Dissecting Male Lower Urinary Tract Symptoms Pathophysiological and

Dissecting Male Lower Urinary Tract Symptoms – Pathophysiological and Pharmacological Perspectives 臺北榮總 泌尿部 林登龍 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Lecture Outline l Pathophysiology of Male LUTS l Pharmacological Principles 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

81 Years old male with urgency, frequency, urge incontinence. No effect twice laser prostatectomy. Urine: Hematuria, pyuria Urinary tract TB ! 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

71 Years old male with urinary retention. TURP: Still Urinary Retention ! 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Urinary Bladder • • STORAGE EMPTYING (Voiding) 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Lower Urinary Tract Symptoms (LUTS) l Storage Symptoms ◦ Urinary frequency ◦ Urgency ◦ Nocturia ◦ Incontinence �Urgency �Stress l Voiding Symptoms ◦ ◦ Hesitancy Small stream Intermittency Terminal dribbling ◦ Urinary retention 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Failure to Store Storage Symptoms Due to the bladder üDetrusor Overactivity üAnatomic small capacity l Due to outlet üDecreased outlet resistance üSevere bladder outlet obstruction l 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Failure to Empty Voiding Symptoms l Due to the bladder l Due to outlet üNeurogenic üMyogenic üOutlet obstruction • Anatomic or functional 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Failure to Empty + Failure to Store Storage Symptoms Voiding Symptoms � Non-Neurogenic BOO : i. e. BPH � Neurogenic bladder: suprasacral cord injury � Detrusor hyperreflexia with impaired contractility (DHIC) 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Male LUTS No BPE l Storage symptom ü Idiopathic D. O. l Voiding symptom üDetrusor under-activity üIncreased outlet sympathetic activity üDysfunctional voiding 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Male LUTS With BPE l Storage symptom ü Idiopathic D. O. only, no BOO ü BOO-induced D. O. l Voiding symptom üDetrusor under-activity üBOO l Storage + voiding symptom ü Idiopathic D. O. + BOO ü BOO-induced D. O. + BOO ü Large PVR induced by BOO 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Non-Neurogenic Detrusor Overactivity � Outflow obstruction � Aging � Idiopathic 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

BOO-Induced Detrusor Overactivity �Increased bladder sensation ◦ Reduced gap junction expression �Connexin-43 [Babaoglu, 2013] ◦ Increased urothelial sensory receptors �TRPV 4 [Cho, 2014] ◦ Augmented release of sensory transmitters by urothelium �P 2 Y 6 receptor-mediated ATP, acetylcholine [Silva, 2015] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

BOO-Induced Detrusor Overactivity �Increased detrusor excitability ◦ Reduced K channel expression [Kita, 2010] ◦ Increased EP 4 expression [Beppu, 2011] ◦ Increased smooth muscle myosin II [Zang, 2011] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Aging-related Detrusor Overactivity �Urothelial changes ◦ A Rise in ATP release from the human urothelium [Yoshida, 2001] ◦ Increased purinergic receptor sensitivity and raised P 2 X 3 receptor expression in the rat urothelium [Daly, 2014] � Detrusor changes ◦ Abundant distinctive protrusion junctions and ultraclose cell abutments(Human) [Elbadwi, 1993] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Idiopathic Detrusor Overactivity � Subclinical � Ischemia neural changes ? ◦ Development of detrusor overactivity progressing to detrusor underactivity [Yamaguchi, 2014] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Non-Neurogenic Detrusor Underactivity � Outflow obstruction � Aging � Idiopathic 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

BOO-Related Detrusor Underactivity � Detrusor damages ◦ Increase bladder wall stiffness, smooth muscle cell degeneration [Lin, 1993] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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 [Di. Santo, 2003] ◦ A loss of protein kinase C dependent contraction [Stanton, 2006] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Male OAB Contributor: Prostate and Bladder Pressure-Flow study (104 patients) Pts (%) Idiopathic OAB BOO 42. 2 57. 8

Male LUTS Prostate Does Matter l Size l does matter Prostate size correlates well with BOO severity [Eckhardt, 2001] l Prostate volume >40 ml has high possibility of BOO [Lin, unpublished data 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Factors Associated with BOO (164 Patients) Odds Ratio 95% CI p Qmax < 15 ml/sec 1. 601 0. 595 – 4. 309 0. 352 Qmean < 10 ml/sec 3. 000 1. 046 – 8. 608 0. 014 PSA >1 1. 560 0. 623 – 3. 909 0. 342 PV > 40 ml 2. 937 1. 433 – 6. 016 0. 003 IPP > 1 cm 0. 935 0. 403 – 2. 170 0. 875 DWT > 2 mm 1. 820 0. 847 – 3. 913 0. 125 * Multivariate analysis 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Possibility of BOO PV > 40 ml Qmean < 10 ml/sec 67. 8% 47. 6% 44. 8% 25. 9% 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Male LUTS Prostate Does Matter l Size does matter Prostate size correlates well with BOO severity l [Eckhardt, 2001] Prostate volume >40 ml has high possibility of BOO [Lin, l unpublished data] l Median ü lobe does matter Intravesical prostate protrusion(IPP) 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Intravesical Prostate Protrusion(IPP) and Storage Symptom Score Positive correlation Negative correlation IPSS-T PSA Q mean, Q max IPSS-V Nil Q mean, Q max IPSS-S IPP, PSA, PVR Q max, Q mean, CMG capacity OABSS IPP Q max, CMG capacity • IPP consistently correlates well with storage symptom as measured by both IPSS storage sub-score and OABSS. [Lu & Lin, 2015] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Male LUTS/BPH Pharmacotherapy 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Autonomic Receptors l Body q Muscarinic(contract) üM 2, M 3 q Beta-adrenergic(relax) ü Beta 3 l Base, BN, prostate, urethra q. Alpha-adrenergic (contract) ü Alpha 1 a 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

EAU Guidelines Male LUTS/BPH Treatment 2015 Recommendation LE GR Alpha 1 -blockers can be offered to men with moderate-tosevere LUTS 1 a A 5 a-Reductase inhibitors can be offered to men who have moderate-to-severe LUTS and an enlarged prostate (>40 m. L) 1 b A Muscarinic receptor antagonists may be used in men with moderate-to-severe LUTS who predominantly have bladder storage symptoms 1 b B Beta-3 agonists may be used in men with moderate-tosevere LUTS who have predominantly bladder storage symptoms. 1 b B PDE 5 Is reduce moderate-to-severe (storage and voiding) LUTS in men with or without erectile dysfunction. 1 a A 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Why Alpha Blocker May Improve BPERelated 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 � 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Why Antimuscarinics are Effective for Storage Symptoms (OAB) ? �Muscarinic receptors are functioning during bladder storage phase and emptying phase 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Muscarinic Receptors Lori A. Birder Am J Physiol Renal Physiol 2005; 289: F 489 F 495 © 2005 by American Physiological Society

Why Beta-3 Agonist are Effective for Storage Symptoms (OAB) ? � 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 e. NOS synthase in rat urinary bladder urothelial cells– may reduce bladder sensation [Birder, 2002; 2012] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Beta-3 Adrenergic Receptor [Birder, 2012] 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

EAU Guidelines Male LUTS/BPH Treatment 2015 Recommendation LE GR Alpha 1 -blockers can be offered to men with moderate-tosevere LUTS 1 a A 5 a-Reductase inhibitors can be offered to men who have moderate-to-severe LUTS and an enlarged prostate (>40 m. L) 1 b A Muscarinic receptor antagonists may be used in men with moderate-to-severe LUTS who predominantly have bladder storage symptoms 1 b B Beta-3 agonists may be used in men with moderate-tosevere LUTS who have predominantly bladder storage symptoms. 1 b B PDE 5 Is reduce moderate-to-severe (storage and voiding) LUTS in men with or without erectile dysfunction. 1 a A 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Why PDE 5 i is Effective for Male LUTS/BPH ? � Upregulating NO/c. GMP activity � Downregulating Rho-kinase activity � Modulating autonomic nervous system overactivity and bladder and prostate afferent nerves � Increasing pelvic blood perfusion � Reducing inflammation Soler, Andderson, et al: Euro Urol 2013 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Nocturia Global Polyuria (>40 ml/Kg/D) Nocturnal Polyuria Alone Nocturnal Polyuria + Diurnal OAB without Nocturnal Polyuria 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Male LUTS No BPE � Storage symptom ◦ Idiopathic D. O. Anti-muscarinics Beta agonist � Voiding symptom ◦ Detrusor under-activity ◦ Increased outlet sympathetic activity Alpha Blocker ◦ Dysfunctional voiding 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Male LUTS With BPE �Storage symptom ◦ Idiopathic D. O. only, no BOO ◦ BOO-induced D. O. �Voiding Anti-muscarinics Beta agonist Alpha Blocker symptom ◦ Detrusor under-activity ◦ BOO � Alpha Blocker PDE 5 i Storage + voiding symptom Anti-muscarinics Alpha Blocker ◦ Idiopathic D. O. + BOO Beta agonist ◦ BOO-induced D. O. + BOO PDE 5 i + Anti-muscarinics Alpha Blocker ◦ Large PVR induced by BOO Beta agonist PDE 5 i Alpha Blocker 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

Do not Forget Surgery ! Bladder Neck Obstruction + VUR 男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015 -08 -02

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