Hypersensitive or Detrusor Overactivity: Which is Associated with Filling Symptoms in Female Bladder Outlet Obstructed Patients? Junlong Zhang1, Mingxin Cao1, Yu Chen1, Weijie Liang1, Yueyou Liang1* Purpose: To investigate and compare detrusor overactivity (DO) and bladder filling sensation characteristics in female bladder outlet obstruction (FBOO) patients with or without overactive bladder (OAB) symptoms. Materials and Methods: One hundred fifty-seven FBOO patients with urodynamic testing were recruited. Pa- tients who showed urinary urgency ( ≥ 6 episodes/3 d), with or without urinary frequency ( ≥8 voids/24 h), and urge incontinence ( ≥ 3 episodes/3 d) were considered to have OAB. The detrusor overactivity (DO) and bladder filling sensation measures including first sensation (FSF), first desire to void (FDV) and strong desire to void (SDV) during filling cystometry were recorded. The associations between urodynamic variables and OAB symp- toms were analysed. Result: FBOO patients had a high incidence (79%) of OAB. FBOO patients with OAB symptoms had significantly younger age, higher incidence of DO (19.4% versus 6.1%) (P = .051) and lower bladder volumes of FSF (180.32 ± 83.48 versus 226.18 ± 100.90 mL), FDV (269.00 ± 109.78 versus 330.45 ± 123.95 mL) and SDV (345.56 ± 135.43 versus 422.33 ± 148.40 mL) (P < .05) compared to patients without OAB. In multivariate analyses, both DO (OR = 4.83, 95% CI: 1.02-22.85, P = .047) and lower bladder volumes at FDV(OR = 2.47, 95% CI: 1.03-5.95, P = .044) and SDV (OR = 3.07, 95% CI: 1.25-7.55, P < .014) were still independently associated with OAB, after adjustment for age and other confounding factors. Conclusion: FBOO patients had a high incidence of OAB. Not only DO but also bladder hypersensitivity were independently associated with OAB symptoms in FBOO patients. Keywords: hypersensitivity;urinary bladder neck obstruction; urinary bladder, overactive; urodynamics; urinary Incontinence, urge INTRODUCTION Female bladder outlet obstruction (FBOO) is a rel-ative uncommon condition in clinical practice(1-4). Overactive bladder (OAB) symptoms, including urgen- cy, frequency and nocturia, are quite common among female patients, especially in patients with bladder outlet obstruction, which severely affect women’s life quality(5-6). The reported incidence of OAB among blad- der outlet obstruction patients was around 50-75%(7). OAB symptoms can be induced either by obstruction or the secondary effects of obstruction on the bladder(8). Whereas, to date, the underlying mechanisms of OAB symptoms in FBOO patients remains the subject of debate and the anticholinergic drugs have many side effects(9). A more thorough investigation of its patho- physiological mechanisms will be helpful in further in- vestigations of therapeutic drugs. Detrusor overactivity (DO), characterized by invol- untary detrusor contractions during the filling phase in urodynamic test, is a known cause for OAB symp- toms(10). However, the antimuscarinic therapy based on this mechanism shows limited efficiency in clinical practice(11). Urologist and clinical researchers have now placed a new focus on the effect of increasing bladder 1 Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, GuangZhou 510080, China. *Correspondence: Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, NO. 58 Zhongshan Er Road, Guangzhou 510080, China. Tel: +86-20-87333300. Fax: +86-20-87333300. Email: lyuey@mail.sysu.edu.cn. Received January 2018 & Accepted December 2018 sensation on OAB symptoms. A few studies have found that OAB patients had lower micturition and decreased bladder volumes, which suggested that bladder hyper- sensitivity contributes to the development of OAB (12-13). However, the association between bladder filling sensa- tion and OAB symptoms was still not adequately inves- tigated in FBOO patients. The objective of this study was to examine the urodynamic parameters associated with OAB symptoms in FBOO patients. MATERIAL AND METHODS Study design and participants This study was an observational study approved by the Institutional Review Board of the First Affiliated Hos- pital of Sun Yat-Sen University. The study was con- ducted according to the principles expressed in the Dec- laration of Helsinki. We screened female patients who referred for evaluation of lower urinary tract symptoms (LUTS) and underwent urodynamic testing in the first affiliated hospital of Sun Yat-sen university from 2008 to 2016. Patients with clinical dysuria symptoms and having the maximum flow rate (Qmax) ≤ 15 ml/s and detrusor pressure at the maximum flow (Pdet. Qmax) ≥ 20 cmH 2 O in urodynamic testing were eligible for FEMALE UROLOGY Female Urology 285 Vol 16 No 03 May-June 2019 286 inclusion as FBOO(1). Exclusion criteria were the pres- ence of diabetes mellitus, bladder stone, bladder tumor, urine infection, nervous diseases, pelvic prolapse, and urological surgery history. The severity of obstruction was assessed using the Blaivas-Groutz Nomogram(3), and further categorized into severe obstruction (Pdet. max ≥ 107 cmH 2 O), moderate obstruction (Pdet.max between 57 to 107 cmH 2 O), and mild obstruction (Pdet. max ≤ 57 cmH 2 O). According to the 3d-voiding diary, patients who showed urinary urgency (≥ 6 episodes/3 d) with or without urge incontinence (≥ 3 episodes/3 d) and urinary frequency (≥8 voids/24 h), were selected as OAB patients.(14) Urodynamic testing According to the suggested urodynamics practice stand- ards of the International Continence Society(15), urody- namic testing was performed by a urotechnician using the Delphis 94-R01-BT UDS system (Laborie Medical Technologies, Canada). During the free-flow measure- ment, the maximum free-flow rate (Free Qmax) was recorded. Subsequently, post-void residual urine (PVR) was measured. The bladder was filled with saline solu- tion at a temperature of around 37℃ at a speed of 50 ml/min during the filling cystometry. Bladder sensation variables were recorded when patients reported the first sensation of bladder filling (FSF), first desire to void (FDV), and strong desire to void (SDV) according to the International Continence Society definitions(15). Lower bladder volumes at FSF, FDV, and SDV were considered as higher bladder sensitivity. DO was con- sidered positive when involuntary detrusor contractions appeared during the filling phase(15). Meanwhile, void- ing variables including Qmax, Pdet. Qmax, maximum detrusor pressure (Pdet. max) were also recorded during the voiding cystometry. Statistical Analysis Data are presented as the mean ± standard deviation (SD) or number (percentage). For comparisons be- tween OAB-FBOO and non-OAB-FBOO patients, a Mann-Whitney test was used for numerical variables and a Chi square test for categorical variables. Multi- variate logistic regression models were used to analyse DO and bladder volumes to predict the occurrence of OAB in FBOO patients separately, adjusting for age and other factors with p values < .1 in univariate analyses. All statistical analyses were pmerfored using SPSS for Windows (Version 13.0, IBM, USA). Two-tail p values < .05 were considered to be statistically significant. RESULTS Among 2600 female patients undergoing urodynamic studies, 157 patients were recruited as FBOO, suggest- ing the prevalence of BOO was approximately 6%. The mean age was 46 ± 14 years old. The incidence of DO among FBOO patients was around 16.6%. Detailed uro- dynamic characteristics of FBOO are listed in Table 1. According to Blaivas-Groutz Nomogram, 116 (73.9%) FBOO patients were mild obstruction, and 36 (22.9%) were moderate obstruction and 5 (3.2%) were severe obstruction. The severe/moderate obstruction group showed a higher incidence of DO (29.3%) compared with the mild obstruction group (12.1%). Nevertheless, all bladder volume measures were not significantly dif- ferent between groups with severe/moderate obstruc- tion and mild obstruction. Among the FBOO patients, 124 (79.0%) had OAB. As shown in Table 2, patients with OAB had a higher inci- dence of DO than patients without OAB (19.4% versus 6.1%, p = .051). FBOO patients with OAB had signif- icantly lower FSF, FDV and SDV than those without OAB (Table 1). Patients with OAB seems to be young- er than those without OAB. After adjusting for age and PVR, DO, FDV and SDV were still independently as- sociated with the occurrence of OAB, and FSF tended to independently associate with OAB symptoms (Table Table 1. Comparisons of clinical and urodynamic parameters in FBOO patients with OAB and non-OAB symptoms. Clincal&Urodynamic Parameters All FBOO (N = 157) OAB -FBOO (N= 124) Non-OAB –FBOO (N = 33) p value Age, years 46.80 ± 14.45 45.44 ± 14.38 51.94 ± 13.71 .010 Free Qmax, mL/s 11.29 ± 4.91 11.11 ± 4.61 11.99 ± 5.91 .473 Qmax, mL/s 7.88 ± 3.43 8.15 ± 3.41 6.86 ± 3.37 .103 Pdet Qmax , cmH 2 O 49.74 ± 80.32 51.46 ± 89.73 43.28 ± 21.15 .838 Pdetmax, cmH 2 O 49.74 ± 23.02 49.50 ± 23.40 50.63 ± 21.86 .687 PVR, mL 87.04 ± 126.60 74.60 ± 109.19 133.42 ± 171.36 .064 DO 26(16.6%) 24 (19.4%) 2 (6.1%) .051 FSF, mL 189.96 ± 89.07 180.32 ± 83.48 226.18 ± 100.90 .011 FDV, mL 281.92 ± 115.28 269.00 ± 109.78 330.45 ± 123.95 .009 SDV, mL 361.70 ± 141.29 345.56 ± 135.43 422.33 ± 148.40 .006 Blaivas-Groutz 1 (1-2) 1 (1-2) .875 Abbreviations: FBOO, female bladder outlet obstruction; OAB, overactive bladder; Free Qmax, the maximum free-flow rate; Qmax, the maximum flow rate; Pdet Qmax, detrusor pressure at maximum flow; Pdetmax, maximum detrusor pressure; PVR, post-void residual urine; DO, detrusor overactivity; FSF, first sensation of bladder filling; FDV, first desire to void; SDV, strong desire to void. Data were showed as means ± SD, numbers (%) or medians (interquartile range). P value for comparison between OAB-FBOO patients and Non-OAB-FBOO patients. Urodynamic Parameters Occurrence of OAB OR (95 % CI) P value DO 4.83 (1.02-22.85) .047 FSF < mean value 2.35 (0.99-5.59) .053 FDV < mean value 2.47 (1.03-5.95) .044 SDV < mean value 3.07 (1.25-7.55) .014 Abbreviations: FBOO, female bladder outlet obstruction; OAB, overactive bladder; DO, detrusor overactivity; FSF, first sensation of bladder filling; FDV, first desire to void; SDV, strong desire to void. HR, hazard ratio; CI, confidence interval. All urodynamic parameters were separately adjusted by age and PVR. Table 2. Results of logistic analyses on urodynamic factors to pre- dict the occurrence of OAB symptoms in FBOO patients DO and bladder hypersensitivity in female BOO-Junlong Zhang et al. 2). One typical urodynamic report of FBOO patients showing both DO and bladder hypersensitivity was showed in Figure 1. DISCUSSION In this cross-sectional study, we observe that both DO and low bladder volumes were correlated with OAB symptoms. Such results may indicate that not only DO but also increased bladder sensitivity could be the underlying pathophysiological mechanisms for OAB symptoms in FBOO patients. Compared with male BOO, FBOO is a relative uncom- mon condition in clinical practice. The reported preva- lence of BOO in female population varies widely from 2.7% to 23% in different studies because of various di- agnostic criteria(1-4,16). In our study, a combined criteria of Qmax ≤ 15 ml/s and Pdet Qmax ≥ 20 cm H 2 O was used to define BOO, which had a sensitivity of 74.3% and a specificity of 91.1% to predict obstruction(1). Such criteria is thought to have good concordance with clini- cally diagnosed obstructions. The incidence of OAB in FBOO patients in our study was similar to the data in the male population (60-70%) (8). After adjusting for age and other confounding fac- tors, the higher DO rates was still independently associ- ated with OAB symptoms in FBOO patients. The high incidence of OAB symptoms with low incidence of DO in FBOO patients was consistent with a previous study, which also demonstrated that only 54% of women with OAB had DO on urodynamic test, and 27% of the women with a diagnosis of DO on urodynamic test had OAB symptoms(17). The inconsistence between OAB and DO rates suggests that other pathophysiological mechanisms might be responsible for OAB symptoms in FBOO patients. Some researchers have placed focus on identifying the associations between bladder sensations and OAB(18- 19). Several studies reported that OAB patients not only had a higher incidence of DO but also revealed low- er bladder volumes of FSF, FDV and SDV compared with non-OAB patients, suggesting hypersensitive bladder in OAB patients(12-13). In our study, we adopted urodynamic variables during filling cystometry as an objective method to record bladder sensations, which has been demonstrated to have good correlations with sensory questionnaire scores in a prior study(13). We found that the bladder volumes were lower in FBOO patients with OAB symptoms than those without OAB symptoms. Thus, this study suggested that FBOO could induce lower bladder volumes which may be related to OAB symptom in these patients. The mechanisms of OAB symptoms in BOO patients remain a matter of debate, with neurogenic mechanism classified as one of the leading causes(20). In the exper- imental studies, various neurochemical, such as nitric oxide synthase and NADPH-diaphorase, have been shown to change in afferent pathways of the animal model of bladder outlet obstruction(21-22). Additionally, short latency micturition reflex was found in urethral obstructed rats(23). These changes in reflex pathways were considered as neuronal plasticity, which indicat- ed that the nerves were influenced by the pathological processes in target organs(24-25). Recently, there are in- creasing interest in the investigation of afferent system (sensory) innervation as an important therapeutic target for lower urinary tract symptoms(26). Our study might further support the neurogenic mechanisms and the im- portance of investigations on therapies directed at the afferent system in FBOO patients with OAB symptoms. This study had several limitations. First, there was no general agreement on the urodynamic parameters for defining FBOO. We used the criteria of Qmax ≤ 15 ml/s and Pdet Qmax ≥ 20 cmH 2 O in this study, which is thought to have high concordance with clinically diag- nosed obstructions (27). Second, this was a cross-section- al study, which could not support the cause and effect associations between DO, bladder hypersensitivity and OAB in FBOO patients. Further longitudinal, prospec- tive, and large-scale studies are warranted to validate these findings. CONCLUSIONS FBOO patients had a high incidence of OAB symp- toms. Both urodynamic DO and bladder volumes in filling cystometry tests were independently associated with the occurrence of OAB symptoms in FBOO pa- tients, suggesting that not only DO but also increased bladder sensitivity may be pathophysiological mecha- nisms underlying this symptomatology. ACKNOWLEDGEMENT This study was supported by grants from science and technology planning project foundation of Guangdong Province, China (Grant No. 2012B031800051). CONFLICT OF INTEREST The authors declare that they have no competing inter- ests. REFERENCES 1. Chassagne S, Bernier PA, Haab F, Roehrborn CG, Reisch JS, Zimmern PE: Proposed cutoff values to define bladder outlet obstruction in women. Urology 1998;51:408-411. 2. Nitti VW, Tu LM, Gitlin J: Diagnosing bladder outlet obstruction in women. J Urol 1999;161:1535-40. DO and bladder hypersensitivity in female BOO-Junlong Zhang et al. Figure 1. One typical urodynamic report of complicated FBOO show high Pdetmax and low Qmax with DO and hypersensitivity. Female Urology 287 Vol 16 No 03 May-June 2019 288 3. Blaivas JG, Groutz A: Bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. Neurourol Urodyn 2000;19:553-64. 4. Choi YS, Kim JC, Lee KS, et al.: Analysis of female voiding dysfunction: a prospective, multi-center study. Int Urol Nephrol 2013;45:989-94. 5. Bykoviene L, Kubilius R, Aniuliene R, Bartuseviciene E, Bartusevicius A: Pelvic Floor Muscle Training With Or Without Tibial Nerve Stimulation and Lifestyle Changes Have Comparable Effects on The Overactive Bladder. A Randomized Clinical Trial. Urol J 2018;15:186-92. 6. Al-Zahrani AA, Gajewski J: Urodynamic findings in women with refractory overactive bladder symptoms. Int J Urol 2016;23:75-9. 7. Oelke M, Baard J, Wijkstra H, de la Rosette JJ, Jonas U, Hofner K: Age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. Eur Urol 2008;54:419- 26. 8. Abdel-Aziz KF, Lemack GE: Overactive bladder in the male patient: bladder, outlet, or both? Curr Urol Rep 2002;3:445-51. 9. Lee KC, Seong BM: Does Systemic Disease Aggravate the Severity of Dry Mouth by Anticholinergics in Overactive Bladder Patients? Urol J 2017;14:3035-9. 10. Abrams P, Cardozo L, Fall M, et al.: The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003;61:37-49. 11. Herbison P, Hay-Smith J, Ellis G, Moore K: Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 2003;326:841-4. 12. Lee SR, Kim HJ, Kim A, Kim JH: Overactive bladder is not only overactive but also hypersensitive. Urology 2010;75:1053-9. 13. Rapp DE, Neil NJ, Govier FE, Kobashi KC: Bladder sensation measures and overactive bladder. J Urol 2009;182:1050-4. 14. Lee SR, Kim HJ, Kim A, Kim JH: Overactive bladder is not only overactive but also hypersensitive. Urology 2010;75:1053-9. 15. Abrams P, Cardozo L, Fall M, et al.: The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. In, 2003:37-49. 16. Lin CD, Kuo HC, Yang SS: Diagnosis and Management of Bladder Outlet Obstruction in Women. Low Urin Tract Symptoms 2016;8:30-7. 17. Digesu GA, Khullar V, Cardozo L, Salvatore S: Overactive bladder symptoms: do we need urodynamics? Neurourol Urodyn 2003;22:105-8. 18. Yamaguchi O, Honda K, Nomiya M, et al.: Defining overactive bladder as hypersensitivity. Neurourol Urodyn 2007;26:904-7. 19. van Brummen HJ, Heintz AP, van der Vaart CH: The association between overactive bladder symptoms and objective parameters from bladder diary and filling cystometry. Neurourol Urodyn 2004;23:38-42. 20. Roosen A, Chapple CR, Dmochowski RR, et al.: A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. Eur Urol 2009;56:810-9. 21. Johansson RK, Poljakovic M, Andersson KE, Persson K: Expression of nitric oxide synthase in bladder smooth muscle cells: regulation by cytokines and L-arginine. J Urol 2002;168:2280-5. 22. Zhou Y, Ling EA: Increased NADPH- diaphorase reactivity in bladder afferent pathways following urethral obstruction in guinea pigs. J Peripher Nerv Syst 1997;2:333- 42. 23. Steers WD, De Groat WC: Effect of bladder outlet obstruction on micturition reflex pathways in the rat. J Urol 1988;140:864-71. 24. Heppenstall PA, Lewin GR: Neurotrophins, nociceptors and pain. In, 2000:573-6. 25. Steers WD, Kolbeck S, Creedon D, Tuttle JB: Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. J Clin Invest 1991;88:1709-15. 26. Chapple C: Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder". Neurourol Urodyn 2014;33 Suppl 3:S6-S13. 27. Akikwala TV, Fleischman N, Nitti VW: Comparison of diagnostic criteria for female bladder outlet obstruction. J Urol 2006;176:2093-7. DO and bladder hypersensitivity in female BOO-Junlong Zhang et al.