Peyronie's disease: Diagnosis and medical management

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's approval of collagenase clostridium histolyticum injections 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 PD is a rare condition, based on previous case reports documenting a prevalence of ≤1 percent [2,3]. Contemporary estimates are several-fold higher, perhaps partly due to the introduction of phosphodiesterase type 5 inhibitors for erectile dysfunction (ED) 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 448 men undergoing evaluation for ED (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 ED, may not be aware there is a problem, as they may not have deformities of the flaccid penis.

PATHOGENESIS — The underlying pathogenesis of 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 be 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 beta-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 contracture 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 nonprogression of deformity.

CLINICAL MANIFESTATIONS — The presenting symptoms of PD include penile pain, nodules/plaques, 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 plaques or nodules, 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 (psychologic), or impaired erections due to veno-occlusive 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 REFERRAL — Diagnosis is usually apparent from patient history and penile examination. Patients can be given a preliminary diagnosis of 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 psychologic effect of PD on the patient and partner, as well as determine the extent of associated erectile dysfunction.

As 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 [18].

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 plaques (figure 2) [19]. 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 [20]. Abnormal tissue may extend beyond the palpable lesion or even into the corporal tissue [21]. 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 [22]. 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 — The diagnosis of PD is usually clinically apparent. 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 plaques/nodules, 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 [23,24].

MANAGEMENT — Patients with PD are generally managed by urologists. The urologist may offer observation, medical therapy, or surgery, depending upon the severity and psychologic impact of the disease.

There are few studies examining the efficacy of the available medical treatment options. The evidence is limited 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]. (See 'Natural history' above.)

Improvement or resolution of penile deformity (curvature measured after an erection elicited by intracavernous injection) and reduction in plaque size are the primary endpoints of most studies [26,27]. Data on improvement in other important outcomes like pain and erectile dysfunction (ED) are limited.

Following a detailed history and penile examination, patients are classified as either in the active or stable phase, which determines the treatments offered. This approach is outlined in the algorithm (algorithm 1).

Active disease — The active phase is characterized by changes in penile curvature or deformity and pain with erection. Nonsteroidal anti-inflammatory drugs are offered for symptomatic relief.

We suggest that patients in the active phase receive pentoxifylline oral therapy (400 mg three times daily) for three months to stabilize the disease (algorithm 1). Pentoxifylline is a nonspecific phosphodiesterase inhibitor that decreases transforming growth factor 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.

If there is no decrease in pain or penile deformity after three months, we offer intralesional injections of collagenase clostridium histolyticum (CCH) followed by penile traction therapy. (See 'Intralesional drug therapy' below and 'Penile traction therapy' below.)

If there is improvement in symptoms after three months, we either continue pentoxifylline for six more months or stop treatment and observe, based on the degree of clinical improvement and patient preference.

While there are no high-quality, randomized trials evaluating pentoxifylline in the treatment of PD, observational studies provide indirect evidence that it may be of benefit in the early active phase [28-32]. In one report, pentoxifylline was associated with higher rates of improved or stabilized ultrasonographic calcifications (92 versus 44 percent) and lower rates of subjective worsening of the curvature (25 versus 78 percent) [30]. Treatment is safe and well tolerated in our experience. However, because of the limited data, the American Urological Association guideline for PD does not recommend pentoxifylline for the treatment of active disease [18].

Stable disease — Stable disease is characterized by absence of pain and nonprogression of deformity.

Penile curvature <30 degrees — Patients with penile curvature <30 degrees are candidates for observation; although, large observational studies and randomized trials are lacking in this population (algorithm 1).

ED, if present, should be managed. (See "Treatment of male sexual dysfunction", section on 'Overview of management approach'.)

If symptoms progress, further treatment should be initiated. (See 'Intralesional drug therapy' below and 'Penile traction therapy' below and "Surgical management of Peyronie's disease".)

Patients with curvature >30 degrees — Such patients are offered intralesional drug therapy with CCH followed by penile traction therapy (algorithm 1). (See 'Intralesional drug therapy' below and 'Penile traction therapy' below.)

Treatment of erectile dysfunction — ED, if present, should be managed and may warrant combination therapy with oral medications and intracavernosal injections. Patients with greater curvature may require a treatment that offers both straightening and treatment of ED in the same setting, such as a penile prosthetic. (See "Treatment of male sexual dysfunction", section on 'Overview of management approach'.)

Intralesional drug therapy — Verapamil and CCH are safe and well-tolerated intralesional drug treatments (figure 4) [33]. However, the following side effects have been reported: penile ecchymosis, swelling, hematoma, blisters, pain, and corporal rupture [18].

●Collagenase clostridium histolyticum – CCH is preferred over verapamil, as it is the only intralesional treatment approved by the US Food and Drug Administration.

The effectiveness of CCH has been studied in multiple trials [34-38]. 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 [34]. Six men experienced serious adverse events (corporeal rupture in three and penile hematoma in three). Other reported adverse effects include postinjection pain, hematoma, and presyncope or syncope, likely due to a vasovagal response [39]. In addition, patients may experience hypersensitivity reactions as well as transient back, chest, and limb pain following injections [39]. Therefore, the potential benefit must be weighed with the risk of adverse events.

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, patients are evaluated before each cycle for efficacy and tolerability. Many men achieve significant improvement only after additional injections beyond four cycles; although, four cycles may be the limit of what is approved by many insurance companies. A smaller group of patients achieve enough benefit to complete treatment after fewer than four cycles.

We 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.)

●Verapamil – Intralesional verapamil is thought to influence fibroblast metabolism by increasing collagenase activity and concurrently decreasing collagen production [40]. Most [41-45], but not all [46,47], trials have shown improvement in symptoms and penile plaques/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 [41]. Verapamil injection is safe, well tolerated, and commonly used as part of nonsurgical PD management.

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 [48-50]. 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 cm), and increased erect girth (0.5 to 1 cm) [48]. There were no adverse events. Further studies have suggested that traction in conjunction with oral agents and intralesional injection therapy may improve curvature and stretched penile length to a greater degree than with traction alone; although, the data have been mixed [47,51-55].

Manual modeling is sometimes offered as an alternative to penile traction therapy. In manual modeling, pressure is applied to bend the penis in the direction opposite to the curve to stretch and elongate the plaque.

Severe or refractory disease — If severe deformity, calcifications, or refractory ED limiting sexual activity are present, surgical therapy is offered. (See "Surgical management of Peyronie's disease".)

TREATMENTS OF UNCERTAIN BENEFIT

●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 [56]. Studies of iontophoresis along with verapamil have had variable results ranging from improvement in plaque size and curvature to no effect [57,58].

Iontophoresis is well tolerated, with the most common side effect being temporary erythema at the electrode site. If future studies on iontophoresis show efficacy in PD, it will be a valuable treatment option, particularly due to ease of use at home [25].

●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 [59].

●Colchicine – Although observational studies demonstrated improvement in penile pain and curvature [60,61], 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 [62]. Due to the side effect profile and lack of efficacy, colchicine is not commonly used to treat PD.

●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 and penile curvature [63]. However, a subsequent study of combination therapy did not replicate this effect [64].

●Potassium para-aminobenzoate – Potassium para-aminobenzoate is an antifibrotic agent that has been used in a variety of disease states. One trial showed a benefit compared with placebo in reduction of plaque size and/or penile curvature [65]. However, of the 51 patients randomized to receive the treatment, 28 terminated therapy due to side effects or noncompliance. Potassium para-aminobenzoate also 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.

●Tamoxifen – The efficacy of tamoxifen has not been shown in controlled trials. 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) [66].

●Carnitine – Carnitine supplements have shown mixed results in comparison with other medications or placebo [67-69].

●Topical therapy – Topical therapy with verapamil or 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 [70]. 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 [71].

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 [72].

●Intralesional 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 [3,41].

●Extracorporeal shockwave therapy – This modality remains an investigational treatment due to the 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 [73].

●Radiation therapy – Radiation therapy for the treatment of PD has yielded mixed results [74,75]. Although radiation therapy may reduce pain and penile curvature, it may also compromise erectile function, especially in the aging male [74]. 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

●Pathogenesis – 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.)

●Symptoms – 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 and referral – PD is usually apparent from patient history and penile examination. On examination, clinicians may observe a penile plaque and penile curvature or deformity. As 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. (See 'Diagnosis and referral' above.)

●Management – The management of PD is summarized in the algorithm (algorithm 1).

•Management of erectile dysfunction – Erectile dysfunction (ED), if present, should be managed. Specific recommendations are provided separately. (See "Treatment of male sexual dysfunction", section on 'Erectile dysfunction'.)

•Active disease – For the initial management of active disease, we suggest oral pentoxifylline, especially within three months of onset (Grade 2C). Treatment is safe and well tolerated, and limited evidence suggests that it may reduce calcifications. Other experts choose not to use this treatment as evidence of efficacy is limited. (See 'Active disease' above and 'Intralesional drug therapy' above and 'Penile traction therapy' above.)

Collagenase clostridium histolyticum (CCH) injections followed by penile traction therapy is an additional treatment option for men who have persistent symptoms beyond three months (algorithm 1). (See 'Active disease' above and 'Intralesional drug therapy' above and 'Penile traction therapy' above.)

•Stable disease and mild curvature – Men with stable disease and mild curvature (≤30 degrees) typically do not require treatment beyond observation. (See 'Penile curvature <30 degrees' above.)

•Stable disease and curvature >30 degrees – For patients with stable disease and penile curvature >30 degrees, we suggest intralesional injection with CCH followed by penile traction therapy (Grade 2C). (See 'Patients with curvature >30 degrees' above.)

•Refractory or severe disease – For patients with stable disease who have severe deformity, large calcifications, or ED refractory to medical therapy, surgical referral is appropriate. Specific indications and surgical techniques are presented separately. (See "Surgical management of Peyronie's disease".)