There has been a lot of interest in recent years in SARMs or selective androgen receptor modulators.
But what are they exactly? Why are people now interested in reading up about current animal and human trials? What’s there to gain once these substances are finally approved for extensive human use?
Let’s begin with basic mechanics of how SARMs work in the body. From the name itself, SARMs are responsible for interacting with androgen receptors in the human body.
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The androgen receptor or AR is part of the nuclear receptor subfamily and is a type of nuclear receptor. A nuclear receptor is actually a class of proteins in the body that is responsible for sensing/acknowledging the presence of steroids and other types of hormones in the body.
Nuclear receptors work primarily in regulating the expression and action of genes. Genes are basically blueprints of the body that dictate how cells and proteins grow, develop and function.
Gene expression is affected when a ligand, a type of molecule, is present. Specific ligands or molecules can bind to nuclear receptors and can cause conformational changes in it. So to recap, nuclear receptors are responsible for gene activity, and gene activities require ligand molecules to change track.
So in the grand scheme of things, the body requires different families of nuclear receptors to function properly at the cellular level, because everything about the body needs to be regulated in order to maintain normal function.
What’s truly fascinating about this class of receptors in the body is that they are able to interact with the human DNA in a very direct and essential way, which means the effects are often immediate in the selectively affected tissues.
When did SARMs begin to take over in terms of popularity in the field of hormone replacement therapy? The first wave of serious researches about SARMs came from the University of Tennessee and the independent firm Ligand Pharmaceuticals. In the beginning, compounds were simply cyclic quinolinones that produced an anabolic effect on the muscles and bones.
When we say anabolic effect, we mean that the the growth and/or development of the said tissues are affected. The work of Dalton and Miller on aryl propionamides also paved the way for more researches in the field of SARMs, which were essentially compounds that contained molecules that mimicked the action of steroids and the naturally occurring male hormone, testosterone.
The decade that brought studies from Ligand Pharmaceuticals and the University of Tennessee also brought a wave of other independent studies from competing pharmaceutical companies who saw a massive opportunity to explore these wondrous compounds that not only enhanced the physique of people under treatment, but were also able to avoid the common, serious side effects of steroids.
The side effects of steroids has caused an endless, serious debate on the use of steroids for improving the aerobic capacity, muscle strength, muscle endurance and lean muscle development of athletes and other professionals who engage in regular training.
The same side effects are also problematic for individuals who are already suffering from chronic, degenerative diseases such as breast cancer, type 2 or adult onset diabetes, muscle disease, brittle bone disease, among other conditions that all rely on the regulation of tissue growth and the retention of the same.
From a medical perspective, the rationale for further developing SARM comes from the most natural process known to man: aging. Now we’re not just talking about geriatric healthcare here, where people in their fifties and onward become the foci of attention.
No, we’re actually talking about the steady and nearly unstoppable decline of the human physiology as the years go by. The overall decline of the human body is natural, but with the birth of substances that can re-regulate the body on demand, it appears that science has found the key that will unlock a potential ‘fountain of youth-‘ a way to slow down tissue degeneration, heal chronic conditions and bring vitality to bodies that have been sapped by age and disease.
For decades, medical science has been largely dependent on male hormone supplementation to address low levels of testosterone in the body. This is considered one of the of the ‘final frontiers’ of medical science because of the known adverse effects of synthetic male hormones on the body.
The problem with the administration of testosterone are the adverse, dose-limiting effects. That when higher doses are administered to patients specifically to remodel the musculoskeletal system, a host of undesirable after-effects come to the fore. Some of these after-effects include erythrocytosis, leg edemas or water retention in the lower part of the body and prostate issues, such as the formation of tumors and enlargement of this sensitive part of the male reproductive system.
As the adverse, dose-limiting after-effects of male hormone therapy continue to plague patients, SARMs have become an extremely attractive option because of the tissue selectivity factor that come with their administration – and the administration of SARMs would still fall under ‘anabolic therapy’ as these compounds mimic the male hormone and bind with the androgen receptor.
The main challenge with the development of safe SARMs for human use is examining the signaling in the body that point to the selective action of compounds as they enhance the bone and muscle development.
Now, there are two kinds of SARMs (though classifications tend to get muddled because of the androgenic effect of these substances). The first type is called steroidal SARM because these compounds modify the naturally-occuring male hormone in the patient’s body. The second type is nonsteroidal SARM, which binds to the androgen receptors but do not affect the testosterone molecule.
The most widely known type of SARMs are nonsteroidal SARMs. The first substantial effort to develop and understand how this class of SARMs work came from GTX, Inc., a private pharmaceutical firm. Other firms that have be to be given due credit are BMS, Ligand Pharmaceuticals, Kaken Pharmaceuticals, Inc., Johnson and Johnson and GlaxoSmithKline.
Obviously, there are massive, multinational firms working nonsteroidal SARMs at the moment, and this shows much promise for patients who will greatly benefit from anabolic treatments, minus the adverse side effects brought about by higher doses of testosterone. So what’s happening essentially is that private pharmaceutical companies are trying to find out if alternative compounds can actually take the place of testosterone in a medical setting.
Let’s talk about the various classes of nonsteroidal SARMs and what existing studies have discovered about them.
S1 & S4 – These two compounds have been tested on castrated mice and both have shown the capacity to bind to the androgen receptor and prevent the reduction of prostate mice in the test mice.
Take note that the testicles are the site of natural testosterone production, which means that once the testicles are removed, testosterone levels drop and secondary sexual characteristics of affected male animals will begin to take an adverse hit.
At a dosage of 3 milligrams per day, the test subjects for S1 and S4 have shown better lean muscle development, higher density (as measured from the bone mineral content of examined tissues) and higher bone strength. There has also been marked suppression of proteins associated with muscle wastage and bone mineral reduction.
Findings for these two classes of nonsteroidal SARMs show lots of potential for treating osteoporosis, as those affected with this condition need not just better bone density, but higher bone strength. Brittle bones easily crack under pressure, and the body must thrive with additional physical activity.
Additionally, both S1 and S4 have shown an ability to reduce gonadotropin reduction, which affects spermatogenesis or the production of motile sperm cells, and this means it can be used for male contraception. Paradoxically, these substances can help quell normal spermatogenesis but can help enhance a man’s libido or natural desire of intercourse, which makes it a double win, considering that chemical contraception so far has been linked to a marked reduction of interest in sex.
Hydantoin derivatives – These are SARM compounds that have been developed by the BMS Pharmaceutical Group. Chemically, hydantoin derivatives are structurally similar to bicalutamide.
This class of nonsteroidal SARM has been proven to be highly selective of the tissues, too, and has been shown to have low affinity to prostate tissue. Currently, BMS-564929 is available in oral form, with an effective time of just eight to fourteen hours in the body. After this period, the compound is completely metabolized.
It should be noted that there can sometimes be marked differences between in vivo (inside the body) and in vitro results when testing compounds like hydantoin derivatives.
The reason for this is that these compounds can and will interact with existing pharmacokinetics in the body, and by virtue of other drugs in the body, the effects can either be reduced, enhanced or cancelled out. That’s why it is exceedingly important to only use these compounds in a clinical setting, with a physician knowledgeable enough to administer the proper dosing after necessary tests have been completed.
Tetrahydroquinoline derivatives – These compounds are being primarily researched by Kaken Pharmaceutical Corporation in Japan, and are being developed mainly as an adjunct treatment for bone density reduction and/or bone mineral loss.
Tetrahydroquinoline derivatives have also shown selectivity in its agonist activity, as it primarily works on bone tissue. This type of SARM is administered subcutaneously and high doses have been indicated to produce desired pharmacological effectiveness.
LGD2226 & LGD 2941 – Devised as bicyclic 6-anilino quinolinone derivatives, LGD226 and LGD 2941 are primarily anabolic in nature and have exhibited high affinity for the levator muscle. Benefits of administration of either of these bicyclic 6-anilino quinolinone derivatives include higher bone mineral density, an increase in bone strength and lean muscle development, too.
Fortunately, current tests show that these two compounds have low affinity for prostate tissue, which translates to a better outlook for patients who will undergo therapy using these two ligand compounds. Human trials are not yet underway. Existing literature and data are currently sourced from extensive animal trials, in male reproductive model tests where test subjects are primarily castrated test mice.
The rationale for using castrated test mice in SARM animal trials is quite simple. As we’ve discussed earlier, the testicles of male mammals are the site of testosterone production.
Castrated mammals will suffer from low testosterone levels, to the point that secondary sexual characteristics, as well as physical adaptation associated with having higher testosterone levels will suffer. The introduction of an agonist factor that binds to the androgen receptor will more clearly show the impact of a SARM, as the primary job of SARM compounds is to act as an alternative to testosterone itself, whether in natural or synthetic form.
Theories on SARM tissue selectiveness
We known now that SARM compounds have three basic characteristics. The first one is that these compounds are quite selective in affecting the body. They’re not ‘interested’ in tissues found the lungs, heart, liver, etc. The current line-up of known nonsteroidal SARMs, specifically, show that such compounds are primarily affective of bone tissue and muscle tissue.
These compounds have low affinity for other types of tissues, which make them safer to use than conventional testosterone and other known anabolic derivatives in hormone replacement therapies. The second characteristic is they tend to improve how energy is stored and used in the body. This often translates to higher muscular strength and endurance, and improvement in the way the body ports energy.
That instead of storing fat, the body burns more energy or calories and in the process, also oxidizes fat faster, leading to its direct expenditure as energy. The third characteristic is the relatively safety of the organs themselves upon the administration of SARMs.
Normally, adverse risk factors are present when higher doses of testosterone are given to patients. SARMs tend to eliminate the risk of organ damage, and this is directly linked to their low affinity to tissues that are non-related to the musculoskeletal system.
On the bright side, soft tissues such as joints and cartilages are still technically part of the muscle-bone marriage in the body, and these tissues also improve greatly when SARMs are introduced.
But how do they do it? We already have a lot of information with the after-effects of direct administration of these compounds, but there is no direct explanation as to why these secondary effects exist in the first place.
While direct answers are still being researched, there are some interesting theories from science that may explain why SARMs do wha they do. The first one is called the co-activator theory. Essentially, the natural proteins that bind to the androgen receptor have a different set of tasks when it comes to gene expression.
When any kind of SARM is introduced to the system, the impact of naturally-occurring proteins are reduced, and impact of the SARM is amplified once it binds to the androgen receptor.
Consequently, this theory leads to the thinking that testosterone-bound proteins have a wildly different set of ‘instructions’ for target genes. The second fold of this theory also suggests that SARMs activate other genes, which would explain the detour of target tissue development.
The second theory is the conformational theory. Essentially what this theory states is that when a SARM is administered to the body and binds with the androgen receptor, it has the capacity to change the surface environment or topology of the androgen receptor.
In layman’s terms, SARMs change the ‘face’ or mapping of the androgen receptor. When the new blueprint is conformed by the action of the SARM, the androgen receptor then continues to interact with other proteins and co-regulating variables in the body, leading to a marked change in how the body regenerates tissues and distributes energy.
To simplify this scenario, think of androgen receptors as guides at a crossroad. Oncoming genes approach androgen receptors, waiting for instructions where to go. SARMs are people with a different set of instructions and information, and once these compounds ‘talk’ with the guide (the androgen receptors), the androgen receptors say “well alright, I have a new set of directions and I’ll make sure the genes know about this for the time being.”
When the administered SARM is metabolized, it exits the system and the nuclear receptor goes back to its old set of instructions for gene expression. So in the end, it’s really all about chemical signaling and the activation of certain genes to achieve certain ends.
The third theory of why SARMs work and why they’re selective concerns the actual distributions of such compounds once administered. Researchers also state that tissue selectivity may actually be more related to how specific proteins interact with SARMs and not the other way around.
There are also instances when SARM compounds are converted to other compounds, before they are able to perform the secondary effects desired for the therapy. Whatever the case may be, it is clear that some transformational effects are experienced by this class of compounds in the body, as they are still metabolized.
Data on early trials of SARMs
Admittedly, much of the clinical data available for SARMs are from the private firms that run them and many of them have not been peer-reviewed and published in international journals. However, they do remain valid take-off points for the continued discussion of SARMs as clinical data is clinical data no matter how you brand it.
SARMs have collectively undergone three kinds of clinical tests: animal testing (as is the case of castrated mice), Phase 1 human trials and Phase 2 human trials. A number of SARM compounds have finally reached Phase 1 human trials, but not specifically for enhancing athletic abilities or physical strength.
These compounds are being further researched as possible treatments for cachexia, cancer, brittle bone disease, and other associated conditions where the body experiences weight loss, bone mineral density reduction and lean muscle reduction. Some types of SARMs, as we’ve already discussed, are being explored as possible male contraceptive substances, as is the case with S1 and S4.
The general point of contention in using SARMs as male contraception is this: that if spermatogenesis is inhibited, what would happen in the long term to the sexual health of the male?
Aromatization or the conversion of SARMs to estrogen after it has been metabolized is also a problem. Many SARMs resist aromatization; testosterone (the naturally occurring compound) is naturally aromatized. Until these issues are sorted out, we can expect a fairly tough battle in getting SARMs approved for widespread use. Until such time, these compounds remain available only for scientific studies and not for athletic enhancement and professional bodybuilding.