Stesura Seveso INTRODUCTION The aim of this study is to evaluate the effectiveness of tamsulosin in patients affected by Low Urinary Tract Symptoms (LUTS) and erectile dysfunction (ED), and also to compare this monotherapy with one combined with sildenafil, belonging to phosphodiesterase type 5 (PDE-5) inhibitors drug class, which are the recom- mended first-line treatment for ED. Type III chronic prostatitis or Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is characterized by 109Archivio Italiano di Urologia e Andrologia 2013; 85, 3 ORIGINAL PAPER Comparison of tamsulosin vs tamsulosin/sildenafil effectiveness in the treatment of erectile dysfunction in patients affected by type III chronic prostatitis Ubaldo Cantoro, Francesco Catanzariti, Vito Lacetera, Luigi Quaresima, Giovanni Muzzonigro, Massimo Polito Institute of Urology, Polytechnic University of Marche, Azienda O.U. Ospedali Riuniti, Ancona, Italy. Aim: We evaluated the effectiveness of tamsulosin monotherapy versus tamsulosin plus sildenafil combination therapy on erectile dysfunction (ED) in young patients with type III chronic prostatitis and ED by using symptom score scales. Materials and methods: 44 male patients were divided into 2 groups: the first group (20 patients) was treated with tamsulosin 0,4 mg monotherapy and the second one (24 patients) was treated with tamsulosin 0,4 mg plus sildenafil 50 mg combination therapy. “International Prostate Symptom Score” (IPSS), “National Institute of Health Chronic Prostatitis Symptom Index” (NIH-CPSI) and “International Index of Erectile Function” (IIEF-5) were inves- tigated in each group of patients, and scores calculated during the first medical examination. Both groups were treated with tamsulosin once daily for 60 days, while sildenafil 50 mg was given on demand (at least 2 times per week) for 60 days. During the second medical examination IPSS, NIH-CPSI and IIEF-5 scores were analyzed once more. Afterwards, the alterations of scores among medical examinations in each group and between both groups were statistically compared. Results: The age average of the 44 cases included was 32.04 ± 3.15 years. Both groups present a statistically significant decrease, between the first and the second medical examination, in IPSS, NIH-CPSI scores and statistically significant increase in IIEF-5 score. In addition, there is no sta- tistically significant difference, in all scores, between mono and combination therapy. Conclusions: tamsulosin monotherapy, as well as a combination therapy (tamsulosin plus silde- nafil) has an improving effect on symptoms and on ED in patients with type III prostatitis. In the near future alpha-blockers monotherapy could be used in the treatment of chronic prostatitis and ED cases instead of phosphodiesterase type 5 (PDE-5) inhibitors combination therapy. KEY WORDS: Chronic prostatitis; Erectile dysfunction; Tamsulosin; Sildenafil. Submitted 8 April 2013; Accepted 30 April 2013 No conflict of interest declared Summary abdominal, pelvic, genital pain, obstructive or irritative LUTS and by the absence of urinary tract infection (1). Many studies showed its association with painful prema- ture ejaculation and with erectile dysfunction. CP/CPPS occurs frequently in young patients and is one of the organ- ic causes of erectile dysfunction (ED) in this age range. Therefore, a common pathogenic mechanism for these two diseases is likely to exist (2). Adult-old patients LUTS affected have two times higher DOI: 10.4081/aiua.2013.3.109 Archivio Italiano di Urologia e Andrologia 2013; 85, 3 U. Cantoro, F. Catanzariti, V. Lacetera, L. Quaresima, M. Giovanni, M. Polito 110 risk to develop ED, since the prevalence of LUTS is of 72.2% in males affected also by ED and of 37.7% in males with no ED (3). Literature data show that ED associates with the severity of LUTS but, although studies pointed out a correlation between CP/CPPS and ED, they do not provide with any explication of pathogenic mechanisms (4). Many pathogenic mechanism were investigated to find an explanation to ED in young patients affected by CP/CPPS. Any connection with hypogonadism neither other endocrine disorders were found, except for a study which, unlike controls, found higher levels of testos- terone in patients with CP/CPPS (5). Another study found an association with hypogonadism, due to the fact that patients took opioids for long periods because of LUTS severity (6). Vascular diseases and arteri- al insufficiency are well known causes of ED, even though they are uncommon in young patients (7). Anyway, one study pointed out alterations in the peripheral arterial tone in patients with CP/CPPS (8), due to a endothelial vascu- lar dysfunction mediated by nitric oxide (9). Moreover, the arterial flow can be compromised from the outside by spastic contractions of pelvic floor (10). It is known muscle relaxant therapies can have positive effects on ED (11). Occlusive vessel disease is a condition which frequently occurs in old patients, also in presence of penile fibrosis. Therefore, also this pathogenic mechanism is uncommon in young patients. Although ED psychogenic cause was not adequately investigated in patients with CP/CPPS, a relation may exist since often patients affected by painful syndromes also suffer from stress, anxiety and maladaptive responses to stressful events (“catastrophizing”) (12). MATERIALS AND METHODS Our study analyzed a number of 44 patients who were examined at our Clinic because affected by type III chron- ic prostatitis associated with erectile dysfunction since at least 6 months. All patients were sexually active. We excluded from the study all patients affected by infections of the urinary system, neoplasia, congenital disorders, previous surgeries, urolithiasis and hyperactive bladder. None of the included patients used PDE-5 in the past. None of the examined patients presented side effects due to the use of alpha-blockers and PDE-5. Patients were examined through anamnesis, which is a clinical exam with neurological evaluation of the pelvic floor and rectal examination, uroflowmetry, suprapubic ultrasound evalu- ation of post-void residual, trans-rectal prostate ultra- sound, total PSA, microscopic and cultural exams of urine and semen and urethral secretion after prostate massage. The 44 patients were divided into 2 groups: the first group (20 patients) was treated with monotherapy, tam- sulosin 0.4 mg, the second one (24 patients) was treated with a combination therapy, tamsulosin 0.4 mg plus sildenafil 50 mg. Patients assignment to one group or the other was random. The average age of patients included in the study is 32.04 ± 3.15 years. None of patients was affected by BPH; prostate volume range was between 15 and 25 ml. Both uroflowmetry parameters and post-void residuals were not pathological. During the first medical examination, all patients were subjected to “International Prostate Symptom Score” (IPSS), “National Institute of Health Chronic Prostatitis Symptom Index” (NIH-CPSI) and “International Index of Erectile Function” (IIEF-5). Both groups were treated with tamsu- losin for 60 days; sildenafil 50 mg was taken when need- ed before a sexual intercourse (at least 2 times per week) and for 60 days by the second group. During the second medical examination, 60 days later, all patients were sub- jected again to IPSS, NIH-CPSI and IIEF-5. We considered mild patients’ symptoms with IPSS score between 0-7 and NIH-CPSI between 0-14; moderate respectively between 8-19 and 15-29 and severe between 20-35 and > 30. We considered mild patients’ erectile dysfunction with IIEF-5 score between 17-21, mild- moderate between 12-16, moderate between 8-11 and severe between 5-7. We statistically evaluated a potential difference in IIEF-5 scores according to the symptomatic severity of IPSS and NIH-CPSI and in the last two questionnaires scores according to IIEF-5 severity. Therefore, we statistically evaluated the differences of questionnaires scores means between the two medical examinations in each group and between the two groups. For the statistic analysis we used Graphpad Prism 5 pro- gram. In addition to the descriptive statistic modes (mean, standard deviation), oneway ANOVA, Kruskal- Wallis, Mann-Whitney and Student t test were used for a statistic evaluation. The results were analyzed with a sig- nificance level of P < 0.05. RESULTS Table 1 shows the mean of questionnaires analyzed and the mean of patients’ figures. According to IPSS questionnaire, 4 patients presented mild symptoms, 26 moderates and 14 severe; according to NIH-CPSI questionnaire 6 patients presented mild symptoms, 29 moderates, 9 severe; accord- ing to IIEF-5 questionnaire 8 patients suffered from mild erectile dysfunction, 17 mild-moderate, 13 moderate, 6 severe. We confronted IIEF-5 score means of patients with mild, moderate and severe symptoms according to IPSS and we did not notice any statistically difference: ANOVA (p = 0,87) and Kruskal-Wallis (p = 0.92) (Table 2). Moreover, there is no statistically difference between IPSS Mean SD Range Age (year) 32.04 3.15 23-35 PV (ml) 17.20 2.56 15-25 Qmax (ml/s) 21.24 3.45 17.8-28.3 PMR (ml) 27.18 8.78 0-42 IPSS 13.52 1.49 8-24 IPSS-QOL 3.87 0.27 0-5 IIEF-5 12.41 0.66 5.21 NIH-CPSI 17.51 1.92 5-28 Table 1. General characteristics and mean symptom scores of the cases. score means of patients with mild, mild-moderate, moder- ate, severe erectile dysfunction: ANOVA (p = 0,43) and Kruskal-Wallis (p = 0,61) (Table 3). We did not notice any statistically difference even through the comparison of IIEF-5 scores according to NIH-CPSI mild, moderate and severe symptoms: ANOVA (p = 0,12), Kruskal-Wallis (p=0,25) (Table 4); any difference also in NIH-CPSI scores according to IIEF-5: ANOVA (p = 0,18), Kruskal-Wllis (p = 0,26) (Table 5). We noticed, inside each therapy group, a statistically rel- evant decrease, between the first medical examination and 60 days later, in IPSS, IPSS-QOL and NIH-CPSI score. We also pointed out a statistically relevant increase in IIEF-5 score (Table 6 -7). We did not notice, in 60 days, a statistically relevant difference, between the two therapy groups, in all questionnaires score, IIEF-5 included (Table 8). DISCUSSION Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a syndrome characterized by pain (abdom- inal, pelvic, genital), obstructive and irritative LUTS in absence of infection (1), causing Quality Of life (QOL) decrease (13). Although it is known that type III chronic prostate asso- ciates with erectile dysfunction, it is still less clear the etiophatogenesis implied in these two nosological enti- ties. Great part of clinical studies examine old patients with LUTS and ED, but also with concomitant BPH and obstruction of urine flow. Still few are studies which investigate the presence of ED in younger patients affect- ed by type III chronic prostatitis in absence of BPH and obstruction. The most supported theory explaining the common pathogenic mechanism of LUTS and concomitant ED, independently from BPH, points out there is a hyperac- tivity of autonomic nervous system and endothelial alterations due to the effects on nitric oxide – cyclic 111Archivio Italiano di Urologia e Andrologia 2013; 85, 3 Comparison of tamsulosin vs tamsulosin/sildenafil effectiveness in the treatment of erectile dysfunction in patients affected by type III chronic prostatitis Visit 1 Visit 2 P IPSS 13.26 ± 0.92 8.23 ± 0.72 < 0.001 IIEF-5 12.54 ± 0.59 17.83 ± 1.46 < 0.001 NIH-CPSI 17.87 ± 1.14 10.54 ± 1.35 < 0.001 IPSS-QOL 3.95 ± 0.22 2.02 ± 0.56 < 0.001 Table 6. Alterations in IPSS, IIEF-5, NIH-CPSI, IPSS-QOL between visit 1 and visit 2 in Group 1 treated with tamsulosin 0,4 mg. Visit 1 Visit 2 P IPSS 13.75 ± 1.84 8.07 ± 0.91 < 0.001 IIEF-5 12.31 ± 0.78 18.75 ± 1.24 < 0.001 NIH-CPSI 17.47 ± 2.09 9.74 ± 1.98 < 0.001 IPSS-QOL 3.65 ± 0.41 1.82 ± 0.25 < 0.001 Table 7. Alterations in IPSS, IIEF-5, NIH-CPSI, IPSS-QOL between visit 1 and visit 2 in Group 2 treated with tamsulosin 0,4 mg plus sildenafil 50 mg. Group 1 Group 2 P IPSS 8.23 ± 0.72 8.07 ± 0.91 0.751 IIEF-5 17.83 ± 1.46 18.75 ± 1.24 0.835 NIH-CPSI 10.54 ± 1.35 9.74 ± 1.98 0.486 IPSS-QOL 2.02 ± 0.56 1.82 ± 0.25 0.574 Table 8. Alterations in IPSS, IIEF-5, NIH-CPSI, IPSS-QOL between Group 1 and Group 2 after 60 days. Mean IIEF-5 score All cases 12.41 ± 0.66 IPSS Mild 13.28 ± 0.89 ANOVA P = 0.87 Moderate 12.85 ± 0.39 Kruskal-Wallis P = 0.92 Severe 12.13 ± 1.98 Table 2. The effect of IPSS level on mean IIEF-5 score. Mean IIEF-5 score All cases 12.41 ± 0.66 NIH-CPSI Mild 14.28 ± 0.27 ANOVA P = 0.12 Moderate 12.05 ± 0.39 Kruskal-Wallis P = 0.25 Severe 15.13 ± 1.16 Table 4. The effect of NIH-CPSI level on mean IIEF-5 score. Mean IPSS score All cases 13.52 ± 1.49 IIEF-5 Mild 13.25 ± 1.17 ANOVA P = 0.43 Mild-moderate 14.48 ± 0.96 Kruskal-Wallis P = 0.61 Moderate 14.81 ± 0.91 Severe 12.84 ± 1.57 Table 3. The effect of IIEF-5 level on mean IPSS score. NIH-CPSI score All cases 17.51 ± 1.92 IIEF-5 Mild 22.92 ± 0.87 ANOVA P = 0.18 Mild-moderate 19.08 ± 0.56 Kruskal-Wallis P = 0.26 Moderate 17.83 ± 0.74 Severe 21.98 ± 1.19 Table 5. The effect of IIEF-5 level on mean NIH-CPSI score. Archivio Italiano di Urologia e Andrologia 2013; 85, 3 U. Cantoro, F. Catanzariti, V. Lacetera, L. Quaresima, M. Giovanni, M. Polito 112 monophosphate guanosine e alterations in Rho-kinase pathway (14). Some studies already evaluated the effectiveness of alpha-blockers in treating erectile dysfunction associated with LUTS (15-16), but it was not compared with PDE- 5 inhibitors and, as stated above, the patients examined were old people with concomitant BPH. In our study, after 60 days of therapy, each group showed statistically relevant improvements in questionnaires scores: IPSS, IPSS-QOL, IIEF-5, NIH-CPSI. In other words, tamsulosin, as well as the combination therapy of tamsulosin and sildenafil, improved both LUTS and ED. Sixty days after the therapy, we did not stress out any statistically relevant difference in question- naires scores between the two groups, despite a PDE-5 inhibitors treatment in the second group. Moreover, there is no correlation between LUTS severity (classified according to IPSS and NIH-CPSI), ED rate and vice versa. These results suggest tamsulosin may improve ED and chronic prostatitis symptoms, reducing the spasm of prostate smooth muscle, the associated inflammation and improving prostate and penis blood flow. Anyway, our study has several limitations; it does not have a placebo control arm and it is circumscribed. We are also persuaded other studies are needed for evaluating monotherapy and combination therapy for a longer peri- od than 60 days. Moreover, patients’ randomization does not guarantee a complete randomness: patients’ assign- ment to one study group or the other was made through their alternated insertion in one of the two groups. CONCLUSIONS LUTS severity in young patients suffering from type III chronic prostatitis does not correlate with the severity of ED and vice versa. Tamsulosin therapy for the treatment of young patients with type III chronic prostatitis togeth- er with erectile dysfunction has the same effectiveness of the most expensive combination therapy (tamsulosin and sildenafil). We are persuaded in the future the cheaper therapy with alpha-blocker will be used in CP/CPPS and ED affected patients. REFERENCES 1. Schaeffer AJ, Datta NS, Fowler JEJ, et al. Overview summary statement. Diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Urology. 2002; 60:1-4. 2. Costabile RA, Steers WD. How can we best characterize the rela- tionship between erectile dysfunction and benign prostatic hyperpla- sia? J Sex Med. 226; 3:676-681. 3. Carson CC. Combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic hyperplasia: treat- ments of lower urinary tract symptoms, erectile dysfunction, or both? BJU Int. 2006; 97:39-43. 4. Shiri R, Ha¨kkinen JT, Hakama M, et al. Effect of lower urinary tract symptoms on the incidence of erectile dysfunction. J Urol. 2005; 174:205-209. 5. Dimitrakov J, Joffe HV, Soldin SJ, et al. Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome. Urology. 2008; 71:261-6. 6. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002; 3:377-84. 7. Gonen M, Kalkan M, Cenker A, et al. Prevalence of premature ejaculation in Turkish men with chronic pelvic pain syndrome. J Androl. 2005; 26:601-3. 8. Shoskes DA, Prots D, Karns J, et al. Greater endothelial dysfunc- tion and arterial stiffness in men with chronic prostatitis/chronic pelvic pain syndrome-a possible link to cardiovascular disease. J Urol. 2011; 186:907-10. 9. Rubinshtein R, Kuvin JT, Soffler M, et al. Assessment of endothe- lial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010; 31:1142-8. 10. Shoskes DA, Berger R, Elmi A, et al. Muscle tenderness in men with chronic prostatitis/chronic pelvic pain syndrome: the chronic prostatitis cohort study. J Urol. 2008; 179:556-60. 11. Anderson RU, Wise D, Sawyer T, et al. Sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome: improve- ment after trigger point release and paradoxical relaxation training. J Urol. 2006; 176:1534-8. 12. Nickel JC, Tripp DA, Chuai S, et al. Psychosocial variables affect the quality of life of men diagnosed with chronic prostatitis/chronic pelvic pain syndrome. BJU Int. 2008; 101:59-64. 13. McNaughton Collins M, Pontari MA, O’Leary MP, et al. Quality of life is impaired in men with chronic prostatitis: the Chronic Prostatitis Collaborative Research Network. J Gen Intern Med. 2001; 16:656-62. 14. Rosen RC, Wei JT, Althof SE, et al. Association of sexual dysfunc- tion with lower urinary tract symptoms of BPH and BPH medical ther- apies: results from the BPH registry. Urology. 2009; 73:562-566. 15. Kirby RS, Andersen M, Gratzke P, et al. A combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gas- trointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. BJU Int. 2001; 87:192-200. 16. De Rose AF, Carmignani G, Corbu C, et al. Observational mul- ticentric trial performed with doxazosin: evaluation of sexual effects on patients with diagnosed benign prostatic hyperplasia. Urol Int. 2002; 68:95-98. Correspondence Ubaldo Cantoro, MD (Corresponding Author) Resident in Urology ubaldocantoro@tiscali.it Francesco Catanzariti, MD Resident in Urology fracatanzariti@libero.it Vito Lacetera, MD Urologist, Resident in Urology vlacetera@gmail.com Luigi Quaresima, MD Resident in Urology luigiquaresima@yahoo.it Giovanni Muzzonigro MD Professor of Urology and Chief Institute of Urology, Resident in Urology g.muzzonigro@univpm.it Massimo Polito, MD Urologist, Resident in Urology max_polito@virgilio.it Institute of Urology, A.O. Ospedali Riuniti Via Conca 71 - I-60020 Ancona, Italy