How long for receptors to clear?

[musclestack]

Hey, fellas. I really feel like posting tonight, so here's another question that I've always pondered: Generally, how long does it take for someone's androgen receptors to clear? And does the amount of time that you were on gear/the dosages you took on your cycle have anything to do with clearance time?

[Got Insulin?]

the best way to do it is time on=time off, but people who are hardcore about it (which im not reccomending), do pct then wait for the blood levels to go back to normal then jump back on.

[musclestack]

Ok, but that really didn't answer my question. I've heard that there is no real way by taking blood tests to see if your receptors are cleared; I was just wondering if anyone here knew a general amount of time it takes for them to clear? Few weeks? Months?

[Got Insulin?]

if theres no way to find out through blood test then how would anyone know
?

[tough old man]

Hey, fellas. I really feel like posting tonight, so here's another question that I've always pondered: Generally, how long does it take for someone's androgen receptors to clear? And does the amount of time that you were on gear/the dosages you took on your cycle have anything to do with clearance time?

As you stated it would depend on several things. How long your cycle was. How much you were doing and what you were doing. Then the only real way to know is through blood work.

[Pinnacle]

Hey, fellas. I really feel like posting tonight, so here's another question that I've always pondered: Generally, how long does it take for someone's androgen receptors to clear? And does the amount of time that you were on gear/the dosages you took on your cycle have anything to do with clearance time?

Tough to say bro.Blood work will show what your Test levels are,but won't give any indication of whether your receptors are clear.It appears to take a good three months "off" (given the cycle was 12-15 weeks)before you'll respond well to an anabolic cycle.

~Pinnacle~

[BajanBastard]

It's a myth androgen receptors do not get blocked up so no need to "clear" them out. In fact receptors increase in number when androgens concentrations increase. Other factors are involved estrogen and shbg levels etc.

[*Narkissos*]

It's a myth androgen receptors do not get blocked up so no need to "clear" them out. In fact receptors increase in number when androgens concentrations increase. Other factors are involved estrogen and shbg levels etc.

[Pinnacle]

It's a myth androgen receptors do not get blocked up so no need to "clear" them out. In fact receptors increase in number when androgens concentrations increase. Other factors are involved estrogen and shbg levels etc.

Could you elaborate in detail please.

Reason I ask is,well,for two reasons.

1).In the past I've ran cycles far to close together and didn't respond well at all on the second go around,even upping the dose.If what you state is fact/true.Why did/does this happen?

2).I'm on year round.I cruise in between cycles at 250 mgs.I really need to bump my dose heavily(when on cycle) in order to see anything substanical.That tells me my receptors are somewhat flooded/saturated.


~Pinnacle~


~Pinnacle~

[*Narkissos*]

Could you elaborate in detail please.

Reason I ask is,well,for two reasons.

1).In the past I've ran cycles far to close together and didn't respond well at all on the second go around,even upping the dose.If what you state is fact/true.Why did/does this happen?

2).I'm on year round.I cruise in between cycles at 250 mgs.I really need to bump my dose heavily(when on cycle) in order to see anything substanical.That tells me my receptors are somewhat flooded/saturated.


~Pinnacle~


~Pinnacle~

Actually, it indicates that your SHBG level has increased...not that your receptors are saturated.

[Pinnacle]

Actually, it indicates that your SHBG level has increased...not that your receptors are saturated.

HAHA...so I'm doomed to run ultra high doses forever...great.


~Pinnacle~

[*Narkissos*]

HAHA...so I'm doomed to run ultra high doses forever...great.


~Pinnacle~

Not necessarily.

There're differing schools of thought on this...and different approaches to the same end.

Proviron is noted to reduce shbg levels.

[BajanBastard]

HAHA...so I'm doomed to run ultra high doses forever...great.


~Pinnacle~

Use low amounts of letro during your cruse period and on cycle.

[Montgomery]

Actually, it indicates that your SHBG level has increased...not that your receptors are saturated.

exactly . . your steroid hormone binding globuling levels are upregulated (increase) and your androgen receptors are downregulated (Decrease in number). Your body is always trying to achieve homeostasis (this is why recreational drug users need to continuosly increase their dosages - their body has downregulated the number of receptors in order to decrease the effects of the drug, thereby decreasing the departure from homeostasis with each dose) So, during and after PCT both your SHBG levels are decreasing back to normal, and the number of androgen receptors in your cells is increasing back to normal. Once this has occured (it takes a few months at least) you'll be able to shock your body again with the same dose as your last cycle.

Note that cellular response to any substance (steroids included) is based on two things :

1. the dose of the drug
2. the number of receptors for that drug.

Thus if you have fewer receptors, or a lower dose, you get a lesser response. Your body tries to maintain homeostasis by lessening the effects of a dose of extra hormone, and it does this by decreasing the number of receptors. This way, even if all the receptors are saturated with hormone the size of the response is still smaller. You need to allow this to reset before your next cycle.

Montgomery

[BajanBastard]

Could you elaborate in detail please.

Reason I ask is,well,for two reasons.

1).In the past I've ran cycles far to close together and didn't respond well at all on the second go around,even upping the dose.If what you state is fact/true.Why did/does this happen?

2).I'm on year round.I cruise in between cycles at 250 mgs.I really need to bump my dose heavily(when on cycle) in order to see anything substanical.That tells me my receptors are somewhat flooded/saturated.


~Pinnacle~


~Pinnacle~

Well Pinnacle as I said other factors are involved. SHBG will bind to the AAS in you blood reducing the cycles effectiveness. Eating to accommodate all this new muscle can be a challenge to some as well. Remember your body wants to keep homeostasis adding new muscle tissue will get harder over time. I'll go into more detail later but i really don't feel like right now. Really though the AR does not get blocked up it's a myth.

[guest589745]

It's a myth androgen receptors do not get blocked up so no need to "clear" them out. In fact receptors increase in number when androgens concentrations increase. Other factors are involved estrogen and shbg levels etc.

Could you elaborate in detail please.

Reason I ask is,well,for two reasons.

1).In the past I've ran cycles far to close together and didn't respond well at all on the second go around,even upping the dose.If what you state is fact/true.Why did/does this happen?

2).I'm on year round.I cruise in between cycles at 250 mgs.I really need to bump my dose heavily(when on cycle) in order to see anything substanical.That tells me my receptors are somewhat flooded/saturated.


~Pinnacle~

Actually, it indicates that your SHBG level has increased...not that your receptors are saturated.

Can anyone explain why increased SHBG levels would result in difficulty in gaining muscle or something related?

SHBG= Sex hormone binding globuline right ?

[vitor]

Can anyone explain why increased SHBG levels would result in difficulty in gaining muscle or something related?

SHBG= Sex hormone binding globuline right ?

Higher levels of SHBG will result in reduced levels of free curculating testosterone, b/c it binds to it. By lowering SHBG levels there will be higher levels of free testosterone to reach androgen recpters.

[guest589745]

Higher levels of SHBG will result in reduced levels of free curculating testosterone, b/c it binds to it. By lowering SHBG levels there will be higher levels of free testosterone to reach androgen recpters.

Agh, I just read the whole thread to get what yu told me at the end of it lol.

[shortie]

Yep, bumpin Nark and K.I.G. on this one-don't believe in receptor saturation myself.

[shortie]

The corresponding raise in SHGB is one of the best reasons to take proviron or winnie toward the end of a long cycle. Tongkat ali might also be beneficial, but not sure exactly how much it inhibits SHGB.

[BajanBastard]

I don't have a facking clue. I guess Hook is right. Anadrol is a DHT derived drug and it does not aromatize yet it has direct estrogenic activity. I'm stuck. Ummmmmmmmm Hooker take over.

[*Narkissos*]

I don't have a facking clue. I guess Hook is right. Anadrol is a DHT derived drug and it does not aromatize yet it has direct estrogenic activity. I'm stuck. Ummmmmmmmm Hooker take over.

lol... and here i was thinking you had my back.

You're fired.

[supersteve]

According to Bill Roberts there is no such thing as receptor down-regulation.
http://www.mesomorphosis.com/article...regulation.htm

Obviously there is some underlying factor that causes a 2nd cycle in quick succession to be less effective, but I don't think shbg is to blame either.

Conclusion: In contrast to general belief, SHBG levels barely influence levels of non-SHBG-bound testosterone both in male newborns and healthy adult men: the influence, if any, is positive. Consequently the age related increase of SHBG does not account for the age related decline in non-SHBG-T in healthy adult men.

Now this doesn't directly relate to AAS obviously. But if there is a surge of shbg before a rise in testosterone, we can assume that the body would actually reduce shbg in response to the use of exogenous androgens.

[Pinnacle]

Obviously there is some underlying factor that causes a 2nd cycle in quick succession to be less effective, but I don't think shbg is to blame either.

I feel there's more to it than SHBG levels as well.I've had this happen,and my dose was significantly higher,diet and training in perfect order.

I will say this about my current cycle.When I discontinued the masteron at week 8,my growth practically halted.My nutritionist,trainer and myself all thought in old school fashion(receptor saturation).It does make sense that once the masteron was discontinued(being a DHT derivative) that my SHGB levels sky rocketed deadening my cycle.

I'm going to spend some time on "cuttingedge" today and research some of the late,great Nandi's thoughts on this topic.


~Pinnacle~

[stupidhippo]

good discussion guys! One question : is this the only reason that causes too early cycle to be non-responsive? I do believe that ppl were right about the receptor thing so that is not the answer. But does the SHBG levels explain all? Are there other factors at play we still dont know about. Is the SHBG really all covering: If some would be able to downgrade SHBG levels would he be able to avaoid the eventual plateau in a cycle, I am doubting it..

[stupidhippo]

where do u base that latter statement because I have read completely opposite statements.. It says the same in all my books also..

[musclestack]

Do SHBG levels decrease after coming off of a cycle? I'm trying to figure out why we all plateau at some point in our cycle, and if the saturation of androgen receptors is a myth, and instead the reason is because our SHBG (I'm still researching on this subject) levels have increased, what exactly allows us to gain again on our next upcoming cycle?

Simply put, if our SHBG levels were the same as they were on our last cycle, and we couldn't gain then (after we've plateaued), why is it that with a certain amount of time off, we can start to gain again?

[Pinnacle]

Posted by Big Cat on cuttingedge muscle.
I'm still looking arounf for info.This is interesting in regards to SHGB levels.


[QUOTE]Originally posted by Big Cat
[B]Ok, I recently had a debate with some guy who designed a supplement for PCT and part of its action is to lower SHBG. I pointed out the ludicracy of this, but I wanted to open it up for debate, get some input from everyone here.
First of all, the amount of SHBG seems to be fairly irrelevant in terms of the amount of free testosterone. I present you this abstract :

My guess previous to the debate would have been that you may want to increase SHBG for PCT purposes, to expedite clearance of androgens. Sadly most used androgens don't have much affinity for SHBG, and given the length of PCT, it would be pretty much moot factor. So I'm back to the conclusion there is no point in manipulating SHBG in PCT either way, but definotely not for lowering it.
A second point that came to my attention was that SHBG is needed for the conversion of androstenedione.

Of course this only deals with erythrocytes, but I think everyone can follow me in the assumption that a similar process takes place in most cells and for most enzymes. Now, one common problem I have seen with people who haven't run proper PCT is that they often have low but normal LH/FSH as well as test, prior to full recovery, but their androstenedione is off the charts. That indicates that one of the slowest mechanisms to repair in a depressed HPTA is androstenedione to testosterone conversion.
i'd like to point out at this time that androgen use decreases SHBG and the use of an estrogen blocker in PCT further decreases that amount. It seems to me that one of the problems when coming off a cycle is actually lowered SHBG. So again, I not only couldn't see a use for decreasing SHBG, from the look of it low SHBG is a contributring factor in slow recovery and muscle loss.
Another study, originally done to test the influence of thyroid hormones (1), demonstrates that a surge in SHBG is seen prior to an expected surge in testosterone. This confirms the fact that SHBG is needed for testosterone synthesis, most likely via the aforementioned mechanism for increasing androstenedione conversion.

[Pinnacle]

More...

Originally posted by jboldman
Talking about shbg is something that you want to make sure your bood sugar is not low when doing. I find it a very complex subject to wrap yourself around. In many ways it seems to be contradictory since common bbr lore would have us believe that increased levels of shbg are a bad thing because they preferentially bind testosterone leading to an increased level of estrogen (ala swales theory of estrogen imbalance) and a decreased T/E ratio. We even have some promoting proviron to free up testosterone for anabolic effect. The first abstract BC posted is exteremly reve****g (btw, what is the study ref for that so i can add it to my lib.) since we now have a contradictory notion that increased levels of shbg, as expected, are positively correlated with increased total T but surprisingly are either slightly positivelly correlated with non-bound T or free T remains unchanged. In another study that i posted sometime ago here, a similar conclusion was reached whre contrary to prevailing opinion. " we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.". So we may have another reason to wish shbg not to be lower in pct since increased levels of E could lead to continued suppression of the hpta, just a thought.
jb
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 157-162
Copyright © 2005 by The Endocrine Society
Associations of Sex-Hormone-Binding Globulin (SHBG) with Non-SHBG-Bound Levels of Testosterone and Estradiol in Independently Living Men
Willem de Ronde, Yvonne T. van der Schouw, Majon Muller, Diederick E. Grobbee, Louis J. G. Gooren, Huibert A. P. Pols and Frank H. de Jong
Department of Internal Medicine (W.d.R., H.A.P.P., F.H.d.J.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands; Julius Center for Health Sciences and Primary Care (Y.T.v.d.S., M.M., D.E.G.), University Medical Center 3508 GA Utrecht, The Netherlands; Department of Endocrinology (W.d.R., L.J.G.G.), Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands; and Department of Epidemiology and Biostatistics (H.A.P.P.), Erasmus Medical Center, 3000 DR Rotterdam, Netherlands
Address all correspondence and requests for reprints to: Frank H. de Jong, Ph.D., Endocrine Laboratory, Room Ee 516, Department of Internal Medicine, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: [email protected].
Results of in vitro experiments indicate that with increasing concentrations of SHBG, testosterone (T) is preferentially bound to SHBG in comparison with estradiol (E2). In these studies, the ratio of non-SHBG-bound E2 (non-SHBG-E2) to non-SHBG-T increased with increasing levels of SHBG. SHBG has consequently been regarded as an estrogen amplifier. In this cross-sectional study in 399 men aged between 40 and 80 yr we tested whether higher levels of SHBG are associated with a higher estrogen/androgen ratio in vivo. The mean T level of these men was in the eugonadal range [536 &#177; 152 ng/dl (18.6 &#177; 5.26 nmol/liter), mean &#177; SD]. With increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T [regression coefficient (&#223 after adjustment for age and body mass index, 286 &#177; 15.8; P < 0.001] and total E2 (&#223; = 4.47 &#177; 0.90; P < 0.001). However, SHBG levels were negatively related with levels of non-SHBG-E2 (&#223; = –1.78 &#177; 0.69; P < 0.001), whereas there was a positive association between levels of SHBG and non-SHBG-T (&#223; = 32.0 &#177; 9.78; P = 0.001). Furthermore, we observed a negative relationship between SHBG levels and the E2/T ratio of either total (&#223; = –0.016 &#177; 0.002; P < 0.001) or non-SHBG-bound (&#223; = –0.011 &#177; 0.002; P < 0.001) hormone. Therefore, we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.

[Pinnacle]

OBJECTIVE: It is generally accepted that SHBG decreases the bioavailability and activity of testosterone (T). In in vitro experiments increased levels of SHBG will be associated with decreased levels of non-SHBG bound testosterone (non-SHBG-T). However, in vivo SHBG can alter both production and clearance rates and thus plasma levels of T. DESIGN AND PATIENTS: In order to study the effect of SHBG on the levels of non-SHBG-T in vivo in the presence of an active hypothalamo-pituitary-gonadal (HPG) axis we conducted a cross sectional study in 400 healthy adult men with an age range of 40-80 years and in 106 newborn boys. MEASUREMENTS: In both groups, regression coefficients (beta) and partial correlation coefficients (r) were calculated for the relationship between SHBG and T or non-SHBG-T. Adult men were divided into age groups per decade (40-50 years, 51-60 years, 61-70 years and 71-80 years) to study possible differences in the impact of SHBG on the level of non-SHBG-T throughout ageing. RESULTS: Higher levels of SHBG were associated with higher levels of total testosterone in neonates (beta = 0.02 +/- 0.004, r = 0.44, P < 0.001) but not with non-SHBG-T (beta = -0.001 +/- 0.001, r = 0.05, P = 0.52). In adult men there was a significant age related increase in levels of SHBG and an age-related decrease of both total and non-SHBG-T. Higher SHBG was strongly associated with higher total testosterone in all age groups (beta = 0.26, 0.26, 0.26 and 0.23 for 40-50 years, 51-60 years, 61-70 years and 71-80 years, respectively, P < 0.001 for all age groups). Higher SHBG was not or only slightly associated with higher non-SHBG-T beta = 0.02 (P = 0.32), beta = 0.04 (P = 0.03), beta = 0.04 (P = 0.02) and beta = 0.02 (P = 0.16) for 40-50 years, 51-60 years, 61-70 years and 71-80 years, respectively. CONCLUSIONS: In contrast to general belief, SHBG levels barely influence levels of non-SHBG-bound testosterone both in male newborns and healthy adult men: the influence, if any, is positive. Consequently the age related increase of SHBG does not account for the age related decline in non-SHBG-T in healthy adult men.

[Pinnacle]

Acta Endocrinol (Copenh). 1981 Jan;96(1):136-40. Related Articles, Links


Influence of sex hormone binding globulin and serum albumin on the conversion of androstenedione to testosterone by human erythrocytes.

Egloff M, Savoure N, Tardivel-Lacombe J, Massart C, Nicol M, Degrelle H.

The influence of human serum albumin and sex hormone binding globulin (SHBG) on the enzymic conversion of androstenedione to testosterone in human erythrocytes was investigated in vitro. Total plasma and albumin delayed the conversion rate of androstenedione, while SHBG increased it markedly. The effect of SHBG was largely abolished by heating to 60 degrees C for 1 h and by saturating its binding sites by DHT. The effect of both proteins was found to be related to their concentration. It appears that the binding sites of albumin provide a mechanism for retarding androstenedione uptake by the erythrocytes and that the high binding affinity of SHBG for testosterone facilitates the diffusion of this steroid out of the cell and thus, displaces the chemical equilibrium within the cell.

[Montgomery]

Lucky that we're men and we see upregulation of AR's when androgen blood levels increase. Women do not see this trend as much. Also, new research indicates that the binding globulins may not decrease effectiveness of exogenous testosterone as concentrations of globulins increase. Remember there is an equilibrium system in the blood, and a certain percentage of testosterone in the blood is bound to the globulin (where it is ineffective). Only when free (unbound) test levels get depleted will the testosterone dissociate from the globulin. Thus if you're training hard and your cells are demanding nutrients (and recieving them) it shouldn't matter how many globulins you have, your body will be able to use the same amount of test via the constant shift of the equilibrium system. What has been found is that the increased globulin levels are only correlates to the real reason for decreased effectiveness of a given level of test in experienced lifters, which is yet to be determined. I speculate that as telomere length decreases as cells age their sensetivity to testosterone decreases (by various mechanisms in the transduction pathway). Also, as cells age they become less efficient and require more energy do do the same things than they used to. Insulin is required for importing sugar (energy) and aa's etc into the cells, and high levels or androgens decrease sensetivity of myocytes to insulin (see a study I posted earlier in November).

I guess this is confusing, sorry.

Montgomery

[BajanBastard]

Lucky that we're men and we see upregulation of AR's when androgen blood levels increase. Women do not see this trend as much. Also, new research indicates that the binding globulins may not decrease effectiveness of exogenous testosterone as concentrations of globulins increase. Remember there is an equilibrium system in the blood, and a certain percentage of testosterone in the blood is bound to the globulin (where it is ineffective). Only when free (unbound) test levels get depleted will the testosterone dissociate from the globulin. Thus if you're training hard and your cells are demanding nutrients (and recieving them) it shouldn't matter how many globulins you have, your body will be able to use the same amount of test via the constant shift of the equilibrium system. What has been found is that the increased globulin levels are only correlates to the real reason for decreased effectiveness of a given level of test in experienced lifters, which is yet to be determined. I speculate that as telomere length decreases as cells age their sensetivity to testosterone decreases (by various mechanisms in the transduction pathway). Also, as cells age they become less efficient and require more energy do do the same things than they used to. Insulin is required for importing sugar (energy) and aa's etc into the cells, and high levels or androgens decrease sensetivity of myocytes to insulin (see a study I posted earlier in November).

I guess this is confusing, sorry.

Montgomery

My......head........hurts..............

You sparked an interest my friend.


The search continues forward.


~Pinnacle~

Cool man.

[oswaldosalcedo]

from bill roberts (mesomorphosis.com)

One of the most common beliefs concerning anabolic/androgenic steroid (AAS) usage is that the androgen receptor (AR) downregulates as a result of such usage. This has been claimed repeatedly in many books and articles, and it is claimed constantly on bulletin boards and the like. If I’ve heard it once, I’ve heard it a thousand times. If it were just being stated as an abstruse hypothesis, with no practical implications, with no decisions being based on it, that might be of little importance.
Unfortunately, this claim is used to support all kinds of arguments and bad advice concerning practical steroid usage. Thus, the error is no small one.


We will look at this matter fairly closely in this article. However, in brief the conclusions may be summed up as follows:

• There is no scientific evidence whatsoever that AR downregulation occurs in human muscle, or in any tissue, in response to above normal (supraphysiological) levels of AAS.
• Where AR downregulation in response to AAS has been seen in cell culture, these results do not apply because the downregulation is either not relative to normal androgen levels but to zero androgen, or estrogen may have been the causative factor, or assay methods inaccurate for this purpose were used, or often a combination of these problems make the results inapplicable to the issue of supraphysiological use of androgens by athletes.
• AR upregulation in response to supraphysiological levels of androgen in cell culture has repeatedly been observed in experiments using accurate assay methods and devoid of the above problems.
• AR downregulation in response to AAS does not agree with real world results obtained by bodybuilders, whereas upregulation does agree with real world results. (A neutral position, where levels in human muscle might be thought not to change in response to high levels of androgen, is not disproven however.)
• The "theoretical" arguments advanced by proponents of AR downregulation are invariably without merit.

The belief that androgen receptors downregulate in response to androgen is one of the most unfounded and absurd concepts in bodybuilding.
While this may seem perhaps an overly strong condemnation of that view, please consider that the claims for downregulation seen in books such as Anabolic Reference Guide (6th Issue), World Anabolic Review, Underground Steroid Handbook, etc. are presented with absolutely no evidence whatsoever to support them. The authors merely assert downregulation. They have done it so many times that by now many people assume it is gospel. In this paper you will be provided with evidence, and the evidence does not support their claim.

Overview of Regulation

Meaning of regulation
"Regulation" of a receptor refers to control over the number of receptors per cell. "Sensitivity," in contrast, refers to the degree of activity each receptor has. It is a possible in many cases for the receptors of a cell to be sensitized or desensitized to a drug or hormone, independently of the number of receptors. Similarly, it is possible for the receptors to upregulate or downregulate, to increase or decrease in number, independently of any changes in sensitivity.
If sensitivity remains the same, then upregulation will yield higher response to the same amount of drug or hormone, and downregulation will result in less response.
So if we are discussing androgen receptor regulation, we are discussing how many ARs are present per cell, and how this may change.
Changes in regulation must, of necessity, be between two different states, for example, levels of hormone. In the case of bodybuilding, we are interested in supraphysiological levels vs. normal levels (or perhaps, a higher supraphysiological level vs. a lower supraphysiological level.) In most research that is done, the comparison is often between normal levels and zero levels, or the castrated state.
We may describe regulation with the two levels being in either order. Upregulation as levels decrease from normal to zero is the same thing, but in the reverse direction, as downregulation as levels increase from zero to normal.
The term which would be used will depend on context, but does not change meaning, so long as the direction of change in level of hormone is understood.
If upregulation occurs as levels decrease from normal to zero, as is probably the case in some tissues, this would imply nothing about what may happen as levels increase beyond normal. It does not prove that downregulation would occur. It would be a serious error to take a study comparing normal levels and zero levels and use that study to argue the effect of supraphysiological levels. Unfortunately, such mistakes are commonly made by authors in bodybuilding.
Forms of regulation
Broadly speaking, there are three things that control the number of receptors. To understand them, let’s quickly review the life-cycle of an individual AR.
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. However, all else rarely is equal.
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.
The third contributing factor to 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.

Scientific Evidence Apparently Favoring Downregulation

While there are no studies showing downregulation in human skeletal muscle resulting from high-dose AAS use, there are some studies in cell culture, and sometimes in vivo, which seem to indicate that downregulation can occur, though not as a result of increase in androgen from normal to supraphysiological.
This is seen both by measurement of AR mRNA, which is in an indicator of the rate of AR production, and in measurement of receptor number.
All of these studies, however, are flawed from the perspective of the bodybuilder wishing to know if downregulation of the AR has ever been observed in any cell in response to increase of androgen from normal to supranormal levels.
Range of measurement
First, the question is, downregulation relative to what? What is the control?
Unfortunately, the control for in vivo studies is castration, not the normal state. The bodybuilder really doesn’t care if normal testosterone levels may result in fewer ARs for some cell types than would be seen with castration. We would not want to get castrated just to have more ARs than in the intact condition, if for no other reason than that the decrease in androgen level would be more significant than any possible increase in AR number.
In vitro studies have generally been done with zero androgen as the control, not normal androgen.
It cannot be projected that if AR number decreased as testosterone level was increased from zero to normal, that therefore it would continue to decrease as level was increased yet further. For example, the cause of this might be that there is a promotion mechanism increasing AR mRNA production as testosterone levels fall to zero. That would not mean that there would be any loss as testosterone levels increase past normal. Or if it is a repression mechanism that comes into play as testosterone levels rise past zero, that mechanism might be fully saturated by the time levels reach normal, and no further repression might occur as levels go past normal.
In fact, papers which report downregulation, even in their titles, often show in the actual data that the range of downregulation was entirely between zero and normal, or even zero and a subnormal level. Thus they give no evidence whatsoever of downregulation occurring with supraphysiological levels of androgen relative to normal levels.
Estrogen
Testosterone can aromatize to estrogen, which can itself lead to downregulation of the AR. Thus, if a study used testosterone but did not verify that the same results were seen with nonaromatizing androgen, or did not verify that use of an aromatase inhibitor did not change results, there is no way to know if any observed downregulation is due to androgen or not. It might be due to estrogen.
Assay
Unfortunately, AR concentrations are very low in cells, and mRNA is not so easily measured. It is possible for measurements to be misleading.
In Biochemical and Biophysical Research Communications (1991) 177 488, Takeda, Nakamoto, Chang et al. determined, "Our immunostaining [for amount of ARs] and in situ hybridization data [for amount of AR mRNA] indicated that in rat and mouse prostate, androgen-withdrawal decreased both androgen receptor content and androgen receptor mRNA level, and that injection of androgen restored normal levels, a process termed ‘upregulation’….However, Northern blot data of Quarmby et al. in rat prostate have shown a different result, downregulation: the amount of androgen receptor mRNA increased by androgen withdrawal and decreased below the control level after androgen stimulation. Our preliminary Northern blot data (unpublished data) also showed the same tendency, downregulation." [emphasis added]
The authors go on to explain in detail, somewhat beyond the scope of this article, why Northern blot analysis can lead to false results. The in situ hybridization method is indisputably a superior, more accurate method.
Many of the studies claiming downregulation depend on Northern blot data as the sole "proof." This study, however, shows that such measurement might be entirely wrong. In any case, regulation properly refers to control of the number of receptors. Production of mRNA is one of the contributing factors, but ultimately what must be measured to determine the matter is the number of receptors. This has been done in some experiments.
Specific papers often cited to support downregulation of the AR
Endocrinology (1981) 104 4 1431. This paper compares the normal state of the rat to the castrated state, and the muscle cytosol AR concentrations of the female rat to the intact (sham-operated) male rat.
Objections to this study include the fact that the effect of supraphysiological levels of androgen was not studied; that cytosolic measurements of AR are unreliable since varying percentages of ARs may concentrate in the nuclear region, and these are more indicative of activity; and that castration of rats is notorious for producing false conclusions. The cells, and indeed the entire system of the animal, undergo qualitative change (e.g., cessation of growth) from the castration relative to the sham-operated animals. Testosterone levels are not the only thing which change upon castration. Another objection is that estrogen was not controlled and the effects of estrogen were not determined or accounted for. Estrogen levels certainly were not constant in this experiment.
Molecular Endocrinology (1990) 4 22. AR mRNA level, in vitro, was seen to increase as androgen levels were reduced below normal. Supraphysiological levels were not tested. Northern blot analysis was used. AR levels were not measured.
Molecular and Cellular Endocrinology (1991) 76 79. In human prostate carcinoma cells, in vitro, androgen resulted in downregulation of AR mRNA relative to zero androgen levels. Levels of androgen receptor, however, increased, relative to when androgen level was zero, by a factor of two. The researchers noted, "At 49 hours, androgen receptor protein increased 30% as assayed by immunoblots and 79% as assayed by ligand binding" [the later method is the more reliable and indicative of biological effect.]
Molecular Endocrinology (1993) 7 924. In vitro, it was determined by Northern blot analysis that mRNA levels decreased when supraphysiological levels of androgen were compared to zero androgen in cancer cells. Levels of ARs were measured, and there was no observed decrease despite the observed decrease in mRNA level (as measured by Northern blot.)
Molecular and Cellular Endocrinology (1995) 115 177. COS 1 cells were transfected with human AR DNA with the CMV promoter. The authors state that the DNA sequence responsible for downregulation of the AR is encoded within the AR DNA, not the promoter region. Dexamethasone [a glucocorticoid drug similar to cortisol] was observed to result in downregulation of AR mRNA relative to zero dexamethasone level. Androgen also had this effect, but did not result in lower levels of androgen receptors. This was attributed to increase in androgen receptor half life caused by androgen administration. The observed androgen downregulation effect relative to zero androgen ended at a concentration of 0.1 nanomolar of androgen (methyltrienolone) – higher doses, to 100 nanomolar, resulted in no further downregulation of AR mRNA production.
While this list is not complete, I am not omitting any studies that appear to have any better evidence – indeed, any evidence at all – that supraphysiological levels of androgen result in downregulation, relative to normal androgen levels, of the AR The above is a reasonably complete picture of the research evidence that might be used to support the bodybuilding theory of AR downregulation. When analyzed closely, no scientific study provides support for that theory.

Scientific evidence indicating that a biochemical mechanism for upregulation does exist
Even in the above evidence which apparently (at first sight) might seem in favor of downregulation, it was sometimes seen that actual levels of the AR increased, even going from zero to normal (rather than normal to supraphysiological.) This is upregulation of the receptor, since as we recall, regulation is the control of the number of receptors, and this control may be achieved by change in the half life of the receptors. Increased half life of the receptor, all else being equal, or perhaps with change in half-life overcoming other factors, can yield higher receptor numbers. Kemppainen et al. (J Biol Chem 267 968) demonstrated that androgen increases the half life of the AR, which is an upregulating effect.
Endocrinology (1990) 126 1165. In fibroblasts cultured from human genital skin which contained very low amounts of 5-alpha reductase, 2 nanomolar tritium-labeled testosterone [which is sufficient to saturate ARs] produced a 34% increase in androgen receptors as measured by specific AR binding, the best assay method known, and 20 nanomolar tritium-labeled testosterone produced an increase of 64% in number of ARs.
Note: 20 nanomolar free testosterone is approximately 400 times physiological level (normal level in humans is approximately 0.05 nanomolar).
J Steroid Biochemistry and Molecular Biology (1990) 37 553. In cultured adipocytes, methyltrienolone and testosterone demonstrated marked upregulation of AR content upon administration of androgen. 10 nanomolar methyltrienolone increased AR content (as measured by binding to radiolabeled androgen) by more than five times, relative to zero androgen.
J Steroid Biochemistry and Molecular Biology (1993) 45 333. In cultured smooth muscle cells from the penis of the rat, mRNA production was found to be upregulated by high dose testosterone (100 nanomolar) or DHT. When 5-alpha reducatase was inhibited by finasteride, thus blocking metabolism to DHT, AR mRNA production was downregulated in response to testosterone. Blockage of the aromatization pathway to estrogen by fadrozole eliminated this downregulation effect. Estradiol itself was found to downregulate AR mRNA production in these cells.
Endocrinol Japan (1992) 39 235. One nanomolar DHT was demonstrated to increase AR protein by over 100% within 24 hours, relative to zero androgen level. The half life of the AR was demonstrated to increase from 3.3 h to 7.5 h as a result of the androgen administration.
Endocrinology (1996) 137 1385. 100 nanomolar testosterone was found to increase AR levels in vitro in muscle satellite cells, myotubes, and muscle-derived fibroblasts.

Conclusions from Scientific Research

As androgen levels decrease from normal to zero, production of AR mRNA may increase in some tissues. However, the number of ARs does not necessarily increase, because the half life of the ARs decreases with lower concentrations of androgen.
As androgen levels increase from normal to supraphysiological, numbers of ARs in some tissues have been shown to increase. Such an increase is upregulation. The increase may be due primarily or entirely to increase in half-life of the AR resulting from higher androgen level.
There is no scientific evidence to support the popular view that AAS use might be expected to result in downregulation of the AR relative to receptor levels associated with normal androgen levels.

Conclusions from Bodybuilding Observations

I find it rather unreasonable to think that the most likely thing is that athletes who have been on high dose AAS for years, and are far more massive than what they could be naturally, and who are maintaining that mass or even slowly gaining more, could possibly have less androgen receptor activity than natural athletes or low-dose steroid users.
It might, hypothetically, be possible that their AR activity is the same, and the extra size due to steroids is due entirely to non-AR mediated activities of the androgens. However there is no evidence for that and it seems unlikely.
I believe the most logical possibility is that these athletes are experiencing higher activity from their androgen receptors than natural athletes, or low dose steroid users, are experiencing. Since the majority of androgen receptors are occupied at quite moderate levels of AAS, the explanation cannot be simply that a higher percentage of receptors is occupied, with the receptor number being the same. That would not allow much improvement. In contrast, upregulation would allow substantial improvement, such as is apparently the case (unless non-AR mediated activities are largely or entirely responsible for improved anabolism, which would be an entirely unsupported hypothesis.)
Upregulation in human muscle tissue, in vivo, is not directly proven but seems to fit the evidence and to provide a plausible explanation for observed results.
I leave the matter, however, to the reader. Weigh the evidence, and decide if downregulation, as popularly advocated, is supported by science, or by what is experienced in bodybuilders.

[BajanBastard]

Good finds but what about other anabolics? SHBG is just one factor involved that slow muscle gains. Hell if we know exectly what is was that slowed muscle gains we would has overcome it by now. This is something we just don't have the answer to....................yet.

[Pinnacle]

Good finds but what about other anabolics? SHBG is just one factor involved that slow muscle gains. Hell if we know exectly what is was that slowed muscle gains we would has overcome it by now. This is something we just don't have the answer to....................yet.

You sparked an interest my friend.


The search continues forward.


~Pinnacle~

[Montgomery]

good thread

looking back in this thread, seems like some blokes are forgetting how an AR works. When testosterone binds to it's receptor, it causes a conformational change in the receptor. This conformational change is what causes the changes in the cell (increased protein synthesis, etc). The androgen then, shortly after binding, dissociates from the receptor. Thus you don't need time to clear your receptors, only time for test levels to decrease back to normal so that your receptors are being stimulated at a physiological rate.

Montgomery

[musclestack]

good thread

looking back in this thread, seems like some blokes are forgetting how an AR works. When testosterone binds to it's receptor, it causes a conformational change in the receptor. This conformational change is what causes the changes in the cell (increased protein synthesis, etc). The androgen then, shortly after binding, dissociates from the receptor. Thus you don't need time to clear your receptors, only time for test levels to decrease back to normal so that your receptors are being stimulated at a physiological rate.

Montgomery

If this is true, and I'm not saying it isn't, how do you explain people who run cycles on and off totally forgetting (or ignorant to) PCT, thus leaving their natural test levels lower and never fully recovering, but still make exceptional gains on each of their cycles?

[Montgomery]

If this is true, and I'm not saying it isn't, how do you explain people who run cycles on and off totally forgetting (or ignorant to) PCT, thus leaving their natural test levels lower and never fully recovering, but still make exceptional gains on each of their cycles?

Sure, they make exceptional gains in consecutive cycles, but they lose most of it after each cycle because their lack of PCT leaves their AR's way way understimulated, and atrophy occurs. Not sure I'm understanding your question though.

Montgomery

[powerliftmike]

I've read that an increase in androgen levels results in a decrease in SHBG levels. This would seem to suggest that if you make little testosterone then you will have an even greater percentage bound by sex-hormone binders.