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The Effect of Terazosin on Functional Bladder Outlet Obstruction in Women: A Pilot Study
The Effect of Terazosin on Functional Bladder Outlet Obstruction in Women: A Pilot Study Thomas M. Kessler, Urs E. Studer and Fiona C. Burkhard* From the Department of Urology, University of Bern, Bern, Switzerland
Purpose: We assessed the effect of terazosin (Hytrin®) on functional bladder outlet obstruction in women. Materials and Methods: Functional bladder outlet obstruction was defined as a maximum flow rate of less than 12 ml per second combined with a detrusor pressure at maximum flow rate of more than 20 cm H2O in pressure flow studies in the absence of neurological disorders or mechanical causes. In a prospective pilot study 15 women with functional bladder outlet obstruction were treated with terazosin. Terazosin was initiated at 1 mg daily and gradually increased to the maintenance dose of 5 mg daily during 2 weeks. Symptoms and urodynamic parameters were assessed before and 3 to 4 weeks after the initiation of ␣-blocker therapy. Results: While on terazosin, voiding symptoms subjectively improved greater than 50% in 10 of the 15 women (p ⫽ 0.002). Median maximum urethral closure pressure at rest decreased significantly from 98 to 70 cm H2O (p ⫽ 0.001), median maximum detrusor pressure decreased from 45 to 35 cm H2O (p ⫽ 0.008), median detrusor pressure at maximum flow decreased from 34 to 27 ml per second and median post-void residual urine decreased from 120 to 40 ml (p ⫽ 0.006 and 0.002, respectively). There was a significant increase in the median maximum flow rate from 9 to 20 ml per second and in median voided volume from 300 to 340 ml (p ⫽ 0.0005 and 0.021, respectively). Storage symptoms, functional urethral length and maximum cystometric capacity did not change significantly with ␣-blocker therapy (p ⬎0.05). Overall terazosin resulted in a significant improvement in symptoms and urodynamic parameters in 10 of the 15 women (67%). Conclusions: Terazosin had a significant symptomatic and urodynamic effect in two-thirds of our patients. These results suggest that terazosin may be an effective treatment option in women with voiding dysfunction due to functional bladder outlet obstruction. Key Words: bladder, terazosine, bladder neck obstruction, female, urodynamics
lpha-blocker therapy is an established treatment for BOO due to prostatic enlargement in men. However, little is known about the effect of ␣-blockers in women. Kumar et al1 and more recently Pischedda et al2 reported significant improvement in symptoms, Qmax and PVR in 50% and 56%, respectively, of women with functional BOO. Thus, ␣-blockers may be an effective treatment option for female functional BOO. Considering that high intravesical pressure may put the upper urinary tract at risk, addressing the urodynamic effect of ␣-blockers, especially on detrusor pressure, becomes imperative. In a prospective pilot study we assessed the effect of terazosin (Hytrin®) on functional BOO in women.
A
PATIENTS AND METHODS Patients In this prospective pilot study 15 women who presented predominantly with voiding symptoms and functional BOO were included. Functional BOO was diagnosed if neurological disorders or mechanical causes were excluded and Qmax
Submitted for publication October 31, 2005. Presented at annual meeting of American Urological Association, San Antonio, Texas, May 21–26, 2005. * Correspondence: Department of Urology, University of Bern, 3010 Bern, Switzerland (telephone: 0041 31 632 36 41; FAX: 0041 31 632 21 81; e-mail: [email protected]).
0022-5347/06/1764-1487/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
was less than 12 ml per second, combined with PdetQmax more than 20 cm H2O in pressure flow studies, as initially described by Lemack and Zimmern.3 All patients were informed about the exact procedure and study purpose, and provided consent. Clinical and Urodynamic Assessment All patients underwent urological evaluation before treatment, including medical history, neurourological examination, urinalysis, urine culture, urethrocystoscopy, urethral diameter calibration, urodynamic studies, including pelvic floor electromyography in 9 that was combined with videourodynamics in 6 with inconclusive electromyographic activity, and magnetic resonance imaging to exclude spinal cord pathology. Urodynamic investigations were performed according to the good urodynamic practices recommended by the International Continence Society.4 The urodynamic parameters assessed were functional urethral length and MUCP, which were measured by a microtip catheter, maximum cystometric capacity, Pdet, PdetQmax, Qmax, VV and PVR. All methods, definitions and units conformed to the standards recommended by the International Continence Society.5
␣-Blocker Treatment Terazosin (Hytrin®) was initiated at 1 mg daily and gradually increased to the maintenance dose of 5 mg daily during
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Vol. 176, 1487-1492, October 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.06.009
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2 weeks. Voiding and storage symptoms, and urodynamic parameters were assessed before and 3 to 4 weeks after the initiation of ␣-blocker therapy.
Statistical Analysis Due to the skewed distribution of data nonparametric statistical tests were performed and data are presented as the median and IQR. To compare related samples the Wilcoxon signed rank test was used for quantitative data and the McNemar test was used for dichotomous data with p ⬍0.05 considered significant. Statistical analyses were performed using SPSS® 11.5.1.
RESULTS Median age in the 15 women was 33 years (IQR 26 to 46). All patients complained about voiding symptoms, including a slow or intermittent stream, hesitancy, straining and/or a feeling of incomplete emptying. In addition, 6 of the 15 women (40%) also had from storage symptoms, including increased daytime frequency, nocturia and/or urgency. Eight of the 15 women (53%) had a history of recurrent urinary tract infections but none had a urinary tract infection during the study period. The urodynamic study before and during ␣-blocker therapy was well tolerated by all patients. No investigation related complications were observed. However, 2 of the 15 women reported slight fatigue and 2 noticed modest dizziness during the first days of terazosin intake. None discontinued ␣-blocker therapy. While on terazosin, voiding symptoms subjectively improved greater than 50% in 10 of the 15 women (p ⫽ 0.002). Median MUCP decreased significantly from 98 to 70 cm H2O, median Pdetmax decreased from 45 to 35 cm H2O, median PdetQmax decreased from 34 to 27 ml per second and median PVR decreased from 120 to 40 ml (figs. 1 to 3). In addition, there was a significant increase in median Qmax from 9 to 20 ml per second and in median VV from 300 to 340 ml (fig. 4). Storage symptoms (6 vs 5 of the 15 patients, p ⫽ 0.99), functional urethral length (median 33 vs 34 mm, p ⫽ 0.21) and maximum cystometric capacity (median 450 vs 440 ml, p ⫽ 0.99) did not change significantly while on ␣-blocker therapy. Pelvic floor dysfunction was found in 2 of the 15 women, including increased electromyographic activity in 1 and radiographic evidence of urethral narrowing with proximal dilatation during voiding in 1. However, this remained unchanged on terazosin, although ␣-blocker therapy had a symptomatic and urodynamic effect in each patient. Of the 15 women 13 had no electromyographic or videourodynamic signs of pelvic floor dysfunction before or during ␣-blocker therapy. Overall while on terazosin, 10 of the 15 women (67%) had significant improvement in voiding symptoms, and in the urodynamic parameters MUCP, Pdetmax, PdetQmax, Qmax, VV and PVR. In the other 5 patients ␣-blocker therapy had no effect. In these women obstruction remained when applying our BOO criteria of Qmax less than 12 ml per second combined with PdetQmax more than 20 cm H2O on pressure flow studies.
FIG. 1
DISCUSSION Although BOO in women has traditionally been considered uncommon, recent studies suggest that it is an under diagnosed cause of female lower urinary tract symptoms with a prevalence of up to 29%6 in women undergoing urodynamic investigation. BOO can be classified as having a mechanical (anatomical) or functional (nonmechanical/nonanatomical) basis. In women mechanical causes include tumor, urethral stricture/bladder neck stenosis, urethral diverticulum, bladder calculus, urogenital prolapse and previous surgical intervention, especially anti-incontinence procedures. When there is a functional etiology, the pathophysiological mechanisms of female voiding dysfunction are poorly understood and no standard definitions or guidelines for diagnosis and treatment exist.7 Although the exact etiology of this entity remains unclear, it has been attributed to detrusor bladder neck and/or external sphincter dyssynergia, dysfunctional voiding, nonrelaxing urethral sphincter obstruction and intrinsic urethral sphincter overactivity, ie Fowler’s syndrome. In the current study functional BOO was diagnosed if neurological disorders or mechanical causes were excluded and Qmax was less than 12 ml per second, combined with PdetQmax more than 20 cm H2O in pressure flow studies, as described by Lemack and Zimmern.3 We are aware that the original study by Lemack and Zimmern included patients with anatomical (mechanical) obstruction. Nevertheless, this BOO definition was used, considering the lack of generally accepted criteria for diagnosing functional BOO uro-
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FIG. 2
dynamically and because this seemed applicable in our patients. However, it must be considered that the original BOO definition by Lemack and Zimmern was redefined in a followup study as Qmax less than 12 ml per second combined
FIG. 3
with PdetQmax more than 25 cm H2O on pressure flow studies.8 Since we started our study before that article was published, we did not adjust our initially defined functional BOO criteria to adhere to our study protocol and avoid a posteriori corrections of the prospective study design, even more since the redefined definitions of Defreitas et al are primarily applicable to anatomical but not to functional BOO.8 In addition, we did this because the urodynamic definition of BOO in females remains a matter of debate. Groutz and Blaivas suggested combining free Qmax (free flow study) with Pdetmax, as determined by pressure flow study.7 This avoids the adverse effect of the transurethral catheter on the urinary flow rate in pressure flow studies9 and allows the measurement of Pdetmax during an attempt to void, also in the absence of measurable urinary flow in patients in complete urinary retention,7 which is not possible for PdetQmax. In addition, separate analysis of PdetQmax revealed no significant difference compared to Pdetmax.7 In contrast, Nitti et al defined BOO in women based on radiographic evidence of obstruction between the bladder neck and distal urethra in the presence of a sustained detrusor contraction on videourodynamic studies.6 However, we believe that radiography is not necessary in all patients because patient history, clinical examination, urethral diameter calibration and cystoscopy can exclude mechanical (anatomical) causes in most patients. Especially in young women radiation should be avoided if possible and perineal ultrasound or magnetic resonance imaging can be performed if necessary. Cormier et al proposed that area under the detrusor pressure curve during voiding, adjusted for VV, would be the most discriminating urodynamic parameter for female BOO.10 However, clinical application remains limited due to a lack of standardization and clinical applicability. Although there is a lack of consensus in regard to the diagnosis of BOO in women, this was not relevant in
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TERAZOSIN AND FUNCTIONAL BLADDER OUTLET OBSTRUCTION IN WOMEN
FIG. 4
the current study since we compared results using the same investigation technique before and during ␣-blocker therapy. The therapeutic rationale of using ␣-blockers for functional BOO in women is based on certain data. The bladder neck and proximal urethra receive noradrenergic excitatory impulses from the sympathetic nervous system, originating in the spinal cord segments T10 to L2, and passing through the sympathetic chain ganglia and then via the hypogastric nerves to the pelvic ganglia in the rat.11 This sympathetic input is mediated by the release of noradrenalin stimulating ␣1-adrenergic receptors. A study in female and male rabbits compared the sex specific density and affinity of ␣1-adrenergic receptors and indicated no difference.12 Thus, similar ␣1-adrenergic mechanisms may be involved in the control of urethral tone in humans. Indeed, in vitro studies in human urethral tissue provided evidence that ␣-adrenergic receptors mediate contraction of the human urethra.13 This is underlined by the findings that ␣-agonists may improve the symptoms of stress urinary incontinence14 but clinical usefulness is limited by the side effects.15 In addition, in urodynamic experiments in healthy females the unspecific ␣-blocker prazosin decreased resting pressure, predominantly in the mid portion of the urethra,16 and tamsulosin induced significant urethral relaxation over the entire urethral length with a slightly stronger effect in the proximal and middle third.17 This may be explained by the fact that that selective ␣1A-blockers such as tamsulosin may be more effective than unselective ␣1-blockers17 because the ␣1A subtype is predominant in the urethra.18 However, animal experiments indicate that facilitatory ␣1-adrenergic receptors are tonically active along the sympathetic as well as the somatic reflex pathways.19 Thus, ␣1-blockers may decrease the dynamic component of obstruction through blockade of ␣1-
adrenergic receptors on urethral smooth muscle and by decreasing the activity of the sympathetic nerve fibers innervating the bladder neck and urethra. Additional therapeutic relief may be provided through a decrease in somatic neural activity to the external urethral sphincter, which might also decrease bladder outlet resistance. Therefore, an unselective ␣1-blocker may be more advantageous by relaxing not only the bladder neck and urethra, but also the external urethral sphincter. In addition, ␣-blockers have an effect on bladder outlet mechanism as well as on detrusor function. In a recent study a significant increase in contractile force to phenylephrine in patients with BOO compared with controls was noted, suggesting up-regulation of ␣1-adrenergic receptor function in BOO since contractile responses were potently inhibited by tamsulosin.20 Consequently symptomatic improvement in storage symptoms and a urodynamic decrease in detrusor pressure in patients with BOO treated with ␣-blocker seem to be partially caused by a direct effect on the detrusor and not only by decreased outlet resistance. In the current study terazosin resulted in significant improvement in voiding symptoms and urodynamic parameters in two-thirds of our patients. This is in line with the findings of Kumar1 and Pischedda2 et al, which showed an approximately 50% success rate of ␣-blockers for functional BOO in women based on symptoms, Qmax and PVR. Although there was a significant decrease in the current study in median Pdetmax from 45 to 35 cm H2O and in median PdetQmax from 34 to 27 ml per second, including the 5 patients in whom ␣-blocker therapy was not effective, detrusor pressure remained relatively high in women. Nevertheless, the upper urinary tract did not seem to be at risk since intravesical pressure was below the generally accepted cutoff of 40 cm H2O.
TERAZOSIN AND FUNCTIONAL BLADDER OUTLET OBSTRUCTION IN WOMEN However, it remains unclear why ␣-blockers may be effective in 1 woman but not in another. Differences in baseline characteristics, such as patients with vs without pelvic floor dysfunction, and in the underlying clinical pathology, such as undetected neurological disorders or mechanical causes, may be assumed. Considering the small number of patients, we performed no subanalysis due to the lack of statistical power to detect significant differences. Despite generally favorable results our study has limitations that should be addressed. Although changes in voiding and storage symptoms with ␣-blocker therapy were studied, the effect on quality of life was not assessed. Due to our definition criteria of functional BOO we may have missed women with functional BOO who were in complete urinary retention because of no measurable urinary flow. In addition, our findings are based on a relatively small number of patients. Moreover, our study has a nonrandomized design without a placebo control group. Although improvement in voiding symptoms and in urodynamic parameters while on terazosin was clearly noted in two-thirds of our patients, the clinical relevance (decreased incidence of urinary tract infections and decreased intravesical pressure and, therefore, decreased long-term detrusor and/or upper urinary tract damage) of these findings remains to be determined, especially in the long-term. Thus, considering the relatively low number of women with functional BOO a long-term, prospective, multicenter, double-blind, placebo controlled trial would be the ideal to further determine the efficacy of ␣-blockers in women. Despite the addressed limitations we strongly recommend ␣-blockers in women with functional BOO as first line therapy before more invasive treatment strategies are considered, such as intermittent self-catheterization, bladder neck incision, periurethral/sphincteric botulinum toxin injections or sacral neuromodulation.
REFERENCES 1.
2.
3.
4.
5.
6. 7. 8.
9.
10.
11.
CONCLUSIONS Terazosin had a significant symptomatic and urodynamic effect in two-thirds of our patients. These results suggest that terazosin may be an effective treatment option in women with voiding dysfunction due to functional BOO.
ACKNOWLEDGMENTS
12.
13.
14.
Statistical analyses were performed in collaboration with the Department of Mathematical Statistics, University of Bern, Bern, Switzerland. 15.
Abbreviations and Acronyms BOO ⫽ bladder outlet obstruction MUCP ⫽ maximum urethral closure pressure at rest Pdetmax ⫽ maximum detrusor pressure PdetQmax ⫽ detrusor pressure at Qmax PVR ⫽ post-void residual urine Qmax ⫽ maximum flow rate VV ⫽ voided volume
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16.
17.
Kumar, A., Mandhani, A., Gogoi, S. and Srivastava, A.: Management of functional bladder neck obstruction in women: use of alpha-blockers and pediatric resectoscope for bladder neck incision. J Urol, 162: 2061, 1999 Pischedda, A., Pirozzi Farina, F., Madonia, M., Cimino, S. and Morgia, G.: Use of alpha1-blockers in female functional bladder neck obstruction. Urol Int, 74: 256, 2005 Lemack, G. E. and Zimmern, P. E.: Pressure flow analysis may aid in identifying women with outflow obstruction. J Urol, 163: 1823, 2000 Schäfer, W., Abrams, P., Liao, L., Mattiasson, A., Pesce, F., Spangberg, A. et al: Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. Neurourol Urodyn, 21: 261, 2002 Abrams, P., Cardozo, L., Fall, M., Griffiths, D., Rosier, P., Ulmsten, U. et al: The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn, 21: 167, 2002 Nitti, V. W., Tu, L. M. and Gitlin, J.: Diagnosing bladder outlet obstruction in women. J Urol, 161: 1535, 1999 Groutz, A. and Blaivas, J. G.: Non-neurogenic female voiding dysfunction. Curr Opin Urol, 12: 311, 2002 Defreitas, G. A., Zimmern, P. E., Lemack, G. E. and Shariat, S. F.: Refining diagnosis of anatomic female bladder outlet obstruction: comparison of pressure-flow study parameters in clinically obstructed women with those of normal controls. Urology, 64: 675, 2004 Groutz, A., Blaivas, J. G. and Sassone, A. M.: Detrusor pressure uroflowmetry studies in women: effect of a 7Fr transurethral catheter. J Urol, 164: 109, 2000 Cormier, L., Ferchaud, J., Galas, J. M., Guillemin, F. and Mangin, P.: Diagnosis of female bladder outlet obstruction and relevance of the parameter area under the curve of detrusor pressure during voiding: preliminary results. J Urol, 167: 2083, 2002 Kihara, K. and de Groat, W. C.: Sympathetic efferent pathways projecting to the bladder neck and proximal urethra in the rat. J Auton Nerv Syst, 62: 134, 1997 Yablonsky, F., Riffaud, J. P., Lacolle, J. Y. and Dausse, J. P.: Alpha 1- and alpha 2-adrenoceptors in the smooth muscle of male and female rabbit urethra. Eur J Pharmacol, 121: 1, 1986 Taki, N., Taniguchi, T., Okada, K., Moriyama, N. and Muramatsu, I.: Evidence for predominant mediation of alpha1adrenoceptor in the tonus of entire urethra of women. J Urol, 162: 1829, 1999 Musselman, D. M., Ford, A. P., Gennevois, D. J., Harbison, M. L., Laurent, A. L., Mokatrin, A. S. et al: A randomized crossover study to evaluate Ro 115-1240, a selective alpha1A/1L-adrenoceptor partial agonist in women with stress urinary incontinence. BJU Int, 93: 78, 2004 Radley, S. C., Chapple, C. R., Bryan, N. P., Clarke, D. E. and Craig, D. A.: Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study. Neurourol Urodyn, 20: 43, 2001 Thind, P., Lose, G., Colstrup, H. and Andersson, K. E.: The effect of alpha-adrenoceptor stimulation and blockade on the static urethral sphincter function in healthy females. Scand J Urol Nephrol, 26: 219, 1992 Reitz, A., Haferkamp, A., Kyburz, T., Knapp, P. A., Wefer, B. and Schurch, B.: The effect of tamsulosin on the resting tone and the contractile behaviour of the female urethra: a
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functional urodynamic study in healthy women. Eur Urol, 46: 235, 2004 18. Testa, R., Guarneri, L., Ibba, M., Strada, G., Poggesi, E., Taddei, C. et al: Characterization of alpha 1-adrenoceptor subtypes in prostate and prostatic urethra of rat, rabbit, dog and man. Eur J Pharmacol, 249: 307, 1993 19. Danuser, H. and Thor, K. B.: Inhibition of central sympathetic and somatic outflow to the lower urinary tract of the cat by
20.
the alpha 1 adrenergic receptor antagonist prazosin. J Urol, 153: 1308, 1995 Bouchelouche, K., Andersen, L., Alvarez, S., Nordling, J. and Bouchelouche, P.: Increased contractile response to phenylephrine in detrusor of patients with bladder outlet obstruction: effect of the alpha1A and alpha1D-adrenergic receptor antagonist tamsulosin. J Urol, 173: 657, 2005
Purpose: We assessed the effect of terazosin (Hytrin®) on functional bladder outlet obstruction in women. Materials and Methods: Functional bladder outlet obstruction was defined as a maximum flow rate of less than 12 ml per second combined with a detrusor pressure at maximum flow rate of more than 20 cm H2O in pressure flow studies in the absence of neurological disorders or mechanical causes. In a prospective pilot study 15 women with functional bladder outlet obstruction were treated with terazosin. Terazosin was initiated at 1 mg daily and gradually increased to the maintenance dose of 5 mg daily during 2 weeks. Symptoms and urodynamic parameters were assessed before and 3 to 4 weeks after the initiation of ␣-blocker therapy. Results: While on terazosin, voiding symptoms subjectively improved greater than 50% in 10 of the 15 women (p ⫽ 0.002). Median maximum urethral closure pressure at rest decreased significantly from 98 to 70 cm H2O (p ⫽ 0.001), median maximum detrusor pressure decreased from 45 to 35 cm H2O (p ⫽ 0.008), median detrusor pressure at maximum flow decreased from 34 to 27 ml per second and median post-void residual urine decreased from 120 to 40 ml (p ⫽ 0.006 and 0.002, respectively). There was a significant increase in the median maximum flow rate from 9 to 20 ml per second and in median voided volume from 300 to 340 ml (p ⫽ 0.0005 and 0.021, respectively). Storage symptoms, functional urethral length and maximum cystometric capacity did not change significantly with ␣-blocker therapy (p ⬎0.05). Overall terazosin resulted in a significant improvement in symptoms and urodynamic parameters in 10 of the 15 women (67%). Conclusions: Terazosin had a significant symptomatic and urodynamic effect in two-thirds of our patients. These results suggest that terazosin may be an effective treatment option in women with voiding dysfunction due to functional bladder outlet obstruction. Key Words: bladder, terazosine, bladder neck obstruction, female, urodynamics
lpha-blocker therapy is an established treatment for BOO due to prostatic enlargement in men. However, little is known about the effect of ␣-blockers in women. Kumar et al1 and more recently Pischedda et al2 reported significant improvement in symptoms, Qmax and PVR in 50% and 56%, respectively, of women with functional BOO. Thus, ␣-blockers may be an effective treatment option for female functional BOO. Considering that high intravesical pressure may put the upper urinary tract at risk, addressing the urodynamic effect of ␣-blockers, especially on detrusor pressure, becomes imperative. In a prospective pilot study we assessed the effect of terazosin (Hytrin®) on functional BOO in women.
A
PATIENTS AND METHODS Patients In this prospective pilot study 15 women who presented predominantly with voiding symptoms and functional BOO were included. Functional BOO was diagnosed if neurological disorders or mechanical causes were excluded and Qmax
Submitted for publication October 31, 2005. Presented at annual meeting of American Urological Association, San Antonio, Texas, May 21–26, 2005. * Correspondence: Department of Urology, University of Bern, 3010 Bern, Switzerland (telephone: 0041 31 632 36 41; FAX: 0041 31 632 21 81; e-mail: [email protected]).
0022-5347/06/1764-1487/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
was less than 12 ml per second, combined with PdetQmax more than 20 cm H2O in pressure flow studies, as initially described by Lemack and Zimmern.3 All patients were informed about the exact procedure and study purpose, and provided consent. Clinical and Urodynamic Assessment All patients underwent urological evaluation before treatment, including medical history, neurourological examination, urinalysis, urine culture, urethrocystoscopy, urethral diameter calibration, urodynamic studies, including pelvic floor electromyography in 9 that was combined with videourodynamics in 6 with inconclusive electromyographic activity, and magnetic resonance imaging to exclude spinal cord pathology. Urodynamic investigations were performed according to the good urodynamic practices recommended by the International Continence Society.4 The urodynamic parameters assessed were functional urethral length and MUCP, which were measured by a microtip catheter, maximum cystometric capacity, Pdet, PdetQmax, Qmax, VV and PVR. All methods, definitions and units conformed to the standards recommended by the International Continence Society.5
␣-Blocker Treatment Terazosin (Hytrin®) was initiated at 1 mg daily and gradually increased to the maintenance dose of 5 mg daily during
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Vol. 176, 1487-1492, October 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.06.009
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2 weeks. Voiding and storage symptoms, and urodynamic parameters were assessed before and 3 to 4 weeks after the initiation of ␣-blocker therapy.
Statistical Analysis Due to the skewed distribution of data nonparametric statistical tests were performed and data are presented as the median and IQR. To compare related samples the Wilcoxon signed rank test was used for quantitative data and the McNemar test was used for dichotomous data with p ⬍0.05 considered significant. Statistical analyses were performed using SPSS® 11.5.1.
RESULTS Median age in the 15 women was 33 years (IQR 26 to 46). All patients complained about voiding symptoms, including a slow or intermittent stream, hesitancy, straining and/or a feeling of incomplete emptying. In addition, 6 of the 15 women (40%) also had from storage symptoms, including increased daytime frequency, nocturia and/or urgency. Eight of the 15 women (53%) had a history of recurrent urinary tract infections but none had a urinary tract infection during the study period. The urodynamic study before and during ␣-blocker therapy was well tolerated by all patients. No investigation related complications were observed. However, 2 of the 15 women reported slight fatigue and 2 noticed modest dizziness during the first days of terazosin intake. None discontinued ␣-blocker therapy. While on terazosin, voiding symptoms subjectively improved greater than 50% in 10 of the 15 women (p ⫽ 0.002). Median MUCP decreased significantly from 98 to 70 cm H2O, median Pdetmax decreased from 45 to 35 cm H2O, median PdetQmax decreased from 34 to 27 ml per second and median PVR decreased from 120 to 40 ml (figs. 1 to 3). In addition, there was a significant increase in median Qmax from 9 to 20 ml per second and in median VV from 300 to 340 ml (fig. 4). Storage symptoms (6 vs 5 of the 15 patients, p ⫽ 0.99), functional urethral length (median 33 vs 34 mm, p ⫽ 0.21) and maximum cystometric capacity (median 450 vs 440 ml, p ⫽ 0.99) did not change significantly while on ␣-blocker therapy. Pelvic floor dysfunction was found in 2 of the 15 women, including increased electromyographic activity in 1 and radiographic evidence of urethral narrowing with proximal dilatation during voiding in 1. However, this remained unchanged on terazosin, although ␣-blocker therapy had a symptomatic and urodynamic effect in each patient. Of the 15 women 13 had no electromyographic or videourodynamic signs of pelvic floor dysfunction before or during ␣-blocker therapy. Overall while on terazosin, 10 of the 15 women (67%) had significant improvement in voiding symptoms, and in the urodynamic parameters MUCP, Pdetmax, PdetQmax, Qmax, VV and PVR. In the other 5 patients ␣-blocker therapy had no effect. In these women obstruction remained when applying our BOO criteria of Qmax less than 12 ml per second combined with PdetQmax more than 20 cm H2O on pressure flow studies.
FIG. 1
DISCUSSION Although BOO in women has traditionally been considered uncommon, recent studies suggest that it is an under diagnosed cause of female lower urinary tract symptoms with a prevalence of up to 29%6 in women undergoing urodynamic investigation. BOO can be classified as having a mechanical (anatomical) or functional (nonmechanical/nonanatomical) basis. In women mechanical causes include tumor, urethral stricture/bladder neck stenosis, urethral diverticulum, bladder calculus, urogenital prolapse and previous surgical intervention, especially anti-incontinence procedures. When there is a functional etiology, the pathophysiological mechanisms of female voiding dysfunction are poorly understood and no standard definitions or guidelines for diagnosis and treatment exist.7 Although the exact etiology of this entity remains unclear, it has been attributed to detrusor bladder neck and/or external sphincter dyssynergia, dysfunctional voiding, nonrelaxing urethral sphincter obstruction and intrinsic urethral sphincter overactivity, ie Fowler’s syndrome. In the current study functional BOO was diagnosed if neurological disorders or mechanical causes were excluded and Qmax was less than 12 ml per second, combined with PdetQmax more than 20 cm H2O in pressure flow studies, as described by Lemack and Zimmern.3 We are aware that the original study by Lemack and Zimmern included patients with anatomical (mechanical) obstruction. Nevertheless, this BOO definition was used, considering the lack of generally accepted criteria for diagnosing functional BOO uro-
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FIG. 2
dynamically and because this seemed applicable in our patients. However, it must be considered that the original BOO definition by Lemack and Zimmern was redefined in a followup study as Qmax less than 12 ml per second combined
FIG. 3
with PdetQmax more than 25 cm H2O on pressure flow studies.8 Since we started our study before that article was published, we did not adjust our initially defined functional BOO criteria to adhere to our study protocol and avoid a posteriori corrections of the prospective study design, even more since the redefined definitions of Defreitas et al are primarily applicable to anatomical but not to functional BOO.8 In addition, we did this because the urodynamic definition of BOO in females remains a matter of debate. Groutz and Blaivas suggested combining free Qmax (free flow study) with Pdetmax, as determined by pressure flow study.7 This avoids the adverse effect of the transurethral catheter on the urinary flow rate in pressure flow studies9 and allows the measurement of Pdetmax during an attempt to void, also in the absence of measurable urinary flow in patients in complete urinary retention,7 which is not possible for PdetQmax. In addition, separate analysis of PdetQmax revealed no significant difference compared to Pdetmax.7 In contrast, Nitti et al defined BOO in women based on radiographic evidence of obstruction between the bladder neck and distal urethra in the presence of a sustained detrusor contraction on videourodynamic studies.6 However, we believe that radiography is not necessary in all patients because patient history, clinical examination, urethral diameter calibration and cystoscopy can exclude mechanical (anatomical) causes in most patients. Especially in young women radiation should be avoided if possible and perineal ultrasound or magnetic resonance imaging can be performed if necessary. Cormier et al proposed that area under the detrusor pressure curve during voiding, adjusted for VV, would be the most discriminating urodynamic parameter for female BOO.10 However, clinical application remains limited due to a lack of standardization and clinical applicability. Although there is a lack of consensus in regard to the diagnosis of BOO in women, this was not relevant in
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TERAZOSIN AND FUNCTIONAL BLADDER OUTLET OBSTRUCTION IN WOMEN
FIG. 4
the current study since we compared results using the same investigation technique before and during ␣-blocker therapy. The therapeutic rationale of using ␣-blockers for functional BOO in women is based on certain data. The bladder neck and proximal urethra receive noradrenergic excitatory impulses from the sympathetic nervous system, originating in the spinal cord segments T10 to L2, and passing through the sympathetic chain ganglia and then via the hypogastric nerves to the pelvic ganglia in the rat.11 This sympathetic input is mediated by the release of noradrenalin stimulating ␣1-adrenergic receptors. A study in female and male rabbits compared the sex specific density and affinity of ␣1-adrenergic receptors and indicated no difference.12 Thus, similar ␣1-adrenergic mechanisms may be involved in the control of urethral tone in humans. Indeed, in vitro studies in human urethral tissue provided evidence that ␣-adrenergic receptors mediate contraction of the human urethra.13 This is underlined by the findings that ␣-agonists may improve the symptoms of stress urinary incontinence14 but clinical usefulness is limited by the side effects.15 In addition, in urodynamic experiments in healthy females the unspecific ␣-blocker prazosin decreased resting pressure, predominantly in the mid portion of the urethra,16 and tamsulosin induced significant urethral relaxation over the entire urethral length with a slightly stronger effect in the proximal and middle third.17 This may be explained by the fact that that selective ␣1A-blockers such as tamsulosin may be more effective than unselective ␣1-blockers17 because the ␣1A subtype is predominant in the urethra.18 However, animal experiments indicate that facilitatory ␣1-adrenergic receptors are tonically active along the sympathetic as well as the somatic reflex pathways.19 Thus, ␣1-blockers may decrease the dynamic component of obstruction through blockade of ␣1-
adrenergic receptors on urethral smooth muscle and by decreasing the activity of the sympathetic nerve fibers innervating the bladder neck and urethra. Additional therapeutic relief may be provided through a decrease in somatic neural activity to the external urethral sphincter, which might also decrease bladder outlet resistance. Therefore, an unselective ␣1-blocker may be more advantageous by relaxing not only the bladder neck and urethra, but also the external urethral sphincter. In addition, ␣-blockers have an effect on bladder outlet mechanism as well as on detrusor function. In a recent study a significant increase in contractile force to phenylephrine in patients with BOO compared with controls was noted, suggesting up-regulation of ␣1-adrenergic receptor function in BOO since contractile responses were potently inhibited by tamsulosin.20 Consequently symptomatic improvement in storage symptoms and a urodynamic decrease in detrusor pressure in patients with BOO treated with ␣-blocker seem to be partially caused by a direct effect on the detrusor and not only by decreased outlet resistance. In the current study terazosin resulted in significant improvement in voiding symptoms and urodynamic parameters in two-thirds of our patients. This is in line with the findings of Kumar1 and Pischedda2 et al, which showed an approximately 50% success rate of ␣-blockers for functional BOO in women based on symptoms, Qmax and PVR. Although there was a significant decrease in the current study in median Pdetmax from 45 to 35 cm H2O and in median PdetQmax from 34 to 27 ml per second, including the 5 patients in whom ␣-blocker therapy was not effective, detrusor pressure remained relatively high in women. Nevertheless, the upper urinary tract did not seem to be at risk since intravesical pressure was below the generally accepted cutoff of 40 cm H2O.
TERAZOSIN AND FUNCTIONAL BLADDER OUTLET OBSTRUCTION IN WOMEN However, it remains unclear why ␣-blockers may be effective in 1 woman but not in another. Differences in baseline characteristics, such as patients with vs without pelvic floor dysfunction, and in the underlying clinical pathology, such as undetected neurological disorders or mechanical causes, may be assumed. Considering the small number of patients, we performed no subanalysis due to the lack of statistical power to detect significant differences. Despite generally favorable results our study has limitations that should be addressed. Although changes in voiding and storage symptoms with ␣-blocker therapy were studied, the effect on quality of life was not assessed. Due to our definition criteria of functional BOO we may have missed women with functional BOO who were in complete urinary retention because of no measurable urinary flow. In addition, our findings are based on a relatively small number of patients. Moreover, our study has a nonrandomized design without a placebo control group. Although improvement in voiding symptoms and in urodynamic parameters while on terazosin was clearly noted in two-thirds of our patients, the clinical relevance (decreased incidence of urinary tract infections and decreased intravesical pressure and, therefore, decreased long-term detrusor and/or upper urinary tract damage) of these findings remains to be determined, especially in the long-term. Thus, considering the relatively low number of women with functional BOO a long-term, prospective, multicenter, double-blind, placebo controlled trial would be the ideal to further determine the efficacy of ␣-blockers in women. Despite the addressed limitations we strongly recommend ␣-blockers in women with functional BOO as first line therapy before more invasive treatment strategies are considered, such as intermittent self-catheterization, bladder neck incision, periurethral/sphincteric botulinum toxin injections or sacral neuromodulation.
REFERENCES 1.
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CONCLUSIONS Terazosin had a significant symptomatic and urodynamic effect in two-thirds of our patients. These results suggest that terazosin may be an effective treatment option in women with voiding dysfunction due to functional BOO.
ACKNOWLEDGMENTS
12.
13.
14.
Statistical analyses were performed in collaboration with the Department of Mathematical Statistics, University of Bern, Bern, Switzerland. 15.
Abbreviations and Acronyms BOO ⫽ bladder outlet obstruction MUCP ⫽ maximum urethral closure pressure at rest Pdetmax ⫽ maximum detrusor pressure PdetQmax ⫽ detrusor pressure at Qmax PVR ⫽ post-void residual urine Qmax ⫽ maximum flow rate VV ⫽ voided volume
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