Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome.
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ABSTRACT:
SUBMITTER: Fertig R
PROVIDER: S-EPMC5264352 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome.
Fertig Raymond R Shapiro Jerry J Bergfeld Wilma W Tosti Antonella A
Skin appendage disorders 20160923 3-4
Postfinasteride syndrome (PFS) is a term recently coined to characterize a constellation of reported undesirable side effects described in postmarketing reports and small uncontrolled studies that developed during or after stopping finasteride treatment, and persisted after drug discontinuation. Symptoms included decreased libido, erectile dysfunction, sexual anhedonia, decreased sperm count, gynecomastia, skin changes, cognitive impairment, fatigue, anxiety, depression, and suicidal ideation. T ...[more]
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Project description:PurposeAlthough five-alpha reductase inhibitor (5-ARI) is one of standard treatment for benign prostatic hyperplasia (BPH) or alopecia, potential complications after 5-ARI have been issues recently. This study aimed to investigate the risk of depression after taking 5-ARI and to quantify the risk using meta-analysis.Materials and methodsA total of 209,940 patients including 207,798 in 5-ARI treatment groups and 110,118 in control groups from five studies were included for final analysis. Inclusion criteria for finial analysis incudes clinical outcomes regarding depression risk in BPH or alopecia patients. Overall hazard ratio (HR) and odds ratio (OR) for depression were analyzed. Moderator analysis and sensitivity analysis were performed to determine whether HR or OR could be affected by any variables, including number of patients, age, study type, and control type.ResultsThe pooled overall HRs for the 5-ARI medication was 1.23 (95% confidence interval [CI], 0.99-1.54) in a random effects model. The pooled overall ORs for the 5-ARI medication was 1.19 (95% CI, 0.95-1.49) in random effects model. The sub-group analysis showed that non-cohort studies had higher values of HR and OR than cohort studies. Moderator analysis using meta-regression showed that there were no variables that affect the significant difference in HR and OR outcomes. However, in sensitivity analysis, HR was significantly increased by age (p=0.040).ConclusionsOverall risk of depression after 5-ARI was significantly not high, however its clinical importance needs validation by further studies. These quantitative results could provide useful information for both clinicians and patients.
| S-EPMC7502319 | biostudies-literature
Project description:Background:The efficacy and safety of 5?-reductase inhibitors (5ARIs) in treating prostate cancer (PCa) have not been fully determined. We performed a meta-analysis to evaluate the effectiveness and safety of 5ARIs for PCa patients. Methods:A comprehensive literature search of online databases was conducted to obtain comparative studies exploring the effectiveness and safety of 5ARIs in treating PCa up to October 2019. Summarized odds ratio s (OR s) or hazard ratio s (HR s) were calculated to compare the outcomes between 5ARI and control groups. Our meta-analysis was registered in PROSPERO under number CRD42018109809. Results:A total of 2,277 patients from 10 studies were included. No significant difference was found in prostate-specific antigen progression between two groups (OR = 0.82, 95% CI [0.52-1.29], P = 0.40). However, 5ARI treatment significantly reduced the total progression of PCa (OR = 0.61, 95% CI [0.48-0.77], P < 0.0001), especially for patients with local (OR = 0.56, 95% CI [0.44-0.73], P < 0.00001) and low-Gleason score (?7) PCa (OR = 0.63, 95% CI [0.48-0.84], P = 0.002). Additionally, 5ARIs also significantly prolonged the progression-free survival time (HR = 0.57, 95% CI [0.34-0.96], P = 0.04) for PCa patients. No significant difference was found in the occurrence of PCa recurrence, metastasis, biopsy reclassification, and side-effects between two groups. Conclusions:Our study suggests that 5ARI treatment can benefit patients with local and low Gleason score (?7) PCa, especially in delaying the disease progression. More studies with larger sample size and comprehensive study design are still needed to verify our outcomes.
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Project description:In the prostate, androgens play a crucial role in normal and cancerous growth; hence the androgenic pathway has become a target of therapeutic intervention. Dutasteride is a 5 alpha-reductase (5AR) inhibitor currently being evaluated both for chemoprevention and treatment of prostate cancer. Dutasteride inhibits both 5AR I and II enzymes, effectively blocking conversion of testosterone to dihydrotestosterone (DHT) in the prostate. This greatly reduces the amount of the active ligand DHT available for binding to the androgen receptor (AR) and stimulating proliferation, making this a good candidate for chemoprevention of prostate cancer. In this study, we sought to determine how dutasteride is functioning at the molecular level, using a prostate cancer xenograft model.Androgen-responsive LuCaP 35 xenograft tumors were grown in Balb/c mice. Subcutaneously implanted time-release pellets were used for drug delivery. Microarray analysis was performed using the Affymetrix HG-U133Av2 platform to examine changes in gene expression in tumors following dutasteride treatment.Dutasteride significantly reduced tumor growth in LuCaP 35 xenografts by affecting genes involved in apoptotic, cytoskeletal remodeling, and cell cycle pathways among others. Notably, genes in the Rho GTPase signaling pathway, shown to be important in androgen-deprivation conditions, were significantly up-regulated.We have identified multiple pathways outside of the androgenic pathway in prostate cancer xenografts affected by treatment with dutasteride. These findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of agents that can be used in combination with this drug to further enhance its effectiveness.
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Project description: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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Project description:Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidisciplinary approach has been used to identify potential finasteride off-target proteins. SPILLO-PBSS software suggests an additional inhibitory activity of finasteride on phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in formation of the stress hormone epinephrine. The interaction of finasteride with PNMT was supported by docking and molecular dynamics analysis and by in vitro assay, confirming the inhibitory nature of the binding. Finally, this inhibition was also confirmed in an in vivo rat model. Literature data indicate that PNMT activity perturbation may be correlated with sexual and psychological side effects. Therefore, results here obtained suggest that the binding of finasteride to PNMT might have a role in producing the side effects exerted by finasteride treatment.
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Project description:We aimed to evaluate the effect of 5 alpha-reductase inhibitor (5-ARI) treatment on prostate cancer (PCa) and clinically significant PCa (csPCa) detection in patients undergoing transrectal ultrasound (TRUS)/magnetic resonance imaging (MRI) fusion biopsy in the current era of multi-parametric MRI (mpMRI). We retrospectively reviewed our TRUS/MRI fusion biopsy database (n?=?706). Eighty (11.3%) patients who had used 5-ARI for more than one year at the time of biopsy were stratified as 5-ARI group. Subsequently, we performed comparative analyses of 5-ARI and non-5-ARI groups. csPCa was defined by a Gleason score ?3?+?4 in a single biopsy core. Chi-squared test was used to evaluate the performance of mpMRI in predicting PCa/csPCa between the two groups. Multivariate logistic regression analyses were performed to evaluate the significant variables associated with PCa detection. There were no significant differences in PCa/csPCa detection rates between 5-ARI and non-5-ARI groups (all, P?>?0.05). In multivariate logistic regression analyses for the evaluation of variables associated with csPCa detection, age (odds ratio [OR], 1.062; 95% confidence interval [CI], 1.035-1.090; P?<?0.001), pre-biopsy PSA (OR, 1.062; 95% CI, 1.034-1.090; P?<?0.001), prostate volume on TRUS (OR, 0.956; 95% CI, 0.943-0.970, P?<?0.001), and PI-RADsV2 category (OR, 5.528; 95% CI, 3.017-10.131; P?<?0.001) were found to be significant predictors. However, 5-ARI had no significant association with PCa detection (P?=?0.384). Conclusively, 5-ARI therapy did not adversely affect PCa/csPCa detection after TRUS/MRI fusion biopsy, which suggests that exposure to 5-ARI may not impair the performance of mpMRI.
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