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[Tim468]

I get a weekly update on the literature - I can not access all of these in their entirety. The LA articles are, as usual, the best, IMHO.

Some are better than others and I bolded some highlights (IMO).

Tim

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<<2>
UI 19138374
AU Muller A.  Mulhall JP.
FA Muller, Alexander.  Mulhall, John P.
IN Department of Urology, Weill Medical College Of Cornell
  University, New York Presbyterian Hospital, New York, NY, USA.
TI Peyronie's disease intervention trials: methodological challenges
  and issues. [Review] [53 refs]
SO Journal of Sexual Medicine.  6(3):848-61, 2009 Mar.
AB INTRODUCTION: Peyronie's Disease (Peyronies Disease) has been studied for more
  than 260 years since Francois de la Peyronie's description in 1743.
  Based on the current literature, the prevalence of Peyronies Disease seems 3-9%
  with an average age of onset in the fifth life decade. Much effort
  has been spent on developing nonsurgical treatment options to cure
  or at least prevent disease progression. AIM: The recent examination
  of drug trials for erectile dysfunction has led us to assess Peyronies Disease
  trial methodology more closely. METHODS: An Iinternet search on
  PubMed was performed using MeSH words Peyronies Disease, clinical trials, oral,
  transdermal, intralesional and shock wave therapy focusing on 26
  representing studies published over the last 15 years. Mean Outcome
  Measures. A comprehensive review of the current literature on
  nonsurgical treatment options for Peyronies Disease was conducted to address
  methodological issues and challenges in Peyronies Disease trials highlighting trial
  design, patient population, and symptom and sign assessment.
  RESULTS: The majority of the reviewed studies are underpowered and
  the heterogeneity in the methodological approach and patient
  assessment between the studies is one of the remarkable findings
  from our review. Studies should use a uniform means of defining the
  degree and type of penile deformity and a large enough cohort of
  patients should be studied for adequate study power. An ideally
  designed Peyronies Disease intervention trial should comprise: (i) a randomized,
  placebo-controlled design; (ii) with a Peyronies Disease patient set representative
  of the general Peyronies Disease population; and (iii) a comprehensive symptom and
  sign assessment before and at the end of treatment which includes an
  assessment of at least deformity, pain, and sexual function.
  CONCLUSION: A number of challenges exist for the design of Peyronies Disease
  intervention trials and deciphering the data generated from them.
  The field would benefit greatly from a consensus statement or
  guidelines development on the design and conduct of such trials.
  [References: 53]
PT Journal Article.  Review.

<3>
UI 19284472
AU Bacal V.  Rumohr J.  Sturm R.  Lipshultz LI.  Schumacher M.
  Grober Erectile Dysfunction.
FA Bacal, Vanessa.  Rumohr, John.  Sturm, Renea.  Lipshultz, Larry
  I.  Schumacher, Michael.  Grober, Ethan D.
IN Division of Urology, Mount Sinai and Women's College Hospital,
  University of Toronto, Toronto, ON, Canada.
TI Correlation of degree of penile curvature between patient
  estimates and objective measures among men with Peyronie's disease.
SO Journal of Sexual Medicine.  6(3):862-5, 2009 Mar.
AB INTRODUCTION: : Among men with Peyronie's disease (Peyronies Disease), the
  degree of penile curvature has significant implications on
  psychological well-being, sexual function, treatment planning, and
  posttherapy evaluations. AIM: The primary objective of the current
  study was to correlate patients' estimates of penile angulation with
  objective measures. MAIN OUTCOME MEASURES: (i) Proportion of
  patients over- or underestimating their actual degree of curvature;
  and (ii) degree differences between patient estimates and objective
  measures of penile curvature. Methods. At baseline, patients with
  established Peyronies Disease were asked to provide a "best estimate" of their
  degree of penile curvature. Objective measures of penile angulation
  were then performed using standardized photographs and
  protractor-based measurement of penile curvature during full
  erection. Correlations were performed between patient estimates of
  penile curvature and objective measures of penile angulation.
  RESULTS: Eighty-one men with established Peyronies Disease and a mean age of 52
  years (range: 20-72 years) were prospectively evaluated. Mean
  duration of disease was 33 months (range: 6-276 months), and mean
  plaque size was 1.4 cm +/- 0.1 standardized error (SE). The
  proportion of patients with dorsal, lateral, and ventral curvatures
  was 39%, 57%, and 4%, respectively. Patient estimates of baseline
  penile curvature (mean 51 degrees +/- 3.1 SE) differed significantly
  from objective measurements (mean 40 degrees +/- 2.4, P = 0.001). A
  significantly higher proportion of patients overestimate their
  actual degree of penile curvature (54% overestimate, 26%
  underestimate, and 20% are accurate within 5 degrees, P = 0.002).
  Compared with objective measures, patients' estimates of degree of
  penile curvature differed by an average of 20 degrees +/- 2.2 SE.
  CONCLUSIONS: Patients with Peyronies Disease tend to overestimate their degree of
  penile curvature. Objective measurement of penile angulation is
  necessary to accurately counsel patients regarding disease severity,
  recommend appropriate treatment strategies, and objectively evaluate
  outcomes following therapy.
PT Journal Article.

<5>
Full Text Link Available
UI 18778497
AU Zimmermann RP.  Feil G.  Bock C.  Hoeltl L.  Stenzl A.
FA Zimmermann, Reinhold P.  Feil, Gerhard.  Bock, Conny.  Hoeltl,
  Lorenz.  Stenzl, Arnulf.
IN Department of Urology, Elisabethinen Hospital, University
  Affiliated Hospital, Universities of Vienna and Innsbruck, Linz,
  Austria.
TI Significant alterations of serum cytokine levels in patients with
  Peyronie's disease.
SO International Braz J Urol.  34(4):457-66; discussion 466, 2008
  Jul-Aug.
AB OBJECTIVE: To determine the expression of the cytokines
  transforming growth factor-beta1 (TGF-beta1), interferon-gamma
  (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha
  (TNF-alpha) in serum from patients with Peyronie's disease (Peyronies Disease)
  compared to healthy controls. MATERIALS AND METHODS: Ninety-one
  consecutive Peyronies Disease patients aged 20 - 74 years were included in this
  study. All patients were diagnosed with symptomatic Peyronies Disease for the first
  time and had a palpable penile plaque. The patients previously had
  the disease for 6 - 72 months. None of the patients had a severe
  infectious disease or known systemic illness. For cytokine analyses,
  peripheral venous blood samples were obtained before treatment.
  Fifty healthy male blood donors aged 22 - 64 years served as the
  control group. TGF-beta1, IFN-gamma, Il-6, and TNF-alpha were
  analyzed quantitatively with commercial immunoassays. RESULTS: Mean
  cytokine levels in serum from patients were increased for TGF-beta1
  and IFN-gamma compared to healthy controls. The difference for
  TGF-beta1 was considered statistically significant (p < 0.001). IL-6
  was not detectable in Peyronies Disease patients (p < 0.01) and TNF-alpha was
  decreased (p < 0.0001). CONCLUSION: The significantly elevated serum
  level of the profibrotic TGF-beta1 cytokine underscores the effect
  of cytokines in the pathophysiology of Peyronies Disease. The significantly
  decreased TNF-alpha serum level suggested no acute immunomodulatory
  process. Therefore, the relevance for therapeutic administration of
  TNF-alpha should be further investigated. Quantification of
  TGF-beta1 in serum of Peyronies Disease patients provides a possible diagnostic
  tool and target for therapy. The data on altered cytokine levels in
  Peyronies Disease patients also provide a new understanding for etiopathogenesis of
  Peyronies Disease, which warrants further investigation.
PT Journal Article.

<6>
UI 19138365
AU Gonzalez-Cadavid NF.  Rajfer J.
FA Gonzalez-Cadavid, Nestor F.  Rajfer, Jacob.
IN Los Angeles Biomedical Research Institute at Harbor-UCLA Medical
  Center-Urology Research Laboratory, Torrance, CA, USA.
  [email protected]
TI Experimental models of Peyronie's disease. Implications for new
  therapies. [Review] [56 refs]
SO Journal of Sexual Medicine.  6(2):303-13, 2009 Feb.
AB INTRODUCTION: Despite its high prevalence and impact on the
  quality of life of patients, and that it is an excellent model for
  the study of fibrotic processes, Peyronie's disease (Peyronies Disease) is an
  orphan disease in biomedical research. The development of animal and
  cell culture models has advanced substantially the understanding of
  its molecular and cellular pathology and the proposal of new
  therapies. AIM: To review the literature pertaining to the use of
  these models for the study of Peyronies Disease. METHODS: PubMed search conducted
  from the first report of an animal model for Peyronies Disease. RESULTS: This
  model, based on the finding that transforming growth factor beta1
  (TGF beta 1) is overexpressed in the Peyronies Disease plaque, consists on the
  injection of TGF beta 1 into the tunica albuginea of the rat. This
  leads to a Peyronies Disease-like plaque retaining many of the histological and
  biochemical features of human Peyronies Disease. Another rat model, based on the
  hypothesis that the Peyronies Disease plaque arises from trauma to the penis,
  causing fibrinogen extravasation that initiates as fibrin a fibrotic
  response, consists on injection of fibrin into the tunica. The cell
  culture model is based on the demonstration that myofibroblasts are
  abundant in the human Peyronies Disease plaque. CONCLUSIONS: These models have: (i)
  clarified the role of microtrauma, myofibroblasts, and oxidative
  stress in plaque development; (ii) demonstrated that this tissue is
  under sustained turnover by fibrotic and antifibrotic mechanisms;
  (iii) showed the interplay of collagenolytic and fibrinolytic
  systems and their inhibitors; (iv) detected an endogenous
  antifibrotic process consisting of the expression of inducible
  nitric oxide synthase that counteracts oxidative stress, collagen
  synthesis, and myofibroblast generation; (v) characterized the
  antifibrotic effects of chronic treatment with phosphodiesterase
  type 5 (PDE5) inhibitors; (vi) discovered the cytogenetic
  instability of Peyronies Disease cells and alterations in their gene expression;
  and (vii) detected stem cells in the tunica albuginea with a
  potential role in fibrosis and ossification. [References: 56] PT Journal Article.  Research Support, N.I.H., Extramural.  Research
  Support, U.S. Gov't, Non-P.H.S..  Review.

<7>
UI 19138361
AU Gontero P.  Di Marco M.  Giubilei G.  Bartoletti R.  Pappagallo
  G.  Tizzani A.  Mondaini N.
FA Gontero, Paolo.  Di Marco, Massimiliano.  Giubilei, Gianluca.
  Bartoletti, Riccardo.  Pappagallo, Giovanni.  Tizzani, Alessandro.
  Mondaini, Nicola.
IN Urology Department, University of Torino, Torino, Italy.
  [email protected]
TI Use of penile extender device in the treatment of penile
  curvature as a result of Peyronie's disease. Results of a phase II
  prospective study.
SO Journal of Sexual Medicine.  6(2):558-66, 2009 Feb.
AB INTRODUCTION: Pilot experiences have suggested that tension
  forces exerted by a penile extender may reduce penile curvature as a
  result of Peyronie's disease. AIM: To test this hypothesis in a
  Phase II study using a commonly marketed brand of penile extender.
  METHODS: Peyronie's disease patients with a curvature not exceeding
  50 degrees with mild or no erectile dysfunction (Erectile Dysfunction) were eligible.
  Fifteen patients were required to test the efficacy of the device
  assuming an effect size of >0.8, consistent with an "important"
  reduction in penile curvature. Changes in penile length over
  baseline and erectile function (EF) domain scores of the
  International Index of Erectile Function (IIEF) constituted
  secondary end points. MAIN OUTCOME MEASURES: Patients were
  counselled on the use of the penile extender for at least 5 hours
  per day for 6 months. Photographic pictures of the erect penis and
  measurements were carried out at baseline, at 1, 3, 6, and 12 months
  (end of study). The IIEF-EF domain scores were administered at
  baseline and at the end of study. Treatment satisfaction was
  assessed at end of study using a nonvalidated institutional 5-item
  questionnaire. RESULTS: Penile curvature decreased from an average
  of 31 degrees to 27 degrees at 6 months without reaching the effect
  size (P = 0.056). Mean stretched and flaccid penile length increased
  by 1.3 and 0.83 cm, respectively at 6 months. Results were
  maintained at 12 months. Overall treatment results were subjectively
  scored as acceptable in spite of curvature improvements, which
  varied from "no change" to "mild improvement." CONCLUSIONS: In our
  study, the use of a penile extender device provided only minimal
  improvements in penile curvature but a reasonable level of patient
  satisfaction, probably attributable to increased penile length. The
  selection of patients with a stabilized disease, a penile curvature
  not exceeding 50 degrees, and no severe Erectile Dysfunction may have led to outcomes
  underestimating the potential efficacy of the treatment.
PT Journal Article.

<8>
UI 19138357
AU Zargooshi J.
FA Zargooshi, Javaad.
IN Kermanshah University of Medical Sciences--Department of Urology,
  Kermanshah, Iran. [email protected]
TI Sexual function and tunica albuginea wound healing following
  penile fracture: An 18-year follow-up study of 352 patients from
  Kermanshah, Iran.
SO Journal of Sexual Medicine.  6(4):1141-50, 2009 Apr.
AB INTRODUCTION: We present a study on the experiences of penile
  fracture in an Iranian population. Aim. To determine the long-term
  outcome of penile fracture. METHODS: Between April 1990 and May
  2008, 373 patients presented with clinical features suggestive of
  penile fracture. Of these, 11 declined surgery. The remaining 362
  were operated upon using a degloving incision. Ten patients had
  venous injury and 352 had penile fracture. At follow-up visits, in
  addition to answering our questionnaire, the patients completed the
  International Index of Erectile Function (IIEF), Erection Hardness
  Grading Scale (EHGS), and global self-assessment of potency (GSAP).
  To enhance documentation and to promote transparency, with the
  patients' permission, their full name and hospital chart number was
  sent to the journal. MAIN OUTCOME MEASURES: Clinical findings and
  IIEF and EHGS scores. RESULTS: Mean patients' age was 29.6 years.
  Mean duration of follow-up was 93.6 months. Diagnosis was solely
  clinical. At presentation, 278 (78.9%) reported no pain.
  Cavernosography, ultrasonography, or magnetic resonance imaging was
  not used in any of the patients. Penile fracture was due to
  taqaandan in 269 patients (76.4%). Patients were treated with
  surgical exploration and repair within 24 hours of admission,
  regardless of delay in presentation. A nodule was found at follow-up
  in 330 patients (93.7%). The painless, mostly proximal nodule was
  palpated at the floor of the corpora cavernosa, in a deep midline
  position above the corpus spongiosum. The non-expansive nodule was
  not associated with erectile dysfunction (Erectile Dysfunction) or Peyronie's disease.
  Postoperative complications included mild penile pain in cold
  weather (two patients), transient wound edema (one patient), mild
  chordee (four patients), and occasional instability of the erect
  penis (one patient). Postoperatively, of the 217 patients who had
  partners, 214 (98.6%) were potent. Mean IIEF Erectile Dysfunction domain score was
  29.8 +/- 1.1. The EHGS score was 4 in 203 and 3 in 11. The GSAP
  score was 0 in 204, 1 in 8, and 2 in 2. Erectile Dysfunction in the remaining three
  could not be explained by penile fracture. Of 10 nonoperated
  patients, eight (80%) developed Erectile Dysfunction. CONCLUSION: Pain is rare in
  penile fracture. Postoperatively, almost all patients develop a
  permanent, inconsequential, fibrotic nodule. Our time-tested
  approach provided excellent long-term sexual function.
PT Journal Article.

<9>
UI 19338644
AU Vardi Y.  Levine LA.  Chen J.  Hatzimouratidis K.  Sohn M.
FA Vardi, Yoram.  Levine, Laurence A.  Chen, Juza.  Hatzimouratidis,
  Konstantinos.  Sohn, Michael.
IN Rambam Medical Center & Technion Faculty of Medicine, Haifa,
  Israel.
TI Is there a place for conservative treatment in Peyronie's
  disease?.
SO Journal of Sexual Medicine.  6(4):903-9, 2009 Apr.
AB INTRODUCTION: Peyronie's disease (Peyronies Disease) is a relatively common
  disorder affecting middle aged men. Conservative nonsurgical
  treatments include oral, topical, and intra-lesional
  pharmacotherapies, vacuum stretching, and mechanical traction.
  METHODS: Four people with expertise and/or interest in the area of
  Peyronies Disease were asked to contribute their opinions with regard to the safety
  and efficacy of nonsurgical conservative treatments. MAIN OUTCOME
  MEASURE: To provide food for thought, discussion, and possible
  further research in a poorly discussed area of sexual medicine.
  RESULTS: Of the four experts writing on the topic, one believes a
  combination of medical therapy and penile traction has positive
  potential for curvature. Another feels that although medical
  therapies have potential to alleviate pain, there is little evidence
  to show that they help with curvature or that penile traction helps.
  A third expert proposes dividing the disease into phases, where
  patients in the acute phase may benefit from conservative therapy,
  whereas patients whose disease is stable require surgical
  intervention. The last expert agrees that the therapy should depend
  on the stage of the disease, but believes like the first expert that
  there is a role for traction therapy for patients with stable
  disease. CONCLUSION: There is a need for guidelines for nonsurgical
  therapies for patients with Peyronies Disease, but there is a paucity of evidence
  as to their efficacy.
PT Journal Article.

<<11>
UI 19267860
AU Gonzalez-Cadavid NF.
FA Gonzalez-Cadavid, Nestor F.
IN Los Angeles Biomedical Research Institute (LABioMed) at
  Harbor-UCLA Medical Center-Urology Research Laboratory, Division of
  Urology, Torrance, CA 90509, USA. [email protected] TI Mechanisms of penile fibrosis. [Review] [68 refs] SO Journal of Sexual Medicine.  6 Suppl 3:353-62, 2009 Mar.
AB INTRODUCTION: Penile fibrosis has been conceptually identified
  with the plaque that develops in the tunica albuginea in Peyronie's
  disease (Peyronies Disease), or with localized processes induced in the corpora
  cavernosa by ischemic or traumatic events. Recently, it has been
  proposed that a diffuse, progressive, and milder intracorporal
  fibrosis, which affects also the media of the penile arteries, is
  responsible for vasculogenic erectile dysfunction (Erectile Dysfunction) associated
  with aging, smoking, diabetes, hypertension, and post-radical
  prostatectomy. These processes differ in etiology, time course,
  target cells, and treatment, but have many features in common. AIM:
  To review the literature pertaining to fibrosis in the penis,
  related to Peyronies Disease and Erectile Dysfunction. METHODS: PubMed search for pertinent
  publications mainly during 2001-2008. RESULTS: This review focuses
  initially on Peyronies Disease and then deals with studies on Erectile Dysfunction in animal and cell
  culture models, discussing some of the pathophysiological
  similarities between tunical fibrosis in Peyronies Disease and corporal fibrosis in
  corporal veno-occlusive dysfunction (CVOD), and emerging therapeutic
  strategies. The role of profibrotic factors, the excessive deposit
  of collagen fibers and other extracellular matrix, the appearance of
  a synthetic cell phenotype in smooth muscle cells or the onset of a
  fibroblast-myofibroblast transition, and in the case of the corporal
  or penile arterial tissue the reduction of the smooth muscle
  cellular compartment, are discussed. This histopathology leads
  either to localized plaques or nodules in penile tissues, or to the
  diffuse fibrosis causing impairment of tissue compliance that
  underlies CVOD and arteriogenic Erectile Dysfunction. The antifibrotic role of the
  sustained stimulation of the nitric oxide/cyclic guanosine
  monophosphate pathway in the penis and its possible relevance to
  exogenous and endogenous stem cell differentiation is also briefly
  presented. CONCLUSIONS: Fibrotic processes in penile tissues share a
  similar cellular and molecular pathophysiology and common endogenous
  mechanisms of defense that have inspired novel pharmacological
  experimental approaches. [References: 68] PT Journal Article.  Review.

[newguy]

I'd seen most of the studies but this one was of interest to me. I wonder why TNF-ALPHA levels are lower than usual. Higher levels sometimes appear to be related to a number of autoimmune issues, but what do lower levels than normal relate to? Would bringing it back up have any real impact, or is it part of the body's efforts to lower the inflammatory processes?

Full Text Link Available
UI 18778497
AU Zimmermann RP.  Feil G.  Bock C.  Hoeltl L.  Stenzl A.
FA Zimmermann, Reinhold P.  Feil, Gerhard.  Bock, Conny.  Hoeltl,
  Lorenz.  Stenzl, Arnulf.
IN Department of Urology, Elisabethinen Hospital, University
  Affiliated Hospital, Universities of Vienna and Innsbruck, Linz,
  Austria.
TI Significant alterations of serum cytokine levels in patients with
  Peyronie's disease.
SO International Braz J Urol.  34(4):457-66; discussion 466, 2008
  Jul-Aug.
AB OBJECTIVE: To determine the expression of the cytokines
  transforming growth factor-beta1 (TGF-beta1), interferon-gamma
  (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha
  (TNF-alpha) in serum from patients with Peyronie's disease (Peyronies Disease)
  compared to healthy controls. MATERIALS AND METHODS: Ninety-one
  consecutive Peyronies Disease patients aged 20 - 74 years were included in this
  study. All patients were diagnosed with symptomatic Peyronies Disease for the first
  time and had a palpable penile plaque. The patients previously had
  the disease for 6 - 72 months. None of the patients had a severe
  infectious disease or known systemic illness. For cytokine analyses,
  peripheral venous blood samples were obtained before treatment.
  Fifty healthy male blood donors aged 22 - 64 years served as the
  control group. TGF-beta1, IFN-gamma, Il-6, and TNF-alpha were
  analyzed quantitatively with commercial immunoassays. RESULTS: Mean
  cytokine levels in serum from patients were increased for TGF-beta1
  and IFN-gamma compared to healthy controls. The difference for
  TGF-beta1 was considered statistically significant (p < 0.001). IL-6
  was not detectable in Peyronies Disease patients (p < 0.01) and TNF-alpha was
  decreased (p < 0.0001). CONCLUSION: The significantly elevated serum
  level of the profibrotic TGF-beta1 cytokine underscores the effect
  of cytokines in the pathophysiology of Peyronies Disease. The significantly
  decreased TNF-alpha serum level suggested no acute immunomodulatory
  process. Therefore, the relevance for therapeutic administration of
  TNF-alpha should be further investigated. Quantification of
  TGF-beta1 in serum of Peyronies Disease patients provides a possible diagnostic
  tool and target for therapy. The data on altered cytokine levels in
  Peyronies Disease patients also provide a new understanding for etiopathogenesis of
  Peyronies Disease, which warrants further investigation.
PT Journal Article.

[Tim468]

It suggests not that there is "no immunomodulatory" issue, but that there may be an imbalance in how we modulate our immune response.

I need to think about why that is lower - I expected the opposite, and I thought a couple of other studies showed that.

Tim

[George999]

Tim, I don't see this as surprising at all.  It is not a case of the immune system being "over active" or "under active".  It is a case of the immune system losing the ability to regulate itself.  Thus the numbers can not be expected to make sense.  It becomes too much of one cytokine and not enough of another.  What is also known about immune system dysfunction is that it is known to be accompanied by vitamin D deficiency and abnormally low levels of endorphins.  Unfortunately, I know of no studies which have looked at these associations in the case of Peyronie's.  I think it would be most interesting to know if Peyronie's follows the same pattern as a number of more intensely studied auto-immune syndromes such as MS.  It wouldn't surprise me at all if it did, but we have no studies to back up that assumption.  But the imbalance of TGF-beta1 and TNF-alpha would certainly suggest that these immune regulatory hormones are likely to be abnormal.  If so, would restoring these to more normal levels result in changes in tissue levels of TGF-beta1 and TNF-alpha?  These are questions we REALLY need answers to.  - George

[Maverick]

In doing some research of my own, I found the similarities between Peyronie and Scleroderma quite evident and surprising when it comes to autoimmune, fibroblasts and collagen production.
http://scleroderma.jhmi.edu/patients/treatment-options.html

I think some of the drugs used on Scleroderma would have benefit to us.

[George999]

Maverick,  Thanks for the link!  While this is a certainly a good read and the parallels are real, unfortunately it really doesn't get us very far.  The general anti-inflammatories are well known and many are used for Peyronie's already.  Their effectiveness is very limited.  The scleroderma specific anti-inflammatory meds suggested are all rather toxic in one way or another as the article points out.  If scleroderma patients are advised not to use these drugs except in extreme cases, they become out of the question for Peyronie's patients.  On the other hand, the anti-fibrotic treatments are critiqued by the article as being generally ineffective and would likely be just as ineffective for Peyronie's.

In doing some research of my own, I found the similarities between Peyronie and Scleroderma quite evident and surprising when it comes to autoimmune, fibroblasts and collagen production.
http://scleroderma.jhmi.edu/patients/treatment-options.html

I think some of the drugs used on Scleroderma would have benefit to us.

[newguy]

George - For what its worth I have read cases of Low Dose Naltrexone helping with scleroderma. We will have to hope that some of the same mechanisms are at play in both conditions, rather than them simply having a few elements in common. Time will tell.

[slowandsteady]

On the other hand, the anti-fibrotic treatments are critiqued by the article as being generally ineffective and would likely be just as ineffective for Peyronie's.

It's my hope at least that anti-fibrotic treatments (like nattokinase) might be more effective if the underlying autoimmune response is resolved.

PMID 19341455: fibrosis regressed in autoimmune hepatitis when immune suppressing drugs were given.
PMID 15030981: corticosteroid therapy improves or prevents hepatic fibrosis.

s&s

[George999]

On the other hand, the anti-fibrotic treatments are critiqued by the article as being generally ineffective and would likely be just as ineffective for Peyronie's.

It's my hope at least that anti-fibrotic treatments (like nattokinase) might be more effective if the underlying autoimmune response is resolved.

PMID 19341455: fibrosis regressed in autoimmune hepatitis when immune suppressing drugs were given.
PMID 15030981: corticosteroid therapy improves or prevents hepatic fibrosis.

s&s

Well ... you won't get any argument from me on that count.  I think you are absolutely on the money.  Before you apply the water to douse the fire, you need to shut of the supply of fuel first.  Once that is done, all kinds of things might be possible.  - George

[newguy]

BACKGROUND: Dupuytren's Disease (DD) is a debilitating contractile fibrosis of the palmar fascia characterised by excess collagen deposition, contractile myofibroblast development, increased Transforming Growth Factor-beta levels and beta-catenin accumulation. The aim of this study was to determine if a collagen-enriched environment, similar to in vivo conditions, altered beta-catenin accumulation by primary DD cells in the presence or absence of Transforming Growth Factor-beta. METHODS: Primary DD and patient matched, phenotypically normal palmar fascia (PF) cells were cultured in the presence or absence of type-1 collagen and Transforming Growth Factor-beta1. beta-catenin and alpha-smooth muscle actin levels were assessed by western immunoblotting and immunofluorescence microscopy. RESULTS: DD cells display a rapid depletion of cellular beta-catenin not evident in patient-matched PF cells. This effect was not evident in either cell type when cultured in the absence of type-1 collagen. Exogenous addition of Transforming Growth Factor-beta1 to DD cells in collagen culture negates the loss of beta-catenin accumulation. Transforming Growth Factor-beta1-induced alpha-smooth muscle actin, a marker of myofibroblast differentiation, is attenuated by the inclusion of type-1 collagen in cultures of DD and PF cells. CONCLUSION: Our findings implicate type-1 collagen as a previously unrecognized regulator of beta-catenin accumulation and a modifier of TGF-beta1 signaling specifically in primary DD cells. These data have implications for current treatment modalities as well as the design of in vitro models for research into the molecular mechanisms of DD. - http://www.ncbi.nlm.nih.gov/pubmed/19545383?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Dupuytren's Disease related but close/interesting enough

[newguy]

Peyronie's disease associated with methotrexate therapy.

-The abstract as yet is not available-

A UK study: http://www.ncbi.nlm.nih.gov/pubmed/19747316?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

No info that I can find thus far. Maybe others will have more luck. I did find a much older artcile saying the same thing tho. From 1992:

We describe two patients with rheumatoid arthritis treated with methotrexate (MTX) who developed Peyronie's disease during the course of their treatment. In one of the patients the penile fibrosis resolved on stopping the drug. The other patient's penile fibrosis partially resolved on stopping the drug. We suggest that Peyronie's disease can be a side-effect of MTX in the treatment of rheumatoid arthritis.

- http://rheumatology.oxfordjournals.org/cgi/content/abstract/31/6/425

Possibly of note. Methotrexate:

- is used to treat autoimmune disorders
- inhibiting the metabolism of folic acid
- increases risk of bruising
- increased risk of pulmonary fibrosis

I'm not trying to link any of those in any way. They are simply facts I gleamed from here:

http://en.wikipedia.org/wiki/Methotrexate

It's positive at least that fibrosis partially reversed when one of the two patients stopped taking methotrexate.

[George999]

It is also an immune suppressant which is why it is used to treat autoimmune conditions.  Just another example of why immune suppressants are not the be all and end all in treating autoimmune diseases.  - George

[newguy]

OBJECTIVES: To assess the effect of transdermal electromotive drug therapy (EMDT) on transforming growth factor-beta (TGF-beta) and basic fibroblast growth factor (bFGF) expression and their receptors in plaques in patients with Peyronie's disease. METHODS: Tissue was obtained from 13 patients with stable Peyronie's disease who had undergone plaque excision because of penile curvature. Of the 13 patients, 7 underwent EMDT with dexamethasone, verapamil, and lidocaine as first-line therapy before plaque excision and 6 were therapy naive. TGF-beta and bFGF mRNA and protein expression and that of their receptors were measured using real-time polymerase chain reaction and Western blotting. RESULTS: The mean patient age was 52.83 years. The mean interval from the end of EMDT to plaque excision was 7.6 months, with stable disease for >or=5 months. The comparison of TGF-beta mRNA expression in the plaques showed no difference between the EMDT and therapy-naive patients (P = .17). Also, TGF-beta protein expression in the plaques was not significantly different between the EMDT and therapy-naive patients (P = .443). TGF-beta receptor 1 mRNA expression in the plaques was significantly different between the EMDT and therapy-naive patients (P = .023), but no difference was found for TGF-beta receptor 2 mRNA (P = .292). The expression of bFGF mRNA (P = .0005) and bFGF protein expression (P = .034) in the plaques was significantly lower after EMDT. bFGF receptor mRNA expression (P = .619) showed no significant differences. CONCLUSIONS: Patients with Peyronie's had significantly lower bFGF mRNA and bFGF protein expression in the plaques after EMDT. Also, overexpression of TGF-beta protein and the TGF-beta receptor was identified in the EMDT plaques compared with the therapy-naive plaques.

- http://www.ncbi.nlm.nih.gov/pubmed/19604562

[newguy]

Combination of Doxazosin and Sildenafil Exerts an Additive Relaxing Effect Compared with Each Compound Alone on Human Cavernosal and Prostatic Tissue

ABSTRACT
Introduction. Phosphodiesterase 5 inhibitors (PDE5) such as sildenafil are first-line treatment for erectile dysfunction (Erectile Dysfunction). Alpha1 (α1)-adrenoceptor antagonists such as doxazosin are indicated for the treatment of patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). Erectile Dysfunction and LUTS/BPH are conditions that are often associated. Accordingly, α1-adrenoceptor antagonists and PDE5 inhibitors will be often prescribed in real life setting together.

Aim. To evaluate the effects of the combination of sildenafil and doxazosin on human cavernosal and prostatic tissue.

Methods. Prostatic and erectile tissues were obtained from nine to 12 patients, respectively. Patients underwent cystoprostatectomy for infiltrating bladder cancer or penile surgery for penile implant, congenital curvature or Peyronie's disease.

Main Outcome Measures. In organ baths, prostatic and cavernosal strips were submitted to either concentration-response curves (CRC) to phenylephrine (Phe) or norepinephrine (NE), respectively, in presence of vehicle, sildenafil (10−6 M, 10−5 M), doxazosin (10−8 M, 3.10−8 M, or 10−7 M), or a combination of both. Continuous electrical field stimulation (EFS; 32 Hz, 5 ms, 5 seconds, 300 mA) was performed on prostatic strips which were incubated with sildenafil 10−6 M or vehicle before the successive addition of doxazosin (10−7 M, 10−6 M) or vehicle. Cavernosal strips were pre-incubated with doxazosin (10−9 M, 10−8 M) or vehicle, then CRC to sildenafil were constructed on NE (3.10−6 M) precontracted cavernosal strips.

Results. Combination of sildenafil and doxazosin exerted a greater relaxing effect on CRC to Phe or NE compared with each compound alone in both tissues. Sildenafil significantly enhanced the relaxing effect of doxazosin on EFS-induced contractions in prostatic strips. Doxazosin significantly increased the ability of sildenafil to inhibit NE-induced contractions in cavernosal strips.

Conclusions. Sildenafil and doxazosin reduced adrenergic tone of prostatic and cavernosal smooth muscle and their combination provided a significant benefit when targeting relaxation of both tissues. These experiments provide support for further clinical evaluation of the sildenafil and doxazosin combination in Erectile Dysfunction patients with LUTS/BPH. Oger S, Behr-Roussel D, Gorny D, Lecoz O, Lebret T, Denoux Y, Faix A, Leriche A, Wayman C, Alexandre L, and Giuliano F. Combination of doxazosin and sildenafil exerts an additive relaxing effect compared with each compound alone on human cavernosal and prostatic tissue. J Sex Med 2009;6:836–847.

I wonder is Doxazosin use would be useful to us? Maybe not but its ability to relax cavernosal smooth muscle caught my eye.

[newguy]

I noticed that study from many moons ago. It appears that the particular formulation of Superoxide Dismutase is still not available, years after the trials. I wonder if there is another useful formulation of the enzyme available. The wikipedia page for Superoxide dismutase states that it is used is cosmetics products to reduce damage, and states that superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts (http://www.ncbi.nlm.nih.gov/pubmed/11134893). Any thoughts?

BERKELEY, CA (UroToday.com) - Peyronie's disease is a fibrotic process of the penile tunica albuginea assumed to be associated with trauma to the erect penis during intercourse. BERKELEY, CA (UroToday.com) - Peyronie's disease is a fibrotic process of the penile tunica albuginea assumed to be associated with trauma to the erect penis during intercourse. Clinically, Peyronie's disease is characterized by the presence of a palpable plaque within the tunica albuginea that leads to penile curvature, localized pain, and, in 20-30% of men with the disorder, erectile dysfunction. It has been postulated that trauma with the consequent extravasation of fibrin from the blood into the tunica albuginea triggers a cascade of local inflammatory events that induce plaque development. The course of Peyronie's disease can be divided into two phases: an initial phase of active inflammatory disease that is commonly associated with pain, and a terminal or stable phase.

Various anti-inflammatory drugs applied topically, by intralesional injection, or by electromotive administration have been investigated in clinical trials. In the 1980's, promising results were obtained in small clinical trials with the bovine enzyme superoxide dismutase (SOD) which is a potent radical scavenger capable or interrupting inflammatory cascades by tissue deprivation of free oxygen radicals. Bovine SOD was withdrawn from further clinical trials due to rare but severe allergic reactions. Recently, a human recombinant Cu/Zn-SOD in a liposomal formulation (lhrSOD) was manufactured which can be administered as a topical gel and adequate tissue penetration of the active ingredient has been demonstrated.

A recent study from C. R. Riedl and colleagues from a multinational trial in Austria examined the efficacy and safety of a topical gel containing liposomally encapsulated recombinant human superoxide dismutase (lhrSOD) in the treatment of painful Peyronie's disease. The study is published in the October 2005 issue of European Urology.

In a placebo-controlled randomized clinical trial, 39 patients with Peyronie's disease and significant pain symptoms were treated with lhrSOD (Lipoxysan) or placebo for a 4 week period. The drug and placebo were delivered in a gel that was topically applied twice daily. The patients were then continued in a cross-over study design to ensure a total of 8 weeks of lhrSOD therapy for all study participants. The primary study endpoint was pain resolution with secondary endpoints being plaque characteristics and curvature assessment.

Analysis of the results revealed that lhrSOD treatment resulted in a statistically significant reduction of pain compared to placebo after only 4 weeks. At week 12, pain was significantly reduced in 89% of patients who had all received 8 weeks of therapy. Response to other disease parameters was assessed at week 12: plaque size was reduced in 47% of patients, as was plaque hardness in 38%. Penile curvature was improved at 5-30 degrees in 23% of patients. The treatment was free of significant side effects.

In conclusion, lhrSOD is an easily administrable, safe and effective local therapeutic for the painful or active phase of Peyronie's disease and may show promise to ameliorate the curvature and reduce plaque size and hardness over a longer course of treatment

[newguy]

Superoxide Dismutase

See below post. It's not the formulation that probably will never see the light of day, but maybe it can be useful.

[newguy]

Protein Biomarker Analysis of Primary Peyronie's Disease Cells.
De Young LX, Bella AJ, O'Gorman DB, Gan BS, Lim KB, Brock GB.

Lawson Health Research Institute, Urology, London, ON, Canada.

ABSTRACT Introduction. The molecular pathogenesis of Peyronie's Disease (Peyronies Disease) remains unclear more than 250 years after its initial description. Because of this, no test is currently available to accurately predict Peyronies Disease progression among those affected. Aim. To investigate the expression of wound healing and fibrosis-associated proteins in primary cell cultures of Peyronies Disease fibroblasts to determine whether altered protein expression patterns can be used as predictors of clinical course and natural history. Methods. Primary cell cultures derived from normal Tunica albuginea tissue and Peyronies Disease plaque tissue were examined by immuno-cytochemistry. Protein expression profiles were analyzed by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) and Western immunoblotting. Main Outcome Measures. Expression of wound healing and fibrosis-associated proteins and protein expression patterns were assessed. Results. Statistically significant increases in smooth muscle alpha-actin, beta-catenin, and Heat shock proteins (Hsp47) were identified in cells derived from Peyronies Disease relative to cells derived from normal Tunica albuginea tissue. Changes in TGFbeta-1 receptor and Fibronectin were also observed. In addition, altered expression of additional as yet unidentified proteins at 4.7, 8.9, 10.8, 16.8, and 76.8 kDa were detected by complementary SELDI-TOF-MS approaches. Conclusions. Primary cells derived from Peyronies Disease plaques display up-regulated expression of several proteins that are established components of fibrosis and wound healing. In addition, changes in other, as yet unidentified proteins were measured. It will be of interest to conduct further studies to see whether these dysregulated protein peaks represent potential biological markers of disease progression. De Young LX, Bella AJ, O'Gorman DB, Gan BS, Lim KB, and BrockGB. Protein biomarker analysis of primary Peyronie's disease cells. J Sex Med **;**:**-**.

- http://www.ncbi.nlm.nih.gov/pubmed/19889147

[slowandsteady]

I noticed that study from many moons ago. It appears that the particular formulation of Superoxide Dismutase is still not available, years after the trials. I wonder if there is another useful formulation of the enzyme available. The wikipedia page for Superoxide dismutase states that it is used is cosmetics products to reduce damage, and states that superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts (http://www.ncbi.nlm.nih.gov/pubmed/11134893). Any thoughts?

Some products increase SOD when taken orally like Glisodin (studies here) and now Extramel. Glisodin binds SOD with the wheat protein gliadin while Extramel uses palm oil. Extramel is sold for topical application too. It's hard to find any products actually using Extramel as it's fairly new. It seems to be available in the UK.

[George999]

Changes in TGFbeta-1 receptor and Fibronectin were also observed.

- http://www.ncbi.nlm.nih.gov/pubmed/19889147

I find this little tidbit fascinating.  So what if TGF-beta1 is NOT the problem?  What if the receptors are the problem?  What might fix the receptors?  Endorphins perhaps?  That would mean that Low Dose Naltrexone might indeed be helpful.  This all gets very interesting.  - George

[newguy]

I find this little tidbit fascinating.  So what if TGF-beta1 is NOT the problem?  What if the receptors are the problem?  What might fix the receptors?  Endorphins perhaps?  That would mean that Low Dose Naltrexone might indeed be helpful.  This all gets very interesting.  - George

There is still so much to be known. The wikipedia page for TGF beta receptors is quite interesting: http://en.wikipedia.org/wiki/TGF_beta_receptors

It mentions that "Recent developments have found that, using certain types of protein antagonists against TGFβ receptors, can halt and in some cases reverse the effects of renal fibrosis". Pehaps this is an angle worth persuing.

[newguy]

ABSTRACT Introduction. Although Peyronie's Disease (Peyronies Disease) was first described over 250 years ago, its precise etiology remains obscure. Aim. Analyze a variety of potential associated factors with Peyronies Disease, including erectile dysfunction. Materials and Methods. This cross-sectional study included 83 consecutive men with Peyronies Disease and 252 age-matched controls. All men completed the International Index of Erectile Function (IIEF) and were evaluated regarding their clinical and demographic characteristics, comorbidities, and used medications. Anthropometric measures included body mass index and waist circumference (WC). Fasting blood glucose, lipid profile, total testosterone, and dehydroepiandrosterone-sulfate were determined. Main Outcome Measures. Clinical and laboratory characteristics associated to Peyronies Disease. Results. The mean age was 59.2 +/- 10 years in the cases and 59.7 +/- 12 years in the controls. Marital status, current smoking, and excessive consumption of alcoholic beverages were similar between groups (P > 0.05). Peyronies Disease was more common among white skin color males (P = 0.001). The mean score for each IIEF domain and the androgen levels were similar in the two groups. Thiazides were the only medication associated to Peyronies Disease (P = 0.03). Dupuytren's disease was more frequent among individuals with Peyronies Disease (P = 0.001). The distribution of all other comorbidities investigated was similar between groups (P > 0.05). The characteristics WC > 102 cm and levels of low-density lipoprotein (LDL) > 130 mg/dL were more prevalent in the controls (P < 0.05). After multivariate analysis, white skin color (OR: 8.47, 95%CI: 1.98-36.24) and thiazide use (OR: 2.29, 95%CI: 1.07-4.90) were associated to Peyronies Disease, and LDL > 130 mg/dL (OR: 0.55, 95%CI: 0.32-0.92) and WC > 102 cm (OR: 0.53, 95%CI: 0.29-0.96) were inversely associated to Peyronies Disease. Conclusions. In this study, Peyronies Disease was more common among white skin colored males. An inverse relationship with the presence of elevated serum levels of LDL and WC was observed. We found no association with medications other than thiazides and comorbidities other than Dupuytren's disease. Androgen serum levels and sexual dysfunction had also no association to Peyronies Disease. Rhoden EL, Riedner CE, Fuchs S, Ribeiro EP, and Halmenschlager G. A cross-sectional study for the analysis of clinical, sexual and laboratory conditions associated to Peyronie's disease. J Sex Med

-http://www.ncbi.nlm.nih.gov/pubmed/19912489

[newguy]

ABSTRACT Introduction. Transforming growth factor-beta1 (TGF-beta1) has been identified as an important fibrogenic cytokine associated with Peyronie's disease (Peyronies Disease). Aim. The aim of this study was to study the differential expression of the TGF-beta1 and Smad transcription factors in plaque tissue from Peyronies Disease patients and to determine the antifibrotic effect of SKI2162 (SK Chemicals, Seoul, South Korea), a novel small-molecule inhibitor of activin receptor-like kinase 5 (ALK5), a type I receptor of TGF-beta, in primary fibroblasts derived from human Peyronies Disease plaque. Methods. Plaque tissue was isolated from five Peyronies Disease patients, and tunica albuginea tissue was obtained from four control patients. Plaque tissues from a patient with Peyronies Disease were used for primary fibroblast culture. Fibroblasts were pretreated with SKI2162 (10 microM) and then stimulated with TGF-beta1 (10 ng/mL). Main Outcome Measures. The plaque or tunica albuginea tissue was stained with Masson's trichrome or antibody to TGF-beta1, phospho-Smad2 (P-Smad2), and P-Smad3. Protein was extracted from treated fibroblasts for Western blotting, and the membranes were probed with antibody to P-Smad2/Smad2, P-Smad3/Smad3, plasminogen activator inhibitor-1, fibronectin, collagen I, and collagen IV. We also determined the inhibitory effect of SKI2162 on TGF-beta1-induced nuclear translocation of Smad2/3 in fibroblasts. Results. The plaque tissue from Peyronies Disease patients showed higher TGF-beta1, P-Smad2, and P-Smad3 immunoreactivity than did the tunica albuginea tissue from control patients. SKI2162 not only blocked TGF-beta1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, but also inhibited the production of extracellular matrix markers in fibroblasts derived from human Peyronies Disease plaque. Conclusion. In light of the pivotal role of TGF-beta and Smads in the pathogenesis of Peyronies Disease, pharmacologic inhibition of ALK5 may represent a novel targeted approach to treating Peyronies Disease.

- http://www.ncbi.nlm.nih.gov/pubmed/20233292

[newguy]

Pentoxifylline Attenuates Transforming Growth Factor-beta1-Stimulated Collagen Deposition and Elastogenesis in Human Tunica Albuginea-Derived Fibroblasts Part 1: Impact on Extracellular Matrix.

University of California-Knuppe Molecular Urology Laboratory, Department of Urology, San Francisco, CA, USA.

Abstract

ABSTRACT Introduction. Transforming growth factor-beta1 (TGF-beta1) has been implicated in the pathogenesis of Peyronie's disease (Peyronies Disease) and also plays a role in collagen and elastin metabolism. Pentoxifylline (PTX) antagonizes the effects of TGF-beta1 and has been utilized in our clinic for the management of Peyronies Disease. Aim. We studied the effects of TGF-beta1 and PTX on collagen metabolism and elastogenesis in tunica albuginea-derived fibroblasts (TADFs). Methods. TADFs from men with and without Peyronies Disease were cultured and treated with TGF-beta1 and PTX as monotherapy at differing concentrations and time points. Combination treatment (TGF-beta1 followed by PTX and vice versa) was also investigated. Main Outcome Measures. Cell proliferation assay, enzyme-linked immunosorbent assay, and immunohistochemistry were utilized to assess the impact of TGF-beta1 and PTX on TADF with respect to elastin and collagen I metabolism. Results. PTX inhibited fibroblast proliferation at doses of 100 microM. TGF-beta1 stimulated elastogenesis and collagen I fiber deposition in TADF in a dose- and time-dependent fashion. Pretreatment with PTX dramatically attenuated TGF-beta1-mediated elastogenesis and collagen fiber deposition in TADF from men with and without Peyronies Disease. Interestingly, production of collagen I was higher in untreated Peyronie's tunica (PT) cells relative to normal tunica (NT) cells; furthermore, PTX attenuated collagen production to levels similar to untreated control TADF in PT cells but not in NT cells, suggesting important intrinsic differences between PT and NT cells. Conclusion. Both elastin and collagen are upregulated by TGF-beta1 in TADF. This likely contributes to the Peyronies Disease phenotype. Pretreatment with PTX attenuates both collagen fiber deposition and elastogenesis in TADF exposed to TGF-beta1; these effects suggest a useful role for PTX in the management of Peyronies Disease.

 - http://www.ncbi.nlm.nih.gov/pubmed/20367772

[newguy]

Immunomodulatory properties of pentoxifylline are mediated via adenosine-dependent pathways.

The phosphodiesterase inhibitor pentoxifylline (PTX) exerts multiple beneficial immunomodulatory effects in states of hyperinflammation. However, the exact mechanism of action still remains elusive, and the clinical effects of PTX cannot be reliably predicted. In immune cells, the G protein-coupled adenosine A2A receptor (A2AR) exerts strong anti-inflammatory effects. As PTX amplifies signaling pathways downstream of Gs protein-coupled receptors, the A2AR-signaling pathway might be involved in the mediation of immune-suppressive effects of PTX. Here, we investigated this assumption in LPS-stimulated human polymorphonuclear (PMN) leukocytes and in anti-CD3/CD28-stimulated human T cells. In stimulated PMN leukocytes, PTX treatment led to a 4.5-fold decrease of the 50% inhibitory concentrations of adenosine on the H2O2 production; i.e., for adenosine plus PTX (in clinically relevant concentrations), an overadditive increase of inhibitory effects from less than 20% (estimated for each) to 56% (+/-5%) was found. In T cells, adenosine plus PTX revealed similar synergistic inhibitory effects on proinflammatory cytokine production. Inhibition of interferon gamma and TNF-alpha production increased from 7% (+/-1%) and 31% (+/-6%) (PTX alone) to 49% (+/-2%) and 69% (+/-6%), respectively. In T cells and PMN leukocytes, mRNA transcription of the A2AR was significantly increased upon stimulation, which was not influenced by PTX. In human PMN leukocytes and T cells, clinically relevant anti-inflammatory effects of PTX can be achieved only in the presence of sufficient adenosine concentrations. Sufficient adenosine levels might be a prerequisite for the accessibility of sepsis patients to treatment with PTX.

- http://www.ncbi.nlm.nih.gov/pubmed/19997047

[newguy]

Relationship between Androgens, Regulators of Collagen Metabolism, and Peyronies

ABSTRACT Introduction. Changes in collagen metabolism have been postulated to play a pivotal role in the pathogenesis of Peyronie's Disease (Peyronies Disease). Androgens such as dehydroepiandrosterone sulfate (DHEA-S) and testosterone influence collagen metabolism by modulating the activity of matrix metalloproteases (MMP) and tissue inhibitors of metalloproteases (TIMP). Aim. The aim of this study was to evaluate the interrelationship between androgens (DHEA-S and testosterone), key regulators of collagen metabolism such as insulin-like growth factor (IGF) 1 and IGF Binding Protein 3 (IGF-BP3), the MMP/TIMP system, and Peyronies Disease. Methods. Age matched Peyronies Disease patients (14) and healthy men (10) who acted as controls were recruited. Blood samples were collected from all subjects in the early morning hours after an overnight fast. Main Outcome Measures. Serum levels of testosterone, sex hormone binding globulin, DHEA-S, 3-alpha-androstanediol glucuronide, pro-MMP-1, MMP-1, MMP-2, TIMP-1, TIMP-2, IGF-1 and IGF-BP3 were measured in both groups. Statistical methods included univariate, bivariate, and multivariate regression models. Results. Levels of DHEA-S (114.5 vs. 169.5 microg/dL; p = 0.03), IGF-BP3 (2.96 vs. 3.79 microg/mL; p = 0.01), and TIMP-1 (173.1 vs. 195 ng/mL; p = 0.01) were significantly lower in Peyronies Disease patients. In contrast, the level of TIMP-2 (102 vs. 85 ng/mL; p = 0.001) was significantly lower in the control group. Using stepwise regression analysis, only TIMP-2 (p < 0.001) and DHEA-S (p = 0.04) were significantly related to Peyronies Disease in the final model (R(2) = 0.63). TIMP-1 and DHEA-S (r = 0.55, p < 0.05) were positively correlated in the Peyronies Disease group, whereas IGF-1 and testosterone (r = -0.54, p < 0.05), and IGF-BP3 and testosterone (r = -0.68, p < 0.05) were negatively correlated in Peyronies Disease patients. Conclusions. Our findings suggest that decreased levels of adrenal androgens may be implicated in the pathogenesis of Peyronies Disease. The mechanism and clinical relevance of this observation remain to be established. Karavitakis M, Komninos C, Simaioforidis V, Kontos S, Lefakis G, Politis V, Koritsiadis G, Konstantellou K, and Doumanis G. The relationship between androgens, regulators of collagen metabolism, and peyronie's disease: A case control study. J Sex Med **;**:**-**.

- http://www.ncbi.nlm.nih.gov/pubmed/20584122

Nicardipine vs. Saline Injection as Treatment for Peyronie's Disease: A Prospective, Randomized, Single-Blind Trial.

ABSTRACT Introduction. Various conservative treatments for Peyronie's disease (Peyronies Disease) have been attempted over the years. Intralesional verapamil injection has been tested in prospective randomized studies, but the effect of this treatment seems insufficient. Nicardipine is a calcium antagonist alternative to verapamil and is reportedly more effective in vitro. Aim. The objective of our study was to evaluate the usefulness of intralesional nicardipine injection as a conservative treatment for Peyronies Disease in the transition period of acute and chronic phase. Methods. Eighty-six patients (age: 38-72 years, mean: 52) were enrolled in this study. A total of 74 patients were assigned randomly to nicardipine group (10 mg diluted in 10 mL of distilled water daily, N = 37) and control group (10 mL of saline water, N = 37). A total of six injections were administrated biweekly. Mean Outcome Measure. The subjects were assessed by International Index of Erectile Function (IIEF)-5 and international pain scale. The plaque size was measured by ultrasonography after 20 microg intracavernosal injection of alprostadil (prostaglandin E1). The penile curvature was also measured by taking a photograph at maximum rigidity. Results. A reduction of pain score was seen throughout the course of treatment in both groups with a significant difference between the nicardipine and control groups (multiple analysis of variance test, P = 0.019). A significant improvement of IIEF-5 score occurred only in the nicardipine group at 48 weeks after the initiation of treatment (P < 0.01). The plaque size was significantly reduced at 48 weeks only in the nicardipine group (12 points, P = 0.0004 by paired t-test). The penile curvature was significantly improved in both groups (P < 0.01) without significant difference between them (P = 0.14). There were no severe side effects, such as hypotension or other cardiovascular events. Conclusion. Our findings indicate that intralesional nicardipine injection is clinically effective as a conservative treatment for Peyronies Disease in the transition period of acute and chronic phase. Soh J, Kawauchi A, Kanemitsu N, Naya Y, Ochiai A, Naitoh Y, Fujiwara T, Kamoi K, and Miki T. Nicardipine vs. saline injection as treatment for Peyronie's disease: A prospective, randomized, single-blind trial. J Sex Med **;**:**-**.

- http://www.ncbi.nlm.nih.gov/pubmed/20584114

Feel free to comment.

[newguy]

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and Its Death Receptor (DR5) in Peyronie's Disease. A Biomolecular Study of Apoptosis Activation.

Abstract

Introduction.  Peyronie's disease (Peyronies Disease) is a connective tissue disorder of tunica albuginea (TA), a thick fibrous sheath surrounding the corpora cavernosa of the penis. Relatively, little is known about the disease itself. Aim.  To investigate whether the apoptosis cascade in degenerated and macroscopically deformed TA from men with Peyronies Disease is activated through the extrinsic pathway, by assessing the immunoexpression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor, DR5. Methods.  TA plaques from 15 men with Peyronies Disease and from four unaffected men were processed for TRAIL and DR5 immunohistochemistry and Western blot analysis. Main Outcome Measures.  A greater understanding of the pathophysiology of Peyronies Disease through a molecular approach, to gain insights that may lead to novel forms of treatment. Results.  Activation of the apoptosis mechanisms through the extrinsic pathway was demonstrated by TRAIL and DR5 overexpression in fibroblasts and myofibroblasts from affected TA. Conclusion.  The finding that apoptosis activation in TA plaques occurs, at least in part, via the extrinsic pathway may help devise novel therapeutic options for these patients. Loreto C, Barbagli G, Djinovic R, Vespasiani G, Carnazza ML, Miano R, Musumeci G, Sansalone S. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR5) in Peyronie's disease. A biomolecular study of apoptosis activation. J Sex Med **;**:**-**.

- http://www.ncbi.nlm.nih.gov/pubmed/20840533

[newguy]

Technique of traction-free nerve-sparing robotic prostatectomy: delicate tissue handling by real-time penile oxygen monitoring.

It is postulated that intraoperative injury to the cavernosal nerves results in hemodynamic and histologic changes within the penis, which manifest clinically as Erectile Dysfunction. We hypothesize that non-neuronal cause, such as vascular insults due to intraoperative tissue handling, may also have a minor but definite role in penile ischemia and consequent postoperative sexual dysfunction. Between May 2008 and July 2008, 64 patients were enrolled in the study (group 1). Following sterilization, the Odissey Tissue Oximeter probe was placed on the shaft of the penis, 2 cm from its base. The patient underwent continuous penile tissue saturation monitoring. Surgical dissection was altered whenever the oxygen saturation alarm went off until it was restored to 85%. In addition, 192 patients, matched for age, preoperative prostate-specific antigen, clinical stage, baseline sexual function, Charlson comorbidity index and nerve-sparing status operated between October 2007 and July 2008, formed the control group (group 2). These patients did not have any intraoperative tissue oxygenation monitoring. Opening of the endopelvic fascia and steps of nerve sparing were associated with significant drops in oxygen levels, especially if done using torque. Drop in oxygen levels were also noted whenever excessive traction was applied on the Foley catheter, seminal vesicles or prostate during apical dissection. We deliberately modified our surgical steps to make surgery more traction free. A significantly higher percentage of group 1 patients with bilateral nerve sparing had no Erectile Dysfunction compared with group 2 patients at 6 weeks (24.5% vs 10.4%; P=0.014) and 52 weeks (83.7% vs 68%; P=0.029). Overall, 93.9% of patients in study group had Sexual Health Inventory for Men (SHIM) score of 17 (mild to no Erectile Dysfunction) at 1 year compared with 78.4% of patients in the control group. We demonstrated that avoidance of ischemic stress, aided by intraoperative penile oxygenation monitoring, may help surgeons improve their technique and thus functional outcomes in patients.International Journal of Impotence Research advance online publication, 18 August 2011; doi:10.1038/ijir.2011.40.