Tadalafil use is associated with a lower incidence of Type 2 diabetes in men with benign prostatic hyperplasia: A population-based cohort study.

BACKGROUND: Tadalafil, commonly prescribed for benign prostatic hyperplasia (BPH), may benefit patients with Type 2 diabetes mellitus (T2DM) for glycemic markers and complications. However, the association between the long-term use of tadalafil and the incidence of T2DM has not been investigated. METHODS: We emulated a target trial of tadalafil use (5 mg/day) and the risk of T2DM using a population-based claims database in Japan. Patients who initiated tadalafil or alpha-blockers for BPH and had no history of diabetes diagnosis, no dispensing of glucose-lowering drugs, and no history of hemoglobin A1c levels of ≥6.5% (47-48 mmol/mol) were included. The primary outcome was the incidence of T2DM. Pooled logistic regression was used to estimate adjusted risk ratios (RRs) and 5-year cumulative incidence differences (CIDs). RESULTS: A total of 5180 participants initiated tadalafil treatment and were compared with 20,049 patients who initiated alpha-blockers. The median follow-up time for each arm was 27.2 months (interquartile range [IQR], 12.0-47.9) in tadalafil users and 31.3 months (IQR, 13.7-57.2) in alpha-blocker users. The incidence rates of T2DM in tadalafil and alpha-blocker users were 5.4 (95% confidence interval [CI], 4.0-7.2) and 8.8 (95% CI, 7.8-9.8) per 1000-person years, respectively. Initiation of tadalafil was associated with a reduced risk of T2DM (RR, 0.47; 95% CI, 0.39-0.62; 5-year CID, -0.031; 95% CI, -0.040 to -0.019). CONCLUSION: The incidence of T2DM was lower in men with BPH treated with tadalafil than in those treated with alpha-blockers. Thus, tadalafil may be more beneficial than alpha-blockers in preventing T2DM.

The effects of antihypertensive drugs on glucose metabolism.

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long-term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while ß-receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use.

Emerging drugs for the treatment of benign prostatic hyperplasia: a 2023 update.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a condition that affects over 50% of men as they enter their fifth decade of life, often leading to lower urinary tract symptoms (LUTS). Primary treatment options include alpha blockers, 5-alpha reductase inhibitors, and phosphodiesterase-5 inhibitors. However, these medications can have some side effects, and there is a noticeable dearth of information addressing the long-term use of these medications. Thus, the exploration of all treatment modalities helps ensure patients receive personalized and effective care. Consequently, the primary objective of this review is to identify potential emerging medications for the treatment of BPH. AREAS COVERED: We conducted an extensive review of articles discussing pharmacotherapy for BPH spanning the last 15 years. Our information gathering process involved Scopus, PubMed-MEDLINE, Cochrane, Wiley Online Library Google Scholar, ClinicalTrials.gov, and the PharmaProjects database. This approach ensures that readers gain an in-depth knowledge of the existing therapeutic agents as well as promising avenues for managing BPH. EXPERT OPINION: BPH treatment targets a patient's specific constellation of symptoms. Therefore, a broad knowledge base encompassing various treatment options is paramount in ensuring optimal treatment. Looking forward, the emphasis on personalization promises to reshape the landscape of BPH treatment and improve patient outcomes.

Suicide and Intentional Self-harm Among Older Men Treated With 5-Alpha Reductase Inhibitor or Alpha-blockers for Benign Prostatic Hyperplasia.

OBJECTIVE: To compare the risk of intentional self-harm (ISH) and suicide in older men using 5-α reductase inhibitors (5-ARIs) and alpha-blockers for benign prostatic hyperplasia (BPH). Observational research of older men with BPH suggested an increase in ISH with 5-ARI use compared with nonuse; we aimed to address potential confounding by indication with an active comparator reference group. METHODS: Using Medicare data linked to the National Death Index (NDI) from 2007-2016, we implemented a retrospective cohort design in males aged ≥65 years who initiated 5-ARI or alpha-blocker use for BPH. ISH was identified using ICD-9-CM and ICD-10-CM diagnosis codes. Suicides were identified through cause-of-death information from the NDI. We used inverse probability of treatment weighted Cox proportional hazards regression to compare time-to-event between treatment groups, with robust variance estimation. RESULTS: The event rates for ISH and suicide, respectively, were 0.314 and 0.308 per 1000 person-years (PY) among 5-ARI users (n = 181,675), and 0.364 and 0.382 per 1000PY among alpha-blocker users (n = 850,476). For 5-ARI use relative to alpha-blocker use, hazard ratios (HRs) for ISH and suicide, respectively, were 0.88 (95% CI:0.62-1.25) and 0.82 (95% CI:0.54-1.24); for the composite outcome (non-fatal ISH or suicide), the HR was 0.88 (95% CI:0.66-1.16). Subgroup and sensitivity analyses supported these results. CONCLUSION: 5-ARI use was not associated with an increased risk for ISH or suicide compared to alpha-blocker use in older men with BPH. Study limitations included low event rates and potentially low sensitivity for ISH events.

[Pheochromocytoma. Preoperative approach]. / Feocromocitoma y su abordaje preoperatorio.

Pheochromocytomas are rare neuroendocrine tumors that derive from the chromaffin cells of the adrenal medulla and secrete catecholamines. The measurement of plasma or fractionated urine metanephrines is the hormonal determination of choice for the biochemical diagnosis. Once the biochemical diagnosis is confirmed, the next step is the localization study. It is recommended to request a genetic study in all patients with pheochromocytomas since 40% of cases are hereditary. Once the diagnostic study is completed, preoperative treatment with alpha blockers should be instituted at least 7-14 days before adrenalectomy. However, in low-risk patients, the omission of presurgical treatment could be considered if the surgery is performed in centers with experience and a strict monitoring of the patient is carried out during the perioperative period. This document offers a practical guide on the diagnosis and perioperative approach in patients with pheochromocytomas.

Exploring pharmacological interventions in benign prostate hyperplasia: the role of cost-effectiveness analysis in daily practice and future directions.

INTRODUCTION: Benign Prostate Hyperplasia (BPH) significantly impacts men's health and quality of life, with its prevalence rising with age. This review critically examines the cost-effectiveness of pharmacological interventions for BPH to optimize patient outcomes and healthcare resource utilization. AREAS COVERED: This review explores the integration of cost-effectiveness analysis (CEA) into clinical practice, balancing clinical efficacy with economic efficiency in BPH management. We performed a critical literature search, including recent studies on the economic evaluation of BPH treatments, focusing on pharmacotherapies such as alpha-blockers and 5-alpha reductase inhibitors. Additionally, we discussed the concept of CEA and evaluated the role of medicinal reconciliation and the avoidance of polypharmacy in favor of optimal BPH treatment. EXPERT OPINION: Cost-effectiveness analysis is crucial for evaluating BPH treatments, with evidence suggesting a shift towards surgical interventions may offer greater long-term economic benefits. However, these models must be applied cautiously, considering clinical evidence and patient preferences to ensure equitable and patient-centric healthcare.

Adherence to AUA guidelines for the work-up, medical management, surgical evaluation and treatment of BPH: Work from a quality improvement collaborative.

INTRODUCTION: Previous studies noted varied adherence to clinical practice guidelines (CPGs), but studies are yet to quantify adherence to American Urological Association BPH guidelines. We studied guideline adherence in the context of a new quality improvement collaborative (QIC). METHODS: Data were collected as part of a statewide QIC. Medical records for patients undergoing select CPT codes from January 2020 to May 2022 were retrospectively reviewed for adherence to selected BPH guidelines. RESULTS: Most men were treated with transurethral resection of the prostate. Notably, 53.3% of men completed an IPSS and 52.3% had a urinalysis. 4.7% were counseled on behavioral modifications, 15.0% on medical therapy, and 100% on procedural options. For management, 79.4% were taking alpha-blockers and 59.8% were taking a 5-ARI. For evaluation, 57% had a PVR, 63.6% had prostate size measurement, 37.4% had uroflowmetry, and 12.3% were counseled about treatment failure. Postoperatively, 51.6% completed an IPSS, 57% had a PVR, 6.50% had uroflowmetry, 50.6% stopped their alpha-blocker, and 75.0% stopped their 5-ARI. CONCLUSIONS: There was adherence to preoperative testing recommendations, but patient counseling was lacking in the initial work-up and preoperative evaluation. We will convey the data to key stakeholders, expand data collection to other institutions, and devise an improvement implementation plan.

Factors Considered by Experienced Urologists when Selecting Alpha-Blockers for Patients with Lower Urinary Tract Symptoms or Benign Prostatic Hyperplasia according to Age.

INTRODUCTION: The objectives of the study were to examine the opinions of urology specialists on whether there are actual differences in efficacy among α1-blockers and to identify the factors that should be considered when prescribing these medications according to age. METHODS: We surveyed 50 South Korean urology specialists with over 3 years of clinical experience in secondary or tertiary hospitals in July-August 2021. The survey covered urologists' demographics, awareness of α1-blocker prescription differences, and key factors in α1-blocker selection based on LUTS severity and patient age. RESULTS: Overall, 82% of the respondents believed that there were differences in the efficacy of α1-blockers in actual practice according to age. Over 90% of the respondents agreed on the need for head-to-head comparison studies to compare the effects of different α1-blockers. Regardless of the severity of LUTS, urologists prioritize cardiovascular side effects when prescribing α1-blockers to patients aged ≥70 years. Further, 19% of the urologists prioritized ejaculatory side effects for mild-to-moderate LUTS and 9% for severe LUTS (p < 0.001). CONCLUSIONS: This study shows that head-to-head studies comparing the efficacy of different α1-blockers are highly valuable for the real-world clinical application of α1-blockers. Notably, urologists prioritize cardiovascular and ejaculatory side effects in older and younger patients while prescribing α1-blockers, respectively.

Efficacy and Safety of Vibegron for Persistent Symptoms of Overactive Bladder in Men Being Pharmacologically Treated for Benign Prostatic Hyperplasia: Results From the Phase 3 Randomized Controlled COURAGE Trial.

PURPOSE: The efficacy and safety of vibegron, a ß3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. MATERIALS AND METHODS: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). RESULTS: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Score‒storage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). CONCLUSIONS: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.

Comparative efficacy and safety of alpha-blockers as monotherapy for benign prostatic hyperplasia: a systematic review and network meta-analysis.

Despite the availability of various drugs for benign prostatic hyperplasia (BPH), alpha(α)-blockers are the preferred first-line treatment. However, there remains a scarcity of direct comparisons among various α-blockers. Therefore, this network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to evaluate the efficacy and safety of α-blockers in the management of BPH. A comprehensive electronic search covered PubMed, Embase, Ovid MEDLINE, and Cochrane Library until August 2023. The primary endpoints comprised international prostate symptom score (IPSS), maximum flow rate (Qmax), quality of life (QoL), and post-void residual volume (PVR), while treatment-emergent adverse events (TEAEs) were considered as secondary endpoints. This NMA synthesized evidence from 22 studies covering 3371 patients with six kinds of α-blockers with 12 dose categories. IPSS has been considerably improved by tamsulosin 0.4 mg, naftopidil 50 mg and silodosin 8 mg as compared to the placebo. Based on the p-score, tamsulosin 0.4 mg had the highest probability of ranking for IPSS, PVR, and Qmax, whereas doxazosin 8 mg had the highest probability of improving QoL. A total of 297 adverse events were reported among all the α-blockers, silodosin has reported a notable number of TEAEs. Current evidence supports α-blockers are effective in IPSS reduction and are considered safer. Larger sample size with long-term studies are needed to refine estimates of IPSS, QoL, PVR, and Qmax outcomes in α-blocker users.

Comparison of the efficacy and complications of tolterodine and α-adrenergic receptor blockers in improving ureteral stent-related symptoms: A systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic evaluation of the therapeutic efficacy and complications of tolterodine and α-adrenergic receptor blockers in alleviating ureteral stent-related symptoms. METHODS: Until August 2023, we conducted a comprehensive literature search on PubMed, Embase, Web of Science, and Cochrane Library to identify randomized controlled trials evaluating the efficacy and complications of tolterodine and α-adrenergic receptor blockers in treating ureteral stent-related symptoms. Two reviewers independently screened studies and extracted data. The scores from various domains of the Ureteral Stent Symptom Questionnaire (USSQ) were summarized and compared, and statistical analysis was performed using RevMan 5.4.0 software. RESULTS: A total of 8 studies met the inclusion criteria for our analysis. These studies were conducted at different centers. All studies were randomized controlled trials, involving a total of 487 patients, with 244 patients receiving α-adrenergic receptor blockers and 243 patients receiving tolterodine. The results showed that tolterodine demonstrated significantly better improvement in body pain (MD, 1.56; 95% CI [0.46, 2.66]; p = 0.005) (MD, 0.46; 95% CI [0.12, 0.80]; p = 0.008) (MD, 3.21; 95% CI [1.89, 4.52]; p = 0.00001) among patients after ureteral stent placement compared to α-adrenergic receptor blockers at different time points. Additionally, at 4 weeks, tolterodine showed superior improvement in general health (MD, 0.15; 95% CI [0.03, 0.27]; p = 0.01) and urinary symptoms (MD, 1.62; 95% CI [0.59, 2.66]; p = 0.002) compared to α-adrenergic receptor blockers, while at 6 weeks, tolterodine showed better improvement in work performance (MD, -1.60; 95% CI [-2.73, -0.48]; p = 0.005) compared to α-adrenergic receptor blockers. Additionally, the incidence of dry mouth (RR, 4.21; 95% CI [1.38, 12.87]; p = 0.01) is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, there were no significant statistical differences between the two drugs in other outcomes. CONCLUSION: This meta-analysis suggests that tolterodine is superior to α-adrenergic receptor blockers in improving physical pain symptoms after ureteral stent placement, while α-adrenergic receptor blockers are more effective than tolterodine in enhancing work performance. Additionally, the incidence of dry mouth is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, higher-quality randomized controlled trials are needed to further investigate this issue.

Do alpha blockers reduce the risk of urinary retention post-transperineal prostate biopsy? A systematic narrative review.

BACKGROUND: Transperineal Prostate Biopsy (TPB) is a commonly used technique for the diagnosis of prostate cancer due to growing concerns related to infectious complications associated with transrectal ultrasound-guided prostate biopsy (TRUSB). TPB is associated with an infective complication rate of near zero, however, acute urinary retention (AUR) remains the leading complication causing morbidity. Previously in TRUSB, there was weak evidence that alpha-blockers reduce AUR rates, and their usage has been extrapolated to clinical practice with TPB. This review aims to explore if there is an evidence base for using alpha-blockers to prevent AUR following TPB. METHODS: A systematic approach was used to search Ovid Medline and Embase using keywords related to "Transperineal" and "Retention". Articles were then screened by applying inclusion and exclusion criteria to find studies that compared alpha-blocker recipients to no alpha-blocker use in the perioperative period and the subsequent effect on AUR in TPB. RESULTS: 361 records were identified in the initial search to produce 5 studies included in the final review. No randomised controlled trials (RCTs) were identified. One observational study showed a reduction in AUR rate from 12.5% to 5.3% with a single dose of tamsulosin. A previous systematic review of complications associated with prostate biopsy concluded there may be a potential benefit to alpha-blockers given in the TPB perioperative period. Three observational studies demonstrated a harmful effect related to alpha-blocker use; however, this was well explained by their clear limitations. CONCLUSION: Based on this review and the extrapolation from TRUSB data, perioperative alpha-blockers may offer some weak benefits in preventing AUR following TPB. However, there is significant scope and need for an RCT to further develop the evidence base further given the significant gap in the literature and lack of a standard alpha blocker protocol in TPB.

Medical management of benign prostatic hyperplasia.

Medical management of benign prostatic hyperplasia (BPH) has progressed gradually in recent years and remains the starting point for most symptomatic patients seeking treatment. Beyond well-known alpha-blockers and 5-alpha reductase inhibitors, there is growing evidence for the use of phosphodiesterase-5 inhibitors and beta-3 agonists in managing the condition, which may afford additional relief of "bothersome" symptoms in some patients. This review details contemporary medical management of BPH with an emphasis on the indications for certain classes of pharmacotherapy and their relative benefits and side effects. Surgical and procedural treatment of BPH is covered in a separate review.

Medical Advancements in Benign Prostatic Hyperplasia Treatments.

PURPOSE OF REVIEW: This review aims to identify and summarize the current literature on the most recent therapeutic agents and combination strategies for the medical management of lower urinary tract symptoms resulting from benign prostatic hyperplasia. RECENT FINDINGS: The latest advancements in BPH therapy have been in combination strategies. Alpha blockers continue to be the mainstay of treatment, but research is exploring the synergistic benefits of combining them with 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase-5 (PDE5) inhibitors, and beta-3 agonists. The alpha-blocker + 5-ARI combination remains ideal for enlarged, significantly reducing clinical progression risk compared to monotherapy. Alpha-blocker + PDE5 inhibitor combinations appear safe and potentially beneficial for men with concomitant erectile dysfunction; sildenafil might hold an edge over tadalafil based on limited data. Beta-3 agonists show synergistic effects with alpha blockers for residual storage symptoms, offering similar efficacy to anticholinergics but with a better side effect profile.

Use of 5-alpha reductase inhibitors and risk of gastrointestinal cancers in men with benign prostatic hyperplasia: A population-based cohort study.

Pre-clinical evidence suggests that 5-alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro-oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro-oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha-blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro-oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro-oesophageal cancer associated with the use of 5ARi's compared to alpha-blockers. During a mean follow-up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91-1.41) or gastro-oesophageal (HR 1.14, 95% CI 0.76-1.63) cancer risk compared to alpha-blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro-oesophageal cancer in men with benign prostatic hyperplasia.

Changes in benign prostatic hyperplasia management in Valencia: a real-world evidence analysis.

INTRODUCTION AND OBJECTIVES: A training program was developed to increase general practitioners' engagement in the optimal management of Benign Prostatic Hyperplasia (BPH). The goal of this study was to evaluate changes in BPH management after the implementation of a training program. MATERIAL AND METHODS: This observational retrospective cohort study was conducted between 2019 and 2020. Aggregated data were analyzed in three evaluation periods (2010, 2012 and 2015), addressing quality indicators for diagnosis, treatment, and treatment outcomes. RESULTS: Overall, 118 795 patients who presented any data points were included. All quality indicators (number of IPSS and PSA determinations) increased between the first period and the last. Combination (α-blocker + 5-ARI) therapy was increasingly prescribed during the study periods whereas the proportion of prescriptions for single-agent α-blocker showed no significant differences among the periods analyzed. However, the total number of patients eligible for combination therapy who actually received this treatment was low in all periods (7.5%, 17.9%, and 20.1%, in 2010, 2012, and 2015, respectively). The outcome indicators revealed a decrease in referrals to the urology unit mostly among newly diagnosed patients. Even though the proportion of patients who underwent BPH-related surgeries increased significantly from the first to the second period, the number of surgeries remained stable between the second and third periods. CONCLUSIONS: The training program had a generally positive impact on the management of BPH patients in PC, but the overall study period may be insufficient to show an effect on some outcome indicators such as the number of surgeries.

Alpha-blockers: the magic pill for endourology-The great delusion.

PURPOSE: The present paper takes a different and more critical look at the role of alpha-blockers, sometimes nicknamed as "magical pills", in particular for stone disease and medical expulsive therapy (MET). METHODS: A non-systematic narrative review was performed, synthesizing pertinent information from selected articles, and critically evaluating their conclusions. Sometimes different views on alpha-blockers were laid bare, including curiosities or other entertaining nuances suitable to the present topic, but always maintaining sharp objectivity and the foremost scientific rigor. RESULTS AND CONCLUSIONS: Alpha-blockers seem to be a panacea, being used to treat a wide variety of non-urological diseases and conditions. Urological applications include erectile dysfunction to benign prostatic hyperplasia, from incontinence to urinary retention, or even to facilitate urinary stone passage along the urinary tract. Due to its versatility, alpha-blockers appear to be the Swiss army knife of urological medications. However, the efficacy of alpha-blockers for MET, pain management, or facilitating upper tract access is very disappointing, bringing no, or in some instances, only marginal benefits. Their treatment results are far from being significant or impressive let alone magical. Regular sexual intercourse is an effective alternative to alpha-blockers, providing faster ureteral stone expulsion rates and reducing the need for pain medication. Most of the research supporting alpha-blockers has been based on single-center, underpowered, low-quality studies. These low-quality studies biased several subsequent meta-analyses, contaminating them with their low-quality data, enhancing and prolonging this delusion. These results emphasize the need for large, multi-centric, unbiased, randomized, double-blinded, placebo-controlled trials to prevent future year-long delusions that may afflict any medical field.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

BACKGROUND: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. METHOD: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. RESULTS: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. CONCLUSIONS: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.

[PHYTOTHERAPY AND NATURAL AGENTS IN SYMPTOMATIC BENIGN PROSTATIC HYPERPLASIA (BPH)].

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a very common condition among men over 50 years of age. Some patients require immediate surgical intervention for urinary retention. However, most men have a variety of symptoms that may require treatment. Medical therapy for BPH has been well known for many years including alpha-adrenergic receptor blockers and 5-alpha reductase inhibitors. In recent years, men also receive anti-cholinergic agents, PDE5 inhibitors and other medical interventions. However, many men pursue alternative treatments and herbal medicines for BPH. We review herbs and herbal medicines that are used worldwide for symptomatic BPH. Many of them are supported by laboratory and clinical data. Mostly, mechanism of action are not fully understood but clinical benefit does support their use. Serenoa repens in hexanic extract (Permixon) is the only medicine that is backed with clinical data in high-quality clinical trials.

Immediate effect of alpha-blockers in predicting LUTS improvement in BPH patients.

INTRODUCTION: Indications for treating Benign Prostatic Hyperplasia include reversing signs and symptoms or preventing the progression of the disease. Alpha-blockers are the most effective, least costly, and best tolerated of the drugs for relieving LUTS. The aim of the study is to investigate the immediate impact of alpha-blocker medications on lower urinary tract symptoms (LUTS). MATERIALS AND METHODOLOGY: About 100 patients were included in the study-50 patients in each of the groups A (tamsulosin) and B (silodosin). The first visit was the baseline examination before starting alpha-blockers and included history, DRE, UFM, USG KUBP with PVR, IPSS, serum PSA, serum creatinine, urine analysis, urine culture, and sensitivity. All above parameters were also at 1 week, 1 month, and 3 months following starting of alpha-blockers respectively, and compared with baseline. RESULT: As of the first, second, third, and fourth visits, the mean Qmax in group A was 10.3 ± 3.3 s, 15.08 ± 2.80 s, 15.66 ± 3.18 s, and 15.12 ± 3.24 s, respectively, while in group B it was 10.1 ± 3.1 s, 14.88 ± 2.80 s, 15.18 ± 3.18 s, and 15.08 ± 3.24 s, respectively (p < 0.001). The mean voiding time was 40.87 ± 23.91 s, 36.41 ± 20.73 s, 34.85 ± 21.37 s, and 32.07 ± 21.81 s, respectively in group A, and 41.27 ± 15.49 s, 37.23 ± 21.34 s, 38.59 ± 20.83 s, and 33.10 ±22.08. In group A, the mean PVR and IPSS scores were improved and also improved in group B. CONCLUSION: The first dose of tamsulosin and silodosin improves UFM and predicts the mid-term change in UFM as well as IPSS indices in the treatment of BPH-related LUTS.