- 11-24-2008, 10:58 PM
So given that one needs increasing dosages of AAS to create the same effects as time passes, this must mean that the body is devloping tolerance to it.
I do have a few questions regarding that
1) how does this tolerance work? Is it the body's tolerance to the AAS itself, or simply because after a cycle, the body attins more muscle and hencem it is harder to gain more muscle WITH more mucle?
2) if one stops AAS usage for an extended period of time (say a year), KEEPS the msucle, and then begins anotehr cycle, would teh second cycle be as good as teh first?
3) if one stops AAS usage for an extended period of time (say a year), LOSES the msucle, and then begins anotehr cycle, would the second cycle be as good as the first?
4) if one's body devlopes tolerance, then wouldnt people who are on long term TRT feel the effects of their TRT decline over time?
- 11-25-2008, 02:52 AM
a lot of variables here.
genetic limit is one. once u pass ur genetic limit u basically have to stay on AAS to stay that size. gains, even on AAS, are hard to produce once passed ones limit. this is when most incorporate HGH.
many have done cycles of test only at moderate doses and still see great gains 10 cycles later at the same dose. this is mainly diet and goal dependent.
as long as u take an adequate break after PCT to allow ur body to recover etc. then gains on ur next cycle should be just as good as ur first.
11-25-2008, 03:05 AM
Whao ok hold on thats a lot of good stuff there.
The thing is, I am on TRT for good now, but only at 200mg/week. Durnig my 'on cycle' I want to stack it with 150mg more TNE per week.
When I go off cycle, and continue with the 200mg/wk TRT, would that be not giving my body a break or?
What I propose to do is this: cycle of 8-12 weeks. Off (still on TRT) for 4-6 weeks, then on again. Repeat until I believe my genetic potential is reached (I have trained for 7 years already, but not much progress due to low testsoterone that required me to seek TRT). WHen I say genetic poetntial, I mean stagnant gains no matter how smart or hard I train.
Does that sound 'ok'?
11-25-2008, 03:18 AM
have u every heard of "blasting" and "cruising"? what u want to do is basically that. except that u will NEVER need to run a PCT, which personally i think is nice.
what u have planned looks fine. what is TNE though?
11-25-2008, 03:40 AM
Do you mean that the main culprit is down-regulation of the androgen receptor? Because that's also not the case. Unlike clen and the adrenoreceptor, steroids actually up-reguate the androgen receptor.
11-25-2008, 04:01 AM
Blasting and cruising. O I like the sound of that. Cruise is to give teh body a break while preserving gained mass right?
TNE = testosterone no ester (test base, test suspension).
Yes receptor down regulation makes no sense also because if they are downregulated, then no matter how much yo increasse dosages, it shoudl not work, as theer are less recptors. Once a receptor is bound, it is bound, adding mroe will not make it bind 'more'.
I think it could possibly be beucase when you run cycle after cycle, you are taxing your msuckes. I think maybe it is the musckles themelsves that need a break, AAS or no AAS. Ofcourse,m thats just an airy assumption..
11-25-2008, 12:37 PM
i blast and cruise, it works but the constant pinning gets pretty annoying, and if i have to travel its a task to bring an amp or often much more with me. only had this problem one time, where i had to miss a pin for over a week due to a vacation which ended in me losing my sex drive at a very important time :P
11-25-2008, 01:22 PM
i think you must consider that the first time you do a cycle, you probably was less strong, smaller; so when you begin at 180 lb you put 15 lb (for example) but when you stay at 200 is more difficoult to put another 15. the same without Roids, in the first years with a normal diet and normal training you get result, than you must train more or eat better to improve. because you're reaching the limit.
the example you posted (like a man lose his muscle or not, in a couple of years, can't explain a lot, because even the other variable are changed, like receptor for example).
for what I know, the androgen receptor don't downregulate for the presence of Androgens, but probably bigger muscle need more androgen (if 10kg of muscle need 100 ng/l testo to survive, probably 50 kg muscle need 500ng/l testo)
11-25-2008, 02:46 PM
11-25-2008, 03:10 PM
"test susp (base) should be shot ED..."
Does this also apply if I am stacking it with test E shot twice weekly?
11-25-2008, 03:12 PM
11-25-2008, 03:24 PM
So if I ran phera at 45/60/60/45 right now, will I still be able to make gains on a later cycle with phera lets say at 15/30/30/45?
11-25-2008, 06:54 PM
A molecule of steroid binds to a receptor. Two receptors bind together to form a homodimer which then binds a "receptor" on DNA called a hormone response element. These response elements can either increase or decrease the expression of the genes that they regulate. So, for every nucleus (muscle cells are multinucleated) you have the genome of DNA and the "receptors" (HRE's) for the steroid-receptor complex. As you increase muscle size, you also increase the number of myonuclei and therefore, the body increases the number of androgen receptors to ensure that there is adequate stimulation per unit of DNA (so for example, you increase one unit of DNA and one unit of receptor but there is still a 1:1 ratio). This is the "upregulation" that a lot of papers mention. There is also another form of upregulation where the number of receptors per unit DNA is increased - this is true upregulation and occurs in the absence of androgen (for instance, castrated animals, women, and chemically castrated men). It is the bodies response to try to increase the likelihood of androgen receptor activation and The corollary also occurs, that is, the number of androgen receptors per unit DNA is decreased -- this occurs in response to androgenic stimulation. So, in the end, you could get an increase in the number of receptors but still have a net downregulation due to the ratio of androgen receptors to unit DNA actually being lower.
11-25-2008, 10:08 PM
I'd argue that what matters is the total number of androgen binding sites. Androgens increase the number of myonuclei in muscle fibers, which in turn increase the total number of androgen binding sites. This makes muscle more susceptible to androgens.
Keep in mind that an increase in myonuclei is not the only mechanism of action for AR upregulation. There's research showing that androgens also increase the half life of the androgen receptor. So not only is there an increase in de novo receptor synthesis, but existing receptors are stabilized.
11-25-2008, 10:15 PM
11-25-2008, 10:21 PM
11-25-2008, 10:35 PM
Reps.A molecule of steroid binds to a receptor. Two receptors bind together to form a homodimer which then binds a "receptor" on DNA called a hormone response element. These response elements can either increase or decrease the expression of the genes that they regulate. So, for every nucleus (muscle cells are multinucleated) you have the genome of DNA and the "receptors" (HRE's) for the steroid-receptor complex. As you increase muscle size, you also increase the number of myonuclei and therefore, the body increases the number of androgen receptors to ensure that there is adequate stimulation per unit of DNA (so for example, you increase one unit of DNA and one unit of receptor but there is still a 1:1 ratio). This is the "upregulation" that a lot of papers mention. There is also another form of upregulation where the number of receptors per unit DNA is increased - this is true upregulation and occurs in the absence of androgen (for instance, castrated animals, women, and chemically castrated men). It is the bodies response to try to increase the likelihood of androgen receptor activation and The corollary also occurs, that is, the number of androgen receptors per unit DNA is decreased -- this occurs in response to androgenic stimulation. So, in the end, you could get an increase in the number of receptors but still have a net downregulation due to the ratio of androgen receptors to unit DNA actually being lower.
If new nuclei are made and fuse with existing cells while those cells are down regulating the androgen receptor, wouldn't you just be breaking even in terms of net androgen receptor availability?With the addition of myonuclei, there might not be an increase of AR per unit DNA, but there would be an increase of AR per muscle fiber.
11-25-2008, 10:46 PM
There are plenty of other possible explanations for the apparent functional loss seen with extended steroid use. Receptor down-regulation is simply not one of them.
11-25-2008, 10:48 PM
11-25-2008, 11:02 PM
If you want to talk about the apparent reduction in general androgen effectiveness, there's definitely more to it than reduced androgen functionality. You need to address antecedant issues that affect androgen availability, such as metabolization by aromatase and 5-alpha-reductase, binding to SHBG, etc.
11-25-2008, 11:13 PM
11-25-2008, 11:20 PM
11-25-2008, 11:31 PM
11-26-2008, 07:55 AM
In their cellular assays they are using GAPDH as a single housekeeping gene. It is well know that you must use more than one housekeeping gene (usually people use three), particularly with nuclear hormones because they can activate many of these so-called housekeeping genes and change their expression. Even using this flawed method in a culture of almost pure staellite cells, they only saw a smal lincrease in AR quantity that was only significant at the 0.05 level and only with DHT, not testosterone.
The sad part is, a lot of papers say upregulation when they are really speaking about nuclear enrichment. The way that you state that upregulation is accepted fact smacks of bro-lore. There is some contention surrounding this topic among some of the best minds in nuclear hormone physiology (even though the experts that write textbooks agree with downreguation) but the bros on the boards have it all figured out. Just because you have a calculator does not make you a mathematician.
11-26-2008, 02:51 PM
The test base is not part of the HRT, only the 200mg/wk of test E is.
The test base is soemthing I added in personally as I figured the HRT dosage is not enough for a true cycle.
As for peaks and valleys, it is actually ok so far because I shoot test E twice a week (once per week indeed does suck towards then end of the week)
The test base I use as a 'booster' b4 work outs.
So no one here thinks that that is a good idea?
11-26-2008, 07:09 PM
Here's a compilation of references that I put together. You've probably already seen it. I could be wrong, but with so many papers saying the same thing, it doesn't sound like bro-lore to me:
This 1992 study (the full text is free), entitled "Androgen Receptor Phosphorylation, Turnover, Nuclear Transport, and Transcriptional Activation" concluded:This 1996 study (the full text is free), entitled "Testosterone Up-Regulates Androgen Receptors... of Porcine Myogenic Satellite Cells in Vitro" concluded:Androgen increased the amount of AR [androgen receptor] phosphorylation simply by slowing the rate of degradation of the AR protein. AR stabilization by androgen was observed previously in binding studies on tissue cytosols (34). Moreover, in a ductus deferens smooth muscle tumor cell line, endogenous AR stabilization increased about 2-fold with androgen, from t1/2 3.1 h without androgen to t1/2 6.6 h with R1881 (55). The mechanism of receptor stabilization by androgen is not known but the striking specificity for androgen suggests it may be closely linked with receptor functional activity. Although other groups have reported on steroidinduced phosphorylation of AR (25) and the glucocorticoid and progesterone receptors (21-24), no androgen-dependent enhancement of recombinant AR phosphorylation was detected in the present study. While the AR is clearly a phosphoprotein, the specific role of phosphorylation in receptor function is unclear. AR sites of phosphorylation are currently being mapped, and it is conceivable that androgen binding may increase phosphorylation of a single site not detectable in our assay system.This 1999 paper, entitled "Effects of anabolic steroids on the muscle cells of strength-trained athletes" stated:In summary, we demonstrate that cultured satellite cells and myotubes possess AR [androgen receptors], which are up-regulated in response to testosterone.This 1999 study (free text), entitled "Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles" spoke to bodybuilders saying:Enhanced satellite cells stimulation would provide more nuclei to the muscle fibers. Because androgen receptors are located in the myonucleus (23,38,47), the increased nuclear number would also give rise to an elevation of the number of androgen binding sites, thus making the muscle more susceptible to the anabolic compounds.In this 2004 study (free full text), the title says it all: "Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment". They concluded:DHT administration to the castrated group upregulated AR levels in the bulbocavernosus and levator ani muscles.
It is intriguing to speculate that the upregulation of AR levels via the administration of pharmacological amounts of androgens might convert some muscles that normally have a minor or no response to muscles with enhanced androgen responsiveness.
Because athletes may self administer synthetic androgens for many months or years at even higher doses than used in this study (17), it is possible that upregulation of AR levels might be an important part in the anabolic effects of androgen abuse.And finally, this 2005 paper (free full text), entitled "Androgen regulation of satellite cell function" couldn't have made it any more explicit:In summary, although multiple cell types within the human skeletal muscle express AR protein, satellite cells, and myonuclei are the predominant sites of AR expression. ARs aggregate within the nucleoli of satellite cells and myonuclei. Testosterone and DHT up-regulate AR expression in vivo and in vitro.Increase in AR levels: Up-regulation of AR levels is one of the documented responses to androgens in target tissues or organs. Up-regulation of AR levels by androgen treatment in skeletal muscle has been observed in rat and human (Antonio et al. 1999, Kadi et al. 2000, Lee et al. 2003). The auto-regulation of AR levels by androgens may occur through stabilizing existing receptors or by increasing de novo receptor synthesis (Kadi et al. 2000). Up-regulation of AR levels by androgens could be one mechanism by which androgens have effects on muscle.
The increase in AR levels with androgen treatment has been demonstrated in satellite cells in pig (Doumit et al. 1996). This study clearly demonstrated the presence and auto-regulation of AR in satellite cells and also myotubes. Immunoblot analysis revealed that AR expression in satellite cells and myotubes was up-regulated in response to testosterone. Moreover, immunocytochemical staining for AR was more intense in the nuclei of satellite cells and myotubes from androgen-treated cells. Because the AR is
located in the myonucleus, the increased nuclear number could potentially give rise to an elevation in the number of androgen binding sites (Kadi et al. 1999). Taken together, these data suggest that androgens may have effects on satellite cells through up-regulation of AR levels in satellite cells, which could enhance the sensitivity of satellite cells to androgens.
11-26-2008, 09:05 PM
As far as my evidence for downregulation:
Goodman and Gilman's The Pharmacological Basis of Therapeutics 10th edition ("the bible" to pharmacologists) pg 36 states "Continued stimulation of cells with agonists generally results in a state of desensitization (also referred to as refractoriness or down-regulation), such that the effect that follows continued or subsequent exposure to the same concentration is diminished.
Androgen deprivation causes up-regulation of androgen receptor transcript in the rat prostate.
Kumar VL, Majumder PK, Kumar V.
Mol Cell Biochem. 1997 Jun;171(1-2):133-8.
In this paper adrogen deprivation is shown to cause up-regulation of the androgen receptor. Granted, this is in the prostate but it is in line with the standard theory put forth by Goodman and Gilman. Agonists down-regulate and therefore antagonsits up-regulate.
further support along these lines:
The rat androgen receptor: primary structure, autoregulation of its messenger ribonucleic acid, and immunocytochemical localization of the receptor protein.
Tan JA, Joseph DR, Quarmby VE, Lubahn DB, Sar M, French FS, Wilson EM.
Mol Endocrinol. 1988 Dec;2(12):1276-85.
This paper shows the same result in 6 different tissues. Upregulation with androgen deprivation, downregulation with agonist.
Autologous down-regulation of androgen receptor messenger ribonucleic acid.
Quarmby VE, Yarbrough WG, Lubahn DB, French FS, Wilson EM.
Mol Endocrinol. 1990 Jan;4(1):22-8.
Another paper supporting this pattern:
Regulation of androgen receptor protein and mRNA concentrations by androgens in rat ventral prostate and seminal vesicles and in human hepatoma cells.
Shan LX, Rodriguez MC, Jšnne OA.
Mol Endocrinol. 1990 Nov;4(11):1636-46.
An abstract showing downregulation to be the standrad model:
Mol Cell Endocrinol. 1995 Dec 29;115(2):177-86. Links
Androgen and glucocorticoid regulation of androgen receptor cDNA expression.Burnstein KL, Maiorino CA, Dai JL, Cameron DJ.
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, FL 33101, USA.
Androgen receptor (AR) levels are regulated by androgens, other steroids and non-steroidal hormones via complex, tissue-specific processes. Since alterations in receptor levels may influence cellular sensitivity to androgens, understanding AR regulation is of fundamental and potentially therapeutic significance. In most target tissues and AR-containing cell lines, AR mRNA is down-regulated in response to androgens. We have reconstituted this androgen-mediated down-regulation of AR mRNA in COS 1 cells transfected with a human AR cDNA under the control of the cytomegalovirus (CMV) promoter. The sequences mediating receptor mRNA down-regulation are represented within the AR cDNA and not within the CMV promoter. Androgenic down-regulation of AR cDNA expression was time- and dose-dependent, resembling native AR mRNA down-regulation. In addition, androgenic regulation of the receptor cDNA was not dependent on protein synthesis suggesting that AR and/or another pre-existing protein(s) is involved in this process. In COS 1 cells co-transfected with androgen and glucocorticoid receptor cDNAs, dexamethasone mimicked the action of androgen in down-regulating AR mRNA. This response depended on glucocorticoid receptors. Androgen had little effect on steady-state levels of AR protein consistent with reports that androgen down-regulates AR mRNA but increases AR protein half-life (Kemppainen et al. (1992) J. Biol. Chem. 267, 968-974; Zhou et al. (1995) Mol. Endocrinol. 9, 208-218). However, glucocorticoids decreased AR protein levels in cells that co-expressed androgen and glucocorticoid receptors. These results indicate that sequences represented in the AR cDNA mediate AR mRNA down-regulation by both androgens and glucocorticoids. Inhibition of AR mRNA and protein by glucocorticoids suggests that these steroids may modulate androgen action in tissues, such as mammary gland and prostate, which express both androgen and glucocorticoid receptors.
PMID: 8824893 [PubMed - indexed for MEDLINE]
This is a case of established science going up against established myth. Unfortunately, upregulation flys in the face of standard receptor theory and logic.
11-26-2008, 09:22 PM
Along these lines, it has been well-established that the anabolic response in skeletal muscles is correlated with androgen receptor quantity. So, when you say that androgens up-regulate the androgen receptor then you are saying that the muscle actually becomes more responsive to androgens which is in direct opposition to what we know to be true, that is that the responsiveness to androgens decreases with androgenic stimulation.
12-02-2008, 11:25 PM
I hope you realize that your "evidence" of down-regulation is incredibly weak. You present an argument of inductive syllogism: since "Continued stimulation of cells with agonists generally results in a state of desensitization," therefore, it's likely that continued stimulation of the AR with androgens results in AR down-regulation. However, the syllogism is crushed when you consider other relevant information, namely, the fact that numerous studies in human cells, both in vitro and in vivo, show AR upregulation. Just because receptors "generally" down-regulate in response to continued agonism does not mean that there are not exceptions. Androgens, nicotine, and the interleukins have been shown to up-regulate their own receptor. To ignore that and to point to a generalization is to present a very week inductive syllogism.
Do you realize that every paper you posted was rat research looking at AR mRNA levels? The fact that androgen deprivation has been shown to up-regulate androgen receptor mRNA in rats is of little consequence. First of all, how about a study in humans, in vivo? Here, just 5 days of anavar administration "significantly increased mRNA concentrations of skeletal muscle AR". Second, you're being short-sighted by looking at AR mRNA while ignoring actual AR density (which is what we're arguing about). There can be down-regulation of AR mRNA while there's up-regulation of the receptor itself. And that's exactly what a nice 2008 review on androgens in humans explained:
AR expression itself is regulated at both the mRNA and protein levels by androgens (Lee and Chang 2002). Androgens predominantly decrease AR mRNA at the transcriptional level (Trapman et al 1990; Krongrad et al 1991) however, they simultaneously increase AR stability and translational efficiency thereby even in the presence of decreased AR mRNA levels, androgens increase AR protein levels in most cell types (Yeap et al 1999).
Do you have even one reference in humans showing that androgens down-regulate the AR itself? In contrast to the several, recent papers with explicit statements of receptor protein up-regulation in humans, you provided only a generalization on receptor function and a bunch of rat research looking at mRNA levels. This is not a case of "established science going up against established myth." It's a case of established science going against a weak inductive syllogism and a myopic look at mRNA animal research.
12-02-2008, 11:36 PM
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