Vitamin E (tocopherol) is a fat-soluble compound that acts as a natural antioxidant to reduce the number of oxygen-free radicals produced in the energy metabolism. It has also been shown to play a role in DNA repair and in immune modulation[11]. The widely accepted use of tocopherol in the treatment of PD attests to the hypothesis that it inhibits fibrosis by acting as a scavenger of oxygen free radicals. In vitro studies examining the effect of free radicals on human cavernosal cells have shown a direct association with increased collagen production[12]. Based upon these findings it is logical to conclude that inhibition of free radicals (i.e., with use of tocopherol) should decrease the rate and degree of fibrosis. However, in vivo data has failed to reveal any concrete benefits in PD patients[13,14]. To date, tocopherol is commonly prescribed by most urologists in once- or twice-daily doses of 400 IU because of its wide availability, low cost, and safety. In 1983, Pryor et al[10] conducted a double-blind, placebo-controlled crossover study evaluating vitamin E for the treatment of PD in 40 patients. No significant improvements were noted in plaque size or penile curvature. The authors therefore did not recommend vitamin E for the treatment of PD as there was no meaningful evidence of its benefit in placebo-controlled trials.

Potassium paraaminobenzoate (Potaba, Glenwood) is a vitamin B complex and is believed to exert an antifibrotic effect through an increase in oxygen uptake by the tissues, a rise in the secretion of glycosaminoglycans, and enhancement of the monoamine oxidases activity in tissues thereby decreasing local levels of serotonin and, in turn, possibly decreasing fibrogenesis. A prospective double-blinded controlled study by Shah et al[15] analyzed 41 patients with PD and showed that, while penile pain was significantly improved by potassium para-aminobenzoate (12 g/d for 12 mo) neither penile curvature nor penile plaque size were affected. Weidner et al[16], in a prospective randomised double-blind placebo-controlled trial evaluating 103 patients with PD, found that potassium para-aminobenzoate (3 g/d four times daily for 12 mo) decreased penile plaque size significantly but had no effect on penile curvature or penile pain. The Treatment-emergent adverse events reported were: nausea, anorexia, pruritus, anxiety, chills, cold sweats, confusion, and difficulty concentrating and therefore no serious adverse events have been reported.

Tamoxifen is a nonsteroidal oestrogen receptor antagonist. The action mechanism which should determines changes in PD is the modulation of the transforming growth factor (TGF)b1 secretion by fibroblasts. Teloken et al[17] published a placebo controlled randomised study performed in 25 patients in the late stages of PD with a mean disease duration of 20 mo. The results of this study showed that Tamoxifen 20 mg twice daily for 3 mo failed to demonstrate significant improvement in pain, curvature, or plaque size[17].

Colchicine is a medication that is commonly employed in the treatment of acute attacks of gout. Its anti-inflammatory effects suggested its possible use in treating PD. Kadioglu et al[18] reported on the results of a study on 24 men, half of whom were given colchicines (0.6-1.2 mg daily for 3-5 mo) and whose painful erections and penile curvature were shown to improve in 50% of them with penile plaque decreasing or disappearing completely. Akkus et al[19] presented the results of a study involving 60 men treated with colchicine 0.5-1 mg daily for 3-5 mo and subsequently increased to 2 mg twice daily. Following this treatment penile pain was resolved in 95% of the cases while penile curvature improved in 30%. The reported treatment-emergent adverse events from the use of colchicine were gastrointestinal effects (nausea, vomiting, diarrhea), which were improved by dose escalation.

Finally, Prieto Castro et al[20] investigated the combination of vitamin E and colchicine (600 mg/d and 1 mg every 12 h, respectively) in patients with early-stage PD for 6 mo. The results of this study showed a significant improvement in plaque size and curvature, but not in pain when compared with ibuprofen 400 mg/d for 6 mo.

It has been suggested that carnitine can reduce intracellular calcium levels in endothelial cells which, in turn, may eventually suppress fibroblast proliferation and collagen production thereby reducing penile fibrosis. To date, only 1 randomised double-blind study evaluating the efficacy of acetyl-L-carnitine has been conducted by Biagiotti and Cavallini[21]. In 48 patients with early-stage PD, subjects were given either tamoxifen 20 mg twice daily or acetyl-L-carnitine 1 g twice daily for 3 mo. After 3 mo, acetyl-L-carnitine was significantly more effective than tamoxifen in reducing pain and curvature and in inhibiting disease progression, but not in reducing penile plaque size (both tamoxifen and carnitine significantly reduced plaque size.

Another study investigated the combination of propionyl-l-carnitine (2 g/d for 3 mo) with intralesional verapamil (10 mg weekly for 10 wk). The results showed that this combination therapy significantly reduced penile curvature, plaque size, and disease progression when compared with intralesional verapamil combined with tamoxifen (40 mg/d) for 3 mo[22].

Pentoxifylline is a nonspecific phosphodiesterase inhibitor that downregulates TGFb1 and increases fibrinolytic activity. Valente et al[23] found that normal human and rat tunica albuginea as well as PD plaque tissue expresses phosphodiesterase (PDE)5A-3 and PDE4A, B and D. In their in vitro study, PD fibroblasts were cultured with pentoxifylline and found to have increased cyclic adenosine monophosphate levels and reduced collagen I levels as compared to controls. An increase of nitric oxide levels may be effective in preventing the progression of PD or reversing fibrosis. Brant et al[24] performed a study on 62 patients with PD, and showed that treatment with pentoxifylline for 6 mo appeared to stabilize or reduce calcium content in penile plaques and also tended to improve penile curvature.

The rationale for the use of a phosphodiesterase type 5 (PDE5-I) in PD comes from animal studies which show that PDE5-I can reduce the collagen/smooth muscle and collagen III/I ratios and increase the apoptotic index in PD like plaque[25]. In a recent retrospective controlled study Chung et al[26] investigated the role of daily tadalafil (2.5 mg for 6 mo) which resulted in a statistically significant (P < 0.05) resolution of the septal scar in 69% of patients compared with 10% in the control group (no treatment). However, this study included patients with isolated septal scars without evidence of penile deformity[26].

The powerful anti-inflammatory effect of steroids makes them obvious agents for intralesional therapy of PD. Steroids operate by counteracting the inflammation responsible for Peyronie’s plaque progression via inhibition of phospholipase A2 and suppression of the immune response and by diminishing collagen synthesis. In 1954, Bodner et al[27] reported improvement in 17 patients treated with intralesional hydrocortisone and cortisone. In 1975, Winter et al[28] showed no difference between patients treated with dexamethasone injections and the natural history of the disease. Cipollone et al[29], in a single-blind placebo-controlled study with intralesional administration of betamethasone, reported that no statistically significant changes were seen in penile deformity, penile plaque size, nor penile pain during erection. Adverse effects included tissue atrophy, thinning of the skin, and immune suppression.

Verapamil is a calcium channel antagonist that is thought to selectively inhibit calcium ion flux in both cardiac muscle and cells responsible for intracardiac conduction, as well as in coronary and systemic arteries. The rationale for its use in the intralesional treatment of patients with PD is based on in-vitro data that demonstrates transport of extracellular matrix molecules that include collagen, fibronectin, and GAGs as a calcium-dependent process[30]. A concomitant increase in collagenase activity, modification of the inflammatory response in the early phase of the disorder, and inhibition of fibroblast proliferation in the plaques are other proposed mechanisms. Shirazi et al[31] reported in a randomized placebo-controlled study that no statistically significant differences in plaque size, penile curvature, penile pain during erection, and plaque ‘‘softening’’ were seen.

Clostridial collagenase is a chromatographically purified bacterial enzyme that selectively attacks collagen and is known to be the primary component of the PD plaque. Collagenase was first studied in vitro by Gelbard et al[32] in 1982. A subsequent clinical trial by that group demonstrated subjective improvement in 64% of patients within 4 wk of treatment[33]. A decade after their initial study, the group published their findings of a double blind trial in 49 men[34]. In this study which compared the effects on plaque size and penile deformity of intralesional purified clostridial collagenase (6000-14000 U) and saline placebo, the overall response was 36% with clostridial collagenase compared with 4% with placebo (P < 0.007). Follow-up was only 3 mo. Response rates were even higher in patients with smaller plaques and curvature < 60°. The efficacy of intralesional collagenase injections (three injections of clostridial collagenase, 10000 U/0.25 cm³ per injection, administered over 7-10 d and subsequently administered over 7-10 d at 3 mo) was assessed over a non-placebo-controlled short-term follow up study in a small population of men with PD[35]. This study showed a significant reduction from baseline in the deviation angle, plaque thickness, and plaque extension, but it was biased by an incorrect scientific approach. The most commonly reported side effects were penile pain, contusions, and ecchymosis.

Duncan et al[36] reported in 1991 that interferons decrease the rate of proliferation of fibroblasts in Peyronie’s plaques in vitro, reduce the production of extracellular collagen, and improve the activity of collagenase. Hellstrom et al[37], demonstrated that intralesional injections (5 × 10⁶ units of interferon a-2b in 10 mL saline two times per week for 12 wk) improved average curvature in the treatment group by 13°vs 4° in the placebo arm, and that 27% of patients in the treatment group had measurable improvement vs 9% of the saline group. Pain resolution was noted in 67% of the treatment patients vs 28% for the placebo[37]. Side effects include myalgias, arthralgia, sinusitis, fever, and flulike symptoms which can be effectively treated with nonsteroidal anti-inflammatory drugs before interferon injection.

Fitch et al[38] presented the results of a small randomised placebo controlled study on topical verapamil applied as gel 15% to the penile shaft twice daily. The penile curvature, plaque size, and penile pain were significantly improved. After 9 mo of treatment better improvement was reported compared with the results at 3 mo, demonstrating that a prolonged treatment period may be important. However, a lack of evidence exists supporting that topical verapamil applied to the penile shaft produces adequate levels of active compound within the tunica albuginea.

To overcome limitations of topical therapies, emphasis has more recently been placed on testing modalities such as iontophoresis, which enhances the local uptake of drugs. Iontophoresis involves the application of an external electric force to induce further (electromotive) penetration of topical medication. Di Stasi et al[39] presented their results of a randomised double blind controlled study, demonstrating that iontophoresis with verapamil 5 mg and dexamethasone 8 mg resulted in a statistically significant improvement in penile curvature and plaque size. On the other hand, Greenfield et al[40] with a randomized double-blind placebo controlled study showed that penile curvature was not statistically improved after iontophoresis with verapamil 10 mg. No significant events with Iontophoresis were reported.

The mechanism of action involved in extracorporeal shock wave lithotripsy (ESWL) for PD is still unclear, but there are two hypotheses. In the first hypothesis, ESWL may work by directly damaging and remodeling the penile plaque. In the second hypothesis, ESWL may increase the vascularity of the area by generating heat, resulting in an inflammatory reaction with increased macrophage activity causing plaque lysis and eventually leading to plaque reduction. Hauck et al[41] in an exploratory meta-analysis detected that ESWT seems to have an effect on penile pain during erection and on the improvement of sexual function. Pain seems to resolve faster after ESWT than during the course of the natural history. The effect on plaque size and penile curvature is less impressive. This result were confirmed by Palmieri et al[42] that published the only existing prospective randomised double-blind placebo-controlled study where they investigated four weekly treatment sessions of ESWL, with each session consisting of 2000 focused shock waves which resulted in significant improvement for penile pain only.

The use of tissue expanders has long been a mainstay of treatment in the orthopedic, oral-maxillofacial and plastic surgical fields. A continuous traction in Dupuytren contracture increases the activity of degradative enzymes. This first leads to a loss of tensile strength and subsequently to solubilization. This is followed by an increase in newly synthesized collagen. Levine et al[43], in an uncontrolled study, applied this technique on 10 patients with PD whereby application of the the FastSize Penis Extender was the only treatment for 2-8 h/d for 6 mo. Penile curvature was reduced in all men from 10° to 45°, with an average reduction of 33% (range: 51°-34°). Stretched penile length increased to 0.5-2.0 cm, and erect girth increased to 0.5-1.0 cm, with a correction of the hinge effect in four of four men. No adverse events such as skin changes, ulcerations, hypoesthesia, or diminished rigidity were reported.

When it comes to vacuum devices the same principles as traction devices are followed. Raheem et al[44], evaluated the efficacy of vacuum devices in an uncontrolled study assessing 31 patients. The vacuum device was applied over a 12-wk period (Osbon ErecAid, MediPlus, High Wycombe, United Kingdom) for 10 min twice daily. Penile pain was reduced significantly (P = 0.012). Stretched penile length also increased significantly (P = 0.029) with a mean of 0.5 cm. Reduction of the curvature was reported in 67% of patients. 10% had worsening curvature and 23% showed no change. Half of the patients were satisfied with the outcome while the remainder had their curvature corrected surgically. Vacuum therapy can improve or stabilize PD curvature, is safe to use in all stages of the disease, and could reduce the number of patients requiring surgery.