Urology UpdateUrology Update

Douglas C. Bauer, MDDouglas C. Bauer, MD

University of California, San FranciscoUniversity of California, San Francisco

No disclosuresNo disclosures

OverviewOverview

• Microscopic hematuriaMicroscopic hematuria

• Urinary incontinenceUrinary incontinence

• Benign prostatic hypertrophyBenign prostatic hypertrophy

• ImpotenceImpotence

• ProstatitisProstatitis

• Prostate cancer treatmentProstate cancer treatment

CasesCases

• 26 WF, 326 WF, 3rdrd episode of gross episode of gross hematuria, one following URIhematuria, one following URI

• 77 BM, microscopic hematuria. 77 BM, microscopic hematuria. Smoker. Asymptomatic. Smoker. Asymptomatic.

Microscopic hematuriaMicroscopic hematuria

• Defined as >3-5 RBC/HPFDefined as >3-5 RBC/HPF

• Common (even in young)Common (even in young)– Yearly UAs in soldiers for 16 yr: 39%Yearly UAs in soldiers for 16 yr: 39%– Fear of malignancy Fear of malignancy

Etiology: age dependentEtiology: age dependent

• Glomerular: IgA, thin basement (<50), Glomerular: IgA, thin basement (<50), Alport’s (>50), other GNAlport’s (>50), other GN

• Non-glomerular (upper): nephrolith, Non-glomerular (upper): nephrolith, renal cell CA (>50), polycystic kidneyrenal cell CA (>50), polycystic kidney

• Non-glomerular (lower): cytitis, Non-glomerular (lower): cytitis, prostatitis, urethritis, bladder CA (>50)prostatitis, urethritis, bladder CA (>50)

• Other: exercise, anti-coag, factitiousOther: exercise, anti-coag, factitious

Diagnostic evaluationDiagnostic evaluation

• Repeat dipstick unless risk factorsRepeat dipstick unless risk factors

• Rule out proteinuria, azotemia, infectionRule out proteinuria, azotemia, infection

• Imaging: helical CT vs. sonoImaging: helical CT vs. sono

• Procedures: cystoscopy if risk factors for Procedures: cystoscopy if risk factors for cancer or >50cancer or >50

Other issuesOther issues

• Cytology not recommendedCytology not recommended

• Phase contrast microscopy identifies Phase contrast microscopy identifies glomerular source (dysmorphic)glomerular source (dysmorphic)

• Screening not cost-effectiveScreening not cost-effective

• Natural history of IgA uncertainNatural history of IgA uncertain

–Fish oil?Fish oil?

CasesCases

• 56 female, 30+ years of worsening UI 56 female, 30+ years of worsening UI with cough, exercise. with cough, exercise.

• 40 female, several years of episodic 40 female, several years of episodic urgency, occasional UI. Worse with urgency, occasional UI. Worse with coffee, EtOHcoffee, EtOH

Urinary incontinenceUrinary incontinence

• CommonCommon

– 25% reproductive age women25% reproductive age women

– 40% postmenopausal women40% postmenopausal women

• Chronic Chronic - social seclusion- social seclusion Falls & FracturesFalls & Fractures 3x Nursing home admits3x Nursing home admits

• CostlyCostly

– $26 billion annually$26 billion annually

– More than all cancer care for womenMore than all cancer care for women

Incontinence definitionsIncontinence definitions

• Overactive Bladder (OAB)Overactive Bladder (OAB)

- urge incontinence , frequency, nocturia- urge incontinence , frequency, nocturia

• StressStress -coughing, sneezing, straining, exercise -coughing, sneezing, straining, exercise

• MixedMixed - both urge and stress - both urge and stress

• Other Other - neurologic, obstruction- neurologic, obstruction

Stress vs. urge incontinenceStress vs. urge incontinence

SymptomSymptom StressStress UrgeUrge

• PrecipitantPrecipitant activity activity urgeurge

• TimingTiming immediate immediate delayeddelayed

• AmountAmount small-mod small-mod largelarge

• Nocturia Nocturia rare rare commoncommon

• RemissionsRemissions rare rare commoncommon

Evidence-based guidelinesEvidence-based guidelines

1996 AHRQ Clinical Practice Guidelines:1996 AHRQ Clinical Practice Guidelines:

Primary Care diagnosis & treatmentPrimary Care diagnosis & treatment

History, neurologic & pelvic exam, PVR, U/AHistory, neurologic & pelvic exam, PVR, U/A

10 years later, where are we?10 years later, where are we?

Barriers for Primary Care:Barriers for Primary Care:

• Work up too time consuming & complexWork up too time consuming & complex

• No pelvic exam tablesNo pelvic exam tables

• PVR frequently not possiblePVR frequently not possible

DDiagnostic iagnostic AAspects of spects of IIncontinence ncontinence SStudtudyy ((DAISyDAISy))

• Cross-sectional study (N = 301), 6 US centersCross-sectional study (N = 301), 6 US centers– 3 incontinence questions (3 IQ) vs. full evaluation3 incontinence questions (3 IQ) vs. full evaluation

• 3 questions3 questions

1.1. During the last 3 months, have you leaked During the last 3 months, have you leaked

urine, even a small amount? If yes:urine, even a small amount? If yes:

2.2. Stress UI:Stress UI: physical activity, coughing, sneezing, lifting, or physical activity, coughing, sneezing, lifting, or exerciseexercise

Urge UI:Urge UI: urge, feeling need to empty but could not get to the urge, feeling need to empty but could not get to the toilet fast enoughtoilet fast enough

3.3. Type of UI Type of UI most oftenmost often: Stress, Urge, Mixed, Other: Stress, Urge, Mixed, Other Brown Annals 2006Brown Annals 2006

Accuracy of 3 IQ Accuracy of 3 IQ compared to full evaluationcompared to full evaluation

SensitivitySensitivity SpecificitySpecificity PPVPPV LR+LR+

UrgeUrge

3IQ3IQ 0.75 0.75 0.770.77 0.790.79 3.263.26

StressStress

3IQ3IQ 0.860.86 0.600.60 0.740.74 2.132.13

Summary: screening for incontinenceSummary: screening for incontinence

Primary Care Clinicians:Primary Care Clinicians:

3 IQ to classify type of UI3 IQ to classify type of UI

DAISy Take Home Message: DAISy Take Home Message:

3 IQ is a good test for type of UI, especially because the 3 IQ is a good test for type of UI, especially because the risk of missed Dx and Rx lowrisk of missed Dx and Rx low

Indentification is critical to reducing burden of UI!Indentification is critical to reducing burden of UI!

Initial visitInitial visit

• Clinical diagnosis - Clinical diagnosis - 3 IQ, UA3 IQ, UA

• Patient informationPatient information

• Urinary diaryUrinary diary

• Bedside commodeBedside commode

• Topical estrogens?Topical estrogens?

• Weight loss?Weight loss?

• Consider RxConsider Rx

Behavioral vs. medsBehavioral vs. meds

• 197 women with Urge UI; RCT197 women with Urge UI; RCT

UIUI

• Biofeedback/behavioral Biofeedback/behavioral 81%81%

• MedicationMedication 69%69%

• PlaceboPlacebo 40%40%

Greater satisfaction in behavioral groupGreater satisfaction in behavioral group

Burgio 1998Burgio 1998

Patient informationPatient information

• 222 women with Urge UI: RCT222 women with Urge UI: RCT

ImprovedImproved

• BiofeebackBiofeeback 63% 63%

• Verbal/vaginal instructVerbal/vaginal instruct 69% 69%

• Self-help bookletSelf-help booklet 59% 59%

Not statistically differentNot statistically different

Burgio JAMA 2002Burgio JAMA 2002

Urinary diaryUrinary diary

• Simple form for recording voids, Simple form for recording voids, incontinent episodes, fluid intakeincontinent episodes, fluid intake

• Excellent education & intervention!Excellent education & intervention!

• Very useful in planning therapyVery useful in planning therapy

-fluid adjustment-fluid adjustment

-timing and type of medications-timing and type of medications

Incontinence treatmentIncontinence treatment

• Initial Rx similar for stress & urge Initial Rx similar for stress & urge

• Behavioral ManagementBehavioral Management

- Fluids modification- Fluids modification

- Pelvic Floor Exercises- Pelvic Floor Exercises

- Bladder training- Bladder training

• Verbal and written instructionsVerbal and written instructions

Successful pelvic floor exercisesSuccessful pelvic floor exercises

• Strengthen levator ani and sphincter Strengthen levator ani and sphincter

• Two fingers in the vagina, one hand on the Two fingers in the vagina, one hand on the abdomenabdomen

• Two types: rapid and prolongedTwo types: rapid and prolonged

• Individualized programIndividualized program

• CoughingCoughing

Bladder trainingBladder training

• Re-establishing voluntary controlRe-establishing voluntary control

• Schedule voids q 30-60 minutes Schedule voids q 30-60 minutes

• Diary, relaxation, urge suppressionDiary, relaxation, urge suppression

• RCT demonstrated:RCT demonstrated:

≥ ≥ 50% improvement in 75% of participants50% improvement in 75% of participants

• Stress and Urge UI (Fantyl 1991)Stress and Urge UI (Fantyl 1991)

OAB medication effectivenessOAB medication effectiveness

• Subjective cureSubjective cure 40-60% 40-60% vs. vs. placeboplacebo 20-40%20-40%

• Long-term “success” Long-term “success” 50%50%• Side effects Side effects 50%50%• Discontinuation Discontinuation 10-65%10-65%

Bottom line: Medications very similar!Bottom line: Medications very similar!

OAB medicationsOAB medications

Side effects:Side effects: dry mouthdry mouthconstipationconstipationdrowsinessdrowsinessblurred visionblurred visiondizzinessdizziness

Contraindications:Contraindications: narrow angle glaucomanarrow angle glaucomahepatic/renal diseasehepatic/renal disease

Medication prescribing guidelineMedication prescribing guideline

Immediate ReleaseImmediate Release

• Oxybutynin (Ditropan) Oxybutynin (Ditropan)

• Tolterodine (Detrol) Tolterodine (Detrol)

• Trospium (Santura)Trospium (Santura)

Extended releaseExtended release

• Darifenacin (Enablex)Darifenacin (Enablex)

• Ditropan XLDitropan XL

• Solifenacin (Vesicare)Solifenacin (Vesicare)

• Detrol LADetrol LA

• Oxybutynin Oxybutynin transdermal (Oxytrol)transdermal (Oxytrol)

CaseCase

• 63 WM, progressive nocturia, 63 WM, progressive nocturia, hesitancy. PSA 6.hesitancy. PSA 6.

Benign prostatic hypertrophyBenign prostatic hypertrophy

• 80% by age 80 years 80% by age 80 years –50% have had a prostatectomy50% have had a prostatectomy

• Prostate grows throughout lifeProstate grows throughout life–Until (unless) testosterone is goneUntil (unless) testosterone is gone

• Two components of BPHTwo components of BPH–DynamicDynamic–MechanicalMechanical

Assessing BPH severityAssessing BPH severity

• 0 to 35 AUA scale (7 questions)0 to 35 AUA scale (7 questions)

• Moderate symptoms = 8 to 18Moderate symptoms = 8 to 18

• Peak urine flow < 10 ml/sec (requires 150cc)Peak urine flow < 10 ml/sec (requires 150cc)

Dynamic therapy of BPHDynamic therapy of BPH

• Contraction = Contraction = adrenergic-mediated adrenergic-mediated

blockers relax smooth muscleblockers relax smooth muscle–prostate, blood vesselsprostate, blood vessels–prazosin, terazosinprazosin, terazosin

1A receptors in prostate only1A receptors in prostate only–tamsulosin = specific tamsulosin = specific 1A blocker1A blocker

Mechanical therapy of BPHMechanical therapy of BPH

• Curious genetic abnormalityCurious genetic abnormality

– 55-reductase deficiency-reductase deficiency

– fail to convert T to DHTfail to convert T to DHT

– no baldness, prostatic hypertrophyno baldness, prostatic hypertrophy

• FinasterideFinasteride

– specific 5specific 5-reductase blocker-reductase blocker

– marked reduction in DHT levelsmarked reduction in DHT levels

Finasteride and BPH Finasteride and BPH

• Somewhat better than placebo (1.5 points!)Somewhat better than placebo (1.5 points!)

• Not as good as Not as good as -blockers in VA study-blockers in VA study

• Combined with Combined with -blockers (NEJM, 12/03)-blockers (NEJM, 12/03)

– Slower progression vs. either one aloneSlower progression vs. either one alone

– Retention, surgery similar to finasterideRetention, surgery similar to finasteride

• May depend upon gland sizeMay depend upon gland size

– works better in large glands, higher PSAworks better in large glands, higher PSA

Herbs and BPHHerbs and BPH

• Beta-sitosterol (plant phytosterol) Beta-sitosterol (plant phytosterol)

– 1 RCT1 RCT

• Saw palmetto Saw palmetto

– 18 RCTs18 RCTs

• Both better than placeboBoth better than placebo

Surgery (TUR-P) and BPHSurgery (TUR-P) and BPH

• Works better than watchful waitingWorks better than watchful waiting

– RCT of 556 menRCT of 556 men

• Especially if sx moderate or severeEspecially if sx moderate or severe

• Surgery group had lessSurgery group had less

–urinary retention, urinary symptomsurinary retention, urinary symptoms

• No diff. in impotence, incontinenceNo diff. in impotence, incontinence

CasesCases

• 38 WM with impotence. Gradual 38 WM with impotence. Gradual worsening. Poor libido, no worsening. Poor libido, no depression.depression.

• 58 male, 3 year S/P total 58 male, 3 year S/P total prostatectomy, impotent ever since. prostatectomy, impotent ever since. Intact libido.Intact libido.

ImpotenceImpotence

• No new developments in diagnosisNo new developments in diagnosis

• Common (25% >65), iatrogenic causesCommon (25% >65), iatrogenic causes

• Laboratory evaluation Laboratory evaluation – not evidence-basednot evidence-based– glucose or glycosylated hemoglobinglucose or glycosylated hemoglobin– TSHTSH– testosterone x 2, then LH/FSH, prolactintestosterone x 2, then LH/FSH, prolactin– ? free testosterone if boarderline? free testosterone if boarderline

Hypogonandism and impotenceHypogonandism and impotence

• Testosterone falls with age (nl >325 ng/dl)Testosterone falls with age (nl >325 ng/dl)

– low in 40% age 50-60, 70% age 70-80 low in 40% age 50-60, 70% age 70-80

• Little evidence that low testosterone is a Little evidence that low testosterone is a common cause of impotencecommon cause of impotence

• Long-term effects of testosterone Long-term effects of testosterone replacement still unknown (IOM report)replacement still unknown (IOM report)

SildenafilSildenafil

• Phosphodiesterase (PDE)-5 inhibitorPhosphodiesterase (PDE)-5 inhibitor– PDE’s normally breaks down cGMPPDE’s normally breaks down cGMP– PDE-5 localizes in prostatePDE-5 localizes in prostate

• cGMP is a second messengercGMP is a second messenger

• Sexual stimulation–> nitric oxide release –Sexual stimulation–> nitric oxide release –> cGMP release –> vasodilation –> > cGMP release –> vasodilation –> obstructs venules –> erectionobstructs venules –> erection

• Sildenafil prolongs half-life of cGMPSildenafil prolongs half-life of cGMP

Nitrates and nitric oxideNitrates and nitric oxide

• Nitrates are metabolized to nitric oxide Nitrates are metabolized to nitric oxide

• Nitric oxide regulates resting vascular Nitric oxide regulates resting vascular tonetone

• cGMP is a common second messenger cGMP is a common second messenger for nitric oxidefor nitric oxide

• Inhibition of cGMP prolongs nitric Inhibition of cGMP prolongs nitric oxide action…oxide action…

Clinical implicationsClinical implications

• Basal NO release means that sildenafil Basal NO release means that sildenafil normally reduces BP by 10-20 mm Hgnormally reduces BP by 10-20 mm Hg– developed as an anti-anginaldeveloped as an anti-anginal

• Exogenous nitrates = substantial effectsExogenous nitrates = substantial effects– 25 - 50 mm Hg drop in SBP25 - 50 mm Hg drop in SBP– sildenafil half-life of 4 hourssildenafil half-life of 4 hours

• Bottom line: nitrates, no sildenafil; & vice-Bottom line: nitrates, no sildenafil; & vice-versaversa

Sildenafil practicalitiesSildenafil practicalities

• $10 per pill (25, 50, 100 mg size)$10 per pill (25, 50, 100 mg size)

• Easy to split in halfEasy to split in half

• ““Works” in 30 minutesWorks” in 30 minutes

• Requires NO releaseRequires NO release

• Prescribe 3 x 50 mgPrescribe 3 x 50 mg

–try 25 mg first, then 50, then 75try 25 mg first, then 50, then 75

Me too drugsMe too drugs

• Vardenafil (Levitra) Vardenafil (Levitra)

– similar efficacy, no direct similar efficacy, no direct comparisonscomparisons

– less effect on PDE-6 (fewer visual less effect on PDE-6 (fewer visual effects?)effects?)

• Tadalafil (Cialis, “Le Weekend pill”)Tadalafil (Cialis, “Le Weekend pill”)

– up to 36 hr. of efficacyup to 36 hr. of efficacy

Other modalitiesOther modalities

• Erec-Aid suction deviceErec-Aid suction device

• Alprostadil intra-urethral pelletsAlprostadil intra-urethral pellets

– smooth muscle relaxant (direct)smooth muscle relaxant (direct)

– determine dose (125, 250, 500, 1000 ug)determine dose (125, 250, 500, 1000 ug)

– Success in 65%Success in 65%

– Penile pain in one-thirdPenile pain in one-third

• Yohimbine (Yohimbine ( 2 antagonist) ? 2 antagonist) ?

CaseCase

• 66 male with urgency, hesitancy, 66 male with urgency, hesitancy, nocturianocturia

ProstatitisProstatitis

• Ascending infectionAscending infection

• Often with partner’s GU organism(s)Often with partner’s GU organism(s)

• Zinc levels low; ?value of Zinc levels low; ?value of supplementssupplements

• Symptoms variableSymptoms variable

• Pain between umbilicus and kneesPain between umbilicus and knees

Prostatitis diagnosisProstatitis diagnosis

TypeRectalexam

EPSwhitecells

EPSCult. UA

Urinecult.

Acute Tender DON’T ++ WBCs e.coli

Chronicbacterial

Usu. nl. Yes ++ WBCs e.coli

Chronicnonbact.

Normal Yes — nl —

Prosta-dynia

Normal nl — — —

Common errorsCommon errors

• Using normal exam, UA to r/o prostatitisUsing normal exam, UA to r/o prostatitis

• Overdiagnosis of acute prostatitisOverdiagnosis of acute prostatitis

• Undertreatment (time-wise)Undertreatment (time-wise)

• Extra-prostatic sourcesExtra-prostatic sources

• Unusual organisms with FoleyUnusual organisms with Foley

• Diagnosis w/o leukocytesDiagnosis w/o leukocytes

Treatment of prostatitisTreatment of prostatitis

• BacterialBacterial

– Acute for 4 weeksAcute for 4 weeks• TMX/Sulfa, CBCN, quinolone

– Chronic for 2 to 4 monthsChronic for 2 to 4 months• TMX/Sulfa, nitrofurantoin

• Non-bacterial (2, then + 4 weeks)Non-bacterial (2, then + 4 weeks)• Erythromycin, TCN or doxycycline

• Prostadynia = ?Prostadynia = ?

Prostate cancerProstate cancer

• 350,000 new cases in U.S. each year350,000 new cases in U.S. each year

• 50,000 deaths per year50,000 deaths per year

• 8.5 million men with the disease (30%)8.5 million men with the disease (30%)

• Leveling off now (PSA penetration)Leveling off now (PSA penetration)

• Average age 73 yearsAverage age 73 years

• One in six dx’ed, one in thirty dieOne in six dx’ed, one in thirty die

Is early detection and treatment good?Is early detection and treatment good?

• Early detection = early treatmentEarly detection = early treatment

• Early treatment = early side effectsEarly treatment = early side effects

• Early side effects = loss of quality-of-lifeEarly side effects = loss of quality-of-life

– Loss of 2 to 7 days of QA lifeLoss of 2 to 7 days of QA life

• Early treatment =? late benefitEarly treatment =? late benefit

• If Tx works & pt. lives long enoughIf Tx works & pt. lives long enough

Prostate cancer classificationProstate cancer classification

• Official system, Stages 0 to IVOfficial system, Stages 0 to IV

• Most pathologist still use dual GleasonMost pathologist still use dual Gleason

• Worst Gleason is 10 =5 + 5, written 5/5Worst Gleason is 10 =5 + 5, written 5/5

0%

20%

40%

60%

80%

100%

2 to 4 5 6 7 8+

Gleason score

Mo

rta

lity

Localized disease: 15-year mortality in untreated 55-year-old men

Prostate cancer treatment (usual)Prostate cancer treatment (usual)

• Stage 0 = watchStage 0 = watch

• Stage I, II = surgery (?radiation)Stage I, II = surgery (?radiation)

• Stage III = radiationStage III = radiation

• Stage IV = hormonal therapyStage IV = hormonal therapy

Early prostate cancer treatment, ? neededEarly prostate cancer treatment, ? needed

• Initial non-randomized studies: Initial non-randomized studies: watchful waiting as good as watchful waiting as good as treatment for most localized dz. treatment for most localized dz.

• Therapies have complicationsTherapies have complications

–Radical prostatectomyRadical prostatectomy• 8% incontinence

• 60% (55%) impotent

Does surgery improve outcomes? Does surgery improve outcomes?

• RCT of watchful waiting vs. surgery in 695 men RCT of watchful waiting vs. surgery in 695 men with local dz (Holmberg, 2002)with local dz (Holmberg, 2002)– 75% had palpable dz, 10% detected from PSA75% had palpable dz, 10% detected from PSA– Mean age 64, 6.2 years follow upMean age 64, 6.2 years follow up

• Prostate cancer death RR = 0.50 (0.27, 0.91)Prostate cancer death RR = 0.50 (0.27, 0.91)

• Distant metastases RR = 0.63 (0.41, 0.96)Distant metastases RR = 0.63 (0.41, 0.96)

• Ongoing trials in USOngoing trials in US

Advanced cancer: hormonal treatmentAdvanced cancer: hormonal treatment

• Surgical or medical castrationSurgical or medical castration– LHRH agonists (leuprolide, goserelin)LHRH agonists (leuprolide, goserelin)– Constant stimulation of LH = Constant stimulation of LH =

tachyphylaxistachyphylaxis– No LH = no testosteroneNo LH = no testosterone– Suppress early LH surgeSuppress early LH surge

• Androgen receptor blockade (flutamide)Androgen receptor blockade (flutamide)

• Adrenal androgen production Adrenal androgen production (ketoconazole)(ketoconazole)

Confusing resultsConfusing results

• Waiting = hormones = orchiectomyWaiting = hormones = orchiectomy

• Flutamide + orchiectomy > orchiectomyFlutamide + orchiectomy > orchiectomy

– 5-year survival: 28% vs. 25%5-year survival: 28% vs. 25%

• Radiation + goserelin > radiationRadiation + goserelin > radiation

– Hit advanced disease early and hardHit advanced disease early and hard

SummarySummary

• Urologic conditions are common in Urologic conditions are common in primary careprimary care

• Many can be successfully managed, Many can be successfully managed, at least initially, without referralat least initially, without referral