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Ask a biochemist anything! Part Deux: The Androgen Receptor

TheProfessor

TheProfessor

Member
I'd prefer to multi-post this to get more viewers but I don't want to get flamed, Ill repost this in the anabolics forum and just remote them back here.

1. I want as many questions as possible
2. I don't know where this thread belongs.

Mods can relocate or delete as they wish.

I am currently doing a literature review of the androgen receptor for undisclosed purposes. While the information is fresh in my head and while I am still seeking out more, people are more than welcome to ask me ANYTHING that involves the androgen receptor, as technical or as non-technical as they want. I might know off hand, if I don't I'll look it up. More information for me. I'll attempt to provide the source with every answer I give as well if you want.

Fire!!

Post your questions in this thread:

Invalid Link Removed

Regards
 
how does adding in a 17a ethyl, to 13b ethyl estra-4,9-dien-17b-ol-3-one effect how it will interact with and bind to the androgen receptor?
 
Unless there are publications that state, I can only hypothesize as I am NOT going to run any SAR programs to answer that question for you.

What is the CAS number of this compound?

I CAN tell you that adding extra length to the carbon at the 17a position DECREASES the binding capacity of steroids to the androgen receptor. SO, that should answer your questions without even knowing about that compound in particular.
 
WHat compounds can make other steroids have more affinity for the AR? Also what binds the strongest the the AR, which steroid that is?
 
Husker89 said:
WHat compounds can make other steroids have more affinity for the AR? Also what binds the strongest the the AR, which steroid that is?
Click to expand...

There is nothing that I know of that would make steroids have more affinity for the AR. It would likely be possible to cause AR sensitization, but that would NOT be tissue specific, and therefore not advisable in any case.

DHT is the strongest endogenous AR agonist.

You want to keep in mind that although binding affinity plays an important role, more is NOT better. You want to keep it bound long enough to cause your signal transduction, but not too long as to cause overexpression of genes you otherwise wouldn't want (relatively) constitutively expressed. Or transduce signals longer than need be. Nothing good comes of an over-amplified signal transduction pathway.
 
so adding in a 17a methyl goup to 17beta-Hydroxyestra-4,9,11-trien-3-one will decrease how strongly it interacts/binds with the androgen receptor?
 
Thanks dude, so what steroid wouls you recommend based of trying to find the golden mean between signal transduction and overexpression.
 
I'm not going to recommend you any steroids lmao. :)

I wouldn't take DHT, or anything that converts to DHT in high amounts. I think a certain brand here advertises that all their stuff converts to DHT on purpose. I think that's stilly. But that's just me.
 
jbryand101b said:
so adding in a 17a methyl goup to 17beta-Hydroxyestra-4,9,11-trien-3-one will decrease how strongly it interacts/binds with the androgen receptor?
Click to expand...

correct alpha alkylation decreases androgen receptor binding capacity. The larger the alkyl group the poorer the binding. It was just a matter of balancing hepatic metabolism and drug function. Frankly, I don't know the compound you are talking about offhand. I don't feel like drawing it out. So if you have structure or a CAS number I could be more helpful. The compound you are talking about might not even bind at all to begin with.

it has just been proven that adding carbons to that position decreases the binding constant.
 
I misred. You are asking if an orally active trenbolone is possible?

Trenbolone was never manufactured for human use. Only agricultural. The reason you never found a methylated derivative is because it was never a drug for humans to begin with. ALthough it is being looked at again for it's pharmacological properties.

Whether or not some underground lab manufactures it? I have no clue.
 
Can The AR actually be desensitized?
 
schwellington said:
Can The AR actually be desensitized?
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Technically yes.

1 way is due to genetic disorder where the gene has mutations which prevent androgens from binding properly. Another would have to do with the post translational modifications to the receptor that might inhibit signal transduction or DNA binding to the androgen response element.

Whether or not this can be achieved through high androgen use (which I am guessing is the root of your question) I really don't think so.

I just think there is a thing as TO MUCH. If you have 10 receptors and 100 testosterones, only 10 testosterones can bind right? It's just a matter of equilibrium. The extra testosterone has to go somewhere and do something, and mostly that isn't good.

Can excess androgens cause phosphorylation of the receptor to prevent steroid binding? Possibly. But considering how huge people get for using Juice for years on end, I don't think it's something to really be worried about.

Genetic disorder is a different monster though.
 
Is something like Erase (Androst-3,5-dien-7,17-dione) going in and PREVENTING estrogen from binding to the estrogen receptors or is it NOT ALLOWING the actual conversion of whatever AAS you're doing to estrogen? I just wanna clear this up.
 
TheProfessor said:
I misred. You are asking if an orally active trenbolone is possible?

Trenbolone was never manufactured for human use. Only agricultural. The reason you never found a methylated derivative is because it was never a drug for humans to begin with. ALthough it is being looked at again for it's pharmacological properties.

Whether or not some underground lab manufactures it? I have no clue.
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i've just been seeing what you know by throwing out compounds that bind/interact strongly with the androgen receptor and are highly androgenic/anabolic compounds.

the first one was di ethyl dienolone, the second one was methyl trenbolone one the most strongest, most potent anabolic/androgenic steroids ever produced, and methyl trenbolone was studied as a drug as well.

"It was used clinically during the late 1960's and early '70's, most notably in the treatment of advanced breast cancer. Here, its exceedingly strong anabolic/androgenic action helps the drug counter the local effects of endogenous estrogens, lending it some efficacy for slowing or even regressing tumor growth. Such application was not long lived, however, as more realistic evaluations of the drug's toxicity soon led to its abandonment in human medicine."

I think you should go back and keep studying, because you really dont know enough about androgenic/anabolic steroids to have a "ask me about steroids" thread my friend.
 
Husker89 said:
LOL ya my bad, what do you think about this compound- 2-cyano-17a-methyl-17b-acetoxy-5a-androst-2-ene
Click to expand...

this is one of the 3 cyano's talked about in vida.

I dubbed it "cynoplex" back when nate put it out on the market. there were test done, and threads all about this.

I was excited for what would of been a very potent compound to be released and got/posted as much info as i could on it.

I can tell you, I was sent a bottle to try for myself, sealed, unopened, and saw nothing from it. maybe im a non responder.

any product on the market that claims to contain this probably doesn't.
 
Sklander said:
Is something like Erase (Androst-3,5-dien-7,17-dione) going in and PREVENTING estrogen from binding to the estrogen receptors or is it NOT ALLOWING the actual conversion of whatever AAS you're doing to estrogen? I just wanna clear this up.
Click to expand...

erase prevents conversion of testosterone and other hormones into the hormone estrogen by binding with the aromatase enzyme.

it does not act as a seclective estrogen receptor modulator (sarm) and bind to, but not interact with the er as a serm like clomid does.
 
jbryand101b said:
i've just been seeing what you know by throwing out compounds that bind/interact strongly with the androgen receptor and are highly androgenic/anabolic compounds.

the first one was di ethyl dienolone, the second one was methyl trenbolone one the most strongest, most potent anabolic/androgenic steroids ever produced, and methyl trenbolone was studied as a drug as well.

"It was used clinically during the late 1960's and early '70's, most notably in the treatment of advanced breast cancer. Here, its exceedingly strong anabolic/androgenic action helps the drug counter the local effects of endogenous estrogens, lending it some efficacy for slowing or even regressing tumor growth. Such application was not long lived, however, as more realistic evaluations of the drug's toxicity soon led to its abandonment in human medicine."

I think you should go back and keep studying, because you really dont know enough about androgenic/anabolic steroids to have a "ask me about steroids" thread my friend.
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The question wasn't ask me about steroids. It was ask me about the androgen receptor. I'm a biochemist, not a pharmacologist.

1. This paper explicitly states that increasing the carbon length at the 17a-position decreases affinity because the steric clash and hinderance of a hydrogen bond the 17b-hydroxyl group has with the receptor. This hypothesis was verified through the use of the crystal structure with bound ligands.

J Biol Chem. 2000 Aug 25;275(34):26164-71.
Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations.
Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, Otto N, Joschko S, Scholz P, Wegg A, Bäsler S, Schäfer M, Egner U, Carrondo MA.
Source
Instituto de Tecnologia Quimica e Biológica, Universidade Nova de Lisboa, Apartado 127, 2780 Oeiras, Portugal.

2. As far as I know, Trenbolone is not currently used as a prescription drug. It's obvious that trenbolone is an effective steroid, but it is only NOW being re-evaluated as a steroidal SARM in rats.

Tissue selectivity and potential clinical applications of trenbolone (17β-hydroxyestra-4,9,11-trien-3-one): A potent anabolic steroid with reduced androgenic and estrogenic activity
Joshua F. Yarrowa, b, , , Sean C. McCoya, b, Stephen E. Borsta, b

a Geriatric Research, Education & Clinical Center, VA Medical Center, Gainesville, FL 32608, United States
b Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, United States
Received 11 August 2009; revised 21 January 2010; Accepted 26 January 2010. Available online 4 February 2010.
 
All I really said was adding bulk to the 17a-carbon decreases binding affinity. Just because it works well with a methyl group there doesn't mean it wouldn't work better without the methyl group there...
 
Yay an anabolic biochemist's "AMA."

I got my college degree in Biophysical Chemistry, but none of my lectures focused expressly on the androgenic systems. We have however touched on the subject in my pharmacy school. It's cool you've granted your accumulated knowledge to the masses.

Anyway, a few questions/points. Answer what you'd like:

1. Have you come across any incidence of single nucelotide polymorphisms significantly affecting the AR functionality in your lit reviews? If so have these SNP's revealed any unknown or crucial aspects of the AR binding domains that are essential for function? Do some people have AR's that are more easily activated for example? Do you know of disease states where individuals have a non-functional AR and suffer chronic issues?

2. Are my thoughts on the following subject correct: With regards to the SARMs, the name suggests they are the androgenic parallel to the SERMs, but it seems like this isn't the case based on your previous posts. The SARMs do not selectively bind to different isoforms of the AR since there is only one isoform as opposed to the SERMs which have different affinities for the different estrogen receptor isoforms. Is this more or less accurate? I'm especially curious about the SARMs since my med chem prof Dr. Miller is on the team that developed Ostarine.

3. I saw someone's post about antiandrogens. Aren't compounds such as cypoterone, bicalutamide, and flutamide viable and available antiandrogens? These are definitely not OTC, but people here have ways of getting what they need. Not that I'd ever use one.

4. In general terms, how can different steroids produce a distinct anabolic/androgenic (muscle hypertrophy vs sex characteristic proliferation) ratio if there is only one AR isoform? Does it have to do with how easily this compounds can migrate in the body to muscle cells vs other tissues or is it something else altogether?

If there's anything you'd like me to clarify, let me know.
 
Jonny784 said:
Yay an anabolic biochemist's "AMA."

I got my college degree in Biophysical Chemistry, but none of my lectures focused expressly on the androgenic systems. We have however touched on the subject in my pharmacy school. It's cool you've granted your accumulated knowledge to the masses.

Anyway, a few questions/points. Answer what you'd like:

1. Have you come across any incidence of single nucelotide polymorphisms significantly affecting the AR functionality in your lit reviews? If so have these SNP's revealed any unknown or crucial aspects of the AR binding domains that are essential for function? Do some people have AR's that are more easily activated for example? Do you know of disease states where individuals have a non-functional AR and suffer chronic issues?
Click to expand...

Androgen insensitivity syndrome definitely disease syndrome I can think of with a genetic component. Although not caused by single nucleotide polymorphisms. There are heavier genetic issues with these people. Most of the SNPs evaluated within the AR gene had more to do with prostate cancer risk than anything else cool from what I have found.

There are microsatellites near the 5' end of the gene that, when there are too many or too few repeates of the glutamine codon (I think?) can cause things like cancer of the sex organs and even retardation.

Am J Med Genet. 1999 Jul 30;85(3):209-13.
CAG repeat contraction in the androgen receptor gene in three brothers with mental retardation.
Kooy RF, Reyniers E, Storm K, Vits L, van Velzen D, de Ruiter PE, Brinkmann AO, de Paepe A, Willems PJ.
Source
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. [email protected]

Here are a few SNPs that were discovered that were believed to cause the sperm failure of these poor chileans

Invalid Link Removed


The most crucial aspects of the AR binding domain actually were determined by mutations made in the phosphosites within the androgen receptor. As the phosphosites likely cause conformational changes at allow co-regulators to bind and initiate transcription. I could probably conclude that a codon change through a SNP could kill a phosphosite and hurt AR activity.

There are DEFINNITELY people that exist that have sensitized androgen receptors. Most of them have what's called 'castration resistant' prostate cancer, where the AR actually functions under EXTREMELY low amounts of ligand and even ANTAGONISTS. There even gets to a point where the androgen receptor will spontaneously phosphorylate and activate with NO LIGAND bound.
 
Jonny784 said:
Yay an anabolic biochemist's "AMA."


2. Are my thoughts on the following subject correct: With regards to the SARMs, the name suggests they are the androgenic parallel to the SERMs, but it seems like this isn't the case based on your previous posts. The SARMs do not selectively bind to different isoforms of the AR since there is only one isoform as opposed to the SERMs which have different affinities for the different estrogen receptor isoforms. Is this more or less accurate? I'm especially curious about the SARMs since my med chem prof Dr. Miller is on the team that developed Ostarine.
Click to expand...

Well, technically there are 2 isoforms of the AR, but from what I remember, it doesn't even have the ligand binding domain :-p

The tissue selectivity involved with the estrogen receptor is most definitely driven by the fact that there are TWO FORMS of the estrogen receptor. AND the fact that the coformational changes in the AR itself dictate it's transcriptional activity. No other steroid receptors have cross-talk between the N and the C terminus and "clamp" on itself. There are other cool differences too. This is why the development of SARMs has not been as straightforward as people wanted. The AR is an enigma of a steroid receptor, not only is the regulation different, but it's functions on the non-genomic level are still hardly elucidated.

There are several hypothesis regarding the tissue selectivity of the androgen receptor.

1. the expression of 5a-reductase is tissue selective really limited to the scalp and the sex organs ( a little in the bone) HOWEVER the AR is still expressed in a variety of other tissues. Why do SARMS exhibit tissue selectivity? My guess is that the DHT binding to the AR (which causes different conformation states in the AR compared to any other steroid, even testosterone, crystal structure shows this) causes differential expression patters.

Mol Interv. 2007 Feb;7(1):10-3.
Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase?
Gao W, Dalton JT.
Source
Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo SUNY, Buffalo, NY 14260, USA.


It's possible that the conformation state that the AR takes when the ligand binds may only expose a certain number of sites that require other co-regulators to bind, and thus differentiates transcription in this fashion. Different ligands cause different conformation states, and therefore differential expression.

2. The non-genomic pathways of the AR- something I am still currently reading into. Basically the AR can act as a signaling protein. Something unheard in the steroid receptor family. So this is something that is being investigated heavily (I'm thumbing around) it's possible that bound ligands can cause conformations that create different cross-talk with other signaling pathways. This is just a guess, like I said I"m looking around.

3. Post translational modification- The AR can be phosphorylated, Methylated, Acetylated, Ubiquitinated etc. I don't know of any differences within each tissue type but I know that the certain methylation sites are critical for the AR to clamp down on itself and I know that almost all of the phosphosites regulate transcription some how. Other other ones, like ubiquitination are likely involved with cell growth, prostate cancer studies suggest this.

Mol Cell Endocrinol. 2011 Jul 24. [Epub ahead of print]
Post-translational modification of the androgen receptor.
Gioeli D, Paschal BM.
Source
Department of Microbiology University of Virginia, Charlottesville, Virginia, USA; UVA Cancer Center University of Virginia, Charlottesville, Virginia, USA.


different tissues might have different post translational modification and thus different affinities for different compounds.

Does this answer?
 
Jonny784 said:
3. I saw someone's post about antiandrogens. Aren't compounds such as cypoterone, bicalutamide, and flutamide viable and available antiandrogens? These are definitely not OTC, but people here have ways of getting what they need. Not that I'd ever use one.
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Yes, these are effective anti-androgen SARMS. And yes, I agree with the second part. I am pretty sure long term use of anti-androgens can cause hormone-refraction. Those genes in the androgen response element NEED to be expressed. If you want to keep your hair you can attempt. But there are other genes at work, and the body will figure out a way to get them going.

You know, things like 'sensitizing' the androgen receptor ;)
 
Jonny784 said:
Yay an anabolic biochemist's "AMA."

4. In general terms, how can different steroids produce a distinct anabolic/androgenic (muscle hypertrophy vs sex characteristic proliferation) ratio if there is only one AR isoform? Does it have to do with how easily this compounds can migrate in the body to muscle cells vs other tissues or is it something else altogether?

If there's anything you'd like me to clarify, let me know.
Click to expand...


DHT is the reason for damn near all sex characteristics. For some crazy ass reason, DHT causes much more transcription levels in the sex organs than any other compound ( at least endogenously). DHT and testosterone look damn near identical, and the conformation of the androgen receptor has incalculable differences when you view the ligand bound AR crystal structure. (an article I posted up previously)

As far as steroids are concerned, The anabolic to androgen ration of steroids has to do with SEVERAL components. These are just a few.

1. If the compound is NOT susceptible to 5a-reductase it is generally MORE anabolic and LESS androgenic.
2. Removing the methyl group on carbon 19 DECREASES androgenic activity and thus has a greater anabolic/androgenic profile
3. Removing an ethylene group and replacing it with an oxygen separates androgen and anabolic activity well (2-oxa steroids are good examples, think oxandrolone)
4. Adding a pyrazole ring increases anabolic activity (think stanozolol) therefore changing the androgenic anabolic profile
5. 17-B hydroxyl group is necessary as a hydrogen bond agent in the AR- possible bioisosteres could replace this, I can't think of any compounds offhand though.

Thats a little bit of a digression, and a much more pragmatic answer anyway. The truth is, people don't know exactly what causes tissue specificity. It'd be the holy grail of anabolic drugs if they did know ;). I only know of a few working hypothesis, which I have already stated.

So, to answer you question, it's the ligand that causes the differences. It seems like black magic, which to me it is at this point.
 
Thanks @TheProfessor. You have answered my questions specifically, thoroughly, and with exquisite detail. I will go through some of the articles you've referenced tomorrow to get a better understanding. I appreciate your time and hope that contemplating the details of my questions has been beneficial in expanding your understanding as well. I hope you are successful with your "undisclosed" project whatever it may be. Signing off for now but will stay tuned in to your thread as it develops. Thanks again
 
TheProfessor said:
You know, things like 'sensitizing' the androgen receptor ;)
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Maybe this was answered, but is there a way to re-sensitize the AR faster when running a PCT from an oral substance? So it would be somewhat possible to run a cycle, pct, then straight into a cycle?
 
Jonny784 said:
Thanks @TheProfessor. You have answered my questions specifically, thoroughly, and with exquisite detail. I will go through some of the articles you've referenced tomorrow to get a better understanding. I appreciate your time and hope that contemplating the details of my questions has been beneficial in expanding your understanding as well. I hope you are successful with your "undisclosed" project whatever it may be. Signing off for now but will stay tuned in to your thread as it develops. Thanks again
Click to expand...

If you have any other biochemistry related questions PLEASE lay them on me. I'm just accumulating as much information as possible and questions like this just give me more tentacles to reach around with.
 
FL3X MAGNUM said:
Maybe this was answered, but is there a way to re-sensitize the AR faster when running a PCT from an oral substance? So it would be somewhat possible to run a cycle, pct, then straight into a cycle?
Click to expand...

This is my OPINION.

Considering how giant people can get with the use of AAS. I don't think desensitization of the AR should be a concern. Some guys are on year-round and they grow and grow. Could it get desensitized through AAS use? Maybe. enough to cause you to shrivel? Not likely.

I don't feel like the argument of "they do more!" is good. Because if they were truly desensitized then these huge freaks of nature would start shrinking regardless of AAS use. If you have any literature regarding this PLEASE throw it toward me and i'll gladly thumb through it.

I'll check around though. If you have anything I can use as a starting point, throw it up.

It's possible this did not answer your question though.

If you wanted to do that, why not just stay on all the time?

Also, you don't want to senstize the AR more than it already is. It's just likely to cause Androgenic related side effects you don't want. This is why antiandrogen therapy eventually fails with prostate cancer. The AR acts as if there is a ghost androgen, even when there isn't. ewwww
 
TheProfessor said:
This is my OPINION.

Considering how giant people can get with the use of AAS. I don't think desensitization of the AR should be a concern. Some guys are on year-round and they grow and grow. Could it get desensitized through AAS use? Maybe. enough to cause you to shrivel? Not likely.

I don't feel like the argument of "they do more!" is good. Because if they were truly desensitized then these huge freaks of nature would start shrinking regardless of AAS use. If you have any literature regarding this PLEASE throw it toward me and i'll gladly thumb through it.

I'll check around though. If you have anything I can use as a starting point, throw it up.
Click to expand...

I'll dig around. Have a couple friends on here with the same question, I will point them your way ;)
 
TheProfessor said:
This is my OPINION.

Considering how giant people can get with the use of AAS. I don't think desensitization of the AR should be a concern. Some guys are on year-round and they grow and grow. Could it get desensitized through AAS use? Maybe. enough to cause you to shrivel? Not likely.

I don't feel like the argument of "they do more!" is good. Because if they were truly desensitized then these huge freaks of nature would start shrinking regardless of AAS use. If you have any literature regarding this PLEASE throw it toward me and i'll gladly thumb through it.

I'll check around though. If you have anything I can use as a starting point, throw it up.

It's possible this did not answer your question though.

If you wanted to do that, why not just stay on all the time?

Also, you don't want to senstize the AR more than it already is. It's just likely to cause Androgenic related side effects you don't want. This is why antiandrogen therapy eventually fails with prostate cancer. The AR acts as if there is a ghost androgen, even when there isn't. ewwww
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So anectodally we could be on cycle forever and pretty much NOT be limited by down regulation of our androgen recepters? (Though I am 100% aware the androgen recepters are not the ONLY pathway to growth). What would this mean for things like LCLT which are supposed to increase androgen sensitivity? Does this just mean that lets say we have 10 recepters, then 10 androgens ALL androgen will find their recepter and bind. While if we weren't on LCLT maybe 2 of them will get "lost" or converted into other hormones?

My question may no make any sense, but I always hear of getting off a PH cycle in order to re sensitize androgen recepters and clean them off. Could it just be that we are LOSING gains in PCT and post pct, and that "Time off" becomes time to shrivel up and make our PH cycle seem better because we've actually lost most of the exogenous androgen gains?
 
I think time off of a PH cycle more has to do with liver stress than anything else.

People are on test for years and years and years (and years). From what I can tell, LCLT doesn't increase AR sensitivity, it just increases the amount of AR receptors, which allows more total androgens to bind.

Interesting. This study suggests that lower amounts of steroid hormone cause a decrease in carnitine. One could (loosely) infer that extra steroid could cause increase in carnitine, and therefore carnitine supplementation in people that use AAS might be negligable?

Effect of dehydroepiandrosterone sulfate on carnitine acetyl transferase activity and l-carnitine levels in oophorectomized rats12
Kit Mui Chiua, Mary J Schmidtb, Austin L Shugb, c, Neil Binkleya, Stefan Gravensteina,

a Institute on Aging/Department of Medicine, University of Wisconsin-Madison, and the Wm. S. Middleton VA GRECC, Madison, WI 53706, USA
b Metabolic Analysis Laboratories, Inc., Madison, WI 53713, USA
c Department of Neurology, University of Wisconsin, Madison, WI 53706, USA
Received 8 April 1996; revised 7 August 1996; Accepted 11 September 1996. Available online 14 August 1997.

This study also makes that suggestion:

Costell M, Grisolia S. Effect of carnitine feeding on the levels of heart and skeletal muscle carnitine of elderly mice. FEBS Lett 1993;315:43-46.

And this study:

Janssen I, Heymsfield SB, Wang ZM, Ross R. Skeletal muscle mass and distribution in 468 men and women aged 18 –88 years. J Appl Physiol 2000;89:81-88.



Basically, old men lose muscle strength and mass at a greater rate than women, this is because muscle mass is more hormone dependent in men than women. Loss of testsosterone correlates with loss of carnitine and then loss of strength and then muscle mass etc etc


I don't know a whole hell of a lot about the action of carnitine, but this was just a quick literature skim that might lead to more open questions or more confusion by be.
 
TheProfessor said:
I think time off of a PH cycle more has to do with liver stress than anything else.

People are on test for years and years and years (and years). From what I can tell, LCLT doesn't increase AR sensitivity, it just increases the amount of AR receptors, which allows more total androgens to bind.

Interesting. This study suggests that lower amounts of steroid hormone cause a decrease in carnitine. One could (loosely) infer that extra steroid could cause increase in carnitine, and therefore carnitine supplementation in people that use AAS might be negligable?

Effect of dehydroepiandrosterone sulfate on carnitine acetyl transferase activity and l-carnitine levels in oophorectomized rats12
Kit Mui Chiua, Mary J Schmidtb, Austin L Shugb, c, Neil Binkleya, Stefan Gravensteina,

a Institute on Aging/Department of Medicine, University of Wisconsin-Madison, and the Wm. S. Middleton VA GRECC, Madison, WI 53706, USA
b Metabolic Analysis Laboratories, Inc., Madison, WI 53713, USA
c Department of Neurology, University of Wisconsin, Madison, WI 53706, USA
Received 8 April 1996; revised 7 August 1996; Accepted 11 September 1996. Available online 14 August 1997.

This study also makes that suggestion:

Costell M, Grisolia S. Effect of carnitine feeding on the levels of heart and skeletal muscle carnitine of elderly mice. FEBS Lett 1993;315:43-46.
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Makes perfect sense about sensitivity. The new AndroSeries makes it seem like you can just blast/cruise on andro products year round. No liver stress there and no talk at all about androgen sensitivity.

Now, is there a way to effectively increase the amount of AR receptors? LCLT is said to do that. But it is dosed at 2g/day. Is there a better dose protocol? And I assume this would all be done while not taking any exogenous hormones.

And are their other ways to increase AR receptors? You say increasing LCLT intake on cycle might be negligible because on AAS carnitine levels are elevated. Are their any other compounds, herbal or synthetic (Aside from the AAS) that increases the amount of AR receptors?
 
Increasing the amount of total muscle cells you have would allow you to create more androgen receptors ;)

I'm not convinced that the effectiveness of AAS will be increased THAT MUCH.

there is no reason to increase the amount of androgen receptors you have when you are off cycle because you clearly don't have enough testosterone to bind them to begin with. At least that's how I would be.

More androgen receptors when you have more testosterone and less androgen receptors when you have less testosterone makes sense to me. It keeps an equillibrium between bound and unbound testosterone.

These are all inferences made by me, I haven't done any literature searching to back this up.
 
TheProfessor said:
Increasing the amount of total muscle cells you have would allow you to create more androgen receptors ;)

I'm not convinced that the effectiveness of AAS will be increased THAT MUCH.

there is no reason to increase the amount of androgen receptors you have when you are off cycle because you clearly don't have enough testosterone to bind them to begin with. At least that's how I would be.

More androgen receptors when you have more testosterone and less androgen receptors when you have less testosterone makes sense to me. It keeps an equillibrium between bound and unbound testosterone.

These are all inferences made by me, I haven't done any literature searching to back this up.
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If we increase the amount of androgen receptors on cycle by increasing muscle mass would that also then mean off cycle when floating androgens are less the body will start deactivating or destroying the extra receptor ? Or would the body try to adapt and create a little more androgens?
 
Just for clarification, more muscle mass is not equal to more muscle cells. The cells grow.

Having new cells come about is entirely a different monster. that's out of the scope of the thead.

And as a rule of thumb, the body will always take the easy way out. It's much easier to stop making something or catabolize than to stay anabolic all the time. It's a matter of energy expenditure.

It doesn't make sense for the body to otherwise adapt to keep bulk it doesn't really need in the first place.
 
TheProfessor said:
Just for clarification, more muscle mass is not equal to more muscle cells. The cells grow.

Having new cells come about is entirely a different monster. that's out of the scope of the thead.

And as a rule of thumb, the body will always take the easy way out. It's much easier to stop making something or catabolize than to stay anabolic all the time. It's a matter of energy expenditure.

It doesn't make sense for the body to otherwise adapt to keep bulk it doesn't really need in the first place.
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care to share with us ways to cause mitochondria to split and make more muscle cells? perhaps in a separate thread ;)
 
That's out of the scope of my education. I don't like to hazard guesses at most physiological things like that. I find it very interesting, it's not something I really like to comment on. Although I could probably dig up some publications for you if you want. I just don't feel comfortable giving a 'cliff notes' version.
 
mattrag said:
care to share with us ways to cause mitochondria to split and make more muscle cells? perhaps in a separate thread ;)
Click to expand...

I'll touch on this briefly, but I'm no expert. Most lean muscle mass increases come from what is called muscle hypertrophy or enlarging the muscle cells we already have. Muscle cells are different in that they fuse into long multinucleated fibers instead of just individual cells with a single nucleus. Therefore the term muscle fiber is often used interchangeably with muscle cell. When we strain our muscles through resistance training, our main result is the increase in the actin and myosin fibers in each muscle fiber, specifically in the individual units of the fiber called sarcomeres. These are the proteins that actually contract and produce our strength. Furthermore, increasing the actin and myosin proteins will increase mass and cell size due to the volume taken up by the new actin and myosin and the increased water volume required to maintain proper intracellular saturation. This is the main mechanism by which we increase our mass and strength.

On the other hand, the growth of new muscle cells is called muscle hyperplasia. This mostly occurs in our developmental phase and generally comes to a stand still upon maturation. In other words, you're more or less bound by the number of muscle fibers you already have. However, this topic is debatable and the current scientific consensus is that it may still be possible for your muscle cells to divide, but the exact requirements of this is unknown. It's similar to the recent debunking of the old myth that old people can't grow new brain cells. They can. Regardless, muscle hyperplasia is not the significant mechanism by which we gain lean mass but rather muscle hypertrophy.

Anyway, with regards to the androgen receptor density in the muscle cells, increasing the muscle fiber volume through muscle hypertrophy would increase the membrane surface area and total volume of each cell. Therefore, I'd guess that it would still be possible to have an upregulation of androgen receptors and an increased total number available for binding even with simple hypertrophy and not hyperplasia. In other words, a swole-ass, hench mother trucker 30 lbs bigger than his smaller counterpart, even if both had the same number of muscle cell fibers, would still have more androgen receptors. I'm just speculating though.
 
TheProfessor said:
This might be of interest to somebody. Particularly Jonny as it is about ostarine
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Good find. Stuff seems pretty efficacious. At 3 mg/day that's around 3 % increase in lean body mass in 12 weeks. Not bad for 60+ year olds with muscle wasting disease lol. This demonstrates that it's certainly effective. Body builders even dose the stuff higher around 25 mg/day with minimal sides.
 
What I can say is this.

Bodybuilders were at a standstill (size wise) until the 90's or so until recombinant proteins became widely available.
They went from huge to stupid.

I just agree with jonny, most of that stuff is just speculatory at this point.

Take that for what it's worth.
 
Jonny784 said:
I'll touch on this briefly, but I'm no expert. Most lean muscle mass increases come from what is called muscle hypertrophy or enlarging the muscle cells we already have. Muscle cells are different in that they fuse into long multinucleated fibers instead of just individual cells with a single nucleus. Therefore the term muscle fiber is often used interchangeably with muscle cell. When we strain our muscles through resistance training, our main result is the increase in the actin and myosin fibers in each muscle fiber, specifically in the individual units of the fiber called sarcomeres. These are the proteins that actually contract and produce our strength. Furthermore, increasing the actin and myosin proteins will increase mass and cell size due to the volume taken up by the new actin and myosin and the increased water volume required to maintain proper intracellular saturation. This is the main mechanism by which we increase our mass and strength.

On the other hand, the growth of new muscle cells is called muscle hyperplasia. This mostly occurs in our developmental phase and generally comes to a stand still upon maturation. In other words, you're more or less bound by the number of muscle fibers you already have. However, this topic is debatable and the current scientific consensus is that it may still be possible for your muscle cells to divide, but the exact requirements of this is unknown. It's similar to the recent debunking of the old myth that old people can't grow new brain cells. They can. Regardless, muscle hyperplasia is not the significant mechanism by which we gain lean mass but rather muscle hypertrophy.

.
Click to expand...

To expand upon this, much of our ability to repair exercise induced muscle fiber damage is via satellite cells, or myogenic stem cells. As a result of a chemical cascade, these cells prolifterate, differentiate, and fuse to the muscle fiber, thus spilling their contents inside. The result is an addition of nuclei, sarcoplasm, and growth factors. Muscle fibers themselves cannot undergo mitosis (divide), however, there is some research that these stem cells can fuse with one another to form new muscle fibers - although, as already stated, it does not account very much if any of increases in muscle size.

Whats more interesting, is the effects of both local and systemic hormones on the poliferation, differentiation, and fusion of these myogenic stem cells. But, that's probably best saved for another thread.

Br
 
Not sure if this is outside the scope of this thread, but here goes:

Several studies indicate that lactate is an effective test-booster, i.e. more testosterone and increased LH. However, in one study, the most advanced athletes had the highest LH-effect of lactate, but their test actually decreased. It also appears to me that advanced athletes may have more androgen reseptors as a result of their training.

Now: Does androgen receptors "suck" free test out of the bloodstream, therefore reducing the amount available? Or is it affecting the androngen receptor when in unbound (free) state?

Lets say athlete A has a free T-level of 5, boosting it to 7 short term due to lactate.
Athlete B also has a free T-level of 5, boosting it to 6 short term due to lactate.

Athlete A has more androgen receptors, sucking more of his free test out of the bloodstream. He ends up with a free test of 4, while athlete B has fewer receptors and is still at 5. However, athlete A has a larger effect in practice, as there is more testosterone bound to the androgen receptor.

Hope you understand my clumsily constructed question :)

Don't mind the values themselves, examples only. We also use different units for blood work here in Norway, which might make the values seem odd.
 
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