Dermatologic Manifestations of Peyronie Disease

In 1587, Guilio Cesare Aranzi was the first to formally describe Peyronie disease (PD) in his book Tumores praeter naturam. He called Peyronie disease "a rare affection of the genitals in people with excessive sexual intercourse: a little penile tumor palpable like a bean in the flaccid penis causing a deformity similar to a ram horn during erection." The disease was not given its current name until 1743, when Francoise de La Peyronie described the cases of 3 men with fibrous thickening of the penile shaft, painful erections, and penile curvature, as demonstrated in the images below.

Medscape Drugs & Diseases article, Peyronie Disease, also may be helpful.

Although the exact etiology of Peyronie disease is not clear, trauma may cause perivascular inflammation.[1] In ordinary tissue, the rupture of blood vessels leads to coagulation and fibrin deposition. Fibrinolysis of the deposited fibrin occurs as tissue cells proliferate to close the site of injury. In Peyronie disease, the tunica albuginea may initially undergo microvascular trauma during sexual intercourse. Adequate postinjury fibrinolysis is prevented because the tunica albuginea is hypovascular.

After multiple microvascular traumas, large quantities of fibrin accumulate in the form of a plaque, generally along the dorsal and ventral midline aspects of the penile shaft. This deposition appears to be immune mediated. Some people may be genetically predisposed to this reaction. The plaque prevents the adequate expansion of the tissue during erection, leading to penile curvature and pain. The relationship of this condition to other fibromatoses suggests a predisposition to fibrous proliferation. Although these microtraumatic events are implicated in the current theory of the pathogenesis of Peyronie disease, no etiology is proven.

Results of animal studies indicate that transforming growth factor-beta (TGF-beta) may be involved in the formation of the plaques via early inflammatory reactions. When TGF-beta analogs are injected into rat tunica albuginea, they form collagen bundles that are morphologically similar to those in Peyronie disease.

Peyronie disease starts in 1 of 2 ways. Most patients report the acute onset of pain accompanied by a lump in the shaft of the penis, followed by gradually increasing curvature with or without pain. Alternatively, a minority of the patients report curvature of the penile shaft that occurs suddenly, seemingly overnight, and remains stable once it occurs.

In the progressive form, the cycle of trauma, fibrin deposition, and attempts at fibrinolysis continue to escalate. Remodeling of the fibrin deposits can take as long as 2 years in the absence of further traumatic events.

Although microtraumatic events are implicated in the current theory of the pathogenesis of Peyronie disease, no etiology is proven. No risk factors are known, but associations do exist. Research has demonstrated increased expression of hypoxia-inducible target genes in lesional tissue, suggesting hypoxic injury may be involved in the pathogenesis.[2]

Peyronie disease occurs in men, particularly in older men with weak erections, who engage in frequent and vigorous intercourse (>4 times per wk).

In some studies, HLA-B7 and HLA-DQ5 appeared to correlate with the prevalence of Peyronie disease. Results of other studies have not confirmed this finding.[3]

Peyronie disease may be associated with erectile dysfunction, diabetes mellitus, and hypertension. Resultant partial erections may lead to buckling during intercourse.

Peyronie disease is associated with Dupuytren contracture. Among patients with Peyronie disease, 10% have Dupuytren contracture, and 3% of patients with Dupuytren contracture have Peyronie disease.[4]

Aponeurotic plantar fibrosis (ie, Ledderhose disease) may be found.

Peyronie disease is associated with sporadic and familial knuckle pads, which are circumscribed fibromatous thickenings overlying the finger joints.

Peyronie disease has been seen in systemic sclerosis.[5]

Occasionally, Peyronie disease is associated with fibromatous degeneration of the external ear cartilage.

Antielastin antibodies, anti-DNA antibodies, and elevated antinuclear antibody (ANA) levels have been found in association with Peyronie disease.[6]

Peyronie disease itself is not associated with penile fracture.

Frequency

United States

The rate for Peyronie disease is 0.3-4% among white men.

International

Peyronie disease is less common in men of African or Asian heritage.

Race

Peyronie disease is well documented in whites. Peyronie disease may occur in black men, often in the presence of preexisting diabetes mellitus and erectile dysfunction.

Age

Peyronie disease predominantly occurs in men aged 40-60 years. The age range of affected persons is 30-80 years.

The spectrum of Peyronie disease ranges from asymptomatic plaques to mild penile curvature or severe curvature that results in a complete inability to have sexual intercourse. Erectile pain can range from none to severe, depending on the site and amount of plaque deposition.

Peyronie disease only occasionally, if ever, disappears completely. The pain may diminish or resolve after the early inflammatory phase, and as many as 13% of patients claim to have some improvement with time. Approximately one half of the remaining individuals have progressive disease, whereas the other half have static disease.

Variable degrees of morbidity may occur. Conditions range from a static painless plaque without penile angulation to painful erections with a curvature significant enough to prevent sexual activity.

Data suggest a combination approach to therapy for Peyronie disease. For instance, the use of partially effective oral therapies with minimally invasive mechanical or intralesional treatments may be more successful than each individual therapy alone.

Patient education in Peyronie disease includes the following:

• Reassurance that lesions are not cancerous or fatal

• An explanation that the condition is not curable but that it is treatable and possibly self-resolving

• An open discussion about the problems with intercourse, the possibility of the resumption of satisfactory sexual activity, and the reduction of pain

Usually in Peyronie disease, the penis hurts only during an erection. This pain occurs in one third of patients. Penile curvature of varying degrees may be observed, only during an erection. No history of a congenital malformation of the penis (eg, chordee) or a metastatic cancer is present. Risk factors for Peyronie disease include history of erectile dysfunction and history of coital trauma to the penis.[7]

On palpation, a fibrotic plaque, usually greater than 1.5 cm in diameter, is felt over the penile shaft, usually either ventrally or dorsally.

The erect penis may be curved, or it may have an hourglass deformity with flaccidity of the distal penis. The patient can obtain photographs of the erect penis in private to demonstrate the increased curvature. Self-taken photographs can be used to establish a reference point for subsequent observation or treatment.

Evidence suggests that pain tends to lessen with time, but fibrosis and/or deformity tend to increase or persist. Waiting 12-24 months for the plaque to stabilize before surgical intervention is typical.

Complications of Peyronie disease include the complete inability to maintain sexual performance.

The diagnosis of Peyronie disease is based on the features of the history and the physical examination findings.

Radiographs depict plaque calcifications in 20% of patients. The presence of calcifications indicates advanced disease that is unlikely to regress spontaneously. Calcifications on radiographs are an indication for surgical intervention.

Doppler studies and dynamic-infusion pharmacocavernosometry can be performed on an artificially erect penis (see Procedures) to further identify lesions and any secondary filling defects.

High-resolution ultrasonography is the definitive imaging study, although it is not frequently required to confirm the diagnosis. Ultrasonography may be helpful before surgical intervention is planned.

MRI of the plaques is experimental and not performed routinely. It can be used to delineate inflamed plaques that are too soft or not dense enough to be detected with ultrasonography or radiography.[8, 9]

The positive results using scintigraphy with technetium Tc 99m human immunoglobulin G may correlate with unstable plaques that may respond to medical treatment. The lack of 99mTc human immunoglobulin G positivity may correlate with stable plaques, which are usually considered resistant to medical therapy and better suited for surgical intervention.[10]

Diagnostic intracorporeal injection may be used if the history is not clear or if a comorbid disease is present. An intracorporeal injection of a vasodilator may be used to determine the patient's erectile capability and the extent of penile distortion. Alprostadil (prostaglandin E1) or various combinations of alprostadil, phentolamine, and/or papaverine can be used to induce this artificial erection.[11]

In early Peyronie disease, an inflammatory reaction occurs, with thickening of the tunica albuginea, deposition of fibrin, and loss of elastic fibers. Soon, nodular and/or diffuse bands of fibroblasts and myofibroblasts are surrounded by dense masses of collagen. These changes may extend into the underlying corpora cavernosa. Late-stage calcification or ossification may be seen.

Medical care for Peyronie disease is focused on patient education and mostly only anecdotally effective medical therapies. See Patient Education.

In December 2013, the FDA approved the first drug treatment, collagenase clostridium histolyticum (Xiaflex), for Peyronie's disease. It is an injectable proteinase that hydrolyzes collagen in its native triple-helical conformation, resulting in lysis of collagen deposits. It is believed to work for Peyronie's disease by breaking down the buildup of collagen that causes the curvature deformity.

FDA approval was established by 2 phase 3 randomized, double-blind, placebo controlled studies (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies [IMPRESS I and II]). These studies included 832 men with Peyronie’s disease with penile curvature deformity of at least 30 degrees. Participants were given up to 4 treatment cycles of collagenase clostridium histolyticum or placebo and were then followed 52 weeks. Treatment with collagenase clostridium histolyticum significantly reduced penile curvature and related bothersome effects compared with placebo (p = 0.0037).[12]

Pentoxifylline, a nonselective phosphodiesterase inhibitor, was found to reduce Peyronie disease plaque size and penile curvature in one double-blind, placebo-controlled trial.[13]

Other medical therapies are mostly of marginal and anecdotal benefit. Their effects are hard to evaluate because of the variable natural history of Peyronie disease. Many remedies exist, but no one medical therapy is clearly superior to any other. Treatments range from oral vitamin E administration to low-dose radiation to intralesional injections of calcium channel blockers. Acetyl-L-carnitine,[14] propionyl-L-carnitine, verapamil,[15, 16, 17] and interferon alfa-2b[18, 19, 20] have limited but reasonable data sets supporting their use.

If erectile dysfunction is present, the condition is unlikely to improve with treatment of the Peyronie plaque alone. The use of sildenafil with an intracavernous injection or a vacuum device is indicated. Intracavernous injections may worsen penile scarring, and the treatments must be monitored carefully. Intralesional injections of interferon alfa-2a may be effective.

Iontophoresis is the use of an electric current to pull medications through the skin to specific sites. This electromotive drug administration has been used to treat Peyronie disease with various combinations of orgotein, dexamethasone, lidocaine, and verapamil. The technique is experimental. Since 2003, several studies have reported some success with a combination of verapamil, lidocaine, and iontophoresis.[21]

Therapies to avoid in Peyronie disease include intralesional steroid injections, which may induce more inflammation, and oral procarbazine administration, which is not effective and may cause blood dyscrasias.[22, 23] Conflicting reports demonstrating some efficacy of intralesional steroid injections may, in fact, represent the mechanical destruction of the plaques with the volume of fluid injected and not the actual compound itself.

Another technique called extracorporeal shockwave therapy, similar to that which is commonly used to destroy kidney and salivary gland stones, has been reported as another treatment modality for Peyronie disease. Conflicting reports and concerns over causing increased inflammation and damage limit its usefulness.[24, 25]

Radiation therapy has been used successfully in Peyronie disease, although standardization of treatment and a determination of the optimal regimen is needed.[26, 27]

Penile traction therapy, while onerous for some, has been shown to be effective in patients with Peyronie disease undergoing intralesional injection therapy.[28, 29, 30]

American Urological Association Guidelines for the management of Peyronie disease have been published. These are useful when determining treatment strategies for a condition with a range of therapies.[31]

Surgical care for Peyronie disease is focused only on those with significant morbidity and Peyronie disease that is resistant to medical treatment. Surgery is only indicated after an observational period during which the Peyronie disease is shown to be stable.

For the best results, the Peyronie disease plaques and the angulation of the penis should be stable for several months prior to surgery. Unless the inflammatory phase of Peyronie disease resolves first, worsening of the plaque may continue after surgery, which increases the likelihood of recurrent curvature.[32]

Common surgical correction methods are described below.

The Nesbit tuck procedure

Unaffected tunica albuginea is removed from the side of the penile shaft immediately opposite the Peyronie disease plaque to straighten and shorten the penis. For this procedure to work, potency should be normal, and the penile curvature should be less than 60°.

Tunica plication procedure

The tunica albuginea is plicated (not excised) to straighten the penis. This technique also causes penile shortening because the longer side of the penis is effectively shortened to produce a more straight erection.[33]  See the intraoperative and postoperative images below.

Plaque excision and grafting

This procedure may be performed to preserve penile length when the curvature is greater than 60°.[34, 35, 36] Autologous tissue-engineered endothelialized grafting has been used.[37]

Penile prosthesis insertion

This method is useful when comorbid severe erectile dysfunction is present.[38]  Adjunctive techniques to manage residual curvature, such as manual modeling, plication, or grafting, can be used during prosthesis insertion.[39]

Newer surgical techniques for Peyronie disease include the thinning of the plaque with carbon dioxide lasers.[40]

Consultation with a urologist is needed for surgical management. Surgical management is indicated when medical management fails or when significant pain and/or a complete inability to have intercourse is present.

A sex therapist may provide useful adjunct care, both to underscore the realistic expectations and to evaluate comorbid sexual dysfunction.

Theoretically, patients with Peyronie disease should avoid vigorous intercourse with a weak erection.

If the patient has diabetes, it should be controlled.

No method for absolute prevention is known.

Radiation treatment may be recommended for early, especially painful situations. Radiation from a beta-beam linear accelerator is used to reduce inflammation. This treatment does not change or remove late-stage postinflammatory plaques.

Extracorporeal shock-wave therapy may help in treating the curvature associated with Peyronie disease. This treatment does not help the pain and is still experimental.

Most of the following treatments for Peyronie disease are only temporizing. In December 2013, the FDA approved the first drug treatment, collagenase clostridium histolyticum (Xiaflex), for Peyronie disease.

The efficacy of Potassium p-aminobenzoate has not been established.[41]

Anti-inflammatory agents, such as colchicine, may help patients with Peyronie disease by reducing inflammation.[42]

Only anecdotal evidence for use exists for estrogen receptor antagonists such as tamoxifen.[14, 43]

Class Summary

Proteinase hydrolyzes collagen.

Collagenase clostridium histolyticum (Xiaflex)

Collagenase clostridium histolyticum hydrolyzes collagen in its native triple-helical conformation, resulting in lysis of collagen deposits. It is indicated in men with a palpable plaque and penile curvature deformity of at least 30 degrees at the start of therapy. It is available for treatment of Peyronie disease only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called the XIAFLEX REMS Program.

Class Summary

The antioxidant properties of vitamin E may limit the extent of inflammation. Vitamin E is inexpensive, has few adverse effects, and has anecdotal usefulness.

Vitamin E (Amino-Opti-E, Aquasol, E-Vitamin)

Vitamin E protects polyunsaturated fatty acids in membranes from attack by free radicals and protects red blood cells against hemolysis.

Class Summary

These agents may improve pain and lessening of penile curvature. Their efficacy is not clearly established.

Potassium p-aminobenzoate (Potaba)

Potassium p-aminobenzoate may enhance monoamine oxidase activity and thereby lower the local level of serotonin that is thought to be a stimulant for fibrosis.

Class Summary

The initial stage of a Peyronie disease plaque involves histamine-mediated inflammation. Anecdotal evidence suggests that an antihistamine may limit this inflammation.

Fexofenadine (Allegra)

Fexofenadine competes with histamine for H1 receptors in the GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. It does not cause sedation.

Class Summary

These agents may help patients with Peyronie disease by reducing inflammation.

Colchicine

Colchicine decreases leukocyte motility and phagocytosis in inflammatory responses.

Class Summary

These agents inhibit TGF-beta actions and inflammatory reactions. TGF-beta and inflammatory mediators are involved in the production of Peyronie disease plaques in animal studies. Only anecdotal evidence for use of these agents exists.

Tamoxifen (Nolvadex)

Tamoxifen competitively binds to estrogen receptors, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects.

Class Summary

Anecdotal evidence shows some lessening of the scarring process after intralesional injections. The theory is based on the known action of verapamil in decreasing the production and secretion of extracellular matrix macromolecules by fibroblasts while increasing collagenase production in the same area.

Verapamil (Calan, Covera-HS, Verelan)

Verapamil relaxes smooth muscles and increases oxygen delivery during vasospasms.

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well; these include the inhibition of the following: leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)

Aspirin is used to treat mild to moderate pain. It inhibits prostaglandin synthesis, which prevents the formation of platelet-aggregating thromboxane A2.

Acetaminophen (Tylenol, Feverall, Tempra, Aspirin Free Anacin)

Acetaminophen is the drug of choice for the treatment of pain in patients with documented hypersensitivity to aspirin or NSAIDs or upper GI disease and who are taking oral anticoagulants.

Ibuprofen (Motrin, Ibuprin)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen (Aleve, Naprelan, Naprosyn, Anaprox)

Naproxen is used for the relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which decreases prostaglandin synthesis.

Etodolac (Lodine)

Etodolac inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclo-oxygenase, which results in decreased formation of prostaglandin precursors, which, in turn, results in reduced inflammation.

Flurbiprofen (Ansaid)

Flurbiprofen may inhibit the cyclo-oxygenase enzyme, which, in turn, inhibits prostaglandin biosynthesis. These activities may result in analgesic, antipyretic, and anti-inflammatory effects.

Ketoprofen (Actron, Orudis, Oruvail)

Ketoprofen is for the relief of mild to moderate pain and inflammation. Small doses initially are indicated in small or elderly patients or those with renal or liver disease. Doses greater than 75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observe the patient for response.

Piroxicam (Feldene)

Piroxicam decreases the activity of cyclo-oxygenase, which, in turn, inhibits prostaglandin synthesis. These effects decrease the formation of inflammatory mediators.

Class Summary

Interferon slows fibrogenesis, inhibits RNA synthesis, and inhibits oxidative stress

Interferon alfa-2b (Intron A)

Intralesional injections of interferon alfa-2a may be effective in decreasing plaques and scarring.

Class Summary

These agents may reduce plaque size and penile curvature.

Pentoxifylline (Trental, Pentoxil)

This would be off-label use. Pentoxifylline may alter the rheology of red blood cells, which, in turn, reduces blood viscosity. It may be used, but with extreme caution for hemorrhage.