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International Journal of Impotence Research (2002) 14, 406–410 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir

Pathophysiology of Peyronie’s disease RB Moreland1 and A Nehra2* 1Department of Urology and Physiology, Boston University School of Medicine, Boston, Massachusetts, USA; and 2Mayo Clinic Foundation, Rochester, Minnesota, USA

Peyronie’s disease is an inflammatory condition characterized by the formation of fibrous, noncompliant nodules in the tunica albuginea which can impede tunical expansion during penile erection, leading to deformity and bending. While the cause of this disease is thought to be due to microvascular trauma and abnormal wound healing, other hypotheses include genetic predisposition. In this review the pathophysiology of Peyronie’s disease is discussed as well as current hypothese regarding its origin. International Journal of Impotence Research (2002) 14, 406–410. doi:10.1038=sj.ijir.3900875 Keywords: Peyronie’s; genetics; TGF-b1

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

*Correspondence: A Nehra MD, Department of Urology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected]

ate the underlying causes of this condition will be discussed in this section.

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

Pathophysiology of Peyronie’s disease RB Moreland and A Nehra

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

sum fits in the indentation between the two corpora cavernosa.22 It has been proposed that this design allows unrestricted expansion of the corpus spongiosum such that ejaculation is unimpeded during penile erection.22 The longitudinal layer is also thinnest at the 3 and 9 o’clock positions; consistent with the greatest number of traumatic penile fractures in those positions.5,6,23 Patients with Peyronie’s disease most often show plaque formation on the dorsal side of the penis.1 – 8,23 There are at least two possible explanations for this observation. First, the dorsal aspect is opposite the portion of the tunica lacking longitudinal fibers and thus upward bending during erection is possible.13 Further, the joining of the septum into the circular inner layers of the tunica may be particularly susceptible to microvascular trauma and tunical delamination.4 – 6 The tunica albuginea is composed of fibrillar (mainly type I but also types III and V) collagen in organized arrays interlaced with elastin fibers.22,24 Peyronie’s plaques are also composed almost entirely of types I and III collagen.24,25 While collagen has a greater tensile strength than steel, it is unyielding. In contrast, elastin can be stretched up to 150%, of its length.22 It is the elastin content that allows the compliance of the tunica albuginea and helps to determine stretched penile length.26 Disorganization of the circular or longitudinal layers in the tunica as well as disruption of elastin or a decrease in elastin content27 has been reported in Peyronie’s disease and can result in penile deformities during erection as well as erectile dysfunction.

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Molecular basis of Peyronie’s disease Tunical mechanical stress and microvascular trauma

The microscopic anatomy of the tunica albuginea and its impact on Peyronie’s disease plaques The tunica albuginea is a multilayered structure of inner circular and outer longitudinal layers of connective tissue encompassing the pair of corpora cavernosa.20 – 22 An incomplete septum separates the two corpora cavernosa and anchors into the circular inner layer. In the distal, pendulous penis, intracavernous pillars anchor the tunica across the corpora cavernosa at the 2 and 6 o’clock positions with minor struts branching off of these pillars at the 5 and 7 o’clock positions. It has been demonstrated that tunical thickness varies from 1.5 to 3 mm thick depending on the circular position around the tunica.20 – 22 The longitudinal outer layer which provides strength to the tunica albuginea is absent at the 6 o’clock position where the corpus spongio-

One of the most likely causes of Peyronie’s disease may be repeated tunical mechanical stress and microvascular trauma. Excessive bending during erection or blunt trauma to the erect penis may result in bleeding into the subtunical spaces or tunical delamination at the point where the septum integrates into the inner circular layer of the tunica albuginea.4 – 6 Such microvascular trauma may come from sexual intercourse; either with the woman on top (torque to the penis with an upward twist applying pressure to the septum tunica junction) or an accident during penetration where the man misses the vagina and fractures the penis. Microvascular trauma or subtunical bleeding can result in fluid and fibrinogen in the subtunical layers. The resulting fibrin deposits may be key in the initiation of a wound healing response which encompasses pain, hematoma and subsequent inflammatory response with recruitment of macrophages and neuInternational Journal of Impotence Research

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trophils.17,28,29 These cells, in response to clot formation, release a variety of cytokines, autocoids and vasoactive factors which may precipitate a fibrotic reaction (see later). In order to better understand the molecular pathology of Peyronie’s disease, it is helpful to review the events in a normal wound healing response.17,28,29 Microvascular trauma leads to extravascular leakage of blood, with thrombus formation. Platelets release their contents including serotonin, platelet derived growth factors (PDGF-A and PDGF-B) as well as transforming growth factorb1 (TGF-b1). Thrombus formation leads to deposition of fibronectin, which binds a variety of growth factors, localizing them to the wound site. Fibrinogen leakage results in fibrin deposits. Fibrin forms a meshwork of fibers which will be the sites of attachment for inflammatory cells and fibroblasts later in the healing process.28,29 The combination of these factors attracts a variety of inflammatory cells to the wound site including macrophages, neutrophils and mast cells. Neutrophils, the predominant inflammatory cells in the site in the first 24 h, function to remove bacteria and debris from the site.17 Macrophages become the predominant cell type by 48 h and in addition to removal of cell and foreign debris from the wound, release a variety of growth factors including TGF-b1. Fibroblasts migrate into the site attracted by growth factors and autocoids released by platelets and macrophages and begin to proliferate as a result of PDGF. These cells probably provide the bulk of the connective tissue synthesis during tissue repair. It is interesting to note that a recent study found immunohistochemical evidence of strong expression of both PDGF-AA and PDGF-BB as well as PDGF-a and PDGF-b receptors in fibroblast-like cells in tunica albuginea surgical specimens from Peyronie’s patients but not in specimens from other patients with veno-occlusive dysfunction.24 Transforming growth factor-b1 has a pleotropic effect on fibroblast function by increasing transcription and synthesis of collagen, proteoglycans and fibronectin while also increasing synthesis of tissue inhibitors of collagenase which prevents connective tissue breakdown. The collagen and connective tissue repair damage while in dermal wounds, re-epithelialization takes place. Finally, in the later stages of healing, the connective tissue is remodeled by specific collagenases and proteases.17 Thus PDGF may exacerbate fibroblast proliferation while TGF-b1 potentiates fibrogenesis. In dermal wound healing, the myofibroblast, a mesenchymal cell type which has characteristics of both smooth muscle (contractile) and fibroblast (synthesis of connective tissue), is thought to play an important role in wound healing.17 However, there has yet to be a detailed examination of this cell type or any evidence of involvement or de-differentitation of corpus cavernosum smooth muscle in the pathology of this

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condition. In Peyronie’s disease, defects in overproduction of collagen and other tissue remodeling mechanisms result in an inability to resolve the injury and in plaque formation. Molecular mechanisms: involvement of TGF-b1 Fibrosis is defined as the over accumulation of connective tissue or the replacement of normal cellular material with connective tissue.17 Transforming growth factor-b1 has been implicated in a number of soft tissue fibroses30,31 as well as erectile dysfunction.32 The pathology observed in these conditions is worthy of consideration here before discussing Peyronie’s disease. Transforming growth factor-b1 is synthesized as an inactive, latent peptide by a variety of cell types including platelets, macrophages and fibroblasts.30 – 32 Upon activation, TGF-b1 binds to specific cell surface receptors and through a signal transduction cascade, results in an increased synthesis of connective tissue and an inhibition of collagenases. It can also induce its own synthesis as well as that of its receptors.30 – 32 This auto-up regulation can set into motion a chain of events that results in continued connective tissue accumulation and what has been termed the dark side of fibrosis.30 The negative regulators of this process are not well characterized. However, in the lung and in the corpus cavernosum, a role for prostaglandin E has been proposed.32 PGE inhibits TGF-b1-induced collagen synthesis both in lung fibroblasts and in corpus cavernosum smooth muscle via cAMP dependent pathways.32 Despite these initial clues, a number of autocoids, vasoactive substances and cytokines can regulate connective tissue metabolism so that these two factors may be involved but not exclusive to the process. A role for TGF-b1 has been proposed in the pathogenesis of Peyronie’s disease.33 – 35 Peyronie’s disease plaques and tunica albuginea biopsies were examined for the presence of expression and compared to specimens from non-Peyronie’s disease patients. In 30 Peyronie’s disease patients, increased protein expression of TGF-b1 (26=30), TGF-b2 (7=30) or TGF-b3 (5=30) were noted as compared to only 18 in the non-Peyronie’s disease group.33 This single patient in the control group had a localized tunical fibrotic reaction. In all of the Peyronie’s disease patients with increased TGF-b1 expression, fibrotic changes in tunica albuginea biopsies were reported.33 If increased expression of TGF-b1 is causal in Peyronie’s disease, one would like to validate this mechanism in a cell culture or animal model where the progression of disease can be followed. As described earlier, would healing processes involve a number of different cell types including neutrophils, macrophages and fibroblasts. These cell types can modulate each other and themselves via complex autocrine and paracrine mechanisms. Further,

Pathophysiology of Peyronie’s disease RB Moreland and A Nehra

the collagenous connective tissue matrix plays a poorly understood role, as neutrophils, macrophages and fibroblasts must migrate through this diffuse connective tissue to the wounding site. Thus, while Peyronie’s disease fibroblasts may be cultured and grown in confluent monolayers, this cell culture model may be of little use in the study of the progression of Peyronie’s disease. A rat model of Peyronie’s disease has been developed using subtunical injections of a synthetic heptapeptide, cytomodulin, which induces increased TGF-b1 expression and=or inflammatory cell recruitment.34,35 Six weeks after cytomodulin injection 15=18 rats exhibited tunical thickening and plaque formation as well as increased TGF-b1 mRNA and protein expression.34 No increases were observed in either TGF-b2 or TGF-b3 mRNA or protein expression.34 Finally, electron microscopy revealed the infiltration of inflammatory cells as well as disorganized collagen fibrils.35 This model is indeed a significant advance as it allows following the progression of disease as well as a system for the evaluation of pharmacotherapeutics for Peyronie’s disease.

Molecular mechanisms: oxidative damage and the role of free radicals During chronic disease states of hepatic, pulmonary, arterial (eg peripheral vascular) and nervous system tissue degeneration, in addition to fibrogenesis and an increase in connective tissue, there is an increase in oxidative stress.36 This stress in the form of free radicals (superoxide, peroxynitrite and peroxide generated species) can result in lipid peroxidation and tissue damage as well as stimulate connective tissue synthesis in fibroblasts and increase activity in inflammatory phagocytic cells such as neutrophils and macrophages.35 Therapeutically, this concept prompted the use of intraplaque injections of superoxide dismutase which scavenges and detoxifies superoxide produced by respiratory enzymes as well as tissue degeneration (see later). The degree that cytokines such as TGF-b1 and PDGF, abnormal wound healing, trauma and=or oxidative damage contribute to Peyronie’s disease remains to be elucidated.

Therapeutics and the molecular pathology of Peyronie’s disease How do these mechanisms correlate with current therapeutic treatment of this disease? There are two basic categories of pharmacotherapeutics that have been used in Peyronie’s disease; anti-oxidants and collagen synthesis inhibitors. As described briefly earlier, it has been hypothesized that oxidative

damage may be causal in the initiation and progression of tissue fibrosis.36 While there is limited reported efficacy and no double blinded trials, both para-aminobenzoic acid37 and vitamin E38 have been reported as a treatment of Peyronie’s disease. Intraplaque injection of the anti-inflammatory protein orgotein39 – 42 which has superoxide dismutase activity or bovine superoxide dismutase43 are reported to improve symptoms in Peyronie’s patients, although adequate clinical trials are lacking. Of the collagen synthesis inhibitors, verapamil, colchicine and interferon as well as collagenase have been reported. Verapamil, a calcium channel blocker, inhibits connective tissue synthesis in fibroblasts and has been shown to be effective in softening and dissolving plaques in the early stages of disease when injected into the plaques.44,45 Colchicine, a microtubule polymerization inhibitor, also inhibits connective tissue synthesis in fibroblasts and has shown limited efficacy in Peyronie’s disease patients when administered orally.46 Initial trials of intra-plaque injection with collagenase have been disappointing.47 Intralesional injection of either alpha 2A or alpha 2B interferon have also been reported with mixed results.48,49 Oral tamoxifen has been tested as a therapeutic agent to treat Peyronie’s disease.50 Tamoxifen, an anti-estrogen, is thought to work by inducing TGF-b1 expression. The authors of this study speculate that increased TGFb1 inhibits inflammatory cell responses that precipitate a fibrotic response. Tamoxifen may act through a different pathway than the one the authors propose. Further research is needed to clarify its mechanism of action. In all of the pharmacotherapeutic treatments briefly reviewed here, patient improvement ranged from a few per cent to 25 – 30% depending on the endpoint used.

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Summary Peyronie’s disease is a fibrotic disorder of the tunica albuginea involving potential trauma to the penis and an inflammatory response. The fibrotic plaques that form are produced most likely by tunical fibroblasts in response to cytokine stimulation. Of the candidate cytokines, TGF-b1 and possibly PDGF play a role. To date, pharmacotherapy has not been effective or widely accepted and surgery to either remove the plaque or insert penile prostheses remains the mainstay of treatment. A better understanding of the molecular pathology of this disease is expected to improve pharmacotherapeutic strategies to treat this condition.

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