G Model
ARTICLE IN PRESS
MAT 6188 1–3
Maturitas xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
1
Mini Review
2
Peyronie’s disease: Review and recent advances
3
Q1
Joshua P. Langston a,∗ , Culley C. Carson III b
4
Q2
a
5
b
Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Rhodes Distinguished Professor of Urology, Chief of Urology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
6
7 20
a r t i c l e
i n f o
a b s t r a c t
8 9 10 11 12 13
Article history: Received 5 May 2014 Received in revised form 27 May 2014 Accepted 28 May 2014 Available online xxx
14
19
Keywords: Peyronie’s disease Erectile dysfunction Penile curvature Penile plaque
21
Contents
15 16 17 18
22 23 24 25 26 27 Q3 28 29 30 31
Peyronie’s disease is an incurable, sexually debilitating fibrotic disease of the penis that results in penile curvature, coital failure, and significant psychological stress for patients and their partners. Appropriate treatment should be individualized and tailored to the patient’s goals and expectations, disease history, physical exam findings, and erectile function. While medical treatments exist, there is little evidence to support their use. High-quality data supporting more recent advances in injectable therapies, interferon ␣-2b and collagenase clostridium histolyticum, show great promise for their application. Once the disease has stabilized, surgical correction is also an excellent option for patients with significant Peyronie’s disease accompanied by functional impairment. Outcomes are satisfactory when proper treatment decisions are made, with the goal being expected return to normal sexual function following treatment. © 2014 Published by Elsevier Ireland Ltd.
1. 2. 3. 4. 5.
Minimally invasive treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00
32 33 34 35 36 37 38 39 40 41
Peyronie’s disease (PD) is a fibrotic disease of the tunica albuginea of the penis which causes penile curvature with a loss of coital function in many patients. This physically and psychologically devastating disease is thought to occur in roughly 7–9% of the male population [1,2] though this may increase up to 20% in men who have concomitant diabetes and erectile dysfunction [3]. In large series, the mean age of diagnosis is 57.4 years and the incidence clearly increases with aging [2,4]. The scar-like plaques that form in the dense tunica are hypothesized to occur
∗ Corresponding author at: 2113 Physicians Office Building, CB 7235, 170 Manning Drive, Chapel Hill, NC 27599-7235, United States. Tel.: +1 919 966 8217; fax: +1 919 966 0098. E-mail address: [email protected] (J.P. Langston).
because of abnormal wound healing in response to repeated microtrauma during intercourse. This is thought to be exacerbated by inflammatory conditions and/or genetic predisposition, though the ultimate pathophysiology is not well understood [5]. Clinically, the plaques are often palpable and present with penile curvature, “hour-glass deformity” of the penis – which may occur without curvature – and/or erectile dysfunction (ED) which may present in its usual form, or manifest only as flaccidity distal to the plaque. Presentation can also include significant penile pain with erection, though this should not be present in the flaccid state. The clinical course of PD includes an active and quiescent phase. The active portion is an inflammatory state characterized by painful erections, an evolving plaque, and progressive penile curvature, and usually lasts 12–24 months from the time of onset. Reports have shown that the vast majority of men (94%) will experience resolution of coital pain within 18 months [2]. The quiescent phase is characterized by stability of the penile deformity, resolution of
http://dx.doi.org/10.1016/j.maturitas.2014.05.024 0378-5122/© 2014 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Langston JP, Carson III CC. Peyronie’s disease: Review and recent advances. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.024
42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
G Model MAT 6188 1–3
J.P. Langston, C.C. Carson III / Maturitas xxx (2014) xxx–xxx
2
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
81
82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
ARTICLE IN PRESS
penile pain, and in some, the onset of ED. Both historic [6] and more current [7] reports have confirmed that without treatment only 12–13% of men will improve, roughly 40–48% will worsen, and 40–47% will maintain a stable deformity. Given these findings, along with the well-documented psychosocial implications of the disease, men for hundreds of years have sought treatment for this debilitating condition. Ultimately, treatment is designed to improve coital function and result in a satisfactory, comfortable erection for both patient and partner. Importantly, the physician should establish early on that return to a completely straight erection is unlikely, and should focus the conversation of recovery of function. The spectrum of treatment spans from oral medications to surgical intervention, though most patients prefer minimally invasive options prior to surgery. As a rule, surgery should be avoided during the active phase of the disease. Montorsi et al. have recommended waiting at least 12 months from the end of the active phase of PD before considering surgery [8]. Non-surgical therapies have included oral medications, topical applications, intralesional injections, extracorporeal shockwave therapy, ultrasound, and actually began with de la Peyronie’s original recommendation to bathe in the warm waters of Barèges in Southern France [9].
1. Minimally invasive treatments Non-surgical treatments center around attempting to break the inflammatory and fibrotic cycles that lead to clinical worsening of the disease. Oral agents are desirable for the treatment of PD, but unfortunately there is a lack of high-level evidence in this area to allow for treatment recommendations. Vitamin E, Colchicine, Potaba (potassium paraminobenzoate), Tamoxifen, Carnitine, Pentoxifylline and PDE5 inhibitors have all been studied and are used by some as treatments, however, none is able to show definitive clinical benefit [10,11]. While evidence is lacking for oral treatments there are injection therapies which have shown more conclusive results. Much like the oral medications, injection therapies deliver intra-lesional agents aimed at breaking the inflammatory fibrotic cascade. Historically, the calcium-channel blocker Verapamil has been utilized for its ability to inhibit fibroblast proliferation and function. Several studies have confirmed the benefit of Verapamil, though the degree of benefit has varied. Levine has shown significant improvement in penile curvature using Verapamil injection, accompanied by the important outcome of improved ability to engage in coitus in 87% of study participants [12]. Another study has shown lesser degrees of curvature improvement (18%), but durable stabilization of curve without worsening in 60%, implying that Verapamil may significantly benefit some portion of patients while it prevents worsening in the majority [13]. In addition to Verapamil, Interferon ␣-2b has shown promise in inhibiting fibroblast function. A blinded, placebo-controlled study showed objective improvement in curvature compared to the placebo group (14◦ vs. 5◦ ) [14], but a second study failed to show perceived improvement in their cohort. The newest injectable therapy, collagenase Clostridium histolyticum (CCH), represents the most exciting advance in the treatment of PD in some time. This therapy has already been used to successfully treat Dupuytren’s contracture, a fibrotic disease of the hand, and works by degrading the collagen-based scar that causes penile curvature. Given as a series of intra-lesional injections, two placebo-controlled, double-blind trials have shown significant improvement in curvature compared to placebo (34% vs. 18% and 33% vs. 22%) as well as statistically significant reduction in patient bother score using a validated Peyronie’s questionnaire [15]. Taken as a whole, all available data on CCH would
suggest mean improvements in penile curvature of 15–20◦ [15,16]. Thus, while this represents a promising minimally invasive therapy for PD, those with significant curvature may not achieve functionally satisfactory results and may need to proceed to surgical intervention.
2. Surgical treatment The choice of a surgical procedure depends on each patient’s needs and preferences. Counseling and decision making should be based on the patient’s current coital function, their deformity on physical exam, and their erectile rigidity. Three surgical categories are used for PD patients and the evaluation process must identify which surgery will best serve each unique patient. Corporoplasty, or penile plication, generally has the best outcome with regard to post-operative sexual satisfaction and erectile function [17], but is reserved for patients with simple curvature of 60 or less, and adequate penile length to undergo the additional shortening which may occur with the procedure. Plaque incision and grafting procedures are used for more severe or complex curves, hour-glass deformities, and in men who have already suffered significant penile shortening secondary to PD, as these procedures will lengthen the tunica. Inflatable penile prosthesis (IPP) implantation is reserved for men with PD and refractory ED, or men who prefer this method of treatment. Men with satisfactory erectile function with or without supportive medications are candidates for straightening using either tunical lengthening or shortening techniques [18]. However, the importance of proper preoperative assessment of erectile function cannot be overstated. Mulhall et al. showed that when incision and grafting was used in patients with pre-operative diminished rigidity that was responsive to medical therapy overall sexual satisfaction decreased significantly post-operatively while this was not the case with patients who underwent corporoplasty [19]. Thus, baseline erectile function is important not only in the decision to proceed with IPP placement, but also in deciding between corporoplasty and grafting. As discussed by Nelson et al. the significant psychosocial impact of PD leads many men to a depressed state with poor self-image and thus many will have overly optimistic expectations as to what is attainable with surgical reconstruction [20]. Because of this, the pre-operative discussion needs to be frank and include details as to realistic expectations and surgical limitations.
3. Summary Peyronie’s disease in an incurable, sexually debilitating disease that results in penile deformity, coital failure, and significant psychological stress for patients and their partners. Appropriate treatment should be individualized and tailored to the patient’s goals and expectations, disease history, physical exam findings, and erectile function. While medical treatments exist there are few with good evidence to support their use. High-quality data supporting more recent advances in injectable therapies, especially collagenase, shows great promise for their application. Once the disease has stabilized, surgical correction is also an excellent option for patients with significant PD accompanied by functional impairment. Outcomes are satisfactory when proper treatment decisions are made, with the goal being expected return to normal sexual function following PD treatment. Overall there remains a great deal of work to do in the understanding and treatment of PD, however, with recent advancements in injectable therapies and well-refined options for surgical intervention, men should be encouraged to seek treatment for this physically and
Please cite this article in press as: Langston JP, Carson III CC. Peyronie’s disease: Review and recent advances. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.024
121 122 123 124 125
126
127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160
161
162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
G Model MAT 6188 1–3
ARTICLE IN PRESS J.P. Langston, C.C. Carson III / Maturitas xxx (2014) xxx–xxx
181
psychologically debilitating disease, as a growing number of solutions do exist.
182
4. Practice points
180
3
Provenance and peer review Commissioned and externally peer reviewed. Appendix A. Supplementary data
195
• Peyronie’s disease in an incurable, sexually debilitating disease resulting in penile deformity, coital failure, and significant psychological stress for patients and their partners. • Incidence increases with aging, and recent reports show that it affects a larger portion of the population than previously thought. • Numerous medical treatments exist with mixed efficacy and relatively poor data, however, recent Level 1 data supporting injectable collagenase shows great promise for a robust minimally invasive treatment. • Good surgical options exist for PD patients. Regardless of preoperative degree of curvature and erectile dysfunction outcomes can be satisfactory for restoration of function in accordance with the patient’s goals and preferences.
196
5. Future research
183 184 185 186 187 188 189 190 191 192 193 194
197 198 199 200 201 202 203 204 205 206 207 208 209 210
211 Q3
• The etiology of Peyronie’s remains unclear. Research into the mechanisms underlying the initial insult and active phase will allow for development of therapies targeted to this early phase of the disease. • The newest injectable medication, XIAFLEX® (collagenase clostridium histolyticum), has been approved for use in nonventral plaques in the chronic phase of the disease. Further investigation is needed to determine if injection for ventral plaques is safe and effective and if treatment earlier in the natural history of the disease could produce more favorable outcomes. • Oral therapies have little substantiated evidence for their use as most studies have small sample size or are retrospective. Further concerted, multi-institutional efforts are needed to discern the proper use of oral therapy for Peyronie’s disease. Contributors
216
Joshua Langston – source review, primary authorship of text; Culley Carson – review and revision of manuscript, subject matter expertise; Joshua P Langston – none; Culley C. Carson – consultant and speaker for American Medical Systems, Auxilium, GlaxoSmithKline, and Lilly.
217
Competing interest
212 213 214 215
218
219
None declared. Funding The authors have received no funding for this article.
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.maturitas.2014.05.024. References [1] La Pera G, Pescatori ES, Calabrese M, et al. Peyronie’s disease: prevalence and association with cigarette smoking. A multicenter population-based study in men aged 50–69 years. Eur Urol 2001;40(5):525–30. [2] Mulhall JP, Creech SD, Boorjian SA, et al. Subjective and objective analysis of the prevalence of Peyronie’s disease in a population of men presenting for prostate cancer screening. J Urol 2004;171:2350. [3] Arafa M, Eid H, El-Badry A, Ezz-Eldine K, Shamloul R. The prevalence of Peyronie’s disease in diabetic patients with erectile dysfunction. Int J Impot Res 2007;19(2):213–7. [4] Schwarzer U, Sommer F, Klotz T, et al. The prevalence of Peyronie’s disease: results of a large survey. BJU Int 2001;88:727–30. [5] Gonzalez-Cadavid NF, Rajfer J. Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie’s disease. Nat Clin Pract Urol 2005;2(6):291–7. [6] Gelbard MK, Dorey F, James K. The natural history of Peyronie’s disease. J Urol 1990;144:1376–9. [7] Mulhall JP, Schiff J, Guhring P. An analysis of the natural history of Peyronie’s disease. J Urol 2006;175:2115. [8] Montorsi F, Salonia A, Maga T, et al. Evidence-based assessment of longterm results in plaque incision and vein grafting for Peyronie’s disease. J Urol 2000;163:1704–8. [9] Carson CC. Francois Gigot de la Peyronie (1678–1747). Invest Urol 1981;19:62. [10] Ralph D, Gonzalez-Cadavid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med 2010;7: 2359–74. [11] Jordan GH, Carson CC, Lipshultz LI. Minimally invasive treatment of Peyronie’s disease: evidence-based progress. BJU Int 2014 [epub ahead of print]. [12] Levine LA. Treatment of Peyronie’s disease with intralesional verapamil injection. J Urol 1997;158:1395. [13] Bennett N, Guhring P, Mulhall J. Intralesional verapamil prevents the progression of Peyronie’s disease. Urology 2007;69:1181. [14] Hellstrom W, Kendirci M, Matern R, et al. Single-blind, multicenter, placebocontrolled, parallel study to assess. J Urol 2006;176:394. [15] Gelbard M, Goldstein I, Hellstrom W, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol 2013;190:199. [16] Gelbard M, Lipshultz L, Tursi J, Smith T, Kaufman G, Levine L. Phase 2b study of clinical efficacy and safety of collagenase clostridium histolyticum in patients with Peyronie’s disease. J Urol 2012;187:2268. [17] Kim D, Lesser T, Aboseif S. Subjective patient-reported experiences after surgery for Peyronie’s disease: corporeal plication versus plaque incision with vein graft. Urology 2008;71:698. [18] Carson CC, Levine L. Outcomes of surgical treatment of Peyronie’s disease. BJU Int 2014;113:704. [19] Mulhall J, Anderson M, Parker M. A surgical algorithm for men with combined Peyronie’s disease and erectile dysfunction: functional and satisfaction outcomes. J Sex Med 2005;2:132. [20] Nelson CJ, Diblasio C, Kendirci M, Hellstrom W, Guhring P, Mulhall J. The chronology of depression and distress in men with Peyronie’s disease. J Sex Med 2008;5:1985.
Please cite this article in press as: Langston JP, Carson III CC. Peyronie’s disease: Review and recent advances. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.024
220
221
222
223 224 225
226
227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277
ARTICLE IN PRESS
MAT 6188 1–3
Maturitas xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
1
Mini Review
2
Peyronie’s disease: Review and recent advances
3
Q1
Joshua P. Langston a,∗ , Culley C. Carson III b
4
Q2
a
5
b
Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Rhodes Distinguished Professor of Urology, Chief of Urology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
6
7 20
a r t i c l e
i n f o
a b s t r a c t
8 9 10 11 12 13
Article history: Received 5 May 2014 Received in revised form 27 May 2014 Accepted 28 May 2014 Available online xxx
14
19
Keywords: Peyronie’s disease Erectile dysfunction Penile curvature Penile plaque
21
Contents
15 16 17 18
22 23 24 25 26 27 Q3 28 29 30 31
Peyronie’s disease is an incurable, sexually debilitating fibrotic disease of the penis that results in penile curvature, coital failure, and significant psychological stress for patients and their partners. Appropriate treatment should be individualized and tailored to the patient’s goals and expectations, disease history, physical exam findings, and erectile function. While medical treatments exist, there is little evidence to support their use. High-quality data supporting more recent advances in injectable therapies, interferon ␣-2b and collagenase clostridium histolyticum, show great promise for their application. Once the disease has stabilized, surgical correction is also an excellent option for patients with significant Peyronie’s disease accompanied by functional impairment. Outcomes are satisfactory when proper treatment decisions are made, with the goal being expected return to normal sexual function following treatment. © 2014 Published by Elsevier Ireland Ltd.
1. 2. 3. 4. 5.
Minimally invasive treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00
32 33 34 35 36 37 38 39 40 41
Peyronie’s disease (PD) is a fibrotic disease of the tunica albuginea of the penis which causes penile curvature with a loss of coital function in many patients. This physically and psychologically devastating disease is thought to occur in roughly 7–9% of the male population [1,2] though this may increase up to 20% in men who have concomitant diabetes and erectile dysfunction [3]. In large series, the mean age of diagnosis is 57.4 years and the incidence clearly increases with aging [2,4]. The scar-like plaques that form in the dense tunica are hypothesized to occur
∗ Corresponding author at: 2113 Physicians Office Building, CB 7235, 170 Manning Drive, Chapel Hill, NC 27599-7235, United States. Tel.: +1 919 966 8217; fax: +1 919 966 0098. E-mail address: [email protected] (J.P. Langston).
because of abnormal wound healing in response to repeated microtrauma during intercourse. This is thought to be exacerbated by inflammatory conditions and/or genetic predisposition, though the ultimate pathophysiology is not well understood [5]. Clinically, the plaques are often palpable and present with penile curvature, “hour-glass deformity” of the penis – which may occur without curvature – and/or erectile dysfunction (ED) which may present in its usual form, or manifest only as flaccidity distal to the plaque. Presentation can also include significant penile pain with erection, though this should not be present in the flaccid state. The clinical course of PD includes an active and quiescent phase. The active portion is an inflammatory state characterized by painful erections, an evolving plaque, and progressive penile curvature, and usually lasts 12–24 months from the time of onset. Reports have shown that the vast majority of men (94%) will experience resolution of coital pain within 18 months [2]. The quiescent phase is characterized by stability of the penile deformity, resolution of
http://dx.doi.org/10.1016/j.maturitas.2014.05.024 0378-5122/© 2014 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Langston JP, Carson III CC. Peyronie’s disease: Review and recent advances. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.024
42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
G Model MAT 6188 1–3
J.P. Langston, C.C. Carson III / Maturitas xxx (2014) xxx–xxx
2
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
81
82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
ARTICLE IN PRESS
penile pain, and in some, the onset of ED. Both historic [6] and more current [7] reports have confirmed that without treatment only 12–13% of men will improve, roughly 40–48% will worsen, and 40–47% will maintain a stable deformity. Given these findings, along with the well-documented psychosocial implications of the disease, men for hundreds of years have sought treatment for this debilitating condition. Ultimately, treatment is designed to improve coital function and result in a satisfactory, comfortable erection for both patient and partner. Importantly, the physician should establish early on that return to a completely straight erection is unlikely, and should focus the conversation of recovery of function. The spectrum of treatment spans from oral medications to surgical intervention, though most patients prefer minimally invasive options prior to surgery. As a rule, surgery should be avoided during the active phase of the disease. Montorsi et al. have recommended waiting at least 12 months from the end of the active phase of PD before considering surgery [8]. Non-surgical therapies have included oral medications, topical applications, intralesional injections, extracorporeal shockwave therapy, ultrasound, and actually began with de la Peyronie’s original recommendation to bathe in the warm waters of Barèges in Southern France [9].
1. Minimally invasive treatments Non-surgical treatments center around attempting to break the inflammatory and fibrotic cycles that lead to clinical worsening of the disease. Oral agents are desirable for the treatment of PD, but unfortunately there is a lack of high-level evidence in this area to allow for treatment recommendations. Vitamin E, Colchicine, Potaba (potassium paraminobenzoate), Tamoxifen, Carnitine, Pentoxifylline and PDE5 inhibitors have all been studied and are used by some as treatments, however, none is able to show definitive clinical benefit [10,11]. While evidence is lacking for oral treatments there are injection therapies which have shown more conclusive results. Much like the oral medications, injection therapies deliver intra-lesional agents aimed at breaking the inflammatory fibrotic cascade. Historically, the calcium-channel blocker Verapamil has been utilized for its ability to inhibit fibroblast proliferation and function. Several studies have confirmed the benefit of Verapamil, though the degree of benefit has varied. Levine has shown significant improvement in penile curvature using Verapamil injection, accompanied by the important outcome of improved ability to engage in coitus in 87% of study participants [12]. Another study has shown lesser degrees of curvature improvement (18%), but durable stabilization of curve without worsening in 60%, implying that Verapamil may significantly benefit some portion of patients while it prevents worsening in the majority [13]. In addition to Verapamil, Interferon ␣-2b has shown promise in inhibiting fibroblast function. A blinded, placebo-controlled study showed objective improvement in curvature compared to the placebo group (14◦ vs. 5◦ ) [14], but a second study failed to show perceived improvement in their cohort. The newest injectable therapy, collagenase Clostridium histolyticum (CCH), represents the most exciting advance in the treatment of PD in some time. This therapy has already been used to successfully treat Dupuytren’s contracture, a fibrotic disease of the hand, and works by degrading the collagen-based scar that causes penile curvature. Given as a series of intra-lesional injections, two placebo-controlled, double-blind trials have shown significant improvement in curvature compared to placebo (34% vs. 18% and 33% vs. 22%) as well as statistically significant reduction in patient bother score using a validated Peyronie’s questionnaire [15]. Taken as a whole, all available data on CCH would
suggest mean improvements in penile curvature of 15–20◦ [15,16]. Thus, while this represents a promising minimally invasive therapy for PD, those with significant curvature may not achieve functionally satisfactory results and may need to proceed to surgical intervention.
2. Surgical treatment The choice of a surgical procedure depends on each patient’s needs and preferences. Counseling and decision making should be based on the patient’s current coital function, their deformity on physical exam, and their erectile rigidity. Three surgical categories are used for PD patients and the evaluation process must identify which surgery will best serve each unique patient. Corporoplasty, or penile plication, generally has the best outcome with regard to post-operative sexual satisfaction and erectile function [17], but is reserved for patients with simple curvature of 60 or less, and adequate penile length to undergo the additional shortening which may occur with the procedure. Plaque incision and grafting procedures are used for more severe or complex curves, hour-glass deformities, and in men who have already suffered significant penile shortening secondary to PD, as these procedures will lengthen the tunica. Inflatable penile prosthesis (IPP) implantation is reserved for men with PD and refractory ED, or men who prefer this method of treatment. Men with satisfactory erectile function with or without supportive medications are candidates for straightening using either tunical lengthening or shortening techniques [18]. However, the importance of proper preoperative assessment of erectile function cannot be overstated. Mulhall et al. showed that when incision and grafting was used in patients with pre-operative diminished rigidity that was responsive to medical therapy overall sexual satisfaction decreased significantly post-operatively while this was not the case with patients who underwent corporoplasty [19]. Thus, baseline erectile function is important not only in the decision to proceed with IPP placement, but also in deciding between corporoplasty and grafting. As discussed by Nelson et al. the significant psychosocial impact of PD leads many men to a depressed state with poor self-image and thus many will have overly optimistic expectations as to what is attainable with surgical reconstruction [20]. Because of this, the pre-operative discussion needs to be frank and include details as to realistic expectations and surgical limitations.
3. Summary Peyronie’s disease in an incurable, sexually debilitating disease that results in penile deformity, coital failure, and significant psychological stress for patients and their partners. Appropriate treatment should be individualized and tailored to the patient’s goals and expectations, disease history, physical exam findings, and erectile function. While medical treatments exist there are few with good evidence to support their use. High-quality data supporting more recent advances in injectable therapies, especially collagenase, shows great promise for their application. Once the disease has stabilized, surgical correction is also an excellent option for patients with significant PD accompanied by functional impairment. Outcomes are satisfactory when proper treatment decisions are made, with the goal being expected return to normal sexual function following PD treatment. Overall there remains a great deal of work to do in the understanding and treatment of PD, however, with recent advancements in injectable therapies and well-refined options for surgical intervention, men should be encouraged to seek treatment for this physically and
Please cite this article in press as: Langston JP, Carson III CC. Peyronie’s disease: Review and recent advances. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.024
121 122 123 124 125
126
127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160
161
162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
G Model MAT 6188 1–3
ARTICLE IN PRESS J.P. Langston, C.C. Carson III / Maturitas xxx (2014) xxx–xxx
181
psychologically debilitating disease, as a growing number of solutions do exist.
182
4. Practice points
180
3
Provenance and peer review Commissioned and externally peer reviewed. Appendix A. Supplementary data
195
• Peyronie’s disease in an incurable, sexually debilitating disease resulting in penile deformity, coital failure, and significant psychological stress for patients and their partners. • Incidence increases with aging, and recent reports show that it affects a larger portion of the population than previously thought. • Numerous medical treatments exist with mixed efficacy and relatively poor data, however, recent Level 1 data supporting injectable collagenase shows great promise for a robust minimally invasive treatment. • Good surgical options exist for PD patients. Regardless of preoperative degree of curvature and erectile dysfunction outcomes can be satisfactory for restoration of function in accordance with the patient’s goals and preferences.
196
5. Future research
183 184 185 186 187 188 189 190 191 192 193 194
197 198 199 200 201 202 203 204 205 206 207 208 209 210
211 Q3
• The etiology of Peyronie’s remains unclear. Research into the mechanisms underlying the initial insult and active phase will allow for development of therapies targeted to this early phase of the disease. • The newest injectable medication, XIAFLEX® (collagenase clostridium histolyticum), has been approved for use in nonventral plaques in the chronic phase of the disease. Further investigation is needed to determine if injection for ventral plaques is safe and effective and if treatment earlier in the natural history of the disease could produce more favorable outcomes. • Oral therapies have little substantiated evidence for their use as most studies have small sample size or are retrospective. Further concerted, multi-institutional efforts are needed to discern the proper use of oral therapy for Peyronie’s disease. Contributors
216
Joshua Langston – source review, primary authorship of text; Culley Carson – review and revision of manuscript, subject matter expertise; Joshua P Langston – none; Culley C. Carson – consultant and speaker for American Medical Systems, Auxilium, GlaxoSmithKline, and Lilly.
217
Competing interest
212 213 214 215
218
219
None declared. Funding The authors have received no funding for this article.
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.maturitas.2014.05.024. References [1] La Pera G, Pescatori ES, Calabrese M, et al. Peyronie’s disease: prevalence and association with cigarette smoking. A multicenter population-based study in men aged 50–69 years. Eur Urol 2001;40(5):525–30. [2] Mulhall JP, Creech SD, Boorjian SA, et al. Subjective and objective analysis of the prevalence of Peyronie’s disease in a population of men presenting for prostate cancer screening. J Urol 2004;171:2350. [3] Arafa M, Eid H, El-Badry A, Ezz-Eldine K, Shamloul R. The prevalence of Peyronie’s disease in diabetic patients with erectile dysfunction. Int J Impot Res 2007;19(2):213–7. [4] Schwarzer U, Sommer F, Klotz T, et al. The prevalence of Peyronie’s disease: results of a large survey. BJU Int 2001;88:727–30. [5] Gonzalez-Cadavid NF, Rajfer J. Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie’s disease. Nat Clin Pract Urol 2005;2(6):291–7. [6] Gelbard MK, Dorey F, James K. The natural history of Peyronie’s disease. J Urol 1990;144:1376–9. [7] Mulhall JP, Schiff J, Guhring P. An analysis of the natural history of Peyronie’s disease. J Urol 2006;175:2115. [8] Montorsi F, Salonia A, Maga T, et al. Evidence-based assessment of longterm results in plaque incision and vein grafting for Peyronie’s disease. J Urol 2000;163:1704–8. [9] Carson CC. Francois Gigot de la Peyronie (1678–1747). Invest Urol 1981;19:62. [10] Ralph D, Gonzalez-Cadavid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med 2010;7: 2359–74. [11] Jordan GH, Carson CC, Lipshultz LI. Minimally invasive treatment of Peyronie’s disease: evidence-based progress. BJU Int 2014 [epub ahead of print]. [12] Levine LA. Treatment of Peyronie’s disease with intralesional verapamil injection. J Urol 1997;158:1395. [13] Bennett N, Guhring P, Mulhall J. Intralesional verapamil prevents the progression of Peyronie’s disease. Urology 2007;69:1181. [14] Hellstrom W, Kendirci M, Matern R, et al. Single-blind, multicenter, placebocontrolled, parallel study to assess. J Urol 2006;176:394. [15] Gelbard M, Goldstein I, Hellstrom W, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol 2013;190:199. [16] Gelbard M, Lipshultz L, Tursi J, Smith T, Kaufman G, Levine L. Phase 2b study of clinical efficacy and safety of collagenase clostridium histolyticum in patients with Peyronie’s disease. J Urol 2012;187:2268. [17] Kim D, Lesser T, Aboseif S. Subjective patient-reported experiences after surgery for Peyronie’s disease: corporeal plication versus plaque incision with vein graft. Urology 2008;71:698. [18] Carson CC, Levine L. Outcomes of surgical treatment of Peyronie’s disease. BJU Int 2014;113:704. [19] Mulhall J, Anderson M, Parker M. A surgical algorithm for men with combined Peyronie’s disease and erectile dysfunction: functional and satisfaction outcomes. J Sex Med 2005;2:132. [20] Nelson CJ, Diblasio C, Kendirci M, Hellstrom W, Guhring P, Mulhall J. The chronology of depression and distress in men with Peyronie’s disease. J Sex Med 2008;5:1985.
Please cite this article in press as: Langston JP, Carson III CC. Peyronie’s disease: Review and recent advances. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.024
220
221
222
223 224 225
226
227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277
