|Year : 2016 | Volume
| Issue : 2 | Page : 53-59
Recent Advances in Pharmacotherapy for Peyronie's Disease
Yang Luan, Jihong Liu
Department of Urology; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
|Date of Web Publication||26-Apr-2016|
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030
Source of Support: None, Conflict of Interest: None
Peyronie's disease (PD) is an acquired fibrotic disease of the penile tunica albuginea accompanied by penile pain, curvature, erectile dysfunction, and psychosocial problems. Recent evidence suggests an increasing prevalence of PD with current uncertainty of its etiology and pathophysiology. According to the natural history of PD, the disease can be divided into acute phase and fibrotic phase that greatly determines the treatment plan. Oral, intralesional medication, and topical therapy are suitable for acute phase while surgical therapy is suggested only in fibrotic phase with the formation of stable plaques. Although a number of pharmacologic agents have been evaluated in preclinical and clinical studies, a few of them can be used in the clinic with satisfactory outcome. Recent studies showed promising results in improving symptoms and limiting disease progression, especially the only Food and Drug Administration-approved collagenase Clostridium histolyticum as well as some multimodal therapies. In this study, we reviewed currently available medications and focused on recent advances in PD pharmacotherapy. However, further high-quality studies are much needed to clarify the pathogenesis of PD and, more importantly, to find out effective and safe medicines for PD treatment.
Keywords: Penile curvature, peyronie′s disease, pharmacotherapy, plaque
|How to cite this article:|
Luan Y, Liu J. Recent Advances in Pharmacotherapy for Peyronie's Disease. J Integr Nephrol Androl 2016;3:53-9
| Introduction|| |
Peyronie's disease (PD) is defined as an acquired fibrotic disease of the penile tunica albuginea, characterized by formation of localized fibrous plaques that cause penile curvature, pain, shortening, erectile dysfunction (ED) and often lead to psychological distress. A population-based study recruiting 11,420 USA males reported that 13% of them had been either diagnosed, treated, or had symptoms of PD.  Another epidemiological study found that younger patients accounted for 16.9% of the whole PD sample, and they usually have more acute onset and severe progression of symptoms. 
Although PD first described in 1743, the etiology and pathophysiology remain unclear. Antecedent injury of tunica albuginea is currently believed as the major reason to induce the remodeling of connective tissue and the formation of fibrous plaques in the penis. , In this process of wound healing cascade, the activation of transforming growth factor b1 (TGFb1) signaling is a pivotal mechanism to induce oxidative stress, inhibit collagenase activity, activate collagen synthesis related factors, and eventually promote extracellular matrix materials deposition. ,, In addition, risk factors such as heredity, connective tissue disorders, hypertension, and cigarette smoking, as well as high level of low-density lipoprotein are considered to be positively associated with the presence of PD. ,
The clinical course of PD can be distinguished into two stages. The initial stage is the acute phase, usually lasts for 12-18 months from the onset of the disease, with unstable symptoms of painful erections, progressive penile deformity (including curvature, shortening, indentation, narrowing, hinge effect, or hourglass deformity), and evolving fibrous plaque. To better understand the natural history of PD, some studies followed treatment naive PD patients for at least 12 months. They found that penile pain would be unchanged or improved in most patients while penile plaque size or deformity was much less likely to resolve over time. ,, The latter stage is the fibrotic phase with relatively stable symptoms for at least 3 months and the formation of hard palpable plaques. At this stage, pain is less common. Penile deformity is no longer progressive and most likely to appear at dorsal, dorsolateral, or ventral sites. Besides some of PD patients may be accompanied by ED, psychological distress such as depression is generally present.
PD is not a life-threatening disease. Therefore, a treatment plan should be decided for each after carefully considering the disease severity, patient's expectation, benefits, and possible side effects of specific treatment. The aim of the treatment is primarily focused on the recovery of coital function, improvement of symptoms, and release of psychological burden. It is important to identify the disease state of a PD patient given the selection of a therapeutic strategy mainly depends on whether his symptoms are stable or not. Conservative treatments are mainly used in the acute phase of disease which contain oral medicines, intralesional injections, and topical treatments.  Surgical treatments should not be suggested until the formation of hard plaques and the stabilization of symptoms for at least 3 to 6 months in the fibrotic phase.  In accordance with the treatment principles above, an investigation of PD treatment options from 639 American urologists reported that of these urologists, 81% preferred initial treatment with oral agents and 86% considered that the optimal timing for surgery is at longer than 12 months after onset of symptoms. 
Although a series of pharmacological agents have been proposed and investigated in PD treatment, effective medicines are limited. Recent studies especially collagenase Clostridium histolyticum (CCH), the only Food and Drug Administration (FDA) approved drug for the treatment of PD, and some multimodal therapies showed impressing results in improving PD symptoms. Moreover, the PD animal models have been successfully created using TGFb1, fibrin, surgical trauma, or tunica albuginea allograft, which is convenient for scientists to explore novel treatment approaches. ,
Surgical therapy is the gold standard for PD treatment in fibrotic phase. However, it is also important and necessary to find reliable minimally invasive methods to alleviate the symptoms, reverse penile plaque formation, and restrict the progression of PD at an early stage. Herein, we review currently available medications for PD treatment and focus on recent advances in PD pharmacotherapy from well-designed preclinical and clinical researches. Although standard conservative treatment plan for PD remains unavailable, this review will provide comprehensive evidence for clinicians to prescribe when they face PD patients with different conditions of disease.
| Oral treatment|| |
Vitamin E, a natural antioxidant, is the earliest and the most commonly used oral medication for PD treatment given its low price and potent ability to resist inflammation.  Unfortunately, a double-blind, placebo-controlled, randomized study (randomized controlled trial [RCT]) showed Vitamin E did not improve the symptoms of penile pain, curvature, or plaque size in patients with PD.  Some studies tried to combine Vitamin E with other treatments, but only one observational study reported a significant decrease in curvature when PD patients received treatment with Vitamin E and extracorporeal shockwave therapy. 
Potaba has been prescribed for PD treatment since 1959 due to its anti-inflammatory and antifibrotic abilities.  In an early, prospective, double-blinded controlled study, oral potaba at 12 g/day for 12 months only improved penile pain.  However, the only RCT reported that potaba administration could decrease plaque size and prevent the deterioration of penile curvature when compared to placebo.  No serious side effects were reported except some light symptoms such as nausea, anorexia, anxiety, and confusion.  More studies are needed to confirm its role in PD therapy.
Tamoxifen is an estrogen receptor antagonist and has the potential to control the release of TGFb1 and block the TGFb receptors in tunica albuginea to withstand fibrogenesis.  However, based on the results of existed studies, tamoxifen could not improve penile pain, curvature, or plaque. 
Colchicine is introduced into PD treatment for its anti-inflammatory ability.  Unfortunately, an RCT and a retrospective study reported that symptoms improvement was found neither in single use of colchicine nor in combined therapy with Vitamin E. ,
Carnitine is an inhibitor of acetyl coenzyme-A and has the potential of antioxidative stress.  As for its use in PD treatment, the results of clinical researches were inconsistent. A randomized trial reported that carnitine had better effect on improving penile curvature than tamoxifen  while another RCT showed that carnitine therapy had no improvement in curvature, pain, or plaque size than placebo. 
Pentoxifylline, a nonspecific phosphodiesterase inhibitor, has the properties of anti-inflammation and anti-fibrogenesis.  In vitro study demonstrated that pentoxifylline could inhibit TGFb1 and reduce the deposition of collagen I as well as elastin. , Animal experiment showed that pentoxifylline could induce the apoptosis of fibroblast in the tunica albuginea and the decrease of plaque volume as well as the ratio of collagen to fibroblast.  A clinical study showed that larger percentage of PD patients in the pentoxifylline group was found with plaque improvement than that in the nontreated group.  In addition, combined treatment of oral pentoxifylline and intralesional verapamil had better pain reduction and ED improvement compared to the pentoxifylline monotherapy.  Unfortunately, clinical evidence could not confirm the efficacy of pentoxifylline in PD treatment due to limited data. High-quality researches with large sample sizes are needed.
Phosphodiesterase type 5 inhibitors
Phosphodiesterase type 5 inhibitors (PDE5i) were introduced into PD treatment on the basis of the results from animal studies that they could decrease the collagen to smooth muscle ratio as well as collagen III to collagen I ratio and enhance the apoptosis level in the fibrotic plaques of PD.  However, clinical studies regarding single or combined use of PED5i showed no effect on symptoms improvement except ED. ,
Omega-3 fatty acids
Omega-3 fatty acids are regarded as anti-inflammatory agents. However, the only human study reported that eicosapentaenoic and docosahexaenoic acids administration at 1.84 g a day for 6 months had no advantage in the symptoms improvement of penile curvature, pain, plaque size, and erectile function over placebo. 
Coenzyme Q10 is an antioxidant and anti-inflammatory medicine. An RCT reported coenzyme Q10 supplementation at 300 mg a day for 24 weeks lead the decrease of plaque volume and penile curvature and improved erectile function in patients with early chronic PD.  Further studies are necessary to confirm its effect on PD treatment.
The theoretical basis of using L-arginine in PD treatment is its ability to activate nitric oxide/ cyclic guanosine monophosphate pathway and inhibit TGFb1 expression.  An animal study showed that L-arginine could reduce collagen I expression and the plaque volume in a TGFb1-induced PD rat model.  However, no clinical study has completed to confirm L-arginine's role in PD treatment.
The role of anthocyanin, extracted from black soybean, was evaluated in a fibrin induced rat model of PD. The authors concluded that oral administration of anthocyanin at 50 mg/kg twice a day for 4 weeks might have anti-inflammatory and antifibrotic effects for penile plaque formation.  Yet, no clinical data are existed to support its use in PD patients.
| Intralesional treatment|| |
As the uncertain efficacy of current oral therapy, direct drug injection into the unstable penile plaque is employed to improve PD symptoms and limit the progression of local fibrotic nodule. Intralesional treatment can provide high concentration of drugs within plaques and reduce systemic adverse events. At present, agents such as steroids, calcium channel blockers (CCBs), interferon, CCH, and mesenchymal stem cells are more common to be involved in PD treatments.
Corticosteroids were reported as the earliest agents for PD intralesional therapy in 1952 due to their well-known anti-inflammatory properties.  However, the inconsistent results from existed studies limit their use in the clinic. For instance, a small retrospective study showed their abilities to improve plaque size and penile pain,  but a further single-blind, placebo-controlled study got a negative conclusion that injection therapy with betamethasone had no significant changes in penile curvature, pain, and plaque volume.  Immunosuppression, tissue atrophy, and thinning of penile skin are relatively common side effects. 
Calcium channel blockers
Two kinds of CCBs are implicated in PD intralesional therapy. One is verapamil as a kind of nondihydropyridine-type CCB, and the other is nicardipine as a representative of dihydropyridine-type CCB. The intralesional injection of verapamil in PD patients is on the basis that it can regulate fibroblast function and extracellular matrix production. However, the results regarding verapamil monotherapy were inconsistent within different studies. Although some studies showed that curvature and plaque size were reduced by verapamil, , an RCT concluded that no significant differences were found on penile curvature, pain, plaque volume between the verapamil and the placebo groups.  More recently, the results of most combination therapies gave us more confidence to use verapamil in PD treatment. The penile curvature, plaque size, and erectile function improvement were simultaneously reported in multimodal therapies such as intralesional injection of verapamil with oral tadalafil, antioxidants, or pentoxifylline. ,,
Nicardipine has the properties of anti-inflammation, anti-nociception, and reduction of collagen as well as glycosaminoglycans in the extracellular matrix.  In a prospective, randomized, and single-blind clinical trial, 74 PD patients in the transition stage of acute to fibrotic phase were recruited to receive intralesional injections of 10 mg nicardipine or saline biweekly with a total of six injections. When compared to the control group, nicardipine improved penile pain, international index of erectile function-5 score, and plaque size. In addition, no severe side effects were reported. 
Although some promising results come out from existed studies, high-quality clinical trials are still needed to confirm the efficacy and safety of CCB in PD treatment.
The intralesional use of interferon a-2b for PD treatment can date back to a study in 1991, which showed the abilities of this drug in decreasing fibroblast proliferation and reducing extracellular matrix as well as collagen production in cultured human PD fibroblasts.  A decade ago, a single-blind, multicenter, placebo-controlled, parallel study evaluated the effect and safety of interferon a-2b in PD patients with average symptom duration of 20 months and reported that intralesional injection of interferon a-2b at a dose of 5 × 10 6 units every two weeks for 12 weeks was effective and safe to reduce penile curvature, plaque volume, and pain.  However, another randomized designed study evaluated PD patients with symptoms <6 months duration, which reported that only pain was resolved in interferon a-2b group or interferon a-2b + Vitamin E group when compared with Vitamin E group.  More recently, some retrospective studies found intralesional therapy with interferon a-2b could only improve penile curvature in consecutive PD patients. , These discrepancies among the studies indicate that the effect of intralesional use of interferon a-2b might partly depend on disease stage. In addition, clinicians should notice its potential adverse events including inflammatory and flu-like symptoms when they prescribe this drug.
CCH, a collagen degradation enzyme from bacteria C. histolyticum, has the potential to decrease both collagen I and collagen III and increase fibroblasts apoptosis.  Till now, CCH is the first and the only FDA approved drug for PD patients with stable plaque and dorsal or dorsolateral curvature more than 30°. This decision was mostly derived from the results of the Investigation for Maximal Peyronie's Efficacy and Safety Studies I and II.  Both of these two large RCTs contained more than 400 patients and up to eight injections of 10,000 U CCH over 24 weeks were conducted with patients' follow-up for a total duration of 1 year. The results showed that compared to the placebo, intralesional injection of CCH improved penile curvature and the PD symptom bother score, indicating the clinical efficacy of CCH on the physical and psychological improvement in PD treatment. Another Phase III, open-label study also came up with similar results.  Side effects of PD treatment with CCH include mild to moderate penile bruising, swelling, and pain, but most of them can automatically resolve, suggesting CCH is a relatively safe drug in PD treatment. 
Mesenchymal stem cells
Adipose tissue-derived stem cells (ADSCs) are one of the most widely used mesenchymal stem cells in regenerative medicine. Recently, several studies evaluated the preventive and therapeutic role of ADSCs in animal models of PD. In a TGFb1-induced rat model of PD, intralesional injection with 0.5 million ADSCs on either day 0 or day 30 of modeling could improve erectile response to cavernous nerve electrostimulation and prevent or reduce Peyronie's-like changes via decreasing the tissue inhibitors of metalloproteinases expression and increasing the level and activity of matrix metalloproteinases.  Similar efficacy and mechanisms were confirmed in another animal study regarding intralesional injection of ADSCs or human interferon a-2b modified ADSCs.  Although only five patients enrolled in the study, the first human trial evaluated the feasibility and effect of placental matrix-derived mesenchymal stem cells (PM-MSC) for PD treatment. PM-MSC injection increased the peak systolic velocity of erectile function, and seven of ten managed plaques disappeared completely after 3 months.  Long-term clinical trials with larger sample size are warranted in the future.
PD treatment through silencing histone deacetylase 2 (HDAC2) was investigated in a fibrin and thrombin-induced rat model of PD. A single intralesional injection of adenovirus encoding HDAC2 small hairpin RNA was conducted on day 15 of modeling, and histological changes of tunica albuginea were evaluated on day 30. Besides, HDAC2 small interfering RNA pretreatment followed by TGFb1 stimulation was applied in fibroblasts isolated from human PD plaque to detect the changes of fibrosis and apoptosis-related genes expressions. It was reported that silencing HDAC2 could decrease inflammatory cell infiltration, reduce phospho-Smad3 expression, and shrink the plaque size in vivo. It also inhibited the TGFb1-induced collagen production and the transdifferentiation of fibroblasts into myofibroblasts and decreased the expressions of poly ADP-ribose polymerase 1 as well as cyclin D1 to regulate apoptosis and cell cycle of fibroblasts in vitro.  These findings suggested a novel target for PD treatment by inhibition of HDAC2.
Another study focused on apoptotic signaling in PD and found that apoptosis appeared in fibrotic plaques partly resulted from the intrinsic pathway. Therefore, molecules such as bax, bcl-2, and caspase 9 involved in this pathway might be new targets for PD treatment. 
Even though most of medications above need more evidence to confirm their roles in PD treatment before clinical use, pharmacological therapy is still the first choice at acute phase of the disease. Unfortunately, there is currently neither consensus on standard treatment plan nor routine use of any oral agent for PD. However, some treatment principles and recommendations are proposed for clinicians to refer according to the latest guidelines from American Urology Association and European Association of Urology. First, clinicians should evaluate the disease condition and psychological state of PD patients and then discuss with them the available options and the known benefits as well as risks associated with each treatment before selecting a final plan. When PD is in the acute phase with active symptoms such as penile pain and deformity deterioration, it is better to choose conservative treatment. Among those existed agents, only intralesional CCH, interferon a-2b, and verapamil may be recommended to improve penile curvature after clinicians counseling PD patients with the potential adverse events of these agents. Besides, clinicians may offer extracorporeal shock wave therapy to reduce penile pain. When the disease moves forward to the fibrotic phase with stable symptoms and penile deformity for at least 3 months or formation of hard plaques, surgical therapy may be offered. In PD patients with satisfied erectile function, tunical plication and incision/excision with grafting can be operated to redress moderate-to-severe penile curvature and shortening. While in PD patients with refractory ED that is nonresponsive to PDE5i or vacuum device treatment, penile prosthesis implantation with or without adjunctive intraoperative procedures will be recommended. However, it is not recommended to make surgical intervention in the patients with penile curvature <30° and without severe deformity or ED.
PD has significant physical and psychosocial impact on male patients. However, its prevalence is even higher than what we estimated before, and the pathophysiology remains incompletely elucidated. Although preclinical and clinical studies have evaluated a number of pharmacological agents in PD treatment by oral administration or intralesional injection, a few treatment plans are confirmed to use in the clinic due to inconsistent results among studies and low significance of studies with small sample size or without natural history control. Fortunately, recent advances in PD pharmacotherapies with interferon a-2b, CCH, and some multimodal therapies revealed promising results. Emerged novel targets such as HDAC2 in basic researches also provided new ways to treat PD. Nevertheless, further high-quality preclinical and clinical studies are much needed to find out effective and safe agents for PD treatment.
Financial support and sponsorship
The study was funded by National Science Foundation of China (81270690).
Conflicts of interest
There are no conflicts of interest.
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