Peyronie disease (PD) is characterized as a fibrous, inelastic lesion of the tunica albuginea. It is thought to result from trauma or microtrauma to the erect penis in genetically susceptible individuals, though the mechanism of disease has not been fully elucidated [1]. The lesion can be painful in some individuals, and can also result in erection deformities making intromission difficult or impossible (Fig. 1). Disease prevalence is often quoted at 3.2% to 8.9% in adult men, though it may be higher due to underreporting. Associated comorbidities include erectile dysfunction (ED), clinical depression, diabetes, hypertension, dyslipidemia, low testosterone, obesity, smoking, and Dupuytren contractures [1,2].

The natural history of PD has two phases. First is the active (or acute) phase, characterized by active inflammation and progressive deformity of the erect penis. Penile pain, when present, also occurs at this time. The acute phase generally lasts from 6 to 18 months, and after this phase, the vast majority of patients go on to have stabilization of the plaque or progression of their disease [2]. This stabilization process is characterized by fibrosis, dystrophic calcifications, and rarely, ossification, and occurs in the chronic (or latent) phase. After the acute phase has ended, only 10% to 15% of patients will have spontaneous resolution of PD, although many will experience resolution of their associated pain [2]. Finally, the presence of intralesional calcifications is significant, as these lesions are traditionally less amenable to non-surgical treatments; PD patients with these characteristics have often been excluded from participation in non-surgical clinical trials.

The pathophysiologic basis for PD relates to the inflammation seen in the acute phase, and the subsequent disordered wound-healing characteristics of the chronic phase. Non-surgical treatment modalities to date have focused on disrupting one or both of these processes. Pluripotent stem cells within the tunica albuginea are an ongoing source of inquiry that may both help explain the disordered wound healing and shed light on novel approaches to help treat this complex disease.

We searched the literature for nonsurgical treatments of PD, including oral or topical therapy, intralesional injections (ILI), iontophoresis, extracorporeal shock wave therapy (ESWT), radiotherapy, penile traction therapy (PTT), and stem cell therapy. Aiming to build on the 2012 updates by Schaeffer and Burnett [3], and Serefoglu and Hellstrom [4], we placed emphasis on the most recent randomized controlled trials (RCTs) in order to provide the most accurate, scientifically based knowledge to guide clinical practice. See Table 1 [5-17] for a summary of recent studies, both RCTs and others, involving non-surgical treatments.

Although a topical treatment approach to PD is appealing to patients for reasons of comfort and accessibility, in practice the results are less than ideal. The greatest argument against topical therapy comes from a study of men pretreated with topical verapamil who then immediately underwent surgical correction for their PD. The excised tunica albuginea tissue samples from these PD patients were examined for the presence of verapamil, which was not seen. From this the authors concluded that with topical therapy the drug was not actually absorbed into the plaque tissue [39]. However, in the largest RCT to date there was statistically significant improvement in curvature and plaque size in patients receiving topical applications of verapamil (15% twice daily) over the course of three months [40]. The effect was statistically superior to that of a placebo, and patients who continued the topical therapy after the three-month trial continued to show improvement throughout the nine months they were followed. Further studies are needed to reconcile these contradictory findings.

Iontophoresis, or transdermal electromotive drug administration, is a method theorized to provide superior tissue penetration for the transdermal application of medications. Two trials in 2000 showed very promising results, utilizing a number of different pharmacologic agents including dexamethasone, lidocaine, orgotein, and verapamil in various combinations. Significant reductions in plaque size, curvature, and pain were found over the course of short, three-week treatment regimens [41,42]. These results were subsequently reinforced by a study of post-operative tunica albuginea tissue in patients pre-treated with iontophoresis that demonstrated a detectable level of the drug in the majority of patients [43]. In 2004, a RCT comparing verapamil and dexamethasone combination therapy to a placebo (lidocaine) demonstrated the superiority of the former, suggesting that verapamil and dexamethasone themselves had some therapeutic effect [44].This assertion was immediately called into question by a subsequent RCT that demonstrated verapamil alone had no superiority to a placebo (saline) [45]. Most recently, an unblinded RCT of 60 patients suggested that verapamil administered with iontophoresis had better results than verapamil administered intralesionally [8]. Again, further large-scale studies are needed to validate these findings.

Two small trials published in 2008 by Levine et al [49] and in 2009 by Gontero et al [50], respectively, showed only mild success with daily use of PTT over the course of six months. In the second trial, these results were not statistically significant, and found to be largely unsatisfactory to the patients involved. Penile remodeling has been found to be synergistic with collagenase treatment [10], suggesting there may be some role for PTT in combination with other treatment modalities. Further studies are needed to define the role of PTT in treating PD.

PD is characterized by disordered wound healing that is often associated with antecedent trauma to the erect penis. Yet not all individuals with a history of penile trauma go on to develop PD, supporting the idea that it is some interplay between trauma and genetic susceptibility that leads to the development of the disease. This idea is supported by the presence of myofibroblasts in PD lesions, which are cells that have long been implicated in the excessive collagen production that characterizes PD. These myofibroblasts originate from pluripotent stem cells in the tunica albuginea, but importantly, are not present in normal tunica albuginea tissue [51]. While therapies to date have focused on treating the consequences of the aberrant healing process caused by myofibroblasts, stem cell therapy offers the hope of altering the disease course before it even begins.

Even though stem cells are implicated in the pathogenesis of PD and offer hope for developing future treatments, barriers to implementing stem cell therapy in practice remain. An incomplete understanding of the pathophysiology of this complex disease has led to difficulty in reproducing the complexity of PD in an animal model. This lack of a universally accepted animal model for PD makes testing novel stem-cell therapies more difficult [52]. That being said, new therapies utilizing adipose tissue-derived stem cells (ADSCs) have been investigated in a rat model, and show early promise. Castiglione demonstrated in 27 male Sprague-Dawley rats that ADSC injection prevented fibrosis in the tunica albuginea during the active phase of a TGF-induced PD-like state [53]. The therapeutic action of these stem cells is thought to derive from their proangiogenic capacity that alters the cycle of vascular injury, ischemia, and fibrosis characteristic of the inflammatory phase of PD [52]. While still in its infancy, stem cell therapy offers perhaps the best hope for a definitive cure for PD.

Challenges in the treatment of PD are multifactorial. Reluctance by both patients and physicians to discuss this sensitive topic are a barrier to patients seeking treatment in the first place. Undoubtedly this contributes to the paucity of large RCTs that have been performed to date. The trials that do exist are often underpowered and utilize a plethora of different treatment modalities in a dizzying array of combinations. This multitude of treatment options for PD is a reflection of their relative ineffectiveness, and the lack of a nonsurgical 'gold standard' of treatment has made it difficult to compare the relatively few RCTs that do exist. Finally, the natural history of the disease in two distinct pathophysiologic phases (acute and chronic) further muddles the assessment of the treatment response, since treatments appropriate at one time may not be effective at another. This is compounded by a variable disease course that can progress, regress, or rarely, even resolve, without any treatment at all. Additional large-scale RCTs are needed in order to further elucidate the current best practices, and additional basic science research is needed to devise more effective treatments for this difficult condition.