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[PeetyPeet]

Hi all,

I've bought the recently published book 'Male Sexual Dysfunction' edited by John Mulhall and Suks Minhas. Suks Minhas is a uroandrologist and is considered one of the current leading researchers and authorities on penile health. Reviews of him (and/or his clinic) on the forum however, are mixed.

The book is mostly about Erectile Dysfunction but there are two chapters dedicated to Peyronies Disease - "Non-surgical therapy for Peyronies Disease' and "Surgical treatment of Peyronies Disease". I'm slowly working my way through making relevant notes which I will post on the forum for info and discussion whenever I can. So far it doesn't look like there's anything new here, but I suppose this book represents current conventional approaches to Peyronies Disease and it might be useful to anyone considering an appt with Mr Minhas. Before you ask, alas, no, he does not prescribe Pentox.

Below is a summary of the 'Oral treatments' section of the first Peyronies Disease chapter. Also included is a relevant intro to the disease. What I've noticed is that there is no discussion or studies which address the timing of oral treatments, even though acute and chronic phases are clearly identified. This seems to be a massive oversight.

Hope this is helpful to someone.

Best

Peety





Intro for Non-surgical therapy for peyronie’s disease:

1.   Characterised by formation of fibrotic plaques within the tunica albuginea leading to penile pain and curvature.
2.   Most common form of presentation is curvature preventing sex but also: pain, worry about palpable lump, Erectile Dysfunction, change in penis shape. Also shortening and a loss of self-esteem and sexual confidence.
3.   Peyronies Disease often depressing condition.
4.   Cause not fully understood but most widely accepted hypothesis is repeated microvascular injury or trauma to tunica albuginea coupled with abnormal wound healing. Result is inelastic fibrous plaque.
5.   Number of conditions support notion of microvascular damage: hypertension, diabetes, smoking, dyslipdemia, and obesity.
6.   Two phases in Peyronies Disease:  Acute = active inflammation with increased proliferation of tunical fibroblasts (cells which produce collagen) which result in excessive deposition of collagen.
7.   Increasing deformityof erect penis and penile pain occur in some but not all patients.
8.   Acute phase usually lasts up to 6 months.
9.   Chronic phase = disordered wound healing resulting in plaque stabilization and resolution of pain.
10.   Variety of molecular mechanisms have been described in connection with Peyronies Disease.
11.   Well described mechanism is involvement of TFG-B1 (Transforming Growth Factor B1) in accumulation of collagen. TGF-B1 activation results in increase in connective tissue synthesis and inhibition of collagenases. TGF-B1 is a cytokine (substance secreted by immune system and have effect on other cells) synthesised by a variety of cells including fibroblasts, macrophages and platelets. TGF-B1 can self-induce which may underpin development of scarring and fibrosis in Peyronies Disease.
12.   Link between TGF-B1 and Peyronies Disease shown in studies where tunica albuginea biopsy in Peyronies Disease patients showed increase in protein expression of TGF-B1 compared to non-Peyronies Disease patients
13.   Also hypothesised that oxidative damage may be causal in initiation and progression of tissue fibrosis seen in Peyronies Disease. So there is an interest in anti-oxidants and their potential effect on disease progression.
14.   Treatment options depend on stage and severity of disease.
15.   Spontaneous improvement in curvature in up to 10% of patients, so there should be at least some period of observation.
16.   Surgical intervention widely accepted as mainstay of treatment in severe cases, once patient has stable disease.
17.   However, primary aim of intervention is to keep patients sexually active by restricting curvature progression, as such considerable interest in attempting to halt disease process in early phase with oral medication and intralesional injections.


Oral Therapies for Peyronies Disease

1.   Focus of oral therapies is to disrupt inflammatory process in acute phase or disordered wound healing in in chronic phase., in order to stabilise or reduce curvature.
2.   Advantages of successful oral therapy: 1. Reduce morbidity due to Peyronies Disease. 2. Reduce need for invasive surgery 3. Offer alternative for patients not suitable for surgery.
3.   There have been a number of trials of oral meds but lack of robust randomised controlled trials that demonstrate clear benefit of any single drug.
4.   FDA has only approved Potaba, which is classed as ‘possible effective’.

Potaba
1.   No studies show convincingly any significant improvement in symptoms, curvature and plaque size.
2.   Decreasing popularity due to high costs and side effects – gastrointestinal, photosensitivity.
3.   Mechanism of action: anti-fibrotic effect but exact mechanism unclear. Theory is that increased oxygen utilization promotes degradation if serotonin by enhancing monoamine oxidases (MAO). This rebalances effects of MAO and serotonin at tissue level.
4.   Evidence: RCT in 2005 – significant plaque related effect. Drug may stabilise disease by preventing curvature progression.
5.   Advantages: Improves penile pain and plaque size but results have not been reproducible.
6.   Disadvantages: Expensive. Multiple dosing. Side effects: nausea, anorexia, photosensitivity, anxiety, difficulty concentrating plus others.

Vitamin E
1.   Initially support for use in literature but more recent studies show now support for practice.
2.   More recently trialled in combo with other therapies with has caused renewed interest in its use.
3.   Individual efficacy is unclear.
4.   More robust RCTs needed to demonstrate potential effect of Vit E.
5.   Mechanism of action: Acts as antioxidant by scavenging oxygen free radicals which are thought to promote fibrosis.
6.   Evidence: Conflicting results. 2 recent studies failed to show stat significant improvements. More encouraging evidence from use with other agents.
7.   Advantages: Widely available. Low toxicity. Low cost.
8.   Disadvantages: Minimal reproducible evidence of any benefits.

Tamoxifen
1.   Study in 1990s after drug shown to be effective in treatment of desmoid tumours. Condition as histological similarities to Peyronies Disease.
2.   It was hoped tamoxifen’s effect on intregal TGF-B1 pathway would provide improvements.
3.   1990s Study had positive results but has not been reproduced successfully more recently.
4.   Mechanism of action: Non-steroidal anti-estrogen. Though to inhibit fibroblast proliferation and decrease collagen production by inhibiting production and release of TGF-B1.
5.   Evidence: Study: Teloken et al – no significant improvement in plaque size, curvature, pain. Study limited by small size and poor description of randomization and blinding.
6.   Advantages: Little side effects
7.   Disadvantages: poor evidence for its use.

Colchicrine
1.   Traditionally used to treat gout.
2.   1994 pilot study produced promising outcomes showing decreased plaque size and improved penile curvature. Recent robust studies have not shown same results.
3.   Also used with vit E and was initially shown to improve symptoms however conflicting evidence and no large randomised trials supporting this.
4.   Nonetheless, used widely by US Urologists to treat Peyronies Disease.
5.   Mechanism of action: not yet complete established. Has been shown to downregulate TGF-B1 in animal models. Has anti-inflammatory properties though to reduce collagen synthesis as well as potentiate collagenase activity.
6.   Evidence: Initial pilot study showed reductions in plaque size and improvements in penile curvature. More recent RCT showed no stat sig benefit. Adequately sized RCT needed for colchicrine + vit E combo.
7.   Advantages: Potential improvements. Has been used in combo. Little Side Effects. Once a day dosing.
8.   Disadvantages: no clear evidence of improved outcomes.

Acetyl Esters of Carnitine (Acetyl L carnitine)
1.   Proposed treatment for Peyronies Disease after shown to be effective in treatment of oxidative diseases and idiopathic infertility.
2.   Initial study had promising results but more recent studies have shown no sig improvements, even when combined with Vit E.
3.   Mechanism of Action: suggested that carnitines reduces intracellular calcium levels in endothelial cells resulting in reduction in collagen production and fibroblast proliferation, which in turn reduces penile fibrosis.
4.   Evidence: Study 2001 Biagiotti & Cavallini showed stat-sig outcomes in patients taking 2g/day of acetyl l-carnitine when compared to those taking tamoxifen. More recently, Safarinejad et al found no sig improvements when taken on own and in combo with vit E. Some evidence that in combo with verapamil intraplaque injection, carnitine may have benefits. However difficult to isolate active drug responsible for improvements.
5.   Advantages: May be effective in combination with other agents
6.   Disadvantages: Minimal rational and evidence for its use.

PDE5 inhibitors (Cialis, Viagra etc)
1.   Proposed that they cause inhibition of tissue remodelling after injury so may be advantageous in treatment of Peyronies Disease.
2.   Mechanism of Action: Increase cyclic GMP levels, which prevent cyclic GMP levels, which prevents deposition of collagen by inhibiting TGF-B1, oxidative stress and myofibroblast accretion.
3.   Evidence: Animal models have shown reduced plaque size and increased fibroblast apoptosis. Retrospective study looking at resolution of penile septal scare with use of PDE5i’s shows sig improvements in scar size and erectile function.
4.   Advantages: Safe. Useful in patients with co-existing erectile functions.
5.   Disadvantages: only studies that look at standard outcomes such as plque size and curvature are rat models. No human trials. Lack of RCTs.

Pentoxifylline
1.   Methylxanthine derivative that inhibits phosphodiesterase.
2.   More commonly used for vascular disease, particularly atherosclerosis in hypertensive patients with type 2 diabetes mellitus.
3.   Given that diabetes and vascular disease are associated with Peyronies Disease above is very interesting.
4.   Shown in rat models to induce regression of collagen and TGF-B1 mediated plaque formation.
5.   Also appears to have anti-inflammatory and anti-fibrogenic properties. Also successful experimental treatment in some autoimmune diseases.
6.   Results are encouraging but outcomes are by no means cures.
7.   Larger and repeated trials needed
8.   Mechanism of action: downregulated TGF-B1 mediated inflammation and inhibits deposition of type 1 collagen. Increases fibrinolytic activity (prevents blood clots).
9.   Evidence: Safarinejad et al’s 2009 RCT placebo trial is main index study supporting use in Peyronies Disease, however study retracted in 2015 due to questions over stats methods and validity. Outcomes were reduced rates of disease progression and improved penile curvature with mean change of 23.25 degrees. Also International Index of Erectile Function scores improved.
10.   Advantages: Safe. Potential benefit but evidence remains in question.
11.   Disadvantages: Minimal evidence. Marginal gains. Main study looked specifically at patients with ‘early chronic’ disease’.

Co-enzyme Q10
1.   Fat soluble vitamin-like quinolone (The quinolones are a family of synthetic broad-spectrum antibiotic drugs – Wikipedia)
2.   Decreased serum levels of CoQ10 have been found in diseases associated with oxidative stress.
3.   Potent anti-oxidant. Theory is that inflammation in acute / early chronic stages of Peyronies Disease is in part due to low anti-oxidant activity.
4.   Also reported that solubilized CoQ10 suppresses expression of TGF-B1.
5.   Mechanism of action: hypothesized that failure to respond to oxygen free radicals produced in inflammatory phase of Peyronies Disease may lead to disease progression ad therefore potent anti-oxidants such as CoQ10 may act as protection against oxidative stress.
6.   Evidence: One RCT. Improvement in erectile function. Also reduction in plaque size and penile curvature.
7.   Advantages: Safe. Cheap. RCT showed positive outcomes.
8.   Disadvantages: Small study (treatment group n=81 who completed trial period).More studies needed reproduce results.. Improvements in penile curvature more pronounced in patients with <30 degrees curves.

Omega 3
1.   Polyunsaturated fatty acid. Suggested suppress disease progression  given its inhibition of inflammation.
2.   One RCT performed. No sig improvement.
3.   Mechanism of action: Inhibits release of inflammatory cytokines and increases collagenase activity.
4.   Evidence: One RCT failed to show sig improvements.
5.   Advantages: Cheap. Safe.
6.   Disadvantages: No evidence supporting use.

[Arabia]

PeetyPeet,

That is very helpful and interesting summary from a textbook that is not even available yet in hardcover.

The underlying problem with all these oral agents is that the studies are small and non-RCT plus some of the more interesting and hopeful studies were done by that urologist in Iran, Safarinejad, who had many of his studies subsequently retracted including the one showing that Pentox might be beneficial.
Link deleted by moderator! Links to commercial sites are not allowed. The site is soliciting for financial support!!!

And I would agree wholeheartedly that with any future studies we need to identify the phase of disease the patient is in prior to starting.  Also measuring the curvature before and after treatment should be mandatory.  The patients could submit photos and researchers could measure the curvature in a standardized fashion.

I'd also like to see an independent third party analysis of any oral agent used in future studies because so many of these supplements do not have the concentration of active ingredient claimed. 

This phenomena  was on full display recently in studies which have looked at using chondroitin sulfate (CS) for osteoarthritis.  One of the reasons the results have been all over the place is that the CS, even the pharmaceutical grade CS, was suspect.  This study showed that out of 15 pharmaceutical-grade CS products sampled only 5 had > 90% CS and 11 had < 15% CS!  And that is pharma grade CS so imagine the retail grade junk you get in the health food stores.  I'm sure the same problem exists with much of the oral product being purchased to treat Peyronies Disease.
https://www.ncbi.nlm.nih.gov/pubmed/26428128   (full free article available)

What we need are much better epidemiology studies looking at what are the factors behind this disease. 

Aside from better prevalence data where is the data on who is getting this disease with regard to type and frequency of sexual activity.  Intercourse vs. masturbation, etc.

A recurring theme that one seems to read on here aside from the disease being more prevalent with age and possibly with more aggressive sexual activity is that the onset seems to often happen during periods of high personal stress or high allostatic load.   What are the hormonal changes under these conditions that might tip the balance towards high TGF-B concentrations and the propensity to form fibrotic penile plaques?  Is high allostatic load a factor in Peyronies Disease formation given we know that with age individuals cope less effectively with high allostatic load.

Too many questions and not enough research going on for a disease that affects 3% to 10% of the male population. 
 

[Arabia]

Retraction Watch is hardly a commercial site any more than is the American Cancer Society's website which asks for "donations" to keep the "volunteer" organization going.

If anything members on this forum should be supportive of it is sites like Retraction Watch (RW) which has a volunteer board plus it is sites like RW which help publicize the junk science and outright fraud in studies that push possible products to members here that are no better than placebo or in fact have dangerous side effects. 

So here is the link to the one retracted Pentox study in question but what Retraction Watch had done is list all six studies which were retracted by this author. One study retracted and we might give the author the benefit of the doubt, but when when RW reports six have been retracted that is important information for members on this forum to be aware of.
https://www.ncbi.nlm.nih.gov/pubmed/19863517

I find the moderating on what is generally an excellent forum at times to be pedantic and rigid which may have the effect of driving away those who expect some nuanced thinking on what one would hope is an evidence-based adult website.

And yes I have read the forum rules several times.

[PeetyPeet]

A recurring theme that one seems to read on here aside from the disease being more prevalent with age and possibly with more aggressive sexual activity is that the onset seems to often happen during periods of high personal stress or high allostatic load.   What are the hormonal changes under these conditions that might tip the balance towards high TGF-B concentrations and the propensity to form fibrotic penile plaques?  Is high allostatic load a factor in Peyronies Disease formation given we know that with age individuals cope less effectively with high allostatic load.

Agreed. Here's an exert of my notes from the Epidemiology chapter.

"Testosterone has a major role in maintaining health of penile tissues. Study by Moreno and Morgentaler – severity of penile curvature correlated significantly with free testosterone level but not with total testosterone level. – suggests link between T deficiency and Peyronies Disease."

I plan to read more about the endocrine system but my layman's understanding is that during periods of stress the body releases the 'stress hormone' cortisone, which in turn raises estrogen and lowers testosterone...which will inevitably have an impact on the body particularly if the stress is sustained. Stress may have its roots in mental health but the physical effects on the body are real.

By the way, the book was published in hardback in February (n the UK at least).

Peety