Why gains slow!

Yes, I know you are serving a very important function in the development of working theory. I know that you are knowledgeable, probably understand what I have presented and disagree. I just started school again so time is tight. However, when I get a chance I will try to find published literature that more directly address your concerns.

Alright, alright, I know I said to not pay too much attention to hypoxia. I found this tonight (you guys can read the whole thing):

If the link dies, you can find the article here:

http://www.ncbi .nlm.nih.gov/en … t_uids=11479135

1: J Endocrinol. 2001 Aug;170(2):395-402. Related Articles, Links

Platelet-derived growth factor (PDGF) and PDGF receptors in rat corpus cavernosum: changes in expression after transient in vivo hypoxia.

Aversa A, Basciani S, Visca P, Arizzi M, Gnessi L, Frajese G, Fabbri A.

AFaR-CRCCS, Ospedale Fatebenefratelli-Isola Tiberina, 00186 Rome, Italy. amfaversa@yahoo.com

Platelet-derived growth factor (PDGF) overactivity has been implicated in atherosclerosis and several fibrotic conditions including lung and kidney fibrosis, liver cirrhosis and myelofibrosis. Low oxygen tension (hypoxia) is a known stimulus for transcriptional induction of PDGF ligand and receptor genes in different tissues. We studied the expression and localization of PDGF-A, PDGF-B, and PDGF receptor (PDGFR)-alpha and -beta subunits in adult rat isolated corpus cavernosum (CC) under generalized transient hypoxia (pO(2) 10%) in comparison with normoxic conditions. Semi-quantitative RT-PCR analysis of mRNA extracted from rat penis showed higher amounts of PDGF-A, PDGF-B and PDGFR-beta mRNA transcripts in hypoxic versus normoxic animals. The immunohistochemical analysis showed that the localization of PDGF subunits and PDGFR-beta was confined to the cytoplasm of the perivascular smooth muscle cells, endothelium and trabecular fibroblasts. Our findings indicate that transient low oxygen tension induces PDGF overexpression in rat CC, which in the long term may lead to an increase of connective tissue production. We suggest that a local impairment of the PDGF/PDGFR system may contribute to CC fibrosis, which is an established cause of erectile dysfunction in man.

PMID: 11479135 [PubMed - indexed for MEDLINE]

"1989). PDGF-mediated events, which include
chemoattraction, activation of inflammatory cells, vasoconstriction
and influence on the synthesis or degradation
of matrix constituents (Heldin 1992), are most likely
exerted locally in an autocrine or paracrine manner and are
involved in natural as well as pathological processes, such as
neoplasia, atherosclerosis and fibrosis (Heldin 1992, Gnessi
et al. 1993). Recently, immunohistochemical and electron
microscopy studies showed that PDGF is highly expressed
in penile tunica albuginea obtained from patients with
veno-occlusive dysfunction and Peyronie’s disease
(Gentile et al. 1996), suggesting that it could be involved
in the pathogenesis of these two conditions that are
frequently associated with erectile dysfunction (ED) in
men….

Indeed, in human
corpus cavernosum smooth muscle cells, TGF-beta1 is a
mitogen and induces a two- to fourfold increase in
collagen synthesis (Moreland et al. 1995); also, it has been
found to be overexpressed in tunica albuginea from men
suffering venocclusive dysfunction (Nehra et al. 1996) and
in plaques obtained from Peyronie’s disease (El-Sakka et al.
1997)."

Most importantly: "TGF-beta1 is a
mitogen and induces a two- to fourfold increase in
collagen synthesis (Moreland et al. 1995); also, it has been
found to be overexpressed in tunica albuginea from men
suffering venocclusive dysfunction"

Modesto Man, these experiments were done with induced systemic hypoxia, does this bring us closer to an agreement?

Maybe I’m having a senior moment here, but the following two quotes were in the same paragraph, yet to me suggest opposing outcomes(?)

If “connective tissue production” and “fibrosis” are different processes, then it almost suggests that PDGF is desirable (or facilitates “neoplasia” …it says here).

I need to catch up on my reading here, but I thought I’d post this very thorough article I just found on PD. It appears to have been written after some of the studies presented here were published, and may answer some of our questions.

Time is short, so I’ll just post the URL for now, and try to interpret/analyze later.

http://www.braz jurol.com.br/ju … tin_326_340.pdf

Perhaps the “local impairment of the PDGF/PDGFR system” actually causes an increase in PDGF output.

Actually, the first sentence of the study’s introduction is most revealing and best supports your point:

This is the only part of the study I’ve found that indicates that PDGF may have any effect on the tunica (which includes fibroblasts). As far as I can see, the rest of the study talks only about smooth muscle.

But the fact that PDGF is a “mitogen” for fibroblasts means only that it promotes fibroblast proliferation. It does not mean, necessarily, that any new fibroblasts are induced to produce collagen. Fibrosis is caused by collagen, not by fibroblasts alone.

It also does not mean conclusively that PDGF causes fibroblast proliferation in the tunica. The tunica is a fairly specialized tissue, and I wouldn’t be surprised to learn that it behaves differently from other tissues in regard to fibroblast production.

As for the role of hypoxia, the study concludes only that hypoxia promotes PDGF expression in smooth muscle, not in the tunica. However, the prior study, which concluded that “PDGF is highly expressed in penile tunica albuginea obtained from patients with veno-occlusive dysfunction” suggests that hypoxia (a seemingly likely consequence of veno-occlusive dysfunction) may promote PDGF expression in the tunica. This supports your point that hypoxia may promote fibrosis in the tunica. But this would only be true if any new fibroblasts induced to develop by the PDGF actually produced collagen.

Pfew! This devil’s advocate stuff is getting to be hard work :) .

Gotta run, but I wanted to post this:

Ultrastructural and immunohistochemical characterization of the tunica albuginea in Peyronie’s disease and veno-occlusive dysfunction
http://www.andr ologyjournal.or … bstract/17/2/96

This is the Gentile study, finding that "PDGF is highly expressed in penile tunica albuginea obtained from patients with veno-occlusive dysfunction and Peyronie’s disease."

Alright, I am confused. Do you think fibrosis is probably caused by PE type exercises that constrict blood flow, cause microvascular injury and/or both? Lets not forget that the penis gets much harder to stretch and that there has to be a reason for that. By far, the simplest explanation is that the tissue is reinforced? What are the known ways that the tissue of the penis could be reinforced?

So we know some sort of structural change is taking place, we know the structural components of the penis. You have taken a look at fibrosis.

What do you think?

Bad link removed

I need to correct something I wrote earlier. I wrote in post 111 that hypoxia is "a seemingly likely consequence of veno-occlusive dysfunction."

I wrote this before I knew what VOD was. Now that I understand it, I doubt that VOD causes hypoxia.

Veno-occlusive dysfunction (VOD) is the dreaded "venous leak" I’ve seen mentioned in other threads. I haven’t been able to find a definition, but I have inferred from various things that I’ve read that it’s the inability of the veins to clamp down during an erection. The result is partial impotence. Studies have shown that Peyronie’s Disease may actually cause veno-occlusive dysfunction: http://www.medi caljournal-ias. … _4/Celiktas.htm .

I had used the apparent connection between VOD and hypoxia to support your theory that hypoxia causes fibrosis in the tunica. But since that connection is not valid, it is not nearly as likely that, simply because "PDGF is highly expressed in penile tunica albuginea obtained from patients with veno-occlusive dysfunction," it necessarily follows that that hypoxia promotes PDGF expression in the tunica. I acknowledge that "Low oxygen tension (hypoxia) is a known stimulus for transcriptional induction of PDGF ligand and receptor genes in different tissues" (Abstract). However, this has not been shown for the tunica, as far as I know.

To answer your question, I personally am not convinced (devil’s advocate BS aside) that PE causes fibrosis of the tunica. It may cause some local inflammation which leads to toughening, but this is far short of fibrosis as I understand it.

I also believe that microvascular injury is probably not terribly relevant to the tunica, which (as I understand) has very little blood supply. Nutrients and wastes are conducted primarily through the tunica’s ground substance, not via blood.

PE exercises that constrict blood flow for extended periods of time may give rise to fibrotic conditions in the smooth muscles of the CCs, but they probably don’t do much to the tunica. The fact that "PDGF is highly expressed in penile tunica albuginea obtained from patients with veno-occlusive dysfunction and Peyronie’s disease" probably just reflects the facts that PD is a fibrotic condition and that VOD is positively correlated with PD.

I think that PE toughens the tunica, plain and simple. This happens not via fibrosis, but via strengthening. Tissues that are stressed tend to strengthen. It happens for muscles, bones, and connective tissues.

Shiver’s thread for science-minded PE’ers links to a fantastic document on connective tissue: . The whole process of inflammation, collagen deposition, and remodeling is discussed. Normal healing causes strengthening; abnormal healing with chronic and prolonged inflammation causes fibrosis. As far as I can tell, that explains it.

Modesto, as I read the last post I’m mentally putting on the brakes big time. There’s a bit of a leap between fibrosis and strengthening of the tunica. Are we sure that ‘strengthening’ and fibrosis are not the same thing? Or (imho) that fibrosis is the extreme example of strengthening?

Fibrosis as I (currently) understand it is the name given to irregular type II collegen fibres laid down after chronic conditions in (for example) peyronies where delamination of the tunical layers occurs. Earlier in that event chain are the fibrins and subsequently fibroblasts which are part of the inflammation process.

The fact that VOD occurs in PD is likely more a result of fibrosis than a cause. I believe that PD is quite preventable, but very difficult to cure. Even something as simple as Bromelain (hence the thread on that) would be enough to prevent it in the majority of cases. The difficulty is having the awareness at an early enough stage and taking action to prevent it. The usual route for PD is to wait a year or two before taking invasive surgery (exchange of Collagen type III to II process). My belief is that preventitive action via Zinc, Magnesium, Potassium balance, and Bromelain and/or other anti-inflammatories would stop the condition progressing to the point where surgery was required.

In our case PD could be viewed as the extreme example of what we do in a very minor way each day. Most non believing doctors in the use of PE suggest that the exercise would cause scar tissue. Most likely they are right, though individual responses may vary. Maybe we are just leveraging the difference between passive indifference and physialogical inevitability(?) I still believe there is a better way though…

Hey Shiver. Good to hear from you!

I just spent the last hour writing a thorough response to your post, only to have IE “terminate” unexpectedly before I could press submit.

I can’t bring myself to retype everything now, but please look at the “book” you posted on tendons and ligaments. The link above is broken, but you can use this one instead:

Look carefully at pages 23 and 26. Normal and pathologic healing are discussed. At page 26, there’s a discussion of remodeling in response to stress, which sounds a lot like the body’s response to PE.

Pathologic healing, including fibrosis, is discussed at page 23. This sounds completely different.

I don’t get the impression that normal healing involves “a little” bit of fibrosis. It looks like fibrosis happens when things go wrong.

I think I’ll try to read the TL_Extract 9 or 10 more times. It’s very rich with information.

Cheers!

Interesting research guys, thanks for putting in your efforts for everyone here. :up:

EDIT: Oooo look I busted the 1000 post mark! :buttrock:

Some of this is a bit over my head.

Have you guys reached any conclusions yet? I’m starting my PE tomorrow and trying to pick up any last-minute tips, IF we can be reasonably certain they are intelligent things to do.

I’ve kinda concluded that I might limit vitamin C on workout days, than increase it on healing days. Couldn’t hurt, I guess.

I’ve seen you talking about enzymes, particularly papain and bromelain. What is the implication? Take them all the time? Take them part of the time, timing it with workouts? Any thoughts? I have an enzyme mix that I take sometimes, but not often, maybe once or twice a week. It’s “Omega Zyme” by Garden of Life.

Probiotics: any thoughts or conclusions on them? I take these too, once or twice a week.

My “battle plan” is simple, the newbie routine. One thing I do think I have the “best information to date” on is with heating: the hot water or infrared methods seems to be the favorites on that, so I have a heating lamp. Other than that, it’s just try to eat good, I’ll take a multivitamin every day, and there’s a couple other things I do: fish oil and alfalfa tablets. I also use flax oil, lecithin, a full spectrum mineral supplement (every other day) and occasionally a chewable chromium supplement. I started using NOX about three weeks ago, so it should be getting into my system pretty good now, sometimes I have only taken half the daily dose though… it definitely works, no doubts about that for me! Hard to remember to take it twice a day sometimes. (I smoke and drink coffee, thats the extent of my evils these days.) :)

If you guys have any input that would be good intelligent things to do, or to add or subtract from the above, I would be grateful. It’s time for me to get started! :)

e

Ok, now we have opposing hypothesis. Well, not really, I do think that normal collagen thickening is completely possible. I also and convinced that fibrosis takes place. It is possible that we do PE on very different levels and this could lead to different views in terms injury. The PE I do is very intense. I also think you are being just a tad stubborn. I think the fibrosis hypothesis is solid.

Alright, just for fun I am going to turn this around for a second. Your citation says nothing of the penis. Please offer very specific evidence in the form of published scientific research that normal healthy tunica collagen thickening takes place (as described in your citation) in PE but not with a normal erection. Length will be easy for you but girth a little harder.

And you don’t think I would have you do such a search unless I had done one of my own do you :)

I want to move forward with this. It occurred to me that it does not really matter who is correct if we look for treatments that will both inhibit collagen and fibrin. Yes, we can limit vitamin C intake to inhibit collagen deposition and we can do other things as well, many are listed.

Can we both agree that inhibitors that work on both collagen and fibrin (as long as they don’t have a negative side effect) will likely result in an elongation of the newbie gain window?
I not sure if I have posted this yet:

Nitric Oxide. 2003 Dec;9(4):229-44. Related Articles, Links

L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie’s fibrotic plaque and related fibroblast cultures.

Valente EG, Vernet D, Ferrini MG, Qian A, Rajfer J, Gonzalez-Cadavid NF.

Division of Urology, Research and Education Institute, Harbor-UCLA Medical Center, Torrance, CA, USA.

Inducible nitric oxide synthase (iNOS) is expressed in both the fibrotic plaque of Peyronie’s disease (PD) in the human, and in the PD-like plaque elicited by injection of TGFbeta1 into the penile tunica albuginea (TA) of the rat. Long-term inhibition of iNOS activity, presumably by blocking nitric oxide (NO)- and cGMP-mediated effects triggered by iNOS expression, exacerbates tissue fibrosis through an increase in: (a) collagen synthesis, (b) levels of reactive oxygen species (ROS), and (c) the differentiation of fibroblasts into myofibroblasts. We have now investigated whether: (a) phosphodiesterase (PDE) isoforms, that regulate the interplay of cGMP and cAMP pathways, are expressed in both the human and rat TA; and (b) L-arginine, that stimulates NOS activity and hence NO synthesis, and PDE inhibitors, that increase the levels of cGMP and/or cAMP, can inhibit collagen synthesis and induce fibroblast/myofibroblast apoptosis, thus acting as antifibrotic agents. We have found by immunohistochemistry, RT/PCR, and Western blot that PDE5A-3 and PDE4A, B, and D variants are indeed expressed in human and rat normal TA and PD plaque tissue, as well as in their respective fibroblast cultures. As expected, in the PD fibroblast cultures, pentoxifylline (non-specific cAMP-PDE inhibitor) increased cAMP levels without affecting cGMP levels, whereas sildenafil (PDE5A inhibitor) raised cGMP levels. Both agents and L-arginine reduced the expression of collagen I (but not collagen III) and the myofibroblast marker, alpha-smooth muscle actin, as determined by immunocytochemistry and quantitative image analysis. These effects were mimicked by incubation with 8-Br-cGMP, which in addition increased apoptosis, as measured by TUNEL. When L-arginine (2.25 g/kg/day), pentoxifylline (10 mg/kg/day), or sildenafil (10 mg/kg/day) was given individually in the drinking water for 45 days to rats with a PD-like plaque induced by TGF beta1, each treatment resulted in a 80-95% reduction in both plaque size and in the collagen/fibroblast ratio, as determined by Masson trichrome staining. Both sildenafil and pentoxiphylline stimulated fibroblast apoptosis within the TA. Our results support the hypothesis that the increase in NO and/or cGMP/cAMP levels by long-term administration of nitrergic agents or inhibitors of PDE, may be effective in reversing the fibrosis of PD, and more speculatively, other fibrotic conditions.

http://www.ncbi .nlm.nih.gov/en … t_uids=14996430