|Year : 2006 | Volume
| Issue : 3 | Page : 246-250
Peyronie's disease and erectile dysfunction: Current understanding and future direction
Laurence A Levine
Department of Urology, Rush University Medical Center, Chicago, Illinois - 60612, USA
Laurence A Levine
Department of Urology, Rush University Medical Center, Chicago, Illinois 60612
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Peyronie's disease is a physically and psychologically devastating disorder affecting close to 10% of adult men. It is currently believed to be a form of wound healing disorder where there is excessive scar formation in response to a triggering process, most commonly following trauma to the erect penis. In this circumstance, the plaque which is an inelastic scar of the tunica albuginea develops which causes a variety of penile deformities including curvature, indentation, loss of girth and shortening. Frequently pain will accompany erection or direct palpation of the plaque in the early, active phase of this disease, but pain does tend to resolve over time but the deformities tend to remain. In up to 90% of patients there is associated diminished erectile capacity. Fifty percent of the time, men note evidence of erectile dysfunction prior to developing the Peyronie's disease. A variety of factors may contribute to erectile dysfunction in this patient population. Most commonly there is an underlying vascular insufficiency, which may be due to the same processes that result in accelerated atherosclerosis including diabetes, hypertension, smoking, and dyslipidemia. There may also be a substantial psychogenic effect, as we know that the majority of men with Peyronie's disease are significantly psychologically distressed by the changes to their penis. Lastly, there has been some suggestion that the abnormal geometry of the penis may contribute to a reduction of intracavernosal pressure resulting in diminished rigidity.
This article briefly reviews what is currently understood about the etiology and presentation of the patient with Peyronie's disease and tries to clarify several of the widely held misconceptions. In addition, there are recommendations for evaluation and a more detailed discussion of the erectile dysfunction associated with Peyronie's disease, as well as appropriate treatment options.
Keywords: Erectile dysfunction, impotence, Peyronie′s disease, type 5 phosphodiesterase inhibitors
|How to cite this article:|
Levine LA. Peyronie's disease and erectile dysfunction: Current understanding and future direction. Indian J Urol 2006;22:246-50
| Introduction|| |
Peyronie's disease (PD) is a physically and psychologically devastating disorder. It is manifest by a fibrous inelastic scar involving the tunica albuginea which results in a palpable scar in the flaccid condition and causes penile deformity, including curvature, narrowing, hinging and shortening as well as painful erections in the acute phase. All of these deformities may cause difficulty with coitus. Multiple treatment options have been available and offered since the time of Franηois de la Peyronie who described this disorder in a classic paper published in 1743. Unfortunately, none of the treatment options offered since de la Peyronie, provide a reliable cure, therefore, Peyronie's disease remains a therapeutic dilemma for the practicing physician.
Research over the past decade has been directed towards a better understanding of the pathophysiology of this disease as well as determining the demographics and its natural history. As a result much of the conventional wisdom regarding PD has been found to be incorrect. Briefly, these misconceptions include that PD is not a rare disorder. In fact the prevalence of a palpable plaque has been recorded in demographic studies in up to nine per cent of adult men. Another misconception is that PD need not be treated, as it resolves spontaneously in up to 50% of cases. On the other hand, more recent natural history studies have demonstrated that no more than 13% of men will have spontaneous resolution of curvature.,, Pain is the only parameter that reliably resolves with time as the acute phase moves into a more stable plaque without the associated inflammatory component. It has also been previously held that PD is caused only by trauma to the erect penis. Although trauma is the most likely inciting event, up to 60% of my patients recall no trauma to their penis and some recall trauma to the flaccid penis ultimately resulting in Peyronie's disease. This disorder has also been reported in up to 11% of men after radical retropubic prostatectomy. Another misconception is that PD is found only in older men. In fact, most studies show that the average age at presentation is in the early to mid-fifties but two case study series found that up to 10% of men with PD were less than 40 years of age., Another misconception is that the erectile dysfunction associated with PD is caused by the deformity and is not a frequent companion to PD; we will address ED later in this article.
The last misconception is that injection therapy with biological modifiers such as verapamil or interferon alpha-2b should not be considered first line therapy. This is a misconception as currently, these two treatments appear to be the most likely agents to result in stabilization and improvement of deformity., Therefore, in men who are not ready or interested in surgery it is reasonable to offer intralesional injection of verapamil or interferon. Overall, patients should be aware that there is no known cure for this disorder but offering no treatment or hope for improvement serves no purpose and typically results in patients seeking unproven therapies and sometimes dangerous ones on the internet.
To further examine the current wisdom of the practicing physician, a survey of primary care physicians (PCPs) and urologists in the Chicagoland area was conducted. This survey found that 41% of urologists and 63% of PCPs estimated the prevalence of PD as less than one percent. With respect to spontaneous resolution, 38% of urologists and 17% of PCPs believed that PD resolved in greater than 50% of cases. Current attitudes regarding the association between PD and ED revealed that 37% of urologists and 48% of PCPs did not believe that PD and ED were frequently associated. Interestingly, there was no significant difference in the perceptions of the physicians in both groups whether they were less than or more than 10 years after completing their training. Therefore, it appears that the medical community needs better distribution of up-to-date information regarding PD so that patients will be properly identified, counseled and receive the appropriate referral.
The current understanding of Peyronie's disease can be simplified by the following: PD is a wound healing disorder occurring in a presumably genetically susceptible individual whose tunica albuginea responds inappropriately to an inciting event, most commonly trauma, with a proliferative fibrotic reaction resulting in an exuberant inelastic scar. At this point it is unclear whether there is a single genetic abnormality resulting in this aberration or whether PD is a syndrome with a variety of irregularities leading to the same endpoint of a penile scar. It is clear that not all men with PD present alike, as there are differences in the size, location and density of the plaque as well as calcification, pain and erectile dysfunction. These variations in presentation support the possibility of multiple abnormalities resulting in the resultant deformities.
There is no accepted international standard for evaluation of the patient with Peyronie's disease or for reporting on treatment outcome results. There is clearly a need for a validated PD questionnaire examining the domains of deformity, sexual function, impact of disease and treatment satisfaction. Fortunately, such a questionnaire is in development. The following measures have been suggested for men presenting with PD: Assessment of penile length should be performed on the stretched flaccid penis. Dorsal length is measured from pubis to corona by compressing the fat pad. In using these two fixed points a more reliable, repeatable measure is obtained. Plaque location is worthy of noting as to whether it is dorsal, septal, circumferential or ventral as well as distal or proximal. But the size of the plaque has not proven to be a useful parameter and it appears to be impossible to measure accurately with regard to length, width or depth. In addition a recent clinical trial of PotabaÒ (Glenwood-LLC, Englewood, NJ) demonstrated reduction of plaque size but no correlation to improvement of curvature. One of the most important parameters to obtain is an objective measure of erect deformity which should be done directly by the investigator if possible rather than relying on photographs. If duplex ultrasound is available, this can provide information on vascular flow parameters, plaque calcification, erectile response to the vasoactive agent and possibly intracorporeal fibrosis, which if present may result in erectile dysfunction. In addition, deformity should be measured in the maximum erect state with a goniometer or protractor. Girth, can be measured at the base, 1-2 cm proximal to the corona and in the area of indention or narrowing. This can be done with a piece of string, in the maximum erect state. If duplex ultrasound technology is not available, an intracorporeal injection with a vasoactive agent such as papaverine or Trimix can be given in the office to allow measurement of deformity.
Before going to our discussion regarding erectile dysfunction and Peyronie's disease let us review who should be considered candidates for medical therapy. Most experts agree that this would include men with early phase disease, which is defined as less than 12 months from the time of onset. These men may have a deformity or plaque that is changing and may also be experiencing pain with erection. Candidates for medical therapy also include men who are not psychologically ready for or interested in surgery regardless of the duration or severity of their disease.
Erectile dysfunction (ED) is frequently associated with PD. Published reports indicate that between 30 to 80% of men may have ED associated with PD and up to 50% may have ED before they develop PD.,, Erectile dysfunction may predispose to the development of PD in the susceptible individual as the less rigid penis may set up an opportunity for the "at-risk" penis to undergo repetitive bending, which may result in a "metal fatigue-like" fracture within the tunica albuginea resulting in the activation of the disordered healing wound process. It is critical to assess for the presence of erectile dysfunction in any patient presenting with PD as the ED may interfere with the ability to assess the deformity objectively and will certainly have an added impact upon subsequent treatment options. Patients with advanced ED who do not respond to erectogenic medications are unsuitable candidates for nonsurgical therapy and should consider penile prosthesis implantation with straightening maneuvers as necessary.
The etiology of the erectile dysfunction in patients with PD has been studied and presented in the literature. Most objective studies have used either pharmacologic color duplex ultrasound or dynamic infusion cavernosometry cavernosography techniques. These studies have demonstrated repeatedly that the ED found in men with PD is most commonly due to vascular insufficiency similar to the etiology found in the general public with ED alone.,, Arterial insufficiency predominates as the primary etiology with or without venous insufficiency. In addition, some men have no evidence of vascular insufficiency which suggests a psychogenic etiology. This is understandable given the significant psychological distress that this disorder causes which can blunt sexual response. Lastly, Pescatori and associates have suggested that the abnormal penile geometry in some men with PD may cause ED. This is the result of diminished intracorporeal pressure, particularly in men where the length to circumference ratio is unfavorable. These authors have suggested that deformity correction in these circumstances either as a shortening procedure or as a girth enhancement procedure may provide an improved structural environment for increased intracorporeal pressure and better erections.
Diabetes mellitus has been suggested as a potential independent risk factor for PD. Multiple demographic studies have shown that up to 28% percent of men with PD have diabetes mellitus. The prevalence of other vascular risk factors for ED have been reported in PD case series including hypertension (18%) and hyperlipidemia (38%)., Therefore it is no surprise that ED is often found in men with PD.
The evaluation of ED in men with PD should be part of the initial consultation to determine if there is a history of diminished rigidity before or after developing PD. The change in rigidity may be throughout the shaft, segmental particularly in an area of narrowing or present as distal flaccidity. Recently, unpublished reports from two investigators have suggested that the distal flaccidity may be actually due to cavernosal tissue fibrosis (Rossello M. and Levine L.A, unpublished reports 2005). This cavernosal tissue scarring may be a variant form of PD and can be best identified during duplex ultrasound prior to vasoactive injection where surveillance of the cavernosal tissue may reveal a scattered punctate hyperechoic pattern. It may be that as a result of this fibrosis the cavernosal tissue cannot expand and properly activate the veno-occlusive mechanism, resulting in the distal flaccidity in spite of satisfactory arterial inflow and veno-occlusion in the proximal shaft.
A useful question to include in the initial consultation is, "If your penis had no deformity would the rigidity that you currently obtain be adequate for intromission?" At Rush University Medical Center in Chicago, we found in a survey of our patients who had undergone penile reconstruction with incision and pericardial grafting that this question was the most useful parameter allowing prediction of postoperative ED as compared to all other factors assessed, including number or type of vascular risk factors, degree of curvature and graft size. Age over 65 did show a trend towards increased postoperative ED and ventral curvature repair with grafting resulted in ED in 50% of cases. Thirty per cent of men who noted a moderate degree of compromise in their erectile capacity before reconstruction with grafting had even further diminished rigidity postoperatively. Men with no vascular risk factors and full preoperative erectile capacity still had a 10% chance of diminished rigidity postoperatively. All of these men responded to PDE5 inhibitor therapy. This type of information can be quite useful in counseling patients whether they should undergo surgical reconstruction with or without placement of a penile prosthesis.
The treatment of men with Peyronie's disease and erectile dysfunction has been controversial. In the current oral erectogenic medication era the PDE5 inhibitors appear to be the best first line treatment. But all three of the FDA approved PDE5 inhibitors (e.g., sildenafil, vardenafil, tadalafil) have cautionary notes in their package inserts regarding use of these agents for men with PD. This is because men with PD were not formally studied during clinical trials. On the other hand, there is one published open-label study of 73 men with PD and ED who were given sildenafil for ED. Curvature in this population was typically less than 60 degrees as it was assumed that this curvature would be less likely to interfere with penetrative sex. Patients were given sildenafil and allowed to titrate to 100 milligrams. Treatment satisfaction was determined by interview in the office as well as using a modified treatment satisfaction (EDITS) questionnaire. Overall 71% were satisfied with their erectile response. Importantly, there was no new pain or exacerbation of deformity.
Sildenafil has also been used as an agent for postoperative rehabilitation following penile reconstruction with incision and grafting. This is contrary to the previous recommendation of suppressing erectile activity postoperatively to reduce the risk of graft disruption, hematoma formation and pain. The goal of rehabilitation in the PD patient following penile reconstruction with grafting is to enhance nocturnal erections to nourish the graft and prevent fibrosis in the healing cavernosal tissue. This concept was examined in a noncontrolled trial comparing men who received sildenafil 25 mg nightly for 40 nights beginning one week after surgery versus those who did not receive it. Overall there was a trend of reduced erectile dysfunction in those who received rehabilitation. Clearly, further study will be necessary to validate this concept.
PDE 5 inhibitors have also been shown experimentally to have a potential anti-fibrotic affect. Research in the laboratory of Gonzalez-Cadavid and Rajfer has demonstrated that an elevated nitric-oxide (NO) to reactive oxygen species (ROS) ratio appears to inhibit fibrosis. This has been demonstrated in several models of fibrosis including lung, heart and kidney. When fibroblasts derived from human PD plaques were exposed to PDE 5 inhibitors this resulted in diminished cellular proliferation and reduced collagen production. In animal models it has similarly been shown that when sildenafil and vardenafil were given to animals in their drinking water shortly after an injection of an agent that triggers development of a Peyronie's-like scar, these agents appeared to substantially reduce the development of fibrotic tissue.
The treatment options for ED associated with PD include vacuum constriction devices that have the potential advantage of being noninvasive and provide stretching forces on the penis which theoretically enhances straightening. Although several cases of PD have been reported as a result of vacuum therapy used to treat ED, there is evidence that the vacuum tube, when used daily may reduce curvature by applying mechanical forces to the penis. It is also important to recognize that all of the available treatments for ED may create an opportunity for a more rigid penis to be injured during coital activity, activating PD in the susceptible individual. Alprostadil (PGE1) is available both as an injectable agent and as an intraurethral suppository known as MUSE (e.g., Medicated Urethral System for Erections, Vivus, Mountain View, CA). Alprostadil has the potential advantage of being a TGF-beta inhibitor, which is the most recognized cytokine involved in the early phases of wound healing that stimulates fibrosis. In spite of this potential advantage I am reluctant to use intracavernosal injection therapy to enhance erections with any agent in men with acute phase PD, as there is the potential risk of increased scarring within the cavernosal tissue as well as in the tunic.
As previously noted, men who have preoperative ED and are unresponsive to erectogenic medication or have advanced distal flaccidity, should be offered implantation of a penile prosthesis which simultaneously addresses the ED and allows correction of curvature. Only a few papers have been published on the outcomes following penile prosthesis for ED associated with PD.,,, One surgical algorithm suggested that a progression of more advanced treatments should be employed as follows: once the prosthesis is placed, curvature should be assessed and if it is less than 20 degrees no further manipulation is necessary as the prosthesis will act as a tissue expander and correct mild residual curvature over the next three to six months. If there is curvature less than 60 degrees it is highly likely that satisfactory straightening will occur as a result of manual modeling as described by Wilson et al . An attempt at manual modeling is advised in all cases regardless of curvature. But if there is inadequate straightening after modeling then a plaque-releasing incision should be considered to obtain adequate straightening. Grafting the tunica defect is recommended when the defect is greater than two centimeters in diameter to prevent prosthesis herniation and recurrent curvature due to contracture of the defect. I prefer the Tutoplast processed pericardial graft (Mentor Corp, Santa Barbara, CA). Dermal grafts are not recommended as bacteria may lurk in the tissue. It has also been shown that the use of the Ultrex® prosthesis (AMS, Minnetonka, MN) is not advised for men with PD as this prosthesis does not attain sufficient cylinder rigidity for manual modeling and tends to take the shape of its container, allowing persistent deformity.
Overall, the primary goal of this review article was to increase recognition of the frequent association between erectile dysfunction and Peyronie's disease; one disorder may in fact induce the other. Treatments for ED may encourage injury to the rigid penis in the susceptible individual thereby activating PD, and ED, in the patient with PD may occur as a result of unfavorable geometry or most commonly due to underlying vascular disease. The most sensible first-line treatment at this time for ED associated with mild to moderate PD is a PDE5 inhibitor, as they are the least invasive and theoretically may increase the NO/ROS ratio in the penis which can have an antifibrotic effect. Several investigators have encouraged the use of L-arginine (500 mg twice daily) as an enhancer of NO production, to be used with pentoxyfiline (400 mg thrice daily). This agent is a nonspecific PDE inhibitor as well as an inhibitor of TNF (Personal communication Jacob Rajfer, May 2006). In men with more advanced PD who do not respond to erectogenic agents, a penile prosthesis should be offered. On the other hand, for those who do respond to oral erectogenic agents and have curvature which compromises or prohibits penetrative sex, penile reconstruction with plication or grafting are the options. These patients must accept the potential risk of postoperative ED. Clearly, as research provides further insights into the pathophysiology of this disorder, we expect to see more effective treatments for this distressing psychological and physical disorder.
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