1
BPHBPH
Edmond Wong

2
Embryology of the prostate
• Prostate develop from week 10-16
• SRY gene product stimulated medullary sex cord to develop into
pre-sertoli cell
• These cells secret Mullerian-inhibiting substance (MIS)
• MIS stimulate Leydig cell to produce testosterone
• Induce development of the Wolffian duct (SV, epididymis, vas
deferrence, ejaculatory duct, central zone)
• Rest of the prostate develop from 5 pair of epithelial buds which
branch out from the posterior aspect of the urogenital sinus
• Invade into the mesenchyme to stimulate development of the
prostatic stroma (upper pair) and transitional zone (lower pair)
• Stromal- epithelial interaction is important thru production of DHT by
stromal cell acting on the androgen receptor of epithelial cells
(paracrine action)

3

4
What are the blood supply to the
prostate?
• Arterial blood supply:
– Inferior vesical artery  Prostatic artery
• Urethral: BN and urethra
– Flock’s artery (1 & 11 oc)
– Badenock’s artery (5 & 7 oc)
• Capsular group: Run with the cavernosal nerves
• Venous drainage:
– Periprostatic venous plexus
– Deep dorsal vein of the peni
– Mumerous vesical vein
• Drain into the internal iliac vein
• LN: Obturator & internal Iliac LN

5
McNeal’s zonal anatomy
• Transitional zone (10%): BPH
• Central zone (25%)
• Peripheral zone (65%): Ca Prostate
• Anterior fibromuscular stroma
• Peri-urethral zone

6

7

8
What are the necessary aetiological riskWhat are the necessary aetiological risk
factors for BPH formation?factors for BPH formation?
• Aetiology of BPH is still not well known
• BPH : a process of increased proliferation (early phase) but
more importantly decrease in apoptosis (established phase)
• “Reawakening” of the inductive effect of the prostate stromal cell
on the epithelial cell (like in fetal development)
• Aetiological risk factors :
1. Age
2. Androgens (a permissive role only)
3. Race
4. Diet
5. Genetics (role again unclear) – 50% of men undergoing
prostatectomy before 60 could be attributed to have some
genetic factors
6. Growth factors (basic fibroblastic GF, insulin-like GF, etc)

9
Relationship between metabolicRelationship between metabolic
syndrome and BPHsyndrome and BPH
• Metabolic syndrome at least 3 out of the 5 following
points
– HT / Abdominal obese / Hyperglycemia /
Hypertriglyceridermia / Hypo-HDL cholersterol
• MS induced BPH
– Chronic inflammation via interleukin and CRP
– Increased insulin like growth factor
– Increased cholesterol > hormonal change
– Autonomic hypersensitivity by neurodegeneration of
parasympathetic neuron
• Weight reduction, statin, cholesterol absorption
inhibition drugs > may reduce prostate growth

10
What are Cunha’s
experiments?
What are McNeal’s
hypothesis?

11
• Cunha
– Prostatic epithelial development and
differentiation is indirectly controlled by
androgens via androgen dependent mediators
of stromal in origin
• McNeal
– BPH is the result of a reawakening of
embryonic processes in stroma which induces
epithelial cell development via growth factors
• (Inhibitory ones like TGF-beta)

12
Role of hormone in BPH
• Testosterone can bind directly to
the AR, or converted to DHT by
5AR
• 2 isoform:
– Type 1: extraprostatic (skin, live)
– Type 2: Prostatic (nuclear
membrane of stromal cell, but not
in epithelial cell)
• Testosterone diffuse into cell:
– Epithelial cell : bind to AR & induce
growth factor
– Stromal cell: Majority convert to
DHT by Type 2 5AR  bind to
androgen receptor or diffuse into
nearby epithelial cell (paracrine
action)
• Complex bind to specific binding
site of nucleus  induce
transcription of androgen-
dependent gene
• Protein synthesis and development
of BPH

13
What is the pathology of
BPH?
• Hyperplastic process
• Earliest sign : micronodule formation in
transitional zone – lateral lobes (mixture of
stromal cell and epithelial component) and in
periurethral region – median lobe within the
smooth muscle collar of the preprostatic
sphincter (mainly connective tissue)
• Further coalescence and growth of micronodule
become macronodule

14
Pathophysiology of BOO
• BOO cause thickening of bladder wall
• High intra-renal pressure  hydronephrosis
• Impair renal function & even renal failure
• Microscopic:
– Smooth muscle cell enlarged
– Increase in connective tissue (collagen and elastin) btw SM
bundles
– Lead to poor compliance
• BOO also cause bladder overactivity
– Prolong increase intravesicle pressure during voiding
– Ischemia of bladder wall
– Damage to neurons within the bladder (denervation)

15
Some clinical definition
• LUTS: Lower urinary tract symptom:
– Non-specific terms for symptom which may be attributable to
lower urinary tract dysfunction
– Storage LUTS (Frequency, Urgency, Nocturia)
– Voiding LUTS (Hesitancy, Straining, Slow stream, intermittency,
terminal dribbling, sense of incomplete voiding)
• BOO: Bladder outflow obstruction
– Urodyanmical diagnosis of an obstruction to passage of urine
• BPE: Benign prostate enlargement:
– Clinical finding of an enlarged prostate
• BPH: Benign prostatic hyperplasia:
– Histological basis of BPE leading to BOO that result in LUTS
• BPO: Benign prostatic obstruction:
– BOO cause by BPE

16
How would described the
relationship btw BOO and LUTS
• What are Hald’s rings?

17
60-yr-old man complaining of LUTS
•Evaluation
– Look for extraprostatic causes of LUTS
– Identify risk factors for progression that may affect treatment
– Identify comordities that may affect treatment
•History
– Age
– Storage and emptying symptoms: Duration, extent , troublesome
– Life style: fluid intake , adjustment has been made
– Incontinence : Type , frequency
– Hematuria, dysuria, bladder pain
– Loin pain , passage of stone
– Drug: Trail of medication , sympathomimetic , anticholinergic
– PMH: Urethral injury/ instrumentation, pelvic surgery, neurological disorder
•Examination
– Ballotable kidneys, palpable bladder, DRE and anal tone
– Signs of renal failure (uraemia, fluid overload)
– Neurological (gait and LL)

18
• Investigations
– PSA
– Serum creatinine
– Urinalysis
– Frequency- volume chart (assess fluid intake)
– Uroflowmetry + PVR
• Only indicated when bother is mod to severe OR invasive treatment
considered (in AUA)
• <10ml/s - 90%obstructed, 10-15ml/s - 60% obstructed, >15ml/s –
30%
– IPSS scores & QOL scores
• Assess severity (guide treatment)
• Risk factor for progression
• Optional
– Upper tract imaging (USG kidney)
– TRUS prostate
– UDS
– Cystoscopy + Cytology

19
Ask specifically
• Bedwetting: high pressure chronic
retention
• Marked frequency + urgency with bladder
Pain  CIS
• Macroscopic hematuria  vascular
prostate or Ca Bladder
• Back pain or neurological symptom

20
Differential Diagnosis of LUTS
• Prostate1
– Obstruction (BPH, BPE, BOO) (30%)
• Bladder1
– Detrusor overactivity (50%)
– Impaired detrusor contractility (30%)
– Sensory urgency
– Sphincteric incontinence
– Polyuria/nocturnal polyuria
• Medications2
– Antihistamines
– Antidepressants
1. Chaikin DC, Blaivas JG. Curr Opin Urol. 2001;11:395-398. 2. Su L et al. J Clin Epidemiol. 1996;49:483-487.

21
When will you consider the
following investigation
• Renal USG:
– Loin pain / mass
– Hematuria
– Presence of renal
insufficiency (AUA)
• Risk of hydronephrosis
<1% if normal RFT
• Cystoscopy + Cytology:
– Hematuria (CIS)
– Equivocal flow
– Previous uro surgery (AUA)
• TRUS +/- Bx
– Abnormal DRE
– Raised PSA (age adj or >
4)
– Surgical txn planning (open
Millin prostatectomy , Laser
surgery) for sizing
– Consideration of 5AR-I txn
• Urodynamic:
– Equivocal Flow rate : VV <
150ml , Qmax > 10ml/s
– Age < 50 or >80
– Previous unsuccessful txn
of BPH
– Neurological hx of sign

22
Why Renal function ?
• Because renal insufficiency associated with
increased risk of postop morbidity (25 vs
17%) in the Mebust study
• Although the incidence of renal insufficiency
among patients with LUTS ~ 10%, there is no
reliable way to single out these patients
based on symptoms or clinical evaluation
alone, and thus a serum creatinine is
necessary

23
How would you instructed the pt for
FR + RU
• Good URF: VV > 150ml
• Attend for 2-3hour
• Drink 500-1000 ml fluid
• Wait for comfortably full bladder
• When pass urine into machine:
– Avoid compressing penis (squeeze artefact)
– Don’t wander around the funnel (abn recording)
– Aim pass at least 150ml
• Repeat if < 150ml , if the flow representative

24
How many types of
uroflowmetry machines are
you aware of?
What are the normal values of a
60-yr-old man ?

25
• Machine mechanisms
1. Rotating disk
2. Weight transducer
3. Dipstick capacitance

26
NORMAL VALUES FOR UROFLOWMETRY
Gender Age (years)
Flow rate
(ml/s)
Males <40 >21
40-60 >18
>60 >13
Females <50 >25
>50 >18
( Abrams and Torrens, 1979 )

27
What do you look in FR+RU?
• Void volume: >150 ml (adequate)
• Overdistension: > 500ml
• Maximum Flow: Qmax
– Risk of BOO in UD in relation to Qmax:
• >15ml/s (30%), 10-15ml/s (60%) < 10ml/s (90%)
– < 12ml/s  3x risk of progression [Jacobsen
1997]

28
What do you look in FR+RU?
• Overall pattern:
– Box-like (plateau curve) : Stricture
– Hyperflow : OAB
– Prolonged time to Qmax: BPH
– Intermittent burst: DSD
• Residual volume: RU
– Vary considerably
– Cannot symptomatic outcome after TURP
– May be safe not to operated on RU< 350 [Wasson VA
study NEJM1995]

29
Why is BOO so important ?
• It underpins the rationale behind disobstruction
operation (TURP) in men with BPH
• 2 component:
– Dynamic :
• Alfa1- adrenoceptor mediate SM contraction
• 40% of area density
– Static: mediate by volume effect of BPE
• Men with BOO: 90% symptomatic improvement
after TURP
• Men without BOO: 60% symptomatic
improvement after TURP
• Abrahms JU 1979

30
How can we tell if patient has
BOO?
• ICS normogram: Categories patient as
obstructed, equivocal or unobstructed
• Abram-Griffith number (BOOI): Single
numerical value:
– Pdet@Qmax – 2x Qmax = AG number
(BOOI)
– > 40  obstructive
– 20-40  equivocal
– < 20  unobstructed

31
ICS nomogram

32
What are the different instrument
for measurement of LUTS in men?
• DAN (Danish Prostate Symptom Score)
• Bristol Male LUTS
• AUA
• IPSS
– Derived from AUA + 1 more QOL question
– Most commonly used
– Valid , Reliable and reproducible

33
What are the domains asked
in the IPSS / AUA-SS?
?Mild/Mod/Severe IPSS

34
IPSSIPSS
• 7 Question + 1 QOL
• How often do you experience:
– Voiding: Straining , intermittency, slow stream, sense of incomplete
voiding
– Storage: Nocturia (times), Frequency (<2 hr) , Urgency
• Frequency:
– not at all 0
– <1/5 : 1
– <1/2 2
– ½ : 3
– > ½ : 4
– all the time : 5 (except nocturia)
• 0-7 mild; 8-19 moderate, 20-35 severe
• QOL: 0:delighted > 6:terrible
• Reliable, reproducible and valid

35

36

37
How many points of IPSS drop
is perceived by patient to be a
‘significant’ improvement ?
?Any factors affecting this

38
Barry et al J Urol 1995
• A 3-point absolute drop in IPSS is
required for the patient to perceive as
improvement
• The required drop in score is greater in
those with higher baseline IPSS

39
Any drawbacks of IPSS?
• Drawbacks
– Does not make a diagnosis, just a symptom
score
– Not prostate / BPH specific – females /
patients with CPPS can have an IPSS score

40
Is there a relationship between
symptoms and other more
objective measures such as
prostate volume or flow rate?

41

42

43
LUTS: Q to answer
• How common is BPH ? Histology , clinical
• Will I progress ? Natural history
• What are the risk factor of progression?
• Management:
– Watchful waiting
– Life style modification
– Medication: AARB, 5ARI, Combination
– Phytotherapy
– Surgery
• TURP
• Electrosurgical: TURVP , TURis
• Laser: PVP, HoLAP, HoLEP, HoLIP
• Ablation: TUMT, TUNA
• Open surgery: open retropubic, open transvesicle

44
How common is BPH?

45
Histology
• Histologically BPH is present
– ~25% in 50 years of age
– ~70% in 70 years of age
– ~90% in 80 years of age
– No histological BPH found before 30
Berry 1984 Autopsy studies
(Berry SJ, Coffey DS, Walsch P: The development of human benign
prostatic hyperplasia with age. J Urol 1984; 132; 474-479.)

46
Clinical LUTS
• Clinically LUTS suggestive of BPH is present
– ~10% in 40s
– ~25% in 50s
– ~40% in 60s
– ~40% in 70s
– Overall 25% in 40-79
– Garraway Lancet 1991 (Stirling study)
Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic
hypertrophy in the community. Lancet. 1991 Aug 24;338(8765):469–
471.

47
Clinical LUTS
• According to OCS: Moderate to severe
urinary symptom in
– 40-49yo 13%
– 70yo 30%

48
What is the natural history
of BPH?
Will I progress?

49
What will happen if I opt for
WW?
• Ball study BJU1981:
– 100men on WW for 5yr
– 25% get better, 30% get worse, 40% same
– 2% AUR, 10% require surgery
– Most patients have stable symptoms
• Wasson VA study on WW vs TURP NEJM 1995:
– Pt on WW: 25% TURP, 30% get worse , 40% get
better

50
Can you briefly tell me about
the Olmstead County Study?

51
• Longitudinal community-based study in
Olmsted County in US where a group of
men with LUTS (n=2115) were observed
over a long period of time without
intervention from the observers
• (Good for looking at natural history of BPH
– better than looking at the placebo arm of
studies like MTOPS)

52
• Olmsted County Study
– Mean decline in Qmx 0.2ml/s/yr (2%)
• Rate of decline faster with increasing age, lower
baseline Qmx, bigger prostates and higher SS
– Mean increase in SS 0.18/yr (0.2)
• Rate of increase faster with increasing age
– Prostate volume increase 2cm3/ yr
• Rate of growth faster with bigger prostates

53
• Olmstead County Study (Jacobsen)
– AUR occurrence : 7 / 1000 person-year on average
– Cumulative incidence in 4 yrs 3%
• Rates increased with
– Age (70-79) risk 8x
– SS (moderate to severe) risk 3x
– Baseline Qmx <12 risk 4x
– Prostate volume > 30cc risk 3x
– BPH related surgery : 16 /1000 py
– Cumulative incidence in 4 yrs 3%
• Rates increased with
– PSA > 1.4 risk 4x

54
OCS

55
In a nutshell …..
• Olmstead tells us that ,if left untreated
• Rise of IPSS 0.2/yr
• Qmax decreases 2%/yr
• TRUS vol increases 2%/yr (mean 0.6cc)
• Incidence of AUR 7/1000-yr
• Incidence of BPHRS 16/1000-yr
• Cumulative incidence of AUR 3% in 4 yrs
• Cumulative incidence of BPHRS 3% in 4 yrs

56
Why is longitudinal community
study better than placebo arm
of RCTs in looking at natural
history?

57
Problems with placebo arm of RCTs
• Strict inclusion criteria leads to regression to
mean effect (RMA)
– eg. PLESS placebo group : patients with the lowest
PSA actually improve their IPSS and Qmx with time
• Placebo
effect
• Possible
Hawthorne
effect

58
Hawthorne effect & RMA
• The Hawthorne effect is a form of reactivity whereby
subjects improve or modify an aspect of their behavior
being experimentally measured simply in response to the
fact that they are being studied, not in response to any
particular experimental manipulation.
• regression toward the mean is the phenomenon that if
a variable is extreme on its first measurement, it will tend
to be closer to the average on a second measurement,
and—a fact that may superficially seem paradoxical—if it
is extreme on a second measurement, will tend to have
been closer to the average on the first measurement

59
What is the risk that I run into
retention ?

60
Retention
• Olmstead
– Cumulative incidence 3% in 4 yrs
– 7 / 1000 person-yr (increase with age)
• 40-49 mild/mod/severe symptoms 3/1000py
• 70-79 mild 9/1000py mod-severe 34/1000py
• MTOPS : 2% in 4.5 yrs
• PLESS : 7% in 4 yrs

61
What are the risk factors for
progression (AUR)?

62
• Olmsted risk factors
1. Age (70-70 8x vs 40-49)
2. Baseline symptom score > 8 (3x moderate c.f. mild)
3. Qmax < 12 (4x vs >12)
4. Large PVR >50cc at baseline (3x vs <50cc)
5. Prostate vol >30cc (3x vs <30cc)
6. PSA > 1.4 (risk 4x)
• Most important
(1/3 of TURP presented with retention of urine)
• Other risk factor:
– Failure to response to medical therapy [Emberton JU2006]
– Deterioration of symptom while on txn
– Presence of inflammation on prostate biopsy [Mishra BJU2007]
• Thus I will look into these factors and counsel the
patient accordingly

63
Girman

64
Girman

65
What is the chance that I will
need a surgery?

66
• Ball study: 10% in 5 yr
• OCS: 3% in 4 yr
Overall, only a minority of patient will require
surgery, thus the reason of WW and
Medical therapy

67
What are the possible
complications of BPH?
How common are they?

68

69
Treatment of BPH

70
Treatments for LUTS, BPH,
BOO
• Watchful waiting
• Medical therapy
– 5α-reductase
inhibitors
α-blockers
– Combination therapy
– Phytotherapy
• Office-based treatment
– TUMT
– TUNA
– WIT
• Surgicenter/
hospital-based treatment
– TURP (gold standard)
– TUIP
– Open surgery
– TUVP
– ILC
– VLAP
– Prostatic stents

71
What are the important factors
in treatment of LUTS/BPH??
Degree of bothersome
Risk of progression

72
What is the treatment option of WW?
• Mild to moderate LUTS
• Moderate to severe symptoms without bothering
• Components for WW
– Reassurance, education and explanation to patients
– Lifestyle advice : esp for storage LUTS
• Reasonable fluid intake, timed voiding
• Reduction of fluid before bedtime (nocturia)
• Avoidance of caffeine and alcohol
• Avoiding medications like antihistamine
• Double voiding and urethral milking (sense of incomplete
voiding and post-micturition dribble)
• Distraction technique for irritative LUTS
• Avoid constipation
– Periodic reevaluation with SS, UFR and PVR to check
for Progression

73
What is the evidence of WW?
• Option for many men as few, if left
untreated, will progress to acute urinary
retention and complications
• Some men’s symptoms may improve
spontaneously, while others’ symptoms
remain stable for many years
• IPSS in Placebo group from PLESS study
even decrease 1.3 after 4 years

74
What is the evidence of WW?
• Ball study (AJ Ball, P Abrams et al, BJUI
1981)
• 100 men with LUTS FU 5 yrs
– 25% get better, 30% get worse, 40% same
• 2% AUR, 10% require surgery

75
What is the evidence of WW?
• Wasson et al NEJM 1995/ 5 yr results (Flanigan JU 1998)
• (~550) men with moderate symptoms randomised to WW to TURP
• 85% of men will be stable on WW at 1 year, deteriorating
progressively to 65% at 5 years
• 1/3 of patients crossed over to surgery in 5 years,
leaving 2/3 doing well in the WW
• surgery had improved bladder function over the WW
group (flow rates and postvoid residual [PVR] volumes),
with the best results being in those with high levels of
bother
• Increasing symptom and RU seem to be strongest
predictor of failure of WW

76

77
What is the mechanism of
AARB?
What is the mechanism of their
side effects?

78
BPH – Medical Therapy
Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; National Cancer Institute. NIH Publication No. 99-4303, 1999.
Alpha blockers 5-Alpha reductase inhibitors
Improve symptoms
and increase urinary
flow rate by relaxing
prostatic and
bladder-neck
smooth muscle
through sympathetic
activity blockade
Improve symptoms,
increase urinary flow
rate, and prevent BPH
outcomes by reducing
prostate enlargement
through hormonal
mechanisms

79
• Mechanisms
– Relaxation of the dynamic smooth muscle component in the
stroma of the prostate via competitive antagonism at the A1R
– Reduce prostate tone and bladder outlet obstruction
• It has been shown that α-blockers have little effect on
urodynamically determined bladder outlet resistance
– For female bladder neck, not supplied by adrenergic nerves
• So other proposed mechanisms
– Induction of apoptosis
• Doxazosin and terazosin have been shown in vitro to induce
apoptosis in prostate cells independent of the A1R (but
contrary to this is the lack of change in size of the prostate
seen clinically)
• By working at extraprostatic sites
– Detrusor (by increasing blood flow)
– Spinal cord ?

80
What is the efficacy of
AARB?

81
Djavan
• Meta-analysis 1999 of AARB [EU]
– Response rate : 30-40%
– Reduce SS by 30% (4pt)
– Improves Qmx by 16-25%
• All alpha·1-adrenoceptor antagonists (alfuzosin,
terazosin, doxazosin and tamsulosin) produce
comparable improvements in LUTS and urinary flow
• Max effect at ~4weeks
• No reason to prolong for more than 1 month if not
efficacious
• 1/3 of men will not experience SS reduction

82
Summary
Terazosin Doxazosin Alfuzosin Tamsulosin
Qmax rise 0.6-2 1.4-3.5 1.3 1.3-1.7
SS drop 1-2.3 2-4 1.6 2.3-3.2

83
How many types of Alpha 1
receptors are you aware of?

84
Alfa1-adrenoceptor (AR)
• Mediate prostates smooth muscle contraction
• Alpha 1 receptor (A1R) can be divided, based on molecular cloning
and in vitro studies
– High affinity for prazosin :
• A1aR, A1bR and A1dR
– Low affinity for prazosin :
• A1LR (may represent a functional phenotype of A1aR)
– A2R
• All three high affinity types have been demonstrated in the prostate
stroma (influence of SM tone)
– 70% predominance A1aR
• Glandular prostate has A1R with A1bR predominating, significance
unknown
• Inferred that dynamic component of the prostate smooth muscle is via
activation of the A1aR but the contribution of the other subtypes are
not clear

85
• Other areas where A1R are found
– Bladder : AAR expression low but mainly A1dR
• Change may occur with obstruction
– Urethra : A1aR mainly
– CNS and spinal cord :
• A1aR widely distributed in brain with A1dR predominance in
spinal cord
• A1aR and A1bR may take part in inhibitory synapses from
CNS onto the voiding reflexes
– Vas : A1aR predominance
– Vascular tree : all types of AAR can be found
(including A2R)

86
AR classification
• According to selectivity: but show “class effect”
• No study has directly compare one alpha-
blocker to another in terms of efficacy or side
effect
• Non selective: phenoxybenzmine
• Alfa-1: prazosin , alfuzosin
• Long acting alfa-1: terazosin , doxazosin ,
alfuzosin XL
• Selective Alfa 1a: Tamsulosin

87
• Rapid relief of symptoms and improvement of
flow rate (days)
• Effective regardless of prostate size3
– Reduces symptoms equally well in patients
with and without BOO
• Effective irrespective of patient symptom (mild ,
moderate or severe)
• Effective across all age group
• Do not reduce prostate size
• Do not prevent AROU
AARB : Summary

88
Summary: α-Blockers
• All alpha-blockers seen to have similar efficacy in
improving symptoms and flow
• Tamsulosin has less effect on blood pressure than
alfuzosin (especially in elderly patients) and causes less
symptomatic orthostatic hypotension
• Tolerability of alfuzosin and tamsulosin is similar and
better than other agent
• Benefit of alfa1-AR has shown to be better than placebo
and finasteride in men with LUTS by RCT
• Low risk of morbidity2
• Differences between agents with regards to
– Cardiovascular side effects
– Sexual side effects: more retrograde Ejaculation in
Tamsolusin
– More vasodilatory SE with alfulzosin

89
What are the side effects of
AAR?

90
What are the side effects of
AAR?
1. Asthenia, dizziness – 10%
2. Postural hypotension (1%)
– doxazosin and terazosin > alfuzosin and tamsulosin
3. Impotence (5-8%)
4. Retrograde ejaculation (8%)
– 1% with doxazosin, terazosin, alfuzosin (Djavan)
– 4% with tamsulosin 0.4mg (Djavan) – more
5. Rhinitis
– Tamsulosin
• In studies, up to 30% withdraw because
– Lack of efficacy
– Adverse effects

91
What are the practical
considerations?
• Dose titration is used to initiate treatment with
doxazosin and terazosin
• This is not necessary with alfuzosin and
tamsulosin.
• AARB do not affect libido
• AARB has small beneficial effect on erectile
function but sometimes cause abnormal
ejaculation (mechanism unknown)
• Can be consider for intermittent use because of
rapid onset of action

92
What is IFIS?
• Intraoperative floppy iris syndrome
• First reported in 2005 in cataract surgery
among patients taking tamsulosin
Chang DF, Campbell JR. Intraoperative floppy-iris syndrome associated with tamsulosin
(Flomax). J Cataract Refract Surg 2005; 31:664–673
• Triad of intraoperative findings during cataract
surgery
1. Poor preoperative pupil dilation
2. Iris billowing and prolapse
3. Progressive intraoperative myosis

93
• Incidence:
– Up to 90% in the largest prospective study to date
(17% mild, 30% moderate, 43% severe)
– 50% in other retrospective reports
– (0-15% in patients taking non selective AARB)
• Has been reported in patients taking
1. Other non selective AARB
2. Finasteride
3. Saw palmetto
4. Some antipsychotic meds with alpha receptor
blocking features
• Tamsulosin : More frequently & more severe
state than other non-selective AARB

94
• Pathophysiology
– A1a is the predominant alpha receptors in iris
– Systemic tamsulosin blocked contraction of
the iris dilator smooth muscle
– Deficient muscle tone led to poor pupil
dilation, iris floppiness, and a propensity to
prolapse
– Increases the cataract surgical complications :
iris damage and posterior capsule rupture

95
Stopping the Rx
• But stopping the drug has not been shown
to decrease incidence of IFIS in
prospective studies
• IFIS was first reported in patient who has
stopped tamsulosin x 1 yr

96
Management
• A variety of pharmacologic and surgical
strategies by ophthalmologists
– Topical atropine
– Intracameral a-agonist injections
– Pupil expansion rings etc
• 21% thought that all patients about to be started
on tamsulosin should be routinely referred for
eye examination
– 2/3 of respondants stated they would not take
tamsulosin themselves in future

97
MCQ ?T/F
• With respect to the intraoperative floppy iris
syndrome
1. Has been reported in patients after taking
finasteride
2. Occurs more commonly in men taking
tamsulosin than other alpha blockers
3. Can be prevented by stopping alpha blockers
before cataract surgery
4. If unexpected, it increases the complications of
cataract surgical complications

98
MCQ 2
• T – has been reported in patients after
finasteride, saw palmetto, AARB
• T – yes because of the Alpha-1A
receptors in iris muscle
• F – of unproven benefit
• T

99
How does 5ARI work?

100
Two types of 5AR (testosterone to
DHT)
• Type 1 : predominance in extraprostatic tissue
(skin, liver), role in BPH remains unclear
• Type 2 : predominance in prostate but also
expressed in extraprostatic tissue, for prostatic
growth, development and hyperplasia process
• Testosterone: DHT in prostate is 1:5
• Causes apoptosis and atrophy of the epithelial
part of the prostate
• Reduce the “static” component of BPH
• Prostate size reduction: 20-25%
• PSA level: ½ after 6-12m of treatment

101
What is the result of dutasteride
VS finasteride?
• Finasteride: Type II inhibitor (5mg)
• Dutasterdie : Type I & II inhibitor (0.5mg))
• Both reduce prostate DHT concentration
by 90%
• Indirect comparison between individual
studies and one unpublished direct
comparative trial indicate that dutasteride
and finasteride are equally effective in the
treatment of LUTS

102
What are the indications of
5ARIs?

103
Indications
• Men with LUTS and an enlarged prostate (> 40cc)
• Boyle meta-analysis of RCTs concluded that finasteride
only be useful if prostate gland > 40cc
• Those with risk for progression – PLESS and MTOPS
can reduce progression
• Effective treatment for refractory hematuria due to
prostate bleeding
– Suppression of VEGF
– Insufficient data to use 5AR before TURP to reduce bleeding

104
What is the efficacy of
5ARIs?

105
ProscarProscar
• PLESS [MaConnell NEJM 1998]
• 4 yrs of Proscar vs placebo
– Increase of Qmax 1.9ml/s (placebo 0.2)
– Decrease in SS by ~3 (placebo 1.3)
– Reduce risk of AUR by ~60% (5% vs 10%)
– Reduce risk of BPHRS by ~60% (3% vs 7%)
– Reduce prostate size by 20% (vs 15% in placebo)
• AUA
– Less effective in improving LUTS than alpha-blocker
• Proscar Long Term Efficacy & Safty Study

106

107
EAU
• Only suitable for long term treatment
• After 2-4 yr of treatment:
– Reduce symptom score by 15%
– Reduce prostate volume: 20-25%
– Increase Qmax: 2ml/s
• Symptom reduction not better than placebo if prostate
size < 40cc
• Dutasteride reduce IPSS, prostate volume & AROU and
increase Qmax even if prostate 30-40cc
• Reduce symptom slower than AARB
• Reduce risk of AROU better than AARB
• Reduce blood loss during TURP (decrease
vascularization)
• High PSA & large prostate seems to be most
beneficial

108
What are the side effects of
Proscar?

109
PLESS
• Decreased libido 6%
• ED 8%
• Ejaculate disorder (retrograde, failure , decrease
semen volume) 4%
• Rash, breast enlargement, tenderness1%
• Most of these occur during the 1st
yr and does
not increase over time
• But leads to withdrawal from PLESS in 30%

110
How does 5ARI affect PSA and
does that mask the early
detection of prostate cancer?

111
EAU
• 5ARI lower the PSA by ~50% after 1 yr.
• Both the PLESS Study Group & Finasteride
PSA study Group (Andriole Urology 1998 and
Oesterling Urology 1997) have verified that :
• doubling the PSA value after taking
finasteride allows appropriate interpretation of
PSA and 5ARI does not mask the detection
of prostate cancer.
• Histologically it has also been shown that
5ARI does not cause problems with
interpretation of TRUS Bx (PLESS study
Group Yang Urology 1999)

112
What are the role of
antimuscarinics?

113
What are muscarinic receptors?
• Five muscarinic receptor subtypes (M1-M5) have been
described in humans, of which the M2 and M3 subtypes
are predominantly expressed in the detrusor
• Although approximately 80% of these muscarinic
receptors are M2 and 20% M3 subtypes, only M3 seems
to be involved in bladder contractions in healthy humans
• The role of M2 subtypes remains unclear. However, in
men with neurogenic bladder dysfunction and in
experimental animals with neurogenic bladders or
bladder outlet obstruction M2 receptors seem to be
involved in smooth muscle contractions as well

114
How dose bladder contraction
mediated?
• Scaral (S2-4) micturition centre connet to
bladder via pelvic nerves
• Acetlcholine stimulate post-synaptic
muscarinic receptor  G-protein mediated
Ca release  opening of Ca channels 
SM contraction
• Anticholinergic inhibitsmuscarinic receptor
stimuation  reduce SM cell contraction

115
What is the use of
antimuscarinic in BPH?
• Muscarinic receptor antagonists might be
considered in men with moderate to
severe LUTS who have predominantly
bladder storage symptoms
• This drug should be used precautiously if
residual urine >250-300ml

116
Is antimuscurinic safe?

117

118
What is the evidence of
Antimuscarinic vs Placebo?
• Randomized, placebo-controlled
trials demonstrated that Tolterodine
can significantly reduce:
1. Urgency incontinence
2. Daytime or 24-hour frequency
3. Urgency related voiding
– Roehrborn et al, et al. Extended-release tolterodine with or
without tamsulosin in men with lower urinary tract symptoms
and overactive bladder: effects on urinary symptoms assessed
by the International Prostate Symptom Score. BJU Int. 2008
Nov;102(9):1133-9. Epub 2008 May 26.

119
What is the evidence of
antimuscarinic?
• If treatment outcome was stratified by PSA,
tolterodine significantly reduced daytime
frequency, 24h voiding frequency and IPSS
storage symptoms in those men with PSA
concentrations below 1.3 ng/mL, which was not
the case in men with PSA of 1.3 ng/mL or more
indicating that men with smaller prostates might
profit more from antimuscarinic drugs
– Roehrborn CG, Kaplan SA, et al. Effects of serum PSA on efficacy of tolterodine
extended release with or without tamsulosin in men with LUTS, including OAB.
Urology 2008 Nov;72(5):1061-7

120
Urodynamic effect of
Antimuscurinic
• Larger bladder volume to first detrussor
contraction
• Higher maximum MCC
• Decrease bladder contractility index
• Qmax is unchange
• Short term txn to men with BOO is safe

121
What are the side-effects of
antimuscarinic?
1. Dry mouth - 25%
2. Constipation (4%) similar to placebo
3. AROU and increase of postvoid residual urine
in men without bladder outlet obstruction is
minimal and not significantly different
compared to placebo
4. Nasopharyngitis (3%)
5. Dizziness (5%)
6. Withdrawal rate – 10%
– Withdrawal due to side-effect <1% (no diff from
placebo)

122
Will it cause retention?
• Increase PVR is minimal and no different from
placebo
• Fesoterodine 8mg show higher PVR than
fesoterodine 4mg or placebo
• Incidence of AROU is comparable to placebo
• Men with BOO : not recommended due to
theoretical risk
• Generally recommend that not for PVR > 200ml
and Qmax < 5ml/s

123

124
What are the studies :
antimuscarinics + AARB?
TIMES JAMA2006
• LUTS +OAB, no prior Rx
• Tolterodine SR (Tsr) + tamsulosin (T) ,either therapy,
placebo
• Tsr +T in general more efficacious than either one
• Tsr = Tsr +T in low PSA and small prostate
• Tsr +T suggested for high PSA and high prostate vol
• Exclude PVR > 40% of CC
• Conclusion: Combination therapy is more efficacious then
mono therapy , esp in pt with high PSA + prostate volume

125
ADAM Pfizer data
• On alpha1 blockers with persistent OAB
• Randomized to continue alpha-1-blockers with Tsr or
placebo
• Did not improve PPBC
– PPBC,:patient perception of bladder condition
• Tsr :Improve OAB Sx
• Tolterodine SR well tolerated
– Significant increase in PVR (13.6ml)
– No increase in AUR
– No decrease in Qmax
• Conclusion: Pt on AARB with persistent OAB
will have improved sym when adding Tsr

126
What are the recommendations
of combination therapy?
• Combination treatment with α-blocker and
muscarinic receptor antagonist might be
considered in patients
– with moderate to severe LUTS if symptom relief has
been insufficient with the monotherapy of either drug
– More effacicious with pt with high PSA + prostate
volume
• Combination treatment should cautiously be
prescribed in men who are suspicious of having
bladder outlet obstruction

127
What phytotherapeutic
agents are you aware of?

128
Is there any role of
phytotherapy?
• EAU Guidelines committee is unable to
make specific recommendations about
phytotherapy of male LUTS because of
the heterogeneity of the products and the
methodological problems associated with
meta-analyses

129
Phytotherapy
• Saw Palmetto berry (Seronoa Repens)
– Anti-inflammatory , antiproliferative , oestrogenic drug
with 5ARI activity
– Previous Meta-analysis : 40% reduction in symptom
score (same as finasteride) [ Wilt JAMA 1998]
– Recent study: no difference vs placebo (see below)
• South African Star Grass (Harzol)
– Contain beta-sitosterol
– Cause apoptosis in prostate stromal cell
– RCT vs placebo: 5pt improvement of SS over placebo
• Others: African plum (Pygeum Africanum)

130
What is the evidence of Saw
Palmetto for BPH?
• Mode of action is unknown
• Double-blind trial, randomly assigned 225 men > 49yo
• Moderate-to-severe symptoms
• One year of treatment : saw palmetto (160 mg BD) or placebo
• Result: There was no significant difference in
1. Change in AUASI scores
2. Qmax
3. Prostate size
4. Residual volume after voiding
5. Quality of life, or serum prostate-specific antigen levels
6. The incidence of side effects was similar in the two groups
• Conclusions: In this study, saw palmetto did not improve symptoms
or objective measures of benign prostatic hyperplasia
N Engl J Med 2006;354: 557-66

131
Desmopressin

132
What is the role of
desmopressin?• Indication: Nocturia with a polyuric background
• MOA:
– Synthetic analogue of vasopressin
– Anti-diuretic effect: increase water re-absorption & urine
osmolality, decrease water excretion & urine volume
– Only V2 affinity: No V1 effect (HT , vasoconstriction)
– Effect of reduce urine volume last 8-12 hour
• Form: IV, Nasal spray , tablet, MELT
• Dosage:
– Initiated at a low dose (0.1 mg/day) PO nocte
– Gradually increased every week until maximum efficacy is
reached
– The maximal daily dose recommended is 0.4 mg/day
• Usage:
– Patients should avoid drinking fluids at least 1 hour before using
desmopressin until 8 hours thereafter

133
• Effect:
– Reduced nocturnal diuresis : 1ml/min
– Reduced number of nocturia: 2x /night
– Extend time to first nocturia by: 1.6 hour
– Reduce % of urine volume excreted at night
• Side effect:
– Headache, naeusea, diarrhoea, abd pain , dizziness , dry mouth
– Hypo Na (< 130mmol/L) (5%)
– Peripheral edema & HT
• Cautions:
– Risk of Hypo Na is 8x in pt > 65yo
– Men aged 65 years or older, desmopressin should not be used if
the serum sodium concentration is below the normal value
– In all other men aged 65 years or older, serum sodium
concentration should be measured at day 3 and 7 as well as
after 1 month and, if serum sodium concentration has remained
normal, every 3-6 months subsequently

134
PDE5 inhibitor

135
LUTs and ED
• ED and LUTs strongly linked
• 4 theories of link between ED and LUTS
– NOS/NO theory
– Autonomic hyperactivity and metabolic Sx hypothesis
– Rho-kinase activation/ endothelin pathway
– Pelvic atherosclerosis
• both highly prevalent in aging men
• co-prescription of both drugs likely to increase
• PED5-i: increase concentration of cGMP 
reduce SM tone of detrussor , prostate and
urethra

136
• Risk of combination therapy:
– Tadalafil : singificant drop of BP with doxazosin , hence to ↓ BP
effect, suggest alfuzosin/ tamsulosin to combine with PDE5i
– sildenafil should not be used in doses exceeding 25 mg within 4
h of taking an α1-AR antagonist
– Tamulosin → dose dependent anejaculation
• AARB on ED:
– Would not worsen ED
– Cardura XL & Alfulzosin may improve IIEF
• Combination Tx
– Pilot study