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| Other names | Ostarine; GTx-024; MK-2866; S-22; VERU-024[1] |
| Routes of administration | By mouth[2] |
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| Bioavailability | 100% (rats)[3] |
| Metabolism | CYP3A4,UGT1A1,UGT2B7[4] |
| Metabolites | Enobosarm glucuronide[4] |
| Eliminationhalf-life | 14–24 hours[5][6][4][7] |
| Excretion | Feces (70%),urine (21–25%) (rats)[3] |
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| Formula | C19H14F3N3O3 |
| Molar mass | 389.334 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 132 to 136 °C (270 to 277 °F) |
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Enobosarm, also formerly known asostarine and by the developmental code namesGTx-024,MK-2866, andS-22, is aselective androgen receptor modulator (SARM) which is under development for the treatment ofandrogen receptor-positivebreast cancer in women and for improvement ofbody composition (e.g., prevention ofmuscle loss) in people takingGLP-1 receptor agonists likesemaglutide.[1][5][7][8][9] It was also under development for a variety of other indications, including treatment ofcachexia,Duchenne muscular dystrophy,muscle atrophy orsarcopenia, andstress urinary incontinence, but development for all other uses has been discontinued.[1][10][2] Enobosarm was evaluated for the treatment ofmuscle wasting related tocancer inlate-stageclinical trials, and the drug improvedlean body mass in these trials, but it was not effective in improvingmuscle strength.[11][2][12][10][13] As a result, enobosarm was not approved and development for this use was terminated.[2] Enobosarm is takenby mouth.[2]
Known possibleside effects of enobosarm includeheadache,fatigue,anemia,nausea,diarrhea,back pain, adverselipid changes like decreasedhigh-density lipoprotein (HDL)cholesterol levels, changes insex hormone concentrations like decreasedtestosterone levels,elevated liver enzymes, andliver toxicity, among others.[6][14][15][16][12] The potentialmasculinizing effects of enobosarm, for instance in women, have largely not been evaluated and are unknown.[17] The potentialadverse effects and risks of high doses of enobosarm are also unknown.[17] Enobosarm is anonsteroidal SARM, acting as anagonist of theandrogen receptor (AR), thebiological target ofandrogens andanabolic steroids liketestosterone anddihydrotestosterone (DHT).[10] However, it shows dissociation of effect between tissues inpreclinical studies, with agonistic andanabolic effects in muscle and bone, agonistic effects inbreast, andpartially agonistic orantagonistic effects in theprostate gland andseminal vesicles.[7][10][2][18][19] The AR-mediated effects of enobosarm in many other androgen-sensitive tissues are unknown.[18][20]
Enobosarm was first identified in 2004[11] and has been under clinical development since at least 2005.[1][18] It is the most well-studied SARM of all of the agents that have been developed.[21] According to GTx, its developer, a total of 25 clinical studies have been carried out on more than 1,700 people involving doses from 1 to 100 mg as of 2020.[10][22] However, enobosarm has not yet completed clinical development or been approved for any use.[1][2] As of November 2023, it is inphase 3clinical trials for the treatment of breast cancer and is inphase 2 studies for improvement of body composition in people taking GLP-1 receptor agonists.[1][9] Enobosarm was developed byGTx, Inc., and is now being developed by Veru, Inc.[1]
Aside from its development as a potentialpharmaceutical drug, enobosarm is on theWorld Anti-Doping Agencylist of prohibited substances and is sold forphysique- and performance-enhancing purposes byblack-market Internet suppliers.[10][17][23] In one survey, 2.7% of young male gym users reported using SARMs.[24] In addition, a Londonwastewater analysis found that enobosarm was the most abundant "pharmaceutical drug" detected and was more prevalent than "classical"recreational drugs likeMDMA andcocaine.[25] Enobosarm is often used in these contexts at doses greatly exceeding those evaluated in clinical trials, with unknown effectiveness andsafety.[17] Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances.[17][26]Social media has played an important role in facilitating the widespread non-medical use of SARMs.[27]
Enobosarm is not approved for any medical use and is not available as a licensedpharmaceutical drug as of 2023.[1][2][10][17]
Generalside effects that have been reported with enobosarm in clinical trials includeheadache,fatigue,anemia,nausea,diarrhea, andback pain.[6][28][14]
Enobosarm has showndose-related adverse effects onserum lipids,sex hormone andgonadotropin levels, andcarrier protein levels in clinical trials.[16][17][29] It decreasesHDL cholesterol levels, reducing them dose-dependently by 17% at a dose of 1 mg/day and by 27% at a dose of 3 mg/day.[16][17][29] Decreases intotal cholesterol levels and intriglyceride levels have also been seen, whereasLDL cholesterol levels are unchanged.[16][17][29] In healthy elderly men, totaltestosterone levels decreased significantly at doses of 1 and 3 mg/day (-31% and -57%, respectively), whereas levels of free testosterone,dihydrotestosterone (DHT),estradiol,luteinizing hormone (LH), andfollicle-stimulating hormone (FSH) did not change significantly at doses up to 3 mg/day.[16][29] In healthy postmenopausal women, LH and FSH decreased significantly only at the 3 mg/day dose (-17% and -30%, respectively), whereas levels of total testosterone, free testosterone, DHT, and estradiol did not clearly change relative to placebo.[16][17][29] SHBG levels were lowered at doses of 1 to 3 mg/day, decreasing dramatically by 61% in men and by 80% in women at the 3 mg/day dose.[16][17][29] For comparison,testosterone enanthate byintramuscular injection at a highlysupraphysiological dose of 600 mg/week resulted in only a 31% decrease in SHBG levels.[29][30] Despite the large changes in SHBG levels, levels of free testosterone did not significantly change in either men or women.[16][17][29] Small but significant increases inhemoglobin andhematocrit, and small but significant decreases infasting blood glucose,insulin levels, andinsulin resistance, have been observed with enobosarm at 3 mg/day.[17][31][29][6]
In small short-term (3-month) clinical trials in healthy elderly or postmenopausal women, enobosarm at doses ranging from 0.1 to 3 mg/day had mixed effects onsebum production and did not increasebody hairgrowth or causehirsutism.[32][29] These effects are measures of androgenic action inskin andhair follicles.[32] In the first study, at doses of 0.1 to 3 mg/day, there were no significant changes relative to placebo in sebum tape scores with enobosarm and there were no consistent increases inFerriman–Gallwey score, with most women having no change in score or a decreased score and only one having an increase in score.[32][29] In the second study, which employed 3 mg/day enobosarm, there was a significant 1.25-fold increase in sebum production from baseline and a significant 1.5-fold increase in sebum production relative to placebo.[32] No differences insebaceous gland volume were apparent uponhistological examination in this study.[32]
At doses ranging from 0.1 to 18 mg/day in clinical trials, enobosarm has been associated withelevated liver enzymes in subsets of individuals.[12][16] Rates of elevated liver enzymes or of elevatedalanine aminotransferase (ALT) levels have ranged from 0.6% to 33% in these trials.[12][16] Liver enzyme elevations with enobosarm are often transient and resolve spontaneously.[12] However, markedly elevated liver enzymes have occasionally occurred with enobosarm in clinical trials and have necessitateddiscontinuation.[12] There have been several publishedcase reports ofhepatotoxicity with enobosarm as of 2023.[12][33][24][34][35][36][37] Between 2020 and 2022, there has been a rapid increase in reported cases of liver toxicity with SARMs.[33] The hepatotoxicity with SARMs may be related to their resistance tohepaticmetabolism, analogously to the case of17α-alkylated anabolic steroids.[12]
SARMs are often advertised and sold on the Internet at doses higher than have been described in the literature.[17][28] Sometimes doses are recommended as several-fold or more greater than the doses used in clinical trials, or seemingly arbitrary doses are advised.[17][28] For instance, enobosarm has been provided at doses of greater than or equal to 20 mg per serving and recommended by bodybuilders and fitness enthusiasts at doses of 10 to 30 mg/day, relative to the most widely assessed highest dose in clinical trials of 3 mg/day—an up to 10-fold difference.[17][28] SARMs, particularly when used at high or excessive doses for prolonged periods of time, may result in substantial suppression ofendogenoussex hormones liketestosterone andestradiol, in turn producing widespread unintended deleterious effects on physiological function.[17] As examples, SARMs may produce potent anabolic effects with deficiency in important androgenic effects, may result inestrogen deficiency with consequences likebone loss among others, and, due to suppression of thehypothalamic–pituitary–gonadal axis (HPG axis), may causeinfertility.[17]
Androgens andanabolic steroids liketestosterone,dihydrotestosterone (DHT),nandrolone, andoxandrolone, which arefull agonists of theandrogen receptor, producevirilizing ormasculinizing effects like increased sebum production andacne, increasedbody hairgrowth,scalp hair loss,voice deepening, increasedmuscle mass,android fat redistribution, skeletal changes likewidening of the shoulders and skull/facial changes, andgenital growth both in males and females.[38][39][17] SARMs, which aretissue-selective mixed orpartial agonists of the androgen receptor, are largely uncharacterized in terms of their masculinizing effects, but are likely to produce many of the same effects.[17][38][40][41] SARMs specifically may be expected to retain masculinizing effects like increased muscle mass and bone changes, while possibly having reduced virilizing effects in certain other areas like androgenic skin and hair changes.[17][16][32][18][20]Anecdotal reports of masculinization with SARMs in women exist in online forums.[27]
TheUnited StatesFood and Drug Administration (FDA) has cautioned that SARMs could have serious adverse effects ranging from risk ofheart attack tostroke andliver damage and has warned against their use inbodybuilding products.[42]
Enobosarm has been assessed in clinical trials at doses ranging from 0.1 to 18 mg/day.[10] However, most research has been done at doses of 0.1 to 3 mg/day, with twophase 3 clinical trials using a dosage of 3 mg/day.[2][15][33][17] A few smallphase 1 andphase 2 trials of enobosarm for breast cancer have employed doses of 9 to 18 mg/day.[43][12][2][44] Larger, phase 3 trials of enobosarm at a dose of 9 mg/day for breast cancer (e.g., ARTEST, n=210) are now underway.[45][46] Doses of up to 100 mg have been assessed in single-dosepharmacokinetic studies and doses of up to 30 mg/day have been given in short 14-day pharmacokinetic studies.[5] Enobosarm sold viablack-market Internet suppliers and used non-medically is often taken at much higher doses than those used widely in clinical trials (e.g., 10–30 mg/day), with unknown adverse effects and risks.[17][28]
Enobosarm is asubstrate of thecytochrome P450enzymeCYP3A4 and theUDP-glucuronosyltransferase (UGT) enzymesUGT1A1 andUGT2B7.[4] It shows very minimalmetabolism by cytochrome P50 enzymes, with CYP3A4 merely responsible for the greatest degree of metabolism.[4] Since enobosarm is metabolized by CYP3A4, UGT1A1, and UGT2B7,inhibitors andinducers of these enzymes can modify the metabolism andpharmacokinetics of enobosarm.[4] The strong CYP3A4 inhibitoritraconazole was shown to have minimal to no influence on the pharmacokinetics of enobosarm, whereas the strong CYP3A4 inducerrifampin reduced enobosarmpeak levels by 23%,elimination half-life by 23%, andarea-under-the-curve levels by 43%.[47][4] The pan-UGT inhibitorprobenecid was shown to not affect peak levels of enobosarm but to increase the elimination half-life of enobosarm by 78% and to increase area-under-the-curve levels of enobosarm by 50%.[47][4] Enobosarm had no effect on the pharmacokinetics ofcelecoxib (aCYP2C9 substrate) orrosuvastatin (aBCRP substrate).[4] Based on the preceding findings, it was concluded that enobosarm poses low risk for clinically relevantdrug interactions.[4]
Enobosarm is aselective androgen receptor modulator (SARM), or atissue-selective mixedagonist orpartial agonist of theandrogen receptor (AR).[20][11][18] This receptor is thebiological target ofendogenousandrogens liketestosterone anddihydrotestosterone (DHT) and ofsyntheticanabolic steroids likenandrolone andoxandrolone.[11][18][38] Theaffinity (Ki) of enobosarm for the AR is high and was measured as 3.8 nM in one study, or approximately 16.8% of that of DHT.[48][49][50] Enobosarm showsenantioselectivity for the AR and has similar but somewhat lowerpotency than DHT in terms of activating the receptor.[7] In addition to general activation of the AR, enobosarm induces the N/C interaction (the interaction of theamino terminus andcarboxyl terminus) of the AR less potently than does DHT, but in any case promotes the N/C interaction concentration-dependently and to the same maximal extent as DHT.[50] The AR is widely expressed intissues throughout the body, including in theprostate gland,seminal vesicles,genitals,gonads,skin,hair follicles,muscle,bone,heart,adrenal cortex,liver,kidneys, andbrain, among others.[18][38] The effects of SARMs including enobosarm in many of these tissues have yet to be characterized.[18][20] In any case, enobosarm has been demonstrated to have varyingfull agonist orpartial agonist orantagonist actions in specific tissues, includingpotent agonistic andanabolic effects inmuscle andbone, potent agonistic effects in AR-expressing humanbreast cancercell lines likeMCF-7 andMDA-MB-231,[19][2] and partially agonistic or antagonistic effects in theprostate gland,seminal vesicles, anduterus.[7][10][2][18][50] Enobosarm has additionally been shown to stimulatesexual motivation in female rats similarly to testosterone.[48][50] Although enobosarm has not been specifically assessed in this area, another structurally unrelatedquinolinone SARM,LGD-2226, has shownprosexual effects in male rats comparable to those of the synthetic androgen and anabolic steroidfluoxymesterone as well.[2][48][51]
Themolecular mechanisms underlying the tissue-selective effects of enobosarm and other SARMs compared to testosterone and other androgens and anabolic steroids remain unknown.[52][17] However, recruitment of bothcoactivators andcorepressors instead of only coactivators and resultant differingreceptor conformations, distinct tissue-specific modulation ofsignaling pathways mediatinggenomic andnon-genomic effects, and differences in within-tissueligandmetabolism and modulation of ligandpotency (i.e., potentiation versus lack thereof), among others, all constitute possible mechanisms.[52][17][53] In terms ofcoregulator recruitment, the ratios of coactivators to corepressors vary in different tissues throughout the body, and it is thought that SARMs may have agonistic effects in tissues with an excess of coactivators relative to corepressors like muscle and bone and may have partially agonistic or antagonistic effects in tissues with an excess of corepressors over coactivators like the prostate.[52] Another mechanism may be that SARMs like enobosarm induce the N/C interaction less readily than AR full agonists like DHT.[17][48][54][50] Induction of the N/C interaction has been associated with the effects ofendogenous andexogenous AR agonists, for instancevirilization and prostate growth.[48][50][55][56]
Inanimal studies, enobosarm has shown potent muscle-promoting effects that were similar to those oftestosterone and DHT.[7][10][57][58][59][49] In one of the first published studies, enobosarm maximally restored prostate weight to 51%, seminal vesicle weight to 98%, and levator ani muscle weight to 136% in castrated male rats relative to gonadally intact control male rats, with anED50 dose for muscle of 0.03 mg/day.[57][52][49] For comparison,testosterone propionate was able to maximally stimulate levator ani muscle to 104% and prostate weight to 121%, with ED50 doses of 0.15 mg/day and 0.13 mg/day, respectively.[7] Hence, enobosarm was able to stimulate the levator ani muscle to a size greater than that in normal male rats or produced with exogenous testosterone in castrated male rats, but was only capable of partially rescuing prostate gland weight.[52][49][7] Additionally, enobosarm fully maintained or restored levator ani weight at doses that did not affect LH or FSH levels in gonadally intact animals (≤0.1 mg/day).[7] As such, it was more potent in stimulating muscle than testosterone at doses that did not affectgonadotropin levels.[5][7] In gonadally intact male rats, enobosarm significantly increased levator ani muscle weight to 131% of intact controls but significantly decreased the weights of the prostate gland and seminal vesicles, demonstrating an antagonistic or partially agonistic effect in these tissues.[7] In another animal study, enobosarm and DHT increased levator ani weights to similar or slightly different extents in intact male rats, but DHT strongly increased prostate weight while enobosarm reduced prostate weight.[7][60][59] Aside from effects in muscle tissue, enobosarm has been assessed and found to completely maintain bone quality and composition in castrated male rats and to partially but not fully prevent bone loss in ovariectomized female rats, indicating potent anabolic effects in bone as well.[7]
In aphase 2 human clinical trial in healthy elderly men and postmenopausal women, enobosarm dose-dependently increasedlean body mass (muscle mass) across doses of 0.1, 0.3, 1, and 3 mg/day, with a significant 1.3 kg gain over placebo at 3 mg/day and a non-significant 0.7 kg gain over placebo at 1 mg/day.[10][29] Similarly, in twophase 3 clinical trials in men and postmenopausal women with muscle wasting due tonon-small-cell lung cancer, enobosarm at 3 mg/day significantly increased lean body mass by 0.41 kg and 0.47 kg.[10] However, enobosarm did not successfully increase muscle strength in these phase 3 trials.[10] In any case, it has been suggested that thestudy designs and physical function outcomes in such trials may have been flawed.[61][62][63][64][2] The increases in lean body mass that have been seen with employed doses of enobosarm in clinical trials are very modest compared to those produced with supraphysiological doses of testosterone over similar timeframes (e.g., 0.5–1.5 kg with enobosarm versus 5–8 kg with 300–600 mg/week intramuscular testosterone enanthate in healthy young men).[54][17][65] The effects of higher doses of enobosarm (9–18 mg/day) on lean body mass and muscle strength are also being evaluated in women with breast cancer.[2][44] There is some evidence that women may be more sensitive to lean body mass increases with SARMs, specificallyGSK-2881078 but potentially also others like enobosarm, than men.[10][17]
In addition to its mixed agonist–antagonist activity at the AR, enobosarm is likely to also differ from steroidal androgens in its effects due to differences in within-tissue ligand metabolism.[38][32][18][53] Thevirilizing and androgenic effects of the traditional steroidal androgens like testosterone inskin,hair follicles, and theprostate gland are attributed to highexpression of5α-reductase in these tissues and consequent local conversion and potentiation into morepotent androgens.[38][32][18] In the case of testosterone, this is via conversion into the 10-fold more potent androgen DHT.[32][18] Enobosarm is not subject to this local transformation and potentiation, and so is theorized to have greatly reduced effects in these tissues relative to testosterone and certain other steroidal androgens.[32][18][20] This is likewise theorized to be the case for non-5α-reductase-potentiated anabolic steroids like nandrolone and oxandrolone, which have highmyotrophic–androgenic potency ratios in animals.[38] The lack of 5α-reduction may result in reduced androgenic side effects likescalp hair loss,facial and body hair growth, andprostate growth.[20][66][11] On the other hand, although SARMs, like enobosarm, as well as anabolic steroids, may have reduced virilizing effects in skin and hair follicles, this is not necessarily the case for virilization in general.[38][17] In particular, the muscle-promoting effects of these agents can be considered a masculinizing effect.[16][67] The potential masculinizing effects of enobosarm and SARMs in general are largely uncharacterized and unknown.[17] Aside from metabolism differences related to 5α-reduction, enobosarm has also shown much greater impact in theliver, specifically on certain aspects ofhepatic protein synthesis like reduction ofsex hormone-binding globulin (SHBG) production, than even highlysupraphysiological doses ofparenteraltestosterone.[29] This phenomenon has also been seen with other SARMs, such asLGD-4033,[17][33][16][68] as well as withsynthetic orally active17α-alkylated anabolic steroids likestanozolol.[20][69][70] It can be attributed to thefirst pass through the liver withoral administration and to the high oralbioavailability and strong resistance to hepatic metabolism of these agents.[20][71][72][12]
Enobosarm has noestrogenic activity, either intrinsic to itself or via itsmetabolites.[32][7][18][20][43] As a result, the drug is not expected to havefeminizing effects or risk ofgynecomastia (breast development) nor to stimulate estrogen-sensitive breast cancer.[18][7] SARMs like enobosarm are not ideal agents forandrogen replacement therapy as they are not expected to reproduce the full spectrum of effects of testosterone and other androgens, including not only AR-mediated effects but also notablyaromatization intoestrogen and required physiologicalestrogenic effects inbone andbrain.[20] Enobosarm has been found to be a weakantagonist of theprogesterone receptor and hence might have some capacity forantiprogestogenic effects.[5][7] Aside from its weak interaction with the progesterone receptor, enobosarm is highlyselective for the AR and does not bind to othernuclear hormone receptors.[7]
Enobosarm isorallybioavailable due to a lack of extensivefirst-pass metabolism.[18] In rats, the oral bioavailability of enobosarm was found to be 100%.[3] Enobosarm is rapidlyabsorbed with oral administration and reachesmaximal concentrations median 1.0 hours (range 1.0–2.0 hours) following administration.[47][5][4] The drug reaches a peak concentration of 56.0 ng/mL (range 53.1–123.0 ng/mL) following a single 3 mg dose and asteady-state peak of 68.1 ng/mL following repeated 3 mg doses.[47][4] Thepharmacokinetics of enobosarm are linear and proportional over a dose range of 1 to 100 mg in single doses in healthy men.[5][7] The pharmacokinetics of enobosarm are similar in young versus elderly individuals.[7] Aconcentration–time curve of enobosarm levels following a single oral dose of enobosarm in humans has been published.[7]
Enobosarm is asmall-molecule and highlylipophiliccompound.[73][74] Compounds of this type are typically able to diffuse freely throughbiological membranes such ascell membranes and barriers like theblood–brain barrier.[75][76] This is in fact essential for the action ofnuclear receptorligands like enobosarm since theirbiological targets (theandrogen receptor in this case) are locatedintracellularly.[75][76] Onein silico study predicted that, on the basis of its overallphysicochemical properties (but not consideringactive transport), enobosarm would be unlikely to cross theblood–brain barrier and hence would be aperipherally selective drug with reduced or nocentral nervous system effects.[77] However, in a rattissue distribution study, enobosarm was found to be concentrated inbrain tissues to a similar extent as other target tissues likeskeletal muscle,bone,prostate, andseminal vesicles.[3] This is consistent with enobosarm producing centrally mediated effects in humans like suppression of LH and FSHsecretion.[16][17][29]
Enobosarm does not bind tosex hormone-binding globulin.[18]
In vitro studies found very minimalmetabolism of enobosarm by humancytochrome P450enzymes.[4] The greatest degree ofoxidativemetabolite generation occurred withCYP3A4.[4] Upon incubation with humanUDP-glucuronosyltransferase (UGT) enzymes, enobosarm glucuronide was generated, with a majority of this inactive metabolite being produced byUGT1A1 andUGT2B7.[4] Enobosarm glucuronide is the primary circulating metabolite of enobosarm.[4]
Coadministration of the strong CYP3A4inhibitoritraconazole had minimal impact on thepharmacokinetics of enobosarm and enobosarm glucuronide, whereas the strong CYP3A4inducerrifampin reduced enobosarm peak levels by 23%,elimination half-life by 23%, andarea-under-the-curve levels by 43%.[47][4] Coadministration of the pan-UGT inhibitorprobenecid with enobosarm resulted in similar peak levels of enobosarm but the elimination half-life of enobosarm was extended by 78% and area-under-the-curve levels increased by 50%.[47][4] These data are consistent with the preclinical findings that enobosarm is asubstrate of CYP3A4 and UGT enzymes.[4]
The metabolism of enobosarm is similar to that of the closely structurally related drugbicalutamide.[3]
In rats, enobosarm wasexcreted approximately 70% infeces and 21 to 25% inurine.[3]
Enobosarm has anelimination half-life of approximately 14 to 24 hours in human volunteers.[5][6][7] In one pharmacokinetic study, the meanterminal half-life was 22.0 ± 5.8 (SD) hours, with a range of 13.7 to 31.3 hours in different individuals[4]
Enobosarm is asmall-molecule (molecular weight = 389.3 g/mol) and highlylipophilic (predictedlog P = 2.7–3.3)compound.[73][74]
Enobosarm and related SARMs likeacetothiolutamide,andarine (acetamidoxolutamide; GTx-007; S-4), andGTx-027 werederived fromstructural modification of the arylpropionamidenonsteroidal antiandrogenbicalutamide.[78][18][79][20][80] They are nonsteroidal arylpropionamides themselves and are closestructural analogues of bicalutamide.[18][79][80][81] Bicalutamide was used to derive acetothiolutamide, andarine was developed from acetothiolutamide, the SARM S-1 was developed from andarine, and finally enobosarm was developed from S-1.[82] Bicalutamide is used clinically as an antiandrogen, but there is some evidence that bicalutamide itself may have some SARM-like properties in certain tissues, for instance in muscle and bone.[83][84][85]
Enobosarm (S-22) and andarine (S-4) and theirchemical structures have sometimes been confused.[86] The chemical structure of enobosarm was not disclosed until November 2011.[48][86]
Novel nonsteroidal antiandrogens have been developed from enobosarm with enhancedpotency and activity relative to conventional antiandrogens like bicalutamide andenzalutamide.[87][88]
The first SARMs were arylpropionamides derived from thenonsteroidal antiandrogenbicalutamide.[7][89] They were discovered byJames T. Dalton and colleagues at theUniversity of Tennessee and other institutions and were first described in a paper published in 1998.[7][89][90] At the time, these AR agonists were referred to as "nonsteroidal androgens", a drug class that had not been previously described.[91] By 1999 however, on the basis of theselective estrogen receptor modulator (SERM)-likemixed agonist–antagonist andtissue-selective activity of these nonsteroidal AR agonists, the term "selective androgen receptor modulator" or "SARM" was introduced and adoption of this name had begun.[91] The arylpropionamide SARMandarine (GTx-007; S-4) was first described in the literature by 2002.[92][93][94] In 2003, arylpropionamide AR agonists, including andarine, were first reported to possess SARM-typetissue selectivityin vivo.[48][93] Enobosarm (GTx-024; S-22), another arylpropionamide SARM, was first identified in 2004[11][90] and was first described in the literature in 2005.[18][49][90]GTx, apharmaceutical company founded inMemphis, Tennessee in 1997, licensed the rights to enobosarm from the University of Tennessee Research Foundation and began developing it as apharmaceutical drug.[1][90]
Aphase 1clinical trial employing enobosarm had been completed by 2005.[18] By 2007, enobosarm was in aphase 2 trial, and that year GTx signed an exclusive license agreement for its SARM program withMerck & Co.[95] The companies ended the deal in 2010.[96] In August 2011, there was a 12-weekdouble-blind, placebo controlled phase 2 trial that focused on elderly men and postmenopausal women which concluded that enobosarm showed statistically significant improvements in total lean body mass and physical function without apparent adverse effects on hair growth or sebum production.[29] In August 2013, GTx announced that enobosarm had failed in twophase 3 clinical trials to treat wasting in people withlung cancer.[97] The company had invested around $35 million in the development of the drug.[98] The company said at that time that it planned to pursue approval of enobosarm in Europe; the company was also still developingGTx-758, anonsteroidal estrogen, for castration-resistantprostate cancer.[99] As of 2018, enobosarm was the only SARM to have reached or completed phase 3 clinical trials.[52]
In 2016, GTx began phase 2 trials, to see if enobosarm might be effective to treatstress urinary incontinence in women.[100] In 2018, GTx announced the phase 2 trials on the effectiveness of enobosarm for stress urinary incontinence in women failed to achieve its primary endpoint in the ASTRID Trial.[101] By September 2023, development of enobosarm for stress urinary incontinence had been discontinued.[1] In 2022, the FDA grantedfast tract designation to enobosarm inAR+,ER+,HER2-metastaticbreast cancer.[102] In January 2024, Veru Inc. submitted anInvestigational New Drug application to the FDA of enobosarm for prevention of muscle loss and augmentation of fat loss in combination withglucagon-like peptide-1 (GLP-1) receptor agonists likesemaglutide forweight loss.[9] In addition, they announced plans to conduct a phase 2b study of enobosarm at doses of 3 to 6 mg/day for this purpose in sarcopenic obese or overweight elderly individuals receiving GLP-1 receptor agonists.[9]
Enobosarm was developed by GTx, Inc., and is now being developed by Veru, Inc.[1]
Enobosarm is thegeneric name of the drug and itsInternational Nonproprietary Name (INN).[103] Ostarine was a tentative brand name of the drug created by GTx, Inc. that did not end up being used for marketing purposes but continues to be used as a synonym for the drug.[1][6] Enobosarm is also known by the pharmaceutical developmental code names S-22 (synthesis paper), GTx-024 (GTx, Inc.), MK-2866 (Merck), and VERU-024 (Veru, Inc.).[1]
Enobosarm and other SARMs are sold asdesigner drugs byblack-market vendors on the Internet.[17][26][23] These agents have increasingly become used by the general public as "gym supplements" such aspre-workout orlifestyle drugs, rather than as an aid to performance in athletic or bodybuilding competitions. In one survey, 2.7% of young male gym users in theNetherlands reported using SARMs.[24] In addition, a 2018 analysis of afatberg from a sewer in centralLondon showed enobosarm to be the most abundant "pharmaceutical drug" detected, and was present at higher concentration thanrecreational drugs such asMDMA andcocaine. While this isolated result may not be representative of overall levels of use, for enobosarm to be detectable in sewer deposits reflects significant levels of enobosarm use in the area close to where the sample was collected.[25] Doses of enobosarm sold online and used non-medically are often many times higher than those assessed in clinical trials.[17][28] Aside from enobosarm, the other most commonly used SARMs includevosilasarm (RAD140; "testolone"),LGD-4033 (VK5211; "ligandrol"), andandarine (GTx-007; S-4).[27] Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances, and doses are also frequently not as labeled.[17][26]Social media has played an important role in facilitating the widespread non-medical use of SARMs.[27]
SARMs including enobosarm may be and have been used by athletes to assist in training and increase physical stamina and fitness, potentially producing effects similar toanabolic steroids. For this reason, SARMs were banned by theWorld Anti-Doping Agency in January 2008, despite no drugs from this class yet being in clinical use, and blood tests for all known SARMs have been developed.[104][105] There are a variety of known cases ofdoping in sports with enobosarm byprofessionalathletes.[106]
In May 2017, Dynamic Technical Formulations voluntarily recalled all lots of Tri-Ton, a dietary supplement that the FDA tested and found to contain Enobosarm andandarine.[107]
In October 2018,UFC fighterSean O'Malley tested positive for Enobosarm and was suspended by theNevada State Athletic Commission andUSADA for six months. O'Malley tested positive again on May 25, 2019 and was suspended for nine months by the same agencies. USADA determined that none of O'Malley's positive tests were consistent with intentional use and he was allowed to compete atUFC 248 as long as he kept his levels below the threshold of 100 ng/ml.[108]
On January 7, 2019, the College National Football Championship was played between University of Alabama and Clemson University. Prior to the College Football National Championship game, three Clemson players who weresuspended — Dexter Lawrence, Braden Galloway and ZachGiellaall — tested positive for a substance known as enobosarm. On June 23, 2019 Clemson did not release enobosarm investigation findings, citing privacy law.[109]
In July 2019,National Football League playerTaylor Lewan failed a drug test for Enobosarm, which Lewan claimed he ingested accidentally as an unlabeled ingredient in a supplement.[110]
On October 23, 2020, theUnion Cycliste Internationale (UCI) announced that the Italian riderMatteo Spreafico has been notified of two adverse analytical findings (AAFs) for Enobosarm in two samples collected during the Giro d'Italia on 15–16 October 2020.[111]
On July 6, 2021, during the2020 Summer Olympics,Brazil women's national volleyball team playerTandara was temporarily suspended for testing positive for enobosarm. The test was carried out and identified by the Brazilian Doping Control Authority (ABDC).[112]
On August 12, 2021, after the2020 Summer Olympics, Chijindu "CJ" Ujah, A member of the silver medal-winning British 4×100 relay team was temporarily suspended for testing positive for both enobosarm andS-23. The sample was collected post event by the International Testing Agency (ITA) and confirmed two days later as positive. The case was referred to the anti-doping division of the Court of Arbitration for Sport.[113] Finally in February 2022, Great Britain were stripped of their silver medal.[114] In October 2022, Ujah was suspended for 22 months by the ITA.[115]
In October 2021, two Thoroughbred horses named Arafat and Komunist tested positive for enobosarm after races atWoodbine Racetrack. In a decision of theAlcohol and Gaming Commission of Ontario issued May 30, 2022, the horses were declared unplaced in the races in question, and their trainer Robert Gerl was fined $100,000 (as well as forfeiting prize money) and suspended from racing for 20 years.[116]
In May 2022, National Football LeagueWide receiverDeAndre Hopkins was suspended six games without pay by the NFL for violating the league's performance-enhancing drug policy. According to Hopkins, he tested positive for enobosarm.[117]
In April 2023, British boxerAmir Khan was banned for two years after an anti-doping test revealed the presence of enobosarm following his fight againstKell Brook in February 2022.[118]
On May 1, 2024, American boxerRyan Garcia tested positive for the performance-enhancing substance Ostarine the day before and the day of his upset win over Devin Haney last month, per a Voluntary Anti-Doping Association letter sent to all parties Wednesday and obtained by ESPN. The samples were taken prior to the fight, but the results weren't known until later. Garcia's A-sample also screened positive for 19-norandrosterone, but its presence is unconfirmed at this time. Garcia floored Haney three times during the majority decision victory, but that result could possibly be overturned because his B-sample tested positive on May 22, 2024. Garcia's fate now rests in the hands of the New York State Athletic Commission, which will adjudicate any suspensions and financial penalties. Sanctions also include the possibility of his win over Haney being overturned to a no-contest or having it changed to a disqualification. Despite his "B" samples returning positive results, Garcia has maintained his innocence and has cited substance contamination.[119]
Enobosarm is currently under development for the treatment ofbreast cancer.[1][8][45][46] It was also previously under development for a variety of other potential uses, including treatment ofcachexia,Duchenne muscular dystrophy,muscle atrophy orsarcopenia, andstress incontinence.[1][10][2] However, development for all other indications has been discontinued.[1]
Enobosarm was assessed for the treatment ofmuscle wasting in people withlung cancer in twophase 3clinical trials.[11][2][12][13] The findings of these trials were reported in 2013.[13] Enobosarm significantly improvedlean body mass in the trials, but it was not effective in improvingmuscle strength, as measured by stair climb power.[11][2][12][13] Consequent to these findings, enobosarm did not gain regulatory approval, and development for this use was terminated.[2] Enobosarm had originally been under development for the treatment of sarcopenia (age-related muscle atrophy).[10] However, the FDA requested a cardiovascular safety study be conducted to proceed with phase 3 trials for this indication.[10] The developer of enobosarm refused to conduct this study due to the considerable costs that would be involved.[10] Instead, it opted to trial enobosarm for muscle wasting in cachexia patients, in whom the FDA was more tolerant to cardiovascular side effects and did not require cardiovascular safety evaluation.[10]
Following negative findings for muscle wasting, enobosarm was evaluated for the treatment ofstress urinary incontinence in postmenopausal women.[1][2] It was expected that enobosarm might be effective for this use by strengthening thepelvic floor muscles.[1][2] Enobosarm reachedphase 2 clinical trials for this indication, but development was discontinued due to lack of effectiveness in a phase 2 study.[1][2]
Subsequently, enobosarm was repurposed again for the treatment ofandrogen receptor-positive (AR+) estrogen receptor-positive (ER+) breast cancer.[1][8] As of November 2023, it is in phase 3 clinical trials for the treatment of this type of breast cancer.[1][45][46] Increases in lean body mass and muscle strength as a secondary benefit with enobosarm are also being evaluated in these women.[2][44] These trials are notably employing several-fold higher doses of enobosarm than were assessed in the muscle wasting phase 3 trials (9 mg/day versus 3 mg/day, respectively).[2][44]
In January 2024, it was announced that enobosarm was being developed for prevention of muscle wasting and augmentation of fat loss in combination withglucagon-like peptide-1 (GLP-1) receptor agonists likesemaglutide forweight loss.[9] A phase 2b clinical trial for this indication with 3 to 6 mg/day enobosarm in sarcopenic obese or overweight elderly individuals is being prepared.[9]
According to GTx, the original developer of enobosarm, a total of 25 clinical studies have been carried out on more than 1,700 people involving doses from 1 to 100 mg as of 2020.[10][22] However, enobosarm has not yet completed clinical development or been approved for any use.[1][2]
Unfortunately, results of recent clinical trials of the SARM GTx-024 (Enobosarm) have tempered expectations for its utility as a therapy for muscle wasting. Early on, GTx-024 appeared to have a very bright future as a treatment for sarcopenia/cachexia. Preliminary clinical trials demonstrated that GTx-024 could increase lean body mass and improve physical function without androgenic side effects (27). However, Enobosarm was dealt a blow after the phase III Prevention and treatment Of muscle Wasting in patients with cancER (POWER) I and II trials, where increases in lean body mass were once again observed, but without improved stair climb power (79,80). Failure to attain both primary endpoints led to a lack of approval by the Food and Drug Administration (FDA), which has cast doubt on the previously charted course for SARMs and has tempered enthusiasm regarding the role of SARMs in the treatment of muscle wasting conditions.
Pharmacokinetics & metabolism: Enobosarm was shown to have linear pharmacokinetics in single-dose studies in healthy male subjects using doses of 1, 3, 10, 30 and 100 mg. In another study enobosarm was given to healthy subjects at doses of 1, 3, 10 and 30 mg over 14 days. Per data from GTx, Inc., the halflife ranged from 14–21 h with similar mean maximum plasma concentration and exposure in subjects of varying ages (Table 1) [20].
[...] to proceed with enobosarm into a phase III clinical trial in patients with sarcopenia, the FDA requested a cardiovascular safety study, which the manufacturer refused to undertake due to considerable costs and decided to test enobosarm in cancer cachexia patients in whom the FDA was more tolerant to the long-term cardiovascular side effects [67]. [...] Enobosarm promotes a similar anabolic response compared with DHT via muscle AR activation, [...] [35]. In a recent study with ovariectomized mice, the weight of the musculus gastrocnemius has been shown to be higher in all groups treated with ostarine as well as bone mineral density and bone biomechanical properties [15]. Moreover, the stimulation of reproductive organs with enobosarm seems to be less pronounced compared to testosterone administration [36] due to its partial agonist and antagonist effect on other androgen-dependent tissues such as prostate and seminal vesicles [37]. [...] In the POWER trials (POWER 1, NCT01355484 and POWER 2, NCT01355497; Table 1), double-blind, placebo-controlled, and multi-center phase III studies [40], patients with non-small-cell lung cancer were given 3 mg of enobosarm or placebo for five months. Despite a lower rate of decline in body weight in the group treated with enobosarm in POWER 1, patients increased LBM at day 84 and day 147 in POWER 1 (+0.41 kg) and POWER 2 (+0.47 kg) compared with patients receiving placebo. However, no physical function improvement has been reported in both studies [41].
Enobosarm has also been evaluated in two phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer 1 and 2 (POWER1 (NCT01355484) and POWER2 (NCT01355497)). [...] The co-primary endpoints of this trial were lean body mass (LBM) response and physical function response for enobosarm vs. placebo after 3 months of treatment. Beneficial effects on both LBM and physical function were found in POWER1, and benefit to LBM but equivocal effects on physical function were found in POWER2.
17α-alkylated AASs have been modified to be more resistant to liver degradation so that they have decreased first-pass metabolism, allowing for better oral bioavailability and more stable serum levels. However, reduced liver clearance increases the potential for hepatotoxicity.19 Much like this class of AASs, SARMs have been designed for adequate oral bioavailability with decreased liver degradation which would likely create a similar potential for hepatotoxicity.8,15 [...] Ostarine was the first SARM to undergo a phase III clinical trial. The POWER1 and POWER2 trials were two identical randomized, double-blind, placebo-controlled studies to evaluate the efficacy of Ostarine for the treatment of muscle wasting in non-small cell lung cancer. Participants were given 3 mg of Ostarine versus placebo. No study results were published; but GTx Incorporated reported that Ostarine failed to meet endpoints for improvement in lean body mass and physical function compared with placebo.
Anabolic androgenic steroids (AASs) comprise synthetic derivatives of testosterone. AASs bind directly to the cytosolic androgen receptor (AR), which is widely distributed across reproductive and non-reproductive tissues, including the prostate, skeletal muscle, liver, skin, and central nervous system (CNS). This binding results in various physiological activities [1], the major one being a masculinizing effect in the skeletal muscle via muscle building [2].
Additionally, reported SARM-induced fat free mass increases are a mere fraction of that reported in modest doses of testosterone derivatives in similar timeframes (~1.5kg versus ~7kg in SARMs and testosterone, respectively) [21].
Selective AR modulators (SARMs) are a class of drugs in development; unlike androgen synthesis inhibitors, they act as selective androgen agonists and show promise as a potential therapeutic strategy in BCa. Enobosarm (GTx024) is the farthest along in clinical development, and demonstrates an agonist effect that in some populations inhibits BCa growth. Preclinical data show antitumor activity of GTx-024 in ARC stably expressing cell lines MCF-7 (ERC) and MDA-MB-231 (TNBC) implanted subcutaneously into nude mice. Tumor growth was reduced more than 75% in MDA-MB-231-AR cells and 50% in MCF-7-AR cells compared with vehicle-treated tumors, demonstrating benefit (Dalton et al. 2013).
Enobosarm, a selective androgen receptor modulator (SARM) has been evaluated in 24 completed or ongoing clinical trials enrolling over 1,500 subjects, of which approximately 1,000 subjects were treated with enobosarm at doses ranging from 0.1 mg to 100 mg.
Common low-grade side effects of ostarine include headache, nausea, fatigue, and back pain. Other observed effects include increases in alanine transaminase and decreases in HDL, blood glucose, and insulin resistance, all of which returned to normal upon stopping ostarine treatment [1,35]. Information from bodybuilding forums and fitness enthusiasts cited 10 mg to 30 mg daily as the optimal dose for a minimum of 12 weeks, which is 10 times higher than the clinically studied dose, with anecdotal evidence suggesting that taking ostarine for much longer than this can suppress free T levels [1].
The reductions in SHBG [with enobosarm] in men and women (−61% and −80%, respectively, at the 3-mg dose) exceed those observed in men treated with a 600-mg intramuscular testosterone enanthate (−31%) [41].
The next invention was that of the first non-steroidal androgen by Dalton et al. [111] in 1998, six decades after the first non-steroidal estrogen [112]. This creates a new class of non-steroidal synthetic androgen, often termed Specific Androgen Receptor Modulators (SARM), a misleading marketing term rather than an accurate pharmacological description [113,114], usurping a speculative but unsound analogy with Specific Estrogen Receptor Modulators (SERM). [...] none of the non-steroidal androgens under development [116,117] are marketed by 2021. Yet hope springs eternal for this new attempt to separate anabolic from androgenic properties of androgens to facilitate marketing for muscle wasting and other selective effects of testosterone.
Although development of the first nonsteroidal androgens (17, 18) as candidate selective AR modulators (19) raises hope of resurrecting this defunct term (20), prereceptor activation mechanisms cannot apply to nonsteroidal androgens, and the singular AR lacks a dual drive mechanism of the other paired sex steroid receptors. Consequently, it is not surprising that available knowledge (21) provides only slender hope that this failed, and probably false, dichotomy will now succeed through a renewed search guided by the same in vivo bioassay.
It is worth noting that SARMs were initially developed to get benefit of their anabolic effect on muscle and bone without much harm to other tissues. One randomized controlled trial [28], recruited male and females with cancer and weight loss showed that enobosarm 1 mg or 3 mg was associated with significant increase in lean body mass compared to placebo. This led to another ongoing trial, with more selection, aiming to evaluate enobosarm (with higher doses 9 or 18 mg) effect on physical function and lean body mass of ER+/AR+ breast cancer patients (NCT02463032). Such additional action of this class of drugs carries major hope for patients with AR-positive advanced breast cancer, where weight loss, muscle weakness and physical inactivity represent a big challenge for the patient's quality of life (QOL).
New information on elimination kinetics and potential drug-drug interactions of the SARM GTx-024 (Enobosarm, Ostarine, S-22, MK-2866) was presented by Coss et al. indicating maximum plasma concentrations of the intact drug and its glucuronic acid conjugate of ca. 60 and 100 ng/mL, respectively, reached between 1 and 2 h following an oral dose of 3 mg.[85] The CYP3A4 inhibitor itraconazole did not affect pharmacokinetic parameters of GTx-024, while the CYP3A4 inducer rifampin reduced maximum plasma concentrations significantly. Conversely, the UGT-inhibitor probenecid increased levels of both GTx-024 and its glucuronide.
The structure and name of Ostarine (GTx-024, MK-2866, Enobosarm, S-22) were disclosed by the USAN Council in November 2011 to establish it as a first member of a new class of drugs furthest in clinical development (Structure 2 in Scheme 1).
At the doses that have been tested, the first generation SARMs induce modest gains in lean body mass in healthy volunteers, which are nowhere near the much greater gains in skeletal muscle mass reported with supraphysiological doses of testosterone. The modest gains of 1.0 to 1.5 kg in fat-free mass with first generation SARMs over 4–6 weeks should be contrasted with the 5–7 kg gains in fat-free mass with 300 and 600 mg doses of testosterone enanthate. However, it is possible that next generation of SARM molecules will have greater potency and selectivity than the first generation SARMs.
Physiologically N/C interaction is indispensable because it delays ligand dissociation from the receptor, protects the ligand binding pocket, and prevents receptor degradation [118]. That N/C interaction is essential in AR physiology is demonstrated by the identification of AR LBD mutations resulting in androgen insensitivity syndromes (AIS) that disrupt N/C interaction without affecting the equilibrium binding affinity for the ligand [119, 120].
Enobosarm was discovered in 2004 as a hyper-myoanabolic SARM that dissociated the anabolic from androgenic effects of AR in terms of potency (ED50) and efficacy (Emax) [29]. Levator ani muscle weight was increased to 131 and 136% of intact controls in intact and castrated (maintenance mode) rats, respectively, without significant increases in ventral prostate and seminal vesicles weights. Importantly, increases in levator ani muscle weight were associated with increases in muscle strength (soleus) in rats. Enobosarm also exerted in-vivo osteoanabolic effects alone and synergistically with alendronate in terms of bone density, strength, and structure [30], which was explained by in-vitro mechanistic studies that demonstrated antiresorptive (osteoclast inhibition) and anabolic (osteoblast differentiation) effects [31].
Similar to other N-arylpropionamide SARMs, in male rats treated for 14 days at 1 mg/day dose S-22 (17) exhibited increased levator ani muscle weight but significantly reduced prostate weight [...]
The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001).
Anabolic–androgenic steroids (AAS) are a class of natural and synthetic hormones that owe their name to their chemical structure (the steroid nucleus, see Figure 1) and the biological effects (anabolic and androgenic) they induce. Anabolic refers to the skeletal muscle-building properties of AAS, whereas androgenic refers to the induction and maintenance of male secondary sexual characteristics (which in principle includes the anabolic action, thereby rendering the term an oxymoron (1)).
Parenteral routes of sex steroid administration. Liver effects could also be diminished by using routes of administration other than oral. First pass effects would be avoided. [...] Although this discussion has focused predominantly on contraceptives, similar principles seem applicable for diminishing the liver side-effects of androgenic preparations. Thus, androgens should be selected which are likely to be metabolized on entering the hepatocyte and a parenteral route of administration may be preferable. Androgens which are not 17 alkylated might produce fewer liver side-effects than 17 alkylated derivatives judging from their relative effects on plasma protein levels [Z].
Androgen and oestrogen receptors have been demonstrated in mammalian liver, but since it is generally accepted that they are probably non-functional at endogenous steroid concentrations, it is not apparent how they mediate physiological influences on this organ. Nor is it certain to what extent pharmacological actions of sex hormones reflect overstimulation of physiological routes or whether alternative mechanisms become available once threshold values have been reached. [...] Many of the dangers inherent in synthetic androgen or anabolic steroid therapy may be due less to the androgenic characteristics than to the structural modifications performed to prevent [hepatic] inactivation (e.g. insertion of an acetylene group at 17α).
Both male (androgens) and female (oestrogens, progestins) sex hormones are steroid hormones. [...] these compounds have several properties in common: they are small, very lipophilic molecules with the potential to freely diffuse through cell membranes. Their receptors also share important features: in all animals, the receptors for steroid hormones are part of the nuclear receptor superfamily of ligand-triggered transcription factors (Mangelsdorf et al. 1995). Unlike membrane receptors that trigger intracellular signalling pathways, these receptors work by influencing gene expression in the cell.
Intracellular receptors account for 10% to 15% of drugs on the market, including drugs that act on cytoplasmic receptors such as androgen receptors (ARs), estrogen receptors, progesterone receptors, and glucocorticoid receptors, and other drugs that act on nuclear receptors such as vitamin D receptor (VDR), thyroid hormone receptors, and peroxisome proliferator-activated receptors [27-30]. Ligands of intracellular receptors include lipophilic vitamins, steroid hormones, and small chemicals such as hydrogen peroxide and nitric oxide, which require membrane permeability for intracellular delivery [30,31]. There are several barriers to the intracellular delivery of therapeutic drugs, such as lysosome degradation and active efflux out of the cell. Lowmolecular-weight lipophilic compounds can diffuse directly into cells, whereas high-molecular-weight compounds usually need membrane transporters or endocytosis [32,33]. Proper entry into the cell and subsequent contact with the exact target lead to better therapeutic effects and reduce undesirable adverse effects [34].
Bone-sparing effects of antiandrogen monotherapy might be due to selective AR modulators, tissue-specific and androgen-responsive, not affected by antiandrogen therapy, resulting in testosterone still being active in bone during non-steroidal antiandrogen administration [90].
Readers are cautioned to note that the name Ostarine is often mistakenly linked to the chemical structure of 8, which is also known as andarine. The chemical structure of Ostarine has not been publicly disclosed. The authors are unable to provide additional information.
Enobosarm: (2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide
One of the NFL's highest-paid offensive linemen claimed Wednesday that he did not knowingly take a banned substance he says got him a four-game suspension — and he took a polygraph test in an attempt to prove it.
