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Review |
From the Sexual & Reproductive Medicine Program, Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
| Correspondence to: Dr John P. Mulhall, Department of Surgery, Urology Service, 525 E 68th St, New York, NY 10021 (e-mail: mulhalj1{at}mskcc.org). |
| Received for publication September 17, 2008; accepted for publication January 29, 2009. |
Since the introduction of the nerve-sparing radical prostatectomy (RP),
potency preservation rates of between 20% and 90% have been reported. It is
irrefutable that the nerve-sparing status of an RP is predictive of recovery
of erectile function. Bilateral nerve sparing is associated with superior
spontaneous and oral therapy–assisted recovery of erectile function
compared to unilateral nerve sparing, which in turn is more likely to lead to
functional erections than non–nerve-sparing surgery. Neural regeneration
is the mechanism by which erectile function improves over time following RP.
Although the degree of neural trauma that occurs intraoperatively is a
determinant of long-term recovery of neural function, biological factors
involved in neural regeneration are likely important determinants of the
completeness of neural recovery. Furthermore, these biological factors are
likely a major reason for the interindividual variation in recovery of
erectile function after this operation. Recently, the development of rat
models of cavernous nerve injury has facilitated the study of neuroprotective
and neuroregenerative agents. This paper reviews the current knowledge on
pharmacological neuromodulation as it pertains to the radical pelvic surgery
patient. The animal evidence is highly supportive of such agents' having a
positive impact on erectile function recovery after RP. Human trial data are
awaited.
Key words: Cavernous nerve, neuropraxia, immunophilin ligand, neuromodulation, erectile function
Nerve-Sparing Surgery
Since the initial description of the anatomic radical retropubic
prostatectomy and the elucidation of the course of the cavernous nerves, many
urologists have been trained to perform nerve-sparing surgery
(Walsh and Donker, 1982). The
variability in the anatomic location and distribution of these nerves,
combined with variations in nerve-sparing technique and nerve handling, has
resulted in variable erectile function outcomes after this operation. Reports
from centers of high volume and excellence (generally single-institution and
single-surgeon series) have cited ED rates following RP of 15%–40%
(Catalona et al, 1999;
Rabbani et al, 2000;
Walsh et al, 2000). However,
including studies of other multi-surgeon and multi-institution experiences,
post-RP ED rates as high as 91% have been reported
(Leandri et al, 1992;
Fowler et al, 1993;
Jonler et al, 1994;
Talcott et al, 1998;
Siegel et al, 2001). The
variability in these rates reflects the difficulty in studying erectile
function after RP.
It is irrefutable that the nerve-sparing status of an RP is predictive of recovery of erectile function. Bilateral nerve sparing is associated with superior spontaneous and oral therapy–assisted recovery of erectile function compared to unilateral nerve sparing, which in turn is more likely to lead to functional erections than non–nerve-sparing surgery (Quinlan et al, 1989; Walsh et al, 1994; Zippe et al, 1998; Catalona et al, 1999; Raina et al, 2008). However, the definition of nerve-sparing is somewhat arbitrary. The term generally refers to the macroscopic preservation of the cavernous nerves. Although rarely reported in a quantitative fashion, the degree to which nerves are spared depends on the amount of nerve handling and stretching and the use of electrocautery during RP.
It is also becoming increasingly appreciated that postoperative factors, such as edema and inflammation around the bladder neck and the cavernous nerves, may in fact have significant impact upon erectile function. It is not uncommon at Memorial Sloan-Kettering for us to see men who respond to phosphodiesterase type 5 (PDE5) inhibitors 4 weeks after surgery but who no longer respond after 3 months, likely because of ongoing postoperative Wallerian degeneration related, in part, to perineural inflammatory response. At the 2007 American Urologic Association (AUA) meeting, we presented data showing that 25% of men who were functional with or without PDE5 inhibitors within the first 3 months were nonfunctional by the sixth month (Bennett et al, unpublished, 2007). Recovery of functional erections was defined as a score of either 4 or 5 on question 3 of the International Index of Erectile Function (IIEF), "Over the course of the past 4 weeks, how often were you able to penetrate your partner?" In this analysis only 14% of men were PDE5 inhibitor responders within 3 months of surgery.
There is a plethora of literature associating cavernous nerve injury with corpus cavernosal smooth muscle structural damage in animal models. Carrier et al (1995) very elegantly demonstrated a reduction in nerves containing nitric oxide synthase (NOS) after cavernous neurotomy in a rat model. Of note, these authors demonstrated that animals that underwent bilateral neurotomy were far less likely to have return of NOS-containing nerves than animals that had undergone unilateral neurotomy. Numerous authorities have demonstrated that cavernous nerve injury results in apoptosis. User et al (2003) demonstrated convincingly that both penile wet weight and DNA content were significantly reduced in rats that had bilateral cavernous neurotomy. Furthermore, these authors demonstrated that the apoptosis was most prominent in the subtunical area of the corpus cavernosum, suggesting that this might be the reason that patients develop venous leak after prostatectomy. Leungwattanakij et al from Tulane (2003) have demonstrated very elegantly that cavernous neurotomy leads to up-regulation of fibrogenic cytokines such as TGF-beta, which mediates fibrosis, in the penis. In our laboratory, we have demonstrated not just smooth-muscle but also endothelial apoptosis in response to cavernous nerve crush injury. Interestingly, the apoptotic response to nerve trauma appears to be slower in onset and more prolonged after cavernous nerve crush compared to neurotomy (unpublished data).
Pharmacological Neuromodulation
Neural regeneration is the mechanism by which erectile function improves
over time following RP. Although the degree of neural trauma that occurs
intraoperatively is a determinant of long-term recovery of neural function,
biological factors involved in neural regeneration are likely important
determinants of the completeness of neural recovery. Furthermore, these
biological factors are likely a major reason for the interindividual variation
in recovery of erectile function after this operation. Neurotrophic factors
are molecular signals that promote nerve cell survival and maintain target
organ function by facilitating axon regeneration
(Burnett, 2003). Animal studies
have implicated a variety of nerve growth factors in ED (Burgers, 1991).
Recently, the development of rat models of cavernous nerve injury has
facilitated the study of neuroprotective and neuroregenerative agents
(Table).
|
Immunophilin Ligands— The term immunophilin refers to 2 families of soluble intracellular proteins that act as receptors for the immunosuppressant drugs tacrolimus (Prograf, FK-506), cyclosporine A, and rapamycin. The group identified as FK-binding proteins (FKBPs) binds to tacrolimus and rapamycin, whereas cyclophilin binds with cyclosporine A (Schreiber and Crabtree, 1997). It is known that the tacrolimus/FKBP-12 complex acts as an immunosuppressant by inhibiting activation of calcineurin, an enzyme required for cytokine transcription and ultimately activation of antigen-reactive T cells. The discovery of increased concentrations of immunophilins in the central nervous system and specifically FKBP-12 in the peripheral nerves has led to further investigation of a potential therapeutic role for immunophilins (Snyder et al, 1998).
Tacrolimus, commercially available as Prograf, is a macrolide immunosuppressant that is FDA-approved for the prevention of allograft rejection in liver and kidney transplantation. Tacrolimus is an immunosuppressant with proven anti-inflammatory, neuroprotective, and neurotrophic effects. It is currently under development in the United States for asthma, acute stroke, psoriasis, and rheumatoid arthritis. The neuroprotective properties of tacrolimus have been demonstrated using various animal models of focal cerebral ischemia that mimic human ischemic brain damage caused by stroke. Sharkey and Butcher (1994) compared tacrolimus to saline in rats that were subjected to middle cerebral artery occlusion. Tacrolimus was found to be neuroprotective at doses of 0.1–1.0 mg/kg body weight; cortical damage was reduced in tacrolimus-treated animals by 58%–65%. This study also examined the timing of drug administration to determine if there was an optimal therapeutic window. Animals that received tacrolimus 60 minutes postocclusion had significantly less reduction in cortical damage than those who received the drug after 1 minute (P < .05). Tacrolimus was the only immunophilin ligand that was found to be effective in these experiments.
The process by which tacrolimus exerts its neuroprotective effects is unknown. It is thought that the inhibition of calcineurin may play an important role in the neuroprotective process, either by regulating calcium channel activity or by reducing free radicals through the inhibition of the calcineurin-mediated dephosphorylation of an enzyme required for nitric oxide production (Sharkey and Butcher, 1994). Gold et al (1994) first reported on the axonal regenerative properties of tacrolimus following a study of sciatic nerve crush in rats. The animals that received tacrolimus had function return in their hind feet more quickly following injury. In additional studies by the same investigators, animals received two 30-second crushes to the sciatic nerve and were administered daily subcutaneous injections of either tacrolimus or saline. Electron microscopy was used to evaluate axon regeneration after 18 days of treatment. Rats that received tacrolimus demonstrated larger, more myelinated axons distal to the crush site than those treated with saline (Gold et al, 1994, 1995).
Previous studies utilized tacrolimus doses that were considered therapeutic for immunosuppressive properties. An efficacy study was completed using low-dose tacrolimus to potentially reduce associated side effects of the drug (Chunasuwankul et al, 2002). Animals were randomized to receive either no treatment or a 0.5 mg/kg dose for 2 or 3 months after a sciatic nerve transaction and suture. This dose was chosen by the investigator because it had been determined to be subtherapeutic in previous allograft transplantation studies. Both groups of tacrolimus-treated animals had a faster functional recovery and demonstrated no drug-related side effects. At the 3-month postsurgical assessment, both the tacrolimus-treated groups had significantly greater muscle mass ratios than the untreated group (P < .05). Both treatment groups had greater fiber density and more neural tissue at the 2- and 3-month assessments despite discontinuation of the study drug at 2 months in half the animals. There was a significant increase in muscle weight in the treated animals between the 2- and 3-month assessments compared to the untreated animals (36% vs 7%, P < .05). This study demonstrated that an immunosuppressive dose of tacrolimus was not required to obtain significant neuroregenerative effects. Several possible pathways have been postulated to explain the regenerative effect of tacrolimus, including increasing growth proteins and stimulating nerve growth factor (Chunasuwankul et al, 2002).
Animal studies also provide support for a potential role for tacrolimus as neuroprotective for penile innervation. Sezen and colleagues (2001, 2002) performed partial penile nerve crush injuries using multiple 15- or 60-second forceps applications to rats in an attempt to mimic the nerve injury associated with nervesparing RP. These rats were treated simultaneously with daily injections of tacrolimus (1 mg/kg) or saline solution. Erectile response was measured by changes in the intracavernosal pressure (ICP) induced by electrical stimulation. Rats that received tacrolimus had a 90% intracavernous pressure response following stimulation of the cavernous nerve compared to the sham-operated side. Saline-treated animals' response was 50% of the sham-operated side. Tacrolimus-treated animals had a significantly greater erectile response on the uncrushed side, 54%, compared to controls, 24% (P < .05).
Surviving unmyelinated axons in the cavernous nerve distal to the crush site were quantified using electron microscopy for each rat. Saline-treated rats had 30%–40% axonal survival compared to 65%–80% in drug-treated animals. In those that received saline, the degenerated axons manifested swelling of the axon profile and clearing of the axoplasm. These results were found at 1, 3, and 7 days after injury (Sezen et al, 2002).
Sezen et al (2001) demonstrated long-term recovery of erectile function with tacrolimus treatment. A limited pelvic dissection and focal transection of the right cavernous nerve were performed on a rat model. Postoperatively the animals received either tacrolimus or saline solution subcutaneously for a period of 5 days. After 4 weeks, rats treated with tacrolimus showed improved penile erection following neurostimulation of both the nontransected left and transected right cavernous nerves, as measured by ICP. The percentage recovery of ICP in the right cavernous nerve was found to be 77% in the animals treated with study drug vs 43% in the saline-treated animals (P = .019).
Although the neuroprotective and neuroregenerative mechanism of action of the immunophilin ligands has not been fully elucidated, it may be through calcineurin inhibition that the FKBP12-tacrolimus complex exerts its effect. In a recent study in rats, tacrolimus was associated with better erectile response after cavernous nerve injury than a nonimmunosuppressive immunophilin ligand (GP1-1460), as measured by stimulated intracavernous pressure (Burnett and Becker, 2004).
The immunophilin ligand tacrolimus has been shown to be both neuroprotective and neurotrophic in numerous animal studies using a variety of models. This effect has significantly improved the erectile function in animals receiving injuries similar to those from nervesparing retropubic RP. Most recently, Mulhall et al (2008, 2008) demonstrated in the rat model of cavernous nerve crush injury that short-term tacrolimus results in significant preservation of cavernous nerve architecture, confirming the findings of Burnett et al in a slightly different model with a different dosing strategy.
Based on these animal data, a multicenter, randomized, placebo-controlled trial has recently been conducted assessing the impact of tacrolimus in men undergoing RP. Patients were randomized to placebo vs tacrolimus (2–3 mg) beginning 7 days before RP and continuing for 6 months after surgery. Data should be available in the first half of 2009.
The major concern about agents like tacrolimus is their immunosuppressant properties (although no signs of such were seen at the doses used in the aforementioned clinical trial). Thus, great interest in the development of nonimmunosuppressant immunophilin ligands was generated, and Guildford Pharmaceuticals (now defunct) developed a series of compounds. GPI-1046 was shown in vitro to stimulate neurite growth in coculture models (Khan et al, 2002). A recent study examined the effect of FK506 and GPI-1046 on rats who had undergone cavernous nerve injury (Burnett and Becker, 2004). This study found that animals treated with either FK506 or GPI-1046 had significantly greater recovery of erectile function compared to animals treated with saline. Electrically stimulated maximal intracavernous pressure and rate of tumescence were better in the treated animals compared to controls. Based on these preliminary animal data, a multicenter, randomized, placebo-controlled trial was conducted assessing 2 doses of GPI-1485 against placebo in patients treated with RP. Six-month data presented at the 2007 annual meeting of the AUA failed to demonstrate any significant differences in IIEF scores between placebo and treatment groups. Because the company has since dissolved, it is unclear whether any later data will ever be seen. Most recently, laboratory data have been presented on FK1706, a nonimmunosuppressant derivative of FK506 (Bella et al, 2007). Human data are awaited.
Erythropoietin— Erythropoietin stimulates erythropoiesis under hypoxic conditions. Recently, it has been shown that erythropoietin protein and its receptor are expressed within the central and peripheral nervous systems (Campana and Myers, 2001). Administration of erythropoietin in animal models of neurodegenerative diseases and toxic insults of the brain, spinal cord, and sciatic nerve results in reduced neuronal damage and improved nerve recovery (Celik et al, 2002). A recent clinical trial confirmed the therapeutic efficacy and safety of recombinant human erythropoietin administration to recover function in patients suffering from acute ischemic stroke (Ehrenreich et al, 2002).
The recently established role of erythropoietin as a neurotrophic agent has stimulated interest in its use in men after RP. In a rat model of cavernous nerve injury, Allaf and colleagues at Johns Hopkins (2005) have shown that erythropoietin promotes the recovery of erectile function. They also confirmed localization of the erythropoietin receptor to the major pelvic ganglia and cavernous nerves (Liu, 2007).
The Johns Hopkins group has recently presented data on the potential clinical use of erythropoietin as a neuromodulatory agent to preserve erectile function in men undergoing RP (unpublished data). In this clinical study, those patients opting for erythropoietin treatment (in a nonrandomized fashion) received a single dose (40 000 IU administered subcutaneously) of recombinant human erythropoietin in the form of epoetin alpha on the day before surgery. This dosing was consistent with dosing used in the clinical trial for acute stroke. The final analysis consisted of 15 erythropoietin-treated patients (treatment group) and 21 patients who did not receive erythropoietin treatment (control group). The mean preoperative IIEF-5 score for both the treatment and control groups was 24. At 12 months, 87% of the erythropoietin-treated and 68% of the untreated patients reported performing sexual activity, although these rates were not significantly different (P = .213). However, a significantly greater proportion of erythropoietin-treated patients reported erections that could be maintained to complete sexual intercourse (47%) compared with that of untreated patients (16%; P < .05).
PDE5 Inhibitors— The nightly sildenafil post-RP study sponsored by Pfizer, which was presented at the 2003 AUA annual meeting and only recently published, randomized patients to sildenafil vs placebo starting at week 4 and continued treatment to week 40 after bilateral nerve-sparing RP (Padma-Nathan et al, 2008). Patients were assessed for spontaneous erectile function at 48 weeks, that is, 8 weeks after cessation of the treatment regimen. To be included in this trial, patients were required to have a sum of 8 on questions 3 and 4 of the erectile function domain of the IIEF. Thus, these patients had robust erectile function at baseline. To be considered responders, patients were required to retain their score of 8 on question 3 and 4. In the sildenafil-treated group, 27% of patients were considered responders compared to only 4% of the placebo group. Regarding the low placebo response rate, it is important to understand that this study assessed the ability of this treatment regimen to preserve preoperative function and did not address what proportion of patients had functional postoperative erections using this regimen. This study encourages serious consideration of the mechanisms by which such protection could occur. The results of the study were originally credited to cavernosal oxygenation during nocturnal erection in men using sildenafil after RP. However, clinicians understand that the vast majority of patients do not respond to PDE5 inhibitors nocturnally in the early stages after RP.
Thus, attention should be focused on the endothelium and neurogeneration. A single paper in the literature reports on the use of sildenafil as a neuromodulatory agent in a rat model of middle cerebral artery occlusion–induced stroke. In this study, 3 different regimens of sildenafil were associated with a significant reduction in the percentage of foot faults, a standardized evaluation of functional recovery in such models, 21 days after induction of stroke in rats (Zhang et al, 2002). These data were replicated by the same group for tadalafil (Zhang et al, 2006). Mulhall et al (2008, 2008) used transmission electron microscopy of the cavernous nerve in animals who underwent bilateral nerve crush. Animals were randomized to no treatment or sildenafil 20 mg/kg subcutaneously daily. Although there was a difference in the cavernous nerve architecture between the control and treated animals, significant neural changes existed in the cavernous nerves 28 days after injury, even in the sildenafil-treated group.
Very recently, the Bayer-sponsored REINVENT study raised questions about the utility of penile rehabilitation (Montorsi et al, 2008). This study has been critiqued in detail elsewhere (Mulhall, 2009). The study was very complicated in its design: specifically, within 14 days of bilateral nerve-sparing RP, patients were randomized in a 1:1:1 ratio to receive either 9 months of treatment with 10 mg nightly vardenafil (which could be decreased to 5 mg if required) plus on-demand placebo for sexual relations; 9 months of treatment with flexible-dose on-demand vardenafil for sexual relations (starting at 10 mg with the option to titrate to 5 mg or 20 mg), plus nightly placebo; or 9 months of treatment with nightly placebo plus on-demand placebo for sexual relations. After this, a 2-month single blind phase was conducted in which all patients received only placebo for sexual relations, and this was, in turn, followed by a 2-month open label phase in which all patients received vardenafil for sexual relations. The inclusion/exclusion criteria were standard for ED post-RP trials. This study failed to demonstrate any difference in erectile function, natural or vardenafil-assisted, between men using vardenafil on demand or daily, thus raising questions about rehabilitation as well as the design of the study.
Future Directions
It is likely that future patients who undergo radical pelvic surgery will
receive multimodal therapies; we will be using agents for endothelium
protection, agents for smooth muscle protection, and possibly agents that are
neuromodulatory. Future directions are likely to include 1) oral systemic
agents that have proven efficacy in humans, 2) the perineural application of
neuromodulatory molecules to the cavernous nerves at the time of RP, 3) the
use of implantable neurostimulators proximal to the site of cavernous
dissection in an effort to promote neuroregeneration
(Burnett et al, 2008), and 4)
sophisticated means of cavernous nerve visualization. A number of laboratories
are exploring proprietary agents that can be applied to the cavernous nerve
intraoperatively, but no data have yet been presented or published. Burnett et
al (2008) have reported on a
feasibility study assessing an implantable electrode around the cavernous
nerve. Prior work has demonstrated that cavernous nerve stimulation can lead
to an intraoperative erection in animal and human models. Electrical
stimulation of the cavernous nerve has resulted in increased arterial flow,
relaxation of cavernous muscles, and venous outflow restriction in monkeys
(Junemann et al,
1989a,b),
dogs (Junemann et al,
1989a,b)
and rats (Quinlan et al,
1989). Intraoperative stimulation of the cavernous nerves to
induce penile erection in humans has previously been performed (Lue, 1995). In
16 men undergoing retropubic RP, electrical stimulation was applied to the
prostatic apex bilaterally, producing visible erection in the RP population
(in 8 of 16 patients).
However, to date, no one has replicated the impressive animal data on immunophilin ligand therapy in the human model. Through the aforementioned human studies, we will find out whether the animal model of cavernous nerve injury can be extrapolated to the human model. The forthcoming data on tacrolimus in RP will shed much light on whether the animal models studied to date are appropriate means of assessing neuromodulatory agents in men undergoing radical pelvic surgery.
Footnotes
This paper is based on a presentation at a Special Symposium on April 12, 2008, "Therapeutic Strategies for Male Sexual and Hormonal Health," associated with the American Society of Andrology Annual Meeting, for which the presenting author received an honorarium.
Dr Mulhall has consulting and/or financial relationships with Pfizer and Eli Lilly and Co.
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