Dysfunction
Prevalence (%)
Erectile dysfunction
20–90
Climacturia
14–28
Arousal incontinence
93
Orgasmic dysfunction (anorgasmia, delayed orgasm, dysorgasmia, decreased orgasm intensity)
18–46
Reduced penile size
68–71
Peyronie’s disease
16
The significant discrepancy in the quoted ED prevalence after RP stems from multiple causes. ED is defined as the consistent inability to obtain or maintain an erection sufficient for sexual activity for at least 3 months duration. This definition is liberally applied throughout the published literature, and there is often no distinction between men who have spontaneous return of erections after RP and men who continue to require erectogenic agents for the duration of their lives. Men who require these aids are still recorded as having “return of erectile function” for the purposes of publication, despite this being significantly different from their baseline function. In many instances, there is no formal assessment of erectile function through the use of validated instruments such as the International Index of Erectile Function (IIEF questionnaire). Merely asking patients “have your erections returned” is an inadequate means of determining erectile function, yet unfortunately this is a common method for determining published outcomes. In addition, the formal evaluation of the effect of RP on erectile function is confounded by the definition of “nerve sparing” being subjectively assessed by the prostatectomist given the lack of any objective way to determine the nerve-sparing status. Retrospective studies often do not include the entire population of men who underwent RP, and the introduction of this selection bias clearly impacts results. Furthermore, duration of follow-up is limited, and there is limited data on ED prevalence beyond several years after surgery. This is important to appreciate because although we know that there is an immediate decline in function after RP that often improves over time, very little is understood regarding the role RP plays in the patient’s long-term erectile function as they undergo the natural process of aging or cope with the ramifications of additional co-morbidities such as diabetes or hypertension.
Optimal evaluation of erectile function would include a prospective baseline pre-RP assessment as well as repeated post-RP evaluations over time. EF should be evaluated in a way that incorporates all aspects of sexual dysfunction into the surgeon’s queries and utilizes objective, validated instruments. Because of the obvious limitations within the published literature, prostatectomists should be encouraged to maintain their own prospective databases in order to be able to accurately inform their patients regarding what their specific functional outcomes truly are.
22.2 Pathophysiology of Erectile Dysfunction After Radical Prostatectomy
Erectile Dysfunction after radical prostatectomy differs from ED due to other causes. Post prostatectomy ED is associated with a life changing diagnosis (cancer); the onset of post prostatectomy ED can be immediate and post prostatectomy ED is relatively refractory to simple therapy (ED response rates to phosphodiesterase type 5 inhibitor (PDE5i) therapy are the lowest of all etiological categories) at least in the first 12 months after surgery. The introduction of nerve-sparing radical prostatectomy reduced direct surgical injury and interruption of the neurovascular bundle, yet even careful low trauma surgical maneuvers can lead to neuropraxia [2]. The cavernous nerve is located on the postero-lateral aspect of the seminal vesicle and the prostate, ascends to the 1 o’clock position and 11 o’clock position along the membranous urethra under the pubic bone and penetrates the hilum of the penis to enervate the corpora cavernosa [3]. Quinlan et al. reported the first series documenting the potential impact of nerve sparing; of 503 patients who were potent preoperatively, 342 (68 %) remained potent at 18 months, though these were self-reports gathered in the era before validated patient reported outcome instruments were introduced [4]. While it has been reported that the advent of robotic surgical techniques appears to have diminished the ED seen after prostatectomy, this has not yet definitively translated into better functional erectile outcomes [5]. Traction, thermal injury and ischemia due to associated vascular injury still accompany all operative techniques (open, conventional laparoscopic and robot-assisted laparoscopic prostatectomy).
The pathophysiology leading to ED after radical prostatectomy has been well documented by Hatzimouratidis et al. and there is significant animal data in the literature to support this mechanism [6]. Neuropraxia is, to a degree, an expected outcome of prostatectomy while complete neural destruction may occur when nerve-sparing is not clinically indicated or possible. The reduction or complete loss of erectile function after radical prostatectomy is a consequence of the cumulative or even synergistic response to multiple injuries of the erectile mechanism.
The response to neural injury or loss is immediate and is initiated at the genetic level. Neuro-modulatory treatment strategies resulting in improved erectile function currently suffer from a lack of knowledge of the complex genetic changes that orchestrate the molecular systems involved in recovery. Initial investigation of the neuro-reparative processes at the gene level was performed by User et al. using nascent gene expression technology [7]. Penile tissue from Sprague Dawley (SD) rats was harvested 48 h after bilateral cavernous nerve injury. Of a possible 8,000 genes analyzed in the array, 126 were found to be significantly altered; 79 were up regulated and 47 genes down regulated. The dominant class of genes activated did not appear to be directly involved in erectile function. Recognizing that erectile recovery was primarily dependent on neuro-regenerative properties, Calenda et al. turned away from the penis, which is the target tissue of enervation, to the injured peripheral nerve itself as the focus of examination [8]. These investigators used the major pelvic ganglion as the target for gene expression analysis in a SD rat model; two time points were examined representing acute (48 h) and chronic (14 days) after bilateral cavernous nerve injury. A significant number (265) of neuro-reparative and neuro-protective genes were uniquely up-regulated acutely, 54 genes uniquely up-regulated at chronic time point, and 60 additional genes were up-regulated at both time points. In addition to genes involved in inflammation and immune responses, genes involved in tissue differentiation, neural growth, and proliferation were significantly involved in the response to injury. Further research based on this novel approach may lead to tailored neuro-modulatory therapy with the hope of significant recovery of pre-surgical erectile function.
With surgical neural injury and loss, cessation of daily and nocturnal erections occurs, leading to significant cavernosal hypoxia with attendant microstructural consequences. Schwartz et al. reported on two groups of post prostatectomy patients who underwent pre-operative penile biopsy, the first group received sildenafil 50 mg every other night for 6 months and the second 100 mg of sildenafil every other night [9]. While a minority of patients returned for a second penile biopsy, there was a difference in percentage of smooth muscle content between the groups; patients receiving 100 mg of sildenafil demonstrated an increase in the percentage of smooth muscle. Despite limitations, this manuscript contributed in part to the concept of chronic PDE5i therapy as a possible penile rehabilitation.
Several authors have utilized a model of radical prostatectomy induced ED in SD rats demonstrating that cavernous nerve injury leads to generation of multiple cytokines (Transforming Growth Factor β[beta], Endothelin1) and significant apoptosis of penile erectile tissue [10, 11], followed by fibrosis [12], depending in part on the severity of the injury. Using the same model of RP induced ED, Leungwattanakij et al. documented increases in hypoxia-inducible factor-1a-(HIF-1a), TGFβ[beta] and collagen I and III (all markers of fibrosis), in penile tissue [13]. Gross morphometric changes in the penis occur subsequent to cavernous nerve injury in this rat model. Penile fibrosis and loss of smooth muscle lead to failure of the veno-occlusive mechanism and the development of erectile dysfunction.
The correlation between the degree of neurovascular injury and the severity of morphometric change and subsequent development of ED was confirmed in a later study by Özden et al. [14]. These investigators used a rat model of ED and compared bilateral cavernous nerve injury (BCN) to unilateral cavernous nerve injury (UCN) and sham operated animals; a subset of animals in each group were given sildenafil after injury. The BCN animals had the largest decrease in penile weight and smooth muscle apoptosis, while UCN animals demonstrated less severe loss of penile weight and apoptosis.
Radical prostatectomy may injure more than just the cavernous nerve. Accessory pudendal arteries (APA’s) are vessels that arise in a supra-diaphragmatic location. Such arteries often course close to the prostate and travel beneath the pubic bone. In some patients, these arteries represent a major source of arterial inflow to the corpora cavernosa. It is estimated that APA’s occur in 30 % of men based on laparoscopic or robotic prostatectomy studies. Neurovascular injury subsequent to radical prostatectomy was documented by Aboseif et al. who evaluated 20 patients with intracavernosal injection (ICI) of prostaglandin E1 (PGE1) with subsequent duplex Doppler ultrasound evaluation of the cavernosal arteries [15]. At 1 year post surgery 8/20 (40 %) had reduced erectile hardness in response to the ICI PGE1 with accompanying decreased in arterial blood flow.
Several morphometric reports document the effects of neurovascular injury with subsequent fibrosis and apoptosis after radical prostatectomy. Penile measurements were made from the symphysis pubis to the mid glans in the stretched penis in 31 men before and 3 months after radical prostatectomy; nearly half of the men experienced a loss of penile length ±1 cm, and an additional 23 % had loss between 0 and 1 cm [16]. A larger series of 124 men undergoing reported by Savoie et al. confirmed that morphometric penile changes were measurable men 3 months after radical prostatectomy [17].
22.3 Rehabilitation and Preservation of Erectile Function After Prostatectomy
Rehabilitation or optimal preservation of natural EF after radical prostatectomy represents the ultimate goal for patients and a challenge for the practicing urologist.
Neuropraxia leads to an impairment of erectile responsiveness to sexual stimuli as well as a reduction of nocturnal and morning erections and is associated with a persistent hypoxia of penile corpora cavernosa, evident immediately following prostatectomy.
Montorsi et al. [18] first suggested the concept of penile rehabilitation, based on the preservation of EF through the improvement of tissue-oxygenation to prevent from endothelial dysfunction and cavernosal smooth-muscle fibrosis.
However, to date no strategy investigated provides the definite answer, and a clear goal for these patients is also to improve EF early after surgery and to retain the best response to PDE5i if they require assistance.
The concept of penile rehabilitation with PDE5i is supported by several well-designed preclinical studies [19]. Promotion of EF-recovery, improvement of the smooth-muscle-to-collagen ratio, reduction of cavernosal apoptotic index, preservation of endothelial function, and neuroprotection during nerve damage have been proven in animal models [19].
In clinical practice, rehabilitative concepts using different PDE5i and schedules for administration are widely adopted based on their potential antifibrotic and neuroprotective properties, but its use is so far not fully supported by high evidence data. While chronic administration of short-acting PDE5i such as sildenafil-citrate or vardenafil HCL has been shown to increase the rate of EF recovery as compared to placebo [20, 21], no study has demonstrated higher efficacy on penile rehabilitation with PDE5i with its chronic use as compared to the respective on-demand administration schedules.
One of the main criticisms of these studies lies in the type of PDE5i used. Both sildenafil-citrate and vardenafil-HCL are characterized by a relatively short half-life, which may prevent them from reaching coverage over a full dosing-interval with a single daily administration. In contrast, the longer half-life of tadalafil confers to this drug the optimal pharmacokinetic profile for its use in the rehabilitative setting with a once-daily administration [22]. However, Montorsi et al. could not demonstrate higher efficacy on unassisted EF with once-daily tadalafil (5 mg) as compared to on-demand administration of 20 mg in a multicenter, randomized, double-blind trial (REACTT) [23]. Chronic use of once-daily tadalafil 5 mg given for 9 months was not superior to tadalafil 20 mg given on demand or to placebo in EF recovery rates at the end of a 6-weeks wash-out (primary endpoint of the trial). Further criticisms of the design of REACTT and all other published evidence are the improper patient selection (men at low risk of postoperative ED) and the relatively short duration of the study-period, as the ultimate rehabilitation analyses should ideally performed at 18–24 months post NSRP [24, 25].
Therefore, none of the currently available PDE5i showed higher efficacy on rehabilitation of unassisted EF within a time-period of approximately 1 year post surgery when administered once-daily as compared to on demand dosing following RP in well-designed, prospective, randomized trials.
However, in the REACTT-Trial, treatment with tadalafil 5 mg once daily provided significant benefit on recovery of assisted EF, as indicated by a significant improvement of achieving penile tumescence (Sexual Encounter Profile Question 1, SEP1) both at the end of the 9-month randomized double-blind, double-dummy treatment phase as well as at the end of the open-label phase at month 13.5 versus placebo, whereas on-demand treatment with tadalafil 20 mg was not significantly superior to placebo at month 13.5. Improvements of successful intercourse (SEP3) were statistically significant versus placebo only for tadalafil once daily and exceeded the minimal clinically important difference (MCID) after double-blind treatment. Results of this trial indicate that active treatment early after NSRP improves responsiveness to PDE5i also in the further course of post-surgery follow-up, as shown by significantly improved SEP3 yes-responses (55.3 %, post-hoc ANCOVA) after re-challenge with tadalafil once-daily during the 3-month open-label treatment, with (absolute) 17.5 % less per-patient yes-responses to SEP3 after OLT in those patients with no active treatment during DBT.
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