# Overview of Contemporary Penile Rehabilitation Therapies

Authors: Peter Hinh; Run Wang
Journal: Advances in Urology
 (2008)

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## Abstract

Introduction. Post-prostatectomy erectile dysfunction affects a considerable number of men and is a significant quality of life issue. There has been a substantial amount of research on the treatment of post-prostatectomy ED, and now there is a rising interest in the concept of penile rehabilitation. The goal of penile rehabilitation is to moderate the destructive processes that occur after prostatectomy in order to preserve erectile function, either through spontaneous or assisted means. Methods. We reviewed published data and experiences of post-prostatectomy penile rehabilitation using regimented interventions of phosphodiesterase inhibitors, vacuum erectile device, and intracavernosal agents, and we present and analyze the research conducted. Results. These studies show improved objective and subjective clinical outcomes in regards to physical parameters, sexual satisfaction, and rates of spontaneous erections. Conclusion. These studies are often limited by small size, study period, and study design. There continues to be a need for large, randomized, placebo controlled trials with adequate followup to fully evaluate the efficacy and cost-effectiveness of the various proposed penile rehabilitation regiments before a clear standard can be established.


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## Body

## 1. Introduction

Erectile dysfunction following prostatectomy remains a
significant quality of life issue for men undergoing prostatectomy. It is
estimated to affect 26–100% of patients
after surgery [1]. Even with advancements in understanding the anatomy of
the prostate and the neurovascular bundle [2], a considerable number of men
undergoing prostatectomy will have resulting erectile dysfunction.Progress has been made in identifying the events that contribute to erectile
dysfunction after prostatectomy. The changes of neuropraxia, ischemic and
hypoxic insults, fibrotic remodeling, and apoptosis are all believed to
contribute to erectile dysfunction [3, 4]. These events can occur even in
attempts at meticulous dissection to preserve the neurovascular bundle. The etiologies of cavernous nerve neuropraxia
include mechanical stretch injury during retraction, ischemia from accessory
vessel disruption in dissection, thermal injury from electrocautery use, and
inflammation from surgical trauma. This
neuropraxia can prevent erections, and the perpetual lack of erection can
itself set up a cascade of deleterious processes. Chronic impotence reduces
blood flow to the corporeal bodies, which leads to fibrosis and transformation
of the trabecular smooth muscle through collagen [5]. Further hypoxic insults
also may trigger apoptosis [6].  Therefore,
the goal of penile rehabilitation is to set up an environment that moderates
these processes in attempt of preserving penile function and earlier return of
potency. Regimented usage of erectile
aids aims to improve the circulation of oxygen and maintain the structure of
the corporeal bodies.However, the research has yet to be translated into a
coherent clinical strategy for penile rehabilitation. As such, there are
no currently accepted guidelines for penile rehabilitation regiments.
Certainly, there exist several popular options that are currently in use.
In practice, three principle modalities of treating post-prostatectomy erectile
dysfunction are employed. This paper will review the efficacy of these
options in this patient population for the purposes of penile rehabilitation.


## 2. Phosphodiesterase 5 Inhibitors

The introduction of phosphodiesterase inhibitors (PDEi) revolutionized
the treatment of erectile dysfunction. Since entering the market in 1998,
these medications have become nearly synonymous with erectile
dysfunction. Their ease of use and relatively safe profile have made them
pervasive in the treatment of erectile dysfunction. They have also been
extensively investigated. A Cochrane meta-analysis looking at many large,
randomized clinical trials concluded that PDEi are efficacious in the treatment
of erectile dysfunction and are generally safe [7]. However, their role
and their administration in penile rehabilitation after prostatectomy remain
undefined. A number of clinical studies
have investigated PDEi use in this population for this intention.One of the first studies on PDEi in rehabilitation looked
at objective data to support this use.
Schwartz et al. conducted a study on 40 men who had undergone nerve
sparing prostatectomy [8]. Prior to prostatectomy, all men had
percutaneous biopsy of cavernous tissue to serve as baseline reference. They were divided into receiving either 50 or
100 mg of Sildenafil every other night. Participant then underwent percutaneous
biopsy of cavernous tissue at 6 months to compare with baseline tissue. Investigators found that the 50 mg group did
not experience any loss of smooth muscle compared with baseline, and the 100 mg
group actually showed an increase of smooth muscle content when compared to the
baseline. There was no control group, and no clinical correlation between
smooth muscle preservation and erectile function is made in this study. A prior animal study had shown that cavernosal
smooth muscle does atrophy after prostatatectomy [9], though this effect is
somewhat mediated with unilateral nerve sparing and it is unclear to what
extent this atrophy would occur with nerve sparing prostatectomy.Bannowski et al. conducted a randomized trial following 43
men who underwent nerve-sparing radical prostatectomy [10]. All men provided baseline International Index of Erectile Function (IIEF) scores prior
to surgery. After catheter removal following
surgery, the men underwent testing for nocturnal tumescence the following
evening measured by the rigiscan. 41 of
43 were found to have spontaneous erections on rigiscan, and these men were
then randomized to receive sildenafil daily or no treatment. They were then followed and evaluated with
IIEF  at 6, 12, 24, 36, and 52 weeks. The
results show that the daily treatment group had significantly higher  IIEF  score
by 36 and 52 weeks. Additionally, 47% of
the daily treatment groups were able to achieve spontaneous, unassisted
erection sufficient for penetration.
This compares to 28% of the control group who were able to have such
erections. Both groups were also allowed
Sildenafil on demand, and accounting assisted erections, 86% of the daily group
had erections sufficient for penetration, compared to 66% of the control
group. The study made no mention of any
participant drop out, and there was no placebo control. However, it does appear that daily Sildenafil
does improve return of spontaneous erections and can augment response to on-demand use of Sildenafil.A stringent, randomized,
double-blinded, placebo controlled study was performed by McCullough et al.
evaluating the efficacy of daily Sildenafil in men after bilateral nerve-sparing
radical prostatectomy [11].  This study
included 54 men with baseline normal EF and NPTR (nocturnal penile tumescence
and rigidity with duration of rigidity >55% of maximal rigidity using
penile plethysmography). After a
pretreatment period of 4 weeks, they were then randomized to either receive
nightly 100 mg Sildenafil (N=18), 50 mg Sildenafil (N=17), or placebo (N=19). The groups were then analyzed at
16, 28, and 40 weeks. Then after 40
weeks, all medications were discontinued and the groups were again analyzed at
48 weeks. At each point, the
participants were evaluated by NPTR and  IIEF .
The study found that the groups receiving daily Sildenafil were able to
have return of rigidity (R>55%) at seven times the nadir value compared to minimal
improvement in the control group. This
improvement of erection was also seen by the investigators for RAU (rigidity-activated unit—a time-intensity measurement that
represents the area under the rigidity curve during a qualified
event), with the additional finding that the 100 mg group experienced continued
improvement after the discontinuation phase, while the 50 mg group began to
experience decline in RAU. Importantly,
the men on daily Sildenafil were five times more likely to have return of spontaneous,
unassisted erection sufficient for intercourse compared to placebo. The authors were able to link objective
measurements of erections with subjective, clinical response. They noted that tip rigidity >55% clearly
separated responders versus nonresponders (responders defined as recovery of
spontaneous, unassisted sufficient erections).
This study may mark objective validation as an important component of
future clinical trials. These initial
results are from a subset analysis performed on men who showed normal EF and
NPTR on baseline, and we await further data and analysis on the entire study
patients.Taken together,
these studies seem to indicate that phosphodiesterase inhibitors have a role in
penile rehabilitation for men after prostatectomy. There may also be a dose-dependent relationship between the medication and outcomes. The studies also confirm the tolerability and
safety of such a regiment, as discontinuation rates were very minimal and no
adverse events were reported.


## 3. Vacuum Erectile Device

The Vacuum erectile device assists erections by drawing blood flow into the
cavernous sinuses through negative pressure, physically causing an
erection. A constrictive band can also be placed at the base of the
penis, preventing backflow and maintaining corporal pressures. This
direct mechanism of action can circumvent the limitation of oral agents, which
requires an intact and functioning neuronal connection to produce
erections. This can be a significant factor even in men undergoing nerve
sparing prostatatectomy, as neuropraxia still occurs and can diminish the
effectiveness of PDEi.This
treatment modality can also be extended to men who have undergone nonnerve
sparing prostatectomy, though not in the context, in penile rehabilitation with
the expectation of return of potency.If not for potency itself, VED usage has also been advocated due to its
possible efficacy in preventing penile shrinkage and maintaining length.
Studies have shown significant shrinkage of penile length, with one
study finding that nearly 20% of men experience a loss of length greater than
15% [12]. In another study examining penile shortening after
prostatectomy, Gontero et al. followed 126 men who had undergone prostatectomies
and measured penile length prior to surgery, at the time of catheter removal,
and then at 3, 6, and 12 months [13]. They found that the greatest amount of
shrinkage occurs in the immediate postoperative period, though shortening
continues at a lesser rate throughout the entire study period. These
authors hypothesize that early hypoxia leads to increased expression of TGF-B
and Collagen I and III fibers. This study also finds that the return of erectile
function, defined as an  IIEF  of 15, was associated with mitigation of the
shrinkage, as well as having a nerve sparing surgery. Several studies looking at the efficacy of
vacuum erectile device in preserving erectile function have also examined
preserved penile length as a secondary endpoint.Raina et al. randomized 109 post-prostatectomy men to
either early VED use daily (N=74) versus no erectogenic aid (N=35) [14].  The men were to use the constriction band
only during intercourse to maintain rigidity. Participants were followed
with SHIM and  IIEF  scores for comparison. For the group using VED, 80%
were able to achieve penetration with use of VED, and this group, not
surprisingly, had a significantly higher SHIM and  IIEF  group compared to no
treatment. The discontinuation rate was 18%, and the majority of the drop
out was for discomfort. In the context
of penile rehabilitation, at 9 months this study found that 17% of those
adhering to daily VED were able to have spontaneous erections sufficient for
erections at 9 months, compared to 11% (n=4) of the control group that had such
erections. In regard of the effect of
VED on penile length, the men who adhered to VED regiment experienced less
subjective penile shrinkage, with 23% reporting less length compared to 85% of
the men who quit treatment and 65% of the control. No objective data was collected concerning
length. The authors conclude that early
use of VED with the purpose of penile rehabilitation improves sexual and
partner satisfaction and allow for earlier return of spontaneous erections. Although,
the rate of return of spontaneous erection is low for both groups, those
numbers include men who had undergone nonnerve sparing prostatectomies. This distinction is necessary, as penile
rehabilitation is more directed for NS men and the inclusion of nonnerve sparing
prostatectomy patients diluted the response to rehabilitation.The timing of when to initiate VED has been questioned,
with some advocating an earlier intervention. Köhler et al. randomized 28
men to either receive early VED regiment (1 month after RP) or delayed VED
regiment (6 months) [15]. The regiment consisted of 10 minutes of VED
usage without the constriction band.  IIEF  was measured at baseline, 1, 3,
6, 9, and 12 months. The mean followup was 9.5 months and the results
analyzed at 3 and 6 months showed that the early intervention group had a statistically higher
IIEF  score. At this point, the comparison shows that VED does improve
IIEF  scores among those who use VED versus those controls that do not. At beyond 6 months, the delayed group began using of VED, and at
short followed up the
two groups converged with no statistical difference in  IIEF
categorization. No patients in this
study had return of spontaneous erections sufficient for penetration at that
followup. This paper was presented as a
pilot study, and more outcomes are expected to follow, especially data
concerning return of spontaneous erections. There are still some important
points that can be gleamed from this study. For one, the authors reported
complete compliance with this regiment, suggesting this short regiment (two five-minute cycles) could
be feasibly implemented. Importantly,
these researchers also looked at penile length and found that the group
performing VED regiment did not experience penile shrinkage, while the group on
delayed VED showed significant penile shrinkage at 3 (mean loss 1.87 cm) and 6
months (mean 1.82 cm). However, after
beginning VED in the delayed group, the loss decreased to a mean of 1 cm and no longer remained
statistically significant. Again, this is short-term followup data in the delayed group, and
further improvement in shrinkage may still yet be seen. We still await data concerning return of
spontaneous erection from this study.The value of VED in penile
rehabilitation remains uncertain. Daily
regimented use of VED requires a motivated patient and does improve sexual
satisfaction in those who responds. If
the stated goal of penile rehabilitation is the return of preexisting potency,
then further studies are needed to show that VED improves the rate of return of
erection. However, VED use may also be advocated for its effects on preventing
penile shrinkage after prostatectomy.


## 4. Intracorporeal Injection

Intracorporeal injection of vasoactive agents increase blood flow into the
cavernous sinuses locally, either through increasing cAMP, by antagonizing alpha-adrenergic
receptors, or by direct smooth muscle relaxation. Like VED, they also do
not require an intact, functional nervous system to produce erections.
Thus, they can also be offered in men who have undergone nonnerve sparing surgery
and men who do not respond to oral agents.Montorsi et al. conducted a randomized trial
investigating whether a regiment of intracavernosal injections improves
erectile function in post-prostatectomy men [16]. 30 men with established
preoperative potency were randomized to either receive a regiment of 3 times
per week injections of alprostadil for 12 weeks versus a control group that did
not receive erectogenic treatment. The groups were then assessed after 3 months
for sexual history, for Doppler response after alprostadil administration, and
for nocturnal tumescence. Of the ICI
regiment group, 80% completed the 12 weeks of treatment with a 20% drop-out
rate and a 17% complication rate. Of
these men, 67% at 3 months were able to have spontaneous erections sufficient
for penetration. This favorably compares to 20% of the control group men that
were able to have such erections. The authors do note that in this group some
still continued to use ICI to achieve erections. However, the authors
considered it a complete response since the majority of sexual encounters
occurred without ICI use (average of one in 4.2 attempts). The study also found
that having normal penile hemodynamics was strongly associated with ICI
complete response. The study suffers from small size and short followup.
However, it was still able to show an improvement in spontaneous erections for
regimented ICI and that regimented ICI is generally well tolerated.Mulhall et al. conducted a trial
that may be more clinically applicable, even though it was not randomized [17]. In
this trial, post-prostatectomy men were committed to penile rehabilitation with
Sildenafil or ICI if there was no response to Sildenafil, versus no penile rehabilitation
program, but they were
not restricted from using erectile aids.
The rehabilitation group used either Sildenafil or ICI three times  per week. Analysis at 18
months revealed that 52% of rehabilitation men were able to have functional
erections, compared to 19% of control group men. Additionally, the rehabilitation group had
significantly higher  IIEF  scores. These
results are impressive, especially considering that the control group was also
able to use erectile aids, including both Sildenafil and ICI, though not in a
regimented manner. The study included men with nonnerve sparing
prostatectomies, which generally are not considered candidates for erectile rehabilitation,
though the authors do note that there was not a differential distribution
between the groups. Additionally, the
average length of time before sexual consultation and therefore the start of
rehabilitation were 4.2 months. Some would suggest that this
length of time is too long removed from the surgery, and the insults of
hypoxia, fibrosis, and apoptosis may have already occurred and be irreversible
at this point. It is also important to note that selection bias may be very
considerable in this study, in that only men who prospectively committed
themselves were included in the rehabilitation group and the study relied on
mainly self-reported, subjective data.


## 5. Combination Therapies

Studies have examined the feasibility and efficacy of
employing two treatment modalities during penile
rehabilitation. Nandipati et al. incorporated both intracavernosal
therapy and PDEi in a group of 22 men who underwent nerve sparing prostatectomy
[18]. All participants received Sildenafil 50 mg daily (25 mg if subjects
complained of headaches). For ICI, 18
patients received PGE 1–4 micrograms and
4 received trimix injection, with ICI being done two to three times per
week. These patients were then analyzed at 3, 6, 9, and 12 months with  IIEF . Doppler studies were performed for dose
optimizations of ICI and at intervals to increase dosage for response. The study reported a mean followup of six
months. At this point, investigators found that 21 of 22 patients were sexually
active, while 12 of the 21 were using ICI alone and 9 of 21 were using combination
therapy. Of the 18 patients using PGE, 12 were able to lower their dosage;
while 1 of the 4 patients on trimix was able to do so. 11 of the 22 men
had return of spontaneous erection, though none graded the erections sufficient
for penetration. The authors concluded
that the addition of Sildenafil could reduce the amount of ICI necessary to
achieve erections. This study had a lower rate of return of functional
erections compared to other studies looking at nightly PDEi 1 [11] or regimented
ICI alone [16], and this difference may be explained by the
shorter followup and the small number of participants. Without proper study design, in such
combination therapy studies, it is difficult to assign particular findings to
specific intervention.


## 6. Novel Therapies

Other therapies outside of these three mainstream
modalities have been investigated for penile rehabilitation after
prostatectomy. Recently, investigators in Korea looked at statins for treating
erectile dysfunction after prostatectomy [19]. The basis for this
hypothesis stems from the known protective effect on vascular endothelium and
increased NO activity. The researchers randomized 50 men post-prostatectomy
to receive 10 mg of atorvastatin for 90 days. All men were then to use
Sildenafil 50 mg per day on demand. The men all had superior function prior to
the surgery with  IIEF  25. At 6 months of followup, the study found that
the statin group had more patients categorized at potent ( IIEF  greater than 16)
with 11 in the statin group and 6 in the control group. Additionally, more men in the statin group were able
to achieve vaginal penetration without PDEi than in the control group (8 versus
4), though this significance did not reach statistical significance. The
study was neither blinded nor placebo-controlled. It is important to note that the
inclusion criteria were extremely stringent, and patients with significant cormidities were excluded. This may affect the
applicability or generalizability of the results.


## 7. Conclusion

Sexual potency after prostatectomy remains a significant quality of life issue
after prostatectomy. There exist many studies on the efficacy of the
various treatment options on this patient population. There are much less data looking on the
effects of regimented usage of PDEi, VED, and/or ICI in improving erectile
function in this group, and no guidelines exist to help steer the
clinician. We are still in need of large, randomized, controlled, clinical
trial with adequate, long-term followup to evaluate this question. Moreover, even after each treatment can be
established to be efficacious in penile rehabilitation, the exact regiment amount and
duration will still be open to further investigations for optimization. This is
a especially important question in dealing with phosphodiesterase inhibitors,
where the cost of treatment is substantial.
However, even though currently sparse, the consistent, growing body of
evidence does support penile rehabilitation in improving return of sexual
functioning. As awareness of penile
rehabilitation increases and becomes more accepted, it is becoming more
difficult to conduct placebo or nonintervention controlled trial. There are
still several ongoing trials evaluating penile rehabilitation, including a
large multicenter study examining penile rehabilitation with medicated urethral system for erection (MUSE), and several of the studies presented here will further analyze with additional data from which the urology community may further define when and how to
implement penile rehabilitation in post-prostatectomy men.Currently, the body of evidence does
seem to suggest a beneficial role for penile rehabilitation after prostatectomy
in improving return of potency. Such a program should begin with a detailed
evaluation on the preoperative sexual performance characteristic of the patient
and then a thorough
discussion of the available rehabilitation regiments. The practitioner should consider factors that
are important to the patient including ease of use and compliance, patient
motivation, conditioning, cost and patient expectations about sexual function,
and penile length. Penile rehabilitation
may continue to remain investigative until more standardized clinical data
becomes available.Table 1
Summary table of penile rehabilitation trials.
AuthorsYear publishedTreatment regimentStudy designNSignificant findingsSchwartz
et al.2004QOD
PDEiProspective21No
loss of smooth muscle in 50 mg group, gain of smooth muscle in 100 mg groupBannowski
et al.2008Daily
PDEiProspective, randomized
control41Treatment
group had significantly higher  IIEF  and higher spontaneous erection ratesMcCullough et al.2008Daily
PDEiProspective,
randomized, placebo control54Treatment
groups had higher return of rigidity, higher rate of spontaneous erectionsRaina
et al.2006Daily
VEDProspective,
randomized control109Improved
sexual satisfaction, higher rate of spontaneous erectionsKöhler
et al.2007Daily
VED (10 mins), immediate versus delayedProspective,
randomized28Delayed
use of VED did not affect sexual satisfaction once use began. There is no
statistical significance in penile shrinkage once VED startedMontorsi et al.1999ICI 3
times weeklyProspective,
randomized control30Higher
percentage of treatment group having spontaneous erectionsMulhall et al.2005ICI
or PDEi to achieve erections 3 times weeklyProspective, control132Treatment
groups had 2.7 times the rate of spontaneous erections, statistically higher
IIEF  scoresNandipati et al.2006Daily
PDEi and ICI 2-3 times weekProspective22Assisted
early sexual activity and satisfaction.
Addition of PDEi allows lower dose of ICI.



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