S23 is undoubtedly one of the strongest SARMs in development right now.
It has an extremely high binding affinity, is very suppressive, and is a very potent muscle builder with a high level of tissue selectivity relative to anabolic androgenic steroids.
Table of Contents
What Is S23?
S23 is a selective androgen receptor modulator (SARM) currently under development for potential use as a male hormonal contraceptive.
It is still in the preclinical stage of development, meaning it has only been tested on animals, not humans.
S23 exhibits a high affinity for the androgen receptor with tissue selective anabolic effects in muscle in bone, with relatively less stimulation of the prostate, seminal vesicles, and other androgen affected tissues.
S23 was created by modifying the structure of an older and less efficacious SARM called C-6 by changing the para-nitro group of C-6 to a cyano group [R].
Pharmacokinetic studies showed that C-6 is 76% orally bioavailable, and by swapping the para-nitro group for a cyano group S23 is able to achieve 96% oral bioavailability [R].
The closer a SARM is to 100% the closer it is to complete absorption after oral dosing.
This means that S23 can be administered orally, as opposed to requiring injections to achieve maximal blood serum concentration levels, which is obviously advantageous when it comes to ease of use and adoption.
The preclinical data revealed that S23 is the most suppressive SARM in development and resulted in infertility in all rats treated.
Expectedly, this raised interest in its potential clinical applications as a form of male birth control.
The most obvious drawback of the long-term utilization of SARMs in a hormone replacement context, or as a male hormonal contraceptive in the case of S23, is their lack of aromatization into Estrogen.
S23 is no different as it does not aromatize into Estrogen in the body, and would require exogenous Estrogen administration in order to maintain normal sexual behavior, among a myriad of other physiological functions that are facilitated by healthy endogenous Estrogen levels.
Contrary to popular belief, this also includes muscle building potential, as a lack of adequate Estrogen in men will not only hinder bone health, it will also severely inhibit the accrual of lean muscle mass.
Its potential efficacy in a hormone replacement therapy context is outlined in the preclinical animal data, but the scientists also acknowledge the limitations of S23 monotherapy when considering it in this context.
S23 has become increasingly popular in the recreational bodybuilding community for its potent muscle building and body recomposition effects.
Recreational users are quick to label S23 as a more potent alternative to S4 (Andarine) without the night vision side effect.
S23 has also shown to decrease prostate size in studies, which is the opposite of a very common negative side effect of anabolic steroids (enlargement of the prostate).
This data is commonly misinterpreted though, as all SARMs will cause prostate hypertrophy in a dose dependent manner, and this is specifically referred to in the study.
S23 in particular was shown to maintain the anabolic activity in muscle tissue equivalent to therapeutic levels of Testosterone at 0.1 mg per day in rats, while only stimulating prostate size up to 30% of an intact control rat (a healthy non-castrated rat with normal Testosterone/DHT levels) [R].
However, at dosages of 1 mg per day S23 maintained the prostate and seminal vesicles at weights equal to or greater than that observed in the intact rats.
Anecdotally, S23 is one of the most side effect ridden SARMs of all due to its high level of androgenic activity relative to other SARMs.
S23 has a very high binding affinity for the androgen receptor (AR) with a Ki of ∼1.7 nM [R].
The structural modification of C-6 didn't just increase S23's oral bioavailability, it also increased its AR binding affinity two times higher than that of C-6, which has a Ki of ∼4.9 nM.
S23 has a binding affinity over four times higher than RAD140, which was already considered impressive.
The binding affinity of Testosterone and DHT remains unclear as each study seems to render significantly different values.
In the RAD140 study the affinity for the androgen receptor for Testosterone was 29 nM, and 10 nM for DHT.
In the study conducted on S23, DHT was stated to have a Ki of 0.45 nM.
Mechanism Of Action
S23 has a very high level of bioavailability which means it can be dosed orally without the need for injections or other inconvenient methods of administration.
S23 does not require 17 alpha-alkylation to achieve 96% oral bioavailability, making it superior to traditional oral anabolic androgenic steroids in the context of liver toxicity.
Oral steroids that feature a methyl or ethyl group at the C17α position are intentionally liver toxic so they are orally bioavailable and won't be destroyed by the liver.
S23 and other SARMs appear to largely circumvent this issue, albeit not entirely, as liver enzyme elevations have been noted in the clinical trials conducted on humans using SARMs.
After administration, S23 binds to the androgen receptor with a very high affinity, and actively competes with Testosterone and DHT for AR activation.
Because of its high binding affinity, it is very effective at outcompeting Testosterone and DHT for receptor sites in muscle tissue and bone.
After binding to the androgen receptor, S23 increases bone mineral density, lean mass, and reduces fat mass in a dose-dependent manner [R].
SARMs, like S23, stimulate androgen receptors in a selective way, whereby they induce a significantly greater amount of anabolic activity in the body relative to androgenic activity [R].
The high level of tissue selectivity and competitive binding affinity at the AR may potentially avert some of the risks and side effects that can occur when endogenous Testosterone is 5α-reduced into the more androgenic metabolite DHT.
Some of these negative effects include but are not limited to benign prostate hyperplasia, prostate carcinoma, acne breakouts, and expedited male pattern baldness.
The relative lack of androgenicity makes S23 a strong candidate for potential clinical applications for both men and women.
However, while its tissue selectivity is superior to most FDA approved anabolic steroids, S23 has shown to be a full agonist in androgenic and anabolic tissues [R].
This makes it unique from other SARMs in development that are more prostate-sparing and selective for muscle tissue and bone, and most likely disqualifies its viability as a treatment for anything other than a male hormonal contraceptive.
Increases Muscle Mass And Bone Mineral Density
During the preclinical profiling of S23, it increased lean mass and bone mineral density [R].
This was not in a dose-dependent manner however, which implies that S23 has a point of diminishing returns in an anabolic context, and dosages higher than that point would just results in higher levels of androgenic activity and HPTA suppression.
In another study comparing the efficacy of S23 to Testosterone, S23 attenuated muscle and bone tissue catabolism induced by the glucocorticoid dexamethasone and castration more effectively than Testosterone, with less androgenic activity [R].
The intention of the study was to establish how effective a SARM like S23 would be at preventing musculoskeletal degeneration in two scenarios that are common among men and women.
One being musculoskeletal degeneration among hypogonadal men, and the other being musculoskeletal degeneration induced by prolonged use of glucocorticoids.
Skeletal muscle wasting currently has no therapy, and the current treatments have all been riddled with severe limitations.
Namely the androgenicity of anabolic steroids inducing virilization in women and androgen derived health ramifications in both men and women, as well as severe insulin resistance among those treated with growth hormone.
Growth hormone still has yet to prove it has any anabolic effect on muscle tissue whatsoever, and it is illogically prescribed in absurd quantities to AIDS patients.
Anecdotally, S23 is reported to be one of the most potent muscle builders among all of the SARMs currently in development.
S23 decreases fat mass in a dose-dependent manner [R].
While the preclinical profiling revealed dose-dependent fat loss, I believe this is an indirect effect, rather than the direct mobilization of stored fat.
In general, anabolic agents do not burn fat.
As a human accrues more muscle mass, their basal metabolic rate will increase in parallel.
This is guaranteed, therefore anything that can increase lean muscle mass will also indirectly impact total daily energy expenditure.
Via increasing muscle mass S23 will also increase the body's metabolic rate (because it has more muscle tissue burning through more calories), which will indirectly result in increased fat loss in a dose-dependent manner in parallel to muscle mass accrual.
It is very likely that S23 can indirectly increase fat loss, and that the amount of fat loss is entirely dependent on how much lean muscle gain is facilitated by the S23.
Male Birth Control
The preclinical assessment of S23's efficacy as a birth control pill is commonly misinterpreted.
S23 showed to be one of the most suppressive SARMs in development, which is what sparked the interest to explore its potential as a form of male birth control.
Despite S23 exhibiting a dose-dependent suppression of spermatogenesis, spontaneous recovery was achieved in all treated rats after cessation of treatment [R].
This makes it an ideal candidate as a potential male hormonal contraceptive.
However, what is often not mentioned is the fact that infertility could only be achieved when S23 was administered in conjunction with Estradiol Benzoate [R].
To put this in perspective, one of the common ways male to female transgender hormone therapy is facilitated is with the administration of an antiandrogen in conjunction with Estradiol.
The reason for this is that Estradiol can lower Testosterone production on its own by as much as 95%, and the antiandrogen is used to clean up the excess androgen receptor activation that would otherwise induce androgenic activity.
The Estradiol also maintains physiological functions that are facilitated via healthy Estrogen levels, as having zero Estrogen in the body is not only horrible for women, but it is unhealthy for men as well.
Estradiol has a dose dependent increase in Testosterone suppression, and because the serum levels in men have to remain below a certain threshold to prevent feminization, Estradiol monotherapy is not an efficacious treatment for male hormonal contraception.
The main purpose exogenous Estradiol serves in a male contraceptive context is filling the void left when Testosterone is severely suppressed by the S23.
This alternative method of therapy will require exogenous Estradiol administration to maintain healthy levels in the body, as there will no longer be any endogenous Testosterone aromatizing into sufficient amounts of Estrogen.
While antiandrogens pick up the slack for transgender hormone therapy, the minimal dosage of Estradiol in conjunction with S23 picks up the slack in a male contraceptive context by further suppressing LH and FSH levels to 100% infertility levels.
Estradiol = suppression of LH and FSH (not enough for complete infertility)
S23 = suppression of LH and FSH (not enough for complete infertility)
Estradiol + S23 = enough suppression of LH and FSH to achieve 100% infertility (at certain dosages)
S23 monotherapy displayed only biphasic effects in the testis and eipdidymides, and Estradiol treatment in conjunction with S23 was necessary to mediate a 100% infertility rate [R].
This infertility rate was inconsistently achieved among the varying dosage groups, and further exemplifies how different bodies will be suppressed to varying degrees, and that complete infertility can likely only be consistently achieved when an exogenous progestin is added to further suppress LH.
Personally, I believe that S23 induced suppression of the HPTA is not unique from other SARMs or Steroids, and the SARM is simply more suppressive than most.
It is commonly believed that S23 inherently has some unique contraceptive effects, but this is not the case, it is just more suppressive milligram for milligram than other SARMs.
Regardless of which androgens are used, eventually the endocrine system will become so taxed from hormone suppression that hormone replacement therapy will become an inevitable practice that will need to be adopted to maintain a high quality of life.
Even if exogenous hormones weren't utilized, this would eventually occur for all men simply due to hormonal decline with aging.
I also do not think that the ability to bounce back from S23 induced infertility is unique as is often implied.
I'm confident that most healthy men will be able to regain fertility regardless of their level of HPTA suppression by utilizing a combination of HMG, HCG and Clomid, and I have yet to find one individual who this hasn't worked for, even among anabolic steroid abusers who have blasted for over a decade straight.
I believe the same results found in the S23 study could be achieved with another very suppressive SARM like RAD140 or LGD-4033 in conjunction with oral Estradiol, but this is just speculation.
S23 is the most promising option among the current SARMs in development as a potential male hormonal contraceptive simply due to its higher level of suppression, however, it is still not a turnkey solo treatment, and will require Estradiol and Progestin use in conjunction with it to truly be a consistently effective contraceptive.
Increased Female Sexual Desire
When a woman goes through menopause their ovaries may start producing fewer hormones.
Menopause induced suboptimal Testosterone, Estrogen and Progesterone levels can result in a severe drop in sex drive.
Estrogen is one of the primary hormones responsible for libido in men and women, and using synthetic Estradiol in menopause to bring levels up to where they should be has shown to alleviate menopausal symptoms in many women.
However, for some women this isn't the root of the issue as they may still be androgen deficient.
In addition, exogenous Estradiol administration will further suppress endogenous Testosterone production and exacerbate the issue if the root of the libido issue is a deficiency of androgens.
This is where therapeutic androgen replacement may become necessary to fill the void left by suboptimal Testosterone production.
However, competent doctors who understand this and are knowledgeable enough to treat it properly are few and far between, and often women are left scratching their heads because their doctor doesn't have an answer for them, or they won't prescribe Testosterone to Testosterone deficient women.
S23 was evaluated in a preclinical model assessing its effects on sexual motivation.
Expectedly, it increased female sexual desire [R].
Anything androgenic will increase libido, and considering the fact that S23 is a full agonist in androgen affected tissues, it is not surprising that it has a positive impact on female libido.
The reason this may be advantageous is that the tissue selectivity of S23 is still much better than Testosterone, so it could be a potentially viable treatment for menopause induced androgen deficiency in women.
S23 Reviews (Anecdotal/Recreational Reports)
Despite S23 being developed as a male hormonal contraceptive, 99% of the anecdotal reports you will find online are in the context of it as a performance enhancer.
When S23 first started being adopted into the bodybuilding world, one of my friends was the first to experiment with it and ran S23 for a duration of 8 weeks for the last 2/3 of his 12 week cut.
The purpose of using it was to maintain lean muscle, maintain strength, and achieve the same drying out effects he would from DHT compounds he would normally use.
He was basing this on the assumption that it would have a similar effect on body composition that Andarine has.
He used a dose of 30 mg of S23 per day, spread out throughout the day into three 10 mg doses.
The half-life of S23 in rats is 11.9 hours, which is why he split up his daily doses.
Granted, this doesn't translate into a human equivalent half-life, but to be cautious, micro-dosing throughout the day will always lead to more stable blood serum concentrations than one single bolus dose per day.
Over the course of those 8 weeks, he reported cosmetic enhancing effects formidable to that of the traditional DHT derived compounds he used to rely on (like Winstrol).
By the time the cut was finished, he had maintained all of his muscle and strength, and had achieved a dryer look than he would have otherwise.
This individual is on TRT, so the most expected side effect was mitigated entirely (suppression).
His conclusion was that he would definitely use it again in the future, and that it is a worthwhile compound to research further.
S23 is commonly reported to be “a jacked up version of S4”, exerting all of the same benefits to an even greater extent, without the vision side effects.
Personally, I think this is blown out of proportion as Andarine is far more tissue selective than S23.
One thing that is important to note is that all SARMs don’t work the same, despite exerting anabolic activity in the same manner.
Based on what I’ve seen through anecdotal logs and personal friends experiences, S23 essentially falls into the “hardener” category.
By this I mean that pre-contest, most bodybuilders utilize DHT derived drugs such as Masteron, Winstrol and Halotestin to harden up and add a level of grainy detail to their physique that would otherwise be unachievable.
S23 seems to loosely fall into this category in a performance enhancing context, and it is reported to excel in cutting phases where the goal is to preserve lean muscle mass, strength, and reach a crazy level of muscular detail.
I have heard it being compared to a high dose of Winstrol on numerous occasions, or just a souped up version of S4 essentially.
10% body fat on S23 tends to look more grainy and dry than 10% body fat off of S23. The same goes for hormones like Masteron and Winstrol, although S23 is more anabolic milligram to milligram than both of them.
DHT derived compounds have a blatant cosmetic effect on the muscle that no other kind of compound can achieve.
These kind of compounds are highly androgenic and are ideally reserved for the home stretch of pre-contest cutting phases, as exposure to these hormones can be very unhealthy.
Having dry, grainy muscles when you are bulking up isn’t a good recipe for success either as your probability of getting injured will greatly increase.
This doesn’t mean that S23 doesn’t have a place in a muscle growth/bulking context at all; I just personally wouldn't use it for that.
Most other S23 reviews report similar findings, with the following characteristics being common among S23 cycles.
- Impressive lean mass builder
- Notable increases in strength
- Improved body composition/fat loss (indirect fat loss via increased muscle mass accrual and thermogenesis)
- Mitigates catabolism in a calorie deficit
- Enhanced levels of muscle hardness, dryness, and vascularity similar to DHT derivatives
- Zero water retention
Despite all of the potential benefits that are typically the focus of S23 reports, the SARM has a handful of common unexpected side effects that have been consistently reported that are unique from most SARMs, and are odd to say the least.
S23 Vs Steroids
S23 is one of the few SARMs that has shown to replicate results equivalent to that of moderate doses of DHT derived anabolic steroids.
Comparisons of S23 to a high dose of Winstrol are very common, and others have also reported it fairing very well in comparison to high doses of Masteron as well.
It seems to be consistent across the board that this is a hardener/dry compound that produces a leaner, more conditioned look to the physique.
S23 Vs Other SARMs
S23 Vs RAD140
S23 has a higher binding affinity than RAD140, is more suppressive, but will also build more muscle and strength.
With that being said, S23 is more androgenic than RAD140 and will result in more androgenic side effects.
Anecdotally RAD140 is much more androgenic than it appeared to be in its preclinical profile, however, S23 still exceeds it in terms of overall androgenicity.
S23 will also dry out the muscle more than RAD140.
Whether this is via dehydration or a direct conditioning effect this remains unknown, but pound for pound it is safe to say that S23 is a more potent anabolic and androgenic agent in general than RAD140.
S23 Vs S4 (Andarine)
S23 is purported by many to be a jacked up version of S4 without the night vision side effect.
It is true that S23 does not cause the same vision side effect as S4 and is a more potent muscle builder.
However, it also has a less favorable level of tissue selectivity than S4 and will induce far more androgenic activity milligram for milligram.
Even at what would be considered recreational high dosages, 30 mg of S23 has shown to be far more androgenic than 100 mg of S4.
In a purely bodybuilding context, S23 is the more effective SARM at building muscle, however, when it comes to tissue selectivity and fitting the description of a novel SARM, S4 significantly outperforms S23 as it acts as a full androgen receptor agonist in muscle tissue and only a partial agonist in the prostate [R].
Dosages of 10 – 30 mg per day are commonly used in a recreational context for muscle building purposes.
There is no established therapeutic dosage of S23.
Anecdotally, S23 is reported to show diminishing returns at dosages above 30 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 mean terminal half-life of S23 in rats is 11.9 hours [R].
The half-life of S23 in humans is unknown, and would require mathematical estimation, or a clinical study (ideally) to determine it.
S23 Side Effects
While S23 is still more tissue selective than non-selective androgens like Testosterone, it has shown to be a full agonist in androgenic and anabolic tissues [R].
This means that SARMs like LGD-4033 which are more tissue selective will induce much less androgenic activity at the same level of anabolic activity in muscle/bone.
While S23 will greatly suppress endogenous Testosterone production, thereby reducing prostate size, this only proves that it is less androgenic than Testosterone and DHT.
The prostate size maintained by S23 is still greater than what SARMs like Andarine and Ostarine would maintain at the dosage required to replicate therapeutic levels of anabolic activity in muscle and bone.
S23 is one of the most misunderstood SARMs, and it will increase prostate size in a dose dependent manner, just to a lesser extent than Testosterone, DHT and other non-selective anabolic steroids.
Increased Body Temperature
A common side effect reported by S23 users is increased body temperature.
As a result, S23 increases sweating and increased water intake seems to become necessary with moderate and high dosages of S23.
Similar to Trenbolone, reports of night sweats from S23 are common.
Why this occurs is unknown, however, it is entirely possible that S23 increases the body's metabolic rate, thereby increasing thermogenesis.
The increase in body temperature would then cause sweating, and can be very noticeable at night when you're lying under the covers and wake up 8 hours later in a puddle of your own sweat.
This is likely derived from the dehydrating effect S23 appears to cause through increased body temperature.
The more you sweat, the more electrolytes you lose.
The more dehydrated you are, your potential for cramping will increase in parallel.
The mechanism behind S23 cramps are likely mediated by this, and may require an increase in water and electrolyte intake.
S23 users commonly report very blatant increases in aggression, similar to that of RAD140 and highly androgenic anabolic steroids.
This further solidifies the androgenicity and relative lack of tissue selectivity of S23, as huge increases in aggression are flagship markers of highly androgenic compounds.
At the dosages being used recreationally, it is very likely that significant amounts of androgenic activity are being induced in the body.
Regardless of the fact that S23 is a SARM on paper, it is not as selective as SARMs like MK-2866.
It is a full agonist in androgen affected tissues, and will display a higher incidence of androgenic side effects as a result of that.
Typically, increased aggression only occurs when androgen index increases in the body.
This is why more androgenic steroids are commonly used pre-workout for a quick boost in aggression before training.
Because S23 is a full agonist in androgen affected tissues, acne breakouts from S23 use are far more common than with other more tissue selective SARMs.
Androgens stimulate the sebaceous glands and induce greater amounts of sebum production.
Sebum is the stuff on your face that causes oily skin.
Excessive amounts of sebum can clog the pores, and ultimately result in acne breakouts.
In general, the more androgenic a compound is, the greater potential it has for causing acne.
Hair loss derives from the androgenicity of S23 as well.
Androgens will cause hair follicle miniaturization, which will ultimately cause hair loss.
The more androgens you exert on your body, the more hair loss potential you will have.
This is commonly misinterpreted by individuals who believe that DHT is the only hormone that can cause hair loss, but the fact is that any androgenic hormone will induce androgenic effects in the body in a dose dependent manner, and S23 is not exempt from that.
The severity of how much hair loss an anabolic agent will cause is generally predicated upon its level of androgenicity, hence why DHT is much worse than Testosterone for hair loss.
Despite the fact that it is so much worse, it does not make Testosterone hair loss safe at all.
Testosterone simply has a lower androgen index than DHT and is more hair safe relative to harsher androgenic metabolites and several DHT derivatives.
It definitely isn't “hair safe” though, and S23 certainly isn't either.
Compared to other SARMs, S23 is one of the least hair safe SARMs in development.
Lowering Of Lipids
Expectedly, S23 induces a dose dependent lowering of HDL cholesterol and triglyceride levels.
Any anabolic androgenic compound will suppress HDL cholesterol in a dose dependent manner.
Every single SARM that has been evaluated has shown this same dose-dependent suppression of lipids.
Just like anabolic steroids, SARMs have all consistently exhibited suppression of luteinizing hormone (LH) and follicle stimulating hormone (FSH) through the Hypothalamus-Pituitary-Testes-Axis.
The result of this is decreased natural testosterone production in a dose-dependent manner [R].
S23 is one of the most suppressive SARMs, hence why it is being evaluated as a potential male hormonal contraceptive.
In intact male rats treated for 14 days, S23 monotherapy suppressed LH levels by more than 50% at doses greater than 0.1 mg per day [R].
While the incidence of gyno is low among users, it is certainly possible.
One advantage S23 has over other SARMs in this context is that its androgenicity will likely have an antagonizing effect on Estrogen in the body.
The more favorable the ratio of androgens to Estrogen is in the body, the less likely the incidence of gyno is, even when Estrogen levels are elevated out of range.
While heightened androgenic activity defeats the purpose of SARMs tissue selectivity, it helps prevent gyno, which is a plus.
All SARMs can cause gynecomastia as they suppress the Hypothalamus-Pituitary-Testes-Axis and can throw off the ratio of androgens to Estrogen in the body.
In addition, by binding harder to the androgen receptors than endogenous androgens, more endogenous Testosterone will divert to aromatize into Estrogen.
Suppressing Testosterone production in itself can cause an imbalance in the ratio of endogenous androgens relative to endogenous Estrogen in the body, creating a hormone imbalance that encourages gynecomastia development.
Estrogen management would be prudent during any usage of SARMs.
Based on what we know, S23 has a more favorable preclinical profile than other SARMs when it comes to gynecomastia risk due to its full agonist activity in androgen affected tissues.
Other SARMs have shown potential liver toxicity concerns, albeit minimal at their therapeutic dosage amounts.
There is no preclinical data on the potential liver toxicity of S23, so it would be prudent to assume that at high enough dosages it could present the same limitations of other SARMs when it comes to taxation on the liver.
S23 PCT (Post Cycle Therapy)
S23 is very suppressive and almost certainly would warrant a PCT phase (post-cycle therapy) for efficient recovery.
The goal of a PCT phase is to restore natural Testosterone production and hormonal balance as quickly as possible and prevent low androgen or high Estrogen side effects from occurring.
Forgoing PCT will greatly increase the risk of muscle loss, fat gain, among all of the other negative side effects associated with low Testosterone levels.
PCT after a cycle of S23 is especially important because of how suppressive it is on the HPTA.
How much time off should be taken after PCT should not be determined with the bro-science “time on = time off” equation, rather it should be dictated by individual specific factors and blood work.