1. Urology Update Douglas C. Bauer, MD University of California, San Francisco No disclosures

2. Overview Microscopic hematuriaMicroscopic hematuria Urinary incontinenceUrinary incontinence Benign prostatic hypertrophyBenign prostatic hypertrophy ImpotenceImpotence ProstatitisProstatitis Prostate cancer treatmentProstate cancer treatment

3. Cases 26 WF, 3 rd episode of gross hematuria, one following URI26 WF, 3 rd episode of gross hematuria, one following URI 77 BM, microscopic hematuria. Smoker. Asymptomatic.77 BM, microscopic hematuria. Smoker. Asymptomatic.

4. Microscopic 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% – Fear of malignancy

5. Etiology: age dependent Glomerular: IgA, thin basement ( 50), other GNGlomerular: IgA, thin basement ( 50), other GN Non-glomerular (upper): nephrolith, renal cell CA (>50), polycystic kidneyNon-glomerular (upper): nephrolith, renal cell CA (>50), polycystic kidney Non-glomerular (lower): cytitis, prostatitis, urethritis, bladder CA (>50)Non-glomerular (lower): cytitis, prostatitis, urethritis, bladder CA (>50) Other: exercise, anti-coag, factitiousOther: exercise, anti-coag, factitious

6. Diagnostic 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 cancer or >50Procedures: cystoscopy if risk factors for cancer or >50

7. Other issues Cytology not recommendedCytology not recommended Phase contrast microscopy identifies glomerular source (dysmorphic)Phase contrast microscopy identifies glomerular source (dysmorphic) Screening not cost-effectiveScreening not cost-effective Natural history of IgA uncertainNatural history of IgA uncertain –Fish oil?

8. Cases 56 female, 30+ years of worsening UI with cough, exercise.56 female, 30+ years of worsening UI with cough, exercise. 40 female, several years of episodic urgency, occasional UI. Worse with coffee, EtOH40 female, several years of episodic urgency, occasional UI. Worse with coffee, EtOH

9. Urinary incontinence CommonCommon –25% reproductive age women –40% postmenopausal women Chronic - social seclusionChronic - social seclusion – Falls & Fractures – 3x Nursing home admits CostlyCostly –$26 billion annually –More than all cancer care for women

10. Incontinence definitions Overactive Bladder (OAB)Overactive Bladder (OAB) - urge incontinence, frequency, nocturia - urge incontinence, frequency, nocturia Stress -coughing, sneezing, straining, exerciseStress -coughing, sneezing, straining, exercise Mixed - both urge and stressMixed - both urge and stress Other - neurologic, obstructionOther - neurologic, obstruction

11. Stress vs. urge incontinence Symptom StressUrge Precipitant activity urgePrecipitant activity urge Timing immediatedelayedTiming immediatedelayed Amount small-modlargeAmount small-modlarge Nocturia rare commonNocturia rare common Remissions rarecommonRemissions rarecommon

12. Evidence-based guidelines 1996 AHRQ Clinical Practice Guidelines: Primary Care diagnosis & treatment Primary Care diagnosis & treatment History, neurologic & pelvic exam, PVR, U/A History, neurologic & pelvic exam, PVR, U/A 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

13. Diagnostic Aspects of Incontinence Study (DAISy) Cross-sectional study (N = 301), 6 US centersCross-sectional study (N = 301), 6 US centers –3 incontinence questions (3 IQ) vs. full evaluation 3 questions3 questions 1. During the last 3 months, have you leaked urine, even a small amount? If yes: urine, even a small amount? If yes: 2. Stress UI: physical activity, coughing, sneezing, lifting, or exercise Urge UI: urge, feeling need to empty but could not get to the toilet fast enough Urge UI: urge, feeling need to empty but could not get to the toilet fast enough 3. Type of UI most often: Stress, Urge, Mixed, Other Brown Annals 2006

14. Accuracy of 3 IQ compared to full evaluation SensitivitySpecificityPPVLR+ Urge 3IQ 3IQ0.750.770.793.26 Stress 0.860.600.742.13

15. Summary: screening for incontinence Primary Care Clinicians: 3 IQ to classify type of UI 3 IQ to classify type of UI DAISy Take Home Message: 3 IQ is a good test for type of UI, especially because the risk of missed Dx and Rx low Indentification is critical to reducing burden of UI!

16. Initial visit Clinical diagnosis - 3 IQ, UAClinical diagnosis - 3 IQ, UA Patient informationPatient information Urinary diary Urinary diary Bedside commodeBedside commode Topical estrogens?Topical estrogens? Weight loss?Weight loss? Consider RxConsider Rx

17. Behavioral vs. meds 197 women with Urge UI; RCT197 women with Urge UI; RCT UI UI Biofeedback/behavioral 81%Biofeedback/behavioral 81% Medication69%Medication69% Placebo40%Placebo40% Greater satisfaction in behavioral group Burgio 1998

18. Patient information 222 women with Urge UI: RCT222 women with Urge UI: RCTImproved Biofeeback 63%Biofeeback 63% Verbal/vaginal instruct 69%Verbal/vaginal instruct 69% Self-help booklet 59%Self-help booklet 59% Not statistically different Burgio JAMA 2002

19. Urinary diary Simple form for recording voids, incontinent episodes, fluid intakeSimple form for recording voids, incontinent episodes, fluid intake Excellent education & intervention!Excellent education & intervention! Very useful in planning therapyVery useful in planning therapy -fluid adjustment -timing and type of medications

21. Incontinence treatment Initial Rx similar for stress & urgeInitial Rx similar for stress & urge Behavioral ManagementBehavioral Management - Fluids modification - Pelvic Floor Exercises - Bladder training Verbal and written instructionsVerbal and written instructions

22. Successful pelvic floor exercises Strengthen levator ani and sphincterStrengthen levator ani and sphincter Two fingers in the vagina, one hand on the abdomenTwo fingers in the vagina, one hand on the abdomen Two types: rapid and prolongedTwo types: rapid and prolonged Individualized programIndividualized program CoughingCoughing

23. Bladder training Re-establishing voluntary controlRe-establishing voluntary control Schedule voids q 30-60 minutesSchedule voids q 30-60 minutes Diary, relaxation, urge suppressionDiary, relaxation, urge suppression RCT demonstrated:RCT demonstrated: 50% improvement in 75% of participants 50% improvement in 75% of participants Stress and Urge UI (Fantyl 1991)Stress and Urge UI (Fantyl 1991)

24. OAB medication effectiveness Subjective cure 40-60% vs. placebo 20-40%Subjective cure 40-60% vs. placebo 20-40% Long-term success 50%Long-term success 50% Side effects 50%Side effects 50% Discontinuation 10-65%Discontinuation 10-65% Bottom line: Medications very similar!

25. OAB medications Side effects:dry mouth constipationdrowsiness blurred vision dizziness Contraindications:narrow angle glaucoma hepatic/renal disease

26. Medication prescribing guideline Immediate Release Oxybutynin (Ditropan)Oxybutynin (Ditropan) Tolterodine (Detrol) Tolterodine (Detrol) Trospium (Santura)Trospium (Santura) Extended release Darifenacin (Enablex)Darifenacin (Enablex) Ditropan XLDitropan XL Solifenacin (Vesicare)Solifenacin (Vesicare) Detrol LADetrol LA Oxybutynin transdermal (Oxytrol)Oxybutynin transdermal (Oxytrol)

27. Case 63 WM, progressive nocturia, hesitancy. PSA 6.63 WM, progressive nocturia, hesitancy. PSA 6.

28. Benign prostatic hypertrophy 80% by age 80 years80% by age 80 years –50% have had a prostatectomy Prostate grows throughout lifeProstate grows throughout life –Until (unless) testosterone is gone Two components of BPHTwo components of BPH –Dynamic –Mechanical

29. Assessing 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)

31. Dynamic therapy of BPH Contraction = adrenergic-mediatedContraction = adrenergic-mediated blockers relax smooth muscle blockers relax smooth muscle –prostate, blood vessels –prazosin, terazosin 1A receptors in prostate only 1A receptors in prostate only –tamsulosin = specific 1A blocker

32. Mechanical therapy of BPH Curious genetic abnormalityCurious genetic abnormality –5 -reductase deficiency –fail to convert T to DHT –no baldness, prostatic hypertrophy FinasterideFinasteride –specific 5 -reductase blocker –marked reduction in DHT levels

33. Finasteride and BPH Somewhat better than placebo (1.5 points!)Somewhat better than placebo (1.5 points!) Not as good as -blockers in VA studyNot as good as -blockers in VA study Combined with -blockers (NEJM, 12/03)Combined with -blockers (NEJM, 12/03) –Slower progression vs. either one alone –Retention, surgery similar to finasteride May depend upon gland sizeMay depend upon gland size –works better in large glands, higher PSA

34. Herbs and BPH Beta-sitosterol (plant phytosterol)Beta-sitosterol (plant phytosterol) – 1 RCT Saw palmettoSaw palmetto – 18 RCTs Both better than placeboBoth better than placebo

35. Surgery (TUR-P) and BPH Works better than watchful waitingWorks better than watchful waiting – RCT of 556 men Especially if sx moderate or severeEspecially if sx moderate or severe Surgery group had lessSurgery group had less –urinary retention, urinary symptoms No diff. in impotence, incontinenceNo diff. in impotence, incontinence

36. Cases 38 WM with impotence. Gradual worsening. Poor libido, no depression.38 WM with impotence. Gradual worsening. Poor libido, no depression. 58 male, 3 year S/P total prostatectomy, impotent ever since. Intact libido.58 male, 3 year S/P total prostatectomy, impotent ever since. Intact libido.

37. Impotence No new developments in diagnosisNo new developments in diagnosis Common (25% >65), iatrogenic causesCommon (25% >65), iatrogenic causes Laboratory evaluationLaboratory evaluation –not evidence-based –glucose or glycosylated hemoglobin –TSH –testosterone x 2, then LH/FSH, prolactin –? free testosterone if boarderline

38. Hypogonandism 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 Little evidence that low testosterone is a common cause of impotenceLittle evidence that low testosterone is a common cause of impotence Long-term effects of testosterone replacement still unknown (IOM report)Long-term effects of testosterone replacement still unknown (IOM report)

39. Sildenafil Phosphodiesterase (PDE)-5 inhibitorPhosphodiesterase (PDE)-5 inhibitor –PDEs normally breaks down cGMP –PDE-5 localizes in prostate cGMP is a second messengercGMP is a second messenger Sexual stimulation–> nitric oxide release – > cGMP release –> vasodilation –> obstructs venules –> erectionSexual stimulation–> nitric oxide release – > cGMP release –> vasodilation –> obstructs venules –> erection Sildenafil prolongs half-life of cGMPSildenafil prolongs half-life of cGMP

41. Nitrates and nitric oxide Nitrates are metabolized to nitric oxideNitrates are metabolized to nitric oxide Nitric oxide regulates resting vascular toneNitric oxide regulates resting vascular tone cGMP is a common second messenger for nitric oxidecGMP is a common second messenger for nitric oxide Inhibition of cGMP prolongs nitric oxide action…Inhibition of cGMP prolongs nitric oxide action…

42. Clinical implications Basal NO release means that sildenafil normally reduces BP by 10-20 mm HgBasal NO release means that sildenafil normally reduces BP by 10-20 mm Hg –developed as an anti-anginal Exogenous nitrates = substantial effectsExogenous nitrates = substantial effects –25 - 50 mm Hg drop in SBP –sildenafil half-life of 4 hours Bottom line: nitrates, no sildenafil; & vice- versaBottom line: nitrates, no sildenafil; & vice- versa

43. Sildenafil 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 75

44. Me too drugs Vardenafil (Levitra)Vardenafil (Levitra) – similar efficacy, no direct comparisons – less effect on PDE-6 (fewer visual effects?) Tadalafil (Cialis, Le Weekend pill)Tadalafil (Cialis, Le Weekend pill) – up to 36 hr. of efficacy

45. Other modalities Erec-Aid suction deviceErec-Aid suction device Alprostadil intra-urethral pelletsAlprostadil intra-urethral pellets –smooth muscle relaxant (direct) –determine dose (125, 250, 500, 1000 ug) –Success in 65% –Penile pain in one-third Yohimbine ( 2 antagonist) ?Yohimbine ( 2 antagonist) ?

46. Case 66 male with urgency, hesitancy, nocturia66 male with urgency, hesitancy, nocturia

47. Prostatitis Ascending infectionAscending infection Often with partners GU organism(s)Often with partners GU organism(s) Zinc levels low; ?value of supplementsZinc levels low; ?value of supplements Symptoms variableSymptoms variable Pain between umbilicus and kneesPain between umbilicus and knees

48. Prostatitis diagnosis

49. Common 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

50. Treatment of prostatitis BacterialBacterial –Acute for 4 weeks TMX/Sulfa, CBCN, quinolone –Chronic 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 = ?

51. Prostate 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 dxed, one in thirty dieOne in six dxed, one in thirty die

52. 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 life Early treatment =? late benefitEarly treatment =? late benefit If Tx works & pt. lives long enoughIf Tx works & pt. lives long enough

53. Prostate 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

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

55. 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

56. Early prostate cancer treatment, ? needed Initial non-randomized studies: watchful waiting as good as treatment for most localized dz.Initial non-randomized studies: watchful waiting as good as treatment for most localized dz. Therapies have complicationsTherapies have complications –Radical prostatectomy 8% incontinence 60% (55%) impotent

57. Does surgery improve outcomes? RCT of watchful waiting vs. surgery in 695 men with local dz (Holmberg, 2002)RCT of watchful waiting vs. surgery in 695 men with local dz (Holmberg, 2002) –75% had palpable dz, 10% detected from PSA –Mean 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

58. Advanced cancer: hormonal treatment Surgical or medical castrationSurgical or medical castration –LHRH agonists (leuprolide, goserelin) –Constant stimulation of LH = tachyphylaxis –No LH = no testosterone –Suppress early LH surge Androgen receptor blockade (flutamide)Androgen receptor blockade (flutamide) Adrenal androgen production (ketoconazole)Adrenal androgen production (ketoconazole)

59. Surgery vs. medical castration Similar effects on survivalSimilar effects on survival Surgery = one-time cost of $7,000Surgery = one-time cost of $7,000 But surgery more cost-effectiveBut surgery more cost-effective

60. Confusing results Waiting = hormones = orchiectomyWaiting = hormones = orchiectomy Flutamide + orchiectomy > orchiectomyFlutamide + orchiectomy > orchiectomy –5-year survival: 28% vs. 25% Radiation + goserelin > radiationRadiation + goserelin > radiation –Hit advanced disease early and hard

61. Summary Urologic conditions are common in primary careUrologic conditions are common in primary care Many can be successfully managed, at least initially, without referralMany can be successfully managed, at least initially, without referral