1. Dissecting Male Lower Urinary Tract Symptoms – Pathophysiological and Pharmacological Perspectives 臺北榮總 泌尿部 林登龍

2. Lecture Outline Pathophysiology of Male LUTS Pharmacological Principles

3. 81 Years old male with urgency, frequency, urge incontinence. No effect twice laser prostatectomy. Urinary tract TB ! Urine: Hematuria, pyuria

4. 71 Years old male with urinary retention. TURP: Still Urinary Retention !

5. Urinary Bladder STORAGE EMPTYING (Voiding)

6. Lower Urinary Tract Symptoms (LUTS) Storage Symptoms ◦ Urinary frequency ◦ Urgency ◦ Nocturia ◦ Incontinence  Urgency  Stress Voiding Symptoms ◦ Hesitancy ◦ Small stream ◦ Intermittency ◦ Terminal dribbling ◦ Urinary retention

7. Failure to Store Storage Symptoms Due to the bladder Detrusor Overactivity Anatomic small capacity Due to outlet Decreased outlet resistance Severe bladder outlet obstruction

8. Failure to Empty Voiding Symptoms Due to the bladder Neurogenic Myogenic Due to outlet Outlet obstruction Anatomic or functional

9. Non-Neurogenic BOO : i.e. BPH Neurogenic bladder: suprasacral cord injury Detrusor hyperreflexia with impaired contractility (DHIC) Failure to Empty + Failure to Store Storage Symptoms Voiding Symptoms

10. Male LUTS No BPE Storage symptom Idiopathic D.O. Voiding symptom Detrusor under-activity Increased outlet sympathetic activity Dysfunctional voiding

11. Male LUTS With BPE Storage symptom Idiopathic D.O. only, no BOO BOO-induced D.O. Voiding symptom Detrusor under-activity BOO Storage + voiding symptom Idiopathic D.O. + BOO BOO-induced D.O. + BOO Large PVR induced by BOO

12. Non-Neurogenic Detrusor Overactivity Outflow obstruction Aging Idiopathic

13. BOO -Induced Detrusor Overactivity Increased bladder sensation ◦Reduced gap junction expression  Connexin-43 [Babaoglu, 2013] ◦Increased urothelial sensory receptors  TRPV4 [Cho, 2014] ◦Augmented release of sensory transmitters by urothelium  P2Y6 receptor-mediated ATP, acetylcholine [Silva, 2015]

14. BOO -Induced Detrusor Overactivity Increased detrusor excitability ◦Reduced K channel expression [Kita, 2010] ◦Increased EP4 expression [Beppu, 2011] ◦Increased smooth muscle myosin II [Zang,2011]

15. BOO -Induced Detrusor Overactivity Increased micturition reflex excitability ◦an upregulated bladder C-fiber activity [Steers, 1988] ◦a decrease of glycinergic neuronal activity in the lumbosacral cord [Miazato, 2008 ] ◦Increased bladder alpha 1-D adrenergic receptor [Yamagishi, 2015] ◦up-regulation of nicotinic acetylcholine receptors in bladder-projecting pelvic ganglion neurons [Chung,2015]

16. Aging-related Detrusor Overactivity Urothelial changes ◦A Rise in ATP release from the human urothelium [Yoshida, 2001] ◦Increased purinergic receptor sensitivity and raised P2X3 receptor expression in the rat urothelium [Daly, 2014] Detrusor changes ◦Abundant distinctive protrusion junctions and ultra- close cell abutments(Human) [Elbadwi, 1993]

17. Idiopathic Detrusor Overactivity Subclinical neural changes Ischemia ? ◦Development of detrusor overactivity progressing to detrusor underactivity [Yamaguchi, 2014]

18. Non-Neurogenic Detrusor Underactivity Outflow obstruction Aging Idiopathic

19. BOO -Related Detrusor Underactivity Detrusor damages ◦Increase bladder wall stiffness, smooth muscle cell degeneration [Lin, 1993]

20. BOO -Related Detrusor Underactivity Detrusor damages ◦Increase bladder wall stiffness, smooth muscle cell degeneration [Lin, 1993] ◦Impaired detrusor energentics [Lin, 1992;1995;1998] ◦A shift from the fast heavy chain B isoform seen in normal tissue to the much slower A isoform [DiSanto, 2003] ◦A loss of protein kinase C dependent contraction [Stanton, 2006]

21. BOO -Related Detrusor Underactivity Increased extracellular matrix deposition ◦Increase collagen deposit [Lin, 1993] ◦A strong correlation between the production of collagen and the reduction of smooth muscle contractile function [Jock, 2014] ◦Increase collagen III in muscle bundles [Kim, 2000]

22. Aging -Related Detrusor Underactivity Faster fatigue ◦ faster fatigue following electrostimulation [Lin, 1997] Reduced detrusor energy production ◦Reduces the mitochondrial enzyme activity [Lin, 2000] Increased bladder wall fibrosis ◦Decline in the ratio of smooth muscle to connective tissue [Lepor, 1992][Osman, 2014]

23. Pts (%) Idiopathic OAB 42.2 BOO 57.8 Male OAB Contributor: Prostate and Bladder Pressure-Flow study (104 patients)

24. Male LUTS Prostate Does Matter Size does matter Prostate size correlates well with BOO severity [Eckhardt, 2001] Prostate volume >40ml has high possibility of BOO [Lin, unpublished data

25. Factors Associated with BOO (164 Patients) Odds Ratio95% CIp Qmax < 15ml/sec1.6010.595 – 4.3090.352 Qmean < 10ml/sec 3.0001.046 – 8.6080.014 PSA >11.5600.623 – 3.9090.342 PV > 40ml2.9371.433 – 6.0160.003 IPP > 1cm0.9350.403 – 2.1700.875 DWT > 2mm1.8200.847 – 3.9130.125 * Multivariate analysis

26. Possibility of BOO PV > 40ml Qmean < 10 ml/sec 67.8% 47.6% 44.8% 25.9%

27. Risk Factors for Prostate Growth Inflammation ◦ In 1700 BPH patients, chronic inflammation and prostate volume were correlated [Di Silverio, 2003] Metabolic syndrome ◦Metabolic syndrome is associated with a higher annual BPH growth rate, increased sympathetic activity, and LUTS [Hammarsten, 2011]

28. Male LUTS Prostate Does Matter Size does matter Prostate size correlates well with BOO severity [Eckhardt, 2001] Prostate volume >40ml has high possibility of BOO [Lin, unpublished data] Median lobe does matter Intravesical prostate protrusion(IPP)

29. Intravesical Prostatic Protrusion(IPP) Trans-abdominal ultrasound sagittal view of bladder and prostate. IPP: from the tip of protruding prostate to the base of bladder. Foo et al: Int J Urol 2010;17:69 The IPP was statistically significant predictor of bladder outlet obstruction Foo et al: BJU Int 2003;91:371 29

30. Intravesical Prostate Protrusion(IPP) and Storage Symptom Symptom Score Positive correlationNegative correlation IPSS-TPSAQ mean, Q max IPSS-VNilQ mean, Q max IPSS-SIPP, PSA, PVRQ max, Q mean, CMG capacity OABSSIPPQ max, CMG capacity IPP consistently correlates well with storage symptom as measured by both IPSS storage sub-score and OABSS. [Lu & Lin, 2015]

31. Male LUTS/BPH Pharmacotherapy

32. Autonomic Receptors Body Body  Muscarinic(contract) M2, M3 M2, M3  Beta-adrenergic(relax) Beta 3 Beta 3 Base, BN, prostate, urethra Base, BN, prostate, urethra  Alpha-adrenergic (contract) Alpha 1a Alpha 1a

33. EAU Guidelines Male LUTS/BPH Treatment 2015 RecommendationLEGR Alpha1-blockers can be offered to men with moderate-to- severe LUTS 1aA 5a-Reductase inhibitors can be offered to men who have moderate-to-severe LUTS and an enlarged prostate (>40 mL) 1bA Muscarinic receptor antagonists may be used in men with moderate-to-severe LUTS who predominantly have bladder storage symptoms 1bB Beta-3 agonists may be used in men with moderate-to- severe LUTS who have predominantly bladder storage symptoms. 1bB PDE5Is reduce moderate-to-severe (storage and voiding) LUTS in men with or without erectile dysfunction. 1aA

34. Why Alpha Blocker May Improve BPE- Related Storage Symptoms Reduce BOO Block increased alpha adrenergic activity in the detrusor Modulate NO production from urothelium, nerve – NO modulates urothelium integrity and afferent activity Reduce nocturnal urine production Modulate reflex

35. Why Alpha Blocker Fail to Improve Storage Symptoms in BPE Patient ? Inadequately relieve BOO Independent idiopathic D.O. Irreversible BOO-induced D.O. Consider adding antimuscarinics or beta-adrenergic agonist

36. Why Antimuscarinics are Effective for Storage Symptoms (OAB) ? Muscarinic receptors are functioning during bladder storage phase and emptying phase

37. Muscarinic Receptors Lori A. Birder Am J Physiol Renal Physiol 2005;289:F489- F495 ©2005 by American Physiological Society

38. Beta-3 receptors ◦Urothelium, detrusor, suburothelial myofibroblast-like cells, intramural ganglion, cells, and Schwann cells of intramural nerves Relax detrusor muscle [Yamaguchi, 2007] Action on voiding reflex involving receptors located in the smooth muscle and in the sensory system including the urothelium. [Kullmann, 2011] Stimulate eNOS synthase in rat urinary bladder urothelial cells– may reduce bladder sensation [Birder, 2002; 2012] Why Beta-3 Agonist are Effective for Storage Symptoms (OAB) ?

39. Beta-3 Adrenergic Receptor [Birder, 2012]

40. EAU Guidelines Male LUTS/BPH Treatment 2015 RecommendationLEGR Alpha1-blockers can be offered to men with moderate-to- severe LUTS 1aA 5a-Reductase inhibitors can be offered to men who have moderate-to-severe LUTS and an enlarged prostate (>40 mL) 1bA Muscarinic receptor antagonists may be used in men with moderate-to-severe LUTS who predominantly have bladder storage symptoms 1bB Beta-3 agonists may be used in men with moderate-to- severe LUTS who have predominantly bladder storage symptoms. 1bB PDE5Is reduce moderate-to-severe (storage and voiding) LUTS in men with or without erectile dysfunction. 1aA

41. Upregulating NO/cGMP activity Downregulating Rho-kinase activity Modulating autonomic nervous system overactivity and bladder and prostate afferent nerves Increasing pelvic blood perfusion Reducing inflammation Why PDE5i is Effective for Male LUTS/BPH ? Soler, Andderson, et al: Euro Urol 2013

42. Nocturia Global Polyuria (>40ml/Kg/D) Nocturnal Polyuria Alone Nocturnal Polyuria + Diurnal OAB Diurnal OAB without Nocturnal Polyuria

43. Male LUTS No BPE Storage symptom ◦ Idiopathic D.O. Voiding symptom ◦Detrusor under-activity ◦Increased outlet sympathetic activity ◦Dysfunctional voiding Anti-muscarinics Alpha Blocker Beta agonist

44. Male LUTS With BPE Storage symptom ◦ Idiopathic D.O. only, no BOO ◦ BOO-induced D.O. Voiding symptom ◦Detrusor under-activity ◦BOO Storage + voiding symptom ◦ Idiopathic D.O. + BOO ◦ BOO-induced D.O. + BOO ◦ Large PVR induced by BOO Anti-muscarinics Alpha Blocker Anti-muscarinics +Anti-muscarinics Beta agonist PDE5i PDE5i PDE5i

45. Bladder Neck Obstruction + VUR Do not Forget Surgery !

46. Thank You