Do Androgen Receptors Downregulate?
There is a very common misconception in the bodybuilding community that androgen receptors downregulate during a steroid cycle, or during long-term steroid use.
A plateau in muscle gain is commonly attributed to this “androgen receptor downregulation”.
If you've ever cycled anabolics, you can also attest to the fact that during a new cycle the gains always seem to come within the first 8 weeks or so, and then the weeks following that it is typical to notice a blatant diminishing returns effect.
If you used a long ester, this may not be the case because it will take longer to saturate the body with the drug, but the same principles still apply, they just take a few weeks longer to occur due to the longer half-life.
For example, if you've taken a fast acting oral like Dbol before, you probably noticed that the increases in strength and size seem to pile on from week 1-6, and then the weeks following that (if you continued using it) are almost unnoticeable in contrast.
This diminishing returns effect is not the result of androgen receptor downregulation, although most will misinterpret it as such.
The reason why you can't gain muscle at a rapid pace continuously while on steroids is because Myostatin increases in the body to inhibit your body from gaining an unhealthy amount of muscle.
Steroids actually upregulate androgen receptors, not downregulate.
Bodybuilding gurus will commonly advise swapping compounds at week 8 of a cycle/blast phase to circumvent plateaus in muscle gain.
This does absolutely nothing.
The misguided belief is that the androgen receptors have become accustomed to the steroid used during the first 8 weeks, and switching to another steroid will circumvent the androgen receptor being desensitized to the first compound.
For example, if someone uses Testosterone and Nandrolone for 8 weeks, the majority of gurus will advise that they swap the Nandrolone for EQ or Tren at the end of week 8.
The androgen receptor doesn't “get used to” Nandrolone by the end of week 8, Myostatin levels have simply increased to a point where muscle accrual is now severely inhibited, despite the presence of supraphysiological amounts of androgens.
Do You Need To Cycle Off Of Testosterone If You Are On TRT?
If you take Testosterone, regardless if it's for performance-enhancing use, or for therapeutic reasons, a common inquiry is whether androgen receptors downregulate from its long-term use.
Will you need to come off of Testosterone to re-sensitize to it because the androgen receptor is becoming resistant to Testosterone?
The answer is no.
When you take your TRT, your androgen receptors upregulate, they don't downregulate.
And what happens after that point is your body actually increases Myostatin to inhibit you from gaining more muscle than you should.
Your Body's Counteracting Mechanism – Myostatin
The mechanism by which your body is inhibited from gaining absurd amounts of muscles is not because your androgen receptors are becoming desensitized to the steroids that you're using.
Rather, it's your body's endogenous production of Myostatin is going up.
The body has a counteracting mechanism for everything.
If you eat carbs, your pancreas releases insulin to bring down your blood sugar.
If you expose your skin to UV rays, your skin will increase melanin production (or try to) to create a tan that will help protect you from further damage.
Myostatin increases to prevent you from gaining unhealthy amounts of muscle
The human body is a big balancing act.
Something most don't realize is that having a lot of muscle mass is extremely unhealthy for the cardiovascular system.
Your body is fighting back to keep muscle off of you, and the more muscle you gain and the more androgens you expose your body to, the more you will induce Myostatin production to make it increasingly difficult to gain more size.
There may be other regulating mechanisms that we are not yet aware of, but Myostatin seems to be the primary one.
Myostatin Related Muscle Hypertrophy
Flex Wheeler is a great example of what Myostatin does to the body, as well as what a lack of it can do.
During a study at the University of Pittsburgh, Flex was found to have a very rare Myostatin mutation at the exon 2 position on the gene.
This gene mutation prevented his body from producing normal amounts of Myostatin, consequently resulting in a much larger number of muscle fibers than the average male.
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Animals and humans with inhibited Myostatin levels have consistently shown to have much greater levels of musculature relative to their non-inhibited counterparts, and based on this it isn't crazy to assume that most genetic freaks in bodybuilding developed their physiques as a result of a similar gene mutation.
In theory, someone with inhibited Myostatin levels could continue to progress at rates that would be impossible for someone with normal levels.
The end result being substantially greater levels of muscle gain from the exact same drugs, diet and training.
Androgen Receptor Activation – Swapping Compounds Is Pointless
As per the advice of a misinformed guru, once you plateau then you should swap compounds because your body is getting used to the androgens you're using.
Let's delve into how the androgen receptor mediates effects in the body quickly just to clarify exactly what really happens.
When you take TRT, does your body suddenly stop transcribing the effects of Testosterone correctly at week 8?
Does your penis suddenly become dysfunctional and lethargy and brain fog kick in?
No, anybody on TRT knows full well that as long as you keep your hormones in check with a properly managed Testosterone to Estrogen ratio, your state of well-being is consistently the same, as is sexual function.
Based on the theory that androgen receptors downregulate, you would only assume that eventually the androgen receptors would also eventually desensitize to Testosterone too, as it is after all the bioidentical androgen our body naturally produces.
Why would the body desensitize to Nandrolone, Dianabol, or Trenbolone, but not Testosterone?
If we adopt this theory, then are we also adopting the premise that you should rotate out Testosterone after the androgen receptors have desensitized to it.
This theory falls apart once you look at it in this capacity, without even delving into the science of androgen receptor activation.
Obviously we don't have to swap from Testosterone to some other random unapproved drug now because we're on TRT and our bodies will supposedly get used to the Testosterone long-term.
Your body doesn't just stop using the Testosterone properly at week eight.
Everything keeps functioning correctly on that Testosterone for the duration of time you use it, but the muscle itself is what's inhibited.
I'm sure guys on TRT for decades plus will attest to the fact that their libido doesn't just crash and stop working at week eight, and that's because the functions mediated through androgen receptor activation are irrelevant to the reason you're not putting on more muscle.
The androgen itself (Testosterone or any other androgen) and the androgen receptor are doing exactly what they're supposed to do.
Androgens bind to the androgen receptor, and after binding they induce anabolic and androgenic activity in affected tissues in the body.
This is mediated via androgen receptor activation, and the androgen receptor continues to function correctly, regardless of androgen concentrations present.
The problem is that your body increases Myostatin to prevent you from gaining more muscle than it wants you to.
The study “Testosterone and trenbolone enanthate increase mature myostatin protein expression despite increasing skeletal muscle hypertrophy and satellite cell number in rodent muscle” exhibits exactly what happens in the body after exposure to supraphysiological amounts of exogenous androgens.
This study showed that after 29 days of administration of either Testosterone or Trenbolone, Myostatin protein levels were 197% higher in the castrated and Testosterone group, and 209% higher in the castrated and Trenbolone groups when compared to the placebo.
Relating this back to steroid cycles for bodybuilding, the efficacy of the drugs is not diminishing whatsoever, nor do androgen receptors downregulate.
The brick wall you hit mid-cycle where you suddenly start plateauing out of nowhere is not something that can be overcome simply by switching to a different androgen.
Once your body has recognized that it is packing on too much size, Myostatin production occurs in parallel to make it increasingly difficult to gain more muscle.
This is why every pound of muscle you gain is harder than the last.
The first 10 pounds you gain when you workout are easy.
The next 10 pounds are fairly easy too.
But you'll notice that the closer you get to the 50 pound mark of lean muscle accrual (even on anabolics) that your body will start fighting back big time, and eventually gaining just a few pounds more muscle will be more difficult for you than gaining the first 20 was.
So what do you do to prevent Myostatin from inhibiting further muscle growth?
That's something to be left for future research and development.
There are no Myostatin inhibitors that are approved for human use, or even have any human trials on them.
Follistatin was a hot topic for a while, and many theorized that it could be used to inhibit Myostatin and unlock elite levels of muscle growth potential.
This was a huge letdown, as research chemical companies started selling vials of Follistatin for upwards of $1000, with none of them yielding any benefits whatsoever.
They were likely not legitimate Follistatin, but the entire hype train behind it left a bad taste in the mouths of bodybuilders around the globe who had all wasted their money on this junk peptide.
YK11 is the most recent Myostatin inhibitor to draw the interest of bodybuilders.
While the limited data on it is impressive, there has been next to no analysis on it, except on a cellular level.
There aren't even animal studies to reference.
Granted, we now have hundreds, if not thousands of anecdotal report to refer to now of users who have experimented with YK11 on themselves, but at the end of the day none of these individuals are getting lab work done to check Myostatin levels before and after in their body, nor do most even know if they have legitimate YK11 or not.
Regardless of the fact that YK11 and other Myostatin inhibitors are in their infancy, I do believe that down the line Myostatin inhibition will pave the future of bodybuilding pharmacology within the next half century.
So, don't just go randomly shoving that in your body because it's not a good idea.
Myostatin inhibition is probably going to be the main pathway by which new extreme developments come out that allow the human body to greatly exceed its natural limits.
Androgens can only take you so far until Myostatin increases to prevent you from getting too muscular.
If you're on TRT from your doctor's prescription, you don't need to go off your prescription and then jump back on your prescription to make it work.
One of the biggest myths in the community is that androgen receptors downregulate, and by realizing how mechanisms in the body actually work, it will help you better prepare for your journey with performance enhancing drugs.