TweetBelow are explanations in regard to AR's up-regulation, down regulation, half lifes, etc.) by Nandi12 admin at CEM. IMO Nandi12 is likely the most brillant researcher and writer (see articles by Karl Hoffman) on these boards.



Nandi12
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.



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.

https://www.cuttingedgemuscle.com/Fo...rticle.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.

Tweetnice read