Medical Meeting Reports

Peyronie’s Disease: AUA 2005

Author: Muammer Kendirci, M.D.; Tulane University, School of Medicine, Department of Urology, New Orleans, LA..

Despite the longtime medical recognition of the entity known as Peyronie's disease (PD), the etiology, pathophysiology, and management of this condition continue to generate controversy. PD is characterized by the development of localized fibrotic plaques, predominantly at a single site in the penile tunica albuginea. Plaque formation causes penile deformity, which is often accompanied by pain and/or erectile dysfunction (ED). Recent epidemiologic surveys suggest that the prevalence of PD is higher than previously believed, and that PD thereby affects a significant portion of the male population. The consequences of PD lead to a substantial decrease in quality of life and adverse physiological effects in approximately 77% of afflicted men. La Rochelle and Levine (Abstract # 941) investigated the understanding and practices of primary care providers and urologists regarding PD. A multiple-choice, 20-question survey, addressing the prevalence, natural history, associated ED, and treatment approaches for PD, was sent to 330 primary care providers and 223 urologists in Illinois. The survey response rate was 46%among primary care providers and 44% among urologists. Data showed that the majority of primary care providers (70%) have seen a patient with PD, indicating the necessity of the education of the primary physicians regarding PD. About half of the responders believed that PD occurs in less than 1% of men. Interestingly, 17% of the primary care providers and 38% of the urologists thought that PD spontaneously resolves in more than 50% of the cases. More than 80% of the responders did not believe that PD occurs in men younger than 40 years of age. Of importance, 21% of the primary care providers and 29% of the urologists did not feel that PD warrants treatment. These results reflect that there is a lack of understanding about PD by primary care providers and urologists and that this may cause delays in diagnosis, referral and initiation of appropriate therapy in men with PD who seek treatment. The authors of this study see their findings as a call to improve education about PD for both primary care physicians and urologists.

Men with PD may present with any combination of complaints, including penile curvature, palpable penile plaque, pain during erection, and ED. The initial occurrence of a penile plaque is usually the inciting factor for penile pain and curvature. Painful erections and a palpable penile plaque are usually manifested as the clinical hallmarks of the acute phase of PD (<12-18 months), while the chronic phase is characterized by stabilization of the penile deformity, hardening of the plaque, and ED. Penile curvature can be classified as mild (< 30°), moderate (30-60°), and severe (> 60°) according to the Kelami classification. Akman et al (abstract #945) evaluated the degree and severity of penile curvature in patients with PD, and discussed the relationship between the severity of penile deformity and clinical parameters. The investigators included into the evaluation 596 PD patients with isolated penile curvature after excluding PD patients without curvature (e.g., notching). These investigators reported that only 17.9% of their PD patients exhibited severe penile curvature (> 60°), while 38.6% of the cases showed moderate (30-60°) and 43.2% mild curvature (< 30°). They compared these results with previous studies, and concluded that severe penile deformity is rare in patients with PD.

Penile duplex Doppler ultrasonography (PDDU) is the preferred method for the functional evaluation of the penile vascular system. It allows individualization of PD patients for surgical therapy. Erectile function and penile hemodynamics are the most important factors in deciding on the form of surgical treatment for PD; only patients with adequate penile vascular status and erectile function can be considered for a reconstructive option. Penile hemodynamics, consisting of an arterial and venous-occlusive response, are quantified by the measurements of parameters of the cavernosal blood flow velocity waveform, such as peak systolic velocity (PSV), end diastolic velocity (EDV) and the calculated resistive index (RI) at well-defined time points following intracavernosal injection of a vasoactive agent accompanying visual sexual stimulation. Whether the type of penile deformity can affect penile vascular status has not been studied in a large PD patient population. A study by Kendirci et al (abstract #942) investigated the relationship between the type of penile deformity and penile vascular status using PDDU. The authors stratified PDDU parameters based on the type of deformity in 523 PD patients, namely dorsal, ventral, lateral, dorsolateral, ventrolateral, hourglass, and pure indentation. The study reported that the mean PSV values were highest in the ventrolateral group and lowest in the hourglass deformity group. Although the hourglass deformity patients were younger than others, this group demonstrated the highest rate of arterial insufficiency. However, patients in the ventral deformity group exhibited the highest rate of veno-occlusive dysfunction. They reported that the ventrolateral group had the best penile vascular status. These investigators concluded that the type of penile deformity can determine the frequency and the severity of penile vascular abnormalities in PD patients.

In another study by Schaeffer et al (abstract #438) using PDDU, the baseline penile vascular parameters in 61 PD men with normal erectile function prior to penile straightening surgery were evaluated and compared to 63 men associated with ED. The prevalence of arterial anomalies was found to be similar for both men with PD (45%) and those with ED (47%). The rate of distal dorsal artery perforators was reported as 10% for each group. As the ligation of these communicating arteries during penile straightening surgery may result in postoperative ED, the authors of this study recommended preoperative PDDU to determine the penile vascular anatomy in patients undergoing penile straightening surgery regardless of potency status, particularly in those patients in whom manipulation of the dorsal neurovascular bundles is anticipated.

Trauma is thought to be the initiating factor in PD based on anatomy, pathology, bioengineering analysis and clinical data. Trauma or excessive bending of the erect penis may result in bleeding into the subtunical spaces or tunical delamination at the point where the septum integrates into the inner circular layer of the tunica albuginea. Current research suggests that PD represents a localized aberration of the wound healing process. Fibrin deposition is an initial consequence of microvascular injury and may be the precursor to PD plaque formation. Stimulation of the cytokine release, mainly transforming growth factor-b (TGF-b) has been suggested to cause deposition of collagen and the extracellular matrix, and an arrangement of organized collagen and elastin fibers. Animal models and plaques derived from PD patients demonstrated increased (TGF-b) expression in the tunica albuginea. Haag et al (abstract #939) investigated the TGF-b pathway, specifically the activation of transcription factors (Smads). Biopsates were taken from the plaques of 16 PD patients and from the tunica albuginea of 7 patients without PD. After initiating the cell culture process from these tissues, the transcriptional factors Smads were investigated on the RNA-, protein-, and cellular levels before and after TGF-b1 stimulation. They documented an increased expression of Smad3 and Smad4 in samples from PD patients. Stimulation of the fibroblasts with TGF-b1 exhibited stronger and earlier Smad3 translocation in the nucleus in plaque-derived fibroblasts from PD patients than from the control. Due to its known antifibrotic effect, the addition of interferon-gamma into the culture resulted in decreased activation of Smad2/3. These investigators concluded that the transcription factors of the TGF-b pathway are increased in patients with PD, and alterations in this pathway may be a possible factor in the pathogenesis of PD.

Matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) are known to be involved in the remodeling of the extracellular matrix. Previous studies have shown that the collagen-degrading enzymes, or collagenases, are reduced in the tunica albuginea of older men, suggesting the contribution of age to the progression of PD and lack of spontaneous healing process. The study by Cole (abstract #944) investigated whether any of the endogenous TIMPs were present in the tunica albuginea of Peyronie's plaque and perilesional tunica compared to young and age-matched controls. The study consisted of 3 groups, mainly tunica albuginea from 9 patients diagnosed with PD, tunica albuginea from 2 age-matched controls undergoing penile prosthesis implantation, and tunica albuginea from 2 young controls obtained post-mortem. She extracted proteins from the samples of the tunica albuginea and subjected them to immunoblotting with antibodies specific for the four types of TIMPs. This study demonstrated the presence of all four types of TIMPs in the tunica albuginea from PD plaques, age-matched old and young controls, with a 2-fold increase in the levels of TIMPs in the plaque and the surrounding perilesional tunica. Furthermore, she found an increased level of all four types of TIMPs in the plaque area compared to the perilesional tunica. These findings further the involvement of the TIMPs in fibrosis occurring in the PD plaque. She concluded that the endogenous inhibitors of collagenases would further decrease the overall degradation of collagen providing excessive collagen deposition, resulting in progressive scar formation without remodeling.

Increased tissue levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of both fibrinolysis and collagenolysis, have been found in a variety of fibrotic conditions. Furthermore, PAI-1-mediated downregulation of MMP activity can lead to inhibition of collagen breakdown. Recently, it has been reported that PAI-1 expression is also increased in the fibrotic plaque in an animal model of PD, induced by the injection of fibrin into the tunica albuginea of the penis. A study by Davila et al (abstract #943) investigated whether the tissue expression of PAI-1 was also increased in the fibrotic plaque of human PD. The investigators obtained tunical samples from PD plaques and from men undergoing penile prosthesis implantation, as well as cells cultured from these tissues, in order to evaluate PAI-1 expression at the transcriptional and protein level using RT real-time PCR and immunohistochemistry. Compared to the tunical samples obtained from men undergoing penile prosthesis implantation, in the human PD plaque, a significant increase of PAI-1 immunostaining expressed as a number of positive cells/field was determined (49 ± 6 vs. 15 ± 4). In addition, they found an increased PAI-1/GAPDH mRNA ratio in the samples obtained from the PD plaques compared to those from penile prosthesis implantation (9.31 ± 0.02 vs 0.55 ± 0.01). The investigators of this study concluded that the observed increase of PAI-1 in the human PD plaque and its fibroblast cultures is in agreement with what has been observed in the rat-PD-like plaque, suggesting that PAI-1 may be a key pro-fibrotic factor in the development of human PD and possibly a therapeutic target for PD.

The use of an acellular matrix graft of the tunica albuginea for functional penile reconstruction for PD has previously been evaluated in rabbits and mongrel dogs. Despite some early failures, an acellular matrix graft of the tunica albuginea in the rabbit study demonstrated rapid integration with no rejection. The study in mongrel dogs employed an acellular matrix graft of the tunica albuginea, resulting in normal healing without contracture in the transplanted tunica abuginea and a histologic appearance similar to the normal tunica albuginea in the 6-month follow-up. A study by Eberli et al (abstract #940) investigated the feasibility of using a naturally derived collagen-based matrix as a potential biomaterial for PD. The investigators processed and fabricated acellular matrices derived from porcine bladders in order to achieve tissue properties similar to those of the tunica albuginea. After biomechanical, ultrastructural and biocompatibility assessment the matrix was interposed and anastomosed to restore the created tunical deficiency by removing 50% of the dorsal penile tunica albuginea in 24 rabbits. The investigators performed serial functional and anatomical studies, and retrieved tissue samples 1, 2, and 3 months after implantation for histological, structural and biomechanical analyses. Cell viability and mitochondrial metabolic activity assays confirmed the biocompatibility of the matrix. Cavernosometry of the repaired rabbits with acellular collagen matrix revealed a normal erectile response to papaverine, and normal integrity of the corpora cavernosa was reported without any evidence of venous leakage or filling defect using cavernosometric studies. Although there was a minimal inflammatory response at 1 month, which gradually decreased over time, the biochemical analysis of the matrices was reported to have a tensile strength similar to that of native fascia. The investigators of this study concluded that pre-fabricated acellular collagen matrices are biocompatible and possess appropriate biomechanical properties for use as a tunical substitution.

Although there are numerous surgical options for the correction of PD, the choice of a conservative treatment is a therapeutic dilemma. Oral treatment alternatives include vitamin E, potassium aminobenzoate, colchicine, tamoxifen, and L-carnitine. On the other hand, intralesional injections of various agents such as steroids, calcium channel blockers, clostridial collegenase, orgotein and interferons (IFNs) have been promulgated as minimally invasive treatment options for PD. Verapamil, a calcium channel blocker, has been reported to reduce intracellular calcium concentration, increase collagenase activity, and affect cytokine expression in the early phases of wound healing and inflammation. It is known to inhibit in vitro fibroblast proliferation in plaques derived from PD patients. Previously, the use of intralesional verapamil as a minimally invasive therapy of PD was documented to have significant improvements in PD parameters. Mulhall et al (abstract #936) investigated the impact of intralesional verapamil injections on the progression and improvement of penile deformity in men with PD. Patients with a palpable plaque, and with penile curvature without associated deformity, presented within 12 months after the onset of PD were included into this nonplacebo-controlled study. Intralesional verapamil was administered every two weeks for a total of 6 injections, and the patients were evaluated at least 3 months after the final injection. A curvature change of equal or greater than 5° was defined as an alteration (improvement or progression). After a mean 5.2 ± 1.8 month of follow-up in 81 men with PD, intralesional injections of verapamil resulted in improvement in 22%, remained stable in 53%, and worsened in 25% of the treated patients. The mean change in penile curvature in men who documented improvement (22 ± 15°) was higher than in those with a documented worsening of conditions (12 ± 7°). The investigators concluded that, compared to their previous natural history population (12% improvement, 40% remain stable, and 48% progress over a 12-month period), intralesional injections of verapamil is associated with a lower rate of deformity progression and a slightly better improvement rate.

After reports documenting the important antifibrotic properties of IFNs in relation to PD fibroblasts, i.e., hindering fibroblast production, decreasing collagen synthesis, and upregulating collagenase activity, a scientific rationale has been suggested for using IFNs to treat men with PD. Previous noncontrolled studies showed some benefit with intralesional IFN a-2b injections in PD therapy. These results motivated a group of PD researchers to conduct an evidence-based study on the use of IFN a-2b for the minimally invasive treatment of PD. A prospective, multi-center, placebo-controlled, parallel study was presented by Kendirci et al (abstract #935) in order to determine the efficacy and safety of intralesional IFN-a2b therapy in 117 PD patients with an mean age of 55 years (62 in the placebo, 55 in the IFN-a2b group). Saline 10 mL for control and IFN a-2b 5x106 units for the study group were administered with 6 biweekly injections over a total of 12 weeks. The patients were evaluated and compared on the basis of penile curvature, plaque size and density, penile pain, erectile function, and penile vascular parameters in both groups before and 3 months after injections. The investigators reported higher improvements in the IFN a-2b-injected group than the in the placebo group in regards to penile curvature, plaque size and density, and pain resolution. Although some improvements in sexual function scores were documented in both groups, there was no statistical difference between groups. Intralesional IFN a-2b injections were reported to be associated with significant improvements in penile vascular parameters. They concluded that intralesional IFN a-2b is an effective and safe, minimally invasive therapy for PD.

The radical scavenging enzyme superoxide dismutase (SOD) has demonstrated promising efficacy as injection therapy for PD previously and in a recent pilot study in form of a topical gel containing liposomal recombinant human SOD (lrhSOD). A randomized, controlled, cross-over clinical trial was presented by Riedl et al (abstract #937) on the efficacy of lrhSOD in PD. Forty-five PD patients with penile pain were randomized in a cross-over design for a treatment period of 12 weeks, receiving lrhSOD gel for 8 weeks and placebo for 4 weeks. Reduction of penile pain was accepted as primary endpoint. lrhSOD gel therapy was reported to cause statistically significant pain reduction after 4 weeks compared to the placebo, with a significant reduction in 89% of lrhSOD-treated patients after 12 weeks. At the end of the 12-week treatment, the authors reported plaque size reduction in 47% of the patients and penile curvature improvement in 16% in the lrhSOD arm. In the treatment group, 71% of the patients reported the general efficacy of the treatment as good. The investigators concluded that lrhSOD is an effective local therapy for the early phase of PD, particularly for the remission of pain symptoms.

The expression of variants of the type 5 phosphodiesterase (PDE5) and PDE4 have previously been demonstrated in normal human and rat tunica albuginea and tunica albuginea obtained from PD plaque tissue, as well as in their respective fibroblast cultures. Furthermore, in the PD fibroblast cultures, pentoxifylline (non-specific cAMP-PDE inhibitor) has been known to increase cAMP levels without affecting cGMP levels, whereas the PDE5 inhibitor, sildenafil, increases cGMP levels. Both agents are reported to reduce the expression of collagen I and the myofibroblast marker, a-smooth muscle actin. It has also been reported that administration of sildenafil, L-arginin and pentoxifylline in drinking water for 45 days in rats with a PD-like plaque induced by TGF-b1 results in an 80-95% reduction in both plaque size and collagen/fibroblast ratio. Also, both sildenafil and pentoxiphylline stimulate fibroblast apoptosis within the tunica albuginea. A study by Minor et al (abstract #1058) further investigated the effects of pentoxiphylline on primary culture fibroblasts derived from normal tunica albuginea and Peyronie's plaques from the same patients. In culture, fibroblasts from normal tunica albuginea and Peyronie's plaques exhibited proliferation at the same rate. The addition of TGF-b1 to the culture medium resulted in a significant increase in cell proliferation and collagen production in plaque-derived cells, but was minimal in normal tunical fibroblasts. When pentoxiphylline was added to culture media, it effectively inhibited the TGF-b1-induced production of collagen I in plaque-derived cells. Collectively, these results, along with previous studies, demonstrate the in vitro beneficial effect of pentoxiphylline in PD and may indicate its clinical usefulness.

A variety of materials have been used as grafts for substitution of tunica albuginea after plaque incision or excision, and all grafting materials have advantages and disadvantages. The choice of graft materials depends on availability, the cost of the product, and the surgeon's familiarity and experience. Grafting materials that do not contract in long-term and better resemble the anatomy of tunica albuginea are more suitable. The technique for penile straightening in PD using a free tunica albuginea graft in humans has previously been reported. A study by Seyam et al (abstract #938) investigated penile hemodynamics using cavernosometry and cavernosography before and 6 months after the implantation of a free tunical graft in 6 sexually active male baboons. Through a perineal incision the investigators harvested a 3.5 x 1 cm tunica albuginea from the right penile crus and implanted it in the left lateral side of the penile shaft. Although the second postoperative month revealed that all animals were sexually active, the postoperative sixth-month cavernosography showed that 4 of the 6 animals developed venous leakage. Despite the fact that both graft and native tunica albuginea were reported to be histologically normal without fibrosis, this study further supports the development of venous leakage as a common complication after free tunica albuginea graft for surgical treatment of PD.

Although plication techniques usually provide a straight penis in penile curvature with or without PD, penile shortening is an unavoidable consequence of this surgery. Greenfield et al (abstract #1275) investigated the factors influencing men who have undergone tunica albuginea plication for either PD (68 patients) or chordee (34 patients). Evaluation parameters for this retrospective study were preoperative and postoperative complaints, physical exam, penile vascular assessment, and operative data, as well as penile length measurement before and after the procedure. After a 29-month-follow-up, the mean loss of penile length following tunica albuginea plication was reported as 0.36 ± 0.5 cm (range 0 - 2.5 cm). When calculated as a percent of length lost from preoperative length, the mean postoperative "% length lost" was 2.4%. When the direction of curvature was stratified, patients with a ventral curvature were documented to have the highest percentage of length loss. While age, the number of plications, plaque size, and hinge/narrowing effect due to a PD plaque did not show a statistically significant impact on penile shortening, preoperative penile length, the direction of and the severity of curvature were reported to significantly increase the rate of penile shortening.

Minor et al (abstract #946) reported on a surgical technique utilizing combined penile fracture repair and tunical plication in 5 nonsurgically treated PD patients who had penile curvature. Four patients presented in the acute post-traumatic setting, while one presented in the6th month. Tunical lacerations were reported in sizes ranging between 1.0 and 1.5 cm, and penile curvature varied between 15 and 80°. The investigators used a 2-0 DexonÒ suture to close the tunical defect followed by tunical plication, using either 2 or 4 sutures of 2-0 TicronÒ. In the postoperative follow-up, 4 of 5 patients were reported to regain their preoperative erectile rigidity. The last patient, who showed a distal cavernosal-spongiosal fistula, underwent penile prosthesis implantation after a failed fistulectomy with a saphenous venous patch. These authors concluded that PD patients may be more prone to penile fracture, and in those who suffer from penile fracture, a combined fracture repair with a tunical plication can be performed at the same setting.