Fact or Fiction: Does Proviron UPREGULATE the androgen receptors?

[Swifto]

Androgens, such as Testosterone up-regulate the AR, not down-regulate it.

So does DHT, so I'd assume Proviron causes up-regulation.

Finally, so does estrogen.

 

[Knight9]

Kaladryn,
If one is going for all out mass perhaps proviron / masteron should be left out completely?

 

[Swifto]

I think this thread isnt applicable to RL results. I dont think one should be concerned with AR down-regulation on cycle really...

As for Proviron and muscle gains...

Proviron (Masterolone) exerts strong androgenic activity but weak anabolic action. How? Because, just like DHT, Masterolone is rapidly metabolised to weak diol metabolites in muscle tissue where concentrations of the 3-hydroxysteroid dehydrogenase enzyme's are high. That means its going to do next to nothing for muscle loss or LBM acurial.

You'll get the positive androgenic effects (aggression, mood, labido, possibly strength, CNS) but thats where it ends.

Masteron on the other hand...

 

[mountaindog1]

In case I forget again, can someone nominate Kaladryn as member of month next month. He is a WEALTH of info.

JM

 

[Achilleos]

That was one hell of a reply Kaladryn. Learning a lot here.

 

[Swifto]

What they discovered was a receptor on the outside of cells for the combination of SHBG with testosterone attached (most hormones are thought to passively cross the membrane into cells). They also discovered that SHBG actually modifies exactly what message that hormone ends up giving to the Androgen Receptor (which is located inside the cell).

From experience, we know that things that bind easily to SHBG have a positive effect (proviron, mast, basically anything DHT like). What we THOUGHT was happening was increased free testosterone having a positive effect, what was probably ACTUALLY happening was the more powerful DHT based hormone (DHT has almost 2x the affinity for the AR as test) was transported into the cell and having a more positive effect than test.

We actually USED to think that the more powerful DHT based steroid was binding to SHBG and freeing up the WEAKER testosterone, it doesn't even make sense that this would lead to more positive result. BUT, what is probably actually happening is that the stronger DHT based steroid is binding to SHBG instead of the weaker testosterone, and thus having a stronger effect once it is transported into the cell.

I'm not suggesting Proviron or Masteron don't work, because they do, I just don't think they operate the way we thought they did. And if you think about it, it doesn't even make sense the way we thought about it, because we know that DHT has a much higher affinity for the AR than testosterone.

Can you please post this paper or PM it to me?

Thanks.

 

[Kaladryn]

Can you please post this paper or PM it to me?

Thanks.

Dunno if I am allowed to link directly to the thread over on Dat's forum, but it's stickied there. I should also give full credit for all this info to VX1 from that forum, and in his original post he sites all his references.

“There are several observations suggesting that SHBG mediates the signal leading to the activation
of a second messenger system. Firstly, antiestrogens do not block the response, which would be
the case if it was mediated through intracellular estrogen receptor. Secondly, diethylstilbestrol
(DES), a potent estrogen that does not bind to SHBG, fails to mimic the effects of estradiol.
Thirdly, DHT, which has a significantly higher affinity for SHBG than estradiol, blocks the
response probably by displacing the bound estradiol from SHBG. Thus, BPH tissue requires
estradiol for the activation of the secondary messenger system, as opposed to LNCaP cells,
which respond to both estrogens and androgens (Nakhla et al., 1990, 1994).
More detailed study of the SHBG receptor-mediated signaling system in prostate tissue suggested
that estradiol could, through SHBG, activate AR via a ligand-independent mechanism.
DHT stimulates the secretion of prostate specific antigen (PSA) by prostate tissue through
classical transcriptional activation mediated by AR (Riegman et al., 1991; Lee et al., 1995;
Henttu et al., 1992). Similar stimulation is achieved by estradiol in the presence of SHBG. As
with DHT alone, the estradiol-SHBG mediated stimulation is inhibited by antiandrogens, but
not by antiestrogens, which suggests that estrogen receptor (ER) does not mediate this response
(Nakhla et al., 1997). SHBG can also mediate the regulation of cell growth by estrogens and
androgens. DHT and estradiol stimulate, in the presence of SHBG, the growth of prostate carcinoma
cells, and this increased cell proliferation is associated with elevated cAMP levels inside the cell
(Nakhla and Rosner, 1996). By contrast, estrogen induced growth of MCF-7 breast cancer cells is
inhibited by SHBG (Fortunati et al., 1996). The reduction in growth rate is accompanied by intracellular
cAMP accumulation, which is absolutely dependent on both estradiol and SHBG. Therefore, it
seems unlikely that SHBG simply sequesters estradiol and restricts its availability to cells, but
may actually transmit the growth inhibitory signal to the cell nucleus.”

 

[discohornet]

Logically, it makes more sense to believe in AAS use causing down regulation as there does appear to be a point of diminishing returns in any cycle.

Logically it makes sense, yes. But when the people who get paid a lot of money to poke stuff in petri dishes and rat muscle decided to see if this was the case, they found no evidence of this.

I believe the diminishing returns come higher up the chain. For instance, we know that Androgens inhibit myostatin for a period of time and then eventually this normalizes. Androgens initiate a cascade of events that lead to more muscle. Somewhere in that chain is the failure you guys are looking for, not the amount of receptors themselves.

 

[discohornet]

What they discovered was a receptor on the outside of cells for the combination of SHBG with testosterone attached (most hormones are thought to passively cross the membrane into cells). They also discovered that SHBG actually modifies exactly what message that hormone ends up giving to the Androgen Receptor (which is located inside the cell).

There is a ton of useful studies, along with some heated discussion, about this **broken link removed**.

 

[Kong]

methandriol dipropinate is what u want. That will make your test work even better. Proviron and Masteron just allow for more free testosterone.

 

[Stewie]

Dunno if I am allowed to link directly to the thread over on Dat's forum, but it's stickied there. I should also give full credit for all this info to VX1 from that forum, and in his original post he sites all his references.

VX1 is a walking PDR, after you had directed that link too me (Thanks!) Some of it I'm still trying to wrap my mind around the complexity of VX1's statements, I've had to read it a few times and even then I was

I will give you Kaladryn kudos for interpretation of VX1's very complex understanding of SHBG.

Mountaindog,I'm with you on FM for Kaladryn ....Valuable Asset to the Board!

 

[raw33man]

this is a good thread, bump

 

[Gunsmith]

Bump

 

[Tomgrass]

No need to worry to add proviron or not if myostatine after around 6 weeks marks show you a middle finger saying: those gains gonna come slow from now on.

 

[Muay Thai]

@Type-IIx

 

[OuchThatHurts]

I don't subscribe to the notion that Proviron increases free T by binding to SHBG. Although 70% of TT is bound with high affinity to SHBG that in no way means it is rendered inert. SHBG itself has its own intracellular role as does T. I'm not certain about the remainder bound with much less affinity to albumin and the 2% of free T which is merely our "running" level.

"For many years it has been widely accepted that the primary function of SHBG is to transport sex steroid hormones to target tissues where SHBG modulates the level of free sex hormones that can enter target cells. However, in recent years, additional roles for SHBG have been identified. There is strong evidence that SHBG mediates steroid hormone signal transduction at the plasma membrane and a growing body of evidence that SHBG may be taken up by cells and have intracellular biological functions."

"In this study we have demonstrated that in the absence of SHBG large amounts of Te rapidly enter the cell where they are inactivated by conjugation to glucuronic acid and effluxed. In the presence of SHBG however, while there is reduced Te uptake, glucuronidation and efflux of Te are also reduced and the effects of Te on androgen responsive genes are enhanced. This in vitro study of the role of SHBG may have significant clinical relevance, and as such, the assessment of androgen deficiency in vivo should simply rely not only on measurements of total Te alone but also on the evaluation of serum SHBG levels."

Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells

Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a ...

www.ncbi.nlm.nih.gov

 

[Biggerp73]

Turns out SHBG is actually an active transport system, so things that bind to it actually are actually MORE active than free testosterone. Higher SHBG has a positive effect on growth...

Another interesting point of contention is whether you actually want upregulation of androgen receptors or not.

Let's say I design a new car, and instead of having only one key-receptor to turn on the ignition, I make three key receptors. So now, instead of only needing one key to turn on the car, I need three. I upregulated the key receptors.

 

[Knight9]

Damn there are some GREAT dudes in this thread that have passed. Just looking through this after it got bumped and RIP to Matt Porter(FutureFreak), John Meadows(Mountaindog1), and Discohornet.

Got brainiacs Stewie, Kaladryn, and Swifto on here too..hope you guys are both well! Goofy ass Ross... also, I wonder what happened to turbobusa?

 

[MR. BMJ]

Damn there are some GREAT dudes in this thread that have passed. Just looking through this after it got bumped and RIP to Matt Porter(FutureFreak), John Meadows(Mountaindog1), and Discohornet.

Got brainiacs Stewie, Kaladryn, and Swifto on here too..hope you guys are both well! Goofy ass Ross... also, I wonder what happened to turbobusa?

Turbo passed away a few years back. Stewie last mentioned on here (awhile back now) that he was taking time away to help his daughter, who was going through some difficult health issues.

 

[Type-IIx]

@Type-IIx

Just seeing this now. For some reason I don't receive notifications for some (many? most?) mentions, so I just happened upon this.

Proviron has never been demonstrated to upregulate AR that I've seen (since it's never been tested). DHT (in C2C12 myotubes) has; and more importantly, testosterone has been shown to upregulate AR in human skeletal muscle at 200 mg weekly. It's probably a class effect of androgens - indeed this may be viewed as a myotrophic mechanism - but I do not believe mesterolone would be likely to have any particularly potency in this effect.

There's no question that upregulating AR increases translational capacity: i.e., the absolute and relative quantity of mRNA destined for muscle protein synthesis. Still, androgen dose-response (dose vs. ΔLBM) is subject to a logarithmic dose/response relationship, despite this discrete mechanism.

What Proviron is associated with is data that it tightly binds SHBG. Whether that meaningfully increases free T has not been demonstrated insofar as I am aware (but we can look at the logic of why we expect that it should).

I'll just mention briefly the tangential matter of whether free T reflects the active hormone: it mostly does; though the free hormone hypothesis has been partly contravened by the existence of megalin (SHBG promoter gene), and evidence of both extracellular & intracellular mechanisms for still not extensively characterized pathways.

For example, SHBG-T complexes can be taken up into (e.g., Sertoli & human skeletal muscle) cells by endocytosis: yet there is no apparent effect on muscle function (e.g., strength) or size (i.e., hypertrophy) by these complexes. The very fact that high SHBG with low-normal TT in men causes hypogonadal symptoms (i.e., a low FAI [free androgen index]) supports the primacy of free hormone in biological activity, as a practical matter. Though certainly, 0 SHBG would cause significant complications - this is a false dilemma - given that AAS-induced SHBG reductions do not absolutely remove SHBG from circulation.

For many decades, SHBG was viewed simply as a high-affinity transport protein in the blood circulation, one molecule binding 2 sex hormones (i.e., DHT > T >> E2). It has been shown that Proviron binds SHBG with 4x the affinity of DHT: thus, it may be inferred that high blood concentrations of Proviron might bind SHBG, freeing up more bioavailable or free androgen.

We now understand this is a bit more complex: SHBG circulates as a homodimer that can bind 2 sex hormone monomers. Upon binding the first, there is conformational change in the protein complex that alters the stereochemical properties of the second (unoccupied) binding site that affect its binding properties (i.e., implicating the validity of calculated free/bound/total T & SHBG values on bloodwork with supraphysiological dosing). SHBG can bind to a cell surface receptor (e.g., megalin) either bound or unbound with a ligand (e.g., T, Proviron), and either activate a pathway inside the cell or be taken up by endocytosis. The intracellular interaction of AR-SHBG complexes with the cell surface receptor increases PKA activity and this could influence AR-mediated transcription by altering AR phosphorylation and that of its coactivators. Or, by uptake into the cell of T-SHBG, T may be freed from SHBG during vesicle acidification and then become localized to intracellular protein targets (e.g., AR) or metabolizing enzymes (e.g., Aromatase).

We know that megalin (SHBG transporter gene) expression is related to secondary sex characteristics, prostate cancer risk, and that it exists in human skeletal muscle - but the SHBG-T complexes, while uptaken, do not apparently influence muscle size nor strength. Thus, the biological relevance of megalin & SHBG-bound androgen, while having some activity, would still be best characterized as limited (but still interesting & relevant; certainly worthy of further exploration) in the face of the FAI having comparatively marked significance in its association with symptoms of hypogonadism with elevated SHBG (i.e., when low) given endogenous T concentrations; and the data as yet shows no association between hypertrophy nor strength and megalin (SHBG transporter gene) expression (unlike AR).

Anyhow, Proviron is used clinically for the treatment of idiopathic male infertility (moderate oligospermia), and to improve sexual function. It is non-erthytopoieitic, does not significantly suppress HPG axis functioning (LH, FSH), and can logically be used as a mild hardening compound (it is a weak androgen), promoting well-being/sexual vitality (increase of mental alertness, mood elevation, improvement of memory and concentration, and reduction of sensations of fatigue, all of which can partly be attribued to CNS ‘stimulatory’ effects of mesterolone; electroencephalographic profiles of varying dosages of mesterolone were found to be very similar to those seen with psychostimulants such as dextroamphetamine and the tricyclic antidepressants; Single oral doses as low as 1 mg were shown to affect brain function).

But its efficacy in increasing free androgen in supraphysiological AAS users by tightly binding SHBG is doubtful: AAS dose is negatively related to serum SHBG levels (AAS dose-dependently lower SHBG anyway), and analysis by Aakvaag & Stromme (1974) revealed that during treatment with mesterolone the binding of testosterone by plasma proteins was significantly reduced, whereas the plasma level of free testosterone appeared to remain unchanged.