Methylated CpG dinucleotides in the 5-α reductase 2 gene may explain finasteride resistance in benign prostatic enlargement patients.
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SUBMITTER: Lin ZM
PROVIDER: S-EPMC8152415 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceThe most prescribed class of medications for benign prostatic hyperplasia (BPH) is α-blockers (ABs). However, the cardiovascular safety profile of these medications among patients with BPH is not well understood.ObjectiveTo compare the safety of ABs vs 5-α reductase inhibitors (5-ARIs) for risk of adverse cardiovascular outcomes.Design, setting, and participantsThis active comparator, new-user cohort study was conducted using insurance claims data from a 20% random sample of Medicare beneficiaries from 2007 to 2019 to evaluate the 1-year risk of adverse cardiovascular outcomes. Males aged 66 to 90 years were indexed into the cohort at new use of an AB or 5-ARI. Twelve months of continuous enrollment and at least 1 diagnosis code for BPH within 12 months prior to initiation were required. Data were analyzed from January 2007 through December 2019.ExposuresExposure was defined by a qualifying prescription fill for an AB or 5-ARI after at least 12 months without a prescription for these drug classes.Main outcomes and measuresFollow-up began at a qualified refill for the study drug. Primary study outcomes were hospitalization for heart failure (HF), composite major adverse cardiovascular events (MACE; hospitalization for stroke, myocardial infarction, or death), composite MACE or hospitalization for HF, and death. Inverse probability of treatment and censoring-weighted 1-year risks, risk ratios (RRs), and risk differences (RDs) were estimated for each outcome.ResultsAmong 189 868 older adult males, there were 163 829 patients initiating ABs (mean [SD] age, 74.6 [6.2] years; 579 American Indian or Alaska Native [0.4%], 5890 Asian or Pacific Islander [3.6%], 9179 Black [5.6%], 10 610 Hispanic [6.5%], and 133 510 non-Hispanic White [81.5%]) and 26 039 patients initiating 5-ARIs (mean [SD] age, 75.3 [6.4] years; 76 American Indian or Alaska Native [0.3%], 827 Asian or Pacific Islander [3.2%], 1339 Black [5.1%], 1656 Hispanic [6.4%], and 21 605 non-Hispanic White [83.0%]). ABs compared with 5-ARIs were associated with an increased 1-year risk of MACE (8.95% [95% CI, 8.81%-9.09%] vs 8.32% [95% CI, 7.92%-8.72%]; RR = 1.08 [95% CI, 1.02-1.13]; RD per 1000 individuals = 6.26 [95% CI, 2.15-10.37]), composite MACE and HF (RR = 1.07; [95% CI, 1.03-1.12]; RD per 1000 individuals = 7.40 [95% CI, 2.88-11.93 ]), and death (RR = 1.07; [95% CI, 1.01-1.14]; RD per 1000 individuals = 3.85 [95% CI, 0.40-7.29]). There was no difference in risk for HF hospitalization alone.Conclusions and relevanceThese results suggest that ABs may be associated with an increased risk of adverse cardiovascular outcomes compared with 5-ARIs. If replicated with more detailed confounder data, these results may have important public health implications given these medications' widespread use.
| S-EPMC10646730 | biostudies-literature
Project description:Gut microbes are closely associated with disease onset and improvement. However, the effects of gut microbes on the occurrence, prevention, and treatment of benign prostatic hyperplasia (BPH) are still unclear. We investigated the alteration of gut microbiota with implications for the diagnosis, prevention, and treatment of BPH and identified correlations among various indicators, including hormone indicators, apoptosis markers in BPH, and finasteride treatment models. BPH induction altered the abundance of Lactobacillus, Flavonifractor, Acetatifactor, Oscillibacter, Pseudoflavonifractor, Intestinimonas, and Butyricimonas genera, which are related to BPH indicators. Among these, the altered abundance of Lactobacillus and Acetatifactor was associated with the promotion and inhibition of prostate apoptosis, respectively. Finasteride treatment altered the abundance of Barnesiella, Acetatifactor, Butyricimonas, Desulfovibrio, Anaerobacterium, and Robinsoniella genera, which are related to BPH indicators. Among these, altered abundances of Desulfovibrio and Acetatifactor were associated with the promotion and inhibition of prostate apoptosis, respectively. In addition, the abundances of Lactobacillus and Acetatifactor were normalized after finasteride treatment. In conclusion, the association between apoptosis and altered abundances of Lactobacillus and Acetatifactor, among other gut microbes, suggests their potential utility in the diagnosis, prevention, and treatment of BPH.
| S-EPMC10057928 | biostudies-literature
Project description:BACKGROUND:Benign prostatic hyperplasia affects older men. This systematic review determined efficacy and adverse effects of finasteride. REVIEW METHODS:PubMed, the Cochrane Library, reference lists of reports, and reviews were searched for randomised, double-blind trials of finasteride in benign prostatic hyperplasia. Outcomes included symptom score, urinary flow rate, prostate volume, discontinuation, and adverse effects. Relative risk and NNT or NNH were calculated for dichotomous data. Sensitivity analyses assessed influences of baseline symptom severity, initial prostate volume, a dominating trial, and previous interventions. RESULTS:Three trials had active controls and 19 had placebo. In placebo-controlled trials, 8820 patients received finasteride 5 mg and 5909 placebo over 3-48 months. Over 48 months finasteride produced greater improvements in total symptom score, maximum urinary flow rate, and prostate volume. Significantly more sexual dysfunction, impotence, ejaculation disorder and decreased libido occurred with finasteride at 12 months; the NNH for any sexual dysfunction at 12 months was 14. Significantly fewer men treated with finasteride experienced acute retention or had surgery at 24 or 48 months than with placebo; at 12 months the NNT was 49 (31 to 112) to avoid one acute urinary retention and 31 (21 to 61) to avoid one surgery. Sensitivity analyses showed benefit with finasteride 5 mg to be constant irrespective of the initial prostate volume. CONCLUSIONS:Information from many patients in studies of high quality showed beneficial effects of finasteride in terms of symptoms, flow rate and prostate volume. More utility would result if patient centred outcomes were reported in dichotomous form.
| S-EPMC140032 | biostudies-literature
Project description:ObjectiveTo compare the risk of prostate cancer mortality among men treated with 5- alpha reductase inhibitors (5-ARIs) with those treated with alpha-adrenergic blockers (ABs) in community practice settings.Patients and methodsA retrospective matched cohort (N=174,895) and nested case-control study (N=18,311) were conducted in 4 regions of an integrated health care system. Men 50 years and older who initiated pharmaceutical treatment for benign prostatic hyperplasia between January 1, 1992, and December 31, 2007, and had at least 3 consecutive prescriptions were followed through December 31, 2010. Adjusted subdistribution hazard ratios, accounting for competing risks of death, and matched odds ratios were used to estimate prostate cancer mortality associated with 5-ARI use (with or without concomitant ABs) as compared with AB use.ResultsIn the cohort study, 1,053 men died of prostate cancer (mean follow-up, 3 years), 15% among 5-ARI users (N= 25,388) and 85% among AB users (N=149,507) (unadjusted mortality rate ratio, 0.80). After accounting for competing risks, it was found that 5-ARI use was not associated with prostate cancer mortality when compared with AB use (adjusted subdistribution hazard ratio, 0.85; 95% CI, 0.72-1.01). Similar results were observed in the case-control study (adjusted matched odds ratio, 0.95; 95% CI, 0.78-1.17).ConclusionAmong men being pharmaceutically treated for benign prostatic hyperplasia, 5-ARI use was not associated with an increased risk of prostate cancer-specific mortality when compared with AB use. The increased prevalence of high-grade lesions at the time of diagnosis noted in our study and the chemoprevention trials may not result in increased prostate cancer mortality.
| S-EPMC8080281 | biostudies-literature
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.
| S-EPMC6169865 | biostudies-literature
Project description:Finasteride, a 5α-reductase inhibitor used in benign prostatic hyperplasia and androgenetic alopecia, has been associated with an increased suicidal risk, whereas it is unclear whether such risk is similar to that for another 5α-reductase inhibitor, dutasteride. We aimed to assess the risk of suicidal behaviours with finasteride relative to dutasteride. A nationwide cohort study was conducted using the French National Health Data System (SNDS). Men aged 50 years or older initiating finasteride 5 mg or dutasteride 0.5 mg in France between 01-01-2012 and 30-06-2016 were included and followed until outcome (suicide death identified from death certificate or self-harm hospitalisation), treatment discontinuation or switch, death, or 31-12-2016. Self-harm by violent means or resulting in admission to an intensive care unit were also examined. Cox proportional hazards models controlled for age and psychiatric and non-psychiatric conditions by inverse probability of treatment weighting (IPTW). Analyses were stratified according to psychiatric history. The study compared 69,786 finasteride new users to 217,577 dutasteride new users (median age: 72.0 years [Q1-Q3 = 64.5-80.2] vs. 71.1 [Q1-Q3 = 65.0-79.2]). During follow-up, 18 suicide deaths (0.57/1000 person-years) and 34 self-harm hospitalisations (1.08/1000) occurred among finasteride users versus 47 deaths (0.43/1000) and 87 hospitalisations (0.79/1000) among dutasteride users. Overall, finasteride was not associated with an increased risk of any suicidal outcome (IPTW-adjusted Hazard Ratio = 1.21 [95% Confidence Interval .87-1.67]), suicide death or self-harm hospitalisation. However, among individuals with a history of mood disorders, finasteride was associated with an increased risk of any suicidal outcome (25 versus 46 events; HR = 1.64 [95% CI 1.00-2.68]), suicide death (8 versus 10 events; HR = 2.71 [95% CI 1.07-6.91]), self-harm by violent means (6 versus 6 events; HR = 3.11 [95% CI 1.01-9.61]), and self-harm with admission to an intensive care unit (7 versus 5 events; HR = 3.97 [95% CI 1.26-12.5]). None of these risks was significantly increased among individuals without a psychiatric history. These findings do not support an increased risk of suicide with finasteride used in the treatment of benign prostatic hyperplasia. However, an increased risk cannot be excluded among men with a history of mood disorder, but this result based on a limited number of events should be interpreted with caution.
| S-EPMC10066399 | biostudies-literature
Project description:To preliminary investigate the effects of silodosin 8 mg once daily on obstruction urodynamic parameters and subjective symptoms in Caucasian patients with lower urinary tract symptoms suggestive of benign prostatic enlargement.We performed a single-center, open-label, single-arm, post-marketing interventional clinical trial. Inclusion criteria were: Caucasian subjects aged ?50 years waiting to undergo surgery for lower urinary tract symptoms suggestive of benign prostatic enlargement, international prostate symptom total score ? 13, international prostate symptom-quality of life score???3, prostate volume ? 30 ml, maximum urine flow rate???15 mL/s, bladder outlet obstruction index >?40. Eligible subjects received one capsule of silodosin 8 mg once daily for 8 weeks. Invasive urodynamic evaluations were performed at baseline and at 8-weeks follow-up. International prostate symptom questionnaire was administered at baseline, after 4-weeks and 8-weeks of treatment.Overall, 34 subjects were included. Mean bladder outlet obstruction index significantly decreased from 70.6 to 39.2 and bladder outlet obstruction index class improved in 16 patients (53.3%). Statistically significant improvements of mean total international prostate symptom score, mean storage sub-score, mean voiding sub-score and mean quality of life sub-score were evident after 4-weeks of treatment with further improvements after 8-weeks. At the end of the treatment, all patients declared that their condition improved enough to spare or delay surgery.Silodosin 8 mg once daily significantly improves benign prostatic obstruction in Caucasian patients with lower urinary tract symptoms suggestive of benign prostatic enlargement waiting for surgery.EudraCT n. 2015-002277-38 Date of registration: 15th December 2017.
| S-EPMC5836453 | biostudies-literature
Project description:OBJECTIVES:To examine the complication rates after benign prostatic enlargement (BPE) surgery and the effects of age, comorbidity and preoperative medical therapy. DESIGN:A retrospective, population-based cohort study using linked administrative data. SETTING:Ontario, Canada. PARTICIPANTS:52 162 men≥66 years undergoing first BPE surgery between 1 January 2003 to 31 December 2014. INTERVENTION:Medical therapy preoperatively and surgery for BPE. PRIMARY AND SECONDARY OUTCOME MEASURES:The primary outcome was overall 30-day postoperative complication rates. Secondary outcomes included BPE-specific event rates (bleeding, infection, obstruction, trauma) and non-BPE specific event rates (cardiovascular, pulmonary, thromboembolic and renal). Multivariable analysis examined the association between preoperative medical therapy and postoperative complication rates. RESULTS:The 30-day overall complication rate after BPE surgery was 2828 events/10 000 procedures and increased annually over the study period. Receipt of preoperative α-blocker monotherapy (relative rate (RR) 1.05; 95% CI 1.00 to 1.09; p=0.033) and antithrombotic medications (RR 1.27; 95% CI 1.22 to 1.31; p<0.0001) was associated with increased complication rates. Among the ≥80-year-old group, the rate of complications increased by 39% from 2003 to 2014 (RR 1.39; 95% CI 1.21 to 1.61; p<0.0001). The mean duration of medical and conservative management increased by a mean of 2.1 years between 2007 and 2014 (p<0.0001 for trend). CONCLUSIONS:Thirty-day complication rates after BPE surgery have increased annually between 2003 and 2014. Preoperative medical therapy with alpha blockers or antithrombotics was independently associated with higher rates of complications. Over this time, the duration of conservative therapy also increased.
| S-EPMC6955543 | biostudies-literature
Project description:ObjectiveTo investigate the use of 5α-reductase inhibitors (5ARIs) and α-blockers among men with benign prostatic hyperplasia (BPH) in relation to prostate cancer (PCa) incidence, severity and mortality.Patients and methodsA retrospective 20-year cohort study in men residing in Saskatchewan, aged 40-89 years, with a BPH-coded medical claim between 1995 and 2014, was conducted. Cox proportional hazards regression was used to compare incidence of PCa diagnosis, metastatic PCa, Gleason score 8-10 PCa, and PCa mortality among 5ARI users (n = 4 571), α-blocker users (n = 7 764) and non-users (n = 11 677).ResultsIn comparison with both non-users and α-blocker users, 5ARI users had a ~40% lower risk of a PCa diagnosis (11.0% and 11.4% vs 5.8%, respectively), and α-blocker users had an 11% lower risk of a PCa diagnosis compared with non-users. Overall, the incidence of metastatic PCa and PCa mortality was not significantly different among 5ARI or α-blocker users compared with non-users (adjusted hazard ratios [HR] of metastatic PCa: 1.12 and 1.13, respectively, and PCa mortality: 1.11 and 1.18, respectively, P > 0.05 for both drugs), but both 5ARI and a-blocker users had ~30% higher risk of Gleason score 8-10 cancer, adjusted HR 1.37, 95% confidence interval [CI] 1.03-1.82, P = 0.03, and adjusted HR 1.28, 95% CI 1.03-1.59, P = 0.02, respectively compared with non-users.ConclusionThe use of 5ARIs was associated with lower risk of PCa diagnosis, regardless of comparison group. Risk of high grade PCa was higher among both 5ARI users and α-blocker users compared with non-users; however, this did not translate into higher risk of PCa mortality.
| S-EPMC6397052 | biostudies-literature
Project description:ObjectiveTo compare the risk of mortality among men treated for benign prostatic hyperplasia (BPH) with 5 alpha-reductase inhibitors (5ARI) to those treated with alpha-blockers (AB) in community practice settings.MethodsWe employed a retrospective matched cohort study in 4 regions of an integrated healthcare system. Men aged 50 years and older who initiated pharmaceutical treatment for BPH and/or lower urinary tract symptoms between 1992 and 2008 and had at least 3 consecutive prescriptions that were eligible and followed through 2010 (N = 174,895). Adjusted hazard ratios were used to estimate the risk of mortality due to all-causes associated with 5ARI use (with or without concomitant ABs) as compared to AB use.ResultsIn this large and diverse sample with 543,523 person-years of follow-up, 35,266 men died during the study period, 18.9% of the 5ARI users and 20.4% of the AB users. After adjustment for age, medication initiation year, race, region, prior AB history, Charlson score, and comorbidities, 5ARI use was not associated with an increased risk of mortality when compared to AB use (Adjusted hazard ratios: 0.64, 95% confidence interval: 0.62, 0.66).ConclusionAmong men receiving medications for BPH in community practice settings, 5ARI use was not associated with an increased risk of mortality when compared to AB use. These data provide reassurance about the safety of using 5ARIs in general practice to manage BPH and/or lower urinary tract symptoms.
| S-EPMC8080272 | biostudies-literature