Alpha‐1 adrenergic antagonists, 5‐alpha reductase inhibitors, phosphodiesterase type 5 inhibitors, and phytotherapic compounds in men with lower urinary tract symptoms suggestive of benign prostatic obstruction: A systematic review and meta‐analysis of urodynamic studies

Fusco, Ferdinando; Creta, Massimiliano; Nunzio, Cosimo De; Gacci, Mauro; Marzi, Vincenzo Li; Agrò, Enrico Finazzi

doi:10.1002/nau.23554

Cited by 26 publications

(19 citation statements)

References 38 publications

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“…However, further studies are needed to confirm these observations. Indeed, given the concomitant bladder outflow benefits and a favourable safety profile, there is a compelling rationale for the prospective evaluation of 5-ARIs as a secondary prevention strategy for BCa recurrence in men [ 31 , 32 , 33 ]. Although androgen suppression has the potential of being a means of radio- and chemiosensitization, further studies are needed to confirm this preclinical evidence.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies

et al. 2021

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Bladder cancer (BCa) is an endocrine-related tumour and the activation of androgen signalling pathways may promote bladder tumorigenesis. We summarized the available preclinical and clinical evidence on the implications of the manipulation of androgen signalling pathways on the outcomes of BCa therapies. A systematic review was performed in December 2020. We included papers that met the following criteria: original preclinical and clinical research; evaluating the impact of androgen signalling modulation on the outcomes of BCa therapies. Six preclinical and eight clinical studies were identified. The preclinical evidence demonstrates that the modulation of androgen receptor-related pathways has the potential to interfere with the activity of the Bacillus Calmette Guerin, doxorubicin, cisplatin, gemcitabine, and radiotherapy. The relative risk of BCa recurrence after transurethral resection of the bladder tumour (TURBT) is significantly lower in patients undergoing therapy with 5 alpha reductase inhibitors (5-ARIs) or androgen deprivation therapy (ADT) (Relative risk: 0.50, 95% CI: 0.30–0.82; p = 0.006). Subgroup analysis in patients receiving 5-ARIs revealed a relative risk of BCa recurrence of 0.46 (95% CI: 0.22–0.95; p = 0.040). A significant negative association between the ratio of T1 BCa patients in treated/control groups and the relative risk of BCa recurrence was observed. Therapy with 5-ARIs may represent a potential strategy aimed at reducing BCa recurrence rate, mainly in patients with low stage disease. Further studies are needed to confirm these preliminary data.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies

et al. 2021

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“…Though it is assumed that prostate smooth muscle contraction is induced by activation of α 1 ‐adrenoceptors, hyperplastic prostate stromal cell growth is mediated by dihydrotestosterone 1,2 . For immediate improvement of symptoms α 1 ‐blockers are often applied, whereas 5α‐reductase inhibitors have long‐term effects through reduction of prostate size 1,3 . Around 612 million men worldwide were affected by LUTS secondary to BPH in 2018, with annual costs peaking up to five billion USD for medical treatment 4–6 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human prostate stromal cell growth and smooth muscle contraction by thalidomide: A novel remedy in LUTS?

et al. 2021

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Background Medical treatment in benign prostatic hyperplasia targets prostate size to prevent disease progression, complications, and surgery, and prostate smooth muscle tone for rapid relief of lower urinary tract symptoms. Combination therapies are still required to target both at once. However, current medications are insufficient, due to an unfavorable balance between side effects and efficacy. The limited efficacy of α1‐blockers may be due to nonadrenergic mediators like endothelin‐1 and thromboxane A2 (TXA2), which keep up prostate smooth muscle contraction even in the presence of α1‐blockers. Consequently, future options with higher efficacy need to target α1‐adrenergic and nonadrenergic contractions as well as stromal cell growth at once. Thalidomide has been approved as an oral medication for various diseases, including the treatment of prostate cancer. Therefore, we investigated the effect of thalidomide on cellular functions of prostate stromal cells and human prostate smooth muscle contraction. Methods Cytoskeletal organization was visualized by phalloidin staining, cell growth was assessed by 5‐ethynyl‐2ʹ‐deoxyuridine assay, cell viability by cell counting kit‐8, and apoptosis and cell death by flow cytometry in cultured prostate stromal cells (WPMY‐1). Contractions of human prostate tissues from radical prostatectomy were studied in an organ bath, where they were induced by the α1‐adrenoceptor agonists methoxamine, noradrenaline, phenylephrine, and the nonadrenergic agonists endothelin‐1, TXA2 analog U46619, or electric field stimulation (EFS). Results Thalidomide significantly reduced the proliferation of WPMY‐1 cells, which was time‐ and concentration‐dependent (10–300 µM). In parallel, organization of actin filaments collapsed after treatment with thalidomide. Thalidomide (30–100 µM) inhibited noradrenaline‐, phenylephrine‐, and methoxamine‐induced contractions, as well as nonadrenergic contractions induced by endothelin‐1 and U46619, and neurogenic contractions induced by EFS. No reduction in viability and no increases in apoptosis or in cell death were observed in WPMY‐1 cells. Conclusions Thalidomide impairs the growth of human prostate stromal cells, without showing a decrease in cell viability. In parallel, thalidomide inhibits adrenergic, neurogenic, and nonadrenergic contractions. This may be explained by a breakdown of the actin cytoskeleton. In vivo, urodynamic effects of thalidomide appear possible and may even exceed those of α1‐blockers or combination therapies.

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“…One more crucial limitation in our study is that several studies among final included studies for meta-analysis do not have clinically significant BOO, which could resulted in lowering efficacy of 5ARI during meta-analysis. Moreover, recent meta-analysis about the efficacy of 5ARI in BOO has showed that BOOI reduction is important clinical outcomes during BPH/LUTS treatment [ 10 ]. Lastly, network analysis among alpha blocker, 5ARI, and placebo are needed to suggest the direct evidence of inferior clinical efficacy of 5ARI compared to alpha blocker.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, treatment using 5ARIs showed a positive effect including decreased prostate volume, improved International Prostate Symptom Score (IPSS), improved Qmax, decreased risk of acute urinary retention (AUR) and decreased operative procedures related with BPH/LUTS [ 5 , 7 – 9 ]. Moreover, several systematic reviews showed that 5ARI, especially, finasteride improves LUTS by long-term treatment, however, combination treatment with alpha blockers showed better improvement than finasteride monotherapy [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of 5 alpha-reductase inhibitor monotherapy in patients with benign prostatic hyperplasia: A meta-analysis

et al. 2018

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BackgroundAlthough combination therapy with 5 alpha-reductase inhibitor (5ARI) and alpha-blocker is one of the standard interventions in symptomatic benign prostatic hyperplasia (BPH), 5ARI monotherapy is seldom the focus of attention. Adverse events associated with 5ARI include depression and suicidal attempts in addition to persistent erectile dysfunction. The aim of this study is to update our knowledge of clinical efficacy and incidence of adverse events associated with 5ARI treatment in symptomatic BPH.Methods and findingsA meta-analysis of randomized controlled clinical trials (RCTs) from 1966 until March, 2017 was performed using database from PubMed, Cochrane Collaboration and Embase. A total of 23395 patients were included in this study and the inclusion criteria were: RCTs with 5ARI and placebo in symptomatic BPH patients. Parameters included prostate specific antigen (PSA), prostate volume (PV), International Prostate Symptom Score (IPPS), post-void residual urine (PVR), voiding symptoms of IPSS (voiding IPSS), maximum urinary flow rate (Qmax), and adverse events (AEs). A meta-analysis with meta-regression was performed for each effect size and adverse events, sensitivity analysis, cumulative analysis along with the analysis of ratio of means (ROM) in the placebo group.A total of 42 studies were included in this study for review, and a total of 37 studies were included in the meta-analysis, including a total of 23395 patients (treatment group: 11392, placebo group: 12003). The effect size of all variables except PVR showed a significant improvement following 5ARI treatment compared with placebo. However, the effect size of differences showed declining trend in PV, IPSS and Qmax according to recent years of publication. In ROM analysis, PV showed no significant increase in the placebo group, with a ROM of 1.00 (95% CI, 0.88, 1.14). The 5ARI treatment resulted in a significantly higher incidence of decreased libido (OR = 1.7; 95% CI, 1.36, 2.13), ejaculatory disorder (OR = 2.94; 95% CI, 2.15, 4.03), gynecomastia (OR = 2.32; 95% CI, 1.41, 3.83), and impotence (OR = 1.74; 95% CI, 1.32, 2.29). Our study has the following limitations: included studies were heterogeneous and direct comparison of efficacy between alpha blocker and 5ARI was not performed. Adverse events including depression or suicidal attempt could not be analyzed in this meta-analysis setting.ConclusionsAlthough there was a significant clinical benefit of 5ARI monotherapy compared with placebo, the effective size was small. Moreover, the risk of adverse events including sexually related complications were high. Additional head-to-head studies are needed to re-evaluate the clinical efficacy of 5ARI compared with alpha-adrenergic receptor blockers.

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Alpha‐1 adrenergic antagonists, 5‐alpha reductase inhibitors, phosphodiesterase type 5 inhibitors, and phytotherapic compounds in men with lower urinary tract symptoms suggestive of benign prostatic obstruction: A systematic review and meta‐analysis of urodynamic studies

Abstract: ABs and 5-ARIs efficiently improve BOOI in men with LUTS/BPO. Both treatments are associated with a clinically significant decrease in PdetQmax but only marginal improvements in Qmax.

Cited by 26 publications

References 38 publications

Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies

Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies

Inhibition of human prostate stromal cell growth and smooth muscle contraction by thalidomide: A novel remedy in LUTS?

Efficacy and safety of 5 alpha-reductase inhibitor monotherapy in patients with benign prostatic hyperplasia: A meta-analysis

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