Penile Rehabilitation After Radical Prostatectomy: Important Therapy or Wishful Thinking?

Transcription

1 MANAGEMENT UPDATE Penile Rehabilitation After Radical Prostatectomy: Important Therapy or Wishful Thinking? Joseph E. Dall Era, MD, Jesse N. Mills, MD, Hari K. Koul, MD, Randall B. Meacham, MD Division of Urology, University of Colorado School of Medicine, Denver, CO On the basis of data accumulated thus far, it is reasonable to discuss the implementation of a penile rehabilitation program with patients undergoing radical prostatectomy. Central to discussions of penile rehabilitation after radical prostatectomy is evidence demonstrating significant fibrotic changes in the corpus cavernosum that occur postoperatively. Several studies have been published evaluating the efficacy of various pro-erectogenic agents. The limited data regarding intracavernous injections and vacuum constriction devices suggest that an increased percentage of treated patients experienced a return of natural erections compared with patients who received no treatment. Longer, prospective, randomized, placebo-controlled studies will be needed to confirm the utility of these treatments. Data from contemporary studies evaluating the chronic use of oral phosphodiesterase type 5 inhibitors suggest a beneficial effect on endothelial cell function among men suffering from erectile dysfunction due to a variety of causes. Limited data suggest that this effect might be seen among post-prostatectomy patients, implying a possible role for these agents in enhancing the return of sexual function in such individuals. [Rev Urol. 2006;8(4): ] 2006 MedReviews, LLC Key words: Radical prostatectomy Erectile dysfunction Hypoxia Penile rehabilitation Intracorporeal injection Vacuum constriction device PDE-5 inhibitors The practice of penile rehabilitation to improve sexual function after radical prostatectomy continues to generate increasing interest among clinicians. Although the reported incidence of erectile dysfunction after nervesparing radical prostatectomy varies in the literature from 30% to 80%, 1-4 most will agree that post-surgical quality of life is becoming a greater concern for patients seeking treatment for prostate cancer in the era of early detection. VOL. 8 NO REVIEWS IN UROLOGY 209

2 Penile Rehabilitation After RP continued The time interval to return of erectile function after radical prostatectomy can be up to 2 years. This 2-year period might be due to neuropraxia, or transient cavernosal nerve dysfunction. Historically, patients have been encouraged during this period to continue waiting for the return of erectile function without the need for active intervention. More recently, a vascular etiology of post-surgical erectile dysfunction has generated considerable interest, suggesting that a prolonged flaccid state might lead to irreversible damage to the cavernous tissue. A variety of erectogenic modalities have been used in an effort to minimize fibrotic changes during the period of penile quiescence after nerve-sparing radical prostatectomy. A number of studies have been conducted to evaluate which pro-erectile agent offers patients the best outcome for future erectile function and at what point in the postoperative period such treatment should be initiated. This review examines the current literature as it pertains to the rationale for penile rehabilitation and the various methods of prophylaxis being used after radical prostatectomy. Histological Changes Associated With Radical Prostatectomy Patients are typically counseled that it may take up to 2 years before the return of spontaneous erectile function after radical prostatectomy. An important study by Mulhall and colleagues 5 evaluating penile hemodynamics showed significant and progressive venous leak ranging from 14% at 4 months to more than 50% at 12 months after nerve-sparing radical prostatectomy. Importantly, only 9% of men with evidence of venous leakage had erections sufficient for intercourse at 12 months, compared with 47% of men with normal hemodynamics. Animal models of cavernous nerve injury have since been used to further characterize the histological changes in the cavernous tissue Only 9% of men with evidence of venous leakage had erections sufficient for intercourse at 12 months, compared with 47% of men with normal hemodynamics. associated with the observation of venous leakage. In early studies, Podlasek and colleagues 6 and User and colleagues 7 used a rat model of bilateral cavernous nerve injury to demonstrate an increase in apoptosis localized to the smooth muscle cells of the corpus cavernosum. Importantly, cell death was noted to peak at 2 days after bilateral neurectomy, suggesting early smooth muscle cell dysfunction as a mechanism for the previously observed veno-occlusive dysfunction seen in post-prostatectomy erectile dysfunction. Additional studies demonstrate increased levels of collagen types I and III in the rat cavernosum 60 days after bilateral neurectomy 8 and in the human cavernosum at up to 12 months after radical prostatectomy. 9 Furthermore, the study by Iacono and colleagues 9 confirmed a concomitant decrease in overall smooth muscle fibers throughout the 12-month postoperative period. Interestingly, these changes are not unique to postprostatectomy patients. A variety of physiologic changes can lead to deterioration of smooth muscle within the corpus cavernosum. Androgen deprivation in rats, for example, also leads to decreased smooth muscle cell content and severe venous leakage, a process that is reversible with testosterone replacement therapy. 10 Although the endpoint of venous leakage remains constant, the etiology of the fibrotic changes within the cavernosum in patients after radical prostatectomy remains unclear. Patients with known injury to the neurovascular bundles likely proceed through a continued cycle of smooth muscle cell death, leading to irreversible veno-occlusive disease. Similarly, patients with preserved neurovascular bundles might demonstrate progressive fibrosis of the cavernosal tissue during the period of neuropraxia, leading to the same endpoint of venous leakage. It is this latter group (ie, patients who are expected to regain at least partial erectile function) that is targeted with penile rehabilitation to decrease the fibrotic changes associated with the temporary period of nerve dysfunction. Role of Hypoxia in Penile Fibrosis In the previously mentioned study by Leungwattanakij and colleagues, 8 the increase in collagen deposition in the Patients with known injury to the neurovascular bundles likely proceed through a continued cycle of smooth muscle cell death, leading to irreversible veno-occlusive disease. rat cavernosum after bilateral neurectomy was accompanied by elevated levels of transforming growth factor β 1 (TGF-β 1 ). These changes have previously been associated with prolonged tissue hypoxia, leading many investigators to propose a causal relationship between hypoxia and the cavernosal changes seen in men with 210 VOL. 8 NO REVIEWS IN UROLOGY

3 Penile Rehabilitation After RP a prolonged flaccid state after nervesparing radical prostatectomy. Normally, the differences in the partial pressure of oxygen (PO 2 ) within the corpus cavernosum during the erect and flaccid states closely resemble those of arterial and venous blood, respectively. Specifically, the PO 2 measures 30 to 40 mm Hg during the flaccid state and 90 to 100 mm Hg during erection. Not surprisingly, men with vasculogenic impotence have been shown to fall in the middle of these ranges. In a study by Brown and coworkers, 11 cavernosal blood samples were drawn after erection was induced in men with confirmed arteriogenic or various degrees of venogenic erectile dysfunction. The PO 2 values in men with arteriogenic and venous leak impotence were 65 mm Hg and 74 mm Hg, respectively. In addition, the investigators found no significant difference between a group of men with severe venous leak and those with arterial disease (71 mm Hg vs 65 mm Hg), suggesting a role of low oxygen tension in men with both arteriogenic and venogenic erectile dysfunction. It has been suggested that the primary messengers for increasing or decreasing collagen synthesis in response to cavernosal PO 2 are TGF-β 1 and prostaglandin E 1 (PGE 1 ), respectively. Moreland and colleagues 12 demonstrated a 2.5- to 4.5-fold increase in collagen synthesis in cultured cavernosal smooth muscle cells in response to TGF-β 1. Furthermore, they demonstrated a 2- to 3-fold increase in TGF-β 1 expression in cells subjected to low oxygen tension (PO 2 30 mm Hg). Interestingly, they found that the addition of PGE 1 suppressed the effect of TGF-β 1 on collagen synthesis. Shortly thereafter, Daley and coworkers 13 performed in vitro experiments using strips of rabbit cavernosum tissue incubated at various oxygen tensions. They showed that hypoxic conditions (no oxygen, PO 2 27 mm Hg) resulted in inhibition of prostanoid release and that this effect was reversible after 2 hours of reoxygenation (21% oxygen, PO mm Hg). Furthermore, this recovery period was significantly shortened by the addition of antioxidant agents, such as catalase and 4,5-dihydroxy-1,3-benzene disulfonic acid, suggesting that reactive oxygen species produced by ischemia and reperfusion might contribute to the injury. An important caveat is that this study was designed to model the cavernosal physiology after a shunt procedure to treat ischemic priapism, in which the cavernosum might go from a hypoxic to a hyperoxic environment. Several investigators, however, have since extrapolated these results to the setting of chronic penile flaccidity in the post radical prostatectomy patient. Arguably, the control oxygen environment created in this study (167 mm Hg) is superphysiologic and therefore should not be applied to the normal environment in the human cavernosum. Together, these studies suggest that the collagen content in the corpus cavernosum is regulated by oxygen tension through the increased or decreased expression of TGF-β 1 and PGE 1. During low oxygen tension, increased expression of TGF-β 1 activates a molecular cascade to increase collagen and other connective tissue synthesis. During high oxygen tension, on the other hand, increased expression of PGE 1 activates an alternate cascade to decrease collagen synthesis. To date, the data are insufficient to confirm that this delicate balance of TGF-β 1 and PGE 1 expression actually dictates the varying amounts of smooth muscle and connective tissue content within the corpus cavernosum at physiologic oxygen tensions. The role of hypoxia in penile fibrosis after nerve-sparing radical prostatectomy, therefore, remains a topic of debate. Critics of the hypoxia theory point out that the effects of physiologic oxygen tensions associated with a flaccid penis on cavernosal tissue remain theoretical. 14 To date, no studies have proven an in vivo derangement of endothelial or smooth muscle cell metabolism secondary to a prolonged flaccid state. Though elegant in design, the in vitro studies of hypoxic environments should be correlated to the situation of a flaccid penis with caution. Critics of the hypoxia theory point out that the effects of physiologic oxygen tensions associated with a flaccid penis on cavernosal tissue remain theoretical. Effect of Penile Rehabilitation on Post Radical Prostatectomy Erectile Dysfunction The exact etiology of the fibrotic changes that occur in the corpus cavernosum after radical prostatectomy remains a topic of discussion. Several studies have been reported, however, evaluating the effectiveness of artificially induced erection after surgery to prevent permanent damage. To date, several prospective studies have been performed with a number of modalities, including PGE 1 injection, vacuum devices, and phosphodiesterase type 5 (PDE-5) inhibitors. A study by Montorsi and colleagues 15 evaluating the use of intracorporeal injections of alprostadil starting at 1 month after bilateral nerve-sparing radical prostatectomy has frequently been cited to support the use of early injection therapy. The investigators VOL. 8 NO REVIEWS IN UROLOGY 211

4 Penile Rehabilitation After RP continued reported a higher rate of recovery of spontaneous erections after 6 months compared with no treatment. Specifically, 67% of men in the study group had return of spontaneous erections sufficient for intercourse at 6 months, compared with 20% of men who did not inject. This study, however, has two important limitations. First is the lack of placebo control. The importance of controlling for the placebo effect in erectile dysfunction treatments is evidenced by several studies of oral PDE- 5 inhibitors. For example, in an early study of tadalafil, 43% of men receiving placebo reported an improvement in erectile function. 16 Similarly, in a study of vardenafil in diabetic men, the placebo group reported an improvement in erectile function twice that of baseline. 17 Therefore, the increase from 20% to 67% in return of spontaneous erections must be considered in light of a possible placebo effect. The second limitation is the inconsistent definition of success between the injectors and non-injectors. In the injection group, complete recovery was defined as requiring an injection every 4.2 times for successful intercourse. However, in the non-injection group, success was defined as a return of spontaneous erections sufficient for intercourse. These different definitions of complete recovery make interpretation of the results more challenging. An important aspect of the Montorsi study was the use of color Doppler sonography to evaluate penile hemodynamics after the study period. Interestingly, the investigators found that 53% of patients who did not receive treatment demonstrated venous leakage, compared with 17% of patients receiving injection therapy. These findings support the hypothesis that cavernosal changes lead to significant venous leakage in the early postoperative period after radical prostatectomy. However, the data leave open the possibility that PGE 1 compound itself might have an impact on the prevention of fibrosis. PGE 1 has been shown in vitro to decrease fibrosis in cavernosal tissue. 12 In a recently published study, Mulhall and coworkers 18 followed 132 patients through an 18-month period after they were placed in rehabilitation or no rehabilitation groups after radical prostatectomy. Patients undergoing rehabilitation agreed to take sildenafil or intracavernosal alprostadil to induce erection 3 times weekly starting within the first 4 weeks after surgery (mean 1.9 erections per week). Patients agreeing to the The importance of controlling for the placebo effect in erectile dysfunction treatments is evidenced by several studies of oral PDE-5 inhibitors. study but not wishing to be included in the rehabilitation protocol used various pharmacologic therapies as needed, but without the goal of achieving 3 erections per week (mean 0.4 erections per week). After 18 months of follow-up, 52% of the men in the rehabilitation protocol group reported spontaneous functional erections, compared with 19% of the men in the no-rehabilitation group. Furthermore, a significantly greater number of men in the rehabilitation group responded to sildenafil treatment after the 18-month period with an erection sufficient for intercourse (64% vs 24%). The limitation of the study, which the investigators acknowledge, is that this was a nonrandomized study, which potentially introduces bias. However, the results are in agreement with those from Montorsi and colleagues 15 and suggest that a regimented rehabilitation protocol might improve overall return of erectile function after radical prostatectomy. A later study, by Gontero and colleagues, 19 investigated alprostadil injections at various time points after non nerve-sparing radical prostatectomy. They found that 70% of patients receiving injections within the first 3 months were able to achieve erections sufficient for intercourse, compared with 40% of patients receiving injections after the first 3 months. Similarly, they found a progressive decrease in the resistive index using color Doppler ultrasound through all time points extending to 1 year after the procedure. These findings are often quoted to strengthen the argument for early penile rehabilitation, preferably within 3 months after surgery. However, because all men received only a single injection treatment, it is unclear whether men who responded in the early group would continue to respond after 12 months. The study does, however, corroborate the vascular changes seen in the Montorsi study. Specifically, the amount of venous leakage increases from time after surgery throughout a 12-month period and parallels the deterioration seen in erectile function. Recently, Raina and coworkers 20 have evaluated the daily use of a vacuum constriction device (VCD) beginning within 2 months after surgery in patients undergoing nerve-sparing radical prostatectomy or non nerve-sparing radical prostatectomy. After 9 months of treatment, 17% of patients using the device had return of natural erections sufficient for intercourse, compared with 11% of patients in the nontreatment group. Although a placebo control group for VCD would be difficult to devise, a possible placebo effect renders the significance of these findings somewhat unclear. An interesting 212 VOL. 8 NO REVIEWS IN UROLOGY

5 Penile Rehabilitation After RP finding in this study was that 23% of patients in the treatment group reported a decrease in penile length and circumference, compared with 60% in the nontreatment group. Though we cannot conclude with certainty that the early use of VCD will improve overall return of erectile function, these data suggest that fibrotic changes leading to penile shortening and possible venous leakage might be minimized. PDE-5 Inhibitors PDE-5 inhibitors have become the first-line treatment for erectile dysfunction of many etiologies, including localized treatment for prostate cancer. It had long been believed that their success required an intact neural pathway, and PDE-5 inhibitors had not, therefore, been advocated as a monotherapy in penile rehabilitation after nerve-sparing radical prostatectomy, owing to the period of neuropraxia. Zagaja and colleagues 21 found that men taking oral sildenafil within the first 9 months of a nerve-sparing procedure might not have any erectogenic response, thus calling into question their use in early penile rehabilitation. Proponents for the use of a PDE-5 inhibitor in a penile rehabilitation protocol, however, argue that this class of medication might also act through a separate, neuralindependent mechanism. Effect of PDE-5 Inhibitors on Endothelial Cell Function Several studies have shown that the use of PDE-5 inhibitors might lead to an overall improvement in endothelial cell function in the corpus cavernosum. Desouza and coworkers 22 recently demonstrated an increase in brachial artery flow mediated dilatation, a measure of global vascular endothelial function, in a group of diabetic men treated with 2 weeks of daily, oral sildenafil. They concluded that daily sildenafil improves overall vascular endothelial cell function. Similarly, Behr-Roussel and colleagues 23 studied chronic sildenafil treatment in rats with 8 weeks of An interesting finding in this study was that 23% of patients in the treatment group reported a decrease in penile length and circumference, compared with 60% in the nontreatment group. subcutaneous injections of the drug followed by a 36-hour washout period. Their subsequent in vitro studies showed an enhanced endotheliumdependent relaxation of cavernosal strips in response to acetylcholine among the sildenafil group compared with the control group. In addition, their in vivo studies using cavernous nerve stimulation revealed a 45% increase in erectile response among the treated rats compared with a control group after an acute intravenous injection of sildenafil. Although the in vivo results might have been influenced by elevated plasma sildenafil levels despite a 36-hour washout period, the investigators concluded that their in vitro tissue results support the concept of profound tissue modifications after chronic treatment with sildenafil. Finally, Foresta and colleagues 24,25 have analyzed the level of bone marrow derived endothelial progenitor cells (PC) in patients with known erectile dysfunction after acute dosages of vardenafil. In one study, 24 they found a significantly decreased number of PC in a cohort of patients with known erectile dysfunction, independent of other cardiovascular risk factors. In a separate study, 25 they found a significant increase in PC among normal men 4 hours after a 20-mg dose of vardenafil compared with a control group. In a recent study, Sommer and Schulze 26 evaluated the daily use of sildenafil over a 12-month period in men with erectile dysfunction due to multiple etiologies. They found that after a 4-week washout period, 59% of men who had taken daily sildenafil for 1 year had an International Index of Erectile Function (IIEF) score greater than 26, compared with 9% in men who took sildenafil on an as needed basis. Interestingly, when followed for an additional 6 months without any treatment, 56% of the chronic sildenafil users continued to have improved erectile function. Similarly, the vascular status of these men improved. The peak systolic velocity The investigators concluded that their in vitro tissue results support the concept of profound tissue modifications after chronic treatment with sildenafil. within the cavernous artery improved from 29 cm/s to 39 cm/s in the chronic sildenafil group, whereas there was no significant change in the as needed group. In addition, as with the findings pertaining to improvement in IIEF score, the increase in peak systolic velocities was maintained after 4-week and 6-month washout periods. Taken together, these studies of endothelial cell function indicate that PDE-5 inhibitors might also act through a mechanism independent of VOL. 8 NO REVIEWS IN UROLOGY 213

6 Penile Rehabilitation After RP continued the neural-induced nitric oxide pathway. This global improvement in endothelial cell function suggests a possible role for PDE-5 inhibition even during the period of neuropraxia after nerve-sparing radical prostatectomy. Role of PDE-5 Inhibitors in Penile Rehabilitation In a study by Padma-Nathan and colleagues, 27 patients were randomized to either nightly sildenafil treatment or placebo for 36 weeks, starting 4 weeks after nerve-sparing radical prostatectomy. After a total of 48 weeks, 27% of the treatment group reported erections sufficient for intercourse, compared with 4% in the placebo group. A 4% potency rate 48 weeks after nervesparing radical prostatectomy seems to be unusually low. For this reason, it is not entirely clear that these results can be extrapolated to the general population of post-prostatectomy patients. Moreover, the study involved only 76 patients (51 men in the treatment group), suggesting the need for a larger trial. Nevertheless, the Padma- Nathan study is thought provoking and again suggests a possible role for PDE-5 inhibitors in penile rehabilitation after radical prostatectomy. Other studies have looked at the efficacy of PDE-5 inhibition after an initial protocol of penile rehabilitation using intracavernosal injections or VCD. Raina and coworkers 28 studied the use of sildenafil in dissatisfied patients after approximately 4 months of VCD after radical prostatectomy. They found improved rigidity and patient satisfaction in 77% of men and a return of natural erections after 8 months of combined treatment in 30%. Similarly, Montorsi and colleagues 29 used a combination of sildenafil and intracavernous alprostadil injections in patients undergoing nerve-sparing radical prostatectomy. Patients were started on intracavernosal injections within 1 month and sildenafil after 4 months versus sildenafil alone after 4 months. The investigators reported that 82% of men in the combination group responded to subsequent sildenafil treatment after 6 months, compared with 52% in the sildenafil-only group. Conclusions In the modern era of early prostate cancer detection, erectile dysfunction after radical prostatectomy is becoming an ever more important topic of discussion. A major advance in the preservation of sexual function after radical prostatectomy was the development of the nerve-sparing procedure by Walsh and colleagues. More recently, the concept of penile rehabilitation after surgery has generated substantial interest. Central to discussions of penile rehabilitation after radical prostatectomy is evidence demonstrating significant fibrotic changes in the corpus cavernosum after a prolonged period of penile flaccidity. Despite the theory that hypoxia is the inciting factor in these fibrotic changes, the exact etiology of this process remains unknown. Even in the absence of a mechanistic explanation, however, many practitioners are using some type of erectogenic treatment after radical prostatectomy in an effort to enhance the return of sexual function. Several studies have been published evaluating the efficacy of various pro-erectogenic agents used for early penile rehabilitation after radical prostatectomy. The limited data regarding intracavernosal injections and VCD suggest that an increased percentage of treated patients experienced a return of natural erections compared with patients who received Main Points Patients are typically counseled that it may take up to 2 years for return of maximum sexual funtion after radical prostatectomy. Although the relative hypoxia thought to be associated with penile flaccidity may contribute to erectile dysfunction after radical prostatectomy, the etiology of post-prostatectomy erectile dysfunction appears to be multifactorial and is incompletely understood. Several studies have been performed to evaluate the effect of artificially induced erection after surgery to prevent permanent damage, with modalities including prostaglandin E 1 injection, vacuum constriction devices (VCD), and phosphodiesterase type 5 (PDE-5) inhibitors. The limited data regarding intracavernosal injections suggest that an increased percentage of treated patients experience a return of natural erections compared with patients who receive no treatment. Although it is not certain that the early use of VCD will improve overall return of erectile function, data suggest that fibrotic changes leading to penile shortening and possible venous leakage might be minimized. The global improvement in endothelial cell function observed with chronic sildenafil treatment suggests a possible role for PDE-5 inhibition even during the period of neuropraxia after nerve-sparing radical prostatectomy. 214 VOL. 8 NO REVIEWS IN UROLOGY

7 Penile Rehabilitation After RP no treatment. However, no studies to date have included an adequate placebo control group, and the number of subjects evaluated has been limited. Longer, prospective, randomized, placebo-controlled studies will be needed to confirm the utility of these treatments in improving longterm sexual function after radical prostatectomy. Contemporary studies evaluating the chronic use of oral PDE-5 inhibitors suggest a beneficial effect on endothelial cell function among men suffering from erectile dysfunction due to a variety of causes. Limited data suggest that this effect might be seen among post-prostatectomy patients, suggesting a possible role for these agents in enhancing the return of sexual function in such individuals. On the basis of data accumulated thus far, it is reasonable to discuss the implementation of a penile rehabilitation program with patients undergoing radical prostatectomy. Preliminary data suggest that such therapy might positively influence the ultimate outcome with regard to sexual function. Patients should be aware, however, that the exact benefit imparted, as well as which treatment regimen would be most effective, will remain highly controversial until better data become available. References 1. Penson DF, McLerran D, Feng Z, et al. 5-year urinary and sexual outcomes after radical prostatectomy: results from the prostate cancer outcomes study. J Urol. 2005;173: Gralnek D, Wessells H, Cui H, Dalkin BL. Differences in sexual function and quality of life after nerve sparing and nonnerve sparing radical retropubic prostatectomy. J Urol. 2000;163: Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA. 2000; 283: Litwin MS, Flanders SC, Pasta DJ, et al. Sexual function and bother after radical prostatectomy or radiation for prostate cancer: multivariate quality-of-life analysis from CAPSURE. Urology. 1999;54: Mulhall JP, Slovick R, Hotaling J, et al. Erectile dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. J Urol. 2002;167: Podlasek CA, Gonzalez CM, Zelner DJ, et al. Analysis of NOS isoform changes in a post radical prostatectomy model of erectile dysfunction. Int J Impot Res. 2001;13:S1-S User HM, Hairston JH, Zelner DJ, et al. Penile weight and cell subtype specific changes in a post-radical prostatectomy model of erectile dysfunction. J Urol. 2003;169: Leungwattanakij S, Bivalacqua TJ, Usta MF, et al. Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl. 2003;24: Iacono F, Giannella R, Somma P, et al. Histological alterations in cavernous tissue after radical prostatectomy. J Urol. 2005;173: Rogers RS, Graziottin TM, Lin CS, et al. Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virusmediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int J Impot Res. 2003;15: Brown SL, Seftel AD, Strohl KP, Herbener TE. Vasculogenic impotence and cavernosal oxygen tension. Int J Impot Res. 2000;12: Moreland RB, Traish A, McMillin MA, et al. PGE1 suppresses the induction of collagen synthesis by transforming growth factor-b1 in human corpus cavernosum smooth muscle. J Urol. 1995;153: Daley JT, Watkins MT, Brown ML, et al. Prostanoid production in rabbit corpus cavernosum. II. Inhibition by oxidative stress. J Urol. 1996;156: Melman A. Editor s note. Is there a role of hypoxemia in penile fibrosis? Int J Impot Res. 1998; 10: Montorsi F, Guazzoni G, Strambi LF, et al. 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J Urol. 2003;169: Raina R, Agarwal A, Ausmundson S, et al. Early use of vacuum constriction device following radical prostatectomy facilitates early sexual activity and potentially earlier return of erectile function. Int J Impot Res. 2006;18: Zagaja GP, Mhoon DA, Aikens JE, Brendler CB. Sildenafil in the treatment of erectile dysfunction after radical prostatectomy. Urology. 2000; 56: Desouza C, Parulkar A, Lumpkin D, et al. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabtes Care. 2002;25: Behr-Roussel D, Gorny D, Mevel K, et al. Chronic sildenafil improves erectile function and endothelium-dependent cavernosal relaxations in rats: lack of tachyphylaxis. Eur Urol. 2005;47: Foresta C, Caretta N, Lana A, et al. Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int J Impot Res. 2005;17: Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, vardenafil, increases circulating progenitor cells in humans. Int J Impot Res. 2005;17: Sommer F, Schulze W. Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors. World J Urol. 2005;23: Padma-Nathan H, McCullough AR, Giuliano F, et al. Postoperative nightly administration of sildenafil citrate significantly improves the return of normal spontaneous erectile function after bilateral nerve-sparing radical prostatectomy [abstract 1402]. J Urol. 2003;169: Raina R, Agarwal A, Allimaneni SSR, et al. Sildenafil citrate and vacuum constriction device combination enhances sexual satisfaction in erectile dysfunction after radical prostatectomy. Urology. 2005;65: Montorsi F, Salonia A, Barbieri L, et al. The subsequent use of IC alprostadil and oral sildenafil is more efficacious than sildenafil alone in nerve sparing radical prostatectomy [abstract 1098]. J Urol. 2002;167:279. VOL. 8 NO REVIEWS IN UROLOGY 215