Conservative and medical treatments of non-sickle cell disease-related ischemic priapism: a systematic review by the EAU Sexual and Reproductive Health Panel.

Conservative and medical treatments are considered the first step in ischemic priapism (IP) management, although there is no clear evidence regarding their efficacy. We conducted a systematic review on behalf of the EAU Guidelines panel on Sexual and Reproductive health to analyse the available evidence on the efficacy and safety of conservative and medical treatment for non-sickle cell disease-related IP. Databases searched for relevant literature investigating efficacy and safety of conservative measures and medical treatment for IP included Medline, EMBASE, Cochrane Libraries and clinicaltrial.gov published up to September 2021. Overall, 41 retrospective, 3 prospective single-arm studies and 3 randomized controlled trials met the inclusion criteria. Intracavernous injection with sympathomimetic (ICIs) agents were the most frequently utilized treatment with efficacy ranging from 0 to 100% of cases. The combination of ICIs with corporeal aspiration with or without irrigation with saline was successful in 70 to 100% of cases. Oral treatment with ß2 receptor agonist (e.g., terbutaline) showed mild to moderate efficacy. Conservative methods including ice pack, exercise, cold enema and ejaculation depicted lower effectiveness in resolving priapism (1-55%). Longer time interval from the onset to the resolution of IP was associated with higher rate of erectile dysfunction at follow-up (30-70%), especially after 24 h.

Clinical Efficacy of Serenoa repens Versus Placebo Versus Alpha-blockers for the Treatment of Lower Urinary Tract Symptoms/Benign Prostatic Enlargement: A Systematic Review and Network Meta-analysis of Randomized Placebo-controlled Clinical Trials.

CONTEXT: International guidelines do not make any specific recommendations on Serenoa repens (SeR) for the treatment of male lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE), due to product heterogeneity and methodological limitations of the published trials and meta-analyses. OBJECTIVE: We aimed to compare the clinical efficacy of hexanic extract of SeR (HESr) versus non-HESr (nHESr) versus placebo versus alpha-blockers (ABs) in patients affected by LUTS secondary to BPE through a network meta-analysis method. EVIDENCE ACQUISITION: The search was conducted until December 31, 2018 using Medline, Scopus, and Web of Science databases without restriction. We included randomized controlled trials (RCTs) with at least one comparison between SeR, ABs, or placebo for the treatment of LUTS/BPE. Outcomes of the study were the mean change in the International Prostate Symptom Score (IPSS) and peak flow (PF). This systematic review has been registered on PROSPERO (CRD42018084360). EVIDENCE SYNTHESIS: In total, 2115 articles were identified. After the global assessment, 22 RCTs matched with the inclusion criteria, including 8564 patients. For IPSS, the mean efficacies against placebo were +0.48 and -1.69 for HESr and nHESr, respectively, at 3 mo; 0.59 for nHESr at 6 mo; and -1.31 and -3.30 for nHESr and HESr, respectively, at 12 mo. For PF, the mean efficacies against placebo were +0.53 and +2.82 for HESr and nHESr, respectively, at 3 mo; +1.85 for nHESr at 6 mo; and +4.05 and +5.52 for HESr and nHESr, respectively, at 12 mo. Based on the surface under the cumulative ranking curve rankograms, terazosin showed the highest score (99.6%), while alfuzosin, tamsulosin, silodosin, HESr, and nHESr showed scores of 53.7%, 42.3%, 68.5%, 36.7%, and 47.3%, respectively. CONCLUSIONS: In this network meta-analysis, we demonstrated that SeR did not show clinically meaningful improvement in LUTS and PF. PATIENT SUMMARY: In the present study, we found no clinically meaningful improvement of Serenoa repens for the treatment of lower urinary tract symptoms/benign prostatic enlargement. The analysis showed that the benefit over placebo was minimal and may not justify its clinical use before higher level of evidence will be available.

Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer.

During the last years, pharmaceutical innovations in primary care are dramatically less frequent and will be even more rare in the next future. In this context, preclinical and clinical research oriented their interest toward natural compounds efficacy and safety, supporting the development of a new "nutraceutical" science. Medicinal plants, in the form of plant parts or extracts of them, are commonly used for the treatment of prostate diseases such as benign hypertrophy, prostatitis and chronic pelvic pain syndrome. The pharmacological properties searched for the treatment of prostatic diseases are anti-androgenic, anti-estrogenic, antiproliferative, antioxidant and anti-inflammatory. The most studied and used medicinal plants are Serenoa repens, Pygeum africanum and Urtica dioica. Other promising plants are Cucurbita pepo, Epilobium spp, Lycopersum esculentum, Secale cereale, Roystonea regia, Vaccinium macrocarpon. In parallel, epidemiological studies demonstrated that diet may play an important role on incidence and development of prostatic diseases. The Mediterranean diet is rich of elements with anti-oxidant properties that act as a protective factor for prostatic cancer. Similarly, low intake of animal protein, high intake of fruits and vegetable, lycopene and zinc are a protective factor for benign prostatic hyperplasia (BPH). Serenoa repens in the treatment of symptoms of BPH has been tested either alone or, more frequently, in combination with other medicinal plants, alpha-blockers and inhibitors of 5- alpha reductase (5-ARI). Recent meta-analyses found the effectiveness of Serenoa repens similar or inferior of that of finasteride and tamsulosin but clearly higher than that of placebo in the treatment of mild and moderate low urinary tract symptoms (LUTS), nocturia and discomfort. Clinical trials showed potential synergistic effect of Serenoa repens with other medicinal plants and drugs. In addition to Serenoa repens, there are many other medicinal plants for which clinical evidence is still controversial. Urtica dioica, Pygeum africanum and Curcubita pepo can be considered as an adjunct to the common therapies and their use is supported by studies showing improvement of symptoms and flowmetric indices. Lycopene and selenium are natural products with antioxidant and anti-inflammatory action. The combination of lycopene and selenium with Serenoa repens was able to reduce inflammation in histological prostate sections and to further improve symptom scores and urinary flow in patients with BPH on tamsulosin treatment. Similar effects could be obtained with the use of other carotenoids, such as astaxanthin, and/or zinc. Efficacy on symptoms of patients with BPH of some polyphenols such as quercitin, equol and curcumin have been demonstrated by clinical studies. Pollen extract is a mixture of natural components able to inhibit several cytokines and prostaglandin and leukotriene synthesis resulting in a potent anti-inflammatory effect. Pollen extracts significantly improve symptoms, pain, and quality of life in patients affected by chronic pelvic pain syndrome and chronic prostatitis. Beta-sitosterol is a sterol able to improve urinary symptoms and flow measures, but not to reduce the size of the prostate gland. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide-signaling molecule with anti-inflammatory and neuroprotective effects that can have an interesting role in the management of chronic pelvic pain syndrome and chronic urological pain. Finally, several plant-based products have been subjected to preclinical, in vitro and in vivo, investigations for their potential pharmacological activity against prostate cancer. Some epidemiological studies or clinical trials evaluated the effects of beverages, extracts or food preparations on the risk of prostate cancer. Some plant species deserved more intense investigation, such as Camelia sinensis (green or black tea), Solanum lycopersicum (common tomato), Punica granatum (pomegranate), Glycine max (common soy) and Linum usitatissimum (linen).

Association between selenium and lycopene supplementation and incidence of prostate cancer: Results from the post-hoc analysis of the procomb trial.

BACKGROUND: Many potential chemopreventive agents have been used in PCa prevention, including selenium (Se) and lycopene (Ly). However, their role has been matter of debate over the years, due to potential of promotion of PCa. PURPOSE: In this study we aimed at evaluating the incidence risk of prostate cancer (PCa) in a cohort of patients treated with Se and Ly. METHODS: The Procomb trial design has been previously published (ISRCTN78639965). From April 2012 to April 2014 209 patients were followed and underwent prostate biopsy when PSA ≥4 ng/ml and/or suspicion of PCa. The all cohort was composed by patients treated with Se and Ly (Group A = 134 patients) and control (Group B = 75 patients). RESULTS: During the follow-up time of 2 years, a total of 24 patients (11.5%) underwent prostate biopsy, of which 9 (4.3%) where diagnosed with PCa and 15 (7.2%) where diagnosed with benign prostatic hyperplasia. We did not observe statistical differences in terms of mean changes of PSA between the two groups (p-value for trend = 0.33). The relative risk (RR) for PCa was 1.07 and 0.89 in group A and B, respectively (p = 0.95). At the multivariate Cox regression analysis supplementation with Se and Ly was not associated with greater risk of PCa (hazard ratio: 1.38; p = 0.67). CONCLUSION: In this analysis we did not show evidences supporting a detrimental role of Selenium and Lycopene supplementation in increasing PCa after 2 years of therapy, nor supporting a protective role.

A phase II, randomized, single-blinded, placebo-controlled clinical trial on the efficacy of Curcumina and Calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III.

OBJECTIVE: The management of chronic prostatitis/ chronic pelvic pain syndrome type III (CP/CPPS) has been always considered complex due to several biopsychological factors underling the disease. In this clinical study, we aimed to evaluate the efficacy of the treatment with Curcumin and Calendula extract in patients with CP/CPPS III. MATERIAL AND METHODS: From June 2015 to January 2016 we enrolled 60 consecutive patients affected by CP/CPPS III in our institution. Patients between 20 and 50 year of age with symptoms of pelvic pain for 3 months or more before study, a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score ≥ 15 point and diagnosed with NIH category III. Patients were then allocated to receive placebo (Group A) or treatment (Group B). Treatment consisted of rectal suppositories of Curcumin extract 350 mg (95%) and Calendula extract 80 mg (1 suppository/die for 1 month). Patients of Group B received 1 suppository/die for 1 month of placebo. The primary endpoint of the study was the reduction of NIH-CPSI. The secondary outcomes were the change of peak flow, IIEF-5, VAS score and of premature ejaculation diagnostic tool (PEDT). RESULTS: A total of 48 patients concluded the study protocol. The median age of the all cohort was 32.0 years, the median NIH-CPSI was 20.5, the median IIEF-5 was 18.5, the median PEDT was 11.0, the median VAS score was 7.5 and the median peak flow was 14.0. After 3 months of therapy in group A we observed a significant improvement of NIH-CPSI (-5.5; p < 0.01), IIEF-5 (+ 3.5; p < 0.01), PEDT (-6.5; p < 0.01), peak flow (+2.8; p < 0.01) and VAS (-6.5; p < 0.01) with significant differences over placebo group (all p-value significant). CONCLUSIONS: In this phase II clinical trial we showed the clinical efficacy of the treatment with Curcumin and Calendula in patients with CP/CPPS III. The benefits of this treatment could be related to the reduction of inflammatory cytokines and of inflammatory cells. These results should be confirmed in further studies with greater sample size.

Conservative Nonhormonal Options for the Treatment of Male Infertility: Antibiotics, Anti-Inflammatory Drugs, and Antioxidants.

The nonhormonal medical treatment can be divided into empirical, when the cause has not been identified, and nonempirical, if the pathogenic mechanism causing male infertility can be solved or ameliorated. The empirical nonhormonal medical treatment has been proposed for patients with idiopathic or noncurable oligoasthenoteratozoospermia and for normozoospermic infertile patients. Anti-inflammatory, fibrinolytic, and antioxidant compounds, oligo elements, and vitamin supplementation may be prescribed. Infection, inflammation, and/or increased oxidative stress often require a specific treatment with antibiotics, anti-inflammatory drugs, and/or antioxidants. Combined therapies can contribute to improve sperm quality.

A combination of tryptophan, Satureja montana, Tribulus terrestris, Phyllanthus emblica extracts is able to improve sexual quality of life in patient with premature ejaculation.

OBJECTIVE: The management of patient affected by premature ejaculation (PE) is nowadays not highly satisfactory. Here, we aimed to evaluate the tolerability and efficacy of a combination of tryptophan, Satureja montana, Tribulus terrestris, Phyllanthus emblica extracts in order to improve sexual quality of life in patients with premature ejaculation. MATERIALS AND METHODS: All patients attending to 5 urological centers from January 2015 to March 2015, due to premature ejaculation were enrolled in this study. At the enrolment visit, all subjects underwent self-administered IIEF-5, Male Sexual Health Questionnaire-Ejaculation Disorder (MSHQEjD), PEDT and IELTS (calculated as mean from that perceived by partner and that perceived by patient) and underwent urological visit and laboratory examinations. All patients received one tablet per day of a combination of tryptophan, Satureja montana, Tribulus terrestris, Phyllanthus emblica extracts for 3 months (Group A). After 3 months all patients underwent follow-up visit with the same investigations that have been carried out in the enrolment visit. The results were compared with a cohort of patients enrolled in the same period in another urological center and considered as a control group (Group B). All patients in the control group underwent counseling and sexual behavioral treatment without any pharmacological compound. RESULTS: At the follow-up analysis, significant changes in terms of IELT in the Group A (mean difference: 31.90; p < 0.05) at 3 months and versus Group B at the intergroup analysis (mean difference: 30.30; p < 0.05) were reported. In the group A, significant differences from baseline to last follow- up were observed relative to IIEF-5 (mean difference: 1.04; p < 0.05), PEDT (mean difference: -2.57; p < 0.05) and FSH (mean difference: -16.46; p < 0.05). CONCLUSION: In conclusion, patients affected by PE may significantly benefit from oral therapy with a combination of tryptophan, Satureja montana, Tribulus terrestris, Phyllanthus emblica extracts in terms of IELT and PEDT scores improvement.

Alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide improve erectile function, sexual quality of life, and ejaculation function in patients with moderate mild-moderate erectile dysfunction: a prospective, randomized, placebo-controlled, single-blinded study.

We aimed to evaluate the efficacy of oral therapy with alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide (Tradamix TX1000) in patients with erectile dysfunction (ED) at 3 months of follow-up. From January 2013 to September 2013, 177 patients diagnosed with mild-moderate ED (IIEF-EF < 26) were enrolled in this multicenter, single-blinded, placebo-controlled study and randomized in Group A (Tradamix, n = 87) and Group B (placebo, n = 90). Penile color Doppler ultrasound measures, IIEF-15 questionnaire, male sexual health questionnaire-ejaculation disorder (MSHQ-EjD), and sexual quality of life (SQoL-M) were collected. We observed significant changes of the IIEF-15 in Group A (mean difference: 11.54; P < 0.05) at 3 months versus Group B (P < 0.05). PSV (P < 0.05), IIEF-intercourse satisfaction (P < 0.05), IIEF-orgasmic function (mean P < 0.05), IIEF-sexual desire (P < 0.05), IIEF-overall satisfaction (P < 0.05), MSHQ-EjD (mean difference: 1.21; P < 0.05), and SQoL-M (mean difference: 10.2; P < 0.05) were significantly changed in Group A versus baseline and Group B. Patients with moderate arterial dysfunction showed significant increase of PSV (P < 0.05), IIEF-EF (P < 0.05), MSHQ-EjD (P < 0.05), and SQoL-M (P < 0.05) in Group A. Therapy with Tradamix improves erectile and ejaculation function and sexual quality of life in patients with mild-moderate ED and in particular for those with moderate arterial dysfunction.

Correlation between lipid profile and heme oxygenase system in patients with benign prostatic hyperplasia.

OBJECTIVE: To investigate the role of heme oxygenase (HO) system in moderate to severe benign prostatic hyperplasia and lower urinary tract symptom patients and the influence of metabolic syndrome (MetS) components on HO-1 or HO-2 prostatic levels. METHODS: One hundred thirty-two consecutive patients who underwent transurethral resection of the prostate were prospectively enrolled. MetS was defined by the International Diabetes Federation. Patients were divided in 2 groups: group A (high-density lipoprotein-cholesterol [HDL-C]≥40 mg/dL and triglycerides<150 mg/dL) and group B (HDL-C<40 mg/dL and triglycerides≥150 mg/dL). Surgical specimens were collected for HO level determination. HO-1 levels were determined by enzyme-linked immunosorbent assay and HO-1 levels by Western blotting. RESULTS: Patients with MetS showed lower levels of HO-1 (5.29 vs 6.28 ng/mL; P=.04), HO-2 (1.01 vs 1.83 ng/mL; P=.04), phosphorylated activated protein kinase (pAMPK; 0.62 vs 1.11 AUI; P<.01), and HO-activity (61.43 vs 70.22 AUI; P<.01) with respect to normal. The Pearson correlation analysis showed that HO-1, HO-2, and HO activity were negatively associated with waist circumference (P<.05), body mass index (P<.05), triglycerides (P<.05) and positively with HDL-C (P<.05). Group B showed lower levels of HO-1 (4.7 vs 6.6 ng/mL; P<.05), HO-2 (1.4 vs 0.4 ng/mL; P=.03), HO-activity (69.63 vs 58.42 AUI; P=.04), and higher International Prostate Symptoms Score (21.4 vs 25.0; P<.05) with respect to group A. The enzyme-linked immunosorbent assay showed that HO-1 and HO activity levels were significantly lower in group B compared with group A. Reduced HDL-C and elevated triglyceride levels decreased HO-1 expression in the prostate tissue. Western blot analysis of tissue samples showed significant differences in basal protein expression levels of HO-2 and pAMPK in group B compared with group A. CONCLUSION: Alteration of serum triglycerides and HDL-C significantly impairs HO-1 and HO-2 levels in benign prostatic hyperplasia patients.

Inhibitors of apoptosis proteins in experimental benign prostatic hyperplasia: effects of serenoa repens, selenium and lycopene.

BACKGROUND: The apoptosis machinery is a promising target against benign prostatic hyperplasia (BPH). Inhibitors of apoptosis proteins (IAPs) modulate apoptosis by direct inhibition of caspases. Serenoa Repens (SeR) may be combined with other natural compounds such as Lycopene (Ly) and Selenium (Se) to maximize its therapeutic activity in BPH. We investigated the effects of SeR, Se and Ly, alone or in association, on the expression of four IAPs, cIAP-1, cIAP-2, NAIP and survivin in rats with experimental testosterone-dependent BPH. Moreover, caspase-3, interleukin-6 (IL-6) and prostate specific membrane antigen (PSMA) have been evaluated.Rats were administered, daily, with testosterone propionate (3 mg/kg/sc) or its vehicle for 14 days. Testosterone injected animals (BPH) were randomized to receive vehicle, SeR (25 mg/kg/sc), Se (3 mg/kg/sc), Ly (1 mg/kg/sc) or the SeR-Se-Ly association for 14 days. Animals were sacrificed and prostate removed for analysis. RESULTS: BPH animals treated with vehicle showed unchanged expression of cIAP-1 and cIAP-2 and increased expression of NAIP, survivin, caspase-3, IL-6 and PSMA levels when compared with sham animals. Immunofluorescence studies confirmed the enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization. SeR-Se-Ly association showed the highest efficacy in reawakening apoptosis; additionally, this therapeutic cocktail significantly reduced IL-6 and PSMA levels. The administration of SeR, Se and Ly significantly blunted prostate overweight and growth; moreover, the SeR-Se-Ly association was most effective in reducing prostate enlargement and growth by 43.3% in treated animals. CONCLUSIONS: The results indicate that IAPs may represent interesting targets for drug therapy of BPH.

Effects of Serenoa repens, selenium and lycopene (Profluss®) on chronic inflammation associated with benign prostatic hyperplasia: results of "FLOG" (Flogosis and Profluss in Prostatic and Genital Disease), a multicentre Italian study.

OBJECTIVE: To evaluate the efficacy of Profluss® on prostatic chronic inflammation (PCI). MATERIALS AND METHODS: We prospectively enrolled 168 subjects affected by LUTS due to bladder outlet obstruction submitted to 12 cores prostatic biopsy for suspected prostate cancer + 2 cores collected for PCI valuation. First group consisted of 108 subjects, with histological diagnosis of PCI associated with BPH and high grade PIN and/or ASAP, randomly assigned to 1:1 ratio to daily Profluss® (group I) for 6 months or to control group (group Ic). Second group consisted of 60 subjects, with histological diagnosis of BPH, randomly assigned to 1:1 ratio to daily Profluss® + a-blockers treatment (group II) for 3 months or to control group (group IIc). After 6 months first group underwent 24 cores prostatic re-biopsy + 2 cores for PCI while after 3 months second group underwent two-cores prostatic for PCI. Specimens were evaluated for changes in inflammation parameters and for density of T-cells (CD3, CD8), B-cells (CD20) and macrophages (CD68). RESULTS: At follow-up there were statistical significant reductions of extension and grading of flogosis, mean values of CD20, CD3, CD68 and mean PSA value in group I compared to Ic, while extension and grading of flogosis in group II were inferior to IIc but not statistical significant. A statistically significant reduction in the density of CD20, CD3, CD68, CD8 was demonstrated in group II in respect to control IIc. CONCLUSIONS: Serenoa repens+Selenium+Lycopene may have an anti-inflammatory activity that could be of interest in the treatment of PCI in BPH and/or PIN/ASAP patients.

Effects of Serenoa Repens, Selenium and Lycopene (Profluss®) on chronic inflammation associated with Benign Prostatic Hyperplasia: results of “FLOG” (Flogosis and Profluss in Prostatic and Genital Disease), a multicentre Italian study

Objective To evaluate the efficacy of Profluss® on prostatic chronic inflammation (PCI). Materials and Methods We prospectively enrolled 168 subjects affected by LUTS due to bladder outlet obstruction submitted to 12 cores prostatic biopsy for suspected prostate cancer + 2 cores collected for PCI valuation. First group consisted of 108 subjects, with histological diagnosis of PCI associated with BPH and high grade PIN and/or ASAP, randomly assigned to 1:1 ratio to daily Profluss® (group I) for 6 months or to control group (group Ic). Second group consisted of 60 subjects, with histological diagnosis of BPH, randomly assigned to 1:1 ratio to daily Profluss® + α-blockers treatment (group II) for 3 months or to control group (group IIc). After 6 months first group underwent 24 cores prostatic re-biopsy + 2 cores for PCI while after 3 months second group underwent two-cores prostatic for PCI. Specimens were evaluated for changes in inflammation parameters and for density of T-cells (CD3, CD8), B-cells (CD20) and macrophages (CD68). Results At follow-up there were statistical significant reductions of extension and grading of flogosis, mean values of CD20, CD3, CD68 and mean PSA value in group I compared to Ic, while extension and grading of flogosis in group II were inferior to IIc but not statistical significant. A statistically significant reduction in the density of CD20, CD3, CD68, CD8 was demonstrated in group II in respect to control IIc. Conclusions Serenoa repens+Selenium+Lycopene may have an anti-inflammatory activity that could be of interest in the treatment of PCI in BPH and/or PIN/ASAP patients. .

Polyphenols: key issues involved in chemoprevention of prostate cancer.

Prostate cancer is is the most common solid neoplasm and it is now recognized as one of the most important medical problems facing the male population. Due to its long latency and its identifiable preneoplastic lesions, prostate cancer is an ideal target tumor for chemoprevention. Different compounds are available and certainly polyphenols represent those with efficacy against prostate cancer. This review take a look at activity and properties of major polyphenolic substances, such as epigallocatechin-3-gallate, curcumin, resveratrol and the flavonoids quercetin and genistein. Although the current studies are limited, mechanisms of action of polyphenols added with the lack of side effects show a a start for future strategies in prostate chemoprevention.