INTRODUCTION — Peyronie's disease (PD) is an acquired, localized fibrotic disorder of the tunica albuginea resulting in penile deformity, mass, pain, and, in some men, erectile dysfunction. The disorder is named after Francois Gigot de la Peyronie, surgeon to King Louis XIV, who in 1743 described "rosary beads" of scar tissue extending the full length of the dorsal penis in a treatise on ejaculatory failure [1].
PD can resolve spontaneously in a minority of cases while others have stable disease. However, nearly half of patients will have worsening within one year. PD can be a psychologically and physically disabling disorder, leading to a lower quality of life. Diagnosis is generally straightforward, based on history and physical examination. Ultrasound can also be used to better define the fibrotic plaque and identify calcifications.
Medical treatment options for PD typically include oral or intralesional drug therapy. The efficacy of medical management for PD has improved since the US Food and Drug Administration (FDA) approval of collagenase Clostridium histolyticum (CCH) injection in 2013. In most cases, medical management should be initiated once the diagnosis of PD is made. Surgical management may be considered for patients who have penile deformity compromising sexual function and whose PD has persisted for more than 12 months, and is refractory to medical therapy.
The diagnosis and medical management of PD will be reviewed here. Surgical management of PD and general issues relating to male sexual dysfunction are discussed separately. (See "Surgical management of Peyronie's disease" and "Epidemiology and etiologies of male sexual dysfunction".)
EPIDEMIOLOGY — Many clinicians, including urologists, have the misconception that Peyronie's disease (PD) is a rare condition, based on previous case reports documenting prevalence of ≤1 percent [2,3]. Contemporary estimates are several-fold higher, perhaps partly due to the introduction of phosphodiesterase type 5 (PDE-5) inhibitors for erectile dysfunction leading to improved general awareness among patients and clinicians.
The prevalence of PD is approximately 5 percent in men. Rates range from 3 percent in a community-based survey of 8000 men (mean age 57.8) to 16 percent among 488 men undergoing evaluation for erectile dysfunction (mean age 52.8) [4,5]. In 534 men undergoing routine prostate screening (without a specific urologic complaint), the prevalence of PD was 8.9 percent [6]. The mean age of those with PD was 68.2 years compared with 61.8 years of those without PD.
According to the same community-based survey mentioned above, the prevalence of PD among the 4432 men who responded was 1.5 percent between the ages of 30 and 39, 3 percent between 40 and 49, 3 percent between 50 and 59, 4 percent between 60 and 69, and 6.5 percent over 70 [4].
The true prevalence of PD may be underestimated as men might be reluctant to report a condition to their clinician that they consider embarrassing, and/or older men may accept the condition as a byproduct of aging. In addition, men who do not engage in sexual intercourse, such as those with erectile dysfunction, may not be aware there is a problem, as they may not have deformities of the flaccid penis.
PATHOGENESIS — The underlying pathogenesis of Peyronie's disease (PD) is unknown but is likely multifactorial with an interplay between genetic predisposition, trauma, and tissue ischemia. The underlying lesion of PD is a fibrous plaque(s) that contains excessive collagen, an altered framework of reduced and fragmented elastic fibers, and fibroblastic proliferation that alters penile anatomy. The fibrous plaque causes focal inelasticity and can compromise erectile function. Plaques may be fibrous, contain areas of calcification, or are completely ossified. Most authorities postulate that PD results from repeated minor, and usually unrecognized, blunt trauma to the penis during intercourse.
PD is thought to be due to a localized aberration of the wound healing process. For susceptible individuals, bleeding within the tunica albuginea, trapping of fibrin and inflammatory cells, and overexpression of matrix proteins secondary to upregulation of cytokines and growth factors in the local environment lead to plaque formation [7]. Excess fibrin deposition in response to microvascular injury and upregulation of transforming growth factor (TGF)-1 results in one or more areas of plaque formation (figure 1) [8].
Risk factors — A family history of PD has been observed in 2 percent of patients [9]. Twenty-one percent of patients with PD may also have Dupuytren's contracture [10]. Patterns of gene expression in families with PD and Dupuytren's disease are similar, particularly in regard to collagen degradation, ossification, and myofibroblast differentiation [11].
Genital and/or perineal injuries, radical prostatectomy, plantar fascial contractures, tympanosclerosis, urethral instrumentation, Paget disease, gout, and lipomas have been associated, albeit weakly, with PD [12,13]. Hypertension, smoking, hyperlipidemia, and diabetes have been proposed as risk factors, but they are more likely related to underlying erectile dysfunction, as research does not show a relation between these factors and severity of penile curvature [13]. An association with vascular comorbidities is controversial [5,6,14], as is the role of overt trauma such as penile fracture [15].
Natural history — Although historical data suggested that the natural history of PD is often one of spontaneous resolution with conservative management, contemporary studies have shown that this is incorrect. Untreated PD improves in only 12 percent of men, with 40 to 48 percent of men demonstrating worsening of curvature at 12 months, while curvature remains stable in the remaining men [16]. The mean change was 15 degrees in those in whom curvature improved, while the mean change was 22 degrees in those in whom curvature worsened.
The disease state is divided into an acute (or inflammatory) phase and a chronic phase. The active phase is characterized by changes in penile curvature or deformity, and pain, while stable disease is characterized by an absence of pain and non-progression of deformity.
CLINICAL MANIFESTATIONS — The presenting symptoms of Peyronie's disease (PD) include penile pain, nodule/plaque, indentation, curvature, deformity, or shortening during erection, as well as sexual dysfunction.
Penile pain occurs primarily during erection and usually resolves within 12 to 24 months of PD onset (94 percent of 246 men who did not receive medical or surgical treatment reported complete resolution of pain, mean 18 months) [16].
PD deformities are varied but may manifest as curvature, indentation, palpable plaque or nodule, hourglass narrowing, penile shortening (with or without curvature), or in combination. PD is most evident during erection, as tunical compliance is compromised and the paired corpora cavernosa are unable to expand normally. In a review of 307 men with PD, 46 percent had dorsal curvature, 29 percent lateral, and 9 percent ventral, with the remaining being a combination of curvatures [17].
Severe or complex curvature and compromised penile rigidity may make penetrative intercourse impossible. Erectile dysfunction is present in 20 to 50 percent of men with PD and occurs due to deformity preventing coitus, flail penis (cavernous fibrosis or vascular compromise), performance anxiety (psychological), or impaired erections due to venoocclusive dysfunction. Patient and partner quality of life are significantly impacted, as men with PD are at increased risk of depression, lowered self-esteem, and relationship difficulties (especially maintenance of intimacy or dating), in addition to body-image issues and pain/discomfort [16].
DIAGNOSIS AND ASSESSMENT — Diagnosis is usually apparent from patient history and penile examination. Patients can be given a preliminary diagnosis of Peyronie's disease (PD) when they present with classic symptoms of the disease: penile nodules (plaques), curvature, and/or pain. Possible associated disorders (eg, Dupuytren's contractures or vascular disease) and inciting events (eg, trauma or genitourinary instrumentation) should be evaluated. It is important to define the psychological effect of PD on the patient and partner, as well as determine the extent of associated erectile dysfunction.
Objectively, clinicians may measure penile length, plaque size, and penile curvature. In classical PD, a well-defined plaque or induration is palpable on physical examination, even if the patient is unaware. Among men with PD affecting the dorsal side of the penis, two-thirds will have associated plaque (figure 2) [18]. Lateral or ventral plaques are less common but, when present, can result in more coital difficulties (figure 3). Plaques located primarily in the penile septum, or equally distributed on both the ventral and dorsal aspects of the penis, may cause penile shortening without angulation [19]. Abnormal tissue may extend beyond the palpable lesion or even into the corporal tissue [20]. It is often helpful to have the patient take photographs of the erect penis at home to characterize the deformity. Home photographs should accurately capture the penile deformity, both in terms of the angle and quality of the erection. If the patient cannot or will not produce a home photograph that accurately demonstrates the deformity, office pharmacoerection can be performed.
If the diagnosis of PD is uncertain after history and physical examination, imaging may be helpful. Various imaging modalities have been used to diagnose PD, including ultrasound, plain radiography, computed tomography, and magnetic resonance. Ultrasound has the highest sensitivity for plaques in the tunica albuginea compared with other methods [21]. Penile ultrasonography has additional advantages due to its easy availability, lower cost, and ability to image and quantify both calcified and soft tissue elements of PD including septal and intracavernous fibrosis. Color duplex ultrasound with pharmacoerection is recommended to assess vascular status if a reconstructive procedure is being considered.
Differential diagnosis — Typically the diagnosis of PD is clinically apparent, but infrequently it can present similarly to developmental penile deformities including congenital ventral curvature, chordee without hypospadias, or curvature associated with epispadias. A congenital chordee is a curved erection of the penis without plaque/nodule, usually due to unequal distensibility between the dorsal and ventral aspects of the tunica albuginea during development. By contrast, PD occurs due to acquired lesions/plaques of the tunica albuginea.
Although rare, other conditions such as sclerosing lymphangitis or rare neoplasms (epithelioid or angiosarcomas) have been reportedly confused with PD [22,23].
INDICATIONS FOR UROLOGY REFERRAL — As Peyronie's disease (PD) is an uncommon condition and most primary care clinicians have limited experience in its management, a urology referral is recommended if the condition is suspected [24]. The urologist can coordinate both medical and surgical therapy for PD. Surgical management is considered for patients who have penile deformity compromising sexual function and whose PD has persisted for more than 12 months, and is refractory to medical therapy. (See "Surgical treatment of erectile dysfunction", section on 'Indications'.)
MEDICAL MANAGEMENT — Options for the management of Peyronie's disease (PD) include observation, medical therapy, or surgery, depending upon the severity and psychological impact of the disease. There are few trials examining the efficacy of the available treatment options. Most studies are hampered by low patient numbers, lack of control groups or reproducibility, and/or the inability to distinguish efficacy from spontaneous improvement of the disease process [25]. Critical appraisal of contemporary literature identifies widespread use of inappropriate clinical endpoints, especially improvement in penile pain, as pain resolves spontaneously in the vast majority of patients. Improvement or resolution of penile deformity (curvature measured after an erection elicited by intracavernous injection) remains the gold standard by which therapies should be measured, while rigorous measurement of plaque size as a secondary endpoint may also be useful. It is important to note, however, that a reduction in plaque size does not correlate with reduction in curvature [26,27]. (See 'Natural history' above.)
Critical analysis of nonsurgical approaches indicates that there is no mode of treatment able to relieve all symptoms for men with PD. Although an American Urological Association guideline recommends deferring treatment (other than pain control) until the chronic phase of the disease, [24], we believe that medical intervention during the active phase is beneficial. Thus, early diagnosis and consideration of treatment of PD is important.
Our approach — The following points outline our approach, which are outlined in the algorithm (algorithm 1):
●Obtain a history of characteristic symptoms including penile pain, nodule/plaque, indentation, curvature, hourglass deformity, shortening during erection, and sexual dysfunction.
●Examine the penis, both flaccid and after induced erection (or ask the patient to bring in erection photos), in order to measure curvature and plaques.
●Classify patients as either in the active or stable phase. As discussed above, the active phase is characterized by changes in penile curvature or deformity, and pain with erection, while stable disease is characterized by an absence of pain and non-progression of deformity.
●Patients in the active phase are offered nonsteroidal antiinflammatory drugs (NSAIDS) for pain control or pentoxifylline oral therapy for three months to stabilize the disease. (See 'Pentoxifylline' below.)
•If there is no decrease in penile deformity or other symptoms after three months, we offer intralesional injections of collagenase Clostridium histolyticum (CCH). (See 'Collagenase Clostridium histolyticum' below.)
•If there is improvement in symptoms after three months, we either continue pentoxifylline for six more months, or stop treatment and observe.
●Men with stable disease and mild curvature (≤30 degrees) who have satisfactory erectile function are candidates for observation, although large observational studies and randomized trials are lacking in this patient population. Such patients should be told that PD may progress with worsening curvature or formation of new penile plaques in the future. If mild curvature worsens or causes sexual dysfunction, medical and/or surgical management should be considered.
●Men with stable disease and curvature over 30 degrees are offered intralesional drug therapy. We use CCH after documentation of curvature and other deformities.
●Men with stable disease, severe indentation or hourglass deformity, erectile dysfunction refractory to medical therapy, and large calcification are offered surgical therapy. (See "Surgical management of Peyronie's disease".)
Oral therapy — Oral therapy is indicated in men with penile deformity. We suggest pentoxifylline (400 mg three times daily) as first-line oral therapy.
Pentoxifylline — Pentoxifylline is a nonspecific phosphodiesterase inhibitor. Pentoxifylline decreases transforming growth factor (TGF) beta-1-mediated fibrosis, prevents deposition of collagen type I, and reduces calcification in experimental animals. This agent has been previously used in humans for a variety of inflammatory and fibrotic conditions.
There are few studies evaluating the use of pentoxifylline in the treatment of PD [28-30]. In one report, pentoxifylline was found to improve or stabilize ultrasonographic calcifications (92 versus 44 percent) and decrease subjective worsening of the curvature (25 versus 78 percent) [28].
Other oral agents — We do not use the following oral agents.
●Vitamin E – Vitamin E is a potent antioxidant that is thought to reduce collagen deposition within the injured tunica albuginea. Although vitamin E is a widely used agent for PD in the United States, the only randomized trial did not show superiority over placebo [31].
●Vitamin E plus colchicine – In a randomized trial comparing colchicine (1 mg twice daily) plus vitamin E (600 mg daily in two divided doses) with ibuprofen in 45 men with mild curvature (<30 degrees) and <6 months from PD onset, this drug combination improved plaque size [32].
●Potassium para-aminobenzoate – Potassium para-aminobenzoate is an antifibrotic agent that has been used in a variety of disease states. It is thought to increase tissue levels of monoamine oxidase, thereby decreasing levels of serotonin, which is thought to contribute to scar formation. One trial showed a benefit compared with placebo in reduction of plaque size and/or penile curvature [33]. However, of the 51 patients randomized to receive the treatment, 28 terminated therapy due to side effects or non-compliance.
Potassium para-aminobenzoate carries a significant cost, requires the patient to ingest up to 24 tablets daily, and is known for its low tolerability due to gastrointestinal side effects.
●Colchicine – Although observational studies demonstrated improvement in penile pain and curvature [34,35], a randomized trial (n = 78) did not demonstrate any difference in plaque size or penile curvature between colchicine (0.5 to 2.5 mg daily) and placebo [36]. Colchicine may be effective in men with mild curvature when used in combination with vitamin E [32].
Gastrointestinal side effects are relatively common. Additionally, colchicine may cause bone marrow suppression. Due to the side effect profile and lack of efficacy, colchicine is not commonly used to treat PD.
●Tamoxifen – The efficacy of tamoxifen has not been shown in controlled trials. It is unlikely that an adequate tamoxifen concentration can be attained in the Peyronie's plaque via oral administration [3]. In a randomized, double-blind trial of tamoxifen versus placebo (n = 25), the proportion of patients who reported reduction in curvature was similar in both groups (46 versus 42 percent) [37].
●Carnitine – Carnitine supplements have shown mixed results in comparison to other medications or placebo [38-40].
Intralesional drug therapy — Intralesional drug injections are generally safe and well-tolerated (figure 4). However, the following side effects have been reported: penile ecchymosis, swelling, hematoma, blisters, pain, and corporal rupture [24]. Intralesional drug treatments commonly used and studied in randomized trials include verapamil and collagenase Clostridium histolyticum (CCH). Of these, we recommend CCH [41].
Collagenase Clostridium histolyticum — CCH is the only intralesional treatment for men with PD approved by the US Food and Drug Administration (FDA). CCH injection is very effective in reducing plaque size but does not change the curvature. Therefore, it should be followed with “modeling,” which is forcible bending of the penis in the direction opposite to the curve. Although we agree that modeling is helpful and it is recommended by many urologists, we prefer instead to use penile traction therapy for four to six weeks after CCH injections to increase the efficacy of correcting penile curvature. (See 'Penile traction therapy' below.)
The effectiveness of CCH has been demonstrated in multiple trials [42-46]. In the largest trial (n = 832), men treated with CCH had a 34 percent improvement in curvature compared with 18 percent in placebo-treated men [42]. Six men experienced serious adverse events (corporeal rupture in three and penile hematoma in three). In the sponsored clinical trials, the injection was limited to four cycles (eight injections), which may not be effective for men with large or multiple plaques, severe curvature, or calcified plaques. In our practice, many men achieved significant improvement only after additional injections beyond the four-cycle limit imposed by many insurance companies.
Verapamil — Intralesional verapamil is thought to influence fibroblast metabolism by increasing collagenase activity and concurrently decreasing collagen production [47]. Most [48-52] but not all [53] trials have shown improvement in symptoms and penile plaque/curvature with intralesional verapamil therapy. In a systematic review including four prospective studies of patients with mild PD (including only one small randomized, placebo-controlled trial), verapamil showed some benefit in penile curvature, plaque size, and penile pain [48]. Verapamil injection is safe, well-tolerated, and commonly used as part of nonsurgical PD management.
Corticosteroids — There is no clinical role for the use of corticosteroid injections into Peyronie's plaques, as few supportive data exist, and therapy carries a risk of tissue atrophy or obliteration of native penile tissue planes which can make surgical correction more difficult [3,48].
Topical therapy — Topical therapy (eg, verapamil, superoxide dismutase) is not recommended for the treatment of PD outside of clinical trials. In a randomized trial, topical verapamil gel was better than placebo in eliminating pain on erection, decreasing plaque size (84.7 versus 55 percent), decreasing curvature (61.1 versus 43.6 percent), and improving erection quality in patients with PD [54]. However, it is uncertain whether topical therapy has an effect on penile plaques, as topically (transdermal) administered verapamil gel has not been shown to penetrate into the tunica albuginea [55].
In a randomized, placebo-controlled, crossover series in 39 men, liposomal recombinant human superoxide dismutase did not demonstrate significant effects upon plaque size or penile curvature, although decreased penile pain was observed over the eight-week treatment course [56].
OTHER TREATMENTS — Penile traction, iontophoresis, extracorporeal shockwave therapy (ESWT), and radiation therapy are other treatment approaches to Peyronie's disease (PD), but none have been shown to be conclusively effective in randomized trials.
Penile traction therapy — Penile traction therapy, usually in conjunction with medical management, has shown some efficacy with a favorable safety profile in small case studies [57-59]. In a study of 10 men with PD, nine of whom had failed medical therapy, traction for two to eight hours a day for six months led to reduced curvature in all men (10 to 45 degrees), increased stretched flaccid penile length (0.5 to 2.0 cm), and increased erect girth (0.5 to 1.0 cm) [57]. There were no adverse events. Further studies have demonstrated that traction in conjunction with oral agents and injection therapy may improve curvature and stretched penile length to a modest degree, although the data have been mixed [60-63]. Traction may also confer a positive effect on patient outcomes after reconstructive surgery [64].
Iontophoresis — Several reports have investigated the effect of electromotive drug administration, also known as iontophoresis. Theoretically, electrokinetic transport of charged ionic molecules may enhance the delivery of transdermal medications to the target tissues, in this case the diseased tunica albuginea, thereby improving local penetration without systemic side effects [65]. Increased levels of verapamil were present after iontophoresis in surgically retrieved tunica albuginea specimens [65].
In a randomized trial of iontophoresis with verapamil (5 mg) plus dexamethasone (8 mg) compared with iontophoresis with 2 percent lidocaine in 96 men, there was objective improvement in plaque size and curvature in the verapamil group [66]. However, in another trial of iontophoresis with verapamil in 42 men with PD, there was no improvement in penile curvature compared with iontophoresis with placebo [67]. Further trials are needed, especially since it is unclear whether the electric current itself may be beneficial for wound healing [68].
Iontophoresis is well-tolerated, with the most common side effect being temporary erythema at the electrode site. If iontophoresis continues to prove efficacious, widespread acceptance of iontophoresis likely would occur since it can readily be performed at home [25].
Extracorporeal shockwave therapy — This modality remains an investigational treatment due to lack of well-designed trials with long-term follow-up. There are also concerns about the potential side effects including penile fibrosis, secondary PD scarring, and development of erectile dysfunction [69].
There are limited clinical trial data evaluating the efficacy of extracorporeal shockwave therapy (ESWT) for the treatment of PD [70-72]. An exploratory meta-analysis of predominantly observational studies determined that ESWT may be somewhat effective in improving penile pain and sexual dysfunction; however, there was insufficient evidence to determine its effect on penile plaque size and curvature [70]. The meta-analysis was limited by several factors, including lack of prospective studies, no blinding in any of the studies, and use of non-standardized outcome measures.
In a subsequent randomized trial comparing ESWT versus placebo in 100 patients who had not previously received PD-related treatment, there was a statistically significant decrease in mean plaque size (-0.6 versus +1.4 mm2) and curvature (-1.4 versus +1.8 degrees), which is of uncertain clinical significance [72].
Radiation therapy — Radiation therapy for the treatment of PD has yielded mixed results [73,74]. Although radiation therapy may reduce pain and penile curvature, it may also compromise erectile function, especially in the aging male [73]. Well-designed trials are required, as no prospective, randomized, placebo-controlled studies have been published. There is insufficient evidence to recommend radiation therapy at this time, particularly since secondary malignancy risks have not been quantified.
SUMMARY AND RECOMMENDATIONS
●The underlying pathogenesis of Peyronie's disease (PD) is unknown and most likely represents a combination of factors including chronic minor injury and genetic susceptibility. (See 'Pathogenesis' above.)
●The presenting symptoms of PD are penile pain, curvature, indentation, hourglass deformity, shortening, and/or sexual dysfunction. Patient and partner quality of life are significantly impacted, as men with PD are at increased risk of depression, relationship difficulties, and body-image issues. (See 'Clinical manifestations' above.)
●Diagnosis is usually apparent from patient history and penile examination. On exam, clinicians may observe a penile plaque and penile curvature or deformity. (See 'Diagnosis and assessment' above.)
●When primary care clinicians have limited experience in managing PD, the primary care clinician should refer the patient to a urologist once the diagnosis of PD is established, or in any patient with a penile deformity. (See 'Indications for urology referral' above.)
●For men with stable, mild curvature (≤30 degrees) who have satisfactory erectile function, observation is an acceptable option (Grade 2C). If mild curvature worsens or causes sexual dysfunction, we suggest medical and/or surgical management (algorithm 1) (Grade 2B). (See 'Our approach' above.)
●For the initial medical management of men with PD, we suggest oral pentoxifylline, especially within three months of onset (Grade 2C). In men who are bothered by penile deformity of more than three months’ duration, we recommend intralesional injection with collagenase Clostridium histolyticum (algorithm 1) (Grade 2B). (See 'Our approach' above and 'Pentoxifylline' above and 'Collagenase Clostridium histolyticum' above.)
