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 100mg 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 in phase 3clinical trials for the treatment of breast cancer and is in phase 2 studies for improvement of body composition in people taking GLP-1 receptor agonists.[1][9] Enobosarm was developed by GTx, Inc., and is now being developed by Veru, Inc.[1]
Aside from its development as a potential pharmaceutical drug, enobosarm is on the World Anti-Doping Agencylist of prohibited substances and is sold for physique- and performance-enhancing purposes by black-market Internet suppliers.[10][17] In one survey, 2.7% of young male gym users reported using SARMs.[23] In addition, a London wastewater analysis found that enobosarm was the most abundant "pharmaceutical drug" detected and was more prevalent than recreational drugs like MDMA and cocaine.[24] Enobosarm is often used in these contexts at doses greatly exceeding those evaluated in clinical trials, with unknown effectiveness and safety.[17] Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances.[17][25]Social media has played an important role in facilitating the widespread non-medical use of SARMs.[26]
In small short-term (3-month) clinical trials in healthy elderly or postmenopausal women, enobosarm at doses ranging from 0.1 to 3mg/day had mixed effects on sebum production and did not increase body hairgrowth or cause hirsutism.[31][28] These effects are measures of androgenic action in skin and hair follicles.[31] In the first study, at doses of 0.1 to 3mg/day, there were no significant changes relative to placebo in sebum tape scores with enobosarm and there were no consistent increases in Ferriman–Gallwey score, with most women having no change in score or a decreased score and only one having an increase in score.[31][28] In the second study, which employed 3mg/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.[31] No differences in sebaceous gland volume were apparent upon histological examination in this study.[31]
At doses ranging from 0.1 to 18mg/day in clinical trials, enobosarm has been associated with elevated liver enzymes in subsets of individuals.[12][16] Rates of elevated liver enzymes or of elevated alanine 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 necessitated discontinuation.[12] There have been several published case reports of hepatotoxicity with enobosarm as of 2023.[12][32][23][33][34][35][36] Between 2020 and 2022, there has been a rapid increase in reported cases of liver toxicity with SARMs.[32] The hepatotoxicity with SARMs may be related to their resistance to hepaticmetabolism, analogously to the case of 17α-alkylated anabolic steroids.[12]
SARMs are often advertised and sold on the Internet at doses higher than have been described in the literature.[17][27] Sometimes doses are recommended as several-fold or more greater than the doses used in clinical trials, or seemingly arbitrary doses are advised.[17][27] For instance, enobosarm has been provided at doses of greater than or equal to 20mg per serving and recommended by bodybuilders and fitness enthusiasts at doses of 10 to 30mg/day, relative to the most widely assessed highest dose in clinical trials of 3mg/day—an up to 10-fold difference.[17][27] SARMs, particularly when used at high or excessive doses for prolonged periods of time, may result in substantial suppression of endogenoussex hormones like testosterone and estradiol, 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 in estrogen deficiency with consequences like bone loss among others, and, due to suppression of the hypothalamic–pituitary–gonadal axis (HPG axis), may cause infertility.[17]
Enobosarm has been assessed in clinical trials at doses ranging from 0.1 to 18mg/day.[10] However, most research has been done at doses of 0.1 to 3mg/day, with two phase 3 clinical trials using a dosage of 3mg/day.[2][15][32][17] A few small phase 1 and phase 2 trials of enobosarm for breast cancer have employed doses of 9 to 18mg/day.[42][12][2][43] Larger, phase 3 trials of enobosarm at a dose of 9mg/day for breast cancer (e.g., ARTEST, n=210) are now underway.[44][45] Doses of up to 100mg have been assessed in single-dose pharmacokinetic studies and doses of up to 30mg/day have been given in short 14-day pharmacokinetic studies.[5] Enobosarm sold via black-market Internet suppliers and used non-medically is often taken at much higher doses than those used widely in clinical trials (e.g., 10–30mg/day), with unknown adverse effects and risks.[17][27]
Interactions
Enobosarm is a substrate of the cytochrome P450enzymeCYP3A4 and the UDP-glucuronosyltransferase (UGT) enzymes UGT1A1 and UGT2B7.[4] It shows very minimal metabolism 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 and inducers of these enzymes can modify the metabolism and pharmacokinetics of enobosarm.[4] The strong CYP3A4 inhibitor itraconazole was shown to have minimal to no influence on the pharmacokinetics of enobosarm, whereas the strong CYP3A4 inducer rifampin reduced enobosarm peak levels by 23%, elimination half-life by 23%, and area-under-the-curve levels by 43%.[46][4] The pan-UGT inhibitor probenecid 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%.[46][4] Enobosarm had no effect on the pharmacokinetics of celecoxib (a CYP2C9 substrate) or rosuvastatin (a BCRP substrate).[4] Based on the preceding findings, it was concluded that enobosarm poses low risk for clinically relevant drug interactions.[4]
The molecular mechanisms underlying the tissue-selective effects of enobosarm and other SARMs compared to testosterone and other androgens and anabolic steroids remain unknown.[51][17] However, recruitment of both coactivators and corepressors instead of only coactivators and resultant differing receptor conformations, distinct tissue-specific modulation of signaling pathways mediating genomic and non-genomic effects, and differences in within-tissue ligandmetabolism and modulation of ligand potency (i.e., potentiation versus lack thereof), among others, all constitute possible mechanisms.[51][17][52] In terms of coregulator 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.[51] Another mechanism may be that SARMs like enobosarm induce the N/C interaction less readily than AR full agonists like DHT.[17][47][53][49] Induction of the N/C interaction has been associated with the effects of endogenous and exogenous AR agonists, for instance virilization and prostate growth.[47][49][54][55]
In animal studies, enobosarm has shown potent muscle-promoting effects that were similar to those of testosterone and DHT.[7][10][56][57][58][48] 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 an ED50 dose for muscle of 0.03mg/day.[56][51][48] For comparison, testosterone propionate was able to maximally stimulate levator ani muscle to 104% and prostate weight to 121%, with ED50 doses of 0.15mg/day and 0.13mg/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.[51][48][7] Additionally, enobosarm fully maintained or restored levator ani weight at doses that did not affect LH or FSH levels in gonadally intact animals (≤0.1mg/day).[7] As such, it was more potent in stimulating muscle than testosterone at doses that did not affect gonadotropin 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][59][58] 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 a phase 2 human clinical trial in healthy elderly men and postmenopausal women, enobosarm dose-dependently increased lean body mass (muscle mass) across doses of 0.1, 0.3, 1, and 3mg/day, with a significant 1.3kg gain over placebo at 3mg/day and a non-significant 0.7kg gain over placebo at 1mg/day.[10][28] Similarly, in two phase 3 clinical trials in men and postmenopausal women with muscle wasting due to non-small-cell lung cancer, enobosarm at 3mg/day significantly increased lean body mass by 0.41kg and 0.47kg.[10] However, enobosarm did not successfully increase muscle strength in these phase 3 trials.[10] In any case, it has been suggested that the study designs and physical function outcomes in such trials may have been flawed.[60][61][62][63][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., 0.5–1.5kg with enobosarm versus 5–8kg with 300–600mg/week intramuscular testosterone enanthate in healthy young men).[53][17][64] The effects of higher doses of enobosarm (9–18mg/day) on lean body mass and muscle strength are also being evaluated in women with breast cancer.[2][43] There is some evidence that women may be more sensitive to lean body mass increases with SARMs, specifically GSK-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.[37][31][18][52] The virilizing and androgenic effects of the traditional steroidal androgens like testosterone in skin, hair follicles, and the prostate gland are attributed to high expression of 5α-reductase in these tissues and consequent local conversion and potentiation into more potent androgens.[37][31][18] In the case of testosterone, this is via conversion into the 10-fold more potent androgen DHT.[31][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.[31][18][20] This is likewise theorized to be the case for non-5α-reductase-potentiated anabolic steroids like nandrolone and oxandrolone, which have high myotrophic–androgenic potency ratios in animals.[37] The lack of 5α-reduction may result in reduced androgenic side effects like scalp hair loss, facial and body hair growth, and prostate growth.[20][65][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.[37][17] In particular, the muscle-promoting effects of these agents can be considered a masculinizing effect.[16][66] 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 the liver, specifically on certain aspects of hepatic protein synthesis like reduction of sex hormone-binding globulin (SHBG) production, than even highly supraphysiological doses of parenteraltestosterone.[28] This phenomenon has also been seen with other SARMs, such as LGD-4033,[17][32][16][67] as well as with synthetic orally active 17α-alkylated anabolic steroids like stanozolol.[20][68][69] It can be attributed to the first pass through the liver with oral administration and to the high oral bioavailability and strong resistance to hepatic metabolism of these agents.[20][70][71][12]
Enobosarm is orallybioavailable due to a lack of extensive first-pass metabolism.[18] In rats, the oral bioavailability of enobosarm was found to be 100%.[3] Enobosarm is rapidly absorbed with oral administration and reaches maximal concentrations median 1.0hours (range 1.0–2.0hours) following administration.[46][5][4] The drug reaches a peak concentration of 56.0ng/mL (range 53.1–123.0ng/mL) following a single 3mg dose and a steady-state peak of 68.1ng/mL following repeated 3mg doses.[46][4] The pharmacokinetics of enobosarm are linear and proportional over a dose range of 1 to 100mg in single doses in healthy men.[5][7] The pharmacokinetics of enobosarm are similar in young versus elderly individuals.[7] A concentration–time curve of enobosarm levels following a single oral dose of enobosarm in humans has been published.[7]
Coadministration of the strong CYP3A4 inhibitoritraconazole had minimal impact on the pharmacokinetics of enobosarm and enobosarm glucuronide, whereas the strong CYP3A4 inducerrifampin reduced enobosarm peak levels by 23%, elimination half-life by 23%, and area-under-the-curve levels by 43%.[46][4] Coadministration of the pan-UGT inhibitor probenecid 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%.[46][4] These data are consistent with the preclinical findings that enobosarm is a substrate of CYP3A4 and UGT enzymes.[4]
The metabolism of enobosarm is similar to that of the closely structurally related drug bicalutamide.[3]
Elimination
In rats, enobosarm was excreted approximately 70% in feces and 21 to 25% in urine.[3]
Enobosarm has an elimination half-life of approximately 14 to 24hours in human volunteers.[5][6][7] In one pharmacokinetic study, the mean terminal half-life was 22.0 ± 5.8 (SD) hours, with a range of 13.7 to 31.3hours in different individuals[4]
Enobosarm and related SARMs like acetothiolutamide, andarine (acetamidoxolutamide; GTx-007; S-4), and GTx-027 were derived from structural modification of the arylpropionamide nonsteroidal antiandrogenbicalutamide.[77][18][78][20][79] They are nonsteroidal arylpropionamides themselves and are close structural analogues of bicalutamide.[18][78][79][80] 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.[81] 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.[82][83][84]
Enobosarm (S-22) and andarine (S-4) and their chemical structures have sometimes been confused.[85] The chemical structure of enobosarm was not disclosed until November 2011.[47][85]
Novel nonsteroidal antiandrogens have been developed from enobosarm with enhanced potency and activity relative to conventional antiandrogens like bicalutamide and enzalutamide.[86][87]
History
The first SARMs were arylpropionamides derived from the nonsteroidal antiandrogenbicalutamide.[7][88] They were discovered by James T. Dalton and colleagues at the University of Tennessee and other institutions and were first described in a paper published in 1998.[7][88][89] At the time, these AR agonists were referred to as "nonsteroidal androgens", a drug class that had not been previously described.[90] By 1999 however, on the basis of the selective estrogen receptor modulator (SERM)-like mixed agonist–antagonist and tissue-selective activity of these nonsteroidal AR agonists, the term "selective androgen receptor modulator" or "SARM" was introduced and adoption of this name had begun.[90] The arylpropionamide SARM andarine (GTx-007; S-4) was first described in the literature by 2002.[91][92][93] In 2003, arylpropionamide AR agonists, including andarine, were first reported to possess SARM-type tissue selectivityin vivo.[47][92] Enobosarm (GTx-024; S-22), another arylpropionamide SARM, was first identified in 2004[11][89] and was first described in the literature in 2005.[18][48][89]GTx, a pharmaceutical company founded in Memphis, Tennessee in 1997, licensed the rights to enobosarm from the University of Tennessee Research Foundation and began developing it as a pharmaceutical drug.[1][89]
A phase 1clinical trial employing enobosarm had been completed by 2005.[18] By 2007, enobosarm was in a phase 2 trial, and that year GTx signed an exclusive license agreement for its SARM program with Merck & Co.[94] The companies ended the deal in 2010.[95] In August 2011, there was a 12-week double-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.[28] In August 2013, GTx announced that enobosarm had failed in two phase 3 clinical trials to treat wasting in people with lung cancer.[96] The company had invested around $35 million in the development of the drug.[97] The company said at that time that it planned to pursue approval of enobosarm in Europe; the company was also still developing GTx-758, a nonsteroidal estrogen, for castration-resistant prostate cancer.[98] As of 2018, enobosarm was the only SARM to have reached or completed phase 3 clinical trials.[51]
In 2016, GTx began phase 2 trials, to see if enobosarm might be effective to treat stress urinary incontinence in women.[99] 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.[100] By September 2023, development of enobosarm for stress urinary incontinence had been discontinued.[1] In 2022, the FDA granted fast tract designation to enobosarm in AR+, ER+, HER2- metastaticbreast cancer.[101] In January 2024, Veru Inc. submitted an Investigational New Drug application to the FDA of enobosarm for prevention of muscle loss and augmentation of fat loss in combination with glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide for weight loss.[9] In addition, they announced plans to conduct a phase 2b study of enobosarm at doses of 3 to 6mg/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]
Society and culture
Names
Enobosarm is the generic name of the drug and its International Nonproprietary Name (INN).[102] 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]
Non-medical use
Enobosarm and other SARMs are sold by black-market vendors on the Internet.[17][25] These agents have increasingly become used by the general public as "gym supplements" such as pre-workout or lifestyle drugs, rather than as an aid to performance in athletic or bodybuilding competitions. In one survey, 2.7% of young male gym users in the Netherlands reported using SARMs.[23] In addition, a 2018 analysis of a fatberg from a sewer in central London showed enobosarm to be the most abundant "pharmaceutical drug" detected, and was present at higher concentration than recreational drugs such as MDMA and cocaine. 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.[24] Doses of enobosarm sold online and used non-medically are often many times higher than those assessed in clinical trials.[17][27] Aside from enobosarm, the other most commonly used SARMs include vosilasarm (RAD140; "testolone"), LGD-4033 (VK5211; "ligandrol"), and andarine (GTx-007; S-4).[26] 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][25]Social media has played an important role in facilitating the widespread non-medical use of SARMs.[26]
Doping in sport
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 to anabolic steroids. For this reason, SARMs were banned by the World 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.[103][104] There are a variety of known cases of doping in sports with enobosarm by professionalathletes.
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 and andarine.[105]
In October 2018, UFC fighter Sean O'Malley tested positive for Enobosarm and was suspended by the Nevada State Athletic Commission and USADA 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 at UFC 248 as long as he kept his levels below the threshold of 100ng/ml.[106]
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 were suspended—Dexter Lawrence, Braden Galloway and Zach Giellaall—tested positive for a substance known as enobosarm. On June 23, 2019 Clemson did not release enobosarm investigation findings, citing privacy law.[107]
In July 2019, National Football League player Taylor Lewan failed a drug test for Enobosarm, which Lewan claimed he ingested accidentally as an unlabeled ingredient in a supplement.[108]
On October23, 2020, the Union Cycliste Internationale (UCI) announced that the Italian rider Matteo 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.[109]
On August12, 2021, after the 2020 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 and S-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.[111] Finally in February 2022, Great Britain were stripped of their silver medal.[112] In October 2022, Ujah was suspended for 22 months by the ITA.[113]
In October 2021, two Thoroughbred horses named Arafat and Komunist tested positive for enobosarm after races at Woodbine Racetrack. In a decision of the Alcohol 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.[114]
In May 2022, National Football League Wide 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.[115]
In April 2023, British boxer Amir Khan was banned for two years after an anti-doping test revealed the presence of enobosarm following his fight against Kell Brook in February 2022.[116]
On May 1, 2024, American boxer Ryan 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.[117]
Enobosarm was assessed for the treatment of muscle wasting in people with lung cancer in two phase 3clinical trials.[11][2][12][13] The findings of these trials were reported in 2013.[13] Enobosarm significantly improved lean body mass in the trials, but it was not effective in improving muscle 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 of stress urinary incontinence in postmenopausal women.[1][2] It was expected that enobosarm might be effective for this use by strengthening the pelvic floor muscles.[1][2] Enobosarm reached phase 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 of androgen 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][44][45] Increases in lean body mass and muscle strength as a secondary benefit with enobosarm are also being evaluated in these women.[2][43] These trials are notably employing several-fold higher doses of enobosarm than were assessed in the muscle wasting phase 3 trials (9mg/day versus 3mg/day, respectively).[2][43]
In January 2024, it was announced that enobosarm was being developed for prevention of muscle wasting and augmentation of fat loss in combination with glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide for weight loss.[9] A phase 2b clinical trial for this indication with 3 to 6mg/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 100mg as of 2020.[10][22] However, enobosarm has not yet completed clinical development or been approved for any use.[1][2]
Nandrolone decanoate, sold under the brand names Rolon and Deca-Durabolin, among others, is an androgen and anabolic steroid (AAS) medication which is used primarily in the treatment of anemias and wasting syndromes, as well as osteoporosis in menopausal women. It is given by injection into muscle or fat once every one to four weeks.
Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in specific tissues, promoting muscle and bone growth while having less effect on male reproductive tissues like the prostate gland.
Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolic steroids have a number of medical uses, but are also used by athletes to increase muscle size, strength, and performance.
BMS-564,929 is an investigational selective androgen receptor modulator (SARM) which is being developed by Bristol-Myers Squibb for treatment of the symptoms of age-related decline in androgen levels in men ("andropause"). These symptoms may include depression, loss of muscle mass and strength, reduction in libido and osteoporosis. Treatment with exogenous testosterone is effective in counteracting these symptoms but is associated with a range of side effects, the most serious of which is enlargement of the prostate gland, which can lead to benign prostatic hypertrophy and even prostate cancer. This means there is a clinical need for selective androgen receptor modulators, which produce anabolic effects in some tissues such as muscle and bone, but without stimulating androgen receptors in the prostate.
S-40503 is an investigational selective androgen receptor modulator (SARM) developed by the Japanese company Kaken Pharmaceuticals, which was developed for the treatment of osteoporosis. SARMs are a new class of drugs which produce tissue-specific anabolic effects in some tissues such as muscle and bone, but without stimulating androgen receptors in other tissues such as in the prostate gland, thus avoiding side effects such as benign prostatic hypertrophy which can occur following treatment with unselective androgens like testosterone or anabolic steroids.
LGD-2226 is an investigational selective androgen receptor modulator (SARM), which is being developed for treatment of muscle wasting and osteoporosis.
Andarine is a selective androgen receptor modulator (SARM) which was developed by GTX, Inc for the treatment of conditions such as muscle wasting, osteoporosis, and benign prostatic hypertrophy (BPH), using the nonsteroidal antiandrogen bicalutamide as a lead compound. Development of andarine for all indications has been discontinued, in favor of the structurally related and improved compound enobosarm.
LGD-4033, also known by the developmental code name VK5211 and by the black-market name Ligandrol, is a selective androgen receptor modulator (SARM) which is under development for the treatment of muscle atrophy in people with hip fracture. It was also under development for the treatment of cachexia, hypogonadism, and osteoporosis, but development for these indications was discontinued. LGD-4033 has been reported to dose-dependently improve lean body mass and muscle strength in preliminary clinical trials, but is still being developed and has not been approved for medical use. The drug is taken by mouth.
Vosilasarm, also known by the development codes RAD140 and EP0062 and by the black-market name Testolone or Testalone, is a selective androgen receptor modulator (SARM) which is under development for the treatment of hormone-sensitive breast cancer. It is specifically under development for the treatment of androgen receptor-positive, estrogen receptor-negative, HER2-negative advanced breast cancer. Vosilasarm was also previously under development for the treatment of sarcopenia, osteoporosis, and weight loss due to cancer cachexia, but development for these indications was discontinued. The drug is taken by mouth.
Nandrolone phenylpropionate (NPP), or nandrolone phenpropionate, sold under the brand name Durabolin among others, is an androgen and anabolic steroid (AAS) medication which has been used primarily in the treatment of breast cancer and osteoporosis in women. It is given by injection into muscle once every week. Although it was widely used in the past, the drug has mostly been discontinued and hence is now mostly no longer available.
Acetothiolutamide is a selective androgen receptor modulator (SARM) derived from the nonsteroidal antiandrogen bicalutamide that was described in 2002 and was one of the first SARMs to be discovered and developed. It is a high-affinity, selective ligand of the androgen receptor (AR), where it acts as a full agonist in vitro, and has in vitro potency comparable to that of testosterone. However, in vivo, acetothiolutamide displayed overall negligible androgenic effects, though significant anabolic effects were observed at high doses. In addition, notable antiandrogen effects were observed in castrated male rats treated with testosterone propionate. The discrepancy between the in vitro and in vivo actions of acetothiolutamide was determined to be related to rapid plasma clearance and extensive hepatic metabolism into a variety of metabolites with differing pharmacological activity, including AR partial agonism and antagonism. In accordance with its poor metabolic stability, acetothiolutamide is not orally bioavailable, and shows activity only via injected routes such as subcutaneous and intravenous.
LG121071 is a selective androgen receptor modulator (SARM) developed by Ligand Pharmaceuticals that was first described in 1999 and was the first orally active nonsteroidal androgen to be discovered. It is a tricyclic quinolone derivative, structurally distinct from other nonsteroidal AR agonists like andarine and enobosarm (ostarine). The drug acts as a high-affinity full agonist of the androgen receptor (AR), with a potency and efficacy that is said to be equivalent to that of dihydrotestosterone (DHT). Unlike testosterone, but similarly to DHT, LG121071 and other nonsteroidal androgens cannot be potentiated by 5α-reductase in androgenic tissues, and for this reason, show tissue-selective androgenic effects. In accordance, they are said to possess full anabolic activity with reduced androgenic activity, similarly to anabolic-androgenic steroids.
MK-0773, also known as PF-05314882, is a steroidal, orally active selective androgen receptor modulator (SARM) that was under development by Merck and GTx for the treatment of sarcopenia in women and men. Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter. MK-0773 was developed as a more advanced version of the related compound TFM-4AS-1.
The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.
JNJ-37654032 is a selective androgen receptor modulator (SARM) which was developed by Johnson & Johnson for the potential treatment of muscular atrophy but was never marketed.
JNJ-26146900 is a selective androgen receptor modulator (SARM) which was developed by Johnson & Johnson for the potential treatment of prostate cancer but was never marketed.
GTx-027 is a selective androgen receptor modulator (SARM) which was under development for or of potential interest in the treatment of breast cancer and stress urinary incontinence (SUI) but was never marketed. It is taken by mouth.
MK-4541 is a dual selective androgen receptor modulator (SARM) and 5α-reductase inhibitor (5α-RI) which has been of interest for the potential treatment of prostate cancer but has not been marketed at this time. It is intended for use by mouth.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Christiansen AR, Lipshultz LI, Hotaling JM, Pastuszak AW (March 2020). "Selective androgen receptor modulators: the future of androgen therapy?". Translational Andrology and Urology. 9 (Suppl 2): S135–S148. doi:10.21037/tau.2019.11.02. PMC7108998. PMID32257854. 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.
1 2 3 4 5 6 Kim J, Wang R, Veverka KA, Dalton JT (November 2013). "Absorption, distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 43 (11): 993–1009. doi:10.3109/00498254.2013.788233. PMID24074268. S2CID6545249.
1 2 3 4 5 6 7 8 Srinath R, Dobs A (February 2014). "Enobosarm (GTx-024, S-22): a potential treatment for cachexia". Future Oncology. 10 (2): 187–194. doi:10.2217/fon.13.273. PMID24490605. 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].
1 2 3 4 5 6 Zilbermint MF, Dobs AS (October 2009). "Nonsteroidal selective androgen receptor modulator Ostarine in cancer cachexia". Future Oncology. 5 (8): 1211–1220. doi:10.2217/fon.09.106. PMID19852734.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Fonseca GW, Dworatzek E, Ebner N, Von Haehling S (August 2020). "Selective androgen receptor modulators (SARMs) as pharmacological treatment for muscle wasting in ongoing clinical trials". Expert Opinion on Investigational Drugs. 29 (8): 881–891. doi:10.1080/13543784.2020.1777275. PMID32476495. S2CID219174372. [...] 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].
1 2 3 4 5 6 7 8 Wu C, Kovac JR (October 2016). "Novel Uses for the Anabolic Androgenic Steroids Nandrolone and Oxandrolone in the Management of Male Health". Current Urology Reports. 17 (10): 72. doi:10.1007/s11934-016-0629-8. PMID27535042. S2CID43199715. 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.
1 2 3 4 5 6 7 8 9 10 11 12 Mohideen H, Hussain H, Dahiya DS, Wehbe H (February 2023). "Selective Androgen Receptor Modulators: An Emerging Liver Toxin". Journal of Clinical and Translational Hepatology. 11 (1): 188–196. PMC9647117. PMID36479151. 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.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Choi SM, Lee BM (2015). "Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids". Expert Opinion on Drug Safety. 14 (11): 1773–1785. doi:10.1517/14740338.2015.1094052. PMID26401842. S2CID8104778. 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].
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Machek SB, Cardaci TD, Wilburn DT, Willoughby DS (December 2020). "Considerations, possible contraindications, and potential mechanisms for deleterious effect in recreational and athletic use of selective androgen receptor modulators (SARMs) in lieu of anabolic androgenic steroids: A narrative review". Steroids. 164: 108753. doi:10.1016/j.steroids.2020.108753. PMID33148520. S2CID225049089. 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].
1 2 Proverbs-Singh T, Feldman JL, Morris MJ, Autio KA, Traina TA (June 2015). "Targeting the androgen receptor in prostate and breast cancer: several new agents in development". Endocrine-Related Cancer. 22 (3): R87–R106. doi:10.1530/ERC-14-0543. PMC4714354. PMID25722318. 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).
1 2 3 4 5 6 7 8 9 10 11 Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, etal. (5 October 2020). "Androgen Physiology, Pharmacology, Use and Misuse". Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. PMID25905231.
↑ Zajac JD, Seeman E, Russell N, Ramchand SK, Bretherton I, Grossmann M, etal. (2020). "Testosterone". Encyclopedia of Bone Biology. Academic Press. pp.533–550. ISBN978-0-12-814082-6.
1 2 3 4 5 6 Hall E, Vrolijk MF (July 2023). "Androgen Receptor and Cardiovascular Disease: A Potential Risk for the Abuse of Supplements Containing Selective Androgen Receptor Modulators". Nutrients. 15 (15): 3330. doi:10.3390/nu15153330. PMC10420890. PMID37571268. 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].
↑ Mertens JE, Bömmer MT, Regier MB, Gabriëls G, Pavenstädt H, Grünewald I, etal. (October 2023). "Liver Injury after Selective Androgen Receptor Modulator Intake: A Case Report and Review of the Literature". Zeitschrift für Gastroenterologie. doi:10.1055/a-2165-6323. PMID37871633. S2CID264426934.
↑ Liang JY, Chang HC, Hsu GL (2018). "Penis Endocrinology". In Skinner MK (ed.). Encyclopedia of Reproduction. Elsevier Science. p.376. ISBN978-0-12-815145-7. Retrieved 23 December 2023.
↑ Handelsman DJ (July 2022). "History of androgens and androgen action". Best Practice & Research. Clinical Endocrinology & Metabolism. 36 (4): 101629. doi:10.1016/j.beem.2022.101629. PMID35277356. 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.
↑ Handelsman DJ (May 2011). "Commentary: androgens and "anabolic steroids": the one-headed janus". Endocrinology. 152 (5): 1752–1754. doi:10.1210/en.2010-1501. PMID21511988. 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.
1 2 3 4 Kassem L, Shohdy KS, Makady NF, Salem DS, Ebrahim N, Eldaly M (2019-11-16). "Efficacy and Safety of Targeting Androgen Receptor in Advanced Breast Cancer: A Systematic Review". Current Cancer Therapy Reviews. 15 (3): 197–206. doi:10.2174/1573394714666180821145032. S2CID58234934. 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).
1 2 3 4 5 6 Thevis M, Kuuranne T, Geyer H, Schänzer W (January 2017). "Annual banned-substance review: analytical approaches in human sports drug testing". Drug Testing and Analysis. 9 (1): 6–29. doi:10.1002/dta.2139. PMID27885819. 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.
1 2 3 4 5 6 7 Zhang X, Sui Z (February 2013). "Deciphering the selective androgen receptor modulators paradigm". Expert Opinion on Drug Discovery. 8 (2): 191–218. doi:10.1517/17460441.2013.741582. PMID23231475. S2CID2584722. 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).
1 2 3 4 5 Kim J, Wu D, Hwang DJ, Miller DD, Dalton JT (October 2005). "The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators". The Journal of Pharmacology and Experimental Therapeutics. 315 (1): 230–239. doi:10.1124/jpet.105.088344. PMID15987833. S2CID30799845.
↑ Miner JN, Chang W, Chapman MS, Finn PD, Hong MH, López FJ, etal. (January 2007). "An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate". Endocrinology. 148 (1): 363–73. doi:10.1210/en.2006-0793. PMID17023534.
1 2 Bhasin S, Jasuja R (May 2009). "Selective androgen receptor modulators as function promoting therapies". Current Opinion in Clinical Nutrition and Metabolic Care. 12 (3): 232–240. doi:10.1097/MCO.0b013e32832a3d79. PMC2907129. PMID19357508. 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.
↑ Hohl A, Marcelli M (2023). "Androgen Receptor in Health and Disease". In Hohl A (ed.). Testosterone. Cham: Springer International Publishing. pp.21–75. doi:10.1007/978-3-031-31501-5_2. ISBN978-3-031-31500-8. 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].
↑ He B, Wilson EM (April 2002). "The NH(2)-terminal and carboxyl-terminal interaction in the human androgen receptor". Mol Genet Metab. 75 (4): 293–8. doi:10.1016/S1096-7192(02)00009-4. PMID12051960.
1 2 Dalton JT, Taylor RP, Mohler ML, Steiner MS (December 2013). "Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer". Current Opinion in Supportive and Palliative Care. 7 (4): 345–351. doi:10.1097/SPC.0000000000000015. PMID24189892. S2CID35120033. 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].
↑ Xie Y, Tian Y, Zhang Y, Zhang Z, Chen R, Li M, etal. (February 2022). "Overview of the development of selective androgen receptor modulators (SARMs) as pharmacological treatment for osteoporosis (1998-2021)". European Journal of Medicinal Chemistry. 230: 114119. doi:10.1016/j.ejmech.2022.114119. PMID35063736. S2CID245941791. 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 [...]
↑ Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, etal. (December 2001). "Testosterone dose-response relationships in healthy young men". American Journal of Physiology. Endocrinology and Metabolism. 281 (6): E1172–E1181. doi:10.1152/ajpendo.2001.281.6.E1172. PMID11701431. S2CID2344757. 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).
↑ Bond P, Smit DL, de Ronde W (2022). "Anabolic-androgenic steroids: How do they work and what are the risks?". Frontiers in Endocrinology. 13: 1059473. doi:10.3389/fendo.2022.1059473. PMC9837614. PMID36644692. 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)).
↑ Sinnecker G, Köhler S (June 1989). "Sex hormone-binding globulin response to the anabolic steroid stanozolol: evidence for its suitability as a biological androgen sensitivity test". The Journal of Clinical Endocrinology and Metabolism. 68 (6): 1195–1200. doi:10.1210/jcem-68-6-1195. PMID2723028.
↑ Eisenfeld AJ, Aten RF (1987). "Estrogen receptors and androgen receptors in the mammalian liver". Journal of Steroid Biochemistry. 27 (4–6): 1109–1118. doi:10.1016/0022-4731(87)90197-x. PMID3320548. 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].
↑ Lax ER (1987). "Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver". Journal of Steroid Biochemistry. 27 (4–6): 1119–1128. doi:10.1016/0022-4731(87)90198-1. PMID3320549. 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).
1 2 "Enobosarm". PubChem. U.S. National Library of Medicine.
1 2 Cleve A, Fritzemeier KH, Haendler B, Heinrich N, Möller C, Schwede W, etal. (2013). "Pharmacology and Clinical Use of Sex Steroid Hormone Receptor Modulators". Sex and Gender Differences in Pharmacology. Handbook of Experimental Pharmacology. Vol.214. pp.543–587. doi:10.1007/978-3-642-30726-3_24. ISBN978-3-642-30725-6. PMID23027466. 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.
1 2 Yoon JH, Kwon KS (June 2021). "Receptor-Mediated Muscle Homeostasis as a Target for Sarcopenia Therapeutics". Endocrinology and Metabolism. 36 (3): 478–490. doi:10.3803/EnM.2021.1081. PMC8258343. PMID34218646. 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].
↑ Mohd Fauzi F, Koutsoukas A, Cunningham A, Gallegos A, Sedefov R, Bender A (July 2013). "Computer-aided (in silico) approaches in the mode-of-action analysis and safety assessment of ostarine and 4-methylamphetamine". Human Psychopharmacology. 28 (4): 365–378. doi:10.1002/hup.2322. PMID23881885. S2CID22800581.
1 2 Hwang DJ, He Y, Ponnusamy S, Mohler ML, Thiyagarajan T, McEwan IJ, etal. (January 2019). "New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity". Journal of Medicinal Chemistry. 62 (2): 491–511. doi:10.1021/acs.jmedchem.8b00973. hdl:2164/13357. PMID30525603. S2CID54472127.
↑ Corona G, Rastrelli G, Vignozzi L, Maggi M (June 2012). "Emerging medication for the treatment of male hypogonadism". Expert Opinion on Emerging Drugs. 17 (2): 239–259. doi:10.1517/14728214.2012.683411. PMID22612692. S2CID22068249.
↑ Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety. 13 (11): 1483–1499. doi:10.1517/14740338.2014.966686. PMID25270521. S2CID207488100. 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].
↑ Allan G, Lai MT, Sbriscia T, Linton O, Haynes-Johnson D, Bhattacharjee S, etal. (January 2007). "A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats". The Journal of Steroid Biochemistry and Molecular Biology. 103 (1): 76–83. doi:10.1016/j.jsbmb.2006.07.006. PMID17049844. S2CID25283876.
↑ Wadhwa VK, Weston R, Parr NJ (June 2011). "Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer". BJU International. 107 (12): 1923–1929. doi:10.1111/j.1464-410X.2010.09726.x. PMID20950306. S2CID205543615.
1 2 Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, etal. (June 2009). "Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit". Journal of Medicinal Chemistry. 52 (12): 3597–3617. doi:10.1021/jm900280m. PMID19432422. 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.
1 2 Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD (March 1998). "Discovery of nonsteroidal androgens". Biochemical and Biophysical Research Communications. 244 (1): 1–4. doi:10.1006/bbrc.1998.8209. PMID9514878.
1 2 3 4 WO 2005120483,Dalton JT, Mille DD, Veverka KA,"Selective androgen receptor modulators and methods of use thereof",published 22 December 2005, assigned to University of Tennessee Research Foundation
1 2 Negro-Vilar A (October 1999). "Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium". The Journal of Clinical Endocrinology and Metabolism. 84 (10): 3459–3462. doi:10.1210/jcem.84.10.6122. PMID10522980.
↑ He Y, Yin D, Perera M, Kirkovsky L, Stourman N, Li W, etal. (August 2002). "Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor". European Journal of Medicinal Chemistry. 37 (8): 619–634. doi:10.1016/s0223-5234(02)01335-1. PMID12161060.
1 2 Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, etal. (March 2003). "Pharmacodynamics of selective androgen receptor modulators". The Journal of Pharmacology and Experimental Therapeutics. 304 (3): 1334–1340. doi:10.1124/jpet.102.040840. PMID12604714. S2CID14724811.
↑ Thevis M, Kohler M, Schlörer N, Kamber M, Kühn A, Linscheid MW, etal. (May 2008). "Mass spectrometry of hydantoin-derived selective androgen receptor modulators". Journal of Mass Spectrometry. 43 (5): 639–650. Bibcode:2008JMSp...43..639T. doi:10.1002/jms.1364. PMID18095383.
↑ Thevis M, Kohler M, Thomas A, Maurer J, Schlörer N, Kamber M, etal. (May 2008). "Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC-MS/MS". Analytical and Bioanalytical Chemistry. 391 (1): 251–261. doi:10.1007/s00216-008-1882-6. PMID18270691. S2CID206899531.
↑ Bieler D (25 July 2019). "Failed PED test has a highly paid offensive lineman sharing polygraph results". Washington Post. Retrieved 25 July 2019. 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.
This page is based on this Wikipedia article Text is available under the CC BY-SA 4.0 license; additional terms may apply. Images, videos and audio are available under their respective licenses.
