Sexual Dysfunction Following Radical Prostatectomy

Authors

  • Cooper R. Benson,

    1. From the Department of Urology, Louisiana State University, New Orleans, Louisiana
    Search for more papers by this author
  • Ege Can Serefoglu,

    1. Department of Urology, Tulane University Medical Center, New Orleans, Louisiana.
    Search for more papers by this author
  • Wayne J. G. Hellstrom

    Corresponding author
    1. Department of Urology, Tulane University Medical Center, New Orleans, Louisiana.
      Department of Urology, Tulane University Medical Center, 1430 Tulane Ave, SL-42, New Orleans, LA 70112 (e-mail: whellst@tulane.edu).
    Search for more papers by this author

Department of Urology, Tulane University Medical Center, 1430 Tulane Ave, SL-42, New Orleans, LA 70112 (e-mail: whellst@tulane.edu).

Abstract

Abstract: Prostate cancer is the most common solid cancer in men and the second leading cause of cancer death in men. A favored treatment option for organ-confined prostate cancer in a middle-aged healthy man is radical prostatectomy (RP). Despite advances in techniques for RP, there remain concerns among physicians and patients alike on its adverse effects on sexual function. Although post-RP erectile dysfunction has been extensively studied, little attention has been focused on the other domains of sexual function, namely loss of libido, ejaculatory dysfunction, orgasmic dysfunction, penile shortening, and Peyronie disease. The aim of this review is to discuss the most recent literature regarding post-RP sexual dysfunctions.

Prostate cancer is the most common solid cancer in men and the second leading cause of cancer death in North American men (American Cancer Society, 2010). In 2010, there were an estimated 217 730 new cases of prostate cancer in the United States alone and 32 050 associated deaths (American Cancer Society, 2010). This translates into a 1 in 6 lifetime risk of developing prostate cancer (American Cancer Society, 2010). Age is the most important risk factor for developing prostate cancer, similar to sexual dysfunction, with a median age of 67 years at the time of diagnosis (Laumann et al, 1999; Hoffman, 2011).

Currently, a favored treatment option for organ-confined prostate cancer in a middle-aged healthy man is radical prostatectomy (RP; Bill-Axelson et al, 2005). There have been a number of technical innovations for RP, including robotic-assisted RP (RARP), laparoscopic approaches, and nerve-sparing techniques; however, there remain concerns among physicians and patients alike on functional outcomes, specifically erectile dysfunction (ED) and urinary incontinence (UI), which are closely correlated with quality of life (QoL) issues (Treiyer et al, 2011). Despite the advances in minimally invasive approaches, ED and UI rates have not seemed to improve compared with those rates for the traditional open nerve-sparing RP (NSRP; Hu et al, 2009; Patel et al, 2011).

Previously several authors noted disparities in physician and patient assessment of QoL issues in men with prostate cancer; the issues focused mostly on sexual and urinary function (Litwin et al, 1998; Ramsawh et al, 2005; Albaugh and Ferrans, 2010). ED has been the most commonly reported health-related QoL issue following RP (Alemozaffar et al, 2011). Unfortunately, little attention has been focused on the other domains of sexual function, namely loss of libido, ejaculatory and orgasmic dysfunction, penile shortening, and Peyronie disease. The purpose of this review is to provide an update on the most recent literature regarding post-RP sexual dysfunction.

ED

ED was defined by the National Institutes of Health in 1992 as an “inability to achieve or maintain an erection sufficient for satisfactory sexual performance” (Droller et al, 1992). More recently, in 2004, the International Society of Sexual Medicine defined ED as the “consistent or recurrent inability of a man to attain and/or maintain penile erection sufficient for sexual activity; a 3 month minimum duration is needed for the establishment of this diagnosis” (Dwyer and Nehra, 2010). The current literature has inconsistently defined and determined erectile outcomes following RP, which has made it difficult to assess its true incidence (Wang, 2007; Dwyer and Nehra, 2010). ED may be defined in different ways—it may be based on the International Index of Erectile Function (IIEF), which provides information regarding erectile function (EF) but does not differentiate among organic, psychological, or surgical etiologies. It may also be defined by objective measures such as color duplex Doppler ultrasonography or nocturnal penile tumescence and rigidity (NPTR) testing (Kawanishi et al, 2001). Furthermore, previous studies assessing EF outcomes after RP did not uniformly define or evaluate for the presence of preoperative ED, thereby making it difficult to accurately compare the incidence of ED following RP (Litwin et al, 1998; Kawanishi et al, 2001; Siegel et al, 2001). Post-RP ED has a reported 20% to 90% incidence and is still the most widely recognized adverse sequelae; recovery is often delayed and may take up to 3 years for return of potency (Burnett, 2005; Mulhall, 2009). Moreover, a myriad of confounding factors such as age and the presence of comorbidities also hinder the ability to determine the true incidence of ED attributed to RP (Siegel et al, 2001). Recently there have been advances in our understanding of the pathophysiology of post-RP ED. These include the introduction of management protocols in the postoperative period and the identification of factors that allow us to predict which patients will most likely have return of normal EF (Penson et al, 2003; Dubbelman et al, 2006; Garcia and Brock, 2010; Kim et al, 2011; Treiyer et al, 2011).

Postprostatectomy Penile Pathophysiology

The pathophysiology of post-RP ED is multifactorial and has been studied in both animals and humans. The etiology of post-RP ED can be categorized into several domains: neurogenic, vasculogenic, and structural changes (Johannes et al, 2000). It has long been recognized that the cavernous nerves are of paramount importance in normal EF and that trauma to these nerves during surgery contributes to post-RP ED (Ahlering et al, 2006). Walsh et al (1983) initially described the nerve-sparing technique for RP, which has resulted in improved potency rates. Normally, cavernous nerve stimulation generates neuronal nitric oxide synthase (nNOS) and releases nitric oxide (NO). NO stimulates increased levels of cGMP, which sequesters intracellular calcium and alters cellular sensitivity to calcium. This allows for full smooth muscle relaxation and an erection, which is sustained by endothelial NOS (eNOS) production of NO (Burnett et al, 1992; Rajfer et al, 1992; Lue, 2000; Somlyo and Somlyo, 2000; Wang et al, 2002; Burnett, 2004; Dean and Lue, 2005b).

Trauma to the cavernous nerves during RP, caused by stretch, heat from electrocautery, or cutting, renders the nerves nonfunctional either temporarily or permanently and results in a reduction in NOS production, which is critical for EF (Carrier et al, 1995; Ahlering et al, 2006). Evidence from animal studies has shown that regeneration of these NOS-producing nerves may take place, and the delay in return of EF represents this period of neuronal healing (Carrier et al, 1995; McCullough, 2001; Dean and Lue, 2005a). This neuronal trauma subsequently induces biochemical changes within the penile cavernous tissues (Leungwattanakij et al, 2003).

During flaccidity, there is a state of relative cavernosal hypoxia, which also contributes to biochemical changes (Leungwattanakij et al, 2003). Hypoxia inhibits prostaglandin E1 (PGE1) and increases production of transforming growth factor β1 (TGF-β1) and TGF-β1–dependant endothelin 1, which promotes deposition of type I and III collagen (Figure; Filippi et al, 2003; Leungwattanakij et al, 2003). Collagen deposition leads to fibrosis, cavernosal smooth muscle atrophy, and endothelial morphological changes, which reduce the functionality of the penile erectile tissues (Filippi et al, 2003; Leungwattanakij et al, 2003). Hypoxia induces apoptosis, further altering the structure of the penile cavernosal tissue (Klein et al, 1997; Leungwattanakij et al, 2003; Lysiak et al, 2008; Mulhall et al, 2008). Conversely, during normal erections, there are elevated cavernosal oxygen levels, which inhibit fibrosis through the secretion of PGE1 (Moreland et al, 1995; Sattar et al, 1995; Daley et al, 1996; Moreland 1998).

Figure Figure.

. Diagram representing the changes that occur in the cavernous tissue after prostatectomy, which contribute to erectile dysfunction and penile fibrotic changes after radical prostatectomy. Adapted from Filippi et al, 2003; Leungwattanakij et al, 2003; and Garcia and Brock, 2010. PGE1 indicates prostaglandin E1; TGF-B1, transforming growth factor β1.

Structural alterations were confirmed with corporal biopsies attained at 2 and 12 months after RP, which revealed a reduction in the amount of smooth muscle and trabecular elastic fibers and increased collagen deposition, as well as replacement of the smooth muscle with fibrotic tissue, which was progressive over time (Iacono et al, 2005). These structural changes also diminish the distensibility of the penis and cause venoocclusive dysfunction (VOD; Ferrini et al, 2006, 2009).

Mulhall (2005) suggested that RP leads to sympathetic hyperactivation and a subsequent hypertonic state in cavernosal smooth muscles through decreased NO bioavailability. Sympathetic hyperactivation causes the penis to be less distensible and therefore renders the penis less likely to exhibit normal EF (Mulhall, 2005). It has been noted that the sympathetic nerves regenerate more rapidly than parasympathetic nerves after injury (Zhou et al, 2004; Mulhall, 2005).

Vascular factors may also contribute to the development of post-RP ED. Arterial insufficiency resulting from injury to the accessory pudendal artery (APA) has been postulated to contribute to post-RP ED; when the APA was preserved, the likelihood of potency was 2-fold greater with a relative risk of 2.65 (Rogers et al, 2004). The APA originates from the external iliac, internal iliac, or obturator arteries and is located superior to the pelvic diaphragm and passes posterior to the pubic bone (Walz et al, 2010). The APA supplies the corpora cavernosa either unilaterally or bilaterally and is susceptible to injury during RP (Dubbelman et al, 2006; Walz et al, 2010). Cadaveric and in vivo studies have revealed the presence of an APA in 4% to 75% of cases (Breza et al, 1989; Rogers et al, 2004; Dubbelman et al, 2006). Doppler studies have suggested the importance of the APA in normal EF: during pharmacologically induced erections, hemodynamic changes were observed in the APA, similar to those changes seen in the cavernosal arteries during penile erections (Droupy et al, 1999). The APA may be the sole arterial supply to the corpora cavernosa, in which case preservation of the APA is critical in preventing arteriogenic ED (Breza et al, 1989; Mulhall et al, 2002; Rogers et al, 2004; Walz et al, 2010).

In men undergoing bilateral NSRP (BNSRP), Mulhall et al (2002) observed that 59% of patients had arterial insufficiency, 26% had venous leak, and all of those with venous leak concomitantly had some degree of arterial insufficiency. It was also demonstrated there was a greater incidence of venous leakage with longer intervals of post-RP ED (Mulhall et al, 2002). Furthermore, arterial insufficiency, as well as venous leakage, resulted in cavernosal hypoxia, which has shown to induce structural changes contributing to VOD post-RP, potentiating the venous leak phenomenon (Mulhall et al, 2002). As a result of smooth muscle fibrosis, there is a decreased ability of the cavernosal tissue to relax, thus preventing the normal restriction of blood through the subtunical veno-occlusion mechanism, normally trapping blood within the penis during an erection (User et al, 2003; Ferrini et al, 2009). These observed postoperative changes have led to modifications in surgical techniques and have provided a target for penile rehabilitation aiming to prevent post-RP ED.

Penile Rehabilitation After RP

Penile rehabilitation is an evolving concept for which the optimal regimen has not been established (DeFade et al, 2011). The landmark study by Montorsi et al (1997) that evaluated the use of intracorporeal injections of alprostadil was one of the first to highlight the concept of penile rehabilitation and has since garnered significant attention by the urology community. The role of penile rehabilitation is important post-RP, with a number of studies evaluating the efficacy of various treatment modalities, including oral phosphodiesterase 5 (PDE5) inhibitors, intracavernosal injections (ICI), vacuum erection devices (VED), intraurethral alprostadil (IUA) suppositories, any combination of the above, and investigational prospects, with penile prosthesis being the last option for those who fail earlier therapies.

One of the major tenants of penile rehabilitation is the concept of early oxygenation of the penile smooth muscle (Filippi et al, 2003; Leungwattanakij et al, 2003). It is understood that penile hypoxia following RP plays an important role in the biochemical and subsequent structural changes that occur (Moreland, 1998; Filippi et al, 2003; Leungwattanakij et al, 2003). During the flaccid state, the corpora cavernosa have a venous PO2that favors the release of fibrogenic cytokines like TGF-β1 (Moreland, 1998; Leungwattanakij et al, 2003).

PDE5 inhibitors have played a substantial role in penile rehabilitation and have been proposed to promote a protective environment for the cavernosal smooth muscle (Lysiak et al, 2008; Mulhall et al, 2008). It is important to recognize that the use of PDE5 inhibitors mandates the presence of functional cavernous nerves. The mechanism increases the levels of cGMP, which is dependent on NO production by nNOS (Hatzimouratidis et al, 2009). Animal studies have demonstrated the protective benefits of the PDE5 inhibitors sildenafil and tadalafil (Lysiak et al, 2008; Mulhall et al, 2008). In mice treated with tadalafil after cavernous nerve resection, there was decreased apoptosis in smooth muscle and endothelial cells and increased activation of 2 survival-associated kinases, Akt and extracellular signal–regulated kinase 1/2 (Lysiak et al, 2008). Schwartz et al (2004) assessed the effect of sildenafil in 21 human volunteers following RP and found that intracorporeal smooth muscle content was better preserved in men following 6 months of treatment with a nightly 50-mg dose and smooth muscle content was increased with 100-mg dosing. Further, animal studies have indicated that the administration of PDE5 inhibitors causes increased activity of inducible eNOS and increased levels of activated Akt, which correlates with decreased apoptosis and inhibits the profibrotic state that accompanies penile hypoxia after RP (Musicki et al, 2005; Lysiak et al, 2008; Mulhall et al, 2008). Furthermore, PDE5 inhibitors amplify the endothelial protective effects of NO, allowing for preservation of endothelial function and recruitment of endothelial progenitor cells (Mulhall et al, 2008; Foresta et al, 2009). The elucidation of the effects of PDE5 inhibitors in the post-RP setting has led to further investigations regarding the optimal use of PDE5 inhibitors in patients with post-RP ED.

Mulhall et al (2005) performed a nonrandomized study in which the patients in the rehabilitation group were given early sildenafil. Those who failed to respond to oral therapy were switched to ICI therapy with alprostadil (3 times per week). They were followed until 18 months post-RP and compared with the nonrehabilitation group that did not follow the protocol (Mulhall et al, 2005). At 18 months, 52% of men in the rehabilitation group were able to achieve unassisted intercourse compared with 19% in the nonrehabilitation group (P < .001), as well as higher IIEF scores, greater mean number of erections, and better likelihood of responding to PDE5 inhibitors or ICI (Mulhall et al, 2005). This indicates that these interventions likely promoted earlier return of spontaneous erections following RP (Mulhall et al, 2005).

Padma-Nathan et al (2008) conducted a randomized, double-blind, placebo controlled trial to evaluate the use of nightly sildenafil 50 mg or 100 mg for 36 weeks and then an 8-week washout period versus placebo in patients undergoing BNSRP to assess recovery of EF based on IIEF scores. They found that 26% in the 50-mg dose arm responded, compared with 29% in the 100-mg dose arm and only 4% in the placebo group (P < .05), suggesting that the use of sildenafil helped the return of spontaneous erections. However, this study was limited by its small numbers, early termination of the study due to low placebo response rate, and high dropout rate (Padma-Nathan et al, 2008). A subanalysis of the data assessed NPTR in 54 patients who were randomized to sildenafil 50 mg or 100 mg or a placebo nightly and showed that those receiving the 100-mg dose of sildenafil had the greatest improvement in rigidity (McCullough et al, 2007).

Similarly, Bannowsky et al (2008, 2010) assessed the use of sildenafil 25 mg nightly in patients with early penile erections determined by NPTR measurements versus no treatment within 2 weeks of NSRP and evaluated IIEF scores up to 78 weeks postoperatively. The authors discovered that those in the treatment arm had higher IIEF scores, faster recovery of EF, and potency rates of 92% versus 68% compared with patients who received no treatment (Bannowsky et al, 2008, 2010). Interestingly, they observed that 95% of patients had erections the first night after catheter removal based on NPTR (Bannowsky et al, 2008, 2010).

Nehra et al (2005) evaluated sexual satisfaction in patients undergoing NSRP (unilateral or bilateral) with the use of on-demand vardenafil 10 mg or 20 mg versus placebo. The patients in the treatment arm had higher satisfaction with intercourse, orgasmic function, erection hardness, and overall sexual experience compared with placebo (Nehra et al, 2005). Montorsi et al (2008) compared the early use of vardenafil, either on demand or nightly use, with placebo in men having undergone BNSRP 9 months before followed by a 2-month washout and 2-month open-label period. After the double-blind period, there was a greater percentage of patients with IIEF >22 in the on-demand group compared with the nightly (P / .0344) and placebo groups (P < .0001). There was no significant difference among the 3 groups after the washout period or in the open-label period in regard to the percentage of patients with IIEF >22 (Montorsi et al, 2008). This study was the first to demonstrate the efficacy of on-demand versus nightly use of vardenafil and supports the paradigm of an on-demand regimen. However, it is limited by the subjective nature of the measurement of EF (Montorsi et al, 2008; Segal and Burnett, 2011). The use of on-demand tadalafil versus placebo in men undergoing BNSRP has also been studied, and it was concluded that those taking on-demand tadalafil had statistically significant higher IIEF scores after treatment compared with those receiving placebo (Montorsi et al, 2004:1036).

The role of ICI therapy has also been evaluated in penile rehabilitation alone and in combination with oral therapy. The 3 medications commonly used for ICI are alprostadil, papaverine, and/or phentolamine, all of which cause relaxation of penile smooth muscle and therefore vasodilation to allow for penile erection, circumventing the need for intact cavernous nerves (Ruiz Rubio et al, 2004; McCullough, 2008). Dennis and McDougal (1988) initially evaluated the use of ICI using a papaverine/phentolamine mixture in patients after RP with an 85% response rate. Montorsi et al (1997) conducted one of the first studies to demonstrate the role of penile rehabilitation in post-RP ED. The authors randomized 30 patients after RP to receive ICI with PGE1 3 times per week or placebo over 3 months and found that 67% compared with 20% of the controls had spontaneous erections (Montorsi et al, 1997). The long-term efficacy and compliance with ICI was evaluated. Among 102 patients in the study, there was a 68% response to therapy (defined as achieving erection sufficient for intercourse). The compliance among responders was 70% with associated increases in IIEF-5 scores with ICI use up to 5.6 years, indicating its long-term efficacy (Raina et al, 2003). The importance of early penile rehabilitation was highlighted in a study comparing a group of 73 patients who underwent non-NSRP (NNSRP) using ICI with PGE1 and who were randomly assigned to initiating therapy within the first 3 months of RP and those starting later (Gontero et al, 2003). They observed that 72% of patient in the early group had grade 3 or 4 erections compared with 40.5% of the late group (P < .05; Gontero et al, 2003).

The use of ICI in combination with oral PDE5 inhibitors has also been evaluated for post-RP ED. A retrospective study that evaluated the addition of ICI in patients previously not responding to sildenafil or vardenafil showed that 68% had improved scores on the Sexual Health Inventory for Men (SHIM) after adding ICI. It also revealed that 36% of those patients were able to decrease the frequency of ICI for adequate erections after 7 months (Mydlo et al, 2005). In a prospective study evaluating 22 patients using a combination therapy of ICI (alprostadil or a combination of PGE1, papaverine, and phentolamine) and sildenafil after BNSRP, with a mean follow-up period of 6 months, it was noted that 50% of the patients had return of partial spontaneous erections, none of which were sufficient for intercourse (Nandipati et al, 2006). The authors also showed that there was a statistically significant (P< .05) increase in SHIM score from post-RP baseline in patients using injections alone and those using combination therapy at the end of the study, of which 57% and 42.9%, respectively, were sexually active (Nandipati et al, 2006). This study supports early rehabilitation following RP (Nandipati et al, 2006).

IUA has also been studied in the management of post-RP ED. Costabile et al (1998) retrospectively investigated the use of medicated urethral suppositories for erection (MUSE) in patients with ED following RP. After 3 months, 57.1% of patients taking the medication were able to have intercourse at least once compared with 6.6% in the placebo group, and patients had a 40.1% overall success rate for the likelihood of intercourse during the study period with the active drug (Costabile et al, 1998). Further, it was determined that IUA was effective despite neurovascular impairment (Costabile et al, 1998). The use of MUSE was also assessed in 54 patients following RP. MUSE was effective in 55% of the patients and was equally effective in those undergoing NSRP and NNSRP (Raina et al, 2005b. In another study, 56 patients who were treated with MUSE 3 times per week for 6 months and 35 control patients without early treatment were followed for 9 months (Raina et al, 2007). In the treatment arm, 68% of patients completed the study, of which 74% were able to have successful intercourse and 75% of those successful patients had recovery of spontaneous erections sufficient for intercourse (SHIM score ≥18) (Raina et al, 2007). This was compared with the 37% of patients in the control group who were able to have intercourse and 11% with natural erections sufficient for intercourse at the completion of the study (Raina et al, 2007). This study supports the notion of early intervention leading to faster recovery of EF (Raina et al, 2007). These studies evaluating IUA also revealed that a significant proportion of patients experienced adverse effects with treatment, most commonly penile and urethral pain (Raina et al, 2005b, 2007).

VED provides another option for managing post-RP ED. Raina et al (2006) looked at the use of VED following RP in 109 patients who were randomized to daily VED use for 9 months or no treatment. In patients using the VED, 80% (60 of 74) had successful intercourse and 32% of responders reported natural erections at 9 months, 17% of which had natural erections sufficient for intercourse, with associated increases in IIEF-5 scores (Raina et al, 2006). This was compared with 37% (13 of 35) of the control group achieving spontaneous erections and only 4 patients (11%) of the control group achieving natural erections sufficient for intercourse; furthermore, these patients overall had lower IIEF-5 scores compared with the VED group (P < .05; Raina et al, 2006). This again supports the notion of early intervention after RP. Kohler et al (2007) completed a randomized controlled trial in 28 men who were assigned to early (starting 1 month post-RP) daily use of VED 10 minutes per day without a constriction ring or late (starting 6 months post-RP) on-demand use and followed for up to 12 months. There was a significant difference in the number of men with IIEF ≥12 at the 3- (P / .005) and 6-month (P = .033) follow-up compared with the control group, indicating the benefit of early VED usage; however, this difference disappeared at the last follow-up (P = .75; Kohler et al, 2007). Interestingly, they also discovered a preservation of penile length in the early VED group compared with the latter (Kohler et al, 2007). Further, it has been shown that VED can also be used effectively in combination with sildenafil as well as ICI (Chen et al, 1995; Raina et al, 2005a; Pahlajani et al, 2012).

Penile prosthesis insertion is typically reserved for men who fail all previous therapies for post-RP ED. Khoudary et al (1997) initially evaluated men undergoing simultaneous RP with placement of penile prosthesis and concluded that it allowed for earlier return of sexual function without concomitant increases in surgical morbidity, blood loss, hospital stay, or postoperative pain compared with RP alone. In patients who had simultaneous RP with penile prosthesis insertion, the patients reported better overall QoL, EF, and greater frequency of sexual contact compared with those undergoing RP alone (Ramsawh et al, 2005).

Recently more novel techniques and therapies have been evaluated to manage post-RP ED. Interposition sural nerve grafting has been investigated in patients undergoing NNSRP (Kim et al, 2001). The authors compared men undergoing NNSRP with bilateral nerve grafts versus no grafting during RP and found that 26% (6 of 23) had spontaneous unassisted erections and 26% (6 of 23) had “40% to 60%” spontaneous erections, indicating a benefit of sural nerve grafting in the population undergoing NNSRP (Kim et al, 2001). Davis et al (2009) conducted a randomized study comparing men undergoing unilateral NSRP (UNSRP) with and without unilateral sural nerve grafting, and they determined that there was no improvement in potency with grafts compared with controls.

Intracavernous injections of adeno-associated virus brain-derived neurotrophic factor in a rat model of cavernous nerve injury showed that there were higher intracavernous pressures with cavernous nerve stimulation, at 4 and 8 weeks after injection, and revealed greater nNOS staining in major pelvic ganglia (MPG) in the treated rats compared with controls (Bakircioglu et al, 2001). This study indicated a potential benefit in neuronal regeneration, which may correlate with enhanced recovery of EF (Bakircioglu et al, 2001). Kato et al (2007) used a herpes simplex virus vector expressing glial cell line–derived neurotrophic factor that was administered directly to and around injured cavernous nerves in a rat model; at 4 weeks, the treated rats showed recovery of intracavernous pressure compared with controls and greater neuron survival in MPG. Immunophilin ligands, which bind to FK506-binding proteins, have also been investigated for their role in neuroprotection after cavernous nerve injury (Lagoda et al, 2009). The authors sought to evaluate the effect of FK506 and rapamycin on EF recovery and FK506-binding protein expression after bilateral cavernous nerve injury in rats (Lagoda et al, 2009). There was preserved EF in the FK506 and rapamycin–treated rats, and this suggested that FK506 and rapamycin administration prevented decreases in specific FK506-binding proteins in the penis and MPG and that these binding proteins may mediate neuroprotective effects through thioredoxin and glutathione redox systems (Lagoda et al, 2009, 2011). Although gene therapy remains investigational at this time, it has furthered our understanding of post-RP ED and may lead to novel strategies for preventing this consequence in humans.

Erythropoietin (EPO) has also been investigated as a potential therapy for post-RP ED. It was previously established that EPO receptors are expressed in human penile tissue and periprostatic neurovascular bundles (Liu et al, 2007). In a rat model of cavernous nerve injury, EPO therapy promoted return of EF with intracavernous pressure normalization in the treatment group compared with controls (P < .05; Allaf et al, 2005). Burnett et al (2008) retrospectively evaluated the effect of preoperative EPO administration on EF recovery in men after RP compared with controls and found that patients receiving EPO had higher IIEF-5 scores with or without the use of on-demand PDE5 and had greater ability to successfully have intercourse with little to no difficulty (P < .05).

Despite these trials and investigations into novel therapies to improve post-RP EF, no consensus or algorithm has been established for penile rehabilitation or the timing of when to begin treatment to provide optimal outcomes (Montorsi et al, 2004a; Mulhall et al, 2010). It is clear that earlier intervention does provide benefit, but the optimal therapy remains in question. Currently most studies lack adequate power. Many are retrospective and case series, with the minority providing significant level 1 evidence to support penile rehabilitation. Attempts have been made to predict erectile outcomes based on patient factors and surgical techniques (Alemozaffar et al, 2011). The current state of penile rehabilitation is that no definitive answer has been identified that provides the best erectile outcome post-RP, and the need for continued research is indicated.

Loss of Libido

The psychological consequences of RP have garnered little attention compared with ED. Dealing with the diagnosis of cancer and recovering from surgery have negative impacts on QoL, sexual desire, and function after RP (Tsivian et al, 2009). A prospective study evaluated the mental health of 236 patients following RP using questionnaires about health-related QoL preoperatively and compared the results with QoL at 3, 6, and 12 months postoperatively (Treiyer et al, 2011). Return to baseline mental health was achieved in 73% of patients, which was associated with a lack of postoperative complications, such as return of full continence (Treiyer et al, 2011). The mean time to return to baseline was 4.5 months (Treiyer et al, 2011). They noted that the mental health domain, specifically vitality and health perception, did not return to baseline before 1 year. Further, this study highlights the mental and psychological impact of surgery as it relates to functional outcomes and indicates a potential need for psychological counseling both before and following RP (Treiyer et al, 2011). Meyer et al (2003) determined that 72% of men (n / 89) believed that QoL was moderately to severely affected, at a median of 92 months postoperatively, mainly because of persistent ED. The impact of ED on QoL is often significant, and many patients experience sexual bother as a result of post-RP ED; however, it is variable and individualized as to the degree that lack of sexual function correlates with sexual bother (Bates et al, 1998; Penson, 2001). However, multiple studies have demonstrated that QoL and sexual satisfaction improve with treatment of post-RP ED (Perez et al, 1997; Ramsawh et al, 2005; Albaugh and Ferrans, 2010). Despite this, one study demonstrated that there was no significant difference in overall QoL between patients using erectile aids post-RP and those not using them (Perez et al, 1997). Interestingly, Perez et al (2002) discovered that sexuality and sexual satisfaction were more important predictors of the partner's QoL than the patient's QoL, and they found that the overall quality of the relationship was more important for the patient. It appears that in addition to managing functional outcomes, we must pay close attention to the psychological component of the patient and partner (Tsivian et al, 2009).

Certainly psychological factors play an important role in a man's ability to achieve an erection (Dwyer and Nehra, 2010). The importance of counseling patients, both before and after surgery, has been established regarding sexual dysfunction and the use of PDE5 inhibitors postoperatively (Bronner et al, 2010). In a subset of 620 men from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database, sexual function and sexual bother were evaluated after administration of the Prostate Cancer Index survey, both at baseline and up to 4 years postoperatively (Le et al, 2010). Sexual desire was shown to have the smallest decrease from baseline following surgery, and it did not improve with time (Le et al, 2010). The other domains of sexual function such as erection and orgasm were more likely to recover over time (Le et al, 2010). Researchers have highlighted the interaction between sexual desire and sexual function, indicating that sexual desire associated with inadequate function resulted in poorer QoL measures (Dahn et al, 2004).

Orgasmic Dysfunction

Orgasmic dysfunction is another lesser recognized sexual consequence of RP, and it has a significant impact on QoL after RP. Because the prostate is removed, along with the seminal vesicles, and the vas deferens are divided during RP, this procedure inevitably results in loss of ejaculation (Magelssen et al, 2006; Tsivian et al, 2009). Most men are not overly bothered by absence of ejaculation, but it has been noted that this absence may interfere with an individual's sexual satisfaction (Tsivian et al, 2009). Orgasm is the result of interplay between physiological and psychological elements, and the exact mechanism is still not well delineated; however, it appears that it is related to ejaculation (Kandeel et al, 2001). During an orgasm, there is contraction of the smooth muscles of the seminal vesicles and prostate, an increase in posterior urethral pressure during emission, closure of the bladder neck, rhythmic contractions of pelvic floor muscles, and a sensation of ejaculation. All are translated in the brain as a pleasurable signal (Kandeel et al, 2001). Orgasmic changes following RP have become increasingly recognized in the literature. Barnas et al (2004) evaluated 239 patients post-RP and noted that 22% of them reported no change in orgasm, whereas 37% reported a complete absence, 37% had decreased intensity, and 4% reported more intense orgasms. Pain during orgasm (dysorgasmia) was experienced in 14% of patients, most of whom experienced penile pain during orgasm (72%); some reported abdominal and rectal pain (Barnas et al, 2004). Among those with dysorgasmia, 33% reported that it was constant, and the pain lasted less than 1 minute for 55% of patients (Barnas et al, 2004). The etiology of pain is poorly understood, but the authors hypothesized that intense bladder neck closure during orgasm is translated into spasms of the vesico-urethral anastomosis or pelvic floor dystonia. These researchers investigated the use of alpha-blockers and observed that they helped to ameliorate this pain in 77% of 98 patients complaining of dysorgasmia (Barnas et al, 2004, 2005). Recently, Matsushita et al (2012) evaluated the natural history of dysorgasmia following RP and concluded that dysorgasmia largely decreases in frequency and degree over time post-RP. They found that at 24 months post-RP, there was a significant decrease in dysorgasmia symptoms with 72%, 26%, and 7% of patients experiencing pain at 12, 18, and 24 months, respectively, leading to a recommendation of only surveillance rather than treatment (Matsushita et al, 2012).

There have also been several studies looking at orgasmic dysfunction post-RP as it relates to nervesparing techniques. One study showed a significant difference in the rate of orgasmic dysfunction post-RP that was related to age (age <60 years correlated with increased rates of orgasm preservation) and nervesparing status (Dubbelman et al, 2010). They found that 54% of men undergoing a NNSRP had preserved orgasmic function compared with 70.9% and 73.4% undergoing UNSRP and BNSRP, respectively (Dubbelman et al, 2010). Similarly, Tewari et al (2011) looked at orgasmic dysfunction as it relates to nerve-sparing techniques in RARP and discovered that orgasm was preserved in 90.7%, 82.1%, and 60.8% (P < .001) of those who underwent BNSRP and UNSRP procedures compared with NNSRP, respectively. Orgasm preservation was also correlated with age <60 years (Tewari et al, 2011). These studies highlight the impact of orgasmic dysfunction on QoL and that it may adversely affect psychological and physical satisfaction post-RP (Dubbelman et al, 2010; Tewari et al, 2011).

Furthermore, UI during orgasm (climacturia) has an adverse effect on sexual function, with reported rates of up to 45% post-RP (Lee et al, 2006). Interestingly, among 1288 men undergoing RP, 20% reported climacturia; however, among those patients with climacturia, 86% reported that they were otherwise continent (Nilsson et al, 2011). They also found that in patients with climacturia, there was a higher prevalence of avoidance of sexual activity for fear of failing, not satisfying their partner, and low orgasmic satisfaction, indicating a negative effect on QoL (Nilsson et al, 2011). In another study, 20% of patients reported climacturia following RP and noted that there was no difference between open and laparoscopic techniques (Choi et al, 2007). The authors also noted that climacturia was more common in patients experiencing dysorgasmia and/or penile shortening (Choi et al, 2007). In some cases, climacturia can be managed by the patient emptying his bladder before sex or using a condom, whereas others have had success with pelvic floor rehabilitation resulting in improvement in climacturia (Lee et al, 2006; Sighinolfi et al, 2009). These orgasmic dysfunctions clearly have an impact on post-RP sexual function and have important implications in regard to QoL.

Penile Shortening and Peyronie Disease

Penile morphological changes occurring after RP may result in the development of penile shortening and/or Peyronie disease. These changes are related to cavernosal hypoxia, which induces a profibrotic state and increased collagen deposition, leading to structural changes in the smooth muscle and endothelium (Ciancio and Kim, 2000; Gontero et al, 2007; Martínez-Salamanca et al, 2010) (Figure).

Penile shortening as a consequence of structural changes post-RP is an underrecognized problem (Gontero et al, 2007; Ko et al, 2010). There has been some debate regarding the methods to determine penile length—whether to include the suprapubic fat and use flaccid length, stretched penile length, or erection length when measuring the penis. Because of these discrepancies, it is difficult to compare the current studies (Martínez-Salamanca et al, 2010). Fraiman et al (1999) observed that the most substantial change in penile length and girth occurred between 4 and 6 months, noting a 9% decrease in length and 22% reduction in penile volume. Similarly in another investigation, 68% of patients undergoing RP had decreases in the size of both flaccid and stretched penile length at the 3-month follow-up and that 19% of these patients had a greater than 15% decrease in length (Savoie et al, 2003).

Gontero et al (2007) prospectively studied 126 patients who underwent RP and measured change in penile length (flaccid and stretched) preoperatively compared with the time at which the catheter was removed and at 3, 6, and 12 months. These authors believe that early and delayed changes were responsible for these changes. The most significant decrease in the length of the penis occurred at the time of catheter removal (0.67 cm flaccid and 0.84 cm stretched), which they associated with sympathetic hyperinnervation causing a hypertonic penile state and that long-term loss in penile length was due to the fibrogenic state previously described (Ciancio and Kim, 2000; Gontero et al, 2007). Additionally, there was further shortening at each of the remaining time points, and they noted that nerve sparing made no difference in the early changes and decreases in penile length over the follow-up time (Gontero et al, 2007). There has been some evidence that early intervention with penile rehabilitation using a daily VED may reduce penile shortening (Kohler et al, 2007; Martínez-Salamanca et al, 2010).

Similarly, it has been reported that there is an increased incidence of Peyronie disease in men following RP in comparison with the general population (Tal et al, 2010). In a series of 110 men with post-RP ED, 41% were found to have penile fibrotic changes (Ciancio and Kim, 2000). Of those patients, 93% presented with penile curvature, and a “waistband” deformity was observed in 24% of them. In a review of 1161 patients undergoing RP, the incidence of Peyronie disease was 16.7% (Tal et al, 2010). The exact etiology of the development of penile curvature may be related to the profibrotic state, but further studies are needed. These penile changes post-RP contribute to sexual dysfunction and can be debilitating to the patient.

Conclusion

Increased detection rate and treatment of younger men with prostate cancer have revealed sexual dysfunction to be a major postoperative concern for both patients and physicians. Although the majority of studies have more frequently focused on ED, other sexual dysfunctions are now being increasingly recognized. RP may result in loss of libido, and this emphasizes the need for counseling before and after surgery. Absence of ejaculation and pain and/or incontinence during orgasm can reduce QoL among RP patients, although alphablocker therapy may be helpful in some cases. Penile shortening and Peyronie disease are observed more frequently in RP patients compared with the general population. Penile rehabilitation is a reasonable option to offer RP patients postoperatively. A standardized algorithm for penile rehabilitation needs to be established in clinical practice.

Ancillary