The purpose of this article is to review the contemporary literature on nonsurgical therapies for Peyronie’s disease (PD); focus on randomized, placebo-controlled trials; and review the latest guidelines for the management of PD from the International Consultation on Sexual Medicine. A combination of oral agents or intralesional injection with traction therapy may provide a synergy between the chemical effects of the drugs and the mechanical effects of traction. Until a reliable treatment emerges, some of the nonsurgical treatments discussed can be used to stabilize the scarring process and may result in some reduction of deformity with improved sexual function.
In 1743 Francois de la Peyronie described and was the first to offer treatment for induration penis plastica , which subsequently became known as Peyronie’s disease (PD). PD is most simply referred to as a fibrotic wound-healing disorder of the tunica albuginea. It is both a physically and psychologically devastating disorder that causes penile deformity, curvature, hinging, narrowing, shortening, and painful erections. Despite a myriad of treatment options, PD remains a considerable therapeutic dilemma because of the paucity of randomized, placebo-controlled trials. The number of medical treatments and arguably their efficacy likely relates to the fact that the true etiopathophysiology of PD and the mechanism of plaque formation are largely unknown. One paradigm is that PD is a disorder in which genetically susceptible individuals experience a localized response to endogenous factors, such as transforming growth factor (TGF)-beta, which are released in response to repeated microtrauma. This response can lead to biologic transformation of cells within the tunica albuginea; cell-cycle dysregulation; genotypic changes; and increased expression of cytokines and free radicals that can lead to unregulated extracellular matrix deposition, including fibronectin and collagen, and ultimately plaque formation, which does not appear to undergo proper scar remodeling, leaving an inelastic segment in the involved tunica albuginea. Del Carlo and colleagues investigated the role of matrix metalloproteinases (MMP), the major identified antifibrotic enzymes, and tissue inhibitors of matrix metalloproteinases (TIMP) in the pathogenesis of PD using harvested plaque from human subjects with PD. PD tissue samples were found to have reduced or absent levels of MMP 1, 8, and 13 when compared with subject-matched perilesional tunica. PD fibroblasts were then cultured with soluble MMP and TIMP after treatment with either TGF-1 or interleukin (IL)-1. They found that IL-1 stimulation increased the production of MMP 1, 2, 8, 9, 10, and 13 in PD fibroblasts; whereas, TGF-1 increased the production of only MMP 10 and decreased the production of MMP-13, but markedly increased the production of all TIMPs. These findings suggest that PD fibroblasts may be manipulated to encourage scar remodeling in the final phase of wound healing.
Nonsurgical therapy for PD
Several nonsurgical options are currently being employed in the treatment of PD that may reduce or stabilize objective measures, such as penile curvature, and also improve subjective measures, such sexual function, pain, and partner satisfaction. PD data outcomes are difficult to interpret without a validated questionnaire and this is further complicated by a reported spontaneous improvement rate of 13% to 39%. A review of the latest literature on nonsurgical options, including oral, topical, intralesional, and external energy, is presented. For further review of PD, the reader is directed to such articles by Akin-olgubade, Trost, and Taylor. The purpose of this article is to review the contemporary literature on nonsurgical therapies for PD, and where possible, focus on randomized, placebo-controlled trials. The recently published guidelines on PD treatment by the International Consultation on Sexual Medicine (ICSM) are noted along with the authors’ expert opinion.
Oral therapies
Vitamin E
Vitamin E is one of the oldest described oral treatments for the treatment of PD and there does appear to be a biochemical mechanism to support its use. Vitamin E, a fat-soluble vitamin metabolized in the liver, excreted in bile is an antioxidant that is thought to limit oxidative stress of reactive oxygen species (ROS) known to be increased during the acute and proliferative phases of wound healing. Increased free-radical expression and a prolonged inflammatory phase of wound healing has been demonstrated in PD. In 1983, Pryor and colleagues conducted a double-blind, placebo-controlled crossover study evaluating vitamin E for the treatment of PD in 40 subjects. No significant improvements were noted in plaque size or penile curvature. Gelbard and colleagues compared vitamin E therapy to the natural history of PD in 97 subjects with disease duration ranging from 3 months to 8 years; no significant differences were found between the 2 groups in terms of curvature, pain, or the ability to have intercourse. In 2007, Safarinejad and colleagues compared the effects of vitamin E to l -carnitine, separately or in combination to placebo, and found no significant difference in the improvement in pain, curvature, or plaque size. The study involved 236 subjects with early chronic PD, which was defined as pain during erection, penile curvature not interfering with vaginal penetration, palpable scar that is not painful, hyperechoic lesions, plaque total area less than 2 cm 2 and without calcification. Subjects had received 2 or more previous treatments for PD, including potassium aminobenzoate, tamoxifen, colchicine, systemic steroids, and intralesional verapamil. To date no placebo-controlled trials using vitamin E have demonstrated any clinical benefit in the treatment of PD. Because there is evidence that vitamin E may also increase the risk of cerebrovascular events and no evidence of clinical improvement, the authors do not recommend the use of vitamin E for PD.
Colchicine
Colchicine inhibits fibrosis and collagen deposition primarily by inhibiting neutrophil microtubules. Colchicine has been used both as a primary oral therapy for PD as well as in combination with other modalities. Akkus and colleagues administered an escalating dose of colchicine in a nonrandomized, nonplacebo-controlled fashion to 19 subjects with PD over a 3- to 5-month period. Of these subjects, 36% noted a reduction in curvature and 63% reported an improvement in the palpable plaque. Of the subjects that were experiencing painful erections at the time of treatment initiation, 78% had resolution of this symptom. Kadioglu and colleagues treated 60 subjects in the acute phase of PD (mean duration 5.7 months ± 4.3 months) using 1 mg of colchicine twice daily, with a mean follow-up of 11 months. They found significant improvement of pain in 95% of men. However, 30% of subjects reported improved curvature; whereas, 22% of subjects reported worsened curvature. Safarinejad performed a randomized, placebo-controlled trial of colchicine in 2004 with 84 men with PD. Mean disease duration was 15 months (range 6–42 months) and 73.8% had previously received 1 or more treatments for PD, including potassium aminobenzoate, vitamin E, and tamoxifen, which had no effect. It was demonstrated that colchicine was no better than placebo in improving pain, curvature, or plaque size as measured by ultrasound. This trial is the only randomized trial looking at the effects of colchicine as a monotherapy. Because of the lack of demonstrable efficacy and a significant side-effect profile (gastrointestinal distress, diarrhea, aplastic anemia) colchicine is currently not recommended by the authors as therapy for PD.
Potassium Aminobenzoate (Potaba)
Zarafonetis and Horrax were the first to describe the use of potassium aminobenzoate (Potaba) for the treatment of PD. It appears to have both an antiinflammatory and an antifibrotic effect caused by stabilization of the tissue serotonin-monoamine oxidase activity and a direct inhibitory effect on fibroblast glycosaminoglycan secretion. In 1999, Weidner and colleagues published a randomized, placebo-controlled trial of potassium aminobenzoate. Subjects were given 3 g orally 4 times per day for 1 year. A significant reduction in plaque size was demonstrated in the treatment group. This finding, however, was not correlated with a decrease in penile curvature. A 2005 follow-up study also by Weidner and colleagues included 103 subjects with disease duration of no greater than 12 months. Subjects were therapy naïve and could not have calcified plaques. This trial was randomized, double-blind, and placebo-controlled, and showed that the use of potassium aminobenzoate may protect against the progression of penile curvature. The study also suggested that penile deviation may be prevented with the use of potassium aminobenzoate in patients with Peyronie’s plaque without penile deviation. In the 13 subjects with an initial straight penis, no subjects developed a deviation while taking potassium para-aminobenzoate. However, 6 of 8 subjects (75%) receiving placebo developed a new penile curvature. There were no relevant differences between potassium aminobenzoate and placebo with regard to improvement of preexisting penile deviation. The authors do not support the use of potassium aminobenzoate as a result of its limited evidence of benefit, side-effect profile, and inconvenient administration (24 tabs/d).
Tamoxifen Citrate
Tamoxifen is a selective estrogen receptor modulator that has both agonist and antagonist effects on target tissues depending on tissue-specific estrogen receptor expression. In addition, tamoxifen is reported to affect the release of TGF from fibroblasts, and blocks TGF-receptors, thus potentially reducing fibrogenesis. A study in 1999 by Teloken and colleagues failed to show any statistically significant difference between tamoxifen and placebo. This study included 25 subjects who were given tamoxifen 20 mg twice daily for 3 months. There was no demonstrable improvement in pain, curvature, or plaque size. Thus, again, the authors do not recommend the use of tamoxifen for the treatment of PD.
Carnitine
Carnitine is a naturally occurring metabolic intermediate. Carnitine facilitates the entry of long-chain fatty acids into muscle mitochondria, which are then used as an energy substrate. Carnitine is hypothesized to inhibit acetyl coenzyme-A, which may help in the repair of damaged cells. Safarinejad and colleagues, in a double-blind, placebo-controlled trial compared l -carnitine, l -carnitine plus vitamin E, and vitamin E alone with placebo. A total of 236 men with PD were randomized amongst the 4 groups for a total of 6 months. The study failed to demonstrate improvement in pain, curvature, or plaque size.
Pentoxifylline
Pentoxifylline (PTX) has been shown in vitro to attenuate both collagen fiber deposition and elastogenesis through an alpha 1 antitrypsin-related mechanism in normal tunica albuginea-derived fibroblasts exposed to TGF-β1 suggesting a possible role for pentoxifylline in the management of PD. PTX is a nonspecific phosphodiesterase inhibitor, with combined antiinflammatory and antifibrogenic properties by downregulating TGF-β and increasing fibrinolytic activity. In the only double-blind placebo-controlled study of the efficacy and safety of pentoxifylline, 228 subjects with early chronic PD, Safarinejad and colleagues demonstrated improvement in penile curvature and plaque volume when compared with placebo. The study population was comprised mostly of subjects who had failed previous oral therapies, including potassium aminobenzoate, carnitine, colchicine, tamoxifen, and vitamin E, or combination thereof. When treated with pentoxifylline, ventral, dorsal, and lateral curvature decreased by 40.0%, 22.2%, and 20.0%, respectively. Curvature was measured using dynamic penile duplex ultrasound (DUS) before and after an intracavernous injection with 20 μg of prostaglandin E1. A second injection was administered as necessary to achieve a maximum erectile response. Within the placebo group, ventral, dorsal, and lateral curvature was shown to increase by 26.9%, 31.4%, and 22.2%, respectively. Treatment satisfaction was assessed using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire developed by Althof and colleagues. Mean EDITS scores after 6 months of treatment were significantly higher when compared with placebo, 64.2 versus 38.3, respectively. Subjects in the treatment group experienced significantly more nausea, vomiting, dyspepsia, and diarrhea. Because this is a single-center study, further randomized, placebo-controlled trials are necessary to optimize treatment regimens and confirm these results. In the authors’ own extensive yet nonrandomized evaluation of pentoxifylline, subjective and objective improvement is limited.
Overall, there appears to be no oral therapy that has been shown to reliably reduce penile deformity in a clinically meaningful way. The authors agree with the recently published guidelines on PD by Ralph and colleagues, which states that, “ There is evidence that there is no benefit with respect to deformity reduction with any oral therapy, including vitamin E, potassium aminobenzoate, colchicine, tamoxifen, and carnitine.” Refer to Table 1 for a summary of oral treatments for PD.
Related posts:
Penile Rehabilitation After Prostate Cancer Treatment: Outcomes and Practical Algorithm
Testosterone and Prostate Cancer: What are the Risks for Middle-Aged Men?
Psychological Factors Associated with Male Sexual Dysfunction: Screening and Treatment for the Urologist
Central Nervous System Agents and Erectile Dysfunction
Priapism: New Concepts in Medical and Surgical Management
Testosterone Deficiency and Risk Factors in the Metabolic Syndrome: Implications for Erectile Dysfunction
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
