alkyl substitution of testosterone (for exampletrestolone) has also been reported to increase its anabolic effects.^[8] However, efforts to develop a steroid with anabolic but minimal androgenic effects were not successful.^[12]

Interest in nonsteroidal AR mixed agonists/antagonists increased after the therapeutic uses ofselective estrogen receptor modulators (SERMs) became evident.^[13] The first SERM,tamoxifen, was originally developed as an anti-estrogen contraceptive. However, it was discovered it promoted ovulation in humans by acting as an agonist in ovaries. The drug was then successfullyrepurposed as a treatment for breast cancer where it was found to act as a full antagonist in breast tissue.^[14] Somewhat unexpectedly, it was also discovered that tamoxifen preserves bone density^[15] by acting as an agonist in bone resorbingosteoclasts.^[16] The clinical success of SERMs stimulated interest in analogous tissue selective drugs that target the AR.^[7]

The chemical starting point for AR mixed agonist/antagonists were nonsteroidal ARantiandrogens such asflutamide,nilutamide,bicalutamide. These antagonists work by binding to the AR to prevent androgenic action; this class of chemicals dates to the 1970s.^[6][13] The discovery ofarylpropionamides, which share structural similarity with bicalutamide andhydroxyflutamide, suggested a way to make compounds that bind to the AR and produce both anabolic and antiandrogenic effects.^[6] 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 theprostate and cardiovascular system.^[9]

The first non-steroidal SARMs were developed in 1998 independently by two research groups, one at theUniversity of Tennessee that created an arylpropionamide SARM andLigand Pharmaceuticals that made a SARM with aquinolone core structure. The name was adopted by analogy with SERMs.^[13] Other SARMs includetetrahydroquinolines,tricyclics,bridged tricyclics,aniline,diaryl aniline,bicylclic hydantoins,benzimidazole,imidazolopyrazole,indole, andpyrazoline derivatives.^[6] SARMs can beagonists,antagonists, orpartial agonists of the AR depending on the tissue, which can enable targeting specific medical conditions while minimizing side effects.^[7] Those that have advanced to human trials show stronger effects in bone and muscle tissue and weaker effects in the prostate.^[8]

Unlike most current forms of testosterone replacement, SARMs are orallybioavailable^[7] and largely eliminated viahepatic metabolism and metabolized throughamide hydrolysis in the case of arylpropionamides and A-ringnitro reduction ofandarine.^[9]

Because of the potentially better side effect profile of SARMs compared to testosterone, SARMs have been proposed for use in the treatment of hypogonadism and for androgen replacement therapy.^[17][18][19] Phase I and II trials have provided preliminary evidence that the SARMsenobosarm andGSK-2881078 (in elderly men and postmenopausal women), and OPL-88004 (prostate cancer survivors with low levels of testosterone) increase lean body mass and muscle size with little effect on the prostate, supporting the potential of SARMs for use in hormone replacement therapy.^[9] However, it has been argued that SARMs are not ideal for use in androgen replacement therapy and could not replace testosterone in this context as they do not reproduce testosterone's full spectrum of effects, including androgenic potentiation via 5α-reduction and aromatization into estrogen.^[20][21] Estrogenic signaling in particular is essential for normal male physiology and health, including for instance maintenance of bone strength.^[22][23]

The mechanism of action of SARMs' tissue-specific effects continues to be debated as of 2020^[update].^[6][24] A number of hypotheses have been advanced. These include the non-activation of SARMs by5α-reductase, tissue selective expression of androgen receptorcoregulators, non-genomic signaling, and tissue selective uptake of SARMs.^[6][25]

Testosterone is active in non-reproductive tissue without activation. In contrast, tissue selective activation by5α-reductase to the more active form DHT is required for significant activity in reproductive tissue. The net result is that testosterone and its metabolite together are not tissue selective.^[26] SARMs are not substrates of 5α-reductase, hence they are not selectively activated like testosterone in tissues such as prostate.^[10] This lack of activation effectively imparts a degree of tissue selectivity to SARMs.^[27]

Tissue selectivetranscription coregulator expression is another possible contributor to the selectivity of SARMs.^[28][25] Like othertype I nuclear receptors, the unliganded androgen receptor (AR) resides in thecytosol complexed withheat shock proteins (HSP). Upon ligand binding, the AR freed from HSPs andtranslocated into the nucleus where it binds to androgenresponse elements on DNA to regulate gene expression.^[29] AR agonists such as testosterone recruitcoactivator proteins to AR that facilitate upregulation of gene expression while antagonists recruitcorepressors which down regulate gene expression. Furthermore, the ratio of coactivators to corepressors is known to vary depending on tissue type.^[28][19] Structurally, pure AR agonists stabilize the position of helix-12 (H12) in theligand binding domain of AR near H3 and H4 to produce a surface cleft that binds to a FxxLF motif contained in coactivators.^[29] Conversely, antagonists destabilize the agonist conformation of H12 blocking the binding of the FXXLF coactivator motif while facilitating the binding of the corepressor LXX(I/H)IXXX(I/L) motif found inNCOR1 andSMRT corepressors.^[29]

In analogy toSERMs, SARMs are mixed agonists/antagonists displaying agonist androgen receptor activity in bone and muscle and partial agonist or antagonist activity in other tissues such as prostate.^[25][7] Non-selective agonists such as testosterone are able to recruit coactivators when bound to AR but not corepressors and hence are agonists in all tissues. In contrast, SARMs can recruit both coactivators and corepressors by partially destabilizing the agonist conformation of H12. In tissues where coactivators are in excess (as in bone and muscle), SARMs act as agonists. Conversely, in tissues where corepressors are in excess (such as prostate), SARMs act as partial agonists or antagonists.^[25]

In vitro testing of the SARMsenobosarm (ostarine) andYK-11 showed that they bound to the AR, but unlike full AR agonists, they blocked interaction between theN-terminus andC-terminus of AR which resulted in a mixed agonist/antagonist mode of action.^[6][25]

In addition to the regulation of gene expression by nuclear AR, membrane associated AR is known to have rapid non-genomic effects on cells throughsignal transduction cascades. Non-genomic effects appear to significantly contribute to the anabolic effects of androgens whereas genomic effects are primarily responsible for the development of male sexual organs. Furthermore, each steroidal androgen or non-steroidal SARM uniquely influences distinct pathways depending on cell type.^[25]

Tissue selective uptake into anabolic tissues presents another potential mechanism for SARM tissue selectivity. Howeverautoradiography studies with radiolabeled SARMs show no preferential distribution to anabolic tissues.^[10]

SARM drug candidates^[30][13]

Name	Class	Developer	Investigated for	Highest development stage reached	Structure
Andarine (S-4, GTx-007)	Arylpropionamide	GTx, Oncternal Therapeutics[31]	Cachexia[31]	Phase I (discontinued)[31]
Arcarine (ORM-11984)[32]	Unknown[30]	Orion Corporation[32]	Benign prostatic hyperplasia, hypogonadism, osteoporosis[30]	Phase I (discontinued)[32][30]	Structure undisclosed[30]
BMS-564,929 (PS-178990)	Pyrroloimidazole[30]	Bristol-Myers Squibb,Ligand Pharmaceuticals[33]	Andropause, cachexia[33][30]	Phase I (discontinued)[33][34][30]	[30]
DT-200 (GLPG-0492)	Imidazolidine-2,4-dione	ProSkelia, Akashi Therapeutics, Galapagos NV[35]	Muscular dystrophy, cachexia[35]	Phase I[30][35][36]
Enobosarm (ostarine, GTx-024, MK-2866, S-22)	Arylpropionamide	GTx, Veru Healthcare[37]	Breast cancer,cachexia,muscular dystrophy,stress urinary incontinence[37]	Phase III[37][38]
GSK-971086	Indole[39]	GlaxoSmithKline[40]	Sarcopenia[40]	Phase I (discontinued)[40][41]	[39]
GSK-2849466	N-arylhydroxyalkyl[42]	GlaxoSmithKline[42]	Cachexia, heart failure[42]	Phase I (discontinued)[42][43]	[42]
GSK-2881078	Indole	GlaxoSmithKline[44]	Cachexia[44][45]	Phase II[44][46]
GTx-027	Arylpropionamide	GTx[47][48]	Breast cancer, stress urinary incontinence[47][48]	Phase I (discontinued)[47][48] or preclinical[19]
LGD-2941 (LGD-122941)	Quinolinone	Ligand Pharmaceuticals[49]	Cachexia, sexual dysfunction, hypogonadism, menopause, osteoporosis[49]	Phase I (discontinued)[49]
LGD-4033 (VK5211, ligandrol)	Pyrrolidinebenzonitrile	Ligand Pharmaceuticals[50]	Muscle wasting due tohip fracture,cachexia,hypogonadism,osteoporosis[24][50]	Phase II[50][51]
LY305	N-arylhydroxyalkyl	Eli Lilly[52]	Osteoporosis[52]	Phase I[52]
MK-0773 (PF-05314882)	Steroid	GTx,Merck[53]	Sarcopenia, osteoporosis[30][53]	Phase II (discontinued)[30][53][54][55]
MK-3984	Benzylpropionamide	Merck	Sarcopenia[30]	Phase I[30]
OPK-88004 (LY-2452473, TT-701)	Indole	Eli Lilly,OPKO[56]	Benign prostatic hyperplasia,quality of life inprostate cancer,erectile dysfunction[56][57]	Phase II[56][58]
PF-06260414	Isoquinoline	Pfizer[59][60]	Cachexia[59]	Phase I (discontinued)[59]
Vosilasarm (RAD140, EP0062, testolone)	Phenyloxadiazole	Ellipsis[61]	Breast cancer, osteoporosis, sarcopenia[62]	Phase I/II[62][63]
YK-11	Steroid	Toho University	Muscle wasting[64]	Preclinical

Certain anabolic steroids, liketrestolone,dimethandrolone undecanoate, and11β-methyl-19-nortestosterone dodecylcarbonate, have also sometimes been classified as SARMs.^[30]

Due to theirtissue 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 ofosteoporosis,cachexia,benign prostatic hyperplasia,stress urinary incontinence,prostate cancer, andbreast cancer and have also been considered for the treatment ofAlzheimer's disease,Duchenne muscular dystrophy,hypogonadism and as amale contraceptive.^[19][7] As of 2023^[update], there are no SARMs which have been approved for therapeutic use by the United StatesFood and Drug Administration or theEuropean Medicines Agency.^[65]

Most SARMs have been testedin vitro or on rodents, while limited clinical trials in humans have been carried out.^[6][66] Initial research focused on muscle wasting.^[25]Enobosarm (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.^[67][24] As of 2020^[update], there is little research distinguishing different SARMs from each other.^[6] Much of the research on SARMs has been conducted by corporations and has not been made publicly available.^[8]

In rat models ofbenign prostatic hyperplasia (BPH), a condition where theprostate is enlarged in the absence ofprostate cancer, SARMs reduced the weight of the prostate.^[66]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.^[19]

SARMs may help treat AR andestrogen receptor (ER) positivebreast cancer, which comprise the majority of breast cancers.^[7][68] AAS were historically used successfully to treat AR positive breast cancer, but were phased out after the development of antiestrogen therapies, due to androgenic side effects and concerns aboutaromatization to estrogen (which does not occur with SARMs).^[68][25] Although a trial on AR positivetriple negative breast cancer (which is ER-) was ended early due to lack of efficacy, enobosarm 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 byimmunohistochemistry, theclinical benefit rate (CBR) was 80 percent and theobjective response rate (ORR) was 48 percent—which was considered promising given that the patients had advanced disease and had been heavily pretreated.^[69][68] In 2022, the FDA grantedfast track designation to enobosarm for AR+,ER+,HER2-metastatic breast cancer.^[70] Other SARMs such asvosilasarm have reached clinical trials in breast cancer patients.^[61]

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 forcachexia andsarcopenia (two types of muscle wasting) is disagreement in what outcomes would demonstrate the efficacy of a drug. 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 enobosarm was proven to increaselean 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 theFood and Drug Administration. It is not known how SARMs interact with dietary protein intake andresistance training in people with muscle wasting.^[24][19]

Phase II trials of enobosarm forstress urinary incontinence—considered promising, given that thelevator ani muscle in thepelvic floor has a high androgen receptor density—did not meet their endpoint and were abandoned.^[19][25]

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.^[19]

In contrast to AAS andtestosterone replacement, which have many side effects that have curtailed their medical use, SARMs are well tolerated and have mild and infrequent adverse events inrandomized controlled trials.^[66] SARMs are sometimes claimed to be non-virilizing (non-masculinizing).^[19][71] However, SARMs are largely uncharacterized clinically in terms of potential virilizing effects.^[6] In addition, SARMs cannot bearomatized toestrogen, thus causing no estrogenic side effects, for instancegynecomastia.^[30][19][7]

SARM use can causeelevated liver enzymes and reduction inHDL cholesterol.^[30][19]Transdermal administration via a skin patch may reduce these effects.^[19][52] Several case reports have associated SARMs with hepatocellulardrug-induced liver injury when used recreationally,^[72] it is not known if the risk is significant for medical use.^[66][7] Whether SARMs increase the risk of cardiovascular events is unknown.^[66][7] 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 increaseinsulin sensitivity and lowertriglycerides.^[7][24]

Although they cause less suppression of thehypothalamic–pituitary–gonadal axis (HPG axis) than testosterone, studies have found thatgonadotropins, free and total testosterone, andSHBG can be reduced in a compound- and dose-dependent fashion in men from SARM usage.^[6][24] Typically, SHBG is reduced along with total testosterone andtotal cholesterol, whilehematocrit is increased. Most studies have found thatfollicle-stimulating hormone (FSH),luteinizing hormone (LH),prostate-specific antigen,estradiol, and DHT levels are not altered.^[66] Of SARMs that have been investigated, enobosarm 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.^[6][24] SARMs' effect in suppressing the gonadotropins FSH and LH is what makes SARMs potentially useful as a male contraceptive.^[73]

Outside of pharmaceutical research, SARMs are agray market substance produced by small laboratories and often marketed as a research chemical supposedly not for human consumption.^[6][74][75] Marketing SARMs for human consumption is illegal in some jurisdictions and has led to criminal convictions in the United States^[76] and the largest-ever fine levied under Australia'sTherapeutic Goods Act 1989.^[77] 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 onsocial media.^[78][30][7] Some compounds are commonly marketed for recreational use as SARMs despite having a differentmechanism of action. These substances includeibutamoren (MK-677), whichincreases secretion ofgrowth hormone;GW501516 (cardarine), anexercise mimetic that works as an agonist of thePPARβ/δ; andSR9009 (Stenabolic), an agonist of theRev-Erb, which plays a role incircadian rhythm.^[6][79]

SARMs are used bybodybuilders and competitive athletes due to their anabolic and lack of androgenic effects,^[7] particularly in the United States, Europe, and other western countries.^[30] 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.^[6] According to one study of SARM users, more than 90 percent were satisfied with their usage and 64 percent would take SARMs again even though a majority experienced adverse effects.^[80]

SARMs were banned by theWorld Anti-Doping Agency (WADA) in 2008.^[6] SARMs can be detected in urine and hair after consumption.^[81] WADA reported its firstadverse analytical finding for SARMs in 2010 and the number of positive tests has increased since then; the most commonly detected SARMs are enobosarm (ostarine) andLGD-4033 (ligandrol).^[82][83] Athletes competing in theNFL,NBA,UFC,NCAA, and theOlympics have tested positive.^[72] There is limited evidence on how SARMs affect athletic performance.^[84]

SARMs are sometimes also referred to as "nonsteroidal androgens",^[1][85] although not all SARMs are nonsteroidal in structure and steroidal SARMs also exist.^[30] In 1999, the term "selective androgen receptor modulator" or "SARM" was introduced, as themixed agonist–antagonist andtissue-selective activity of these nonsteroidal androgen receptor agonists had similarities withselective estrogen receptor modulators (SERMs).^[17] Despite its widespread use, the term "selective androgen receptor modulator" has been criticized by some authors, likeDavid Handelsman, who argue that it is a misleading pharmaceutical marketing term rather than an accurate pharmacological description.^[20] He has also critiqued notions that SARMs isolate anabolic effects from androgenic or virilizing effects, as has been previously claimed in the case ofanabolic steroids.^{[20][86][87][88]}

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