New Concepts and Pathophysiology of Lower Urinary Tract symptoms in Men

1. New Concepts and Pathophysiology of Lower Urinary Tract symptoms in Men 가톨릭대학교 비뇨기과학교실 이 용 석

2. 1. Lower urinary tract symptoms and obstruction due to benign prostate hyperplasia: only part of the story

3. Classic paradigm, in BPH - increase in prostate volume obstructs urinary flow - causing LUTS • Prostatectomy - resolves the obstruction - therefore resolves LUTS - In reality, this concept is only partly true

4. Neal et al. Outcome of elective prostatectomy.BMJ 1989 11 months follow up of 217 prostatectomy ; surgery - resolved obstructive symptoms - did not resolve storage symptoms - urgency; persist in half of Pts. - urgency & incontinence; continued in 1/3

5. Thomas et al. J Urol 2005 in a study of the natural history of LUTS - 217 men underwent TUR-P - 13 years follow up : symptoms returned in up to 2/3 of Pts. in Urodynamic study - detrusor dysfunction detrusor overactivity (in 64% of Pts.)

7. 2. The role of the bladder

8. Frequencyof detrusor dysfunction - bladder contribute to LUTS • Storage LUTS & OAB symptoms are the same the only difference: order of impotence Storage LUTS; frequency & nocturia OAB; mainly urgency & frequency - additional evidence supports the involvement of the bladder in LUTS

9. Oelke et al. Eur Urol 2008 - severity of BOO and DO are closely related • 80% of Pts. with severe form of BOO had DO (confirmed by pressure flow study) - twice times higher than accidental finding of DO among normal subjects

10. 3. What causes detrusor overactivity?

11. Increased sympathetic stimulation • Supersensitivity to acetylcholine • Local segmental contractility • Increase in nerve growth factor These findings raise the issue of what causes DO Several explanations have been proposed

12. Increased sympathetic stimulation • BOO affects the sympathetic system by shifting the predominant subtype of α-adrenoreceptors

13. Increased sympathetic stimulation • BOO six-fold increase in bladder weight striking shift in α1-adrenoreceptor expression 70% α1A and 25% α1D → 23%α1A and 75% α1D

14. Increased sympathetic stimulation • 10- to 100-fold higher affinity of α1D subtype for endogenous norepinephrine could explain bladder contractility ↑ Hampel et al. J Urol 2002 • Experimental study in human normal & obstructed bladder the presence of these receptors in human bladder → negligible Nomiya et al. J Urol 2003

15. Increased sympathetic stimulation • Silodosin in clinical medicine α1-adrenoreceptor antagonist highly selective for α1A subtype as effective as tamsulosin (α1A and α1D antagonist) relieves LUTS and BPH Pts. Kawabe et al. BJU Int 2006

16. Increased sympathetic stimulation • Role for α1A in the origin of storage LUTS still poorly understood involve the blockade of α1A receptor expressed in C-fibers and in the spinal cord Yokoyama et al. World J Urol In press.

17. Increased sympathetic stimulation • Sympathetic system relevant for DO through the Rho-kinase pathway BOO upregulate RhoA/Rho-kinase pathway ↑ phosphorilation of myosin light chain - ↑contractility of detrusor smooth muscle cell Bing et al. Am J Physiol Renal Physiol 2003

18. Increased sympathetic stimulation • Hypertensive rats exhibit upregulation of this pathway bladder overactivity → suppressed by Rho-kinase inhibitor Rajasekaran et al. Neuroirol Urodyn 2005

19. Supersensitivity to acetylcholine • Explanation of DO BOO produces supersensitivity to acetylcholine in parasympathetic denervation making contraction stronger & intense Brading AF. Urology 1997

20. Supersensitivity to acetylcholine • Partial outlet obstruction - in detrusor muscle (both rabbit & human) ↓ choline acetyltransferase Levin et al. Neurourol Urodyn 2000

21. Supersensitivity to acetylcholine • Denervation - due to ischemia BOO ass. with reduction in blood flow in dysfunctional bladder not in compensated bladder Schröder et al. J Urol 2001

22. Supersensitivity to acetylcholine • Reduction in blood flow to the bladder cause of bladder contractile dysfunction not vice versa

23. Local segmental contractility • BOO changes cell-to-cell contacts (between detrusor smooth muscle cells) 51 Pts. of both sex with neurogenic bladder dysfunction ultrastructural study of detrusor smooth muscle & intrinsic nerves → protrusion of muscle cell junction and ultraclose abutments Elbadawi et al. J Urol 2003

24. Local segmental contractility • Abnormal cell-to-cell signaling induce segmental contraction such contraction or detrusor micromotions detected in human bladder significantly more frequent in urgency than normal (85% of 14 Pt. vs 30% of 6 volunteers) Drake et al. BJU Int 2005

25. Local segmental contractility • McCarthy et al. J Urol 2009 proved to evoke afferent nerve activity increasing afferent noise triggering micturition reflex • Abolish DO inhibiting sensory fibers support this hypothesis Yokoyama et al. J Urol 2000 Intravesical lidocaine administration - block C-fiber sensory transmission - increase bladder capacity

26. Local segmental contractility • Bladder C-fiber desensitizing by intravesical resiniferatoxin ; providing long-lasting relief from LUTS significant improvements in IPSS (International Prostate Symptom Score) in severity of storage symptoms (urgency, nocturia and frequency) persist for 3 months Dinis et al. Eur Urol 2004

28. Local segmental contractility • Selective α1A blocker silodosin improve bladder storage function via suppression of C-fiber afferent activity (in cerebral infarction model on rat) Yokoyama et al. World J Urol. In press

29. Local segmental contractility • Urothelium release excessive neurotransmitters - sensory fibers abnormally stimulated Bladder stretch induces ; pressure-dependent ATP release from urothelium

30. Local segmental contractility • Adenosine triphosphate (ATP) bind purinergic receptor P2X3 (abundantly in bladder sensory fibers) - controlling urinary bladder volume reflexes Vlaskovska et al. J Neurosci 2001 Cockayne et al. Nature 2000 • P2X3 antagonist therapeutic potential in treatment of LUTS and OAB

31. Increase in nerve growth factor • BOO increase NGF in bladder (rat & human) increase does not fully reverse after removal of the obstruction Steers et al. J Clin Invest 1991

32. Increase in nerve growth factor • Nerve growth factor (NGF) administration of NGF - activation of micturition reflex - appearance of DO in filling cystograms

33. Increase in nerve growth factor • NGF important tropic effects in bladder sensory C-fibers by promoting their sprouting in the CNS changing receptor expression in sensory fibers decreasing their threshold to respond to natural stimuli Charrua et al. Neurourol Urodynam 2009 Steers et al. Neurourol Urodyn 1994

34. 4. Urologic disorders and metabolic syndrome

35. recently been found to be associate with urologic disorders • Metabolic syndromes a complex incompletely understood syndrome due to abdominal fat deposits; inducing insulin resistance

36. Several international definitions - World Health Organization (WHO) - National Cholesterol Education Program (NCEP) set up by cardiologists - International Diabetes Federation (IDF) criteria differ somewhat (eg, the WHO & IDF; cut-off of >94㎝ for waist vs NCEP cut-off of >102㎝ for waist circumference)

37. Basically define metabolic syndrome centrally distributed obesity hyperinsulinemia with underlying insulin resistance plus two other cardiovascular risk factors impaired glucose regulation ↑ level of triglycerides ↓ levels of high-density lipoprotein cholesterol ↑ blood pressure Meigs JB. Am J Manag Care 2002

38. Metabolic syndrome is not a disease in itself a pathway to disease doubles the risks of death associated with a 25-fold increase in risk of developing type 2 diabetes Hu et al. Arch Intern Med 2004

39. In a survey in Germany Moebus et al. Cardiocasc Diabetol 2007 MS prevalence increase with age half of elderly men had MS

40. Hypotestosteronemia • Metabolic syndrome is associated with a reduction in testosterone levels in Tuscany, Italy, in the InCHIANTI study >500 elderly men representative of general population (13.8% had metabolic syndrome) Maggio et al. J Androl 2010

41. Hypotestosteronemia • Study in Argentina negative correlation between waist circumference total testosterone in 95 eugonadal subjects 78 ED 17 normal control Knoblovits et al. J Androl in press

42. Hypotestosteronemia • The phenomenon occur via 3 mechanism - aromatase activity of adipocytes converts testosterone into estradiol - increase in leptin - increase in insulin levels → Leydig cells respond : reducing production of testosterone

43. Erectile dysfunction • Inthe Argentinean study Maggio et al. J Androl 2010 waist circumference - negatively correlated with IIED (International Index of Erectile dysfunction) • In Turkey Bal et al. Urology 2007 40-70 yr 393 Pts. (39.9% with MS) Metabolic syndrome - strongly associated with ED

44. Erectile dysfunction • Underlying cause of ED : insulin resistance - lower synthesis & release of NO → endothelial dysfunction

45. Benign prostatic hyperplasia and lower urinary tract symptoms • A body of evidence suggests metabolic syndrome is also associated with BPH and LUTS • In study of 307 Pts. with LUTS in Sweden Hammarsten et al. Eur Urol 2001 correlation was found between median annual prostate volume growth rate & fasting plasma insulin values

46. Benign prostatic hyperplasia and lower urinary tract symptoms • In a study of 78 BPH in Turkey Ozden et al. Eur Urol 2007 total prostate volume increase with metabolic syndrome : 1.0ml/yr without metabolic synd. : 0.6ml/yr

47. Benign prostatic hyperplasia and lower urinary tract symptoms • Kaplan et al J Urol 2007 positive correlation between waist circumference/metabolic syndrome prostate volume IPSS Negative correlation maximum flow rate

48. Benign prostatic hyperplasia and lower urinary tract symptoms • The Prostate Cancer Prevention Trial Kristal et al. J Urol 2007 in 5667 subjects correlation between BPH and abdominal obesity • Desgrandchamps Eur Urol Suppl 2008 association between excessive waist circumference LUTS

49. Benign prostatic hyperplasia and lower urinary tract symptoms • A few studies do not support • 1206 Vietnam War Veterans using registry data median follow up periods 15.6 yr did not show any relationship between BPH Metabolic syndrome Gupta et al. Urology 2006

50. Benign prostatic hyperplasia and lower urinary tract symptoms • Health screening projects in Austria of 2371 men mean age: 46.1 yr 33.8% had metabolic syndrome 13.8% had IPSS>7 Temmi et al. Urology 2009