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1.
Hum Genomics ; 18(1): 49, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38778357

ABSTRACT

BACKGROUND: Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. METHODS: A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. RESULTS: Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. CONCLUSIONS: In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.


Subject(s)
Genetic Predisposition to Disease , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Prostatic Hyperplasia , Humans , Male , Prostatic Hyperplasia/genetics , Prostatic Hyperplasia/pathology , Aged , Middle Aged , Polymorphism, Single Nucleotide/genetics , Retrospective Studies , Multifactorial Inheritance/genetics , Asian People/genetics , Risk Factors , 5-alpha Reductase Inhibitors/therapeutic use , Prostate-Specific Antigen/blood , Prostate-Specific Antigen/genetics , Taiwan/epidemiology , Prognosis , Prostate/pathology , Genetic Risk Score , East Asian People
2.
J Ethnopharmacol ; 330: 118207, 2024 Aug 10.
Article in English | MEDLINE | ID: mdl-38636573

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Benign prostatic hyperplasia (BPH), characterized by prostate enlargement due to cell proliferation, is a common urinary disorder in men over 50, manifesting as lower urinary tract symptoms (LUTS). Currently, several therapeutic options are accessible for treating BPH, including medication therapy, surgery and watchful waiting. Conventional drugs such as finasteride and dutasteride are used as 5α-reductase inhibitors for the treatment of BPH. However long-term use of these drugs is restricted due to their unpleasant side effects. Despite the range of available medical therapies, the effective treatment against BPH is still inadequate. Certain therapeutic plants and their phytochemicals have the aforementioned goals and work by regulating this enzyme. AIM OF THE STUDY: This review aims to provide a comprehensive insight to advancements in diagnosis of BPH, modern treatment methods and the significance of ethnobotanically relevant medicinal plants as alternative therapeutics for managing BPH. MATERIAL AND METHODS: A thorough and systematic literature search was performed using electronic databases and search engines such as PubMed, Web of Science, NCBI and SciFinder till October 2023. Specific keywords such as "benign prostatic hyperplasia", "medicinal plants", "phytochemicals", "pharmacology", "synergy", "ethnobotany", "5-alpha reductase", "alpha blocker" and "toxicology". By include these keywords, a thorough investigation of pertinent papers was assured, and important data about the many facets of BPH could be retrieved. RESULTS: After conducting the above investigation, 104 herbal remedies were found to inhibit Phosphodiesterase-5 (PDE-5) inhibition, alpha-blockers, or 5α -reductase inhibition effects which are supported by in vitro, in vivo and clinical trial studies evidence. Of these, 89 plants have ethnobotanical significance as alpha-blockers, alpha-reductase inhibition, or PDE-5 inhibition, and the other fifteen plants were chosen based on their ability to reduce BPH risk factors. Several phytocompounds, including, rutaecarpine, vaccarin, rutin, kaempferol, ß-sitosterol, quercetin, dicaffeoylquinic acid, rutaevin, and phytosterol-F have been reported to be useful for the management of BPH. The use of combination therapy offers a strong approach to treating long-term conditions compare to single plant extract drugs. Furthermore, several botanical combinations such as lycopene and curcumin, pumpkin seed oil and saw palmetto oil, combinations of extracts from Funtumia africana (Benth.) Stapf and Abutilon mauritianum (Jacq.) Medik., and Hypselodelphys poggeana (K.Schum.) Milne-Redh. and Spermacoce radiata (DC.) Sieber ex Hiern are also supported through in vitro and in vivo studies for managing BPH through recuperation in patients with chronic long-term illnesses, as measured by the International Prostate Symptom Score. CONCLUSION: The review proposes and endorses careful utilization of conventional medications that may be investigated further to discover possible PDE-5, 5 alpha-reductase, an alpha-blocker inhibitor for managing BPH. Even though most conventional formulations, such as 5 alpha-reductase, are readily available, systemic assessment of the effectiveness and mechanism of action of the herbal constituents is still necessary to identify novel chemical moieties that can be further developed for maximum efficacy. However, there exist abundant botanicals and medicinal plants across several regions of Africa, Asia, and the Americas, which can be further studied and developed for utilization as a potential phytotherapeutic for the management of BPH.


Subject(s)
Phytochemicals , Plants, Medicinal , Prostatic Hyperplasia , Prostatic Hyperplasia/drug therapy , Humans , Male , Phytochemicals/therapeutic use , Phytochemicals/pharmacology , Plants, Medicinal/chemistry , Animals , Phytotherapy/methods , Plant Extracts/therapeutic use , Plant Extracts/pharmacology , 5-alpha Reductase Inhibitors/therapeutic use , 5-alpha Reductase Inhibitors/pharmacology
3.
Zhongguo Zhong Yao Za Zhi ; 49(4): 858-867, 2024 Feb.
Article in Chinese | MEDLINE | ID: mdl-38621893

ABSTRACT

Benign prostatic hyperplasia(BPH) is a common disease of the male urinary system, and its incidence rate in China is increasing. However, the mechanism underlying the pathogenesis of BPH remains unclear. Some studies demonstrated that the incidence of BPH was related to the change in the levels of steroid hormones. Too high content of dihydrotestosterone(DHT) in the body may cause BPH and other related diseases. Testosterone(T) is converted to DHT by 5α-reductase(SRD5A). By inhibiting the activity of this enzyme, the production of DHT can be reduced, and then the incidence of BPH can be lowered. Therefore, it has drawn great attention to screen and discover safer and more effective 5α-reductase inhibitors from natural medicines to treat prostatic hyperplasia without affecting the physiological function of men. This review summarizes the characteristics and tissue distribution of 5α-reductase, the discovery of 5α-reductase inhibitors in traditional Chinese medicine and natural medicines, 5α-reductase inhibitors commonly used in clinical practice and their side effects, as well as the animal models of prostatic hyperplasia and common detection indicators, aiming to provide a reference for more in-depth understanding and research about BPH and development of drugs.


Subject(s)
5-alpha Reductase Inhibitors , Prostatic Hyperplasia , Animals , Humans , Male , 5-alpha Reductase Inhibitors/therapeutic use , Cholestenone 5 alpha-Reductase , Dihydrotestosterone , Prostatic Hyperplasia/drug therapy , Testosterone
4.
Cleve Clin J Med ; 91(3): 163-170, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38429006

ABSTRACT

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.


Subject(s)
Prostatic Hyperplasia , Male , Humans , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/diagnosis , 5-alpha Reductase Inhibitors/therapeutic use , Adrenergic alpha-Antagonists/therapeutic use
5.
J Dermatol ; 51(5): 684-690, 2024 May.
Article in English | MEDLINE | ID: mdl-38321615

ABSTRACT

Dutasteride 0.5 mg is a dual inhibitor of 5α-reductase type I and II and was approved in Korea in 2009 for treating androgenetic alopecia (AGA) in men. We investigated the 5-year efficacy and safety of dutasteride 0.5 mg in Korean men with AGA using the basic and specific (BASP) classification. This retrospective analysis included 99 male AGA patients aged ≥18 years who were treated with dutasteride 0.5 mg for at least 5 years from October 2009 to December 2016 at Kyung Hee University Hospital in Gangdong. Patient photographs were scored using the BASP classification, and the Investigator Global Assessment (IGA) was performed using a seven-point scale. Patient improvement (IGA score ≥1) and prevention of disease progression (IGA score ≥0) were 89.9% (89/99) and 93.9% (93/99), respectively. According to the BASP classification, 52.5% (52/99) of the basic type, 75% (15/20) of the specific F type, and 82.2% (60/73) of the specific V type showed clinical improvement after 5 years of treatment. Dutasteride demonstrated long-term safety and efficacy in Korean male patients with AGA over a period of at least 5 years, with results comparable to those of other long-term efficacy studies of finasteride 1 mg in male patients with AGA.


Subject(s)
5-alpha Reductase Inhibitors , Alopecia , Dutasteride , Humans , Male , Alopecia/drug therapy , Dutasteride/adverse effects , Dutasteride/administration & dosage , Dutasteride/therapeutic use , Retrospective Studies , Adult , 5-alpha Reductase Inhibitors/adverse effects , 5-alpha Reductase Inhibitors/administration & dosage , 5-alpha Reductase Inhibitors/therapeutic use , Republic of Korea , Middle Aged , Treatment Outcome , Young Adult , Disease Progression , Time Factors , Aged
6.
World J Urol ; 42(1): 70, 2024 Feb 03.
Article in English | MEDLINE | ID: mdl-38308714

ABSTRACT

PURPOSE: To compare the urological and sexual outcomes of using either tamsulosin/finateride or tadalafil/finasteride as combination therapies in patients with large prostate. PATIENTS AND METHODS: Selection criteria included prostate volume > 40 ml and IPSS > 7. Patients with severe erectile dysfunction (IIEF-erectile functions ≤ 10) were excluded. Patients were randomized into group I (tamsulosin/finasteride) and group II (tadalafil/finasteride). The primary endpoint was to define urinary and sexual function changes (IPSS, IPSS-quality of life, urinary flow rates and IIEF domains) within each group. The secondary endpoint was to compare the treatment induced changes between both groups. RESULTS: At 4th and 12th weeks, 131 and 127 patients were available in both groups, respectively. Both groups showed significant LUTS improvement (IPSS changes: - 4.9 ± 2.7 and - 4.3 ± 2.9 at 4th week and - 6.1 ± 3 and - 5.4 ± 2.8 points by the 12th week in both groups, respectively). Group I had better average flow rates at both follow-up visits. Meanwhile, maximum flow rates were comparable in both groups at 12th week (13.5 ± 3.9vs. 12.6 ± 3.7, p > 0.05). In group I, all IIEF domains were significantly lowered at both visits (p < 0.05). Group II showed significant increase in IIEF-erectile function scores (1.3 ± 1.1 and 1.8 ± 1.2 at the 4th and 12th weeks) with a transient significant reduction of IIEF-orgasm and sexual desire noted only by the 4th week (- 0.8 ± 0.4 and - 0.6 ± 0.4, respectively). CONCLUSION: Within three months, both combinations are comparably effective in improving BPH related LUTS. Tamsulosin/finasteride provided significantly better Qmax only at 4th week. Tadalafil/finasteride had the advantage of improving sexual performance over the other combination.


Subject(s)
Erectile Dysfunction , Lower Urinary Tract Symptoms , Prostatic Hyperplasia , Humans , Male , 5-alpha Reductase Inhibitors/therapeutic use , Drug Therapy, Combination , Erectile Dysfunction/prevention & control , Finasteride/therapeutic use , Lower Urinary Tract Symptoms/prevention & control , Prostatic Hyperplasia/complications , Prostatic Hyperplasia/drug therapy , Quality of Life , Tadalafil/therapeutic use , Tamsulosin/therapeutic use , Treatment Outcome
7.
J Dermatol ; 51(4): 552-557, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38293734

ABSTRACT

Finasteride is commonly used for androgenetic alopecia (AGA) treatment. The aim of this study was to assess the therapeutic maintenance effect of a finasteride every other month (EOM) regimen and analyze clinical and laboratory differences in patients with AGA according to their treatment response. One hundred males with AGA who received finasteride 1 mg daily treatment for a year were enrolled in the study. At 1 year follow-up, treatment responses of patients who completed the visit schedule were assessed using five scales. The patients were assigned to good or bad response groups according to their assessment. Further, they were randomly divided into two groups (daily vs. EOM) and treated with finasteride (1 mg) for 1 more year. At 2 years follow-up, treatment efficacy was assessed. At 1-year follow-up, 36 patients completed the schedule, including eight and three patients in the good and bad response groups, respectively. At the 2-year follow-up, 23 patients completed the schedule, with nine in the daily group and 14 in the EOM group. Changes in global photographic assessment in the second year were 1.33 and 1.29 for the daily and EOM groups, respectively. The daily group showed an elevated hair density and lower concentration of dihydrotestosterone (DHT) and the DHT to testosterone ratio (DHT/T). However, the EOM group showed decreased hair density and elevated DHT and DHT/T. Following treatment response assessment after 1 year of treatment, the good response group showed early onset which was associated with maternal AGA. Analysis of serum androgen hormone magnitude of DHT reduction was much greater (54.4% vs. 44.4%). DHT/T was higher in the bad response group (1.98 vs. 2.33). We concluded that the finasteride EOM regimen showed similar maintenance effects to the daily regimen.


Subject(s)
Alopecia , Finasteride , Male , Humans , Finasteride/therapeutic use , Prospective Studies , Alopecia/chemically induced , Hair , Dihydrotestosterone/pharmacology , Dihydrotestosterone/therapeutic use , 5-alpha Reductase Inhibitors/therapeutic use
8.
Prostate ; 84(5): 441-459, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38168866

ABSTRACT

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.


Subject(s)
5-alpha Reductase Inhibitors , Prostatic Hyperplasia , Male , Humans , 5-alpha Reductase Inhibitors/pharmacology , 5-alpha Reductase Inhibitors/therapeutic use , Prostate/pathology , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/genetics , Prostatic Hyperplasia/pathology , Critical Pathways , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Interleukin-13/therapeutic use , Interleukin-6 , Hedgehog Proteins , Adrenergic alpha-Antagonists/therapeutic use , Gene Expression Profiling , Drug Therapy, Combination , Chromatin
9.
Eur Urol Oncol ; 7(3): 376-400, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38277189

ABSTRACT

CONTEXT: Active surveillance (AS) is a standard of care for patients with low-risk and selected intermediate-risk prostate cancer (PCa). Nevertheless, there is a lack of summary evidence on how to impact disease trajectory during AS. OBJECTIVE: To assess which interventions prevent PCa progression effectively during AS. EVIDENCE ACQUISITION: We queried PubMed, Scopus, and Web of Science databases to identify studies examining the impact of interventions aimed at slowing disease progression during AS. The primary endpoint was PCa progression, the definition of which must have included pathological upgrading. The secondary endpoint included treatment toxicities. EVIDENCE SYNTHESIS: We identified 22 studies, six randomized controlled trials and 16 observational studies, which analyzed the association between different interventions and PCa progression during AS. The interventions considered in the studies included 5-alpha reductase inhibitors (5-ARIs), statins, diet, exercise, chlormadinone, fexapotide triflutate (FT), enzalutamide, coffee, vitamin D3, and PROSTVAC. We found that administration of 5-ARIs was associated with improved progression-free survival (PFS; hazard ratio: 0.59; 95% confidence interval 0.48-0.72), with no increased toxicity signals. Therapies such as vitamin D3, chlormadinone, FT, and enzalutamide have shown some efficacy. However, these anticancer drugs have been associated with treatment-related adverse events in up to 88% of patients. CONCLUSIONS: The use of 5-ARIs in PCa patients on AS is associated with longer PFS. However, for the other interventions, it is difficult to draw clear conclusions based on the weak available evidence. PATIENT SUMMARY: Patients with prostate cancer managed with active surveillance (AS) who are treated with 5-alpha reductase inhibitors have a lower risk of disease progression, with minimal adverse events. Other interventions require more studies to determine their efficacy and safety profile in men on AS.


Subject(s)
Disease Progression , Prostatic Neoplasms , Watchful Waiting , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , 5-alpha Reductase Inhibitors/therapeutic use
10.
J Cosmet Dermatol ; 23(1): 154-160, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37386777

ABSTRACT

BACKGROUND: Minoxidil and the 5-alpha reductase inhibitors (5-ARIs), specifically, dutasteride and finasteride, are usually used to treat pattern hair loss (PHL), but evidence on the relative effectiveness of these drugs is far less for women than men. AIMS: We performed an age-adjusted network meta-analysis (NMA) to determine the comparative efficacy of monotherapy with the three agents-in any dosage and administrative route-on PHL in adult women. METHODS: The peer-reviewed literature was systematically reviewed to obtain data for our NMA. The outcome measure for our NMA was "change in total hair density." We referred to "regimen" as an "agent and its dosage;" our Bayesian NMA estimated regimens' surface under the cumulative ranking curve (SUCRA) values and pairwise relative effects. RESULTS: Our NMA used data from 13 trials-across which the following 10 regimens were identified (in decreasing order of SUCRA): 5 mg/day finasteride for 24 weeks (SUCRA = 95.7%), 5% topical minoxidil solution twice daily for 24 weeks (SUCRA = 89.5%), 1 mg/day minoxidil for 24 weeks (SUCRA = 78.1%), 5% topical minoxidil foam 1 half capful/day for 24 weeks (SUCRA = 66.5%), 3% topical minoxidil solution 1 mL twice daily for 24 weeks (SUCRA = 45.1%), 2% topical minoxidil solution 1 mL twice daily for 24 weeks (SUCRA = 44.6%), 5% topical minoxidil solution 1 mL/day for 24 weeks (SUCRA = 41.7%), 0.25 mg/day minoxidil for 24 weeks (SUCRA = 35.5%), 1.25 mg/day finasteride for 24 weeks (SUCRA = 24.8%) and 1 mg/day finasteride for 24 weeks (SUCRA = 4.3%). CONCLUSION: Our findings can improve clinical guidelines and help dermatologists manage female PHL more optimally with the available options.


Subject(s)
5-alpha Reductase Inhibitors , Minoxidil , Male , Adult , Female , Humans , 5-alpha Reductase Inhibitors/therapeutic use , Finasteride/therapeutic use , Network Meta-Analysis , Bayes Theorem , Treatment Outcome , Alopecia/drug therapy
11.
Prostate ; 84(4): 403-413, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38149792

ABSTRACT

BACKGROUND: It is uncertain how long combination therapy should be continued in patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). We investigated the withdrawal effects of α1-adrenergic receptor blocker (AB) or 5α-reductase inhibitor (5ARI) following successful combination therapy. METHODS: This prospective, randomized, open-label, parallel trial enrolled 222 patients with BPH/LUTS who showed at least a seven-point improvement in International Prostate Symptom Score-total (IPSS-T) and a ≥ 20% reduction in prostate volume (PV) following the initiation of combination therapy. Patients were randomized in a 1:1:1 ratio into continued-combination, AB-withdrawal, and 5ARI-withdrawal groups. IPSS, overactive bladder symptom score, EuroQol-five-dimensional questionnaire (EQ-5D-5L), EuroQol-visual analog scale (EQ-VAS), prostate volume (PV), maximal flow rate, postvoid residual urine (PVR), and prostate-specific antigen level were assessed every 6 months for 24 months. The predictors of IPSS-T deterioration were evaluated. RESULTS: At Month 24, IPSS-T deterioration (≥2 point) was observed in 20/72 (27.8%) and 19/72 (26.4%) patients in the AB- and 5ARI-withdrawal groups, respectively. Among them, 4/72 (5.6%) and 4/70 (5.7%) patients required readdition of the withdrawn drug (p = 0.868). In the continued combination group, EQ-VAS improved at Month 24 compared to baseline (p = 0.028). At Month 24, the AB-withdrawal group showed improvements in EQ-5D-5L, EQ-VAS, and PVR (all p < 0.005), while the 5ARI-withdrawal group showed improvement in IPSS-S (p = 0.011). Diabetes mellitus was associated with IPSS-T deterioration at Month 24 (p = 0.020). CONCLUSIONS: In patients with BPH/LUTS who are reluctant to continue combination therapy, AB or 5ARI withdrawal may be offered in men with improvement in IPSS-T by at least seven points and reduction in PV by at least 20%.


Subject(s)
Lower Urinary Tract Symptoms , Prostatic Hyperplasia , Urinary Retention , Male , Humans , Prostatic Hyperplasia/drug therapy , Prospective Studies , Drug Therapy, Combination , 5-alpha Reductase Inhibitors/therapeutic use , Adrenergic alpha-Antagonists/therapeutic use , Lower Urinary Tract Symptoms/etiology , Urinary Retention/etiology , Oxidoreductases/therapeutic use , Treatment Outcome
12.
Future Med Chem ; 15(23): 2149-2163, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37955117

ABSTRACT

Background: 5α-Reductase type II (5αR2) inhibition is a promising strategy for benign prostatic hyperplasia treatment. A computational approach including virtual screening, ligand-based 3D pharmacophore modeling, 2D quantitative structure-activity relationship and molecular docking simulations were adopted to develop novel inhibitors. Results: Hits were first filtered via the validated pharmacophore and 2D quantitative structure-activity relationship models. Docking on the recently determined cocrystallized structure of 5αR2 showed three promising hits. Visual inspection results were compared with finasteride ligand and dihydrotestosterone as reference, to explain the role of binding to Glu57 and Tyr91 for 5αR2 selective inhibition. Conclusion: Alignment between Hit 2 and finasteride in the binding pocket showed similar binding modes. The biological activity prediction showed antitumor and androgen targeting activity of the new hits.


Subject(s)
Prostatic Hyperplasia , Male , Humans , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/pathology , 5-alpha Reductase Inhibitors/pharmacology , 5-alpha Reductase Inhibitors/therapeutic use , Finasteride/pharmacology , Finasteride/therapeutic use , Molecular Docking Simulation , Ligands , Quantitative Structure-Activity Relationship
13.
Curr Urol Rep ; 24(12): 579-589, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37987980

ABSTRACT

PURPOSE OF REVIEW: Despite the widespread utilization of 5-alpha reductase inhibitors (5-ARIs) for managing benign prostatic hyperplasia (BPH), certain BPH patients exhibit unresponsiveness to 5-ARIs therapy. This paper provides a comprehensive overview of the current perspectives on the mechanisms of 5-ARIs resistance in BPH patients and integrates potential biomarkers and underlying therapeutic options for 5-ARIs resistance. These findings may facilitate the development of novel or optimize more effective treatment options, and promote personalized medicine for BPH. RECENT FINDINGS: The pathways contributing to resistance against 5-ARIs in certain BPH patients encompass epigenetic modifications, shifts in hormone levels, autophagic processes, and variations in androgen receptor structures, and these pathways may ultimately be attributed to inflammation. Promisingly, novel biomarkers, including intravesical prostatic protrusion, inflammatory factors, and single nucleotide polymorphisms, may offer predictive insights into the responsiveness to 5-ARIs therapy, empowering physicians to fine-tune treatment strategies. Additionally, on the horizon, GV1001 and mTOR inhibitors have emerged as potential alternative therapeutic modalities for addressing BPH in the future. After extensive investigation into BPH's pathological processes and molecular landscape, it is now recognized that diverse pathophysiological mechanisms may contribute to different BPH subtypes among individuals. This insight necessitates the adoption of personalized treatment strategies, moving beyond the prevailing one-size-fits-all paradigm centered around 5-ARIs. The imperative for early identification of individuals prone to treatment resistance will drive physicians to proactively stratify risk and adapt treatment tactics in future practice. This personalized medicine approach marks a progression from the current standard treatment model, emerging as the future trajectory in BPH management.


Subject(s)
Prostatic Hyperplasia , Male , Humans , Prostatic Hyperplasia/drug therapy , Precision Medicine , 5-alpha Reductase Inhibitors/therapeutic use , 5-alpha Reductase Inhibitors/adverse effects , Prostate/pathology , Biomarkers
14.
World J Urol ; 41(11): 2967-2974, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37787941

ABSTRACT

PURPOSE: The primary aim of this study was to evaluate if exposure to 5-alpha-reductase inhibitors (5-ARIs) modifies the effect of MRI for the diagnosis of clinically significant Prostate Cancer (csPCa) (ISUP Gleason grade ≥ 2). METHODS: This study is a multicenter cohort study including patients undergoing prostate biopsy and MRI at 24 institutions between 2013 and 2022. Multivariable analysis predicting csPCa with an interaction term between 5-ARIs and PIRADS score was performed. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values of MRI were compared in treated and untreated patients. RESULTS: 705 patients (9%) were treated with 5-ARIs [median age 69 years, Interquartile range (IQR): 65, 73; median PSA 6.3 ng/ml, IQR 4.0, 9.0; median prostate volume 53 ml, IQR 40, 72] and 6913 were 5-ARIs naïve (age 66 years, IQR 60, 71; PSA 6.5 ng/ml, IQR 4.8, 9.0; prostate volume 50 ml, IQR 37, 65). MRI showed PIRADS 1-2, 3, 4, and 5 lesions in 141 (20%), 158 (22%), 258 (37%), and 148 (21%) patients treated with 5-ARIs, and 878 (13%), 1764 (25%), 2948 (43%), and 1323 (19%) of untreated patients (p < 0.0001). No difference was found in csPCa detection rates, but diagnosis of high-grade PCa (ISUP GG ≥ 3) was higher in treated patients (23% vs 19%, p = 0.013). We did not find any evidence of interaction between PIRADS score and 5-ARIs exposure in predicting csPCa. Sensitivity, specificity, PPV, and NPV of PIRADS ≥ 3 were 94%, 29%, 46%, and 88% in treated patients and 96%, 18%, 43%, and 88% in untreated patients, respectively. CONCLUSIONS: Exposure to 5-ARIs does not affect the association of PIRADS score with csPCa. Higher rates of high-grade PCa were detected in treated patients, but most were clearly visible on MRI as PIRADS 4 and 5 lesions. TRIAL REGISTRATION: The present study was registered at ClinicalTrials.gov number: NCT05078359.


Subject(s)
Prostate-Specific Antigen , Prostatic Neoplasms , Male , Humans , Aged , Cohort Studies , 5-alpha Reductase Inhibitors/therapeutic use , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/drug therapy , Magnetic Resonance Imaging/methods , Oxidoreductases , Image-Guided Biopsy/methods
16.
World J Urol ; 41(10): 2783-2791, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37548746

ABSTRACT

BACKGROUND: Chemoprotective effect of 5-alpha reductase inhibitors (5-ARi) on bladder cancer (BCa) risk in men with Benign Prostatic Hyperplasia (BPH) has been explored with conflicting results. We sought to examine the effect of 5-ARi on new BCa diagnoses in a large US database. METHODS: Men ≥ 50 y/o with a prescription for 5-ARi after BPH diagnosis were identified in the IBM® Marketscan® Research de-identified Databases between 2007 and 2016 and matched with paired controls. Incident BCa diagnoses were identified after BPH diagnosis and/or pharmacologic treatment. Multivariable regression modeling adjusting for relevant factors was implemented. Sub-group analyses by exposure risk were performed to explore the association between 5-ARi and BCa over time. Administration of alpha-blockers (α-B) w/o 5-ARi was also examined. RESULTS: In total, n = 24,036 men on 5-ARi, n = 107,086 on 5-ARi plus alpha-blockers, and n = 894,275 without medical therapy for BPH were identified. The percentage of men diagnosed with BCa was 0.8% for the 5-ARi, 1.4% for the 5-ARi + α-B, and 0.6% for the untreated BPH group of incident BCa (adjusted hazard ratio [aHR], 0.90, 95% confidence interval [CI] 0.56 - 1.47), and 1.08, 95%CI 0.89 - 1.30, respectively). This was also true at both shorter (≤ 2 yr) and longer-term (> 2 yr) follow up. In addition, α-B alone had no change in BCa risk (HR 1.06, 0.86-1.30). CONCLUSIONS: We did not find any diminished risk of new BCa in men treated with 5-ARi (i.e., chemoprotective effect). The current report suggests that 5-ARi do not change a man's bladder cancer risk.


Subject(s)
Insurance , Prostatic Hyperplasia , Urinary Bladder Neoplasms , Male , Humans , United States/epidemiology , 5-alpha Reductase Inhibitors/therapeutic use , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/epidemiology , Risk , Urinary Bladder Neoplasms/epidemiology , Urinary Bladder Neoplasms/drug therapy
18.
Am Fam Physician ; 107(6): 613-622, 2023 06.
Article in English | MEDLINE | ID: mdl-37327163

ABSTRACT

Lower urinary tract symptoms from benign prostatic hyperplasia affect 25% of U.S. men, nearly one-half of whom have at least moderate symptoms. Sedentary lifestyle, hypertension, and diabetes mellitus increase risk of symptoms. Evaluation is focused on determining severity of symptoms and therapy to improve symptoms. Rectal examination has limited accuracy in evaluating prostate size. Transrectal ultrasonography is preferred to verify size when starting 5-alpha reductase therapy or considering surgery. Serum prostate-specific antigen testing is not recommended in routine evaluation of lower urinary tract symptoms, and shared decision-making should be used for cancer screening decisions. The International Prostate Symptom Score is the best way to track symptoms. Self-management methods, including limiting evening fluid intake, reducing caffeine and alcohol intake, toilet and bladder training, pelvic floor exercises, and mindfulness techniques, can improve symptoms. Although saw palmetto is not effective, the herbal treatments Pygeum africanum and beta-sitosterol may be effective. Primary medical treatment involves alpha blockers or phosphodiesterase-5 inhibitors. Alpha blockers offer rapid benefit and can be used for acute urinary retention. Combining alpha blockers and phosphodiesterase-5 inhibitors is not beneficial. For uncontrolled symptoms, 5-alpha reductase inhibitors should be started if the prostate volume is 30 mL or greater by ultrasonography. 5-Alpha reductase inhibitors take up to one year to be fully beneficial and are more effective when taken with alpha blockers. Only 1% of patients with lower urinary tract symptoms require surgery. Although transurethral resection of the prostate improves symptoms, many less invasive options with varying effectiveness can be considered.


Subject(s)
Lower Urinary Tract Symptoms , Prostatic Hyperplasia , Transurethral Resection of Prostate , Male , Humans , Prostatic Hyperplasia/diagnosis , Prostatic Hyperplasia/therapy , 5-alpha Reductase Inhibitors/therapeutic use , Cyclic Nucleotide Phosphodiesterases, Type 5 , Adrenergic alpha-Antagonists , Lower Urinary Tract Symptoms/diagnosis , Lower Urinary Tract Symptoms/surgery
19.
JAMA Netw Open ; 6(5): e2313667, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37191958

ABSTRACT

Importance: The antiandrogenic effect of the 5α-reductase inhibitor (5-ARI) has been investigated for its role in preventing male-predominant cancers. Although 5-ARI has been widely associated with prostate cancer, its association with urothelial bladder cancer (BC), another cancer experienced predominantly by males, has been less explored. Objective: To assess the association between 5-ARI prescription prior to BC diagnosis and reduced risk of BC progression. Design, Setting, and Participants: This cohort study analyzed patient claims data from the Korean National Health Insurance Service database. The nationwide cohort included all male patients with BC diagnosis in this database from January 1, 2008, to December 31, 2019. Propensity score matching was conducted to balance the covariates between 2 treatment groups: α-blocker only group and 5-ARI plus α-blocker group. Data were analyzed from April 2021 to March 2023. Exposure: Newly dispensed prescriptions of 5-ARIs at least 12 months prior to cohort entry (BC diagnosis), with a minimum of 2 prescriptions filled. Main Outcomes and Measures: The primary outcomes were the risks of bladder instillation and radical cystectomy, and the secondary outcome was all-cause mortality. To compare the risk of outcomes, the hazard ratio (HR) was estimated using a Cox proportional hazards regression model and difference in restricted mean survival time analysis. Results: The study cohort initially included 22 845 males with BC. After propensity score matching, 5300 patients each were assigned to the α-blocker only group (mean [SD] age, 68.3 [8.8] years) and 5-ARI plus α-blocker group (mean [SD] age, 67.8 [8.6] years). Compared with the α-blocker only group, the 5-ARI plus α-blocker group had a lower risk of mortality (adjusted HR [AHR], 0.83; 95% CI, 0.75-0.91), bladder instillation (crude HR, 0.84; 95% CI, 0.77-0.92), and radical cystectomy (AHR, 0.74; 95% CI, 0.62-0.88). The differences in restricted mean survival time were 92.6 (95% CI, 25.7-159.4) days for all-cause mortality, 88.1 (95% CI, 25.2-150.9) days for bladder instillation, and 68.0 (95% CI, 31.6-104.3) days for radical cystectomy. The incidence rates per 1000 person-years were 85.59 (95% CI, 80.53-90.88) for bladder instillation and 19.57 (95% CI, 17.41-21.91) for radical cystectomy in the α-blocker only group and 66.43 (95% CI, 62.22-70.84) for bladder instillation and 13.56 (95% CI, 11.86-15.45) for radical cystectomy in the 5-ARI plus α-blocker group. Conclusions and relevance: Results of this study suggest an association between prediagnostic prescription of 5-ARI and reduced risk of BC progression.


Subject(s)
Prostatic Neoplasms , Urinary Bladder Neoplasms , Humans , Male , Aged , Cohort Studies , 5-alpha Reductase Inhibitors/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/epidemiology , Oxidoreductases
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