Peyronies Disease: A Guide to Clinical Management (Current Clinical Urology)

Peyronie's Disease: A Guide to Clinical Management (Current Clinical Urology): Medicine & Health Science Books @ leondumoulin.nl
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Extracellular SOD plays an essential role in maintaining the redox state, blocking negative local effects of. The superoxide anion also has a direct vasoconstrictive effect through mobilization of calcium ions and can therefore cause erectile dysfunction [ 44 ]. However, can also react with through the Haber-Weiss reaction to produce Table 1.

­­­ ­­­Recent advances in managing Peyronie’s disease

Subsequently, HOCl and react to form singlet oxygen , another highly toxic reactive species Table 1. In the course of PD, the iNOS enzyme is mainly produced by macrophages, smooth muscle cells, and myofibroblasts [ 22 ]. Induction of an upregulation of iNOS therefore produces high local levels of nitric oxide and a series of its metabolites called reactive nitrogen species RNS , which are free radicals like ROS but can cause greater cell and tissue damage [ 34 ].

In normal conditions, nitric oxide NO is the main mediator of penile erection and acts as a nonadrenergic and noncholinergic neurotransmitter, causing release of the smooth muscles of the corpora cavernosa. The chemical reaction producing NO occurs thanks to the presence of amino acid L-arginine via nitric oxide synthase NOS activity and leads to final synthesis of L-citrulline and NO Table 1.

Furthermore, the presence of certain cofactors is necessary: It must be stressed that the effects of nitric oxide radical depend on its concentration, so when local levels increase significantly as in PD a high oxidation state is produced. In these conditions, starts to compete with SOD, removing superoxide anion and causing the formation of peroxynitrite Table 1 [ 37 ].

Peroxynitrite is a highly toxic, reactive molecule, which can cause cell damage by lipid peroxidation and DNA fragmentation , tissue damage depletion of plasmatic antioxidants, endothelial smooth muscle relaxation impairment, vascular tone change, and organ dysfunction [ 34 ]. When peroxynitrite is protonated, peroxynitrous acid HOONO forms, another highly toxic reactive molecule which rapidly breaks down into hydroxyl radical and nitrogen dioxide radical , two other highly reactive cytotoxic molecules Table 1.

This liposoluble substance was first suggested for PD treatment in by Scott and Scardino [ 47 ]. It has many properties.

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Vitamin E inhibits inflammatory cell ROS release respiratory burst [ 48 ]. Furthermore, vitamin E inhibits platelet adhesion and aggregation, improves endothelial function, and can repair DNA [ 54 , 55 ]. Vitamin E is the oldest substance still currently in use in PD treatment. Scardino and Scott and Steinberg pioneered the use of vitamin E in medical treatment of PD [ 56 , 57 ]. Pryor and Farell and Safarinejad et al. However, several studies have shown that vitamin E is effective only when combined with other treatments combination or multimodal therapy [ 60 — 62 ].

This molecule is very similar to an amino acid; in humans, it is synthesized in the liver, brain, and kidneys from essential amino acids lysine and methionine by ALC transferase. The carnitine system is comprised of L-carnitine, its esters acetyl L-carnitine, propionyl-L-carnitine , and a complex enzymatic system located in the mitochondrial membrane. It has been estimated that carnitine produced endogenously is 1. Meat is the main external source of carnitine, but it is present in lower concentrations in cod and dairy and in even lower concentrations in plant-based products.

Its main role is that of mitochondrial long-chain fatty acid transport; therefore it works to convert fat to energy.

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It is scavenger and neutralizer of superoxide anion , hydrogen peroxide , and peroxynitrite [ 64 ]. L-Carnitine inhibits proliferation and osteoblastic differentiation of fibroblasts [ 65 ]. L-Carnitine also increases eNOS expression, contrasting the negative effects of nitric oxide radical and related reactive nitrogen species production peroxynitrite, etc.

It is important to mention that L-carnitine is a peripheral antagonist of thyroid hormone action: L-carnitine inhibits triiodothyronine T3 and thyroxine T4 entry into the cell nuclei. Carnitine has been successfully used to treat PD. PTX is a synthetic xanthine derivative structurally related to theophylline and caffeine. As hemorheologic agent, it was initially used to treat peripheral vascular diseases, cerebrovascular insufficiency, sickle cell disease, and diabetic neuropathy.

PTX inhibits platelet aggregation and improves blood flow by increasing erythrocyte and leukocyte deformability [ 73 ]. Furthermore, PTX has been shown to have hydroxyl radical scavenging activity [ 76 ]. PTX is also a nonspecific phosphodiesterase PDE inhibitor and therefore has further antifibrotic activity by reducing iNOS and collagen expression and stimulating fibroblast apoptosis within the tunica albuginea [ 81 , 82 ].

Besides treatment of peripheral artery disease, PTX has been used multiple times in man to treat various inflammatory conditions associated with fibrosis radiation-induced and pulmonary fibrosis, scleroderma, etc. A article by Valente et al. The authors concluded that PTX was effective in stimulating fibroblast apoptosis in the tunica albuginea and therefore suggested PTX may be effective in reversing PD fibrosis [ 82 ].

The patient continued the same therapy for 2 more years; at follow-up the dorsal plaque had decreased in volume and consistency, erectile function had significantly improved, and ultrasound confirmed disappearance of dorsal calcification with persistence of ventral calcific plaque. In , Lin et al.

The specimens of plaque containing tunica albuginea were harvested from 12 patients with chronic PD, during surgery for curvature correction. Biopsy samples of healthy tunica albuginea were taken from 6 patients during surgery for penile prosthesis positioning. The study yielded the following results: In , the first cohort study was published in which PTX was used to treat a group of 62 patients with PD and sonographic evidence of penile calcification [ 84 ].

After treatment, patients were reassessed with a clinical exam and gray-scale or duplex ultrasound. Compared to the no-treatment group, patients who took PTX had a reduction in calcification volume Moreover, PTX-treated patients were much more likely to have stabilization no change or improvement in their calcium burden compared to patients of the control group Seventy-four PD patients were divided into two treatment groups: Mean penile curvature improvement was Although PTX was not used exclusively, the study demonstrated that combined treatment without PTT still led to significant penile curvature improvement [ 85 ].

Another report about exclusive use of PTX was published in , describing PTX treatment in a year-old PD patient with a large plaque in the distal third of the penis. Even though he had no bending, the patient complained of difficulty in coital penetration due to a lack of rigidity and tumescence in the terminal part of the penis.

In , Alizadeh et al. Ninety PD patients were randomized and divided into three treatment groups: The outcomes were the following: We published a controlled study last year in which PTX was used for 6 months in association with other antioxidant and anti-inflammatory substances for PD treatment [ 89 ]. All patients of the study had PD in its evolutionary phase; the control group group C, no treatment included patients. The treated patients were divided into two groups and differed only in whether they received penile PTX injections. The most significant results were as follows: Incidence of side-effects after oral administration of PTX: The only adverse effect of the penile PTX injection was local bruising at the infiltration site 3.

The most important outcome was that PTX via perilesional penile injection was shown to be effective in treating PD and greatly statistically significantly improved the already positive results obtained with combined oral therapy alone. This study confirmed a peculiarity of PTX already mentioned in previous studies: CoQ10, also known as ubiquinone, ubidecarenone, coenzyme Q, CoQ, or Q10, is a fat-soluble molecule involved in mitochondrial electron transport and oxidative phosphorylation and necessary for cellular respiration and adenosine triphosphate ATP production.

CoQ10 inhibits increased ROS production, by blocking mitochondrial membrane depolarization. In its reduced form, CoQ10 acts as a potent endogenous antioxidant, interacting with oxygen-related radicals, hydrogen peroxide, and singlet oxygen and inhibiting lipid peroxidation Table 1 [ 90 ]. CoQ10 prevents nitrosative stress by inhibition of excess nitric oxide radical production, and it participates in vitamin E and C regeneration [ 91 , 92 ].

A single study exists where CoQ10 was used to treat PD; this prospective, double-blind placebo-controlled randomized clinical trial demonstrated significant positive results: At the end of treatment, results were the following: Propolis has been used by mankind since ancient times for its curative properties. It is plant-based and consists in a mixture of compounds which bees Apis mellifera L.

The resinous substances extracted by the bees are then processed with the addition of wax, pollen, and saliva enzymes. The final product is a resinous mixture with a color varying in shade from yellow to black. Bees produce propolis to seal any small opening in their beehives, protecting themselves from the cold, rain, wind, and possible attacks by other insects.

The most interesting property of propolis is that of preventing disease, protecting the bees in the beehive from parasites, bacteria, viruses, and microbes in general. Many polyphenolic compounds, flavonoids, phenolic acids caffeic acid and cinnamic acid , and esters and fatty acids have been found in propolis. Flavonoids commonly contained in propolis are acacetin, apigenin, catechin, chrysin, galangin, kaempferol, luteolin, myricetin, naringenin, pinocembrin, quercetin, and rutin.

Since propolis indirectly derives from plants, its composite content varies depending on the geographical position and climate of the area of production. For instance, the characteristic compounds of Chinese propolis are caffeic acid, caffeic acid phenethyl ester CAPE , caffeic acid benzyl ester, 5-methoxy pinobanksin, pinobanksin, pinobanksinO-acetate, pinocembrin, chrysin, and galangin [ 97 ].

Brazilian propolis contains the following: Geographical differences of propolis are significant. Poplars, and their buds in particular, are considered the main indirect source of propolis in Europe and North America, nontropical Asia, New Zealand, and North Africa especially the Nile delta [ ]. Considering the heterogeneous nature of the composition of propolis, pharmaceutical industries use standard quantities of the individual compounds by chemical extraction, choosing the substances based on their particular properties.

It affects lipid peroxidation and helps preserve other antioxidants such as vitamin E and vitamin C [ , ].

Peyronie's Disease : A Guide to Clinical Management

It is able to scavenge highly reactive species such as peroxynitrite, hydroxyl radical, superoxide anion, singlet oxygen, and lipid peroxyl radicals [ ]. CAPE exhibits a stronger antioxidant activity than galangin [ ]. It hinders oxidative burst and related polymorphonuclear neutrophil production of superoxide anion, hydrogen peroxide, and hypochlorous acid HOCl by activated leukocytes; moreover, it suppresses lipid peroxidation activity [ ].

It inhibits xanthine oxidase activity, which is responsible for superoxide anion production; it also inhibits the release of NADPH-oxidase and the oxidative burst of neutrophils [ ]. Pinocembrin possesses a high oxygen radical antioxidant capacity and nitrite scavenging capacity, inhibiting xanthine oxidase activity, which usually induces the generation of superoxide radicals; it also inhibits lipid peroxidation [ , ].

It inhibits xanthine oxidase activity, which is responsible for superoxide radical production; it can also inhibit lipid peroxidation [ , ]. Pinobanksin also has antiproliferative and proapoptotic activity [ ].


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Apigenin is an antioxidant; it inhibits xanthine oxidase activity responsible for ROS and hydrogen peroxide production. There may be a preceding history of trauma 3. The aetiology of the disease is thought to be repeated minor microvascular trauma during intercourse, resulting in intra-tunical bleeding and subsequent inflammation and fibrosis.

INTRODUCTION

This may not refute the hypothesis but points further to a multifactorial process. Transforming growth factor beta is thought to exacerbate the irregular healing response. Subsequently, the dysfunctional tunical tissue restricts normal expansion of the underlying corpus cavernosum, creating the observed curvature. Surgical correction is traditionally the mainstay of treatment, although there is associated morbidity, most commonly in terms of infection and haematoma in the early post-operative period, and later penile shortening, erectile dysfunction, recurrent curvature, and glans hypoesthesia.

Therefore, remedial intervention is undertaken with a degree of reluctance in most men seeking corrective surgery. This can result in delayed definitive treatment, often causing anxiety and dissatisfaction in patients because of impairment of their sexual health. As a result, there has been extensive research into non-surgical interventions that may be implemented earlier in the disease process, thus improving patient quality of life and reducing surgical morbidity. The aim of this review article is to summarise recent advances in PD treatment, including surgical, non-surgical, and pharmacological interventions.

A literature review was performed by using a Medline review of publications from onwards, focusing on randomised controlled trials where available. Treatment comes in the form of an injection of two collagenases which act synergistically to cleave tropocollagen. The regimen involves up to four cycles of treatment 6 weeks apart, each cycle requiring two injections of 0. Patients are also educated in penile modelling to occur three times daily.

PDQ bother and symptom scores were reduced by Serious adverse events were noted in six patients, of whom four three corporeal rupture and one haematoma required surgery. All corporeal ruptures were related to intercourse. Overall, there does appear to be at least a modest benefit and it remains the most promising non-surgical therapy. Modification of the trial protocol to reduce the total number of injections and cycles alongside the use of a traction device appears to represent improved health economics and we await availability of published data to that effect.

The role of calcium channel blocker verapamil in PD is thought to be due to an upgrade of collagenase activity and inhibition of extracellular collagen transport 6. Whilst both intra-lesional and electromotive drug administration EMDA verapamil have been shown to provide some benefit in historic studies, direct comparison has not been previously reported.

A randomised trial by Mehrsai et al. The authors found no significant difference in reduction of plaque size alongside a noted improvement in erectile function albeit not significant. Penile pain assessed by visual analogue scale was significantly reduced in the EMDA group compared with the injection group Penile curvature was improved in both groups, and increased shift towards a less-thandegree group was noted especially in the EMDA category.

This improvement, however, was not quantified in more detail or statistically significant. Adverse events were not reported. They concluded that EMDA was at least a comparable and less invasive treatment modality. Notably, the study excluded patients with curvature of greater than 45 degrees and those unable to achieve penetrative intercourse. The study compared verapamil weekly and tadalafil daily alone and in combination. No significant improvement in curvature was noted in any group over the course of a 3-month study period.

There was improvement in pain for all groups, most notably in the combination arm; however, statistical significance was not achieved. The authors acknowledge that small numbers limit their study; however, the role of daily tadalafil may augment more traditional strategies First reported by Duncan et al. There is a paucity of randomised trial data during this period of review, and the last significant trials were conducted in These data concluded that interferon provided only modest benefit in conjunction with significant side effects 12 , A retrospective review by Trost et al.

A further review in from Stewart et al. The treatment is currently included in both the American Urological Association and European Association of Urology guidance. Vitamin E has been the subject of numerous historical trials and the general consensus is that its antioxidant properties improve pain during the acute phase, but not curvature. The most recent controlled trial, by Paulis et al. The noted reduction was modest but statistically significant: Significant improvements were noted in the treatment group in terms of plaque size as well as subgroup analysis of IIEF scores.

Medium-term follow-up of these patients demonstrated durability of these findings and further supported combination therapy A further randomised trial, by Favilla et al. No improvement in curvature was noted. Overall, there is limited evidence to support the use of vitamin E and antioxidants other than as an adjunct to more recognised therapies. There are multiple oral agents promoted for use in the early phase of PD development. Typically, tamoxifen and Potaba fall victim to problems similar to those of alternatives such as colchicine and acetyl- l -carnitine because of a lack of recent randomised data to support their routine use.

Both treatments are endorsed by international guidelines for improvement in penile pain but not specifically for reduction in curvature. Perhaps the most striking result was that two-thirds of the patients in the Potaba arm withdrew for varying reasons, although treatment side effects were cited as the largest single factor.

Resolution of pain was once again significant, and more so in the combination group. Extracorporeal shockwave therapy ESWT remains second- or third-line treatment in PD, and decreased efficacy has been highlighted in a single-blinded randomised trial by Hatzichristodoulou et al. No randomised data exist for these treatment modalities.

Objective improvement has been seen in a recent controlled study of traction devices, as have significant improvements in curvature, erectile function, and pain. These may be a useful adjunct to treatment, although larger studies are needed and the daily traction time required up to 8 hours may prove to be a limiting factor. However, as highlighted in the first section, these devices may have a renewed role in penile modelling techniques with plaque dissolution seen in collagenase-style therapies.

There have been no significant advances in PD surgical management in terms of randomised controlled data. In keeping with historical trends, there have been numerous retrospective reviews of modifications to traditional plication and grafting techniques. Suffice to say, plication remains the standard for patients without erectile dysfunction and a curvature of less than 60 degrees provided that the associated loss of length is not problematic. Incision and grafting are indicated in patients falling outside these criteria, although plaque excision without grafting is reported as a simplified technique Inflatable penile prosthesis and manual remodelling have been re-assessed in a retrospective review by Chung et al.

Further results regarding implant insertion and simultaneous plication demonstrated similar levels of satisfaction Implant surgery remains the mainstay of treatment for patients with significant curvature and erectile dysfunction. More data are emerging regarding surgery following failed intra-lesional collagenase treatment, suggesting that there is no additional operative complexity following previous local therapy Traditionally, patients with PD are counselled well regarding the natural course of the disease and morbidity associated with the relevant treatment options.

Less attention is given to what may be a significant psychological impact of the disease and its diagnosis. They assessed the validity of this tool in and found its three domains addressing symptoms, pain, and bother useful and reliable in categorising disease impact. Recent publication of a single-arm interventional study investigating the role of intra-lesional hyaluronic acid in PD represents a low-cost and low-side-effect avenue for intervention