Androgen Receptors Downregulate - Don't They? Part 2

[Born2Juice4Ever]

Here is part two, for those who asked me to post it
Enjoy, excellent article IMO
i will not be posting any more info for some time. I think it is best if you assimilate what I have posted recentelly and dicuss on that

B2J4E
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Androgen Receptors Downregulate - Don't They? Part 2
By Bryan Haycock MS

Please send us your feedback on this article.

In part 1 of this article we discussed the mistake of thinking about androgen receptors (testosterone receptors) in the same way we think of other receptors such as beta-receptors. Beta-receptors down regulate in response to beta-adrenergic stimulation whereas there is good evidence that androgen receptors increase in numbers in response to androgens. We also discussed the various affects of testosterone on muscle growth. Testosterone does far more than simply increase the rate of protein synthesis!

Now in part 2 we will finish our discussion of androgen receptor regulation as it pertains to the way muscle cells grow. The very mechanism of real muscle growth opens the door for increased androgen receptor number in response to testosterone treatment.

Don’t forget Satellite cells!

Satellite cells are myogenic stem cells, or pre-muscle cells, that serve to assist regeneration of adult skeletal muscle. Following proliferation (reproduction) and subsequent differentiation (to become a specific type of cell), satellite cells will fuse with one another or with the adjacent damaged muscle fiber, thereby increasing the number of myonuclei for fiber growth and repair. Proliferation of satellite cells is necessary in order to meet the needs of thousands of muscle cells all potentially requiring additional nuclei. Differentiation is necessary in order for the new nucleus to behave as a nucleus of muscle origin. The number of myonuclei directly determines the capacity of a muscle cell to manufacture proteins, including androgen receptors.

In order to better understand what is physically happening between satellite cells and muscle cells, try to picture 2 oil droplets floating on water. The two droplets represent a muscle cell and a satellite cell. Because the lipid bilayer of cells are hydrophobic just like common oil droplets, when brought into proximity to one another in an aqueous environment, they will come into contact for a moment and then fuse together to form one larger oil droplet. Now whatever was dissolved within one droplet (i.e. nuclei) will then mix with the contents of the other droplet. This is a simplified model of how satellite cells donate nuclei, and thus protein-synthesizing capacity, to existing muscle cells.

Enhanced activation of satellite cells by testosterone requires IGF-1. Those androgens that aromatize are effective at not only increasing IGF-1 levels but also the sensitivity of satellite cells to growth factors.3 This action has no direct effect on protein synthesis, but it does lead to a greater capacity for protein synthesis by increasing fusion of satellite cells to existing fibers. This increases the number of myonuclei and therefore the capacity of the cell to produce proteins. That is why large bodybuilders will benefit significantly more from high levels of androgens compared to a relatively new user.

Testosterone would be much less effective if it were not able to increase myonucleation. There is finite limit placed on the cytoplasmic/nuclear ratio, or the size of a muscle cell in relation to the number of nuclei it contains.4 Whenever a muscle grows in response to training there is a coordinated increase in the number of myonuclei and the increase in fiber cross sectional area (CSA). When satellite cells are prohibited from donating viable nuclei, overloaded muscle will not grow.5,6 Clearly, satellite cell activity is a required step, or prerequisite, in compensatory muscle hypertrophy, for without it, a muscle simply cannot significantly increase total protein content or CSA.

More myonuclei mean more receptors

So it is not only true that testosterone increases protein synthesis by activating genetic expression, it also increases the capacity of the muscle to grow in the future by leading to the accumulation of myonuclei which are required for protein synthesis. There is good reason to believe that testosterone in high enough doses may even encourage new fiber formation. To quote the authors of a recent study on the effects of steroids on muscle cells:

"Intake of anabolic steroids and strength-training induce an increase in muscle size by both hypertrophy and the formation of new muscle fibers. We propose that activation of satellite cells is a key process and is enhanced by the steroid use."7

Simply stated, supraphysiological levels of testosterone give rise to increased numbers of myonuclei and thereby an increase in the number of total androgen receptors per muscle fiber. Keep in mind that I am referring to testosterone and testosterone esters. Not the neutered designer androgens that people take to avoid side effects.

Another group of researchers are quoted as saying:

"…it is intriguing to speculate that the upregulation of AR levels via the administration of pharmacological amounts of androgens might convert some muscles that normally have a minor or no response to muscles with enhanced androgen responsiveness"(8)

This is not an argument to rapidly increase the dosages you use. It takes time for these changes to occur and the benefits of higher testosterone levels will not be immediately realized. It does shed some light however on the proportional differences between natural and androgen assisted bodybuilders physiques.

Maintenance of the kind of muscle mass seen in top-level bodybuilders today requires a given level of androgens in the body. That level will vary from individual to individual depending on their genetics. Nevertheless, if the androgen level drops, or if they were to "cycle off" the absolute level of lean mass will also drop. Likewise, as the level of androgens goes up, so will the level of lean mass that individual will be able to maintain. All of this happens without any evidence of AR down regulation. More accurately it demonstrates a relationship between the amount of androgens in the blood stream and the amount of lean mass that you can maintain. This does not mean that all you need is massive doses to get huge. Recruitment of satellite cells and increased myonucleation requires consistent "effective" training, massive amounts of food, and most importantly, time. Start out with reasonable doses. Then, as you get bigger you can adjust your doses upwards.

References:

1. Kemppainen JA, Lane MV, Sar M, Wilson EM. Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. Specificity for steroids and antihormones. J Biol Chem 1992 Jan 15;267(2):968-74

2. Fryburg DA., Weltman A., Jahn LA., et al: Short-term modulation of the androgen milieu alters pulsatile, but not exercise- or growth hormone releasing hormone-stimulated GH secretion in healthy men: Impact of gonadal steroid and GH secretory changes on metabolic outcomes. J Clin Endocrinol. Metab. 82(11):3710-37-19, 1997

3. Thompson SH., Boxhorn LK., Kong W., and Allen RE. Trenbolone alters the responsiveness of skeletal muscle satellite cells to fibroblast growth factor and insulin-like growth factor-I. Endocrinology. 124:2110-2117, 1989

4. Rosenblatt JD, Yong D, Parry DJ., Satellite cell activity is required for hypertrophy of overloaded adult rat muscle. Muscle Nerve 17:608-613, 1994

5. Rosenblatt JD, Parry DJ., Gamma irradiation prevents compensatory hypertrophy of overloaded extensor digitorum longus muscle. J. Appl. Physiol. 73:2538-2543, 1992

6. Phelan JN, Gonyea WJ. Effect of radiation on satellite cell activity and protein expression in overloaded mammalian skeletal muscle. Anat. Rec. 247:179-188, 1997

7. Kadi F, Eriksson A, Holmner S, Thornell LE. Effects of anabolic steroids on the muscle cells of strength-trained athletes. Med Sci Sports Exerc 1999 Nov;31(11):1528-34

8. Antonio J, Wilson JD, George FW. Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles. J Appl Physiol. 1999 Dec;87(6):2016-9.

[Bammy]

This is a great article, seems like cutting edge info.

Originally Posted by Born2Juice4Ever

"…it is intriguing to speculate that the upregulation of AR levels via the administration of pharmacological amounts of androgens might convert some muscles that normally have a minor or no response to muscles with enhanced androgen responsiveness"

So maybe there is hope for my calves!

[iron-game]

Born2juice GREAT article,
One question, ok all things being equil (training and diet)
why would one guy grow great off low levels of test another guy not grow much at all off major amounts of test. Is this an Androgen Receptor issue?

[Ronn]

It's been a while since I read that article, but there are other factors to consider such as SHBG (which will up-regulate) and how a particular persons endocrine system chooses to employ the extraneous hormones (into DHT, into an Estradiol, etc.). So it's not just a matter of receptors.

Ronn

[iron-game]

Originally Posted by Ronn

It's been a while since I read that article, but there are other factors to consider such as SHBG (which will up-regulate) and how a particular persons endocrine system chooses to employ the extraneous hormones (into DHT, into an Estradiol, etc.). So it's not just a matter of receptors.

Ronn

can you expand on this or have a link

[Ronn]

iron game,

Outside of AR down regulation (which part one of the above article clearly questions if my memory serves), I think another way of perceiving the “stall” or “plateau” one usually hits after long term use of AAS is the basic biological inclination towards homeostasis.

As we know, add an extraneous source of androgens and the hypothalamus reacts by slowing or stopping the pituitary’s production of GNRH and LH (in order to lower the blood levels). By doing so, the body has also eliminated it primary means to maintain homeostasis through it’s own production of steroidal compounds (such as progesterone, the estrogens, cortisol, and aldosterone—this latter hormone being an often overlook cause of bloat during cycles).

Therefore, it begins converting the extraneous testosterone (note I’m addressing only non-DHT derived AAS at this juncture) in to other compounds, the best know of which would be estrogens and DHT. Variations in individual response dictate what pathway(s) will be primarily activated.

As we know, some people are “inclined” towards gyno (as I happen to be having had adolescent onset gyno when I was younger). The aromatase enzymes convert the circulating test in estrogen in order to maintain homeostasis. Now, it doesn’t necessarily follow that those pro to gyno are aromatizing more test into estro, it simply means their breast tissue is more susceptible to higher estrogen concentrations—we’re all losing some test to estrogen (which isn’t so bad, estrogen does have many positive effects on the body). Therefore, it not to far fetched a conclusion that the longer test levels are kept abnormally high, the more efficient the body will get in aromatizing it. Thereby eventually diminishing some the positive effects of the AAS. And lets remember, when we “stall out” on a cycle, we don’t go back to are “un-supplemented” state—we just stop growing. Usually maintaining what we’ve gained…homeostasis.

Another player in the gane is the 5alpha reductase enzyme, Type 1 5-alpha-reductase is found primarily in the skin and Type 2 5-alpha-reductase is found primarily in the prostate and inner sheath of the hair follicle. As well all know, some people are prone to ance and/or hair loss while on cycle—this is a clear indicator that the DHT conversion is taking place (and the lack of symtoms is not an indication of the lack of 5AR response, but merely an individuals lack of response to DHT). Again, the end result in longer cycles is homeostasis and a “platue.”

Finally we have Sex hormone-binding globulin (SHBG). Normally 60-80% of our circulating test is bound to SHBG and rendered ineffectual to bodily tissue. About 20% is attached to albumin—which can leave as little as 10% of our test “free”—or has high as 30%. Now we can begin to see what some guys are natural “twice as big as me.” So logic would seem to indicatehat if in normal circumstances the body holds most of it’s test in check, homeostasis dictates an increased production of SHBG to compensate.

Now, this is an N=1 antidotal observation, but I’ve found adding Proviron (which has a very strong affinity to SHBG) towards the end of the cycle can get me going again. Don’t get me wrong, it’s not like adding in dbol, but I see progress begin again.

Unfortunately, I can’t find some articles I’ve had that discus how the body can actually break down testosterone to “reproduce” other steroidal agents as well (like aldosterone), so I can really spell out that process for you. But hopefully it’s sufficient to say from what I have outlines, homeostasis’s is a much better explanation for the “stall” one has in longer cycles than AR down regulation.

Hope that helps,

Ronn

[mjfit]

so much to lern this was a great read. im still confused but trying to understand it I think I am at a stall right now. what can taking anavar for to long do. would that make me feel like crap and not even work any more. I am on a trt 250 test e a week . I took var for 10 weeks then stoped for 2 and went back on.dont even get a pump any more and feel pretty tired. sorry if the ? dosent make since

[iron-game]

Truely a great article, a little over my head but still great.
One more simple question,lol. so say you cycle on and off right, eat right, train right and sleep right. You also have gone too very high doses of anabolics, after many years with low doses and nothing in the way of awesome gains, and your friends are still making awesome gains off much less (they also have the neg affects which i have none of!!!) And even off almost 2gr of stuff im just not growing. What would you do. what would you try and please dont say quit or give up thats not a option (kind of stuff i have heard befor) I have been bodybuilding for over 20 years it keeps me sane, you know what I mean...

[iron-game]

Originally Posted by mjfit

so much to lern this was a great read. im still confused but trying to understand it I think I am at a stall right now. what can taking anavar for to long do. would that make me feel like crap and not even work any more. I am on a trt 250 test e a week . I took var for 10 weeks then stoped for 2 and went back on.dont even get a pump any more and feel pretty tired. sorry if the ? dosent make since

mjfit what are you expecting off anavar? As I understand its very mild.

[mjfit]

not much but it makes me realy hard and the pumps wher realy good kinda fell in love with it but not so much any more. I think I would haft to up it to 80-100 wich is a waste of money with everything els. this time my boy gave me some so I took it Im going to stop today.