Erectile dysfunction is common following radical prostatectomy

Recent data suggest that approximately 161 000 men per year undergo a radical prostatectomy in the United States.¹ It is thought that many more men who are diagnosed with early-stage prostate cancer would accept this surgical form of treatment for their newly diagnosed disease if it were not for the possibility of the development of erectile dysfunction (ED). This common complication after radical prostatectomy is largely due to trauma sustained by the cavernosal nerves and is still widely encountered even after the most recent advances in surgical technique to spare the nerves.^{2, 3, 4, 5} Of men that are potent before surgery, only about 40–74% of men regain sexual function.^{4, 5, 6, 7} In fact, 41.9% of men reported that their sexual performance was a moderate to large problem after surgery⁷ and patients appear to value sexual function so highly that they are often willing to choose therapy that offers better potency with lower life expectancy than options that offer longer life expectancy and lower potency rates.⁸

Radical prostatectomy seems to disrupt and/or damage the neurovascular mechanisms responsible for eliciting an erection thereby resulting in either temporary or permanent ED postoperatively. In its mildest form, apparent in a successful bilateral nerve sparing prostatectomy, the trauma resulting from surgical manipulation of the neurovascular bundles may result in a neuropraxia leading to temporary ED. The most severe form of ED results from a non-nerve sparing prostatectomy where both nerves are transected, either volitionally or unrecognized at the time of surgery, and this leads to the complete loss of neuroregulatory functions in the corpora cavernosa.

CVOD is the most common form of ED following radical prostatectomy

Injury to the cavernosal nerves results in the atrophy and degradation of the underlying cavernosal smooth muscle, which, besides resulting in ED, may also lead to a decrease in penile weight.⁹ Histologically, such a neuropraxia/neurotomy leads to apoptosis of the cavernosal smooth muscle and an excessive deposition of collagen within the cavernosa, which clinically results in corporal veno-occlusive dysfunction (CVOD). CVOD or venous leakage occurs because of the inability of the cavernosal smooth muscle cell mass to adequately compress the subtunical veins and prevent leakage of blood out of the cavernosa during tumescence. With CVOD, the patient complains of the inability to obtain and maintain an erection sufficient for completion of the sexual act and CVOD has been recognized as the major cause of ED subsequent to radical prostatectomy.^{10, 11}

Therefore, the poor response of many patients to the oral phosphodiesterase 5 inhibitors (PDE5) inhibitors given on demand post-radical prostatectomy could be due either to the neural injury which prevents the normal release of nitric oxide from the cavernosal nerve endings (a necessary requirement for the synthesis of the second messenger cyclic guanosine monophosphate (cGMP) within the cavernosa) or the subsequent loss of some of the corporal smooth muscle mass as elucidated above due to the neural injury or a combination of both conditions. In addition, the failure of vasoactive drugs injected intracorporeally into the penis to induce an erection in post-prostatectomy patients suggests that the corporal smooth muscle mass has most likely been impacted by the surgery in these patients. While arterial insufficiency post-prostatectomy due to intraoperative damage to the arteries supplying blood to the cavernosa is another means by which some of these men may experience ED,¹² it is CVOD that is the predominant cause of ED post-prostatectomy.

Although the hypoxia theory has been promulgated as the reason why there is a loss of corporal smooth muscle and an increase in collagen following this neural injury post-prostatectomy, the scientific evidence to show that intracellular hypoxia occurs during detumescence is very weak at best. This hypoxia theory states that low-oxygen tension occurs within the cavernosal tissue when there is detumescence and this leads to the induction of elevated levels of the profibrotic cytokine, transforming growth factor-1 (TGF1), within the cavernosa.^{13, 14} However, to date, the only p02 that has been measured within the penis in such a setting is the sinusoidal p02 and there is no scientific evidence that the smooth muscle and other components of the cavernosal tissue obtain O₂ from the sinusoids rather than their own capillaries.

Antifibrotic role of NO following cavernosal nerve resection

The one theory that seems to be the most plausible in explaining why the corporal smooth muscle deteriorates in tandem with an increase in collagen content following radical prostatectomy is that it is the neural injury itself that induces proapoptotic (loss of smooth muscle) and profibrotic (increase in collagen) factors within the cavernosa. It is possible that the ablation by neuropraxia of certain key growth factors produced by the cavernosal nerves may be responsible for eliciting the smooth muscle fibrosis and atrophy observed in corporal tissue. However, the production of cytokines and noxious agents by the damaged nerve axons may also be the causal factor of the increased early smooth muscle apoptosis,^{15, 16} which in turn may trigger collagen deposition to replace the lost cells. Similarly to the situation with skeletal muscle atrophy after denervation,^{17, 18} the molecular and cellular etiology of the tissue atrophy subsequent to cavernosal nerve damage remains to be elucidated.

In an attempt to counteract this proapoptotic and profibrotic cascade induced by such a neural injury, the cavernosal tissue itself then initiates an antiapoptotic and an antifibrotic defense mechanism via the formation of nitric oxide and cGMP within the smooth muscle itself (Figure 1).¹⁹ The key to erectile function post-radical prostatectomy in patients who are potent before the prostatectomy is maintenance of the integrity of the corporal histology (that is, prevention of both fibrosis and apoptosis of the smooth muscle). Therefore, in the post-prostatectomy patient, tumescence should be attainable au natural if both the nerves and blood vessels are not injured during the surgery. However, even if the nerves are injured but the histology of the cavernosal tissue can be preserved, as long as the arterial inflow is not impeded then tumescence in these patients may be achieved albeit with the use of intracorporeal injections and possibly with intraurethral applications of vasoactive substances.

Figure 1.

Effect of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) from inducible isoform of nitric oxide synthase (iNOS) in combating reactive oxygen species (ROS), fibrosis and apoptosis. (-), inhibitory effect.

Full figure and legend (4K)

Nitric oxide, as the case of its subsequent downstream second messenger cGMP that also acts as an antifibrotic agent in the setting of cavernosal nerve injury, does not emanate from the nitrergic nerve endings of the cavernosal nerve but is induced by the smooth muscle itself.¹⁸ The nitric oxide from the nerve endings of the cavernosal nerve is produced by the neuronal isoform of the nitric oxide synthase (nNOS) enzyme²⁰ whereas the nitric oxide that emanates from the cavernosal smooth muscle cells once the neural injury occurs is derived, at least in part, from the induction of the inducible isoform of nitric oxide synthase (iNOS).^{15, 16} There is a marked distinction between these two isoforms. While nitric oxide in the corpora during sexual stimulation is believed to be produced immediately upon sexual stimulation, albeit in small amounts, primarily by the activation of nNOS, the production of nitric oxide from iNOS in the corpora is very different from that of nNOS in that it is unrelated to sexual stimulation and occurs by transcriptional induction that results in the production of sustained amounts of nitric oxide, although somewhat delayed in its onset.

The evidence supporting the view that iNOS undergoes spontaneous induction in the corpora cavernosa in certain conditions such as aging, diabetes and specifically cavernosal nerve damage by protecting the histological and functional integrity of the corpora through combating fibrosis, stems from four main sources of experimental data. First, the fact that general inhibition of the activity of all NOS isoforms, and hence nitric oxide production, by prolonged sustained administration of N(G)-nitro-L-arginine methyl ester to rats, leads to considerable fibrotic degeneration in organs such as the heart, liver and kidney, independent of hemodynamic factors that may contribute to this process.^{21, 22, 23, 24, 25} Second, specific genetic blockade of iNOS in the iNOS knockout mice leads to exacerbation of experimental fibrosis of the kidney and liver,^{26, 27} and the chronic inhibition of iNOS activity in rats by N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) intensifies aging-related fibrosis of the arterial wall and of the experimentally induced Peyronie's disease-like fibrotic plaque in the penis.^{28, 29} Third, administration of iNOS cDNA in the latter model reduces the fibrotic plaque.³⁰ Finally, specifically in cavernosal nerve damage, a similar treatment with L-NIL exacerbates CVOD and the underlying fibrosis of the corpora.¹⁶

It is assumed that prolonged endogenous induction of iNOS to moderate levels produces sufficient nitric oxide as to reduce collagen synthesis, quench reactive oxygen species (ROS), inhibit TGF1 expression and myofibroblast differentiation, and activate metalloproteinases that break down collagen.¹⁷ If nitric oxide reaches excessive levels it may turn to be deleterious by causing cell death and oxidative stress, and this will depend on the tissue environment.

PDE5 inhibitors protect the integrity of the corporal smooth muscle following cavernosal nerve resection: experimental evidence

There is quite an amount of emerging scientific evidence to suggest that prolonged elevated levels of nitric oxide and cGMP can have an antifibrotic effect on a variety of tissues including tunica albuginea and corporal tissue (Figure 2).^{19, 20, 31} Since PDE5 inhibitors work by inhibiting the enzyme that degrades cGMP, and since cGMP via activation of PKG inhibits collagen synthesis, this may be the preferential route of antifibrotic action when cGMP levels are maintained high for sustained periods. Although cGMP seems to stabilize iNOS mRNA or activate its transcription,³² and thus may upregulate nitric oxide production, recent evidence suggest that this is not the case for the long-term effects of tadalafil on corporal fibrosis after cavernosal nerve damage in the rat.¹⁶ Although there have been reports in the literature regarding the clinical effects of administration of these PDE5 inhibitors post-prostatectomy,^{33, 34, 35, 36} the rationale behind the use of these drugs on a prolonged and continuous basis in the post-prostatectomy patient has never been fully and scientifically delineated. The recent publication by Ferrini et al.¹⁵ examined the effects of the administration of the PDE5 inhibitor, vardenafil, and demonstrated that the prolonged and continuous administration of the compound was effective in preventing both the fibrosis and loss of smooth muscle seen following bilateral cavernosal nerve resection (Figure 3). Compared with the sham group, the bilateral cavernosal nerve resection rats demonstrated a threefold increase in intracorporeal apoptosis, a 60% reduction in the smooth muscle to collagen ratio, a twofold increase in iNOS expression and development of CVOD (Table 1). When vardenafil was given daily for 45 days to the animals that underwent bilateral cavernosal nerve resection, CVOD did not develop and the abnormal corporal smooth muscle to collagen ratio seen in the bilateral cavernosal nerve-resected group was normalized. Similar results have been reported in the both the unilateral and bilateral nerve resection models using continuous long-term administration of sildenafil.¹⁶

Figure 2.

Relationship between reactive oxygen species (ROS) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) following cavernosal nerve resection.

Full figure and legend (3K)

Figure 3.

Effect of bilateral cavernosal nerve resection (BCNR) and vardenafil treatment on the smooth muscle/collagen ratio in the rat corpora cavernosa. Bilateral cavernosal nerve resection leads to a decrease in the smooth muscle/collagen ratio, which leads to the development of CVOD. The ratio becomes similar to the control group after treatment with vardenafil. Values determined by quantitative image analysis. BCNR (b) vs sham (a) or BCNR+V (c): P<0.001; sham (a) vs BCNR+V (c): not significant. Ferrini et al.¹⁵ with permission.

Full figure and legend (4K)

Table 1 - Dynamic infusion cavernosometry.

Full table

A parallel study by Vignozzi et al.³⁷ also found that chronic tadalafil administration (120 days) to rats similarly reversed the decline in the cavernosal smooth muscle to collagen ratio that occurred after a bilateral cavernous neurotomy. Although Vignozzi et al. hypothesized that the effect of the tadalafil may have been due to the reversal of hypoxia induced by the neurotomy, these studies taken together suggest that PDE5 inhibitors can potentially protect and preserve the integrity of the corpora after cavernosal nerve damage when given on a prolonged and continuous basis.

PDE5 inhibitors protect the integrity of the corporal smooth muscle following cavernosal nerve resection: clinical evidence

The only clinical trial to suggest vaguely that chronic PDE5 inhibition post-prostatectomy may preserve the integrity of the corpora emanates from Schwartz et al.³⁵ who performed post-prostatectomy biopsies on men on chronic sildenafil treatment and found that the corporal smooth muscle to collagen ratio was maintained in those patients treated with chronic sildenafil while those who did not take sildenafil showed loss of smooth muscle content with a concomitant increase in collagenization of the corpora.

Clinical trials have also examined whether the routine use of PDE5 inhibitors on an on-demand basis to induce an erection post-prostatectomy, as opposed to its chronic use on a daily basis, may be beneficial long term in treating or correcting the ED that occurs after radical prostatectomy. Indeed, there are a number of such on-demand treatment studies using each one of the PDE5 inhibitors, vardenafil,³³ sildenafil³⁴ and tadalafil,³⁶ and each one touting the efficacy of their compound in improving post-prostatectomy potency rates. Although the theory promulgated by these latter nonrandomized, noncontrolled studies to explain the efficacy of the PDE5 inhibitors is via cavernosal oxygenation, as enumerated earlier in this review there is as yet no direct scientific evidence to support that these compounds improve tissue oxygenation within the corporal tissue itself.

What is apparent from the emerging clinical and experimental data on the use of PDE5 inhibitors post-prostatectomy is that these drugs appear to play some role in preserving the integrity of the corporal tissue following cavernosal nerve damage (Figure 3). The importance of this observation is that regardless of whether the neural injury to the penis following surgery is permanent or not, preservation of the normal histology of the preoperative cavernosa will allow the corporal tissue to respond normally to the administration of locally administered proerectogenic agents even if the tissue should fail to respond normally to the on-demand agents. Emerging studies focusing on the molecular mechanisms of apoptosis and fibrosis are beginning to shed some light as to why the chronic and prolonged use of PDE5 inhibitors is proving to be beneficial. Obviously, further animal and randomized clinical studies are needed to confirm these exciting preliminary observations. A paradigm involving the discontinuation of the PDE5 inhibitor administration after the long-term post-prostatectomy treatment would allow one to verify whether indeed the improved erectile response is maintained in the total absence of the drug. The latter would suggest that the beneficial effects of this regimen with PDE5 inhibitors on the underlying corporal histology seen in the rat model would also occur in men, and support the role of smooth muscle fibrosis in the etiology of CVOD.

References

1. DeFrances CJ, Hall MJ. 2002 National Hospital Discharge Survey. Advance Data from Vital and Health Statistics; no. 342. National Center for Health Statistics: Hyattsville, MD, 2004 Adv Data 2004; 21: 1–29.
2. Montorsi F, Burnett AL. Erectile dysfunction after radical prostatectomy. BJU Int 2004; 93: 1–2. | Article | PubMed | ISI | ChemPort |
3. Mulhall JP, Slovick R, Hotaling J, Aviv N, Valenzuela R, Waters WB et al. Dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. J Urol 2002; 167: 1371–1375. | Article | PubMed | ISI |
4. Menon M, Kaul S, Bhandari A, Shrivastava A, Tewari A, Hemal A. Potency following robotic radical prostatectomy: a questionnaire based analysis of outcomes after conventional nerve sparing and prostatic fascia sparing techniques. J Urol 2005; 174: 2291–2296, discussion 2296. | Article | PubMed | ISI |
5. Quinlan DM, Epstein JI, Carter BS, Walsh PC. Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol 1991; 145: 998–1002. | PubMed | ISI | ChemPort |
6. Catalona WJ, Carvalhal GF, Mager DE, Smith DS. Potency, continence and complication rates in 1870 consecutive radical retropubic prostatectomies. J Urol 1999; 162: 433–438. | Article | PubMed | ISI | ChemPort |
7. Stanford JL, Feng Z, Hamilton AS, Gilliland FD, Stephenson RA, Eley JW et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000; 283: 354–360. | Article | PubMed | ISI | ChemPort |
8. Penson DF. The effect of erectile dysfunction on quality of life following treatment for localized prostate cancer. Rev Urol 2001; 3: 113–119. | PubMed | ChemPort |
9. User HM, Hairston JH, Zelner DJ, McKenna KE, McVary KT. Penile weight and cell subtype specific changes in a post-radical prostatectomy model of erectile dysfunction. J Urol 2003; 169: 1175–1179. | Article | PubMed | ISI |
10. Rajfer J, Rosciszewski A, Mehringer M. Prevalence of corporeal venous leakage in impotent men. J Urol 1988; 140: 69–71. | PubMed | ISI | ChemPort |
11. Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999; 161: 5–11. | Article | PubMed | ISI | ChemPort |
12. Mulhall JP, Graydon RJ. The hemodynamics of erectile dysfunction following nerve-sparing radical retropubic prostatectomy. Int J Impot Res 1996; 8: 91–94. | PubMed | ChemPort |
13. Leungwattanakij S, Bivalacqua TJ, Usta MF, Yang DY, Hyun JS, Champion HC et al. Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl 2003; 24: 239–245. | PubMed | ISI |
14. Moreland RB. Pathophysiology of erectile dysfunction: the contributions of trabecular structure to function and the role of functional antagonism. Int J Impot Res 2000; 12: S39–S46. | Article | PubMed | ISI |
15. Ferrini MG, Davila HH, Kovanecz I, Sanchez SP, Gonzalez-Cadavid NF, Rajfer J. Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat. Urology 2006; 68: 429–435. | Article | PubMed | ISI |
16. Kovanecz I, Rambhatla A, Ferrini MG, Vernet D, Sanchez S, Rajfer J et al. Long term sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats. Int J Impot Res 2007 Prel acceptance.
17. Gonzalez-Cadavid NF, Rajfer J. The pleiotropic effects of inducible nitric oxide synthase on the physiology and pathology of penile erection. Curr Pharm Des 2005; 11: 4041–4046. | Article | PubMed | ISI | ChemPort |
18. Midrio M. The denervated muscle: facts and hypotheses. A historical review. Eur J Appl Physiol 2006; 98: 1–21. | Article | PubMed | ISI |
19. Valente EG, Vernet D, Ferrini MG, Qian A, Rajfer J, Gonzalez-Cadavid NF. L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie's fibrotic plaque and related fibroblast cultures. Nitric Oxide 2003; 9: 229–244. | Article | PubMed | ISI | ChemPort |
20. Magee TR, Ferrini M, Garban HJ, Vernet D, Mitani K, Rajfer J et al. Gene therapy of erectile dysfunction in the rat with penile neuronal nitric oxide synthase. Biol Reprod 2002; 67: 1033–1041. | Article | PubMed |
21. Zhou X, Frohlich ED. Analogy of cardiac and renal complications in essential hypertension and aged SHR or L-NAME/SHR. Med Chem 2007; 3: 61–65. | Article | PubMed | ChemPort |
22. Okazaki H, Minamino T, Tsukamoto O, Kim J, Okada K, Myoishi M et al. Angiotensin II type 1 receptor blocker prevents atrial structural remodeling in rats with hypertension induced by chronic nitric oxide inhibition. Hypertens Res 2006; 29: 277–284. | Article | PubMed | ISI | ChemPort |
23. Boffa JJ, Lu Y, Placier S, Stefanski A, Dussaule JC, Chatziantoniou C. Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases. J Am Soc Nephrol 2003; 14: 1132–1144. | Article | PubMed | ISI | ChemPort |
24. Tarsitano CA, Paffaro Jr VA, Pauli JR, da Silva GH, Saad MJ, Salgado I et al. Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with N(omega)-nitro-L-arginine methyl ester (L-NAME). Cell Tissue Res 2007; 329: 45–58. | Article | PubMed | ISI | ChemPort |
25. Criado M, Flores O, Vazquez MJ, Esteller A. Role of prostanoids and nitric oxide inhibition in rats with experimental hepatic fibrosis. J Physiol Biochem 2000; 56: 181–188. | PubMed | ISI | ChemPort |
26. Hochberg D, Johnson CW, Chen J, Cohen D, Stern J, Vaughan Jr ED et al. Interstitial fibrosis of unilateral ureteral obstruction is exacerbated in kidneys of mice lacking the gene for inducible nitric oxide synthase. Lab Invest 2000; 80: 1721–1728. | Article | PubMed | ISI | ChemPort |
27. Chen Y, Hozawa S, Sawamura S, Sato S, Fukuyama N, Tsuji C et al. Deficiency of inducible nitric oxide synthase exacerbates hepatic fibrosis in mice fed high-fat diet. Biochem Biophys Res Commun 2005; 326: 45–51. | Article | PubMed | ISI | ChemPort |
28. Ferrini MG, Davila H, Valente EG, Gonzalez-Cadavid NF, Rajfer J. Aging-related induction of inducible nitric oxide synthase (iNOS) is vasculo-protective in the arterial media. Cardiovascular Res 2004; 61: 796–805. | Article | ISI | ChemPort |
29. Ferrini MG, Vernet D, Magee TR, Shahed A, Quian A, Rajfer J et al. Antifibrotic role of inducible nitric oxide synthase (iNOS). Nitric Oxide 2002; 6: 283–294. | Article | PubMed | ISI | ChemPort |
30. Davila HH, Magee TR, Rajfer J, Gonzalez-Cadavid NF. Gene therapy with the inducible nitric oxide synthase (iNOS) cDNA regresses the fibrotic plaque in an animal model of Peyronie's disease. Biol Reprod 2004; 71: 1568–1577. | Article | PubMed | ISI | ChemPort |
31. Ferrini MG, Kovanecz I, Nolazco G, Rajfer J, Gonzalez-Cadavid NF. Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease. BJU Int 2006; 97: 625–633. | Article | PubMed | ISI | ChemPort |
32. Bojunga J, Dresar-Mayert B, Usadel KH, Kusterer K, Zeuzem S. Antioxidative treatment reverses imbalances of nitric oxide synthase isoform expression and attenuates tissue-cGMP activation in diabetic rats. Biochem Biophys Res Commun 2004; 316: 771–780. | Article | PubMed | ISI | ChemPort |
33. Brock G, Nehra A, Lipshultz LI, Karlin GS, Gleave M, Seger M et al. Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy. J Urol 2003; 170: 1278–1283. | Article | PubMed | ISI | ChemPort |
34. Lowentritt BH, Scardino PT, Miles BJ, Orejuela FJ, Schatte EC, Slawin KM et al. Sildenafil citrate after radical retropubic prostatectomy. J Urol 1999; 162: 1614–1617. | Article | PubMed | ISI | ChemPort |
35. Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomy. J Urol 2004; 171: 771–774. | Article | PubMed | ISI |
36. Montorsi F, Nathan HP, McCullough A, Brock GB, Broderick G, Ahuja S et al. Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized double-blind, placebo controlled trial. J Urol 2004; 172: 1036–1041. | Article | PubMed | ISI | ChemPort |
37. Vignozzi L, Filippi S, Morelli A, Ambrosini S, Luconi M, Vannelli GB et al. Effect of chronic tadalafil administration on penile hypoxia induced by cavernous neurotomy in the rat. J Sex Med 2006; 3: 419–431. | Article | PubMed | ISI | ChemPort |