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Safety and efficacy of low intensity shockwave (LISW) treatment in patients with erectile dysfunction

A. Ruffo 1, M. Capece 1, D. Prezioso 1, G. Romeo 1, E. Illiano 1, L. Romis 2, G. Di Lauro 2, F. Iacono 1

Abstract
The primary goal in the management strategy of a patient with ED would be to deter- mine its etiology and cure it when possible, and not just to treat the symptoms alone. One of the new therapeutic strategies is the use of low intensity extracorporeal sho- ckwave (LISW) therapy. The mechanism of shockwave therapy is not completely clear. It is suggested that LISW induces neovascularization and improvement of cavernosal arterial flow which can lead to an improvement of erectile function by releasing NO, VEGF and PCNA.
Materials and Methods: 31 patients between February and June 2013 with mild to se- vere ED and non-Phosphodiesterase 5 inhibitors responders were enrolled. Patients un- derwent four weekly treatment sessions. During each session 3600 shocks at 0.09mJ/ mm2 were given, 900 shocks at each anatomical area (right and left corpus caverno- sum, right and left crus). Improvement of the erectile function was evaluated using the International Index of Erectile Function (IIEF-EF), the Sexual Encounter Profile (SEP) diaries (SEP-Questions 2 and 3) and Global Assessment Questions (GAQ-Q1 and GAQ-
-Q2).
Results: At 3-month follow-up IIEF-EF scores improved from 16.54±6.35 at baseline to 21.03±6.38. Patients answering ‘yes’ to the SEP-Q2 elevated from 61 to 89 and from 32 to 62 in the SEP-Q3. A statistically significant improvement was reported to the Global Assessment Questions (GAQ-Q1 and GAQ-Q2).
Conclusion: In conclusion, we can affirm that LISW is a confirmed therapeutic appro- ach to erectile dysfunction that definitely needs more long-term trials to be clarified and further verified.

Introduction
Erectile dysfunction (ED) is the main com- plaint in male sexual medicine and is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Although ED is a benign disorder, it may affect phy- sical and psychosocial health and may have a signi- ficant impact on the quality of life (QoL) of patients and their partners (1).

ED seems to affect 52 of 40-70-year-old men (2). Advances in basic and clinical research on ED during the past 15 years have led to the de- velopment of a variety of new treatment options, including pharmacological agents for intracaver- nous, intraurethral, and oral use and the use of vacuum erection devices (1).
Oral therapies have changed the diagnostic and therapeutic approach to ED becoming a ma- jor tool in treating ED. In fact, phosphodiesterase-5 inhibitors (PDE5-i) in the late 1990s and early 2000s completely revolutionized the field of sexual medi- cine becoming the most popular treatment and the first-line monotherapy for ED (3).
Unfortunately, they are limited for being used before the sexual act and do not modify the physiologic mechanism of penile erection (4).
After the initial enthusiasm of the use of the PDEi, the psychological impact–artificiality of erec- tions and planning for sexual intercourse as well as a not proven curative effect (5) have slightly limited the use of these drugs, leaving the field open to the development of new therapies to treat or maybe cure patients with ED. Furthermore, the frequently repor- ted side-effects of PDE5i, such as headache, dyspep- sia, muscular pains, and hot flushes can affect a nor- mal sexual intercourse (6).
The primary goal in the management stra- tegy of a patient with ED would be to determine its etiology and cure when possible, and not just the treatment of symptoms. One of the new therapeutic strategies is the use of low intensity extracorporeal shockwave (LISW) therapy.
Shockwaves (SWs) are longitudinal acoustic waves that travel in the speed of water in ultrasound through body tissue and that carry energy (7). SWs have been widely used in urology to treat urinary stone disease (8), and less often in Peyronie’s disease
(9) or chronic pelvic pain syndrome (CPPS) in males (10).
The mechanism of action of low-intensity shock waves (LISW) is still not very clear. Many au- thors suggested that LISW improves erectile function increasing cavernous blood flow and inducing a neo- vascularization (11). Neovascularization is promoted by the expression of angiogenesis-related growth factors, such as endothelial nitric oxide synthase (NOS), vascular endothelial growth factor (VEGF), and endothelial cell proliferation factors, e.g., prolife- rating cell nuclear antigen (PCNA) (12).
The aim of our study is to evaluate the im- provement of erectile function after therapy with LISW in men affected by mild to moderate ED.


Materials and Methods

Study population
31 patients between February and June 2013 with mild to severe ED, and non-Phosphodiesterase 5 inhibitors responders were assessed for this study. Only 2 (6.4 ) underwent treatment with PDE5-i in the last four weeks before starting the treatment (Ta- ble-1). They all signed an informed consent.
Inclusion criteria were: good general health, ED for at least six months, IIEF-EF between 7 to 24 (=mild to moderate).
Exclusion criteria included: neurological pathology, past radical prostatectomy or extensive pelvic surgery, recovering from cancer during the last year, any unstable medical, psychiatric disorder, spinal cord injury, penile anatomical abnormalities, clinically significant chronic hematological disease, anti-androgens or radiotherapy treatment of the pel- vic region.
The medical and psychosexual history of all patients were evaluated at baseline to detect comor- bidities. Table-2 summarizes the patients’ organic co-
-morbidities: cardiovascular diseases in 7 pts (22 ), hypertension in 18 pts (58 ), diabetes in 12 pts (38 ) and abnormal total serum cholesterol in 13 pts (41 ).


Table 1 - The pretreatment characteristics of population.

Variable

Patients

P value

Age (years)

  0.39

Mean±SD

59.93±12.16  

N.of subjects analysed

31  

Time suffering from ED (yrs)

  0.50

Mean±SD

3.66±4.57  

N. of subjects analysed

31  
Treatment with pDE5-I in the last 4 weeks (%)
 6.45  0.12
 Proportion  2/31  



Table 2 - Analysis of self-reported measures at baseline , 1-month and 3-month follow up by treatment cohort.

Variable

Baseline

Follow-up 1 month

p value

Follow-up 3 months

P value

IIEf Ef

16.54±6.35

21.13±6.31

P=0.0075

21.03±6.38

p=0.0096

sEp-q2 (%)

61 (yes)

38 (no)

86 (yes)

13 (no)

P=0.0292

89 (yes)

10 (no)

P=0.0112

 

 

2 drop-out

 

 

 

sEp-q3 (%)

32 (yes)

58 (yes)

P=0.0402

62 (yes)

P=0.0207

 

67 (no)

41 (no)

 

37 (no)

 

 

 

2 drop-out

 

 

 


(IIEf-Ef): International Index of Erectile Function; (sEp-q2): Sexual Encounter Profile-Q2; (sEp-q3): Sexual Encounter Profile-Q3


Study design
This is a pilot clinical study evaluating sa- fety and efficacy of LISW treatment (performed with Renova ®) on symptomatic ED patients ver- sus baseline.

Study schedule
a) screening
Patients were visited (visit 1) and those who were using PDE5-i had to go to a flush-out period of three weeks before starting the treat- ment. Furthermore, they committed to refrain from usage of PDE5-i during the duration of the treatment session.

b) Treatment
Patients underwent four weekly treatment sessions. During each session 3600 shocks at 0.09 mJ/mm2 were given. Shocks were applied at the penis shaft at right corpus cavernosum and left corpus cavernosum, right crus and left crus, 900 shocks at each area.
The treatment areas were the same for every session, so that at the end of the full treat- ment (four sessions) each area received 3600 sho- cks at an average 0.09mj/mm. We used this proto- col under the guidance of Direx Group LTD.
LISW utilize low energy-0.09mJ/mm2-
-equivalent to 10 of the energy used by conven- tional kidney stone lithotripters in the treatment of urinary tract stones. This device generates a low intensity shockwave focused along a line of 70mm and hence is able to apply shockwaves to the cor- pora cavernosa and crura effectively.

For the past 3 years, a similar LISW tech- nique has been used in different sites using the same level of energy density to treat ED (13). Sho- ckwaves are created by a special generator and are focused using a specially designed shockwave ap- plicator apparatus. The shockwaves are delivered through the applicator covering the entire corpora cavernosa of the penis.
The treatment does not inflict pain and does not require any anesthesia or sedation.
Each session lasts approximately 30 minutes.

c) Primary efficacy objective
To evaluate the increase of number of points in the International Index of Erectile Func- tion (IIEF-EF) questionnaire from baseline (visit
1) to 1 and 3 months after treatment regarding the severity of the symptoms according to mini- mal clinically important differences in the erectile function domain of the IIEF scale (14). The IIEF-EF was chosen as primary clinical efficacy assessment tool in this study. It has been reported to be brief and reliable, psychometrically sound, and easy to administer in both research and clinical settings. It is available (and cross-culturally validated) in 10 languages and demonstrates adequate sensiti- vity and specificity for detecting treatment-related changes in erectile function (15).

d) Secondary efficacy objective
To study the clinical efficacy of LISW in terms of improvement in sexual activity leading to optimal penetration at 1 and 3 months post--treatment by using the Sexual Encounter Profile (SEP) diaries (SEP-Questions 2 and 3). Patients re- corded efficacy information after each sexual en- counter by answering the two yes/no questions of the test: SEP Question 2:‘‘Were you able to insert your penis into your partner’s vagina?’’ and SEP Question 3:‘‘Did your erection last long enough for you to have successful intercourse?’’.
In addition, patients underwent further evaluation with the Global Assessment Question (GAQ) by answering the two yes/no questions of the test: (GAQ-Q1) ‘‘Over the past four weeks has the treatment you have been taking improved your erectile function?’’ and (GAQ-Q2) ‘‘If yes, has the treatment improved your ability to engage in sexual activity over the past four weeks’’.

statistical analysis
Statistical analysis was performed by the program Statistical Package for Social Sciences for Windows, version 11.5.1 (SPSS Inc., Chicago, IL, USA), using X2 test and T-student for categori- cal data comparisons.

Results
All patients had mild to severe ED at le- ast six months, were non PDE-5i responders, with a mean age of 59.93±12.16 years. Median

follow-up was of 3 months (range 2-5 mon- ths). Global patient perceptions after treatment with LISW significantly improved. Indeed IIEF-
-EF score showed significant improvement (ba- seline 16.54±6.35 vs 21.13±6.31 after 1 month
P=0.0075; baseline 16.54±6.35 vs 21.03±6.38
after 3 months p=0.0096) (Table-2; Figure 1-3). About 86 (P=0.0292) and 89 (P=0.0112) of pa- tients answered with a positive answer to SEP Q2 question (‘‘Were you able to insert your penis into your partner’s vagina?’’ ) 1 month and 3 months after treatment, respectively, versus 61 positive answers pre-treatment (Table-2). SEP Q3 question (‘‘Did your erection last long enough for you to have successful intercourse?’’) was answered posi- tively by 58 (P=0.0402) 1 month after LISW tre- atment and 62 (P=0.0207) after 3 months. After 1 month of treatment there were two drop-outs (Table-2). Table-3 shows patients’ satisfactions of treatment with GAQ-Q1 (“Over the past four weeks has the treatment you have been taking improved your erectile function?’’) and GAQ-Q2 questions (“If yes, has the treatment improved your abili- ty to engage in sexual activity over the past four weeks’’). Regarding the individual answers for the GAQ questions, we noticed that 89 and 62 of patients at 1 and 3 months respectively answe- red “Yes” to the GAQ-Q1 while in the same period 79 and 76 of patients answered “Yes” to the


figure 1 - IIEf-Ef score at baseline and after 1 month follow-up
figure1_1213

figure 2 - IIEf-5 score at baseline and after 3 month follow-up
figure2_1256

figure 3 - Dispersion date IIEf score baseline and 3 month follow-up
figure3_1284



GAQ-Q2 demonstrating success with the treat- ment (Table-3).
No adverse events were reported during and following treatment.

Discussion
According to others author’s data LISW appears to be significantly effective for increasing erectile function thanks to the improvement in


penile hemodynamics (13, 11). By releasing neo-
-angiogenic factors and subsequent neovasculari- zation of the treated tissue, LISW therapy leads to tissue regeneration (16). In fact, it has been shown that this low intensity energy acts on vasculariza- tion inducing a non-enzymatic production of phy- siologic amounts of nitric oxide (17). Nitric oxide (NO), the smallest known signaling molecule, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). Neuronal NOS (nNOS, NOS I) is


Table 3 - Analysis of self-reported measures at 1-month and 3-month follow up by treatment cohort.

  • location: Department of Urology, Federico II University, Naples, Italy; 2 Department of Urology, Hospital Santa Maria delle Grazie, Naples, Italy

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