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

New Concepts and Pathophysiology of Lower Urinary Tract symptoms in

Men

가톨릭대학교비뇨기과학교실

이 용 석

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

• 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

• 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

• 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.)

2. The role of the bladder

• Frequency of detrusor dysfunction- bladder contribute to LUTS

• Storage LUTS & OAB symptomsare the samethe only difference: order of impotence

Storage LUTS; frequency & nocturiaOAB; mainly urgency & frequency

- additional evidence supports the involvement of the bladder in LUTS

• Oelke et al. Eur Urol 2008

- severity of BOO and DO are closely related

• 80% of Pts. with severe form of BOOhad DO (confirmed by pressure flow study)- twice times higher than accidental finding of DO among normal subjects

3. What causes detrusor overactivity?

•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

Increased sympathetic stimulation

• BOO affects the sympathetic system

by shifting the predominant subtype of α-adrenoreceptors


• BOO

six-fold increase in bladder weight striking shift in α1-adrenoreceptor

expression70% α1A and 25% α1D

→ 23% α1A and 75% α1D


• 10- to 100-fold higher affinity of α1D subtype for endogenous norepinephrinecould explain bladder contractility ↑

Hampel et al. J Urol 2002

• Experimental studyin human normal & obstructed bladder

the presence of these receptorsin human bladder

→ negligible Nomiya et al. J Urol 2003


• Silodosinin 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


• 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.


• 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


• Hypertensive rats

exhibit upregulation of this pathwaybladder overactivity

→ suppressed by Rho-kinase inhibitor

Rajasekaran et al. Neuroirol Urodyn 2005

Supersensitivity to acetylcholine

• Explanation of DO

BOO produces supersensitivity to acetylcholinein parasympathetic denervation

making contraction stronger & intense

Brading AF. Urology 1997


• Partial outlet obstruction

- in detrusor muscle (both rabbit & human)

↓ choline acetyltransferase

Levin et al. Neurourol Urodyn 2000


• Denervation- due to ischemia

BOO ass. with reduction in blood flowin dysfunctional bladdernot in compensated bladder

Schröder et al. J Urol 2001


• Reduction in blood flow to the bladder

cause of bladder contractile dysfunctionnot vice versa

Local segmental contractility

• BOO changes cell-to-cell contacts (between detrusor smooth muscle cells)

51 Pts. of both sex with neurogenic bladder dysfunctionultrastructural study of detrusor smooth muscle &

intrinsic nerves

→ protrusion of muscle cell junctionand ultraclose abutments

Elbadawi et al. J Urol 2003


• Abnormal cell-to-cell signalinginduce segmental contractionsuch contraction or detrusor micromotions

detected in human bladdersignificantly more frequent in

urgency than normal(85% of 14 Pt. vs 30% of 6 volunteers)

Drake et al. BJU Int 2005


• McCarthy et al. J Urol 2009

proved to evoke afferent nerve activityincreasing afferent noisetriggering 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


• Bladder C-fiber desensitizingby 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 monthsDinis et al. Eur Urol 2004


• 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


• Urotheliumrelease excessive neurotransmitters- sensory fibers abnormally stimulated

Bladder stretch induces; pressure-dependent ATP release from urothelium


• Adenosine triphosphate (ATP)

bind purinergic receptor P2X3(abundantly in bladder sensory fibers)

- controlling urinary bladder volume reflexes

Vlaskovska et al. J Neurosci 2001Cockayne et al. Nature 2000

• P2X3 antagonisttherapeutic potential in treatment of LUTS

and OAB

Increase in nerve growth factor

• BOO

increase NGF in bladder (rat & human)

increase does not fully reverseafter removal of the obstruction

Steers et al. J Clin Invest 1991


• Nerve growth factor (NGF)

administration of NGF

- activation of micturition reflex- appearance of DO in filling cystograms


• NGF

important tropic effectsin bladder sensory C-fibers by

promoting their sprouting in the CNSchanging receptor expression in sensory fibersdecreasing their threshold to respond to natural

stimuliCharrua et al. Neurourol Urodynam 2009

Steers et al. Neurourol Urodyn 1994

4. Urologic disorders and metabolic syndrome

• recently been found to be associate with urologic disorders

• Metabolic syndromes a complexincompletely understood syndromedue to abdominal fat deposits;

inducing insulin resistance

• 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)

• 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

• Metabolic syndromeis not a disease in itselfa pathway to diseasedoubles the risks of deathassociated with a 25-fold increase

in risk of developing type 2 diabetes

Hu et al. Arch Intern Med 2004

• In a survey in GermanyMoebus et al. Cardiocasc Diabetol 2007

MS prevalence increase with agehalf of elderly men had MS

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

Hypotestosteronemia

• Study in Argentinanegative correlation between

waist circumferencetotal testosterone

in 95 eugonadal subjects78 ED17 normal control

Knoblovits et al. J Androl in press

Hypotestosteronemia

• The phenomenon occur via 3 mechanism

- aromatase activity of adipocytesconverts testosterone into estradiol

- increase in leptin- increase in insulin levels

→ Leydig cells respond: reducing production of testosterone

Erectile dysfunction

• In the Argentinean studyMaggio 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

Erectile dysfunction

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

Benign prostatic hyperplasia and lower urinary tract symptoms

• A body of evidence suggestsmetabolic 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 betweenmedian annual prostate volume growth rate

& fasting plasma insulin values


• In a study of 78 BPH in TurkeyOzden et al. Eur Urol 2007

total prostate volume increasewith metabolic syndrome : 1.0ml/yrwithout metabolic synd. : 0.6ml/yr


• Kaplan et al J Urol 2007

positive correlation betweenwaist circumference/metabolic syndromeprostate volumeIPSS

Negative correlationmaximum flow rate


• The Prostate Cancer Prevention TrialKristal et al. J Urol 2007

in 5667 subjects

correlation betweenBPH and abdominal obesity

• Desgrandchamps Eur Urol Suppl 2008

association betweenexcessive waist circumferenceLUTS


• A few studies do not support

• 1206 Vietnam War Veteransusing registry datamedian follow up periods 15.6 yr

did not show any relationship betweenBPHMetabolic syndrome

Gupta et al. Urology 2006


• Health screening projects in Austria of 2371 menmean age: 46.1 yr

33.8% had metabolic syndrome13.8% had IPSS>7

Temmi et al. Urology 2009


• These negative outcome

supported by weak data retrospective study very few subjects actually had clinically important LUTS


• Finding of correlations between the metabolic syndrome and BPH suggest

lifestyle changes (recommended for metabolic syndrome)

→ benefit for urologic patients


• Esposito et al JAMA 2004

randomized, single-blind trial

110 obese mendesigned to reduce body weight over 2 yr(calorie intake reduction & increase physical activity)

→ improvement in sexual function(1/3 of Pts. with baseline ED)


• Platz et al Arch Intern Med 1998

30,634 men aged 40-70 yr in USmonitored for 8 yr

walking; inversely proportional to risk

undergoing BPH surgery

5. Conclusions

• Bladder dysfunction caused by prolonged BOO- important cause of LUTS in BPH- involves both motor (detrusor) and

sensory dysfunction

• associated with metabolic syndrome- benefit from lifestyle changes

• These new concepts should be used to design novel treatment for BPH/LUTS

THANKS FOR YOUR ATTENTION !

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