S4 (Andarine) is an abandoned selective androgen receptor modulator (SARM) that was intended mainly for treatment of benign prostatic hypertrophy.
What Is S4 (Andarine)?
S4, also known as Andarine (not to be confused with S-40503), is a selective androgen receptor modulator (SARM) originally developed by developed by GTx, Inc. with the intention of treating a variety of degenerative musculoskeletal diseases and benign prostatic hypertrophy.
It was also being evaluated for its potential therapeutic applications in males and females for modulation of fertility, erythropoiesis, osteoporosis, sexual libido and in men with or at high risk for prostate cancer.
It is orally bioavailable (no injections needed), non-steroidal and has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic effects that come from anabolic androgenic steroids (AAS).
Testosterone and DHT are the main endogenous androgens produced in the body that fulfill basic physiological functions in men.
They are essential for male development, as well as the maintenance of male secondary characteristics.
The ability to build muscle, maintain bone mineral density, among several other key processes are facilitated via these hormones, but they are inherently flawed by their lack of tissue selectivity.
DHT is several-fold more androgenic than Testosterone, and even in the absence of DHT if 5-alpha reduction is manually inhibited with a drug like Finasteride or Dutasteride, Testosterone itself only exhibits a 2:1 selectivity for muscle to prostate [R, R].
The effects of these two androgens are transcribed and executed predominantly through the androgen receptor.
While they fulfill necessary physiological functions in the body, their very presence often induces a variety of negative health consequences too due to their androgenicity.
Just some of these include a dose dependent increased risk of prostatic hypertrophy, unhealthy serum lipids, and cardiovascular disease.
The scope of anabolic androgenic steroid use in a clinical setting to treat degenerative musculoskeletal diseases is extremely limited too, as their androgenicity disqualifies them from being viable treatment options for women entirely, and men in many cases too.
Consequently, the need in modern medicine for anabolic agents that exhibit a complete selectivity for muscle and bone with a lack of stimulation in the prostate and other negatively affected androgen sensitive tissues was/still is very high.
In general, SARMs exhibit much greater androgen receptor specificity, oral bioavailability, and tissue selectivity than steroids.
At a time, S4 was one of the lead candidates in the scope of promising SARMs, being described as the ideal SARM due to once per day dosing, high level of bioavailability, and the significant amount of preclinical data exhibiting a desirable level of anabolic effects in muscle and bone relative to androgenic activity [R].
Andarine was eventually abandoned and didn't undergo any published phase 1 human clinical trials.
We can only guess why this was, but it was more likely than not its lack of potency relative GTx's current lead candidate (Ostarine).
Even if Andarine went on to human trials, it almost undoubtedly would have been discontinued anyways due to the night vision side effect that likely disqualifies it as a viable treatment option.
Mechanism Of Action
S4 acts as a full androgen receptor agonist in muscle tissue and a partial agonist in the prostate [R].
The in-vitro activity of S4 demonstrated high androgen receptor binding affinity (Ki=7.5 nM).
It is rapidly absorbed following oral dosing and peaks in the blood stream between 48-84 min [R].
It exerts tissue-specific anabolic effects in vivo, with a favorable selectivity for muscle and bone to prostate and seminal vesicles.
After binding to the androgen receptor S4 exerts tissue-specific anabolic effects in vivo in a dose dependent manner by inhibiting bone turnover, stimulating bone formation and building muscle mass, while stimulating prostate and seminal vesicles to a much lesser extent [R, R].
Increases Muscle Mass With High Selectivity
S4 Versus Testosterone Propionate Study
The anabolic activity of S4 is much more selective than Testosterone, and is accomplished with a relatively minor effect on prostate size, and other androgen affected tissues (like hair follicles).
Treatment of castrated rats with S4 (GTX-007) showed greater anabolic activity than rats treated with Testosterone Propionate.
The levator ani muscle maintained the same weight as intact control rats and was greater the same dose of Testosterone achieved.
What this demonstrates is that milligram:milligram, Andarine more potent than Testosterone when it comes to building muscle (at the dosages tested), and it was able to prevent muscle wasting with greater efficacy than Testosterone, with far less prostate stimulation.
When an animal is castrated, its endogenous androgen levels plummet because it is no longer capable of producing them through the main mechanism by which the body facilitates it.
Consequently, prostate weight, seminal vesicle weight and muscle weight all plummet in parallel to the crashing androgen levels (hence why low Testosterone in men causes loss of muscle tissue).
This allows scientists to administer exogenous androgens and SARMs to evaluate how potently and selectively they transcribe their anabolic effects in the animal body, as the ideal SARM with optimal selectivity would restore muscle weight (levator ani) to that of a healthy intact control animal with normal endogenous androgen production, but prostate weight would not be stimulated whatsoever and would remain the weight of castrated control rats.
S4 doesn't accomplish this, but it's one of the closest to accomplishing it [R].
This was one of the first experiments ever conducted in-vivo that demonstrated the efficacy and selective nature of SARMs.
In this study S4 (GTX-007) selectively promoted prostate weight to 33.8% and levator ani muscle weight to 101% of intact control, while Testosterone Propionate (TP) non-selectively increased prosate weight to 121% and levator ani muscle weight to 104% of intact control.
At the time, S4 was the most efficacious SARM in development and revealed some of the most promising preclinical data of a SARM demonstrating potent anabolic effects with less androgenic activity than naturally produced endogenous androgens.
S4 Versus DHT Study
In another study where S4 is compared to Dihydrotestosterone (DHT), S4 restored levator ani and soleus muscle mass post-castration, and skeletal muscle strength was also restored to intact levels [R].
Male Sprague Dawley rats were castrated and left alone for 12 weeks to allow maximum decrease in soleus muscle mass and strength to occur.
They were then treated with either 3 mg/kg of S4, 10 mg/kg of S4, 3 mg/kg of DHT, or nothing (vehicle) for 8 weeks.
S4 selectively restored the tissue weight loss that occurred after castration.
As seen in the chart above, S4 exhibited a dose dependent increase in androgenic activity, however, the ratio of its anabolic activity relative to its androgenic activity is far more favorable than DHT.
It is not absent of prostate stimulation, but it has a far better efficacy profile than DHT does, which just so happens to be one of the two main hormones humans endogenously rely on for androgen mediated functions.
At a dose of 3 mg/kg/day, S4 restored prostate weight to less than 20% of the intact level.
The intact level is the weight of the rat prostate based on stimulation from their own endogenous natural hormone production (Testosterone and DHT).
The 3 mg/kg/day dose of S4 fully restored the levator ani muscle to control level.
This means that the dosage required to replicate the anabolic-related therapeutic benefits fulfilled by Testosterone and DHT that the body endogenously produces can be accomplished by a dose of S4 that only stimulates prostate growth enough to sustain 20% of its natural level.
While it isn't totally absent of androgenic activity, the fact that prostate weight can drop by -80% and 100% of muscle mass can be maintained at that dosage exhibits just how much potential this SARM has for potential applications in treating muscle and bone wasting diseases in men and women, reversing prostate hypertrophy, and HRT.
Strength levels were also restored to that of intact levels as well [R].
Tissue Selectivity Of S4 In Intact Rats Study
This was the first study that assessed the pharmacological effects of S-4 in intact rats [R].
Both S1 and S4 demonstrated partial agonist activity in the androgenic tissues (prostate) and full agonist activity in muscle (levator ani muscle) in both castrated and intact rats [R].
However, in castrated rats, prostate weight dropped down far lower than in the intact rat group.
This implies that S4 may actually be more androgenic than implied by the castration models.
Prostate weight only dropped about 20% in intact rats, and while the levator ani muscle in this group actually went to slightly suraphysiological levels, the ideal candidate would drop prostate size to castration vehicle levels while maintaining 100% therapeutic anabolism.
Perhaps the study length isn't long enough to make an accurate assessment, as castration causes prostate weight to plummet, and S4 administration at “therapeutic” levels doesn't increase the weight above 40% of the intact vehicle control while simultaneously restoring anabolic activity to 100%, but S4 in intact rats only decreases prostate size by about 20%.
If S4 were to be used in a therapeutic context, patients would not be castrated prior to using it, so the intact rat model sheds a bit more light on what is realistic to expect from this compound at a low dosage.
Perhaps if it was used for a longer duration of time, prostate size would have continued to drop, although that would need to be determined by further testing.
I would be interested to see if there was a middle ground where the castrated group and intact group on S4 would eventually meet, equal out and plateau in regards to androgenic activity.
Another more likely possibility is that the dosage of S4 used was just not high enough to yield as much of a prostate weight decrease as would be ideal.
As the dosage of S4 increases, further suppression of Testosterone, and consequently DHT, would occur, thereby reducing prostate size more and more until a middle ground is reached between endogenous androgen suppression induced prostate weight decrease, and Andarine's inherent prostate stimulation effects, which is more likely representative in the castrated rat models.
Reduces Prostate Size
Androgen suppression with 5-alpha reductase inhibitors and anti-androgens are two of the main treatments for benign prostate hyperplasia.
Based on Andarine's partial agonistic activity in the prostate relative to full agonistic activity in lean muscle tissue, investigating whether it could be used as an alternative treatment for benign prostate hyperplasia was desirable [R].
S1 is another SARM that was assessed in this study as well.
0.5 mg per day of S1 or S4 were given to the treated rats, and compared to castrated and intact rats who were treated with either nothing, or 0.5 mg per day of Testosterone Propionate.
While S1 and S4 both showed similar selectivity, milligram:milligram, S4 was a more potent agonist of muscle and less suppressive than S1 [R].
While this is desirable for certain treatment options (like HRT), when it comes to treating benign prostate hyperplasia, the goal is suppressing endogenous androgens as much as possible, and S1's potency in prostate weight suppression via endogenous androgen suppression was more potent.
While S4 could have resulted in the same level of endocrine suppression at higher dosages (and higher anabolic activity as well), in this model where lowering prostate weight with as low of a dosage of a drug as possible is the goal, S1 had a greater efficacy profile.
To clarify, in terms of overall anabolic efficacy, S4 is a better alternative to S1 in terms of potency, just not in the therapeutic context of lowering prostate size where a more suppressive SARM would yield better results closer to castration vehicles.
S4 was not compared to Hydroxyflutamide or Finasteride in this study as it exhibited a lower efficacy profile than S1 in regards to endogenous androgen suppression and decreasing prostate weight.
In this animal model, S1 was just as effective at lowering prostate weight as Hydroxyflutamide and Finasteride, while being more effective than both at maintaining muscle mass [R].
In the Finasteride treated group, muscle mass slightly increased, which was likely due to the 15% boost in Testosterone Finasteride causes when endogenous DHT production is inhibited via 5-alpha reductase inhibition.
Hydroxyflutamide caused a loss of muscle in a dose dependent manner which is to be expected when endogenous androgens are unable to bind to androgen receptors and exert their effects in the body.
S1 caused a dose dependent increase in muscle mass, with muscle mass exceeding that of the control group at each dosage.
This is important to note because this is an example of the efficacy of SARMs when it comes to preventing prostate issues induced by natural endogenous androgen production, while simultaneously inducing more anabolic activity than those same levels of endogenous androgens are capable of providing.
Increases Bone Mineral Density
Testosterone's ability to maintain bone mineral density is mediated through the androgen receptor, but is not potentiated via 5-alpha reductase and its conversion of Testosterone to DHT.
While Testosterone isn't a selective androgen by any means, it exhibits a far more favorable anabolic:androgenic selectivity than DHT.
We can assert that Testosterone's ability to maintain optimal anabolic effects in bone on its own irrespective of DHT exemplifies how using an even more selective anabolic agent to fulfill the same function with a lower level of androgenicity could very well lead to the same outcomes in bone with a greater safety profile.
Hence, why SARMs are being looked at as potential treatment options for bone wasting diseases like osteoporosis.
S4's ability to maintain and increase bone mineral density was evaluated in several preclinical animal models.
They also exhibited a greater level of efficacy of bone retention than DHT.
May Enhance Fat Loss
In a study conducted on ovariectomized female rats S4 treatment maintained whole body and trabecular bone mineral density, cortical content, and increased bone strength while lowering body fat [R].
Body fat content can be influenced by a variety of things irrespective of S4 administration, and there is data to support that Andarine has no effect on enhancing fat loss [R].
Personally, I believe the positive effect anabolic agents have on body fat is an indirect result of increased muscle mass which then increases metabolism and results in more fat being burned at rest and an increase in total daily energy expenditure.
Therefore, S4 (if anything) likely increases basal metabolic rate indirectly via its ability to build supraphysiological amounts of lean muscle mass, but doesn't inherently accelerate lipolysis.
S4 Results (Anecdotal/Recreational Use)
The most commonly reported Andarine results among recreational users are significant muscle and strength gains, an increase in muscular detail, dryness and vascularity, as well as an overall improvement in body composition.
Muscle hardness, and lean dry muscle gain are the major appeals of S4 for recreational users.
One thing that is important to note is that all SARMs don’t work the same, despite exerting anabolic activity in the same manner.
Each SARM has a different way it affects the body, as they each have their own anabolic transcription effects, as well as individual specific potency and level of tissue selectivity.
Consequently, results from a SARM like Andarine will likely differ from that of Ostarine or LGD-4033.
Milligram:Milligram Andarine is not as potent of a muscle builder as LGD-4033, but it is still an effective muscle building agent nonetheless while simultaneously being less suppressive than LGD.
S4 is commonly referred to as a “cutting SARM” due to the uniquely apparent muscular detail it brings out at low levels of body fat, similar to that of DHT.
S4 Versus Other SARMs
Although the mechanism by which Andarine exerts anabolic activity at the androgen receptor is the same as other SARMs, it ultimately leads to different effects on body composition than other SARMs.
How Andarine differs from most other SARMs (aside from S23) in particular results wise is the cosmetic look it gives that no other compound can seem to replicate.
The hard and dry look that Andarine can bring to the muscle is not matched by almost any other SARM.
Andarine isn’t as much of a traditional mass builder, and it is most comparable to something like a moderate dose of Winstrol.
S4 Versus S23
When comparing S4 to S23, the first thing we can establish is that S23 is far more suppressive than S4.
It is more potent of an anabolic agent milligram:milligram, however, even low dosages will suppress endogenous androgens much closer to castration levels than S4 will.
While this is favorable for certain therapeutic applications, it makes S23 a poor option for recreational users who are looking to avoid endocrine suppression, or recover after a “cycle” quickly with ease.
For those on Testosterone Replacement Therapy however, this can make S23 a potentially more attractive alternative, as it can induce more anabolic activity at lower dosages.
This is why S23 is commonly used alongside exogenous Testosterone (test base) in a recreational context.
This is also why S23 is in development right now as a potential male contraceptive [R].
While the data is extremely limited for both SARMs, there is much less preclinical data on S23, even anecdotally.
Anecdotally, both SARMs seem to create a similar muscular hardness that can be compared to that of Winstrol or Masteron, but being more similar to Winstrol when it comes to muscle growth potential.
S4 Versus Ostarine
With the large amount of data on Ostarine it is much easier to make a more accurate comparison between these two SARMs.
Both SARMs were developed by GTx, but Andarine was abandoned even after a significant amount of extremely promising preclinical data.
We can only assume that the reason for this was because Ostarine was determined to have a greater efficacy and safety profile than S4.
That doesn't mean that in certain contexts S4 wouldn't be a more ideal candidate (more likely just with recreational users who prefer it or respond better to it), but in general Ostarine appears to be a more ideal SARM candidate for therapeutic applications.
In development, it is also very possible that the eye sight side effect was discovered in humans, and resulted in the projects abandonment, similar to the Cardarine cancer data that was seemingly suppressed for a couple years before being publicly presented.
S4 Versus Steroids
When it comes to anabolic:androgenic activity, S4 outperforms every single known anabolic androgenic steroid.
However, this has its limitations, as there seems to be a lower threshold of diminishing returns with S4 (and SARMs in general) than there is with steroids.
When it comes to SARMs and steroids, SARMs are extremely selective at certain dosages, but there is a ceiling where increasing the dosage only increases the potential for side effects in the body, with a greatly diminishing level of muscle growth potential.
Muscle:prostate (anabolic:androgenic) ratio of tissue selectivity is far less favorable with steroids (particularly with DHT and DHT derived steroids), but there is a higher ceiling of diminishing returns when it comes to anabolic activity potential with many steroids.
Essentially, SARMs appear to be more favorable in a tissue selectivity context when it comes to therapeutic application, but in a bodybuilding context, building a significant amount of muscle beyond the genetic potential of an individual (largely determined by their endogenous androgen production) is limited, and megadosing SARMs appears to build minimal muscle beyond this ceiling and just stimulates greater androgenic activity.
Whereas with steroids, while the ratio is far less favorable in a tissue selectivity context when it comes to therapeutic applications, in a bodybuilding context, the ceiling for diminished returns in regards to anabolic activity is much higher (with certain steroids).
Despite the high levels of androgenic activity of steroids at this level of diminishing returns for anabolic activity, the fact remains that the ceiling for anabolism when it comes to steroids is higher.
Therefore, in a therapeutic context, SARMs will likely become regarded as the better alternative for inducing anabolism with minimal androgenic activity, but in a supraphysiological bodybuilding context, SARMs will not be building the physiques of any Mr Olympia competitors anytime soon.
At least not until more selective SARMs with higher ceilings of diminishing returns are developed.
In layman's terms, building a massive IFBB pro open bodybuilder caliber ripped physique is impossible with the current SARMs in development, but achieving a muscular and slightly supraphysiological physique with only SARMs with a simultaneous reduction of androgenic side effects in the body (what the majority of the population would prefer) is realistic if one were to evaluate efficacy relative to recreational standards.
S4 Versus Winstrol
Milligram:Milligram Andarine exhibits similar levels of muscle building potential to Winstrol, but with far less endocrine suppression and androgenic activity in the body.
Winstrol is very androgenic (it is a DHT derivative), and will suppress natural Testosterone levels by as much as 55% within just 2 weeks of using 10 mg per day [R].
Most bodybuilders use no less than 30 mg of Winstrol per day, and dosages of 50 – 100 mg per day are far more common in a recreational capacity.
Consequently, S4 typically results in similar levels of muscle growth, with less androgenic side effects (including natural testosterone suppression).
Winstrol has a bit more of a cosmetic drying out effect that is favorable for bodybuilders stepping on stage.
While this makes Andarine sound like a better compound, it needs to be noted that at formidable dosages (where both compounds exhibit significant muscle building potential), S4 typically results in significant night vision complications.
Both compounds have severe limitations.
S4 Versus DHT
In all preclinical animal models that compared equal dosages of S4 and DHT, S4 consistently outperformed DHT in all efficacy measures.
DHT in general is a very poor anabolic agent, and excels only in stimulating androgenic activity in androgen sensitive tissues like the prostate gland and hair follicles.
Dosages of 25 – 100 mg per day are commonly used in a recreational context for muscle building purposes.
There is no established therapeutic dosage of S4.
Typically, users report more favorable outcomes splitting their daily dosage up into increments throughout the day to maintain stable blood serum concentration levels to account for Andarine's short 4 hour half-life.
Anecdotally, S4 is reported to exhibit diminishing returns at dosages above 100 mg per day, with 100 mg commonly being referred to as “the sweet spot” dosage.
Vision side effects are reported to occur in a significant amount of users at dosages above 50 mg per day.
These dosages were determined by recreational users based upon personal experimentation and anecdotal experiences, and are not indicative of correct or incorrect use.
The half-life of S4 is 4 hours in humans [R].
The data assessing the pharmacokinetics of S4 in humans was never officially published, but it is referenced a few times, thus we can assume that there was a trial conducted on humans at some point.
Vision impairment in dark settings is the most notorious S4 side effect.
While this was not reported in any of the preclinical data (likely because no human data was ever published and we can only reference preclinical animal models), Andarine exhibits a very unique and strange side effect.
At high enough dosages (50 mg per day or higher seems to be the standard dosage where this side effect kicks in for most individuals) Andarine can cause a temporary yellow tint to be noticed in sight, and significant issues adjusting from dark to light settings.
This is most notable during the night time.
There are no anecdotal reports of this being permanent, and vision seems to return to normal after discontinuation.
The theory behind the cause of this side effect is that Andarine binds to the ocular receptors in the eyes.
My theory is a bit different, but more or less the same.
SARMs bind tightly to androgen receptors as that is what they were designed to do in a selective manner, and there are androgen receptors in cells of the cornea, lens, iris, and ciliary body of the eye (at least in mice) [R].
I propose that S4 likely binds to the androgen receptors in these parts of the eye (as it is designed to) and affects other cells in these tissues directly through its interaction with the androgen receptor specifically, and this is done in a unique way that impairs vision adjustment, rather than competing and binding to ocular receptors that are otherwise responsible for dark to light vision adjustment.
I believe this side effect specifically may have led to the abandonment of S4 in preclinical trials.
Decreased Good Cholesterol (HDL)
HDL wasn't a health marker evaluated in any of the preclinical animal models conducted using S4.
However, bioidentical androgens always exhibit a dose dependent suppression of HDL cholesterol, and this is demonstrated in clinical trials conducted using SARMs as well, just to a lesser extent [R, R].
The clinical data shows dose-dependent suppression of HDL cholesterol and triglyceride levels with LGD-4033 usage, as well as all other SARMs that have been evaluated at therapeutic dosages for humans.
Andarine is no different, and will also suppress HDL in a dose dependent manner.
This suppression is far less extreme than with traditional anabolic steroids, but it exists nonetheless.
I assert this based on personal blood work and countless anecdotal logs, not based on official trial data, which should be noted.
However, if an official trial was to be conducted on S4, I believe that HDL suppression would be noted.
A negative effect on HDL levels is consistently noted as a common side effect of all traditional steroids, and other SARMs.
With that being said, S4 doesn't exhibit as much HDL suppression as some other SARMs, at least anecdotally.
Based on anecdotal blood work, Ostarine seems to have a more detrimental impact on lipids than S4, but that comes at a trade off for other side effects (e.g. night vision impairment).
Of all of the mainstream SARMs, S4 is one of the most forgiving on HDL levels.
SARMs have consistently demonstrated suppression of luteinizing hormone (LH) and follicle stimulating hormone (FSH) through the hypothalamus-pituitary-testis axis, thus decreasing testosterone in a dose-dependent manner [R].
S4 is one of the least suppressive SARMs that still retains a promising efficacy profile.
While S4 isn't as suppressive as some of the more potent SARMs like S23 or LGD-4033, it will still cause endocrine suppression in a dose dependent manner.
Luteinizing hormone levels in castrated rats treated with Testosterone Propionate and GTX-014 (another abandoned SARM) were significantly lower than those of castrated untreated rats (the control for the study) at doses greater than or equal to 0.3 mg per day.
S4 (GTx-007) did not cause significant decreases in luteinizing hormone levels until a dosage of 0.5 mg per day or higher was administered [R].
Therefore, S4 exhibited the ability to elicit maximal stimulation of muscle growth at a dosage that does not suppress LH levels [R].
In another preclinical animal model comparing S4 to DHT, S4 did not suppress LH levels or FSH levels at doses that were capable of eliciting maximal stimulation of muscle growth [R].
The way you can interpret these charts is by looking at where the LH levels and FSH levels are in the intact control rats first and using that as your reference point.
As you can see, intact rats (untreated and non-castrated rats) have LH levels ≈ 5 ng/ml and FSH levels ≈ 20 ng/ml.
Once a rat is castrated, their LH and FSH levels dramatically spike up as a way to signal to the body to produce more endogenous androgens, as their systemic levels plummet as a result of castration.
Its the body's feedback loop that occurs when androgen levels are too low in the body, and its trying to signal to start producing Testosterone.
Obviously because the rats are castrated, they aren't able to naturally produce Testosterone like intact rats, so LH and FSH levels go sky high and remain there.
The only way to drop those levels would be to endogenously produce a sufficient amount of androgens to fulfill physiological functions, or to administer an exogenous compound that can fulfill those same functions and mitigate the need to produce Testosterone in the first place.
Exogenous DHT treatment handily drops FSH and LH levels back to baseline as it is so androgenic.
S4 on the other hand was able to restore all muscle loss that occurred after castration, thus fulfilling the critical need for endogenous androgens when it comes to muscle and bone retention, while simultaneously maintaining LH and FSH levels higher than intact rats that weren't castrated.
The agonist activity of S4 in the pituitary is measured by evaluating the plasma concentrations of LH and FSH.
It took a dosage of S4 over three times higher than DHT to restore LH levels to intact levels, but this dosage was still not even high enough to return FSH levels to the intact control level.
The preclinical data suggests that S4 is a very selective SARM and only exhibits a mild amount of suppression at what would be considered therapeutic dosages [R].
Increased Estrogen Or Decreased Estrogen
S4 does not aromatize into Estrogen, but it can still cause a systemic increase or decrease in Estrogen levels.
S4 suppresses natural Testosterone levels, which can result in an unfavorable balance between Testosterone and Estrogen levels in the body.
In addition, S4 has a high binding affinity at the androgen receptor, meaning it is possible that it could divert Testosterone to aromatize that wouldn't have otherwise, consequently increasing Estrogen levels.
The systemic elevation of Estrogen levels in the body is commonly misinterpreted as the result of prohormone laced SARMs.
High Estrogen Symptoms
- Acne, oily skin
- Erectile dysfunction
- Low libido
- Gynecomastia (man boobs)
- Water retention
- High blood pressure
- Enlarged prostate
- Shrunken testicles
- Sugar cravings
High dosages and/or long-term use of S4 can cause a decrease in systemic Estrogen levels via higher levels of endocrine suppression.
Estrogen facilitated physiological functions in the body are mediated through the aromatization of Testosterone into a sufficient amount of Estrogen.
If S4 usage suppresses endogenous Testosterone levels too low, it can result in Estrogen levels dropping as a consequence of the sheer lack of aromatization occurring in the body in a suppressed state.
When Estrogen levels get too low, an entirely new set of side effects can occur.
Low Estrogen Symptoms
- Dull weak orgasms
- Dry skin and lips
- Erectile dysfunction
- Low libido
- Mood swings
- Loss of appetite
S4 did not exhibit androgenic activity in preclinical rat models equivalent to that of intact rat controls (non-castrated untreated rats with normal endogenous androgen production) even when used in very high dosages.
The dosage of S4 that would be required to yield the same amount of androgenic activity in the body that natural endogenous androgens do would be higher than the therapeutic dosage required.
While S4 will increase androgen activity in the body in a dose dependent manner, the selectivity of its anabolic activity:androgenic activity is favorable enough that the therapeutic dosage to reach sufficient anabolic activity in muscle and bone would lower systemic androgenic activity.
On the other side of the spectrum, if megadoses of S4 were used daily, it would likely eventually exceed baseline androgenic activity in the body, but this is likely irrelevant for the context in which this compound would hypothetically be used as a treatment anyways.
In a performance enhancement context, very high dosages may result in some notable androgenic side effects in the body, while more moderate dosages may reduce androgenic side effects in the body.
All androgens cause androgenic alopecia in a dose dependent manner, but the extent to which they do this is dependent on their tissue selectivity, binding affinity, and the dosage used.
In general, S4 should not cause any male pattern baldness progression, and it may in fact support its reversal to some extent as a result of endogenous androgen suppression (the decrease of natural Testosterone and DHT that Andarine will cause).
This does not exclude temporary shedding (acute telogen effluvium) which can be triggered by a hormonal fluctuation.
Hormonal shifts can cause roots to be pushed into the resting state prematurely, and the result of that can be a temporary shedding phase.
Temporary shedding phases are commonly caused by hormonal fluctuations, stressors, autoimmune responses, nutrient deficiencies, or chemical imbalances.
This is not androgenic alopecia, which is caused by follicular miniaturization induced by androgens.
Based on the efficacy data comparing S1 to Finasteride, it is likely that S4 (if anything) would reduce the progression of hair loss at therapeutic dosages based on its similar tissue selectivity [R].
AST and ALT levels weren't evaluated in any of the S4 preclinical animal models, so we can only extrapolate data from other clinical trials with similar SARMs.
In an Ostarine trial conducted on humans (a very similar SARM to Andarine developed by the same company), short-lived increases in ALT to above the upper limit of normal were observed in eight subjects [R].
Considering this, it's possible that S4 could also elevate ALT levels and exhibit some degree of liver toxicity.
Potential Hormone Replacement Therapy Applications In Men
S4 doesn't aromatize into Estrogen, therefore it would lack the efficacy profile Testosterone has when it comes to complete hormone replacement therapy.
Estrogen is a vital hormone not only in women, but in men as well, just in lower amounts.
If S4 in a hypothetical hormone replacement therapy context was not used concurrently with exogenous estrogen in hypogonadal men, low estrogen side effects would start to occur.
It is not a viable standalone treatment for hormone replacement therapy.
While high levels of estrogen can cause a variety of health complications, low estrogen levels can be just as deleterious.
PCT (Post Cycle Therapy)
While S4 seems to be one of the least suppressive “mainstream” SARMs, it will still suppress natural Testosterone levels in a dose-dependent manner.
It may be prudent to complete a PCT phase (post-cycle therapy) after discontinuing Andarine usage.
Due to the half-life of S4, PCT should be started the day after the last dosage was taken.
An adequate PCT phase will stimulate the restoration of natural Testosterone production and greatly lower the likelihood of low Testosterone side effects from occurring.
Forgoing PCT may increase the risk of muscle loss, fat gain, among all of the other standard side effects associated with Testosterone suppression.
How much time off should be taken after PCT should not be dictated by an arbitrary bro-science rule like “time on = time off”, rather it should be dictated by individual specific factors and blood work.
Disclaimer: The information included in this article is intended for entertainment and informational purposes only. It is not intended nor implied to be a substitute for professional medical advice.