Sexual and Reproductive Health

8. PENILE CURVATURE

8.1. Congenital penile curvature

8.1.1. Epidemiology/aetiology/pathophysiology

Congenital penile curvature (CPC) is a rare condition, with a reported incidence of < 1% [838], although some studies have reported higher prevalence rates of 4-10%, in the absence of hypospadias [839]. Congenital penile curvature results from disproportionate development of the tunica albuginea of the corporal bodies and is not associated with urethral malformation. In most cases, the curvature is ventral, but it can also be lateral or, more rarely, dorsal [840].

8.1.2. Diagnostic evaluation

Taking a medical and sexual history is usually sufficient to establish a diagnosis of CPC. Patients usually present after reaching puberty as the curvature becomes more apparent with erections and sexual activity. The more severe curvatures can make intercourse difficult or impossible. Physical examination and photographic documentation during erection (preferably after intracavernous injection [ICI] of vasoactive drugs) are both mandatory to document the curvature and exclude other pathologies [840].

8.1.3. Disease management

Surgery is the definitive treatment for this disorder and can be deferred until after puberty. However, a survey has suggested that men with untreated ventral penile curvature report more dissatisfaction with penile appearance, increased difficulty with intercourse, and psychological problems; supporting surgical correction of CPC in childhood, although this should be discouraged as penile growth will not have maximised [841]. Surgical treatments for CPC generally share the same principles as in PD. Plication techniques (Nesbit, 16-dot, Yachia, Essed-Schröeder, and others) with or without neurovascular bundle elevation (medial/lateral) and complete penile degloving, have been described [842-851]. Other approaches are based on corporal body de-rotation with different technical refinements that enable correction of a ventral curvature, with reported minimal narrowing and shortening [852-855]. There are no direct comparative studies; therefore, no single technique can be recommended for surgical correction.

8.1.4. Summary of evidence and recommendation for diagnosis and treatment of congenital penile curvature

8.1.5. Recommendation for the treatment of congenital penile curvature

8.2. Peyronie’s Disease

(A discussion on the Aetiology, Risk factors and Pathophysiology of PD can be found in Appendix 4, online supplementary evidence.)

8.2.1. Epidemiology

Epidemiological data on PD are limited. Prevalence rates of 0.4-20.3% have been reported, with a higher prevalence in patients with ED and diabetes [856-864]. A recent survey has indicated that the prevalence of definitive and probable cases of PD in the USA is 0.7% and 11%, respectively, suggesting that PD is an under-diagnosed condition [865]. Peyronie’s disease often occurs in older men with a typical age of onset of 50-60 years. However, PD also occurs in younger men (< 40 years), with a reported prevalence of 1.5-16.9% [860,866,867].

8.2.2. Diagnostic evaluation

The initial evaluation aims to obtain information on the presenting symptoms and their duration (e.g., pain on erection, palpable nodules, deformity, length and girth and erectile function). It is important to obtain information on the distress caused by the symptoms and the potential risk factors for ED and PD. A disease-specific questionnaire (Peyronie’s disease questionnaire [PDQ]) has been developed for use in clinical practice and trials. The Peyronie’s disease questionnaire measures three domains, including psychological and physical symptoms, penile pain and symptom bother [868].

Clinicians should take a focused history to distinguish between active and stable disease, as this will influence medical treatment and the timing of surgery. Patients who are still likely to have active disease are those with a shorter symptom duration, pain on erection, or a recent change in penile deformity. Resolution of pain and stability of the curvature for at least three months are accepted criteria of disease stabilisation as well as patients’ referral for specific medical therapy [869,870] or surgical intervention, if indicated [871].

The examination should start with a focused genital assessment that is extended to the hands and feet for detecting possible Dupuytren’s contracture or Ledderhose scarring of the plantar fascia [872]. A penile examination is performed to assess the presence of a palpable nodule or plaque. There is no correlation between plaque size and degree of curvature [873]. Measurement of the stretched or erect penile length is important because it may have an impact on the subsequent treatment decisions and potential medico-legal implications [874-876].

An objective assessment of penile curvature with an erection is mandatory. This can be obtained by several approaches, including home (self) photography of a natural erection (preferably), using a vacuum-assisted erection test or an ICI using vasoactive agents. However, it has been suggested that the ICI method is superior, as it can induce an erection similar to or better than that which the patient would experience when sexually aroused [877-879]. Computed tomography and MRI have a limited role in the diagnosis of the curvature and are not recommended on a routine basis. Erectile function can be assessed using validated instruments such as the IIEF although this has not been validated in PD patients [880]. Erectile dysfunction is common in patients with PD (30-70.6%) [881,882]. The presence of ED and psychological factors may also have a profound impact on the chosen treatment strategy [883]. Ultrasound measurement of plaque size is not accurate but may be helpful to assess the presence of the plaque and its calcification and location [884,885]. Doppler US may be used for the assessment of penile haemodynamics and ED aetiology [882]. In particular to assess penile arterial inflow in the context of the interventional modality to be undertaken (eg plaque incision and grafting) to exclude arteriogenic ED.

8.2.2.1. Summary of evidence and recommendations for diagnosis of Peyronie’s disease

8.2.3. Disease management

8.2.3.1. Conservative treatment

Conservative treatment of PD is primarily focused on patients in the early stage of the disease as an adjunct treatment to relieve pain and prevent disease progression or if the patient declines other treatment options during the active phase [871,872]. Several options have been suggested, including oral pharmacotherapy, intralesional injection therapy, shockwave therapy (SWT) and other topical treatments (Table 18).

The results of the studies on conservative treatment for PD are often contradictory, making it difficult to provide recommendations in everyday, real-life settings [886]. The Guidelines do not recommend the use of oral treatments for PD including pentoxifylline, vitamin E, tamoxifen, procarbazine, potassium para-aminobenzoate (potaba), omega-3 fatty acids or a combination of vitamin E and L-carnitine because of their lack of proven efficacy [871,887-889]. Studies of these treatments have numerous methodological problems including their uncontrolled nature, the limited number of patients treated, the short-term follow-up and the different outcome measures used [890,891]. Even in the absence of adverse events, treatment with these agents may delay the use of other more efficacious treatments.

Table 18: Conservative treatments for PD

8.2.3.1.1. Oral treatment

Phosphodiesterase type 5 inhibitors

Phosphodiesterase type 5 inhibitors were first suggested as a treatment for PD in 2003 to reduce collagen deposition and increase apoptosis through the inhibition of transforming growth factor (TGF)-b1 [892-894]. The results of a retrospective study of 65 men indicated that treatment with tadalafil was helpful in decreasing helped decrease curvature and remodel septal scars when compared to controls [895]. Another study concluded that sildenafil was able to improve erectile function and pain in PD patients. Thirty-nine patients with PD were divided into two groups receiving vitamin E (400 IU) or sildenafil 50 mg for twelve weeks with significantly better outcomes in pain and mean IIEF scores were seen in the sildenafil group [896]. Findings from a observational retrospective study including patients in the acute phase of PD and ED who had been treated with Tadalafil 5 mg once daily compared to patients with comparable baseline parameters who decided not to take the daily compound (i.e., 108 intervention vs. 83 controls) showed that treated men had lower curvature progression rates at 12 weeks (25.9% vs. 39.7%, p = 0.042) [897]. Similarly, mean SHIM score and PDQ-Overall and PDQ-Penile Pain scores significantly improved in the intervention group (p < 0.001).

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be offered to patients in active-phase PD to ameliorate penile pain. Pain levels should be periodically reassessed whilst monitoring treatment efficacy.

8.2.3.1.2. Intralesional treatment

Injection of pharmacologically active agents directly into penile plaques represents another treatment option. It allows a localised delivery of a pharmacological agent that provides higher concentrations of the drug inside the plaque. However, delivery of the compound to the target area is difficult to ensure, particularly when a dense or calcified plaque is present.

Calcium channel antagonists: verapamil and nicardipine

The rationale for intralesional use of channel antagonists in patients with PD is based on in vitro research [898,899]. Due to the use of different dosing schedules and the contradictory results obtained in published studies, the evidence is not strong enough to support the clinical use of injected channel blockers verapamil and nicardipine and the results do not demonstrate a meaningful improvement in penile curvature compared to placebo [900-905]. In fact, most of the studies did not perform direct statistical comparisons between these groups.

Collagenase of Clostridium histolyticum

Collagenase of Clostridium histolyticum (CCH) is a chromatographically purified bacterial enzyme that selectively targets collagen, the primary component of the PD plaque [906-909]. Intralesional injection of CCH has been used in the treatment of PD since 1985. In 2014 the EMA approved CCH for the non-surgical treatment of the stable phase of PD in men with palpable dorsal plaques in whom abnormal curvature of 30-90o and non-ventrally located plaques are present. It should be administered by a healthcare professional who is experienced and properly trained in the administration of CCH treatment for PD [910,911]. However, CCH has been officially withdrawn from the European market by its manufacturer. Despite this the evidence and recommendations for CCH have been maintained by the Guidelines for completeness.

The original treatment protocol in all studies consists of two injections of 0.58 mg of CCH 24-72 hours apart every six weeks for up to four cycles. Data from IMPRESS (Investigation for Maximal Peyronie´s Reduction Efficacy and Safety Studies) II and II studies [976], as well as post-approval trials [912], which demonstrated the efficacy and safety of this treatment, are summarised in Table 8.2 online Appendix 5.

The average improvement in curvature was 34% compared to 18.2% in the placebo group. Three adverse events of corporeal rupture were surgically repaired. The greatest chance of curvature improvement was for curvatures between 30° and 60°, longer duration of disease, IIEF > 17, and no calcification [870]. An 18.2% improvement from baseline in the placebo arm was also observed. These findings raise questions regarding the proposed role of plaque injection and penile modelling, regardless of the medication, in improving outcomes in men with PD as the placebo or modelling arm resulted in relatively high curvature reduction compared to the treatment arm.

The conclusion of the IMPRESS I and II studies is that CCH improves PD both physically and psychologically [913]. A post hoc meta-analysis of the IMPRESS studies demonstrated better results in patients with curvatures < 60^o, > 2 years of onset, no calcification in the plaque and good erectile function [912].

Thereafter, a modified short protocol consisting of administration of a single (0.9 mg, one vial) injection per cycle distributed along three lines around the point of maximum curvature up to three cycles, separated by 4-weekly intervals, has been proposed and rapidly popularised replacing physician modelling with a multi-modal approach through penile stretching, modelling and VED at home [914]. The results from this modified protocol were comparable to the results of the IMPRESS trials and appeared to decrease the cost and duration of treatment, although these studies were non-randomised. However, these results were further explored in a prospective non-randomised multi-centre study [982]. In another large single-arm multi-centre clinical study using the shortened protocol, longer PD duration, greater baseline PC and basal and dorsal plaque location were identified as clinically significant predictors of treatment success [915]. Accordingly, a nomogram developed to predict treatment success after CCH for PD showed that patients with longer PD duration, greater baseline penile curvature and basal plaque location had a greater chance of treatment success [915]; however, these findings need to be externally validated.

Regarding safety concerns, most PD patients treated with CCH experienced at least one mild or moderate adverse event localised to the penis (penile haematoma (50.2%), penile pain (33.5%), penile swelling (28.9%) and injection site pain (24.1%), which resolved spontaneously within 14 days of injection [916]. The adverse reaction profile was similar after each injection, regardless of the number of injections administered. Serious treatment-emergent adverse events (TEAEs) (0.9%) included penile haematoma and corporeal rupture that require surgical treatment. According to IMPRESS data and the shortened protocol, to prevent serious TEAEs men should be advised to avoid sexual intercourse in the four weeks following injection. Recent preliminary data suggest that treatment in the acute phase of the disease is effective and safe [880,917-921].

In conclusion, CCH is a safe and established treatment for stable-phase disease wit more recent evidence suggesting that CCH also has a role in affecting the progression of active-phase disease. It should also be noted that there is a large effect of traction or modelling in controlled studies, whilst studies reporting on modified protocols have small numbers of patients and are largely uncontrolled. Therefore, patients should be counselled fully on the efficacy of collagenase and the high cost of treatment.

It has been suggested that those patients with severe curvature may also benefit from CCH injections because of a potential downgrading of the penile curvature: a decrease in curvature may allow for a penile plication procedure instead of a plaque incision and grafting procedure, therefore avoiding the more negative impact on erectile function from plaque incision and grafting. However, further studies are required to validate these initial findings [880,921].

Interferon α-2b

Intralesional injections (5x10^6 units of IFN-α2b in 10 mL saline every 2 weeks over 12 weeks for a total of six injections) significantly improved penile curvature, plaque size and density, and pain compared to placebo. Additionally, penile blood flow parameters are benefited by IFN-α2b [911,922,923]. Regardless of plaque location, IFN-α2b is an effective treatment option. Treatment with IFN-α2b provides a > 20% reduction in curvature in most men with PD, independent of plaque location [924]. Given the mild adverse effects, which include sinusitis and flu-like symptoms, which can be effectively treated with NSAIDs before IFN-α2b injection, and the moderate strength of data available, IFN-α2b is currently recommended for treatment of stable-phase PD.

Steroids, hyaluronic acid and botulinum toxin (botox)

In the only single-blind, placebo-controlled study with intralesional administration of betamethasone, no statistically significant changes in penile deformity, penile plaque size, and penile pain during erection were reported [925]. Adverse effects include tissue atrophy, thinning of the skin and immunosuppression [926]. The effect of hyaluronic acid treatment in patients with PD was investigated in a non-randomised study; intralesional injection of hyaluronic acid was compared to intralesional verapamil in acute phase PD and significant improvement of pain, curvature and IIEF-15 were observed [927]. In an RCT, oral administration of hyaluronic acid combined with intralesional injection was found to be superior to intralesional injection only and an improvement of 7.8±3.9 degrees in curvature and reduction in plaque size of 3.0 mm was observed [928]. There is only a single study evaluating intralesional botox injections in men with PD; therefore, there is insufficient evidence to support this treatment in clinical practice [929].

Platelet Rich Plasma (PRP)

Few studies in humans have evaluated the effect of PRP on penile curvature, plaque size, PDQ and IIEF [930-935]. The effect of PRP in patients with PD remains to be proven and should be considered experimental. An ongoing phase 2b randomized placebo-controlled crossover trial has enrolled 25 patients with a planned target of 80 men with PD: first ongoing data on nine patients in the treatment group vs eight in the placebo group showed no difference in curvature at three months in comparison to baseline [936].

8.2.3.1.3. Topical treatments

Topical verapamil and H-100 Gel

There is insufficient evidence that topical treatments (verapamil and H-100 Gel) applied to the penile shaft, with or without the use of iontophoresis (now known as transdermal electromotive drug administration), result in adequate levels of the active compound within the tunica albuginea [937-940].

8.2.3.1.4. Other treatments

Extracorporeal shockwave treatment

The mechanism of action involved in ESWT for PD is still unclear.

Four RCTs and one meta-analysis [941-945] assessed the efficacy of ESWT for PD. Three were sham-controlled trials while one compared ESWT with the combination of ESWT and PDE5I (tadalafil) [946].

All trials showed positive findings in terms of pain relief, but no effect on penile curvature and plaque size. Inclusion criteria varied widely among studies and further investigation is needed. Therefore, ESWT should not be used as a primary treatment for penile curvature in men with PD. The results are summarised in Table 8.4 online Appendix 5.

Penile traction therapy

In men with PD, potential mechanisms for disease modification with penile traction therapy (PTT) have been proposed, including collagen remodelling via decreased myofibroblast activity and matrix metalloproteinase up-regulation [947,948].

The stated clinical goals of PTT are to non-surgically reduce curvature, enhance girth, and recover lost length, which are attractive to patients with PD. However, clinical evidence is limited due to the small number of patients included (267 in total), the heterogeneity in the study designs, and the non-standardised inclusion and exclusion criteria which make it impossible to draw any definitive conclusions about this therapy [949-953].

Most of the included patients will need further treatment to ameliorate their curvature for satisfactory sexual intercourse. Moreover, the effect of PTT in patients with calcified plaques, hourglass or hinge deformities which are, theoretically, less likely to respond to PTT has not been systematically studied. In addition, the treatment can result in discomfort and be inconvenient as the device needs to be used for an extended period (2-8 hours daily), but has been shown to be tolerated by highly-motivated patients. There were no reported serious adverse effects, including skin changes, ulcerations, hypo-aesthesia or diminished rigidity [951,954].

In conclusion, PTT seems to be effective and safe for patients with PD [955], but there is still lack of evidence to give any definitive recommendation in terms of its use as a monotherapy for PD.

Vacuum erection device

Vacuum erection device (VED) therapy results in dilation of cavernous sinuses, decreased retrograde venous blood flow and increased arterial inflow [956]. Intracorporeal molecular markers are affected by VED application, including decreases in hypoxia-inducible factor-1α, TGF-β1, collagenase, and apoptosis, and increases in endothelial nitric oxide synthase (eNOS) and α-smooth muscle actin, given their role in the pathogenesis of PD [957]. Only two retrospective studies assessed the efficacy of VED therapy in mechanically straightening the penile curvature of PD as monotherapy and further studies are needed [958,959].

Multimodal treatment

There is some evidence suggesting that a combination of different oral agents can be used for the treatment of the acute phase of PD. However, there does not seem to be a consensus on which drugs to combine or the optimum drug dosage; nor has there been a comparison of different drug combinations.

A long-term study assessing the role of multimodal medical therapy (injectable verapamil associated with antioxidants and local diclofenac) demonstrated that treatment was efficacious to treat PD patients. It concluded that combination therapy reduced pain more effectively than verapamil alone, making this specific combination treatment more effective compared to monotherapy [957]. Furthermore, combination protocols including injectable therapies, such as CCH, have been studied in controlled trials. The addition of adjunctive PTT and VED has been described; however, limited data are available regarding their use [960].

Penile traction therapy has been evaluated as an adjunct therapy to intralesional injections with interferon, verapamil, or CCH [901,961,962]. These studies have failed to demonstrate significant improvements in penile length or curvature, except for one subset analysis identifying a 0.4 cm length increase among men using the devices for > 3 hours/day [962]. A meta-analysis demonstrated that men who used PTT as an adjunct to surgery or injection therapy for PD had, on average, an increase in stretched penile length (SPL) of 1 cm compared to men who did not use adjunctive PTT. There was no significant change in curvature between the two groups [963].

Data available on the combined treatment of CCH and the use of VED between injection intervals have shown significant mean improvements in curvature (-17^o) and penile length (+0.4 cm) after treatment. However, it is not possible to determine the isolated effect of VED because of a lack of control groups [914,963].

Also, a combination of PDE5I (sildenafil 25 mg twice daily) after CCH treatment (shortened protocol combined with VED) is superior to CCH alone for improving penile curvature and erectile function [964]. Further studies are necessary to externally validate those findings.

8.2.3.1.5. Summary of evidence and recommendations for conservative treatment of Peyronie’s disease

8.2.3.2. Surgical treatment

Although conservative treatment for PD may resolve painful erections in most men, only a small percentage experience significant straightening of the penis. The aim of surgery is to correct curvature and allow penetrative intercourse. Surgery is indicated in patients with significant penile deformity and difficulty with intercourse associated with sexual bother. Patients must have a stable disease for three to six months (or more than nine to twelve months after onset of PD) [871,965,966]. In addition to this requirement, other situations that may precipitate an indication for surgery, such as failed conservative or medical therapies, extensive penile plaques, or patient preference, when the disease is stable [967,968].

Before considering reconstructive surgery, it is recommended to document the size and location of penile plaques, the degree of curvature, complex deformities (hinge or hourglass), the penile length and the presence or absence of ED. The potential aims and risks of surgery should be fully discussed with the patient so that he can make an informed decision [966]. Specific issues that should be mentioned during this discussion are: risk of penile shortening; ED, penile numbness; and delayed orgasm, the risk of recurrent curvature, potential for palpation of knots and stitches underneath the skin, potential need for circumcision at the time of surgery, residual curvature and the risk of further penile wasting with shortening procedures [871,969]. Selection of the most appropriate surgical intervention is based on penile length assessment, curvature severity and erectile function status, including response to pharmacotherapy in cases of ED [871]. Patient expectations from surgery must also be included in the pre-operative assessment. The main objective of surgery is to achieve a “functionally straight” penis, and this must be fully understood by the patient to achieve the best possible satisfaction outcomes after surgery [966,970].

Three major types of reconstruction may be considered for PD: (i) tunical shortening procedures; (ii) tunical lengthening procedures; and, (iii) penile prosthesis implantation, with or without straightening techniques in the presence of concomitant ED and residual curvature [971,972].

Penile degloving with associated circumcision (as a means of preventing post-operative phimosis) should be considered the standard approach for all types of procedures, although modifications have been described. Only one study has suggested that circumcision is not always necessary (e.g., in cases where the foreskin is normal pre-operatively) [973]. Non-degloving techniques have been described that have been shown to prevent ischaemia and lymphatic complications after subcoronal circumcision [974,975].

There are no standardised questionnaires for the evaluation of surgical outcomes. Data from well-designed prospective studies are scarce, with low levels of evidence. Data are mainly based on retrospective single-centre studies, typically non-comparative and non-randomised, or expert opinion [871]. Therefore, surgical outcomes must be treated with caution.

8.2.3.2.1. Tunical shortening procedures

Tunical shortening procedures achieve straightening of the penis by shortening the longer, convex side of the penis. For men with good erectile function, adequate penile length, without complex deformities, such as an hourglass or hinge type narrowing abnormalities, and non-severe curvature, a tunical shortening procedure can be considered an appropriate surgical approach. Numerous different techniques have been described, although they can be classified as excisional, incisional and plication techniques. The Nesbit procedure operation is based on an elliptical excision of tunica albuginea opposite to the point of maximum curvature [977,978].

The Yachia technique is based on a completely different concept, as it utilises the Heinke-Mikowitz principle for which a longitudinal tunical incision is closed transversely to shorten the convex side of the penis. This technique, initially described by Lemberger in 1984, was popularised by Yachia in 1990, when he reported a series of 10 cases [979-984].

Pure plication techniques are simpler to perform. They are based on single or multiple plications performed without making excisions or incisions on the tunical albuginea, to limit the potential damage to the veno-occlusive mechanism [874,985-1001]. Another modification described the ’16-dot’ technique that consists of the application of two pairs of parallel Essed-Schroeder plications tensioned more or less depending on the degree of curvature [1002-1005]. Results and satisfaction rates are similar to both incision/excision techniques.

In general, using these tunical shortening techniques, complete penile straightening is achieved in > 85% of patients. Recurrence of the curvature and penile hypo-aesthesia is uncommon (~10%) and the risk of post-operative ED is low. Penile shortening is the most commonly reported adverse outcome of these procedures. Shortening of 1-1.5 cm has been reported for 22-69% of patients, which is rarely the cause of post-operative sexual dysfunction and patients may perceive the loss of length as greater than it actually is. It is therefore strongly advisable to measure and document the penile length peri-operatively, both before and after the straightening procedure, whichever technique is used (Table 19).

As mentioned above, there are multiple techniques with small modifications and all of them have been reported in retrospective studies, most of them without appropriate comparison between techniques and therefore the level of evidence is not sufficient to recommend one particular method over another.

Table 19: Results of tunical shortening procedures for PD (data from different, non-comparable studies) [874,979-1002,1006-1009]

*Data are expressed as weighted average. ^† Defined as > 30 degrees of curvature. Ranges are in parentheses. ED = Erectile dysfunction.

8.2.3.2.2. Tunical lengthening procedures

Tunical lengthening procedures are performed on the concave side of the penis after making an incision or partial excision of the plaque, with coverage of the defect with a graft. Although tunical lengthening procedures rarely lead to long-term penile length gain, they aim to minimise penile shortening caused by plication of the tunica albuginea, and correct complex deformities. In practice, tunical lengthening procedures are often combined with penile plication or shortening procedures to correct residual curvature and therefore may also result in penile shortening [1010]. Tunical lengthening surgery is preferable in patients with significant penile shortening, severe curvature and/or complex deformities (hourglass or hinge) but without underlying ED. The definition of severe curvature has been proposed to be > 60^o, although no studies have validated this threshold. On the concave side of the penis, at the point of maximum curvature, which usually coincides with the location of the plaque, an incision is made, creating a defect in the albuginea that is covered with a graft. Complete plaque removal or plaque excision may be associated with higher rates of post-operative ED due to venous leak, but partial excision in cases of florid calcification may be permissible [1011,1012]. Patients who do not have pre-operative ED should be informed of the significant risk of post-operative ED of up to 50% [969].

A large number of different grafts have been used. The ideal graft should be resistant to traction, easy to suture and manipulate, flexible (although not too much, to avoid aneurysmal dilations), readily available, cost-effective, and morbidity should be minimal, especially when using autografts. No graft material meets all of these requirements. Moreover, the studies performed did not compare different types of grafts and biomaterials and were often single-centre retrospective studies so there is not a single graft that can be recommended for surgeons [1013]. The use of geometric principles introduced by Egydio may help to determine the exact site of the incision, and the shape and size of the defect to be grafted [1014].

Grafts for PD surgery can be classified into four types (Table 20) [1015]:

• Autografts: taken from the individual himself, they include the dermis, vein, temporalis fascia, fascia lata, tunica vaginalis, tunica albuginea and buccal mucosa.
• Allografts: also of human origin but from a deceased donor, including the pericardium, fascia lata and dura mater.
• Xenografts: extracted from different animal species and tissues, including bovine pericardium, porcine small intestinal submucosa, bovine and porcine dermis, and TachoSil^® (matrix of equine collagen).
• Synthetic grafts: these include Dacron^® and Gore-Tex^®.

All the autologous grafts have the inconvenience of possible graft harvesting complications. Dermal grafts are commonly associated with veno-occlusive ED (20%) due to lack of adaptability, so they have not been used in contemporary series [1013,1016-1027]. Vein grafts have the theoretical advantage of endothelial-to-endothelial contact when grafted to underlying cavernosal tissue. The saphenous vein has been the most commonly used vein graft [1028-1043]. For some extensive albuginea defects, more than one incision may be needed. Tunica albuginea grafts have perfect histological properties but have some limitations: the size that can be harvested, the risk of weakening penile support and making future procedures (penile prosthesis implantation) more complicated [1044-1046]. Tunica vaginalis is easy to harvest and has little tendency to contract due to its low metabolic requirements, although better results can be obtained if a vascular flap is used [1047-1051]. Under the pretext that by placing the submucosal layer on the corpus cavernosum the graft feeds on it and adheres more quickly, the buccal mucosal graft has recently been used with good short-term results [1052-1058].

Cadaveric dura mater is no longer used due to concerns about the possibility of infection [1059,1060]. Cadaveric pericardium (Tutoplast^©) offers good results by coupling excellent tensile strength and multidirectional elasticity/expansion by 30% [950,1012,1023,1061,1062]. Cadaveric or autologous fascia lata or temporalis fascia offers biological stability and mechanical resistance [1063-1065].

Xenografts have become more popular in recent years. Small intestinal submucosa (SIS), a type I collagen-based xenogenic graft derived from the submucosal layer of the porcine small intestine, has been shown to promote tissue-specific regeneration and angiogenesis, and supports host cell migration, differentiation and growth of endothelial cells, resulting in tissue structurally and functionally similar to the original [1066-1075]. As mentioned above, pericardium (bovine, in this case) has good traction resistance and adaptability, and good host tolerance [1043,1076-1079]. Grafting by collagen fleece (TachoSil^©) in PD has some major advantages such as decreased operating times, easy application and an additional haemostatic effect [1080-1085].

It is generally recommended that synthetic grafts, including polyester (Dacron^®) and polytetrafluoroethylene (Gore-Tex^®) are avoided, due to increased risks of infection, secondary graft inflammation causing tissue fibrosis, graft contractures, and possibility of allergic reactions [982,1086-1089].

Post-operative penile rehabilitation to improve surgical outcomes has been suggested with a number of studies describing the use of VED and PTT to prevent penile length loss of up to 1.5 cm [1090]. Daily nocturnal administration of PDE5I enhances nocturnal erections, encourages perfusion of the graft, and may minimise post-operative ED rates [1091]. Massages and stretching of the penis have also been recommended once wound healing is complete.

Table 20: Results of tunical lengthening procedures for PD (data from different, non-comparable studies) [950,982,1012,1016-1085,1092,1093]

*Data are expressed as weighted average. Ranges are in parentheses.
ED = Erectile dysfunction; SIS = Small intestinal submucosa.

It must be emphasised that there have been no RCTs comparing surgical outcomes in PD. The risk of ED seems to be greater for penile lengthening procedures [871]. Recurrent curvature is likely to be the result of failure to wait until the disease has stabilised before surgery is undertaken, re-activation of the condition following the development of stable disease, or the use of early re-absorbable sutures (e.g., Vicryl) that lose their tensile strength before ensuing fibrosis has resulted in acceptable strength of the repair. Accordingly, it is recommended that only non-absorbable sutures or slowly re-absorbed absorbable sutures (e.g., polydioxanone) should be used. With non-absorbable sutures, the knot should be buried to avoid troublesome irritation of the penile skin, but this issue may be alleviated by the use of slowly re-absorbable sutures (e.g., polydioxanone) [1094]. Penile numbness is a potential risk of any surgical procedure, involving mobilisation of the dorsal neurovascular bundle. This is usually a temporary neuropraxia, due to bruising of the dorsal sensory nerves. Given that the usual deformity is dorsal, the procedure most likely to induce this complication is a lengthening (grafting) procedure, or the association with (albeit rare) ventral curvature [971].

8.2.3.2.3. Penile prosthesis

Penile prosthesis (PP) implantation is typically reserved for the treatment of PD in patients with concomitant ED not responding to conventional medical therapy (PDE5I or intracavernous injections of vasoactive agents) [871]. Although inflatable prostheses (IPPs) have been considered more effective in the general population with ED, some studies support the use of malleable prostheses in these patients with similar satisfaction rates [871,1095,1096]. The evidence suggests that there is no real difference between the available IPPs [1097]. Surgeons can and should advise on which type of prosthesis best suits their patients but it is the patient who should ultimately choose the prosthesis to be implanted [1098].

Most patients with mild-to-moderate curvature can expect an excellent outcome simply by cylinder insertion [1041,1099]. If the intra-operative curvature after placement of the prosthesis is < 30° no further action is indicated, since the prosthesis itself will act as an internal tissue expander to correct the curvature during the subsequent six to nine months. If, the curvature is > 30°, the first-line treatment should be modelling with the prosthesis maximally inflated (manually bent on the opposite side of the curvature for 90 seconds, often accompanied by an audible crack) [1100,1101]. If, after performing this manoeuvre, a deviation > 30° persists, subsequent steps to be considered include incision with or without collagen fleece coverage (if the defect is small, it can be left uncovered) or plaque incision and grafting are performed [1102-1107]. However, the defect may be covered if it is larger, and this can be accomplished using grafts commonly used in grafting surgery (described above) which prevent herniation and recurrent deformity and buckling due to the scarring of the defect [1108,1109]. The risk of complications (infection, malformation, etc.) is not increased compared to that in the general population. However, a small risk of urethral perforation (3%) has been reported in patients with ‘modelling’ over the inflated prosthesis [1100].

In selected cases of end-stage PD with ED and significant penile shortening, a lengthening procedure, which involves simultaneous PP implantation and penile length restoration, such as the “sliding” technique has been proposed [1110]. However, the “sliding” technique is not recommended due to reported cases of glans necrosis because of the concomitant release of the neurovascular bundle and urethra, new approaches for these patients have been recently described, such as the MoST (Modified Sliding Technique), MUST (Multiple-Slit Technique) or MIT (Multiple-Incision Technique) techniques, but these should only be used by experienced high-volume surgeons and after full patient counselling [1111-1114].

While patient satisfaction after IPP placement in the general population is high, satisfaction rates have been found to be significantly lower in those with PD. Despite this, depression rates decreased after surgery in PD patients (from 19.3%-10.9%) [1115]. The main cause of dissatisfaction after PPI in the general population is shortening; therefore, patients with PD undergoing PP surgery must be counselled that the prostheses are not designed to restore the previous penile length [1115,1116].

8.2.3.2.4. Summary of evidence and recommendations for surgical treatment of Peyronie’s disease

Figure 10: Treatment algorithm for Peyronie’s disease

ED = erectile dysfunction; LI-ESWT= low-intensity extracorporeal shockwave treatment; NSAIDs =non-steroidal anti-inflammatory drugs; CCH = Collagenase Clostridium histolyticum; IFN-α2b = Interferon-α2b.