As humans, we’re always looking for a competitive advantage. Virtually all living organisms in the world compete with members of their own species. Some individuals are highly competitive and eager to get access to high-quality resources, while others seem to avoid competition all together. SARMS or selective androgen receptor modulators are highly bioavailable investigational non-steroidal alternatives to anabolic steroids, made to help mitigate the long-term side effects. We’re going to talk about what SARMS are, the most popular types of SARMS and how they work.
In this series, we will be comprehensively discussing individual selective androgen receptor modulators (SARMS), their uses, benefits, and preclinical as well as clinical data.
In this series we will be covering the most common and well known SARMS
As well, as SARM like compounds
Selective androgen receptor modulators (SARMS) are non-steroidal compounds that promote anabolism, that bind to selective androgen receptors. SARMS were developed in the early 2000s, in an attempt to overcome the pharmacologic and pharmacokinetic limitations of steroidal androgen receptor agonists (i.e., testosterone and DHT), which have known associations with liver and heart disease [R]. SARMS have been investigated for several indications muscle wasting (cachexia), osteoporosis, stress urinary incontinence, erectile dysfunction, symptomatic benign prostatic hyperplasia, Alzheimer’s disease, muscular dystrophy, breast cancer [R].
SARMS are not anabolic steroids; rather, they are synthetic ligands that bind to androgen receptors. Depending on their molecular structure, they act as agonists, partial agonists, and antagonists. It is thus in a selective manner, that SARMS modulate or mediate coregulators and transcription factors or signaling cascade proteins to promote anabolic activity.
Unlike anabolic steroids which bind to androgen receptors in many tissues all over the body, individual SARMs selectively bind to androgen receptors in certain tissues, but not in others. Nonetheless, they are still exhibit androgenic and anabolic effects.
Androgen receptors are ubiquitous in muscle tissue and bone, thus making them highly receptive to activate or be inhibited my anabolic agents, creating undesirable systemic effects. SARMS have a high binding affinity for muscle tissue and bone, in a dose dependent selective manner, thus limiting growth in undesirable tissue, such as the prostate.
Nonsteroidal SARMS serve as alternative to anabolic-androgenic steroids, with fewer limitations, also exhibiting high-bioavailability.
All SARMS bind to androgen receptors and display tissue-selective activation of androgenic signaling. Non-steroidal SARMS do not serve as substrates CYP19 aromatase or 5-alpha reductase, as full agonists in muscle and bone, and partial agonists in prostate.
Thus, SARMs do not undergo aromatization to estrogen or 5-alpha reduction which may contribute to their prostate-sparing effect. Non-steroidal SARMs also exhibit diminished androgenic activity because they are not metabolized to dihydrotestosterone (DHT).
SARMS are being developed for treatment of functional limitations with aging, such as cachexia, osteoporosis, breast cancer, and Alzheimer’s while reducing harmful side effects of anabolic steroids to liver and heart disease.
Unique interactions of SARM ligands with androgen receptor result in specific conformational change in the androgen receptor protein, recruitment of a unique repertoire of co-regulator proteins thus contributing to their tissue-specific transcriptional regulation of gene expression.
Individual SARMS do, however, have different etiologies, to some degree.
Each SARM-AR complex possesses a different conformation, and various tissues (e.g., skeletal muscle, bone, prostate, brain, skin, liver) display a unique pattern of AR expression.
For example, Ostarine, or MK-2866 has a significant effect on the intensity of lipid metabolism. Ostarine downregulates the expression of leptin and adiponectin mRNAs. Leptin is one of the hunger hormones, that provides the sensation of satiety, or being full. According to preliminary trials, ostarine acts via androgen receptors with a similar effect as testosterone in the regulation of lipid metabolism [R]. Thus, ostarine may in fact be used for weight loss purposes.
SARMS selectively target androgen receptors in the muscle tissue and bone, thus, initiating the increase of lean muscle mass. With similar mechanistic aspects of anabolic agents, SARMS have similar results.
In August of 2011, MK-2866, Osatarine, entered into Phase II clinical trials, investigating the effects on Cachexia, also known as muscle wasting. Cachexia, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function.
A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men, with the primary endpoint to increase lean body mass and secondary endpoint an improvement in physical function.
After 12 weeks at a 3mg application, significant improvements were seen in total body mass and physical function [R].
Two additional studies, one investigating the effects of enobosarm on muscle wasting in patients with cancer, found positive improvements in lean muscle mass, without toxic effects associated with anabolic or androgenic agents [R].
Similar results were observed in a randomized, prospective, double-blinded study of 170 sarcopenic women without cancer [R].
LDG-4033 (Ligandrol), has shown extreme positive outcomes on androgenic activity, exhibiting a greater than 500:1 selectivity to muscle than prostate, making it the most selective and bioavailable nonsteroidal SARM to date.
LGD-4033 is significantly more potent than many very well-known testosterone analogs [R].
Milligram to milligram, All SARMS, such as RAD-140, MK-2866, S-4, and LGD-4033 show greater anabolic propensity and high androgen receptor affinity than several anabolic agents.
SARMS are potent in anabolic tissue, but not in androgenic tissues since they are partial agonists in the prostate, they show considerably less favorable selectivity towards prostate weight and stimulation.
In addition to high tissue-selectivity of androgen receptors in muscle and bone, preclinical data shows that SARMS, specifically RAD-140 has neuroprotective effects. The natural decline in testosterone levels is normal of the aging process, with increased risk in androgen responsive tissues. These tissues also include the brain. Testosterone replacement therapy (TRT) has the risk of inducing changes in tissues other than muscle and bone and accelerating the progression of cancer. To overcome these limitations, research is currently on going with SARMS as a potential alternative.
Preclinical data shows that RAD-140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126 [R].
These findings show initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer’s disease and other age-related neurodegenerative disease states.
SARMS are also under investigation for the treatment of breast cancer. Preclinical research has shown that androgen receptor activation exerts potent antitumor activity across a number of ER+/AR+ breast tumors, including those resistant to standard-of-care endocrine therapy and CDK4/6 inhibitors [R].
Phase 1 study of RAD-140 safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and antitumor activity of RAD140, was exhibited and investigated with postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).
21 patients were enrolled, and dosed at levels of 50, 100, and 150mg once daily. Most frequent treatment-emergent adverse events (TEAEs) were elevated AST (59.1%), ALT (45.5%), and total blood bilirubin (27.3%), and vomiting, dehydration, and decreased appetite and weight (27.3% each).
SARMS have several etiologies as agonists of androgen receptors. Mechanistically, RAD-140 showed agonist activation of AR and alters the genomic distribution of estrogen receptors and essential co-activators resulting in repression of estrogen receptor-regulated cell cycle genes and up-regulation of androgen receptor target genes, including known tumor suppressors.
Future, phase 2 studies will investigate safety and efficacy, as well as establish a threshold for patient selection as well as efficacy combined with established standard of care therapies [R].
SARMS share several of the same side effects, due to their specific mechanism on androgen receptors. However, not all SARMS are created equal.
SARMS are non-steroidal compounds that promote anabolism, that bind to selective androgen receptors.
“Anabolic” refers to tissue building (mainly muscle), and “androgenic” refers to a group of sex hormones called androgens. Testosterone is the main androgen. It stimulates the development of male characteristics.
Unlike anabolic steroids which bind to androgen receptors in many tissues all over the body, individual SARMs selectively bind to androgen receptors in certain tissues, but not in others. Although SARMS can be more anabolic milligram per milligram and more efficacious than testosterone, it will still induce and exhibit androgenic effects at some level.
Individual SARMS are not equal in efficacy or tissue-selectivity. Therefore, the side effects also differ.
SARMS suppress high-density lipoproteins, (HDL), LDL and triglycerides in a dose-dependent manner [R]. Negative effects are also notorious and associated with therapeutic application of all anabolic steroids and non-steroidal anabolics.
SARMs have been shown to suppress luteinizing hormone (LH) and follicle stimulating hormone (FSH) through the hypothalamus-pituitary-testis axis, thus decreasing testosterone in a dose-dependent manner [R]. They also reduce sex hormone-binding globulin (SHBG).
Commonly reported symptoms and findings for all SARMs were headaches, dry mouth, and upper respiratory infections (URIs), constipation, dyspepsia, and nausea.
SARMS, suppresses natural Testosterone levels, which can result in an disparaging balance between Testosterone and Estrogen levels in the body. SARMS do not aromatize into Estrogen, yet it can still cause a systemic increase or decrease in Estrogen levels.
This can result in symptoms such as
- Low Libido
- Depressive Mood State
- High Blood Pressure
- Change in testicular size
Any anabolic agent, SARMS or not, increase androgen activity. While SARMS are selective for muscle and bone relative to androgen modulation there is still potential for androgen related side effects.
Therefore, post cycle therapy is recommended to be started immediately after application has been concluded.
Anabolic agents are well known to cause liver damage which may manifest with elevated liver enzymes. Selective androgen receptor modulators (SARMs) have been heavily marketed as alternatives to androgenic anabolic steroids (AASs) for muscle gain and physical performance because of their perceived superior side-effect profile.
SARMS do express changes in AST or ALT levels in human trials at doses much higher than those shown for efficacy.
At therapeutic dosages, there appears to be a low risk associated with use and liver damage. However, it should be noted, that any anabolic modulator may have some degree of liver toxicity with ergogenic dosages.
With therapeutic and efficacious dosages, there appears to be a strong safety profile and the data suggests a complete absence of liver toxicity.
As of, Q3 2023, S-4 Andarine, was abandoned due before phase 1, due to vision impairment. This was a product of GTX pharmaceuticals, and some believe it was abandoned to pursue their stronger and more robust compound Ostarine.
Ostarine, MK-2866, GTX-024, Enobosarm, failed to meet the primary endpoint in two phase 3 studies, the POWER trials, in patients with non-small cell lung cancer (NSCLC) receiving chemotherapy.
Enobosarm was reevaluated and went back to Phase II, for evaluation for Stress Urinary Incontinence Disorder (ASTRID) trial and failed to meet the primary endpoint.
RAD-140 is currently in the process of Phase 3 trials, with safety and efficacy established for metastatic breast cancer.
Ligandrol, LGD-4033, after showing extreme positive response, is still under investigation, however at this point, it seems the drugs progression into Phase 3 clinical trials, has come to a halt.
Per the FDA requirement for Phase 3, an “approvable endpoint” for a Phase 3 trial would require showing a functional benefit, rather than just an increase in muscle mass. This requirement makes it more challenging to design a trial with confidence since it becomes nearly impossible to account for the uncontrollable aspects of such things like a patient’s willpower to push forward. Finding investment to take on the possibility or risk of potentially failure to get approval, seems unlikely.
SARMS have shown to have powerful tissue-selective anabolic effects. Clinical study and evaluation has shown a high binding affinity and the ability to build muscle mass at an impressive rate, more so than some anabolic agents.
SARMS are still investigational and are not intended for use, but for research purposes only. Long term toxicity studies have not been conducted, therefore it is impossible to know the long term side effects.
All agents that promote anabolism, will have some degree of liver toxicity, and elevated liver enzymes, above clinical therapeutic dosages.
SARMs do not undergo aromatization to estrogen or 5-alpha reduction, which can result in unfavorable hormonal levels, suppressing natural testosterone levels as well as luetenizing hormone, FSH, and SHBG.
This article is for informational and research purposes only. We do not sell, nor promote the use of SARMS or experimental drugs for research design.
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