In today’s bodybuilding scene, SARMS are a commonly used ergogenic aid, for performance enhancement. One of the most common S-4 (andarine), also known as Gtx-007, is an investigational compound, specifically selective androgen receptor modulator (SARM), originally developed for muscle wasting, osteoporosis, and benign prostatic hypertrophy. We’re going to discuss the research behind S-4, the benefits, risks, and how this investigational chemical compound works.
S-4, marketed as andarine, is an orally bioavailable, non-steroidal selective androgen receptor modulator (SARM). Andarine is a partial agonist of the androgen receptor.
S-4 like other 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).
Compound S-4 was used in animal studies but was abandoned before any Phase I human clinical trials, due to visual impairments. These effects occur as the S-4 molecule binds to the receptors in the eye; the more aggressive the binding, the more discomfort that is experienced. Visual disturbances were found to be so common, due to unique mechanistic action, for the drug that the trials were abandoned.
One of the suggested mechanisms of S4, is that it completely blocks the binding of DHT. Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex hormone. Relative to testosterone, DHT is considerably more potent as an agonist of the androgen receptor.
S-4 has a high androgen receptor (AR) binding affinity. Studies have shown that S-4 is less potent and efficacious than testosterone propionate (TP) in androgenic activity, but their anabolic activity was similar to or greater than that of TP (R).
S-4 is a full androgen receptor agonist in muscle tissue, and a partial agonist in the prostate (R). Thus, S-4 potently stimulates muscle growth, but is unable to maintain prostate size. Testosterone stimulates muscle and prostate growth to the same extent. S-4 causes significant luteinizing hormone (LH) or follicle stimulating hormone suppression.
Although many investigational studies have been conducted, more research is ongoing and in the early stages of development. The development of SARMS for clinical and therapeutic use as an androgen alternative, is promising based on preclinical data.
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.
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.
Studies have shown S-4 is a full androgen receptor agonist in muscle tissue, and a partial agonist in the prostate (R), making it an ideal candidate as an alternative to steroidal androgen receptor agonists (i.e., testosterone and DHT), due to associated adverse effects on liver, heart, and fertility.
The selective binding effects of S-4, and it high androgen binding affinity, can increase muscle tissue and size.
One of the first preliminary and pivotal studies in the investigation of S-4, was conducted on castrated (orchidectomized) male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 weeks.
S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were seen in DHT treatment at 3mg/kg.
Compared to the anabolic effects of DHT which restored androgenic organs by 2-fold, S-4 only restored androgenic organs, such as prostate and seminal vesicle 16-17%. S-4 did show stronger anabolic effects in lean muscle mass as well as larger increase in total body bone mineral density.
When an animal is castrated, endogenous androgen levels rapidly decline, due to the inability to produce them. Consequently, prostate weight, semi vesicle weight, and muscle tissue all decline along with androgen levels in parallel.
This methodology and study design, effectively allows researchers to investigate how potent and efficacious exogenous androgens and SARMS can be to selectively transcribe and exhibit androgenic and anabolic activity.
The same study showed that S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. Consequently, this can protect against bone less in elderly populations.
The effects of testosterone in bone may be mediated directly by androgen receptors.
Conversion of testosterone to DHT by 5α-reductase is not required for the process or indirectly via aromatization of testosterone into estrogen and subsequent stimulation of the estrogen receptor (ER).
DHT is a nonaromatizable androgen and was used as a positive control to avoid the indirect actions of androgens through conversion to estrogen. S-4 does not interact with the ER and cannot be aromatized. Thus, the effects of S-4 on bone should be mediated only by direct action on the AR, providing a valid and direct comparison to DHT.
S-4’s ability to maintain and increase bone mineral density was evaluated in several preclinical animal studies.
Like other commonly used SARMS, they do exhibit several side effects. Without long-term efficacy and toxicity studies, it is impossible to know the long term detriment, these compounds can create.
Although preclinical trials did not exhibit the effect, (since humans were not subjected to trials) the major side effect of S-4 was found to be vision impairment.
Andarine exhibits a unique characteristic in high binding capabilities to the ocular receptors. Androgen receptors exist in the in cells of cornea, lens, iris, and ciliary body of the eye. Therefore, based on the selectivity of androgen receptors, SARMS of any kind can bind to these receptors, thus impairing vision (R).
At high doses, reports of impaired vision and eye discomfort are common with andarine use. Users often experience blurred and yellowish vision, especially at night, and vision flashes have also been reported.
Other adverse events reported in SARM clinical trials, show a reduction in high-density lipoproteins, (HDL) otherwise known as good cholesterol (R). Negative effects are also notorious and associated with therapeutic application of all anabolic steroids.
In addition to testosterone, studies also show a reduction in other hormones such as reduced levels of 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.
Moreover, S4 does not aromatize into Estrogen, yet it can still cause a systemic increase or decrease in Estrogen levels.
S4, like other SARMS, suppresses natural Testosterone levels, which can result in an disparaging balance between Testosterone and Estrogen levels in the body.
Although S-4 is the least suppressive of the mainstream SARMS, it will still suppress natural testosterone levels.
This can result in symptoms such as
- Low Libido
- Depressive Mood State
- High Blood Pressure
- Change in testicular size
The average terminal half-life of S-4 in animals is four hours. After oral dosing, S-4 was rapidly absorbed and completely bioavailable.
Pharmacokinetics studies show that the terminal half-life of SARMs range from 4.1 to 14.7 hours. S-4 cleared much more rapidly with an average half-life of about 4 hours, making it highly bioavailable, rapidly absorbed within 48-84 minutes (R).
Therefore, post cycle therapy is recommended to be started immediately after application has been concluded.
Any anabolic agent, SARMS or not, increase androgen activity. While ostarine is selective for muscle and bone relative to androgen modulation there is still potential for androgen related side effects.
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.
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.
Andarine, also known as S-4 and GTx-007, is classified as experimental.
Andarine is classified as an investigational new drug by the FDA, meaning that it is still being studied and has not been approved for human use. As such, it is illegal to sell or distribute ostarine in the U.S. for any purpose other than FDA-approved clinical trials.
Thus, it is legal to sell and buy SARMs that are marketed for research purposes, which commonly occurs online. However, it is illegal to sell and buy those that are packaged in capsules for human consumption and/or labeled as dietary supplements. Furthermore, SARMS cannot be marketed to the public as dietary supplements, and claims regarding their benefits cannot be made.
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.
Considering that trials were abandoned before Phase 1 human clinical trials, it’s more than likely, that this occured to pursue more potent SARMS such as Osterine, by Gtx Pharmaceuticals.
Studies show that, Andarine is more potent than steroidal agents such as testosterone when it comes to building muscle and it is able to prevent muscle wasting with greater efficacy than Testosterone, with far less prostate stimulation. Therefore, this could be an ideal candidate with less adverse effects on liver health, heart disease, and fertility. However, S-4 does like other SARMS suppress testosterone levels due to hits high selectivity to androgen receptors.
Further investigational studies are needed to determine the long-term efficacy, risks and toxicity associated with the use of S-4 Andarine as a performance enhancing non-steroidal agent.
Swolverine is no way supports or condones the use of illegal or nefarious substances or compounds. This article is for informational purposes only.
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