Transurethral Resection of Prostate and Bleeding: A Prospective,Randomized,Double-Blind Placebo-Controlled Trial to See the Efficacy of Short-Term Use of Finasteride and Dutasteride on Operative Blood Loss and Prostatic Microvessel Density

Abstract

Objective:

The aim of this study was to determine the efficacy of short-duration use of finasteride and dutasteride before transurethral resection of the prostate (TURP) on intraoperative blood loss and microvessel density (MVD) of prostate stroma and suburethral tissues in benign prostatic hyperplasia (BPH).

Methods:

This study includes 450 patients who were planned for TURP. They were prospectively randomized into three groups (150 patients each). Group 1 received placebo, group 2 received finasteride, 5 mg per day, and group 3 patients received dutasteride, 0.5 mg per day, for 4 weeks before surgery. The total blood loss, requirement of blood, and MVDs in prostate stroma and suburethral tissues were calculated in each patient and then compared among three groups.

Results:

There was significant reduction in mean blood loss, blood loss/time, and total blood loss per gram of resected tissue in finasteride and dutasteride groups compared with placebo. Prostate stromal and suburethral MVDs were significantly higher compared with placebo. Blood transfusion was required in 9.3%, 2.7%, and 2% of the patients, respectively (p = 0.004). However, no statistically significant differences were observed between finasteride and dutasteride groups for these parameters (p > 0.05). The weight of resected prostate, operating time, and amount of irrigation fluid used did not show any significant difference between the three groups.

Conclusion:

Short-term pretreatment with finasteride and dutasteride has similar efficacy and significantly reduces perioperative bleeding during TURP and has minimal negative impact on sexual function. According to our findings, a 4-week prior administration of 5-alpha-reductase inhibitors may reduce operative blood loss and prostatic MVD in TURP, thus potentially decreasing blood loss-related complications and the requirement of blood transfusion.

Introduction

Benign prostatic hyperplasia (BPH) is the most common disorder in men beyond the fifth decade. Transurethral resection of the prostate (TURP) is the standard treatment of BPH in those who fail to respond to medical therapy. Literature reports a morbidity rate of ∼18%.¹ Hemorrhage is one of the most dreadful and serious complications of TURP. If it persists, it may necessitate blood transfusion and can lead to clot retention in the postoperative period.¹

Medical therapies have now become the first-line treatment for symptoms suggestive of BPH and include alpha blockers, 5-alpha-reductase inhibitors (5-ARIs), and phytotherapeutic agents. Finasteride and dutasteride are 5-ARIs that act by inhibiting the transformation of testosterone (T) to dihydrotestosterone (DHT) and are used to manage hematuria related to BPH.²

Hagerty and colleagues³ observed that finasteride before surgery is useful in decreasing perioperative bleeding during TURP. Since then, a large number of trials have shown similar findings.^4

–10 However, this potential of 5-ARIs in reducing perioperative hemorrhage during surgery remains debatable, and numerous studies have shown no substantial benefit.^11

–14 Till date, there has been no study in the literature comparing the effect of short-duration use of finasteride vs dutasteride on perioperative bleeding and microvessel density (MVD) of prostate stroma and suburethral tissues in patients undergoing TURP in a double-blind, prospective, randomized placebo-controlled manner.

Methods

The study was undertaken in a tertiary center from July 2010 to December 2015. All patients presenting with complaints of lower urinary tract symptoms (LUTS) were examined for prostate size with postvoid residual volume (PVR) with ultrasound, prostate-specific antigen (PSA), digital rectal examination, American Urological Association (AUA) symptoms, and uroflowmetry. Urodynamic study was done when indicated. The patients who were found to have BPH and were planned for surgery were included in this trial. BPH patients treated earlier with 5-ARIs or phytotherapeutic drugs within the past 1 year, previous pelvic surgery, any urologic malignancy, history of anticoagulant intake, deranged liver function test, unstable cardiac disease, kidney failure, or hematological disorders were excluded. The Ethics Committee approved this study. Using computer-generated randomization chart, patients were allocated randomly into three groups:

• Group 1: Placebo (sugar pills) for 28 days before TURP.

• Group 2: Finasteride, 5 mg, once a day for 28 days before TURP.

• Group 3: Dutasteride, 0.5 mg, once a day for 28 days before TURP.

All patients underwent TURP in regional anesthesia with 24F resectoscope sheath (Karl Storz, Germany). The operating surgeons were blinded to the treatment group and were equally experienced. During the procedure, glycine solution (1.5%) was used for irrigation. Heparin (1000 U) was added to collection buckets to avoid coagulation of irrigant. When the prostate curettings were irrigated out of the bladder, the fluid aspirated was returned to the collection bucket. After the procedure was completed, 5-mL sample of irrigant fluid was taken and transferred to a vial for hemoglobin estimation. The HemoCue method was used to calculate the amount of intraoperative hemorrhage.¹⁵ In this method, the hemoglobin (gram/dL) of irrigation fluid was multiplied by total volume of irrigant (dL) used. The result was divided by the value of hemoglobin before surgery, which gives the value of amount of total blood loss. Serum hemoglobin level was measured 1 hour before procedure and then 8 hours after the procedure to calculate the change. The resected prostate tissue chips were also weighed after the surgery. The drug was stopped in the postoperative period. Twenty-two French three-way catheter was used for irrigation and was continued for 6–8 hours postoperatively. Trial without catheter was performed on postoperative day 2 during this study period. The indication of blood transfusion at our institution during this study was hematocrit of ∼30%. The floor staffs were blinded to the treatment group.

Outcome analyses

The primary postoperative outcomes evaluated were duration of surgery, weight of resected tissue, irrigation fluid amount, total volume of blood loss, blood loss per gram of resected prostate tissue, and blood loss per minute of operative time. The secondary postoperative outcomes recorded were fall in serum hemoglobin level, requirement of blood transfusion, duration of hospital stay, and prostatic and suburethral MVDs (microvessel count). An independent investigator blinded to the treatment received by each patient assessed these measures.

Histopathologic examination

The histopathology examination was done by one of the authors (A.A.) blinded to the treatment groups. Histopathology of all specimens confirmed the diagnosis of BPH. Immunohistochemistry was done on the sections from the formalin-fixed, paraffin-embedded prostatic tissue showing stromal and suburethral tissue. MVD count was used as a parameter to evaluate angiogenesis. The hematoxylin–eosin-stained slides were examined at low magnification (x40 and x100) to look for areas showing the highest MVD. These sections were also taken up for immunohistochemistry using CD34 antibody. Areas showing the highest intensity of angiogenesis were located at 40x. MVD counts were done in these areas under high power (objective of 20x and eye piece of 0.739 mm²). Each cell highlighted with CD34 antibody or cell clusters easily separable from neighboring microvessel and stromal components was regarded as one microvessel. The presence of red blood cells within the vascular lumens was not considered as a requirement for calculating the microvessel.

Sample size

Mebust and colleagues¹ found a transfusion rate of 3.9% and clot retention rate of 3.3% with 18% cumulative incidence of perioperative and postoperative complications of TURP. Assuming a significance level of 5% and power of 80% (with α of 0.05 and β of 0.20), the minimum sample size per treatment arm required was 147, as per Dawson and Trapp.¹⁶

Statistical analysis

One-way analysis of variance was performed to analyze continuous parameters. Fischer exact test was performed to analyze categorical parameters. Intergroup comparison was performed to find out the groups with statistically significant differences. This was done by applying the post hoc comparison test with adjustment for multiple comparisons using the Bonferroni method. Statistical analysis was done with SPSS^® software, version 16. A p-value of <0.05 was considered to be statistically significant.

Results

A total of 3367 men who presented with LUTS were evaluated, and 555 cases of BPH who needed surgery (TURP) were included in this trial. One hundred five cases were excluded [patients with a previous pelvic surgery (n = 5), 5-ARI or phytotherapeutic drug intake within the past 1 year (n = 42), any urological cancer (n = 6), anticoagulant usage (n = 17), any hematological disease (n = 7), deranged renal function (n = 19), abnormal liver function test (n = 4), and unstable cardiovascular disease (n = 5)]. The remaining 450 cases were divided into three groups randomly (each group contains 150 patients). Seven patients failed to take medicine as prescribed and were excluded from the study (4 in the finasteride group and 3 in the dutasteride group). Urodynamic study was done in 41 patients: group 1 (n = 14), group 2 (n = 11), and group 3 (n = 16). The flow of cases during the study period is summarized in Figure 1.

FIG. 1.

Flow of patients during the study period. 5-ARIs = 5-alpha-reductase inhibitors; BPH = benign prostatic hyperplasia.

The mean ages (range) of the patients were 56.3 (43–80), 52.8 (40–77), and 57.2 (44–79) years in groups 1, 2, and 3, respectively (p = 0.39). Baseline parameters showed no significant differences among the three groups in terms of total prostate volume, PVR, total PSA, AUA symptom score, maximum urine flow rate (Qmax), durations of symptoms, and number of patients who presented with catheter preoperatively (Table 1).

Table 1.

Comparison of Baseline Parameters Among the Three Groups

Parameters	Placebo group	Finasteride group	Dutasteride group	p
No. of patients	150	146	147
Age (years)	56.3 (43–80)	52.8 (40–77)	57.2 (44–79)	0.39
Total prostate volume (cm³)	53.4 (32–79)	49.5 (32–75)	51.6 (30–73)	0.98
Postvoid residual urine (mL)	45.7 (29–105)	52.3 (33–117)	49.4 (25–103)	0.56
PSA (ng/dL)	2.9 (0.6–6.7)	2.4 (0.9–9.2)	2.6 (1.0–8.8)	0.37
AUA score	16.4 (9–35)	15.8 (6–35)	17.1 (7–35)	0.41
Qmax^a	10.2 (7–13)	9.8 (6–11)	10.7 (8–14)	0.63
Duration of symptoms (months)	14.6 (8–23)	15.8 (11–43)	17.3 (15–41)	0.47
No. of patients on catheter preoperatively (n, %)	7 (4.6)	9 (6.1)	11 (7.4)	0.97

Data are presented as mean with maximum and minimum values in parentheses.

The patients who are able to void.

AUA = American Urological Association; PSA = prostate-specific antigen; Qmax = maximum urine flow rate.

Table 2 compares the primary postoperative parameters among the three groups. Significant differences were observed in total blood loss (265.3 vs 168.7 vs 162.4 mL; p = 0.003), blood loss per gram of resected prostatic tissue (10.74 vs 7.3 vs 7.4 mL/gm; p = 0.01), and total blood loss per minute of operating time (6.59 vs 4.23 vs 4.3 mL/min; p = 0.002). However, mean operating times (40.2 vs 39.8 vs 37.8 minutes; p = 0.48), weight of resected prostate tissue group (24.7 vs 22.8 vs 21.9 gm; p = 0.34), and amount of irrigation fluid (143 vs 140 vs 146 dL; p = 0.64) showed no significant difference among the three groups.

Table 2.

Comparison of Primary Postoperative Outcomes Among the Three Groups

Parameters	Placebo group	Finasteride group	Dutasteride group	p
Operating time (minutes)	40.2 (24–73)	39.8 (22–68)	37.8 (29–77)	0.48
Weight of resected tissue (grams)	24.7 (8–48)	22.8 (7–43)	21.9 (9–50)	0.34
Amount of irrigation fluid (dL)	143 (65–350)	140 (55–310)	146 (60–325)	0.64
Total blood loss (mL)	265.3 (32–1522)	168.7 (37–1431)	162.4 (29–1395)	0.003
Total blood loss/weight of resected prostate (mL/gm)	10.74 (1.7–43.4)	7.3 (1.2–46.7)	7.4 (1.1–40.9)	0.01
Total blood loss/operating time (mL/min)	6.59 (0.7–25.1)	4.23 (0.9–23.6)	4.3 (0.6–22.4)	0.002

Data are presented as mean with maximum and minimum values in parentheses.

Table 3 compares the secondary postoperative parameters among the three groups. Significant differences were observed in fall of hemoglobin (1.6 vs 0.8 vs 0.7 gm; p = 0.002), prostatic MVD (27.6 vs 17.2 vs 16.8; p = 0.01), and suburethral MVD (21.3 vs 14.2 vs 13.3; p = 0.02). In placebo, finasteride, and dutasteride groups, blood transfusion was required in 14 (9.3%), 4 (2.7%), and 3 (2%) cases, respectively (p = 0.004). The mean blood requirement in 14 patients who required transfusion in the placebo group was 520 mL. No significant differences were observed in terms of duration of hospital stay among the three groups (p = 0.8).

Table 3.

Comparison of Secondary Postoperative Outcomes Among the Three Groups

Parameters	Placebo group	Finasteride group	Dutasteride group	p
Fall of hemoglobin (gm/dL)	1.6 (0.5–4.3)	0.8 (0.3–3.9)	0.7 (0.6–4.0)	0.002
Requirement of blood transfusion (n, %)	14/150 (9.3)	4/146 (2.7)	3/147 (2)	0.004
Postoperative hospital stay (days)	1.15 (1–3)	1.3 (1–2)	1.2 (1–3)	0.8
Prostatic MVD (microvessel count)	27.6 (16–43)	17.2 (13–37)	16.8 (11–40)	0.01
Suburethral MVD (microvessel count)	21.3 (11–38)	14.2 (9–33)	13.3 (8–29)	0.02

Data are presented as mean with maximum and minimum values in parentheses.

MVD = microvessel density.

Intergroup comparison showed that blood loss, blood loss per gram of resected prostatic tissue, and blood loss per minute of operating time in the placebo group were significantly more in comparison with other two groups after adjusting for multiple comparisons (Table 4). Fall in hemoglobin, requirement of blood transfusion, and prostatic stromal and suburethral tissue MVDs were also significantly higher. However, we found no significant differences between finasteride and dutasteride groups for these parameters (p > 0.4).

Table 4.

Intergroup Comparison of Parameters (Whose p-Value is Significant in Tables 2 and 3) to Find Groups with Significant Differences

	p-Value of intergroup comparison
Parameters	Placebo vs Finasteride group	Placebo vs Dutasteride group	Finasteride vs Dutasteride group
Total blood loss (mL)	0.001	0.001	0.67
Total blood loss/weight of resected prostate	0.003	0.001	0.79
Total blood loss/operating time	0.001	0.002	0.89
Fall of hemoglobin (gm/dL)	0.006	0.002	0.43
Requirement of blood transfusion	0.02	0.01	1.00
Prostatic MVD (microvessel count)	0.004	0.006	0.96
Suburethral MVD (microvessel count)	0.007	0.002	0.75

No major complications were found in the postoperative period. Decreased libido was found in four (2.7%) patients in the finasteride group and three (2.0%) patients in the dutasteride group. Erectile dysfunction was observed in three (2.0%) patients in the finasteride group and two (1.3%) patients in the dutasteride group. None of these complications were found in the placebo group. However, these problems disappeared within 3 months of discontinuing the drugs.

Discussion

BPH presenting with LUTS is a common problem in elderly men.^17,18 The most reliable and effective treatment option to relieve bladder outlet obstruction due to BPH is TURP. However, bleeding is one of the most dreadful complications of TURP in the early postoperative period and, if prolonged, it can lead to retention of clot and requirement of blood transfusion.¹ Another common perioperative complication is dilutional hyponatremia (TURP syndrome), which results form extravasation and absorption of irrigant fluid. The overall morbidity rate of TURP is 18%, of which hemorrhage is a major contributor.¹

Puchner and Miller postulated that 5-ARIs act by blocking the transformation of testosterone to DHT, leading to low level of androgen-derived growth factors required for angiogenesis. This results in decreased blood flow and vascular density of the prostate and reduces the rate of hematuria associated with BPH.¹⁹

However, this ability of 5-ARIs to reduce perioperative hemorrhage during TURP is not universally accepted. Although 98% of urologists used 5-ARIs for hematuria of BPH origin, only 4% of urologists used it before TURP according to a United Kingdom-based survey.²⁰

Both drugs have been studied in the literature to see their effects on perioperative bleeding and MVDs, but to date, in the English literature, these drugs have never been compared with each other. We attempted to compare the results of preoperative short-term use of finasteride vs dutasteride on perioperative hemorrhage, while performing TURP, and MVD of prostate stroma and suburethral tissues in a double-blind, placebo-controlled, prospective randomized manner.

In this trial, total amount of blood loss, blood loss per gram of resected tissue, and total blood loss per minute of operating were significantly more in the placebo group compared with the finasteride or dutasteride group. Fall of hemoglobin and requirement of blood transfusion were also significantly higher. However, all these parameters did not significantly differ between the finasteride and dutasteride groups. Fourteen (9.3%), four (2.7%), and three (2%) patients, respectively, required blood transfusion in the postoperative period due to persistent hematuria in the immediate postoperative period. Our results are mostly consistent with other studies in the literature. Hagerty and colleagues³ found that patients receiving finasteride before surgery required less blood transfusion, with the incidence of perioperative bleeding being 4% compared with 14% in patients who did not receive the drug. Crea and colleagues⁴ reported the efficacy of finasteride on hemorrhage due to BPH and showed that it was markedly lower in patients who had taken finasteride compared with placebo. Donohue and colleagues⁵ and Ozdal and colleagues⁶ showed that fall in the hemoglobin level and amount of hemorrhage during TURP are significantly higher in the placebo group compared with the finasteride group. Kim and colleagues⁷ found that treatment with dutasteride (0.5 mg × 14 days) led to significant decrease in surgical bleeding. Pastore and colleagues⁸ concluded that dutasteride treatment for 6 weeks before TURP reduced blood loss.

Contrary to the above facts, various studies have reported that there is no significant benefit of using preoperative 5-ARIs.^11

–14 Lund and colleagues¹¹ concluded that treatment with finasteride (5 mg once a day × 3 months) before TURP did not have any advantage in decreasing perioperative hemorrhage during surgery. This was probably due to a small sample size (n = 35; placebo-17, finasteride-16). Arratia-Maqueo and colleagues¹² and Tuncel and colleagues¹³ showed that dutasteride was not superior to placebo for perioperative bleeding during TURP. The results might be due to the small sample size and nonrandomized study design. Hahn and colleagues,¹⁴ in their double-blind, placebo-controlled randomized trial, reported no significant difference in dutasteride and placebo.

In our study, 5-ARIs were given preoperatively for 4 weeks as we hypothesized that this duration would give adequate exposure to reduce neovascularization. This hypothesis was supported by our results and other studies in the literature.^6,21 The resected tissue and duration of surgery should be considered while evaluating blood loss as roughly 50% of the variation in the result can be due to these variables.¹⁵ The weight of prostatic tissue resected was comparable among the three groups as 5-ARIs were given for only 4 weeks preoperatively. For the prostate gland to shrink, 5-ARI therapy for duration of 6 months is usually required.²² This hypothesis was also supported by Zhu and colleagues²³ who demonstrated that pretreatment with neither dutasteride nor finasteride could reduce the weight of the resected prostatic tissue as mostly 5-ARIs are used for 2–12 weeks preoperatively, which is not enough to shrink the prostate gland.

Moreover, the mean operating time and amount of irrigation fluid used were also comparable among the three groups. Zhu and colleagues²³ in their study also found that operative time was not reduced by either finasteride or dutasteride. Ozdal and colleagues⁶ reported that there was no statistical significance in the total operating time and irrigating fluid amount during TURP between the control and treatment groups (finasteride 5 mg OD × 4 weeks before TURP).

Marshall and colleagues²⁴ hypothesized that BPH with high acinar and proliferation of stromal cell promotes angiogenesis. MVD is the histologic indicator of angiogenesis, which may be a significant risk factor for hemorrhage during TURP. A possible explanation for prostatic bleeding is the increased vascularity in prostatic urethra and its close proximity to mucosa. Hemorrhage following ulceration of mucosa will lead to hematuria more readily.²⁵ 5-ARI suppresses angiogenesis and MVD by decreasing DHT concentration, which in turn decreases androgen-controlled growth factors required for angiogenesis.

In our study, prostate stromal and suburethral MVDs were significantly more in the placebo group than in the finasteride or dutasteride group (27.6 vs 17.2 vs 16.8; p = 0.01; and 21.3 vs 14.2 vs 13.3; p = 0.02, respectively; Figs. 2 –5). However, they were similar between finasteride and dutasteride groups. This explains that both drugs are equally efficacious and better than placebo in decreasing prostatic and suburethral MVDs and hence BPH-associated bleeding. Our results were also consistent with those of Hochberg and colleagues²⁶ who reported that suburethral prostatic MVD significantly decreased in patients with BPH taking finasteride. Bailey and colleagues¹⁰ noted reduction in prostate stromal MVD in patients on finasteride undergoing TURP. Neal and colleagues²⁷ showed that MVD in prostates of canine models pretreated with finasteride decreased by 20 vessels per cm². Zaitsu and colleagues²⁸ showed that dutasteride therapy leads to decreased vessel density and area in BPH. A change in vascularity of prostate in BPH was also seen by ultrasound color Doppler after short-term dutasteride therapy by Kravchick and colleagues.⁹

FIG. 2.

H&E-stained section showing suburethral microvessel density. (A) High MVD in the placebo group. (B) Low MVD in the finasteride group. (C) Low MVD in the dutasteride group. H&E = hematoxylin and eosin; MVD = microvessel density.

FIG. 3.

H&E-stained section showing prostatic stromal microvessel density. (A) High MVD in the placebo group. (B) Low MVD in the finasteride group. (C) Low MVD in the dutasteride group.

FIG. 4.

Immunohistochemical staining of suburethral prostate tissue with CD34. (A) High MVD in the placebo group. (B) Low MVD in the finasteride group. (C) Low MVD in the dutasteride group.

FIG. 5.

Immunohistochemical staining of prostatic stromal tissue with CD34. (A) High MVD in the placebo group. (B) Low MVD in the finasteride group. (C) Low MVD in the dutasteride group.

However, Canda and colleagues²⁹ showed that finasteride does not lower MVD and vascular endothelial growth factor expression in rat prostate. They, however, emphasized that the drug reduces hemorrhage in BPH due to its effectiveness in reducing hyperplasia of the gland, which in turn increases vessel wall stability rather than decreasing vascularity of prostate tissue. Hahn and colleagues¹⁴ and Tuncel and colleagues¹³ compared placebo with dutasteride and reported that MVD was similar in both.

The meta-analysis done by Zhu and colleagues²³ showed that treatment with finasteride before TURP for BPH reduces perioperative hemorrhage. However, no difference was observed in blood loss, reduction in hemoglobin, prostate size, number of transfusions required, operative time, and reduction in MVD when dutasteride was compared with the control group.¹³ This could possibly be due to the fact that dutasteride was a newer drug and the patient group selected for randomized control trials (RCTs) was not similar to those selected for the finasteride RCTs. However, the exact reason for dutasteride being ineffective in decreasing the blood loss and MVD is not clear. Hence, this well-designed, double-blind placebo-controlled RCT will actually establish its actual role. The results of our present trial are novel and significantly contribute to the knowledge of the role of 5-ARIs in reducing bleeding during TURP. Our study is a step forward than others as it compares the efficacy of dutasteride vs finasteride in preventing blood loss during TURP. Second, we evaluated a greater number of patients (450 patients). The administration of 5-ARI for a duration of 4 weeks is usually well tolerated and is helpful in cases with cardiac disease who are prone to blood loss. Erectile dysfunction and reduced libido were seen in few patients, which disappeared within 3 months of discontinuing the drugs. The limitation of this study was that Doppler sonography was not done before and after 5-ARI therapy to evaluate the quantitative reduction in prostatic vascularity.

Conclusion

Short-term pretreatment with finasteride and dutasteride has similar efficacy and significantly reduces perioperative bleeding during TURP and has minimal negative impact on sexual function. According to our findings, a 4-week prior administration of 5-ARIs may reduce operative blood loss and prostatic MVD in TURP, thus potentially decreasing blood loss-related complications and the requirement of blood transfusion.

Footnotes

Acknowledgment

The authors thank Satyanarayan Sankhwar for his guidance.

Ethical Approval

Ethical approval has been taken from the Institutional Ethics Committee.

Informed Consent

Written consent was obtained from all participants.

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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