Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 1 REVIEW INTRODUCTION Benign prostatic hyperplasia (BPH) is a common urological disease that is strongly associated with the aging process (1). Prostate growth is influenced by a combination of intrinsic and extrinsic factors that interact in a complex manner. The pathophysiological pathway includes hor- mone and androgen exposure as well as growth factors, chronic inflammation and genetics (2). Lower urinary tract symptoms (LUTS) due to BPH can have a significant impact on patients’ quality of life (3). For most patients with symptomatic benign prostatic hyperplasia, medical management remains the cornerstone of treatment. Pharmacologic measures are often preferred as a first approach as they can relieve symptoms and improve the patient’s well-being (4). The landscape of medical treat- ment for BPH is constantly evolving. The efficacy of over- the-counter medications, plant extracts and natural sup- plements has not yet been adequately researched and their benefits are still unclear. At the same time, ongoing studies of new pharmacologic agents, such as beta-3 ago- nists, have the potential to expand the available thera- peutic options, providing hope for more targeted and effective strategies in the future. With this review, we aimed to provide an up-to-date overview of the most common medical treatments for LUTS including phy- totherapy in the context of BPH. MATERIALS AND METHODS In July 2024, a systematic review of medical therapy for BPH was conducted using relevant articles in PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The review focused on phytotherapy and medical Introduction: Benign prostatic hyperplasia (BPH) is a common urological disease that is strongly associated with the aging process and can lead to lower urinary tract symptoms (LUTS). LUTS due to BPH can signifi- cantly affect the quality of life of many patients. Among the treatments available for BPH to improve symptoms and func- tional outcomes, drug therapy and surgical therapy are the options of choice. However, for most patients with symptomatic BPH, medical management remains the cornerstone of treat- ment. Pharmacologic interventions are often preferred as a first approach, being less invasive compared to surgery. Although the medical treatment of BPH is currently defined by the algorithms of international guidelines, the need for a more personalized approach is increasingly recognized given the wide and hetero- geneous range of therapeutic options available. Materials and methods: A review of medical therapy for BPH was conducted using relevant articles in PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. In this review, all drug treatments currently available on the interna- tional market whose efficacy is scientifically proven are reviewed and described (phytotherapy, alpha-blockers, mus- carinic receptor antagonists, 5-alpha-reductase inhibitors, combination therapies, etc.). Results: A total of 17 randomized clinical trials were selected for review. Further 75 studies were included for analysis and discussion. Conclusions: As the treatment landscape continues to evolve, tailoring therapy to individual patient needs and preferences is likely to become increasingly important to ensure that treatment strategies are both effective and meet patient expectations. KEY WORDS: Benign prostatic hyperplasia; Medical therapy; Alpha-blockers; Antimuscarinics; Phytotherapy. Submitted 13 September 2024; Accepted 23 November 2024 Non-surgical management of BPH: An updated review of current literature and state of the art on natural compounds and medical therapy Guglielmo Mantica 1, 2, Francesca Ambrosini 2, Giovanni Drocchi 1, Zlata Zubko 1, Lorenzo Lo Monaco 1, Angelo Cafarelli 3, Alessandro Calarco 4, Renzo Colombo 5, Ottavio de Cobelli 6, Ferdinando De Marco 7, Giovanni Ferrari 8, Giuseppe Ludovico 9, Stefano Pecoraro 10, Domenico Tuzzolo 11, Carlo Terrone 1, 2, Rosario Leonardi 12 1 Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genova, Genova, Italy; 2 IRCCS Ospedale Policlinico San Martino, Genova, Italy; 3 Urology Unit, Villa Igea, Ancona, Italy; 4 Department of Urology, San Carlo di Nancy Hospital, Rome, Italy; 5 Department of Urology, Vita e Salute San Raffaele University, Milan, Italy; 6 Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, Italy; 7 I.N.I. Grottaferrata, Rome, Italy; 8 Hesperia Hospital, Modena, Italy; 9 Ospedale Miulli, Acquaviva delle Fonti, Bari, Italy; 10 NEUROMED, Avellino, Italy; 11 Urologi Ospedalità Gestione Privata (UrOP), Italy; 12 Casa di Cura Musumeci-Gecas, Gravina di Catania, Italy. DOI: 10.4081/aiua.2024.13098 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 G. Mantica, F. Ambrosini, G. Drocchi, et al. 2 treatment of BPH. Three authors (GM, FA, GD) inde- pendently screened the titles and abstracts of the datasets for eligibility. Reviews, original articles, and case reports were included, while other types of articles were exclud- ed. Evidence was limited to human data and experimen- tal animal studies. Only publications in English were con- sidered. In addition, manuscripts that were not focused on the purpose of the review were not included. The orig- inal list of selected articles was supplemented by individ- ual suggestions from the co-authors of the present review. Similarly, articles published before 1990 but considered interesting for the purpose of the review were suggested by the authors and assessed by the screening team. The reference lists of the selected articles/systematic reviews/meta-analyses were also screened to identify fur- ther potentially relevant studies, using the same criteria as for the initial search. RESULTS The search strategy has been highlighted using the PRIS- MA flowchart (5) (Figure 1) and PICO model (6) (Supplementary matherial) to summarize the results. The risk of bias of the 17 randomized controlled trials included has been evaluated using the ROB 2 – revised tool (7) (Figure 2). Figure 1. PRISMA flowchart. Source: Page MJ, et al. BMJ 2021; 372: n71. Figure 2. Risk of bias of the 17 randomized controlled trials evaluated using the ROB 2 – revised tool. Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 3 Non-surgical management of BPH Watchful waiting and dietary lifestyle Many men with mild LUTS do not find their symptoms bothersome enough to warrant medical treatment or sur- gery. In addition, many patients are concerned about the potential complications associated with taking medica- tion. In selected cases without clinical complications (renal insufficiency, hematuria, hydronephrosis, urinary tract infections, acute urinary retention…), Watchful Waiting (WW) might therefore be an even more attractive choice. In patients with mild LUTS (International Prostate Symptom Score - IPSS), the condition can remain stable many times without complications such as acute urinary retention (8). The key issues in the treatment of BPH with WW are the establishment of patient selection criteria and the assessment of risk factors for disease progression. Longitudinal studies such as the Baltimore Longitudinal Study of Aging (9) and the Olmstead County Study (10) have shown that advanced age, a larger prostate, and decreased urinary flow can predict the need for treat- ment. The Veterans Administration Cooperative Study has shown that in properly selected patients, especially those with low baseline values, watchful waiting can be a viable and safe strategy (11). Before or alongside treatment, lifestyle counseling and self-care information can posi- tively impact men with LUTS due to BPH (12). Key com- ponents of this strategy include patient education, reas- surance and regular monitoring, combined with specific lifestyle advice aimed at reducing urinary symptoms (12). It is often recommended to reduce fluid intake at times that minimize discomfort, such as before bedtime, and to limit the consumption of caffeine and alcohol, which can exacerbate symptoms such as frequency, urinary urgency and nocturia due to their diuretic effects (13). Techniques such as double voiding, urethral milking and bladder training are also recommended to improve bladder con- trol and reduce dribbling (14). Another important meas- ure is to avoid constipation and situations in which a per- son has to hold urine. Systematic reviews and meta-ana- lyzes have found that self-management measures that include these lifestyle changes can significantly reduce the severity of symptoms and slow the progression of the disease, thus providing relief (14). This holistic approach not only improves quality of life, but also empowers patients to actively manage their disease. Phytotherapy Phytotherapy is a science that uses plant extracts, from leaves to roots to seeds, to achieve benefits in the treat- ment of diseases (15-17). There are numerous in vitro studies in the literature on the potential benefits of phy- totherapy in the treatment of BPH, but little is known about the actual in vivo effects. Serenoa repens Serenoa Repens, also known as saw palmetto, is probably the best-known plant available for the treatment of BPH (18). The dried, ripe berry is used for the extraction. Serenoa repens has anti-androgenic activity with inhibi- tion of 5α-reductase and therefore reduces prostate vol- ume; its activity is associated with the action of free fatty acids such as lauric and palmitic acid, which are also responsible for reducing inflammation. For these reasons, saw palmetto can slow down the development of BPH and improve patients' quality of life (QoL), IPSS and symptoms (19). There are many different types of extrac- tion from the plant. Hexane extraction has proven to be the most reliable and provides the best results. Currently, Serenoa repens is the only phytotherapy recommended in most of the major international guidelines for the treat- ment of BPH and its symptoms (20, 21). Most tablets available on the market are 320 mg and are taken once daily. Nevertheless, the dose and efficacy also depend on the extraction method itself. Cucurbita The seeds of Cucurbita pepo L. appear to have the prop- erty of inhibiting 5α-reductase and testosterone-induced hypertrophy by lowering dihydrotestosterone (DHT) levels. Some clinical studies showed an improvement in quality of life and IPSS without altering patients’ sexual function during treatment (22, 23). Urtica Urtica dioica, the active ingredient of which is the dried root, is frequently used in traditional European medicine for the treatment of BPH. Urtica can reduce the conver- sion of testosterone into DHT. Several studies have shown a proliferation-inhibiting effect by binding to the mem- brane receptors of the prostate, thereby inhibiting its pro- liferative activity in prostate tissue. In vivo studies in rats showed a possible inhibition of 5α-reductase. However, more extensive studies in humans are needed to confirm its benefits (24-26). Curcuma Curcuma longa Linn. is often used to treat urinary tract diseases due to its antioxidant and anti-inflammatory properties. In a recent study (27), this plant was able to improve LUTS symptoms, IPSS and Qmax score. An improvement was observed both in untreated patients and in patients already treated with alpha-blockers and/or 5α-reductase inhibitors (5-ARI). Pygeum africanum Pygeum africanum (Prunus) is known among the indige- nous population of Africa for its antiproliferative and anti- inflammatory properties. It appears to be able to inhibit prostate growth factors and reduce the production of prostaglandins in the prostate (28). This leads to a reduc- tion in chronic prostatitis and the inflammatory symptoms of BPH. The evidence in the literature regarding the mech- anism of actions and the clinical effect is weak. Pollens Cernitin, the best-known pollen, is an extract of Secale cereale that has an interesting effect on BPH and can improve both irritative and obstructive symptoms (29). Its effect is achieved by relaxing the smooth muscles of the urethra and apoptosis of the cells of the prostatic tran- sition zone. Some studies based on small samples showed an improvement in IPSS and a decrease in prostate vol- ume after long-term treatment with pollen (30, 31). Peony pollen, the pollen of Paeonia suffruticosa, also appears to be able to attenuate oxidative stress and Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 G. Mantica, F. Ambrosini, G. Drocchi, et al. 4 inflammation. They could be directly involved in the reg- ulation of the gut microbiota. In addition, some pollen in combination with vitamins (Deprox 500®) showed an improvement in the IPSS and the NIH Chronic Prostatitis Symptom Index (NIHCPSI), alone or in combination with Serenoa repens (32-35). The literature lacks strong evi- dence on this drug. Epilobium Epilobium species are perennial plants whose flowers and leaves are used for the presence of some substances such as phenolic acids, flavonoids, and tannins. The therapeu- tic effect of Epilobium has been demonstrated in vitro, with a reduction in PSA levels and a reduction in the inflammatory response and oxidative stress of prostate cells. In a randomized, placebo-controlled trial, epilobi- um was shown to improve post-void residual (PVR), increase IPSS, and reduce nocturia (36). Other studies have investigated the efficacy of epilobium and showed similar results (37). Palmitoylethanolamide (PEA) PEA is an endocannabinoid-like bioactive lipid mediator that belongs to the N-acylethanolamine family. The prop- erties of PEA include a known anti-inflammatory effect and the reduction of testosterone and DHT levels in both the prostate and serum. In addition, PEA can reduce the upregulation of 5α-reductase 2 and androgen receptor induced by BPH (38-40). Most of the available studies were conducted in vitro, while the literature contains only a few in vivo studies. Other plants Other plant extracts are used in traditional medicine to treat BPH and its symptoms. Some of these plants are: Hypoxis hemerocallidea, Pinus pinaster, Roystonea regia, Solanum lycopersicum. The substances extracted from these plants appear to have a positive effect on BPH thanks to their antioxidant, anti-inflammatory and anti- carcinogenic properties. However, the current literature is minimal and of limited significance (41-43). Conventional therapies Alpha blockers Among the drugs available for the treatment of LUTS and bladder outlet obstruction (BOO) due to BPH, alpha-block- ers are the most frequently used. The literature is full of data evaluating the therapeutic benefits of these drugs, which are also recommended in the most widely followed guidelines (12, 44-45). Their mechanism of action is closely related to the presence of many smooth muscle cells in the prostate that are amenable to alpha-adrenergic stimulation (46). This stimulation leads to relaxation of the prostate and bladder neck. The bladder and prostate contain predominantly alpha-1 receptors, which enables the use of selective blockers. The most commonly sold alpha-blockers today are tamsulosin, alfuzosin, doxazosin, silodosin, naftodipil and terazosin (47). The data available in the literature show that alpha-blockers can reduce the IPSS score by 30-40% and improve Qmax by 20-25%. One of their most important effects is to reduce the risk of acute urinary retention (48). Unfortunately, these drugs are not free of side effects, such as hypotension and retro- grade ejaculation, which are often significant for some patients. Alpha reductase inhibitors Another important drug for the treatment of BPH are 5- alpha-reductase inhibitors (5-ARI). There are two types of 5α-reductase enzymes, but type 2 is most common in the prostate. This enzyme converts a portion of testosterone into dihydrotestosterone (DHT), which plays a role in prostate growth (49). The 5-ARIs act by suppressing the enzyme 5α-reductase. Dutasteride and finasteride are the most commonly used 5-ARIs and are equivalent in terms of results and effect. The PLESS study has shown that finasteride reduces the relative long-term risk of acute urinary retention and the need for surgery compared to placebo. 5-ARIs are able to improve LUTS and Qmax (50- 52) and their effect may also be important before surgery by reducing prostate bleeding during TURP (53, 54). 5- ARIs are not free from potential side effects such as decreased sexual desire, impotence, gynecomastia, depression and anxiety. One of the properties of 5-ARIs is the lowering of PSA levels. This effect, which has already been observed with other drugs (55) with a dif- ferent mechanism, is much more pronounced with 5- ARIs. Therefore, the use of 5-ARIs must always be con- sidered in the diagnosis of prostatic neoplasia in order to best select patients with a clinically significant risk of pro- static neoplasia who are candidates for prostate biopsy (56-58). Muscarinic receptor antagonists Normal physiological bladder emptying depends on the activation of the contractile muscarinic receptors on the smooth muscle of the bladder tricuspid. This activation is triggered by the neurotransmitter acetylcholine. Five subtypes of G-protein-coupled muscarinic receptors (M1; M2; M3; M4; M5) have been characterized phar- macologically. Most muscarinic receptors in the detrusor muscle are M2 (70%) and M3 (30%) (59). Currently, the most commonly used antimuscarinic drugs are oxybu- tynin, propiverine, tolterodine and solifenacin (60, 61). The current EAU guidelines recommend the use of mus- carinic receptors in men with moderate to severe LUTS who have mainly bladder storage symptoms (12). A con- siderable number of muscarinic receptors are located in different parts of the body (salivary glands, gastrointesti- nal tract and central nervous system). Therefore, the side effects of antimuscarinics may affect these areas (62). The most frequently reported adverse effects include blurred vision, constipation and dry mouth (61). Their main effect is to reduce the urge to urinate and the fre- quency of urination. In addition, they are able to increase bladder capacity, allowing patients to hold urine for longer periods of time without discomfort. This improvement can significantly increase the quality of life of BPH patients as they need to urinate less frequently. Usually, these drugs are used in combination with alpha-blockers. This combination can be particularly effective in treating both the obstruc- tive and irritative symptoms of BPH. Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 5 Non-surgical management of BPH Beta 3 agonists Humans have three different subtypes of β-adrenoceptors (β1, β2 and β3). In human bladder tissue, β3-adreno- ceptors are predominantly expressed (63). Activation of this receptor is associated with detrusor smooth muscle relaxation during the storage phase of micturition and therefore improves bladder compliance and capacity. Mirabegron is the first β3-adrenoceptor agonist approved in clinical practice and may be an alternative treatment option to antimuscarinics for patients with overactive bladder symptoms (64-66). The efficacy and safety of mirabegron 50 mg compared to placebo and antimus- carinics was evaluated in male patients with overactive bladder in five phase III studies. Mirabegron showed sig- nificant improvements in the reduction of micturition fre- quency compared to placebo. Mirabegron 50 mg has been shown to be relatively safe. Gastrointestinal symp- toms and dry mouth are the most commonly reported adverse effects. Mirabegron 100 mg, on the other hand, showed a slightly increased risk of high blood pressure and cardiac arrhythmia (68). Phosphodiesterase 5 inhibitors Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil and avanafil) are the gold standard in the treatment of patients with erectile dysfunction (ED). These drugs block the enzyme PDE5 and thus regulate the level of cyclic guanosine monophosphate (cGMP) by breaking it down to inactive 5′-guanosine monophosphate (5′-GMP). This process leads to smooth muscle relaxation in the corpus cavernosum of the penis (69, 70). This relaxation increases the arterial inflow into the penis, which is necessary to achieve and maintain an erection. In addition, tadalafil relaxes the smooth muscles of the blad- der and prostate and can thus improve LUTS (71). Therefore, the daily intake of 5 mg tadalafil has been approved for the treatment of BPH. Compared to a place- bo, 5 mg tadalafil once daily as monotherapy or in com- bination with alpha-blockers can significantly improve quality of life and IPSS (72, 73). Phosphodiesterase type 5 inhibitors are generally well tolerated, especially at low doses. The most common side effects are headache, red- ness of the skin, and nasal congestion (69, 70). Combination therapy Although alpha blockers are the treatment of choice in most cases, in many cases their effect alone is not suffi- cient to relieve the symptoms of BPH. It is therefore pos- sible to combine this therapy with 5-ARIs, PDE5 inhibitors, Mirabegon, antimuscarinics and, of course, phytotherapy, which generally leads to good results. Studies such as COMBAT and CONDUCT have shown that dutasteride plus tamsulosin can improve Qmax and IPSS and reduce the risk of acute urinary retention (74, 75). Therefore, combination therapy with 5-ARI and alpha-blockers could be an option for patients with large prostate volume and severe LUTS. Similar studies looking at the combination of alpha-blockers and PDE5 inhibitors (tadalafil), alpha-blockers and mirabegone or alpha- blockers and antimuscarinics have shown that combina- tion therapy is able to reduce LUTS without a significant increase in side effects (76, 77). DISCUSSION Medical treatment for BPH has evolved significantly over the years, offering a variety of treatment options aimed at alleviating symptoms and improving overall patient out- comes (78-80). In selected uncomplicated cases, WW and lifestyle changes can play a positive role in the man- agement of BPH symptoms (14). Systematic reviews and meta-analyzes have shown that such self-management measures can significantly alleviate symptoms and con- trol the progression of the disease (14). Nevertheless, the elements of self-care management have not been assessed individually and the lifestyle advice is derived from a for- mal consensus method, so further research is needed in this area (12). Among the approved drugs for the medical management of BPH, alpha-blockers have been consid- ered a cornerstone of BPH treatment for many years. They provide rapid relief of symptoms, often within a few weeks, and are generally well tolerated (81). However, some patients may experience side effects such as dizzi- ness, orthostatic hypotension, and ejaculatory dysfunc- tion (82). Despite these potential problems, alpha-block- ers remain a widely used drug due to their efficacy and rapid onset of action (12). 5-ARI, by lowering dihy- drotestosterone levels, can shrink the prostate and improve LUTS over time (12). However, relief may be slower to come compared to alpha-blockers, and poten- tial side effects include sexual dysfunction (83). Moreover, their impact on PSA needs to be considered in relation to prostate cancer screening (12). Despite these concerns, they are a valuable option for the treatment of BPH, especially in patients with prostate enlargement > 40 mL. Treatments with phosphodiesterase-5 inhibitors such as tadalafil, have also shown promise in the man- agement of BPH. These drugs can provide additional relief from symptoms such as urinary urgency and fre- quency, improve erectile function and help to maintain ejaculatory function (84). They offer a different mecha- nism of action to conventional BPH therapies and can be particularly useful for patients suffering from both BPH and erectile dysfunction. However, they can cause side effects such as headaches and gastrointestinal discomfort, and interactions with other medications must be careful- ly monitored. Research on newer agents such as beta-3 agonists, such as mirabegron, is ongoing. These medica- tions target bladder function rather than prostate size and may help relieve storage symptoms such as urinary urgency and frequency. Although the long-term efficacy and safety of these drugs are still under investigation, the available literature suggests that beta-3 agonists may be an effective addition to the BPH treatment options (12). A further possibility that has emerged in recent years is that of suspension therapy for fragile patients or for patients with a combination of different therapies in order to reduce the risk of side effects. However, still few studies are currently available on the topic (85, 86). One of the most evolving and extensive fields related to the medical treatment of BPH is phytotherapy. Several plant- derived substances are commercially available, including both herbal medicines and dietary supplements (87). Phytotherapy has undeniable advantages, including high tolerability and low side effects (16). They are also easily available online or over the counter. Sometimes patients Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 G. Mantica, F. Ambrosini, G. Drocchi, et al. 6 find it difficult to adhere to the treatments because the side effects, including retrograde ejaculation, can significantly affect the patient’s psychological well-being, leading them to prefer phytotherapy. On the other hand, the evidence on phytotherapy is not conclusive, the mechanism of action is not always fully understood and many of these substances have not undergone the rigorous testing that drugs normally receive. Considering their mostly moder- ate efficacy, which is inferior to that of approved drugs, there is a lack of strong recommendations in European (EAU) or American Urological Association (AUA) guidelines (12). However, in a historical period in which there is the threat of further pandemics (88) which can cause an increase in the waiting list of patients suffering from BPH, a correct knowledge of the medical therapy of BPH is of fundamental importance, allowing to manage the patient also through telemedicine and while waiting for surgery (89-91). CONCLUSIONS In conclusion, the medical management of BPH is cur- rently defined by the algorithms of the EAU and AUA guidelines (12, 92). However, given the broad and het- erogeneous range of therapeutic options available, the need for a more personalized approach is increasingly recognized. As the treatment landscape continues to evolve, tailoring therapy to individual patient needs and preferences is likely to become increasingly important to ensure that treatment strategies are both effective and meet patient expectations. REFERENCES 1. GBD 2019 Benign Prostatic Hyperplasia Collaborators. The glob- al, regional, and national burden of benign prostatic hyperplasia in 204 countries and territories from 2000 to 2019: a systematic analy- sis for the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2022; 3:e754-e776. 2. Devlin CM, Simms MS, Maitland NJ. Benign prostatic hyperpla- sia - what do we know? BJU Int. 2021; 127:389-399. 3. Montiel-Jarquín ÁJ, Gutiérrez-Quiroz CT, Pérez-Vázquez AL, et al. Quality of life and erectile dysfunction in patients with benign pro- static hyperplasia. Cir Cir. 2021; 89:218-222. 4. Haile ES, Sotimehin AE, Gill BC. Medical management of benign prostatic hyperplasia. Cleve Clin J Med. 2024; 91:163-170. 5. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372:n71. 6. Frandsen TF, Bruun Nielsen MF, Lindhardt CL, Eriksen MB. Using the full PICO model as a search tool for systematic reviews resulted in lower recall for some PICO elements. J Clin Epidemiol. 2020; 127:69-75. 7. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366:l4898. 8. Djavan B, Fong YK, Harik M, et al. Longitudinal study of men with mild symptoms of bladder outlet obstruction treated with watch- ful waiting for four years. Urology. 2004; 64:1144-8. 9. Arrighi HM, Metter EJ, Guess HA, Fozzard JL. Natural history of benign prostatic hyperplasia and risk of prostatectomy. The Baltimore Longitudinal Study of Aging. Urology. 1991; 38(Suppl 1):4-8. 10. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J Urol. 1999; 162:1301-6. 11. Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med. 1995; 332:75-9. 12. EAU Guidelines. Edn. presented at the EAU Annual Congress Paris April 2024. ISBN 978-94-92671-23-3. 13. Brown CT, Yap T, Cromwell DA, et al. Self management for men with lower urinary tract symptoms: randomised controlled trial. BMJ. 2007; 334:25. 14. Albarqouni L, Sanders S, Clark J, et al. Self-Management for Men With Lower Urinary Tract Symptoms: A Systematic Review and Meta-Analysis. Ann Fam Med. 2021; 19:157-167. 15. Gerber GS. Phytotherapy for benign prostatic hyperplasia. Curr Urol Rep. 2002; 3:285-91. 16. Kim SW. Phytotherapy: emerging therapeutic option in urologic disease. Transl Androl Urol. 2012; 1:181-91. 17. Antoniou V, Gauhar V, Modi S, Somani BK. Role of Phytotherapy in the Management of BPH: A Summary of the Literature. J Clin Med. 2023; 12:1899. 18. Nickel JC, Chughtai B, De Nunzio C, et al. Rethinking the Role of Saw Palmetto Extract for Men with Lower Urinary Tract Symptoms in North America. Uro. 2022; 2:137-150. 19. Tacklind J, Macdonald R, Rutks I, et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2012; 12:CD001423. Update in: Cochrane Database Syst Rev. 2023; 6:CD001423. 20. Barry MJ, Meleth S, Lee JY, et al. Effect of Increasing Doses of Saw Palmetto Extract on Lower Urinary Tract Symptoms: A Randomized Trial. JAMA. 2011; 306:1344-1351. 21. Giulianelli R, Pecoraro S, Sepe G, et al. Multicentre study on the efficacy and tolerability of an extract of Serenoa repens in patients with chronic benign prostate conditions associated with inflamma- tion. Arch Ital Urol Androl. 2012; 84:94-8. 22. Theil G, Richter M, Schulze M, et al. Extract from Cucurbita pepo improves BPH symptoms without affecting sexual function: a 24-month noninterventional study. World J Urol. 2022; 40:1769- 1775. Erratum in: World J Urol. 2022; 40:2589-2590. 23. Damiano R, Cai T, Fornara P, et al. The role of Cucurbita pepo in the management of patients affected by lower urinary tract symp- toms due to benign prostatic hyperplasia: A narrative review. Arch Ital Urol Androl. 2016; 88:136-43. 24. Moradi HR, Erfani Majd N, Esmaeilzadeh S, Fatemi Tabatabaei SR. The histological and histometrical effects of Urtica dioica extract on rat's prostate hyperplasia. Vet Res Forum. 2015; 6:23-9. 25. Bougueroua K, Boufadi MY, Latreche B, et al. Effects of algerian nettle (Urtica dioica L.) on benign prostatic hyperplasia and their mechanism of action elucidation: in vivo and in silico approaches. Nat Prod Res. 2024; 38:4017-4027. 26. Sens-Albert C, Weisenburger S, König BC, et al. Effects of a pro- Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 7 Non-surgical management of BPH prietary mixture of extracts from Sabal serrulata fruits and Urtica dioica roots (WS® 1541) on prostate hyperplasia and inflammation in rats and human cells. Front Pharmacol. 2024; 15:1379456. 27. Crocerossa F, Cantiello F, Bagalá L, et al. Clinical Effects of Oral Supplementation of Gamma-Cyclodextrin Curcumin Complex in Male Patients with Moderate-To-Severe Benign Prostatic Hyperplasia-Related Lower Urinary Tract Symptoms. Urol Int. 2023; 107:924-934. 28. Rubegeta E, Makolo F, Kamatou G, et al. The African cherry: A review of the botany, traditional uses, phytochemistry, and biological activities of Prunus africana (Hook.f.) Kalkman. J Ethnopharmacol. 2023; 305:116004. 29. Antonelli M, Donelli D, Firenzuoli F. Therapeutic efficacy of orally administered pollen for nonallergic diseases: An umbrella review. Phytother Res. 2019; 33:2938-2947. 30. Yasumoto R, Kawanishi H, Tsujino T, et al. Clinical evaluation of long-term treatment using cernitin pollen extract in patients with benign prostatic hyperplasia. Clin Ther. 1995; 17:82-7. 31. F Chen, X Zhang, J Bai, et al. Anti-proliferative effect and mech- anisms of Peony pollen on BPH via inhibition of inflammatory fac- tors, oxidative damage and modulation of gut microbiota and SCFAs metabolism, Pharmacological Research - Modern Chinese Medicine, 2024; 12:100472. 32. Macchione N, Bernardini P, Piacentini I, et al. Flower Pollen Extract in Association with Vitamins (Deprox 500®) Versus Serenoa repens in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Comparative Analysis of Two Different Treatments. Antiinflamm Antiallergy Agents Med Chem. 2019; 18:151-161. 33. Cai T, Luciani LG, Caola I, et al. Effects of pollen extract in asso- ciation with vitamins (DEPROX 500®) for pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome: results from a pilot study. Urologia. 2013; 80(Suppl 22):5-10. 34. Cai T, Wagenlehner FM, Luciani LG, et al. Pollen extract in association with vitamins provides early pain relief in patients affect- ed by chronic prostatitis/chronic pelvic pain syndrome. Exp Ther Med. 2014; 8:1032-1038. 35. Maurizi A, De Luca F, Zanghi A, et al. The role of nutraceutical medications in men with non bacterial chronic prostatitis and chron- ic pelvic pain syndrome: A prospective non blinded study utilizing flower pollen extracts versus bioflavonoids. Arch Ital Urol Androl. 2019; 90:260-264. 36. Esposito C, Santarcangelo C, Masselli R, et al. Epilobium angusti- folium L. extract with high content in oenothein B on benign prostatic hyperplasia: A monocentric, randomized, double-blind, placebo-con- trolled clinical trial. Biomed Pharmacother. 2021; 138:111414. 37. Deng L, Zong W, Tao X, et al. Evaluation of the therapeutic effect against benign prostatic hyperplasia and the active constituents from Epilobium angustifolium L. J Ethnopharmacol. 2019; 232:1-10. 38. Cicero AFG, Allkanjari O, Busetto GM, et al. Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer. Arch Ital Urol Androl. 2019; 91:139. 39. D'Amico R, Genovese T, Cordaro M, et al. Palmitoylethanolamide/ Baicalein Regulates the Androgen Receptor Signaling and NF-κB/Nrf2 Pathways in Benign Prostatic Hyperplasia. Antioxidants (Basel). 2021; 10:1014. 40. Cordaro M, Impellizzeri D, Siracusa R, et al. Effects of a co- micronized composite containing palmitoylethanolamide and poly- datin in an experimental model of benign prostatic hyperplasia. Toxicol Appl Pharmacol. 2017; 329:231-240. 41. Drewes SE, Elliot E, Khan F, et al. Hypoxis hemerocallidea--not merely a cure for benign prostate hyperplasia. J Ethnopharmacol. 2008; 119:593-8. 42. Carbajal D, Molina V, Mas R, Arruzazabala ML. Therapeutic effect of D-004, a lipid extract from Roystonea regia fruits, on prostate hyperplasia induced in rats. Drugs Exp Clin Res. 2005; 31:193-7. 43. Lambertini L, Di Maida F, Tellini R, et al. Impact of the Treatment of Serenoa repens, Solanum lycopersicum, Lycopene and Bromelain in Combination with Alfuzosin for Benign Prostatic Hyperplasia. Results from a Match-Paired Comparison Analysis. Uro 2021; 1:228-237. 44. Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenocep- tors in the urinary bladder, urethra and prostate. Br J Pharmacol. 2006; 147(Suppl 2):S88-119. 45. Kortmann BB, Floratos DL, Kiemeney LA, et al. Urodynamic effects of alpha-adrenoceptor blockers: a review of clinical trials. Urology. 2003; 62:1-9. 46. Michel MC, Mehlburger L, Bressel HU, Goepel M. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prostatic Dis. 1998; 1:332-335. 47. Karavitakis M, Kyriazis I, Omar MI, et al. Management of Urinary Retention in Patients with Benign Prostatic Obstruction: A Systematic Review and Meta-analysis. Eur Urol. 2019; 75:788-798. 48. Gwon YN, Park JJ, Yang WJ, et al. Comparing effects of alpha- blocker management on acute urinary retention secondary to benign prostatic hyperplasia: A systematic review and network meta-analy- sis. Prostate Int. 2023; 11:91-99. 49. Andriole G, Bruchovsky N, Chung LW, et al. Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol. 2004; 172:1399-403. 50. Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finas- teride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ. 1996; 155:1251-9. 51. Naslund MJ, Miner M. A review of the clinical efficacy and safe- ty of 5alpha-reductase inhibitors for the enlarged prostate. Clin Ther. 2007; 29:17-25. 452. Roehrborn CG, Siami P, Barkin J, et al. The effects of dutas- teride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008; 179:616-21. Erratum in: J Urol. 2008; 180:1191. 53. Khwaja MA, Nawaz G, Muhammad S, et al. The Effect of Two Weeks Preoperative Finasteride Therapy in Reducing Prostate Vascularity. J Coll Physicians Surg Pak. 2016; 26:213-5. 54. Hirshburg JM, Kelsey PA, Therrien CA, et al. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. J Clin Aesthet Dermatol. 2016; 9:56-62. 55. Mantica G, Chierigo F, Cassim F, et al. Correlation Between Long-Term Acetylsalicylic Acid Use and Prostate Cancer Screening with PSA. Should We Reduce the PSA Cut-off for Patients in Chronic Therapy? A Multicenter Study. Res Rep Urol. 2022; 14:369-377. 56. De Nunzio C, Lombardo R, Baldassarri, et al. Rotterdam mobile phone app including MRI data for the prediction of prostate cancer: A multicenter external validation. Eur J Surg Oncol. 2021; 47:2640- 2645. 57. Cindolo L, Bertolo R, Minervini A, et al. External validation of Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 G. Mantica, F. Ambrosini, G. Drocchi, et al. 8 Cormio nomogram for predicting all prostate cancers and clinically significant prostate cancers. World J Urol. 2020; 38:2555-2561. 58. Mantica G, Pacchetti A, Aimar R, et al. Developing a five-step training model for transperineal prostate biopsies in a naïve resi- dents' group: a prospective observational randomised study of two different techniques. World J Urol. 2019; 37:1845-1850. 59. Hegde SS, Eglen RM. Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Life Sci. 1999; 64:419-28. 60. Mansfield KJ, Liu L, Mitchelson FJ, et al. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioli- gand binding and quantitative competitive RT-PCR: changes in age- ing. Br J Pharmacol. 2005; 144:1089-99. 61. Abrams P, Andersson KE. Muscarinic receptor antagonists for overactive bladder. BJU Int. 2007; 100:987-1006. 62. Abrams P, Andersson KE, Buccafusco, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol. 2006; 148:565-78. 63. Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev. 2004; 56:581-631. 64. Andersson KE, Martin N, Nitti V. Selective β₃- adrenoceptor agonists for the treatment of overactive bladder. J Urol. 2013; 190:1173-80. 65. Chapple CR, Cardozo L, Nitti VW, et al. Mirabegron in overac- tive bladder: a review of efficacy, safety, and tolerability. Neurourol Urodyn. 2014; 33:17-30. 66. Chapple CR, Siddiqui E. Mirabegron for the treatment of over- active bladder: a review of efficacy, safety and tolerability with a focus on male, elderly and antimuscarinic poor-responder popula- tions, and patients with OAB in Asia. Expert Rev Clin Pharmacol. 2017; 10:131-151. 67. Tubaro A, Batista JE, Nitti VW, et al. Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies. Ther Adv Urol. 2017; 9:137-154. 68. Sebastianelli A, Russo GI, Kaplan SA, et al. Systematic review and meta-analysis on the efficacy and tolerability of mirabegron for the treatment of storage lower urinary tract symptoms/overactive bladder: Comparison with placebo and tolterodine. Int J Urol. 2018; 25:196-205. 69. Huang SA, Lie JD. Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Dysfunction. P T. 2013; 38:407-19. 70. ElHady AK, El-Gamil DS, Abdel-Halim M, Abadi AH. Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives. Pharmaceuticals (Basel). 2023; 16:1266. 71. Yokoyama O, Igawa Y, Takeda M, et al. Tadalafil for lower uri- nary tract symptoms secondary to benign prostatic hyperplasia: a review of clinical data in Asian men and an update on the mechanism of action. Ther Adv Urol. 2015; 7:249-64. 72. Cui J, Cao D, Bai Y, et al. Efficacy and Safety of 12- week Monotherapy With Once Daily 5 mg Tadalafil for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: Evidence-based Analysis. Front Med (Lausanne). 2021; 8:744012. 73. Brock G, Broderick G, Roehrborn CG, et al. Tadalafil once daily in the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in men without erectile dys- function. BJU Int. 2013; 112:990-7. 74. Siami P, Roehrborn CG, Barkin J, et al. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Contemp Clin Trials. 2007; 28:770-9. 75. Roehrborn CG, Oyarzabal Perez I, Roos EP, et al. Efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin treatment (Duodart®) compared with watchful waiting with initia- tion of tamsulosin therapy if symptoms do not improve, both provid- ed with lifestyle advice, in the management of treatment-naïve men with moderately symptomatic benign prostatic hyperplasia: 2-year CONDUCT study results. BJU Int. 2015; 116:450-9. 76. Brasure M, MacDonald R, Dahm P, et al. Newer Medications for Lower Urinary Tract Symptoms Attributed to Benign Prostaic Hyperplasia: A Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 May. Report No.: 16- EHC024-EF. 77. Kakizaki H, Lee KS, Yamamoto O, et al. Mirabegron Add-on Therapy to Tamsulosin for the Treatment of Overactive Bladder in Men with Lower Urinary Tract Symptoms: A Randomized, Placebo- controlled Study (MATCH). Eur Urol Focus. 2020; 6:729-737. 78. Stewart KL; Lephart ED. Overview of BPH: Symptom Relief with Dietary Polyphenols, Vitamins and Phytochemicals by Nutraceutical Supplements with Implications to the Prostate Microbiome. Int J Mol Sci. 2023; 24:5486. 79. Kaltsas A, Kratiras Z, Zachariou A, et al. Evaluating the Impact of Benign Prostatic Hyperplasia Surgical Treatments on Sexual Health. Biomedicines. 2024; 12:110. 80. Hughes T, Harper P, Somani BK. Treatment Algorithm for Management of Benign Prostatic Obstruction: An Overview of Current Techniques. Life. 2023; 13:2077. 81. Barendrecht MM, Abrams P, Schumacher H, et al. Do alpha1- adrenoceptor antagonists improve lower urinary tract symptoms by reducing bladder outlet resistance? Neurourol Urodyn. 2008; 27:226-230. 82. Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular- related safety profile and efficacy of alpha-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract. 2008; 62:1547-1559. 83. Corona G, Tirabassi G, Santi D, et al. Sexual dysfunction in sub- jects treated with inhibitors of 5α-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis. Andrology. 2017; 5:671-678. 84. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012; 61:994-1003. 85. van der Worp H, Jellema P, Hordijk I, et al. Discontinuation of alpha-blocker therapy in men with lower urinary tract symptoms: a systematic review and meta-analysis. BMJ Open. 2019; 9:e030405. 86. Sebastianelli A, Spatafora P, Frizzi J, et al. Which Drug to Discontinue 3 Months After Combination Therapy of Tadalafil plus Tamsulosin for Men with Lower Urinary Tract Symptom and Erectile Dysfunction? Results of a Prospective Observational Trial. Eur Urol Focus. 2021; 7:432-439. 87. Morgia G, Lo Giudice A, Carrino M, et al. Efficacy of Palmitoylethanolamide, Epilobium and Calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III. Arch Ital Urol Androl. 2024; 96:12582. Archivio Italiano di Urologia e Andrologia 2024; 96(4):13098 9 Non-surgical management of BPH 88. Leonardi R, Bellinzoni P, Broglia L, et al. Hospital care in Departments defined as COVID-free: A proposal for a safe hospital- ization protecting healthcare professionals and patients not affected by COVID-19. Arch Ital Urol Androl. 2020; 92:67. 89. Ambrosini F, Di Stasio A, Mantica G, et al. COVID-19 pandem- ic and uro-oncology follow-up: A "virtual" multidisciplinary team strategy and patients' satisfaction assessment. Arch Ital Urol Androl. 2020; 92:78. 90. Mirone V, Di Bello F, Morra S, et al. Telemedicine and social media: A contemporary analysis of the most shared content by inter- net users. Arch Ital Urol Androl. 2024; 96:11206. 91. Carrión DM, Gómez Rivas J, Rodríguez-Socarrás ME, et al. Implementación de la teleconsulta en la práctica urológica durante la era Covid-19: ¿qué hemos aprendido? [Implementation of Remote Clinics in urology practice during the COVID-19 era: What have we learned?]. Arch Esp Urol. 2020; 73:345-352. 92. Sandhu JS, Bixler BR, Dahm P, et al. Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023. J Urol. 2024; 211:11-19. Correspondence Guglielmo Mantica (Corresponding Author) guglielmo.mantica@gmail.com Giovanni Drocchi g.drocchi@hotmail.it Zlata Zubko zlata@zubko.it Lorenzo Lo Monaco lomonaco_lorenzo@libero.it Carlo Carlo Terrone carlo.terrone@med.uniupo.it Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genova, Genova, Italy Francesca Ambrosini IRCCS Ospedale Policlinico San Martino, Genova, Italy f.ambrosini1@gmail.com Angelo Cafarelli info@angelocafarelli.it Urology Unit, Villa Igea, Ancona, Italy Alessandro Calarco segreteria@alessandrocalarco.com Department of Urology, San Carlo di Nancy Hospital, Rome, Italy Renzo Colombo colombo.renzo@hsr.it Department of Urology, Vita e Salute San Raffaele University, Milan, Italy Ottavio de Cobelli ottavio.de-cobelli@ieo.it Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, Italy Ferdinando De Marco info@clinicavillamargherita.it I.N.I. Grottaferrata, Rome, Italy Giovanni Ferrari visite@giovanniferrariurologo.it Hesperia Hospital, Modena, Italy Giuseppe Ludovico g.ludovico@miulli.it Ospedale Miulli, Acquaviva delle Fonti, Bari, Italy Stefano Pecoraro cup@diagnosticamedica.org NEUROMED, Avellino, Italy Domenico Tuzzolo info@casadelsole.it Urologi Ospedalità Gestione Privata (UrOP), Italy Rosario Leonardi leonardi.r@tiscali.it Casa di Cura Musumeci-Gecas, 95030 Gravina di Catania, Italy Conflict of interest: The authors declare no potential conflict of interest.