UROLOGY AND WOMEN
| URINARY INCONTINENCE: PATHOPHYSIOLOGY AND PHARMACOLOGIC MANAGEMENT —Karl Luber, MD,
Clinical Professor, University of California, San Diego, School of Medicine, and Director, Female Pelvic Medicine and Reconstructive
Pelvic Surgery, Kaiser Foundation Hospital, San Diego
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| Neurophysiology of lower urinary tract: neurotransmitters and segmental regulation control storage and voiding
of urine throughout lower urinary tract
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 | Anterior cingulate gyrus (ACG): site where decision-making occurs, eg, individual with severe cerebrovascular accident
(CVA) affecting ACG experiences marked neurogenic-like incontinence; point—adding antimuscarinic agent at bladder
level appears to be “blunt instrument” for managing centrally (forebrain) mediated changes in neurotransmission
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| Pontine micturition center: dopamine (DA) mediation (down-regulation with dopamine type 1 [DA-1], up-regulation
with dopamine type 2 [DA-2]); Parkinson’s disease—disrupts DA secretion; patients can develop detrusor hyperreflexia
(DA-1 inhibition decreases at micturition center); most drugs for Parkinson’s disease exacerbate incontinence by
further offsetting balance between DA-1 and DA-2 at level of micturition center; point—new therapeutic modalities
may target specific patients with DA-1 agonist
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| Spinal cord injury: causes areflexia followed by hyperreflexia; effect provides window into plasticity of lower urinary
tract physiology; urothelium—key to managing lower urinary tract storage; changes dramatically ≤72 hr after injury;
dyssynergia—can be down-regulated by overdriving vanilloid receptors; C-fibers, once believed to function primarily
as pain receptors, suddenly become mechanoreceptors at segmental level after spinal injury
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| Bladder overactivity: heterogeneous condition; usually idiopathic
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| Factors under investigation: changes that transform detrusor muscle function from independent firing mechanism to syncytium;
messenger RNA (mRNA) production in obstructed vs unobstructed bladders; bladder pressure during urge—
does not increase in most patients; finding suggests involvement of some other nonmotor-related activity; age-related
changes (atropine resistant contractions)—density of muscarinic receptors in bladder decreases with age; purinergic
receptors increase in importance as individuals age (primarily mediated by adenosine triphosphate [ATP]; ability to
block receptors with tetrodotoxin suggests scenario may involve presynaptic modification); treatment targeting muscarinic
receptors probably inappropriate; β3 -adrenergic stimulation—hypogastric-mediated; occurs early in storage
phase; relaxes bladder; 50% of selected patients with overactive bladders have specific mutation of β-adrenergic receptors;
clinical trials currently investigating role of β3 -adrenergic feedback agonists in treatment of bladder overactivity;
controlling bladder overactivity at level of motor end plate—interstitial cells, neurotransmitters (generated and received),
and receptors play key role in afferent nerve activity; changes at level of urothelium affect adjacent nerves
(changes in release of ATP and nitric oxide occur);
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| Studies of receptor binding—high density of muscarinic receptors at level of urothelium and interstitial cells; bottom
line—better understanding of multifactorial nature of detrusor overactivity will lead to more focused care
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| Antimuscarinics: helpful; change concentration of calcium within cell by blockading postganglionic M3 receptors; although
difficult to distinguish from one another in clinical setting, each drug in class has particular characteristic; eg, because
high levels of active trospium chloride (Sanctura) excreted in urine, drug may exert more effect on urothelial cells;
therapeutic results can be idiosyncratic (eg, patient who responds poorly to one antimuscarinic may do well with different
antimuscarinic); bottom line—although useful option now, antimuscarinics may have more limited role in future;
recommendations—use all available pharmacologic options; if results unsatisfactory, switch drugs; do not double-up on
medications (all antimuscarinics have same mechanism of action; “overpopulating” receptors with blockade probably ineffective);
be flexible when changing drugs and dosing; provide patient with realistic expectations about efficacy of drug
therapy (some patients do not respond to antimuscarinics)
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| Vanilloid receptor agonists at level of urothelium: resiniferatoxin (RTX)—overdrives afferent receptors in
urothelium (C-fibers); depletes neurotransmitter supply; in absence of detrusor contractions, bladder continues to fill;
factors preventing widespread use—lack of reproducible results; difficulty producing marketable quantities of compound
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| Botulinum toxin type A (Botox) administered at level of urothelium: focuses on end point, not cause of
bladder dysfunction; patients perceive afferent change (eg, reduction in pain) before experiencing change in motor function;
when injected into bladder—interrupts mechanism by which vesicles fuse with cell membrane and release neurotransmitters,
ie, cleaves synaptosome-associated protein of 25 kDa (SNAP-25); exerts afferent effect by changing
receptor density; Botox administered to patients with neurogenic disease probably valuable management tool; in nonneurogenic
disease, can probably achieve good outcome at lower doses; clinical data on Botox—when injected into
smooth muscle of bladder, lasts longer than when injected into skeletal muscle; higher doses seem to be associated with
longer duration of therapy; predisposes patients to urinary retention (retention in study population resolved at ≤6 mo)
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| URETHRAL PRESSURE PROFILES: WHY I USE THEM —Peter K. Sand, MD, Professor, Department of Obstetrics
and Gynecology, Director, Division of Urogynecology, and Director, Evanston Continence Center, Evanston Northwestern
Healthcare, Northwestern University Feinberg School of Medicine, Chicago, IL
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| Urinary stress incontinence (USI): urine loss occurring when increased intra-abdominal pressure and subsequent increase
in bladder pressure overcomes intrinsic urethral pressure at specific moment in time; incontinence in women—
unequal transmission of pressure to bladder and urethra caused by loss of posterior urethral support (eg, patient who has sustained
neuromuscular damage cannot generate normal reflex contraction of skeletal muscle)
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| Intrinsic sphincteric dysfunction (ISD): develops when there is loss of intrinsic smooth and skeletal muscle function;
proximal urethra—no longer functions as sphincter in vesical neck; may be open at rest in absence of bladder contraction;
diagnostic tools—standing stress test (objective demonstration of stress incontinence); supine empty-bladder
stress test (useful screening tool; 90% positive predictive value for leak point pressures and low-pressure urethras on urethral
closure pressure profile [UCPP]); urethral closure pressure profilometry (maximum cystometric capacity occurs with
sitting; predicts surgical outcome and ISD); Valsalva leak point pressure (VLPP); cystourethroscopy (evaluate open bladder
neck at rest)
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| Evaluation of UCPP: helps in understanding normal urethral physiology, pathophysiology of USI, and effect of urethral
abnormalities on function; diagnoses ISD; predicts surgical outcome for USI
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| Sphincteric function: normal sphincteric function—intrinsic component (factors creating pressure in urethral wall at
rest); extrinsic component (adequate anatomic support to allow for equal transmission of increased abdominal pressure to
bladder and urethra); intrinsic sphincteric mechanism—has mucosal seal; intrinsic urethral pressure (intrinsic smooth and
skeletal muscle and periurethral vasculature each contribute ≈30% of baseline urethral pressure; fibroconnective tissues
contribute ≈10% of resting pressure); with stress and increased abdominal pressure, capillary beds empty out and reduce
their contribution to maintaining intrinsic pressure; smooth muscle and fibroconnective tissue activity decreases in importance;
skeletal muscle takes control of urethral function; extrinsic sphincteric mechanism—passive transmission of intra-
abdominal pressure to lumen; active contraction of pelvic floor skeletal muscle
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| Measuring urethral function: stress UCPP—measures intrinsic and extrinsic sphincteric mechanisms; evaluates
pressure transmission ratios; Valsalva and cough leak point pressures—measures extrinsic and intrinsic sphincteric
mechanisms; best test for measuring USI and assessing voiding artifacts; resting UCPP—best way to measure intrinsic
sphincteric function or mechanism; evaluates status of anatomic factors contributing to resting urethral tone; best test for
measuring ISD
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| UCPP in practice: approach—pull microtip transducer catheter through length of urethra and measure urethral pressures;
calculate urethral closure pressure by subtracting bladder pressure from urethral pressure; utility of dynamic UCPP
data—evaluate activity (eg, coughing, Valsalva maneuver, lifting) that can cause urine leakage and determine whether
patient has positive or negative pressure transmission; calculate pressure transmission ratios to determine incremental
differences in urethral pressure, compared to differences in bladder pressure; predict surgical outcome; women with
UCPP values of—≤20 cm H2 O at increased risk of failing Burch retropubic urethropexy; ≤42 cm H2 O at markedly increased
risk of failing transobturator midurethral sling surgery, compared to retropubic midurethral sling surgery;
point—UCPP evaluation can be reimbursed using current procedural terminology code (CPT) 51772
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| INTERSTITIAL CYSTITIS: RECENT ADVANCES IN MANAGEMENT —Raymond Rackley, MD, Professor of Surgery,
Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, and Co-Section Head, Section of
Voiding Dysfunction and Female Urology, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH
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| Interstitial cystitis (IC): cognitive diagnosis based on symptoms; urgency/frequency—bladder pain revolves around
cycle of filling and emptying; patients must urinate day-and-night to relieve pain; diagnosis—urethral syndrome (patient
limits voiding to avoid dysuria); irritable bowel syndrome (IBS; diarrhea and constipation alternate with pain)
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| Three-visit evaluation process to confirm or exclude IC
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| Visit 1: history and physical examination—evaluate symptomatology; assess most recent pelvic imaging data (magnetic
resonance imaging [MRI] of pelvis preferable); perform physiologic testing; obtain cultures—essential; rule out bacterial
and fungal infections; obtain acid-fast bacilli and tuberculosis evaluation when patient has pyuria; Ureaplasma/
Mycoplasma—involved in development of irritative voiding symptoms in lower urinary tract; should be cultured as
part of diagnosis of exclusion; responsible for symptoms in 48% of patients believed to have IC (inadequate culture
evaluation responsible for misdiagnosis; problem resolves with proper treatment); women with muscle-invasive infections
have undergone cystectomies after 6 mo of ineffective antibiotic therapy; vaginal swab—key to diagnosing
lower urinary tract infections, ie, infections move from vagina, to bladder, and into upper tract; antimicrobial options
doxycycline 100 mg bid for ≥14 days preferred; ofloxacin (second-favorite drug; only quinolone capable of killing
Ureaplasma and Mycoplasma); azithromycin (expensive); levofloxacin (Levaquin; reserved for patients requiring
broad-spectrum coverage); many drugs do not eradicate organisms on first pass—rugae of vaginal wall provide hiding
spaces for bacteria; proper environmental pH necessary for antibiotic to dissociate; patient can be reinfected by asymptomatic
carrier (ie, sexual partner who has keratinized epithelium along phallus and does not develop intracellular
infection per se); points—treat infection as sexually transmitted disease, not normal vaginal flora; cytologic evaluation
facilitates detection of Trichomonas and fungal infections
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| Visit 2: lidocaine instillation test—diagnostic; indicated if urodynamic evaluation suggestive of IC (ie, pain prevents patient
from holding much fluid during early filling); positive for IC if lidocaine eliminates pain; if test positive, treatment
can probably be initiated; MRI of pelvis—best study for looking through bony pelvis; rules out occult urethral
diverticulum (second most common diagnosis when trying to exclude IC); obtain T2-weighted image in sagittal plane
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| Visit 3: when necessary, examination can be performed under anesthesia; hydrodistention—can help bladder heal; if
technique beneficial previously, procedure can be performed; positive effect temporary; diagnostic laparoscopy—
performed when indicated
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| Algorithm for urothelial injury: if epithelial layer damaged—pentosan polysulfate sodium (Elmiron) may be administered;
avoid potassium-containing foods that activate C-fibers and anti-inflammatory agents that cause further tissue
damage; sleep medications—zolpidem (Ambien); acetaminophen with diphenhydramine (Tylenol PM); pain
medications—phenazopyridine/hyoscyamine/butabarbital (Pyridium Plus); gabapentin (Neurontin); cystectomy—
eliminates pain in select patients when other treatment options fail; if pain persists after surgery, IC wrongly diagnosed;
other options—Bacillus Calmette-Guérin (BCG); immunosuppression; neuromodulation (results poor)
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| Background data: IC—contains inflammatory component (indicated by pain with urgency/frequency); involves
urothelial disease (glomerulization and ulcerations in bladder); hypothesis—individuals with IC have genetic predisposition
to develop urothelial cell apoptosis when clinically challenged; concept supported by data showing that in IC, cells
develop increased rate of apoptosis when stressed by cytokine (eg, tumor necrosis factor [TNF]-α); genetic epithelial cell
predisposition—can be protective; originated as defense against schistosomiasis; reduces risk for epithelial malignancy;
aspirin and celecoxib (Celebrex; cyclooxygenase-2 [COX-2] inhibitor)—cause epithelial cells to undergo apoptosis; create
iatrogenic problem when given to individuals with IC
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| Uroepithelial healing in patients with pelvic pain : eliminate aspirin and NSAIDs; alternative agents include tramadol
(Ultram), acetaminophen, and narcotics (when necessary); to offset adverse effects of NSAIDs, administer misoprostol
(Cytotec; has eliminated need for cystectomy; patients can receive oral Cytotec 200 µg bid or tid)
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| Instillation approach: most effective means to facilitate recovery; achieves 100% bioavailability; teach patients intermittent
catheterization—infuse 1 vial Cytotec (50 mL) with combination of 1% lidocaine and 1 capsule sodium bicarbonate
into bladder (sodium bicarbonate alkalinizes urine and enhances tissue penetration of lidocaine); points—
improvement in 4 to 6 wk; number of daily infusions can be reduced over time; when IC and pain eliminated, switch to
oral Cytotec; contraindicated in pregnant women—Cytotec affects prostaglandins and causes spontaneous abortion;
as precaution, women undergoing therapy require contraceptives
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| Additional points: oral Cytotec can also be used to manage—pelvic pain syndrome; IBS (100% bioavailable in gastrointestinal
tract); endometriosis (drug increases turnover of parietal epithelium); physician’s role—provide patient with
pain relief; promote healing of uroepithelium; eliminate offending agents; caveats—patients with IC do not realize that
aspirin-type phytochemicals found in diet, and that naproxen and ibuprofen can be harmful
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Suggested Reading
Biers SM et al: The effects of a new selective ⓷-adrenoceptor agonist (GW427353) on spontaneous activity and detrusor
relaxation in human bladder. BJU Int 98:1310, 2006; Hegde SS: Muscarinic receptors in the bladder: from basic research
to therapeutics. Br J Pharmacol 147:S80, 2006; Kelly JD et al: Clinical response to an oral prostaglandin
analogue in patients with interstitial cystitis. Eur Urol 34:53, 1998; Kuo HC et al: Therapeutic effect of multiple resiniferatoxin
intravesical instillations in patients with refractory detrusor overactivity: a randomized, double-blind, placebo
controlled study. J Urol 176:641, 2006; Payne CK, Kelleher C: Redefining response in overactive bladder syndrome.
BJU 99:101, 2007; Rackley RR: Association of chronic urinary symptoms in women and Ureaplasma urealyticum.
Urology 55:486, 2000; Sahai A et al: Botulinum toxin for detrusor overactivity and symptoms of overactive bladder:
where we are now and where we are going. Nat Clin Pract Urol 4:379, 2007; Sand PK et al: The prognostic significance
of augmentation of urethral closure pressure and functional length. Int J Gynaecol Obstet 33:135, 1990; Sellers DJ,
McKay N: Developments in the pharmacotherapy of the overactive bladder. Curr Opin Urol 17:223, 2007.
Educational Objectives
| The goal of this program is to improve management of urinary incontinence and interstitial cystitis (IC) in women. After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe the pathophysiology of bladder overactivity.
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| 2. Assess the role of antimuscarinic drug therapy, vanilloid-receptor agonists, botulinum toxin, and β3 -adrenergic replacement
therapy in the management of bladder overactivity.
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| 3. Define the diagnostic role of urethral pressure profile studies.
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| 4. Review current data on the pathophysiology of IC.
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| 5. Implement a therapeutic approach that promotes uroepithelial healing in patients with IC.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Rackley is affiliated with Allergan, AMS,
Astellas Pharma Inc, BSC, ICA, NDI Medical, Novartis, and Pfizer; Dr. Sand is affiliated with AMS and Boston Scientific.
Acknowledgments
Drs. Luber and Rackley gave their scientific presentations at 2006 Update in Female Urology and Urogynecology presented
October 27-28, 2006, in Cleveland, OH, by the Cleveland Clinic; Dr. Sand gave his scientific presentation at Advances
in Urogynecology and Reconstructive Pelvic Surgery, presented June 8-10, 2006, in Chicago, IL, by the
Northwestern University Feinberg School of Medicine and the Evanston Continence Center, Evanston Northwestern
Healthcare. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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