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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 REFERENCES
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