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Peyronie's disease: overview and recent treatment advances.

Peyronie's disease is a chronic condition affecting approximately 3% to 9% of adult males and is associated with significant negative effects on physical and psychosocial well-being and quality of life. Historically, treatment has been limited by a lack of understanding of the pathophysiology. Recent advances have led to the first FDA-approved therapy for the treatment of Peyronie's disease. Evaluation, treatment, and management of patients with this condition, including use of an algorithm and pre-/post-treatment questionnaire, will be discussed.

Key Words: Peyronie's disease, penile curvature, plaque, collagenase Clostridium histolyticum, intralesional, advanced practice registered nurse (APRN).

Objectives:

1. Define Peyronie's disease.

2. Discuss the procedure to evaluate for Peyronie's disease.

3. Describe current treatment therapies for Peyronie's disease.

4. Explain advances in treatment therapies for Peyronie's disease.

doi: 10.7257/1053-816X.2015.35.4.164

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Peyronie's disease (PD) was first noted in 1561 by Fallopius and Vesalius (Filkin & Hog, 1999; Ralph & Pryor, 1999). However, credit for describing the condition is given to Francois Gigot de La Peyronie, a surgeon to Louis XIV of France in 1773 (Peyronie, 1743). Peyronie's disease was first characterized as beads of scar tissue that caused the penis to curve upward during erection (Filkin & Hog, 1999). The symptomatic (i.e., pain, penile curvature interfering with penetration) incidence of PD has been estimated at 1%, and the asymptomatic (i.e., palpable plaque) prevalence is estimated between 0.4% to 1.0% (Carson, Jordan, & Gelbard, 1999; Gelbard, Dorey, & James, 1990; Greenfield & Levine, 2005; Lindsay et al., 1991). A questionnaire-based survey sent to 8,000 males (response rate 55.4%) identified a prevalence of 1.5% in males 30 to 39 years of age, 3.0% in the age groups 40 to 49 years and 50 to 59 years, 4.0% in those 60 to 69 years, and 6.5% in males greater than 70 years of age (Schwarzer et al., 2001). Mulhall and colleagues (2004) noted a prevalence of 8.9% in a population of men presenting for prostate cancer screening. The prevalence may be under-estimated due to a reluctance of men to seek treatment because of embarrassment, lack of awareness of available treatments, or because the patient did not feel the symptoms were disabling enough to justify seeking treatment (DiBenedetti, Nguyen, Zografos, Ziemiecki, & Zhou, 2011). Approximately two-thirds of patients will be between 40 and 60 years, with the youngest reported patient being 15 years and the oldest being 80 years (Chilton, Castle, Westwood, & Pryor, 1982; Poley, 1928; Tal, Hall, Alex, Choi, & Mulhall, 2012).

Etiology

The etiology and pathophysiology of PD are not clearly identified. Lack of a true, natural occurring animal model makes understanding of this condition even more difficult (Gur, Limin, & Hellstrom, 2011). However, it appears that a genetic predisposition and/or autoimmunity, trauma, and inflammation may all be involved in the pathogenesis (Gonzalez-Cadavid & Rajfer, 2005).

Trauma

A long-standing theory for the etiology of PD is repeated minor sexual trauma, such as hitting or bumping of the erect penis against the pubic bone (Furey, 1957; Jarow & Lowe, 1997). Furey (1957) hypothesized that rupture of small vessels resulted in small hematomas that were replaced by fibrous tissue. More recently, histologic studies have demonstrated fibrin in the plaque tissue of 18/19 patients with PD that were biopsied but not in tunica obtained in control patients (Somers & Dawson, 1997). Somers and Dawson (1997) have also shown that PD most likely begins with buckling (bending, crumpling) trauma that causes injury to the septal insertion of the tunica albuginea. This trauma results in intravasation of blood into the tunica albuginea with activation of fibrinogen. As a sequela of the trauma, inflammatory cells, including macrophages, neutrophils, and mast cells, migrate to the area along with platelets. A variety of inflammatory mediators, including cytokines, autacoids, vasoactive factors, serotonin, platelet-derived growth factors, and transforming growth factors, are released, which lead to fibrosis. It is thought that the avascular nature of the tunica albuginea may impede the clearance of many of the growth factors, such as transforming growth factorbeta, which increases the fibrotic response (Border, & Noble 1994; Border, & Ruoslahti 1992; Davis, 1997; Diegelmann, 1997; Moreland, 1998; Mulhall, Thorn, Lubrano, & Shankey, 2001; Van de Water, 1997). Down regulation (i.e., decreased function/activity) of matrix metallopreoteinase (enzyme involved in the remodeling of extracellular matrix proteins) has also been implicated as a possible mechanism for the scarring process in PD (Jordan & McCammon, 2012).

Most patients with PD, however, do not give a history of sexual trauma. Thus, although trauma may be involved, it appears that patients must also have an inherited predisposition for the disease (Hinman, 1980).

Genetic Predisposition

Genetic predisposition appears to play a role in the development of PD. A family history of this disease is noted in 2% of patients (Chilton et al., 1982), and there is a significant association with Dupuytren's palmar fibromatosis in 16% to 20% of patients (Bystrom, & Rubio, 1976; Chilton et al., 1982; Ling, 1963). Other associated fibrotic conditions include contracture of the plantar fascia (Ledderhose disease) and tympanosclerosis (Jordan & McCammon, 2012). There also appears to be a relationship with Paget disease of the bone (Lyles et al., 1997). Associations with certain tissue types, including human leukocyte antigen B-27 (HLA-B27) (Ralph et al., 1997). HLA-Al and HLA-DQw2 (Rompel, Weidner, & Mueller-Eckhardt, 1991) and human leukocyte antigen DQ5 (HLA-DQ5) (Nachtsheim, & Rear den, 1996) have been demonstrated as well. In addition, anti-elastin antibodies have been identified in the sera of patients with PD (Stewart, Malta, Sandberg, & Colburn, 1994) and features of cell-mediated immunity in the Peyronie's tissue, suggesting an underlying autoimmune etiology (Ralph, Marikina, Pryor, & Bottazzo, 1996). Thus, there may be a genetic predisposition to PD; however, trauma and an altered immune response also play a role in the etiology.

Arterial Disease

Premature atherosclerosis has been proposed as an initiator of the vasculitis associated with the early stages of PD (Smith, 1969). Additionally, premature aging of the vascular connective tissue may result in an increased susceptibility to minor trauma (Muralidhar, Kumar, Sharma, Sharma & Mardal, 1997). In a review of 1,001 men with PD, medical diagnoses included diabetes mellitus--26%, hypercho lesterolemia--24%, hypertension --17.9%, hyperlipidemia 12%, and ischemic heart disease --8.5%., all risk factors for systemic vascular disease (Kadioglu et al., 2013).

Clinical Presentation

Individuals with PD may present with 1) presence of a plaque or area of induration on the shaft of the penis, 2) penile deformity, both flaccid and erect, 3) penile pain with erection, 4) penile shortening with and without erection, and 5) erectile dysfunction (Jordan & McCammon, 2012). An area of induration or a well-defined plaque is present in all patients with Peyronie's disease; however, 38% to 62% of patients with PD are unaware of the plaque (Burford, Glenn, & Burford, 1946; Bystrom, & Rubio, 1976; Furlow, Swenson, & Lee, 1975; Williams, & Green, 1980). The plaque is most commonly located on the dorsal surface of the penis and is associated with dorsal penile curvature. Patients with dorsal penile curvature up to 45 degrees are often able to remain sexually active. Laterally and ventrally located plaques are less common but are associated with greater coital difficulty due to the greater deviation from the natural coital angle (Ralph & Pryor, 1999). Individuals with multiple plaques located on opposite sides of the penis may not present with complaints of penile deformity but may note penile shortening (Bella, Sener, Foell, & Brock, 2007). Patients with extensive plaque formation and/or circumferential plaques will have an unstable penis due to the resulting hinge effect.

Plaque Calcification

The incidence of plaque calcification has been estimated between 20% and 25% of males with PD (Smith et al., 2009). Other contemporary studies demonstrated occurrence in 34% of men with long-standing or chronic lesions (Bekos et al., 2008; Breyer et al., 2010; Kalokairinou et al., 2012). Levine, Rybak, Corder, and Farrel (2013) noted that plaque calcification did not appear to be an indicator of stable disease because plaque calcification was identified in 37% of patients less than 12 months after the onset of symptoms. It is generally thought that calcified Peyronie's plaques are less responsive to nonsurgical therapies, with several investigators noting that plaque calcification was strongly correlated to progression to surgery (Bekos et al., 2008; Breyer et al., 2010; Serefoglu, Mandava, Sikka, & Hellstrom, 2012). One study noted that calcification alone was not a predictor of the need to progress to surgery unless grade 3 plaque calcification (plaque maximum dimension of [greater than or equal to] 1.5 cm or [greater than or equal to] 2 plaques > 1.0 cm) on penile duplex ultrasonography was noted (Levine et al., 2013). Plaque calcification did not appear to have a significant impact on the degree of penile curvature but did appear to be associated with increased pain (Levine et al., 2013).

Pain may be present in the acute, inflammatory phase of the disease. Though typically not severe in nature, pain is often experienced during erections and may interfere with sexual function. Some individuals may awaken with pain during nocturnal erections. With resolution of the inflammatory phase, pain complaints generally declined within six months, and virtually all men experienced resolution of pain by 18 months (95% of 246 men treated conservatively) (Bella et al., 2007; Levine, & Greenfield, 2003; Mulhall, Schiff, & Guhring, 2006; Pryor et al., 2004; Pryor & Ralph, 2002).

Erectile Dysfunction

The relationship of PD to erectile dysfunction has not been well defined. Erectile dysfunction associated with PD is variable and has been reported in up to 58% of men with Peyronie's disease (Schwarzer et al., 2001). A variety of factors may be involved in erectile dysfunction associated with PD, including psychological factors, anatomic factors related to the penile deformity, and fibrosis, as well as concomitant vascular disease (arteriogenic) and venoocclusive dysfunction (venogenic) (Lopez & Jarow, 1993). Venoocclusive dysfunction is thought to result from lack of compression of the emissary veins by the reduced compliance of the tunic albuginea of the plaque, leading to venous leakage (Levine & Coogan, 1996; Montorsi et al., 1994).

Natural History

Peyronie's disease is a progressive disorder, with up to 48% of men having disease progression if not treated (Mulhall et al., 2006). There are generally two phases of PD: an active first phase and a quiescent secondary phase. The first phase, the active phase, often is associated with painful erections and changing deformity of the penis (Levine & Greenfield, 2003; Mulhall et al., 2006; Pryor et al., 2004; Pryor & Ralph, 2002; Ralph et al., 2010). This phase may last from 6 to 18 months with spontaneous resolution of PD occurring in only 10% to 15% of patients (Gur et al., 2011). In the second phase, the quiescent phase, there is stabilization of the deformity; resolution of painful erections, if present; and overall stability of the process. Up to one-third of patients will present with a sudden development of painless deformity (Jordan & McCammon, 2012).

Evaluation

The diagnosis of PD is clinically determined by the patient's history and penile examination. The key components of the history include the duration of symptoms; nature of the penile curvature, including timing of change in penile deformity; presence of pain; and erectile dysfunction. The physical examination focuses on the penile examination with attention to locating the area of plaque or induration, as well as the consistency of the plaque (i.e., soft, tender, calcified) (Ralph et al., 2010). Ideally, the assessment of penile curvature occurs during an erection, which may require office intracavernous injection of a vasoactive agent or use of the vacuum device. Alternately, the patient can take a photograph of his erect penis at home (Ohebshalom, Mulhall, Guhring, & Parker, 2007). A determination of stretched penile length should be obtained, particularly in individuals considering surgical intervention. Penile shortening is present in almost all patients with PD. Thus, it is important to document the penile length prior to surgical intervention so patients realize that the length loss post-operatively is mainly the result of the PD and not the surgery (Nelson et al., 2008; Rosen et al., 2008; Smith, Walsh, Conti, Turek, & Lue, 2008). Erectile dysfunction is a common finding in patients with PD. Therefore, a detailed history of any arterial risk factors should be noted, as well as an assessment of erectile function, ideally with the validated International Index of Erectile Function-5 (IIEF) questionnaire (Rosen et al., 1997). Additionally, if erectile dysfunction is noted, a vascular assessment using Duplex ultrasound may be helpful to assess for vascular disease (Aversa & Sarteschi, 2007).

The role of the advanced practice registered nurse (APRN) in subspecialty areas, including urology, continues to evolve, with an emphasis on helping provide service and access to care. Nursing staff and APRNs are an important component of the overall evaluation and management of men with PD. Many men may suffer in silence due to self-imposed isolation and embarrassment in discussing such sensitive issues. The use of open, non-judgmental communication by clinicians and the primary care provider can aid in identifying such individuals and facilitate referral to urology. In the urology office, the APRN and staff nurses should feel comfortable taking a sexual history. Asking permission to take a detailed sexual history, as well as the use of open-ended questions, may put the patient at ease.

Most men who present with PD are usually dealing with a cascade of emotions stemming from altered body image to relationship issues to depression and pain. The APRN in the urology setting can be a key asset in helping men navigate through these complex issues. Therefore, educational initiatives that emphasize the importance of increasing education and training to maintain an educational level consistent with the increasing complexity of today's patients are even more vital (Quallich, 2011). While the relationship of PD to erectile dysfunction is unclear, it is conceivable that an alteration in body image may play a role in how men internalize how they are perceived by their partner. Such potential misconceptions can lead to avoidance of intimacy and adversely affect sexual function. Thus, it is crucial during the history component of the evaluation for the clinician to include the patient's partner, with his permission, to try and tease out such issues and the partner's role in sexual intimacy. If there is no partner, the clinician may need to ascertain if the penile curvature or erectile dysfunction problem is a root cause in the lack of intimacy.

Management

The management of PD has been limited by a lack of clear understanding of the etiology and pathophysiology of the condition. Treatment varies with the duration and stability of symptoms (acute versus chronic phase), how bothersome the symptoms are to the patient, and presence/absence of erectile dysfunction. Based on current information regarding the various therapies, our practice has developed an algorithm for use in clinical practice to guide treatment of patients with PD. This algorithm provides a consistent approach to the management of PD based on current literature and evidence-based guidelines (see Figure 1). Traditionally, oral and minimally invasive therapies had been utilized in men who were in the acute phase or who had painful erections. However, until recently, none of these therapies had been approved by the Food and Drug Administration (FDA) for use in the treatment of PD. The goals of such therapies are stabilization of the plaque, decreasing disease progression, and decreasing penile curvature (Jordan, Carson, & Lipshultz, 2014). Their usage has also been extended to treat men in the chronic phase who either decline or are psychologically not prepared for surgery (Levine & Lenting, 1997; Ralph et al., 2010). Such initial therapies have included oral medications, topical agents, intralesional injections, mechanical stretching or vacuum devices, and extracorporeal shockwave therapy (Gur et al., 2011; Raph et al., 2010). There is a lack of high-level, evidence-based research for the use of such therapies. Most of the minimally invasive treatments available lack critical support for effectiveness as a result of the absence of randomized, placebo-controlled trials or non-significant results after randomized clinical trials (RCTs). Mixed or negative results have been published for iontophoresis, oral therapies (vitamin E, potassium para-aminobenzoate, tamoxifen, carnitine and colchine), extracorporeal shockwave therapy, and intralesional injection with verapamil or nicardipine (Jordan et al., 2014). These oral therapies are summarized in Table 1. At the present time, extracorporeal shockwave lithotripsy has not been studied in the United States (Jordan & McCammon, 2012).

Other Non-Invasive Therapy

Electromotive Drug Administration (EMDA)/Iontophoresis

EMDA/iontophoresis, with the topical application of verapamil or verapamil plus dexamethasone, is thought to enhance transcutaneous absorption of the drugs via electrophoresis, electroosmosis, or enhanced diffusion using surface-delivered heat or current (Greenfield, Shah, & Levine, 2007). Treatment sessions are usually two to four times per week over two to three months and are usually well tolerated. One study demonstrated the presence of verapamil in 72% of the tunica albuginea specimens after EMDA (Levine, Estrada, Shou, & Cole, 2003), whereas topical verapamil without EMDA has not been demonstrated to penetrate the tunica albuginea (Martin, Badwan, Parker, & Mulhall, 2002; Ralph et al., 2010).

Minimally Invasive Therapy

Intralesional Injection Therapy

Intralesional injection of corticosteroids was the first form of intralesional injection therapy. Initial use demonstrated favorable results (Ralph et al., 2010); however, subsequent studies failed to reproduce the positive results, and identified side effects of local tissue atrophy and fibrosis (Serefoglu & Hellstrom, 2011). A variety of other medications have been used for intralesional injection, including verapamil, nicardipine, interferon alpha-2b, and more recently, collagenase clostridium histolyticum (CCH) (Jordan et al., 2014) Only collagenase Clostridium histolyticum is FDA-approved for intralesional injection for treatment of PD. Verapamil, a calcium channel blocker, is thought to increase the activity of collagenase, reduce fibroblast proliferation, and inhibit local extracellular matrix production by fibroblasts (Mulhall, Anderson, Lubrano, & Shankey, 2002; Rehman, Benet, & Melman, 1998). Results of intralesional injection of verapamil have demonstrated variable results. A nonrandomized study by Levine, Merrick, and Lee (1994) demonstrated 10 mg of verapamil injected intralesionally decreased pain in 93% of men, and resulted in an objective improvement in curvature in 42% and improvement in erectile dysfunction in 58% of the men. A subsequent six-month randomized, placebo-controlled, single blind study involving 14 subjects, however, showed that while intralesional injection of 10 mg of verapamil per week significantly decreased plaque volume (p < 0.04), it did not significantly improve penile curvature deformity (Rehman et al., 1998). Conversely, another randomized, placebo-controlled study involving 80 individuals over a six-month period demonstrated no statistically significant benefit of intralesional injection of 10 mg of verapamil, two injections per week for three months in plaque size, degree of penile curvature and erectile function (Shirazi, Haghpanah, Badiee, Afrasiabi, & Haghpanah, 2009). An alternative calcium-channel blocker, nicardapine, has also been used for intralesional injection therapy for PD. A randomized controlled trial of nicardipine 10 mg versus saline intralesional injection in 74 patients demonstrated that nicardapine injection, 10 mg every other week for 2.5 months, was superior to saline in decreasing pain (p = 0.019) and plaque size [p < 0.01), as well as improving the International Index of Erectile Function (IIEF) score (Soh et al., 2010).

Interferon has also been used for intralesional injection. Interferons have been shown to decrease production of fibroblasts and collagen in vitro (Hellstrom, 2009). Contradictory results were demonstrated in two randomized trials using interferon alpha intralesional injection for PD. One study demonstrated no statistically significant difference between interferon alpha intralesional injection alone, oral vitamin E alone, or combined therapy in regard to plaque size or degree of curvature (Inal, Tokatli, Akand, Ozdiler, & Yaman, 2006). In a separate randomized study of 117 subjects comparing intralesional injection of interferon alpha to saline, a statistically significant improvement was demonstrated in penile curvature (p < 0.01), plaque size (p < 0.001), and plaque density (p < 0.001) in subjects treated with interferon alpha (Hellstrom et al., 2006). In two other placebo-controlled studies, one involving 21 treated patients (Dang, Matern, Bivalacque, Sikka & Hellstrom, 2004) and the other 13 subjects (Judge & Wisniewski, 1997), interferon alpha decreased penile curvature and pain. Pain resolved in 67.7% of men treated with interferon compared to 28.1% treated with placebo. There was also an improvement of 20% or more in penile curvature in 14 (67%) of 21 patients (no statistical analysis provided) in the Dang et al. (2004) study; pain decreased in 8 out of 10 patients, and 6 out of 10 noted improvement in penile deformity in the study by Judge and Wisniewski (1997). The remaining 3 patients in the study by Judge and Wisniewski (1997) received injection of intralesional saline. Variations in the dose of interferon administered, as well as frequency of intralesional injection, may account for differences in the trial results (Shaw, Mitchell, Tan, Sangkum, & Hellstrom, 2013).

Intralesional Injection of Collagenase Clostridium Histolyticum

In December 2013, collagenase Clostridium histolyticum (Xiaflex[R]) was the first FDA-approved medicine to treat PD specifically for patients with Peyronie's disease with a plaque in the penis that resulted in a curvature of at least 30 degrees upon erection. Two large double blind, randomized, placebo-controlled Phase 3 studies were performed evaluating the clinical efficacy, safety, and tolerability of collagenase Clostridium histolyticum for the treatment of PD (Gelbard et al., 2013). The co-primary outcomes in these two Phase 3 trials were the percent change in the penile curvature abnormality and the change in the PD questionnaire symptom bother score from baseline to 52 weeks. The studies comprised a total of 822 patients (417 and 415). Each treatment cycle included two injections of collagenase Clostridium histolyticum (0.58 mg) or placebo, which were directly injected into the primary plaque at the point of maximal abnormality via a standardized injection technique with an interval of approximately 24 to 72 hours between each injection. Approximately 24 to 72 hours after the second injection of each treatment cycle, patients underwent investigator penile plaque modeling. This modeling involved using the plaque as a fulcrum point, applying steady pressure to elongate and stretch the penis, which was held in this position for 30 seconds. The modeling technique was repeated three times. Patients were instructed to perform a specified home penile modeling three times per day during the six-week period between each treatment cycle. The treatment cycle was repeated after six weeks for up to four treatment cycles. Further treatment cycles were not administered if the penile curvature abnormality was decreased to less than 15 degrees or the investigator determined that further treatment was not clinically indicated (Gelbard et al., 2013).

A post-hoc meta-analysis of the two studies demonstrated that men treated with collagenase Clostridium histolyticum had a statistically significant mean 34% improvement in penile curvature compared to a mean 18.2% improvement in placebo treated men (p < 0.0001). The mean change in PD symptom bother score was significantly improved in treated men versus men on placebo (-2.8 [+ or -] 3.8 vs. -1.8 [+ or -] 3.5, p = 0.0037) (Gelbard et al., 2013). Treatment-related adverse events local to the penis and groin after up to four treatment cycles were found in 84% of those treated with collagenase Clostridium histolyticum compared to 36.3% of those treated with placebo. The most frequently reported adverse events in the collagenase Clostridium histolyticum treatment group included penile ecchymosis, penile swelling, and penile pain. Six men experienced serious treatment-related adverse events, three with corporeal rupture and three with penile hematoma. All six men were treated successfully with surgery. These serious adverse reactions resulted in collagenase Clostridium histolyticum being available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Further, the drug should be administered only by a qualified health care professional that has enrolled and completed training in the administration of collagenase Clostridium histolyticum. Additionally, the health care facility where the drug is administered must be certified (prescribing information, Xiaflex[R]).

The roles of APRNs vary from state to state, and their scope of practice and authority depends on state law. Currently, many APRNs may be involved in teaching men how to perform penile injections for erectile dysfunction and have administered intralesional injections of verapamil for PD. However, the role of the APRN in the administration of intralesional collagenase Clostridium histolyticum is unclear at this time. While current administration may not be possible, these clinicians can and do assist with the education and peri-procedural management of patients with PD. At present, nursing care plans exist for the evaluation and management of erectile dysfunction, but they are not specific to patients with PD (Nursing Care Plan, 2009). Development of a nursing care plan for PD could provide a systematic method for a nursing approach to the evaluation and management of this condition. In anticipation of APRNs administering intralesional injection of collagenase Clostridium histolyticum in the future, a pre-/posttreatment evaluation questionnaire was developed by our practice to review with the patients.

Validated questionnaires, such as the International Index of Erectile Dysfunction (Rosen et al, 1997), exist in identifying men with erectile dysfunction. Guidelines also exist regarding the evaluation and management of men with erectile dysfunction (American Urological Association [AUA], 2005). More recently, a Peyronie's Disease Questionnaire has been validated. This 15-question self-reported survey measures the impact and severity of PD symptoms in terms of psychological and physical symptoms, pain, and symptom bother (Hellstrom et al., 2013). This tool could be utilized by an APRN when evaluating and treating patients with PD; however, it is not specific to the treatment with collagenase Clostridium histolyticum. Thus, a questionnaire was developed in our practice for use by the APRN to counsel patients so they have a clearer understanding of goals of care, expectations, and treatment outcomes with collagenase Clostridium histolyticum therapy (see Table 2). This questionnaire has not been validated. However, specific questions and validated assessment tools have been demonstrated to be helpful, particularly if there is no partner, to help the patient feel more comfortable answering the specifics of his disease process (Hartzell, 2014). It is hoped this questionnaire will prove beneficial for both the patient and the urology staff, and improve patient experience and outcomes.

Surgical Management

Surgical management of PD is indicated for patients with deformity that impairs sexual function, such as severe penile curvature, penile instability due to an hourglass deformity, or other narrowing deformities. Patients who have failed minimally invasive therapy, have underlying refractory erectile dysfunction, have stable disease, or who desire rapid and reliable results may be surgical candidates as well (Kadioglu, Kucukdurmaz, & Sanli, 2011; Ralph et al., 2010). The goal of surgical treatment is to straighten the penile curvature deformity, preserve or restore erectile function, and preserve penile length and girth (Carson & Levine, 2014; Kadioglu et al., 2006; Kumar & Nehra, 2009). The choice of surgical procedure will need to take into consideration the extent of the plaque, location, degree of penile curvature deformity, and the baseline erectile function (Kadioglu et al., 2011; Kumar & Nehra, 2009; Levine & Lenting, 1997; Tornehl & Carson, 2004). Extensive pre-operative counseling is recommended to ensure the patient has realistic expectations and understands that the main goal of surgery is to correct the curvature deformity rather than restoration to the pre-PD state (Kadioglu et al., 2006, 2011). Surgical procedures for the management of PD include tunical shortening, tunical lengthening (plaque incisions or partial excision and grafting), and insertion of penile prosthesis (Kadioglu et al., 2006). The choice of procedure will vary with severity of penile curvature, penile length, and erectile function.

Tunical shortening procedures are the least invasive surgical procedure and are considered when there is adequate erectile function pre-operative with or without pharmacologic therapy, adequate penile length, penile curvature less than 60 degrees, or distal penile curvature without an hour glass deformity or hinge, and the shortening will not lead to a loss of length greater than 20% of total erect length (Ralph et al., 2010; Kadioglu et al., 2011; Levine & Lenting, 1997). A variety of tunical shortening procedures have been utilized, some of which involve excision of tunica albuginea, such as the Nesbit procedure, whereas others involve plication of the tunica albuginea (Daitch, Angermeier, & Montague, 1999; Ding, Lu, Zhang, Wei, & Ding, 2010; Dugi & Morey, 2010; Friedrich, Evans, Noldus, & Huland, 2000; Gholami & Lue, 2002; Giammusso, Burrello, Branchina, Nicolosi, & Motta, 2004; Lemberger, Bishop, & Bates, 1984; Paez et al., 2007; Rehman, Benet, Minsky, & Melman, 1997; Syed, Abbasi, & Hargreave, 2003; Taylor & Levine, 2008; Van der Horst, Martinez Portillo, Seif, Aiken, & Juenemann, 2004). The primary goal of all of these procedures is to shorten the tunica albuginea of the penis opposite of the Peyronie's plaque to straighten the penis. The penile length, degree (greater than 60 degrees), and direction of the curvature deformity (ventral curve) correlate with length lost after the procedure (Carson & Levine, 2014; Greenfield, Lucas, & Levine, 2006). Patient satisfaction with the Nesbit procedure was reported at 76.2% (Syed et al., 2003), and 100% patients were satisfied with a modified plication procedure (Ding et al., 2010), with penile straightening and improved sexual performance being the primary outcomes determining satisfaction.

Graft incision and grafting, or partial plaque excision and grafting, is indicated for the patient with a complex penile curvature deformity greater than 60 degrees, a large size plaque, a destabilized hourglass or hinge configuration, or a short penile length who can achieve adequate rigidity with or without pharmacologic therapy (Kadioglu et al., 2011; Levine & Lenting, 1997; Ralph et al., 2010). The graft placement restores penile length on the affected side. Complete plaque excision is not recommended due to concerns for disruption of the venocclusive mechanism of the penis, resulting in erectile dysfunction due to a venous leak (Gelbard & Hayen, 1991). A number of grafts have been used, including autologous (derived from the individual's own body), allografts (derived from a donor of the same species), and xenografts (derived from different species) (see Table 3). Due to concerns of the risk of infection and fibrosis, synthetic grafts are not recommended (Carson & Levine, 2014). Success and satisfaction rates vary with the different procedures. Pre-operative erectile function can have a significant impact on post-operative erectile function, which has an effect on patient satisfaction (Levine, Greenfield, & Estrada, 2005; Taylor, Abern, & Levine, 2012). A review of tunical lengthening procedures reported between 2005 and 2010 noted overall satisfaction rates ranging from 35% to 93%, varying with the type of graft and the material used. Autologous graft satisfaction rates ranged from 35% to 93.3%, and allograft satisfaction rates ranged from 75% to 93%. There were limited satisfaction data available for xenografts (Carson & Levine, 2014). One study noted a 100% satisfaction rate with a relaxing incision and fascia lata grafting for PD (Kargi et al., 2004).

Nursing staff play a significant role in the post-operative care of patients undergoing grafting procedures. At approximately two weeks post-operative, the patient and partner are instructed regarding massage and stretch therapy by the nursing staff and/ or physician during an office visit. The patient and partner continue with massage and stretch therapy at home twice a week for four weeks. The procedure involves pulling the penis away from the body while massaging the graft area. In addition, phosphodiesterase type 5 inhibitors (PDE 5 inhibitors) have been recommended starting once a week after surgery and continuing for six weeks. PDE 5 inhibitors, including sildenafil, vardenafil, and tadalafil, are used to enhance nocturnal erections, which will stretch the tissue and increase blood flow to the graft (Levine et al., 2005) Penile traction therapy may also be used to decrease the risk of post-operative penile shortening in patients who have undergone plication and grafting procedures. Traction therapy is usually started two to three weeks post-operative and continued for three months post-operative (Moncata-Iribarren, Jara, Martinez-Salamanca, Cabello, & Hernandez. 2007).

Penile Prosthesis

Placement of an inflatable penile prosthesis is indicated for the patient with PD who has pharmacologic therapy-refractory erectile dysfunction. In addition to placement of the prosthesis, further intervention may be needed to straighten the penis. One study noted that inflatable penile prostheses are associated with greater functional satisfaction and lower rates of persistent penile curvature deformity compared to malleable prostheses (Kadioglu et al., 2011). Guidelines for placement of penile prostheses for PD are available (Levine & Dimitriou, 2000; Ralph et al., 2010). Intra-operative penile modeling is indicated if a penile curvature deformity greater than 30 degrees remains after prosthetic placement. If the penile curvature deformity remains greater than 30 degrees after the modeling procedure, then a plaque-releasing incision should be considered. If the defect post-incision is greater than 2.0 cm, then a graft is recommended to cover the defect to prevent implant herniation or cicatrix contracture (Levine, Benson, & Hoover, 2010). Modeling is performed after the prosthesis is in place and the corporotomies are closed. The prosthesis is inflated, and the penis is bent in the contralateral direction to the curvature to maintain pressure on the bent penis for 30 to 60 seconds. When performing the intra-operative inflation and modeling, a separate reservoir of saline is used, and the tubing between the pumps and cylinders is occluded with rubbershod hemostats to prevent damage to the pump. Care should be taken to avoid pressure on the glans to prevent urethral erosion. The corporotomy should be inspected after the modeling procedure to make sure there has been no disruption of the closure (Ralph et al., 2010). Success rates with penile prosthesis implantation for PD range from 84% to 100% (Austoni et al., 2005; Grasso, Lania, Fortuna, Blanco, & Piacentini 2008; Levine et al., 2010; Levine & Dimitriou, 2000; Shaeer 2011). Partner satisfaction after placement of a penile prosthesis for PD was reported at 60% to 88.8% (Austoni, et al., 2005; Levine & Dimitriou, 2000).

Extensive patient counseling is recommended prior to placement of a penile prosthesis. The APRN can help ensure that the patient and partner have realistic expectations and are aware of the risks associated with placement of a penile prosthesis. Complications associated with penile prostheses include infection, loss of penile length, decreased penile sensitivity, malfunction of the prosthesis, erosion of the prosthesis, and persistent curvature (Carson & Levine, 2014). Post-operative care for placement of a penile prosthesis for PD is similar to that for placement for erectile dysfunction from other causes.

Summary

Peyronie's disease is estimated to affect 3% to 9% of men in the general population and is associated with significant negative effects on physical and psychosocial well-being, and quality of life. Embarrassment and lack of awareness of available treatments may prevent patients from seeking care. A variety of therapies have been used to treat PD with little available evidence to support their usage. Failure to respond to such therapies may result in a number of patients remaining untreated and reluctant to explore further treatment options. Recent advances in the understanding of the pathophysiology of PD have resulted in the first FDA-approved therapy for this condition. Evaluation and treatment algorithms may assist in providing a systematic way to evaluate and treat patients with PD (see Figure 1). Nurses and APRNs play an important role in the evaluation and management of patients with PD. In time, it is possible that intralesional injection of collagenase Clostridium histolyticum may be performed by qualified APRNs. For now, use of a questionnaire to evaluate treatment expectations, goals of care, and responses of patients undergoing collagenase Clostridium histolyticum intralesional injections for Peyronie's disease can assist nursing staff/APRNs in their assessment process.

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Smith, J.F., Shindel, A.W., Huang, Y.C., Clavijo, R.I., Flechner, L., Breyer, B.N. ... Lue, T.F. (2011) Pentoxifylline treatment and penile calcifications in men with Peyronie's disease. Asian Journal of Andrology, 33(2), 322-325.

Smith, J.F., Walsh, T.J., Conti, S.L., Turek, P., & Lue T. (2008). Risk factors for emotional and relationship problems in Peyronie's disease. Journal of Sexual Medicine, 5(9), 2179-2184.

Soh, J., Kawauchi, A., Kanemitsu, N., Naya, Y., Ochiai, A., Naitoh, Y., ... Miki, T. (2010). Nicardipine vs. saline injection as treatment for Peyronie's disease: A prospective, randomized, single-blind trial. Journal of Sexual Medicine, 7(11), 3743-3749.

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Jacqueline Pires, BA, is a Second-Year Medical Student, University of Massachusetts Medical School, Worcester, MA.

Michelle Travis, MSN, FNP-BC, CUNP, is an Advanced Practice Nurse/Nurse Practitioner in the Urology Division at the Providence Veteran's Administration Hospital and Rhode Island Hospital, Providence, RI.

Pamela Ellsworth, MD, is a Professor of Urology; Vice-Chair, Department of Urology; Chief, Division of Pediatric Urology, UMassMemorial Medical Center, University of Massachusetts Medical School, Worcester, MA.

Table 1.
Oral Therapies Used for the Treatment of Peyronie's Disease (Not FDA
Approved)

                            Method of
       Drug               Administration         Mechanism of Action

Vitamin E             Divided doses 800 to     Antioxidant effect,
                      1,000 units per day      involves scavenging
                      (Jordan &                free radicals thought
                      McCammon, 2012).         to contribute to the
                                               fibrosis seen in PD
                                               (Gur, Limin, &
                                               Hellstrom, 2011).

POTABA (potassium     3 grams orally four      Anti-fibrotic agent
para-aminobenzoate)   times a day (12 gm       with monoamine-oxidase
                      total per day) (Jordan   activity.
                      & McCammon, 2012).

Tamoxifen             20 mg orally twice a     Modulation of
                      day (Jordan &            transforming growth
                      McCammon, 2012).         factor beta secretion
                                               from fibroblasts,
                                               thereby decreasing
                                               fibrogenesis within the
                                               tunica albuginea
                                               (Hellstrom, 2009).

Colchicine            0.6 mg orally three      Antimucrotubule agent
                      times a day with meals   thought to treat
                      (Jordan &                Peyronie's disease
                      McCammon, 2012).         through inhibition of
                                               collagen secretion from
                                               fibroblasts and
                                               increasing collagenase
                                               activity (Hellstrom,
                                               2009).

Acetyl esters of      1,000 mg (1 gm) orally   Proposed to inhibit
carnitine--acetyl-    twice a day (Biagiotti   acetyl coenzyme-A
L-carnitine and       & Cavallini, 2001).      yielding
propionyl-L-                                   antiproliferative
carnitine                                      effect on human
                                               endothelial cells which
                                               may effect inflammation
                                               and fibrosis
                                               (Gur et al., 2011;
                                               Biagiotti & Cavallini,
                                               2001).

Pentoxifylline        400 mg orally twice a    Nonselective
                      day (Safarinejad,        phosphodiesterase
                      Asgari, Hosseini, &      inhibitor with anti-
                      Dadkhah, 2010).          inflammatory and anti-
                                               fibrogenic properties.
                                               It acts to prevent
                                               TGF-beta-mediated
                                               inflammation and
                                               plaque deposition of
                                               type 1 collagen
                                               (Safarinejad et al.,
                                               2010).

Coenzyme Q            300 mg daily             Anti-oxidant and anti-
                      (Safarinejad et al.,     inflammatory
                      2010).                   properties and is
                                               thought to regenerate
                                               other antioxidants
                                               within the body
                                               (Safarinejad et al.,
                                               2010).

       Drug                Study Results             Side Effects

Vitamin E             First used for PD in      Conflicting evidence
                      1949.                     as to long-term
                      In RCTs vitamin E         cardiovascular
                      treatment alone not       effects at large
                      superior to placebo       doses used by
                      (Hashimoto et al.,        urologists for PD.
                      2006; Safarinejad,        (Abner, Schmitt, &
                      Hosseini, & Kolahi,       Mendiondo, Marcum, &
                      2007).                    Kryscio, 2011; Gerss
                                                & Kopcke, 2009).

POTABA (potassium     2005 RCT--significant     Gastrointestinal upset
para-aminobenzoate)   decrease in plaque        and photosensitivity
                      size vs PBO over 12       (expensive).
                      months--but no
                      significant improvement
                      in erectile
                      curvature from baseline
                      (Peyronie's
                      Disease Study Group
                      of German Urologists;
                      Weidner, Hauck, &
                      Schnitker, 2005).

Tamoxifen             No statistically          Headaches, nausea,
                      significant benefit       vomiting, decreased
                      over placebo in RCTs      libido.
                      (Teloken et al., 1999).

Colchicine            RCT of 84 patients--no    Gastrointestinal
                      superiority over          adverse effects.
                      PBO over 4 month of
                      treatment (Safarinejad,
                      2004).
                      When used with
                      vitamin E, is superior
                      to ibuprofen
                      monotherapy, including
                      statistically
                      significant
                      improvements in
                      plaque size and penile
                      curvature in patients
                      with early stage
                      Peyronie's disease.
                      (Prieto Castro et al.,
                      2003).

Acetyl esters of      Mixed results in          Well tolerated.
carnitine--acetyl-    clinical trials. An RCT
L-carnitine and       in 2001 demonstrated
propionyl-L-          statistically
carnitine             significant improvement
                      in penile curvature vs
                      tamoxifen (Biagiotti et
                      al., 2001). A trial in
                      2002 demonstrated
                      efficacy in treating
                      advanced and resistant
                      Peyronie's disease
                      when used in
                      combination with
                      verapamil intralesional
                      injection, which was
                      superior to tamoxifen
                      plus verapamil
                      intralesional injection
                      (Cavallini, Biagiotti,
                      Koverech, & Vitali,
                      2002). RCT in 2007
                      showed no superiority
                      to placebo, either
                      alone or in
                      combination with
                      vitamin E (Safarinejad
                      et al., 2007).

Pentoxifylline        2010 RCT                  Nausea, vomiting and
                      demonstrated              dyspepsia; blood
                      improvement in penile     pressure needs to be
                      curvature, plaque area    monitored due to
                      and international index   potential for
                      of erectile function      hypotension due to
                      (IIEF) score vs PBO       peripheral
                      (Safarinejad et al.,      vasodilation.
                      2010).                    (Jordan, Carson, &
                      A retrospective cohort    Lipshultz, 2014).
                      study found significant
                      improvement in penile
                      calcifications over one
                      year of treatment vs
                      PBO (Smith et al.,
                      2011).

Coenzyme Q            In first RCT, Coenzyme
                      Q demonstrated
                      statistically
                      significant improvement
                      in the IIEF score, mea
                      plaque area and penile
                      curvature compared to
                      PBO over the course
                      of 6 months
                      (Safarinejad et al.,
                      2010).

Notes: PD = Peyronie's disease, PBO = placebo, RCT = randomized
controlled trial, vs. = versus.

Table 2.
Peyronie's Pre/Post CCH Treatment Evaluation

                                Pre-     2       4     Cycle   Cycle
          Question               RX    Weeks   Weeks     1       2

What are your goals with this
treatment program?

Have you discussed this with
your partner?

Are you currently sexually
active?

Is your partner supportive?

Have all your questions been
answered?

Do you understand the
potential risks of treatment?

Are you ready to proceed?

Have you seen an improvement
with treatment?

Do you have questions about
home modeling?

Have you had intercourse and
was penetration successful?

                                Cycle   Cycle    1     Post-
          Question                3       4     Year    RX

What are your goals with this
treatment program?

Have you discussed this with
your partner?

Are you currently sexually
active?

Is your partner supportive?

Have all your questions been
answered?

Do you understand the
potential risks of treatment?

Are you ready to proceed?

Have you seen an improvement
with treatment?

Do you have questions about
home modeling?

Have you had intercourse and
was penetration successful?

Source: Developed by Michelle Travis, MSN, FNP-BC, CUNP.

Table 3.
Graft Materials Used for the Surgical Management
of Peyronie's Disease

Type         Material

Autologous   Rectus sheath
             Tunica vaginalis
             Dermal
             Buccal mucosa
             Fascia lata
             Venous patch

Allograft    Pericardium
             Fascia lata
             Dura mata
             Dermis

Xenograft    Bovine pericardium
             Porcine four-layer small intestinal submucosa
             Porcine dermis

Other        Tachosil (haemostatic surgical patch)
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Article Details
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Title Annotation:CNE SERIES
Author:Pires, Jacqueline; Travis, Michelle; Ellsworth, Pamela
Publication:Urologic Nursing
Article Type:Disease/Disorder overview
Date:Jul 1, 2015
Words:10273
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