Review of medical treament - nothing new

I've not added much to my blog posts because very little is happening with the understanding or management of Peyronie's Disease. I try to post when I find something novel.

This article doesn't have anything new, but it's a good summary of the urologist's current medical approach (emphasis mine and I've reformatted for readability):

Medical Management of Peyronie's Disease. [J Androl. 2008] - PubMed Result

Peyronie's disease (PD) is a wound healing disorder in which a fibrotic plaque forms in the tunica albuginea layer of the penis. It clinically presents as any combination of penile pain, angulation, and erectile dysfunction (ED).

Recent studies indicate that PD has prevalence of 3-9% in adult men.

While the exact etiology has not been established, PD likely results from a predisposing genetic susceptibility combined with an inciting event such as microtrauma during intercourse. During the initial acute phase (6-18 months), the condition may progress, stabilize, or regress.

For this reason authorities recommend a more conservative treatment approach with a trial of oral and/or intralesional pharmacotherapy before surgical reconstruction is considered.

Oral therapies most commonly employed include tocopherol (vitamin E), and para-aminobenzoate (Potaba), with colchicine, tamoxifen, propoleum and acetyl-L-carnitine being used less often. There are a limited number of long-term placebo- controlled studies with these oral agents and for the most part, studies have failed to show a consistent beneficial effect.

Intralesional injection therapy for PD is more commonly being used as a first line therapy. The current standard of care includes injection with interferon-alpha-2b, verapamil, or collagenase.

Interferon-alpha-2b, in particular, has been documented in a large, multicenter, placebo-controlled study to show significant benefit over placebo in decreasing penile curvature, plaque size, penile pain, and plaque density.

However, intralesional interferon is associated with post treatment flu-like symptoms unless premedicated with a non-steroid anti-inflammatory agent. Other available therapies that have not consistently shown efficacy in placebo-controlled studies include corticosteroids, orgotein, radiation, and extracorporeal shockwave therapy (ESWT).

Surgery is considered when PD men do not respond to conservative or medical therapy for approximately 1 year and cannot perform satisfactory sexual intercourse...

Translating from the jargon I'd summarize this as:

1. Most treatments have been shown not to work and should be abandoned.
2. Interferon-alpha-2b injection may be worth trying in the acute phase, but be ready for side-effects. I'd recommend asking for an explanation of exactly how much improvement was found, and whether the improvement was age group specific. Interferon injections have been proposed for many problems and they are usually found to be ineffective. This would be more persuasive if there were solid physiologic reasons to think it should work.
3. The "wound healing" explanation is not confirmed. I suspect the cause varies with age of onset, and that there may be a common predisposition both to injury and to dysfunctional healing.
   

The article does not address how well surgery works, it's a medical review. Long term surgical outcomes have been mixed at best.

The take away is to consider the interferon but cautiously. We haven't learned all that much about Peyronie's in the past 10 years, but at maybe we're using fewer ineffective treatments.

Another 1960s article on Peyronie's and other "collagen" disorders

This French article from 1964 is the second I've come across discussion combinations of Peyronie's disordr with other disorders of fibrosis ("collagen" in those days): [A COLLAGEN TRIAD: LA PEYRONIE'S DISEASE, DUPUYTRE...[J Urol Nephrol (Paris). 1964]

It's an area of research that died out in the 1960s apparently.

The triad was "PEYRONIE'S DISEASE, DUPUYTREN'S DISEASE AND FIBROSIS OF THE AURICULAR CARTILAGE". I don't know the last, but for what it's worth I used to have odd lumps of fibrous material in my pinnae (soft tissue at base of the auricle) though they've since faded.

It would be interesting to get hold of one of these old, old articles ....

Peyronie's Disease: Type I and Type II?

I've been thinking about the results of a very recent study of the natural history of Peyronie's Disease. I'm thinking the study suggests that there may be two types of Peyronie's disease, early onset (Type I?) and late onset (Type II?) with an age cutoff of 50.

Fifty is a special age. Throughout most of human evolution men did not live past fifty. Nothing is really designed to last that long; life much past fifty requires a cozy environment and, often, some medical care. So things that go wrong after fifty are often normal "wear and tear". That's a clue.

My guess is that Peyronie's after 50 is mostly a bit of bad luck. The course of late onset Peyronie's is relatively benign. Progression is limited. Symptoms may resolve. It sounds more like an unlucky tear or injury to a sub-optimal tunica albuginea than a true disease. It's a vulnerable structure, sometimes it's less well made, it can tear.

Early onset Peyronie's, developing before age 50, is another story. The disease seems to progress, and may do so without evidence of repeated trauma. This seems more like a pathologic process, a genetic disorder of fibrocyte perhaps.

They may be the same condition of course, or related conditions, but I suspect we'll learn more about Peyronie's if we study early onset and late onset disease separately. If we study them together, we may miss important signals in the noise.

Why research Peyronies? To understand asthma, heart disease, chronic cystitis ...

If Peyronie's is best understood as a hyperactive fibrosis disorder, then it makes sense to look at other fibrotic disorders for clues to Peyronie's. This 2007 article provides a nice overview of current thinkings on disorders of the fibrotic response (emphases mine, I've always been fond of moncytes ..):

The role of the fibrocyte, a bone marrow-derived m...[Lab Invest. 2007] - PubMed Result

... Human fibrocytes are mesenchymal progenitors that exhibit ... characteristics of hematopoietic stem cells, monocytes and fibroblasts. They likely represent the obligate intermediate stage of differentiation into mature mesenchymal cells of a bone marrow-derived precursor of the monocyte lineage ...

... human fibrocytes produce large quantities of extracellular matrix components and further differentiate into cells identical to the contractile myofibroblasts that emerge at the tissue sites during repair processes and in some fibrotic lesions. ...

...a causal link between fibrocyte accumulation and ongoing tissue fibrogenesis or vascular remodeling in response to tissue damage or hypoxia. Fibrocytes synthesizing new collagen or acquiring myofibroblast markers have been detected in human hypertrophic scars, in the skin of patients affected by nephrogenic systemic fibrosis, in human atherosclerotic lesions, and in pulmonary diseases characterized by repeated cycles of inflammation and repair, like asthma. The presence of fibrocyte-like cells has been reported in human chronic pancreatitis and chronic cystitis. Similar cells also populate the stroma surrounding human benign tumors...

Well, there you go. Perhaps understanding Peyronie's may provide valuable clues for understanding asthma, atherosclerosis (heart disease) and chronic pancreatitis. After all, the lesions of Peyronie's are much easier to biopsy than those of cardiac vessels or pulmonary alveoli. If that's not good for funding, I don't know what is.

I looked earlier for an association between keloid (hypertrophic) scars and Peyronie's, but I couldn't find any. That would be a good question for the Peyronie's Society forum though. For the record, I have both Peyronie's and a nasty keloid scar.

Chronic cystitis is the bane of urologists. One wonders if it could be the female equivalent to Peyronie's. Now I admit that's a bit nutty, but it wouldn't hurt to ask women with chronic cystitis if they have relatives with Dupuytren's contractures (they probably wouldn't know of male relatives with Peyronie's).

Update 7/4/07: After my wild speculation on Dupuytren's and chronic insterstitial cystitis I tried a Google search on the combo and got this tantalizing fragment from last year:

Dupuytren's contracture is associated with sprouting of substance ...
... 10 We propose that Dupuytren's contracture is an inflammatory disease dominated by mast cells, bearing similarities to interstitial cystitis. ...
ard.bmjjournals.com/cgi/content/full/65/3/414

I swear I didn't know that was out there. Alas, I can't get at the full text of the article, I'll have to try it from my U account another time. It's the only one and it sounds like an aside deep in the text, but maybe my speculation wasn't quite as whacky as I thought it was ...

Peyronie's and chromosomal abnormalities

In my prior post I reviewed the OMIM entry on Peyronie's. That entry cited a 1987 and a 1991 (yeah, research is slow in this domain) article on chromosomal anomalies in the abnormal plaque tissue of the tunica albuginea found in Peyronie's disease.

These articles make the plaques seem more like a tumor than a conventional scar. Pubmed lets one query for "related articles" on a given topic, here's what that query looks like:

• Multiple clonal chromosome abnormalities in Peyronie's disease - 1991

One of the articles that turned up was interesting, emphases mine:

Mulhall JP et al. Chromosomal instability is de...[PMID: 14961053]

... Peyronie's disease is a fibrotic disorder, a condition characterized by cellular proliferation and excess extracellular matrix production. Previous work in related conditions has demonstrated chromosomal instability. This investigation was undertaken to analyze fibroblasts derived from Peyronie's disease tunical tissue for abnormalities of chromosome number and progression of cytogenetic aberrations during cell culture...

... Peyronie's disease plaque-derived fibroblasts demonstrated frequent aneusomies in chromosomes 7, 8, 17, 18 and X and recurrent deletions of chromosome Y. Peyronie's disease nonplaque tunica-derived fibroblasts demonstrated infrequent chromosomal changes early in culture; however, with repeated passaging the majority of cell cultures demonstrated aneusomies [ed: extra copies] in at least one chromosome. These data indicate that Peyronie's disease plaque-derived fibroblasts have consistent aneusomies even at early passage and that nonplaque tunica-derived cells from men with Peyronie's disease also demonstrate chromosomal instability. This suggests that the tunica albuginea of men with Peyronie's disease may be predisposed to undergoing unregulated fibrosis. These findings confirm the transformed nature of the Peyronie's disease tunical fibroblasts studied in this analysis. While the etiology of these findings is not clear, it is likely that these pathobiological characteristics contribute to the pathophysiology of this disease process.

In other words men who develop Peyronie's Disease have something wrong with all the cells of their "tunica albuginea", not only those involved in Peyronie's. Of course this implies there's something wrong with at least those cells everywhere in the body.

In particular the cells are prone to a crazed kind of fibrosis (tough fiber generation) instead of a reasoned, measured, sort of fibrotic reaction.

It would be interesting to know what other conditions this presumably genetic defect may predispose to -- besides Dupuytren's contracture.

From a science point of view, this study tells us something fairly interesting. There's very little active research in Peyronie's, but it's studied using tools that are developed for other, actively studied, domains. A competent researcher can simply repeat a study from 10 years ago, and by virtue of better tools new knowledge will emerge.

OMIM - The Peyronie Discussion

OMIM, the "online mendelian inheritance in man" NIH database, published out of Johns Hopkins, is a formidable reference source. The discussion of "Peyronie Disease", however, is a bit eccentric. For example: "An anonymous nongeneticist suggested to me in 1980 that Peyronie disease is 'sex-linked with reduced penetrance.'" Cough. That doesn't show up in most of the OMIM posts, I get a feeling this one is under-edited.

Even so, I've excerpted and bolded some sections.

OMIM - PEYRONIE DISEASE

... Bias et al. (1982) concluded that this phenotype is a male-limited, autosomal dominant trait. They traced Peyronie disease through several families. Dupuytren contracture was often present in both males and females. In 1 kindred, males in 3 successive generations had Peyronie disease and Dupuytren contractures, and the latter was present in a fourth generation. Close linkage with HLA (see 142800) was excluded. Chromosomal abnormalities were described by Somers et al. (1987) and by Guerneri et al. (1991).

In Rome, Carrieri et al. (1998) performed a case-control study of 134 men with Peyronie disease and 134 male controls. Men who had undergone invasive procedures on the penis (e.g., urethral catheterization, cystoscopy, and transurethral prostatectomy) had a 16-fold increased risk of Peyronie disease, while a nearly 3-fold increase was observed among men who had genital and/or perineal trauma. ...

... Dupuytren contracture was found in 21% of cases and none of the controls, and 4% of the cases and none of the controls reported familial history for Peyronie disease.

Note that the key research on the genetics of Peyronie's was done twenty-five years ago, and yet it's omitted from most discussions of the disorder (I'll be adding it to Wikipedia.) I was very surprised by the 16-fold increase with urethral catheterization.

If I were a urologist, I would routinely ask prior to any urologic procedure whether the patient had any relatives with Dupuytren's contracture. If they did, I'd reconsider the need for the procedure. A 16-fold increase is enormous.

It's most likely that Peyronie's Disease is a pathologic reaction to common micro-trauma of the penile vasculature. Men who don't carry* the gene may develop small scars or non-significant plaques, men who carry the gene* develop plaques and pathologic scarring.

* Genetics is far more complex than it once was. Now when we say "carry" we mean something like "a complex of interacting genetic material" with one or more interacting mutations.