Transcript The Effect of 3 Years of Raloxifene on Vertebral and Non

Urology Update
Douglas C. Bauer, MD
University of California, San Francisco
No disclosures
Overview
• Microscopic hematuria
• Urinary incontinence
• Benign prostatic hypertrophy
• Impotence
• Prostatitis
• Prostate cancer treatment
Cases
• 26 WF, 3rd episode of gross
hematuria, one following URI
• 77 BM, microscopic hematuria.
Smoker. Asymptomatic.
Microscopic hematuria
• Defined as >3-5 RBC/HPF
• Common (even in young)
– Yearly UAs in soldiers for 16 yr: 39%
– Fear of malignancy
Etiology: age dependent
• Glomerular: IgA, thin basement (<50),
Alport’s (>50), other GN
• Non-glomerular (upper): nephrolith,
renal cell CA (>50), polycystic kidney
• Non-glomerular (lower): cytitis,
prostatitis, urethritis, bladder CA (>50)
• Other: exercise, anti-coag, factitious
Diagnostic evaluation
• Repeat dipstick unless risk factors
• Rule out proteinuria, azotemia, infection
• Imaging: helical CT vs. sono
• Procedures: cystoscopy if risk factors for
cancer or >50
Other issues
• Cytology not recommended
• Phase contrast microscopy identifies
glomerular source (dysmorphic)
• Screening not cost-effective
• Natural history of IgA uncertain
–Fish oil?
Cases
• 56 female, 30+ years of worsening UI
with cough, exercise.
• 40 female, several years of episodic
urgency, occasional UI. Worse with
coffee, EtOH
Urinary incontinence
• Common
– 25% reproductive age women
– 40% postmenopausal women
• Chronic - social seclusion
– Falls & Fractures
– 3x Nursing home admits
• Costly
– $26 billion annually
– More than all cancer care for women
Incontinence definitions
• Overactive Bladder (OAB)
- urge incontinence , frequency, nocturia
• Stress -coughing, sneezing, straining, exercise
• Mixed - both urge and stress
• Other - neurologic, obstruction
Stress vs. urge incontinence
Symptom
• Precipitant
Stress
activity
Urge
urge
• Timing
immediate
delayed
• Amount
small-mod
large
• Nocturia
rare
common
• Remissions
rare
common
Evidence-based guidelines
1996 AHRQ Clinical Practice Guidelines:
 Primary Care diagnosis & treatment
History, neurologic & pelvic exam, PVR, U/A
10 years later, where are we?
Barriers for Primary Care:
• Work up too time consuming & complex
• No pelvic exam tables
• PVR frequently not possible
Diagnostic Aspects of Incontinence Study
(DAISy)
• Cross-sectional study (N = 301), 6 US centers
– 3 incontinence questions (3 IQ) vs. full evaluation
• 3 questions
1. During the last 3 months, have you leaked
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
3. Type of UI most often: Stress, Urge, Mixed, Other
Brown Annals 2006
Accuracy of 3 IQ
compared to full evaluation
Sensitivity Specificity
PPV
LR+
Urge
3IQ
0.75
0.77
0.79
3.26
0.86
0.60
0.74
2.13
Stress
3IQ
Summary: screening for incontinence
Primary Care Clinicians:
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!
Initial visit
• Clinical diagnosis - 3 IQ, UA
• Patient information
•
Urinary diary
• Bedside commode
• Topical estrogens?
• Weight loss?
• Consider Rx
Behavioral vs. meds
• 197 women with Urge UI; RCT
 UI
• Biofeedback/behavioral 81%
• Medication
69%
• Placebo
40%
Greater satisfaction in behavioral group
Burgio 1998
Patient information
• 222 women with Urge UI: RCT
Improved
• Biofeeback
63%
• Verbal/vaginal instruct
69%
• Self-help booklet
59%
Not statistically different
Burgio JAMA 2002
Urinary diary
• Simple form for recording voids,
incontinent episodes, fluid intake
• Excellent education & intervention!
• Very useful in planning therapy
-fluid adjustment
-timing and type of medications
Incontinence treatment
• Initial Rx similar for stress & urge
• Behavioral Management
- Fluids modification
- Pelvic Floor Exercises
- Bladder training
• Verbal and written instructions
Successful pelvic floor exercises
• Strengthen levator ani and sphincter
• Two fingers in the vagina, one hand on the
abdomen
• Two types: rapid and prolonged
• Individualized program
• Coughing
Bladder training
• Re-establishing voluntary control
• Schedule voids q 30-60 minutes
• Diary, relaxation, urge suppression
• RCT demonstrated:
≥ 50% improvement in 75% of participants
• Stress and Urge UI (Fantyl 1991)
OAB medication effectiveness
• Subjective cure
vs. placebo
• Long-term “success”
• Side effects
• Discontinuation
40-60%
20-40%
50%
50%
10-65%
Bottom line: Medications very similar!
OAB medications
Side effects:
dry mouth
constipation
drowsiness
blurred vision
dizziness
Contraindications:
narrow angle glaucoma
hepatic/renal disease
Medication prescribing guideline
Immediate Release
Extended release
• Darifenacin (Enablex)
• Oxybutynin (Ditropan)  • Ditropan XL
• Solifenacin (Vesicare)
• Tolterodine (Detrol) 
• Detrol LA
• Trospium (Santura)
• Oxybutynin
transdermal (Oxytrol)
Case
• 63 WM, progressive nocturia,
hesitancy. PSA 6.
Benign prostatic hypertrophy
• 80% by age 80 years
–50% have had a prostatectomy
• Prostate grows throughout life
–Until (unless) testosterone is gone
• Two components of BPH
–Dynamic
–Mechanical
Assessing BPH severity
• 0 to 35 AUA scale (7 questions)
• Moderate symptoms = 8 to 18
• Peak urine flow < 10 ml/sec (requires 150cc)
Dynamic therapy of BPH
• Contraction =  adrenergic-mediated
•  blockers relax smooth muscle
–prostate, blood vessels
–prazosin, terazosin
• 1A receptors in prostate only
–tamsulosin = specific 1A blocker
Mechanical therapy of BPH
• Curious genetic abnormality
– 5-reductase deficiency
– fail to convert T to DHT
– no baldness, prostatic hypertrophy
• Finasteride
– specific 5-reductase blocker
– marked reduction in DHT levels
Finasteride and BPH
• Somewhat better than placebo (1.5 points!)
• Not as good as -blockers in VA study
• Combined with -blockers (NEJM, 12/03)
– Slower progression vs. either one alone
– Retention, surgery similar to finasteride
• May depend upon gland size
– works better in large glands, higher PSA
Herbs and BPH
• Beta-sitosterol (plant phytosterol)
– 1 RCT
• Saw palmetto
– 18 RCTs
• Both better than placebo
Surgery (TUR-P) and BPH
• Works better than watchful waiting
– RCT of 556 men
• Especially if sx moderate or severe
• Surgery group had less
–urinary retention, urinary symptoms
• No diff. in impotence, incontinence
Cases
• 38 WM with impotence. Gradual
worsening. Poor libido, no
depression.
• 58 male, 3 year S/P total
prostatectomy, impotent ever since.
Intact libido.
Impotence
• No new developments in diagnosis
• Common (25% >65), iatrogenic causes
• Laboratory evaluation
– not evidence-based
– glucose or glycosylated hemoglobin
– TSH
– testosterone x 2, then LH/FSH, prolactin
– ? free testosterone if boarderline
Hypogonandism and impotence
• 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 impotence
• Long-term effects of testosterone
replacement still unknown (IOM report)
Sildenafil
• Phosphodiesterase (PDE)-5 inhibitor
– PDE’s normally breaks down cGMP
– PDE-5 localizes in prostate
• cGMP is a second messenger
• Sexual stimulation–> nitric oxide release –
> cGMP release –> vasodilation –>
obstructs venules –> erection
• Sildenafil prolongs half-life of cGMP
Nitrates and nitric oxide
• Nitrates are metabolized to nitric oxide
• Nitric oxide regulates resting vascular
tone
• cGMP is a common second messenger
for nitric oxide
• Inhibition of cGMP prolongs nitric
oxide action…
Clinical implications
• Basal NO release means that sildenafil
normally reduces BP by 10-20 mm Hg
– developed as an anti-anginal
• Exogenous nitrates = substantial effects
– 25 - 50 mm Hg drop in SBP
– sildenafil half-life of 4 hours
• Bottom line: nitrates, no sildenafil; & viceversa
Sildenafil practicalities
• $10 per pill (25, 50, 100 mg size)
• Easy to split in half
• “Works” in 30 minutes
• Requires NO release
• Prescribe 3 x 50 mg
–try 25 mg first, then 50, then 75
Me too drugs
• Vardenafil (Levitra)
– similar efficacy, no direct
comparisons
– less effect on PDE-6 (fewer visual
effects?)
• Tadalafil (Cialis, “Le Weekend pill”)
– up to 36 hr. of efficacy
Other modalities
• Erec-Aid suction device
• Alprostadil 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) ?
Case
• 66 male with urgency, hesitancy,
nocturia
Prostatitis
• Ascending infection
• Often with partner’s GU organism(s)
• Zinc levels low; ?value of
supplements
• Symptoms variable
• Pain between umbilicus and knees
Prostatitis diagnosis
Type
Rectal
exam
EPS
white
cells
EPS
Cult.
UA
Urine
cult.
Acute
Tender
DON’T
++
WBCs
e.coli
Chronic
bacterial
Usu. nl.
Yes
++
WBCs
e.coli
Chronic
nonbact.
Normal
Yes
—
nl
—
Prostadynia
Normal
nl
—
—
—
Common errors
• Using normal exam, UA to r/o prostatitis
• Overdiagnosis of acute prostatitis
• Undertreatment (time-wise)
• Extra-prostatic sources
• Unusual organisms with Foley
• Diagnosis w/o leukocytes
Treatment of prostatitis
• Bacterial
– Acute for 4 weeks
• TMX/Sulfa, CBCN, quinolone
– Chronic for 2 to 4 months
• TMX/Sulfa, nitrofurantoin
• Non-bacterial (2, then + 4 weeks)
• Erythromycin, TCN or doxycycline
• Prostadynia = ?
Prostate cancer
• 350,000 new cases in U.S. each year
• 50,000 deaths per year
• 8.5 million men with the disease (30%)
• Leveling off now (PSA penetration)
• Average age 73 years
• One in six dx’ed, one in thirty die
Is early detection and treatment good?
• Early detection = early treatment
• Early treatment = early side effects
• Early side effects = loss of quality-of-life
– Loss of 2 to 7 days of QA life
• Early treatment =? late benefit
• If Tx works & pt. lives long enough
Prostate cancer classification
• Official system, Stages 0 to IV
• Most pathologist still use dual Gleason
• Worst Gleason is 10 =5 + 5, written 5/5
Localized disease: 15-year mortality in
untreated 55-year-old men
Mortality
100%
80%
60%
40%
20%
0%
2 to 4
5
6
7
Gleason score
8+
Prostate cancer treatment (usual)
• Stage 0 = watch
• Stage I, II = surgery (?radiation)
• Stage III = radiation
• Stage IV = hormonal therapy
Early prostate cancer treatment, ? needed
• Initial non-randomized studies:
watchful waiting as good as
treatment for most localized dz.
• Therapies have complications
–Radical prostatectomy
• 8% incontinence
• 60% (55%) impotent
Does surgery improve outcomes?
• 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)
• Distant metastases RR = 0.63 (0.41, 0.96)
• Ongoing trials in US
Advanced cancer: hormonal treatment
• Surgical or medical castration
– LHRH agonists (leuprolide, goserelin)
– Constant stimulation of LH =
tachyphylaxis
– No LH = no testosterone
– Suppress early LH surge
• Androgen receptor blockade (flutamide)
• Adrenal androgen production
(ketoconazole)
Confusing results
• Waiting = hormones = orchiectomy
• Flutamide + orchiectomy > orchiectomy
– 5-year survival: 28% vs. 25%
• Radiation + goserelin > radiation
– Hit advanced disease early and hard
Summary
• Urologic conditions are common in
primary care
• Many can be successfully managed,
at least initially, without referral