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A PROSPECTIVE STUDY OF THE NATURAL HISTORY OF HEMATURIA ASSOCIATED WITH BENIGN PROSTATIC HYPERPLASIA AND THE EFFECT OF FINASTERIDE
0022-5347/00/1632-0496/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 163, 496 – 498, February 2000 Printed in U.S.A.
A PROSPECTIVE STUDY OF THE NATURAL HISTORY OF HEMATURIA ASSOCIATED WITH BENIGN PROSTATIC HYPERPLASIA AND THE EFFECT OF FINASTERIDE STEPHEN J. FOLEY, LEMKIE Z. SOLOMAN, ANDREW W. WEDDERBURN, KASHIF M. KASHIF, DUNCAN SUMMERTON, VANESSA BASKETTER AND SIMON A. V. HOLMES From the Departments of Urology, St. Mary’s Hospital, Portsmouth, Royal Hospital, Haslar and Southampton General Hospital, Southampton, Hampshire, United Kingdom
ABSTRACT
Purpose: We prospectively studied the effect of finasteride on chronic hematuria associated with benign prostatic hyperplasia. Materials and Methods: We prospectively evaluated 57 patients with chronic intermittent hematuria who were randomized to a finasteride treated or a control arm. Results: In the untreated control group hematuria recurred in 17 patients (63%) within a year but in only 4 (14%) in the finasteride group, which was a statistically significant difference (p ,0.05). Surgery was required for bleeding in 7 controls (26%), while no patient on finasteride required surgery. Conclusions: Hematuria secondary to prostatic bleeding may be significant if not treated. Finasteride appears to be effective for suppressing hematuria caused by benign prostatic hyperplasia and should be considered as treatment. KEY WORDS: prostate, hematuria, prostatic hyperplasia, finasteride
Recurrent hematuria of prostatic origin is distressing to the patient and may be debilitating. The prevalence of gross hematuria in patients with benign prostatic hyperplasia (BPH) is unknown. However, Mebust et al retrospectively reviewed the records of more than 3,000 men who underwent transurethral prostatic resection and noted that hematuria was an indication for surgery in 12%.1 In previous hematuria studies BPH was the only pathological condition identified in approximately 20% of cases.2, 3 The prevalence of intermittent hematuria after transurethral prostatic resection is difficult to ascertain because to our knowledge none of the studies of the long-term outcome of transurethral prostatic resection has addressed this point. BPH with increased acinar and stromal cell proliferation stimulates increased vasculartiy (angiogenesis) of vessels, which may be easily disrupted, providing the basis for recurrent bleeding. The role of male sex hormones on the prostate has been studied previously. Suppressing prostatic cell growth by androgen ablation with estrogen or antiandrogen therapy results in cessation of cell proliferation, activating programmed cell death of these androgen dependent prostatic cells, apoptosis and ultimately involution of the prostate. Marshall and Narayan postulated that angiogenesis is critical in BPH and androgen deprivation leads to the suppression of angiogenesis.4 A 5a-reductase inhibitor, such as finasteride, is known to block the conversion of testosterone to dihydrotestosterone, resulting in decreased activity of the androgen controlled growth factors responsible for angiogenesis, which leads to decreased angiogenesis and, therefore, theoretically less prostatic bleeding. Bailey and Foley recently reported that patients with hematuria have a much higher concentration of blood vessels in the suburothelial prostatic urethra,5 which presumably bleed after excursion. The role of hormones for stimulating and suppressing angiogenesis in the prostate has been demonstrated in animal models.6, 7 Bailey et al showed that prostatic vessel density in humans decreases in response to finasteride.8 Accepted for publication August 6, 1999.
Recently finasteride has been suggested as an option for treating hematuria associated with BPH with promising results in uncontrolled retrospective studies.9 –13 We prospectively evaluated the natural history of hematuria and the effect of finasteride in a multicenter prospective randomized trial. MATERIALS AND METHODS
All patients underwent evaluation for the causes of hematuria, including a complete history, physical examination, digital rectal examination, upper tract imaging with excretory urography (IVP) or ultrasound, midstream urine specimen, prostate specific antigen (PSA) determination and flexible cystoscopy. Only those men with negative evaluations for tumor, including a normal digital rectal examination, and evidence of bleeding from friable prostatic tissue on flexible cystoscopy were included in our prospective randomized multicenter trial. All men had had at least 2 episodes of gross hematuria during the preceding 6 months. After patients were completely evaluated and considered eligible for the trial they were counseled. Participants were then randomized into those receiving 5 mg. finasteride once daily or informed that there was no morbid pathological condition and placed in a watchful waiting arm. The study was unsponsored, and so no placebo was available. Most patients had intermittent hematuria but 6 were actively bleeding at study entry. The severity of hematuria was graded according to the method of Puchner and Miller9 as minor—a single episode of bleeding or small clots, moderate— bleeding during multiple voids in any 24-hour period with resolution within 1 day and severe— clot retention, or bleeding so significant that a catheter was placed and/or cystoscopy was performed (table 1). Patients were interviewed by telephone or in the outpatient department 3, 6 and 12 months after the diagnosis. Any new episodes of hematuria were noted as well as complications associated with hematuria, especially further surgery. All followup interviews were done by the same research
496
497
HEMATURIA AND BENIGN PROSTATIC HYPERPLASIA TABLE 1. Severity of bleeding in study patients Hematuria Grade
No. Finasteride Group
Overall: Minor Moderate Severe After 1 yr.: Minor Moderate Severe * Previous transurethral prostatic
No. Control Group
TABLE 2. Further treatment requirements in patients with continued gross hematuria in control group during 1 year Pt. No.
7 18 3 3 1* 0 resection.
8 16 3 7 6* 4*
nurse. During a 1-year period 57 patients were randomized among 5 units. RESULTS
Of the 57 randomized patients 55 had 1 year of followup. One man in the finasteride arm died of an unrelated condition and 1 in the control arm was lost to followup. Mean age of the 28 men in the finasteride group was 76 years (range 55 to 89) and 19 had previously undergone transurethral prostatic resection. Mean age of the 27 men in the control group was 79 years (range 55 to 86) and 18 had previously undergone transurethral prostatic resection. The figure shows the rates of hematuria in each group, which were significantly different (chi-square test p ,0.05) at 1 year. Hematuria was more frequent and severe in the control arm. Mild hematuria recurred in only 4 patients in the finasteride group, which was minor in 3 and moderate in 1. In each case the duration of hematuria was less than 24 hours and surgery was not required. Significant and heavier hematuria recurred in 17 controls, of whom 7 required further treatment (table 1). Of the controls 4 were hospitalized in clot retention, 2 who underwent transurethral prostatic resection for persistent grade 2 hematuria refused medical treatment, 2 who underwent cystoscopy under anesthesia were started on finasteride with no further bleeding and 2 who underwent transurethral prostatic resection due to anemia caused by severe bleeding were considered by the operating surgeon to be at high risk for further hematuria. In each group two-thirds of the men had previously undergone prostate surgery. When left untreated, they were most likely to have recurrent and more severe hematuria (table 2). DISCUSSION
Hematuria that is associated with primary BPH or develops after transurethral prostatic resection is distressing to patients and is often difficult to treat. Nevertheless, chronic intermittent hematuria attributed to BPH occurs often enough for most urologists to have had experience with this problem, as shown in the hematuria clinic studies of Lynch2 and Hasan3 et al in which 20% of patients with hematuria were diagnosed with bleeding and BPH only. These patients
1 2 3 4 5 6 7
Treatment Transurethral prostatic resection Transurethral prostatic resection Cystoscopy under general anesthesia, finasteride Cystoscopy under general anesthesia, finasteride Transurethral prostatic resection Repeat cystoscopy, local anesthesia Transurethral prostatic resection
often have recurrent bleeding and they undergo reinvestigation with major cost implications. To our knowledge our report represents the initial prospective randomized study to examine the natural history of hematuria associated with BPH. It is evident that this condition is not benign. When left untreated, more than 60% of patients had recurrent hematuria within a year and more importantly almost 30% required surgical intervention. However, when the men were treated with finasteride, the incidence of hematuria significantly decreased. When hematuria recurred, it was less severe and did not require surgical intervention. Interestingly our results indicate the speed with which finasteride seems to stop hematuria when administered during active bleeding. Hematuria resolved within 4 weeks in all patients. If the effect were due to prostate involution, which has been shown to require more than 6 months, bleeding would have been expected to continue. In our series hematuria stopped almost immediately, suggesting that the effect occurs via an alternative mechanism to that producing the volume change. The theory of decreasing angiogenesis by decreasing hormone levels6 – 8 is in accordance with the speed of action noted clinically, since angiogenesis is known to be a rapid process and we would expect the vessels to decrease quickly in size and number. This finding has major implications for treating hematuria secondary to BPH. Finasteride has been shown to decrease significant bleeding, so that hematuria is no longer an indication for surgery. In addition, treating all larger vascular prostates with finasteride appears to be a logical step because it prevents bleeding and may decrease the incidence of retention or surgery.14 If surgery is necessary, finasteride administration may decrease intraoperative blood loss, because the prostate is smaller and less vascular. However, this latter point clearly requires further study. Several questions remain to be addressed. What is the optimum dose in these patients and how long should they be treated? In our study all men in the finasteride group were treated for 12 months and the medication was then discontinued. In the initial 3 months after the drug was withdrawn 6 of 12 patients (50%) had recurrent hematuria, suggesting that many require long-term treatment. Bleeding recurred within 6 weeks, confirming the speed of the events underlying hematuria. Treatment with 5 mg. finasteride once daily or on alternate days for 12 months is recommended. If hematuria recurs, finasteride may be readministered. Our series should be viewed as a pilot study. The next step is to develop a larger, placebo controlled study to confirm our findings. CONCLUSIONS
Incidence of hematuria in finasteride and control groups at up to 1 year of followup.
To our knowledge our report represents the initial prospective study of chronic hematuria and the effect of finasteride. Hematuria associated with BPH is not a benign condition. When left untreated, two-thirds of the patients continue to bleed and a third require surgery. Finasteride significantly decreases the incidence of bleeding and in our series no patient required surgery. This study is obviously limited by small numbers. A larger, placebo controlled, international study is needed.
498
HEMATURIA AND BENIGN PROSTATIC HYPERPLASIA
D. Tulloch, B. H. Walmsley, S. G. Chiverton, J. Cumming, B. R. Birch and C. J. Smart allowed their patients to participate in this trial. REFERENCES
1. Mebust, W. K., Holtgrewe, H. L., Cockett, A. T. K. et al: Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol, 141: 243, 1989 2. Lynch, T. H., Waymont, B., Dunn, J. A. et al: Rapid diagnostic service for patients with haematuria. Br J Urol, 73: 147, 1994 3. Hasan, S. T., German, K. and Derry, C. D.: Same day diagnostic service for new cases of haematuria—a district general hospital experience. Br J Urol, 73: 151, 1994 4. Marshall, S. and Narayan, P.: Treatment of prostatic bleeding: suppression of angiogenesis by androgen deprivation. J Urol, 149: 1553, 1993 5. Bailey, D. M. and Foley, S. J.: Microvascular anatomy in patients with recurrent haematuria related to prostatic hypertrophy (BPH). J Urol, suppl., 161: 225, abstract 865, 1999 6. Franck-Lissbrant, I., Haggestrom, S., Damber, J.-E. et al: Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats. Endocrinology, 139: 451, 1998 7. Levine, A. C., Liu, X.-H., Greenberg, P. D. et al: Androgens induce the expression of vascular endothelial growth factors in human fetal prostatic fibroblasts. Endocrinology, 139: 4672, 1998 8. Bailey, D. M., Foley, S. J. and Wedderburn, A.: Effect of Finasteride on microvessel density (MVD) in patients with recurrent haematuria related to prostatic hypertrophy (BPH). J Urol, suppl., 161: 363, abstract 1406, 1999 9. Puchner, P. J. and Miller, M. I.: The effects of finasteride on hematuria associated with benign prostatic hyperplasia: a preliminary report. J Urol, 154: 1779, 1995 10. Miller, M. I. and Puchner, P. J.: Effects of finasteride on hematuria associated with benign prostatic hyperplasia—long term follow-up. Urology, 51: 237,1998 11. Carlin, B. I., Bodner, D. R., Spirnak, J. P. et al: Role of finasteride in the treatment of recurrent haematuria secondary to benign prostatic hyperplasia. Prostate, 31: 180, 1997 12. Sieber, P. R., Rommel, F. M., Huffnagle, H. W. et al: The treatment of gross hematuria secondary to prostatic bleeding with Finasteride. J Urol, 159: 1232, 1998 13. Kashif, K. M., Foley, S. J., Basketter, V. et al: Haematuria in
BPH-Natural history and a new treatment option. Prostate Cancer Prostate Dis, 1: 154, 1998 14. McConnell, J. D., Bruskewitz, R., Walsh, P. C. et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. New Engl J Med, 338: 557, 1998 EDITORIAL COMMENT To my knowledge this is the first randomized prospective study that demonstrates that finasteride therapy decreases the incidence of repeat bleeding in patients with BPH. Puchner et al were the first to report this beneficial effect of finasteride (reference 9 in article). In their report and all subsequent reports, including the current one, the finasteride effect on hematuria was rapid, more rapid than may reasonably be attributed to decreased prostate size due to apoptosis and/or decreased angiogenesis. BPH associated hematuria has been postulated to be due to the increased fragility of blood vessels in the suburothelial prostatic urethra secondary to increased pressure. Any treatment that decreases edema in the extravascular space would be expected to decrease intravascular pressure and the incidence of hematuria. We previously demonstrated that vascular endothelial growth factor, a potent angiogenic factor, is highly expressed in smooth muscle cells in BPH (reference 7 in article). In addition, we demonstrated that androgenic effects on vascular endothelial growth factor messenger RNA transcription and protein secretion are rapid, peaking at 2 and 4 hours, respectively, after androgen addition. Vascular endothelial growth factor was originally described as the vascular permeability factor and it is reported to be 50,000 times more potent than histamine in its ability to enhance vascular permeability.1 I postulate that the rapid decrease in hematuria associated with finasteride is due to rapid decreases in vascular endothelial growth factor-vascular permeability factor, which decrease vascular permeability and edema with a resultant decrease in intravascular pressure and vessel fragility. Alexander Kirschenbaum Department of Urology Mount Sinai Medical Center New York, New York 1. Senger, D. R., Galli, S. J., Dvorak, A. M. et al: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 219: 983, 1983
Vol. 163, 496 – 498, February 2000 Printed in U.S.A.
A PROSPECTIVE STUDY OF THE NATURAL HISTORY OF HEMATURIA ASSOCIATED WITH BENIGN PROSTATIC HYPERPLASIA AND THE EFFECT OF FINASTERIDE STEPHEN J. FOLEY, LEMKIE Z. SOLOMAN, ANDREW W. WEDDERBURN, KASHIF M. KASHIF, DUNCAN SUMMERTON, VANESSA BASKETTER AND SIMON A. V. HOLMES From the Departments of Urology, St. Mary’s Hospital, Portsmouth, Royal Hospital, Haslar and Southampton General Hospital, Southampton, Hampshire, United Kingdom
ABSTRACT
Purpose: We prospectively studied the effect of finasteride on chronic hematuria associated with benign prostatic hyperplasia. Materials and Methods: We prospectively evaluated 57 patients with chronic intermittent hematuria who were randomized to a finasteride treated or a control arm. Results: In the untreated control group hematuria recurred in 17 patients (63%) within a year but in only 4 (14%) in the finasteride group, which was a statistically significant difference (p ,0.05). Surgery was required for bleeding in 7 controls (26%), while no patient on finasteride required surgery. Conclusions: Hematuria secondary to prostatic bleeding may be significant if not treated. Finasteride appears to be effective for suppressing hematuria caused by benign prostatic hyperplasia and should be considered as treatment. KEY WORDS: prostate, hematuria, prostatic hyperplasia, finasteride
Recurrent hematuria of prostatic origin is distressing to the patient and may be debilitating. The prevalence of gross hematuria in patients with benign prostatic hyperplasia (BPH) is unknown. However, Mebust et al retrospectively reviewed the records of more than 3,000 men who underwent transurethral prostatic resection and noted that hematuria was an indication for surgery in 12%.1 In previous hematuria studies BPH was the only pathological condition identified in approximately 20% of cases.2, 3 The prevalence of intermittent hematuria after transurethral prostatic resection is difficult to ascertain because to our knowledge none of the studies of the long-term outcome of transurethral prostatic resection has addressed this point. BPH with increased acinar and stromal cell proliferation stimulates increased vasculartiy (angiogenesis) of vessels, which may be easily disrupted, providing the basis for recurrent bleeding. The role of male sex hormones on the prostate has been studied previously. Suppressing prostatic cell growth by androgen ablation with estrogen or antiandrogen therapy results in cessation of cell proliferation, activating programmed cell death of these androgen dependent prostatic cells, apoptosis and ultimately involution of the prostate. Marshall and Narayan postulated that angiogenesis is critical in BPH and androgen deprivation leads to the suppression of angiogenesis.4 A 5a-reductase inhibitor, such as finasteride, is known to block the conversion of testosterone to dihydrotestosterone, resulting in decreased activity of the androgen controlled growth factors responsible for angiogenesis, which leads to decreased angiogenesis and, therefore, theoretically less prostatic bleeding. Bailey and Foley recently reported that patients with hematuria have a much higher concentration of blood vessels in the suburothelial prostatic urethra,5 which presumably bleed after excursion. The role of hormones for stimulating and suppressing angiogenesis in the prostate has been demonstrated in animal models.6, 7 Bailey et al showed that prostatic vessel density in humans decreases in response to finasteride.8 Accepted for publication August 6, 1999.
Recently finasteride has been suggested as an option for treating hematuria associated with BPH with promising results in uncontrolled retrospective studies.9 –13 We prospectively evaluated the natural history of hematuria and the effect of finasteride in a multicenter prospective randomized trial. MATERIALS AND METHODS
All patients underwent evaluation for the causes of hematuria, including a complete history, physical examination, digital rectal examination, upper tract imaging with excretory urography (IVP) or ultrasound, midstream urine specimen, prostate specific antigen (PSA) determination and flexible cystoscopy. Only those men with negative evaluations for tumor, including a normal digital rectal examination, and evidence of bleeding from friable prostatic tissue on flexible cystoscopy were included in our prospective randomized multicenter trial. All men had had at least 2 episodes of gross hematuria during the preceding 6 months. After patients were completely evaluated and considered eligible for the trial they were counseled. Participants were then randomized into those receiving 5 mg. finasteride once daily or informed that there was no morbid pathological condition and placed in a watchful waiting arm. The study was unsponsored, and so no placebo was available. Most patients had intermittent hematuria but 6 were actively bleeding at study entry. The severity of hematuria was graded according to the method of Puchner and Miller9 as minor—a single episode of bleeding or small clots, moderate— bleeding during multiple voids in any 24-hour period with resolution within 1 day and severe— clot retention, or bleeding so significant that a catheter was placed and/or cystoscopy was performed (table 1). Patients were interviewed by telephone or in the outpatient department 3, 6 and 12 months after the diagnosis. Any new episodes of hematuria were noted as well as complications associated with hematuria, especially further surgery. All followup interviews were done by the same research
496
497
HEMATURIA AND BENIGN PROSTATIC HYPERPLASIA TABLE 1. Severity of bleeding in study patients Hematuria Grade
No. Finasteride Group
Overall: Minor Moderate Severe After 1 yr.: Minor Moderate Severe * Previous transurethral prostatic
No. Control Group
TABLE 2. Further treatment requirements in patients with continued gross hematuria in control group during 1 year Pt. No.
7 18 3 3 1* 0 resection.
8 16 3 7 6* 4*
nurse. During a 1-year period 57 patients were randomized among 5 units. RESULTS
Of the 57 randomized patients 55 had 1 year of followup. One man in the finasteride arm died of an unrelated condition and 1 in the control arm was lost to followup. Mean age of the 28 men in the finasteride group was 76 years (range 55 to 89) and 19 had previously undergone transurethral prostatic resection. Mean age of the 27 men in the control group was 79 years (range 55 to 86) and 18 had previously undergone transurethral prostatic resection. The figure shows the rates of hematuria in each group, which were significantly different (chi-square test p ,0.05) at 1 year. Hematuria was more frequent and severe in the control arm. Mild hematuria recurred in only 4 patients in the finasteride group, which was minor in 3 and moderate in 1. In each case the duration of hematuria was less than 24 hours and surgery was not required. Significant and heavier hematuria recurred in 17 controls, of whom 7 required further treatment (table 1). Of the controls 4 were hospitalized in clot retention, 2 who underwent transurethral prostatic resection for persistent grade 2 hematuria refused medical treatment, 2 who underwent cystoscopy under anesthesia were started on finasteride with no further bleeding and 2 who underwent transurethral prostatic resection due to anemia caused by severe bleeding were considered by the operating surgeon to be at high risk for further hematuria. In each group two-thirds of the men had previously undergone prostate surgery. When left untreated, they were most likely to have recurrent and more severe hematuria (table 2). DISCUSSION
Hematuria that is associated with primary BPH or develops after transurethral prostatic resection is distressing to patients and is often difficult to treat. Nevertheless, chronic intermittent hematuria attributed to BPH occurs often enough for most urologists to have had experience with this problem, as shown in the hematuria clinic studies of Lynch2 and Hasan3 et al in which 20% of patients with hematuria were diagnosed with bleeding and BPH only. These patients
1 2 3 4 5 6 7
Treatment Transurethral prostatic resection Transurethral prostatic resection Cystoscopy under general anesthesia, finasteride Cystoscopy under general anesthesia, finasteride Transurethral prostatic resection Repeat cystoscopy, local anesthesia Transurethral prostatic resection
often have recurrent bleeding and they undergo reinvestigation with major cost implications. To our knowledge our report represents the initial prospective randomized study to examine the natural history of hematuria associated with BPH. It is evident that this condition is not benign. When left untreated, more than 60% of patients had recurrent hematuria within a year and more importantly almost 30% required surgical intervention. However, when the men were treated with finasteride, the incidence of hematuria significantly decreased. When hematuria recurred, it was less severe and did not require surgical intervention. Interestingly our results indicate the speed with which finasteride seems to stop hematuria when administered during active bleeding. Hematuria resolved within 4 weeks in all patients. If the effect were due to prostate involution, which has been shown to require more than 6 months, bleeding would have been expected to continue. In our series hematuria stopped almost immediately, suggesting that the effect occurs via an alternative mechanism to that producing the volume change. The theory of decreasing angiogenesis by decreasing hormone levels6 – 8 is in accordance with the speed of action noted clinically, since angiogenesis is known to be a rapid process and we would expect the vessels to decrease quickly in size and number. This finding has major implications for treating hematuria secondary to BPH. Finasteride has been shown to decrease significant bleeding, so that hematuria is no longer an indication for surgery. In addition, treating all larger vascular prostates with finasteride appears to be a logical step because it prevents bleeding and may decrease the incidence of retention or surgery.14 If surgery is necessary, finasteride administration may decrease intraoperative blood loss, because the prostate is smaller and less vascular. However, this latter point clearly requires further study. Several questions remain to be addressed. What is the optimum dose in these patients and how long should they be treated? In our study all men in the finasteride group were treated for 12 months and the medication was then discontinued. In the initial 3 months after the drug was withdrawn 6 of 12 patients (50%) had recurrent hematuria, suggesting that many require long-term treatment. Bleeding recurred within 6 weeks, confirming the speed of the events underlying hematuria. Treatment with 5 mg. finasteride once daily or on alternate days for 12 months is recommended. If hematuria recurs, finasteride may be readministered. Our series should be viewed as a pilot study. The next step is to develop a larger, placebo controlled study to confirm our findings. CONCLUSIONS
Incidence of hematuria in finasteride and control groups at up to 1 year of followup.
To our knowledge our report represents the initial prospective study of chronic hematuria and the effect of finasteride. Hematuria associated with BPH is not a benign condition. When left untreated, two-thirds of the patients continue to bleed and a third require surgery. Finasteride significantly decreases the incidence of bleeding and in our series no patient required surgery. This study is obviously limited by small numbers. A larger, placebo controlled, international study is needed.
498
HEMATURIA AND BENIGN PROSTATIC HYPERPLASIA
D. Tulloch, B. H. Walmsley, S. G. Chiverton, J. Cumming, B. R. Birch and C. J. Smart allowed their patients to participate in this trial. REFERENCES
1. Mebust, W. K., Holtgrewe, H. L., Cockett, A. T. K. et al: Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol, 141: 243, 1989 2. Lynch, T. H., Waymont, B., Dunn, J. A. et al: Rapid diagnostic service for patients with haematuria. Br J Urol, 73: 147, 1994 3. Hasan, S. T., German, K. and Derry, C. D.: Same day diagnostic service for new cases of haematuria—a district general hospital experience. Br J Urol, 73: 151, 1994 4. Marshall, S. and Narayan, P.: Treatment of prostatic bleeding: suppression of angiogenesis by androgen deprivation. J Urol, 149: 1553, 1993 5. Bailey, D. M. and Foley, S. J.: Microvascular anatomy in patients with recurrent haematuria related to prostatic hypertrophy (BPH). J Urol, suppl., 161: 225, abstract 865, 1999 6. Franck-Lissbrant, I., Haggestrom, S., Damber, J.-E. et al: Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats. Endocrinology, 139: 451, 1998 7. Levine, A. C., Liu, X.-H., Greenberg, P. D. et al: Androgens induce the expression of vascular endothelial growth factors in human fetal prostatic fibroblasts. Endocrinology, 139: 4672, 1998 8. Bailey, D. M., Foley, S. J. and Wedderburn, A.: Effect of Finasteride on microvessel density (MVD) in patients with recurrent haematuria related to prostatic hypertrophy (BPH). J Urol, suppl., 161: 363, abstract 1406, 1999 9. Puchner, P. J. and Miller, M. I.: The effects of finasteride on hematuria associated with benign prostatic hyperplasia: a preliminary report. J Urol, 154: 1779, 1995 10. Miller, M. I. and Puchner, P. J.: Effects of finasteride on hematuria associated with benign prostatic hyperplasia—long term follow-up. Urology, 51: 237,1998 11. Carlin, B. I., Bodner, D. R., Spirnak, J. P. et al: Role of finasteride in the treatment of recurrent haematuria secondary to benign prostatic hyperplasia. Prostate, 31: 180, 1997 12. Sieber, P. R., Rommel, F. M., Huffnagle, H. W. et al: The treatment of gross hematuria secondary to prostatic bleeding with Finasteride. J Urol, 159: 1232, 1998 13. Kashif, K. M., Foley, S. J., Basketter, V. et al: Haematuria in
BPH-Natural history and a new treatment option. Prostate Cancer Prostate Dis, 1: 154, 1998 14. McConnell, J. D., Bruskewitz, R., Walsh, P. C. et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. New Engl J Med, 338: 557, 1998 EDITORIAL COMMENT To my knowledge this is the first randomized prospective study that demonstrates that finasteride therapy decreases the incidence of repeat bleeding in patients with BPH. Puchner et al were the first to report this beneficial effect of finasteride (reference 9 in article). In their report and all subsequent reports, including the current one, the finasteride effect on hematuria was rapid, more rapid than may reasonably be attributed to decreased prostate size due to apoptosis and/or decreased angiogenesis. BPH associated hematuria has been postulated to be due to the increased fragility of blood vessels in the suburothelial prostatic urethra secondary to increased pressure. Any treatment that decreases edema in the extravascular space would be expected to decrease intravascular pressure and the incidence of hematuria. We previously demonstrated that vascular endothelial growth factor, a potent angiogenic factor, is highly expressed in smooth muscle cells in BPH (reference 7 in article). In addition, we demonstrated that androgenic effects on vascular endothelial growth factor messenger RNA transcription and protein secretion are rapid, peaking at 2 and 4 hours, respectively, after androgen addition. Vascular endothelial growth factor was originally described as the vascular permeability factor and it is reported to be 50,000 times more potent than histamine in its ability to enhance vascular permeability.1 I postulate that the rapid decrease in hematuria associated with finasteride is due to rapid decreases in vascular endothelial growth factor-vascular permeability factor, which decrease vascular permeability and edema with a resultant decrease in intravascular pressure and vessel fragility. Alexander Kirschenbaum Department of Urology Mount Sinai Medical Center New York, New York 1. Senger, D. R., Galli, S. J., Dvorak, A. M. et al: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 219: 983, 1983