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The Etiology of Peyronie’s Disease: Pathogenesis and Genetic Contributions
REVIEW
The Etiology of Peyronie’s Disease: Pathogenesis and Genetic Contributions Kiran L. Sharma, PhD, Manaf Alom, MBBS, and Landon Trost, MD
ABSTRACT
Introduction: Peyronie’s disease (PD) is a chronic fibrosing condition that contributes to penile deformity, curvature, and pain. Initial familial studies demonstrated potential genetic links to PD. Since that time, very few investigations have significantly advanced the science in this area. Hence, there is a large opportunity and significant need to better study the underlying genomics and pathogenesis of PD. Aim: To summarize the current genomic literature relevant to PD. Methods: A review was performed of all PubMed-indexed literature from 1970e2018 relating to the pathophysiology and genetics of PD. Key findings were categorically summarized to include epidemiology, risk factors, inheritance patterns, chromosomal instability, genetic associations, epigenetics, differential gene expression, and preclinical models of PD. Main Outcome Measures: Summary of the current literature on the genetics of PD. Results: PD is a common condition and has several known risk factors and comorbid disease associations. Although men with PD are believed to be genetically predisposed, there are likely several subtypes of the condition, each with varied pathophysiological disorders and contributing factors. Available data suggest that PD is associated with underlying genetic instability, including dysregulation of genes relating to fibrosis and cellular degradation, thus, resulting in abnormal plaque development and penile deformity. Preclinical models, including cell cultures and rat models, demonstrate several consistencies with PD clinical and histopathologic characteristics; however, an ideal model with spontaneous development of PD is lacking. Conclusion: Based on limited data, PD likely represents a heterogeneous condition, with both heritable and environmentally-driven epigenetic factors contributing to its development and progression. However, there remains a significant gap in the literature on the underlying cause and pathophysiology of the condition, suggesting a substantial need for further investigation and study. Sharma KL, Alom M, Trost L. The Etiology of Peyronie’s Disease: Pathogenesis and Genetic Contributions. Sex Med Rev 2019;XX:XXXeXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Peyronie’s Disease; Molecular Genetics; Dupuytren’s Disease; Ledderhose Disease; Transforming Growth
INTRODUCTION Peyronie’s disease (PD) is a localized connective tissue disorder that leads to penile deformity via development of fibrous collagen plaques in the tunica albuginea and may cause vascular or mechanical abnormalities or both. The condition has long been recognized in clinical medicine and received its contemporary moniker from François Gigot de la Peyronie, who defined the disorder in 1743.1 Additional historical reports date to the 13th century, and some have suggested that it may have been
Received April 9, 2019. Accepted June 11, 2019. Mayo Clinic, Rochester, MN, USA Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.sxmr.2019.06.004
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recognized as far back as 3000 BC, when it appeared in Minoan sculpture.2,3 Clinical presentation of the disease is variable and may include erectile dysfunction (ED), penile pain, shortening, deformity, curvature, and palpable plaque, among others. The condition is also commonly associated with other fibrosing conditions, which share a similar pathophysiology, including Dupuytren’s disease (DD) and Ledderhose disease (LD).4e7 The clinical presentation of penile abnormalities likely relates to involvement of the tunica albuginea (TA) of the corpus cavernosum, which consists of interlinked collagen and elastic fibers. During an ordinary erection, penile stimulus leads to discharge of nitric oxide, which increases blood circulation to the penis and relaxes corpus cavernosum smooth muscle. This increases cavernosal hydrostatic pressure and obstructs small venules that perforate the TA.8 In contrast, among men with PD, scanning electron microscopy 1
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Table 1. Prevalence of Peyronie’s disease First author (Year)
Country
Population
Prevalence (%)
Lindsay20 (1991) La Pera24 (2001) Rhoden23 (2001) Schwarzer22,71 (2001 & 2002) Mulhall25 (2004) El-Sakka72 (2006) Arafa73 (2007) Stuntz74 (2016)
USA Italy Brazil Germany USA Saudi Arabia Egypt USA
General population General population Men >50 years screened for prostate cancer General population Men screened for prostate cancer Men with ED Diabetic men with ED General population
0.4 7.1 3.7 3.2 8.9 7.9 20.3 0.5
ED ¼ erectile dysfunction.
demonstrates deformed collagen TA architecture, with an increased ratio of collagen I and III fibers to elastin.9 This contributes to the formation of scar tissue and penile inelasticity, deformity, and curvature.10 The underlying pathophysiology of PD has not been fully elucidated. Proposed mechanisms include increased chromosomal instability, autoimmune response involving T-cells, fibrogenic cytokines, and subtunical vasculitis, among others.11-16 The possibility of a genetic predisposition has also been described through recognition of HLA associations, pedigree analyses suggesting potential autosomal dominant transmission, and gene expression studies.17-19 Because PD likely represents a spectrum disorder, contributing mechanisms are likely multifactorial and may involve the interaction of multiple autoimmune and genetic pathways. To date, there have been relatively few transformative studies relating to the pathophysiology of PD. Most genetic investigations were performed in the 1980s and 1990s, with few significant advancements reported since that time. This slow progress may highlight the complexity of the condition or relate to other factors, such as limited funding, minimal impact on overall health, lack of association with more severe comorbid conditions, and relative paucity of PD specialists. The objective of this article is to provide a thorough review of the known pathogenesis and genetic contributions to PD. Specifically, findings are organized to review the epidemiology and risk factors of PD, inheritance patterns, chromosomal instability, associated genes, epigenetics, and gene expression. Additionally, a brief commentary will be made on available experimental models and their strengths and limitations.
METHODS A comprehensive literature review was conducted of all PubMed-indexed articles from inception to 2019 relating to the cause and genetics of PD. Search terms included Peyronie’s, Peyronie, gene, genetic, genome, chromosome, epigenetics, familial, Dupuytren’s, Dupuytren, and inheritance. Key findings from these studies were categorically summarized to include epidemiology and risk factors, genetic alterations in PD,
inheritance patterns, chromosomal instability, genetic associations, epigenetics, differential gene expression, and preclinical experimental models.
EPIDEMIOLOGY AND RISK FACTORS The reported epidemiology of PD varies depending on definition used and may be under-representative, given the sensitive nature of the condition. Roughly 0.4e0.5% of men carry a diagnosis of PD, 1% have a combination of plaque, pain, and curvature, 3e4% self-identify penile plaques, 6% of older men have curvature, 9% of older men are found to have a plaque on examination by a specialist, and 13% have some finding possibly consistent with PD (diagnosis, plaque, curve, or deformity).20-25 Although the overall incidence is 22e25 per 100,000 men, it is relatively uncommon in younger men, with those <40 accounting for only 10% of PD cases.26,27 In contrast, most studies report a mean age of presentation in the 45- to 60-year range, often corresponding with the onset of erectile dysfunction.26,28e31 See Table 1 for reported prevalence rates of PD by population and geographic region. Reported risk factors for PD include comorbid conditions such as advancing age, obesity, dyslipidemia, diabetes, atherosclerosis, and psychosomatic disorders.32e37 Genetic predisposition (family history) and penile trauma (including iatrogenic and unrecognized) have also been linked to PD. In a study of 134 PD men, Carrieri and colleagues38 reported a 21% rate of comorbid DD and 4% with a family history of PD. In their analysis, the authors concluded that men with genital/perineal trauma had a 3 greater risk for development of PD, whereas those undergoing more invasive procedures, such as transurethral resection of the prostate, had up to 16 greater likelihood for development of PD. Other proinflammatory or neoplastic conditions are also linked to PD, including urethritis, elevated uric acid levels, and the presence of lipomas.38 Substance use has also been implicated, with men who smoke having a 4.6 greater likelihood of having PD compared with non-smokers, whereas no association has been consistently shown with alcohol.24 The use of b-blockers has further been linked to PD, with some hypothesizing that the therapy results in Sex Med Rev 2019;-:1e10
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Genetics and Pathogenesis of Peyronie’s Disease
Table 2. Genetic and familial studies in Peyronie’s disease First author (Year)
Associated antigens
Study type
No. of families/patients
Case report
11 patients
HLA-B27 HLA-B7
Bias44 (1982)
Family pedigree analysis
3 families
HLA-B7
Leffell19 (1982)
Case report
28 idiopathic PD
HLA A, B, and C
Nyberg18 (1982)
Family pedigree analysis
3 families
HLA-B7
Ziegelbaum45 (1987)
Twin study
HLA-B7
Ralph17 (1997)
Case report
1 family with identical twins 51 PD (15 with DD)
43
Willscher
(1979)
HLA-A1, DR3, DQw2, HLA-B7, and HLA-B27
Results Significant association of HLA B7 cross-reacting group with PD (7/8) patients Male-limited, autosomal dominant trait Traced PD through several families DD contracture present in both males and females Non-association of PD with HLA antigens Antigens of HLA-B7 cross-reacting group present in 3 kindreds Possible association of PD, HLA, and autosomal dominant inheritance Association of PD with HLA B7 Association of PD and HLA-B27
DD ¼ Dupuytren’s disease; HLA ¼ human lymphocyte antigen; PD ¼ Peyronie’s disease.
disequilibrium among a- and b-receptors and results in a proinflammatory state within penile connective tissue.39,40 Finally, reduced levels of trace elements such as manganese, copper, zinc, and iron have been found more commonly in men with PD compared with control subjects in a limited series of 56 men.41
1987.45 In the study, a family, including twin brothers, underwent HLA immunotyping and demonstrated a positive B7 crossreactive antigen in the father, twin brothers, and 1 child of 1 of the twins. All of those with B7 positivity were found to have penile deformities consistent with PD, confirming a common genetic cause.
As noted earlier, PD likely represents a spectrum disorder, with multiple subtypes present. As just 1 example, Tal and colleagues42 compared characteristics of PD in teenagers with those in men >40 years of age. In contrast to the older cohort, teenagers were 7 more prone to multiple plaques (37% vs 5%, respectively) and more likely to have HbA1c levels >5%.42 This varying nature of PD adds to the complexity of understanding the condition, because there may be multiple pathways that each lead to a PD-like state but have differing underlying mechanisms.
However, despite these intriguing early findings, subsequent studies have not consistently identified positive family histories in the majority of men with PD. In a report of 408 men with PD, only 1.9% of men had a positive family history for PD, whereas DD was present in 15.4%.35 The lack of a consistent family history may indicate that only certain subtypes of PD are due to a heritable genetic condition. It may also be related to the fact that PD is a sensitive topic and that many affected men will not discuss the condition with family members or would have heard about the condition from others within the family. Thus, the true rate of familial penetrance is likely underestimated. Table 2 summarizes studies demonstrating potential genetic associations with PD.
GENETIC ALTERATIONS IN PEYRONIE’S DISEASE Inheritance The first familial study suggesting a genetic origin for PD was reported in 1979 by Willscher and colleagues,43 who noted an association with HLA-B7 histocompatibility antigens. Subsequently, PD was proposed to be a sex-linked condition with reduced penetrance. However, a later attempt to trace PD through multiple families led to the suggestion that PD is an autosomal dominant trait (identified in 3 consecutive generations), and that the associated condition of DD was observed equally in males and females.44 The strongest evidence for a genetic link, however, came from a twin-twin study performed in Sex Med Rev 2019;-:1e10
Chromosomal Instability Associated with Peyronie’s Disease Chromosomal abnormalities with PD were first described by Somers and colleagues in 1987.11 Using cell cultures from PD and control men, samples were obtained from the PD plaque, adjacent tunica albuginea, dermis, and lymphocytes. Results demonstrated chromosomal abnormalities in 58% of sampled plaques, whereas adjacent tissues and control men demonstrated no such abnormalities. Interestingly, there was a wide variety of
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Table 3. Studies evaluating chromosomal abnormalities in men with Peyronie’s disease First author (Year)
Technique
Sample
Study finding
Somers11 (1987)
Cytogenetic
9 plaque-derived cell cultures from 7 PD men
Guerneri12 (1991)
Cytogenetic
Plaque-derived cell cultures from 9 PD men
Mulhall46 (2004)
FISH
Plaque-derived cell cultures from 5 PD men
Trisomy 7 and 8 45X,-Y deletion Structural chromosomal alterations & reciprocal translocations 46XY, t(11;12)(q11,p11) 46XY, t(1;5)(q25;q11) Inversion of 46XY, inv (7)(p22q36) Presence of chromosome instability 8 with Y-chromosome aneusomy 3 with chromosomal translocations Hybridization probes targeted to chromosomes 7, 8, 17, 18, X, and Y Aneusomies observed at early passage Chromosomal instability Aneuploidy with chromosomes 7, 8, 17,18, X Y
PD ¼ Peyronie’s disease.
abnormalities noted, including 5 numerical changes, 4 structural rearrangements, chromosomal additions (trisomy 7 and 8), deletions (45X, -Y), and reciprocal translocations and inversions. Some samples even demonstrated multiple, independent chromosomal abnormalities. Similar findings were observed in a later study by Guerneri and colleagues.12 In their study of 14 men with PD, cell plaque metaphases were abnormal in 9, with 2 suggesting clonal evolution and 4 demonstrating unrelated clonal lines. Overall, the Y-chromosome was the most frequently involved in numerical changes. The authors concluded that the condition may be of a multiclonal origin and highlighted that significant chromosomal abnormalities contributed to progression of the condition. A subsequent evaluation by Mulhall and colleagues46 built on these earlier findings and identified findings consistent with a possible field abnormality among men with PD. The authors obtained tissue samples of diseased and non-diseased regions of the penis in men with PD and compared them against tissue samples from control subjects without PD. Initial evaluation of the cell cultures demonstrated abnormalities in the regions of plaque and predominantly normal findings in non-diseased regions. Similar to other studies, common abnormalities were noted in the Y-chromosome, as well as with 7, 8, 17, 18, and X. Interestingly, although non-plaque TA cells demonstrated normal findings initially, repeated passage led to subsequent aneusomies in 1 chromosome, suggesting that even non-diseased regions exhibited chromosomal instability. Table 3 summarizes studies evaluating chromosomal abnormalities in men with PD.
Genetic Association Studies Reported in PD Relatively limited data are available from genetic association studies and PD. 1 of the earliest studies evaluating single-nucleotide polymorphisms associated with PD was
conducted by Hauck and colleagues.47 The authors compared 111 men with PD to control subjects and evaluated for differential rates of 2 polymorphisms known to upregulate transforming growth factor b-1 (TGF-b1). Results demonstrated slightly elevated rates of the G915C single-nucleotide polymorphisms (89% vs 79% in control subjects) and no differences in allelic frequencies of T869C. The authors concluded that, although this may contribute to the pathogenesis of PD, it is not likely a major genetic risk factor. To date, no genome-wide association sequencing or DNA sequencing studies have been performed in PD. However, a large genome-wide association sequencing study of 2,325 men with DD demonstrated 11 single-nucleotide polymorphisms from 9 chromosomal loci that were linked to DD predisposition.48 6 of the genes were associated with the Wnt-signaling pathway, which is a pathway responsible for various cell functions, including regulation of gene transcription, cytoskeleton, and intracellular calcium. It is also activated by chronic inflammation (via prostaglandin E2), which is also consistent with the pathogenesis of PD. The authors subsequently performed a follow-up study evaluating for these 9 loci in men with PD.49 Results demonstrated that only 1 of the 9 was positively associated, with that gene involved in the Wnt pathway and located on chromosome 7. These findings are particularly interesting, given the previously described studies that highlighted chromosome 7 as a common region of abnormality in PD plaques.11,46 An additional, recent study was reported of a family with heart disease secondary to a heterozygous LMNA mutation.50 Among the family members, multiple were noted to have DD and LD (PD history not obtained). Interestingly, when family members were tested for the LMNA mutation, Sex Med Rev 2019;-:1e10
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Genetics and Pathogenesis of Peyronie’s Disease
Table 4. Genetic association studies relevant to Peyronie’s disease First author (Year)
Study type
Population
Genetic variation Identified
Associated genes
Hauck47 (2003) Dolmans48 (2011)
Case control GWAS
111 PD, 100 controls 2,325 DD, 11,562 controls, PD not reported
TGF-b1, rs1800471, (G915C) WNT4 (rs7524102)
rs1800471 9 chromosomal loci associated with DD
Dolmans49 (2012)
Case Control
111 PD, 490 controls
SFRP4 (rs16879765) WNT2 (rs4730775) RSPO2 (rs611744) SULF1 (rs2912522) WNT7B (rs6519955) rs4730775
WNT2 locus chr 7
DD ¼ Dupuytren’s disease; GWAS ¼ genome-wide association study; PD ¼ Peyronie’s disease.
4 of those who were carriers (along with the proband) demonstrated DD and LD, whereas the 1 non-carrier did not have DD or LD. Although the exact role for LMNA is not fully elucidated, it is known to code for several lamin proteins, which have roles in regulating the activity of select genes. Table 4 summarizes genetic association studies relevant to PD.
Epigenetics Epigenetics refers to changes that occur secondary to modification of gene expression rather than alterations of the underlying DNA sequence. These changes most often occur via DNA methylation and histone after translational modification. More specifically, histone acetylase and histone deacetylase (HDAC) function in a counter-regulatory manner to switch the equilibrium of histone acetylation and deacetylation. This facilitates/ restricts transcriptional potential by providing/limiting access of its promoter to transcriptional regulatory proteins. These specific pathways are relevant to PD, because they have been shown to play a role in the pathogenesis of various fibrotic conditions. 1 potential mechanism of PD epigenetic modulation involves HDAC inhibition. Ryu and colleagues performed an analysis of small interfering RNA (siRNA)emediated silencing of HDAC2 in PD plaque fibroblasts.51 Among fibroblast cultures pretreated with siRNA (HDAC2 knockdown) and subsequently treated with the profibrotic TGF-b1, downstream expression of extracellular matrix proteins was significantly blunted. Additionally, TGF-b1einduced transdifferentiation of fibroblasts into myofibroblasts was inhibited, and decreased expression was noted with plasminogen activator inhibitore1, fibronectin, collagens I and IV, and smooth muscle a-actin. Each of these observations suggests that inhibition of HDAC2 could potentially significantly offset the profibrotic actions of TGF-b1. Kwon and colleagues52 subsequently validated these findings in a rat model using adenovirus encoded HDAC2 small hairpin RNA (HDAC2 knockdown). The authors observed that injected rats developed fewer fibrotic plaques, decreased inflammatory cells, reduced nuclear translocation of phosphorylated SMAD3 (protein responsible for receptor signal transduction for TGF-b), reduced transdifferentiation of fibroblasts to myofibroblasts, and Sex Med Rev 2019;-:1e10
reduced collagen production. Additionally, the treatment induced apoptosis and decreased expression of cyclin D1 (cellcycle regulator). A more recent study evaluated the differential gene expression of HDACs in fibroblasts extracted from PD plaques and normal TA.53 Results demonstrated a higher expression of HDAC 2, 3, 4, 5, 7, 8, 10, and 11 in plaques from PD compared with normal TA tissue. Subsequent knockdown of HDAC7 by siRNA-mediated silencing in PD fibroblasts repressed the TGF-b1emediated nuclear transport of Smad2 and Smad3 proteins, fibroblast to myofibroblast transdifferentiation, and impaired production of extracellular matrix protein induced by TGF-b1.
Differential Gene Expression in Peyronie’s Disease Several authors have investigated dysregulation of select genes associated with fibrosis in men with PD. Magee and colleagues54 performed a DNA microarray analysis of PD plaques and demonstrated upregulation in pleiotrophin (osteoblast recruitment), monocyte chemotactic protein 1 (inflammation), early growth response protein (fibroblast proliferation), elastase (elastic fiber degradation), and myofibroblast markers (a and g smooth muscle actin, desmin, and others). Several genes were also noted to be downregulated, including ubiquitin and ID-2 (tissue remodeling), collagenase IV (degrades collagen), and TGF-b modulators. The authors concluded that overall findings indicated upregulation of genes associated with fibrosis (collagen synthesis, myofibroblast differentiation, tissue remodeling, inflammation, ossification, and proteolysis) and downregulation of genes inhibiting fibrosis compared PD plaques with normal TA, DD, and normal plantar fascia.55 Interestingly, both PD and DD demonstrated upregulated collagen degradation (matrix metalloproteinases [MMP- 2, MMP- 9 and thymosins b-10 and b-4), ossification (osteoblast-specific factor 1), and myofibroblast differentiation (RhoGDP dissociation inhibitor 1). PD also exhibited upregulation of early growth response protein and decorin, which serves to inhibit TGF-b1. Zorba and colleagues56 performed a reverse transcriptase PCR analysis to evaluate messenger RNA expression in PD plaques. Overall downregulation of apoptotic proteins (Fas, Fas Ligand, Bcl-2,
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Table 5. Summary of differential gene expression in Peyronie’s disease First author (Year) Upregulated Genes Del Carlo75 (2008) Szardening-Kirchner76 Magee54 (2002)
Technique MMP protein microarrays WB (2009) RT-PCR Clontech DNA microarray Affymetrix DNA microarray
Pathway
Genes
MMP pathway
MMP 1,3,10,13
Inflammation Differentiation of fibroblasts into myofibroblasts
RT-PCR, WB, IF ELISA, RT-PCR IHC & biochemical assays ELISA
Elastin degradation TGF-b pathway Extracellular matrix alterations Multiple pathways FGF Pathway
MCP1 Fibroblast muscle type TPM, 20-kDa, MYL, FLN, gamma and alpha-smooth muscle actin (ACTA2), DES, 22-kDa smooth muscle protein Cadherin, TGFb1, and IGF binding protein-6 Heat-shock protein 28 and 28-kDa heat shock protein Elastase IIB24 Smad3 and Smad4 TGF-b, IL6 AQP1 FGF
DNA microarrays
Osteoblast recruitment
Pleiotrophin
Fibroblast proliferation Elastic fiber degradation
EGR Elastase
Ubiquitination
Ubiquitin
DNA binding (ID)
DNA-binding inhibitor Id-2 Calcineurin A Collagenase IV TGF modulators/decorin Collagenase IV(SPARC/Osteonectin) ATF4 (ATF4) SPARC/Osteonectin Decorin Collagenase IV, (SMAD7) HLA-B Bcl-2, p53, Caspase 3 and Caspase 8 All IGF1 isoform (Ea, Eb and Ec) expressions
Fibroblast attachment and collagen production Cellular stress response
Haag61 (2007) Watanabe77 (2017) Castorin63 (2016) Mulhall14 (2001) Jalkut78 (2004)
Downregulated genes Jalkut78 (2004)
Magee54 (2002)
DNA microarrays
Clontech DNA microarray
Collagen breakdown Limit TGF activity Collagen degradation HLA complex
Zorba56 (2012)
RT-PCR
Pro-apoptotic genes
Thomas62 (2016)
IF, RT-PCR
IGF Pathway
Other altered gene expression Clontech DNA microarray Magee54 (2002)
Collagen degradation (MMP)
MMP2 and MMP9, and thymosins (MMP activators), with TMbeta10 and TMbeta4; elastase IIB SMAD7
DES ¼ desmin; EGR ¼ early growth response protein; ELISA ¼ enzyme-linked immunosorbent assay; FLN ¼ filamin; IF ¼ immunofluorescence; IGF ¼ insulin growth factor; IHC ¼ immunohistochemistry; kDa ¼ kilodalton; MCP ¼ monocyte chemotactic protein; MMP ¼ matrix metalloproteinase; MYL ¼ myosin light chain; RT-PCR ¼ reverse-transcriptaseepolymerase chain reaction; TPM ¼ tropomyosin; WB ¼ Western blot.
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Genetics and Pathogenesis of Peyronie’s Disease
p53, Caspase 3 and 8) occurred more frequently in PD plaques compared with controls. These findings are also consistent with an earlier study, which demonstrated defunctionalization of p53 in PD cells compared with normal TA.57 Both of these studies suggested that the high cell proliferation rate observed in PD may be due, in part, to this downregulation of the apoptotic pathway. Several authors also performed cell culture analyses to help better differentiate diseased vs non-diseased tissue factor expression and responsiveness to various stimuli. Mulhall and colleagues14 performed an indirect analysis of supernatants derived from PD plaque cell cultures and compared against non-diseased TA biopsy specimens. Results showed an upregulation of basic fibroblast growth factor among the PD fibroblast cell line compared with in the control subjects without PD, again confirming the presence of notable profibrotic factors in phenotypically diseased cell lines. In examining protein profiles more broadly, De Young and colleagues58 performed surface-enhanced laser desorption/ionization time-of-flight mass spectrometry of PD plaque tissue cultures. Results demonstrated significant increases in smooth muscle a-actin, b-catenin, and heat shock protein 47 compared with normal TA, with other changes noted in TGF-b1 and fibronectin. Altered expression was also noted for several unidentified proteins, ranging from 4.7e76.8 kDa, suggesting the presence of several upregulated pathways that had not yet been identified. In a somewhat related study, cell cultures of PD plaques were stimulated with TGF-b and interleukin-1b to observe for induction of MMPs and tissue inhibitors of MMPs (TIMPs). Whereas interleukin-1b increased production of MMP 1, 3, 10, and 13, TGF-b failed to induce MMPs and instead demonstrated abundant TIMP 14 proteins compared with non-diseased TA. These findings overall suggested that TGF-b may result in PD progression via inhibition of MMPs and upregulation of TIMPs. The authors also hypothesized that PD plaques may exhibit this pattern of expression secondary to chronic exposure to TGF-b. Also related to TGF-b, SMAD proteins are important intracellular signal-transducer molecules for TGF-b receptors, with stimulatory (Smad2, Smad3, and Smad4) and inhibitory functions (Smad6 and Smad7) recognized.59,60 Using fibroblast cultures grown from PD plaques, Haag and colleagues61 identified elevated levels of Smad3 and 4 compared with control subjects. When the cultures were stimulated with TGF-b1, Smad2 and 3 demonstrated rapid nuclear translocation, which occurred sooner and in a more pronounced manner compared with control subjects. Smad4 also demonstrated prolonged nuclear retention time in PD fibroblasts compared with control subjects. These findings further supported TGF-b as an important pathogenic factor in the development of PD. Other studies of PD plaques have identified reduced genetic expression of insulin-like growth factor 1 isoforms (anabolic effects) and upregulation of aquaporin 1 (role in connective tissue resistance to mechanical stress).62,63 Although intriguing,
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the significance and role of these findings remains unclear, with further study required to both validate and contextualize outcomes. Table 5 summarizes studies of differential gene expression observed in PD.
PRECLINICAL EXPERIMENTAL MODELS 1 of the most commonly used models in PD is in vitro cell cultures. Often, these models consist of cells (predominantly fibroblasts) grown from various areas, including PD plaques, unaffected TA from PD individuals, foreskin, or TA from individuals without PD. Although many studies have examined cells obtained from human plaques, some have used convenience samples in animal (rat) models. To induce the disease state, cultured fibroblasts are often exposed to profibrotic agents (typically TGF-b1), and the resultant cells (myofibroblasts) are examined for various pathologic parameters.64 In vivo animal models have similarly used rats induced with various treatments to create a PD-like state. The most common model includes injection of TGF-b1 (or agents with TGF-b1 activity) to the rat penis to create penile nodularity and deformity.65 Resultant plaques in this model resemble the human PD condition both histologically and biochemically.66 A second model uses fibrin injected into the TA and is based on the hypothesis that penile injury leads to fibrinogen activation, followed by penile fibrosis.67 A third model involves a surgical incision to the rat penis to simulate trauma. In the earliest investigation of this approach, histologic changes were noted initially consistent with the acute phase of PD; however, overt chronic-phase PD was not achieved.68 A more recent attempt performed repeated injections of chlorhexidine gluconate with 15% ethanol and demonstrated penile curvature, plaques, erectile dysfunction, and increased smooth muscle a-actin and TGF-b1.69 In addition to TGF-b1, several other pathways have been identified in animal models leading to penile fibrosis, including HDAC2, Smad3, and RhoA-ROCK.70 Studies have also shown blunting of fibrosis via intratunical injection of TGF-b1 receptor kinase inhibitors, adipose tissueederived stem cells, HDAC2, shRNA, and anthocyanin.70 The strength of many of the animal models is that a reproducible disease state can be achieved secondary to fibrosis and phenotypically and histologically mimics PD. This permits experimental testing of various agents to determine how they impact either the progression of fibrosis or treatment of the final fibrotic state. It should be noted, however, that none of these models accurately reproduces the true pathophysiology of PD. Because PD is believed to occur as a result of underlying genetic instability, no model, to date, attempts to recreate that key aspect of PD. As such, neither in vitro nor in vivo animal models are able to test or make any conclusions with regard to the efficacy of any treatment on the prevention of PD. Similarly, the efficacy of any treatment in an experimental model should be considered preliminary and requiring confirmation in the human condition.
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CONCLUSION
Category 3
Despite the long-standing recognition of PD as a condition, relatively little is known regarding the underlying pathophysiology. Because PD likely represents a spectrum disorder, multiple potential pathways may result in the development of penile fibrosis and deformity. Overall, the condition affects a relatively large number of men and is associated with various comorbid conditions. Some subtypes of PD have demonstrated a clear heritable pattern, with 1 exhibiting autosomal dominant inheritance, whereas most cases appear to occur in the absence of a clear family history. Genetic evaluations of men with PD have identified findings consistent with chromosomal instability and include the possible development of multiple chromosomal abnormalities with subsequent cellular generations. Epigenetic gene modification may also play a significant role in PD, including the extent of fibrosis that may occur after disease activation. Numerous profibrotic genes have further been identified as being upregulated in PD-affected tissue, whereas those inhibiting cell progression and fibrosis are often inversely downregulated. Several preclinical models have been developed to better study the pathophysiology of PD, including cell cultures and rat models. Although these consistently demonstrate profibrotic conditions, no models, to date, have been able to replicate the spontaneous development of the condition in vivo.
(a) Final Approval of the Completed Article Kiran L. Sharma; Manaf Alom; Landon Trost
ACKNOWLEDGMENT The authors wish to acknowledge the generous gift from a patient who wishes to remain anonymous and that has facilitated Peyronie’s disease research. Corresponding Author: Landon Trost, MD, 200 First St SW, Rochester, MN 55905, USA. Tel: 507-284-4248; Fax: 507-2844951; E-mail: [email protected] Conflicts of Interest: The authors report no conflicts of interest. Funding: None
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Kiran L. Sharma; Manaf Alom; Landon Trost (b) Acquisition of Data Kiran L. Sharma; Manaf Alom; Landon Trost (c) Analysis and Interpretation of Data Kiran L. Sharma; Manaf Alom; Landon Trost Category 2 (a) Drafting the Article Kiran L. Sharma; Manaf Alom; Landon Trost (b) Revising It for Intellectual Content Kiran L. Sharma; Manaf Alom; Landon Trost
REFERENCES 1. Peyronie DL. Memoire sur quelques obstacles quis’ opposent a l’ ejaculation naturelle de la semence. Memoires de l’ Acad Roy de Chir 1743: 425e434. 2. Musitelli S, Bossi M, Jallous H. A brief historical survey of "Peyronie’s disease’. J Sex Med 2008;5:1737-1746. 3. Laios K, Tsoucalas G, Karamanou M, et al. Peyronie’s disease in Minoan art. J Sex Med 2013;10:3144-3145. 4. Nugteren HM, Nijman JM, de Jong IJ, et al. The association between Peyronie’s and Dupuytren’s disease. Int J Impot Res 2011;23:142-145. 5. Michou L, Lermusiaux JL, Teyssedou JP, et al. Genetics of Dupuytren’s disease. Joint Bone Spine 2012;79:7-12. 6. Noss MB, Day NS, Christ GJ, et al. The genetics and immunology of Peyronie’s disease. Int J Impot Res 2000;12(Suppl. 4):S127-S132. 7. Bystrom J, Rubio C. Induratio penis plastica Peyronie’s disease. Clinical features and etiology. Scand J Urol Nephrol 1976;10:12-20. 8. Ostrowski KA, Gannon JR, Walsh TJ. A review of the epidemiology and treatment of Peyronie’s disease. Res Rep Urol 2016;8:61-70. 9. Somers KD, Sismour EN, Wright GL Jr, et al. Isolation and characterization of collagen in Peyronie’s disease. J Urol 1989; 141:629-631. 10. Brock G, Hsu GL, Nunes L, et al. The anatomy of the tunica albuginea in the normal penis and Peyronie’s disease. J Urol 1997;157:276-281. 11. Somers KD, Winters BA, Dawson DM, et al. Chromosome abnormalities in Peyronie’s disease. J Urol 1987;137:672-675. 12. Guerneri S, Stioui S, Mantovani F, et al. Multiple clonal chromosome abnormalities in Peyronie’s disease. Cancer Genet Cytogenet 1991;52:181-185. 13. Ralph DJ, Mirakian R, Pryor JP, Bottazzo GF. The immunological features of Peyronie’s disease. J Urol 1996;155:159162. 14. Mulhall JP, Thom J, Lubrano T, et al. Basic fibroblast growth factor expression in Peyronie’s disease. J Urol 2001;165:419423. 15. El-Sakka AI, Hassoba HM, Pillarisetty RJ, et al. Peyronie’s disease is associated with an increase in transforming growth factor-beta protein expression. J Urol 1997;158:1391-1394. 16. Smith BH. Peyronie’s disease. Am J Clin Pathol 1966; 45:670-678. 17. Ralph DJ, Schwartz G, Moore W, et al. The genetic and bacteriological aspects of Peyronie’s disease. J Urol 1997; 157:291-294.
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Genetics and Pathogenesis of Peyronie’s Disease 18. Nyberg LM Jr, Bias WB, Hochberg MC, et al. Identification of an inherited form of Peyronie’s disease with autosomal dominant inheritance and association with Dupuytren’s contracture and histocompatibility B7 cross-reacting antigens. J Urol 1982;128:48-51. 19. Leffell MS, Devine CJ Jr, Horton CE, et al. Non-association of Peyronie’s disease with HLA B7 cross-reactive antigens. J Urol 1982;127:1223-1224. 20. Lindsay MB, Schain DM, Grambsch P, et al. The incidence of Peyronie’s disease in Rochester, Minnesota, 1950 through 1984. J Urol 1991;146:1007-1009. 21. Dibenedetti DB, Nguyen D, Zografos L, et al. A populationbased study of Peyronie’s disease: Prevalence and treatment patterns in the United States. Adv Urol 2011;2011:282503. 22. Schwarzer U, Sommer F, Klotz T, Braun M, Reifenrath B, Engelmann U. The prevalence of Peyronie’s disease: results of a large survey. BJU Int 2001;88:727-730. 23. Rhoden EL, Teloken C, Ting HY, et al. Prevalence of Peyronie’s disease in men over 50-y-old from Southern Brazil. Int J Impot Res 2001;13:291-293. 24. La Pera G, Pescatori ES, Calabrese M, et al. Peyronie’s disease: Prevalence and association with cigarette smoking. A multicenter population-based study in men aged 50-69 years. Eur Urol 2001;40:525-530. 25. Mulhall JP, Creech SD, Boorjian SA, et al. Subjective and objective analysis of the prevalence of Peyronie’s disease in a population of men presenting for prostate cancer screening. J Urol 2004;171:2350-2353. 26. Kadioglu A, Tefekli A, Erol B, et al. A retrospective review of 307 men with Peyronie’s disease. J Urol 2002;168:10751079. 27. Deveci S, Martin D, Parker M, et al. Penile length alterations following penile prosthesis surgery. Eur Urol 2007;51:11281131. 28. Mulhall JP, Schiff J, Guhring P. An analysis of the natural history of Peyronie’s disease. J Urol 2006;175:2115-2118. discussion 2118. 29. Rhoden EL, Riedner CE, Fuchs SC, et al. A cross-sectional study for the analysis of clinical, sexual and laboratory conditions associated to Peyronie’s disease. J Sex Med 2010; 7:1529-1537. 30. Grasso M, Lania C, Blanco S, et al. The natural history of Peyronie’s disease. Arch Esp Urol 2007;60:326-331. 31. Chung E, Yan H, De Young L, et al. Penile Doppler sonographic and clinical characteristics in Peyronie’s disease and/or erectile dysfunction: An analysis of 1500 men with male sexual dysfunction. BJU Int 2012;110:1201-1205. 32. Bjekic MD, Vlajinac HD, Sipetic SB, et al. Risk factors for Peyronie’s disease: A case-control study. BJU Int 2006; 97:570-574. 33. Casabe A, Bechara A, Cheliz G, et al. Risk factors of Peyronie’s disease. What does our clinical experience show? J Sex Med 2011;8:518-523. Sex Med Rev 2019;-:1e10
9 34. El-Sakka AI, Tayeb KA. Peyronie’s disease in diabetic patients being screened for erectile dysfunction. J Urol 2005; 174:1026-1030. 35. Chilton CP, Castle WM, Westwood CA, et al. Factors associated in the aetiology of peyronie’s disease. Br J Urol 1982;54:748750. 36. Pavone C, D’Amato F, Dispensa N, et al. Smoking, diabetes, blood hypertension: Possible etiologic role for Peyronie’s disease? Analysis in 279 patients with a control group in Sicily. Arch Ital Urol Androl 2015;87:20-24. 37. Herati AS, Pastuszak AW. The genetic basis of Peyronie disease: A review. Sex Med Rev 2016;4:85-94. 38. Carrieri MP, Serraino D, Palmiotto F, et al. A case-control study on risk factors for Peyronie’s disease. J Clin Epidemiol 1998; 51:511-515. 39. Kristensen BO. Labetalol-induced Peyronie’s disease? A case report. Acta Med Scand 1979;206:511-512. 40. Paladini G. Peyronie’s disease and systemic lupus erythematosus syndrome associated with metoprolol administration: A case report. Int J Tissue React 1981;3:95-98. 41. Gunes M, Aslan R, Eryilmaz R, et al. Levels of serum trace elements in patients with Peyronie. Aging Male 2018:1-4. 42. Tal R, Hall MS, Alex B, Choi J, Mulhall JP. Peyronie’s disease in teenagers. J Sex Med 2012;9:302-308. 43. Willscher MK, Cwazka WF, Novicki DE. The association of histocompatibility antigens of the B7 cross-reacting group with Peyronie’s disease. J Urol 1979;122:34-35. 44. Bias WB, Nyberg LM Jr, Hochberg MC, et al. Peyronie’s disease: A newly recognized autosomal-dominant trait. Am J Med Genet 1982;12:227-235. 45. Ziegelbaum M, Thomas A Jr, Zachary AA. The association of Peyronie’s disease with HLA B7 cross-reactive antigens. A case report of identical twins. Cleve Clin J Med 1987;54:427430. 46. Mulhall JP, Nicholson B, Pierpaoli S, et al. Chromosomal instability is demonstrated by fibroblasts derived from the tunica of men with Peyronie’s disease. Int J Impot Res 2004; 16:288-293. 47. Hauck EW, Hauptmann A, Schmelz HU, et al. Prospective analysis of single nucleotide polymorphisms of the transforming growth factor beta-1 gene in Peyronie’s disease. J Urol 2003;169:369-372. 48. Dolmans GH, Werker PM, Hennies HC, et al. Wnt signaling and Dupuytren’s disease. N Engl J Med 2011;365:307-317. 49. Dolmans GH, Werker PM, de Jong IJ, et al. WNT2 locus is involved in genetic susceptibility of Peyronie’s disease. J Sex Med 2012;9:1430-1434. 50. Zaragoza MV, Nguyen CHH, Widyastuti HP, et al. Dupuytren’s and Ledderhose diseases in a family with LMNA-related cardiomyopathy and a novel variant in the ASTE1 gene. Cells 2017;6(4). 51. Ryu JK, Kim WJ, Choi MJ, et al. Inhibition of histone deacetylase 2 mitigates profibrotic TGF-beta1 responses in fibroblasts derived from Peyronie’s plaque. Asian J Androl 2013; 15:640-645.
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52. Kwon KD, Choi MJ, Park JM, et al. Silencing histone deacetylase 2 using small hairpin RNA induces regression of fibrotic plaque in a rat model of Peyronie’s disease. BJU Int 2014; 114:926-936.
65. Chung E, De Young L, Brock GB. Rat as an animal model for Peyronie’s disease research: A review of current methods and the peer-reviewed literature. Int J Impot Res 2011;23:235241.
53. Kang DH, Yin GN, Choi MJ, et al. Silencing histone deacetylase 7 alleviates transforming growth factor-beta1-induced profibrotic responses in fibroblasts derived from Peyronie’s plaque. World J Mens Health 2018;36:139-146.
66. El-Sakka AI, Hassoba HM, Chui RM, et al. An animal model of Peyronie’s-like condition associated with an increase of transforming growth factor beta mRNA and protein expression. J Urol 1997;158:2284-2290.
54. Magee TR, Qian A, Rajfer J, et al. Gene expression profiles in the Peyronie’s disease plaque. Urology 2002;59:451-457.
67. Davila HH, Ferrini MG, Rajfer J, et al. Fibrin as an inducer of fibrosis in the tunica albuginea of the rat: a new animal model of Peyronie’s disease. BJU Int 2003;91:830-838.
55. Qian A, Meals RA, Rajfer J, et al. Comparison of gene expression profiles between Peyronie’s disease and Dupuytren’s contracture. Urology 2004;64:399-404. 56. Zorba OU, Sirma S, Ozgon G, et al. Comparison of apoptotic gene expression profiles between Peyronie’s disease plaque and tunica albuginea. Adv Clin Exp Med 2012;21:607-614. 57. Mulhall JP, Branch J, Lubrano T, et al. Perturbation of cell cycle regulators in Peyronie’s disease. Int J Impot Res 2001;13(Suppl. 5):S21-S28.
68. El-Sakka AI, Selph CA, Yen TS, et al. The effect of surgical trauma on rat tunica albuginea. J Urol 1998;159:1700-1707. 69. Jiang H, Gao Q, Che X, et al. Repeated micro-trauma of the penile tunica albuginea: A new animal model of Peyronie’s disease. Urol Int 2018;100:228-239. 70. Cho MC, Song WH, Paick JS. Suppression of cavernosal fibrosis in a rat model. Sex Med Rev 2018;6:572-582. 71. Sommer F, Schwarzer U, Wassmer G, et al. Epidemiology of Peyronie’s disease. Int J Impot Res 2002;14:379-383.
58. De Young LX, Bella AJ, O’Gorman DB, et al. Protein biomarker analysis of primary Peyronie’s disease cells. J Sex Med 2010; 7:99-106.
72. El-Sakka AI. Prevalence of Peyronie’s disease among patients with erectile dysfunction. Eur Urol 2006;49:564-569.
59. Nakao A, Imamura T, Souchelnytskyi S, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J 1997;16:5353-5362.
73. Arafa M, Eid H, El-Badry A, et al. The prevalence of Peyronie’s disease in diabetic patients with erectile dysfunction. Int J Impot Res 2007;19:213-217.
60. Afrakhte M, Moren A, Jossan S, et al. Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members. Biochem Biophys Res Commun 1998;249:505-511. 61. Haag SM, Hauck EW, Szardening-Kirchner C, et al. Alterations in the transforming growth factor (TGF)-beta pathway as a potential factor in the pathogenesis of Peyronie’s disease. Eur Urol 2007;51:255-261. 62. Thomas CG, Psarros C, Gekas A, et al. Alternative splicing of IGF1 gene as a potential factor in the pathogenesis of Peyronie’s disease. In Vivo 2016;30:251-256. 63. Castorina A, Loreto C, Vespasiani G, et al. Increased aquaporin 1 expression in the tunica albuginea of Peyronie’s disease patients: An in vivo pilot study. Histol Histopathol 2016; 31:1241-1249. 64. Mateus M, Ilg MM, Stebbeds WJ, et al. Understanding the role of adenosine receptors in the myofibroblast transformation in Peyronie’s disease. J Sex Med 2018;15:947-957.
74. Stuntz M, Perlaky A, des Vignes F, et al. The prevalence of Peyronie’s disease in the United States: A population-based study. PLoS One 2016;11:e0150157. 75. Del Carlo M, Cole AA, Levine LA. Differential calcium independent regulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases by interleukin-1beta and transforming growth factor-beta in Peyronie’s plaque fibroblasts. J Urol 2008;179:2447-2455. 76. Szardening-Kirchner C, Konrad L, Hauck EW, et al. Upregulation of mRNA expression of MCP-1 by TGF-beta1 in fibroblast cells from Peyronie’s disease. World J Urol 2009; 27:123-130. 77. Watanabe MS, Theodoro TR, Coelho NL, et al. Extracellular matrix alterations in the Peyronie’s disease. J Adv Res 2017; 8:455-461. 78. Jalkut M, Gonzalez-Cadavid N, Rajfer J. New discoveries in the basic science understanding of Peyronie’s disease. Curr Urol Rep 2004;5:478-484.
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The Etiology of Peyronie’s Disease: Pathogenesis and Genetic Contributions Kiran L. Sharma, PhD, Manaf Alom, MBBS, and Landon Trost, MD
ABSTRACT
Introduction: Peyronie’s disease (PD) is a chronic fibrosing condition that contributes to penile deformity, curvature, and pain. Initial familial studies demonstrated potential genetic links to PD. Since that time, very few investigations have significantly advanced the science in this area. Hence, there is a large opportunity and significant need to better study the underlying genomics and pathogenesis of PD. Aim: To summarize the current genomic literature relevant to PD. Methods: A review was performed of all PubMed-indexed literature from 1970e2018 relating to the pathophysiology and genetics of PD. Key findings were categorically summarized to include epidemiology, risk factors, inheritance patterns, chromosomal instability, genetic associations, epigenetics, differential gene expression, and preclinical models of PD. Main Outcome Measures: Summary of the current literature on the genetics of PD. Results: PD is a common condition and has several known risk factors and comorbid disease associations. Although men with PD are believed to be genetically predisposed, there are likely several subtypes of the condition, each with varied pathophysiological disorders and contributing factors. Available data suggest that PD is associated with underlying genetic instability, including dysregulation of genes relating to fibrosis and cellular degradation, thus, resulting in abnormal plaque development and penile deformity. Preclinical models, including cell cultures and rat models, demonstrate several consistencies with PD clinical and histopathologic characteristics; however, an ideal model with spontaneous development of PD is lacking. Conclusion: Based on limited data, PD likely represents a heterogeneous condition, with both heritable and environmentally-driven epigenetic factors contributing to its development and progression. However, there remains a significant gap in the literature on the underlying cause and pathophysiology of the condition, suggesting a substantial need for further investigation and study. Sharma KL, Alom M, Trost L. The Etiology of Peyronie’s Disease: Pathogenesis and Genetic Contributions. Sex Med Rev 2019;XX:XXXeXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Peyronie’s Disease; Molecular Genetics; Dupuytren’s Disease; Ledderhose Disease; Transforming Growth
INTRODUCTION Peyronie’s disease (PD) is a localized connective tissue disorder that leads to penile deformity via development of fibrous collagen plaques in the tunica albuginea and may cause vascular or mechanical abnormalities or both. The condition has long been recognized in clinical medicine and received its contemporary moniker from François Gigot de la Peyronie, who defined the disorder in 1743.1 Additional historical reports date to the 13th century, and some have suggested that it may have been
Received April 9, 2019. Accepted June 11, 2019. Mayo Clinic, Rochester, MN, USA Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.sxmr.2019.06.004
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recognized as far back as 3000 BC, when it appeared in Minoan sculpture.2,3 Clinical presentation of the disease is variable and may include erectile dysfunction (ED), penile pain, shortening, deformity, curvature, and palpable plaque, among others. The condition is also commonly associated with other fibrosing conditions, which share a similar pathophysiology, including Dupuytren’s disease (DD) and Ledderhose disease (LD).4e7 The clinical presentation of penile abnormalities likely relates to involvement of the tunica albuginea (TA) of the corpus cavernosum, which consists of interlinked collagen and elastic fibers. During an ordinary erection, penile stimulus leads to discharge of nitric oxide, which increases blood circulation to the penis and relaxes corpus cavernosum smooth muscle. This increases cavernosal hydrostatic pressure and obstructs small venules that perforate the TA.8 In contrast, among men with PD, scanning electron microscopy 1
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Table 1. Prevalence of Peyronie’s disease First author (Year)
Country
Population
Prevalence (%)
Lindsay20 (1991) La Pera24 (2001) Rhoden23 (2001) Schwarzer22,71 (2001 & 2002) Mulhall25 (2004) El-Sakka72 (2006) Arafa73 (2007) Stuntz74 (2016)
USA Italy Brazil Germany USA Saudi Arabia Egypt USA
General population General population Men >50 years screened for prostate cancer General population Men screened for prostate cancer Men with ED Diabetic men with ED General population
0.4 7.1 3.7 3.2 8.9 7.9 20.3 0.5
ED ¼ erectile dysfunction.
demonstrates deformed collagen TA architecture, with an increased ratio of collagen I and III fibers to elastin.9 This contributes to the formation of scar tissue and penile inelasticity, deformity, and curvature.10 The underlying pathophysiology of PD has not been fully elucidated. Proposed mechanisms include increased chromosomal instability, autoimmune response involving T-cells, fibrogenic cytokines, and subtunical vasculitis, among others.11-16 The possibility of a genetic predisposition has also been described through recognition of HLA associations, pedigree analyses suggesting potential autosomal dominant transmission, and gene expression studies.17-19 Because PD likely represents a spectrum disorder, contributing mechanisms are likely multifactorial and may involve the interaction of multiple autoimmune and genetic pathways. To date, there have been relatively few transformative studies relating to the pathophysiology of PD. Most genetic investigations were performed in the 1980s and 1990s, with few significant advancements reported since that time. This slow progress may highlight the complexity of the condition or relate to other factors, such as limited funding, minimal impact on overall health, lack of association with more severe comorbid conditions, and relative paucity of PD specialists. The objective of this article is to provide a thorough review of the known pathogenesis and genetic contributions to PD. Specifically, findings are organized to review the epidemiology and risk factors of PD, inheritance patterns, chromosomal instability, associated genes, epigenetics, and gene expression. Additionally, a brief commentary will be made on available experimental models and their strengths and limitations.
METHODS A comprehensive literature review was conducted of all PubMed-indexed articles from inception to 2019 relating to the cause and genetics of PD. Search terms included Peyronie’s, Peyronie, gene, genetic, genome, chromosome, epigenetics, familial, Dupuytren’s, Dupuytren, and inheritance. Key findings from these studies were categorically summarized to include epidemiology and risk factors, genetic alterations in PD,
inheritance patterns, chromosomal instability, genetic associations, epigenetics, differential gene expression, and preclinical experimental models.
EPIDEMIOLOGY AND RISK FACTORS The reported epidemiology of PD varies depending on definition used and may be under-representative, given the sensitive nature of the condition. Roughly 0.4e0.5% of men carry a diagnosis of PD, 1% have a combination of plaque, pain, and curvature, 3e4% self-identify penile plaques, 6% of older men have curvature, 9% of older men are found to have a plaque on examination by a specialist, and 13% have some finding possibly consistent with PD (diagnosis, plaque, curve, or deformity).20-25 Although the overall incidence is 22e25 per 100,000 men, it is relatively uncommon in younger men, with those <40 accounting for only 10% of PD cases.26,27 In contrast, most studies report a mean age of presentation in the 45- to 60-year range, often corresponding with the onset of erectile dysfunction.26,28e31 See Table 1 for reported prevalence rates of PD by population and geographic region. Reported risk factors for PD include comorbid conditions such as advancing age, obesity, dyslipidemia, diabetes, atherosclerosis, and psychosomatic disorders.32e37 Genetic predisposition (family history) and penile trauma (including iatrogenic and unrecognized) have also been linked to PD. In a study of 134 PD men, Carrieri and colleagues38 reported a 21% rate of comorbid DD and 4% with a family history of PD. In their analysis, the authors concluded that men with genital/perineal trauma had a 3 greater risk for development of PD, whereas those undergoing more invasive procedures, such as transurethral resection of the prostate, had up to 16 greater likelihood for development of PD. Other proinflammatory or neoplastic conditions are also linked to PD, including urethritis, elevated uric acid levels, and the presence of lipomas.38 Substance use has also been implicated, with men who smoke having a 4.6 greater likelihood of having PD compared with non-smokers, whereas no association has been consistently shown with alcohol.24 The use of b-blockers has further been linked to PD, with some hypothesizing that the therapy results in Sex Med Rev 2019;-:1e10
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Genetics and Pathogenesis of Peyronie’s Disease
Table 2. Genetic and familial studies in Peyronie’s disease First author (Year)
Associated antigens
Study type
No. of families/patients
Case report
11 patients
HLA-B27 HLA-B7
Bias44 (1982)
Family pedigree analysis
3 families
HLA-B7
Leffell19 (1982)
Case report
28 idiopathic PD
HLA A, B, and C
Nyberg18 (1982)
Family pedigree analysis
3 families
HLA-B7
Ziegelbaum45 (1987)
Twin study
HLA-B7
Ralph17 (1997)
Case report
1 family with identical twins 51 PD (15 with DD)
43
Willscher
(1979)
HLA-A1, DR3, DQw2, HLA-B7, and HLA-B27
Results Significant association of HLA B7 cross-reacting group with PD (7/8) patients Male-limited, autosomal dominant trait Traced PD through several families DD contracture present in both males and females Non-association of PD with HLA antigens Antigens of HLA-B7 cross-reacting group present in 3 kindreds Possible association of PD, HLA, and autosomal dominant inheritance Association of PD with HLA B7 Association of PD and HLA-B27
DD ¼ Dupuytren’s disease; HLA ¼ human lymphocyte antigen; PD ¼ Peyronie’s disease.
disequilibrium among a- and b-receptors and results in a proinflammatory state within penile connective tissue.39,40 Finally, reduced levels of trace elements such as manganese, copper, zinc, and iron have been found more commonly in men with PD compared with control subjects in a limited series of 56 men.41
1987.45 In the study, a family, including twin brothers, underwent HLA immunotyping and demonstrated a positive B7 crossreactive antigen in the father, twin brothers, and 1 child of 1 of the twins. All of those with B7 positivity were found to have penile deformities consistent with PD, confirming a common genetic cause.
As noted earlier, PD likely represents a spectrum disorder, with multiple subtypes present. As just 1 example, Tal and colleagues42 compared characteristics of PD in teenagers with those in men >40 years of age. In contrast to the older cohort, teenagers were 7 more prone to multiple plaques (37% vs 5%, respectively) and more likely to have HbA1c levels >5%.42 This varying nature of PD adds to the complexity of understanding the condition, because there may be multiple pathways that each lead to a PD-like state but have differing underlying mechanisms.
However, despite these intriguing early findings, subsequent studies have not consistently identified positive family histories in the majority of men with PD. In a report of 408 men with PD, only 1.9% of men had a positive family history for PD, whereas DD was present in 15.4%.35 The lack of a consistent family history may indicate that only certain subtypes of PD are due to a heritable genetic condition. It may also be related to the fact that PD is a sensitive topic and that many affected men will not discuss the condition with family members or would have heard about the condition from others within the family. Thus, the true rate of familial penetrance is likely underestimated. Table 2 summarizes studies demonstrating potential genetic associations with PD.
GENETIC ALTERATIONS IN PEYRONIE’S DISEASE Inheritance The first familial study suggesting a genetic origin for PD was reported in 1979 by Willscher and colleagues,43 who noted an association with HLA-B7 histocompatibility antigens. Subsequently, PD was proposed to be a sex-linked condition with reduced penetrance. However, a later attempt to trace PD through multiple families led to the suggestion that PD is an autosomal dominant trait (identified in 3 consecutive generations), and that the associated condition of DD was observed equally in males and females.44 The strongest evidence for a genetic link, however, came from a twin-twin study performed in Sex Med Rev 2019;-:1e10
Chromosomal Instability Associated with Peyronie’s Disease Chromosomal abnormalities with PD were first described by Somers and colleagues in 1987.11 Using cell cultures from PD and control men, samples were obtained from the PD plaque, adjacent tunica albuginea, dermis, and lymphocytes. Results demonstrated chromosomal abnormalities in 58% of sampled plaques, whereas adjacent tissues and control men demonstrated no such abnormalities. Interestingly, there was a wide variety of
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Table 3. Studies evaluating chromosomal abnormalities in men with Peyronie’s disease First author (Year)
Technique
Sample
Study finding
Somers11 (1987)
Cytogenetic
9 plaque-derived cell cultures from 7 PD men
Guerneri12 (1991)
Cytogenetic
Plaque-derived cell cultures from 9 PD men
Mulhall46 (2004)
FISH
Plaque-derived cell cultures from 5 PD men
Trisomy 7 and 8 45X,-Y deletion Structural chromosomal alterations & reciprocal translocations 46XY, t(11;12)(q11,p11) 46XY, t(1;5)(q25;q11) Inversion of 46XY, inv (7)(p22q36) Presence of chromosome instability 8 with Y-chromosome aneusomy 3 with chromosomal translocations Hybridization probes targeted to chromosomes 7, 8, 17, 18, X, and Y Aneusomies observed at early passage Chromosomal instability Aneuploidy with chromosomes 7, 8, 17,18, X Y
PD ¼ Peyronie’s disease.
abnormalities noted, including 5 numerical changes, 4 structural rearrangements, chromosomal additions (trisomy 7 and 8), deletions (45X, -Y), and reciprocal translocations and inversions. Some samples even demonstrated multiple, independent chromosomal abnormalities. Similar findings were observed in a later study by Guerneri and colleagues.12 In their study of 14 men with PD, cell plaque metaphases were abnormal in 9, with 2 suggesting clonal evolution and 4 demonstrating unrelated clonal lines. Overall, the Y-chromosome was the most frequently involved in numerical changes. The authors concluded that the condition may be of a multiclonal origin and highlighted that significant chromosomal abnormalities contributed to progression of the condition. A subsequent evaluation by Mulhall and colleagues46 built on these earlier findings and identified findings consistent with a possible field abnormality among men with PD. The authors obtained tissue samples of diseased and non-diseased regions of the penis in men with PD and compared them against tissue samples from control subjects without PD. Initial evaluation of the cell cultures demonstrated abnormalities in the regions of plaque and predominantly normal findings in non-diseased regions. Similar to other studies, common abnormalities were noted in the Y-chromosome, as well as with 7, 8, 17, 18, and X. Interestingly, although non-plaque TA cells demonstrated normal findings initially, repeated passage led to subsequent aneusomies in 1 chromosome, suggesting that even non-diseased regions exhibited chromosomal instability. Table 3 summarizes studies evaluating chromosomal abnormalities in men with PD.
Genetic Association Studies Reported in PD Relatively limited data are available from genetic association studies and PD. 1 of the earliest studies evaluating single-nucleotide polymorphisms associated with PD was
conducted by Hauck and colleagues.47 The authors compared 111 men with PD to control subjects and evaluated for differential rates of 2 polymorphisms known to upregulate transforming growth factor b-1 (TGF-b1). Results demonstrated slightly elevated rates of the G915C single-nucleotide polymorphisms (89% vs 79% in control subjects) and no differences in allelic frequencies of T869C. The authors concluded that, although this may contribute to the pathogenesis of PD, it is not likely a major genetic risk factor. To date, no genome-wide association sequencing or DNA sequencing studies have been performed in PD. However, a large genome-wide association sequencing study of 2,325 men with DD demonstrated 11 single-nucleotide polymorphisms from 9 chromosomal loci that were linked to DD predisposition.48 6 of the genes were associated with the Wnt-signaling pathway, which is a pathway responsible for various cell functions, including regulation of gene transcription, cytoskeleton, and intracellular calcium. It is also activated by chronic inflammation (via prostaglandin E2), which is also consistent with the pathogenesis of PD. The authors subsequently performed a follow-up study evaluating for these 9 loci in men with PD.49 Results demonstrated that only 1 of the 9 was positively associated, with that gene involved in the Wnt pathway and located on chromosome 7. These findings are particularly interesting, given the previously described studies that highlighted chromosome 7 as a common region of abnormality in PD plaques.11,46 An additional, recent study was reported of a family with heart disease secondary to a heterozygous LMNA mutation.50 Among the family members, multiple were noted to have DD and LD (PD history not obtained). Interestingly, when family members were tested for the LMNA mutation, Sex Med Rev 2019;-:1e10
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Table 4. Genetic association studies relevant to Peyronie’s disease First author (Year)
Study type
Population
Genetic variation Identified
Associated genes
Hauck47 (2003) Dolmans48 (2011)
Case control GWAS
111 PD, 100 controls 2,325 DD, 11,562 controls, PD not reported
TGF-b1, rs1800471, (G915C) WNT4 (rs7524102)
rs1800471 9 chromosomal loci associated with DD
Dolmans49 (2012)
Case Control
111 PD, 490 controls
SFRP4 (rs16879765) WNT2 (rs4730775) RSPO2 (rs611744) SULF1 (rs2912522) WNT7B (rs6519955) rs4730775
WNT2 locus chr 7
DD ¼ Dupuytren’s disease; GWAS ¼ genome-wide association study; PD ¼ Peyronie’s disease.
4 of those who were carriers (along with the proband) demonstrated DD and LD, whereas the 1 non-carrier did not have DD or LD. Although the exact role for LMNA is not fully elucidated, it is known to code for several lamin proteins, which have roles in regulating the activity of select genes. Table 4 summarizes genetic association studies relevant to PD.
Epigenetics Epigenetics refers to changes that occur secondary to modification of gene expression rather than alterations of the underlying DNA sequence. These changes most often occur via DNA methylation and histone after translational modification. More specifically, histone acetylase and histone deacetylase (HDAC) function in a counter-regulatory manner to switch the equilibrium of histone acetylation and deacetylation. This facilitates/ restricts transcriptional potential by providing/limiting access of its promoter to transcriptional regulatory proteins. These specific pathways are relevant to PD, because they have been shown to play a role in the pathogenesis of various fibrotic conditions. 1 potential mechanism of PD epigenetic modulation involves HDAC inhibition. Ryu and colleagues performed an analysis of small interfering RNA (siRNA)emediated silencing of HDAC2 in PD plaque fibroblasts.51 Among fibroblast cultures pretreated with siRNA (HDAC2 knockdown) and subsequently treated with the profibrotic TGF-b1, downstream expression of extracellular matrix proteins was significantly blunted. Additionally, TGF-b1einduced transdifferentiation of fibroblasts into myofibroblasts was inhibited, and decreased expression was noted with plasminogen activator inhibitore1, fibronectin, collagens I and IV, and smooth muscle a-actin. Each of these observations suggests that inhibition of HDAC2 could potentially significantly offset the profibrotic actions of TGF-b1. Kwon and colleagues52 subsequently validated these findings in a rat model using adenovirus encoded HDAC2 small hairpin RNA (HDAC2 knockdown). The authors observed that injected rats developed fewer fibrotic plaques, decreased inflammatory cells, reduced nuclear translocation of phosphorylated SMAD3 (protein responsible for receptor signal transduction for TGF-b), reduced transdifferentiation of fibroblasts to myofibroblasts, and Sex Med Rev 2019;-:1e10
reduced collagen production. Additionally, the treatment induced apoptosis and decreased expression of cyclin D1 (cellcycle regulator). A more recent study evaluated the differential gene expression of HDACs in fibroblasts extracted from PD plaques and normal TA.53 Results demonstrated a higher expression of HDAC 2, 3, 4, 5, 7, 8, 10, and 11 in plaques from PD compared with normal TA tissue. Subsequent knockdown of HDAC7 by siRNA-mediated silencing in PD fibroblasts repressed the TGF-b1emediated nuclear transport of Smad2 and Smad3 proteins, fibroblast to myofibroblast transdifferentiation, and impaired production of extracellular matrix protein induced by TGF-b1.
Differential Gene Expression in Peyronie’s Disease Several authors have investigated dysregulation of select genes associated with fibrosis in men with PD. Magee and colleagues54 performed a DNA microarray analysis of PD plaques and demonstrated upregulation in pleiotrophin (osteoblast recruitment), monocyte chemotactic protein 1 (inflammation), early growth response protein (fibroblast proliferation), elastase (elastic fiber degradation), and myofibroblast markers (a and g smooth muscle actin, desmin, and others). Several genes were also noted to be downregulated, including ubiquitin and ID-2 (tissue remodeling), collagenase IV (degrades collagen), and TGF-b modulators. The authors concluded that overall findings indicated upregulation of genes associated with fibrosis (collagen synthesis, myofibroblast differentiation, tissue remodeling, inflammation, ossification, and proteolysis) and downregulation of genes inhibiting fibrosis compared PD plaques with normal TA, DD, and normal plantar fascia.55 Interestingly, both PD and DD demonstrated upregulated collagen degradation (matrix metalloproteinases [MMP- 2, MMP- 9 and thymosins b-10 and b-4), ossification (osteoblast-specific factor 1), and myofibroblast differentiation (RhoGDP dissociation inhibitor 1). PD also exhibited upregulation of early growth response protein and decorin, which serves to inhibit TGF-b1. Zorba and colleagues56 performed a reverse transcriptase PCR analysis to evaluate messenger RNA expression in PD plaques. Overall downregulation of apoptotic proteins (Fas, Fas Ligand, Bcl-2,
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Table 5. Summary of differential gene expression in Peyronie’s disease First author (Year) Upregulated Genes Del Carlo75 (2008) Szardening-Kirchner76 Magee54 (2002)
Technique MMP protein microarrays WB (2009) RT-PCR Clontech DNA microarray Affymetrix DNA microarray
Pathway
Genes
MMP pathway
MMP 1,3,10,13
Inflammation Differentiation of fibroblasts into myofibroblasts
RT-PCR, WB, IF ELISA, RT-PCR IHC & biochemical assays ELISA
Elastin degradation TGF-b pathway Extracellular matrix alterations Multiple pathways FGF Pathway
MCP1 Fibroblast muscle type TPM, 20-kDa, MYL, FLN, gamma and alpha-smooth muscle actin (ACTA2), DES, 22-kDa smooth muscle protein Cadherin, TGFb1, and IGF binding protein-6 Heat-shock protein 28 and 28-kDa heat shock protein Elastase IIB24 Smad3 and Smad4 TGF-b, IL6 AQP1 FGF
DNA microarrays
Osteoblast recruitment
Pleiotrophin
Fibroblast proliferation Elastic fiber degradation
EGR Elastase
Ubiquitination
Ubiquitin
DNA binding (ID)
DNA-binding inhibitor Id-2 Calcineurin A Collagenase IV TGF modulators/decorin Collagenase IV(SPARC/Osteonectin) ATF4 (ATF4) SPARC/Osteonectin Decorin Collagenase IV, (SMAD7) HLA-B Bcl-2, p53, Caspase 3 and Caspase 8 All IGF1 isoform (Ea, Eb and Ec) expressions
Fibroblast attachment and collagen production Cellular stress response
Haag61 (2007) Watanabe77 (2017) Castorin63 (2016) Mulhall14 (2001) Jalkut78 (2004)
Downregulated genes Jalkut78 (2004)
Magee54 (2002)
DNA microarrays
Clontech DNA microarray
Collagen breakdown Limit TGF activity Collagen degradation HLA complex
Zorba56 (2012)
RT-PCR
Pro-apoptotic genes
Thomas62 (2016)
IF, RT-PCR
IGF Pathway
Other altered gene expression Clontech DNA microarray Magee54 (2002)
Collagen degradation (MMP)
MMP2 and MMP9, and thymosins (MMP activators), with TMbeta10 and TMbeta4; elastase IIB SMAD7
DES ¼ desmin; EGR ¼ early growth response protein; ELISA ¼ enzyme-linked immunosorbent assay; FLN ¼ filamin; IF ¼ immunofluorescence; IGF ¼ insulin growth factor; IHC ¼ immunohistochemistry; kDa ¼ kilodalton; MCP ¼ monocyte chemotactic protein; MMP ¼ matrix metalloproteinase; MYL ¼ myosin light chain; RT-PCR ¼ reverse-transcriptaseepolymerase chain reaction; TPM ¼ tropomyosin; WB ¼ Western blot.
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p53, Caspase 3 and 8) occurred more frequently in PD plaques compared with controls. These findings are also consistent with an earlier study, which demonstrated defunctionalization of p53 in PD cells compared with normal TA.57 Both of these studies suggested that the high cell proliferation rate observed in PD may be due, in part, to this downregulation of the apoptotic pathway. Several authors also performed cell culture analyses to help better differentiate diseased vs non-diseased tissue factor expression and responsiveness to various stimuli. Mulhall and colleagues14 performed an indirect analysis of supernatants derived from PD plaque cell cultures and compared against non-diseased TA biopsy specimens. Results showed an upregulation of basic fibroblast growth factor among the PD fibroblast cell line compared with in the control subjects without PD, again confirming the presence of notable profibrotic factors in phenotypically diseased cell lines. In examining protein profiles more broadly, De Young and colleagues58 performed surface-enhanced laser desorption/ionization time-of-flight mass spectrometry of PD plaque tissue cultures. Results demonstrated significant increases in smooth muscle a-actin, b-catenin, and heat shock protein 47 compared with normal TA, with other changes noted in TGF-b1 and fibronectin. Altered expression was also noted for several unidentified proteins, ranging from 4.7e76.8 kDa, suggesting the presence of several upregulated pathways that had not yet been identified. In a somewhat related study, cell cultures of PD plaques were stimulated with TGF-b and interleukin-1b to observe for induction of MMPs and tissue inhibitors of MMPs (TIMPs). Whereas interleukin-1b increased production of MMP 1, 3, 10, and 13, TGF-b failed to induce MMPs and instead demonstrated abundant TIMP 14 proteins compared with non-diseased TA. These findings overall suggested that TGF-b may result in PD progression via inhibition of MMPs and upregulation of TIMPs. The authors also hypothesized that PD plaques may exhibit this pattern of expression secondary to chronic exposure to TGF-b. Also related to TGF-b, SMAD proteins are important intracellular signal-transducer molecules for TGF-b receptors, with stimulatory (Smad2, Smad3, and Smad4) and inhibitory functions (Smad6 and Smad7) recognized.59,60 Using fibroblast cultures grown from PD plaques, Haag and colleagues61 identified elevated levels of Smad3 and 4 compared with control subjects. When the cultures were stimulated with TGF-b1, Smad2 and 3 demonstrated rapid nuclear translocation, which occurred sooner and in a more pronounced manner compared with control subjects. Smad4 also demonstrated prolonged nuclear retention time in PD fibroblasts compared with control subjects. These findings further supported TGF-b as an important pathogenic factor in the development of PD. Other studies of PD plaques have identified reduced genetic expression of insulin-like growth factor 1 isoforms (anabolic effects) and upregulation of aquaporin 1 (role in connective tissue resistance to mechanical stress).62,63 Although intriguing,
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the significance and role of these findings remains unclear, with further study required to both validate and contextualize outcomes. Table 5 summarizes studies of differential gene expression observed in PD.
PRECLINICAL EXPERIMENTAL MODELS 1 of the most commonly used models in PD is in vitro cell cultures. Often, these models consist of cells (predominantly fibroblasts) grown from various areas, including PD plaques, unaffected TA from PD individuals, foreskin, or TA from individuals without PD. Although many studies have examined cells obtained from human plaques, some have used convenience samples in animal (rat) models. To induce the disease state, cultured fibroblasts are often exposed to profibrotic agents (typically TGF-b1), and the resultant cells (myofibroblasts) are examined for various pathologic parameters.64 In vivo animal models have similarly used rats induced with various treatments to create a PD-like state. The most common model includes injection of TGF-b1 (or agents with TGF-b1 activity) to the rat penis to create penile nodularity and deformity.65 Resultant plaques in this model resemble the human PD condition both histologically and biochemically.66 A second model uses fibrin injected into the TA and is based on the hypothesis that penile injury leads to fibrinogen activation, followed by penile fibrosis.67 A third model involves a surgical incision to the rat penis to simulate trauma. In the earliest investigation of this approach, histologic changes were noted initially consistent with the acute phase of PD; however, overt chronic-phase PD was not achieved.68 A more recent attempt performed repeated injections of chlorhexidine gluconate with 15% ethanol and demonstrated penile curvature, plaques, erectile dysfunction, and increased smooth muscle a-actin and TGF-b1.69 In addition to TGF-b1, several other pathways have been identified in animal models leading to penile fibrosis, including HDAC2, Smad3, and RhoA-ROCK.70 Studies have also shown blunting of fibrosis via intratunical injection of TGF-b1 receptor kinase inhibitors, adipose tissueederived stem cells, HDAC2, shRNA, and anthocyanin.70 The strength of many of the animal models is that a reproducible disease state can be achieved secondary to fibrosis and phenotypically and histologically mimics PD. This permits experimental testing of various agents to determine how they impact either the progression of fibrosis or treatment of the final fibrotic state. It should be noted, however, that none of these models accurately reproduces the true pathophysiology of PD. Because PD is believed to occur as a result of underlying genetic instability, no model, to date, attempts to recreate that key aspect of PD. As such, neither in vitro nor in vivo animal models are able to test or make any conclusions with regard to the efficacy of any treatment on the prevention of PD. Similarly, the efficacy of any treatment in an experimental model should be considered preliminary and requiring confirmation in the human condition.
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CONCLUSION
Category 3
Despite the long-standing recognition of PD as a condition, relatively little is known regarding the underlying pathophysiology. Because PD likely represents a spectrum disorder, multiple potential pathways may result in the development of penile fibrosis and deformity. Overall, the condition affects a relatively large number of men and is associated with various comorbid conditions. Some subtypes of PD have demonstrated a clear heritable pattern, with 1 exhibiting autosomal dominant inheritance, whereas most cases appear to occur in the absence of a clear family history. Genetic evaluations of men with PD have identified findings consistent with chromosomal instability and include the possible development of multiple chromosomal abnormalities with subsequent cellular generations. Epigenetic gene modification may also play a significant role in PD, including the extent of fibrosis that may occur after disease activation. Numerous profibrotic genes have further been identified as being upregulated in PD-affected tissue, whereas those inhibiting cell progression and fibrosis are often inversely downregulated. Several preclinical models have been developed to better study the pathophysiology of PD, including cell cultures and rat models. Although these consistently demonstrate profibrotic conditions, no models, to date, have been able to replicate the spontaneous development of the condition in vivo.
(a) Final Approval of the Completed Article Kiran L. Sharma; Manaf Alom; Landon Trost
ACKNOWLEDGMENT The authors wish to acknowledge the generous gift from a patient who wishes to remain anonymous and that has facilitated Peyronie’s disease research. Corresponding Author: Landon Trost, MD, 200 First St SW, Rochester, MN 55905, USA. Tel: 507-284-4248; Fax: 507-2844951; E-mail: [email protected] Conflicts of Interest: The authors report no conflicts of interest. Funding: None
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Kiran L. Sharma; Manaf Alom; Landon Trost (b) Acquisition of Data Kiran L. Sharma; Manaf Alom; Landon Trost (c) Analysis and Interpretation of Data Kiran L. Sharma; Manaf Alom; Landon Trost Category 2 (a) Drafting the Article Kiran L. Sharma; Manaf Alom; Landon Trost (b) Revising It for Intellectual Content Kiran L. Sharma; Manaf Alom; Landon Trost
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