The Possibility of Multiple Components ...Causing Peyronie's

[George999]

There has been much discussion as to the underlying cause of Peyronie's.  But before trying to decide which factor is the cause, perhaps we need to be open to the possibility that there are multiple related factors acting in concert.  I was taken aback by a recent article related to Multiple Sclerosis which has long been considered an auto-immune syndrome.  It seems an Italian doctor trying everything to cure his wife of MS discovered that she had a jugular vein anomaly.  Just to cover his bases, he corrected that anomaly surgically, apparently a rather simple procedure, and, lo and behold, her MS was cured.  So now he is convinced that physiological issues, and not auto-immune issues, are the cause of MS.  And, by the way, he has found in examining other MS sufferers, that they ALL have some sort of jugular vein issue going on.  And additional successful surgeries of this type have been performed since.  So this guy is being branded as a hero by some in the medical establishment and a heretic by others.  What does this have to do with Peyronie's?  Well, I think it is a clear message that we need to keep an open mind as to the possible causative factors involved.  In the case of the MS discovery, I would say that BOTH auto-immune AND circulatory issues are acting in concert to create the problem.  Circulatory issues CAN trigger auto-immune processes and auto-immune processes can cause circulatory issues.  So we need to be careful not to argue over A, B or C when the answer is more likely ALL OF THE ABOVE.  AND we need to always be open to new and radical explanations IF they are accompanied by substantiating evidence.  Most of the research on the relationship of circulation and disease is concentrated on the arterial end.  Perhaps more examination of venous drainage is in order.  That side of the equation is seldom looked at.  Another possible component would be viral infection.  And none of these potential components really acts alone.  They are all tied together in this strange dance that results in a disease state.  But where to find the weak spot to break the chain is the question.  - George

[BentYoung]

An excellent point George -the problem now is to find our "jugular vein anomaly." I was diagnosed with glaucoma at 19, which is unheard of rare (24 now), and have some other health issues that I could look at. Maybe I will look for a connection...If we can find our common denominator we may be able to beat this.    

[skunkworks]

I think I can be reasonably certain that in my case, peyronie's is mostly auto immune, as I also have psoriasis, dermatitis and a few other auto immune conditions.

I don't doubt that circulatory issues could and most probably are involved, but how would they be found/investigated? Would it not show up in the tests that those with venous leakage undergo?

Although I suppose those tests really only concentrate on the specific genital region, if the venous issue was outside that focus, we might never discover it.

[Woodman]

I too believe my Peyronies Disease is due to a large part of an auto immune problem. I developed Achalasia in August of 07. Its a disease of the esophagus witch paralyzes the lower third of the esophagus and the lower esophageal sphincter. This in turn makes very difficult or close to imposable to get food or liquids down because the valve stops working and stays in the closed position. I had surgery in July of 08 to have my the lower sphincter (valve) cut so it permanently stays open for food and liquids to pass.

I developed Peyronies Disease in July of 07 Just one month before my Achalasia. Its another disease that they do not understand very well at all and has been discovered for several 100 years. The doctors told me they think its either auto immune or possably viral. The disease damages the neuro pathways that go from the brain to the muscles telling them to open and close the valve and move the esophagus so nourishment can get to the stomach.

I had both of these diseases happen to me at least start to show there symptoms within one month of each other that both are strange and not very well understood. Both thought to be auto immune possably. Iam 36 right now. The doctors told me I was rare to be so young with Achalasia.

Also to add to this I was born with bad allergies took shots most of my life to keep them in check and developed asthma at 17 after getting chicken poxs being that old.

All of this put together with what I have read on the subject with Peyronies makes me think an auto immune component has a lot to do with the cause of Peyronies Disease.

I wonder if we all listed our other health issues we think are linked to Peyronies Disease how many similarities we would notice.

Woodman

[Skjaldborg]

I think it is a clear message that we need to keep an open mind as to the possible causative factors involved.  In the case of the MS discovery, I would say that BOTH auto-immune AND circulatory issues are acting in concert to create the problem.  Circulatory issues CAN trigger auto-immune processes and auto-immune processes can cause circulatory issues.  So we need to be careful not to argue over A, B or C when the answer is more likely ALL OF THE ABOVE.  AND we need to always be open to new and radical explanations IF they are accompanied by substantiating evidence.

I agree that an open mind is necessary for looking at the potential multiple causes of Peyronie's, multiple not only in that two people might have separate causes but that within one person multiple factors may be at work. However, an open mind must be tempered with a healthy dose of skepticism. The doctor in the story you posted has actually achieved significant results whereas most of the treatments discussed on this forum unfortunately have not been as effective in treating or curing Peyronie's as those in the article purportedly were for MS. Worse, some of the theories and treatments preached here are utter nonsense. For any theory about the causes of Peyronie's to be considered plausible, it must be tested and shown effective in stopping, preventing or reversing the disease.

Where does that leave us right now? We currently have viagra, pentox and VED. Each seeks to alleviate various symptoms or treat possible causes of the disease. Indeed, the results of these treatments are generally of limited efficacy but they are based on good science and are therefore better than the sundry dietary restrictions, teetotalism, beams of infrared light, herbs and other supplements bandied about on the forums. In some cases people have claimed that these, how should I say, alternative treatments have been effective. I do not doubt this on an individual basis but I am not confident that these treatments work across the board. Many have no basis in science and are instead based on personal belief systems, particularly those involved with abstaining from food or drink. It is only human that being made desperate by this terrible disease and finding so little succor that we feel impelled to try anything, so we fire up the infrared beam, pore over diagrams of the penile circulatory system to match up with our scars, slam a few vitamin E pills and hope for the best. I am not sure that qualifies as open-minded, unless it starts to work.

In my case, I have no other autoimmune conditions. None. I am 30, in very good health, have a solid family history (some arthritis, but most everyone lived a long time, hale and hearty into their 80s). I have taken very few medications in my adult life, no allergies and rarely get sick. I got a slight injury during sex one evening and *POOF* a few days later the business below my navel looks weird, hurts and I suddenly spend more time than I should talking to strangers on the internet about my penis. I have no explanation for it and neither do the fine doctors I have seen.

I will be open minded once I see a viable treatment besides pentox. I will be the first in line to have my jugular vein roto-rootered or whatever the hell it is they do. Until then, I remain a skeptic.

-Skjald

[LWillisjr]

Great post Skjald

[George999]

Skjald,  I agree completely with your post.  As I said in my original post "we need to always be open to new and radical explanations IF they are accompanied by substantiating evidence".  That is the big IF.  We also, of course, need to remember that MS is actually easier to treat, believe it or not, than Peyronie's.  In the case of MS, all you need to do is stop it in order to cure it.  With MS you don't need to actually repair the prior damage because the brain will rewire itself.  Unfortunately Penises and other body parts don't have that capability.  But my point with the post was that real solutions can come from directions we don't expect and we need to be careful not to get fixated on any one silver bullet.  I think that most of us already have that down, but there are a few of us that are so overly focused on what we think the underlying cause is that we are not taking advantage of what is already there, namely things like Pentox and the VED that are known to work well enough to at least stop Peyronie's from continuing to progress.  So I think we ARE on the same wavelength in this discussion.  - George

[BentYoung]

The more I research, the more I am seeing certain similarities in conditions that must be related to Peyronies Disease. Things like diabetes, angina (heart palpitations - which I have) and Vascular Disease are all mentioned within the scope of Peyronies Disease. Being young with this condition- I can certainly believe that I have congenital markers for Peyronies Disease. My grandmother has bad diabetes - my father has angina and Peyronies Disease and poor leg circulation leading to restless leg syndrome. This has to be a circulatory disorder. For my entire life I have has extra cold extremities like hands feet etc. I have never had ED, but I am thinking more and more that my extremities, including the most important of these, are slightly weakened due to poor blood flow - thus very vulnerable to injury.  So for now I am taking L-carintine, L Arginine and Pentox. Anyone have similar backgrounds?  

[slowandsteady]

I've had cold extremities too. I think there might be something to that. LED therapy to improve circulation might be an option too.

[newguy]

I've always had cold extremities too. My toes especially.

[skunkworks]

Not I, my extremities have been a source of warmth for all those who have encountered them.

[George999]

Perhaps we can add bacterial infections to the list of suspects?

Bacteria linked to autoimmune disease

According to this new research, if bacteria infest a specific tissue, they can contaminate that tissue with weird lipids that cause the body to attack those body tissues.  Seemingly, even if the immune system kills off the bacterial infection in question, it has already been sensitized to the body tissue in which it found the bacteria and the auto-immune issue remains.  Yuck!  - George

[SSmithe]

Hello,
I am 30 and I have had Peyronie's for about 7 years now.  I only recently saw a urologist and was diagnosed.  I think I got Peyronies Disease from repetitive downward force and injury to my suspensory ligament during sex.  I have hourglass at base, pain with erection, and a dorsal band of plaque the whole length of my penis, but minimal curvature.

I have been trying to find any connections between Peyronies Disease and other heath issues I have had.  Below is a list, and I would love to hear if anyone else has similar matches. (some I already know exist, like low testosterone)

- Low testosterone (338) with low LH and FSH to match.
- Caffeine allergy when young. (migraines 24 hours after drinking)
- Gynecomastia (hard, harmless lumps in nipples which appeared around 13 years old, and still remain)
- Tight pelvic and low back muscles. Seemingly unable to consistently relax my perenium. Basically constant tension in that area that led to poor posture.
- Chronic Sinus infections
- Staff infections
- Low blood pressure

Please let me know if anyone has any similarities...  
Thanks,
SS

[slowandsteady]

Interesting list. I have some similarities. My testosterone is quite good for someone in their mid-forties. I am a slow caffeine metabolizer (too bad since I like coffee), had some painful lumps behind my nipples at about that age (but they went away at some point in my youth), some muscle issues with trigger points, chronic sinus infections yes (very low grade but they seem to linger), and my blood pressure is fairly low (on waking, 103/54 and 66 bpm).

s&s

[SSmithe]

S&S,
Yes they are interesting similarities.  I have always wondered why the lumps in my nipples have remained.  I was told they would go away one day but they never did.
Guessing by the lack of respondents to my list, there doesn't seem to be a lot of people with similar traits...
Take care,
SS

[newguy]

I had the hard nipple thing as a teenager, but not since then.  

[newguy]

Yes, I think you're right OldMan. I don't personally think that it's an indicator of peyronie's.  

[LWillisjr]

I had it as well. I don't remember the mdeical term my doctor used. I think it is pretty typical of teen males entering puberty.

[ComeBacKid]

I hard big /hardened nipples during puberty to, luckily they shrank when I got to like 19, as I didn't think they looked good.  My one friend had huge nipples in puberty and in swimming class they used to call them "dinner plates" I just gotta laugh, gotta love high school.

Comebackid

[BrooksBro]

Big nipples in men are one of the ways that gynecomastia (aka man boobs) presents.  As you say, it is most common among adolescents.  http://en.wikipedia.org/wiki/Gynecomastia

I hard big /hardened nipples during puberty to, luckily they shrank when I got to like 19, as I didn't think they looked good.  My one friend had huge nipples in puberty and in swimming class they used to call them "dinner plates" I just gotta laugh, gotta love high school.

Comebackid

[boomerang]

I have had many symptoms all my life most minor but some have really had adverse effects on my quality of life.

I had migraines when young (which incidentally is also an indicator of an auto immune disease called Hughes Syndrome)
I have been affected by caffeine from my early 20s in that it gave me rapid heart rate(Atrial fibrilation/flutter) either that day or the day after consumption.
I don't take caffeine now in any form.
I had stiff lower back since teenage years.
My sinus infections started in my 30s which were made worse by food intolerances particularly milk and dairy products but also wheat.
My blood pressure was always low which my doctors thought was very healthy.
I have a feeling that my testosterone levels are much lower now I am in my late 50s.

I have always been very physically active in sporting fields and this I suspect has helped keep me healthier than otherwise would be but my sporting achievements have been severely affected by physical effects of my disease even though I excelled at any sport I chose.

I have had multiple symptoms which I think all relate to my blood being too thick all my life.

The symptoms appear to relate to cellular Hypoxia (low oxygen in the cells, not blood) and cellular Hypoglycaemia (low glucose to the cells, but not of the blood)

[slowandsteady]

Many of these symptoms seem related to magnesium deficiency, I can't help but notice.

[DannyOcean]

A few of these resonated with me as well.  

Sinus infections - I had these constantly as a kid and was on antibiotics much of the time.  There was probably a 10 year stretch where I was on antibiotics at least 3-4x/year.  My senior year of high school I was probably on antibiotics more than I was off them.

Tight lower back/pelvic muscles - In high school my nickname on the track team was "Mr. Stiffy".

Unable to relax perenium - This one, in my mind, might be the biggest one that sounded alarms.  I've noticed over the last couple of years that I have a lot of tension in this area of my body.  My theory (and it's certainly only a theory) is that the tension here has restricted circulation to my penis and this caused, or at least contributed, to my Peyronies.  What's interesting is that the two times in the last 5 years where I've had the biggest problems (when I first "discovered" Peyronies about 4 years ago and more recently when I discovered a new nodule) where the times I was under the greatest stress.  Obviously stress reeks havoc on the immune system generally but my guess is that during this period of time I was tensing up this area of the body more than normal.

I'd love to explore this last piece in more detail.

[SSmithe]

DannyOcean,
I have looked into the "inability to relax my perenium" symptoms for myself.  For me, I think I have a mild form of what is called CPPS or chronic pelvic pain symptoms.  It is often confused with prostatitis.  However it can be caused by chronic muscle tension due to stress.  I agree with you in that I have read that the muscle tension can cause low blood flow and increase inflammation...  

I have looked into trying to reduce stress via the Paradoxical Relaxation... mostly used for CPPS sufferers.  It will probably do nothing for the Peyronie's, but less stress couldn't hurt either.
SSmithe

[slowandsteady]

I'm fighting a bout of plantar fasciitis over the past 5 months or so. Recently it has gotten painful enough to prevent me from running some days.

I got an x-ray done yesterday, and there was a bone spur at the insertion point of the plantar fascia and my heel. I didn't expect that as I thought my vitamin K levels would have prevented soft tissue calcification. I've been taking 100 mcg of K2-MK7 weekly, but maybe that's not enough. I'd like to cover my bases and take 2 mg or so of K2-MK4 as well.

Anyone else get bone spurs? How about cupped ears? I had those when I was young, and it's listed as a sign of vitamin K deficiency (PMID 9382132).

[fubar]

Slowandsteady

What are the symptoms of planter fasciitis as I have many markers for Peyronie's  Disease and symptoms related to Peyronie's. I have diabetes. And have definately have not  lost any sensitivity to the feet.I have gout and when it outbreaks hurts like hell.,

I ask about the symptoms because if I bend at the waist I feel like a rubber band effect in the Middle of my heal like something is going to snap and it is quite uncomfortable.

Fubar

[slowandsteady]

What are the symptoms of planter fasciitis

For me it's a pain at the bottom of the heel where the plantar fascia join the heel. With inflammation you can get abnormal collagen deposition and soft tissue calcification on the heel. Sound familiar?

I gave me the opportunity to do another vitamin K trial. Surprisingly, it really helped more than I expected. I've been taking 200 mcg/day of K2-MK7 and 10 mg a day of K2-MK4. Inflammation is way down and so is pain. I'd say it about 70% fixed the issue.

[Tristen]

I'm curious how many people think Peyronies may be caused by an AI (autoimmune) problem?  I have looked at every possible cause, and have now narrowed it down to this problem.  I don't have any really pronounced AI, but I just don't see any other possibilities.  One could ask why worry about the cause....well, the answer on that for me is that I don't want to be taking any immune modifying medications if this were the case.  I had been on Interferon just a few months prior to onset of my Peyronies, but everyone says there is no way that could have caused it, and that the drug is often used to inject into the plaque. But, Interferon is an immune modulator.  Anyhow, how many people feel Peyronies is autoimmune?

Thanks everyone

[George999]

For sure Peyronie's has an autoimmune aspect.  But the question is why is the immune system doing what it is doing?  The major reason for Pentox's demonstrated effectiveness is precisely because it modulates the immune system.  On the other hand, many immune modulators have no effect on Peyronie's and still others quite possibly make it worse.  The key is that you want to start with those treatments that have been shown effective by independent well done studies.  That equates to Pentoxifylline, CoQ10 and ALC.  Most physicians want to see anti-nuclear antibodies in the blood or other conclusive evidence before they are willing to declare a disease to be "autoimmune".  So the jury is out as to whether Peyronie's is "autoimmune".  My personal belief is that it is more like "all of the above".  In other words there are a lot of different factors at play in a way that bring about Peyronie's.  - George

[fubar]

Yes

Micro trauma, constriction and autoimmune.

That is my own assumption.

Fubar ( do not choke your chicken) think i have heard that before!just putting it out there!

[fubar]

Slowand steady

Is this potassium by chance. Going to check it out.Yes the pain is familliar.

Fubar  

[George999]

Slowand steady

Is this potassium by chance. Going to check it out.Yes the pain is familliar.

Fubar

Its Vitamin K.

[fubar]

Thanks george? Thought it was ,a doctor sent me a prescription I threw it out.It was like anti potassium in liquid form.
Fubar

[George999]

I don't understand the potassium connection.  Vitamin K and potassium have no connection that I know off other than the fact that the letter K is used to represent potassium as an element.

[fubar]

George

Not sure that it matters but I had to much vit k at one time and needed much vit d. You guys have spoken of this stuff many times.Where it stands in my Peyronie's I do not know.Just some deficiencies when I took on this disease.

Fubar

[George999]

With all the Vitamin D studies out there anyone in their right mind should be getting their vitamin D levels tested regularly.  There are all sorts of environmental issues that can radically affect Vitamin D levels.  The ONLY way to effectively manage it is via regular testing.  Ditto with things like Testosterone.  Insurance companies dole out 100s of thousands very willingly for surgeries and stuff but they don't like to pay out a few paltry dollars for a Vitamin D test.  They will be making a huge mistake if they abandon PSA testing just to save some bucks, but it wouldn't surprise me if they did.  They are determined to optimize revenues, NOT quality of patient care in spite of all the propaganda to the contrary.  Vitamin D testing should be routine and until it is, I will gladly pay out of pocket for it if need be.  - George

[Tristen]

Thanks for the input guys.   It makes perfect sense to me that it would be autoimmune.  Yes, something has to call the immune response the area (penis), and that may only take a slight bit of trauma.  I think the Interferon exacerbated the response.  

[Woodman]

Yes, I believe its auto immune related in my experience. I developed another auto immune disease thats incurable about 5 weeks after developing Peyronies. I ve discussed the possability and my theory with my PCP and he agreed without hesitating.

[crashbandit]

Yes, I believe its auto immune related in my experience. I developed another auto immune disease thats incurable about 5 weeks after developing Peyronies. I ve discussed the possability and my theory with my PCP and he agreed without hesitating.

Hi woodman,

Could you elaborate please? Can you tell us how you know it's an AI problem?

[Woodman]

Well, like I mentioned before I believe it stems from a AI problem for myself. I also believe that it is or plays a major role in causing Peyronie's in general.

For myself I believe its auto immune because in a 5 week time period I developed Peyronie's then Achalasia. Achalasia is a disease that is also incurable and only treatable to diffrent degrees. Its where your lower esophageal spinker " or valve " on the top of your stomach quits functioning causing you not to be able to get food or liquids to pass to your stomach. It also involves the lower third of your esophagus to become paralyzed. I had to have a Heller myotomy to cut my "valve" to so it will stay open all the time so I can eat and drink. This happens for some reason where the muscles and nerves on the valve quit communicating with the brain. Its another disease that they do not know the cause but is thought to stem from a AI problem.

In the next 11 months I developed corpal tunnel in my left hand so bad I couldn't lift anything heavier then a cup. One month later my right hand followed. So in a 1 year time period I went from a pretty healthy guy in my early 30's to this state.

I ve been seeing my PCP to try and manage my inflammation problems from the Peyronies and Corpal Tunnel. This is when I asked him about what I learned and what he thought about my theory about my situation. I told him I can see one thing happening and that's it but when I get all 3 in such a short period of time and all 3 came on very sudden. Also that my Peyronie's and Achalasia came in tandem then the Corpal tunnel with all the inflammatory disorders along with the AI nature of Peyronies and Corpal tunnel it seems to be the case. That's when I asked for his opinion and he agreed with me.

This is my line of thinking why my Peyronie's stems from a AI condition. Sorry for this being long winded.

[crashbandit]

Yes definitely that would imply an underlying condition other then just wear and tear or trauma. I have had something similar happen to myself as well. Within a 2 year period, I first suffered with golfer's elbow, then inflicted with lower back problems and finally Peyronies Disease symptoms. I went from a healthy, feeling no pain 30 year old like yourself, to feeling like the most unlucky person in the world. It has been quite depressing to say the least but the world keeps turning.

Has anyone else in your family been diagnosed with an AI disorder? Do you have any idea in how to fight your AI problem? I'm thinking it can be like finding a needle in a hay stack or being a multi-millionaire to be able to get to the bottom of an AI issue.  

[Woodman]

No, no one else has any AI disorders in my immediate family. I try to research on the internet from time to time to find a direction to go in but I really don't have the resources to take shots in the dark on non traditional doctors. I am thinking about asking my PCP whos been helping me try and manage my inflammatory problems if he knows someone to refer me to that specializes in that area. I have to agree with you about it being a needle in a hay stack and just about being a multimillionaire to get to the bottom of a AI issue.

My biggest fear is it causing more health problems in the future. AI problems are so complex that I do not think most of the medical field understands them for the most part. Lately I ve spent the better part of my days trying to get a game plan to try and get a handle on this problem. I am going back to the doctor soon to discuss more options to try and curb my inflammation and go over my test results in more detail. Also while Iam there I am gonna ask him about the referral. Whatever I learn I will post after my visit.

[crashbandit]

I'd love to hear the progress you make. I guess the best thing to do in the immediate future for anyone, is use what they know works best and just keep plugging away for answers.

You ever watch that show, Mystery Diagnoses? It's so amazing how the people on the show suffer for so long before a cure can be administered or illness labeled.  

[slowandsteady]

I think that generalized inflammation plays a role too. For that, I made changes in my diet. I've found eating paleo to be very helpful (improvement in sense of well being, my weight is just where I want it, good blood pressure). I had GERD too, but by eliminating nightshades (tomatos, red peppers, eggplants, but not potatoes) it went away, and it was quite uncomfortable for a while.

If inflammation is high, that's going to affect the whole body.

[George999]

And of course, inflammation and autoimmunity are linked.  Idiopathic inflammation WILL eventually result in autoimmunity AND autoimmunity will result in inflammation.

[justbob]

http://www.nature.com/ijir/journal/v14/n5/full/3900875a.html

October 2002, Volume 14, Number 5, Pages 406-410
Table of contents    Previous  Article  Next   [PDF]

Paper
Pathophysiology of Peyronie's disease

R B Moreland1 and A Nehra2

1Department of Urology and Physiology, Boston University School of Medicine, Boston, Massachusetts, USA

2Mayo Clinic Foundation, Rochester, Minnesota, USA

Correspondence to: A Nehra, Department of Urology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA. E-mail: nehra.ajay@mayo.edu


Abstract

Peyronie's disease is an inflammatory condition characterized by the formation of fibrous, noncompliant nodules in the tunica albuginea which can impede tunical expansion during penile erection, leading to deformity and bending. While the cause of this disease is thought to be due to microvascular trauma and abnormal wound healing, other hypotheses include genetic predisposition. In this review the pathophysiology of Peyronie's disease is discussed as well as current hypothese regarding its origin.

International Journal of Impotence Research (2002) 14, 406-410. doi:10.1038/sj.ijir.3900875


Keywords

Peyronie's; genetics; TGF-1



Introduction

Peyronie's disease (indurato penis plastica) is an inflammatory condition which is characterized by the formation of fibrous, noncompliant nodules within the tunica albuginea.1,2,3,4,5,6,7,8 These plaques impede tunical expansion during erection resulting in penile bending. In some extreme cases, these plaques can induce a collar-like or an hourglass-like appearance in the erect penis. Unlike normal wound healing following trauma, plaques in patients with Peyronie's disease do not resolve. Subsequent to inflammation and cessation of pain, in the chronic stages of the disease, the plaques may ossify.1,2,3,4,5,6,7 One can subclassify Peyronie's patients into three categories: (i) patients with asymptomatic plaques or some penile bending which does not affect intercourse; (ii) patients whose plaques exacerbate penile bending to the point that intercourse is either painful and/or no longer physically possible; and (iii) patients whose Peyronie's disease is also associated with erectile dysfunction.8 In patients with erectile dysfunction, penile arterial inflow is usually unimpeded with the major abnormality observed being venous leakage, usually at the site of the plaque.9,10 This may be due to an undermining of the tunical venule drainage system important for effective veno-occlusion. While the molecular basis of Peyronie's disease is unknown, the recent theories and research progress to delineate the underlying causes of this condition will be discussed in this section.


Genetics and occurrence

The search for a genetic link for Peyronie's disease has yet to identify a genetically predisposed population. This does not mean that there is not a genetic link to Peyronie's disease, but rather we have yet to find the tools to identify this link and/or it is difficult to distinguish potential genetic Peyronie's disease from that disease which may be associated with microvascular trauma. However, there are reports associating this condition and Paget's disease of the bone,11 Dupuytren's contracture12 and specific HLA subtypes.12,13,14 In all of these studies, patients reporting one of the traits (Paget disease of the bone, Dupuytren's contracture or specific HLA subtypes) did not always report symptoms of Peyronie's disease. Studies of Peyronie's patients have implicated an auto-immune component. It was shown that Peyronie's disease patients had at least one abnormal immunologic test (75.8%), alterations in cell-mediated immunity (48.5%) and in markers of auto-immune disease (37.9%).15 Another study found higher than normal levels of anti-elastin antibodies in the serum of patients with Peyronie's disease, suggesting an autoimmune etiology.16 It is likely that a certain proportion of men in this age group respond to mechanical tunical stress and microvascular trauma4,5,6 with an aberrant or hyperactive wound healing response.17 Thus, there may be a subpopulation whose genetic background is such that response to wound healing predisposes development of Peyronie's plaques.

There are few reports examining the incidence and prevalence of Peyronie's disease. A 35-y retrospective study in Rochester, Minnesota is notable.18 In this study, comprised primarily of Caucasian men, the average age of onset was 53 y old, with a prevalence of 388.6/100 000 (0.4%) and an age-adjusted annual incidence rate of 25.7/100 000 men (0.3%).18 At the time of the study 9 y ago, this translated into 32 000 new cases in the USA annually with approximately 423 000 men with Peyronie's disease at any given time.18 Contrary to the genetic studies described above, there was no significant association with Dupuytren's contracture and Peyronie's disease. Further, over the 35-y period, both total Peyronie's disease and Peyronie's disease associated with pain and impotence increased. This may be an actual increase in disease occurrence or due to heightened patient awareness and seeking of medical attention. Interestingly, rheumatoid arthritis (P<0.0001) and hypertension (P<0.01) were the most commonly associated conditions reported in this group of Peyronie's disease patients.18 It should be noted that the study described above probably underestimates the true prevalence of Peyronie's disease as indicated by autopsy studies.19 In a study of 100 men who had no known Peyronie's disease, 22/100 had asymptomatic, fibrotic lesions of the tunica albuginea.19 This suggests that in the natural course of aging and sexual activity, these asymptomatic lesions may develop. The prevalence of Peyronie's disease is probably much higher than 0.4% if one includes subclinical, asymptomatic cases.17,18 Regardless, the number of patients presenting with Peyronie's disease in the USA is expected to increase as the 'baby boom' generation progresses through ages 50-70.


The microscopic anatomy of the tunica albuginea and its impact on Peyronie's disease plaques

The tunica albuginea is a multilayered structure of inner circular and outer longitudinal layers of connective tissue encompassing the pair of corpora cavernosa.20,21,22 An incomplete septum separates the two corpora cavernosa and anchors into the circular inner layer. In the distal, pendulous penis, intracavernous pillars anchor the tunica across the corpora cavernosa at the 2 and 6 o'clock positions with minor struts branching off of these pillars at the 5 and 7 o'clock positions. It has been demonstrated that tunical thickness varies from 1.5 to 3 mm thick depending on the circular position around the tunica.20,21,22 The longitudinal outer layer which provides strength to the tunica albuginea is absent at the 6 o'clock position where the corpus spongiosum fits in the indentation between the two corpora cavernosa.22 It has been proposed that this design allows unrestricted expansion of the corpus spongiosum such that ejaculation is unimpeded during penile erection.22 The longitudinal layer is also thinnest at the 3 and 9 o'clock positions; consistent with the greatest number of traumatic penile fractures in those positions.5,6,23 Patients with Peyronie's disease most often show plaque formation on the dorsal side of the penis.1,2,3,4,5,6,7,8,23 There are at least two possible explanations for this observation. First, the dorsal aspect is opposite the portion of the tunica lacking longitudinal fibers and thus upward bending during erection is possible.13 Further, the joining of the septum into the circular inner layers of the tunica may be particularly susceptible to microvascular trauma and tunical delamination.4,5,6 The tunica albuginea is composed of fibrillar (mainly type I but also types III and V) collagen in organized arrays interlaced with elastin fibers.22,24 Peyronie's plaques are also composed almost entirely of types I and III collagen.24,25 While collagen has a greater tensile strength than steel, it is unyielding. In contrast, elastin can be stretched up to 150%, of its length.22 It is the elastin content that allows the compliance of the tunica albuginea and helps to determine stretched penile length.26 Disorganization of the circular or longitudinal layers in the tunica as well as disruption of elastin or a decrease in elastin content27 has been reported in Peyronie's disease and can result in penile deformities during erection as well as erectile dysfunction.


Molecular basis of Peyronie's disease

Tunical mechanical stress and microvascular trauma

One of the most likely causes of Peyronie's disease may be repeated tunical mechanical stress and microvascular trauma. Excessive bending during erection or blunt trauma to the erect penis may result in bleeding into the subtunical spaces or tunical delamination at the point where the septum integrates into the inner circular layer of the tunica albuginea.4,5,6 Such microvascular trauma may come from sexual intercourse; either with the woman on top (torque to the penis with an upward twist applying pressure to the septum tunica junction) or an accident during penetration where the man misses the vagina and fractures the penis. Microvascular trauma or subtunical bleeding can result in fluid and fibrinogen in the subtunical layers. The resulting fibrin deposits may be key in the initiation of a wound healing response which encompasses pain, hematoma and subsequent inflammatory response with recruitment of macrophages and neutrophils.17,28,29 These cells, in response to clot formation, release a variety of cytokines, autocoids and vasoactive factors which may precipitate a fibrotic reaction (see later).

In order to better understand the molecular pathology of Peyronie's disease, it is helpful to review the events in a normal wound healing response.17,28,29 Microvascular trauma leads to extravascular leakage of blood, with thrombus formation. Platelets release their contents including serotonin, platelet derived growth factors (PDGF-A and PDGF-B) as well as transforming growth factor-1 (TGF-1). Thrombus formation leads to deposition of fibronectin, which binds a variety of growth factors, localizing them to the wound site. Fibrinogen leakage results in fibrin deposits. Fibrin forms a meshwork of fibers which will be the sites of attachment for inflammatory cells and fibroblasts later in the healing process.28,29

The combination of these factors attracts a variety of inflammatory cells to the wound site including macrophages, neutrophils and mast cells. Neutrophils, the predominant inflammatory cells in the site in the first 24 h, function to remove bacteria and debris from the site.17 Macrophages become the predominant cell type by 48 h and in addition to removal of cell and foreign debris from the wound, release a variety of growth factors including TGF-1. Fibroblasts migrate into the site attracted by growth factors and autocoids released by platelets and macrophages and begin to proliferate as a result of PDGF. These cells probably provide the bulk of the connective tissue synthesis during tissue repair. It is interesting to note that a recent study found immunohistochemical evidence of strong expression of both PDGF-AA and PDGF-BB as well as PDGF- and PDGF- receptors in fibroblast-like cells in tunica albuginea surgical specimens from Peyronie's patients but not in specimens from other patients with veno-occlusive dysfunction.24 Transforming growth factor-1 has a pleotropic effect on fibroblast function by increasing transcription and synthesis of collagen, proteoglycans and fibronectin while also increasing synthesis of tissue inhibitors of collagenase which prevents connective tissue breakdown. The collagen and connective tissue repair damage while in dermal wounds, re-epithelialization takes place. Finally, in the later stages of healing, the connective tissue is remodeled by specific collagenases and proteases.17 Thus PDGF may exacerbate fibroblast proliferation while TGF-1 potentiates fibrogenesis. In dermal wound healing, the myofibroblast, a mesenchymal cell type which has characteristics of both smooth muscle (contractile) and fibroblast (synthesis of connective tissue), is thought to play an important role in wound healing.17 However, there has yet to be a detailed examination of this cell type or any evidence of involvement or de-differentitation of corpus Cavernosum smooth muscle in the pathology of this condition. In Peyronie's disease, defects in overproduction of collagen and other tissue remodeling mechanisms result in an inability to resolve the injury and in plaque formation.

Molecular mechanisms: involvement of TGF-1

Fibrosis is defined as the over accumulation of connective tissue or the replacement of normal cellular material with connective tissue.17 Transforming growth factor-1 has been implicated in a number of soft tissue fibroses30,31 as well as erectile dysfunction.32 The pathology observed in these conditions is worthy of consideration here before discussing Peyronie's disease. Transforming growth factor-1 is synthesized as an inactive, latent peptide by a variety of cell types including platelets, macrophages and fibroblasts.30,31,32 Upon activation, TGF-1 binds to specific cell surface receptors and through a signal transduction cascade, results in an increased synthesis of connective tissue and an inhibition of collagenases. It can also induce its own synthesis as well as that of its receptors.30,31,32 This auto-up regulation can set into motion a chain of events that results in continued connective tissue accumulation and what has been termed the dark side of fibrosis.30 The negative regulators of this process are not well characterized. However, in the lung and in the corpus cavernosum, a role for prostaglandin E has been proposed.32 PGE inhibits TGF-1-induced collagen synthesis both in lung fibroblasts and in corpus cavernosum smooth muscle via cAMP dependent pathways.32 Despite these initial clues, a number of autocoids, vasoactive substances and cytokines can regulate connective tissue metabolism so that these two factors may be involved but not exclusive to the process.

A role for TGF-1 has been proposed in the pathogenesis of Peyronie's disease.33,34,35 Peyronie's disease plaques and tunica albuginea biopsies were examined for the presence of expression and compared to specimens from non-Peyronie's disease patients. In 30 Peyronie's disease patients, increased protein expression of TGF-1 (26/30), TGF-2 (7/30) or TGF-3 (5/30) were noted as compared to only ⅛ in the non-Peyronie's disease group.33 This single patient in the control group had a localized tunical fibrotic reaction. In all of the Peyronie's disease patients with increased TGF-1 expression, fibrotic changes in tunica albuginea biopsies were reported.33 If increased expression of TGF-1 is causal in Peyronie's disease, one would like to validate this mechanism in a cell culture or animal model where the progression of disease can be followed. As described earlier, would healing processes involve a number of different cell types including neutrophils, macrophages and fibroblasts. These cell types can modulate each other and themselves via complex autocrine and paracrine mechanisms. Further, the collagenous connective tissue matrix plays a poorly understood role, as neutrophils, macrophages and fibroblasts must migrate through this diffuse connective tissue to the wounding site. Thus, while Peyronie's disease fibroblasts may be cultured and grown in confluent monolayers, this cell culture model may be of little use in the study of the progression of Peyronie's disease. A rat model of Peyronie's disease has been developed using subtunical injections of a synthetic heptapeptide, cytomodulin, which induces increased TGF-1 expression and/or inflammatory cell recruitment.34,35 Six weeks after cytomodulin injection 15/18 rats exhibited tunical thickening and plaque formation as well as increased TGF-1 mRNA and protein expression.34 No increases were observed in either TGF-2 or TGF-3 mRNA or protein expression.34 Finally, electron microscopy revealed the infiltration of inflammatory cells as well as disorganized collagen fibrils.35 This model is indeed a significant advance as it allows following the progression of disease as well as a system for the evaluation of pharmacotherapeutics for Peyronie's disease.

Molecular mechanisms: oxidative damage and the role of free radicals

During chronic disease states of hepatic, pulmonary, arterial (eg peripheral vascular) and nervous system tissue degeneration, in addition to fibrogenesis and an increase in connective tissue, there is an increase in oxidative stress.36 This stress in the form of free radicals (superoxide, peroxynitrite and peroxide generated species) can result in lipid peroxidation and tissue damage as well as stimulate connective tissue synthesis in fibroblasts and increase activity in inflammatory phagocytic cells such as neutrophils and macrophages.35 Therapeutically, this concept prompted the use of intraplaque injections of superoxide dismutase which scavenges and detoxifies superoxide produced by respiratory enzymes as well as tissue degeneration (see later). The degree that cytokines such as TGF-1 and PDGF, abnormal wound healing, trauma and/or oxidative damage contribute to Peyronie's disease remains to be elucidated.

Therapeutics and the molecular pathology of Peyronie's disease

How do these mechanisms correlate with current therapeutic treatment of this disease? There are two basic categories of pharmacotherapeutics that have been used in Peyronie's disease; anti-oxidants and collagen synthesis inhibitors. As described briefly earlier, it has been hypothesized that oxidative damage may be causal in the initiation and progression of tissue fibrosis.36 While there is limited reported efficacy and no double blinded trials, both para-aminobenzoic acid37 and vitamin E38 have been reported as a treatment of Peyronie's disease. Intraplaque injection of the anti-inflammatory protein orgotein39,40,41,42 which has superoxide dismutase activity or bovine superoxide dismutase43 are reported to improve symptoms in Peyronie's patients, although adequate clinical trials are lacking. Of the collagen synthesis inhibitors, verapamil, colchicine and interferon as well as collagenase have been reported. Verapamil, a calcium channel blocker, inhibits connective tissue synthesis in fibroblasts and has been shown to be effective in softening and dissolving plaques in the early stages of disease when injected into the plaques.44,45 Colchicine, a microtubule polymerization inhibitor, also inhibits connective tissue synthesis in fibroblasts and has shown limited efficacy in Peyronie's disease patients when administered orally.46 Initial trials of intra-plaque injection with collagenase have been disappointing.47 Intralesional injection of either alpha 2A or alpha 2B interferon have also been reported with mixed results.48,49 Oral tamoxifen has been tested as a therapeutic agent to treat Peyronie's disease.50 Tamoxifen, an anti-estrogen, is thought to work by inducing TGF-1 expression. The authors of this study speculate that increased TGF-1 inhibits inflammatory cell responses that precipitate a fibrotic response. Tamoxifen may act through a different pathway than the one the authors propose. Further research is needed to clarify its mechanism of action. In all of the pharmacotherapeutic treatments briefly reviewed here, patient improvement ranged from a few per cent to 25-30% depending on the endpoint used.

Summary

Peyronie's disease is a fibrotic disorder of the tunica albuginea involving potential trauma to the penis and an inflammatory response. The fibrotic plaques that form are produced most likely by tunical fibroblasts in response to cytokine stimulation. Of the candidate cytokines, TGF-1 and possibly PDGF play a role. To date, pharmacotherapy has not been effective or widely accepted and surgery to either remove the plaque or insert penile prostheses remains the mainstay of treatment. A better understanding of the molecular pathology of this disease is expected to improve pharmacotherapeutic strategies to treat this condition.


References

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[justbob]

Would off-label use of Rituximab be worth exploring?  Not a drug to be taken lightly due to risk of potentially serious side effects but has been used in established autoimmune disorders with good outcome.  To what extent is there agreement that Peyronie's has a major autoimmune component?


http://www.medscape.com/viewarticle/538093

Jan 24, 2005

Paris, France - Although the B-cell depleter rituximab (Rituxan, MabThera; Genentech/IDEC) is not yet marketed for use in the treatment of autoimmune diseases, it is already being used off label in routine clinical practice, a French survey has found. Dr Xavier Mariette (Service de Rhumatologie Hopital Bicetre, Le Kremlin-Bicetre, France) and colleagues report on rituximab treatment of 43 patients identified in a survey of 866 rheumatologists and internists published online December 15, 2004 in the Annals of the Rheumatic Diseases [ 1 ].

Our main findings were that rituximab had considerable efficacy in rheumatoid arthritis, systemic lupus erythematosus, primary Sjogren's syndrome, vasculitis, and some other inflammatory arthritides and was relatively well tolerated in these patients.

The researchers were surprised at how frequently rituximab was being used in patients with systemic autoimmune diseases. "Despite the absence of marketing authorization in these indications and taking into account that the drug is available for lymphoma and well tolerated, leader clinicians in some teaching hospitals have used it in cases of severe refractory autoimmune diseases, but with the agreement of the local committees on prescription of new drugs, in most cases," Mariette says.

Retrospective study finds widespread use

This retrospective study found that rituximab was prescribed for lymphoma in 2 patients with RA and 2 with pSS and because the autoimmune disease was refractory in the other 39 cases.

Efficacy was assessed by Disease Activity Score in 28 joints (DAS28) in RA, the SLE Disease Activity Index (SLEDAI) in SLE, and the clinician's estimate of a decrease of 50% or more in disease activity in other autoimmune diseases.

Rituximab was judged effective in 11 of 14 RA patients, 9 of 13 SLE patients, 5 of 6 pSS patients, 2 of 5 systemic vasculitis patients, and 3 of 5 patients with other autoimmune diseases. Responders were able to decrease daily corticosteroid intake by a mean 9.5 mg/day.

The researchers judged that tolerance of rituximab was good. There were 11 adverse events in 10 patients, in 6 of whom treatment was discontinued due to adverse effects.

Mariette says that trying an empirical course of rituximab might be a reasonable approach in RA patients who have not responded to TNF inhibitors, in severe refractory lupus, in severe Sjogren's with systemic involvement, or in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis refractory to cyclophosphamide.

"Controlled trials [of rituximab] are in process in RA and in ANCA-associated vasculitis. They are going to start in lupus in the next few weeks. Our group is working to begin a controlled study in Sjogren's, I hope before the end of the year," Mariette says.

[George999]

Note that there is a lot of disagreement.  Nobody seems to get that ALL of these "causes" are inter related, not stand alone.  Eventually they will realize that all of these factors are involved in one way or another.  - George

[George999]

Would off-label use of Rituximab be worth exploring?  Not a drug to be taken lightly due to risk of potentially serious side effects but has been used in established autoimmune disorders with good outcome.  To what extent is there agreement that Peyronie's has a major autoimmune component?

I think you would be hard pressed to find a doc that would prescribe this kind of drug for Peyronie's.  They don't even like to prescribe Pentox which is cheap and safe.  Rituximab is extremely expensive and has horrendous side effects.  When they use the term "well tolerated", this is only in comparison to other options for treating DEADLY diseases.  People DIE from serious cases of the diseases you mentioned.  People do not DIE from Peyronie's.  Rituximab is in a class of meds that docs are VERY careful about.  - George

[Tristen]

I appreciate everyone's input.  The more I look into this the more I believe at least for me it's AI.  Needs to be some kind of micro trauma in the penis, and that starts an autoimmune process over compensating a mending process (plaque) to the injured area .

My Urologist believes it to be genetic, and not AI.  But I have other arthritic syndrome type things happening that lead me to believe it's AI.  Valuable info.

Thanks everyone