Management of Peyronie's Disease in the Aging Male

Medical Management

Options for the management of PD include observation in select cases, as well as medical or surgical therapy, dependent upon the severity of the disease. There few well-designed methodologically sound prospective 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.^[24] Critical appraisal of contemporary literature identifies widespread use of inappropriate clinical end points, 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 end point may also be useful. However, it is important to note, that a reduction in plaque size has not been shown to correlate with reduction in curvature.^[23–26]

Critical analysis of nonsurgical approaches indicates that there is no mode of treatment able to relieve all symptoms for men with PD. Nonetheless, early medical intervention while the disease is still evolving is more likely to have therapeutic effect compared with intervention when the disease is stable or even calcified. Thus, the need for early diagnosis and consideration of treatment of PD is important.

Observation

Watchful waiting is an appropriate option for select patients with PD. Observation may be indicated in men with satisfactory erectile function and mild curvature (generally no greater than 30°, which does not prevent successful penetration during intercourse), and an understanding is required that PD may progress with worsening curvature or formation of new penile plaques in the future. If mild curvature worsens, medical management should be considered; persistent mild curvature may be treated if it causes sexual dysfunction.

Oral Therapy

Medical management is indicated in men with moderate-to-severe curvature (>30°) or curvature that causes ED. However, no single agent has been found to be completely efficacious for the treatment of PD.

Pentoxifylline The evidence for pentoxifylline is more robust than other oral agents, given a recent well-designed, double-blind, placebo-controlled trial demonstrating efficacy.^[27] The exact mechanism of action of pentoxifylline is not known. Pentoxifylline blocks TGF-β1-mediated inflammation, prevents deposition of collagen type I and acts as a nonspecific phosphodiesterase inhibitor. In a rat model, both sildenafil and pentoxifylline reduced the plaque size in tunical fibrosis, induced by injection of TGF-β1.^[28] This agent has been used previously in humans for a variety of inflammatory and fibrotic conditions.^[27] In a 6-month placebo-controlled trial of pentoxifylline (400 mg orally twice daily) versus placebo in 228 patients with PD for less than 12 months (early patient presentation), mean reductions in penile curvature were significantly better in the pentoxifylline group (-22, -20 and -40° compared with baseline in those with dorsal, lateral and ventral curvature, respectively) compared with an increase in curvature of +31, +22 and +27°, respectively, in the placebo group.^[29] Total plaque volumes, erectile function and peak systolic velocity of blood flow through the cavernous arteries improved significantly for the pentoxifylline group compared with the placebo group.^[29,30] Pentoxifylline was safe and well-tolerated in this study. Further investigations are required to optimize patient response, including timing, dosing and duration of treatment, combination with intralesional treatments and use for men with a delayed presentation or planned for surgery.

Vitamin E (β-tocopherol) Vitamin E is a potent antioxidant, which is thought to reduce collagen deposition within the injured tunica albuginea. Although vitamin E is a widely used agent for PD in the USA, there is little evidence to support its superiority over placebo.^[31–33] It is not recommended as a treatment for PD, owing to unsatisfactory results compared with placebo.

Potassium para-aminobenzoate Potassium para-aminobenzoate (Potaba™) 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 are thought to contribute to scar formation. Although potassium para-aminobenzoate has been available for decades, very few studies have examined its efficacy in the treatment of PD, change in pain or improvement in curvature.^[1] Current evidence does not support potassium para-aminobenzoate for first-line therapy of PD.

Colchicine Based upon basic science and animal model investigations of PD, colchicine inhibits collagen synthesis and subsequent fibrosis. Although observational studies demonstrated improvement in penile pain and curvature,^[34,35] a randomized, placebo-controlled trial did not demonstrate any difference in plaque size or penile curvature between colchicine (0.5–2.5 mg daily) and placebo.^[36] Gastrointestinal side effects are relatively common. In addition, colchicine may cause bone marrow suppression. Owing to the side-effect profile and lack of efficacy, colchicine is not commonly used to treat PD.^[1]

Tamoxifen Efficacy of tamoxifen in the treatment of PD has not been shown in controlled trials, to date. It is unlikely that an adequate tamoxifen concentration can be attained in the Peyronie's plaque via oral administration. In a randomized, double-blind trial of tamoxifen versus placebo, there was no difference in correction of curvature (46 vs 42%).^[37]

Acetyl-L-carnitine Initial studies failed to demonstrate efficacy of this treatment; however, subsequent data is encouraging, as an adjunct to verapamil with regards to plaque reduction, pain and limited degrees of curvature reduction.^[1,38] In the absence of decisive data demonstrating a beneficial effect of acetyl-L-carnitine on PD, we cannot advise the routine employment of this drug in the treatment of PD, but encourage its investigation in controlled trials.

Intralesional Drug Therapy

Intralesional drug injections are generally safe, well-tolerated, and performed by urologists (Figure 3). In general, a full penile block should be performed, to allow for several passes of the needle in and out of the lesion, seeding the tracts with the agent-of-choice. There are three intralesional drug treatments that have shown efficacy in randomized controlled trials: verapamil (by far the most commonly used), IFN-β_2b and collagenase. There is currently no clinical role for the use of corticosteroid injections into Peyronie's plaques, as little supportive data exist, and therapy carries a risk of tissue atrophy.^[39]

(Enlarge Image)

Figure 3.

Intralesional delivery of medication. After penile block, a 10 ml syringe and most commonly a 25 or 27 gauge 5/8 inch needle is used, although larger bores may be required for dense plaques. The glans is grasped and the penis is stretched, and the lesion palpated or identified with ultrasound guidance. The free hand is used to inject drug intralesionally with multiple injections delivered into the plaque in the tunica albuginea of the penis. The objective is to inject drug into the middle of the plaque through small channels and continue to deliver drug as the needle is withdrawn each time.
Reproduced with permission from.⁸³

Verapamil Intralesional verapamil is thought to influence fibroblast metabolism by increasing collagenase activity and concurrently decreasing collagen production.^[40] Most,^[39,41–43] but not all,^[44] 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 (with only one randomized, placebo-controlled trial), verapamil showed some benefit in penile curvature, plaque size and penile pain.^[39] Verapamil injection is safe, well-tolerated and commonly used as part of nonsurgical Peyronie's management.

IFN-β_2b Limited clinical evidence suggests that IFN-β_2b treatment may be efficacious for mild-to-moderate PD. The interferons are low-molecular-weight proteins that are known to inhibit the proliferation of fibroblasts, increase collagenase activity and decrease collagen production.^[39] In a nonrandomized study of IFN-β_2b or placebo in 117 patients, there was greater improvement in curvature and plaque size in men administered IFN-β_2b.^[45] Interferon injections appear safe, with a primary side effect of flu-like symptoms in some patients, although cost of treatment may be a barrier for widespread utilization.

Collagenase Collagenase, a purified bacterial enzyme targeting collagen for breakdown, has shown some efficacy in improving plaque size and curvature in small observational studies.^[46] In a blinded randomized trial of collagenase versus placebo in 49 men, there was a small, but significant improvement in curvature (maximal change: 15–20°) in the collagenase group.^[47] The treatment effect was mostly limited to patients with mild Peyronie's curvature (<30°; plaque size: <2 cm). Treatment was well-tolerated. A larger multicenter clinical trial is concluding and, at this time, collagenase remains an experimental agent.

Topical Therapy

Topical therapy (e.g., verapamil or superoxide dismutase) is not currently recommended for the treatment of PD outside of clinical trials. As an example, topically (transdermal) administered verapamil gel has not been shown to penetrate into the tunica albuginea.^[48] However, in a blinded randomized trial with several methodological concerns, topical verapamil gel did show some benefit versus placebo in eliminating pain on erection, decreasing plaque size, decreasing curvature and improving erection quality in patients with PD – further investigation and confirmatory studies are requried.^[49] 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 8-week treatment course.^[50] In one study, topical verapamil hydrochloride applied twice daily (0.5 ml) over the entire shaft of the penis led to significant improvement in penile curvature and plaque size. However, another study could not replicate theses results, and reported poor drug absorption through the cutaneous route to the tunica albuginea. Thus, we cannot, at this point, recommend the trial of transdermal verapamil in the treatment of PD. Of note, several nonstandard topical formulations are available using internet-based sources, and caution is recommended, as these are not US FDA or EMA approved, nor studied in well-designed trials, subsequently published in peer-reviewed medical literature.

Iontophoresis

Several studies explored the benefit of electromotive drug administration (EMDA) in the improvement of penile curvature.^[51–53] Drugs used included superoxide dismutase and verapamil. Controversial evidence exists regarding the usefulness of such treatment modality. While Di Stasi et al., in a double-blind, randomized trial, demonstrated that electromotive verapamil therapy with dexamethasone significantly decreased penile curvature (50 vs 0% decrease; p < 0.0001) and plaque size (60 vs 0% decrease; p < 0.0001) relative to a lidocaine control when given as four treatments per week for 6 weeks with only mild side effects,^[54] a recent randomized controlled study of 42 patients treated twice weekly with EMDA for 3 months did not demonstrate any improvement in penile curvature or plaque size when using verapamil versus saline.^[55] Further studies are needed to confirm any potential advantage of the use of EMDA.

Extracorporeal Shockwave Therapy

Evidence is still lacking to support the use of this modality in the management of PD; recent controlled data suggests little therapeutic effect compared with placebo, there remains concern about subsequent intracorporeal fibrotic change secondary to extracorporeal shockwave lithotripsy (ESWL) – recent guidelines state that there is no evidence to show that extracorporeal shockwave therapy (ESWT) improves PD-related deformity.^[1] Previously, a retrospective study reported decreased penile angulation over a 6–12-month follow-up period in 75% of 25 patients studied.^[56] However, these interesting results were coupled with minor skin hematoma in 76% of patients, which resolved conservatively. A similar study reported significant improvement in penile curvature in only 17% of 24 patients studied, and was associated with significant discomfort.^[57] Care must be taken in interpreting these studies, specifically for primary (nonstandard) end points and duration of follow-up

Penile Traction

The use of tissue expanders has long been a mainstay of treatment in the orthopedic, oralmaxillofacial and plastic surgical fields. It is well documented that gradual expansion of tissue results in the formation of new bone and connective tissue. Recently, two studies examined the effect of penile physiotherapy in the treatment of PD. In one report, ten men with PD completed a noncontrolled pilot study of traction therapy using the FastSize Penile Extender (Figure 4). Nearly all (90%) had failed prior medical therapy. Traction was applied as the only treatment for 2–8 h/day for 6 months, and resulted in reduced curvature in all men from 10 to 45°; average reduction for the group was 33% (34–51°). Stretched penile length increased 0.5–2.0 cm, and erect girth increased 0.5–1.0 cm, with correction of hinge effect in four out of four men. IIEF erectile function domain increased from 18.3–23.6 for the group.^[58] In the second study, 15 patients with PD (curvature less than 50° and mild or no ED) used the penile extender for at least 5 h/day for 6 months.^[59] The mean stretched and flaccid penile length increased by 1.3 and 0.83 cm, respectively, at 6 months, but with minimal improvement of penile curvature. Overall, these results show a potential for a successful treatment option to reduce the loss of penile length and decrease the penile curvature inpatients with PD.

(Enlarge Image)

Figure 4.

Traction device. Example of a penile traction device. Most commonly this modality is used at home in conjunction with intralesional therapy, although its use must still be considered experimental due to limited peer-reviewed publication of results.
Reproduced with permission from.⁸³

Combination Therapy

Combining more than one nonsurgical modality to treat PD simultaneously (oral, injection or mechanical traction) is currently under investigation. Some authorities with concentrated PD practices routinely treat their patients with a combination of pentoxifylline (potentially in combination with L-arginine), penile traction and intralesional verapamil injections.^[60] While combined nonsurgical therapy seems a reasonable approach, and takes advantage of multiple potential mechanisms of action to treat PD, the literature is till lacking data from robust studies comparing single versus multimodal approaches.

Box Executive summary
Peyronie's disease (PD) involves the development of inelastic scar of the tunica albuginea of the penis, resulting in penile curvature, deformity and sexual dysfunction. The underlying pathogenesis of PD is unknown, and most likely represents a combination of factors, including chronic minor injury and genetic susceptibility. The presenting symptoms of PD are penile pain, induration, curvature and/or sexual dysfunction. Patient and partner quality of life are significantly impacted, as men with PD are at an increased risk of depression, relationship difficulties and body-image issues. Diagnosis is usually apparent from patient history and penile examination. On examination, clinicians may observe a penile plaque and penile curvature or deformity. When primary-care clinicians have limited experience in managing PD, they should refer the patient to an urologist once the diagnosis of PD is established, or in any patient with a penile deformity. For patients who do not have penile deformity compromising sexual function, and whose PD has persisted for less than 12 months, we suggest medical management rather than surgical management. For men with stable, mild curvature (≤30°), who have satisfactory erectile function, we suggest observation. If mild curvature worsens, or causes sexual dysfunction, we suggest medical and/or surgical management. Surgical management is indicated for patients whose PD has persisted for more than 12 months, and is associated with a penile deformity compromising sexual function. The length of the penis, nature (e.g., hourglass or curved), and severity of the deformity, erectile capacity and patient expectations, are important factors to consider when determining the surgical approach. Surgical techniques used for penile reconstruction in PD include plication, grafting or placement of a penile prosthesis. Plication shortens the convex side of the penis, whereas grafting techniques lengthen the concave side. Penile implants are used in patients with pre-existing erectile dysfunction (ED). Plaque incision is often combined with these techniques to improve the mobility of the plaque. Erectile dysfunction occurs in up 20% of patients following nonplication surgical reconstruction for PD, and can occur without a prior history of ED; however, ED is more likely to complicate procedures requiring dissection of the neurovascular bundle, or in patients with pre-existing ED.

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