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9th Congress of the European Society for Sexual Medicine

Vienna, Austria / December 3-6, 2006

Reported by: Gerald B. Brock, MD, FRCSC

St. Joseph’s Health Centre London, Ontario

Professor of Surgery Division of Urology University of Western Ontario London, Ontario

NEUROGENIC FACTORS CONTRIBUTING TO ERECTILE DYSFUNCTION

Treatment of post-prostatectomy erectile dysfunction (ED) has conventionally centred on watchful waiting with conservative measures, vacuum instruments, intracavernosal or intraurethral procedures, and penile implants. However, neurogenic factors appear to be the most common reason for ED after nerve-sparing radical retropubic prostatectomy (nsRRP), especially injury to cavernosal nerve bundles. This is indicated by the clear correlation between the preservation of nerve bundles during surgery and maintenance of erectile function. Sparing bilateral nerve bundles is, in fact, the most effective means of preserving erectile function.

The time required for recovery of erectile function after surgery ranges from six to 48 months. The lack of natural erections during that period of neuropraxia produces cavernosal hypoxia, which, over time, is likely a predisposing factor for cavernosal fibrosis and ED. The first step in preserving the ability of erection is nsRRP. Avoiding thermal coagulation and meticulous preparation of the surgical site are critical to success. The most important prognostic factors for recovery of sexual potency are the number of spared neurovascular bundles, age and sexual activity before surgery.

According to Dr. Steven Joniau, University Hospital, Leuven, Belgium, prostate cancer is being increasingly detected at earlier stages and in younger patients, resulting in a greater need for functional preservation involving not only erections but also orgasms and continence. His study to define significant predictors of functional outcome assessed 161 patients 45 to 75 years of age who underwent nsRRP, took sildenafil on demand and were questioned on functional outcome, including a single-item assessment of erectile and orgasmic function and continence; patients were followed for 18 months.

Two surgical factors—blood loss and the quality of nerve-sparing—were predictive; blood loss for potency, orgasm and continence, and nerve-sparing for orgasmic function and borderline for potency. Patient age is a strong predictor for the entire functional domain and prostate volume was significant in potency and orgasm. Other important observations were duration of surgery and clinical and pathologic stage. Gleason score did not influence sexual outcome.

PATHOPHYSIOLOGY OF POST-SURGICAL ERECTILE DYSFUNCTION

Because the microarchitecture of erectile tissue is closely related to its function, RRP often results in ED due to lesions inflicted during surgery to nerves serving that tissue. Denervation and/or ischemic processes leading to fibrosis with clearly decreased elastic and smooth muscle fibres and a progressive increase in collagen deposit renders the corpus cavernosum less functional and less responsive to local and systemic vasodilators. This negatively affects both erectile quality and the potential for rehabilitation therapy after radical prostatectomy. An effective nerve-sparing technique is mandatory in RRP, but may not be sufficient for potency rehabilitation after surgery.

An important development in post-operative ED therapy has been the advent of phosphodiesterase type 5 (PDE-5) inhibitors. Researchers have indicated that they are effective and well tolerated in the management of ED after radical prostatectomy, particularly in younger patients.

STUDY FINDINGS

Dr. Milos Brodak, Department of Urology, Charles University, Hradec Kralove, Czech Republic, presented study findings on ED management after radical prostatectomy. Thirty-nine evaluable patients (mean age 65 years) who were all sexually active before surgery had stage T1 malignancies in eight cases, T2 in 24 and T3 in seven. They underwent bilateral nerve-sparing radical prostatectomy and completed the International Index of Erectile Function (IIEF-5) questionnaires.

The evaluable patients were prescribed sildenafil 50 mg on demand which could be increased to 100 mg if needed. Of the 39 evaluable post-operative patients, 22 (54%) responded to treatment and their mean IIEF-5 score increased from 4.4 to 14.4 (P=0.001). Average improvement among younger patients was from 4.8 to 16.6 and among older men was from 3.5 to 9.1. No serious side effects were recorded, although one patient complained of temporary blue vision, which later resolved. The most common mild adverse event was headache in two patients. Researchers noted that sildenafil appears to be ineffective in the first six to nine months following prostatectomy but the effect increases with time; the best results are observed in the 12 to 24 months after surgery. The quality of response depends on age, dose and the extent of damage to the cavernosal nerves.

Other studies and researchers have shown superior earlier responsiveness in larger cohorts, demonstrating that early non-response to therapy may likely be salvaged with resolving neuropraxia.

INHIBITING HYPOXIA AND SUBSEQUENT FIBROTIC PROCESS

Dr. Andreas Bannowsky, Urology Department, University Hospital Schleswig-Holstein, Kiel Campus, Germany, explained that as penile oxygenation increases during nocturnal erections from 25 to 40 mm in the flaccid state to 90 to 100 mm during erection, this process reduces fibrosis and involutional atrophy. Even with the preservation of neurovascular bundles during surgery, it is not sufficient to prevent a decrease in nocturnal erections that leads to lowering of penile oxygen levels and thereby apoptosis and fibrosis. If the same patients are treated with a PDE-5 inhibitor, the resulting upsurge in nocturnal erections will increase penile oxygenation and, in turn, decrease fibrosis/apoptosis resulting in better erections and rehabilitation.

The administration of sildenafil soon after radical prostatectomy appears to exert an antifibrotic effect, perhaps through an antiproliferative effect on fibroblasts, on the corpus cavernosum of prostate cancer patients with a consequent recovery of erectile function.

Pathologists led by Dr. Fabrizio Iacona, Department of Urology, Federico II University, Naples, Italy, assessed the efficacy of a PDE-5 inhibitor on the fibrotic process with pre- and post-prostatectomy cavernosal biopsy specimens. Twenty-one patients were treated with sildenafil 50 mg three times a week for two months shortly after undergoing radical prostatectomy. All underwent corpus cavernosum biopsies prior to surgery and after two months of medical treatment.

Both before and two months after surgery plus sildenafil treatment, the percentage of connective tissue in the corpus cavernosum specimens varied between 30 and 40% in the per area analysis. Similarly, the mean number of elastic fibres in the corpus cavernosum between before and after biopsies did not differ; the mean number of fibres per high-power field was 111.23 ± 10.81 SD before surgery and 124 ± 31.12 SD two months after surgery. As early as two months’ post-surgery, six of the 21 patients (30%) reported spontaneous nocturnal erections and four (20%) achieved recovery of sexual activity with valid penetration.

This is likely an important previously unrecognized effect of sildenafil and serves as a key tenet of most contemporary rehabilitation programs.

RECOVERY TIME TO ERECTILE FUNCTION

As yet, there is no consensus concerning the time lapse to recovery of erectile function with sildenafil after nsRRP, but it has been shown that intracorporal injections of PGE1 soon after bilateral nsRRP speeds the recovery rate of spontaneous erections. Investigators assessed the efficacy and time to rehabilitation of penile function of therapy with those two agents in combination.

In this study, 26 sexually-active men undergoing nsRRP for local prostate cancer were randomly assigned to receive either oral sildenafil (100 mg three times a week) plus alprostadil intracavernosal (10 µg twice weekly) or oral sildenafil (100 mg three time weekly) alone. Rehabilitation therapy started after catheter removal on post-operative day 7. In the first group, four of 13 patients increased their PGE1 dose to a maximum of 20 µg at three months, two decreased the dose of alprostadil to 2.5 or 5 µg and one patient receiving PGE1 dropped out of the study because of discomfort. Two patients in the monotherapy group dropped out of the trial and two decreased their dose to 50 mg. Erectile function was evaluated with the IIEF questionnaire at baseline and at three, six and nine months.

Researchers reported that spontaneous partial erections returned in seven (26.9%) patients at nine months. At the end of the study, 23 of the 26 patients had resumed sexual activity. Investigators concluded that early combination therapy with sildenafil and a PGE1 following radical prostatectomy promotes sexual activity and an earlier return of natural erections.

While many men will not achieve complete rigidity with PDE-5 inhibition alone in the early post-RRP recovery period, use of complementary intermittent PGE-1 injections can allow for early return to sexual activity while use of a daily or thrice-weekly PDE-5 inhibitor can promote long-term recovery.

DOSING STRATEGIES

Some researchers maintain that sildenafil given only at its customary dose of 50 to 100 mg on demand is sufficient to rehabilitate ED patients following nsRRP. However, data now indicate that daily lower doses improve blood flow to the penis and promote erectile recovery after prostatectomy. Dr. Bannowsky told the audience that he has demonstrated some nocturnal penile tumescence and rigidity (NPTR) in 93% of patients during the first night after catheter removal, which he believes is the basis of a physiologic protective effect that will allow lower dosing of sildenafil.

This study of low-dose sildenafil included 43 sexually-active patients, mean age 62.5 years, 11 of whom received unilateral and 32 had bilateral nsRRP. Catheters were removed and NPTR measurements (Rigi-Scan) of nocturnal erections were taken seven to 14 days after the operation. Results demonstrated that 41 of 43 patients (93%) had at least one measurable nocturnal erection, range 1-5 mm, as early as the day of catheter removal. Twenty-three men with preserved nocturnal erections were assigned to receive low-dose sildenafil 25 mg nightly and 18 underwent follow-up without treatment.

In the treated group, IIEF-5 scores decreased from preoperative means of 20.8 to 3.6 at six weeks, 3.8 at 12 weeks, 5.9 at 24 weeks, 9.6 at 36 weeks and 14.1 at 52 weeks after prostatectomy. Mean figures for the control group were 21.2 preoperatively, 2.4 at six weeks, 3.8 at 12 weeks, 5.3 at 24 weeks, 6.4 at 36 weeks and 9.3 at 52 weeks, at which time the difference was significantly in favour of the treated group (Figure 1).

Figure 1. Recovery of Erectile Function after nsRRP

Potency without additional PDE-5 inhibitors on demand was evident in approximately 50% of active-treated men vs. about 30% in the control group. Among men in both groups who received additional sildenafil on demand, potency increased to 66% in the control group compared to 86% in the sildenafil arm, which was a statistically significant difference.

The key messages of this study were that erectile function may be perceived even on the first night after catheter removal. The Rigi-Scan NPTR measurement appears to be very important and no difference has been noted so far in outcome between the uni- and bilateral nerve-sparing groups; the small number of patients was probably a factor and the result may change over time. The demonstration of significantly improved erectile function with low-dose sildenafil accompanied by more rapid rehabilitation and increased potency rates was also notable.

In another study of post-nsRRP patients, Dr. Pekka Kunelius, Oulu University Hospital, Finland, and colleagues were unable to find a significant response to PDE-5 inhibition compared to placebo, even among the few who experienced some tumescence after surgery. The equivalent outcome between placebo and sildenafil was attributed exclusively to surgical technique. Investigators reported a dramatic drop in post-operative IIEF scores at one month in both groups, which recovered more rapidly in men randomized to the PDE-5 inhibitor. Sildenafil was well tolerated in this study.

The performance of the surgeon is the major predictor of all functional outcomes. The number of spared neurovascular bundles is one of the most important prognostic factors for post-operative erectile function. The better the nerves are preserved, the better the potency rate and eventually the orgasmic function. Data also show that better nerve preservation can also result in improved continence.