| "text": "This is an academic paper. This paper has corpus identifier PMC2531200\nAUTHORS: Peter Hinh, Run Wang\n\nABSTRACT:\nIntroduction. Post-prostatectomy erectile dysfunction affects a considerable number of men and is a significant quality of life issue. There has been a substantial amount of research on the treatment of post-prostatectomy ED, and now there is a rising interest in the concept of penile rehabilitation. The goal of penile rehabilitation is to moderate the destructive processes that occur after prostatectomy in order to preserve erectile function, either through spontaneous or assisted means. Methods. We reviewed published data and experiences of post-prostatectomy penile rehabilitation using regimented interventions of phosphodiesterase inhibitors, vacuum erectile device, and intracavernosal agents, and we present and analyze the research conducted. Results. These studies show improved objective and subjective clinical outcomes in regards to physical parameters, sexual satisfaction, and rates of spontaneous erections. Conclusion. These studies are often limited by small size, study period, and study design. There continues to be a need for large, randomized, placebo controlled trials with adequate followup to fully evaluate the efficacy and cost-effectiveness of the various proposed penile rehabilitation regiments before a clear standard can be established.\n\nBODY:\n1. INTRODUCTIONErectile dysfunction following prostatectomy remains a\nsignificant quality of life issue for men undergoing prostatectomy. It is\nestimated to affect 26–100% of patients\nafter surgery [1]. Even with advancements in understanding the anatomy of\nthe prostate and the neurovascular bundle [2], a considerable number of men\nundergoing prostatectomy will have resulting erectile dysfunction.Progress has been made in identifying the events that contribute to erectile\ndysfunction after prostatectomy. The changes of neuropraxia, ischemic and\nhypoxic insults, fibrotic remodeling, and apoptosis are all believed to\ncontribute to erectile dysfunction [3, 4]. These events can occur even in\nattempts at meticulous dissection to preserve the neurovascular bundle. The etiologies of cavernous nerve neuropraxia\ninclude mechanical stretch injury during retraction, ischemia from accessory\nvessel disruption in dissection, thermal injury from electrocautery use, and\ninflammation from surgical trauma. This\nneuropraxia can prevent erections, and the perpetual lack of erection can\nitself set up a cascade of deleterious processes. Chronic impotence reduces\nblood flow to the corporeal bodies, which leads to fibrosis and transformation\nof the trabecular smooth muscle through collagen [5]. Further hypoxic insults\nalso may trigger apoptosis [6]. Therefore,\nthe goal of penile rehabilitation is to set up an environment that moderates\nthese processes in attempt of preserving penile function and earlier return of\npotency. Regimented usage of erectile\naids aims to improve the circulation of oxygen and maintain the structure of\nthe corporeal bodies.However, the research has yet to be translated into a\ncoherent clinical strategy for penile rehabilitation. As such, there are\nno currently accepted guidelines for penile rehabilitation regiments.\nCertainly, there exist several popular options that are currently in use.\nIn practice, three principle modalities of treating post-prostatectomy erectile\ndysfunction are employed. This paper will review the efficacy of these\noptions in this patient population for the purposes of penile rehabilitation.2. PHOSPHODIESTERASE 5 INHIBITORSThe introduction of phosphodiesterase inhibitors (PDEi) revolutionized\nthe treatment of erectile dysfunction. Since entering the market in 1998,\nthese medications have become nearly synonymous with erectile\ndysfunction. Their ease of use and relatively safe profile have made them\npervasive in the treatment of erectile dysfunction. They have also been\nextensively investigated. A Cochrane meta-analysis looking at many large,\nrandomized clinical trials concluded that PDEi are efficacious in the treatment\nof erectile dysfunction and are generally safe [7]. However, their role\nand their administration in penile rehabilitation after prostatectomy remain\nundefined. A number of clinical studies\nhave investigated PDEi use in this population for this intention.One of the first studies on PDEi in rehabilitation looked\nat objective data to support this use. \nSchwartz et al. conducted a study on 40 men who had undergone nerve\nsparing prostatectomy [8]. Prior to prostatectomy, all men had\npercutaneous biopsy of cavernous tissue to serve as baseline reference. They were divided into receiving either 50 or\n100 mg of Sildenafil every other night. Participant then underwent percutaneous\nbiopsy of cavernous tissue at 6 months to compare with baseline tissue. Investigators found that the 50 mg group did\nnot experience any loss of smooth muscle compared with baseline, and the 100 mg\ngroup actually showed an increase of smooth muscle content when compared to the\nbaseline. There was no control group, and no clinical correlation between\nsmooth muscle preservation and erectile function is made in this study. A prior animal study had shown that cavernosal\nsmooth muscle does atrophy after prostatatectomy [9], though this effect is\nsomewhat mediated with unilateral nerve sparing and it is unclear to what\nextent this atrophy would occur with nerve sparing prostatectomy.Bannowski et al. conducted a randomized trial following 43\nmen who underwent nerve-sparing radical prostatectomy [10]. All men provided baseline International Index of Erectile Function (IIEF) scores prior\nto surgery. After catheter removal following\nsurgery, the men underwent testing for nocturnal tumescence the following\nevening measured by the rigiscan. 41 of\n43 were found to have spontaneous erections on rigiscan, and these men were\nthen randomized to receive sildenafil daily or no treatment. They were then followed and evaluated with\nIIEF at 6, 12, 24, 36, and 52 weeks. The\nresults show that the daily treatment group had significantly higher IIEF score\nby 36 and 52 weeks. Additionally, 47% of\nthe daily treatment groups were able to achieve spontaneous, unassisted\nerection sufficient for penetration. \nThis compares to 28% of the control group who were able to have such\nerections. Both groups were also allowed\nSildenafil on demand, and accounting assisted erections, 86% of the daily group\nhad erections sufficient for penetration, compared to 66% of the control\ngroup. The study made no mention of any\nparticipant drop out, and there was no placebo control. However, it does appear that daily Sildenafil\ndoes improve return of spontaneous erections and can augment response to on-demand use of Sildenafil.A stringent, randomized,\ndouble-blinded, placebo controlled study was performed by McCullough et al.\nevaluating the efficacy of daily Sildenafil in men after bilateral nerve-sparing\nradical prostatectomy [11]. This study\nincluded 54 men with baseline normal EF and NPTR (nocturnal penile tumescence\nand rigidity with duration of rigidity >55% of maximal rigidity using\npenile plethysmography). After a\npretreatment period of 4 weeks, they were then randomized to either receive\nnightly 100 mg Sildenafil (N = 18), 50 mg Sildenafil (N = 17), or placebo (N = 19). The groups were then analyzed at\n16, 28, and 40 weeks. Then after 40\nweeks, all medications were discontinued and the groups were again analyzed at\n48 weeks. At each point, the\nparticipants were evaluated by NPTR and IIEF . \nThe study found that the groups receiving daily Sildenafil were able to\nhave return of rigidity (R > 55%) at seven times the nadir value compared to minimal\nimprovement in the control group. This\nimprovement of erection was also seen by the investigators for RAU (rigidity-activated unit—a time-intensity measurement that\nrepresents the area under the rigidity curve during a qualified\nevent), with the additional finding that the 100 mg group experienced continued\nimprovement after the discontinuation phase, while the 50 mg group began to\nexperience decline in RAU. Importantly,\nthe men on daily Sildenafil were five times more likely to have return of spontaneous,\nunassisted erection sufficient for intercourse compared to placebo. The authors were able to link objective\nmeasurements of erections with subjective, clinical response. They noted that tip rigidity >55% clearly\nseparated responders versus nonresponders (responders defined as recovery of\nspontaneous, unassisted sufficient erections). \nThis study may mark objective validation as an important component of\nfuture clinical trials. These initial\nresults are from a subset analysis performed on men who showed normal EF and\nNPTR on baseline, and we await further data and analysis on the entire study\npatients.Taken together,\nthese studies seem to indicate that phosphodiesterase inhibitors have a role in\npenile rehabilitation for men after prostatectomy. There may also be a dose-dependent relationship between the medication and outcomes. The studies also confirm the tolerability and\nsafety of such a regiment, as discontinuation rates were very minimal and no\nadverse events were reported.3. VACUUM ERECTILE DEVICEThe Vacuum erectile device assists erections by drawing blood flow into the\ncavernous sinuses through negative pressure, physically causing an\nerection. A constrictive band can also be placed at the base of the\npenis, preventing backflow and maintaining corporal pressures. This\ndirect mechanism of action can circumvent the limitation of oral agents, which\nrequires an intact and functioning neuronal connection to produce\nerections. This can be a significant factor even in men undergoing nerve\nsparing prostatatectomy, as neuropraxia still occurs and can diminish the\neffectiveness of PDEi.This\ntreatment modality can also be extended to men who have undergone nonnerve\nsparing prostatectomy, though not in the context, in penile rehabilitation with\nthe expectation of return of potency.If not for potency itself, VED usage has also been advocated due to its\npossible efficacy in preventing penile shrinkage and maintaining length.\nStudies have shown significant shrinkage of penile length, with one\nstudy finding that nearly 20% of men experience a loss of length greater than\n15% [12]. In another study examining penile shortening after\nprostatectomy, Gontero et al. followed 126 men who had undergone prostatectomies\nand measured penile length prior to surgery, at the time of catheter removal,\nand then at 3, 6, and 12 months [13]. They found that the greatest amount of\nshrinkage occurs in the immediate postoperative period, though shortening\ncontinues at a lesser rate throughout the entire study period. These\nauthors hypothesize that early hypoxia leads to increased expression of TGF-B\nand Collagen I and III fibers. This study also finds that the return of erectile\nfunction, defined as an IIEF of 15, was associated with mitigation of the\nshrinkage, as well as having a nerve sparing surgery. Several studies looking at the efficacy of\nvacuum erectile device in preserving erectile function have also examined\npreserved penile length as a secondary endpoint.Raina et al. randomized 109 post-prostatectomy men to\neither early VED use daily (N = 74) versus no erectogenic aid (N = 35) [14]. The men were to use the constriction band\nonly during intercourse to maintain rigidity. Participants were followed\nwith SHIM and IIEF scores for comparison. For the group using VED, 80%\nwere able to achieve penetration with use of VED, and this group, not\nsurprisingly, had a significantly higher SHIM and IIEF group compared to no\ntreatment. The discontinuation rate was 18%, and the majority of the drop\nout was for discomfort. In the context\nof penile rehabilitation, at 9 months this study found that 17% of those\nadhering to daily VED were able to have spontaneous erections sufficient for\nerections at 9 months, compared to 11% (n = 4) of the control group that had such\nerections. In regard of the effect of\nVED on penile length, the men who adhered to VED regiment experienced less\nsubjective penile shrinkage, with 23% reporting less length compared to 85% of\nthe men who quit treatment and 65% of the control. No objective data was collected concerning\nlength. The authors conclude that early\nuse of VED with the purpose of penile rehabilitation improves sexual and\npartner satisfaction and allow for earlier return of spontaneous erections. Although,\nthe rate of return of spontaneous erection is low for both groups, those\nnumbers include men who had undergone nonnerve sparing prostatectomies. This distinction is necessary, as penile\nrehabilitation is more directed for NS men and the inclusion of nonnerve sparing\nprostatectomy patients diluted the response to rehabilitation.The timing of when to initiate VED has been questioned,\nwith some advocating an earlier intervention. Köhler et al. randomized 28\nmen to either receive early VED regiment (1 month after RP) or delayed VED\nregiment (6 months) [15]. The regiment consisted of 10 minutes of VED\nusage without the constriction band. IIEF was measured at baseline, 1, 3,\n6, 9, and 12 months. The mean followup was 9.5 months and the results\nanalyzed at 3 and 6 months showed that the early intervention group had a statistically higher\nIIEF score. At this point, the comparison shows that VED does improve\nIIEF scores among those who use VED versus those controls that do not. At beyond 6 months, the delayed group began using of VED, and at\nshort followed up the\ntwo groups converged with no statistical difference in IIEF \ncategorization. No patients in this\nstudy had return of spontaneous erections sufficient for penetration at that\nfollowup. This paper was presented as a\npilot study, and more outcomes are expected to follow, especially data\nconcerning return of spontaneous erections. There are still some important\npoints that can be gleamed from this study. For one, the authors reported\ncomplete compliance with this regiment, suggesting this short regiment (two five-minute cycles) could\nbe feasibly implemented. Importantly,\nthese researchers also looked at penile length and found that the group\nperforming VED regiment did not experience penile shrinkage, while the group on\ndelayed VED showed significant penile shrinkage at 3 (mean loss 1.87 cm) and 6\nmonths (mean 1.82 cm). However, after\nbeginning VED in the delayed group, the loss decreased to a mean of 1 cm and no longer remained\nstatistically significant. Again, this is short-term followup data in the delayed group, and\nfurther improvement in shrinkage may still yet be seen. We still await data concerning return of\nspontaneous erection from this study.The value of VED in penile\nrehabilitation remains uncertain. Daily\nregimented use of VED requires a motivated patient and does improve sexual\nsatisfaction in those who responds. If\nthe stated goal of penile rehabilitation is the return of preexisting potency,\nthen further studies are needed to show that VED improves the rate of return of\nerection. However, VED use may also be advocated for its effects on preventing\npenile shrinkage after prostatectomy.4. INTRACORPOREAL INJECTIONIntracorporeal injection of vasoactive agents increase blood flow into the\ncavernous sinuses locally, either through increasing cAMP, by antagonizing alpha-adrenergic\nreceptors, or by direct smooth muscle relaxation. Like VED, they also do\nnot require an intact, functional nervous system to produce erections.\nThus, they can also be offered in men who have undergone nonnerve sparing surgery\nand men who do not respond to oral agents.Montorsi et al. conducted a randomized trial\ninvestigating whether a regiment of intracavernosal injections improves\nerectile function in post-prostatectomy men [16]. 30 men with established\npreoperative potency were randomized to either receive a regiment of 3 times\nper week injections of alprostadil for 12 weeks versus a control group that did\nnot receive erectogenic treatment. The groups were then assessed after 3 months\nfor sexual history, for Doppler response after alprostadil administration, and\nfor nocturnal tumescence. Of the ICI\nregiment group, 80% completed the 12 weeks of treatment with a 20% drop-out\nrate and a 17% complication rate. Of\nthese men, 67% at 3 months were able to have spontaneous erections sufficient\nfor penetration. This favorably compares to 20% of the control group men that\nwere able to have such erections. The authors do note that in this group some\nstill continued to use ICI to achieve erections. However, the authors\nconsidered it a complete response since the majority of sexual encounters\noccurred without ICI use (average of one in 4.2 attempts). The study also found\nthat having normal penile hemodynamics was strongly associated with ICI\ncomplete response. The study suffers from small size and short followup.\nHowever, it was still able to show an improvement in spontaneous erections for\nregimented ICI and that regimented ICI is generally well tolerated.Mulhall et al. conducted a trial\nthat may be more clinically applicable, even though it was not randomized [17]. In\nthis trial, post-prostatectomy men were committed to penile rehabilitation with\nSildenafil or ICI if there was no response to Sildenafil, versus no penile rehabilitation\nprogram, but they were\nnot restricted from using erectile aids. \nThe rehabilitation group used either Sildenafil or ICI three times per week. Analysis at 18\nmonths revealed that 52% of rehabilitation men were able to have functional\nerections, compared to 19% of control group men. Additionally, the rehabilitation group had\nsignificantly higher IIEF scores. These\nresults are impressive, especially considering that the control group was also\nable to use erectile aids, including both Sildenafil and ICI, though not in a\nregimented manner. The study included men with nonnerve sparing\nprostatectomies, which generally are not considered candidates for erectile rehabilitation,\nthough the authors do note that there was not a differential distribution\nbetween the groups. Additionally, the\naverage length of time before sexual consultation and therefore the start of\nrehabilitation were 4.2 months. Some would suggest that this\nlength of time is too long removed from the surgery, and the insults of\nhypoxia, fibrosis, and apoptosis may have already occurred and be irreversible\nat this point. It is also important to note that selection bias may be very\nconsiderable in this study, in that only men who prospectively committed\nthemselves were included in the rehabilitation group and the study relied on\nmainly self-reported, subjective data.5. COMBINATION THERAPIESStudies have examined the feasibility and efficacy of\nemploying two treatment modalities during penile\nrehabilitation. Nandipati et al. incorporated both intracavernosal\ntherapy and PDEi in a group of 22 men who underwent nerve sparing prostatectomy\n[18]. All participants received Sildenafil 50 mg daily (25 mg if subjects\ncomplained of headaches). For ICI, 18\npatients received PGE 1–4 micrograms and\n4 received trimix injection, with ICI being done two to three times per\nweek. These patients were then analyzed at 3, 6, 9, and 12 months with IIEF . Doppler studies were performed for dose\noptimizations of ICI and at intervals to increase dosage for response. The study reported a mean followup of six\nmonths. At this point, investigators found that 21 of 22 patients were sexually\nactive, while 12 of the 21 were using ICI alone and 9 of 21 were using combination\ntherapy. Of the 18 patients using PGE, 12 were able to lower their dosage;\nwhile 1 of the 4 patients on trimix was able to do so. 11 of the 22 men\nhad return of spontaneous erection, though none graded the erections sufficient\nfor penetration. The authors concluded\nthat the addition of Sildenafil could reduce the amount of ICI necessary to\nachieve erections. This study had a lower rate of return of functional\nerections compared to other studies looking at nightly PDEi 1 [11] or regimented\nICI alone [16], and this difference may be explained by the\nshorter followup and the small number of participants. Without proper study design, in such\ncombination therapy studies, it is difficult to assign particular findings to\nspecific intervention.6. NOVEL THERAPIESOther therapies outside of these three mainstream\nmodalities have been investigated for penile rehabilitation after\nprostatectomy. Recently, investigators in Korea looked at statins for treating\nerectile dysfunction after prostatectomy [19]. The basis for this\nhypothesis stems from the known protective effect on vascular endothelium and\nincreased NO activity. The researchers randomized 50 men post-prostatectomy\nto receive 10 mg of atorvastatin for 90 days. All men were then to use\nSildenafil 50 mg per day on demand. The men all had superior function prior to\nthe surgery with IIEF 25. At 6 months of followup, the study found that\nthe statin group had more patients categorized at potent ( IIEF greater than 16)\nwith 11 in the statin group and 6 in the control group. Additionally, more men in the statin group were able\nto achieve vaginal penetration without PDEi than in the control group (8 versus\n4), though this significance did not reach statistical significance. The\nstudy was neither blinded nor placebo-controlled. It is important to note that the\ninclusion criteria were extremely stringent, and patients with significant cormidities were excluded. This may affect the\napplicability or generalizability of the results.7. CONCLUSIONSexual potency after prostatectomy remains a significant quality of life issue\nafter prostatectomy. There exist many studies on the efficacy of the\nvarious treatment options on this patient population. There are much less data looking on the\neffects of regimented usage of PDEi, VED, and/or ICI in improving erectile\nfunction in this group, and no guidelines exist to help steer the\nclinician. We are still in need of large, randomized, controlled, clinical\ntrial with adequate, long-term followup to evaluate this question. Moreover, even after each treatment can be\nestablished to be efficacious in penile rehabilitation, the exact regiment amount and\nduration will still be open to further investigations for optimization. This is\na especially important question in dealing with phosphodiesterase inhibitors,\nwhere the cost of treatment is substantial. \nHowever, even though currently sparse, the consistent, growing body of\nevidence does support penile rehabilitation in improving return of sexual\nfunctioning. As awareness of penile\nrehabilitation increases and becomes more accepted, it is becoming more\ndifficult to conduct placebo or nonintervention controlled trial. There are\nstill several ongoing trials evaluating penile rehabilitation, including a\nlarge multicenter study examining penile rehabilitation with medicated urethral system for erection (MUSE), and several of the studies presented here will further analyze with additional data from which the urology community may further define when and how to\nimplement penile rehabilitation in post-prostatectomy men.Currently, the body of evidence does\nseem to suggest a beneficial role for penile rehabilitation after prostatectomy\nin improving return of potency. Such a program should begin with a detailed\nevaluation on the preoperative sexual performance characteristic of the patient\nand then a thorough\ndiscussion of the available rehabilitation regiments. The practitioner should consider factors that\nare important to the patient including ease of use and compliance, patient\nmotivation, conditioning, cost and patient expectations about sexual function,\nand penile length. Penile rehabilitation\nmay continue to remain investigative until more standardized clinical data\nbecomes available.\n\nREFERENCES:\n1. BurnettALAusGCanby-HaginoEDErectile function outcome reporting after clinically localized prostate cancer treatmentThe Journal of Urology2007178259760117570435\n2. WalshPCPartinAWWeinAJKavoussiLRNovickACPartinAWPetersCAAnatomic radical retropubic prostatectomyCampbell-Walsh Urology20079th editionPhiladelphia, Pa, USASaunders2956 pages\n3. McculloughARRehabilitation of erectile function following radical prostatectomyAsian Journal of Andrology2008101617418087645\n4. WangRPenile rehabilitation after radical prostatectomy: where do we stand and where are we going?The Journal of Sexual Medicine200744, part 21085109717466058\n5. MorelandRBIs there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of ImpotenceInternational Journal of Impotence Research19981021131209647948\n6. McVaryKTPodlasekCAWoodDMcKennaKEApoptotic pathways are employed in neuropathic and diabetic models of erectile dysfunctionThe Journal of Urology2006175387 pagesAbstract 1203\n7. FinkHAMac DonaldRRutksIRNelsonDBWiltTJSildenafil for male erectile dysfunction: a systematic review and meta-analysisArchives of Internal Medicine2002162121349136012076233\n8. SchwartzEJWongPGraydonRJSildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomyThe Journal of Urology20041712, part 177177414713808\n9. UserHMHairstonJHZelnerDJMcKennaKEMcVaryKTPenile weight and cell subtype specific changes in a postradical prostatectomy model of erectile dysfunctionThe Journal of Urology200316931175117912576876\n10. BannowskyASchulzeHvan der HorstCHautmannSJünemannK-PRecovery of erectile function after nerve-sparing radical prostatectomy: improvement with nightly low-dose sildenafilBJU International2008101101279128318284406\n11. McculloughARLevineLAPadma-NathanHReturn of nocturnal erections and erectile function after bilateral nerve-sparing radical prostatectomy in men treated nightly with sildenafil citrate: subanalysis of a longitudinal randomized double-blind placebo-controlled trialThe Journal of Sexual Medicine20085247648418086170\n12. SavoieMKimSSSolowayMSA prospective study measuring penile length in men treated with radical prostatectomy for \nprostate cancerThe Journal of Urology200316941462146412629384\n13. GonteroPGalzeranoMBartolettiRNew insights into the pathogenesis of penile shortening after radical prostatectomy and the role of postoperative sexual functionThe Journal of Urology2007178260260717570431\n14. RainaRAgarwalAAusmundsonSEarly use of vacuum constriction device following radical prostatectomy facilitates early sexual activity and potentially earlier return of erectile functionInternational Journal of Impotence Research2006181778116107868\n15. KöhlerTSPedroRHendlinKA pilot study on the early use of the vacuum erection device after radical retropubic prostatectomyBJU International2007100485886217822466\n16. MontorsiFGuazzoniGStrambiLFRecovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trialThe Journal of Urology1999161619141915\n17. MulhallJLandSParkerMWatersWBFlaniganRCThe use of an erectogenic pharmacotheraphy regimen following radical prostatectomy improves recovery of spontaneous erectile functionThe Journal of Sexual Medicine20052453254016422848\n18. NandipatiKRainaRAgarwalAZippeCDEarly combination therapy: intracavernosal injections and sildenafil following radical prostatectomy increases sexual activity and the return of natural erectionsInternational Journal of Impotence Research200618544645116482200\n19. HongSKHanBKJeongSJByunS-SLeeSEEffect of statin therapy on early return of potency after nerve sparing radical retropubic prostatectomyThe Journal of Urology2007178261361617570410" |
