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).

The modern clinical research on prostatitis started with the work of Stamey and coworkers who developed the basic principles we are still using. They established the segmented culture technique for localizing the infections in the males to the urethra, the bladder, or the prostate and to differentiate the main categories of prostatitis. Such categories with slight modifications are still used according to the NIH classification: acute bacterial prostatitis, chronic bacterial prostatitis, Chronic Pelvic Pain Syndrome (CPPS) and asymptomatic prostatitis. Prostatic inflammation is considered an important factor in influencing both prostatic growth and progression of symptoms of benign prostatic hyperplasia and prostatitis. Chronic inflammation/neuroinflammation is a result of a deregulated acute phase response of the innate immune system affecting surrounding neural tissue at molecular, structural and functional levels. Clinical observations suggest that chronic inflammation correlates with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and benign prostatic hyperplasia (BPH) and an history of clinical chronic prostatitis significantly increases the odds for prostate cancer. The NIHNIDDK classification based on the use of the microbiological 4- glasses localization test or simplified 2-glasses test, is currently accepted worldwide. The UPOINT system identifies groups of clinicians with homogeneous clinical presentation and is used to recognize phenotypes to be submitted to specific treatments. The UPOINTS algorithm implemented the original UPOINT adding to the urinary domains (U), psycho-social (P), organspecific (O), infection (I), neurological (N), muscle tension and tenderness (T) a further domain related to sexuality (S). In fact sexual dysfunction (erectile, ejaculatory, libido loss) has been described in 46-92% of cases with a high impact on the quality of life of patients with CP/CPPS. Prostatic ultrasound represents the most popular imaging test in the work-up of either acute and chronic prostatitis although no specific hypo-hyperechoic pattern has been clearly associated with chronic bacterial prostatitis and CPPS. Use of a digital-processing software to calculate the extension of prostatic calcification area at ultrasound demonstrated a higher percentage of prostatic calcification in patients with chronic bacterial prostatitis. Multiparametric Magnetic Resonance Imaging (mpMRI) is the current state-of-the art imaging modality in the assessment of patients with prostate cancer although a variety of benign conditions, including inflammation, may mimic prostate cancer and act as confounding factors in the discrimination between neoplastic and non-neoplastic lesions. Bacteria can infect prostate gland by: ascending the urethra, reflux of urine into the prostatic ducts, direct inoculation of bacteria through inserted biopsy needles or hematogenous seeding. Enterobacteriaceae are the predominant pathogens in acute and chronic bacterial prostatitis, but an increasing role of Enterococci has been reported. Many strains of these uropathogens exhibit the ability to form biofilm and multidrug- resistance. Sexually Transmitted Infections (STI) agents, in particular Chlamydia trachomatis and Mycoplasma genitalium, have been also considered as causative pathogens of chronic bacterial prostatitis. On the contrary the effective role in genital diseases of other "genital mycoplasmas" is still a much debated issue. Sexually Transmitted Infections agents should be investigated by molecular methods in both patient and sexual partner. “Next generation” investigations, such as cytokine analysis, cytological typing of immune cells could help stratifying the immune response. Epigenetic dysregulation of inflammatory factors should be investigated according to systemic and compartment-specific signals. The search for biomarkers should also include evaluation of hormonal pathways, as measurement of estrogen levels in semen. Antimicrobials are the first line agents for the treatment of bacterial prostatitis. The success of antimicrobial treatment depends on the antibacterial activity and the pharmacokinetic characteristics of the drug which must reach high concentrations in prostate secretion and prostate tissue. Acute bacterial prostatitis can be a serious infection with a potential risk for urosepsis For iInitial treatment of severely ill patients, intravenous administration of high doses of bactericidal antimicrobials, such as broad-spectrum penicillins, third-generation cephalosporins or fluoroquinolones, is recommended in combination with an aminoglycoside. Use of piperacillin-tazobactam and meropenem is justified in presence of multiresistant gramnegative pathogens. The antibiotic treatment of chronic prostatitis is currently based on the use of fluoroquinolones that, given for 2 to 4 weeks, cured about 70% of men with chronic bacterial prostatitis. For the treatment of Chlamydial prostatitis macrolides were shown to be more effective than fluoroquinolones, whereas no differences were observed in microbiological and clinical efficacy between macrolides and tetracyclines for the treatment of infections caused by intracellular pathogens. Aminoglycosides and fosfomycin could be considered as a therapeutic alternative for the treatment of quinolone resistant prostatitis. Use of alpha-blockers in CP/CPPS patients with urinary symptoms and analgesics +/- non steroidal anti-inflammatory drugs (NSAID), in presence of pain demonstrated a reduction of symptoms reduction and an improvement of quality of life, although long term use of NSAID is limited by side effect profile. However, the multimodal therapeutic regimen by contemporary use of alphablockers, antibiotics and anti-inflammatory showed a better control of prostatitis symptoms than single drug treatment. Novel therapeutic substances for the treatment of pain, such as the cannabinoid anandamide would be highly interesting to...

Previous data have shown that patients with metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE) could be refractory to the medical treatment. In this context, the evidence suggests a role for statin use in LUTS/BPE patients. The present systematic review aimed to evaluate the impact of statins on the treatment of men with LUTS/BPE. This review has been registered on PROSPERO (CRD42019120729). A systematic review of English-language literature was performed up to January 2020 in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA statement) criteria. Retrieved studies had to include adults with LUTS connected to BPE treated with statins drugs for metabolic syndrome. After removing duplicates, a total of 381 studies were identified by the literature search and independently screened. Of these articles, 10 fit the inclusion criteria and were further assessed for eligibility. Data from our systematic review suggest that a long-term therapy with statins, at least 6 months, is required to achieve significant impacts on prostate tissue and LUTS. Moreover, besides statins’ direct activity, the risk reduction of LUTS might be connected to the improvement of hypercholesterolemia and MetS. The role of statins for the treatment of LUTS/BPE may be beneficial; however, evidence from robust studies is not enough, and more clinical trial are required.