Background
Transurethral resection of the prostate (TURP) remains the gold standard for patients with benign prostatic hyperplasia (BPH) that failed medical therapy. Perioperative hemorrhage is one of the major complications of TURP, and prolonged bleeding will lead to blood transfusion and clot retention [
1]. 5α-Reductase inhibitors (5ARIs), including finasteride and dutasteride, can block the conversion of testosterone to dihydrotestosterone (DHT) and has been used to treat BPH and BPH-related hematuria [
2].
Since Hagerty et al. [
3] first reported that pretreatment with finasteride appears useful in reducing perioperative bleeding in patients undergoing TURP, emerging studies have reported similar results [
4‐
18]. However, the ability of 5ARI to decrease blood loss during TURP for BPH remains controversial, and several studies have reported no significant benefit of preoperative 5ARIs [
19‐
21]. One systematic review also demonstrated that preoperative finasteride can reduce blood loss during TURP while dutasteride cannot [
22]. However, the systematic review was criticized for including a nonrandomized trial [
23] and a study comparing photoselective vaporization of the prostate (PVP) instead of TURP with controls [
24]. Therefore, we aimed to conduct a meta-analysis of all randomized controlled trials (RCTs) to establish the role of 5ARI use prior to TURP.
Methods
Data sources and search strategy
The present meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [
25].No protocol exists for this meta-analysis. We searched studies from the electronic databases PubMed, Embase, Scopus, and Cochrane Library from inception to March25, 2014.The search terms used were 5α-reductase inhibitor, TURP, transurethral resection of the prostate, 5ARI, BPH, dutasteride, and finasteride. Meanwhile, references from all retrieved papers were manually searched for further relevant articles. We also searched for abstracts of randomized trials from conference proceedings. If the results of the same population were reported more than one time, only the most recent and complete data were included. No language or other restrictions were used in the search.
Study selection
Studies were considered eligible if they met the following criteria: (1) the study was a RCT, (2) the study participants were BPH patients undergoing monopolar TURP, (3) the main exposure of interest was use of 5ARI in the preoperative period, and (4) the study reported at least one of the following: estimated blood loss(EBL), decrease in hemoglobin (Hb) level, resection weight, blood loss per gram of resected tissue, microvessel density (MVD), and vascular endothelial growth factor (VEGF) level.
We excluded studies if(1) the study was nonrandomized, (2)the full text of the study could not be accessed, (3)outcomes relevant to our interests were not reported, (4) we could not extract data in the appropriate format and failed to obtain the data from the authors, or (5) interventions were bipolar TURP, PVP, or holmium laser enucleation of the prostate (excluded because only one study using PVP and one study using bipolar TURP used 5ARI in the preoperative period, indicating that we could not pool the data into a meta-analysis and perform subgroup analysis because the sample size was too small).
Data extraction and risk of bias assessment
Data were independently extracted from each study applying a standardized form by two reviewers and then cross-checked. Any disagreement was resolved by discussion between the two authors. If these two authors could not reach a consensus, another author was consulted to resolve the dispute and a final decision was made by a majority vote. The quality of the included RCTs was assessed by the Cochrane Risk of Bias Tool.
Data synthesis and analysis
We used the mean difference (MD) and relative risk with a 95% confidence interval (CI) for continuous and dichotomous data, respectively. For studies that presented continuous data as median and range values, the means and standard deviations were calculated using statistical algorithms described by Hozo et al. [
26].The DerSimonian and Laird random-effects model was used if there was evidence of heterogeneity between the studies, based on the χ
2 test for heterogeneity and the
I2 test. A
P value <0.10 and an
I2 value >50%, respectively, were considered high [
27]. Otherwise, the fixed-effect model (Mantel-Haenszel) was selected. Publication bias was assessed using inverted funnel plots. Sensitivity analysis was performed to examine whether the effect estimate was robust to exclusion of different criteria. Analysis was performed using the statistical software Review Manager version 5.1.
Discussion
5ARI is commonly used for treating BPH and hematuria of prostatic origin. However, the concept of preoperatively administering 5ARI to reduce blood loss during TURP has not been accepted by most urologists. In a United Kingdom-based survey, although 98% of urologists used finasteride for hematuria of prostatic origin, only 4% used it before TURP [
30]. In the present meta-analysis involving 17 RCTs and 1489 participants, we demonstrated that preoperative treatment with finasteride for 2 weeks to 6 months could decrease blood loss during TURP for BPH. In contrast, pretreatment with dutasteride before TURP did not change the total blood loss.
Testosterone is a stimulator of VEGF, and androgen deprivation leads to decreased blood flow in the prostate [
31,
32]. Finasteride blocks the conversion of testosterone to DHT, resulting in decreased activity of the androgen-controlled growth factors, such as VEGF. MVD is another histologic indicator of angiogenesis in BPH patients. Emerging data have shown that finasteride treatment prior to TURP significantly decreased MVD in the prostate tissue [
9‐
13]. Our meta-analysis confirmed the results of previous studies, demonstrating that finasteride could significantly decrease MVD and VEGF of the prostate tissue compared with controls.
Finasteride, a type II 5ARI, has been shown to decrease the size of the prostate, and therefore the operative time might also be decreased secondary to the smaller gland. However, the present meta-analysis showed that neither finasteride nor dutasteride prior to TURP reduced operative time, prostate volume, or weight of the gland resected. One possible explanation is that a decrease in the size of the prostate gland requires up to 6 months of finasteride to occur [
33]. However, most RCTs in our meta-analysis used finasteride ranging from 2 to 12 weeks, not enough for shrinkage of the prostate gland. On the contrary, the effect of finasteride on hematuria was more rapid than may reasonably be attributed to decreased prostate size. Liu et al. [
5] showed that MVD and VEGF decreased obviously in patients treated with finasteride for 14 days. Taken together, the mechanism by which finasteride decreased blood loss during TURP was probably related to decreased vascularity in the prostate rather than to a smaller prostate and shorter operative time.
Dutasteride, a dual 5ARI, provides greater suppression of 5α-reductase because it antagonizes both type I and II receptors [
34]. In theory, it should produce an effect that is better than, or at least similar to, finasteride. However, in our meta-analysis, we did not find any differences between the dutasteride and control groups with regard to EBL, decrease in Hb, resection weight, prostate volume, transfusions needed, and operative time. Only one RCT with limited cases showed that pretreatment with dutasteride could decrease blood loss per gram of resected tissue [
21].To our surprise, unlike finasteride, pooling data of two RCTs including 181 cases showed that dutasteride treatment did not decrease MVD, which might partially explain why dutasteride was not effective in reducing EBL. In addition, because dutasteride is a newer drug, the patient populations recruited to these RCTs were certainly different from the cohorts that were available for the finasteride RCTs. Thus, selection bias maybe another plausible explanation for the failure to find a difference in the dutasteride group. The exact reason dutasteride was not effective in reducing EBL and MVD remains unclear, and additional well-designed RCTs are needed to establish its actual role.
Because approximately 50% of the variability in blood loss can be accounted for by the amount of resected tissue in TURP, the resection weight and/or prostate size should be taken into account when calculating EBL [
35]. In one study by Sandfeldt et al. [
10], a positive correlation between EBL and resection weight was reported. According to Hagerty et al. [
3], patients with resected weights of >30 g who received finasteride before TURP needed fewer blood transfusions than those who did not receive the drug. Although we found no differences between 5ARI and control groups with regard to transfusions needed, it may be that the trial sample sizes were not large enough to generate enough data for detecting significant effects. In addition, most RCTs in our meta-analysis did not perform subgroup analysis based on resection weight (e.g.,>30g) or prostate size. Further studies are required to fully assess the hypothesis that the benefit of 5ARI treatment would manifest at resected weights of >30 or >40 g or set a cutoff value for prostate size.
The present meta-analysis had some limitations. First was the quality of the studies assessed; most of the included RCTs did not describe randomization concealment and blinding techniques. Second was the substantial heterogeneity among studies, which was probably caused by the variability among oral 5ARI regimens and outcome measurements. Oral 5ARI regimens were not standardized, and the studies varied in the dose of 5ARI used as well as the drug duration and frequency. Data were therefore analyzed using a random-effects model, which accounts for both within-study and between-study variability. Finally, inherent in any meta-analysis is the possibility of publication bias; that is, small studies with null results tend not to be published. However, several RCTs included in the meta-analysis also contained negative results [
11,
19‐
21], and the funnel plot did not provide any evidence of publication bias.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
YPZ and DB performed the systematic review and meta-analysis. HLZ, GHS, and DWY identified the studies and participated in critical evaluation and discussion. All authors read and approved the final manuscript.