Do Androgen Receptors Downregulate When on Cycle?

[eazy]

CLIFFS

Over time the exposure to anabolics does result in a decreased response. the biological base to that isn't the receptor getting downregulated it's much more technical.

It's not you reach this cap and you're not growing anymore because there's a downregulation of androgen receptors, it's myostatin or whatever unknown regulatory factors.

Androgen receptors upregulate to occupy the dose that's being taken.

There will be a point where there is going to be a plateau and it's not because the drugs are at fault it's probably more than likely training, recovery, nutrition, or a level of genetic influence on myostatin, "basically going okay there's a lot of muscle tissue having been put on here" there's a genomic influence there to stop you from putting on more and more and more metabolically active muscle tissue.

when someone hits a plateau we rule out training, nutrition, and recovery as the cause because they are optimal. At this point, you have to increase the dose of androgens in order to increase the androgen receptors to allow more genomic expression.

There is a level of genetic downregulation that happens when you reach that ceiling where the cell is not growing anymore when you lower your exposure to androgens you're lowering that protein synthesis or nitrogen retention and back off from that cellular protective aspect that's when you go back on again and or you increase your dose again where you drive more androgen receptors to force more genomic expression and you start growing again.

Don't fall into the trap of trying to bully more muscle tissue on by going much higher with dosage rather than understanding that there's some biological safety mechanism. Backing off here will probably be better for you, take one step back to take two steps forward. Just because you've doubled the dose or doubled the action at the AR doesn't mean twice the growth.

 

[eazy]

CREDIT TO VISION.
REPOSTED WITH PERMISSION.



Androgen receptor down-regulation is simply not true!

Recently I've seen a few questions or concerns regarding AR (androgen receptors) site saturation.. Let me start off by stressing this, it's a myth that has been regurgitated over the years, it simply does NOT exist. In fact AR's do NOT down regulate, there's no such thing as receptor down-regulation (pertaining to AAS usage) in fact with the presence of AAS/Androgens concerning a supraphysiological level they will up-regulate, increasing, and constantly expressing new AR sites THROUGH OUT THE BODY AND TISSUE!.. (However, there is 2-3 culprits that will hinder ones gains when ON cycle, fueling the myth of AR site saturation.."1-Progesterone 2-Mysostatin, 3- and at times E1/E2 estro" but we'll get to that later)

About the AR

The AR gene principals are to provide instructions for creating proteins called "androgen receptors".. As we all know, Andro's are hormones and the first one that comes to mind is? That's right, the king, Testosterone...AR's allow the body to react/respond accordingly to these hormones allowing them to preform their direct action (sexual development, muscle growth and recovery, as well as other strong male sexual characteristics and growth and development)..Receptors are found present throughout the body/tissue.. This is where they attach/bind to androgens resulting in AR complex binding to DNA in which regulates the activity of AR genes.. DNA is the only thing that can turn the GENE off/on if necessary, NOT AAS!

FYI- AR's belong to a family of genes known as NR (nuclear hormone receptors), which are proteins that are found within cells that are responsible for sensing steroid hormones, and also play a pivotal role with homeostasis, which finds balance in the endocrine!

Why do my gains seem to diminish after 10-14 weeks?
This study below can explain why our gains tend to become stagnate,or slow down when using Test, deca/primo..
( IMO this is the ideal time to add an oral such as Dbol, drol, Tbol, Winny, or Var, which predominantly work as a non AR mediated mechanism,
unlike Testosterone, Deca, Primo.. As these agents express differentiation of the satellite cells of the muscle, maturing muscle cells, thus this is independent of ARs)

Mol Cell Endocrinol. 2009 Apr 10;302(1):26-32. doi: 10.1016/j.mce.2008.12.019. Epub 2009 Jan 21.Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration.

Abstract

Methodological problems, including binding of myostatin to plasma proteins and cross-reactivity of assay reagents with other proteins, have confounded myostatin measurements. Here we describe development of an accurate assay for measuring myostatin concentrations in humans. Monoclonal antibodies that bind to distinct regions of myostatin served as capture and detector antibodies in a sandwich ELISA that used acid treatment to dissociate myostatin from binding proteins. Serum from myostatin-deficient Belgian Blue cattle was used as matrix and recombinant human myostatin as standard. The quantitative range was 0.15-37.50 ng/mL. Intra- and inter-assay CVs in low, mid, and high range were 4.1%, 4.7%, and 7.2%, and 3.9%, 1.6%, and 5.2%, respectively. Myostatin protein was undetectable in sera of Belgian Blue cattle and myostatin knockout mice. Recovery in spiked sera approximated 100%. ActRIIB-Fc or anti-myostatin antibody MYO-029 had no effect on myostatin measurements when assayed at pH 2.5. Myostatin levels were higher in young than older men (mean+/-S.E.M. 8.0+/-0.3 ng/mL vs. 7.0+/-0.4 ng/mL, P=0.03). In men treated with graded doses of testosterone, myostatin levels were significantly higher on day 56 than baseline in both young and older men; changes in myostatin levels were significantly correlated with changes in total and free testosterone in young men. Myostatin levels were not significantly associated with lean body mass in either young or older men.

CONCLUSION:

Myostatin ELISA has the characteristics of a valid assay: nearly 100% recovery, excellent precision, accuracy, and sufficient sensitivity to enable measurement of myostatin concentrations in men and women.
Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration. - PubMed - NCBI

Progestin and AR's

Progesterone has powerful antiadrogenis effect in humans at sufficient levels,capable of decreasing circulating androgens,and estrogen concentraions to castrate levels on both sexes and significantly lowering the expression of the androgen receptor (AR), and the estrogen receptor - (which posses a pivotal in homeostasis/balance and growth)..

Testosterone and up-regulation!

Testosterone up-regulates androgen receptors and decreases differentiation of porcine myogenic satellite cells in vitro.

Abstract

Accumulation of DNA is essential for muscle growth, yet mechanisms of androgen-induced DNA accretion in skeletal muscle are unclear. The purpose of this study was to determine whether androgen receptors (AR) are present in cultured skeletal muscle satellite cells and myotubes and examine the effects of testosterone on satellite cell proliferation and differentiation. Immunoblot analysis using polyclonal AR antibodies (PG-21) revealed an immunoreactive AR protein of approximately 107 kDa in porcine satellite cells and myotubes. Immunocytochemical AR staining was confined to the nuclei of satellite cells, myotubes, and muscle-derived fibroblasts. Administration of 10(-7) M testosterone to satellite cells, myotubes, and muscle-derived fibroblasts increased immunoreactive AR. In satellite cells and myotubes, AR increased incrementally after 6, 12, and 24 h of exposure to testosterone. Testosterone (10(-10) - 10(-6) M), alone or in combination with insulin-like growth factor I, basic fibroblast growth factor, or platelet-derived growth factor-BB, had no effect (P > 0.01) on porcine satellite cell proliferation, and testosterone pretreatment for 24 h did not alter the subsequent responsiveness of cells to these growth factors. Satellite cell differentiation was depressed (20-30%) on days 2-4 of treatment with 10(-7) M testosterone. This effect was not reversible within 48 h after treatment withdrawal and replacement with control medium. These data indicate that satellite cells are direct targets for androgen action, and testosterone administration increases immunoreactive AR protein and reduces differentiation of porcine satellite cells in vitro.
Testosterone up-regulates androgen receptors and decreases differentiation of porcine myogenic satellite cells in vitro. - PubMed - NCBI

Androgen receptor in rat skeletal muscle: characterization and physiological variations.

Abstract

Androgen binding has been studied in the quadriceps femoris of recently castrated adult and intact immature male and female rats using a variety of techniques for separating and measuring hormone-receptor complexes. [3H]Testosterone, [3H]androstanolone (or 5 alpha-dihydrotestosterone). [3H]methyltrienolone (a potent synthetic androgen), and [3H]estradiol bind to the androgen receptor. Affinities are identical for the first two hormones (Kd = approximately 70 pM) and lower for estradiol (Kd = approximately 0.2 nM), as determined by Scatchard plots of binding data. Competition experiments indicate that in addition to the nonradioactive steroids corresponding to the above-cited tritiated compounds, progesterone, cyproterone acetate (an antiandrogen), and spironolactone compete for [3H]androgen binding by the receptor, but diethylstilbestrol, moxestrol (a potent synthetic steroidal estrogen), and cortisol do not. 3 alpha- and 3 beta-androstanediols slightly inhibit testosterone binding. Therefore, striated muscle androgen receptor specificity is identical to that of all androgen receptors of target tissues which have been previously studied. Binding is abolished by pronase and heat treatment, and displays an approximate 7S sedimentation coefficient in low salt ultracentrifugation gradient analysis. Preliminary observations suggest hormone-induced receptor translocation into the nucleus. No evidence has been found for an independent estrogen receptor. In the course of the binding experiments, extensive metabolism of androstanoloe and testosterone was observed in muscle cytosol at 0-4 C, during the 2-h incubation period used for most binding studies. Metabolite formation can jeopardize the binding data, specifically altering the significance of competition experiments with relatively high concentrations of steroids approaching the Km of metabolizing enzymes. Therefore, most quantitative studies were performed in enzyme-free, receptor-containing cytosol preparations. In adult male rats castrated for 2 days, the concentration of receptor in the cytosol was of the order of 1 fmol/mg protein and corresponded to 72 fmol/mg tissue DNA (that is, 100 and 20 times less than that in corresponding prostatic cytosol, respectively). In the adult female rat 2 days after castration, the concentration of receptor in the cytosol was 0.34 fmol/mg protein. Treatment with testosterone pellets (20 mg for 15 days) increased androgen receptor concentration significantly. In spite of the relatively low concentration of androgen-binding sites, the typical binding specificity of the androgen receptor and the regulatory effects of androgens on their own receptor support the possibility that some effect(s) of androgens upon skeletal muscles may be initiated directly at the cellular level through this receptor, a concept which is also in agreement with recently demonstrated in vitro effects of androgens on cultured myoblasts.
Androgen receptor in rat skeletal muscle: characterization and physiological variations. - PubMed - NCBI

Steroid receptor phosphorylation: a key modulator of multiple receptor functions.

Abstract

Steroid receptors are hormone-activated transcription factors, the expression and activities of which are also highly dependent upon posttranslational modifications including phosphorylation. The remarkable number of phosphorylation sites in these receptors and the wide variety of kinases participating in their phosphorylation facilitate integration between cell-signaling pathways and steroid receptor action. Sites have been identified in all of the functional domains although the sites are predominantly in the amino-terminal portions of the receptors. Regulation of function is receptor specific, site specific, and often dependent upon activation of a specific cell-signaling pathway. This complexity explains, in part, the early difficulties in identifying roles for phosphorylation in receptor function. With increased availability of phosphorylation site-specific antibodies and better means to measure receptor activities, numerous roles for site-specific phosphorylation have been identified including sensitivity of response to hormone, DNA binding, expression, stability, subcellular localization, and protein-protein interactions that determine the level of regulation of specific target genes. This review summarizes current knowledge regarding receptor phosphorylation and regulation of function. As functional assays become more sophisticated, it is likely that additional roles for phosphorylation in receptor function will be identified.

Pharmacological doses of testosterone upregulated androgen receptor and 3-Beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase and impaired leydig cells steroidogenesis in adult rats.

Abstract

Anabolic androgenic steroids (AAS) are testosterone derivatives originally designed to enhance muscular mass and used for the treatment of many clinical conditions as well as in contraception. Despite popular interest and abuse, we still lack a broad understanding of effects of AAS on synthesis of steroid hormones on the molecular level. This study was designed to systematically analyze the effects of pharmacological/high doses of testosterone on steroidogenic machinery in Leydig cells. Two different experimental approaches were used: (1) In vivo experiment on groups of adult male rats treated with testosterone for 1 day, 2 weeks, and 2 months; (2) Direct in vitro testosterone treatment of Leydig cells isolated from intact rats. Result showed that prolonged in vivo treatment with testosterone decreased the expression of Scarb1 (scavenger receptor class B type 1), Tspo (translocator protein), Star (steroidogenic acute regulatory protein), Cyp11a1 (cholesterol side-chain cleavage enzyme), and Cyp17a1 (17α-hydroxylase/17, 20 lyase) in Leydig cells. Oppositely, the expression of Hsd3b (3-beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase), Ar (androgen receptor), and Pde4a/b (cyclic adenosine monophosphate-dependent phosphodiesterases) was increased. Androgenization for 2 weeks inhibited Cyp19 (aromatase) transcription, whereas 2-month exposure caused the opposite effect. Direct in vitro testosterone treatment also decreased the expression of Cyp11a1, Cyp17a1, and Cyp19a1, whereas Hsd3b was upregulated. The results of expression analysis were supported by declined steroidogenic capacity and activity of Leydig cells, although conversion of pregnenolone to progesterone was stimulated. The upregulation of AR and 3βHSD in testosterone-impaired Leydig cells steroidogenesis could be the possible mechanism that maintain and prevent loss of steroidogenic function.

Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment

Abstract

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.
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Memorandum from Dr Henning Wackerhage and Dr Aivaras Ratkevicius, School of Medical Sciences, College of Life Sciences & Medicine, University of Aberdeen

ANTI-MYOSTATIN DRUGS: THE NEW ANABOLIC STEROIDS?

1. Myostatin function
Myostatin is a key regulator of muscle mass: it is a peptide that potently inhibits muscle growth. Experimental myostatin knockout in mice or some natural mutations of the myostatin gene increase muscle mass dramatically in mice, cattle and human beings. The case of a boy with twice the normal muscle mass due to a "natural" myostatin mutation was reported widely.

2. Anti-myostatin drugs
Muscle wasting is a problem in a wide variety of conditions that include normal ageing, HIV/AIDS and some forms of cancer. Anti-myostatin therapy seems suitable for many of these conditions. Myostatin is an "easy" drug target because it can be targeted extracellularly, acts tissue specific and because endogenous inhibitors can be mimicked. It is also a commercially attractive drug target because it is suitable for the prevention of muscle wasting in the whole elderly population. This could be a crucial intervention leading to greater independence in ageing Western societies.

3. Current drug development
Wyeth are currently testing the effectiveness of a monoclonal anti-myostatin antibody (MYO-029) on patients with facioscapulohumeral muscular dystrophy (FSHD), Becker muscular dystrophy (BMD) and limb-girdle muscular dystrophy (LGMD). Results are expected for late 2006. Thus it seems likely that anti-myostatin drugs will become available well before the 2012 London Olympics. Bogus anti-myostatin treatments (Myozap) are commercially available showing the desire of bodybuilders and others to achieve muscle growth by inhibiting myostatin.

4. Likelihood of abuse and dangers
Many doping scandals are linked to bodybuilders or strength/power athletes taking agents that aim to increase muscle mass. Thus muscle growth-promoting myostatin inhibitors are likely to be (ab-) used once they become available. At the same time myostatin inhibitors are probably safer than anabolic steroids because myostatin action is muscle specific whereas anabolic steroid affect many organs other than muscle. Anti-myostatin drugs are likely to be the new anabolic steroids.

5. Challenges for drug testers
Monoclonal antibodies (ie the anti-myostatin treatment currently tested) is a new kind of doping agent. It should be easy to detect these antibodies in blood because they are raised in another species. However we are unsure whether such antibodies or their degradation products can be detected in urine. It is, however, likely that future myostatin treatments will not be limited to monoclonal antibodies. There is a series of papers reporting the existence of endogenously produced myostatin-inhibiting peptides. These are nature's models for anti-myostatin therapy and it seems likely that pharmaceutical companies or others will attempt to copy these. Myostatin-inhibiting compounds might be detected by screening libraries of chemical compounds.

6. Executive summary
Myostatin inhibitors are likely to become available well before the 2012 Olympic Games in London. There is little doubt that they will be abused by bodybuilders and other strength/power athletes. Myostatin inhibitors are likely to be safer than anabolic steroids, growth hormone and clenbuterol which are drugs currently used to attempt to increase muscle mass. If monoclonal anti-myostatin antibodies are used to inhibit myostatin then the detection in blood should be easy but it is unclear whether the detection in urine is feasible. Research is needed to develop urine-based detection methods.

ADDITIONAL INFORMATION

The potential for different HETs, including drugs, genetic modification and technological devices, to be used legally or otherwise for enhancing sporting performance, now and in the future

I wish to comment on the likelihood that new HETs will be developed and used in sport. Currently molecular biologists and sports and exercise scientists discover at new mechanisms and genetic variations that regulate factors such as muscle growth, capillarity, oxygen transport capacity, energy metabolism and heart growth. Mechanistic knowledge allows us to understand how physical training induces adaptations. It is also crucial knowledge for developing treatments (or HETs) that target these mechanisms for therapeutic aims. For example, the discovery of erythropoietin (EPO) laid the foundation for the synthesis of this hormone. Synthetic EPO can be used to increase red blood cell production in patients with low red blood cell count and in endurance athletes where it increases oxygen transport capacity. The discovery of the muscle growth inhibitor myostatin triggered the development of monoclonal antibodies against myostatin. These can potentially be used to increase muscle mass in > 75 year olds or in strength athletes. Novel HETs are likely to be developed especially for mechanisms that can be targeted extracellularly (both EPO and myostatin can be targeted extracellularly). In my opinion serious genetic manipulation of athletes is unlikely to be attempted before 2012 because it is technically difficult and the type of desired and side effects are unclear. To conclude it seems likely that novel HETs will be developed and used by athletes before the London 2012 Olympics.

Steps that could be taken to minimize the use of illegal HETs at the 2012 Olympics

I don't have any new ideas to contribute.

The case, both scientific and ethical, for allowing the use of different HETs in sport and the role of the public, Government and Parliament in influencing the regulatory framework for the use of HETs in sport

Without being a legal expert I feel that there is a case for a strong legal deterrent against using the most dangerous doping agents such as EPO. Seven elite cyclists died of sudden cardiac death between 2003 and 2004 alone (The Observer, Sunday 7 March 2004) and it seems very likely if not obvious that most if not all of these deaths are related to the use of EPO or related agents. Thus, government may wish to consider strengthening the law to try to prevent the use of such agents by athletes.

For all other agents I feel that the anti-doping policies by most sporting associations are adequate. The government and parliament should consider lobbying for removing sports from the Olympic programme that do not sufficiently control doping.

The state of the UK research and skills base underpinning the development of new HETs, and technologies to facilitate their detection
Sports and exercise research is probably less well funded in the UK than in the US or Scandinavia. There are several researchers [Goldspink, Harridge, Montgomery (London), Wagenmakers (Birmingham), Rennie, Greenhaff (Derby/Nottingham). Harris (Chichester), Maughan (Loughborough) and Baar, Sakamoto, Hardie (Dundee)] that make important contributions to the discovery of exercise mechanisms and genetic variations that are related to performance, therapies and HET development. Additional financial support for such research is desirable.

It is unfortunate that the practical skills (ie biochemical, molecular biology and genetic techniques) necessary for mechanistic exercise research are not often taught as part of sports and exercise science degrees. At Aberdeen we have thus decided to develop a MSc in Molecular Exercise Physiology where hands on training in such techniques is a key component. It is desirable that such skills are also developed as part of other sports and exercise science programmes.

The great challenge for HET detection is the detection of HETs or their degradation products in urine unless blood samples are taken. Some new classes of HETs (for example antibodies) require novel approaches for their detection in urine which may be difficult.

Follistatin

Follistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene.[SUP][1][/SUP][SUP][2][/SUP] Follistatin is an autocrineglycoprotein that is expressed in nearly all tissues of higher animals.[SUP][2][/SUP]
Its primary function is the binding and bioneutralization of members of the TGF-β superfamily, with a particular focus on activin, a paracrine hormone.
An earlier name for the same protein was FSH-suppressing protein (FSP). At the time of its initial isolation from follicular fluid, it was found to inhibit the anterior pituitary's secretion of follicle-stimulating hormone(FSH).

Biochemistry

Follistatin is part of the inhibin-activin-follistatin axis.
Currently there are three reported isoforms, FS-288, FS-300, and FS-315. Two, FS-288 and FS-315, are known to be created by alternative splicing of the primary mRNA transcript. FS-300 (porcine follistatin) is thought to be the product of posttranslational modification via truncation of the C-terminal domain from the primary amino-acid chain.
Although FS is ubiquitous its highest concentration has been found to be in the female ovary, followed by the skin.
The activin-binding protein follistatin is produced by folliculostellate (FS) cells of the anterior pituitary. FS cells make numerous contacts with the classical endocrine cells of the anterior pituitary including gonadotrophs.
In the tissues activin has a strong role in cellular proliferation, thereby making follistatin the safeguard against uncontrolled cellular proliferation and also allowing it to function as an instrument of cellular differentiation. Both of these roles are vital in tissue rebuilding and repair, and may account for follistatin's high presence in the skin.
In the blood, activin and follistatin are both known to be involved in the inflammatory response following tissue injury or pathogenic incursion. The source of follistatin in circulating blood plasma has yet to be determined, but due to its autocrine nature speculation suggests the endothelial cellslining all blood vessels, or the macrophages and monocytes also circulating within the whole blood, may be sources.
Follistatin is involved in the development of the embryo. It has inhibitory action on bone morphogenic proteins (BMPs); BMPs induce the ectoderm to become epidermal ectoderm. Inhibition of BMPs allows neuroectoderm to arise from ectoderm, a process which eventually forms the neural plate. Other inhibitors involved in this process are noggin and chordin.
Follistatin and BMPs are also known to play a role in folliculogenesis within the ovary. The main role of follistatin in the oestrus/menstrus ovary, so far, appears to be progression of the follicle from early antral to antral/dominant, and importantly the promotion of cellular differentiation of the estrogen producing granulosa cells (GC) of the dominant follicle into the progesterone producing large lutein cells(LLC) of the corpus luteum.

Clinical significance

Follistatin is being studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin(also known as GDF-8, a TGF superfamily member) which inhibitsexcessive muscle growth. Lee & McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in greatly increased muscle mass.[SUP][3][/SUP][SUP][4][/SUP] In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength. This research paves the way for human clinical trials, which are hoped to begin in the summer of 2010 on Inclusion body myositis.[SUP][5][/SUP]
A study has also shown that increased levels of follistatin, by leading to increased muscle mass of certain core muscular groups, can increase life expectancy in cases of spinal muscular atrophy (SMA) in animal models.[SUP][6][/SUP]
It is also being investigated for its involvement in polycystic ovary syndrome (PCOS), though there is debate as to its direct role in this infertility disease.

_______________________________________

From Dr. Pangloss;

The following may be the answer (tentatively). this report on myostatin (a powerful muscle growth inhibitor) shows that after 8 weeks on Testoterone, myostatin levels rise significantly. Fortunately it's dependent on Testosterone levels and not muscle mass. When you stop the Test, myostatin levels go back to normal....

8-10 weeks is when the gains from a cycle peeter out. Wish i had some solutble activinIIB receptor or myo-29 antibody to knock that down....
: Mol Cell Endocrinol. 2009 Apr 10;302(1):26-32. Epub 2009 Jan 21. Links

Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration.

Lakshman KM, Bhasin S, Corcoran C, Collins-Racie LA, Tchistiakova L, Forlow SB, St Ledger K, Burczynski ME, Dorner AJ, Lavallie ER.
Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, 670 Albany Street, Boston, MA 02118, United States.
Methodological problems, including binding of myostatin to plasma proteins and cross-reactivity of assay reagents with other proteins, have confounded myostatin measurements. Here we describe development of an accurate assay for measuring myostatin concentrations in humans. Monoclonal antibodies that bind to distinct regions of myostatin served as capture and detector antibodies in a sandwich ELISA that used acid treatment to dissociate myostatin from binding proteins. Serum from myostatin-deficient Belgian Blue cattle was used as matrix and recombinant human myostatin as standard. The quantitative range was 0.15-37.50 ng/mL. Intra- and inter-assay CVs in low, mid, and high range were 4.1%, 4.7%, and 7.2%, and 3.9%, 1.6%, and 5.2%, respectively. Myostatin protein was undetectable in sera of Belgian Blue cattle and myostatin knockout mice. Recovery in spiked sera approximated 100%. ActRIIB-Fc or anti-myostatin antibody MYO-029 had no effect on myostatin measurements when assayed at pH 2.5. Myostatin levels were higher in young than older men (mean+/-S.E.M. 8.0+/-0.3 ng/mL vs. 7.0+/-0.4 ng/mL, P=0.03). In men treated with graded doses of testosterone, myostatin levels were significantly higher on day 56 than baseline in both young and older men; changes in myostatin levels were significantly correlated with changes in total and free testosterone in young men. Myostatin levels were not significantly associated with lean body mass in either young or older men. CONCLUSION: Myostatin ELISA has the characteristics of a valid assay: nearly 100% recovery, excellent precision, accuracy, and sufficient sensitivity to enable measurement of myostatin concentrations in men and women.
PMID: 19356623 [PubMed - in process]

:winkfinger:The final analysis, the conclusion of Vision's take away notes!:winkfinger:

Now that we've read the studies and what science has demonstrated and well articulated in the installations, I feel its fair to say that AR down regulation does not exist in the presence of Androgen's, and furthermore to speculate that AR's as a perennial position for the androgen ligand.. Truth (supported by medical journals world wide) AR's up-regulate, increasing, and constantly expressing new AR sites THROUGH OUT THE BODY AND TISSUE!

(articles in medicine/science suggest the following)

When unattached to an androgen they have a half life of approximately three hours and are ultimately replaced with new ones. However, in the presence of an androgen (i.e. when they're attached), they become more sensitive, their half life is doubled and the amount of new receptors being formed also increases substantially. It's also important to remember that AR-mediated effects are not the whole story when it comes to anabolic steroid activity in the body. There are still a host of other effects that have little to nothing at all to do with AR, known as non-AR dependent effects, which include central nervous system stimulation and a host of other anabolic and potentially anabolic activities. But that still leaves us with the question of why our gains seem to slow down after a few cycles, and why we need to keep upping the dose. In truth, the answer probably has more to do with the body attempting to return to homeostasis through other mechanisms than it has with the androgen receptor.
I hope this brings some clarification to the subject!

 

[eazy]

CLIFF I missed.

test and tren both raise igf in the cell but nandrolone does not