Stesura Seveso Archivio Italiano di Urologia e Andrologia 2013; 85, 4184 INTRODUCTION Lower urinary tract symptoms due to benign prostatic hyperplasia (BPH/LUTS) and benign prostatic enlarge- ment are very common diseases in men older than 40 years (1). Male sexual dysfunction are, also, very common ORIGINAL PAPER An improvement in sexual function is related to better quality of life, regardless of urinary function improvement: Results from the IDIProst® Gold Study Tommaso Cai 1, Giuseppe Morgia 2, Giuseppe Carrieri 3, Carlo Terrone 4, Ciro Imbimbo 5, Paolo Verze 5, Vincenzo Mirone 5, IDIProst® Gold Study Group * 1 Department of Urology, Santa Chiara Regional Hospital, Trento, Italy; 2 Department of Urology and Department of Hygiene and Public Health, University of Catania, Catania, Italy; 3 Department of Urology and Renal Transplantation, University of Foggia, Foggia, Italy; 4 Division of Urology, ASO Maggiore della Carità University Hospital, University of Eastern Piedmont, Novara, Italy; 5 Department of Urology, University Federico II of Naples, Italy. Objective. The relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) has recently received increased attention. The aim of this study was to evaluate the efficacy of the Alfa-5® association of Serenoa repens, Pinus massoniana Bark Extract (PMBE) and Crocus sativus (IDIProst® Gold) in improvement of patient’s quality of life, when compared with Serenoa repens alone. Materials and Methods. All patients with clinical and instrumental diagnosis of LUTS due to Benign Prostatic Hyperplasia (BPH) and ED, attending 5 Italians Urological Institutions from May to December 2012 were enrolled in this prospective, multicentre, phase 3 study. Participants were assigned to receive oral capsules of IDIProst® Gold (one capsule q24 h) or Serenoa repens 320 mg (one capsule q24h) for 3 months. Clinical and instrumental analyses were carried out at the enrolment and at the end of therapy. IPSS, IIEF-5 and SF-36 question- naires have been used. The main outcome measure was the improvement of quality of life at the end of the whole study period. Results. 129 (mean age 45-71 ± 4.36) men were randomly allocated to IDIProst® Gold (n = 83) or Serenoa repens (n = 46). The baseline questionnaire mean scores were 17.1 ± 6.4, 14.9 ± 3.7, 96.3 ± 1.2 for IPSS, IIEF-5 and SF-36, respectively. At the follow-up examination, statistically significant differences have been reported in terms of IPSS (11.9 vs 13.8; p < 0.001), IIEF-5 and SF-36 mean scores (19.3 vs 16.1; 99.7 vs 96.3; p < 0.003; p < 0.001). Moreover, statistically significant differences were then reported between the two visits, in terms of IPSS, IIEF-5 and SF-36 scores (p < 0.003; p < 0.001; p < 0.001), only in the IDIProst® Gold group. Conclusions. In conclusions, we found that IDIProst® Gold significantly improve the quality of life of patients affected by LUTS due to BPH and ED, specifically in terms of sexual function, high- lighting that a better sexual quality of life is correlated with an higher overall quality of life regardless of the urinary function. KEY WORDS: BPH; LUTS; Erectile Dysfunction; Serenoa repens; Crocus sativus; Quality of Life. Submitted 27 July 2013; Accepted 5 October 2013 No conflict of interest declared Summary in this population; in the European Male Ageing Study of 3,369 community-dwelling men aged 40-79 years, mod- erate or severe erectile dysfunction (ED) was reported by 6% of men in their forties, rising to 64% of men aged over DOI: 10.4081/aiua.2013.4.184 Cai_Stesura Seveso 18/12/13 10:43 Pagina 184 185Archivio Italiano di Urologia e Andrologia 2013; 85, 4 Sexual function improvement and quality of life 70 years (2). Moreover, in the Multinational Survey of the Ageing Male (MSAM-7) the overall prevalence of LUTS was 90%, while the overall prevalence of ED was 49%, high- lighting that rate of ED was significantly dependent on age and correlated highly with the severity of LUTS (3). Both BPH⁄ LUTS and sexual dysfunction have a substantial neg- ative impact on a man’s quality of life and are considered a serious socio-economic problem (4). The current thera- pies for BPH/LUTS are associated with bothering sexual side effects, however, differing in rate and characteristics between different classes of medications, different medica- tions within the same classes, and different combinations of drugs (5). For these reasons, PDE5-Is are introduced in the Italian pharmacopeia as an effective and treatment for LUTS associated with ED. Even if PDE5-Is are effective either alone or in combination with !-blockers in men with BPH/LUTS, some adverse events, such as headache, dyspepsia, and back pain, are commonly reported (5). Furthermore, future studies are needed to evaluate the long-term safety and efficacy outcomes and the overall cost-effectiveness analysis of this treatment (5). On the basis of the evidences, the use of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyper- plasia has been popular in Europe for many years with promising results. In the last years, the attention has been focused on the both LUTS/BPH and ED treatment, due to the patient’s request to improve his sexual and urinary quality of life. Recently, the Alfa-5® association of Serenoa repens, Pinus massoniana Bark Extract (PMBE) and Crocus sativus, named IDIProst® Gold, has been produced in order to improve the micturition parameters and sexual function in patients affected by LUTS/BPH and ED. The effects on micturition parameters are due to the effects of Serenoa repens, as well known, and the effect on sexual function has due to PMBE and Crocus sativus. We aimed to evalu- ate the efficacy of the Alfa-5® association Serenoa repens, PMBE and Crocus sativus (IDIProst® Gold) in improvement of patient’s quality of life, when compared with Serenoa repens alone. MATERIALS AND METHODS Study design All patients with clinical and instrumental diagnosis of LUTS due to BPH and ED, attending 5 Italians Urological Institutions from May to December 2012 were enrolled in this prospective, multicentre, phase 3 study. All patients underwent clinical and instrumental exami- nations and IPSS, IIEF-5 and SF-36 questionnaires. After enrolment, all patients were assigned to receive oral cap- sules of IDIProst® Gold (one capsule q24h) or Serenoa repens 320 mg (one capsule q24h) for 3 months. The main outcome measure was the improvement of quality of life at the end of the whole study period, evaluated by questionnaires results. Inclusion and exclusion criteria Patients were eligible for inclusion if they had to meet all of the following criteria: age of 50 years or older; to be sex- ually active; maximal urinary flow rate (Cmax) of less than 15 mL/s; post-residual voided volume less than 100 cc; an International Prostate Symptom Score (IPSS) of 8 or greater and an IPSS-quality of life (QOL) score of 2 or greater; Prostate Specific Antigen (PSA) less than 4 ng/ml, or high- er if negative prostate biopsy; an International Index of Erectile Function (IIEF-5) score less than 21; to be untreat- ed for LUTS/BPH; testosterone level more than 3 ng/dL. We excluded all patients affected by major concomitant diseases such as diabetes, liver, and/or renal failure; had known anatomical abnormalities or malignancy of the uri- nary tract, bladder, or upper tract stones, diverticula, for- eign bodies, prostatitis, active urinary tract infection, chronic retention or had polycystic kidney disease. Moreover, we excluded all patients with urethral stenosis interfering with the evaluation of voiding function; patients with a history of transurethral resections of the prostate (TURP), laser therapy, or thermotherapy. Similarly, all patients who tested positive for Sexually Transmitted Diseases such as Chlamydia trachomatis, Ureaplasma urealyticum or Neisseria gonorrhoeae were excluded. Moreover, all patients with allergy to one or more compounds of IDIProst® Gold were also excluded. All patients treated with PDE5-Is were excluded too. Study and treatment schedule On arrival at each Centre, all eligible individuals signed written informed consent and underwent a baseline ques- tionnaire, urological examination with anamnestic inter- view and uroflowmetry (Cmax) with evaluation of post voided residual volume (PVR), in accordance with the procedure described in EAU guidelines (6). PSA value has been previously evaluated. All patients who met the inclu- sion criteria were assigned to groups according to a 1:1 randomization (Figure 1). Group A: IDIProst® Gold (one capsule q24h). Group B: Serenoa repens 320 mg (one capsule q24h). All patients underwent treatment for 3 months. All patients were contacted by telephone on day 30 of the therapy to ensure correct timing and dose treatment. Each subject was scheduled for follow-up examination at 3 months from starting therapy, with a urological visit, uroflowmetry with evaluation of PVR and questionnaires to be filled in. No placebo arm was included. The possi- ble biases caused by the lack of placebo arm were con- sidered in the results analysis. The main outcome meas- ure was the improvement of quality of life at the end of the whole study period, in terms of changes in IPSS, IPSS-QOL, Cmax, PVR, SF-36 and the IIEF-5 from base- line to the evaluation point, that is, 3 months. Clinical failure was defined as the persistence of symptoms after the treatment, or the suspension of therapy for signifi- cant reported adverse effects. In addition, spontaneously reported adverse events, or those noted by the investiga- tor, were recorded during the whole study period. The study was conducted in line with Good Clinical Practice guidelines, with the ethical principles laid down in the latest version of the Declaration of Helsinki. Questionnaires and urological examinations The validated Italian versions of the International Prostatic Symptom Score (IPSS) (7), International Index of Erectile Function (IIEF-5) (8) and SF-36 (9) were administered to each patient. Cai_Stesura Seveso 18/12/13 10:43 Pagina 185 Archivio Italiano di Urologia e Andrologia 2013; 85, 4 T. Cai, G. Morgia, G. Carrieri, C. Terrone, C. Imbimbo, P. Verze, V. Mirone, IDIProst® Gold Study Group 186 The questionnaire was offered to the patient on arrival at each Centre. All questionnaires were also used in deter- mining clinical therapy efficacy. Composition and characterisation of the extracts used All patients assigned to Group A were orally adminis- tered IDIProst® Gold once daily. IDIProst® Gold Each capsule (950 mg) contains the Alfa-5® association consists of Serenoa repens 320 mg, Crocus sativus 100 mg, Pinus massoniana 120 mg. All compound analyses were carried out according to Fiamegoset et al. (10). All patients assigned to Group B were orally administered Serenoa repens 320 mg. Statistical analysis In order to analyse the homogeneity of the two groups, the baseline characteristics were compared using the t test and Wilcoxon-Mann-Whitney test for continuous vari- ables and by the chi-square test for categorical variables. The sample size was calculated prospectively under the following conditions: difference between the groups = 10%, Alpha Error Level = 0.05 two-sided, statistical power = 80% and anticipated effect size (Cohen’s d = 0.5). The calculation yielded 2 ! 64 individuals per group. Analysis of variance (ANOVA) was used for comparing means. Bonferroni adjustment test was also used at the second stage of the analysis of variance. The effect size between the means (Cohen's d) was also calculated. The differences between the groups regarding semen parame- ters were obtained using chi-square or Fisher’s exact tests. Statistical significance was achieved when p was < 0.05. All reported p-values were two-sided. Statistical analyses were performed using SPSS 11.0 for Apple-Macintosh (SPSS, Inc., Chicago, Illinois). RESULTS From a total population of 146 patients with LUTS/BPH and ED, 132 patients were eventually enrolled and ran- domised. Out of the 14 patients excluded from the study, 10 had refused to be enrolled and 4 were lost at the follow-up. Finally, 132 were allocated (Figure 2). Anamnestic and clinical data at enrolment are described in Table 1. No statistically significant differences between the groups were found. From 132 enrolled patients, 85 were allocated to IDIProst® Gold and 46 to Serenoa repens 320 mg. Compliance to treatment schedule and adverse effects In Group A 83 patients (97.6%) were analysed after 2 were lost at follow up. In Group B 46 patients (97.8%) were analysed after 1 was lost at follow up (Figure 2). Accordingly, compliance to this study protocol was sat- isfactory. The IDIProst® Gold formulation was well toler- ated in all patients analysed and there were no significant drug-related side effects. In Group A, 1 out of 83 patients (1.2%) had mild adverse effects that did not require treatment suspension. Also in Group B, 1 out of 46 patients (2.1%) reported mild adverse effects. Clinical and laboratory results at follow up At the follow-up examination (3 months after treatment), statistically significant differences have been reported between the two groups in terms of IPSS (11.9 vs 13.8; df = 127; t = 10.3; p < 0.001), IIEF-5 and SF-36 mean scores (19.3 vs 16.1; 99.7 vs 96.3; df = 127; t = 17.4; p < 0.003; df = 127; t = 18.4; p < 0.001). Moreover, sta- tistically significant differences were then reported between the two visits, in terms of IIEF-5 and SF-36 scores (p < 0.001; p < 0.001), in the IDIProst® Gold group. Very few AEs have been reported in the both groups without any significant difference. Figure 1. The figure shows the study design. Cai_Stesura Seveso 18/12/13 10:43 Pagina 186 187Archivio Italiano di Urologia e Andrologia 2013; 85, 4 Sexual function improvement and quality of life The Table 2 shows all questionnaires results between the two groups at the enrolment and at the follow-up visit. DISCUSSION LUTS due to BPH and sexual dysfunction are very com- mon in men and the association between LUTS/BPH and ED is very intriguing. Moreover, some epidemiological studies demonstrated that the association between LUTS/BPH and sexual dysfunction in ageing men is inde- pendent of the effects of age, other comorbidities and lifestyle factors (11). On the other hand, there is an increasing needed for drugs able to improve the patient’s quality of life without adverse side effects. In the present study we evaluate the efficacy of IDIProst® Gold in improvement of patient’s quality of life. We found some important findings: 1) the efficacy of IDIProst® Gold in improve urinary and sexual function in patients affected by LUTS/BPH and ED, when compared with Serenoa repens alone; 2) the improvement in sexual quality of life is linked with an higher overall quality of life regardless of the urinary function; 3) very few adverse side effects have been found in the IDIProst® Gold group. The efficacy of IDIProst® Gold in the management of uri- nary and sexual function is due to the association between Serenoa repens, PMBE and Crocus sativus. Even if the effi- cacy of Serenoa repens appears to be a useful option for improving lower urinary tract symptoms (12), the associa- tion with PMBE and Crocus sativus is able to improve the efficacy of Serenoa repens due to: a) antioxidant effect, free radical scavenging activities and vasoprotective effect due to oligomeric proanthocyanidin complexes (OPC) of Pinus massoniana Bark Extract (PMBE) (13-14), b) increasing of nitric oxide activity by antioxidant effect of PMBE, c) apop- tosis inducing properties of PMBE (15), d) promotion of the diffusion of oxygen in tissues due to Crocus sativus effect (16) and e) the aphrodisiac properties of Crocus sativus (17). Recently, Hosseinzadeh et al. demonstrated in an animal model study the aphrodisiac activity of Crocus sativus aqueous extract and its constituent crocin (18). Moreover, they demonstrated that crocetin, a constituent of saffron, significantly restored the endo thelium-de pen - dent relaxation of the thoracic aorta in hypercholes- terolemic rabbit, which might be explained by its action to increase the vessel eNOS activity, leading to elevation of NO production (18). Figure 2. The figure shows the study flow-chart. Cai_Stesura Seveso 18/12/13 10:43 Pagina 187 Archivio Italiano di Urologia e Andrologia 2013; 85, 4 T. Cai, G. Morgia, G. Carrieri, C. Terrone, C. Imbimbo, P. Verze, V. Mirone, IDIProst® Gold Study Group 188 The same authors highlighted that as crocin (the crocetin digentiobiosyl-ester) converts to crocetin, it is possible that this component acts in a way similar to PDE-5 inhibitors such as sildenafil (18). Furthermore, Crocus sativus seems to have affinity to bind benzodiazepine receptors (19) and exhibited antidepres- sant activity that it might inhibit the reuptake of sero- tonin (20). Moreover, Shamsa et al. in a clinical trial found that after the ten days of taking saffron there was a statistically sig- nificant improvement in tip rigidity and tip tumescence as well as base rigidity and base tumescence, highlighting that Crocus sativus showed a positive effect on sexual func- tion with increased number and duration of erectile events seen in patients with ED even only after taking it for ten days (21). These are the pharmacological basis justifying the effec- tiveness of IDIProst® Gold. Another aspect to discuss is the fact that we have found that an improvement in sex- ual quality of life is linked with a higher overall quality of life regardless of the urinary function. It could be due to the fact that the impact of sexual dysfunction on pa - tients’ quality of life is higher than LUTS, as demonstrat- ed by several authors (3, 22.) Finally, the present study shows few limitations to take into account; firstly, the lacks of placebo arm. However, we planned this study without a placebo arm due to the fact that we think that is not ethical to not treat patients with LUTS/BPH and ED. Moreover, the short follow-up period that not allows to evaluate the possible adverse side effect at long time. IDIProst®Gold mean (SD or %) Serenoa repens 320 mg mean (SD or %) Patients (n°) 83 46 Background information • Age 58.9 (± 3.56) 59.1 (± 3.68) • Marital status Married 53 (63.8) 30 (65.3) Unmarried 20 (24.0) 11 (23.9) Divorced 10 (12.2) 5 (10.8) • Educational qualification Primary School 30 (36.2%) 18 (39.1%) High School 29 (35.0%) 15 (32.7%) University 24 (28.8%) 13 (28.2%) • Smooking Yes 28 (33.8) 16 (34.7) No 55 (66.2) 30 (65.3) • Comorbidity Charlson Index 1.9 (± 0.8) 2.0 (± 0.9) • BMI (Body Mass Index) 26.9 (± 1.3) 27.1 (± 1.1) Baseline clinical data • PSA total (ng/mL) 2.02 (± 1.45) 2.08 (± 1.59) • PVR (mL) 29.9 (± 28.8) 32.8 (± 29.9) • Uroflowmetry data Qmax (mL/sec) 11.7 (± 2.2) 11.9 (± 2.1) • Prostate volume (mL) 43.9 (± 21.1) 41.4 (± 17.2) • IPSS 17.1 (± 5.9) 16.9 (± 5.8) • IIEF-5 14.9 (± 3.5) 15.1 (± 3.7) • SF-36 96.4 (± 1.1) 96.9 (± 1.2) Table 1. Clinical, instrumental and laboratory patient’s data. IDIProst®Gold Serenoa repens 320 mg mean (SD) mean (SD) IPSS v1 17.1 (± 5.9) 16.9 (± 5.8) v2 11.9 (± 1.1) 13.8 (± 1.3) IIEF-5 v1 14.9 (± 3.5) 15.1 (± 3.7) v2 19.3 (± 1.0) 16.1 (±1.2) SF-36 v1 96.4 (± 1.1) 96.9 (± 1.2) v2 99.7 (± 1.2) 96.3 (± 2.3) Table 2. Questionnaires results at the enrolment and at the follow-up visit. The table shows the anamnestic, clinical and instrumental data from all patients at the enrolment time. n° = number; SD or % = Standard Deviation or percentage; PVR = post-residual voided volume; IPSS = International Prostate Symptom Score; IIEF-5 = International Index of Erectile Function; SF-36 = Short Form-36. The table shows all questionnaires results between the two groups at the enrolment and at the follow-up visit. v1 = visit 1 (time 0); v2 = visit 2 (after 3 months). SD = Standard Deviation; IPSS= International Prostate Symptom Score; IIEF-5 = International Index of Erectile Function; SF-36 = Short Form-36 Cai_Stesura Seveso 18/12/13 10:43 Pagina 188 189Archivio Italiano di Urologia e Andrologia 2013; 85, 4 Sexual function improvement and quality of life CONCLUSION In conclusions, we found that IDIProst® Gold significantly improve the quality of life of patients affected by LUTS due to BPH and ED, specifically in terms of sexual func- tion, highlighting that a better sexual quality of life is cor- related with an higher overall quality of life regardless of the urinary function. REFERENCES 1. Girman CJ, Jacobsen SJ, Guess HA, et al. Natural history of prosta- tism: relationship among symptoms, prostate volume and peak urinary flow rate. J Urol. 1995; 153:1510-5. 2. Corona G, Lee DM, Forti G, et al. Age-related changes in general and sexual health in middle aged and older men: results from the European Male Ageing Study (EMAS). 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Università degli Studi di Napoli “Federico II” - Prof. Vincenzo Mirone: Marco Franco, Roberto La Rocca. Università degli Studi di Catania - Prof. Giuseppe Morgia: Costanza Salamone, Claudia Calì. Università degli Studi di Foggia - Prof. Giuseppe Carrieri: Giuseppe Di Fino, Mario De Siati. Università degli Studi del Piemonte Orientale - Prof. Carlo Terrone: Angela Maurizi. Università degli Studi di Milano - Prof. Francesco Rocco: Franco Gadda. Correspondence Tommaso Cai, MD (Corresponding Author) Department of Urology, Santa Chiara Regional Hospital, Trento, Italy. Largo Medaglie d'Oro, 9 ktommy@libero.it Giuseppe Morgia, MD Department of Urology and Department of Hygiene and Public Health University of Catania, Catania, Italy Giuseppe Carrieri, MD Department of Urology and Renal Transplantation University of Foggia, Foggia, Italy Carlo Terrone, MD Division of Urology, ASO Maggiore della Carità University Hospital University of Eastern Piedmont, Novara, Italy Ciro Imbimbo, MD Paolo Verze, MD Vincenzo Mirone, MD Department of Urology University Federico II, Napoli, Italy Cai_Stesura Seveso 18/12/13 10:43 Pagina 189