How long for receptors to clear?

[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

[oswaldosalcedo]

I would not advise you to run an A.I for lenghly periods due to cholesterol issues. Best bet would be to get blood work and use it as your guide.

for letro: (i can post for aromasin and others also)

Ann Oncol. 2005 May;16(5):707-15. Epub 2005 Apr 7.

The influence of letrozole on serum lipid concentrations

Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, Tu D, Ingle JN, Heath M, Deangelis D, Perez EA.

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada. [email protected]

BACKGROUND: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). PATIENTS AND METHODS: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. RESULTS: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. CONCLUSIONS: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy."

[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.

[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?

[BajanBastard]

Real world evidence states otherwise oswaldosalcedo. Also the women in the study were taking letrozole only. (2.5mg ed + 5 yrs) While bodybuilders take it as a much lesser dose and shorter time period it is usually combined with AAS with negative effects on cholesterol. Thanks for the study though, maybe letro is not as harsh as i thought?

[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.

[oswaldosalcedo]

Real world evidence states otherwise oswaldosalcedo. Also the women in the study were taking letrozole only. (2.5mg ed + 5 yrs) While bodybuilders take it as a much lesser dose and shorter time period it is usually combined with AAS with negative effects on cholesterol. Thanks for the study though, maybe letro is not as harsh as i thought?

first,real world evidence is no science.
and, i use 600 mg nandro and 600 mg boldelone weekly and i have normal levels of cholesterol (140).
and, i can post studies with nandro or test and the changes in cholesterol are minimal 5-10 %, only oxymetholone in studies (anadrol) produces more cholesterol 20 % (not too much, anyway)

[oswaldosalcedo]

I would not advise you to run an A.I for lenghly periods due to cholesterol issues. Best bet would be to get blood work and use it as your guide.

see anyway:
http://forums.steroid.com/showthread.php?t=125162
Arimidex (Ldex, Anastrozole), Femara (Letrozole), Nolvadex(Tamoxifen) & Cholesterol

[Pinnacle]

AWESOME CONVERSATION!!!There should be more intellectual threads like this.

Question still remains :

How does one acquire significant gains on cycles that are in close succession to one another?

~Pinnacle~

[oswaldosalcedo]

true,as the time goes is more dificult acquire more mass,but that fact, perhaps do not be related to the androgen receptors.

i post this new study:

J Steroid Biochem Mol Biol. 2005 Jan;93(1):35-42. Epub 2005 Jan 25.

Androgen receptor content following heavy resistance exercise in men.

Ratamess NA, Kraemer WJ, Volek JS, Maresh CM, Vanheest JL, Sharman MJ, Rubin MR, French DN, Vescovi JD, Silvestre R, Hatfield DL, Fleck SJ, Deschenes MR.

Human Performance Laboratory, Department of Kinesiology, Unit 1110, University of Connecticut, Storrs, CT 06269-1110, USA.

The purpose of the present investigation was to examine androgen receptor (AR) content in the vastus lateralis following two resistance exercise protocols of different volume. Nine resistance-trained men (age=24.3+/-4.4 years) performed the squat exercise for 1 (SS) and 6 sets (MS) of 10 repetitions in a random, counter-balanced order. Muscle biopsies were performed at baseline, and 1h following each protocol. Blood was collected prior to, immediately following (IP), and every 15 min after each protocol for 1h. No acute elevations in serum total testosterone were observed following SS, whereas significant 16-23% elevations were observed at IP, 15, and 30 min post-exercise following MS. No acute elevations in plasma cortisol were observed following SS, whereas significant 31-49% elevations were observed for MS at IP, 15, and 30 min post-exercise. Androgen receptor content did not change 1h following SS but significantly decreased by 46% following MS. These results demonstrated that a higher volume of resistance exercise resulted in down-regulation of AR content 1h post-exercise. This may have been due to greater protein catabolism associated with the higher level of stress following higher-volume resistance exercise.

Ratamess and coworkers recently published the results of a study that looked at the hormonal profile and androgen receptor content in the vastus lateralis muscle (a portion of the muscles comprising the quadriceps) of men following two exercise protocols [1]. The results were a bit surprising in light of some previous studies, and suggest a possible supplement regimen to offset some of the negative effects that were observed. The salient results of their research were (a) an increase in both cortisol and testosterone levels after multiple sets of squats; and (b) a significant downregulation of the androgen receptor in biopsied muscle tissue.


Several previous studies have examined hormonal changes in cortisol, testosterone, and growth hormone (GH) during and following resistance exercise [2–4]. In [2] Kraemer et.al. observed an increase in both testosterone and GH after heavy resistance exercise. Hakkinen and Pakarinen observed increases in free and total testosterone, cortisol, and GH after an acute bout of heavy squatting [3]. Kraemer et.al. examined plasma hormone changes after an intense bout of cycling and noted a significant increase in cortisol [4]. The current study and the earlier ones cited show a trend of increased cortisol and testosterone immediately after strenuous exercise.


The current study by Ratamass et.al. is the first to look at androgen receptor content in worked muscle immediately post-exercise. While the elevated testosterone that many studies show occurs after exercise sounds beneficial, if receptor levels are low, then the increased testosterone would be of less anabolic value than if receptor levels were unchanged or increased. In fact, a depressed level of AR is exactly what Ratamass and coworkers found. The downregulation of AR coupled with high cortisol levels post-exercise would be expected to make for a metabolic state characterized by net catabolism.


To quote from the current study under investigation,


“…acute hormonal elevations are without context unless subsequent interaction with a specific membrane bound or nuclear receptor occurs and the appropriate signal is transduced”.


In other words, what good is the extra testosterone produced during lifting if the receptors aren’t there to accept it?

The authors of the present study attribute the decline in androgen receptors to an overall loss of protein due to the demands of strenuous exercise. Cortisol is highly catabolic to proteins and does not discriminate between contractile proteins and noncontractile proteins, such as the androgen receptor, which itself is a protein. A number of studies have shown that the AR is upregulated after a longer post exercise time period. For example, Bamman & Shipp reported that in humans AR messenger RNA in the vastus lateralis increased 63% and 102% respectively 48 hours following 8 sets of 8 reps of either eccentric (110% of 1 RM) or concentric ( 85% of 1RM) squats [5]. Thus resistance exercise may ultimately upregulate the AR, but the initial response appears to be a catabolic one, based on the current study.


One might be tempted to speculate the increased testosterone and decreased AR may cancel each other out. This may not be the case. Another interesting finding of this study was the individual baseline 1 RM was independent of plasma testosterone levels, but correlated highly with androgen receptor content. So an individual’s AR levels may be more indicative of their strength that their testosterone levels.

1. MR, French DN, Vescovi JD, Silvestre R, Hatfield DL, Fleck SJ, Deschenes MR. Androgen receptor content following heavy resistance exercise in men. J Steroid Biochem Mol Biol. 2005 Jan;93(1):35-42.
2. Kraemer WJ, Gordon SE, Fleck SJ, Marchitelli LJ, Mello R, Dziados JE, Friedl K, Harman E, Maresh C, Fry AC. Endogenous anabolic hormonal and growth factor responses to heavy resistance exercise in males and females. Int J Sports Med. 1991 Apr;12(2):228-35.
3. Hakkinen K, Pakarinen A. Acute hormonal responses to two different fatiguing heavy-resistance protocols in male athletes. J Appl Physiol. 1993 Feb;74(2):882-7.
4. Kraemer WJ, Patton JF, Knuttgen HG, Marchitelli LJ, Cruthirds C, Damokosh A, Harman E, Frykman P, Dziados JE. Hypothalamic-pituitary-adrenal responses to short-duration high-intensity cycle exercise. J Appl Physiol. 1989 Jan;66(1):161-6.
5. Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR, Goodman A, McLafferty CL Jr, Urban RJ. Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab. 2001 Mar;280(3):E383-90.
6. Sheffield-Moore M, Urban RJ, Wolf SE, Jiang J, Catlin DH, Herndon DN, Wolfe RR, Ferrando AA Short-term oxandrolone administration stimulates net muscle protein synthesis in young men. J Clin Endocrinol Metab. 1999 Aug;84(8):2705-11.
7. Tiao G, Fagan J, Roegner V, Lieberman M, Wang JJ, Fischer JE, Hasselgren PO. Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids. J Clin Invest. 1996 Jan 15;97(2):339-48.
8. Zhao J, Bauman WA, Huang R, Caplan AJ, Cardozo C. Oxandrolone blocks glucocorticoid sign****g in an androgen receptor-dependent manner. Steroids. 2004 May;69(5):357-66.
9. Navegantes LC, Resano NM, Migliorini RH, Kettelhut IC. Catecholamines inhibit Ca(2+)-dependent proteolysis in rat skeletal muscle through beta(2)-adrenoceptors and cAMP. Am J Physiol Endocrinol Metab. 2001 Sep;281(3):E449-54.
10. Yimlamai T, Dodd SL, Borst SE, Park S. Clenbuterol induces muscle-specific attenuation of atrophy through effects on the ubiquitin-proteasome pathway. J Appl Physiol. 2005 Mar 17;
11. Wolfe RR. Effects of insulin on muscle tissue. Curr Opin Clin Nutr Metab Care. 2000 Jan;3(1):67-71
12. Bennett RG, Hamel FG, Duckworth WC. Insulin inhibits the ubiquitin-dependent degrading activity of the 26S proteasome. Endocrinology. 2000 Jul;141(7):2508-17.

[goose]

AWESOME CONVERSATION!!!There should be more intellectual threads like this.

Question still remains :

How does one acquire significant gains on cycles that are in close succession to one another?

~Pinnacle~

I have no answers here,but to get a greater understanding of how complex your question is Pinn,with bioligical science we have a correlation with an affinty of similar situations that can help us with human receptors.

For example,an alcoholic.For these people to get drunk.The longer you are an alcoholic,the harder it is to get drunk.What can they do?

1.They must increase the dose
2.Switch,types of Liquor,introduce drugs.

The neroligical receptors have to be pushed higher to get the required effect.

The question you have displayed,you know the answers My freind.You have to increase the dose,I believe you have reached the point when 2-3g of test does very little to you,however,for a newbie they will explode.The second option us guys have,and your the only guys that I have read that understands this ideology, you have to switch anabolics around,never use the same anabolics in sucsesive cycles,even test ,always alternate.This is a very obvious technique that we apply.The interesting question
is why.The answers are all related to the human evolution of are species, homosapeians (humans).Humans have evolved over Millions of years,to reach the biolgical level we are today.What does this mean to receptors,why at a certain point a drug becomes ineffective due to abuse.The human receptors have not evolved to handle and require certain doses,therefore,as a defensive mechanism they become harder to stimulate them.The brain is so complicated,it will ask,why do I need all this test, alcohol,MDMA ? It`s like defence,the more you take,the less I will let the compound perform.

This is a reason why your first cycle is the best.This is all new to your biolgical body,even tho it`s not an artificial SubStance,like test,your body will respond.Very similar to recrational drugs like MDMA, users report that their first experience is never matched,never the same,the first time was the most plesureable and memorable,this is why your question was such broad based,we can relate to so many POSSIBILITIES,it`s quite endless.The other way to improve cycles is using compounds to produce effective Synergy,this like us,is used very effective in aids treatments,even reaches psychological diseases,where a number of drugs become more effective and powerfull together.But this is another thread,these are hypothetical ideas,what you need to do Pinn,is to introduce rIL-15 to your program,something new,take you to the next level,cus I want you to win next year Just joking

goose4..............

[goose]

This is a quote from Red Baron,a very smart guy on this board.I like when he uses the word sensitivity.



`The pro's have most certainly blown away their receptors to just about every substance available ... that is why their cycles and doses are fringing on insane. They have lost all sensitivity to the lower and safer doses. Since their livlihood depends on showing up to the couple (or one) contest a year to support themselves and their families, I can't say that I blame them ... it just really stinks they have to go to those extremes to compete. The officials and judges need to be horse-whipped and the criteria needs to change to allow them to compete using more system-friendly doses ... but that whole discussion is another can of worms.`

goose4.............

[oswaldosalcedo]

J Clin Endocrinol Metab. 2004 Oct;89(10):5245-55.


Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment.

Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S.

Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059, USA.

Androgens stimulate myogenesis, but we do not know what cell types within human skeletal muscle express the androgen receptor (AR) protein and are the target of androgen action. Because testosterone promotes the commitment of pluripotent, mesenchymal cells into myogenic lineage, we hypothesized that AR would be expressed in mesenchymal precursor cells in the skeletal muscle. AR expression was evaluated by immunohistochemical staining, confocal immunofluorescence, and immunoelectron microscopy in sections of vastus lateralis from healthy men before and after treatment with a supraphysiological dose of testosterone enanthate. Satellite cell cultures from human skeletal muscle were also tested for AR expression. AR protein was expressed predominantly in satellite cells, identified by their location outside sarcolemma and inside basal lamina, and by CD34 and C-met staining. Many myonuclei in muscle fibers also demonstrated AR immunostaining. Additionally, CD34+ stem cells in the interstitium, fibroblasts, and mast cells expressed AR immunoreactivity. AR expression was also observed in vascular endothelial and smooth muscle cells. Immunoelectron microscopy revealed aggregation of immunogold particles in nucleoli of satellite cells and myonuclei; testosterone treatment increased nucleolar AR density. In enriched cultures of human satellite cells, more than 95% of cells stained for CD34 and C-met, confirming their identity as satellite cells, and expressed AR protein. AR mRNA and protein expression in satellite cell cultures was confirmed by RT-PCR, reverse transcription and real-time PCR, sequencing of RT-PCR product, and Western blot analysis. Incubation of satellite cell cultures with supraphysiological testosterone and dihydrotestosterone concentrations (100 nm testosterone and 30 nm dihydrotestosterone) modestly increased AR protein levels. We conclude that AR is expressed in several cell types in human skeletal muscle, including satellite cells, fibroblasts, CD34+ precursor cells, vascular endothelial, smooth muscle cells, and mast cells. Satellite cells are the predominant site of AR expression.These observations support the hypothesis that androgens increase muscle mass in part by acting on several cell types to regulate the differentiation of mesenchymal precursor cells in the skeletal muscle."

--------------------------------------

....................................OBJECTIVE KNOWLEDGE.

[Pinnacle]

I have no answers here,but to get a greater understanding of how complex your question is Pinn,with bioligical science we have a correlation with an affinty of similar situations that can help us with human receptors.

For example,an alcoholic.For these people to get drunk.The longer you are an alcoholic,the harder it is to get drunk.What can they do?

1.They must increase the dose
2.Switch,types of Liquor,introduce drugs.

The neroligical receptors have to be pushed higher to get the required effect.

The question you have displayed,you know the answers My freind.You have to increase the dose,I believe you have reached the point when 2-3g of test does very little to you,however,for a newbie they will explode.The second option us guys have,and your the only guys that I have read that understands this ideology, you have to switch anabolics around,never use the same anabolics in sucsesive cycles,even test ,always alternate.This is a very obvious technique that we apply.The interesting question
is why.The answers are all related to the human evolution of are species, homosapeians (humans).Humans have evolved over Millions of years,to reach the biolgical level we are today.What does this mean to receptors,why at a certain point a drug becomes ineffective due to abuse.The human receptors have not evolved to handle and require certain doses,therefore,as a defensive mechanism they become harder to stimulate them.The brain is so complicated,it will ask,why do I need all this test, alcohol,MDMA ? It`s like defence,the more you take,the less I will let the compound perform.

This is a reason why your first cycle is the best.This is all new to your biolgical body,even tho it`s not an artificial SubStance,like test,your body will respond.Very similar to recrational drugs like MDMA, users report that their first experience is never matched,never the same,the first time was the most plesureable and memorable,this is why your question was such broad based,we can relate to so many POSSIBILITIES,it`s quite endless.The other way to improve cycles is using compounds to produce effective Synergy,this like us,is used very effective in aids treatments,even reaches psychological diseases,where a number of drugs become more effective and powerfull together.But this is another thread,these are hypothetical ideas,what you need to do Pinn,is to introduce rIL-15 to your program,something new,take you to the next level,cus I want you to win next year Just joking

goose4..............

I agree that it's mandatory to increase dosage.Some might disagree that we don't get a tolerance to anabolics at certain doses.I beg to differ.Case in point.Try running dbol up front in your cycle,then again on the later half.Try to tell me with a straight face the results/effects were the same at exact same dosage.You'd be lying if you said yes.Same goes for anadrol.I've ran it up front and at cycles end.The later was a big disappointment.Even running them in cycles back to back,the results/effects were disappointing.I've encounter the same with injectable anabolics as well.I totally agree it's a must to change drugs up totally on your next cycle.It took me awhile to figure this out,but once I did,the gains kept coming.I'm still searching for a way to slow down the process of having to bump tp megs doses to see gains.As that surely isn't a healthy approach.Not that I'm looking to live forever,I just want my doses to be reasonably affordable.

Here's an interesting post by Nandi on cuttingedgemuscle

AAS in vitro and in vivo
It's well known that several anabolic steroids that bind to the AR only weakly still exert potent anabolic effects. These binding assays are typically carried out in vitro.

One theory that I have expounded on is that certain steroids that bind only weakly to the AR are still capable of turning on "anabolic genes".

The abstract below proposes a somewhat different theory, that in vitro studies do not reflect the true binding affinity of certain steroids. Some steroids that bind the AR weakly in vitro bind to it and activate it strongly in vivo.

J Steroid Biochem Mol Biol. 2005 Apr;94(5):481-7. Epub 2005 Mar 17.

Anabolic-androgenic steroid interaction with rat androgen receptor in vivo and in vitro: a comparative study.

Feldkoren BI, Andersson S.

Department of Obstetrics-Gynecology and Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9032, USA.

Anabolic steroids are synthetic derivatives of testosterone and are characterized by their ability to cause nitrogen retention and positive protein metabolism, thereby leading to increased protein synthesis and muscle mass. There are disagreements in the literature in regards to the interaction of anabolic steroids with the androgen receptor (AR) as revealed by competitive ligand binding assays in vitro using cytosolic preparations from prostate and skeletal muscle. By use of tissue extracts, it has been shown that some anabolic steroids have binding affinities for the AR that are higher than that of the natural androgen testosterone, while others such as stanozolol and methanedienone have significantly lower affinities as compared with testosterone. In this study we show that stanozolol and methanedienone are low affinity ligands of the rat recombinant AR as revealed by a ligand binding assay in vitro, however, based on a cell-based AR-dependent transactivation assay, they are potent activators of the AR. We also show that a single injection of stanozolol and methanedienone causes a rapid cytosolic depletion of AR in rat skeletal muscle. Based on these results, we conclude that anabolic steroids with low affinity to AR in vitro, can in fact in vivo act on the AR to cause biological responses.

[oswaldosalcedo]

I agree that it's mandatory to increase dosage.Some might disagree that we don't get a tolerance to anabolics at certain doses.I beg to differ.Case in point.Try running dbol up front in your cycle,then again on the later half.Try to tell me with a straight face the results/effects were the same at exact same dosage.You'd be lying if you said yes.Same goes for anadrol.I've ran it up front and at cycles end.The later was a big disappointment.Even running them in cycles back to back,the results/effects were disappointing.I've encounter the same with injectable anabolics as well.I totally agree it's a must to change drugs up totally on your next cycle.It took me awhile to figure this out,but once I did,the gains kept coming.I'm still searching for a way to slow down the process of having to bump tp megs doses to see gains.As that surely isn't a healthy approach.Not that I'm looking to live forever,I just want my doses to be reasonably affordable.

Here's an interesting post by Nandi on cuttingedgemuscle

AAS in vitro and in vivo

It's well known that several anabolic steroids that bind to the AR only weakly still exert potent anabolic effects. These binding assays are typically carried out in vitro.

One theory that I have expounded on is that certain steroids that bind only weakly to the AR are still capable of turning on "anabolic genes".

The abstract below proposes a somewhat different theory, that in vitro studies do not reflect the true binding affinity of certain steroids. Some steroids that bind the AR weakly in vitro bind to it and activate it strongly in vivo.

"J Steroid Biochem Mol Biol. 2005 Apr;94(5):481-7. Epub 2005 Mar 17.

Anabolic-androgenic steroid interaction with rat androgen receptor in vivo and in vitro: a comparative study.

Feldkoren BI, Andersson S.

Department of Obstetrics-Gynecology and Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9032, USA.

Anabolic steroids are synthetic derivatives of testosterone and are characterized by their ability to cause nitrogen retention and positive protein metabolism, thereby leading to increased protein synthesis and muscle mass. There are disagreements in the literature in regards to the interaction of anabolic steroids with the androgen receptor (AR) as revealed by competitive ligand binding assays in vitro using cytosolic preparations from prostate and skeletal muscle. By use of tissue extracts, it has been shown that some anabolic steroids have binding affinities for the AR that are higher than that of the natural androgen testosterone, while others such as stanozolol and methanedienone have significantly lower affinities as compared with testosterone. In this study we show that stanozolol and methanedienone are low affinity ligands of the rat recombinant AR as revealed by a ligand binding assay in vitro, however, based on a cell-based AR-dependent transactivation assay, they are potent activators of the AR. We also show that a single injection of stanozolol and methanedienone causes a rapid cytosolic depletion of AR in rat skeletal muscle. Based on these results, we conclude that anabolic steroids with low affinity to AR in vitro, can in fact in vivo act on the AR to cause biological responses."

----------------------------------------


great post,there are others mechanism at stake !

upregulation !

sensitivity ? what ?

[goose]

unfortnatly,this is when your genetics come into play.Arnold said BB is 60% diet,20% training and 20% AAS.Me ,you,we can play around with these factors,eat better,train harder,cycle harder,you cant with your genetics code.We can play around with this a bit with anabolics that produce hyperplasia.What did you gain on your last cycle? No need to show the cycle.I guess 8,is a good gain for you.No wonder you dont gain,doing a Dbol only....I wish that guy was right

goose4.......

[Pinnacle]

unfortnatly,this is when your genetics come into play.Arnold said BB is 60% diet,20% training and 20% AAS.Me ,you,we can play around with these factors,eat better,train harder,cycle harder,you cant with your genetics code.We can play around with this a bit with anabolics that produce hyperplasia.What did you gain on your last cycle? No need to show the cycle.I guess 8,is a good gain for you.No wonder you dont gain,doing a Dbol only....I wish that guy was right

goose4.......

9.5 lbs(tickled with that!)...But alot of different compounds came into play. Like I said earlier in the thread.Once I stopped the masteron(DHT Derivative)My gains ceased(week 8).So that leads me to believe my SHBG levels rose extremely high,and caused a shut down in growth.
Next cycle I will add proviron and run either low dose winny(20 mgs ED) all the way through,or masteron once again.


~Pinnacle~

[BUYLONGTERM]

This is a great conversation, because just like Pinn, when I was on for a long period of time, I could NOT gain unless I upped my dose!!!! 500-750+ does nothing for me after say 15 weeks or so. Pinn, Keep me updated on your blood work. As you know, being on for a year and a half, my cholesterol was out of control (thus, I am NOT on a cycle anymore). I am very curious to know at what dose does it start to effect cholesterol. Meaning, if I was on a HRT dose (which I'm suppose to anyway), would that have an effect on Cholesterol

Peace,

BLT

[Drummerboy]

would someone please offer a bottom line to all this... im getting a headache trying to digest it all...

[*Narkissos*]

would someone please offer a bottom line to all this... im getting a headache trying to digest it all...

Stick around...

[vitor]

After the body(muscles) has grown alot from a cycle(8-10 weeks), it is less likely to grow much more(right after that). Your body has to adapt and recover. Thats one of the reasens doing 2-cycles with short breaks is not the best idea. I prefer shortet cycles, as recovering hpta will be easier as well.

[j martini]

Istituto di Endocrinologia, Universita di Pisa, Italy.

L-asparaginase, an antineoplastic drug used in the treatment of acute lymphoblastic leukemia (ALL), has been previously shown to inhibit the hepatic synthesis of thyroxine-binding globulin (TBG). In two children treated by this drug for ALL, a dramatic decrease in serum sex hormone-binding globulin (SHBG) concentrations was also observed. Serum SHBG levels were still below normal 10 days after L-asparaginase withdrawal. To ascertain whether this reduction was due to the inhibition of SHBG synthesis, SHBG was measured by an immunoradiometric assay (IRMA) in the medium from human hepatoblastoma-derived cells, Hep G2 cells, grown in the absence or presence of graded amounts of the drug from 0.1 nM to 0.1 mM. The results showed a dose-dependent inhibition of SHBG synthesis, with a 50% reduction of SHBG in the medium, assayed by IRMA, using 250 nM L-asparaginase. Furthermore, a time-dependent inhibition was observed using a fixed concentration of the drug (50 nM) added for variable time intervals (1-4 days). These data suggest that the changes observed in vivo are likely due to the inhibitory effect exerted by the drug on SHBG synthesis. This action is not specific, but is part of a general effect at the hepatic level.

[j martini]

Very interesting subject, unfortunately it has left me totally confused.

On another note i will see continued gains with test when cycled for long periods all be it slow gains, but with other AAS deca for example after about 8-10 weeks i will see nothing.

[Pinnacle]

More from Nandi as my quest to find answers to the questions posed continues.......

Originally posted by Nandi
Although reported half-lives and production rates of the androgen receptor (AR) vary somewhat according to the cells examined, the values reported in the abstract below are fairly typical. In the absence of androgen the AR has a half-life of about 3 hours. This means that after 3 hours 50% of the androgen receptors initially present have been degraded and replaced with new androgen receptors. In the presence of ligand, the half life of the AR is extended to over 6 hours and the production rate of new AR was almost doubled.
Androgen receptors do not fill up. They are constantly being produced, enzymatically degraded, and replaced with new receptors.

J Biol Chem. 1985 Jan 10;260(1):455-61.
Mechanism of androgen-receptor augmentation. Analysis of receptor synthesis and degradation by the density-shift technique.
Syms AJ, Norris JS, Panko WB, Smith RG.
The ductus deferens smooth muscle tumor cell line (DDT1MF-2) contains receptors for, and is stimulated by, androgens. Cells cultured in the absence of androgens maintain a basal level of androgen receptors. Following incubation with various concentrations of the synthetic androgen methyltrienolone (R1881) for 1-6 h, the concentration of these receptors increased from 6.0 to 12.2 fmol/micrograms of DNA, while the equilibrium dissociation constant (Kd) of 0.5 nM for this steroid remained unchanged. The steroid-induced increase in androgen receptor levels was specific for androgens and dependent upon protein synthesis. The mechanism of receptor augmentation was examined by utilization of isotopically dense amino acids to determine rates of receptor appearance and degradation in the presence or absence of [3H]R1881. In the absence of androgens, the half-life of the androgen receptor was 3.1 h, with a rate constant (kD) of 0.22/h. In the presence of 1 nM [3H]R1881, however, the half-life was 6.6 h, with kD = 0.11/h. The rate constant for receptor synthesis (ks) in the absence or presence of [3H]R1881 was calculated to be 1.35 and 2.23 fmol/micrograms of DNA/h, respectively. Thus, androgen-induced androgen-receptor augmentation is explained by an increase both in receptor half-life and in rates of receptor synthesis.

[Pinnacle]

And more thoughts by Nandi.....

Originally posted by Nandi
You can read some of my speculations, based on published research, why gains seem to slow after a while here, in the article archives. There are many other posssible explanations as well, including Big Cat's. Another reason why bodybuilders just don't get infinitely large after years of AAS use is that there may be a limit to the ability of satellite cells to keep proliferating and contributing to muscle hypertrophy. The number of divisions a cell can undergo is finite (except for immortalized, cancerous cells) due to the fact that normal cells lack telomerase. Telomeres are sections of DNA that shorten each time a cell divides. Eventually the telomeres are "used up" and the cell can no longer divide. Telomerase replaces the telomeres allowing for continued cell division. Since anabolic steroids promote satellite cell proliferation, they may lead to the premature exhaustion of the ability of satellite cells to proliferate and contribute to hypertrophy. This is speculation; the real answer to your question is yet to be determined.
http://www.cuttingedgemuscle.com/For...ticle.php?id=8
Q: Often times you hear people talking about taking a break from taking steroids so their receptors can clean out otherwise their gains will come to a halt. Is there any truth to this?
A: Receptors are continually being degraded and remanufactured in cells, so they never really clog up and require cleaning. I think this is a sort of fanciful way of talking about receptor upregulation/downregulation, which is a complex topic. “Do gains slow because receptors downregulate (decrease in number and/or sensitivity) during a cycle?” is probably a more accurate way of posing the question. There are conflicting data in this regard. Short-term in vitro and in vivo studies generally show that androgens upregulate the androgen receptor (AR) in skeletal muscle. For example, in humans given 15 mg of oxandrolone daily for 5 days, the skeletal muscle AR density nearly doubled (13). When exposed to testosterone in vitro, skeletal muscle AR expression increased significantly (14).
In longer-term studies the picture is somewhat different. One study looked at AR expression in androgen treated sedentary rats vs nontreated exercised rats over 8 weeks. The androgen treated rats showed a decrease in the number of receptors, whereas the exercise trained rats showed an increase. (15) Unfortunately, the authors failed to address the question of interest to bodybuilders, and that would be the combined effects of exercise and androgen use on skeletal muscle AR regulation.
In long term studies in humans we get yet a different picture. In work conducted by Sheffield-Moore et. al., (16) older men were supplemented with testosterone so as to bring their testosterone levels into the mid to high physiological range. Androgen receptor expression had more than doubled after one month of treatment, yet by 6 months had returned to baseline. If this downregulation occurs when supraphysiological doses of testosterone are used, it could very well explain why gains tend to slow during a long cycle.
So, unfortunately the data are equivocal. The definitive experiment of combining supraphysiological AAS with resistance training and looking at AR regulation does not appear to have been carried out yet. Would exercise combined with AAS maintain increased AR expression, or would the addition of exercise serve to offset the AAS induced AR downregulation observed in the study by Bricout et al? Do the extremely high doses of AAS used by bodybuilders lead to more or less downregulation ( or even upregulation ) compared to what was seen by Sheffield-Moore et al? These are just a couple of questions that require further research, and could lead to answers on why exercise combined with AAS use is so much more productive than simply using steroids alone when it comes to building muscle mass.

[Pinnacle]

More by Nandi.....As i'm reading through all his posts and by others,it seems clear to me that receptors do not down regulate,but many factors come into play here.SHGB levels are clearly a culptrit as well as one needs to increase dosage.Also it's quite clear reading through his thougts/studies that it is neccesary to 'somewhat fool" your body by changing drug types from cycle to cycle.

The study below (which I think I've posted before) shows that testosterone and various AAS bind to and activate androgen responsive genes differently because the have different affinities to different gene promoters.
A gene which is androgen sensitive (like the gene for IGF-1 in muscle) consists in part of an exon, which actually codes for IGF-1, and one or more promoters, which are stretches of DNA upstream and downstream from the exon.
The steroid/receptor complex binds the so called "androgen response element" which is a part of the promoter region. This activates other transcription factors which detemine whether the gene will be transcribed (or repressed) and the rate of transcription.
There is no need to invoke non AR mediated actions for AAS. They may exist, but the varying effects of the different AAS are much more likely determined by which promoters they bind to and activate.
For instance, if a certain androgen suppressed hematopoiesis instead of stimulating it, all it means is most likely the androgen/receptor complex has bound to a promoter that represses transcription of the gene(s) responsible for red blood cell production.

J Steroid Biochem Mol Biol 2002 Nov;82(4-5):269-275

Anabolic steroids, testosterone-precursors and virilizing androgens induce distinct activation profiles of androgen responsive promoter constructs.
Holterhus PM, Piefke S, Hiort O.
Department of Pediatrics, Medical University of Lubeck, Lubeck, Germany
Different androgens, e.g. virilizing androgens such as testosterone and its precursors as well as synthetic anabolic steroids, respectively, induce diverse biological effects. The molecular basis for this variety in biological actions, however, is not well understood. We hypothesized that this variability of actions may be due to steroid-specific target gene expression profiles following androgen receptor (AR)-activation. Therefore, we investigated androgen receptor dependent transactivation of three structurally different androgen responsive promoter constructs ((ARE)(2)TATA-luc, MMTV-luc, GRE-OCT-luc) in co-transfected Chinese hamster ovary (CHO)-cells as an artificial model simulating different natural target genes. Three virilizing androgens (dihydrotestosterone, testosterone, methyltrienolone), three anabolic steroids (oxandrolone, stanozolol, nandrolone) and two testosterone-precursors of gonadal and adrenal origin (dehydroepiandrosterone, androstenedione) were used as ligands (0.001-100nM). All steroids proved to be potent activators of the AR. Remarkably, anabolic steroids and testosterone-precursors showed characteristic promoter activation profiles distinct from virilizing androgens with significantly lower (ARE)(2)TATA-luc activation. Hierarchical clustering based on similarity of activation profiles lead to a dendrogram with two major branches: first virilizing androgens, and second anabolics/testosterone-precursors. We conclude that steroid-specific differences in gene transcription profiles due to androgen receptor activation could contribute to differences in biological actions of androgens. [/B]

[Pinnacle]

By Karl Hoffman

ANABOLIC STEROIDS DOWNREGULATE THE ANDROGEN RECEPTOR

Or is it upregulate? It seems there are two schools of thought on this, with the answer probably lying somewhere in between. Short-term in vitro and in vivo studies generally show that androgens upregulate the androgen receptor (AR) in skeletal muscle. For example, in humans given 15 mg of oxandrolone daily for 5 days, the skeletal muscle AR density nearly doubled (15). When exposed to testosterone in vitro, skeletal muscle AR expression increased significantly (16).

In longer-term studies the picture is somewhat different. One study looked at AR expression in androgen treated sedentary rats vs nontreated exercised rats over 8 weeks. To quote from the abstract:

Results show that contractile muscular activity always increased the quantity of receptors whereas the steroid treatment decreased it. Thus for EDL (extensorum digitorum longus) and SOL (soleus) of control trained rats the quantity of receptors was 0.78 and 0.82 fmol/mg protein, respectively, compared to 0.23 and 0.43 fmol/mg protein for sedentary testosterone-treated rats. (17)

In long term studies in humans we get yet a different picture. In work conducted by Sheffield-Moore et. al., (18) older men were supplemented with testosterone so as to bring their testosterone levels into the mid-to-high physiological range. Androgen receptor expression had more than doubled after one month of treatment, yet by 6 months had returned to baseline. This pattern suggested to the authors that cycling androgen replacement much as bodybuilders cycle AAS might be a viable strategy:

This pattern of AR expression raises the possibility that cycling of testosterone administration could produce effects on skeletal muscle analogous to continuous administration. Such a paradigm would be beneficial by administering significantly less testosterone for similar anabolic outcomes, thus minimizing the possibility of side effects.

So despite the passion with which advocates of either AR upregulation or downregulation defend their positions, the research is equivocal. Would exercise combined with AAS maintain increased AR expression, or would the addition of exercise serve to offset the AAS induced AR downregulation observed in the study by Bricout et al? These are just a couple of questions that require further research, and could lead to answers on why exercise combined with AAS use is so much more productive than simply using steroids alone when it comes to building muscle mass.

(17) Bricout VA, Germain PS, Serrurier BD, Guezennec CY.Cell Mol Biol (Noisy-le-grand) 1994 May;40(3):291-4

(18) Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieberman SA, Tipton K, Wolfe RR, Urban RJ.
Am J Physiol Endocrinol Metab 2002 Mar;282(3):E601-7

[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

[arnold_of_malta]

ok !!! so if i want to cycle a cycle after a cycle say 12-16weeks on 4-6weeks of and agian 12-16 weeks on! what shall i do so i will keep on gaining????????

[Pinnacle]

ok !!! so if i want to cycle a cycle after a cycle say 12-16weeks on 4-6weeks of and agian 12-16 weeks on! what shall i do so i will keep on gaining????????

Change up compounds totally....use something to block elevated SHBG levels......and up your dose.....

This is the conclusion I've came to thus far with all this friggin' reading I've done.


~Pinnacle~

[Pinnacle]

Anyone else want in the discussion?

[BajanBastard]

first,real world evidence is no science.
and, i use 600 mg nandro and 600 mg boldelone weekly and i have normal levels of cholesterol (140).
and, i can post studies with nandro or test and the changes in cholesterol are minimal 5-10 %, only oxymetholone in studies (anadrol) produces more cholesterol 20 % (not too much, anyway)

Although 'real world' is "no science" it should never be discredited IMO. Trenbolone on paper is 5 times as anabolic and androgenic as testosterone. In the real world does tren make you 5 times stronger and 5 time bigger? Nope. Nandrolone and boldenone are not especially harsh on the blood lipid profile. Some studies even show that nandrolone is cholesterol friendly. If you were using a high dose of oral stanozolol I’m sure your cholesterol would not be as good as it is.

[Pinnacle]

Although 'real world' is "no science" it should never be discredited IMO.

I'm in agreement.One must look at both perspectives objectively.
There most certainly is a science behind all this(Bodybuilding),but one must look at real world results and learn to bring a correlation between the two worlds together as one.As the quest for the perfect physique(with in ourselves) treks forward.

~Pinnacle~

[oswaldosalcedo]

Although 'real world' is "no science" it should never be discredited IMO. Trenbolone on paper is 5 times as anabolic and androgenic as testosterone. In the real world does tren make you 5 times stronger and 5 time bigger? Nope. Nandrolone and boldenone are not especially harsh on the blood lipid profile. Some studies even show that nandrolone is cholesterol friendly. If you were using a high dose of oral stanozolol I’m sure your cholesterol would not be as good as it is.

now 1gr test and cholesterol levels ok. (myself)

what is real worl evidence?

loose especulation?

there is a lot of dogma and mith in bodibuilding.

-----------------------------------------------------------

research research..................

[BajanBastard]

now 1gr test and cholesterol levels ok. (myself)

what is real worl evidence?

loose especulation?

there is a lot of dogma and mith in bodibuilding.

-----------------------------------------------------------

research research..................

'Real world' evidence is BLT cholesterol levels after his cycle. I agree with what you're saying though, the science is the most important part. Just don't discredit experiences in the field altogether.

[oswaldosalcedo]

unfortnatly,this is when your genetics come into play.Arnold said BB is 60% diet,20% training and 20% AAS.Me ,you,we can play around with these factors,eat better,train harder,cycle harder,you cant with your genetics code.We can play around with this a bit with anabolics that produce hyperplasia.What did you gain on your last cycle? No need to show the cycle.I guess 8,is a good gain for you.No wonder you dont gain,doing a Dbol only....I wish that guy was right

goose4.......

deep truth.

[colie]

guys guys guys.... i think that u all r gettin a wee bit carried away with ur chemistry books here.....surely the main reason that a quickly started second cycle is not as effective as the previous, is that the body has much more muscle to sustain from the previous cycle and has not yet built the support systems(adequate blood supply in the form of capilaries/nervous system etc.) the body just hasnt yet gotten used to the new YOU. it just isnt ready to grow any more. thats my take anyhow...

[Pinnacle]

guys guys guys.... i think that u all r gettin a wee bit carried away with ur chemistry books here.....surely the main reason that a quickly started second cycle is not as effective as the previous, is that the body has much more muscle to sustain from the previous cycle and has not yet built the support systems(adequate blood supply in the form of capilaries/nervous system etc.) the body just hasnt yet gotten used to the new YOU. it just isnt ready to grow any more. thats my take anyhow...

So you're saying homeostasis is the only reason?

If that's the case,then upping you caloric intake would force your body to break out of the "set point".

~Pinnacle~

[BajanBastard]

guys guys guys.... i think that u all r gettin a wee bit carried away with ur chemistry books here.....surely the main reason that a quickly started second cycle is not as effective as the previous, is that the body has much more muscle to sustain from the previous cycle and has not yet built the support systems(adequate blood supply in the form of capilaries/nervous system etc.) the body just hasnt yet gotten used to the new YOU. it just isnt ready to grow any more. thats my take anyhow...

The latter part of your statement is correct. However we trying to determine WHY the body is not ready to grow more.

It does not work like that in fact. AAS promote RBC production, angiogenesis and motor neuron recruitment and replenishment.

[Drummerboy]

Change up compounds totally....use something to block elevated SHBG levels......and up your dose.....

This is the conclusion I've came to thus far with all this friggin' reading I've done.


~Pinnacle~

i thought i just read that elevated levels of shbg precedes an increase in test levels, and plays a role in getting natty test back up... ???