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a report by
Hossein Sadeghi-Nejad, MD, FACS and Allen Seftel, MD, FACS
Peyronie’s disease (PD) is named after François de la Peyronie (1678–1747), surgeon to King Louis XV and a founder of the French Académie Royale de Chirurgie (Royal Academy of Surgery). In 1743, he described the pathology by way of three cases of plastic induration and curvature of the penis in the paper “Sur quelques obstacles qui s’opposent à l’éjaculation naturelle de la sémence” (On obstacles in the way of the natural ejaculation of semen).1
However, the condition had apparently been recognized many years prior to de la Peyronie’s paper, and was discussed in the Ephemerides (1687) and the booklet Venus Minzieke Gasthuis (Venus Hospital for the lovesick) (1688), as well as in a Dutch case report and a general discussion by Nicolaas Tulp (1593–1674) and Fredrik Ruysch (1638–1731), respectively.2 The pathology is a localized connective tissue disorder affecting the tunica albuginea of the penis and is manifested by various degrees of penile curvature during erection. Despite numerous reports on possible etiologies, a clear understanding of the pathophysiology is lacking. Upregulation of genes involved in collagen synthesis and downregulation of genes that normally inhibit inflammation and tissue remodeling have been reported in PD plaques.3
Similarities in upregulation of certain gene families in both PD and Dupuytren’s contracture may suggest common roots in these connective tissue disorders.4 The role of profibrotic factors in the origin of PD has attracted much attention in recent literature. Examples include documentation of plaque formation or induction of fibrosis upon tunical injection of fibrin or transforming growth factor (TGF)to promote fibrin release.5,6
An overview of the various theories implicated in the development of PD plaques was described by Mulhall in 2003 and included a combination of the following factors: penile trauma in genetically susceptible men, leading to a localized autoimmune response with alteration of genetic regulators and tunical cell transformation; overexpression of cytokines and excess free radical production; and plaque formation due to unregulated extracellular matrix deposition.7
PD can affect men across a wide range of ages and is not limited to older men. Tefekli et al. have reported that the incidence of PD in men younger than 40 is 8.2%, and that the majority have a dorsal curvature, with a 21% incidence of erectile dysfunction (ED).8
Similarly, Levine et al. have reported that patients younger than 40 who have PD are more likely to suffer from ED, but less likely to recall a traumatic event or report pain associated with PD.Whereas earlier reports of PD prevalence from the 1960s had documented a prevalence of 0.3–0.7%, the results of a large European survey in 2001 indicated that PD affects a much larger segment (3.2%) of the male population.9,10 Others have postulated that the actual prevalence may be higher, as many men would be expected not to report the condition due to embarrassment. A study of 534 men who had originally presented to their urologist for prostate cancer screening in the US reported objective evidence of PD in 8.9% of the patients.11
An important note concerns the controversies surrounding the natural history of PD. A review of 63 patients with PD by Kadioglu et al. in 2002 revealed that, with a six-month follow-up, only two patients reported spontaneous resolution, whereas 67% had stable disease and 30% had worsening of their condition.12 Another study by Gelbard et al. reported that in a group of 97 men with PD, 47% reported stable disease, 40% worsened and only 13% improved.13
As in the evaluation of any disease process, the history and physical examination are critical components of the interaction with the patient. The history should focus on the circumstances surrounding the onset of the deformity—e.g. following trauma, urethral instrumentation, or a gradual process—as well as the duration of the problem. Sexual function should be assessed with a validated questionnaire. Questions should be asked pertaining to perceived loss of length or girth, pain, quality of erections and ejaculatory function, although the latter is not commonly affected.
A focused physical examination should evaluate the possible presence of Dupuytren’s contracture in the palms of the hands, as well as the size and location of the penile plaque/s, which are best assessed with the penis in a stretched position. Penile length is evaluated on the dorsal aspect of the fully stretched penis from the base to the meatus.14
Objective measurement of the plaque size and penile curvature may be challenging, and an effort should be made to standardize the measurements by using calipers for plaque size and a protractor or goniometer for penile curvature.Although an estimate of plaque length may be obtained with calipers, the depth of the plaque is difficult to assess. Some investigators recommend penile duplex Doppler sonography with injection of pharmacological agents to identify various plaque features, as well as any abnormalities in penile blood flow characteristics. Baseline penile hemodynamic parameters may be helpful in patients who will later undergo corrective surgery. Calcified plaques and thickened tunica albuginea without calcification can be readily identified with sonography.15
Despite a large number of publications on various potential medical remedies for PD, there are few randomized studies with adequate follow-up or objective documentation of improvement. Among the investigated and available oral therapies, a few are noteworthy. Vitamin E was described as potentially beneficial for PD more than half a century ago, and is widely used as first-line therapy for PD.16,17 Despite a few reports on the antioxidant properties of vitamin E in PD, concrete evidence supporting the efficacy of this regimen is lacking.18 However, low cost and absence of serious adverse events contribute to the lasting popularity of this treatment. Other investigators have reported improved efficacy when vitamin E is combined with colchicine for early-stage, mild PD (curvature less than 30º) that is not associated with ED.19 Tamoxifen (Nolvadex®, AstraZeneca) appears to have some efficacy in early- phase PD, but is rarely used clinically, due to potential serious adverse events and lack of objective evidence from placebo-controlled studies.20 Comparison of tamoxifen with placebo in the treatment of PD by Teloken et al. failed to show a significant difference between the two.21 Among other therapies that have been used in uncontrolled studies, Potaba—paraaminobenzoate, a mast-cell blocker—is also noteworthy. Experience by the authors and a number of other investigators has shown poor efficacy, poor tolerability due to a high incidence of gastrointestinal adverse events, and low compliance due to high cost and the need for ingestion of a large number of pills daily.6 Oral ingestion of carnitine (Carnitor®, Sigma Tau), an inhibitor of acetyl coenzyme-A, has been reported to be better tolerated and significantly more effective than tamoxifen in reducing pain, penile curvature, and inhibition of disease progression. However, more objective measures of improvement are needed before a definitive conclusion can be drawn.22
Intralesional steroid injection for PD was started in the early 1950s, but the questionable efficacy and potential for tissue atrophy and distortion of anatomical planes have contributed to the abandonment of this mode of therapy.6,23 Levine first reported use of verapamil as an intralesional injectable agent in 1994.24 Much credit for the evolution of this mode of therapy is also due to the early work of Kelly, in 1985, who reported on the role of calcium ion channels in the formation of plaque components—i.e. collagen, fibronectin, and glycosaminoglycans. 6,25 A small, single-blind study of verapamil as an intralesional agent demonstrated advantages to verapamil compared with placebo in plaque volume and quality of erections.26 A larger and more recent non-placebo-controlled investigation of intralesional verapamil (10mg diluted in saline for a total volume of 10cc) by Levine et al. reported that, with a mean follow-up of 30.4 months, 60% of the 140 patients who completed treatment had an objectively measured decrease in curvature, 83% reported an increase in girth, 80% noted an increase in rigidity distal to the plaque, and 71% had an improvement in sexual function.27 The authors’ personal experience with this regimen over the past eight years has been consistent with these results.
Based on the effects on inhibition of fibroblast proliferation and enhancement of collagenase function, interferons (IFNs) were proposed as potential intralesional agents for PD therapy in the early 1990s.28 This therapy has gained popularity among ED specialists in the past few years.Various studies over the past decade have demonstrated improved penile hemodynamics and subjective, as well as objective, improvements in PD symptoms and findings.29-35 Specifically, Dang et al. reported improvements of 20% or more in penile curvature in 14 (67%) of 21 men. Decreased penile pain (80%) and subjective decrease in plaque size (71%), as well as significant improvement of ED (71%), based on a validated questionnaire,were also reported in this small study.31 Bellorofonte reported on the possible use of shockwave therapy to correct Peyronie’s curvature in 1989.36 The application of shockwave therapy for treatment of fibrotic disorders can be traced back to the orthopedic literature, where epicondylopathies, including tennis and golfers’ elbow, as well as painful heel and shoulder pathologies, have been treated. Among the hypotheses that have been proposed as the mechanism for clinical improvement in these orthopedic ailments, improved vascularization, resorption of calcification, hyper-stimulation analgesia in non-calcific disease, and disturbance of pain receptors are noteworthy.37,38
However, there are no long-term data on the effect of shockwave therapy on fibrous plaques seen in PD, nor are there concrete explanations, to why the therapy should work at all. Interestingly, a recent survey reported that shockwave therapy for PD is widely used in Europe and is the third most frequent ‘conservative’ modality for PD in Germany, after the administration of potassium paraaminobenzoate and vitamin E.39
Decreased packing and clumping of collagen fibers after shockwave therapy may serve as a potential rationale for use of this modality in PD.40 Conversely, this rationale for use of shockwave therapy is countered by arguments that induction of microinjuries of the tunica albuginea by repeated shockwaves will actually propagate the disease process.41,42
Hauck and associates published the results of a prospective study on the effects of extracorporeal shockwave therapy (ESWT) on PD in 114 patients. They concluded that, despite improvements in a select subgroup of patients, ESWT cannot be recommended as a standard procedure for PD, since it is not significantly effective for decreasing penile curvature and plaque size or for improving sexual function.43
An exploratory meta-analysis of various studies on treatment outcomes in PD concluded that ESWT had a beneficial effect on more rapid pain resolution than would have been expected during the course of the natural history of the disease (and possibly on sexual function), but that this therapy had questionable efficacy in resolving penile plaque size and curvature.44 Although the potential beneficial effects on pain resolution is encouraging, it also raises some questions, since at least some experts would regard the painful phase of PD as the evolving or unstable phase of the pathology. In summary, there is currently not enough evidence in the literature to adopt shockwave therapy as standard therapy for any phase of PD.
Montorsi et al. and a few other investigators have reported improved patient symptoms and reduced need for penile surgery with the use of transdermal electromotive drug administration (EMDA) for PD.45 More recently, a prospective controlled study compared the efficacy of intraplaque electromotive verapamil/ dexamethasone against an electromotive lidocaine control group.46 The authors concluded that intraplaque electromotive verapamil and dexamethasone induced substantial objective improvement in PD compared to the control group. More studies are needed to assess the role of electric current in amelioration of PD objective and subjective findings.
There is little disagreement regarding the ideal therapy for the patient suffering from both ED and PD. In these cases, penile prosthesis placement is effective treatment for both pathologies.20,47 For the patient with severe PD, penile prosthesis surgery may be combined with manual modeling over the inflatable implant to achieve penile straightening.This technique was first described by Wilson et al. in 1994, who later published results of a long-term follow-up (average more than five years) in both Mentor Alpha 1 and AMS 700CX prostheses.48 The authors concluded that implantation and modeling appear to provide permanent straightening without an increase in revisions. Importantly, however, they cautioned that in modeled cases, the Mentor Alpha 1 appeared less likely to fail mechanically than the AMS 700CX, and that modeling may predispose the AMS 700CX to earlier mechanical failure. Some authors have described an algorithm for penile prosthesis surgery alone or in combination with tunical excision and/or grafting.49 The authors’ experience has suggested that nearly all cases can be managed with a prosthesis and modeling without a need for plaque excision and grafting. In patients who have undergone a course of intralesional verapamil or IFN injection, partial plaque disruption and softening due to the injections may further contribute to the success of modeling without a need for grafts.
In PD cases not associated with ED, the surgical options include the tunical shortening procedures (i.e. Nesbit and modifications of various ‘plication’ procedures typically preferred by the authors as these rarely cause ED) or plaque excision combined with grafting procedures. The latter involves incision or excision of the diseased tunica albuginea and coverage of the defect with various materials. Although excellent cosmetic results have been achieved, there is concern regarding prospects of long-term ED associated with this procedure.50 An international expert panel recommendation, based on evidence-based medical literature for the treatment of PD in 2004, concluded that a Nesbit procedure should be the first-line surgical procedure for a stable deformity, as it is associated with the least postoperative ED. The same panel recommended that plaque incision and grafting be reserved for men with good erectile function and marked penile shortening, but warned that there is a higher incidence of ED.51 Human cadaveric pericardium, bovine pericardium, collagen fleece covered with tissue sealant, and buccal mucosa grafts are among many different grafting materials that have been proposed as coverage for the tunical defect.52-54
Hatzchristou et al. have described a procedure whereby a Nesbit plication procedure is combined with grafting.55 In order to minimize the penile shortening typically associated with the plication procedure, the authors recommend using the normal, excised tunical ellipse to cover the incision defect in the area of scarring. Although based on a small study group of 17 patients, the results appear promising, and penile shortening was reportedly reduced by 50%. Further confirmatory studies are needed before this approach can be widely adopted.
Despite advances in the understanding of the epidemiology, pathophysiology, diagnosis, and treatment—both medical and surgical—of PD in the past decade, a ‘cure’ for the plaques that have not disappeared spontaneously is still missing. A conservative, non-operative approach in the early phases of the pathology is recommended. Surgery is reserved for those severe and refractory cases interfering with satisfactory intercourse, and should be performed when the disease is stable. Penile prosthesis surgery, with possible penile modeling, is recommended for cases associated with ED. Plication procedures are ideal for PD with mild to moderate deformity and are rarely associated with ED. Severe curvatures associated with large or calcified plaques may require excision/incision procedures with grafting, but the patient should be advised that there is higher incidence of long-term ED associated with these procedures.
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