The Efficiency Paradox in Anabolic Pharmacology

[Stewie]

Thank you very much for this, Stewie. You’ve brought several critical mechanisms to light that I was completely unaware of.

The structural crowding of the AR pool leading to the AR45 variants trapping molecules is a fascinating concept, a literal molecular dead-end.
It makes perfect sense that the upregulation of AR45 by myostatin is a core component of how the body aggressively pulls the emergency brake to maintain cellular homeostasis.

Your critique also has me digging deeper into Androgen Response Elements (AREs).
Because these are physically embedded along the chromosome, they represent the literal genetic blueprint we are born with; no amount of chemical intervention will alter or expand that landscape.

It perfectly validates the factory analogy I’ve been visualizing to map out this entire process:

• The Signal (exogenous androgens) is broadcast globally.
• The Antennas (the AR pool) pick up the signal on the roof.
• The Internal Teams (the transcriptional co-activators) must physically carry those instructions across the factory floor.
• They deliver them directly to The Production Equipment (the hard-coded genomic AREs) to manufacture the final product (myofibrillar protein synthesis).

If all the production equipment is already 100% occupied and running at absolute capacity, blasting a louder signal and building more antennas on the roof is completely moot. The factory floor has simply hit its structural limits.
Pushing beyond that point doesn't create more manufacturing equipment; it just causes the systems to overheat and trigger the defensive shutdowns you outlined.

Truly appreciate you elevating the quality of this discussion.

You're welcome. Your autodidactic mindset will take you down some very interesting interactive pathways.

This thread from 6 years ago may help put some of the pieces together– undoubtedly there are several other mediators that I'm not aware of. If you find something intriguing – definitely share to brainstorm on.

Note: there are a few inaccuracies I blundered—

Do Esters change how the hormones react in the body?

A longer ester like Enanthate will allow blood hormone levels to rise to a much higher level than a short ester like Ace or prop. I am wondering how each effects the body. Is there any science behind this. I always hear longer esters are more anabolic while short esters are better for cutting...

www.professionalmuscle.com

 

[Stewie]

Wanna go down a rabbit hole — ER (endoplasmic reticulum) stress converging with UPR (unfolded protein response) and how that potentially links back to ARE (androgen response element) engagement. There's an intersection there worth exploring.

TBH– I'm still trying to map it all together–

 

[Jose1990]

There is also the conception that not all steroids are created equal, but they are treated as so by us, in the sense that we are always talking about total dosage, and coaches are asking, ok "what is the totals you ran past offseason".

For example, 500mg of tren is not the same as 500mg of Masteron - so why are we talking about total mg doses? why are we using total anabolic load as reference points?

one running 500mg test 500mg primo and 1000mg masteron, a 2g load vs someone running 1000mg test, 300mg equipoise and 700mg tren a 2g load also, they will yield different results and have different genomic and non-genomic effects in the body. Why are we simplifying the dosages? (we do it because we dont have any reliable anabolic ratio to rely on other than our empiricism).

Nevertheless, a consideration to make.

 

[specter]

There is also the conception that not all steroids are created equal, but they are treated as so by us, in the sense that we are always talking about total dosage, and coaches are asking, ok "what is the totals you ran past offseason".

For example, 500mg of tren is not the same as 500mg of Masteron - so why are we talking about total mg doses? why are we using total anabolic load as reference points?

one running 500mg test 500mg primo and 1000mg masteron, a 2g load vs someone running 1000mg test, 300mg equipoise and 700mg tren a 2g load also, they will yield different results and have different genomic and non-genomic effects in the body. Why are we simplifying the dosages? (we do it because we dont have any reliable anabolic ratio to rely on other than our empiricism).

Nevertheless, a consideration to make.

Thats a whole rabbit hole hahaha... What was that coach guy´s name that said all steroids are created pretty much equal in the gains department.

 

[hawkmoon]

Thats a whole rabbit hole hahaha... What was that coach guy´s name that said all steroids are created pretty much equal in the gains department.

Yes. IMO I don't see that being true, but for the majority of cases the differences may be small enough not to matter much.
I am no authority there and cannot say - especially since no one has performed a proper assay for AAS and hypertoropy - nor likely will it ever happen.

 

[hawkmoon]

You're welcome. Your autodidactic mindset will take you down some very interesting interactive pathways.

This thread from 6 years ago may help put some of the pieces together– undoubtedly there are several other mediators that I'm not aware of. If you find something intriguing – definitely share to brainstorm on.

Note: there are a few inaccuracies I blundered—

Do Esters change how the hormones react in the body?

A longer ester like Enanthate will allow blood hormone levels to rise to a much higher level than a short ester like Ace or prop. I am wondering how each effects the body. Is there any science behind this. I always hear longer esters are more anabolic while short esters are better for cutting...

www.professionalmuscle.com

The part you raised on Zinc Finger Motifs (Cys4) and how zinc impacts aminio acids chains raised some interesting reading

 

[massephase]

Same here, as I've grown older I've lowered my dosages every year and also focused more on improving my training, diet, sleep and feel i look and feel better/healthier in my 40s than 30s and 20s at lower dosages. Just my experience.

Did you get bigger as you lowered your doses?

Or were you even trying to get bigger at that point.
I mean sure you feel and look healthier if you pin a gram less, but for someone trying to build the next 10lbs of muscle that might not be their top priority or useful advice

 

[Stewie]

The part you raised on Zinc Finger Motifs (Cys4) and how zinc impacts aminio acids chains raised some interesting reading

View attachment 254431

Good find! This completely validates what you’ve been saying throughout this thread about testosterone acting as a genetic mechanism strictly through the androgen response element (ARE). Excellent research on that.

I totally scrambled my biology terminology there in that thread I shared. I inversely flipped transcription and translation, and talking about translating motifs. For the record, DNA is transcribed to RNA, and RNA is translated to proteins. The motifs are just the DNA directional recognition sites.

Definitely fubared that up. That would have been a failing grade in molecular genomics

 

[Sectør]

Appreciate it. This is exactly what science is at its core, hypothetical frameworking. Nothing settled, everything testable. You've brought a measurable amount of N=1 already. It's a hypothesis worth exploring.

I believe you may recall the stoichiometry mathematical expedition I plugged awhile back of 2,500mg weekly you're looking at roughly 5,600 testosterone molecules per available AR. To reiterate– this was purely based on a theoretical model I created– the literature simply doesn't exist.

Your paper covers the coactivator side well but there's no acknowledgement of repressors. The AR transcriptional complexity is bidirectional– activation and repression is happening simultaneously at the same domain. I've mildly touched on these in the past.

Another noteworthy mention are nonfull-length ARs– namely AR45 splice variants. This specific AR lacks one of the more prominent serine residues sites related to phosphorylation and transactivation within the N-terminal. As I've mentioned in the past, these specific splice variants are highly abundant in cardiac myocytes. They're also expressed in skeletal muscle tissue. Basically they form inhibitory heterodimers with full-length AR, silencing transactivation regardless of how much ligand is present. Interesting stuff too on a paper I recently stumbled across with the whole myostatin chatter that was brought back to life. Apparently in murine models, myostatin inhibition paradoxically upregulated AR45 expression, blunting anabolic signalling. Can I say with high certainty this will occur in humans– no. I'm not of the mindset of extrapolating exclusively to humans. Given so, it would be plausible to presume this may be a negative regulatory mechanisms in humans.

Last thing — the myostatin section undersells itself. Smad3 doesn't just put the brakes on mTORC1. It also functions as a direct AR corepressor independently. So myostatin upregulation is a dual hit — your paper only accounts for one of them.

I touched on this previously — non-genomic AR actions generally initiate genomic response through second messengers. Mechanistically this plays out through SRC-1 phosphorylation via ERK1/2, potentiating coactivator activity at the NTD. Pure speculation on my part — megadosing creates a non-genomic signal amplifying a coactivator pool that's already being competitively displaced by repressors. The amplification has nowhere productive to interact.

Man I’m so glad you’re here. I’ve learned so much from you, and you’ve given me so many different paths to research that I didn’t even know existed.

Also credits to hawkmoon for this post. Very well written, and I respect his decades of firsthand experience

Really enjoying this thread

 

[qbkilla]

Did you get bigger as you lowered your doses?

Or were you even trying to get bigger at that point.
I mean sure you feel and look healthier if you pin a gram less, but for someone trying to build the next 10lbs of muscle that might not be their top priority or useful advice

Good questions. Alex azarian would keep me around 215 as my coach, never fat, and I did my own thing with gear (1 to 1.5g I think). High bp, palpitations, and hating the distended look i had going made me really aim to have a leaner more athletic look and I settled at around 180. Obviously reducing calories was how I got there but I also started using less gear each year because no one at 180 needs much. Losing 35lbs Obviously had to result in some muscle loss but I don’t feel like it shows because less weight, less fat, less food, less gear my waist is now around 32 where it would be 36ish before (wide hips, inflammation, poor digestion, food volume).

So i guess in conclusion it's hard to tell how my "downsizng" ...would have went had i jist lowered calories but kept gear the same. If I wanted to ever add 10lbs lbm..Definitely agree gear and aas would need to increase.

 

[Siggy]

I can see where 500-600 may be the dose for getting the most bang for your buck for most people. With returns diminishing at that point. I never did the doses that many have. I tended to be around 1000 gr for the most part. As i increased my doses more i did not see much more if any gains. So i dropped the dose back down. Food seemed to be the mitigating factor at that point.

Respect for having the balls to take 1000 grams.

 

[buck]

Respect for having the balls to take 1000 grams.

My bad! That would take one huge ass syringe. I might have gotten some PIP from that.

 

[specter]

My bad! That would take one huge ass syringe. I might have gotten some PIP from that.

Lets fuckin go !!

 

[Stewie]

Good find! This completely validates what you’ve been saying throughout this thread about testosterone acting as a genetic mechanism strictly through the androgen response element (ARE). Excellent research on that.

Just wanted to add some clarity so it doesn’t sound like I’m contradicting myself earlier. The complex region of the DBD/ARE (DNA binding domain/androgen response element) is still very important. That’s what actually gets the receptor positioned to the right links to our specific DNA. Dose responsiveness definitely depends on this step working well.

That said, when we look at the N-terminal domain (NTD)–this is the domain I pitched awhile back dreaming-up a hypothetically drug to increase serine residue phosphorylation. That’s where most of the common genetic variants (SNPs) at least in up-to-date literature, especially the CAG repeat segment resides and drive big differences in how strongly people respond to the same dose. Shorter repeats push out stronger transactivation, longer repeats weakens sensitivity. From my understanding, the DBD is what positions the receptor to the correct genomic loci. On the other hand the NTD primarily dictates how pronounced the signal is once it’s there.

This may explain why two guys on the exact same dose may experience different hypertrophic stimuli.

With that being said, I would like to believe there's some relationship with negative regulators (repressors) that *may* interface with the androgen response element that determines a genetic setpoint to intraindividualized dosages, as your intuitions suspect? It's a territory that's been identified but nowhere near adequately mapped. Could it be inadequate coactivator recruitment, or contrastingly repressor genes modulating as a protectant? Or could it be PK (pharmakinetic) related or some other catalytic response?

Man I’m so glad you’re here. I’ve learned so much from you, and you’ve given me so many different paths to research that I didn’t even know existed.

Also credits to hawkmoon for this post. Very well written, and I respect his decades of firsthand experience

Really enjoying this thread

I appreciate that–I'm just another face in the crowd.

 

[specter]

Just wanted to add some clarity so it doesn’t sound like I’m contradicting myself earlier. The complex region of the DBD/ARE (DNA binding domain/androgen response element) is still very important. That’s what actually gets the receptor positioned to the right links to our specific DNA. Dose responsiveness definitely depends on this step working well.

That said, when we look at the N-terminal domain (NTD)–this is the domain I pitched awhile back dreaming-up a hypothetically drug to increase serine residue phosphorylation. That’s where most of the common genetic variants (SNPs) at least in up-to-date literature, especially the CAG repeat segment resides and drive big differences in how strongly people respond to the same dose. Shorter repeats push out stronger transactivation, longer repeats weakens sensitivity. From my understanding, the DBD is what positions the receptor to the correct genomic loci. On the other hand the NTD primarily dictates how pronounced the signal is once it’s there.

This may explain why two guys on the exact same dose may experience different hypertrophic stimuli.

With that being said, I would like to believe there's some relationship with negative regulators (repressors) that *may* interface with the androgen response element that determines a genetic setpoint to intraindividualized dosages, as your intuitions suspect? It's a territory that's been identified but nowhere near adequately mapped. Could it be inadequate coactivator recruitment, or contrastingly repressor genes modulating as a protectant? Or could it be PK (pharmakinetic) related or some other catalytic response?



I appreciate that–I'm just another face in the crowd.

Would this show up in blood test results ? Not like a positive/Negative result, but more could one look at blood work and make a guess as wichones gentic respons could be ?
Let me explain shortly, my body burns thru test like its paid to do so, when i was on Nebido and they where trying to stabilize my levels i would burn thru 4ml or 1000mg in like 6-7 weeks, my levels would fall below mid range around week 6 and at week 8 i was clinicly hypo again it was insane.

 

[Stewie]

Would this show up in blood test results ? Not like a positive/Negative result, but more could one look at blood work and make a guess as wichones gentic respons could be ?
Let me explain shortly, my body burns thru test like its paid to do so, when i was on Nebido and they where trying to stabilize my levels i would burn thru 4ml or 1000mg in like 6-7 weeks, my levels would fall below mid range around week 6 and at week 8 i was clinicly hypo again it was insane.

What you're describing is likely your hydrolysis rate. This is how efficiently your esterase enzymes cleaves the ester from theT molecules. No there's nothing that would show-up on any comprehensive set of labs that would lead you to suspect some wild variant(s). Or perfectly fine.

You would have to pull some genetic testing of different microsomal cytochrome isoenzymes for an accurate picture. Such as CYP3A4 and CYP3A5– I'm sure there's others that may be relevant?

If you were to take a sneak-peak at these exotic types of pharmacogenetic isoenzymes– I'm not sure there's much workarounds, that one could apply epigenetic modifications to manipulate the hydrolysis rate? Grapefruit and St. John's Wort intermingles with those isoenzymes. I've never taken a stroll down that lane– I dunno, maybe there are workarounds.

 

[Stewie]

Would this show up in blood test results ? Not like a positive/Negative result, but more could one look at blood work and make a guess as wichones gentic respons could be ?
Let me explain shortly, my body burns thru test like its paid to do so, when i was on Nebido and they where trying to stabilize my levels i would burn thru 4ml or 1000mg in like 6-7 weeks, my levels would fall below mid range around week 6 and at week 8 i was clinicly hypo again it was insane.

What you're describing is likely your hydrolysis rate. This is how efficiently your esterase enzymes cleaves the ester from theT molecules. No there's nothing that would show-up on any comprehensive set of labs that would lead you to suspect some wild variant(s). Or perfectly fine.

You would have to pull some genetic testing of different microsomal cytochrome isoenzymes for an accurate picture. Such as CYP3A4 and CYP3A5– I'm sure there's others that may be relevant?

If you were to take a sneak-peak at these exotic types of pharmacogenetic isoenzymes– I'm not sure there's much workarounds, that one could apply epigenetic modifications to manipulate the hydrolysis rate? Grapefruit and St. John's Wort intermingles with those isoenzymes. I've never taken a stroll down that lane– I dunno, maybe there are workarounds.

My geriatric memory is failing me sometimes. Too many thought processes going at once

That said, digging back into these decade-old threads helps clarify the actual genes and enzymatic pathways more accurately than the isoenzymes I mentioned earlier.


PDE7B (phosphodiesterase 7B) appears to be a major player in the hydrolysis rate — it helps cleave the ester from injectable testosterone. Certain variants can lead to noticeably faster or slower bioavailability.


UGT2B17 is also relevant, mainly for glucuronidation/conjugation and how your body clears androgens/metabolites afterward.


These two seem to be the biggest genetic contributors discussed in relation to the kind of rapid clearance you described. Routine bloodwork still won’t flag the variants themselves. You’d still need pharmacogenetic testing for that.

If nothing else– now you know what not to tabletalk about when, and if there's discussions about metabolic pathways related to hydrolysis.

Androgen receptor down-regulation and its effects on muscle growth. Short vs Long Cycles.

For a clear mind, just think logically - how many training units per muscle group are we able to do in 6 weeks? especially when it comes to advanced lifters 6-10? how much hypertrophy will occur after one training unit? after all, these are not the amounts that will give us a phenomenal...

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whole blood or double red cell donation?

Has your treating physician run an anemia panel or specifically looking at your iron parameters?

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Pros and low doses

How do you get 1g of test from a doc? Are they bribing them or somthing? lol Theres many "progressive" anti aging docs that have a lot of bodybuilder clients. Test,deca,var,anti e's, gh... Check out florida [emoji14]

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Your blood type dictating what compounds you should run?

I have seen this referenced almost in passing that depending on you blood type certain compounds will work better for you. Has anybody else heard this? I'm guessing there aren't any studies on this topic

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[hawkmoon]

FWIW my UGT2B17 (UDP- Glucuronosyltransferase 2B17). Genotype rs7436962 (AA) indicates fast clearance. This may account for my lower side effects that others.

My ester-cleaving genes are rs71647871: CC (Wild Type / Standard Function) and rs2244613: GG (Associated with lower trough levels) which means function is relatively normal, despite my perceived difficulty with enanthate.

 

[Mufasa123]

Great fricking thread. Has moved far beyond me. Topic is spot on and crucial yet largely fumbled around by all users and hopefully they find a sweet spot or scale to their goals. Appreciate all the contributions.

 

[specter]

What you're describing is likely your hydrolysis rate. This is how efficiently your esterase enzymes cleaves the ester from theT molecules. No there's nothing that would show-up on any comprehensive set of labs that would lead you to suspect some wild variant(s). Or perfectly fine.

You would have to pull some genetic testing of different microsomal cytochrome isoenzymes for an accurate picture. Such as CYP3A4 and CYP3A5– I'm sure there's others that may be relevant?

If you were to take a sneak-peak at these exotic types of pharmacogenetic isoenzymes– I'm not sure there's much workarounds, that one could apply epigenetic modifications to manipulate the hydrolysis rate? Grapefruit and St. John's Wort intermingles with those isoenzymes. I've never taken a stroll down that lane– I dunno, maybe there are workarounds.

Me and my professor friend was talkin about it could be a polymorfism, the way i overall just "burn through" medication, same goes for anesthesia the second they pull it out im up and clear minded, usually after a operation we would have wait a mandatory 20-30mins in the ward where you wake up, but couple mins in and im totally lucid.