Analysis of information sources in references of the Wikipedia article "Enobosarm" in English language version.
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.
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].
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.
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).
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.
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).
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.
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.
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.
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.
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.
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).
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].
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.
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)).
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].
[...] 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.
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].
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).
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).
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).
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].
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.
Enobosarm: (2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide
