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Doi:10.1016/j.juro.2007.03.132
Effect of Statin Therapy on Early Return of Potency After Nerve Sparing Radical Retropubic Prostatectomy Sung Kyu Hong, Byung Kyu Han, Seong Jin Jeong, Seok-Soo Byun and Sang Eun Lee* From the Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea Purpose: We prospectively investigated whether postoperative statin use would contribute to earlier recovery of erectile function in men who underwent bilateral nerve sparing radical retropubic prostatectomy for clinically localized prostate cancer. Materials and Methods: A total of 50 potent men without hypercholesterolemia undergoing bilateral nerve sparing radical retropubic prostatectomy for clinically localized prostate cancer were prospectively randomized into 2 equal groups. Group 1 patients were instructed to ingest only 50 mg sildenafil per day if needed following hospital discharge after radical retropubic prostatectomy. Group 2 patients were prescribed atorvastatin at a dose of 10 mg daily from postoperative days 1 to 90 and they were also instructed to ingest sildenafil, as in group 1. Patient status regarding potency and adverse events were assessed 6 months after surgery. Results: The 2 groups demonstrated no significant differences regarding various baseline factors, including International Index of Erectile Function-5 scores. Group 2 had a significantly higher postoperative International Index of Erectile Function-5 score than group 1 at 6 months postoperatively (p ϭ 0.003). Meanwhile, as judged by a preset definition, the incidence of potent patients 6 months after prostatectomy was 26.1% in group 1 and 55% in group 2 (p ϭ 0.068). Also, 17.4% and 40% of the men reported achieving intercourse by vaginal penetration without a phosphodiesterase 5 inhibitor in groups 1 and 2, respectively (p ϭ 0.172). No serious adverse events associated with medication were reported. Conclusions: Postoperative treatment with atorvastatin in men who report normal erectile function preoperatively may contribute to earlier recovery of erectile function after nerve sparing radical retropubic prostatectomy. Key Words: prostate, prostatic neoplasms, prostatectomy, impotence, hydroxymethylglutaryl-CoA reductase inhibitors
With the adoption by many surgeons of anatomical costofthevariousPDE5inhibitorsavailable,nightlymed-
RRP using cavernous nerve preservation the rate of
ication with PDE5 inhibitor for penile rehabilitation follow-
postoperative recovery of erectile function suffi-
ing RRP may not be a realistic option for all patients.
cient for sexual intercourse has improved dramatically. At
Statins, which are known to have a protective effect on
major academic centers reported rates of erectile function
vascular endothelium, leading to increased nitric oxide ac-
recovery are between 60% and On the other hand, it
tivity, may also have protective effect on corporeal endothe-
can also be easily understood from looking at currently re-
Also, the statin class of drugs is generally much less
ported data in the literature that a nerve sparing procedure
costly than PDE5 inhibitors. In that sense daily medication
does not always guarantee the complete recovery of potency
using a statin combined with on-demand PDE5 inhibitor
regardless of how meticulously the procedure is performed.
may prove to be an effective and viable approach for post-
Today ED still lingers as a major postoperative problem.
prostatectomy restoration of erectile function. Thus, we pro-
Currently oral PDE5 inhibitors have been widely pre-
spectively investigated the effectiveness and safety of com-
scribed for the treatment and prevention of post-prostatec-
bined therapy with a daily statin plus on-demand PDE5
tomy ED, showing varying degrees of success. Some groups
inhibitor for the early return of erectile function in a select
reported that nightly medication with PDE5 inhibitor fol-
group of patients who underwent bilateral nerve sparing
lowing RRP would be a more effective approach for recover-
RRP for clinically localized prostate cancer at our institu-
ing potency following nerve sparing RRP compared with
on-demand A postulated mechanism for thepotential benefits of nightly PDE5 inhibitor medication iscorporeal endothelial protection. However, considering the
MATERIALS AND METHODS
A total of 50 potent men undergoing bilateral nerve sparingRRP for clinically localized prostate cancer were prospec-
Submitted for publication January 9, 2007.
tively enrolled after institutional review board approval. All
Study received institutional review board approval. Supported by a grant from the Seoul National University Bundang
patients provided written informed consent. All men were 65
years or younger, sexually active and potent before RRP
* Corresponding author: Department of Urology, Seoul National
with a preoperative 5-item IIEF-5 score of greater than 21
University Bundang Hospital, 300, Gumi-dong, Bundang-gu, Seong-
without PDE5 inhibitors for achieving such erections. Also,
nam, Kyunggi-do, Korea 463-707 (telephone: 82-31-787-7341; FAX:82-31-787-4057; e-mail: selee@snubh.org).
patients with a history of unstable cardiovascular disease,
Copyright 2007 by AMERICAN UROLOGICAL ASSOCIATION
DOI:10.1016/j.juro.2007.03.132
ERECTILE FUNCTION AFTER PROSTATECTOMY AND STATIN
uncontrolled diabetes mellitus, thyroid disorders, clinically
TABLE 1. Characteristics of patients in 2 subject groups
significant renal or hepatic disease, prior pelvic surgery orradiation therapy, preoperative treatment for erectile dys-
function or penile deformity and a history or current use ofany cholesterol lowering agent were excluded at enrollment.
In all patients laboratory analysis, including a fasting lipid
profile to assess total and LDL cholesterol, was performed
before surgery to exclude those with hypercholesterolemia,
defined as LDL cholesterol greater than 120 mg/dl.
Enrolled patients were randomized into 2 equal groups.
Group 1 patients were instructed to ingest only 50 mg sil-
denafil per day if needed following hospital discharge afterRRP. Group 2 patients were prescribed atorvastatin at adose of 10 mg daily from postoperative days 1 to 90 and theywere also instructed to ingest 50 mg sildenafil per day if
1 and a 41% decrease in group 2 (p ϭ 0.001). Group 2 demon-
needed following hospital discharge after RRP. A single sur-
strated a significantly higher IIEF-5 score than group 1
geon performed all surgeries. When bilateral nerve sparing
6 months after RRP. As judged by a preset definition, the
was not possible during the surgery, the patient was ex-
incidence of potent patients 6 months after RRP was 26.1%
cluded and another was enrolled until each group had 25
(6 of 23) in group 1 and 55% (11 of 20) in group 2. Four
patients. All patients were discharged from the hospital
(17.4%) and 8 patients (40%) reported achieving intercourse
within 14 days after surgery without any serious complica-
by vaginal penetration without PDE5 inhibitor in groups 1
Postoperatively patient erectile function status with or
Group 2 showed significantly larger decreases in total
without PDE5 inhibitor was also assessed with the IIEF-5
and LDL cholesterol than group 1, as analyzed 6 months
questionnaire 6 months after surgery only in those who had
after RRP (p Ͻ0.0001). When analyzing only group 2, no
received at least 4 doses of 50 mg sildenafil. Patients were
significant associations were observed between postopera-
considered potent after surgery when with or without silden-
tive changes in total and LDL cholesterol and postoperative
afil they had a total IIEF-5 score of 16 or greater, or a score
changes in the IIEF-5 score or with postoperative recovery of
of 4 or greater was obtained for the question, “In the last 4
potency and erections sufficient for vaginal intercourse with-
weeks, when you attempted sexual intercourse, how often
out oral PDE5 inhibitor (data not shown).
was it satisfactory for Postoperative return of erec-
During our study no serious adverse events were re-
tions sufficient for vaginal intercourse without oral PDE5
ported. In general treatments with atorvastatin and/or sil-
inhibitor were also assessed. Total and LDL cholesterol were
denafil were well tolerated. The most frequent adverse
followed 6 months after surgery. Any adverse events related
events observed with atorvastatin medication were consti-
to medication were also assessed. Observed data were ana-
pation in 9.2% of patients and indigestion in 4.7%, which
lyzed using the chi-square, Fisher exact and paired t tests,
were mild. With sildenafil headache in 3% of patients, flush-
assuming equal variance. Correlations of continuous vari-
ing in 3% and rhinitis in 3% were the most commonly re-
ables were analyzed via the Spearman rank procedure with
DISCUSSION
Currently statins have an important part in the secondary
Two patients in each of the 2 groups could not be contacted
prevention of cardiovascular diseases, of which the incidence
6 months after operation. One patient in group 2 indicated
continues to increase around the world. Even in those with
that he achieved adequate erections for intercourse but was
normal cholesterol statin therapy is considered beneficial for
not sexually active because of the lack of interest of himself
decreasing the risk of atherosclerotic vascular
and his partner. Also, another 2 patients in group 2 stated
Moreover, it is known to improve endothelial function by
that they did not receive atorvastatin as recommended.
decreasing the action of LDL cholesterol on endothelial cells
Thus, 23 patients in group 1 and 20 in group 2 were included
and up-regulating endothelial nitric oxide synthase expres-
sion, leading to improved nitric oxide bioavailability.
For all analyzed patients mean age was 60.8 years (range
Previously hypercholesterolemia treatment with atorva-
48 to 64). Mean preoperative serum PSA was 7.7 ng/ml
statin was reported to improve Still, the question
(range 0.8 to 12). The 2 groups demonstrated no significant
remains as to whether the improvement in erectile function
differences regarding various factors, such as preoperative
was directly related to a decrease in cholesterol and/or the
PSA, body mass index, cholesterol and operative time
nonlipid related effects of atorvastatin. Statins are known to
The mean preoperative IIEF-5 score for all patients was
preferentially lower total and LDL cholesterol as well as
23.1. Patients in the 2 groups showed no significant differ-
increase HDL cholesterol. On the other hand, other studies
ence in the total dose of sildenafil ingested as needed during
showed that statins, especially atorvastatin, exert beneficial
the 6 months following RRP (p Ͼ0.05). All analyzed patients
effects on vascular endothelial cells independent of lowering
received at least 5 doses of 50 mg sildenafil during the
period. The mean postoperative IIEF-5 score in groups 1 and
Drugs of the statin class have favorable properties re-
2 was 10.6 and 13.5, respectively (p ϭ 0.003, This
lated to endothelium mediated vasoactive, antithrombotic,
represented a 54% decrease from preoperative levels in group
antiproliferative and anti-inflammatory Statins
ERECTILE FUNCTION AFTER PROSTATECTOMY AND STATIN
cavernous structures in animal models but only in large
TABLE 2. Descriptive statistics in 2 subject groups
vessels in Therefore, the effects of statins on
human cavernous vessels can only be inferred from animal
studies at this time. Moreover, to our knowledge the effects
of statin treatment on cavernous nerve injury has not been
published. Further studies must be done to confirm the
mechanism of the statin action in human cavernous tissues,
including nerves, endothelium and smooth muscle.
In regard to safety, no patients reported side effects se-
vaginal intercourse withoutoral PDE5 inhibitor (%)
rious enough to discontinue atorvastatin or sildenafil. The
incidence of adverse events observed in our study was com-
parable to previously published data on sildenafil and ator-These adverse events were generally mild. Inaccordance with other published data on regular
up-regulate endothelial cell nitric oxide synthase activity,
atorvastatin in men with normal cholesterol did not result in
improving nitric oxide dependent vasorelaxation in various
vascular Statins may also exert an antioxidant effect,
Our study may be limited by the relatively small number
enhancing nitric oxide bioavailability by preventing nitric
of patients. Also, to minimize the confounding effect of sur-
gical skill and technique we confined our study to a single
In our study immediate statin treatment following nerve
surgeon. Accordingly our results may not be directly appli-
sparing RRP was observed to enhance the postoperative
cable to others who may use a different surgical technique or
recovery of erectile function. On the other hand, the degree
approach. Also, the doses of sildenafil and atorvastatin were
of postoperative changes in erectile function in patients who
fixed, leaving the possibility that changes in the doses given
received statin therapy were not significantly associated
may have resulted in a different outcome. In addition, our
with the cholesterol lowering effects of statin therapy. Thus,
investigation was not placebo controlled. Considering recent
it can be speculated that statins may enhance erectile func-
reports, statin alone may not account for all of the beneficial
tion in men without hypercholesterolemia and clinically ev-
effects observed in our study, and statin and sildenafil may
ident cardiovascular disease. However, further investigation
have acted in Still, we believe that our study
would be needed on the actual mechanism of the statin effect
design, in which patients were instructed to ingest PDE5
in men with post-prostatectomy ED but without clinically
inhibitor if needed, reflects actual clinical setting well. Al-
though data on the incidence of potent patients and those
For patients who underwent nerve sparing RRP the pri-
with erections sufficient for vaginal intercourse without
mary underlying mechanism of postoperative ED is known
PDE5 inhibitor only demonstrated a trend toward the effi-
to be nerve injury and hypoxia. Even with the nerve sparing
cacy of statin treatment, our results may well show the
technique the nerves may be injured inadvertently. How-
potential efficacy of daily statin medication for earlier recov-
ever, as shown with early postoperative sildenafil nightly
ery of erectile function after nerve sparing RRP.
and intracavernous alprostadil injection, early erectogenictreatment following nerve sparing RRP may facilitate the
CONCLUSIONS
recovery of spontaneous The recovery of spon-taneous erections may be due to improved oxygenation of the
According to our results treatment with atorvastatin in men
corpora cavernosa, endothelial protection and/or improved
who report normal erectile function preoperatively may en-
hance erectile function recovery after nerve sparing RRP.
Since corporeal endothelium function would be prone to
Further investigations in a larger cohort of patients and
be altered after RRP, regular postoperative medication with
with a different dose or duration of medication would be
statins may well be beneficial for rehabilitating erectile
function, as in our study. A recent report indicated thatatorvastatin treatment attenuated nerve injury induced tis-sue damage, neuronal apoptosis and demyelination, result-
Abbreviations and Acronyms
ing in improved functional outcome in an animal model of
spinal cord This study showed that statins may
ϭ International Index of Erectile Function
Because statins have been linked to down-regulation of
RhoA activation, the improved functional outcome after
nerve injury could be attributable to statin mediated RhoA
inactivation, resulting in attenuated neuronal As is widely known, the RhoA/Rho-kinase pathway is in-volved in the smooth muscle contraction/relaxation process
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Publikationsverzeichnis Prof. Dr. med. Michael J. Reinhardt Inhalt: (379 Veröffentlichungen, davon 284 Schriften, 185 nach der Habilitation) Abschnitt A: Originalarbeiten (21x Erst-, 11x Letztautor) Seite 01 Abschnitt B: Wissenschaftliche Übersichtsartikel Abschnitt C: Vortragskurzfassungen Abschnitt D: Buchbeiträge Abschnitt E: Sonstige Veröffentlichungen
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