ORIGINAL RESEARCH—PEYRONIE’S DISEASE

The Role of PDE5 Inhibitors in Penile Septal Scar Remodeling:Assessment of Clinical and Radiological Outcomesjsm_2217 1472..1477

Eric Chung, MD, Ling DeYoung, MD, and Gerald B. Brock, MD

Division of Urology, St Joseph Health Care, London, Ontario, Canada

DOI: 10.1111/j.1743-6109.2011.02217.x

A B S T R A C T

Introduction. Effective oral medication for use in men with Peyronie’s disease (PD) has been an area of interest of themedical community and lay public for decades. Isolated septal scars (ISS) without evidence of penile deformity is arelatively new clinical entity, and at present, there is paucity in the published literature regarding its treatment. Currentresearch into the use of phosphodiesterase type 5 (PDE5) inhibitors in regulating penile erectile response has revealedan alternative role for PDE5 inhibitors in decreasing oxidative stress-associated inflammatory change as seen in PD.Aim. To examine the presence of ISS and assess the efficacy of PDE5 inhibitor use in septal scar remodeling.Methods. Retrospective review of prospective database on all men who underwent penile Doppler ultrasoundbetween December 2007 and December 2009.Main Outcome Measures. Of the 65 men with ultrasonographic-confirmed ISS, 35 men received tadalafil 2.5 mgdaily over a 6-month period. The clinical outcomes between the two groups were compared using InternationalIndex of Erectile Function (IIEF)-5 score and 6 months penile Doppler ultrasound follow up.Results. The mean age for the tadalafil group was 43.2 (20–65) years, similar to the control group at 44.2 (34–72) years.The length of time from onset to presentation was 22 (6 to 40) months. The majority of ultrasonographic-proven ISS wasnot clinically palpable and complaint of decreased penile rigidity (66%) was the predominant feature. Treatment withlow-dose daily tadalafil did not result in any significant side effects (such as headache and flushing) or discontinuation.The tadalafil group reported higher IIEF-5 score (pretreatment 11/25 to post-treatment 18/25) (P < 0.01) and resolutionof septal scar were recorded in 24 patients (69%) compared to three patients (10%) in the control group.Conclusion. Low-dose daily tadalafil is a safe and effective treatment option in septal scar remodeling. Chung E,DeYoung L, and Brock GB. The role of PDE5 inhibitors in penile septal scar remodeling: Assessment ofclinical and radiological outcomes. J Sex Med 2011;8:1472–1477.

Key Words. Phosphodiesterase Type 5 Inhibitors; Penile Septal Scar Remodeling; Peyronie’s Disease

Introduction

P eyronie’s disease (PD) is associated withpenile pain, deformity, and palpable plaque,

resulting in some degree of sexual dysfunction [1].As part of the comprehensive evaluation of menwith PD-like symptoms, high-resolution penileDoppler ultrasonography has been utilized toevaluate the plaque size and diagnose abnormalvascular flow patterns suggestive of arterialinsufficiency or veno-occlusive dysfunction [2].Recent penile sonographic studies by Lue and

associates [3–5] showed that among men diag-nosed with PD but without clinically palpableplaques, penile ultrasound is often demonstrativeof septal fibrosis, intracavernosal fibrosis, or sub-tunical calcification.

The unusual presence of a septal mass or dis-crete fibrosis without evident penile deformity wasfirst described in 1984 [6]. The reported incidenceof septal fibrosis ranges from 5.6% to 20% in menwho present for penile Doppler sonography orwith PD [3–5,7]. Bella [7] demonstrated strongcorrelation between these discrete nonpalpable

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isolated septal scars (ISS) and men with sexualconcerns who present with decreased penile rigid-ity, length loss, and chronic pain with erection.

At present, there is paucity in the publishedliterature regarding the treatment of ISS. Thenotion of aspirating septal hematomas under ultra-sound guidance appears invasive given the uncer-tainties of this condition and would only beapplicable to a very small number of men who areclinically evaluated early in the post-traumaticperiod. The efficacy of medical therapies in PD forthis condition is not known or defined but onewould suspect that their overall cure rate would below, as disappointing results have been generallyobtained in men with classic PD. However, recentanimal studies have shown promising outcomes inlong-term administration of phosphodiesterasetype 5 (PDE5) inhibitors in remodeling of PD-likeplaques [8–10].

The appeal of PDE5 inhibitors in scar remod-eling, particularly in this variant of PD, relies onthe high association of a component of ED asso-ciated with PD and the animal data supportingreduced fibrosis from this class of drugs. Studiesfrom UCLA group [8–10] showed that a singledaily dose of PDE5 inhibitor prevented corporalveno-occlusive dysfunction and the underlyingcorpora cavernosa fibrosis in rats. In the animalmodel, daily PDE5 inhibitors normalized theincrease in penile shaft collagen content and thereduction in corporal smooth muscle cell contentsand smooth muscle to collagen ratio as well asselectively increased the apoptotic index in thePD-like plaque. This protective effect has recentlybeen shown in patients after radical retropubicprostatectomy [11]. Apart from restoration of cor-poral smooth muscle, long-term use of PDE5inhibitors normalized the low response to othervasoactive drugs and potentially underlie therecovery of erectile function in human study [9]. Inthis study, we examine the presence of ISS in ourseries of penile Doppler sonography and assess theefficacy of PDE5 inhibitor use in septal scarremodeling among men with PD.

Material and Methods

Following approval from the Internal EthicsReview Board, all men who underwent penileDoppler ultrasound between December 2007 andDecember 2009 were enrolled in this study. A totalof 65 men with ultrasonographic confirmed ISSwere identified out of the 550 penile Dopplerultrasonograph performed during that 2-year

period. A retrospective review of patient chartsshowed 35 men received tadalafil 2.5 mg daily overa 6-month period, while the other 30 men whodeclined and/or did not receive tadalafil wereobserved clinically and assigned as control cohort.All patient demographics, comorbidities, historyof presenting complaint, time interval from onsetof symptom to clinical assessment, and Interna-tional Index of Erectile Function-5 (IIEF-5) scoreswere completed prior to penile Doppler ultra-sonography. Physical examination was conductedto characterize any palpable plaque, while penileDoppler ultrasonography with pharmacological-induced erections using 5–10 mg prostaglandin E1was performed to document the size of ISS as wellas any penile curvature. At 6 months follow-upvisit, all patients were requested to completeIIEF-5 scores and undergo another penileDoppler ultrasonography (Figure 1).

Categorical variables were tested using achi-squared and paired Student’s t-test withSTATA®10 (StataCorp, TX, USA) software. Asignificance level of 0.05 was utilized and all testswere two-sided.

Results

During the 2-year study period, the mean age forthe tadalafil group was 43.2 (20–65), similar to thecontrol group at 44.2 (34–72) years. The intervalfrom onset of symptom to presentation was 22 (6to 40) months (Table 1). Common presentingsymptoms were decreased penile rigidity (66%),penile shortening (14%), inability to sustain anerection (9%), and penile curvature (11%). Noneof the ISS plaques were clinically palpable. Themean maximal diameter of ISS on the transversepenile Doppler sonograph view was 65 ¥ 52(28 ¥ 27 to 90 ¥ 76) mm in the tadalafil and62 ¥ 48 (27 ¥ 30 to 88 ¥ 82) mm in the controlgroups. There was no significant difference inpatient comorbidities (P > 0.05).

Treatment with low-dose daily tadalafil did notresult in any clinically significant side effects (suchas headache and flushing) or increased rates ofdiscontinuation. The tadalafil group reportedhigher IIEF-5 score (pretreatment 11/25 to post-treatment 18/25) (P < 0.05) compared to thecontrol group (pretreatment 12/25 to post-treatment 10/25) (P > 0.05) (Figure 2). Of note,three men on the control group reported worsen-ing of initial penile curvature at the subsequentfollow-up. During the 6-month period, two addi-tional men in the control and one man in the

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tadalafil group developed a mild penile deformityconsistent with PD, in the absence of clinical orDoppler sonography-identified tunical plaque.Resolution of ISS was recorded in 24 patients(69%) in the tadalafil group compared to threepatients (10%) in the control group (P < 0.05). Atotal of five patients received intracavenous injec-tion and two patients underwent surgical interven-tion for subsequent ED.

Discussion

Medical management of PD has progressed sur-prisingly slowly, despite the long history of thiscondition. To date, owing to a lack of true under-standing of the pathogenesis of the condition, fewetiologically based therapies are possible. Signifi-cant gaps in our knowledge and understanding of

PD remains at the molecular level. It is a widelyaccepted view that Peyronie’s plaques develop as aresult of progressive accumulation from repeatedbuckling penile injury leading to tunical scarringfrom vascular inflammation between the tunicaand corporeal tissue [12–14]. The inflammatoryprocess and aberrant wound healing lead to fibro-sis, loss of elastic tissues, and excessive collagendeposition, which may account for the initialpenile pain, and later development of penileplaque and deformity.

In contrast to the classic peripherally locatedPeyronie’s plaque on the dorsal aspect of the penis,ISS is thought to be a result of fracture in theintracavernous septum. Brant [5] postulated thatthese septal fractures and resulting hematomasmay possibly be a precursor lesion for septal fibro-sis. While in theory it seems likely that traumatic

Figure 1 Transverse view of penile Doppler ultrasonograph showing the initial ISS (left) and subsequent normal penileseptum (right) after 6 months of daily tadalafil treatment (images obtained from the same site within the penis).

Table 1 Comparison between tadalafil and control groups clinical data

Tadalafil group(N = 35) (%)

Control group(N = 30) (%) P value

Main presenting complaintDecreased penile rigidity 23 (66%) 20 (67%) P > 0.05Penile shortening 5 (14%) 4 (13%) P > 0.05Inability to maintain erection 3 (9%) 3 (10%) P > 0.05Penile curvature 4 (11%) 3 (10%) P > 0.05

Mean ISS measurement (mm) 65 ¥ 52 62 ¥ 48 P > 0.05Co-morbidities

Diabetes 3 (9%) 2 (7%) P > 0.05Smoker 10 (29%) 9 (30%) P > 0.05Ischemic heart disease 1 (3%) 0 P > 0.05Hypercholesterolemia 12 (34%) 10 (33%) P > 0.05

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injury to septal strands could contribute to septalscarring, the exact mechanism of development ofISS remains unknown. These centrally locatedseptal scars could contribute to loss of penile rigid-ity distal to the lesion, penile length loss and painas well as inadequacy of the veno-occlusive mecha-nism leading to erectile concerns [7]. There havebeen few published studies on the sonographiccharacteristics of men with PD over time[4,15,16]. Published literatures suggest up to 20%of men with PD would have ISS on penile Dopplerultrasonography [3–5]. At present, even less isknown about ISS, whether it is part of the PDcomplex, a variant of the condition, and whether itis associated with long-term ED.

Recent animal models for PD using injection oftransforming growth factor beta 1 (TGFb-1) orfibrin to create a PD-like plaque [17,18] showed anincrease expression of the inducible form of nitricoxide synthase (iNOS). It is thought that bothiNOS and NO acts as an antifibrotic defensemechanism, while administration of iNOS inhibi-tor (L-N-[1-iminoethyl]-lysine,acetate) enhancesfibrosis of the PD-like plaque and induces generalcorporal fibrosis [18]. Both NO and cyclic gua-nosine monophosphate (cGMP) inhibit collagensynthesis and myofibroblast differentiation in cellcultures from PD plaque and normal tunica albug-inea [19] as well as in other tissues [20].

Current research into the use of PDE5 inhibi-tors in regulating penile erectile response hasrevealed an alternative role for PDE5 inhibitors indecreasing oxidative stress-associated inflamma-tory change by reducing the collagen/smoothmuscle and collagen III/I ratios, and the numbersof myofibroblasts and TGFb-1-positive cells. Thisantifibrotic action through cGMP-related mecha-

nism appears to be independent of iNOS induc-tion. Long-term use of PDE5 inhibitors asantifibrotic agent by maintaining or increasing theNO and cGMP levels in the target tissues has beenpromising and provides a much needed armamen-tarium in the medical therapy for PD. The apop-totic effect on penile myofibroblast with PDE5inhibitors has been shown in sildenafil [10,18],vardenafil [8], and tadalafil [9]. Ferrini [8] reportedthat long-term oral treatment with vardenafilslows and reverses the early stages of an experi-mental PD-like plaque in rats and potentiallymight play a role to ameliorate a more advancedplaque. However, the efficacy of continuous treat-ment with vardenafil appears less effective once thePD-like plaque was formed. Apart from PDE5inhibitors, other compounds such as pentoxifyllineand L-arginine have been shown to have similarantifibrotic action through NO/cGMP pathway[21,18].

A prospective study by Mulhall [22] on menwith PD undergoing expectant managementshowed worsening of penile curvature in 48% ofpatients (mean 52% deterioration of curvaturecompared to baseline). While no statistical differ-ence in the number of men who reported ED atbaseline compared to follow-up (83% vs. 79%),there was a significant difference in the number ofmen who had difficulty with penetration (42% atbaseline to 67% at follow-up). In our study, threemen in the control group reported worsening intheir existing penile curvatures and three patientsdeveloped mild penile deformities. This lower rateof deterioration in penile curvature could beexplained by the short-term follow-up. Alterna-tively, tadalafil may play a role in stabilizing Pey-ronie’s fibrosis and curvature; however, this study

Figure 2 Changes in IIEF-5 scoresbetween tadalafil and control groups atinitial visit (pre-) and 6 months (post-)follow-up (P < 0.05 between pre- andpost-tadalafil groups; NS in controlgroups).

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is not sufficiently powered to analyze thisoutcome. The increase in IIEF-5 scores in thetadalafil group is to be expected.

At present, the optimal treatment strategies formen presenting with ISS and ED are undefined. Itis common for men with PD-like symptoms to bereferred to tertiary care erectile dysfunction unithaving already been prescribed and trialed withPDE5 inhibitors. Previous study on the use ofPDE5 inhibitors in men with ISS has been disap-pointing [7] and is likely attributed to the lack ofcontinuous and long-term administration ofPDE5 inhibitors. To our knowledge, this is thefirst study to demonstrate the effectiveness oflong-term daily use of oral PDE5 inhibitor atreducing and/or dissolving ISS using both objec-tive and subjective end points.

We acknowledge the significant limitations toour study. The small sample size precludes anysignificant multivariate analysis on variables suchas presenting complaint, patient comorbidities,and size of ISS lesion. The short duration offollow-up does not address the natural course ofISS or long-term efficacy of tadalafil. Althoughpatients were divided into two groups, tadalafil vs.no treatment, this was patient driven and notblinded. In spite of this, the control group wasmatched to the tadalafil group, in all measureablevariables including age, ED, and penile deformity.While ultrasonograph is a user-dependant modal-ity, all penile Doppler sonographs were performedunder the supervision of one of the authors(G.B.B.) and with the results interpreted andreported in a blinded fashion where the reader wasunaware of the treatment received.

This study demonstrates an interesting thera-peutic signal in which tadalafil used daily had ameaningful impact on intraseptal scars and sexualfunction among a cohort of men compared to con-servative therapy. The utility of PDE5 inhibitorsin animal model for the treatment of corporalfibrosis and the potential of this class of drugs tomitigate sexual dysfunction from PD and its vari-ants is exciting. Future research on the naturalhistory of ISS, combination of PDE5, and otherPD-type medical therapies and larger cohort ofpatients will assist our understanding and definebetter management strategies for this group ofmen.

Conclusion

At present, very little is known about the entityISS, whether it belongs to PD complex or is asso-

ciated with the risk of long-term ED. Low-dosedaily tadalafil is safe and appears effective in themanagement of septal scar remodeling.

Corresponding Author: Eric Chung, MD, UrologicalSociety of Australia and New Zealand, Suite 512 East-point, 180 Ocean St, Edgecliff Edgecliff New SouthWales 2027, Australia. Tel: +1-5196466042; Fax:+1-5196466037; E-mail: ericchg@hotmail.com

Conflict of Interest: GB Brock is consultant/adviser forBayer, Pfizer, Eli-Lilly, AMS, and Coloplast.

Statement of Authorship

Category 1(a) Conception and Design

Eric Chung; Ling DeYoung; Gerald B. Brock(b) Acquisition of Data

Eric Chung(c) Analysis and Interpretation of Data

Eric Chung; Ling DeYoung; Gerald B. Brock

Category 2(a) Drafting the Article

Eric Chung(b) Revising It for Intellectual Content

Eric Chung; Ling DeYoung; Gerald B. Brock

Category 3(a) Final Approval of the Completed Article

Eric Chung; Ling DeYoung; Gerald B. Brock

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