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

Efficacy and safety of 5 alpha-reductase inhibitor monotherapy in patients with benign prostatic... OPENACCESS Citation: Kim JH, Baek MJ, Sun HY, Lee B, Li S, Khandwala Y, et al. (2018) Efficacy and safety of 5 Background alpha-reductase inhibitor monotherapy in patients Although combination therapy with 5 alpha-reductase inhibitor (5ARI) and alpha-blocker is with benign prostatic hyperplasia: A meta-analysis. one of the standard interventions in symptomatic benign prostatic hyperplasia (BPH), 5ARI PLoS ONE 13(10): e0203479. https://doi.org/ 10.1371/journal.pone.0203479 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 Editor: Peter F.W.M. Rosier, University Medical Center Utrecht, NETHERLANDS this study is to update our knowledge of clinical efficacy and incidence of adverse events associated with 5ARI treatment in symptomatic BPH. Received: April 23, 2018 Accepted: August 21, 2018 Methods and findings Published: October 3, 2018 A meta-analysis of randomized controlled clinical trials (RCTs) from 1966 until March, 2017 Copyright:© 2018 Kim et al. This is an open was performed using database from PubMed, Cochrane Collaboration and Embase. A total access article distributed under the terms of the Creative Commons Attribution License, which of 23395 patients were included in this study and the inclusion criteria were: RCTs with 5ARI permits unrestricted use, distribution, and and placebo in symptomatic BPH patients. Parameters included prostate specific antigen reproduction in any medium, provided the original (PSA), prostate volume (PV), International Prostate Symptom Score (IPPS), post-void author and source are credited. residual urine (PVR), voiding symptoms of IPSS (voiding IPSS), maximum urinary flow rate Data Availability Statement: The authors have (Qmax), and adverse events (AEs). A meta-analysis with meta-regression was performed outlined how authors can recreate their dataset in for each effect size and adverse events, sensitivity analysis, cumulative analysis along with the methods and materials section. The articles used for this study are outlined in the MS and SI the analysis of ratio of means (ROM) in the placebo group. files. A total of 42 studies were included in this study for review, and a total of 37 studies were Funding: This work was supported by included in the meta-analysis, including a total of 23395 patients (treatment group: 11392, Soonchunhyang University Hospital Research placebo group: 12003). The effect size of all variables except PVR showed a significant Fund. The funders had no role in study design, data improvement following 5ARI treatment compared with placebo. However, the effect size of collection and analysis, decision to publish, or preparation of the manuscript. differences showed declining trend in PV, IPSS and Qmax according to recent years of PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 1 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Competing interests: The authors have declared publication. In ROM analysis, PV showed no significant increase in the placebo group, with that no competing interests exist. 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. Conclusions Although there was a significant clinical benefit of 5ARI monotherapy compared with pla- cebo, 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. Introduction Benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS) is one of the most common diseases prevalent in old men. The prevalence of BPH among men in their 50s and 60s is 50% rising to 90% by the age of 80s and beyond based on autopsy findings [1, 2]. Medical treatment including alpha-blockers and 5 alpha-reductase inhibitors (5ARI) take possession of the primary treatment strategy in patients with BPH/LUTS [3, 4]. The combina- tion of alpha-blockers and 5ARI improved LUTS and maximal urinary flow rate (Qmax)[2, 3]. In earlier 2000s, two important randomized controlled studies (RCTs) including the Medical Therapy of Prostatic Symptoms (MTOPS) [5] and the Combination of Avodart1 and Tamsu- losin (CombAT) study [6] established the superiority of long-term combination therapy over alpha-blocker monotherapy or placebo in the treatment of patients with BPH/LUTS. Further- more, 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]. However, recent studies reported persistent complications of 5ARI including erectile dys- function (ED) and decreased libido even after discontinuation of 5ARI [12±14]. Similarly, treatment with finasteride 1mg for androgenic alopecia has shown persistent ED after its with- drawal [15]. Currently, FDA recommends a change in 5ARI labeling to include the possibility of persistent adverse events even after discontinuation in several post-marketing studies [16, 17]. Two recent reviews of 5ARI are warning clinicians to inform their patients fully regarding the adverse events of erectile dysfunction, decreased libido, gynecomastia, and anxiety [18, 19]. Moreover, this 5ARI advisory was issued again about the possible risks for suicidal attempts and depression in many recent observational studies [20]. Evidence supports the efficacy of 5ARI treatment when combined with alpha-blockers. Sev- eral reviews and meta-analyses were limited to only adverse events. Therefore, we have PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 2 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy provided an update on the clinical efficacy and adverse events in an effort to develop a rational therapeutic strategy using 5ARI in BPH/LUTS. Methods The systematic review with meta-analysis and meta-regression were conducted according to the guidelines provided by the PRISMA guidelines (S1 Text). Inclusion criteria This meta-analysis has inclusion criteria as randomized controlled clinical trials (RCTs) with 5ARI and placebo, disease indication of BPH/LUTS, and types of measure has to include at least one of followings: 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). Searching strategies Based on the PICO (population, intervention, control, and outcomes) process, the following strategies were used: P (patients with symptomatic BPH); I (daily or regular maintenance treat- ment with 5ARI without any other treatment); C (comparing measured effect size with placebo group); and O (PSA, PV, IPSS, and Qmax). A MEDLINE search from 1966 to March 3, 2017 was performed using specific MeSH headings, including prostatic hyperplasia, lower urinary tract symptoms and 5 alpha-reductase inhibitors, dutasteride, and finasteride. Supplementary terms included dutasteride and finasteride. For natural headings, placebo, dutasteride and finasteride were included. A similar strategy was used for Cochrane collaboration and Embase (S2 Fig and S3 Fig). Detailed inclusion criteria for the final data extraction in the meta-analysis were: 1) reported outcomes of at least one of the variables included PSA, PV, IPSS, voiding IPSS, PVR, Qmax or adverse events; 2) daily 5ARI treatment; 3) indication for 5ARI use con- fined to BPH; 4) intention-to-treat analysis with placebo-controlled RCTs. Data extraction strategies After merging all the search studies (n = 1312) from MEDLINE, Cochrane collaboration and Embase, duplicate studies (n = 605) were filtered (Fig 1). A total of 707 studies were screened by title, and a total of 245 studies involving unrelated topics were excluded. A total of 462 stud- ies were screened by abstract and additionally, a total of 306 studies were excluded. Initial screening was performed by JHK and HYS. A total of 156 studies were reviewed for full text. Two authors (JHK and HYS) independently performed screening and full-text assessment, and all disagreements about final inclusion were reviewed by all authors. Data extraction was performed by independent fashion using standardized data extraction form. Assessment of methodological and reporting bias in included studies Cochrane collaboration tools including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting were used to assess the risk of methodological bias. Egger's linear regression test was conducted to assess the publication bias. Statistical analysis The effect of continuous outcomes was summarized as the standardized mean difference (SMD), which was estimated as the difference between the mean change in the treatment and PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 3 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Fig 1. PRISMA flow diagram. https://doi.org/10.1371/journal.pone.0203479.g001 placebo groups divided by the pooled standard deviation (SD). The unreported SDs were esti- mated from the reported ranges, p-values, standard errors, and sample sizes as described by Hozo, et al.[21] The SMD was interpreted as Cohen's d: an SMD of 0.2 ~0.5 was considered small, an SMD of 0.5 to 0.8 moderate, and an SMD over 0.8 as a large effect [22]. The SMD exceeding 0.5 represented a clinically meaningful result. To identify the effect of pla- cebo on the continuous outcomes, the ratio of means (ROM), which was a measure of relative change compared with the baseline, was used[23]. Binary outcomes were determined by estimat- ing the odds ratio (OR) and 95% confidence interval (CI) using the Mantel-Haenszel methods. To combine the results of individual studies, a meta-analysis was conducted based on the random effects model as described by DerSimonian and Laird using inverse variance weight- ing [24]. We pre-specified the type of medicine (finasteride, dutasteride, and 5ARI) as the stratified variable based on the assumption that the impact of the treatment varied by the type of medicine. The heterogeneity between studies was assessed for each outcome using I mea- sure of inconsistency [25]. An I of 25±49% was interpreted as low heterogeneity, 50±74% was moderate, and high when it was greater than 75% [26]. Publication bias was examined by gen- erating a funnel plot and performing the Egger's asymmetry test. PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 4 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Potential source of heterogeneity was investigated via cumulative meta-analysis (including sequential studies according to the publication year) and influential meta-analysis (deriving the pooled estimates by omitting one study at a time). The meta-regression analyses were per- formed using the publication year and follow-up duration to determine the related effect of the ROM in the placebo group. Two-sided p value of <0.05 was considered as statistically significant and all the analyses were performed using R (version 3.4.1; The R Foundation for Statistical Computing, Vienna, Austria). Results Study inclusion A total of 42 studies were included in this meta-analysis, involving a total of 37449 patients (treatment group: 18587, placebo group: 19162)(Table 1 and Fig 1). Five studies were excluded in the final analysis due to insufficient data. A total of 37 studies were finally included in the meta-analysis, involving a total of 23395 patients (treatment group: 11392, placebo group: 12003). Risk of bias For random sequence generation, most of the included studies showed a low risk and only a single study showed unclear risk (S1 Table). For allocation concealment, 28 studies showed unclear risk and 14 studies showed low risk. For blinding of participants and personnel (per- formance bias), 7 studies showed high risk, one study showed unclear risk and 34 studies showed low risk. Effective size of PSA, PV, IPSS, and Qmax of 5ARI compared with placebo For PSA, a total of 13 studies were included in the meta-analysis. The overall effective size based on SMD was -0.76 (95% CI, -1.31, -0.22)(S1 Fig), which showed a significant decrease in PSA level after 5ARI treatment compared with placebo. The overall effective size showed moderate effect of improvement by Cohen's cutoff. The overall effective size based on WMD was -1.27 (-2.29, -0.24). For PV, a total of 26 studies were included in the meta-analysis. The overall effective size based on SMD was -0.63 (95% CI, -0.74, -0.52)(S2 Fig), which showed a significant decrease of PV after 5ARI medication compared with placebo. The overall effec- tive size showed moderate effect of improvement by Cohen's cutoff. The overall effective size based on WMD was -11.13 (-13.34, -8.93). For PVR, a total of 5 studies were included in the meta-analysis. The overall effective size by SMD was 0.1 (95% CI, -0.48, 0.68), which showed insignificant decrease of PVR after 5ARI treatment compared with placebo. For IPSS, a total of 18 studies were included in the meta-analysis. The overall effective size by SMD was -0.19 (95% CI, -0.27, -0.11)(Fig 2), which showed a significant decrease of IPSS after 5ARI inter- vention compared with placebo. The overall effective size showed small effect of improve- ment by Cohen's cutoff. The overall effective size based on WMD was -1.21(-1.72, -0.70). Finasteride showed a significant improvement of IPSS as -0.18 (95% CI, -0.26, -0.10). How- ever, dutasteride showed no significant improvement in IPSS as -0.21 (95% CI, -0.42, 0.00). For Qmax, a total of 23 studies were included in the meta-analysis, and the overall effective size by SMD was 0.29 (95% CI, 0.22 to 0.36)(S3 Fig), which showed significant improvement of Qmax after 5ARI treatment compared with placebo. The overall effective size based on WMD was -1.16 (0.88, 1.43). PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 5 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. Characteristics of all studies included in meta-analysis. Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) Beisland European 1992 NA 94 88 60 60 Qmax<15mL/s 1 0 0 Finasteride 5 6 Urology Gormley The New 1992 USA, Canada 297 300 64 64 Qmax<15mL/s, 1 0 0 Finasteride 5 12 England voided Journal of volume>150mL Medicine Kirby British Journal 1992 UK 31 21 64.4 64.4 Qmax<15mL/s, 1 1 0 Finasteride 5 3 of Urology voided volume>150mL, detrusor pressure during voiding>50cmH2O2 Stoner The Journal of 1992 USA 18 25 63.9 63.9 Enlarged prostate 1 0 1 Finasteride 5 6 Urology gland of greater than 30cc Tammela The Journal of 1993 Finland 19 17 65 65 Qmax<15mL/s, 1 1 0 Finasteride 5 6 Urology voided volume>150mL Tempany The Prostate 1993 USA 12 8 NA NA NA 1 0 0 Finasteride 1 or 12 The The Prostate 1993 Australia, 246 255 66 66 Qmax<15mL/s, 1 0 1 Finasteride 5 12 finasteride Belgium, PV>30cm study Brazil, France, group Italy, Mexico, Netherlands, New Zealand, Portugal, Spain, Swizerland, Germany, UK, USA Stoner UROLOGY 1994 USA 291 299 64 64 Qmax<15mL/s, 1 0 0 Finasteride 5 12 voided International 242 254 66 66 volume>150mL study Andersen UROLOGY 1995 Scandinavian 347 346 65.5 65.5 Qmax5-15mLs, 1 0 0 Finasteride 5 24 countries PSA10ng/mL, (Denmark, PVR150cc Finland, Iceland, Norway, Sweden) Tammela The Journal of 1995 Finland 12 15 65 65 Qmax<15mL/s, 1 1 0 Finasteride 5 6 Urology voided volume>150mL Yu Journal of the 1995 Taiwan 24 22 66.4 65.2 NA 1 0 0 Finasteride 5 6 Formosan Medical Association Lepor The New 1996 USA 305 310 65 65 AUA>8, Qmax4- 1 0 0 Finasteride 5 13 England 15mL/s, voided Journal of volume>125mL Medicine (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 6 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. (Continued ) Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) Nickel Canadian 1996 Canada 310 305 63 63.5 Qmax5-15mLs, 1 0 0 Finasteride 5 24 Medical voided Association volume>150mL, PVR150cc, PSA<10ng/mL Habib Clinical 1997 Scotland 19 9 68.7 66.7 NA 1 0 0 Finasteride 5 3 Endocrinology Lepor The Journal of 1998 USA 44 39 62.5 62.5 Qmax4-15mL/s, 0 0 0 Finasteride 5 13 Urology voided volume125mL, PVR300mL, AUA-SI score8 Marberger UROLOGY 1998 USA 1450 1452 63 63.4 Qmax5-15mL/s, 1 0 0 Finasteride 5 24 voided volume>150mL McConnell The New 1998 USA 1524 1516 64 64 Qmax15mL/s, 1 0 0 Finasteride 5 48 England voided Journal of volume>150mL Medicine Pannek The Journal of 1998 USA 26 14 65 64 IPSS>9, PSA10ng/ 0 0 0 Finasteride 5 6 Urology mL Abrams The Journal of 1999 USA 69 37 68.1 67.4 NA 0 0 0 Finasteride 5 9 Urology Lukkarinen Annales 1999 Finland 33 31 65 65 Boyarsky<15mL/s, 1 0 0 Finasteride 5 24 Chirurgiae et PV>30cc Gynaecologiae Schafer UROLOGY 1999 Germany, 81 40 68.1 NA PSA<10ng/mL 1 1 0 Finasteride 5 12 Finland, UK, Sweden, Netherland, Denmark, Portugal, USA Feneley Prostate cancer 2000 UK, 18 9 67.5 67.5 BPH/BOO 1 1 0 Finasteride NA 6 and prostatic Netherland diseases Isotalo British Journal 2001 Finland 29 19 71 71 NA 1 0 1 Finasteride 5 18 of Urology Espana BJU 2002 Spain 30 10 66.7 69.5 Qmax15mL/s, 1 0 0 Finasteride NA 9 International IPSS>7, PVR<150mL, tPSA<20ng/mL Haggstrom Scandinavian 2002 Sweden 13 15 NA NA NA 0 0 0 Finasteride 5 3 Journal of Urology and Nephrology Roehrborn UROLOGY 2002 Global study 2167 2158 66.5 66.1 Qmax15mL/s, 1 0 0 Dutasteride 0.5 24 PSA1.5ng/mL, PV30cc, AUA-SI score12 Kirby UROLOGY 2003 Europe 239 253 63 64 Qmax5-15mLs, 1 0 0 Finasteride 5 13 voided volume150mL, IPSS12, Prostate volume nearest 5g (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 7 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. (Continued ) Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) McConnell The New 2003 NA 89 128 62.6 62.5 Qmax4-15mL/s, 1 0 0 Finasteride 5 54 England voided Journal of volume125mL, Medicine AUA-SI score 8±35 Roehrborn The Journal of 2004 USA 1524 1516 64 63.9 Qmax15mL/s, 1 0 0 Finasteride 5 48 Urology voided volume>150mL Crawford The Journal of 2006 NA NA 737 - 62.5 Qmax4-15mL/s, 1 0 0 Finasteride 5 54 Urology AUA-SI score>8, voided volume125mL Gittelman The Journal of 2006 NA 2167 2158 65.8 65.5 Qmax>15mL/s, 1 0 0 Dutasteride 0.5 48 Urology AUA_SI>12, PV>30cc, PSA1.5- 10ng/mL Kaplan The Journal of 2006 USA 232 250 61 60.5 AUA8-35, Qmax4- 1 0 1 Finasteride 5 54 Urology 15mL/s, voided volume>125mL, TPV<25 281 274 61.8 62.4 AUA8-35, Qmax4- 15mL/s, voided volume>125mL, TPV<40 252 213 65.1 64.8 AUA8-35, Qmax4- 15mL/s, voided volume>125mL, TPV>40 Kaplan The Journal of 2008 USA 768 737 62.6 62.5 Qmax 4-15mL/s, 0 0 0 Finasteride 5 54 Urology voided volume>125mL, AUA-SI score 8±30 Bepple UROLOGY 2009 USA 30 29 66 66 NA 0 0 0 Dutasteride 0.5 12 Tsukamoto Hinyokika 2009 Japan 70 70 66.1 65.8 Qmax>15mL/s, 0 0 0 Dutasteride 0.5 6 Kiyo IPSS>3 Tsukamoto International 2009 Japan 193 185 67.7 64.4 Qmax<15mLs, 1 0 0 Dutasteride 0.5 13 Journal of IPSS8, voided Urology volume150mL, PV>30mL Tsukamoto Hinyokika 2010 Japan 184 181 68 66.9 Qmax<15mLs, 1 0 0 Dutasteride 0.5 13 Kiyo IPSS8, PV<30cc Kaplan The Journal of 2011 USA 281 276 60.7 60.3 Qmax 4-15mL/s, 0 0 0 Finasteride 5 54 Urology AUA-SI score 8±30 voided volume>125mL, PV<30mL 295 288 63.9 64.1 Qmax4-15mL/s, AUA-SI score 8±30 voided volume>125mL, PV>30mL (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 8 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. (Continued ) Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) Roehrborn UROLOGY 2011 USA 4049 4073 62.7 62.7 50±60 years old: 1 0 0 Dutasteride 0.5 48 PSA2.5-10ng/mL, >60 years old: 3.0- 10ng/mL Yanqun Clinical Drug 2012 China 126 127 65.8 66.9 Qmax 5-15mL/s, 1 0 0 Dutasteride 0.5 6 Investigation AUA-SI score>12 voided volume>125mL, Kacker Androlodia 2015 USA 11 11 57.7 57.7 Testosterone (T) for at 0 0 0 Dutasteride 0.5 12 least 3 months, and a current serum T within the normal range (300±1000ng dl) Qian The Aging 2015 China 45 42 70.1 72.3 PV>80mL, IPSS13, 1 0 0 5ARI 5 or 6 Male QoL3, PVR200mL, Finasteride 0.5 Qmax<15mL/s, or refractory HU history, Dutasteride bladder stone history, AUR history, refractory UTI history NA, not available; BPH, benign prostatic hyperplasia; 5ARI, 5 alpha reductase inhibitor; PVR, post voided residual volume; PSA, prostatic specific antigen; PV, prostatic volume; IPSS, International Prostate Symptom Score; Qmax, maximal urinary flow rate; QoL, quality of life. UTI, urinary tract infection https://doi.org/10.1371/journal.pone.0203479.t001 Cumulative analysis Cumulative meta-analysis was performed to investigate the trend according to years. For PSA, in 1990s, effective size showed no significant difference compared with placebo. However, starting with 2000s, the effective size showed a significant difference compared with placebo, resulting in a stable outcome from -0.77 to -0.60. For PV, the effect size showed a constant and significant difference compared with placebo, which showed stable outcome from -0.70 to -0.40 (Fig 3A). For IPSS, there was no marked change in the trend of effective size compared with placebo, however, the effective size of difference compared with placebo showed a decreasing trend (Fig 3B). For Qmax, the effective size showed a large difference compared with placebo until 1993. However, from 1994, the effective size of difference showed a decreas- ing trend as a convergence of 0.3 (Fig 3C). Sensitivity analysis Considering the relatively high heterogeneity, sensitivity analysis was performed to analyze the effect of each study. Overall effect size of all variables except PVR showed no impact of individ- ual studies (S4 Fig). However, the effect size of PVR was affected by one study, which resulted in a different outcome without that study. Meta-regression To investigate the reasons for heterogeneity of effect, a meta-regression analysis was per- formed. Moderating factor was suggested as IPSS at baseline, follow-up duration and race. Effective sizes of all variables except PVR showed no significant moderating effect. However, PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 9 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Fig 2. Meta-analysis of effective sizes in prostate specific antigen (PSA), International Prostate Symptom Score (IPSS), prostate volume and maxima urinary flow rate (Qmax). https://doi.org/10.1371/journal.pone.0203479.g002 the effective size of PVR was affected by IPSS at baseline. The effective size of PVR decreased according to high IPSS at the baseline: -0.29 (95% CI, -0.46,-0.12) in univariate analysis. Multi- variable analysis was not performed due to the small number of included studies. ROM analysis of placebo group To show the placebo effect of each variable, a ROM analysis was performed (Table 2). For PSA, although it did not show a significant effective size, it still showed a decrease by 10% (0.90 (95% CI, 0.81, 1.00) during follow-up. For PV, there was no change during follow-up: 1.00 (95% CI, 0.88, 1.14). For IPSS, there was a significant decrease during follow-up: 0.77 (95% CI, 0.68, 0.88), suggesting a 23% improvement. For Qmax, there was significant increase during the follow-up: -1.13 (95% CI, 1.06, 1.20), suggesting a 13% aggravation. Meta-regression of ROM analysis in placebo group To investigate the reasons for the placebo effect in ROM analysis, the published year and fol- low-up duration were suggested as moderators (S2 Table). For PSA, there was no significant PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 10 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 11 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Fig 3. Cumulative analysis of effective sizes in prostate volume, International Prostate Symptom Score (IPSS), and maxima urinary flow rate (Qmax). https://doi.org/10.1371/journal.pone.0203479.g003 moderator effect. However, for PV, IPSS, and Qmax, both published year and follow-up dura- tion were significant moderators. The effective size of PV and IPSS was decreased according to years of recent publication (p<0.001), and was increased according to follow-up duration (p<0.001). In contrast, the effective size of Qmax was increased according to years of recent publication (p<0.001), and decreased by the follow-up duration (p = 0.020). For PVR, only the year of publication affected the effective size, which showed a decreased effect according to the year of recent publication (p<0.001). Adverse events The 5ARI treatment prevented exacerbation of BPH and urinary retention compared with pla- cebo (Table 3). However, compared with placebo, 5ARI showed a significantly higher inci- dence 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). Decreased libido and impotence was affected by the moderating effect of fol- low-up duration. After meta-regression of follow up duration, decreased libido (OR = 0.98, 95% CI, 0.97, 0.99) and increased impotence (OR = 0.98, 95% CI, 0.97, 0.99) were significantly related to longer follow-up duration. Publication bias There was no publication bias detected following Egger's test (S5 Fig). Discussion Although current guidelines suggest the use of 5ARI in patients with prostate size greater than 30cc, our study does not support the wide use of 5ARI, rather it needs specific indication. Although there has been a systematic review about this issue, especially for finasteride [11], it needs to be upgraded. The main academic basic hypothesis of our study is based on the most recent focus on androgens in aged men. It is well known that androgens profoundly regulate prostate growth and differentiation, as well as sexual function [12, 18]. However, it is also asso- ciated with general health of aged men including cardiovascular disease. A recent RCT showed that a 1-year treatment of testosterone showed superior outcomes compared with placebo in coronary artery non-calcified plaque volume [27]. In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, the dutasteride treatment group showed larger rate of cardiac failure compared with placebo [28]. Moreover, the 5ARI treatment was again associated with the possible risk of suicidal attempts and depression in many observational studies [20]. It is beyond dispute that the combination treatment of alpha-blocker and 5ARI is superior to alpha-blocker monotherapy or placebo group [5, 6]. In early trials, the effect of combination treatment was mainly attributed to alpha-blocker and also to the double-placebo effect. In MTOPS trial, the overall effect of two placebo combinations was -4.0 at 1 year and also -4.0 at 4 years, which suggests a 23.8% improvement in placebo effect [5]. Further, at 1 year, there was no significant difference in symptom improvement between the alpha-blocker and combina- tion groups [5]. Due to the absence of meta-analysis involving alpha-blocker, 5ARI, and pla- cebo, this study failed to confirm the poor clinical efficacy of 5ARI compared with alpha- blockers. However, this is the first meta-analysis investigating the clinical efficacy of 5ARI monotherapy among RCTs, which showed that overall effective size of IPSS improvement by PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 12 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 2. Ratio of means meta-analysis of the efficacy of placebo group. Author (year) No. of samples Ratio of mean (95% CI) PSA PV PVR IPSS voiding IPSS Qmax Gormley (1992) 300 0.98 (0.89, 1.08) 0.90 (0.81, 0.99) 0.88 (0.80, 0.97) 1.02 (0.96, 1.08) Kirby (1992) 10 0.80 (0.39, 1.64) 0.96 (0.49, 1.87) 0.52 (0.16, 1.64) 0.81 (0.48, 1.39) 0.90 (0.54, 1.51) Tempany (1993) 8 1.01 (0.63, 1.62) Tammela (1993) 17 1.10 (0.64, 1.88) 1.12 (0.90, 1.41) Andersen (1995) 197 1.28 (1.04, 1.56) 1.02 (0.93, 1.11) 0.98 (0.90, 1.06) 0.97 (0.93, 1.02) Tammela (1995) 15 0.96 (0.72, 1.27) 1.19 (0.63, 2.24) 1.11 (0.87, 1.42) Yu (1995) 22 0.89 (0.51, 1.58) 1.06 (0.83, 1.37) 0.86 (0.73, 1.01) 1.01 (0.80, 1.29) Habib (1997) 1.26 (0.77, 2.05) Lepor (1998) 258 1.01 (0.94, 1.09) 0.84 (0.79, 0.89) 1.13 (1.08, 1.20) Marberger (1998) 800 1.04 (0.99, 1.09) Pannek (1998) 10 0.73 (0.28, 1.88) 0.97 (0.69, 1.37) Abrams (1999) 0.82 (0.69, 0.96) 0.99 (0.88, 1.11) Lukkarinen (1999) 31 0.92 (0.76, 1.10) 0.84 (0.67, 1.06) Feneley (2000) 9 0.82 (0.52, 1.31) 1.23 (0.85, 1.77) Isotalo (2001) 19 0.66 (0.53, 0.81) 0.91 (0.75, 1.11) 1.09 (0.76, 1.56) Haggstrom (2002) 1.02 (0.86, 1.21) Kirby (2003) 1.12 (0.96, 1.29) 0.69 (0.63, 0.74) 1.12 (1.06, 1.18) McConnell (2003) 0.76 (0.73, 0.80) 1.13 (1.10, 1.16) Roehrborn (2004) 0.89 (0.84, 0.95) 0.97 (0.94, 1.00) Crawford (2006) 1.13 (1.11, 1.16) Kaplan (2008) 249 1.34 (1.22, 1.46) Kaplan (2008)a 214 1.12 (1.04, 1.21) Kaplan (2008)b 112 1.20 (1.08, 1.32) Kaplan (2008)c 161 1.21 (1.16, 1.27) Tsukamoto (2009) 70 0.81 (0.69, 0.95) 0.73 (0.62, 0.85) 1.12 (0.99, 1.27) Qian (2015) 42 0.81 (0.77, 0.86) 0.60 (0.57, 0.63) 0.06 (0.05, 0.07) 0.36 (0.32, 0.41) 2.79 (2.36, 3.30) Overall 0.90 (0.81, 1.00) 1.00 (0.88, 1.14) 0.44 (0.06, 3.22) 0.77 (0.68, 0.88) 0.93 (0.84, 1.03) 1.13 (1.06, 1.20) p = 0.056 p = 0.97 p = 0.42 p<0.001 p = 0.159 p<0.001 HeterogeneityÐI (%) 73.3 (47.8, 86.3) 96.3 (95.1, 97.1) 98.5 (97.6, 99.0) 96.7 (95.4, 97.6) 61.9 (0.0, 91.2) 91.3 (87.5, 93.9) p-value <0.001 <0.001 <0.001 <0.001 0.105 <0.001 CI, confidence interval; PSA, prostate specific antigen; PV, prostate volume; PVR, post voided residual volume; IPSS, International Prostate Symptom Score; Qmax, maximal urinary flow rate. The process of meta-analysis with paired difference data: estimates using the Hegde's corrected standardized mean difference assuming the random-effect model https://doi.org/10.1371/journal.pone.0203479.t002 5ARI compared with placebo was small. Moreover, the overall effective size of PV and PSA was moderate. For PV growth, previous studies reported an annual growth rate of 0.6 cc per year (−- 9.9~11.8) [29]. Interestingly, the negative PV growth rate represents the diversity of growth rate according to individual characteristics. Loeb et al [30] reported that a considerable pro- portion of aging men do not show progressive PV enlargement, and a few manifested decreas- ing pattern. In their study of median follow up of 4.3 years, a progressive PV growth was noted in 61.9%. However, 38.1% of men showed no increase or decrease in PV with the rate of PV changing by 0.6cc annually (-9.9~62.1). They speculated that aging could induce prostate shrinkage in healthy community men due to genetic, hormonal or environmental factors. In another study of Olmsted county survey, the median growth rate of PV was 1.9% per year [31]. PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 13 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. Meta-analysis and meta-regression of effective sizes in adverse events. Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Abdominal pain 1.16 (0.78±1.74) 0.455 0.0% 0.97 (0.91±1.04) 0.377 Gormley (1992) 3.37 (0.32±35.31) 0.311 Marberger (1998) 1.06 (0.68±1.67) 0.784 Stoner (1994) 1.7 (0.41±7.09) 0.464 Tsukamoto (2009) 0.14 (0.01±2.62) 0.186 Tsukamoto (2009) 2.03 (0.53±7.8) 0.303 Angina pectoris 1.01 (0.55±1.84) 0.977 NA% NA NA Marberger (1998) 1.01 (0.55±1.84) 0.977 Any AE 0.98 (0.88±1.09) 0.767 56.8% 1.01 (0.99±1.03) 0.368 Andersen (1995) 1.3 (0.83±2.05) 0.251 Beisland (1992) 1 (0.75±1.33) 0.992 Kacker (2015) NA (NA-NA) NA Nickel (1996) 1 (0.93±1.08) 0.922 The finasteride study group (1993) 12.44 (1.63±94.95) 0.015 Tsukamoto (2009) 0.98 (0.91±1.05) 0.505 Tsukamoto (2009) 0.83 (0.67±1.03) 0.09 Asthenia 0.86 (0.59±1.25) 0.43 2.5% 0.93 (0.87±1) 0.046 Gormley (1992) 1.01 (0.21±4.96) 0.99 Kirby (2003) 1.02 (0.45±2.31) 0.964 Lepor (1996) 1.08 (0.61±1.91) 0.797 Marberger (1998) 0.46 (0.23±0.94) 0.033 Stoner (1994) 1.28 (0.34±4.73) 0.714 Back pain 0.61 (0.39±0.95) 0.028 0.0% NA NA Marberger (1998) 0.59 (0.37±0.95) 0.029 Tsukamoto (2009) 0.76 (0.18±3.28) 0.713 BPH worsening 0.55 (0.37±0.83) 0.004 NA% NA NA Marberger (1998) 0.55 (0.37±0.83) 0.004 Breast pain 2.49 (0.88±7.01) 0.084 0.0% NA NA Gormley (1992) 3.03 (0.12±74.09) 0.497 McConnell (1998) 2.43 (0.81±7.26) 0.112 Bronchitis 1.15 (0.7±1.91) 0.579 NA% NA NA Marberger (1998) 1.15 (0.7±1.91) 0.579 Decreased libido 1.67 (1.35±2.06) <0.001 9.8% 0.98 (0.97±0.99) 0.004 Bepple (2009) 6.53 (0.35±120.66) 0.208 Gormley (1992) 3.63 (1.19±11.01) 0.023 Kirby (2003) 1.83 (0.62±5.4) 0.271 Lepor (1996) 3.44 (1.15±10.34) 0.028 Marberger (1998) 1.44 (0.99±2.11) 0.057 McConnell (1998) 1.01 (0.65±1.56) 0.965 Nickel (1996) 1.59 (0.92±2.76) 0.095 Roehrborn (2002) 1.97 (1.39±2.79) <0.001 Stoner (1994) 2.04 (0.93±4.51) 0.077 Tsukamoto (2009) 4.77 (0.23±98.64) 0.312 Yanqun (2012) 2.02 (0.19±21.95) 0.565 Yu (1995) 4.59 (0.23±90.58) 0.316 Diarrhea 1.05 (0.58±1.9) 0.863 0.0% NA NA (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 14 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. (Continued ) Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Gormley (1992) NA (NA-NA) NA Marberger (1998) 1.15 (0.56±2.35) 0.696 Tsukamoto (2009) 0.87 (0.31±2.46) 0.792 Dizziness 1.06 (0.74±1.52) 0.754 0.0% 1.09 (0.88±1.34) 0.451 Gormley (1992) 0.19 (0.01±3.99) 0.288 Kirby (2003) 1.07 (0.59±1.93) 0.822 Lepor (1996) 1.16 (0.67±2.01) 0.588 Stoner (1994) 1.02 (0.26±4.07) 0.975 Tsukamoto (2009) 4.77 (0.23±98.64) 0.312 Tsukamoto (2009) 0.68 (0.2±2.29) 0.53 Dyspepsia 0.34 (0.01±8.16) 0.504 NA% NA NA Tsukamoto (2009) 0.34 (0.01±8.16) 0.504 Dysuria 1.34 (0.66±2.72) 0.417 0.0% NA NA Gormley (1992) 5.05 (0.24±104.75) 0.295 Marberger (1998) 1.24 (0.6±2.57) 0.56 Ejaculatory disorder 2.89 (2.12±3.93) <0.001 0.0% 1 (0.98±1.03) 0.689 Gormley (1992) 2.57 (0.94±7.08) 0.067 Kirby (2003) 1.53 (0.44±5.35) 0.507 Lepor (1996) 1.48 (0.42±5.18) 0.543 Marberger (1998) 3.7 (1.78±7.7) <0.001 McConnell (1998) 3.01 (1.33±6.81) 0.008 McConnell (1998) 1.99 (0.28±14.11) 0.491 Nickel (1996) 4.69 (1.81±12.14) 0.001 Roehrborn (2002) 2.81 (1.62±4.87) <0.001 Tsukamoto (2009) 4.06 (0.46±35.41) 0.205 Erectile dysfunction 1.51 (0.15±15.27) 0.725 34.1% NA NA Tsukamoto (2009) 3.81 (0.43±33.8) 0.229 Yanqun (2012) 0.34 (0.01±8.17) 0.503 Flatulence 1.39 (0.45±4.34) 0.568 0.0% NA NA Gormley (1992) 1.44 (0.25±8.36) 0.682 Stoner (1994) 1.36 (0.31±6.04) 0.687 Gastritis 1.3 (0.65±2.6) 0.463 NA% NA NA Marberger (1998) 1.3 (0.65±2.6) 0.463 Gynecomastia 2.29 (1.4±3.76) 0.001 19.9% 0.98 (0.95±1.01) 0.119 McConnell (1998) 1.61 (0.88±2.95) 0.124 Roehrborn (2002) 3.11 (1.78±5.45) <0.001 Yanqun (2012) 3.02 (0.12±73.53) 0.497 Headache 0.97 (0.62±1.52) 0.906 38.0% 0.96 (0.91±1.01) 0.137 Beisland (1992) 1.4 (0.52±3.78) 0.502 Gormley (1992) 0.96 (0.14±6.63) 0.969 Lepor (1996) 1.87 (0.88±3.95) 0.102 Marberger (1998) 0.92 (0.58±1.48) 0.743 Marberger (1998) 0.42 (0.2±0.88) 0.021 Stoner (1994) 1.7 (0.41±7.09) 0.464 Tsukamoto (2009) 0.51 (0.1±2.68) 0.424 Hypertension 0.82 (0.58±1.14) 0.239 0.0% NA NA (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 15 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. (Continued ) Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Kirby (2003) 0.75 (0.35±1.6) 0.452 Marberger (1998) 0.83 (0.57±1.22) 0.347 Hypotension 0.51 (0.09±2.76) 0.434 NA% NA NA Kirby (2003) 0.51 (0.09±2.76) 0.434 Impotence 1.68 (1.3±2.17) <0.001 58.1% 0.98 (0.97±0.99) 0.001 Gormley (1992) 1.98 (0.69±5.68) 0.204 Kirby (2003) 1.47 (0.64±3.38) 0.363 Lepor (1996) 2.04 (1.1±3.78) 0.024 Marberger (1998) 1.42 (1.06±1.89) 0.018 McConnell (1998) 1 (0.74±1.36) 0.981 Nickel (1996) 2.52 (1.52±4.18) <0.001 Roehrborn (2002) 1.83 (1.42±2.36) <0.001 Stoner (1994) 3.07 (1.31±7.15) 0.01 Influenza 0.89 (0.58±1.37) 0.602 NA% NA NA Marberger (1998) 0.89 (0.58±1.37) 0.602 Lens change 1.2 (0.3±4.81) 0.793 12.7% NA NA Gormley (1992) 5.05 (0.24±104.75) 0.295 Gormley (1992) 0.19 (0.01±3.99) 0.288 Stoner (1994) 1.36 (0.31±6.06) 0.684 Myocardial infarction 2.9 (1.3±6.46) 0.009 NA% NA NA Marberger (1998) 2.9 (1.3±6.46) 0.009 Nausea 0.73 (0.23±2.28) 0.582 0.0% NA NA Gormley (1992) 0.67 (0.11±4) 0.664 Stoner (1994) 0.76 (0.17±3.4) 0.724 orgasm dysfunction 0.8 (0.08±8.3) 0.85 31.3% NA NA Gormley (1992) 2.24 (0.19±26.87) 0.523 Stoner (1994) 0.2 (0.01±4.25) 0.305 Pelvic pain 0.48 (0.04±5.18) 0.546 NA% NA NA Gormley (1992) 0.48 (0.04±5.18) 0.546 Pharyngitis 1.6 (0.78±3.28) 0.202 NA% NA NA Marberger (1998) 1.6 (0.78±3.28) 0.202 Postural hypotension 1.18 (0.27±5.12) 0.821 46.5% NA NA Kirby (2003) 0.51 (0.09±2.76) 0.434 Lepor (1996) 2.3 (0.6±8.8) 0.225 Rash 1.59 (0.63±4.01) 0.326 38.4% 1.03 (0.97±1.09) 0.39 Gormley (1992) 2.24 (0.19±26.87) 0.523 Marberger (1998) 0.82 (0.43±1.54) 0.532 McConnell (1998) 5.31 (0.93±30.3) 0.061 Stoner (1994) 2.04 (0.38±11.11) 0.408 Rhinitis 0.56 (0.24±1.32) 0.186 NA% NA NA Lepor (1996) 0.56 (0.24±1.32) 0.186 Sinusitis 0.98 (0.25±3.9) 0.982 NA% NA NA Lepor (1996) 0.98 (0.25±3.9) 0.982 Somnolence 1.36 (0.48±3.86) 0.565 NA% NA NA Kirby (2003) 1.36 (0.48±3.86) 0.565 Syncope 1.63 (0.08±31.47) 0.747 46.0% NA NA (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 16 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. (Continued ) Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Kirby (2003) 0.34 (0.01±8.3) 0.508 Lepor (1996) 6.89 (0.36±132.77) 0.201 Testicular pain 1.4 (0.45±4.35) 0.565 0.0% NA NA Gormley (1992) 1.44 (0.25±8.36) 0.682 Stoner (1994) 1.36 (0.31±6.06) 0.684 upper respiratory infection 0.7 (0.41±1.19) 0.191 NA% NA NA Marberger (1998) 0.7 (0.41±1.19) 0.191 urinary retention 0.49 (0.28±0.87) 0.015 NA% NA NA Marberger (1998) 0.49 (0.28±0.87) 0.015 Urinary tract Infection 0.71 (0.44±1.14) 0.154 NA% NA NA Marberger (1998) 0.71 (0.44±1.14) 0.154 Vertigo 2.04 (0.52±8.06) 0.31 NA% NA NA Kirby (2003) 2.04 (0.52±8.06) 0.31 OR, odds ratio; CI, confidence interval. https://doi.org/10.1371/journal.pone.0203479.t003 In our study, it was not logical to estimate the annual grow rate because this study does not contain direct population data. However, this study demonstrated the changes of PV in pla- cebo group, which suggested that the PV growth rate was 1.00 by ROM (95% CI, 0.88±1.14), which showed lack of increase in PV size during the years of investigation of enrolled studies. For adverse events, two recent reviews reported adverse effects including ED, decreased libido, gynecomastia, and anxiety following 5ARI therapy [18, 19]. Our study also found simi- lar adverse effects including decreased libido, ejaculatory disorder, gynecomastia and impo- tence. Interestingly, Corona et al [18] reported that adverse events were inversely correlated with study duration. Our study also showed similar findings of decreased libido and impotence affected by the moderating effect of follow-up duration, which showed attenuation of decreased libido and impotence during a longer follow-up. Further studies are needed by merging data of 5ARI studies with other indications such as alopecia. Moreover, comorbidity status should be taken into account when considering the incidence of ED in patients receiving 5-ARIs. 5-ARIs are often prescribed to older patients with high comorbidity status, which could also increase the risk of ED [32]. The comorbidity status is often underreported in pub- lished studies and this may represent a bias. The detailed mechanism underlying the negative impact of 5ARI on ED or decreased libido has not been fully demonstrated. Several suggested theories include: 1) Decrease synthesis of neurostransmitters by 5ARI [13], which is related to sexual desire; 2) 5ARIs induce structural and functional degeneration of penile tissue, which results in penile fibrosis due to cholinergic and nitrergic sensitivity [13]. In animal studies, finasteride suppressed neurosteroid synthesis, which resulted in anxiety and depression [33±35], which could explain the possible association between 5ARI treatment and depression or suicidal attempts. Our study is academically sound and robust due to several reasons: 1) It is the first scientific review including meta-analysis of RCTs investigating the efficacy and adverse events associ- ated with 5ARI monotherapy; 2) It shows an indirect effect of the reported years using a cumu- lative meta-analysis; 3) It shows indirect outcomes of prostate growth using a single-placebo- controlled meta-analysis. In our study, although the effective size of PSA, IPSS, PV, and Qmax showed significantly superior outcome compared with the placebo group, the effective size, PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 17 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy especially for IPSS (-0.19, 95%CI: -0.27- -0.11) was small. Considering the effective size was analyzed by SMD, it could be interpreted as 7.5% by two sided test and as 15% by one sided test. By subgroups, although finasteride showed a significant improvement of IPSS, dutasteride showed not significant improvement, which is due to relatively lower published studies of dutasteride than finasteride. The included studies showed a lower clinical improvement in IPSS, PV and Qmax when recent publications were considered. PV showed a relatively slower growth than in previous clinical studies. Due to limitation of meta-analysis, detailed individual level data could not be extracted. Furthermore, we could not find a long term complication including depression and suicidal attack, which could not be reported in ITT study design. For those complications, observa- tional studies have to be included. This study also included outdated studies which only have focused on finasteride, which could result in favorable effect of finasteride than dutasteride during meta-analysis. 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 out- comes 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 com- pared to alpha blocker. In future, the accurate prevalence rate of persistent adverse events after 5ARI discontinua- tion needs to be investigated. Moreover, considering the long-term clinical efficacy of 5ARI, long-term adverse events need to be investigated more clearly. This meta-analysis provides useful information for clinicians and clinical investigators to design controlled studies investi- gating long-term outcomes following 5ARI therapy. Conclusions In this meta-analysis with an average follow-up duration of 21.8 months, the efficacy outcomes of 5ARI showed a small clinical improvement in improvement of LUTS. In future, well designed studies are needed to overcome placebo effect and heterogeneities and possible bias. Considering persistent and well known adverse events including ED and decreased libido even after discontin- uation of 5ARI, 5ARI therapy should be prescribed with great caution and patients need to be fully informed about the possible adverse events. A more selective rationale is needed considering the diverse growth rate of PV, and a relatively low growth rate observed in our study. Supporting information S1 Text. PRISMA checklist. (DOC) S2 Text. Searching strategies using Pubmed database. (PDF) S3 Text. Searching strategies using Cochrane database. (PDF) S1 Table. Methodological qualities of included studies. (DOCX) S2 Table. Meta-regression analysis for ratio of means meta-analysis of the efficacy of pla- cebo group. (DOCX) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 18 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy S1 Fig. Meta-analysis of effective sizes in prostate specific antigen (PSA). (JPG) S2 Fig. Meta-analysis of effective sizes in prostate volume. (TIF) S3 Fig. Meta-analysis of maxima urinary flow rate (Qmax). (TIF) S4 Fig. Sensitivity analysis of effective sizes in prostate volume, International Prostate Symptom Score (IPSS), and maxima urinary flow rate (Qmax). (TIF) S5 Fig. Funnel plots for PSA, PV, IPSS, and Qmax. (JPG) Author Contributions Conceptualization: Jae Heon Kim, Benjamin I. Chung. Data curation: Min Jung Baek, Hwa Yeon Sun. Formal analysis: Jae Heon Kim, Min Jung Baek, Bora Lee, Shufeng Li. Investigation: Jae Heon Kim, Hwa Yeon Sun, Shufeng Li, Yash Khandwala, Francesco Del Giudice, Benjamin I. Chung. Methodology: Jae Heon Kim, Hwa Yeon Sun, Shufeng Li, Yash Khandwala, Francesco Del Giudice, Benjamin I. Chung. Project administration: Benjamin I. Chung. Resources: Jae Heon Kim. Supervision: Benjamin I. Chung. Validation: Shufeng Li, Yash Khandwala, Francesco Del Giudice. Writing ± original draft: Jae Heon Kim, Benjamin I. Chung. Writing ± review & editing: Jae Heon Kim, Min Jung Baek, Hwa Yeon Sun, Bora Lee, Shufeng Li, Yash Khandwala, Benjamin I. Chung. References 1. McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care. 2006; 12(5 Suppl):S122±8. PMID: 16613526. 2. Yuan JQ, Mao C, Wong SY, Yang ZY, Fu XH, Dai XY, et al. Comparative Effectiveness and Safety of Monodrug Therapies for Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia: A Network Meta-analysis. Medicine (Baltimore). 2015; 94(27):e974. https://doi.org/10.1097/MD. 0000000000000974 PMID: 26166130; PubMed Central PMCID: PMCPMC4504542. 3. 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Horm Behav. 2002; 41(3):306±15. https://doi.org/10. 1006/hbeh.2002.1763 PMID: 11971664. 35. Rhodes ME, Frye CA. Inhibiting progesterone metabolism in the hippocampus of rats in behavioral estrus decreases anxiolytic behaviors and enhances exploratory and antinociceptive behaviors. Cogn Affect Behav Neurosci. 2001; 1(3):287±96. PMID: 12467128. PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 21 / 21 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png PLoS ONE Public Library of Science (PLoS) Journal

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

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Copyright: © 2018 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors have outlined how authors can recreate their dataset in the methods and materials section. The articles used for this study are outlined in the MS and SI files. Funding: This work was supported by Soonchunhyang University Hospital Research Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
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Abstract

OPENACCESS Citation: Kim JH, Baek MJ, Sun HY, Lee B, Li S, Khandwala Y, et al. (2018) Efficacy and safety of 5 Background alpha-reductase inhibitor monotherapy in patients Although combination therapy with 5 alpha-reductase inhibitor (5ARI) and alpha-blocker is with benign prostatic hyperplasia: A meta-analysis. one of the standard interventions in symptomatic benign prostatic hyperplasia (BPH), 5ARI PLoS ONE 13(10): e0203479. https://doi.org/ 10.1371/journal.pone.0203479 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 Editor: Peter F.W.M. Rosier, University Medical Center Utrecht, NETHERLANDS this study is to update our knowledge of clinical efficacy and incidence of adverse events associated with 5ARI treatment in symptomatic BPH. Received: April 23, 2018 Accepted: August 21, 2018 Methods and findings Published: October 3, 2018 A meta-analysis of randomized controlled clinical trials (RCTs) from 1966 until March, 2017 Copyright:© 2018 Kim et al. This is an open was performed using database from PubMed, Cochrane Collaboration and Embase. A total access article distributed under the terms of the Creative Commons Attribution License, which of 23395 patients were included in this study and the inclusion criteria were: RCTs with 5ARI permits unrestricted use, distribution, and and placebo in symptomatic BPH patients. Parameters included prostate specific antigen reproduction in any medium, provided the original (PSA), prostate volume (PV), International Prostate Symptom Score (IPPS), post-void author and source are credited. residual urine (PVR), voiding symptoms of IPSS (voiding IPSS), maximum urinary flow rate Data Availability Statement: The authors have (Qmax), and adverse events (AEs). A meta-analysis with meta-regression was performed outlined how authors can recreate their dataset in for each effect size and adverse events, sensitivity analysis, cumulative analysis along with the methods and materials section. The articles used for this study are outlined in the MS and SI the analysis of ratio of means (ROM) in the placebo group. files. A total of 42 studies were included in this study for review, and a total of 37 studies were Funding: This work was supported by included in the meta-analysis, including a total of 23395 patients (treatment group: 11392, Soonchunhyang University Hospital Research placebo group: 12003). The effect size of all variables except PVR showed a significant Fund. The funders had no role in study design, data improvement following 5ARI treatment compared with placebo. However, the effect size of collection and analysis, decision to publish, or preparation of the manuscript. differences showed declining trend in PV, IPSS and Qmax according to recent years of PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 1 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Competing interests: The authors have declared publication. In ROM analysis, PV showed no significant increase in the placebo group, with that no competing interests exist. 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. Conclusions Although there was a significant clinical benefit of 5ARI monotherapy compared with pla- cebo, 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. Introduction Benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS) is one of the most common diseases prevalent in old men. The prevalence of BPH among men in their 50s and 60s is 50% rising to 90% by the age of 80s and beyond based on autopsy findings [1, 2]. Medical treatment including alpha-blockers and 5 alpha-reductase inhibitors (5ARI) take possession of the primary treatment strategy in patients with BPH/LUTS [3, 4]. The combina- tion of alpha-blockers and 5ARI improved LUTS and maximal urinary flow rate (Qmax)[2, 3]. In earlier 2000s, two important randomized controlled studies (RCTs) including the Medical Therapy of Prostatic Symptoms (MTOPS) [5] and the Combination of Avodart1 and Tamsu- losin (CombAT) study [6] established the superiority of long-term combination therapy over alpha-blocker monotherapy or placebo in the treatment of patients with BPH/LUTS. Further- more, 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]. However, recent studies reported persistent complications of 5ARI including erectile dys- function (ED) and decreased libido even after discontinuation of 5ARI [12±14]. Similarly, treatment with finasteride 1mg for androgenic alopecia has shown persistent ED after its with- drawal [15]. Currently, FDA recommends a change in 5ARI labeling to include the possibility of persistent adverse events even after discontinuation in several post-marketing studies [16, 17]. Two recent reviews of 5ARI are warning clinicians to inform their patients fully regarding the adverse events of erectile dysfunction, decreased libido, gynecomastia, and anxiety [18, 19]. Moreover, this 5ARI advisory was issued again about the possible risks for suicidal attempts and depression in many recent observational studies [20]. Evidence supports the efficacy of 5ARI treatment when combined with alpha-blockers. Sev- eral reviews and meta-analyses were limited to only adverse events. Therefore, we have PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 2 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy provided an update on the clinical efficacy and adverse events in an effort to develop a rational therapeutic strategy using 5ARI in BPH/LUTS. Methods The systematic review with meta-analysis and meta-regression were conducted according to the guidelines provided by the PRISMA guidelines (S1 Text). Inclusion criteria This meta-analysis has inclusion criteria as randomized controlled clinical trials (RCTs) with 5ARI and placebo, disease indication of BPH/LUTS, and types of measure has to include at least one of followings: 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). Searching strategies Based on the PICO (population, intervention, control, and outcomes) process, the following strategies were used: P (patients with symptomatic BPH); I (daily or regular maintenance treat- ment with 5ARI without any other treatment); C (comparing measured effect size with placebo group); and O (PSA, PV, IPSS, and Qmax). A MEDLINE search from 1966 to March 3, 2017 was performed using specific MeSH headings, including prostatic hyperplasia, lower urinary tract symptoms and 5 alpha-reductase inhibitors, dutasteride, and finasteride. Supplementary terms included dutasteride and finasteride. For natural headings, placebo, dutasteride and finasteride were included. A similar strategy was used for Cochrane collaboration and Embase (S2 Fig and S3 Fig). Detailed inclusion criteria for the final data extraction in the meta-analysis were: 1) reported outcomes of at least one of the variables included PSA, PV, IPSS, voiding IPSS, PVR, Qmax or adverse events; 2) daily 5ARI treatment; 3) indication for 5ARI use con- fined to BPH; 4) intention-to-treat analysis with placebo-controlled RCTs. Data extraction strategies After merging all the search studies (n = 1312) from MEDLINE, Cochrane collaboration and Embase, duplicate studies (n = 605) were filtered (Fig 1). A total of 707 studies were screened by title, and a total of 245 studies involving unrelated topics were excluded. A total of 462 stud- ies were screened by abstract and additionally, a total of 306 studies were excluded. Initial screening was performed by JHK and HYS. A total of 156 studies were reviewed for full text. Two authors (JHK and HYS) independently performed screening and full-text assessment, and all disagreements about final inclusion were reviewed by all authors. Data extraction was performed by independent fashion using standardized data extraction form. Assessment of methodological and reporting bias in included studies Cochrane collaboration tools including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting were used to assess the risk of methodological bias. Egger's linear regression test was conducted to assess the publication bias. Statistical analysis The effect of continuous outcomes was summarized as the standardized mean difference (SMD), which was estimated as the difference between the mean change in the treatment and PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 3 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Fig 1. PRISMA flow diagram. https://doi.org/10.1371/journal.pone.0203479.g001 placebo groups divided by the pooled standard deviation (SD). The unreported SDs were esti- mated from the reported ranges, p-values, standard errors, and sample sizes as described by Hozo, et al.[21] The SMD was interpreted as Cohen's d: an SMD of 0.2 ~0.5 was considered small, an SMD of 0.5 to 0.8 moderate, and an SMD over 0.8 as a large effect [22]. The SMD exceeding 0.5 represented a clinically meaningful result. To identify the effect of pla- cebo on the continuous outcomes, the ratio of means (ROM), which was a measure of relative change compared with the baseline, was used[23]. Binary outcomes were determined by estimat- ing the odds ratio (OR) and 95% confidence interval (CI) using the Mantel-Haenszel methods. To combine the results of individual studies, a meta-analysis was conducted based on the random effects model as described by DerSimonian and Laird using inverse variance weight- ing [24]. We pre-specified the type of medicine (finasteride, dutasteride, and 5ARI) as the stratified variable based on the assumption that the impact of the treatment varied by the type of medicine. The heterogeneity between studies was assessed for each outcome using I mea- sure of inconsistency [25]. An I of 25±49% was interpreted as low heterogeneity, 50±74% was moderate, and high when it was greater than 75% [26]. Publication bias was examined by gen- erating a funnel plot and performing the Egger's asymmetry test. PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 4 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Potential source of heterogeneity was investigated via cumulative meta-analysis (including sequential studies according to the publication year) and influential meta-analysis (deriving the pooled estimates by omitting one study at a time). The meta-regression analyses were per- formed using the publication year and follow-up duration to determine the related effect of the ROM in the placebo group. Two-sided p value of <0.05 was considered as statistically significant and all the analyses were performed using R (version 3.4.1; The R Foundation for Statistical Computing, Vienna, Austria). Results Study inclusion A total of 42 studies were included in this meta-analysis, involving a total of 37449 patients (treatment group: 18587, placebo group: 19162)(Table 1 and Fig 1). Five studies were excluded in the final analysis due to insufficient data. A total of 37 studies were finally included in the meta-analysis, involving a total of 23395 patients (treatment group: 11392, placebo group: 12003). Risk of bias For random sequence generation, most of the included studies showed a low risk and only a single study showed unclear risk (S1 Table). For allocation concealment, 28 studies showed unclear risk and 14 studies showed low risk. For blinding of participants and personnel (per- formance bias), 7 studies showed high risk, one study showed unclear risk and 34 studies showed low risk. Effective size of PSA, PV, IPSS, and Qmax of 5ARI compared with placebo For PSA, a total of 13 studies were included in the meta-analysis. The overall effective size based on SMD was -0.76 (95% CI, -1.31, -0.22)(S1 Fig), which showed a significant decrease in PSA level after 5ARI treatment compared with placebo. The overall effective size showed moderate effect of improvement by Cohen's cutoff. The overall effective size based on WMD was -1.27 (-2.29, -0.24). For PV, a total of 26 studies were included in the meta-analysis. The overall effective size based on SMD was -0.63 (95% CI, -0.74, -0.52)(S2 Fig), which showed a significant decrease of PV after 5ARI medication compared with placebo. The overall effec- tive size showed moderate effect of improvement by Cohen's cutoff. The overall effective size based on WMD was -11.13 (-13.34, -8.93). For PVR, a total of 5 studies were included in the meta-analysis. The overall effective size by SMD was 0.1 (95% CI, -0.48, 0.68), which showed insignificant decrease of PVR after 5ARI treatment compared with placebo. For IPSS, a total of 18 studies were included in the meta-analysis. The overall effective size by SMD was -0.19 (95% CI, -0.27, -0.11)(Fig 2), which showed a significant decrease of IPSS after 5ARI inter- vention compared with placebo. The overall effective size showed small effect of improve- ment by Cohen's cutoff. The overall effective size based on WMD was -1.21(-1.72, -0.70). Finasteride showed a significant improvement of IPSS as -0.18 (95% CI, -0.26, -0.10). How- ever, dutasteride showed no significant improvement in IPSS as -0.21 (95% CI, -0.42, 0.00). For Qmax, a total of 23 studies were included in the meta-analysis, and the overall effective size by SMD was 0.29 (95% CI, 0.22 to 0.36)(S3 Fig), which showed significant improvement of Qmax after 5ARI treatment compared with placebo. The overall effective size based on WMD was -1.16 (0.88, 1.43). PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 5 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. Characteristics of all studies included in meta-analysis. Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) Beisland European 1992 NA 94 88 60 60 Qmax<15mL/s 1 0 0 Finasteride 5 6 Urology Gormley The New 1992 USA, Canada 297 300 64 64 Qmax<15mL/s, 1 0 0 Finasteride 5 12 England voided Journal of volume>150mL Medicine Kirby British Journal 1992 UK 31 21 64.4 64.4 Qmax<15mL/s, 1 1 0 Finasteride 5 3 of Urology voided volume>150mL, detrusor pressure during voiding>50cmH2O2 Stoner The Journal of 1992 USA 18 25 63.9 63.9 Enlarged prostate 1 0 1 Finasteride 5 6 Urology gland of greater than 30cc Tammela The Journal of 1993 Finland 19 17 65 65 Qmax<15mL/s, 1 1 0 Finasteride 5 6 Urology voided volume>150mL Tempany The Prostate 1993 USA 12 8 NA NA NA 1 0 0 Finasteride 1 or 12 The The Prostate 1993 Australia, 246 255 66 66 Qmax<15mL/s, 1 0 1 Finasteride 5 12 finasteride Belgium, PV>30cm study Brazil, France, group Italy, Mexico, Netherlands, New Zealand, Portugal, Spain, Swizerland, Germany, UK, USA Stoner UROLOGY 1994 USA 291 299 64 64 Qmax<15mL/s, 1 0 0 Finasteride 5 12 voided International 242 254 66 66 volume>150mL study Andersen UROLOGY 1995 Scandinavian 347 346 65.5 65.5 Qmax5-15mLs, 1 0 0 Finasteride 5 24 countries PSA10ng/mL, (Denmark, PVR150cc Finland, Iceland, Norway, Sweden) Tammela The Journal of 1995 Finland 12 15 65 65 Qmax<15mL/s, 1 1 0 Finasteride 5 6 Urology voided volume>150mL Yu Journal of the 1995 Taiwan 24 22 66.4 65.2 NA 1 0 0 Finasteride 5 6 Formosan Medical Association Lepor The New 1996 USA 305 310 65 65 AUA>8, Qmax4- 1 0 0 Finasteride 5 13 England 15mL/s, voided Journal of volume>125mL Medicine (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 6 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. (Continued ) Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) Nickel Canadian 1996 Canada 310 305 63 63.5 Qmax5-15mLs, 1 0 0 Finasteride 5 24 Medical voided Association volume>150mL, PVR150cc, PSA<10ng/mL Habib Clinical 1997 Scotland 19 9 68.7 66.7 NA 1 0 0 Finasteride 5 3 Endocrinology Lepor The Journal of 1998 USA 44 39 62.5 62.5 Qmax4-15mL/s, 0 0 0 Finasteride 5 13 Urology voided volume125mL, PVR300mL, AUA-SI score8 Marberger UROLOGY 1998 USA 1450 1452 63 63.4 Qmax5-15mL/s, 1 0 0 Finasteride 5 24 voided volume>150mL McConnell The New 1998 USA 1524 1516 64 64 Qmax15mL/s, 1 0 0 Finasteride 5 48 England voided Journal of volume>150mL Medicine Pannek The Journal of 1998 USA 26 14 65 64 IPSS>9, PSA10ng/ 0 0 0 Finasteride 5 6 Urology mL Abrams The Journal of 1999 USA 69 37 68.1 67.4 NA 0 0 0 Finasteride 5 9 Urology Lukkarinen Annales 1999 Finland 33 31 65 65 Boyarsky<15mL/s, 1 0 0 Finasteride 5 24 Chirurgiae et PV>30cc Gynaecologiae Schafer UROLOGY 1999 Germany, 81 40 68.1 NA PSA<10ng/mL 1 1 0 Finasteride 5 12 Finland, UK, Sweden, Netherland, Denmark, Portugal, USA Feneley Prostate cancer 2000 UK, 18 9 67.5 67.5 BPH/BOO 1 1 0 Finasteride NA 6 and prostatic Netherland diseases Isotalo British Journal 2001 Finland 29 19 71 71 NA 1 0 1 Finasteride 5 18 of Urology Espana BJU 2002 Spain 30 10 66.7 69.5 Qmax15mL/s, 1 0 0 Finasteride NA 9 International IPSS>7, PVR<150mL, tPSA<20ng/mL Haggstrom Scandinavian 2002 Sweden 13 15 NA NA NA 0 0 0 Finasteride 5 3 Journal of Urology and Nephrology Roehrborn UROLOGY 2002 Global study 2167 2158 66.5 66.1 Qmax15mL/s, 1 0 0 Dutasteride 0.5 24 PSA1.5ng/mL, PV30cc, AUA-SI score12 Kirby UROLOGY 2003 Europe 239 253 63 64 Qmax5-15mLs, 1 0 0 Finasteride 5 13 voided volume150mL, IPSS12, Prostate volume nearest 5g (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 7 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. (Continued ) Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) McConnell The New 2003 NA 89 128 62.6 62.5 Qmax4-15mL/s, 1 0 0 Finasteride 5 54 England voided Journal of volume125mL, Medicine AUA-SI score 8±35 Roehrborn The Journal of 2004 USA 1524 1516 64 63.9 Qmax15mL/s, 1 0 0 Finasteride 5 48 Urology voided volume>150mL Crawford The Journal of 2006 NA NA 737 - 62.5 Qmax4-15mL/s, 1 0 0 Finasteride 5 54 Urology AUA-SI score>8, voided volume125mL Gittelman The Journal of 2006 NA 2167 2158 65.8 65.5 Qmax>15mL/s, 1 0 0 Dutasteride 0.5 48 Urology AUA_SI>12, PV>30cc, PSA1.5- 10ng/mL Kaplan The Journal of 2006 USA 232 250 61 60.5 AUA8-35, Qmax4- 1 0 1 Finasteride 5 54 Urology 15mL/s, voided volume>125mL, TPV<25 281 274 61.8 62.4 AUA8-35, Qmax4- 15mL/s, voided volume>125mL, TPV<40 252 213 65.1 64.8 AUA8-35, Qmax4- 15mL/s, voided volume>125mL, TPV>40 Kaplan The Journal of 2008 USA 768 737 62.6 62.5 Qmax 4-15mL/s, 0 0 0 Finasteride 5 54 Urology voided volume>125mL, AUA-SI score 8±30 Bepple UROLOGY 2009 USA 30 29 66 66 NA 0 0 0 Dutasteride 0.5 12 Tsukamoto Hinyokika 2009 Japan 70 70 66.1 65.8 Qmax>15mL/s, 0 0 0 Dutasteride 0.5 6 Kiyo IPSS>3 Tsukamoto International 2009 Japan 193 185 67.7 64.4 Qmax<15mLs, 1 0 0 Dutasteride 0.5 13 Journal of IPSS8, voided Urology volume150mL, PV>30mL Tsukamoto Hinyokika 2010 Japan 184 181 68 66.9 Qmax<15mLs, 1 0 0 Dutasteride 0.5 13 Kiyo IPSS8, PV<30cc Kaplan The Journal of 2011 USA 281 276 60.7 60.3 Qmax 4-15mL/s, 0 0 0 Finasteride 5 54 Urology AUA-SI score 8±30 voided volume>125mL, PV<30mL 295 288 63.9 64.1 Qmax4-15mL/s, AUA-SI score 8±30 voided volume>125mL, PV>30mL (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 8 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 1. (Continued ) Publication Country No. of patients Mean age Subject Description Symptom of BPH Experimental description (year) Author Journal Year Tx Placebo Tx. Placebo BPH BOO LUTS Drug dose F/U (mg) duration (month) Roehrborn UROLOGY 2011 USA 4049 4073 62.7 62.7 50±60 years old: 1 0 0 Dutasteride 0.5 48 PSA2.5-10ng/mL, >60 years old: 3.0- 10ng/mL Yanqun Clinical Drug 2012 China 126 127 65.8 66.9 Qmax 5-15mL/s, 1 0 0 Dutasteride 0.5 6 Investigation AUA-SI score>12 voided volume>125mL, Kacker Androlodia 2015 USA 11 11 57.7 57.7 Testosterone (T) for at 0 0 0 Dutasteride 0.5 12 least 3 months, and a current serum T within the normal range (300±1000ng dl) Qian The Aging 2015 China 45 42 70.1 72.3 PV>80mL, IPSS13, 1 0 0 5ARI 5 or 6 Male QoL3, PVR200mL, Finasteride 0.5 Qmax<15mL/s, or refractory HU history, Dutasteride bladder stone history, AUR history, refractory UTI history NA, not available; BPH, benign prostatic hyperplasia; 5ARI, 5 alpha reductase inhibitor; PVR, post voided residual volume; PSA, prostatic specific antigen; PV, prostatic volume; IPSS, International Prostate Symptom Score; Qmax, maximal urinary flow rate; QoL, quality of life. UTI, urinary tract infection https://doi.org/10.1371/journal.pone.0203479.t001 Cumulative analysis Cumulative meta-analysis was performed to investigate the trend according to years. For PSA, in 1990s, effective size showed no significant difference compared with placebo. However, starting with 2000s, the effective size showed a significant difference compared with placebo, resulting in a stable outcome from -0.77 to -0.60. For PV, the effect size showed a constant and significant difference compared with placebo, which showed stable outcome from -0.70 to -0.40 (Fig 3A). For IPSS, there was no marked change in the trend of effective size compared with placebo, however, the effective size of difference compared with placebo showed a decreasing trend (Fig 3B). For Qmax, the effective size showed a large difference compared with placebo until 1993. However, from 1994, the effective size of difference showed a decreas- ing trend as a convergence of 0.3 (Fig 3C). Sensitivity analysis Considering the relatively high heterogeneity, sensitivity analysis was performed to analyze the effect of each study. Overall effect size of all variables except PVR showed no impact of individ- ual studies (S4 Fig). However, the effect size of PVR was affected by one study, which resulted in a different outcome without that study. Meta-regression To investigate the reasons for heterogeneity of effect, a meta-regression analysis was per- formed. Moderating factor was suggested as IPSS at baseline, follow-up duration and race. Effective sizes of all variables except PVR showed no significant moderating effect. However, PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 9 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Fig 2. Meta-analysis of effective sizes in prostate specific antigen (PSA), International Prostate Symptom Score (IPSS), prostate volume and maxima urinary flow rate (Qmax). https://doi.org/10.1371/journal.pone.0203479.g002 the effective size of PVR was affected by IPSS at baseline. The effective size of PVR decreased according to high IPSS at the baseline: -0.29 (95% CI, -0.46,-0.12) in univariate analysis. Multi- variable analysis was not performed due to the small number of included studies. ROM analysis of placebo group To show the placebo effect of each variable, a ROM analysis was performed (Table 2). For PSA, although it did not show a significant effective size, it still showed a decrease by 10% (0.90 (95% CI, 0.81, 1.00) during follow-up. For PV, there was no change during follow-up: 1.00 (95% CI, 0.88, 1.14). For IPSS, there was a significant decrease during follow-up: 0.77 (95% CI, 0.68, 0.88), suggesting a 23% improvement. For Qmax, there was significant increase during the follow-up: -1.13 (95% CI, 1.06, 1.20), suggesting a 13% aggravation. Meta-regression of ROM analysis in placebo group To investigate the reasons for the placebo effect in ROM analysis, the published year and fol- low-up duration were suggested as moderators (S2 Table). For PSA, there was no significant PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 10 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 11 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Fig 3. Cumulative analysis of effective sizes in prostate volume, International Prostate Symptom Score (IPSS), and maxima urinary flow rate (Qmax). https://doi.org/10.1371/journal.pone.0203479.g003 moderator effect. However, for PV, IPSS, and Qmax, both published year and follow-up dura- tion were significant moderators. The effective size of PV and IPSS was decreased according to years of recent publication (p<0.001), and was increased according to follow-up duration (p<0.001). In contrast, the effective size of Qmax was increased according to years of recent publication (p<0.001), and decreased by the follow-up duration (p = 0.020). For PVR, only the year of publication affected the effective size, which showed a decreased effect according to the year of recent publication (p<0.001). Adverse events The 5ARI treatment prevented exacerbation of BPH and urinary retention compared with pla- cebo (Table 3). However, compared with placebo, 5ARI showed a significantly higher inci- dence 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). Decreased libido and impotence was affected by the moderating effect of fol- low-up duration. After meta-regression of follow up duration, decreased libido (OR = 0.98, 95% CI, 0.97, 0.99) and increased impotence (OR = 0.98, 95% CI, 0.97, 0.99) were significantly related to longer follow-up duration. Publication bias There was no publication bias detected following Egger's test (S5 Fig). Discussion Although current guidelines suggest the use of 5ARI in patients with prostate size greater than 30cc, our study does not support the wide use of 5ARI, rather it needs specific indication. Although there has been a systematic review about this issue, especially for finasteride [11], it needs to be upgraded. The main academic basic hypothesis of our study is based on the most recent focus on androgens in aged men. It is well known that androgens profoundly regulate prostate growth and differentiation, as well as sexual function [12, 18]. However, it is also asso- ciated with general health of aged men including cardiovascular disease. A recent RCT showed that a 1-year treatment of testosterone showed superior outcomes compared with placebo in coronary artery non-calcified plaque volume [27]. In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, the dutasteride treatment group showed larger rate of cardiac failure compared with placebo [28]. Moreover, the 5ARI treatment was again associated with the possible risk of suicidal attempts and depression in many observational studies [20]. It is beyond dispute that the combination treatment of alpha-blocker and 5ARI is superior to alpha-blocker monotherapy or placebo group [5, 6]. In early trials, the effect of combination treatment was mainly attributed to alpha-blocker and also to the double-placebo effect. In MTOPS trial, the overall effect of two placebo combinations was -4.0 at 1 year and also -4.0 at 4 years, which suggests a 23.8% improvement in placebo effect [5]. Further, at 1 year, there was no significant difference in symptom improvement between the alpha-blocker and combina- tion groups [5]. Due to the absence of meta-analysis involving alpha-blocker, 5ARI, and pla- cebo, this study failed to confirm the poor clinical efficacy of 5ARI compared with alpha- blockers. However, this is the first meta-analysis investigating the clinical efficacy of 5ARI monotherapy among RCTs, which showed that overall effective size of IPSS improvement by PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 12 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 2. Ratio of means meta-analysis of the efficacy of placebo group. Author (year) No. of samples Ratio of mean (95% CI) PSA PV PVR IPSS voiding IPSS Qmax Gormley (1992) 300 0.98 (0.89, 1.08) 0.90 (0.81, 0.99) 0.88 (0.80, 0.97) 1.02 (0.96, 1.08) Kirby (1992) 10 0.80 (0.39, 1.64) 0.96 (0.49, 1.87) 0.52 (0.16, 1.64) 0.81 (0.48, 1.39) 0.90 (0.54, 1.51) Tempany (1993) 8 1.01 (0.63, 1.62) Tammela (1993) 17 1.10 (0.64, 1.88) 1.12 (0.90, 1.41) Andersen (1995) 197 1.28 (1.04, 1.56) 1.02 (0.93, 1.11) 0.98 (0.90, 1.06) 0.97 (0.93, 1.02) Tammela (1995) 15 0.96 (0.72, 1.27) 1.19 (0.63, 2.24) 1.11 (0.87, 1.42) Yu (1995) 22 0.89 (0.51, 1.58) 1.06 (0.83, 1.37) 0.86 (0.73, 1.01) 1.01 (0.80, 1.29) Habib (1997) 1.26 (0.77, 2.05) Lepor (1998) 258 1.01 (0.94, 1.09) 0.84 (0.79, 0.89) 1.13 (1.08, 1.20) Marberger (1998) 800 1.04 (0.99, 1.09) Pannek (1998) 10 0.73 (0.28, 1.88) 0.97 (0.69, 1.37) Abrams (1999) 0.82 (0.69, 0.96) 0.99 (0.88, 1.11) Lukkarinen (1999) 31 0.92 (0.76, 1.10) 0.84 (0.67, 1.06) Feneley (2000) 9 0.82 (0.52, 1.31) 1.23 (0.85, 1.77) Isotalo (2001) 19 0.66 (0.53, 0.81) 0.91 (0.75, 1.11) 1.09 (0.76, 1.56) Haggstrom (2002) 1.02 (0.86, 1.21) Kirby (2003) 1.12 (0.96, 1.29) 0.69 (0.63, 0.74) 1.12 (1.06, 1.18) McConnell (2003) 0.76 (0.73, 0.80) 1.13 (1.10, 1.16) Roehrborn (2004) 0.89 (0.84, 0.95) 0.97 (0.94, 1.00) Crawford (2006) 1.13 (1.11, 1.16) Kaplan (2008) 249 1.34 (1.22, 1.46) Kaplan (2008)a 214 1.12 (1.04, 1.21) Kaplan (2008)b 112 1.20 (1.08, 1.32) Kaplan (2008)c 161 1.21 (1.16, 1.27) Tsukamoto (2009) 70 0.81 (0.69, 0.95) 0.73 (0.62, 0.85) 1.12 (0.99, 1.27) Qian (2015) 42 0.81 (0.77, 0.86) 0.60 (0.57, 0.63) 0.06 (0.05, 0.07) 0.36 (0.32, 0.41) 2.79 (2.36, 3.30) Overall 0.90 (0.81, 1.00) 1.00 (0.88, 1.14) 0.44 (0.06, 3.22) 0.77 (0.68, 0.88) 0.93 (0.84, 1.03) 1.13 (1.06, 1.20) p = 0.056 p = 0.97 p = 0.42 p<0.001 p = 0.159 p<0.001 HeterogeneityÐI (%) 73.3 (47.8, 86.3) 96.3 (95.1, 97.1) 98.5 (97.6, 99.0) 96.7 (95.4, 97.6) 61.9 (0.0, 91.2) 91.3 (87.5, 93.9) p-value <0.001 <0.001 <0.001 <0.001 0.105 <0.001 CI, confidence interval; PSA, prostate specific antigen; PV, prostate volume; PVR, post voided residual volume; IPSS, International Prostate Symptom Score; Qmax, maximal urinary flow rate. The process of meta-analysis with paired difference data: estimates using the Hegde's corrected standardized mean difference assuming the random-effect model https://doi.org/10.1371/journal.pone.0203479.t002 5ARI compared with placebo was small. Moreover, the overall effective size of PV and PSA was moderate. For PV growth, previous studies reported an annual growth rate of 0.6 cc per year (−- 9.9~11.8) [29]. Interestingly, the negative PV growth rate represents the diversity of growth rate according to individual characteristics. Loeb et al [30] reported that a considerable pro- portion of aging men do not show progressive PV enlargement, and a few manifested decreas- ing pattern. In their study of median follow up of 4.3 years, a progressive PV growth was noted in 61.9%. However, 38.1% of men showed no increase or decrease in PV with the rate of PV changing by 0.6cc annually (-9.9~62.1). They speculated that aging could induce prostate shrinkage in healthy community men due to genetic, hormonal or environmental factors. In another study of Olmsted county survey, the median growth rate of PV was 1.9% per year [31]. PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 13 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. Meta-analysis and meta-regression of effective sizes in adverse events. Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Abdominal pain 1.16 (0.78±1.74) 0.455 0.0% 0.97 (0.91±1.04) 0.377 Gormley (1992) 3.37 (0.32±35.31) 0.311 Marberger (1998) 1.06 (0.68±1.67) 0.784 Stoner (1994) 1.7 (0.41±7.09) 0.464 Tsukamoto (2009) 0.14 (0.01±2.62) 0.186 Tsukamoto (2009) 2.03 (0.53±7.8) 0.303 Angina pectoris 1.01 (0.55±1.84) 0.977 NA% NA NA Marberger (1998) 1.01 (0.55±1.84) 0.977 Any AE 0.98 (0.88±1.09) 0.767 56.8% 1.01 (0.99±1.03) 0.368 Andersen (1995) 1.3 (0.83±2.05) 0.251 Beisland (1992) 1 (0.75±1.33) 0.992 Kacker (2015) NA (NA-NA) NA Nickel (1996) 1 (0.93±1.08) 0.922 The finasteride study group (1993) 12.44 (1.63±94.95) 0.015 Tsukamoto (2009) 0.98 (0.91±1.05) 0.505 Tsukamoto (2009) 0.83 (0.67±1.03) 0.09 Asthenia 0.86 (0.59±1.25) 0.43 2.5% 0.93 (0.87±1) 0.046 Gormley (1992) 1.01 (0.21±4.96) 0.99 Kirby (2003) 1.02 (0.45±2.31) 0.964 Lepor (1996) 1.08 (0.61±1.91) 0.797 Marberger (1998) 0.46 (0.23±0.94) 0.033 Stoner (1994) 1.28 (0.34±4.73) 0.714 Back pain 0.61 (0.39±0.95) 0.028 0.0% NA NA Marberger (1998) 0.59 (0.37±0.95) 0.029 Tsukamoto (2009) 0.76 (0.18±3.28) 0.713 BPH worsening 0.55 (0.37±0.83) 0.004 NA% NA NA Marberger (1998) 0.55 (0.37±0.83) 0.004 Breast pain 2.49 (0.88±7.01) 0.084 0.0% NA NA Gormley (1992) 3.03 (0.12±74.09) 0.497 McConnell (1998) 2.43 (0.81±7.26) 0.112 Bronchitis 1.15 (0.7±1.91) 0.579 NA% NA NA Marberger (1998) 1.15 (0.7±1.91) 0.579 Decreased libido 1.67 (1.35±2.06) <0.001 9.8% 0.98 (0.97±0.99) 0.004 Bepple (2009) 6.53 (0.35±120.66) 0.208 Gormley (1992) 3.63 (1.19±11.01) 0.023 Kirby (2003) 1.83 (0.62±5.4) 0.271 Lepor (1996) 3.44 (1.15±10.34) 0.028 Marberger (1998) 1.44 (0.99±2.11) 0.057 McConnell (1998) 1.01 (0.65±1.56) 0.965 Nickel (1996) 1.59 (0.92±2.76) 0.095 Roehrborn (2002) 1.97 (1.39±2.79) <0.001 Stoner (1994) 2.04 (0.93±4.51) 0.077 Tsukamoto (2009) 4.77 (0.23±98.64) 0.312 Yanqun (2012) 2.02 (0.19±21.95) 0.565 Yu (1995) 4.59 (0.23±90.58) 0.316 Diarrhea 1.05 (0.58±1.9) 0.863 0.0% NA NA (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 14 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. (Continued ) Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Gormley (1992) NA (NA-NA) NA Marberger (1998) 1.15 (0.56±2.35) 0.696 Tsukamoto (2009) 0.87 (0.31±2.46) 0.792 Dizziness 1.06 (0.74±1.52) 0.754 0.0% 1.09 (0.88±1.34) 0.451 Gormley (1992) 0.19 (0.01±3.99) 0.288 Kirby (2003) 1.07 (0.59±1.93) 0.822 Lepor (1996) 1.16 (0.67±2.01) 0.588 Stoner (1994) 1.02 (0.26±4.07) 0.975 Tsukamoto (2009) 4.77 (0.23±98.64) 0.312 Tsukamoto (2009) 0.68 (0.2±2.29) 0.53 Dyspepsia 0.34 (0.01±8.16) 0.504 NA% NA NA Tsukamoto (2009) 0.34 (0.01±8.16) 0.504 Dysuria 1.34 (0.66±2.72) 0.417 0.0% NA NA Gormley (1992) 5.05 (0.24±104.75) 0.295 Marberger (1998) 1.24 (0.6±2.57) 0.56 Ejaculatory disorder 2.89 (2.12±3.93) <0.001 0.0% 1 (0.98±1.03) 0.689 Gormley (1992) 2.57 (0.94±7.08) 0.067 Kirby (2003) 1.53 (0.44±5.35) 0.507 Lepor (1996) 1.48 (0.42±5.18) 0.543 Marberger (1998) 3.7 (1.78±7.7) <0.001 McConnell (1998) 3.01 (1.33±6.81) 0.008 McConnell (1998) 1.99 (0.28±14.11) 0.491 Nickel (1996) 4.69 (1.81±12.14) 0.001 Roehrborn (2002) 2.81 (1.62±4.87) <0.001 Tsukamoto (2009) 4.06 (0.46±35.41) 0.205 Erectile dysfunction 1.51 (0.15±15.27) 0.725 34.1% NA NA Tsukamoto (2009) 3.81 (0.43±33.8) 0.229 Yanqun (2012) 0.34 (0.01±8.17) 0.503 Flatulence 1.39 (0.45±4.34) 0.568 0.0% NA NA Gormley (1992) 1.44 (0.25±8.36) 0.682 Stoner (1994) 1.36 (0.31±6.04) 0.687 Gastritis 1.3 (0.65±2.6) 0.463 NA% NA NA Marberger (1998) 1.3 (0.65±2.6) 0.463 Gynecomastia 2.29 (1.4±3.76) 0.001 19.9% 0.98 (0.95±1.01) 0.119 McConnell (1998) 1.61 (0.88±2.95) 0.124 Roehrborn (2002) 3.11 (1.78±5.45) <0.001 Yanqun (2012) 3.02 (0.12±73.53) 0.497 Headache 0.97 (0.62±1.52) 0.906 38.0% 0.96 (0.91±1.01) 0.137 Beisland (1992) 1.4 (0.52±3.78) 0.502 Gormley (1992) 0.96 (0.14±6.63) 0.969 Lepor (1996) 1.87 (0.88±3.95) 0.102 Marberger (1998) 0.92 (0.58±1.48) 0.743 Marberger (1998) 0.42 (0.2±0.88) 0.021 Stoner (1994) 1.7 (0.41±7.09) 0.464 Tsukamoto (2009) 0.51 (0.1±2.68) 0.424 Hypertension 0.82 (0.58±1.14) 0.239 0.0% NA NA (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 15 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. (Continued ) Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Kirby (2003) 0.75 (0.35±1.6) 0.452 Marberger (1998) 0.83 (0.57±1.22) 0.347 Hypotension 0.51 (0.09±2.76) 0.434 NA% NA NA Kirby (2003) 0.51 (0.09±2.76) 0.434 Impotence 1.68 (1.3±2.17) <0.001 58.1% 0.98 (0.97±0.99) 0.001 Gormley (1992) 1.98 (0.69±5.68) 0.204 Kirby (2003) 1.47 (0.64±3.38) 0.363 Lepor (1996) 2.04 (1.1±3.78) 0.024 Marberger (1998) 1.42 (1.06±1.89) 0.018 McConnell (1998) 1 (0.74±1.36) 0.981 Nickel (1996) 2.52 (1.52±4.18) <0.001 Roehrborn (2002) 1.83 (1.42±2.36) <0.001 Stoner (1994) 3.07 (1.31±7.15) 0.01 Influenza 0.89 (0.58±1.37) 0.602 NA% NA NA Marberger (1998) 0.89 (0.58±1.37) 0.602 Lens change 1.2 (0.3±4.81) 0.793 12.7% NA NA Gormley (1992) 5.05 (0.24±104.75) 0.295 Gormley (1992) 0.19 (0.01±3.99) 0.288 Stoner (1994) 1.36 (0.31±6.06) 0.684 Myocardial infarction 2.9 (1.3±6.46) 0.009 NA% NA NA Marberger (1998) 2.9 (1.3±6.46) 0.009 Nausea 0.73 (0.23±2.28) 0.582 0.0% NA NA Gormley (1992) 0.67 (0.11±4) 0.664 Stoner (1994) 0.76 (0.17±3.4) 0.724 orgasm dysfunction 0.8 (0.08±8.3) 0.85 31.3% NA NA Gormley (1992) 2.24 (0.19±26.87) 0.523 Stoner (1994) 0.2 (0.01±4.25) 0.305 Pelvic pain 0.48 (0.04±5.18) 0.546 NA% NA NA Gormley (1992) 0.48 (0.04±5.18) 0.546 Pharyngitis 1.6 (0.78±3.28) 0.202 NA% NA NA Marberger (1998) 1.6 (0.78±3.28) 0.202 Postural hypotension 1.18 (0.27±5.12) 0.821 46.5% NA NA Kirby (2003) 0.51 (0.09±2.76) 0.434 Lepor (1996) 2.3 (0.6±8.8) 0.225 Rash 1.59 (0.63±4.01) 0.326 38.4% 1.03 (0.97±1.09) 0.39 Gormley (1992) 2.24 (0.19±26.87) 0.523 Marberger (1998) 0.82 (0.43±1.54) 0.532 McConnell (1998) 5.31 (0.93±30.3) 0.061 Stoner (1994) 2.04 (0.38±11.11) 0.408 Rhinitis 0.56 (0.24±1.32) 0.186 NA% NA NA Lepor (1996) 0.56 (0.24±1.32) 0.186 Sinusitis 0.98 (0.25±3.9) 0.982 NA% NA NA Lepor (1996) 0.98 (0.25±3.9) 0.982 Somnolence 1.36 (0.48±3.86) 0.565 NA% NA NA Kirby (2003) 1.36 (0.48±3.86) 0.565 Syncope 1.63 (0.08±31.47) 0.747 46.0% NA NA (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 16 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy Table 3. (Continued ) Complication Effect size Meta-regression on f/u duration (month) OR (95% CI) p-value I OR (95% CI) p-value Kirby (2003) 0.34 (0.01±8.3) 0.508 Lepor (1996) 6.89 (0.36±132.77) 0.201 Testicular pain 1.4 (0.45±4.35) 0.565 0.0% NA NA Gormley (1992) 1.44 (0.25±8.36) 0.682 Stoner (1994) 1.36 (0.31±6.06) 0.684 upper respiratory infection 0.7 (0.41±1.19) 0.191 NA% NA NA Marberger (1998) 0.7 (0.41±1.19) 0.191 urinary retention 0.49 (0.28±0.87) 0.015 NA% NA NA Marberger (1998) 0.49 (0.28±0.87) 0.015 Urinary tract Infection 0.71 (0.44±1.14) 0.154 NA% NA NA Marberger (1998) 0.71 (0.44±1.14) 0.154 Vertigo 2.04 (0.52±8.06) 0.31 NA% NA NA Kirby (2003) 2.04 (0.52±8.06) 0.31 OR, odds ratio; CI, confidence interval. https://doi.org/10.1371/journal.pone.0203479.t003 In our study, it was not logical to estimate the annual grow rate because this study does not contain direct population data. However, this study demonstrated the changes of PV in pla- cebo group, which suggested that the PV growth rate was 1.00 by ROM (95% CI, 0.88±1.14), which showed lack of increase in PV size during the years of investigation of enrolled studies. For adverse events, two recent reviews reported adverse effects including ED, decreased libido, gynecomastia, and anxiety following 5ARI therapy [18, 19]. Our study also found simi- lar adverse effects including decreased libido, ejaculatory disorder, gynecomastia and impo- tence. Interestingly, Corona et al [18] reported that adverse events were inversely correlated with study duration. Our study also showed similar findings of decreased libido and impotence affected by the moderating effect of follow-up duration, which showed attenuation of decreased libido and impotence during a longer follow-up. Further studies are needed by merging data of 5ARI studies with other indications such as alopecia. Moreover, comorbidity status should be taken into account when considering the incidence of ED in patients receiving 5-ARIs. 5-ARIs are often prescribed to older patients with high comorbidity status, which could also increase the risk of ED [32]. The comorbidity status is often underreported in pub- lished studies and this may represent a bias. The detailed mechanism underlying the negative impact of 5ARI on ED or decreased libido has not been fully demonstrated. Several suggested theories include: 1) Decrease synthesis of neurostransmitters by 5ARI [13], which is related to sexual desire; 2) 5ARIs induce structural and functional degeneration of penile tissue, which results in penile fibrosis due to cholinergic and nitrergic sensitivity [13]. In animal studies, finasteride suppressed neurosteroid synthesis, which resulted in anxiety and depression [33±35], which could explain the possible association between 5ARI treatment and depression or suicidal attempts. Our study is academically sound and robust due to several reasons: 1) It is the first scientific review including meta-analysis of RCTs investigating the efficacy and adverse events associ- ated with 5ARI monotherapy; 2) It shows an indirect effect of the reported years using a cumu- lative meta-analysis; 3) It shows indirect outcomes of prostate growth using a single-placebo- controlled meta-analysis. In our study, although the effective size of PSA, IPSS, PV, and Qmax showed significantly superior outcome compared with the placebo group, the effective size, PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 17 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy especially for IPSS (-0.19, 95%CI: -0.27- -0.11) was small. Considering the effective size was analyzed by SMD, it could be interpreted as 7.5% by two sided test and as 15% by one sided test. By subgroups, although finasteride showed a significant improvement of IPSS, dutasteride showed not significant improvement, which is due to relatively lower published studies of dutasteride than finasteride. The included studies showed a lower clinical improvement in IPSS, PV and Qmax when recent publications were considered. PV showed a relatively slower growth than in previous clinical studies. Due to limitation of meta-analysis, detailed individual level data could not be extracted. Furthermore, we could not find a long term complication including depression and suicidal attack, which could not be reported in ITT study design. For those complications, observa- tional studies have to be included. This study also included outdated studies which only have focused on finasteride, which could result in favorable effect of finasteride than dutasteride during meta-analysis. 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 out- comes 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 com- pared to alpha blocker. In future, the accurate prevalence rate of persistent adverse events after 5ARI discontinua- tion needs to be investigated. Moreover, considering the long-term clinical efficacy of 5ARI, long-term adverse events need to be investigated more clearly. This meta-analysis provides useful information for clinicians and clinical investigators to design controlled studies investi- gating long-term outcomes following 5ARI therapy. Conclusions In this meta-analysis with an average follow-up duration of 21.8 months, the efficacy outcomes of 5ARI showed a small clinical improvement in improvement of LUTS. In future, well designed studies are needed to overcome placebo effect and heterogeneities and possible bias. Considering persistent and well known adverse events including ED and decreased libido even after discontin- uation of 5ARI, 5ARI therapy should be prescribed with great caution and patients need to be fully informed about the possible adverse events. A more selective rationale is needed considering the diverse growth rate of PV, and a relatively low growth rate observed in our study. Supporting information S1 Text. PRISMA checklist. (DOC) S2 Text. Searching strategies using Pubmed database. (PDF) S3 Text. Searching strategies using Cochrane database. (PDF) S1 Table. Methodological qualities of included studies. (DOCX) S2 Table. Meta-regression analysis for ratio of means meta-analysis of the efficacy of pla- cebo group. (DOCX) PLOS ONE | https://doi.org/10.1371/journal.pone.0203479 October 3, 2018 18 / 21 Efficacy and safety of 5 alpha-reductase inhibitor monotherapy S1 Fig. Meta-analysis of effective sizes in prostate specific antigen (PSA). (JPG) S2 Fig. Meta-analysis of effective sizes in prostate volume. (TIF) S3 Fig. Meta-analysis of maxima urinary flow rate (Qmax). (TIF) S4 Fig. Sensitivity analysis of effective sizes in prostate volume, International Prostate Symptom Score (IPSS), and maxima urinary flow rate (Qmax). (TIF) S5 Fig. Funnel plots for PSA, PV, IPSS, and Qmax. (JPG) Author Contributions Conceptualization: Jae Heon Kim, Benjamin I. Chung. Data curation: Min Jung Baek, Hwa Yeon Sun. Formal analysis: Jae Heon Kim, Min Jung Baek, Bora Lee, Shufeng Li. Investigation: Jae Heon Kim, Hwa Yeon Sun, Shufeng Li, Yash Khandwala, Francesco Del Giudice, Benjamin I. Chung. 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