1. Benign
Prostatic Hyperplasia

2. Understanding the prostate
 Walnut-shaped gland that forms part of the
male reproductive system
 Surrounds the urethra - the tube that
carries urine from the bladder out of the
body

3. Understanding the prostate
 Secretes semen which
carries sperm
 Duringorgasm, prostate
muscles contract and
propel ejaculate out of
the penis

4. BPH
 The size of prostate enlarged microscopically since the
age of 40.Half of all men over the age of 60 will develop
an enlarged prostate
 By the time men reach their 70’s and 80’s, 80% will
experience urinary symptoms
But only 25% of men aged 80 will be receiving BPH
treatment

5. What is Benign Prostatic
Hyperplasia?
Peripheral zone
Transition zone
Urethra

6. Peripheral zone
Transition zone
Urethra

7. What causes BPH?
 BPH is part of the natural
aging process, like getting
gray hair or wearing glasses
 BPH cannot be prevented
 BPH can be treated

8. What’s LUTS?
Voiding (obstructive) Storage (irritative or
symptoms filling) symptoms
• Hesitancy • Urgency
• Weak stream • Frequency
• Straining to pass urine • Nocturia
• Prolonged micturition • Urge incontinence
• Feeling of incomplete
bladder emptying
• Urinary retention
LUTS is not specific to BPH – not everyone with
LUTS has BPH and not everyone with BPH has LUTS
Blaivas JG. Urol Clin North Am 1985;12:215–24

9. Diagnosis of BPH
• Symptom assessment
– the International Prostate Symptom Score (IPSS) is recommended as it is used
worldwide
– IPSS is based on a survey and questionnaire developed by the American Urological
Association (AUA). It contains:
• seven questions about the severity of symptoms; total score 0–7 (mild), 8–19 (moderate),
20–35 (severe)
• eighth standalone question on QoL
• Digital rectal examination(DRE)
– inaccurate for size but can detect shape and consistency
• PV determination- ultrasonography
• Urodynamic analysis
– Qmax >15mL/second is usual in asymptomatic men from 25 to more than 60 years of
age
• Measurement of prostate-specific antigen (PSA)
– high correlation between PSA and PV, specifically TZV
– men with larger prostates have higher PSA levels 1
– PSA is a predictor of disease progression and screening tool for CaP
– as PSA values tend to increase with increasing PV and increasing age, PSA may
be used as a prognostic marker for BPH

10. Interfere with sexual life
Sexual Activity Decreases with
Average sex intercourse/activity/ month
9 8.5 n=12,815
Age and LUTS: MSAM-7 Survey
8 7.6 IPSS = 0
7 6.6 IPSS 1–7
5.7 5.7 IPSS 8–19
6
4.9 IPSS 20–35
5 4.6
4.0
4 3.7 3.5
2.6
3 1.7
2
1
0
50–59 years 60–69 years 70–79 years
Rosen et al. Eur Urol 2003 n=12815

11. When should BPH be treated?
BPH needs to be treated ONLY IF:
 Symptoms are severe enough to bother
the patient and affect his quality of life
 Complications related to BPH

12. Choosing the right treatment
 Consider risks, benefits
and effectiveness of each
treatment
 Consider the outcome and
lifestyle needs

13. Treatment options
 “Watchful waiting”
 Medication
 Surgical approaches
Minimal invasive
TURP
Invasive “open” procedures

14. “watchful waiting”
 For mild symptoms. follow up1 to 2 times
yearly
 Offer suggestions that help reduce
symptoms
 Avoid caffeine and alcohol
 Avoid decongestants and antihistamines

15. Medication
 First line of defense against
bothersome urinary symptoms
 Two major types:
 α blockers - relax the smooth
muscle of prostate and provide a
larger urethral opening
(Hytrin,Doxaben, Harnalidge)
5 α reductase inhibitor -
Shrink the prostate gland
(Proscar, Avodart)

16. Medication
Benefits Disadvantages
 Convenient  Drug Interactions
 No loss of work  Must be taken every day
time
 Manages the problem
 Minimal risk instead of fixing it

17. Possible side effects of
medication
• Impotence

• Dizziness

• Headaches

• Fatigue

• Loss of sexual drive


18. α-Adrenergic Blockers: Rationale
• Prostate smooth muscle tone is mediated via
α1-adrenergic receptor
• Blockage of the receptor leads to improvement
of flow rate and LUTS1
• Central α-receptors and the effect of agents on
these receptors likely play an additional role
• Density of adrenergic receptors changes with
prostate size and age
• Three α1-adrenergic receptor subtypes
have been identified (A, B, D)
Schwinn DA. BJU Int. 2000;86(suppl 2):11-22.

19. Distribution of α1-Adrenergic Receptors

20. Localization of α1-Adrenergic
Receptors (α1-ARs)

21. α-Blockers
• Nonselective
– Phenoxybenzamine
• Short-acting selective α1-blocker
– Prazosin, Alfuzosin
• Long-acting selective α1-blockers
– Terazosin
– Doxazosin
• Long-acting selective α1A-subtype
– Tamsulosin
– Alfuzosin-SR

22. α1-Adrenergic Blockers: Summary
• All currently available α1-blockers induce fast
improvement in LUTS and flow rate parameters
with similar efficacy
• They are all well tolerated; however, the adverse
event spectrum differs between the agents
– Terazosin and doxazosin induce more dizziness, fatigue,
and asthenia
– Tamsulosin induces more ejaculatory disturbances
• None of the α1-blockers alter urodynamic parameters,
prostate volume or serum PSA
• None have been shown to alter the natural history of
the disease or prevent AUR / Surgery

23. 5α-Reductase Inhibitor: Rationale
• Prostatic differentiation & growth depend on androgenic
stimulation
• Testosterone is converted to dihydrotestosterone (DHT)
within the prostatic stromal & basal cells facilitated by
5α-reductase enzyme
• 5α-reductase inhibitor: deprive the prostate of its
testosterone support
• 5α-reductase enzyme:
Type I: skin & liver
Type II: stromal & basal cells of prostate, seminal vesicle,
epididymis
Kirby RS et al. Br J Urol. 1992;70:65-72
Tammela TLJ et al. J Urol. 1993;149:342-344

24. Regulation of cell growth in the
prostate in BPH
Serum testosterone (T) Serum Dihydrotestosterone
(DHT)
T Prostate
5AR (1 and 2) DHT cell
Growth DHT-androgen
factors receptor complex
Cell death
Increased Unbalanced
Cell growth

25. 5α-reductase inhibition
Mode of action
OH OH
5 α-reductase type 1 and 2
O O
NADPH NADP H
Testosterone Dihydrotestosterone
Avodart (dutasteride) - Dual (type 1&2) 5ARI
Proscar(finasteride) - Only type 2 5ARI

26. Greater and more consistent suppression
of DHT observed with dutasteride
versus finasteride (n=399)
DHT (% change from baseline)
40 Treatment
withdrawn Placebo
20 Fin 5.0 mg
Dut 0.5 mg
0
-20
-40
-60 100% Dut patients
>70% 49% Fin patients
-80
>90% 85.4% Dut patients
-100 2.2% Fin patients
0 4 8 12 16 20 24 28 32 36 40
Time (weeks)
Richard V. Clark et al. J Clin Endocrinol Metab 89:2179-2184, 2004
Roehrborn et al (2003)

27. Comparison of adverse events:
Dutasteride vs. finasteride vs. placebo
(n=399)
Patients (%)
100
Placebo
Dutasteride 0.5 mg
80
Dutasteride 5.0 mg
Finasteride 5.0 mg
60
40
20
0
Any AE Drug-related Serious AE Withdrawal
AE due to AE
Richard V. Clark et al. J Clin Endocrinol Metab 89:2179-2184, 2004

28. Dutasteride 4-year studies
(2-year double-blind and 2-year open-label)
Randomised to double-blind phase
n=4325
Key inclusion criteria:
aged ≥ 50 years, diagnosis of BPH, PV ≥ 30 cc,
AUA-SI score ≥ 12, Qmax ≤ 15 mL/sec, PSA ≥ 1.5 ng/mL
Placebo Dutasteride
n=2158 n=2167
Entered open-label phase Entered open-label phase
on dutasteride n=1152 on dutasteride n=1188
P/D D/D
Roehrborn CG et al Urol 63:709-15,2004

29. Dutasteride therapy results in reductions
in total prostate volume from 1– 24
months that are sustained to 4 years
Placebo Dutasteride Open-label dutasteride after placebo
Mean change (%)
5 * * *† *‡
1.4
0.2
0
-0.6 -1.5
-2.1
-5
-5.2
-10
-15 -13.8
-20
-19.9
-21.7
-25 -23.6
-26.0
-30 -27.3
Treatment month 1 3 6 12 24 48
*p<0.001 for differences between treatment groups
†p<0.001 for change from Month 24 to Month 48
‡p=0.07 for change from Month 24 to Month 48
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

30. Dutasteride therapy results in symptom
improvements from 6 months, with continuing
improvements over 4 years (completers)
Change in AUA-SI (units)
0 Double-blind Open-label
-1 P/D (n=1152)
-2 D/D (n=1188)
*
-3
-2.7
-4
-5
*†
-5.0 -5.6
-6
-6.5
-7
0 3 6
9 12 15 18 21 24 27 30 33 36 39 42 45 48
*p<0.001 between treatment groups
Treatment month
†p<0.001 for differences within treatment groups from Month 24
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

31. Dutasteride therapy results in improvements
in urinary flow from 1 month, with
continuing improvements over 4 years
Mean change P/D (n=1152)
(mL/sec)
D/D (n=1188)
3.0 †
* × 2.7
2.5 2.2
2.0 ¤
1.9
1.5
1.0
0.5
0.6
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Treatment month
*p<0.001 between treatment groups
†p=0.042 between treatment groups
¤p<0.001 vs. Month 24
×p=0.007 vs. Month 24
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

32. Acute urinary retention
Kaplan-Meier estimates: time to first event
Patients (%)
7 Double-blind Open-label 6.7%
6
5 P/D
4 D/D
57
3 3.3%
%
2
1
0
0 6 12 18 24 30 36 42 48
Treatment month
Roehrborn CG et al Urol 63:709-15,2004; M.Emberton et al. 2004 EAU Abstract

33. BPH-related surgery
Kaplan-Meier estimates: time to first event
Patients (%)
7 Double-blind Open-label
6
5.6%
5 P/D
4 D/D
48
3 3.3%
%
2
1
0
0 6 12 18 24 30 36 42 48
Treatment month
Roehrborn CG et al Urol 63:709-15,2004; M.Emberton et al. 2004 EAU Abstract

34. PSA is reduced in a predictable
manner preserving its prostate cancer
screening utility
Double-blind Open-label
20
Mean (+/- SE) % Change
10
0
-10
-20
-30
-40
-50
-60 -57.2
0 6 12 18 24 30 36 42 48
Treatment Month
Placebo n=1152
Dutasteride
n=1188
Data on File GlaxoSmithKline

35. Long-term change in prostate volume
Indirect comparison of dutasteride,
finasteride and a-blockers
% Change in prostate
volume from baseline Dutasteride
30 Finasteride
α-blockers
20
10
0
-10
-20
-30 2 yr 4 yr PLESS MTOPS 6 yr MTOPS
DB OL 4 yr 4 yr OL Dox
4 yr
McConnell et al. (1998); McConnell et al. (2003); Roehrborn et al. (2002); Lowe et al. (2003)

36. Symptom improvement
Indirect comparison of a-blockers,
finasteride and dutasteride
Mean AUA-SI score Dutasteride
reduction from baseline Finasteride
9 α-blockers
8
7
6
5
4
3
2
1
0
1y 2y 4y AUA PLESS MTOPS 5y Tam Tam Tam Alf Tera Dox Dox
DB DB OL 1y 4y 4y OL label label 5y 1y AUA AUA 4y
13 wk 13 wk OL OL 1y 1 y MTOPS
study 1 study 2
McConnell et al. (1998); McConnell et al. (2003); Roehrborn et al. (2002); AUA (2003)

37. Combination therapy with
5aRIs and a1 blockers

38. Rationale for Combination Therapy
 Alpha blockers relax the smooth muscle of bladder neck
and prostatic capsule/adenoma, thereby improving
symptoms and flow rates, relieving obstruction
 5 ARIs reduce the action of androgens in the prostate,
inducing apoptosis, atrophy, and, by shrinking the
prostate improve symptoms, relieve obstruction and
prevent AUR & prostate surgery
5ARIs α1-adrenergic
? blockers
Arrest disease progression Rapidly relieve symptoms

39. Medical Therapy of Prostatic
Symptoms (MTOPS)

40. Change in AUA Symptom Score
at Year 4
Placebo 4.0
Doxazosin 6.0 (p<0.001)
Finasteride 5.0 (p<0.047)
Combination 7.0 (p<0.001)
2 4 6 8 10
Median point decrease from baseline
Median baseline AUA SS = 17.0

41. Change in Qmax at Year 4
Placebo 1.4
Doxazosin 2.5 (p<0.001)
Finasteride 2.2 (p<0.047)
Combination 3.7 (p<0.001)
1 2 3 4 5
Median point decrease from baseline
Median baseline Qmax = 10.6

42. Conclusions
 Single arm therapy with alpha blocker
 Improve symptoms and prevent symptom progression
 Does not alter natural history or cross over to invasive therapy
 Single arm therapy with 5 ARI
 Treats symptoms only when LUTS associated with BPH (ie
enlargement or high PSA)
 Alters natural history in pts at risk (large gland, high PSA)
 Combination (doxazosin+finasteride) therapy is the most
effective form of treatment for LUTS and BPH
 Improve symptoms and flow rate
 Prevent AUR and/or surgery
 Alter the natural history of the disease

43. Symptom Management After
Reducing Therapy: SMART–1
SMART–1 was designed to examine
short-term dutasteride and a1-blocker
combination therapy, followed by
dutasteride monotherapy
Entry criteria:
 IPSS ≥ 12
 PV ≥ 30 cc, estimated by DRE
 PSA 1.5 – 10.0 ng/ml
Barkin et al (2002)

44. SMART-1: study design
DT24 + D12
DT36
dutasteride 0.5mg
Combination + placebo
Placebo
Placebo dutasteride 0.5mg (tamsulosin)
run-in + tamsulosin 0.4mg
once daily
Combination
4 weeks 24 weeks 12 weeks 1 week
Single Single Double blind Single
blind blind blind
Wk 30 Wk 36
Barkin et al (2002)

45. SMART-1: primary endpoint question
at week 30 by baseline IPSS
Moderate Severe
(baseline IPSS <20) (baseline IPSS ≥20)
(n=220) (n=82)
100 93%
84% 86%
80
Patients (%)
57.5%
60
40
Severe pts need longer AB treatment
20
0
DT36 DT24 + D12 DT36 DT24 + D12
% patients better/same
Barkin et al (2002)

46. 5 α Reductase Inhibitors
成份 Finasteride Dutasteride*
Compared to
PROWESS1 PLESS2 MTOPS3 2yrs4 4yrs5,6,7
Baseline
Duration (yr) 2 4 4 2 4
Total Prostate Volume -15.3% -18% -19% -25.7% -27.3%
Symptoms -2.1 -3.3 -5.6 -4.5 -6.5
Urinary Flow Rate 1.5 1.9 3.2 2.2 2.7
Continue
Risk of AUR -57% -57% -68% -57% Reduction
Continue
Risk of BPH Surgery -40% -55% -64% -48% Reduction
Note: Not from a comparative trial, all result abstracted from treatment group.
PROWESS=Proscar Worldwide Efficacy and Safety Study; PLESS=Proscar Long-term Efficacy and Safety Study;
MTOPS=Medical Therapy of Prostatic Symptoms
*: Avodart Phase III trial 為在 2 年的 double blind 後再延長 2 年至 4 年的 open-label study
References:
1. Marberger MJ. Urol.51:677-86,1998 。 2. McConnell JD et al. N Engl J Med 338(9):577-63,1998 。 3. McConnell JD et
al. N Engl J Med 349(25):2387-98,2003 。 4. Roehrborn CG et al.Urol.60:434-41,2002 。 5. T.Tammela et al. 2004 EAU
Abstract 。 6. F.Debruyne et al. 2004 EAU Abstract 。 7.M.Emberton et al. 2004 EAU Abstract 。

47. Conclusions
 In MTOPS study, finasteride afforded long-term reduction
in risk of AUR on surgery when combined with alpha 1-
blocker doxazosin
 In SMART-1 study, dutasteride can be used in
combination with tamsulosin to achieve fast symptom
relief that is maintained with alpha 1- blocker is removed
after 6 months

48. Medical Therapy Algorithm
Patient
IPSS IPSS
≤7 >7
No or Moderate to
little severe
bother bother
Prostate Prostate Prostate Prostate
small large small large
PSA low PSA high PSA low PSA high
No α-
Preventive therapy 5α-Reductase
Treatment Adrenergic
5α-Reductase Inhibitor Inhibitor
Blocker
Combination Rx
IPSS <19 IPSS >19
(Moderate) (Severe)
Short term Long term

49. Surgical treatment

50. Treatment Modalities for BPH
 Watchful waiting  Surgicenter/Hospital-based
 Medical therapy treatment
 Phytotherapy  TURP (gold standard)
 α-adrenergic blockers  TUIP
 5α-reductase inhibitors  Open surgery (prostatectomy)
 Combination therapy  TUVP
 Office-based treatment  ILC
 TUMT  VLAP
 TUNA  Prostatic stents
 WIT
Chatelain C et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health
Publication Ltd; 2001;519-534. McConnell JD et al. Benign Prostatic Hyperplasia: Diagnosis and
Treatment. Clinical Practice Guideline, Number 8.

51. Indication of surgical intervention
• Acute urinary retention
• Gross hematuria
• Frequent UTI
• Vesical stone
• BPH related hydronephrosis or renal
function deterioration
• Obstruction
IPSS≧8, prostate size, image study, UFR
cystoscopic findings, residual urine

52. Conventional Surgical Therapy
• Transurethral resection of the prostate
(TURP)
• Open simple prostatectomy

53. TURP
(transurethral resection of the prostate)
 “Gold Standard” of care for BPH
 Uses an electrical “knife” to surgically cut
and remove excess prostate tissue
 Effective in relieving symptoms and
restoring urine flow

54. TURP
• “Gold standard” of surgical treatment for
BPH
• 80~90% obstructive symptom improved
• 30% irritative symptom improved
• Low mortality rate 0.2%

55. The “gold standard”- TURP
Benefits Disadvantages
 Widely available  Greater risk of side
effects and complications
 Effective
 1-4 days hospital stay
 Long lasting
 1-3 days catheter
 4-6 week recovery

56. Complication of TURP
• Immediate complication
bleeding
capsular perforation with fluid extravasation
TUR syndrome
• Late complication
urethral stricture
bladder neck contracture (BNC)
retrograde ejaculation
impotence (5-10%)
incontinence (0.1%)

57. Open Simple Prostatectomy
• “too large prostate” -- >100 gm
• Combined with bladder diverticulum or
vesical stone surgery
• Suprapubic or retropubic method

58. Minimally invasive therapy
• During the last decade, numerous amounts of
minimally invasive therapy modalities have
been developed to challenge the traditional
surgery of TURP
• The aim of these therapies is to achieve
results similar to TURP but with minimal
anesthesia, complication, risk and hospital
stay.

59. Minimally invasive therapy for
BPH
• transurethral balloon dilatation of the prostate
(TUBDP)
• transurethral incision of the prostate (TUI)
• intraprostatic stent
• transurethral microwave thermotherapy (TUMT)
• transurethral needle ablation of the prostate (TUNA)
• transurethral electrovaporization of the prostate
(TUVP)
• photoselective vaporization of the prostate (PVP),
• Cryotherapy
• Transurethral ethanol ablation of the prostate
(TEAP),

60. Minimally invasive therapy for
BPH
• transurethral laser-induced prostatectomy
(TULIP)
• visual laser ablation of the prostate (VLAP)
• contact laser prostatectomy (CLP)
• interstitial laser coagulation of the prostate (ILC)
• holmium:YAG laser resection of the prostate
(HoLRP)
• holmium:YAG laser enucleation of the prostate
(HoLEP)
• high-intensity focused ultrasound (HIFU)
coagulation
• botulinum toxin-A injection of the prostate

61. HoLEP Vs. TURP
• IPSS & urodynamic findings: no statistically significant
differences
• Operation time:
HoLEP 74 +/- 19.5 vs. TURP 57 +/- 15 mins (p <0.05)
• Catheterization time:
31 +/- 13 vs 57.78 +/- 17.5 hours (p <0.001)
• Hospital stay:
59 +/- 19.9 vs 85.8 +/- 18.9 hours (p <0.001)
• Urge incontinence: more common in the HoLEP group
• The overall complication rate was comparable in the 2
groups
Journal of Urology. 172(5, Part 1 of 2):1926-1929, November 2004

62. TURP vs HIGH POWER (80 W) POTASSIUM TITANYL
PHOSPHATE (KTP) LASER VAPORIZATION
• Hemostasis: standardized ablation volume of 16 cm 3
tissue (23.3 vs 2.1 ml per minute, p <0.0001).
• Tissue ablation: more rapid in the resection group
(100 vs 20 seconds, p <0.001).
• Histological examinations: larger coagulation zones for
the KTP group compared to conventional tissue resection
(0.9 vs 0.6 mm, p <0.01).
• 80 W KTP laser vaporization: bloodless ablative
procedure, but more time-consuming
Journal of Urology. 171(6, Part 1 of 2):2502-2504, June 2004

63. How does PVP work?
 Uses a very high powered green laser and
a thin, flexible fiber
 Fiber is inserted into
the urethra through a
cystoscope

64. How does PVP work?
 Quickly
and precisely vaporizes and
removes the enlarged prostate tissue
 The green laser energy is hemostatic, so
there is almost no bleeding

65. Enlarged Prostate After GreenLight PVP
 Urethra is obstructed  Urethra is open
 Urine flow blocked  Normal urine flow is
restored

66. Summary
• Minimally invasive therapies for the treatment of BPH
has the advantages such as less blood loss, less
occurrence of hyponatremia, quicker recovery, and
reduced risk of urethral stricture.
• However, it also has the disadvantages such as long-
lasting bladder irritation owing to higher temperature
during therapy and possible longer catheterization
period due to swelling of the prostate.
• It is still too early to make a definitive conclusion
concerning the future role of these minimally invasive
therapies for the treatment of BPH.