The Myth of Desensitization to AAS; Four (4) Modes of Receptor Regulation & Upregulation of AR by AAS

Type-IIx

Well-known Member
I was requested by PM to address the claim that androgen receptor (AR) "resensitization" is a rationale for discontinuing AAS, meaning that supraphysiologic androgen dose (AUC; nmol * h/L) induces tachyphylaxis (desensitization) analogous to opioid/opiate & Opioid Receptors (i.e., κ-, δ-, μ- OR) or clenbuterol & β₂Adrenergic Receptors (B2AR). Since I have some time and think that this is important, I will oblige.

Tachyphylaxis or desensitization is a feature of G-protein-coupled receptors (GPCRs) that AR is not. In the case of opioid/opiate drugs, the μ- OR is a GPCR subject to phosphorylation that recruits β-arrestin, an accessory protein that induces tachyphylaxis, requiring increasing doses to elicit the same efficacy in subsequent doses. Clenbuterol activates the B2AR, a GPCR, thereby stimulating phosphorylation of downstream elements, binding β-arrestin, to regulate signaling pathways involved in muscle growth and decreased fat mass (recomp), as well as increased strength, sprint, power (performance). In the cases of both of these types of drugs, opioids/opiates & B2ARs like clenbuterol, the dose must be increased with subsequent uses in order to elicit comparable effects due to tachyphylaxis.

AR Regulation
AR, by contrast, is not a GPCR, and so is not associated with tachyphylaxis.

AR expression (the number/# of receptor proteins in our bodies) is regulated in several ways:

Broadly speaking, there are four (4) forms of regulation that control the number of receptors in the body. These are:

1. Transcription rate (i.e., up-regulate AR by increased transcriptional AR mRNA synthesis)
2. Translational efficiency (i.e., up-regulate AR by increased AR mRNA synthesis per ribosome)
3. Translational capacity (i.e., up-regulate AR by increased AR mRNA synthesis as a result of increased ribosomal biogenesis [suggesting ↑ ribosome #])
4. Receptor turnover (i.e., up-regulate AR by decreased degradation/synthesis balance of AR mRNA)

To understand them, let’s quickly review the life-cycle of an individual AR.

? Transcription rate
There is a single gene in the DNA of each cell that codes for the AR. In the transcription process, the DNA code is copied to mRNA. The rate (frequency) of this process can be either increased (promoted) or decreased (repressed) depending on what other proteins are bound to the DNA at the time. Increase or decrease of this rate can be a form of regulation: the more AR mRNA is produced, all else being equal, the more ARs there will be. Bill Roberts.

✖ Translational efficiency
If efficiency is 100%, each mRNA will be used by a ribosome to produce an AR, which is a protein molecule. The process of making protein from the mRNA code is called translation. In practice efficiency will not be 100%. Changes in efficiency of translation can also be a form of regulation. Bill Roberts.

This, if it were a mechanism by which androgen regulated AR #, would be marked by mTOR activity (ie, myogenic markers, rpS6 or p70S6K increases in human skeletal muscle cells in vivo).

Translational capacity
By increasing the # of ribosomes, the absolute # of AR produced by translation will increase. This is an important mechanism by which androgens ↑AR # in vivo.

Test-upregulates-AR-expression-SCR-Figure.MesoRx.png

The increase to AR # reflects, in part (r = 0.467), increased translational capacity, reflected by an increased muscle total RNA content (Δ μg RNA/mg muscle) that since ribosomal RNA comprises > 85% of cellular RNA, describes an increased ribosome # (suggesting that androgen/T stimulates ribosomal biogenesis):

Test-Delta-Total-RNA-Bar-Graph.MesoRx.png
Test-Delta-Total-RNA-AR-log2-Graph.MesoRx.png


? Receptor turnover
The final form of potential post-translational regulation is the rate of loss of ARs. If the cell produces x ARs per hour, and their half life is say 7.5 hours, then the number of ARs will be higher than if ARs are produced at that same rate but the half life is say only 3.3 hours. Thus, control of rate of turnover, or change in half-life, can be another means of regulation. Bill Roberts.

Conclusions
1. AR is up-regulated (AR # & density increased) by testosterone/androgen in human skeletal muscle cells in vivo.
2. This up-regulation is known to be a result of increased translational capacity by testosterone/androgen; and not translational efficiency a la mTOR.
3. Regulation of AR is not subject to desensitization; so, by corollary, there is no rationale to support cessation for resensitization.
 
Great post @Type-IIx

The rationale of "taking a break" inherently never made much sense to me. Mainly due to upregulation of AR, as you mentioned, while using AAS. This thought process should lead to the conclusion that stopping use of AAS won't change anything except up-regulation, but not cause extreme down-regulation inversely.

I believe most recreational AAS users want to take breaks due to the belief that it's healthier (disagree), but clearly some also want to "chase the dragon" so to speak, and believe resensitizing themselves will give some sort of crazy effects for their next cycle.
 
Great post @Type-IIx

The rationale of "taking a break" inherently never made much sense to me. Mainly due to upregulation of AR, as you mentioned, while using AAS. This thought process should lead to the conclusion that stopping use of AAS won't change anything except up-regulation, but not cause extreme down-regulation inversely.

I believe most recreational AAS users want to take breaks due to the belief that it's healthier (disagree), but clearly some also want to "chase the dragon" so to speak, and believe resensitizing themselves will give some sort of crazy effects for their next cycle.
Oh, yeah, I think that benefits of cessation include:

1. preserving fertility & endogenous T levels
2. avoiding life-long dependence on some form of exogenous androgen
3. health, especially if TRT still requires additional treatments like phlebotomy & antiestrogens (AIs, SERMs)
4. getting a break from intramuscular injections and all that entails: (a) possible pain/swelling, (b) socio-relational stress arising out of your use of hypodermic needles, (c) rare pulmonary oil microembolism events like coughing/wheezing, (d) having to procure & dispose of medical supplies, etc.

Plenty of good reasons for a true off period, just not on the basis of resensitization.
 
Oh, yeah, I think that benefits of cessation include:

1. preserving fertility & endogenous T levels
2. avoiding life-long dependence on some form of exogenous androgen
3. health, especially if TRT still requires additional treatments like phlebotomy & antiestrogens (AIs, SERMs)
4. getting a break from intramuscular injections and all that entails: (a) possible pain/swelling, (b) socio-relational stress arising out of your use of hypodermic needles, (c) rare pulmonary oil microembolism events like coughing/wheezing, (d) having to procure & dispose of medical supplies, etc.

Plenty of good reasons for a true off period, just not on the basis of resensitization.
I should've been more specific about taking breaks -- I meant the difference between blasting/cruising vs. blasting/PCT'ing. But yeah, you are absolutely correct. I'd also like to add the financial aspect, gear can get fuckin' expensive.

I think if a user can return to healthy levels, not just T but other markers as well without any sort of detriment to their physical or mental health, then that's a personal decision and the benefits would probably outweigh the negatives.

This isn't completely off-topic, but not exactly what we're talking about: Do you personally believe or have any data (even anecdotal) that would show blasting/cruising to be "healthier" for the user vs. blasting/PCT'ing all the time, or vice versa?
 
I should've been more specific about taking breaks -- I meant the difference between blasting/cruising vs. blasting/PCT'ing. But yeah, you are absolutely correct. I'd also like to add the financial aspect, gear can get fuckin' expensive.

I think if a user can return to healthy levels, not just T but other markers as well without any sort of detriment to their physical or mental health, then that's a personal decision and the benefits would probably outweigh the negatives.

This isn't completely off-topic, but not exactly what we're talking about: Do you personally believe or have any data (even anecdotal) that would show blasting/cruising to be "healthier" for the user vs. blasting/PCT'ing all the time, or vice versa?
Good point, financial expense another consideration indeed. Also, for some, staying plugged into the black market and such. Not only socio-relational but legal risks can apply also.

I think that the [1] practice of one (1) single 13 week cycle with hCG & hMG maintenance of LH/FSH, meaning total cessation or a brief optional "PCT" phase using SERM/AI drugs and 48 weeks of no AAS use whatsoever in a calendar year is definitely healthier vs. either [2] cycling based on normalization of bloodwork parameters (that do not reflect morphological & functional changes) or [3] blast & cruising, even if cruising on a true TRT dose (250 mg testosterone enanthate every 21 days to start, adjusted to a mid-interval target of 500 - 800 ng/dL total testosterone).

Between these 3 practices (1 > 2 > 3 in terms of health/safety) are permutations that illustrate that risks really accrue (cardiovascularly, reproductively, renally, nephrally, thromembolically) while on exogenous AAS dose-dependently (fAUC as nmol*h/L), such that the more time on, the less healthy. This is true despite the physical, psychological & emotional stress of withdrawal and all that it entails. Since withdrawal necessarily precedes a return to homeostasis, it's safe to say that without experiencing it, you'd be worse off than having done so, if you are a long-term user of AAS.
 
Between these 3 practices (1 > 2 > 3 in terms of health/safety) are permutations that illustrate that risks really accrue (cardiovascularly, reproductively, renally, nephrally, thromembolically) while on exogenous AAS dose-dependently (fAUC as nmol*h/L), such that the more time on, the less healthy. This is true despite the physical, psychological & emotional stress of withdrawal and all that it entails. Since withdrawal necessarily precedes a return to homeostasis, it's safe to say that without experiencing it, you'd be worse off than having done so, if you are a long-term user of AAS.
Thank you.
 
I'd like to add to this title post, under the subheading Transcription rate:

During nuclear transcription (the primary mechanism of AAS action), AR binding by an androgen/AAS (e.g., T) results in specific conformational changes in the ligand-binding domain of the AR, thereby triggering dissociation of heat shock proteins, dimerization and transport from the cytosol to the cell nucleus where the T-AR dimer complex binds to androgen response elements (AREs).

We know that there are coregulators, proteins that interact with the AR to enhance (coactivators) or reduce (corepressors) transactivation of target genes but that do not significantly alter the basal transcription rate.

Coactivators that have been identified include ARA70 (ARA₇₀), steroid receptor coactivator 1, and RAC3/ACTR. Proteins that enhance AR binding to DNA include RAF. GRIP1 & cJun increase activity.

Corepressors that have been identified include ZBTB7A that recruits NCOR1 and NCOR2 to the AREs on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation

Proteins that decrease AR # include nuclear factor kappa B (NF-κB). CFes & RelA inhibit transactivation and/or transcription.

Although the role of coactivators in androgenic action is clear in sexual & reproductive tissue, their role in AR action in (skeletal) muscle has not been comprehensively demonstrated. There are efforts underway to further investigate anabolic activity with respect to coactivators.
 
I always assumed the “desensitization” thing was broscience arising from noticing the increased glycogen/water weight/etc as one starts a cycle, and misconstruing that as actual muscle gain. When those weight increases taper off they then assume the cycle is losing potency because the body is losing sensitivity to the drugs, where in reality very little of that weight gain was muscle and they were gaining muscle steadily throughout.
 
Q&A:

But what about bodyweight?

Do we need higher doses as our bodyweight increases?
Yep, because concentrations (mg/mL) depend on volume (1 mL = 1 cm³), such that the more mass that you hold, the higher the dose needed to reach a given (e.g., blood) concentration.

Then, too, skeletal muscle contains AR that we care about for these concentrations to activate. Muscle mass is related to dose (mg/mL) in the same manner.

The primary manner of AR regulation that occurs by AAS dose is an increased translational capacity, meaning that ribosome number increases, the μg RNA/mg muscle increases (increased ribosomal density), in turn, increasing the absolute rate of translation of AR proteins for every kg of muscle you carry. But this rate of increase in AR # is far from exponential like the increase to requirements for doses to hit a given concentration as you gain mass (for changes in body or muscle mass vs. AAS dose needed to maintain a given concentration, think a plot or graph of y = X³), rather this rate of increase is merely logarithmic (think a plot or graph of y = log(X)).

To illustrate, visualize the rate or degree of change needed in mg dose of AAS per mL (volume) of your 3-dimensional muscle mass as you grow as the green curve below. Visualize the rate of increase in AR number per mg increase in mg dose of AAS as the purple curve below:

Graph-concentrations-per-volume-vs-AR-number-per-muscle-mass-Xpow3-vs-logX.ProM.png
 
I always assumed the “desensitization” thing was broscience arising from noticing the increased glycogen/water weight/etc as one starts a cycle, and misconstruing that as actual muscle gain. When those weight increases taper off they then assume the cycle is losing potency because the body is losing sensitivity to the drugs, where in reality very little of that weight gain was muscle and they were gaining muscle steadily throughout.
Good point, androgens increase glycogen synthetase activity. Glycogen stores in man are limited, only about 15 g/kg, or 1.275 kg (2.8 lb) total for an 85 kg man. However, each g of stored glycogen pulls in ~3 g of water. So that same 85 kg man can rapidly gain > 5 kg (11.22 lb) merely from this increased glycogenesis/storage (including liver stores) upon initiating, e.g., a 17AA oral AAS. The transient and rapid de- and/or re- pletion of muscle glycogen stores (and therefore water) is reflected by the fact that voluminous total-body resistance training using short rest intervals done over 2 consecutive days will totally deplete muscle glycogen stores, and can be supercompensated (> base-line) by implementing a carbohydrate-rich refeed.
 
Lol long story short, broken down by a idiot, have you ever been a pot smoker and noticed after a while u dont get as high or need more to get the same feeling, or been prescribed say vicodin for a injury , tooth, pain broke leg ect. You take 2 the first time ur like wow I feel kinda nice relaxed a little high. After a week of taking 2 a few times a day u dont get that feeling. U have to bump it up to 3 pills to get that original feeling.

With aas that is not the case.

Anyone feel free to chime in.
 
Lol long story short, broken down by a idiot, have you ever been a pot smoker and noticed after a while u dont get as high or need more to get the same feeling, or been prescribed say vicodin for a injury , tooth, pain broke leg ect. You take 2 the first time ur like wow I feel kinda nice relaxed a little high. After a week of taking 2 a few times a day u dont get that feeling. U have to bump it up to 3 pills to get that original feeling.

With aas that is not the case.

Anyone feel free to chime in.
Right, exactly. Also, as you grow, you need to increase dose at an increasing rate (up the dose significantly and, assuming continuous growth, continuously) for the 600 mg equivalent when you started at say 85 kg growing even to 90 kg.

The AR upregulation thing is a little more complex, but basically, AAS do the opposite of street drugs. They actually increase responsiveness with dose increase. However, this increased responsiveness does not keep pace with the fact that you are growing in size, and so practically you do still need to up the dose to get the same effect because of that.
 
I think that the [1] practice of one (1) single 13 week cycle with hCG & hMG maintenance of LH/FSH, meaning total cessation or a brief optional "PCT" phase using SERM/AI drugs and 48 weeks of no AAS use whatsoever in a calendar year is definitely healthier
My apologies for rehashing this, but when you said 48 weeks of no anabolic use whatsoever, was this meant to say 4-8 weeks or did you mean the heathiest option is ~11 months of no anabolic use with a 13 week "cycle"? Just want to make sure I'm understanding this correctly.
 
My apologies for rehashing this, but when you said 48 weeks of no anabolic use whatsoever, was this meant to say 4-8 weeks or did you mean the heathiest option is ~11 months of no anabolic use with a 13 week "cycle"? Just want to make sure I'm understanding this correctly.
Adhering to a calendar year structure, 13 weeks on followed by 39 weeks off (time off = time on * 3) is as aggressive as I can deem safe since 16 weeks on (900 mg weekly testosterone-equivalent for 16 weeks on) has only been shown to reverse the cardiac maladaptations that accrued during that 16 weeks after 1 full year (52 months) off.

Note that the cardiac maladaptations from this 16-week 900 mg/w testosterone-equivalent cycle, that are not reflected by bloodwork changes, include:

LV mass ↑ 28.3 g, remaining significant even when adjusted for increased body surface area
↑HR of 10.0 bpm
Mean systolic & diastolic pressure ↑ by 6 mmHg & 5 mmHg, respectively

Left ventricular changes:
- The increase in LV mass was due to an increase in interventricular septum & posterior wall thickness
- ↓left ventricular ejection fraction by 5%
- LV mass ↑ 28.3 g from T₀ to T₁, trend same adjusted for BSA
- intraventricular end-diastolic septal thickness (mm) & left ventricular end-diastolic posterior wall thickness (mm) ↑ 0.87 mm & 1.18 mm, respectively
- There was a positive correlation between AAS weekly dose & LV mass, intraventricular end-diastolic septal thickness, and left ventricular end-diastolic posterior wall thickness. Conversely, intraventricular end-diastolic septal thickness was negatively associated with training time
- LV mass, intraventricular end-diastolic septal thickness, and left ventricular end-diastolic posterior wall thickness all returned to baseline by T₂

Diastolic functional changes:
- e' early diastolic, a' late diastolic, s' systolic velocities (peak)
- E/A-ratio by T₁ declined -0.45, returning to baseline by T₂
- There was a decline by of lateral e' by T₁ with -1.8 cm/s
- Age, cocaine use, and training time were positively correlated with E/e' septal by T₁, whereas AAS dose was negatively correlated with E/e' septal
- Paresternal long-axis view ↑ 1.9 mm (> for oral AAS, β=3.7!)
- Left atrial 3D volume ↑ 9.2 mL

RhGH use (rhGH+AAS) was associated with a higher left ventricular end-diastolic volume 3D & left ventricular end-systolic volume 3D (mL) post-cycle (T₁), whereas the number (quantity) of AAS used was negatively associated with both.
 
Great post, I appreciate the time it takes to get these put together. I read a paper on Telemisartan specifically protecting from ventricular thickening do you think there is any weight to that concept? The concept was that Telmisartan may reduce cardiac hypertrophy by indirectly ameliorating hypertensive symptoms and directly inhibiting the cardiac Ang II receptor. Basically am I fooling myself thinking that taking it daily provides some protection?
 
Great post, I appreciate the time it takes to get these put together. I read a paper on Telemisartan specifically protecting from ventricular thickening do you think there is any weight to that concept? The concept was that Telmisartan may reduce cardiac hypertrophy by indirectly ameliorating hypertensive symptoms and directly inhibiting the cardiac Ang II receptor. Basically am I fooling myself thinking that taking it daily provides some protection?
It might do a bit, but AAS-induced LVH only partly overlaps with the etiology of pressure overload.

RhGH-induced cardiomyopathy is totally distinct from pressure overload.

Basically, let me put it straightforwardly: if you're not hypertensive, you don't need an ARB or ACE inhibitor. They just don't do much; and (especially ACE inhibitors) probably make you weaker, to boot.

AAS induce hypertrophy.... not only in skeletal muscle, but smooth cardiac muscle also.
 
It might do a bit, but AAS-induced LVH only partly overlaps with the etiology of pressure overload.

RhGH-induced cardiomyopathy is totally distinct from pressure overload.

Basically, let me put it straightforwardly: if you're not hypertensive, you don't need an ARB or ACE inhibitor. They just don't do much; and (especially ACE inhibitors) probably make you weaker, to boot.

AAS induce hypertrophy.... not only in skeletal muscle, but smooth cardiac muscle also.
Taking us off-topic again: Do you have any solid information on what does or potentially can reduce cardiac remodeling?
 
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