Peyronie’s disease (curvature)
Peyronie’s disease (PD) presents a physically and psychologically devastating problem to the affected man. It is manifest by a fibrous inelastic scar involving the tunica albuginea, which in the flaccid condition results in a palpable scar causing penile deformity in the erect state, including bending, narrowing, hinging, and oftentimes the most devastating consequence, shortening of the penis. There may also be painful erections in the early, acute stage of this disease, but pain may persist as a result of strong erections, causing a torque effect on the deformed penis. All of these manifestations can result in difficulty with sexual intercourse. In spite of the multiple treatment options, which have been available since the time of de la Peyronie, it remains a therapeutic dilemma to the practicing physician. Unfortunately there are only few high level evidence based medicine treatment studies available. This review will briefly outline what is known about the etiopathology, prevalence, natural history, evaluation and treatment options for PD.
A historical survey of Peyronie’s disease revealed that it was de la Peyronie who was in fact the first to describe and treat this problem, although Guilielmus of Saliceto in the thirteenth century was likely to first describe a case of Peyronie’s disease. François Gigot de la Peyronie was the first surgeon to King Louis XV and founded the Académie Royale de Chirurgie in 1731. He described two cases of Peyronie’s disease in his classic paper of 1743, as likely the scarred remains of venereal disease. Peyronie’s disease can present with a variety of deformities, including dorsal, lateral, or ventral curve, as well as varying degrees of shaft indentation and hourglass deformities, which can cause a reduction of the ability of the penis to withstand axial forces, resulting in what is known as a hinge effect.
The prevalence of Peyronie’s disease has been examined in a variety of studies and ranges from 2% to as high as 8.9%. The discrepancy here may be due to the way the study was conducted. When men are simply asked the question “Do you have a deformed in penis in the erect state?,” this may result in different outcomes as compared to when a trained specialist examines the penis for a palpable scar. Regardless, what is important is that Peyronie’s disease is not a rare disorder as previously thought, and it appears to increase in prevalence with aging. The natural history of Peyronie’s disease has been researched in several recent studies, suggesting that pain will tend to resolve in 89-100% of patients with time, ranging from weeks to months. Penile deformity may get worse in the first 12-18 months after onset of the condition in 42-48% of men, and will remain stable in 40-45%, but will have some spontaneous improvement in only 12-13%. Therefore, any spontaneous deformity resolution is not common and it is extremely rare to have complete resolution.
The following caveats provide useful information to gain a better understanding of Peyronie’s disease:
First, that it is not a rare disorder and it does not tend to resolve spontaneously as previously thought. Peyronie’s disease is frequently associated with erectile dysfunction. In fact 50% of men will have ED before developing PD, and the other 50% will develop ED subsequently. This may be due to vascular changes, but may also be contributed to by psychogenic inhibition. There is no reliable non-surgical cure currently for Peyronie’s disease, but current treatments have been shown to stabilize the deformity, and may reduce the deformity and improve sexual function. Should non-surgical treatments be used, it should be recognized that treatment-related change occurs at “glacial speed.” Surgery is the most rapid and reliable treatment, and diagnosis is easy, but treatment remains a challenge.
Much has been written about the pathogenesis of Peyronie’s disease, and yet it is still unclear as to the etiopathology of this disorder. The current paradigm suggests that it is a wound-healing disorder occurring in a presumed genetically susceptible individual whose tunica albuginea responds inappropriately to an inciting event, most commonly following trauma to the erect penis, with a proliferative fibrotic reaction resulting in an exuberant, inelastic scar (plaque) that does not resolve. It is important to know that only 20% of men who present for evaluation of Peyronie’s disease recall a specific event where they may have injured their penis, most commonly during sexual activity. A small group recall an injury to the flaccid penis activating the Peyronie’s process, but clearly most men do not recall a specific event, suggesting that even a subclinical, silent injury may activate this process, or there may be other not yet understood mechanisms responsible.
One area of interesting research is examining why the scar tissue fails to undergo the normal resolution process. Studies have suggested that the enzymes which are responsible for scar remodeling known as metalloproteinases, or collagenases, are either absent or fragmented. In addition there are elevated levels of inhibitors of metalloproteinases, preventing scar resolution. Future research will focus on activating those collagenases and reducing the inhibitors. In the meantime multiple treatment options are being explored. Many elegant and unique experiments have been performed to determine the cause of Peyronie’s disease, but most have not been confirmed in other labs, and therefore a clear understanding of why Peyronie’s disease occurs is not currently available.
The evaluation of Peyronie’s disease has not been standardized with an established and accepted international means for evaluation or for reporting on treatment outcomes. This has certainly compromised the ability to evaluate successful treatment. In addition, the need for a validated questionnaire with appropriate domains focusing on deformity, sexual function, impact of disease and patient satisfaction, is not yet available, but is in the final phase of validation and hopefully will be available in 2010. Suggested objective measures include an assessment of stretched penile length, which has been recommended to be performed on the dorsal surface of the penis by compressing the fat pad down to the pubis with a rigid ruler, and then measuring the penis to either the corona or meatus. Stretched length is important to assess, as men with PD frequently experience a loss of penile length and it is important to have a baseline measurement. Plaque location should be recorded, but plaque size has never been shown to be a significant measure, in that reduction of plaque size has not been shown to correlate with reduction of penile deformity. Also it is important to note that an accurate measurement of plaque size is virtually impossible with any modality. Probably the most important but difficult to measure parameter is erect deformity. It has been determined that it is best to do this in the full erect state, which is induced by an intracavernosal injection of a vasoactive agent. The angle can then be measured with a goniometer or protractor, and girth can be assessed with a string and ruler.
Peyronie’s disease oftentimes presents with a variety of common co-morbidities. It is unclear as to the significance of these comorbidities with respect to the development of Peyronie’s disease. Hypertension, diabetes and dyslipidemia are three important vascular risk factors associated with ED, which have also been shown to be found in men with Peyronie’s disease. A recent publication suggested that up to 70% of men presenting with Peyronie’s disease have low free and total testosterone. The significance of this remains unknown. In addition, other site-specific fibrotic disorders have been shown to be associated with Peyronie’s disease, including Dupuytren’s disease (a scarring disorder of the palm of the hand), which was found to occur in up to 20% of men with Peyronie’s disease and infrequently, Ledderhose disease, which involves the plantar (sole of the foot) fascia.
Candidates for non-surgical therapy include those men with early phase disease of less than 12 months, or in those who have an unstable progressive deformity or plaque, and/or painful erections associated with inflammation. In addition, men who are not psychologically ready or interested in surgery regardless of duration or severity of disease, may also be candidates for non-surgical therapy. It should be noted that currently there are no FDA approved non-surgical treatment options, as the proper studies have not been done. In the meantime non-approved treatments are offered by quality physicians.
As a brief review of oral therapy we can see that there are only a few well controlled and designed trials, but there have been several placebo-controlled trials examining the most commonly used oral agents, including vitamin E, Potaba, colchicine, tamoxifen, carnitine, and recently, omega-3 fatty acids, all of which have not been shown to offer any benefit over placebo. Two oral agents, including pentoxifylline, a non-specific phosphodiesterase inhibitor, and L-arginine, a precursor of nitric oxide, have been shown in the rat model of Peyronie’s disease to have an anti-scarring effect. When rats had a penile scar induced in the laboratory, those animals who had Pentoxifylline, L-arginine or any of the three phosphodiesterase type-5 inhibitors (Viagra, Levitra, Cialis) in their drinking water, developed less scar than those who had plain drinking water. It was also found that there was not a significant reduction of scar when the scar was well established before the animals were allowed to consume those agents. Therefore, if the animal model correlates to the human, we would expect that the best response to these oral treatments to be during the early, acute phase, while the scar is growing.
A variety of intralesional injection therapies have been used over the past several decades, beginning with steroids, with which the rationale is reasonable as an anti-scarring agent, but no real benefit has been demonstrated, as no objective measures are found in the published literature. There is also evidence that steroids can destroy the plane between the tunica albuginea and the overlying neurovascular bundle, contained within Buck’s fascia, making surgery, if necessary, more difficult to perform. Intralesional verapamil appears to make scientific sense, in that it has been shown to decrease cellular growth of fibroblasts harvested from Peyronie’s plaques, and has also been shown to reduce extracellular matrix production, including collagen. In non-controlled trials of intralesional verapamil, a measured improvement of deformity has been reported in anywhere between 30-60% of subjects given verapamil injection therapy, with a mean reduction of curvature in responders ranging from 15 to 30 degrees. Intralesional interferon is also a biological modifier that has been proposed to have similar effects to intralesional verapamil. Previous studies were not favorable, but a single multicenter placebo-controlled trial did show an advantage of intralesional interferon over saline. In this important study, the sizable placebo group (n=62) showed a small response in terms of measured improvement. Less than 9% of men receiving saline had measured reduction of curvature, with an average reduction of 9 degrees, both of which are considered clinically insignificant.
Finally, intralesional collagenase has been used since the 1980s and is only recently being examined in large scale, multicenter, placebo, controlled trials. Collagenase works like a chemical knife, where it is designed to break down the collagen within the scar, with hopes that this will result in deformity reduction.
Topical verapamil gel has also been recommended as a treatment option. As there are no independent controlled trials, and no evidence of adequate levels measured within the target tissue of the tunica albuginea, topical verapamil is not a recommended treatment. It is expensive and unproven.
Topical energy treatment with laser and/or ultrasound with or without steroids have been discussed in the literature, but all in poorly controlled studies with no objective measures. Therefore, no recommendation can be made about topical energy therapy of this sort. On the other hand, Iontophoresis, also known as electromotive drug administration (EMDA), has been shown initially in non-controlled trials to have benefit. Several controlled trials using verapamil with dexamethasone as compared to saline alone, did show some reduction in deformity, and in an experimental trial where verapamil was administered via EMDA. 71% of those who were exposed to verapamil had measured levels of the drug in the excised tunica albuginea. This indicates that with EMDA there can be some penetration through the skin to the tunica albuginea. As to whether an adequate level to induce cellular or scar change is reached, is not known.
Lastly, verapamil was compared to saline in a placebo-controlled EMDA trial, which showed improvement of deformity in a similar number of patients in both groups. The conclusion by the authors was that it may not be the drug, so much as the energy, which provides the beneficial effects.
Several recent physician surveys have been sponsored by the American Urological Association and by other investigators, which showed that the primary agent used by both urologists and primary care physicians for the treatment of Peyronie’s disease is vitamin E, in spite of the fact that several placebo-controlled trials have shown no benefit with this agent. Therefore it is clear that physician education about PD remains an important goal so that more potentially effective treatments can be offered.
Shockwave therapy (ESWT) has been used in a variety of trials, including a recent well-done placebo-controlled trial which demonstrated no improvement in Peyronie’s-related penile deformity, although there can be acceleration of pain resolution. At this time, no recommendation can be made to use shockwave therapy to treat PD.
It does appear that if one hopes to have the best chance to reduce deformity with non-surgical therapy, that combination therapy may be the best approach, allowing a synergy between the chemical effects of the administered drugs combined with the mechanical effects of either vacuum or stretching devices. A recent non-published trial comparing the results of intralesional verapamil alone or in combination with daily vacuum therapy did not show a treatment advantage with vacuum therapy. On the other hand, external traction therapy has been shown in recent studies to provide a reduction of curvature and recovery of lost length. Traction therapy remains an attractive non-invasive treatment, as it has been used in multiple medical applications, such as orthodonture to straighten teeth, orthopedics to elongate shortened limbs, and following surgery in patients with Dupuytren’s contracture of the hand.
Three mechanisms have been identified in non-penile experimental models of traction therapy to be responsible for cellular growth as a result of continuous traction. In addition, histologic (tissue) studies have demonstrated in Dupuytren’s contracture, a realignment of collagen fibers parallel to the traction forces. Therefore the goals of penile traction therapy for PD include stopping progression of scarring, recovering length and girth, reducing curvature, enhancing sexual function, and possibly avoiding or simplifying surgery by taking someone with a severe deformity which may require grafting, and reducing it to a curvature which would respond better to a less risky operation known as plication. In one published pilot study, 10 men with Peyronie’s disease used traction for a minimum of 2-8 hours daily for 6 months. This study showed that all 10 subjects had measured reduction of curvature ranging from 10-45 degrees, and that all men gained stretched length from 0.5-2 cm. There was also evidence of reduced narrowing and improvement of measured erectile function by the International Index of Erectile Function (IIEF) questionnaire. Importantly, there was no change in sensation, skin lesions or new ED during this trial. A subsequent trial at another institution demonstrated less reduction of curvature, but did show an increase in penile length. This study was somewhat different, in that 37% of men did have plaque calcification, which was excluded in the first study. Therefore, plaque calcification may have compromised the treatment response to traction. The primary drawback of traction therapy is the requirement for daily extended use, which can be difficult to incorporate into a busy patient’s life.
Finally, an ongoing single center trial has examined verapamil injection only vs. verapamil injection with daily traction therapy, and has shown a more robust response with regard to curvature reduction and a greater number of men responding to the combination treatment. Preliminary results show that in the verapamil-only group, only 50% had measured improvement with a mean of 14 degrees vs. 65% were responders in the combination group, with a mean curvature reduction of 21 degrees. This study is still ongoing.
The indications for surgical reconstruction include men with stable disease for at least 6 months who have a painless deformity. It would also be expected that the surgery would not be performed before one year after onset of disease. The patient should also have a compromised or inability to engage in coital activity due to deformity and/or inadequate rigidity. The patient with extensive plaque calcification may also be a good candidate for surgery, and certainly those who want the most rapid and reliable result are best treated with surgical correction. The preoperative consent is critical in this patient population, as these men are oftentimes unhappy with their deformity and in fact, up to 40% have been shown to have evidence of clinical depression. Therefore, setting appropriate expectations regarding outcomes before surgery is critical to ensure that the patient understands the limitations and possible side effects of surgery. These side-effects include a persistent or recurrent curvature. The goal of surgery is to make the patient “functionally straight,” which has been loosely defined as less than 20 degrees of curvature in any direction, which should not interfere with penetrative sex. There could be shortening of the penis, more commonly noted with plication than grafting procedures, as well as diminished rigidity (ED), which has been reported in all surgical studies, especially with the grafting operations, but appears to be most dependent upon preoperative erectile status. Lastly there could be diminished sexual sensation. This tends to be common in the early postoperative period but usually resolves.
Three surgical algorithms have been published since 1997 and have essentially agreed that there are two important factors determining the surgical approach. The first is that the patient can develop adequate penile rigidity for coitus with or without drug assistance, and the second is the degree of deformity. In those men who have adequate preoperative rigidity and a simple curvature of 60-70 degrees or less with no hinge effect or hourglass deformity, then a tunica plication technique can be used. For those who have a more severe or complex curvature or a destabilizing hourglass narrowing, then plaque incision or partial excision and grafting is recommended. Several surgical plication techniques have been developed since the 1960’s, including the Nesbit procedure, which is performed by cutting out a wedge of tunic on the convex (longer aspect of the penis) with closure of that defect to straighten the penis. There are a variety of plication operations, where incisions or sutures are placed to shorten the longer side of the penis without excising the tunic. There is no evidence that one particular procedure is superior to the other. The most important factor here appears to be physician preference and expertise with a particular approach. Overall, the plication operations have been shown to allow “functional straightness” in 85-100% of patients with up to 13% experiencing new ED.
Incision or partial excision and grafting is indicated for those who have strong erections preoperatively, curvature greater than 60-70 degrees and significant shaft narrowing, especially when there is a hinge effect. The goal of the operation is to limit trauma to the underlying cavernosal tissue so as to maintain the venous trapping relationship between the tunic and the graft with the underlying penile vascular (cavernosal) tissue. A variety of surgical grafting approaches have been used, including using grafts such as dermis, vein, tunica vaginalis, buccal mucosa, and postauricular skin, as well as allografts and xenografts, including processed, human and bovine pericardium, porcine subintestinal submucosa, and pig dermis. No graft has been found at this time to be the ideal graft, which would always have complete take, not contract, have adequate strength, resist infection, and reduce the risk of postoperative erectile dysfunction. Overall it appears that procedures with autologous grafts require more time and a second incision, whereas processed, off-the-shelf allograft and xenograft procedures appear shorter in duration with no reported transmission of disease. Synthetic grafts such as PTFE (Gore-Tex) and Dacron, increase the risk of infection and are palpable and therefore, not recommended. The primary concern is that there is an increased risk of postoperative erectile dysfunction with grafting procedures. In review of the literature, it appears that satisfactory straightening occurs with grafting in 74-100% of patients, with a range of new ED following surgery in 5-53%. Recent studies performed by centers of excellence show new ED rates in the 5-30% range.
In addition, recent studies have examined preoperative factors to determine if there are predictors of developing post-operative erectile dysfunction. A recent presentation examining all vascular risk factors, as well as: patient age, severity and direction of deformity, graft size, and pre-operative penile duplex ultrasound parameters demonstrated no statistically significant predictor for post-operative ED. It therefore appears that the most critical factors will be the patient’s preoperative erectile status and the experience of the surgeon.
In those patients with inadequate rigidity, placement of a penile prosthesis is recommended. Occasionally just placement of a prosthesis alone will provide adequate straightening, but in those patients with more severe deformity, a stepwise approach is taken to straighten the penis. It should be noted that a prosthesis that provides good axial rigidity is more likely to result in straightening than those which can expand in girth and length. In addition, malleable prostheses do not appear to provide good axial rigidity resulting in suboptimal straightening postoperatively. When penile prosthesis placement alone does not provide enough straightening, manual modeling as described by Wilson in 1994 appears to result in satisfactory straightening in the great majority of patients. This must be done with care to reduce the likelihood of urethral trauma. When there is inadequate straightening following manual modeling, Buck’s fascia can be mobilized followed by an incision of the scarred tunic. If the incision leaves a substantial tunic defect, which might result in prosthesis herniation, then grafting of the defect is recommended.
A recent presentation (Nov. 2009) examined 89 patients undergoing placement of a penile prosthesis for Peyronie’s disease with drug refractory erectile dysfunction. The study had up to a 9 year follow-up, and revealed a low prosthesis mechanical failure rate of approximately 4%, and an overall high patient satisfaction rate of 85%.
In summary, with respect to surgery, a detailed pre-operative consent is imperative to set appropriate patient expectations. A plication procedure is recommended for mild to moderate deformities (less than 60 degrees), and when there is borderline erectile dysfunction. Grafting is reserved for severe deformity greater than 60-70 degrees, and/or when there is a hinge effect. Most importantly these procedures should be offered when there is good pre-operative erectile function and when the procedure is being performed by an experienced surgical team. Prosthesis placement with additional maneuvers is recommended when the patient has erectile dysfunction that fails to respond to medical therapy.
In conclusion, it appears that Peyronie’s disease is far more prevalent than previously thought, and can be a devastating physical and psychological problem for the affected man. It rarely resolves spontaneously and left untreated during the acute phase, the deformity may get worse in up to 50% of men. As a result of failure to understand the cause of this disorder, reliable, effective treatment has not emerged, and therefore large scale multicenter placebo-controlled trials will be necessary. At the current time, combination therapy may be the best approach to take advantage of the potential chemical effects of the drugs and the mechanical effects of traction therapy. Surgery does remain as the gold standard when the disease is stable, but preoperative counseling is critical because there is a risk of recurrent curvature, incomplete straightening, shaft shortening, diminished sensation, and erectile dysfunction. As a result of improved surgical technique, and better patient selection, surgery remains an excellent option for the motivated patient.