- Email: [email protected]
Conservative Treatment of Female Stress Incontinence with Imipramine
0022· 584 'i' /24/1325-0909$02.CO/G Vol. 132 1 ~Jovernbe:'
THE JOURNAL OF UROLOGY
Print2d in U.S.A..
Copyright© 1934 ·oy ':'he Vlilharr1s & \.1/ilkins Co.
CONSERVATIVE TREAT1VIENT OF FEI\1ALE STRESS INCONTINENCE WITH: IMIPRAMINE IVAN GILJA, MARJAN RADEJ, MARIJAN KOVACIC AND JOSIP PARAZAJDER From the Department of Urology, General Hospital "Dr. Josip Kajfes", Zagreb, Yugoslavia
ABSTRACT
The results of a clinical study of conservative treatment of women with stress incontinence are presented. A daily dose of 75 mg. imipramine hydrochloride was given for 4 weeks. Special attention was paid to the effects of imipramine on the functional urethral length and maximum urethral closure pressure. A total of 21 women (71 per cent) stated that they were continent after treatment with imipramine, while 9 (29 per cent) did not improve and treatment was stopped. According to our results, imipramine extended the functional urethral length and made it independent of stress factors in women who were continent after treatment with imipramine. In patients with persistent incontinence the functional urethral length was extended significantly but was shortened with stress despite imipramine therapy. We believe that imipramine could be an alternative treatment in selected cases with stress incontinence. Experimental and clinical evidence demonstrated the importance of sympathetic innervation of the vesical neck and proximal urethra. 1- 4 Clinical studies have shown that the function of the bladder neck and urethra during pathological conditions can be altered by sympathomimetic agents and a-adrenergic blocking drugs, 5 ' 6 The effects of sympathomimetics 7- 9 and {:/-blocking agents 10 in the treatment of stress incontinence have been described previously. We present our experience with imipramine, an aadrenergic agonist 11 - 13 with an anticholinomimetic effect,1 4 in the treatment of female stress incontinence. Special attention was paid to the effects of imipramine on functional urethral length and maximum urethral closure pressure. PATIENTS AND METHODS
Cystometric investigation of the bladder and urethral pressure profiles were done on 30 women with stress incontinence before and after imipramine treatment. Patient age ranged from 28 to 64 years, The daily dose of medication was 75 mg. for 4 weeks. Diagnosis of stress incontinence was established on the basis of typical history of disease, decrease of urethral length with the patient in the upright position and straining, and normal cystometric findings with the patient in the supine and upright positions. All patients suspected of having concomitant urge incontinence were excluded from this investigation. Criteria for exclusion were a hyperreflexic cystometric pattern, stress vesical AH hyperreflexia and diminished bladder -w,~,-·v, ( <200 patients who had undergone a previous g-ynecological or urological operation for correction of stress incontinence also were excluded. Cystometry was performed with an 18F Foley balloon catheter inserted in the bladder per urethram. The catheter was connected to a 3-way stopcock and then to a Datascope recording and monitoring system via a physiological transducer. The perfusion rate was 40 ml. saline per minute. After cystometry the bladder was emptied and urethral pressure profile studies were performed according to the technique of Brown and Wickham. 15 The pressure profiles were obtained with an 8F catheter with a single side hole 2 cm. from the tip. The procedure was performed with the patient in the lithotomy position without stress (in the relaxed passive state with no attempt by the patient to void) and in the sitting position with stress (continuous straining). The catheter was pulled through Accepted for publication May 25, 1984. 909
the urethra at a rate of 1 mm. per second with a mechanical pullet. Sterile saline was infused at a rate of 4 ml. per minute. Pressures were measured on a Datascope recording and monitoring system. Paper speed was 1 mm. per second. RESULT§
As a result of treatment with imipramine 21 women (71 per cent) stated that they were continent, while 9 (29 per cent) did not improve and treatment was stopped. Since clinical evaluation of treatment effects was based mainly on the subjective feelings of the patient measurements of functional urethral length and maximum urethral closure pressure served as an objective control. 16 Table 1 demonstrates values of functional urethral length in all 30 women before and after treatment with imipramine. Statistical significance was tested with the paired t test. Generally, the over-all functional urethral length was increased significantly after treatment with imipramine (p <0.01). When the 21 continent women were analyzed more closely it was evident that the functional urethral length not only was extended but also fixed (no shortening or lengthening with stress) (table 2). When measured with the patient in the lithotomy position and the bladder empty the functional urethral length did not differ from that obtained in healthy women, 17 • 18 while under conditions of stress the functional urethral length was shortened significantly (32A6 ± 6.69 versus 28.34 ± 6.14 mm., respectively). per cent) who were incontinent In the remaining 9 women despite imipramine administration the functional urethral length was increased significantly (p but was shortened with stress. Table 3 demonstrates the values regarding the maximum urethral closure pressure before and after imipramine treatment. The maximum urethral closure pressure increased significantly after treatment (p <0.01). In addition, the maximum urethral closure pressure increased markedly in all women regardless of whether they were continent or remained incontinent after treatment. Side effects, such as momentary nausea and insomnia, were recorded in 2 women (6.6 per cent). DISCUSSION
We summarize our initial experience with nonoperative management of female stress incontinence. Our results with imipramine in the treatment of stress incontinence are similar to
910
GILJA AND ASSOCIATES
TABLE 1. Results of functional urethral length measurements in 30 women with stress incontinence before and after imipramine therapy
Imipramine (mm.)
Controls (mm.) Pt. No.
Supine Position (no stress)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
22 15 30 26 32 33 30 29 24 32 28 35 34 32 30 40 30 39 35 39 39
22 23 24 25 26 27 28 29 30
40 35 34 32 28 26 42 50 38
Sitting Position (straining)
Sitting Position (straining)
Supine Position (no stress)
Continent, 21 pts. 20 12 28 24 28 30 26 23 22 28 19 33 27 30 28 38 28 36 30 36 36
34 40 34 34 35 37 38 34 34 40 36 35 34 32 30 37 29 38 35 40 39
34 40 34 34 35 37 38 34 34 40 36 35 34 32 30 37 29 38 35 40 39
40 35 40 35 34 28 42 50 38
36 32 35 28 32 26 38 44 36
Incontinent, 9 pts.
TABLE 2.
36 32 31 25 26 22 35 39 36
Effects of imipramine on functional urethral length in patients with stress incontinence
TABLE 3.
Maximum urethral closure pressure before and after imipramine therapy
Pt. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Mean ± standard deviation
Control (mm.Hg)
Imipramine (mm. Hg) 52 54 48 44 38 36 57 36 42 43 45 62 58 57 45 42 36 43 40 46 56 57 48 48 61 62 45 46 48 62 48.23 ± 8.67
40 36 36 30 28 20 42 24 26 31 38 44 46 40 33 30 22 22 28 36 38 40 40 32 46 38 30 28 36 42 34.06 ± 7.29 p <0.01
thral length was increased owing to imipramine in 9 patients who still were incontinent. However, during stress the functional urethral length was shortened. This effect might be owing to insufficient stimulation of a-receptors of the bladder neck.
Functional Urethral Length (mm.)* No. Pts. Continentt Incontinent+ Totalst
21 9
30
Controls
Imipramine
REFERENCES
No Stress
Stress
No Stress
Stress
1. Todd, J. K. and Mack, A. J.: A study of human bladder detrusor
30.90 ± 5.88 36.11 ± 7.38 32.46 ± 6.69
27.42 ± 6.10 31.33 ± 5.83 28.34 ± 6.14
35.41 ± 3.07 38.00 ± 6.14 36.23 ± 4.28
35.41 ± 3.07 34.11 ± 5.39 35.09 ± 3.86
muscle. Brit. J. Urol., 41: 448, 1969. 2. Awad, S. A., Bruce, A. W., Carro-Ciampi, G., Downie, J. W. and Lin, M.: Distribution of a- and /3-adrenoceptors in human urinary bladder. Brit. J. Pharm., 50: 525, 1974. 3. Benson, G. S., Wein, A. J., Raezer, D. M. and Corriere, J. N., Jr.: Adrenergic and cholinergic stimulation and blockade of the human bladder base. J. Urol., 116: 174, 1976. 4. Nergardh, A. and Boreus, L. 0.: Autonomic receptor function in the lower urinary tract of man and cat. Scand. J. Urol. Nephrol., 6: 32, 1972. 5. Kleeman, F. J.: The physiology of the internal urinary sphincter. J. Urol., 104: 549, 1970. 6. Stockamp, K. and Schreiter, F.: Alpha-adrenolytic treatment of the congenital neuropathic bladder. Urol. Int., 30: 33, 1975. 7. Diokno, A. C. and Taub, M.: Ephedrine in the treatment of urinary incontinence. Urology, 5: 624, 1975. 8. Stewart, H. B., Banowsky, L. H. W. and Montague, D. K.: Stress incontinence: conservative therapy with sympathomimetic drugs. J. Urol., 115: 558, 1976. 9. Jonas, D.: Treatment offemale stress incontinence with midodrine: preliminary report. J. Urol., 118: 980, 1977. 10. Gleason, D. M., Reilly, R. J., Bottaccini, M. R. and Pierce, M. J.: The urethral continence zone and its relation to stress incontinence. J. Urol., 112: 81, 1974. 11. Sigg, E. B.: Pharmacological studies with tofranil. Canad. Psychiat. Ass. J., suppl., 4: 75, 1959. 12. Castleden, C. M., George, C. F., Renwick, A. G. and Asher, M. J.: Imipramine-a possible alternative to current therapy for urinary incontinence in the elderly. J. Urol., 125: 318, 1981. 13. Axelrod, J., Whitby, L. G. and Hertting, G.: Effect of psychotropic drugs on the uptake of H 3-norepinephrine by tissues. Science, 133: 383, 1961.
* Mean ± standard deviation. t p <0.01. +P <0.05.
findings with ephedrine,7 phenylpropanolamine8 and dimethoxybetahydroxyphenthylglycinamide. 9 Although our results should be considered preliminary it seems that they justify the more extensive application of sympathomimetic drugs, that is imipramine, in the treatment of women with stress incontinence. Our study confirms that imipramine extends the functional urethral length and makes it independent of stress factors in women who are continent after treatment with imipramine. Furthermore, these observations support the view that a shortened urethra leads to urinary incontinence and lengthening of the urethra by imipramine or vesicopexy will correct the dysfunction. 19 The increase in functional urethral length might be caused by imipramine stimulation of the a-adrenergic receptors of the bladder neck and proximal urethra but such a statement should be proved objectively. Since the maximum urethral closure pressure increased owing to imipramine in all women, regardless of whether they were continent or still incontinent after imipramine administration, the external urethral sphincter might have a secondary role in the female continence mechanism. The functional ure-
911
TREATMENT OF FEMALE STRESS INCONTINENCE VVITH IMIPRAMl_NE 14. Labay, P. and Boyarsky, S.: The action of imipramine on the bladder musculature. J. Urol., 109: 385, 1973. 15. Brown, M. and Wickham, J. E. A.: The urethral pressure profile. Brit. J. Ural., 41: 211, 1969. 16. Bates, P., Bradley, W. E., Glen, E., Griffiths, D., Melchior, H., Rowan, F., Sterling, A., Zinner, N. and Hald, T.: The standardization of terminology of lower urinary tract function. J. Urol., 121: 551, 1979. 17. Plante, P. and Susset, J.: Studies of female urethral pressure profile. Part I. The normal urethral pressure profile. J. Urol., 123: 64, 1980. 18. Susset, J. and Plante, P.: Studies of female urethral pressure profile. Part II. Urethral pressure profile in female incontinence. J. Urol., 123: 70, 1980. 19. Lapides, J., Ajemian, E. P., Stewart, B. H., Lichtwardt, J. R. and Breakey, B. A.: Physiopathology of stress incontinence. Surg., Gynec. & Obst., 111: 224, 1960.
EDITORIAL COMMENT These results of the treatment of women with stress incontinence with imipramine hydrochloride are somewhat difficult for me to accept. My own experience with elderly women and this agent, usually in combination with estrogens, has been reasonably good but not as good as reported in this article. Furthermore, the reported values for functional urethral length and for maximum urethral closure pressure are dramatically changed after imipramine therapy. These values are somewhat difficult to reconcile with my own data accumulated during the years. Nevertheless, a double-blind, controlled study of tricyclic antidepressants in women with stress incontinence should be done to confirm these results.
Edward J. McGuire Department of Urology University Hospitals Ann Arbor, Michigan
THE JOURNAL OF UROLOGY
Print2d in U.S.A..
Copyright© 1934 ·oy ':'he Vlilharr1s & \.1/ilkins Co.
CONSERVATIVE TREAT1VIENT OF FEI\1ALE STRESS INCONTINENCE WITH: IMIPRAMINE IVAN GILJA, MARJAN RADEJ, MARIJAN KOVACIC AND JOSIP PARAZAJDER From the Department of Urology, General Hospital "Dr. Josip Kajfes", Zagreb, Yugoslavia
ABSTRACT
The results of a clinical study of conservative treatment of women with stress incontinence are presented. A daily dose of 75 mg. imipramine hydrochloride was given for 4 weeks. Special attention was paid to the effects of imipramine on the functional urethral length and maximum urethral closure pressure. A total of 21 women (71 per cent) stated that they were continent after treatment with imipramine, while 9 (29 per cent) did not improve and treatment was stopped. According to our results, imipramine extended the functional urethral length and made it independent of stress factors in women who were continent after treatment with imipramine. In patients with persistent incontinence the functional urethral length was extended significantly but was shortened with stress despite imipramine therapy. We believe that imipramine could be an alternative treatment in selected cases with stress incontinence. Experimental and clinical evidence demonstrated the importance of sympathetic innervation of the vesical neck and proximal urethra. 1- 4 Clinical studies have shown that the function of the bladder neck and urethra during pathological conditions can be altered by sympathomimetic agents and a-adrenergic blocking drugs, 5 ' 6 The effects of sympathomimetics 7- 9 and {:/-blocking agents 10 in the treatment of stress incontinence have been described previously. We present our experience with imipramine, an aadrenergic agonist 11 - 13 with an anticholinomimetic effect,1 4 in the treatment of female stress incontinence. Special attention was paid to the effects of imipramine on functional urethral length and maximum urethral closure pressure. PATIENTS AND METHODS
Cystometric investigation of the bladder and urethral pressure profiles were done on 30 women with stress incontinence before and after imipramine treatment. Patient age ranged from 28 to 64 years, The daily dose of medication was 75 mg. for 4 weeks. Diagnosis of stress incontinence was established on the basis of typical history of disease, decrease of urethral length with the patient in the upright position and straining, and normal cystometric findings with the patient in the supine and upright positions. All patients suspected of having concomitant urge incontinence were excluded from this investigation. Criteria for exclusion were a hyperreflexic cystometric pattern, stress vesical AH hyperreflexia and diminished bladder -w,~,-·v, ( <200 patients who had undergone a previous g-ynecological or urological operation for correction of stress incontinence also were excluded. Cystometry was performed with an 18F Foley balloon catheter inserted in the bladder per urethram. The catheter was connected to a 3-way stopcock and then to a Datascope recording and monitoring system via a physiological transducer. The perfusion rate was 40 ml. saline per minute. After cystometry the bladder was emptied and urethral pressure profile studies were performed according to the technique of Brown and Wickham. 15 The pressure profiles were obtained with an 8F catheter with a single side hole 2 cm. from the tip. The procedure was performed with the patient in the lithotomy position without stress (in the relaxed passive state with no attempt by the patient to void) and in the sitting position with stress (continuous straining). The catheter was pulled through Accepted for publication May 25, 1984. 909
the urethra at a rate of 1 mm. per second with a mechanical pullet. Sterile saline was infused at a rate of 4 ml. per minute. Pressures were measured on a Datascope recording and monitoring system. Paper speed was 1 mm. per second. RESULT§
As a result of treatment with imipramine 21 women (71 per cent) stated that they were continent, while 9 (29 per cent) did not improve and treatment was stopped. Since clinical evaluation of treatment effects was based mainly on the subjective feelings of the patient measurements of functional urethral length and maximum urethral closure pressure served as an objective control. 16 Table 1 demonstrates values of functional urethral length in all 30 women before and after treatment with imipramine. Statistical significance was tested with the paired t test. Generally, the over-all functional urethral length was increased significantly after treatment with imipramine (p <0.01). When the 21 continent women were analyzed more closely it was evident that the functional urethral length not only was extended but also fixed (no shortening or lengthening with stress) (table 2). When measured with the patient in the lithotomy position and the bladder empty the functional urethral length did not differ from that obtained in healthy women, 17 • 18 while under conditions of stress the functional urethral length was shortened significantly (32A6 ± 6.69 versus 28.34 ± 6.14 mm., respectively). per cent) who were incontinent In the remaining 9 women despite imipramine administration the functional urethral length was increased significantly (p but was shortened with stress. Table 3 demonstrates the values regarding the maximum urethral closure pressure before and after imipramine treatment. The maximum urethral closure pressure increased significantly after treatment (p <0.01). In addition, the maximum urethral closure pressure increased markedly in all women regardless of whether they were continent or remained incontinent after treatment. Side effects, such as momentary nausea and insomnia, were recorded in 2 women (6.6 per cent). DISCUSSION
We summarize our initial experience with nonoperative management of female stress incontinence. Our results with imipramine in the treatment of stress incontinence are similar to
910
GILJA AND ASSOCIATES
TABLE 1. Results of functional urethral length measurements in 30 women with stress incontinence before and after imipramine therapy
Imipramine (mm.)
Controls (mm.) Pt. No.
Supine Position (no stress)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
22 15 30 26 32 33 30 29 24 32 28 35 34 32 30 40 30 39 35 39 39
22 23 24 25 26 27 28 29 30
40 35 34 32 28 26 42 50 38
Sitting Position (straining)
Sitting Position (straining)
Supine Position (no stress)
Continent, 21 pts. 20 12 28 24 28 30 26 23 22 28 19 33 27 30 28 38 28 36 30 36 36
34 40 34 34 35 37 38 34 34 40 36 35 34 32 30 37 29 38 35 40 39
34 40 34 34 35 37 38 34 34 40 36 35 34 32 30 37 29 38 35 40 39
40 35 40 35 34 28 42 50 38
36 32 35 28 32 26 38 44 36
Incontinent, 9 pts.
TABLE 2.
36 32 31 25 26 22 35 39 36
Effects of imipramine on functional urethral length in patients with stress incontinence
TABLE 3.
Maximum urethral closure pressure before and after imipramine therapy
Pt. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Mean ± standard deviation
Control (mm.Hg)
Imipramine (mm. Hg) 52 54 48 44 38 36 57 36 42 43 45 62 58 57 45 42 36 43 40 46 56 57 48 48 61 62 45 46 48 62 48.23 ± 8.67
40 36 36 30 28 20 42 24 26 31 38 44 46 40 33 30 22 22 28 36 38 40 40 32 46 38 30 28 36 42 34.06 ± 7.29 p <0.01
thral length was increased owing to imipramine in 9 patients who still were incontinent. However, during stress the functional urethral length was shortened. This effect might be owing to insufficient stimulation of a-receptors of the bladder neck.
Functional Urethral Length (mm.)* No. Pts. Continentt Incontinent+ Totalst
21 9
30
Controls
Imipramine
REFERENCES
No Stress
Stress
No Stress
Stress
1. Todd, J. K. and Mack, A. J.: A study of human bladder detrusor
30.90 ± 5.88 36.11 ± 7.38 32.46 ± 6.69
27.42 ± 6.10 31.33 ± 5.83 28.34 ± 6.14
35.41 ± 3.07 38.00 ± 6.14 36.23 ± 4.28
35.41 ± 3.07 34.11 ± 5.39 35.09 ± 3.86
muscle. Brit. J. Urol., 41: 448, 1969. 2. Awad, S. A., Bruce, A. W., Carro-Ciampi, G., Downie, J. W. and Lin, M.: Distribution of a- and /3-adrenoceptors in human urinary bladder. Brit. J. Pharm., 50: 525, 1974. 3. Benson, G. S., Wein, A. J., Raezer, D. M. and Corriere, J. N., Jr.: Adrenergic and cholinergic stimulation and blockade of the human bladder base. J. Urol., 116: 174, 1976. 4. Nergardh, A. and Boreus, L. 0.: Autonomic receptor function in the lower urinary tract of man and cat. Scand. J. Urol. Nephrol., 6: 32, 1972. 5. Kleeman, F. J.: The physiology of the internal urinary sphincter. J. Urol., 104: 549, 1970. 6. Stockamp, K. and Schreiter, F.: Alpha-adrenolytic treatment of the congenital neuropathic bladder. Urol. Int., 30: 33, 1975. 7. Diokno, A. C. and Taub, M.: Ephedrine in the treatment of urinary incontinence. Urology, 5: 624, 1975. 8. Stewart, H. B., Banowsky, L. H. W. and Montague, D. K.: Stress incontinence: conservative therapy with sympathomimetic drugs. J. Urol., 115: 558, 1976. 9. Jonas, D.: Treatment offemale stress incontinence with midodrine: preliminary report. J. Urol., 118: 980, 1977. 10. Gleason, D. M., Reilly, R. J., Bottaccini, M. R. and Pierce, M. J.: The urethral continence zone and its relation to stress incontinence. J. Urol., 112: 81, 1974. 11. Sigg, E. B.: Pharmacological studies with tofranil. Canad. Psychiat. Ass. J., suppl., 4: 75, 1959. 12. Castleden, C. M., George, C. F., Renwick, A. G. and Asher, M. J.: Imipramine-a possible alternative to current therapy for urinary incontinence in the elderly. J. Urol., 125: 318, 1981. 13. Axelrod, J., Whitby, L. G. and Hertting, G.: Effect of psychotropic drugs on the uptake of H 3-norepinephrine by tissues. Science, 133: 383, 1961.
* Mean ± standard deviation. t p <0.01. +P <0.05.
findings with ephedrine,7 phenylpropanolamine8 and dimethoxybetahydroxyphenthylglycinamide. 9 Although our results should be considered preliminary it seems that they justify the more extensive application of sympathomimetic drugs, that is imipramine, in the treatment of women with stress incontinence. Our study confirms that imipramine extends the functional urethral length and makes it independent of stress factors in women who are continent after treatment with imipramine. Furthermore, these observations support the view that a shortened urethra leads to urinary incontinence and lengthening of the urethra by imipramine or vesicopexy will correct the dysfunction. 19 The increase in functional urethral length might be caused by imipramine stimulation of the a-adrenergic receptors of the bladder neck and proximal urethra but such a statement should be proved objectively. Since the maximum urethral closure pressure increased owing to imipramine in all women, regardless of whether they were continent or still incontinent after imipramine administration, the external urethral sphincter might have a secondary role in the female continence mechanism. The functional ure-
911
TREATMENT OF FEMALE STRESS INCONTINENCE VVITH IMIPRAMl_NE 14. Labay, P. and Boyarsky, S.: The action of imipramine on the bladder musculature. J. Urol., 109: 385, 1973. 15. Brown, M. and Wickham, J. E. A.: The urethral pressure profile. Brit. J. Ural., 41: 211, 1969. 16. Bates, P., Bradley, W. E., Glen, E., Griffiths, D., Melchior, H., Rowan, F., Sterling, A., Zinner, N. and Hald, T.: The standardization of terminology of lower urinary tract function. J. Urol., 121: 551, 1979. 17. Plante, P. and Susset, J.: Studies of female urethral pressure profile. Part I. The normal urethral pressure profile. J. Urol., 123: 64, 1980. 18. Susset, J. and Plante, P.: Studies of female urethral pressure profile. Part II. Urethral pressure profile in female incontinence. J. Urol., 123: 70, 1980. 19. Lapides, J., Ajemian, E. P., Stewart, B. H., Lichtwardt, J. R. and Breakey, B. A.: Physiopathology of stress incontinence. Surg., Gynec. & Obst., 111: 224, 1960.
EDITORIAL COMMENT These results of the treatment of women with stress incontinence with imipramine hydrochloride are somewhat difficult for me to accept. My own experience with elderly women and this agent, usually in combination with estrogens, has been reasonably good but not as good as reported in this article. Furthermore, the reported values for functional urethral length and for maximum urethral closure pressure are dramatically changed after imipramine therapy. These values are somewhat difficult to reconcile with my own data accumulated during the years. Nevertheless, a double-blind, controlled study of tricyclic antidepressants in women with stress incontinence should be done to confirm these results.
Edward J. McGuire Department of Urology University Hospitals Ann Arbor, Michigan