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Downstream target of TGF-beta, fibroblast to myofibroblast conversion.

Downstream target of TGF-beta, fibroblast to myofibroblast conversion.

TGF-beta is a protein that sticks to connective tissue in an inactive form and is activated and released by shear stress, tension, at least some wavelengths of light, and many other things. The activated TGF-beta then interacts with a few different TGF-beta receptors which can do a very wide array of things in various kinds of cells. One of the things it can do is convert fibroblasts to myofibroblasts.

Myofibroblasts are, generally, a temporary kind of muscle cell (muscle meaning they contract). They adhere to connective tissue and then build a scaffold within the cell to contract and pull the connective tissue they’re attached to together. Myofibroblasts are meant to be temporary, they pull wounded tissue closed and the connective tissues are enzymatically glued back together with something like LOX. They should exist as myofibroblasts for about 6 hours if I remember right, then they either apoptose or they convert back to fibroblasts. The problem often arises in fibrotic tissue that they remain active for much longer in a self sustaining, which drives aberrant fibrosis and contracture (shortening of tissue).

There are several small molecule interventions that interrupt the conversion of fibroblasts to myofibroblasts, there are also small molecule interventions for eliminating persistent myofibroblasts.

They have similar problems related to all substances that might be useful for PE, there isn’t a good way for local administration and while the penis is a unique tissue, it’s not that unique, so administering something systemically would have systemic effects.

TGF-beta is a very integrated protein, it’s part of the core mechanisms that regulate multicellular structuring.

Dealing with myofibroblasts is a more downstream mechanism, so the side effects of modulating it would probably be more minimal.

The penis enlargement plateau might be caused solely by the accumulation of persistent myofibroblasts, or just an upregulation of sensitivity of fibroblasts to TGF-beta in its active form, or just the increased expression of inactive TGF-beta.

I have inadvertently tested 1 substance that prevents the conversion of fibroblasts to myofibroblasts already, the test was motivated by weak, but intriguing, correlations that showed up in some data, not studies into the activity of the substance. It didn’t have a noticeable impact on the growth rate.

I’ve also tested several antifibrotics which way or may not individually have anything to do with fibroblast to myofibroblast conversion or myofibroblast persistence. Again no gains noticed.

I’m thinking about moving on to testing low risk epigenetic modulating drugs, since there’s reason to believe that you can simply prevent the phenotype change and get rid off persistent myofibroblasts on that level with limited systemic risk. Local administration again is a problem, the HDACis I have on hand are rapidly metabolized. The problem with HDACis is that when used as an antifibrotic they can increase calcification of existing fibrotic tissue (probably because they interfere with the matrix metalloproteinases). I don’t know if that would be an issue if the HDACis were cycled, but calcification of the penis is definitely not something we want to happen.

Maybe this post will get some fruitful discussion going on the deeper mechanics of PE and the plateau. I’d like to know if anyone has any ideas about the relationship between myofibroblasts and PE. The relation between myofibroblasts and PE I’m presenting is just speculative and hypothetical. Since I don’t have tissue samples from men’s penises before and after they plateau on gains, speculation is the best I can do right now.


Starting: 7"bplx5.2" 2017 (shrunk from disuse)(originally 8"bplx4.5", gained to 9"bplx6")

Current: 9.0"bplx6.125" 2020

Goal: 11.5"bplx7" 2021.

Originally Posted by Sigmoid
TGF-beta is a protein that sticks to connective tissue in an inactive form and is activated and released by shear stress, tension, at least some wavelengths of light, and many other things. The activated TGF-beta then interacts with a few different TGF-beta receptors which can do a very wide array of things in various kinds of cells. One of the things it can do is convert fibroblasts to myofibroblasts.

Myofibroblasts are, generally, a temporary kind of muscle cell (muscle meaning they contract). They adhere to connective tissue and then build a scaffold within the cell to contract and pull the connective tissue they’re attached to together. Myofibroblasts are meant to be temporary, they pull wounded tissue closed and the connective tissues are enzymatically glued back together with something like LOX. They should exist as myofibroblasts for about 6 hours if I remember right, then they either apoptose or they convert back to fibroblasts. The problem often arises in fibrotic tissue that they remain active for much longer in a self sustaining, which drives aberrant fibrosis and contracture (shortening of tissue).

There are several small molecule interventions that interrupt the conversion of fibroblasts to myofibroblasts, there are also small molecule interventions for eliminating persistent myofibroblasts.

They have similar problems related to all substances that might be useful for PE, there isn’t a good way for local administration and while the penis is a unique tissue, it’s not that unique, so administering something systemically would have systemic effects.

TGF-beta is a very integrated protein, it’s part of the core mechanisms that regulate multicellular structuring.

Dealing with myofibroblasts is a more downstream mechanism, so the side effects of modulating it would probably be more minimal.

The penis enlargement plateau might be caused solely by the accumulation of persistent myofibroblasts, or just an upregulation of sensitivity of fibroblasts to TGF-beta in its active form, or just the increased expression of inactive TGF-beta.

I have inadvertently tested 1 substance that prevents the conversion of fibroblasts to myofibroblasts already, the test was motivated by weak, but intriguing, correlations that showed up in some data, not studies into the activity of the substance. It didn’t have a noticeable impact on the growth rate.

I’ve also tested several antifibrotics which way or may not individually have anything to do with fibroblast to myofibroblast conversion or myofibroblast persistence. Again no gains noticed.

I’m thinking about moving on to testing low risk epigenetic modulating drugs, since there’s reason to believe that you can simply prevent the phenotype change and get rid off persistent myofibroblasts on that level with limited systemic risk. Local administration again is a problem, the HDACis I have on hand are rapidly metabolized. The problem with HDACis is that when used as an antifibrotic they can increase calcification of existing fibrotic tissue (probably because they interfere with the matrix metalloproteinases). I don’t know if that would be an issue if the HDACis were cycled, but calcification of the penis is definitely not something we want to happen.

Maybe this post will get some fruitful discussion going on the deeper mechanics of PE and the plateau. I’d like to know if anyone has any ideas about the relationship between myofibroblasts and PE. The relation between myofibroblasts and PE I’m presenting is just speculative and hypothetical. Since I don’t have tissue samples from men’s penises before and after they plateau on gains, speculation is the best I can do right now.

The premises being there is an injury with a TGF-B induced conversion of fibroblasts to myofibroblasts. What is the injury you are healing?
What if we are dealing with healthy tissues all along, I am questioning the IPR model in general for PE.


START 18/13.15 cm Jul 24th 18 (7.09/5.18") NOW 22.5/15.2 cm Fer 12th 20 (8.86/5.98") GOAL 8.5"/ 6"

When connective tissue is stretched within therapeutic temperatures ranging 102 to 110 F (38.9- 43.3 C), the amount of structural weakening produced by a given amount of tissue elongation varies inversely with the temperature. This is apparently related to the progressive increase in the viscous flow properties of the collagenous tissue when it is heated. (Warren et al (1971,1976)

Interesting thread - thanks for posting. I am not well informed in biochemistry but I do have a few opinions to share:

Yes, I think TGF-Beta plays a role in PE;

I believe there is a strong correlation between Peyronie’s, Dupuytren’s, frozen shoulders, and other connective tissue disorders which may center around TGF-Beta and inflammatory cytokines;

Commercial development of drug therapy (for example Xiaflex) is very slow so anecdotal approaches (for example Vitamin E) are common.

Originally Posted by Kyrpa
The premises being there is an injury with a TGF-B induced conversion of fibroblasts to myofibroblasts. What is the injury you are healing?
What if we are dealing with healthy tissues all along, I am questioning the IPR model in general for PE.

I don’t think fibroblasts require an injury to be present. Injury is a term with a broad range of usage, sometimes with quixotical application. For instance, jogging causes cells to rupture in the feet, in the blood, it breaks various ECM structures, but people don’t call it an injury because the net effect on the body is generally positive.

Fibroblasts, and most things in the world, don’t play by the rules of languages we make up.

Ultimately, I guess the core of what causes the phenotype change is histone coiling, acetylation on a few sites, and probably methylation, assuming all the machinery that facilitates the phenotype shift is intact. Upstream there seems to be a bottle neck in the cascade at mitochondrial calcium being reduced causing an increase in alpha-ketoglutarate. So there are many things that cause the phenotype shift, not necessarily “injury”.


Starting: 7"bplx5.2" 2017 (shrunk from disuse)(originally 8"bplx4.5", gained to 9"bplx6")

Current: 9.0"bplx6.125" 2020

Goal: 11.5"bplx7" 2021.

Originally Posted by Sigmoid
I don’t think fibroblasts require an injury to be present. Injury is a term with a broad range of usage, sometimes with quixotical application. For instance, jogging causes cells to rupture in the feet, in the blood, it breaks various ECM structures, but people don’t call it an injury because the net effect on the body is generally positive.

Fibroblasts, and most things in the world, don’t play by the rules of languages we make up.

Ultimately, I guess the core of what causes the phenotype change is histone coiling, acetylation on a few sites, and probably methylation, assuming all the machinery that facilitates the phenotype shift is intact. Upstream there seems to be a bottle neck in the cascade at mitochondrial calcium being reduced causing an increase in alpha-ketoglutarate. So there are many things that cause the phenotype shift, not necessarily “injury”.

Lets put it this way, injury was brought by you, if you allow me to remind you bringing the wound healing in the picture. And I was not saying the fibroblast being present by injury was the case.

What I was asking that is it really a concern to be worried about fibroblasts being converted to myofibroblasts. The context was missing if it was not the injury as your example presented.

Because you are seemingly very deep into knowledge of biochemistry, I would like to know if the conversion happens if there are no markers of inflammation cytokines or other markers of any traumatic events.

Is your scientific approach on PE build on IPR cycle which has the presumption there is inflammatory response needed for the growth to happen?

If it is I would suggest you to push the envelope and direct your scientific mind more out of the box for a while if you really like to contribute to PE.


START 18/13.15 cm Jul 24th 18 (7.09/5.18") NOW 22.5/15.2 cm Fer 12th 20 (8.86/5.98") GOAL 8.5"/ 6"

When connective tissue is stretched within therapeutic temperatures ranging 102 to 110 F (38.9- 43.3 C), the amount of structural weakening produced by a given amount of tissue elongation varies inversely with the temperature. This is apparently related to the progressive increase in the viscous flow properties of the collagenous tissue when it is heated. (Warren et al (1971,1976)

Originally Posted by Kyrpa
Lets put it this way, injury was brought by you, if you allow me to remind you bringing the wound healing in the picture. And I was not saying the fibroblast being present by injury was the case.

What I was asking that is it really a concern to be worried about fibroblasts being converted to myofibroblasts. The context was missing if it was not the injury as your example presented.

Because you are seemingly very deep into knowledge of biochemistry, I would like to know if the conversion happens if there are no markers of inflammation cytokines or other markers of any traumatic events.

Is your scientific approach on PE build on IPR cycle which has the presumption there is inflammatory response needed for the growth to happen?

If it is I would suggest you to push the envelope and direct your scientific mind more out of the box for a while if you really like to contribute to PE.

I haven’t read through all the literature on fibroblast to myofibroblast conversion, so I don’t know all the causes of the conversion and it seems likely to me that there are probably some unpublished ones.

The conversion definitely can happen in the absence of a signalling cascade associated with injury such as in the example of light (though light penetration might be considered associated with injury), drugs that interact epigenetically, or changes to the salt balance that reduce mCa2+.

The hypothesis I’ve been experimenting with with some good results I guess I would say is focused on simply making small adjustments to the connective tissue matrix with light forces while avoiding what I’ve been calling the contraction response so that the tissue is gradually remodeled in the new bigger size, rather than contracting and remodeling in a smaller or same size.

Inflammation is kind of a vague term for a collection of phenomenon with different causes, it might be too vague to be accurate when talking about things like TGF-beta. Inflammation is sort of tangential to my ideas about PE right now. I don’t know how much TGF-beta is integrated with inflammation, it seems to be more of a sensor of extra cellular matrix damage in connective tissue, which I guess could be ultimately caused by inflammation, among other things.

My ideas about PE right now aren’t based on inflammation, proliferation, and remodeling. They’re mostly focused on just the remodeling. I don’t think inflammation as most people understand it (redness, swelling, warmth, and pain) is necessary for tissue growth. But inflammatory signalling, probably. To get a better idea you would need to culture all the cell types in a medium that blocked all inflammatory molecules to see if you can still grow them and then test the conditions that still allowed growth without inflammatory molecules in an animal model. Even with the four signs of inflammation inflammatory signalling is always going on and these cascades in the body are so interconnected it’s likely to be necessary somewhere in all the complicated machinery. Proliferation is certainly necessary to a degree. Remodeling is necessary unless you’re okay with a nonfunctional penis. I don’t know if you need to try to cause inflammation or proliferation though. It’s a very tough question to answer because it requires addressing so many different things to answer it to the best of my knowledge.

I guess there is an element of science to my approach. I’m coming up with hypotheses and testing them to see if they increase the gain rate or don’t, and making conclusions at least. Sometimes it feels like I’m just rubbing strange substances on my penis rather than doing an act of science though.

I’m a little out of it today, I hope that answers the question and I didn’t make some mistake in what I wrote.


Starting: 7"bplx5.2" 2017 (shrunk from disuse)(originally 8"bplx4.5", gained to 9"bplx6")

Current: 9.0"bplx6.125" 2020

Goal: 11.5"bplx7" 2021.

Thank you for the answer.I appreciate. .

The thing is I am as interested as you are for the causes of plateau. And I am not a bio scientist so the approach is more a bio-engineering based.

Let me describe my case in a more pragmatic model.
The thing is when the collagen based ECM is put under strain the TGF-beta is agonist for the elevated expression of collagen 1 without inflammatory cytokines present.
If there a inflammatory responses involved by the overuse, excessive forces or sub-failure strain the same TGF-b actuallly increase the collagen 3 expression as well.

Thats the actual reason why I asked about the conversion mechanism, the enviromental context being in crucial role for these bio-molecular events take the direction.

The proliferation with a collagen 1 expression is direct result of mechanotransduction the ECM adapting in our case to the residual strain caused by the successful elongation exercises.
Provenzano study (2005) indicated inflammatory cytokines being absent even in the Grade 2 sprain, which means enormous permanent displacement and laxity of the joint.
In this context really question the model people causing self-inflicted inflammatory responses like they were somehow needed for the growth to take place.

Its all about the displacement achieved during practice , certain strain rates are needed for the positive reactions we are after.
Surely the consequence of necessary strain can trigger inflammatory reactions if the displacement is forcefully produced with primitive applications by excessive forces which are commonly used in most of the IPR protocols in PE.
If the inflammatory reactions are not needed in grade 2 sprains to induce adaptive growth responses I think we are entitled to assume not necessary in our case either.
Surely extenders provide gains this way with a great success by the similar approach you described as well.

For the plateau we donĀ“t know , the science does not have the conclusive answer why the the residual stress take up to years to come down even the remolling for the new elongated form of the tissue should be completed.
The common uniting aspect amongst the studies is that the internal pressure in ECM modulates the growth. In natural growth it is suspected to be in crucial role why the growth diminishes. If the modulator is cellular pressure or the fibroblasts remains unknowm. I have wrote about the theme in my log and continue to do so. If there will ever be a case to present is another thing.

I build on this and now that I know you are not fixed in this IPR model , surely read your scientific approaches with greater interests.
I am studying the mechanotansduction encouraged by the personal observations and the growing interests inthe scientific field in the subject.


START 18/13.15 cm Jul 24th 18 (7.09/5.18") NOW 22.5/15.2 cm Fer 12th 20 (8.86/5.98") GOAL 8.5"/ 6"

When connective tissue is stretched within therapeutic temperatures ranging 102 to 110 F (38.9- 43.3 C), the amount of structural weakening produced by a given amount of tissue elongation varies inversely with the temperature. This is apparently related to the progressive increase in the viscous flow properties of the collagenous tissue when it is heated. (Warren et al (1971,1976)


Last edited by Kyrpa : 05-19-2020 at .
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