Evolving Terminology: Lower
Urinary Tract Symptoms (LUTS)
Men With Lower Urinary Tract – May result from various pathologic conditions, including
BOO and DO
Symptoms: It’s Not All BPH – Should be used as a general term if disease is not
confirmed by histology or urodynamics
– Include all storage and voiding/ postmicturition symptoms
David O. Sussman, DO, FACOS that may result from prostatic disease or bladder
Department of Surgery dysfunction, or both
Division of Urology • Storage symptoms encompass OAB
University of Medicine and Dentistry of New Jersey
Stratford, New Jersey The use of incorrect and inconsistent terminology
Section Head, Urology may lead to confusion and mismanagement
Kennedy Health System of the conditions underlying male LUTS
Sewell, New Jersey
LUTS = lower urinary tract symptoms; BOO = bladder outlet obstruction;
DO = detrusor overactivity; OAB = overactive bladder. Chapple CR et al. Eur Urol . 2006;49:651 -659.
LUTS Are a Constellation of Prevalence of LUTS
Storage and Voiding Symptoms Increases With Age
Symptoms Often Relate to Bladder and Prostate 90
Storage Voiding Postmicturition 70
60 Weak stream
Urgency Hesitancy Postvoid dribble
Sense of 40 Frequency
Frequency Poor flow
Nocturia Intermittency 20
<49 50-59 60-69 70-79 80-84
Other incontinence Terminal dribble Age, years
Abrams P et al. Neurol Urodyn. 2002;21:167-178. N = 168. Homma Y et al. Scand J Urol Nephrol Suppl . 1994;157:27 -30.
LUTS Can Be Associated With the Evolving Terminology:
Bladder, the Prostate, or Both Prostatic Conditions
Bladder Condition Male Prostate Condition
Lower Urinary • Terms for prostatic conditions
Benign Prostatic Hyperplasia (BPH) – Prostatism implies prostatic disease
Histology – BPH means histopathologically confirmed
Urodynamic observation of
involuntary detrusor hyperplastic changes in the prostate
contractions during the filling Benign Prostatic Enlargement (BPE)
phase, which may be
– BPE is prostatic enlargement caused by BPH that
spontaneous or provoked has not been histologically confirmed
Benign Prostatic Obstruction (BPO) – BOO may be caused by BPE and is diagnosed by
OAB Prostate Obstruction due to size urodynamic pressure-flow studies
Urgency, with or without
urgency incontinence, usually BOO
– LUTS suggestive of BOO implies that BOO has
with frequency and nocturia not been confirmed with pressure-flow studies
Obstruction during voiding
characterized by increased detrusor
pressure and reduced
• Terms should be used only after confirmation of
urine flow rate the condition using the appropriate diagnostic
Abrams P et al. Urology.2003;61:37-49.
procedures Chapple CR et al. Eur Urol . 2006;49:651 -659.
BPH in Relation to Lower Urinary
Benign Prostatic Hyperplasia Tract Symptoms (LUTS)
• BPH is a potentially serious medical problem • BPH1
present in >50% of men older than 60 years of – Histologic evidence
age of stromal and
• Approximately 15%-30% of these men have epithelial hyperplasia
LUTS, but not all symptoms are caused by BPH • LUTS2
• BPH not only affects urination, but also – Presence of irritative
negatively affects patient quality of life (QOL) or obstructive voiding
symptoms, or both
• The pathophysiology of BPH, as a complex
disorder, is becoming increasingly understood Obstruction Hyperplasia
1. Bostwick DG. In: Kirby R et al, eds.Textbook of Benign
Thorpe A, Neal D. Lancet. 2003; 361:1359-1367. Prostatic Hyperplasia.Oxford, UK: Isis Medical Media Ltd; 1996.
Dull P et al. Am Fam Physician. 2002; 66:77-84,87-8. 2. Rosen R et al. Eur Urol. 2003;44:637-649.
Role of DHT in the
Development of BPH Consequences of BPH
Testosterone • LUTS
• Chronic urinary retention
• Incomplete Emptying
• Acute urinary retention
5-A R • Detrusor instability
• Sudden Urge
• Urinary tract infection • Weak Stream
DHT (UTI) • Straining
• Hematuria • Nighttime Frequency
• Renal insufficiency
5-AR = 5 -alphareductase. Lepor H, Lowe FC. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed.
DHT = dihydrotestosterone. Philadelphia, Pa: WB Saunders; 2002:1337-1377.
Prevalence of Histologic BPH
Increases With Age Pathophysiology of BPH
100 Dynamic Component Static Component
90 Detrusor Muscle Hypertrophy
80 Pradhan (1975)
Swyer (1944) Bladder
50 Harbitz (1972)
40 Fang-Liu (1991)
Franks (1954) Prostate
Karube (1961) Urethra
20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age, years Urinary Flow Obstruction
Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s
Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:1297-1336. Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:1297-1336.
Negative Effect of BPH on Daily QOL
Increases With Symptom Severity Evaluation of BPH
25 • AUA Symptom Score/(IPSS)
More Than a Little Interference
Percentage of Men Reporting
20 • QOL assessment
• Bother score
• Noninvasive uroflowmetry
5 * – Peak flow rate (PFR) (mL/s)
Getting enough Going places with Playing outdoor
• Postvoid residual urine
sleep no toilet sports
Mild symptoms Moderate or severe symptoms
– Ultrasound bladder scan
N = 2115. AUA=American Urological Association; Lepor H, Lowe FC. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed.
*Reported as 2%-4%. Girman CJ et al. Urology. 1994;44:825 -831. IPSS=International Prostate Symptom Score. Philadelphia, Pa: WB Saunders; 2002:1337-1377.
Goals of Therapy for BPH Treatment Options for BPH
• Minimally invasive therapy
Successful treatment of BPH results in • Watchful waiting
• Relieving LUTS • Pharmacologic therapy – TUNA
– Alpha-blockers (for BPH – WIT
• Decreasing BOO/improving bladder symptoms) • Less invasive surgery
emptying – 5-ARIs – VLAP
• Improving patient QOL – Combinations of the – TUVP
above • Major surgery
• Ameliorating detrusor instability – TURP (gold standard)
• Preventing progressive renal damage 5-ARIs=5a-reductase inhibitors; ILC = interstitial laser
– Open surgery
coagulation (also known as LITT); TUIP = transurethral
incision of prostate; TUMT = transurethral microwave (prostatectomy)
• Preventing episodes of hematuria, UTI, thermotherapy; TUNA = transurethral needle ablation;
TURP = transurethral resection of prostate; TUVP =
and AUR Lepor H, Lowe FC. In: Walsh PC et al, eds. Campbell’s Urology. 8th
transurethral electroevaporation of prostate; VLAP =
visual laser ablation of prostate; WIT = water
ed. Philadelphia, Pa: WB Saunders; 2002:1337 -1377. thermotherapy AUA Practice Guidelines Committee. J Urol. 2003;170:530-547.
First-Line Therapy Alpha-blockers in BPH
• Prescribed first-line medical therapy for BPH • Terazosin
– Long-acting α 1-blocker, available in 1-, 2-, 5-,
– Efficacy documented by multiple clinical and 10- mg doses; requires dose titration
– Long-term efficacy is less well documented – Long-acting α 1-blocker, available in 1-, 2-, 4-,
• Efficacy comparable among long-acting agents and 8-mg doses; requires dose titration
at appropriate therapeutic doses • Tamsulosin
– Long-acting α 1A-blocker, available as tablet in 0.4-mg dose;
• Results in improvement in symptoms dose titration suggested in case of insufficient efficacy
• Low risk for morbidity • Alfuzosin
– Can be discontinued at any time – Long-acting α 1-blocker, available as 2.5 mg tid,
5 mg bid, and 10 mg qd; no dose titration recommended
The Italian Alfuzosin Co-Operative Group. Eur Urol. 2000;37:680-686.
Narayan P, Tewari A. Urology. 1998;51(suppl 4A):38 -45. Physician’s Desk Reference 2004. Montvale, NJ: Thomson PDR; 2004.
Vallancien G. Urology. 1999;54:773-775. Roehrborn CG. AUA 2005.
Role of 5-ARIs in the
Development of BPH Overlapping of Conditions in Men
5-ARI >40 Years
Reduced prostate size
Knutson T et al. Neuro Urodyn. 2001;20:237 -247.
ICS Definition: Overactive Bladder Prevalence of OAB in EU and US
EU SIFO Study US NOBLE Study
• OAB is defined as urgency, with or
Milsom I et al. 2001 Stewart et al. 2003
without urgency incontinence, usually 40 35
with frequency and nocturia
30 Women Women
40–44 45–49 50–54 55–59 60–64 65–69 70–74 75+ 18-2 4 25-3 4 35-4 4 45-5 4 55-6 4 65-7 4 75+
Age, years Age, years
Milsom I et al. BJU Int. 2001;87:760-766.
ICS = International Continence Society. Abrams P et al. Urology.2003;61:37-49. EU = European Union. Stewart W et al. World J Urol . 2003;20:327-336.
Symptoms That Define OAB OAB: Pathophysiology
Storage Voiding Postmicturition • Storage
Urgency Hesitancy Postvoid dribble – Sympathetic nerve fibers originating from
Sense of the TH11 to L2 segments of the spinal cord
Frequency Poor flow
innervate smooth muscle fibers around the
bladder neck and proximal urethra
incontinence • Muscle fibers contract for normal filling
Terminal – Somatic fibers innervate the external
sphincter and are responsible for the
voluntary control of continence during a
Abrams P et al. Urology.2003;61:37-49
pressing desire to void
OAB in Men Can Be Diagnosed
OAB: Pathophysiology (cont) Using LUTS Assessment Protocol
• Voiding LUTS OAB
– Upon filling, sensory stretch receptors in the
bladder wall trigger a central nervous system
(CNS) response Symptoms
IPSS Questionnaire (storage and voiding)
– The parasympathetic nervous system (PNS), from
S2-S4 segment, causes contraction of the
detrusor muscle; muscles of the pelvic floor and Physical examination
external sphincter relax
– Urination can be prevented by cortical
suppression of the PNS or by voluntary PSA (as indicated, based on age)
contraction of the external sphincter
IPSS = International Prostate Symptom Score.
Current Therapeutic Options: Men With LUTS Are Predominantly Treated
Men With OAB Symptoms With BPH Agents Rather Than OAB Agents
• Although other pharmacologic 60
OAB & BPH (n = 4806)
mechanisms are theoretically attractive
50 47 OAB & No BPH (n = 12,192)
and some show promise in animal 40
models, strong clinical proof of concept is 30
lacking for all except 20
– α1-Adrenergic receptor antagonists 10 8
(α-blockers) No Rx BPH Rx OAB Rx OAB &
only only BPH Rx
– Antimuscarinic agents
*Type of Treatment
– 5-ARIs Athanasopoulos A et al. J Urol. 2003;169:2253-2256. *Data were obtained from medical and pharmacy claims
Naderi N et al. Curr Opin Urol. 2004;14:41-44. databases of diverse managed care plans.
Roehrborn CG et al. Urology. 2004;63:709-715. Rx = treatment. Jumadilova Z et al. Abstract. ICS 2005.
Recent Clinical Data Support Antimuscarinic Therapy in
the Use of Antimuscarinics in Men Patients With OAB: Rationale
• Several recent studies evaluated tolterodine in • Etiology
male patients with DO and concomitant BOO – Neurogenic
(symptomatic, urodynamic, or both) • Lack of CNS inhibition
– Tolterodine IR added to doxazosin in doxazosin • Parasympathetic leak during filling/storage
nonresponders • Increased afferent input or sensitivity, or both
– Tolterodine ER monotherapy in men who were – Myogenic
nonresponsive to a-blocker therapy • Denervation with increased spontaneous action
– Tolterodine IR added to tamsulosin potentials and coupling
• Micromotion (PS leak)
– Safety of tolterodine IR in men with DO and BOO
• Exaggerated or uninhibited autonomous activity
Lee JY et al. BJU Int. 2004; 94:817-820.
Kaplan S et al. J Urol. 2005;174:2273 -2276.
Athanasopoulos A et al. J Urol. 2003; 169:2253-2256.
IR = immediate release; ER = extended release. Abrams P et al. Neurourol Urodyn. 2001; 547-548.
Antimuscarinic Treatment Options Tolterodine IR Added to Doxazosin in
for Patients With OAB α -Blocker Nonresponders : Study Design
Drug Dose Frequency • Prospective, controlled trial
Darifenacin 7.5 – 15 mg QD • Study objective
Oxybutynin 5 – 30 mg BID or TID – To determine whether adding tolterodine IR to
Oxybutynin XL 5 – 15 mg QD a-blocker therapy, versus a-blocker alone,
Oxybutynin (patch) 3.9 mg/d 1 patch × 2W provides clinical benefit
Solifenacin 5 – 10 mg QD • Patient population
Tolterodine LA 4 mg QD – Male patients (n = 144) with mild to moderate
Trospium 20 mg BID BOO, alone or with DO
– PSA <6 ng/mL, no history of urologic surgery
• Improvement defined as >3-point reduction in
QD = once daily; BID = twice daily;
TID = three times daily; 2W = twice weekly. Adapted from Medical Letter. 2005; 47:23-24 PSA = prostate-specific antigen. Lee JY et al. BJU Int. 2004;94:817-820.
Tolterodine IR Added to Doxazosin in Tolterodine IR Added to Doxazosin
α-Blocker Nonresponders: Results in α-Blocker Nonresponders: Safety
Improvement was defined as >3 -point reduction in IPSS
• Addition of tolterodine IR did not increase
BOO and DO the incidence of AUR
Improved – AUR occurred in 1 of 60 patients taking
n = 24 Improved
35% n = 32 tolterodine IR + doxazosin (1.7%) and in 1
73% NOT of 84 patients receiving doxazosin
n = 44 n = 12
– Both cases of AUR resolved after drug
+ cessation and overnight catheterization
Lee JL et al. BJU Int.2004;94:817-820.
Lee JL et al. BJU Int. 2004;94:817-820. Data on file. Pfizer Inc.
Acute Urinary Retention Experimental Pharmacotherapy
in Perspective Alternatives in OAB
• In the general population, BPH can progress to BOO and Agent Proposed Mechanism of Action
then to AUR GABA receptor agonists Inhibits voiding reflex
– AUR occurred in 2.4% (n = 737) of men with BPH receiving Inhibits acetylcholine release at neuromuscular
placebo for 4.5 years in the MTOPS study junction
– AUR occurred in 2.9% (n = 556) of men with BPH over a 3- Vanilloids/afferent nerve Desensitize unmyelinated C fibers
year period from the Veterans Affairs Cooperative Study in inhibitors
the watchful- waiting arm Decrease Ca++ available for smooth
Calcium channel blockers
• Published open -label and active-comparator studies muscle contraction
show that tolterodine LA (long-acting) is associated with Inhibitors of prostaglandin May increase contraction of bladder
no increased risk for AUR synthesis smooth muscle
Decrease spontaneous smooth
• Placebo-controlled studies show that tolterodine LA is Potassium channel openers muscle contractions
associated with no increased risk for AUR (versus Dopamine D1 receptor agonists Inhibits the voiding reflex
Nerve growth factor inhibitors Modulates sensory afferent function
Gonzalez RR et al. Curr Urol Reports. 2003;4:429-435.
McConnell JD et al. N Engl J Med 2003;349:2387-2398. Enkephalins Suppress the voiding reflex
Wasson JH et al. N Engl J Med 1995;332:76-79.
Abrams P et al. Neurourol Urodyn. 2005;24:495 -496.
Abrams P et al. Neurourol Urodyn. 2001;20:547 -548. Ouslander JG. N EnglJ Med. 2004;350:786-799.
Gaps in Current Data on Redefining the Treatment of Men
Treating OAB in Men With LUTS: Summary
• Efficacy • 6 of 10 men have LUTS
– Small, open -label, non –placebo- controlled studies – Storage symptoms are more prevalent than voiding
symptoms in men
– Patients enrolled based on a urodynamic rather than a
symptomatic OAB diagnosis • In men with LUTS, BPH is the presumed diagnosis, and the
– No data collected via OAB instruments (eg, micturition initial treatment is with α -blockers
diary, patient-centric end points, QOL) • Men with LUTS may have OAB
• Safety – OAB and prostatic conditions may coexist
– The number of patients treated with antimuscarinics alone • The prevalence of OAB is as high in men as in women
or in combination with a-blockers is small • Many men with LUTS and OAB treated with α-blockers
– Duration is mostly 3 months (43 patients—for 6 months) continue to have persistent storage (or OAB) symptoms
after pharmacologic or surgical prostate treatment
Irwin et al. Abstract. EAU 2006.
Stewart WF et al. World J Urol . 2003;20:327-336.
Knutson T et al. Neuro Urodyn. 2001;20:237 -247.
Jumadilova Z et al. ICS 2005.
Kaplan S et al. J Urol. 2005;174:2273 -2276. Machino R et al. Neurourol Urodyn. 2000;21:444 -449.
Redefining the Treatment of Men Redefining the Treatment of Men
With LUTS: Summary (cont’d) With LUTS: Summary (cont’d)
• Tolterodine LA is approved for the treatment of • Published open-label and active -
OAB in men and women
comparator studies show that tolterodine
• Treatment with tolterodine of OAB in men and LA is associated with no increased risk
women showed significant effectiveness on
OAB symptoms for AUR
• Male patients with LUTS and presumed BOO are • Placebo-controlled studies show that
generally treated for prostate -related conditions tolterodine LA is associated with no
increased risk for AUR (versus placebo)
• An antimuscarinic can be added if OAB
symptoms persist Kaplan S et al. J Urol. 2005;December.
Jumadilova Z et al. ICS 2005. Kaplan S et al. J Urol. 2005;174:2273 -2276.
Lee JY et al. BJU Int. 2004;94:817 Lee JY et al. BJU Int. 2004;94:817.
Athanasopoulos A et al. J Urol. 2003;169:2253-2256. Athanasopoulos A et al. J Urol. 2003;169:2253-2256.
Abrams P et al. Neurourol Urodyn. 2001;20:547 -548. Abrams P et al. Neurourol Urodyn. 2001;20:547 -548.