1. health and fitness
2. disease
3. incontinence

UAA Consensus on the
Management of BPH/Male
st
LUTS (1 Edition)
Edited and written by Masayuki Takeda,
Md Afiquor Rahman, M A Salam, Masaki Yoshida, Hideki Kobayashi,
Norifumi Sawada, Momokazu Gotoh, Koji Yoshimura, Jun Hyuk
Hong, Kyu-Sung Lee, Joon Chul Kim, Rohan Malek, Selvalingam
Sothilingam, Jose Albert C.Reyes III, Kok Bin Lim, Keong Tatt Foo,
Colin Teo, Shih-Ping Liu, Shing-Hwa Lu, Chih-Shou Chen, Sathit
Ruangdilokrat, Wachira Kochakarn and other UAA Guideline
members.
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Foreword
These Proceedings represent the consensus and recommendation
of Benign Prostatic Hyperplasia (BPH)/Male Lower Urinary Tract
Symptoms (LUTS) by the 16 countries that met in Pattaya, Thailand
at the occasion of the 11th Asian Congress of Urology, on August
22nd 2012, and in Hong Kong on November 10th 2012.
On behalf of Urological Association of Asia (UAA), we would like to
thank the chairman, the committee members, and Ms. Angie See,
Executive Secretary of UAA Central Office.
We also would like to thank JUA, AUA, EAU, and ICUD for kind
allowance to use some parts of their Guidelines.
This is the 1st Clinical Guideline published by UAA, hence, is a
milestone for UAA.
UAA Representatives
Keong Tatt Foo, Osamu Ogawa, Masayuki Nakagawa
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Contents
Preface
COI (Conflict of interest)
Methodology
Committee Members
1.
2.
3.
4.
Algorithm
CQ(Clinical Question)s
Introduction
Definition, and Terminology of Benign Prostatic Hyperplasia
(BPH) and related disorders
5. Risk factors
6. Epidemiology & Natural history
7. Pathophysiology
8. Complications by BPH
9. Diagnosis & Investigation of BPH/Male LUTS
10. Recommendation grade for treatment: Pharmacological &
Conservative Treatments
11. Recommendation grade for treatment: Surgery
12. Abbreviations
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Preface
1. Purposes of guideline: Practical Consensus Statement on the Management
of BPH/Male LUTS
2. Target doctors: Both Urologists and General Practitioners
3. Target patients: 40 years or older male patients with BPH/LUTS
4. Ownership and responsibility of this guideline: UAA
Conflict of interest
All members of the BPH/Male LUTS working group have provided disclosure
statements on all relationships that they have and that might be perceived to be
a potential source of conflict of interest. This information is kept on file in the
Urological Association of Asia Central Office database. These guidelines
document was developed with the financial support of the Urological Association
of Asia. No external sources of funding and support have been involved.
The UAA is a non-profit organization and funding is limited to administrative
assistance and travel and meeting expenses. No honorarium or other
reimbursements.
Methodology
1. The BPH/Male LUTS Guidelines have been developed by committee
members recommended by the Urological Association of Asia (UAA).
2. The members have meticulously reviewed relevant references, retrieved via
the PubMed and MEDLINE databases, published between 1966 through
Dec 31st, 2011.
3. The search strategy includes the Medical Subject Headings (MeSH) for BPH
and LUTS: “Prostatic Hyperplasia”[MeSH] AND Benign; “Urinary tract”
4. [MeSH] AND Symptoms AND Lower. Other key words for searching
references will be selected by each committee.
5. Other sources of information include
1)
JUA clinical guidelines for benign prostatic hyperplasia,
2)
The BPH Guidelines 2010 published by The American Urological
Association (AUA)
3)
Guidelines on the Treatment of Non-neurogenic Male LUTS2011
The European Association of Urology (EAU),
4)
The meeting reports of the 6th International Consultation on
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New Developments in Prostatic Cancer and Prostatic Diseases.
“MALE LOWER URINARY TRACT DYSFUNCTION; Evaluation
and Management”
6. Level of Evidence & Grade of Recommendation for each treatment will be
made according to the following strategy. The recommendations of the
treatments are based on a non-structured literature search, which has been
previously shown, and labeled with a Level of Evidence (LE), according to a
classification system modified from the Oxford Centre for Evidence-based
Medicine Levels of Evidence*, ranging from LE:1 (highest evidence level) to
LE:5 (case study or expert opinion).
*Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001).
Produced by Bob Phillips, et al., Since November 1998.
http://www.cebm.net/index.aspx?o=1025 [accessed March 2012].
7. For each subsection, the conclusion(s) drawn from the relevant articles and
evidence levels have been judged using a Grade of Recommendation (GR),
ranging from a strong recommendation (Grade A) to recommendation not to
do (Grade D).
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As presented above, Level of Evidence for each reference will be made
according to the following strategy in CQ6-14(pages 24-48), however, Level of
Evidence will not be shown for each reference in either “Chapter 10.
Recommendation grade for treatment: Pharmacological & Conservative
Treatments”, or in “Chapter 11.Recommendation grade for treatment: Surgery”.
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Committee Members of Guideline (should be correctly written)
1. UAA Representative
Prof. Keong Tatt Foo, Prof. Osamu Ogawa, Prof. Masayuki Nakagawa
2. 8 core member countries: Korea, Taiwan, Japan, Singapore, Malaysia,
Thailand, Bangladesh, Philippines
3. Members from 16 countries (Alphabetical orders)
Bangladesh
Dr. Md Afiquor Rahman, Dr. M A Salam
Cambodia
Dr. Prak Seng Hour
China
Dr. Song Bo
Hong Kong
Dr. Steve Chan, Dr. In Chak Law
India
Dr. R M Meyyappan
Indonesia
Dr. Chaidir Arif Mochtar
Iran
Dr. Seyed Mohammad Kazemeyni
Japan
Dr. Momokazu Gotoh, Dr. Hideki Kobayashi
Dr. Masayuki Nagakawa, Dr. Osamu Ogawa
Dr. Norifumi Sawada, Dr. Masayuki Takeda
Dr. Masaki Yoshida, Dr. Koji Yoshimura
Korea
Dr. Jun Hyuk Hong, Dr. Kyu-Sung Lee
Dr. Joon Chul Kim
Malaysia
Dr. Zulkifli Md Zainuddin, Dr. Rohan Malek
Dr. Selvalingam Sothilingam
Philippines
Dr. Eduardo R Gatchalian, Dr. Jose Albert C.Reyes III
Singapore
Dr. Kok Bin Lim, Keong Tatt Foo,
Dr. Colin Teo
Sri Lanka
Dr. Srinath Chandrasekera
Taiwan
Dr. Shih-Ping Liu, Dr. Shing-Hwa Lu
Dr. Chih-Shou Chen
Thailand
Dr. Sathit Ruangdilokrat, Dr. Wachira Kochakarn
Vietnam
Dr. Vu Le Chuyen
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1. Algorithms
Algorithms are made for general practitioner (GP; a) and Urologist (b-d),
separately.
1.1Treatment Algorithm of Male LUTS for General Practitioner (GP)
*Neurological disorders, Pelvic surgery, Radiation Therapy, DM, Drugs
**In patients with life expectancy of less than 10 years, or without indication for
prostatic cancer treatment, serum PSA may not be routinely measured.
(See page 22, in Chapter 2. CQ5)
***Assessment of shape and size of prostate is recommended.
(See page 15 in Chapter 2. CQ2)
GP: General practitioner
DRE: digital rectal examination
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1.2 Treatment Algorithm of Male LUTS; Basic Options for Urologist
Using Medical/ Conservative Treatments
*In patients with life expectancy of less than 10 years, or without indication for
prostatic cancer treatment, serum PSA may not be routinely measured.
(See page 22 in Chapter 2. CQ5, and page 93 in Chapter 9. Diagnosis &
Investigation for BPH/Male LUTS)
**Assessment of shape and size of prostate is recommended.
*** IPP=1 and good flow is good indication.
IPP=3 and poor flow is a potential risk for urinary retention.
IPP: Intravesical prostatic protrusion.
(See page 15 in Chapter 2. CQ2, and page 74–75 in Chapter 7.
Pathophysiology of BPH)
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1.3 Specialized Management for Persistent Bothersome LUTS after
Basic Management for Urologist
BOO: Bladder outlet obstruction
PFS: Pressure-flow study
*Urethrocystoscopy is indicated if urethral stricture or bladder neck sclerosis is
suspected.
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1.4Treatment Algorithm of Bothersome Male LUTS Refractory to
Medical/Conservative Treatment or Absolute Surgical Indications
for Urologist
TURP: Transurethral resection of the prostate
TUIP: Transurethral incision of the prostate
TUEB: Transurethral enucleation of the prostate using bipolar electrode
TUERP: Transurethral enucleation and resection of the prostate
(either using bipolar or monopolar electrode)
TUVP: Transurethral vaporization of the prostate
PVP: Photoselective vaporization of the prostate
HoLAP: Holmium laser ablation of the prostate
HoLEP: Holmium laser enucleation of the prostate
TUMT: Transurethral microwave thermotherapy of the prostate
TUNA: Transurethral needle ablation of the prostate
CIC: Clean intermittent catheterization
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2. Clinical Question (CQ)
Masayuki Takeda, M.D., Ph.D., Hideki Kobayashi, M.D., Ph.D.,
Norifumi Sawada, M.D., Ph.D., Masaki Yoshida, M.D., Ph.D., Koji
Yoshimura, M.D., Ph.D., Momokazu Gotoh, M.D., Ph.D., Japan.
As described in page 5, the recommendations of the treatments (CQ6-14)
are based on a non-structured literature search, which has been previously
shown, and labeled with a Level of Evidence (LE), according to a classification
system modified from the Oxford Centre for Evidence-based Medicine Levels of
Evidence, ranging from LE:1 (highest evidence level) to LE:5 (case study or
expert opinion). However, Grade of Recommendations for examinations and
methods for diagnosis (CQ1-CQ5) are made by the consensus of the committee
members, not solely according to the above strategy.
CQ1
What questionnaires should be recommended for initial evaluation of BPH/Male
LUTS ?
Answer:
IPSS: Recommendation Grade A
QOL in IPSS: Recommendation Grade A
Frequency volume chart (FVC) or Bladder diary: Recommendation Grade B
The OABSS: Recommendation Grade B
Systematic diagnostic work-up should be begun by history, validated symptom
questionnaires. International Prostate Symptom Score (IPSS) and QOL score
are the most prevalent, highly validated questionnaire for BPH patients [1-4].
Freuqeuncy volume chart (time and volume of voids and including any episodes
of incontinence) or a bladder diary (a 24 hour recording of your liquid intake and
urine output) is recommended for men with daytime or nocturnal frequency.
Nocturnal polyuria (> 33% of the 24-hour urine excretion overnight) can be made
only by a bladder diary, whereas the diagnosis of all other forms of
non-neurogenic benign forms of LUTS in men aged 40 years or older is mainly
made by exclusion.
The diary records individual voiding prospectively, enabling the accurate
evaluation of voiding time, individual volumes voided, and total urinary
volume. This information is useful for the differential diagnosis of urinary
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frequency, which can be classified as a decrease in the volume voided, polyuria,
or both [5–7]. Ideally, the diary should be kept over a period of 3–7 days,
although keeping the diary for over 1 or 2 days may be sufficient [8–11].
The OABSS, the sum score of four symptoms (daytime frequency, nighttime
frequency, urgency, and urgency incontinence), has been developed and
validated [12, 13]. OABSS can be applied efficiently to the evaluation of OAB in
patients with BPH [14].
The different QOL instruments are discussed in relation to their correlation with
symptom evaluation in studies of treatment options for BPH, however, there is
neither agreement nor data to decide which QOL instrument is preferable.
The most widely used QOL instrument is the disease-specific QOL, single
question added to the IPSS, and BPH Impact Index (BII). Symptom-specific QOL
is also used. Disease-specific QOL domains (interference with daily activities)
tend to improve more with treatment interventions than general health measures
(i.e. general well-being). Symptom-specific QOL of BPH patients cannot be
estimated by physically measurable variables [15–17].
References of CQ1
1. Bolognese JA, Kozloff RC, Kunitz SC, Grino PB, Patrick DL, Stoner E.
Validation of a symptoms questionnaire for benign prostatic hyperplasia.
Prostate 1992; 21: 247–54.
2. Epstein RS, Deverka P, Chute CG et al. Validation of a new quality of life
questionnaire for benign prostatic hyperplasia. J. Clin. Epidemiol. 1992; 45:
1431–45.
3. Bosch JL, Hop WC, Kirkels WJ, Schroder FH. The International Prostate
Symptom Score in a community-based sample of men between 55 and 74
years of age: prevalence and correlation of symptoms with age, prostate
volume, flow rate and residual urine volume. Br. J. Urol., 1995; 75: 622–30.
4. Netto Junior NR, D'Ancona CA, De Lima ML. Correlation between the
International Prostatic Symptom Score and a pressure-flow study in the
evaluation of symptomatic benign prostatic hyperplasia J. Urol., 1996; 155:
200–2.
5. Homma Y, Araki I, Igawa Y et al. Clinical guideline for male lower urinary
tract symptoms. Int. J. Urol. 2009; 16: 775–90.
6. Homma Y, Kawabe K, Tsukamoto T et al. Estimate criteria for efficacy of
treatment in benign prostatic hyperplasia. Int. J. Urol. 1996; 3: 267–73.
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7. Abrams P, Chapple C, Khoury S, Roehrborn C, De la Rosette J. Evaluation
and treatment of lower urinary tract symptoms in older men. J. Urol. 2009;
181: 1779–87.
8. EAU Guidelines on the Management of Male Lower Urinary Tract Symptoms
(LUTS), incl. Benign Prostatic Obstruction (BPO)
(http://www.uroweb.org/gls/pdf/12_Male_LUTS_LR%20May%209th%20201
2.pdf)
9. Weiss JP, Van Kerrebroeck PE, Klein BM, Norgaard JP. Excessive nocturnal
urine production is a major contributing factor to the etiology of nocturia. J.
Urol. 2011; 186: 1853–63.
10. Vaughan CP, Endeshaw Y, Nagamia Z, Ouslander JG, Johnson TM. A
multicomponent behavioural and drug intervention for nocturia in elderly
men: rationale and pilot results. BJU Int. 2009; 104: 69–74.
11. Gisolf KW, Van Venrooij GE, Eckhardt MD, Boon TA. Analysis and reliability
of data from 24-hour frequency-volume charts in men with lower urinary tract
symptoms due to benign prostatic hyperplasia. Eur. Urol. 2000; 38: 45–52.
12. Homma Y, Yoshida M, Seki N et al. Symptom assessment tool for overactive
bladder syndrome – overactive bladder symptom score. Urology 2006; 68:
318–23.
13. Homma Y, Kakizaki H, Yamaguchi O et al. Assessment of overactive bladder
symptoms: comparison of 3-day bladder diary and the overactive bladder
symptoms score. Urology 2011; 77: 60–4.
14. Tsujimura A, Takao T, Miyagawa Y et al. Survey of overactive bladder
symptoms influencing bother before and after treatment with tamsulosin
hydrochloride in Japanese patients with benign prostatic hyperplasia.
Urology 2011; 78: 1058–62.
15. Batista-Miranda JE, Diez MD, Bertran PA, Villavicencio H. Quality-of-life
assessment in patients with benign prostatic hyperplasia: effects of various
interventions, Pharmacoeconomics 2001; 19: 1079–90.
16. Arai Y, Ishitoya S, Okubo K, Suzuki Y. Transurethral interstitial laser
coagulation for benign prostatic hyperplasia: treatment outcome and quality
of life. Br. J. Urol. 1996; 78: 93–8.
17. Yoshimura K, Arai Y, Ichioka K, Terada N, Matsuta Y, Okubo K.
Symptom-specific quality of life in patients with benign prostatic hyperplasia.
Int. J. Urol. 2002; 9: 485–90.
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CQ2
Should ultrasonography be recommended for the anatomical evaluation of
BPH ?
Answer:
Ultrasonography (IPP, Prostate volume) is recommended for the
anatomical evaluation of the prostate (Recommendation Grade A).
Compared with a digital rectal examination and other imaging tests,
ultrasonography is more accurate and minimally invasive [1–3]. Transabdominal
ultrasonography is easily performed and readily able to detect both bladder
pathology, and kidney lesion, whereas trans-rectal ultrasonography permits the
detailed imaging of the inner structures. The type of ultrasonography performed
depends on the equipment available, as well as on the objective of the
examination. PV is predictive of both clinical progression and the therapeutic
outcomes of surgical or medical treatment [4, 5].
Urethrography provides information in the post prostatectomy patients with
residual symptoms [6, 7].
Intravesical Protrusion of Prostate (IPP) is the distance measured from the tip of
the protruding lobes to the base of the prostate at the circumference of the
bladder, seen in the sagittal view on transabdominal ultrasonography.
A grading system for IPP is well established. Grade 1 IPP is 5mm or less, grade
2 IPP is more than 5mm to 10mm, grade 3 IPP is more than 10mm. Recent
studies have shown good correlation between IPP grade and urodynamic
evidence of obstruction [8–10].
For the estimation of histologically measured components, various ultrasonographic parameters obtained by transrectal method (TRUS) were effectively
compared with using ultrasonic power Doppler imaging (PDI) of the prostate [7].
CT scans and MR imaging are expensive and have no routine use in evaluating
patients with BPH [6].
Ultrasound derived measurements of bladder and detrusor wall thickness, and
ultrasound estimated bladder weight is potential noninvasive clinical tools for
assessing the lower urinary tract [11, 12].
Retrograde urethrography has no routine use except for the case highly
suspicious of urethral stricture.
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References of CQ2
1. Homma Y, Araki I, Igawa Y et al. Clinical guideline for male lower urinary
tract symptoms. Int. J. Urol. 2009; 16: 775–90.
2. Homma Y, Kawabe K, Tsukamoto T et al. Estimate criteria for efficacy of
treatment in benign prostatic hyperplasia. Int. J. Urol. 1996; 3: 267–73.
3. Abrams P, Chapple C, Khoury S, Roehrborn C, De la Rosette J. Evaluation
and treatment of lower urinary tract symptoms in older men. J. Urol. 2009;
181: 1779–87.
4. Marks LS, Roehrborn CG, Wolford E, Wilson TH. The effect of dutasteride
on the peripheral and transition zones of the prostate and the value of the
transition zone index in predicting treatment response. J. Urol. 2007; 177:
1408–13.
5. Peeling WB. Diagnostic assessment of benign prostatic hyperplasia.
Prostate Suppl, 1989; 2: 51–68.
6. Scheckowitz EM, Resnick MI. Imaging of the prostate. Benign prostatic
hyperplasia. Urol. Clin. North. Am. 1995; 22: 321–32.
7. Hayami S, Ushiyama T, Kurita Y, Kageyama S, Suzuki K, Fujita K. The value
of power doppler imaging to predict the histologic components of benign
prostatic hyperplasia. Prostate 2002; 53: 168–74.
8. Foo KT. Decision making in the management of benign prostatic
enlargement and the role of transabdominal ultrasound. Int. J. Urol. 2010;
17: 974–9.
9. Chia SJ, Heng CT, Chan S, Foo KT. Correlation of intravesical prostatic
protrusion with bladder outlet obstruction. BJU Int. 2003; 91: 371–4.
10. Nose H, Foo KT, Lim KB, Yokoyama T, Ozawa H, Kumon H. Accuracy of two
noninvasive methods of diagnosing bladder outlet obstruction using
ultrasonography: intravesical prostatic protrusion and velocity-flow video
urodynamics. Urology 2005; 65: 493–7.
11. Lovvik A, Yaqub S, Oustad H, Sand TE, Nitti VW. Can noninvasive
evaluation of benign prostatic obstruction be optimized? Curr. Opin. Urol.
2012; 22: 1-6.
12. Bright E, Oelke M, Tubaro A, Abrams P. Ultrasound estimated bladder
weight and measurement of bladder wall thickness – useful noninvasive
methods for assessing the lower urinary tract? J. Urol. 2010; 184: 1847–54.
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CQ3
Should evaluation of upper urinary tract be recommended in the initial evaluation
of all BPH/Male LUTS patients?
Answer:
Routine evaluation of the upper urinary tract is not recommended in the
initial evaluation.
It is recommended for men with abnormal urinalysis, a large amount of
PVR, renal insufficiency, symptoms suggestive of upper urinary tract
disorder (stone, cancer, infection and so on ) or a history of other
urological diseases (Recommendation Grade B).
A structured MEDLINE review of the literature on the association between BPH
and CRF from 1966 to 2003 was performed. The extent of the association
between BPH and CRF is unknown and more community based, observational
studies are needed. However, an association exists and it should be considered
in men presenting with obstructive BPH or CRF [1].
Discharges for primary BPH with acute renal failure increased >400% (OR 4.28,
95% CI 3.22-5.71, P-trend <0.001) from 1998 to 2008 in USA. Severe AEs of
BPH persist despite widespread use of oral therapies in the USA [2]
Renal ultrasonography in 556 men with BPH detected hydronephrosis, renal
cysts, and renal cancer in 2.5, 11.7 and 0.18% of men, respectively [3].
According to those data, evaluation of the upper urinary tract is not to be
performed routinely. It is recommended for men with abnormal urinalysis, a large
amount of PVR, renal insufficiency, or a history of other urological diseases.
In these cases, ultrasonography is recommended as the initial method of
assessment [4, 5].
References of CQ3
1. Rule AD, Lieber MM, Jacobsen SJ. Is benign prostatic hyperplasia a risk
factor for chronic renal failure? J. Urol. 2005; 173: 691–96.
2. Stroup SP, Palazzi-Churas K, Kopp RP, Parsons JK. Trends in adverse
events of benign prostatic hyperplasia (BPH) in the USA, 1998 to 2008. BJU
Int. 2012; 109: 84–7.
3. Koch WF, Ezz el Din K, De Wildt MJAM, Debruyne FMJ, De la Rosette
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JJMCH. The outcome of renal ultrasound in the assessment of 556
consecutive patients with benign prostatic hyperplasia. J. Urol. 1996; 155:
186–9.
4. Homma Y, Araki I, Igawa Y et al. Clinical guideline for male lower urinary
tract symptoms. Int. J. Urol. 2009; 16: 775–90.
5. Homma Y, Kawabe K, Tsukamoto T et al. Estimate criteria for efficacy of
treatment in benign prostatic hyperplasia. Int. J. Urol. 1996; 3: 267–73.
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CQ4
In which case should urodynamic study (except for uroflowmetry ) be
recommended ?
Answer:
Urodynamic examinations, including PFS and CMG, are recommended to
delineate BOO, DU, and DO. PFS and CMG should be performed in whom
DU or DO is suspected due to failure to respond to medication/surgery, or
neurogenic lower urinary tract dysfunction is suspected
(Recommendation Grade B).
In this section, pressure flow study (PFS) and filling cystometry (CMG) are
included in the terminology of urodynamic study (UDS). TURP is effective,
especially for patients with BOO. From symptoms alone, it is not possible to
diagnose BOO. PFS and symptom profiles measure different aspects of the
clinical condition that should be viewed separately in the evaluation and
treatment decision of the patient presenting with lower urinary tract symptoms [1].
BOO and detrusor underactivity (DU) can be correctly evaluated, and outcome
of surgery may be predicted by PFS. Detrusor overactivity (DO) can be
evaluated by CMG. However, routine CMG or routine PFS is not necessary for
initial diagnosis of BPH [2]. BOO, DU, and DO are all important prognostic
variables for the surgical outcomes of BPH [3].
The surgical indication should be circumspect for patients who do not have BOO
but have DO [2]. Symptom improvement is less likely for men with no or
equivocal BOO compared with men with evident BOO [4].
Both DU without BOO and DO without BOO strongly predict treatment failure for
TURP [5]. The presence of a higher degree of BOO is associated with
improvements in both symptoms and QOL [6].
A significant proportion (23%) of the patient with symptomatic BPH was
urodynamically unobstructed group to which prostatectomy should not be
offered. To identify unobstructed patients, PFS is recommended in all BPH
patients with dominant irritative symptoms [7].
PFS can be used to allocate patients with LUTS due to suspected BOO into
different treatment arms with good clinical outcome and less complications [8].
While uroflowmetry cannot replace PFS in the diagnosis of BOO, it can provide a
valuable improvement over symptoms alone in the diagnosis of the cause of
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lower urinary tract dysfunction in men presenting with LUTS.
Predicting BOO using simpler parameters such as uroflowmetry and PV may be
a viable alternative because of the invasiveness of PFS and CMG [9].
The ICS-'BPH' Study provided performance statistics for Qmax with respect to
BOO: such statistics may be used to define more accurately the presence or
absence of BOO in men presenting with LUTS [10].
References of CQ4
1. De la Rosette JJ, Witjes WP, Schafer W et al. Relationships between lower
urinary tract symptoms and bladder outlet obstruction: results from the
ICS-"BPH" study. Neurourol. Urodyn. 1998; 17: 98–108.
2. Tanaka Y, Masumori N, Itoh N, Furuya S, Ogura H, Tsukamoto T. Is the
short-term outcome of transurethral resection of the prostate affected by
preoperative degree of bladder outlet obstruction, status of detrusor
contractility or detrusor overactivity? Int. J. Urol. 2006; 11: 1398–04.
3. Thomas AW, Cannon A, Bartlett E, Ellis-Jones J, Abrams P. The natural
history of lower urinary tract dysfunction in men: the influence of detrusor
underactivity on the outcome after transurethral resection of the prostate
with a minimum 10-year urodynamic follow-up. BJU Int. 2004; 93: 745–50.
4. Van Venrooij GE, Von Melick HHE, Boon TA. Comparison of outcomes of
transurethral prostate resection in urodynamically unobstructed or equivocal
men. Urology 2003; 62: 672–6.
5. Machino R, Kakizaki H, Ameda K et al. Detrusor instability with equivocal
obstruction: a predictor of unfavorable symptomatic outcomes after
transurethral prostatectomy. Neurourol. Urodyn. 2002; 21: 444–9.
6. Seki N, Takei M, Yamaguchi A, Naito S. Analysis of prognostic factors
regarding the outcome after a transurethral resection for symptomatic
benign prostatic enlargement. Neurourol. Urodyn. 2006; 25: 428–32.
7. Cetinel B, Turan T, Talat Z, Yalcin V, Alici B, Solok V. Update evaluation of
benign prostatic hyperplasia: when should we offer prostatectomy? Br. J.
Urol. 1994; 74: 566–71.
8. Knutson T, Pettersson S, Dahlstrand C. Pressure-flow studies for patient
selection in the treatment of symptomatic BPH – a one-year follow-up study.
Scand. J. Urol. Nephrol. 2001; 35: 470–75.
9. Homma Y. Pressure flow studies in benign prostatic hyperplasia: to do or not
to do for the patient? BJU Int. 2001; 87: 19–23.
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10. Reynard JM, Yang Q, Donovan JL et al. The ICS-'BPH' Study: uroflowmetry,
lower urinary tract symptoms and bladder outlet obstruction. Br. J. Urol.
1998; 82: 619–23.
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CQ5
Should serum PSA be measured in BPH/Male LUTS patients?
Answer:
In the patients at risk of prostate cancer, measurement of serum PSA
concentration is strongly recommended (Recommendation Grade A).
However, factors affecting on serum PSA concentration, such as enlarged
prostate volume, urinary retention, prostatitis/UTI, and treatment with
5ARIs should be considered.
In patients with life expectancy of less than 10 years, or without indication
for prostatic cancer treatment, serum PSA may not be routinely measured.
As higher serum PSA concentrations are indicative of prostate cancer [1–3]),
and useful for estimation of enlarged prostate volume [4]. Not only prostate
cancer, serum PSA concentrations are increased in men with enlarged adenoma,
urinary retention, prostatitis, and massage of prostate [5]. On the other hand,
anti-androgens or 5ARIs can reduce the PSA concentrations by approximately
50% [6–10]. In patients treated with the drugs, careful follow-up of serum PSA
concentrations should be needed.
References of CQ5
1. Homma Y, Araki I, Igawa Y et al. Clinical guideline for male lower urinary
tract symptoms. Int. J. Urol. 2009; 16: 775–90.
2. Abrams P, Chapple C, Khoury S, Roehrborn C, De la Rosette J, the
International Scientific Committee and members of the committees, 6th
International Consultation on New Developments in Prostate Cancer and
Prostate Diseases. Evaluation and treatment of lower urinary tract
symptoms in older men. J. Urol. 2009; 181: 1779–87.
3. EAU Guidelines on the management of male lower urinary tract symptoms
(LUTS), incl. benign prostatic obstruction (BPO).
(http://www.uroweb.org/gls/pdf/12_Male_LUTS_LR%20May%209th%20201
2.pdf)
4. Gupta A, Aragaki C, Gotoh M et al. Relationship between prostate specific
antigen and indexes of prostate volume in Japanese men. J. Urol. 2005;
173: 503–6.
5. Gretzer MB, Partin AW. Prostate cancer tumor markers. In: Wein AJ,
- 22 -
Kavoussi LR, Novick AC, Partin AW, Peters CA (eds). Campbell-Walsh
Urology. 9th ed., Philadelphia, Saunders, 2007; 2896.
6. D’Amico AV, Roehrborn CG. Effect of 1 mg/day finasteride on concentrations
of serum prostate specific antigen in men with androgenic alopecia: a
randomised controlled trial. Lancet Oncol. 2007; 8: 21–5.
7. Tsukamoto T, Endo Y, Narita M. Efficacy and safety of dutasteride in
Japanese men with benign prostatic hyperplasia. Int. J. Urol. 2009; 16: 745–
50.
8. Andriole GL, Kirby R. Safety and tolerability of the dual 5α-reductase
inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur.
Urol. 2003; 44: 82–8.
9. Andriole GL, Marberger M, Roehrborn CG. Clinical usefulness of serum
prostate specific antigen for the detection of prostate cancer is preserved in
men receiving the dual 5α-reductase inhibitor dutasteride. J. Urol. 2006; 175:
1657–62.
10. Marks LS, Andriole GL, Fitzpatrick JM, Schulman CC, Roehrborn CG. The
interpretation of serum prostate specific antigen in men receiving
5α-reductase inhibitors: a review and clinical recommendations. J. Urol.
2006; 176: 868–74.
- 23 -
CQ6
Is long-term treatment with 1 blocker recommended ?
Answer:
Many studies have been reported regarding the efficacy and safety of α1
blockers up to1 year. However, there is a relative paucity of long-term data
over 3 years regarding the maintained efficacy of these drugs
(Recommendation Grade A).
Most long-term studies for the efficacy of α1 blockers are open-label extension
studies of the previous short-term trials [1, 2] or retrospective studies in clinical
practice. The studies showed that the efficacy and safety of α1 blockers up to1
year. In long-term studies (over 3 years; range 4–10 years), the withdraw rates
were approximately 18, 64, and 36–80% of patients in 2, 3, and >4 years after
starting of the studies, respectively [3–6]. The risk factors for treatment failure
were severe LUTS, low urinary flow rate, large prostate volume (>30–40 mL),
large PVR or a history of urinary retention, concomitant OAB symptoms,
urodynamically proven BOO, and insufficient effects with short-term therapy [5–
7]. In the comparative long-term studies of mono- and combination treatment
with α1 blockers and 5ARI, the efficacy of α1 blockers appears to be maintained
over at least 4 years [8, 9]. However, the combination therapy was significantly
effective as compared with α1 blocker mono-therapy. It may suggest that the
long-term efficacy of α1 blockers mono-therapy of is not sufficient. Alpha-1
blockers do not prevent acute urinary retention in long-term studies, so that
eventually some patients will have to be surgically treated [8].
References of CQ6
1. Kawabe K, Yoshida M, Arakawa S, Takeuchi H. Silodosin Clinical Study
Group. Long-term evaluation of silodosin, a new α1A-adrenoceptor selective
antagonist for the treatment of benign prostatic hyperplasia: phase III
long-term study. Jap. J. Urol. Surg. 2006; 19: 153–64. (4)
2. Marks LS, Gittelman MC, Hill LA, Volinn W, Hoel G. Silodosin in the
treatment of the signs and symptoms of benign prostatic hyperplasia: a
9-month, open-label extension study. Urology 2009; 74: 1318–24. (4)
3. Narayan P, Evans CP, Moon T. Long-term safety and efficacy of tamsulosin
for the treatment of lower urinary tract symptoms associated with benign
- 24 -
prostatic hyperplasia. J. Urol. 2003; 170: 498–502. (5)
4. Schulman CC, Lock TMTW, Buzelin J-M, Boeminghaus F, Stephenson TP,
Talja M. European Tamsulosin Study Group: Long-term use of tamsulosin to
treat lower urinary tract symptoms/benign prostatic hyperplasia. J. Urol.
2001; 166: 1358–63. (5)
5. Masumori N, Hashimoto J, Itoh N, Tsukamoto T, the Sapporo Medical
University Naftopidil Study Group. Short-term efficacy and long-term
compliance/treatment failure of the α1 blocker naftopidil for patients with
lower urinary tract symptoms suggestive of benign prostatic hyperplasia.
Scand. J. Urol. Nephrol. 2007; 41: 422–9. (5)
6. De la Rosette JJ, Kortman BBM, Rossi C, Sonke GS, Floratos DL, Kiemeney
LALM. Long-term risk of re-treatment of patients using a-blockers for lower
urinary tract symptoms. J. Urol. 2002; 167: 1734–9. (5)
7. Kawachi Y, Sakurai T, Sugimura S et al. Long-term treatment and prognostic
factors of a1-blockers for lower urinary tract symptoms associated with
benign prostatic hyperplasia: a pilot study comparing naftopidil and
tamsulosin hydrochloride. Scand. J. Urol. Nephrol. 2010; 44: 38–45. (3)
8. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of
doxazosin, finasteride, and combination therapy on the clinical progression
of benign prostatic hyperplasia. N. Engl. J. Med. 2003; 349: 2387–98. (1)
9. Roehrborn CG, Siami P, Barkin J et al. The effects of combination therapy
with dutasteride and tamsulosin on clinical outcomes in men with
symptomatic benign prostatic hyperplasia: 4-year results from the CombAT
study. Eur. Urol. 2010; 57: 123–31. (1)
- 25 -
CQ7
Is long-term treatment with 5ARI recommended ?
Answer:
5ARIs should be offered to men who have moderate-to-severe lower
urinary tract symptoms and enlarged prostates (≥ 30 mL) or elevated
serum PSA concentrations (> 1.4 – 1.6 µg/L). Efficacy for subjective and
objective parameters of long-term treatment is reported. Long term
treatment of 5ARIs can also prevent disease progression with regard to
acute urinary retention and the need for surgery (Recommendation Grade
B).
After 2 to 4 years of treatment, 5ARIs reduce LUTS (IPSS) by approximately
15-30%, decrease prostate volume by approximately 18-28% and increase
Qmax of free uroflowmetry by approximately 1.5-2.0 mL/s in patients with LUTS
due to prostate enlargement [1–10].
Comparative studies with α1 blockers have demonstrated that 5ARIs reduce
symptoms more slowly and, for finasteride, less effectively [1, 2, 7]. A long-term
trial with dutasteride in symptomatic men with a prostate volume ≥ 30 mL
(average prostate volume in the CombAT trial was approximately 55 mL)
showed that the 5ARI reduced LUTS in these patients at least as much or even
more effectively than tamsulosin [8, 9]. The greater the baseline prostate volume
(serum PSA concentration), the faster and more pronounced the symptomatic
benefit of dutasteride [11]. 5ARIs, but not α1 blockers, reduce the long-term (> 1
year) risk of acute urinary retention or need for surgery [5, 7, 11, 12]. Prevention
of disease progression by 5ARIs is already detectable with prostate sizes
considerably smaller than 40 mL [9, 10, 12]. The precise mechanism of action of
5ARIs in reducing disease progression is unclear, but it was demonstrated that
reductions of voiding parameters after computer-urodynamic re-evaluation in
men who were treated at least 3 years with finasteride [13, 14, 15].
References of CQ7
1. Lepor H, Williford WO, Barry MJ et al. The efficacy of terazosin, finasteride,
or both in benign prostatic hyperplasia. N. Engl. J. Med. 1996; 335: 533–9.
(1)
- 26 -
2. Kirby R, Roehrborn CG, Boyle P et al. Efficacy and tolerability of doxazosin
and finasteride, alone or in combination, in treatment of symptomatic benign
prostatic hyperplasia: the Prospective European Doxazosin and
Combination Therapy (PREDICT) trial. Urology 2003; 61: 119–26. (1)
3. Andersen JT, Ekman P, Wolf H et al. Can finasteride reverse the progress of
benign prostatic hyperplasia? A two-year placebo-controlled study. The
Scandinavian BPH Study Group. Urology 1995; 46: 631–7. (1)
4. Nickel JC, Fradet Y, Boake RC et al. Efficacy and safety of finasteride
therapy for benign prostatic hyperplasia: results of a 2-year randomised
controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy
Canadian Two year Study. CMAJ 1996; 155: 1251–9. (1)
5. McConnell JD, Bruskewitz R, Walsh P et al. The effect of finasteride on the
risk of acute urinary retention and the need for surgical treatment among
men with benign prostatic hyperplasia. N. Engl. J. Med. 1998; 338: 557–63.
(1)
6. Marberger MJ, on behalf of the PROWESS Study Group. Long-term effects
of finasteride in patients with benign prostatic hyperplasia: a double-blind,
placebo-controlled, multicenter study. Urology 1998; 51: 677–86. (1)
7. McConnell JD, Roehrborn CG, Bautista O et al. Medical Therapy of Prostatic
Symptoms (MTOPS) Research Group. The long-term effect of doxazosin,
finasteride, and combination therapy on the clinical progression of benign
prostatic hyperplasia. N. Engl. J. Med. 2003; 349: 2387–98. (1)
8. Roehrborn CG, Boyle P, Nickel JC et al. Efficacy and safety of a dual
inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign
prostatic hyperplasia. Urology 2002; 60: 434–41. (1)
9. Roehrborn CG, Siami P, Barkin J et al. The effects of dutasteride, tamsulosin
and combination therapy on lower urinary tract symptoms in men with
benign prostatic hyperplasia and prostatic enlargement: 2-year results from
the CombAT study. J. Urol. 2008; 179: 616–21. (1)
10. Roehrborn CG, Siami P, Barkin J et al. The effects of combination therapy
with dutasteride and tamsulosin on clinical outcomes in men with
symptomatic benign prostatic hyperplasia: 4-year results from the
CombATstudy. Eur. Urol. 2010; 57: 123–31. (1)
11. Debruyne FM, Jardin A, Colloi D et al. Sustained-release alfuzosin,
finasteride and the combination of both in the treatment of benign prostatic
hyperplasia. Eur. Urol. 1998; 34: 169–75. (1)
- 27 -
12. Roehrborn CG, Siami P, Barkin J et al. The influence of baseline parameters
on changes in International Prostate Symptom Score with dutasteride,
tamsulosin, and combination therapy among men with symptomatic benign
prostatic hyperplasia and enlarged prostate: 2-year data from the CombAT
Study. Eur. Urol. 2009; 55: 461–71. (1)
13. Roehrborn CG. BPH progression: concept and key learning from MTOPS,
ALTESS, COMBAT, and ALF-ONE. BJU Int. 2008; 101 (Suppl 3): 17–21. (1)
14. Kirby RS, Vale J, Bryan J, Holmes, K, Webb, JA. Long-term urodynamic
effects of finasteride in benign prostatic hyperplasia: a pilot study. Eur. Urol.
1993; 24: 20–6. (3)
15. Tammela TLJ, Kontturi MJ. Long-term effects of finasteride on invasive
urodynamics and symptoms in the treatment of patients with bladder outflow
obstruction due to benign prostatic hyperplasia. J. Urol. 1995; 154: 1466–9.
(3)
- 28 -
CQ8
Is anticholinergic monotherapy recommended for BPH/OAB patient ?
Answer:
Monotherapy of anticholinergic drugs might be considered in men with
moderate to severe lower urinary tract symptoms who have predominantly
bladder storage symptoms. However, careful follow-up is recommended in
men with bladder outlet obstruction. Low grade IPP with good flow rate is
indication for anti-cholinergic monotherapy (Recommendation Grade B)
The efficacy of the anticholinergic drugs was tested as a single agent in adult
men with bladder storage symptoms (OAB symptoms) but without bladder outlet
obstruction. In open-label trials with tolterodine, daytime frequency, nocturia,
urgency incontinence, and IPSS were all significantly reduced compared to
baseline values after 12-25 weeks [1, 2]. In an open-label study with α1 blocker
non-responders, each storage and voiding symptom of IPSS was improved
during tolterodine treatment [1]. Randomized, placebo-controlled trials
demonstrated that tolterodine can significantly reduce urgency incontinence and
daytime or 24-hour frequency compared to placebo. It was also demonstrated
that urgency related voiding is significantly reduced by tolterodine [3–5].
Treatment outcome analyzed by PSA-concentration (prostate volume),
tolterodine significantly reduced daytime frequency, 24h voiding frequency and
IPSS storage symptoms only in those men with PSA concentrations below 1.3
ng/mL indicating that men with smaller prostates might profit more from
anticholinergic drugs [6]. Increase of post-void residual urine in men without
bladder outlet obstruction is minimal and not significantly different compared to
placebo (0 to 5 mL vs. -3.6 to 0 mL). However, fesoterodine 8 mg showed higher
post-void residuals (+20.2 mL) compared to placebo (-0.6 mL) or fesoterodine 4
mg (+9.6 mL) [7]. The incidence of urinary retention in men treated with
tolterodine without bladder outlet obstruction was comparable with placebo (0 to
1.3 vs. 0 to 1.4%). In men under fesoterodine 8 mg treatment, 5.3% had
symptoms suggestive of urinary retention that was higher compared to placebo
or fesoterodine 4 mg (0.8% each). In men with bladder outlet obstruction,
anticholinergic drugs are not recommended due to the theoretical decrease of
bladder strength which might be associated with post-void residual urine [8] or
urinary retention. In addition, long-term studies on the efficacy of muscarinic
- 29 -
receptor antagonists in men with LUTS/BPH are still missing, therefore, these
drugs should be prescribed with caution, and regular re-evaluation of IPSS and
post-void residual urine is advised. For patients complaining nocturia, not OAB,
desmopressin is effective for nocturia due to nocturnal polyuria [9–12].
References of CQ8
1. Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates
lower urinary tract symptoms in men with benign prostatic hyperplasia. J.
Urol. 2005; 174: 2273–5. (4)
2. Höfner K, Burkart M, Jacob G, Jonas U. Safety and efficacy of tolertodine
extended release in men with overactive bladder symptoms and presumed
non-obstructive benign prostatic hyperplasia. World J. Urol. 2007; 25: 627–
33. (3)
3. Kaplan SA, Roehrborn CG, Chancellor M, Carlsson M, Bavendam T, Guan Z.
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; 102:
1133–9. (2)
4. Kaplan SA, Roehrborn CG, Dmochowski R, Rovner ES, Wang JT, Guan Z.
Tolterodine extended release improves overactive bladder symptoms in men
with overactive bladder and nocturia. Urology 2006; 68: 328–32. (1)
5. Dmochowski R, Abrams P, Marschall-Kehrel D, Wang JT, Guan Z. Efficacy
and tolerability of tolterodine extended release in male and female patients
with overactive bladder. Eur. Urol. 2007; 51:1054–64. (1)
6. Roehrborn CG, Kaplan SA, Kraus SR, Wang JT, Bavendam T, Guan Z.
Effects of serum PSA on efficacy of tolterodine extended release with or
without tamsulosin in men with LUTS, including OAB. Urology 2008; 72:
1061–7. (1)
7. Herschorn S, Jones JS, Oelke M, MacDiarmid S, Wang JT, Guan Z. Efficacy
and tolerability of fesoterodine in men with overactive bladder: a pooled
analysis of 2 phase III studies. Urology 2010; 75: 1149–55. (1)
8. Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability of
tolterodine for the treatment of overactive bladder in men with bladder outlet
obstruction. J. Urol. 2006; 175: 999–1004. (1)
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9. Mattiasson A, Abrams P, Van Kerrebroeck P, Walter S, Weiss J. Efficacy of
desmopressin in the treatment of nocturia: a double-blind placebo-controlled
study in men. BJU Int. 2002; 89: 855–62. (1)
10. Van Kerrebroeck P, Rezapour M, Cortesse A, Thuroff J, Riis A, Norgaard JP.
Desmopressin in the treatment of nocturia: a double blind placebo-controlled
study. Eur. Urol. 2007; 52: 221–9. (1)
11. Weatherall M. The risk of hyponatremia in older adults using desmopressin
for nocturia: a systematic review and meta-analysis. Neurourol. Urodyn.
2004; 23: 302–5. (1)
12. Wang CJ, Lin YN, Huang SW, Chang CH. Low dose oral desmopressin for
nocturnal polyuria in patients with benign prostatic hyperplasia: a
double-blind, placebo controlled, randomized study. J. Urol. 2011; 185: 219–
23. (1)
- 31 -
CQ9
In which case should combination use of α1 blocker and 5ARI be
recommended ?
Answer:
Combination use of 1 blocker and 5 alpha-reductase inhibitors (5ARIs)
are recommended for symptomatic BPH, especially for patients with a
relatively large-sized prostate. (Recommendation Grade A)
Non-selective 1 blockers have a potentially higher risk of orthostatic
hypotension.
The Medical Therapy of Prostatic Symptoms (MTOPS) study was a double-blind
trial involving 3047 men to compare the effects the effects of placebo, doxazosin,
finasteride and combination therapy on measures of the clinical progression of
BPH [1]. Inclusion criteria were age ≥50, IPSS ≥8 and a maximum urinary flow
rate between 4 and 15 mL/s, and the mean follow-up was 4.5 years. The
reduction in risk of clinical progression associated with combination therapy
(66%) was significantly greater than that associated with doxazosin (39%,
p<0.001) or finasteride (34%, p<0.001) alone. The improvement in symptoms
scores of combination therapy (-7.4 at 4 years) was significantly greater than
doxazosin (-6.6, p=0.006) and finasteride (-5.6, p<0.001) alone. The rates of
adverse events were higher in combination therapy group than in each single
treatment groups, in the aspects of abnormal ejaculation, peripheral edema and
dyspnea.
The Combination of Avodart® and Tamsulosin (CombAT) study was a 4-yr.,
multicenter, randomized, double-blind, parallel-group study in 4844 men ≥50
years of age with a clinical diagnosis of BPH, IPSS ≥12, prostate volume ≥30mL,
PSA 1.5-10 ng/mL and maximum urinary flow rate >5 and ≤15 mL/s with
minimum voided volume ≥125mL [2]. At 4 yr., combination therapy was
significantly superior to both monotherapies at reducing the relative risk of BPH
progression (31% from dutasteride, 44% from tamsulosin), and provided
significantly greater symptom benefit (-6.3) than dutasteride (-5.3, p<0.001) and
tamsulosin (-3.8, p<0.001) alone. The occurrence of drug-related adverse
events was significantly greater in the combination group. However, withdrawal
rates due to drug-related adverse events were similar across treatment groups
(4-6%). These observations were also similar in Asian men [3].
- 32 -
In both trials, post hoc analyses showed that patients with larger prostate volume
(≥25 mL in MTOPS study, and ≥40 mL in CombAT study) at baseline had a
greater benefit in reduction of clinical progression from combination therapy than
those with small prostate [4, 5].
Analyses on cost-effectiveness of combination therapy using Norwegian model
estimated that incremental cost-effectiveness ratios, which means the cost per
quality-adjusted life-years (QALYs) gained, are higher in combination therapy
than in alpha blocker monotherapy both at 4 years and at the lifetime. However,
the incremental QALYs gained for combination therapy are twice those of 
blocker monotherapy. If willingness to pay per QALY gained is above €6000,
fixed-dose combination therapy with dutasteride becomes the preferred
treatment [6].
References of CQ9
1. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of
doxazosin, finasteride, and combination therapy on the clinical progression
of benign prostatic hyperplasia. N. Engl. J. Med. 2003; 349: 2387–98. (1)
2. Roehrborn CG, Siami P, Barkin J et al. The effects of combination therapy
with dutasteride and tamsulosin on clinical outcomes in men with
symptomatic benign prostatic hyperplasia: 4-year results from the CombAT
study. Eur. Urol. 2010; 57: 123–31. (2)
3. Chung B-H, Roerhborn CG, Siami P et al. Efficacy and safety of dutasteride,
tamsulosin and their combination in a subpopulation of the CombAT study:
2-year results in Asian men with moderate-to-severe BPH. Prostate Cancer
Prostatic. Dis. 2009; 12: 152–9. (1)
4. Kaplan SA, McConnell JD, Roerhborn CG, Meehan AG, Lee MW, Noble WR.
Combination therapy with doxazosin and finasteride for benign prostatic
hyperplasia in patients with lower urinary tract symptoms and a baseline
total prostate volume of 25 mL or greater. J. Urol. 2006; 175: 217–21. (1)
5. Roehrborn CG, Barkin J, Siami P et al. Clinical outcomes after combined
therapy with dutasteride plus tamsulosin or either monotherapy in men with
benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year
results from the randomized, double-blind Combination of Avodart and
Tamsulosin (CombAT) trial. BJU Int. 2011; 107: 946–54. (1)
6. Johansen TEB, Baker TM, Black LK. Cost-effectiveness of combination
therapy for treatment of benign prostatic hyperplasia: a model based on the
- 33 -
findings of the Combination of Avodart and Tamsulosin trial. BJU Int. 2012;
109: 731–8.
- 34 -
CQ10
In which case should combination use of 1 blocker and anticholinergic drug be
recommended ?
Answer:
Patients with LUTS/BPH associated with OAB are recommended to use
combination of 1 blocker and anticholinergic drug. There are sufficient
evidences supporting the efficacy and safety of combination therapy with
1 blocker and anticholinergic drug for LUTS/BPH associated with OAB.
Especially, the patients still having OAB symptoms after 1 blockers
treatment are good candidates for the combination treatment.
(Recommendation Grade B). Low grade IPP with good flow is an indication
for combination therapy.
It is suggested that 50-70 % of patients with BPH have OAB symptoms [1]. For
male OAB symptoms, monotherapy with 1 blockers is effective and may be a
first line treatment [2], although the efficacy of 1 blockers is limited for patients
with detrusor overactivity [3]. Several reports suggested that combined therapies
with anticholinergic drugs and 1 blockers are more effective than monotherapy
with 1 blockers in improving storage symptoms, with urinary retention being
rare [4–13]. Meta-analysis of the combination therapy showed that the therapy
did not affect to urinary flow rate, increased average post-void residual urine by
11.6mL, and caused urinary retention just 0.3% [14]. Urodynamic study showed
that combination therapy increased bladder volume at the first involuntary
contraction and maximum bladder capacity [7]. Although the combination
therapy did not cause the change of total IPSS, it improved the storage
sub-score [8]. There remains a concern about the exacerbation of voiding
difficulties and possible urinary retention in a practice setting [2]. Grade 3 IPP is
risk factor for possible urinary retention with combination therapy.
References of CQ10
1. Yamaguchi O, Nishizawa O, Takeda M et al. Clinical guidelines for
overactive bladder. Int. J. Urol. 2009; 16: 126–42. (guideline)
2. Homma Y, Araki I, Igawa Y et al. Clinical guideline for male lower urinary
tract symptoms. Int. J. Urol. 2009; 16: 775–90. (guideline)
3. Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of
- 35 -
doxazosin with or without tolterodine in men with symptomatic bladder outlet
obstruction and an overactive bladder. BJU Int. 2004; 94: 817–20. (2)
4. Chapple C, Herschorn S, Abrams P, Sun F, Brodsky M, Guan Z. Tolterodine
treatment improves storage symptoms suggestive of overactive bladder in
men treated with α-blockers. Eur. Urol. 2009; 56: 534–43. (1)
5. MacDiarmid SA, Peters KM, Chen A et al. Efficacy and safety of
extended-release oxybutynin in combination with tamsulosin for treatment of
lower urinary tract symptoms in men: randomized, double-blind,
placebo-controlled study. Mayo Clin. Proc. 2008; 83: 1002–10. (1)
6. Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W. Safety and
tolerability of solifenacin add-on therapy to α-blocker treated men with
residual urgency and frequency. J. Urol. 2009; 182: 2825–30. (1)
7. Athanasopoulos A, Gyftopoulos K, Giannistas K, Fisfis J, Perimenis P,
Barbalias G. Combination treatment with an α-blocker plus an anticholinergic
for bladder outlet obstruction: a prospective, randomized, controlled study. J.
Urol. 2003; 169: 2253–6. (2)
8. Lee KS, Choo MS, Kim DY et al. Combination treatment with propiverine
hydrochloride plus doxazosin controlled release gastrointestinal therapeutic
system formulation for overactive bladder and coexisting benign prostatic
obstruction: a prospective, randomized, controlled multicenter study. J. Urol.
2005; 174: 1334–8. (2)
9. Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z.
Tolterodine and tamsulosin for treatment of men with lower urinary tract
symptoms and overactive bladder. A randomized controlled trial. JAMA
2006; 296: 2319–28. (1)
10. Maruyama O, Kawauchi Y, Hanazawa K et al. Naftopidil monotherapy vs
naftopidil and an anticholinergic agent combined therapy for storage
symptoms associated with benign prostatic hyperplasia: a prospective
randomized controlled study. Int. J. Urol. 2006; 13: 1280–5. (2)
11. Yokoyama T, Uematsu K, Watanabe T et al. Naftopidil and propiverine
hydrochloride for treatment of male lower urinary tract symptoms suggestive
of benign prostatic hyperplasia and concomitant overactive bladder: a
prospective randomized controlled study. Scand. J. Urol. Nephrol. 2009; 43:
307–14. (2)
12. Nishizawa O, Yamaguchi O, Takeda M, Yokoyama O, for the TAABO Study
Group. Randomized controlled trial to treat benign prostatic hyperplasia with
- 36 -
overactive bladder using an alpha-blocker combined with anticholinergics.
LUTS 2011; 3: 29–35. (2)
13. Yamaguchi O, Kakizaki H, Homma Y et al. Solifenacin as add-on therapy for
overactive bladder symptoms in men treated for lower urinary tract
symptoms – ASSIST, randomized controlled study. Urology 2011; 78: 126–
33. (1)
14. Blake-James BT, Rashidian A, Ikeda Y, Emberton M. The role of
anticholinergics in men with lower urinary tract symptoms suggestive of
benign prostatic hyperplasia: a systemic review and meta-analysis. BJU Int.
2007; 99: 85–96. (1)
- 37 -
CQ11
In which case should surgical intervention be recommended ?
This CQ should be modified into 2 categories;
In which case should surgical intervention be recommended ?
1. Absolute indications ?
2. Relative indications ?
Answer:
Absolute indications are patients with refractory urinary retention,
recurrent UTI, vesical stone, renal insufficiency, refractory gross
hematuria (Recommendation Grade A) .
Relative indications are patients unresponsive to medical treatment, or
patients who cannot maintain medical treatments due to adverse events,
or patients who are not satisfied with medical treatments.
Pressure-flow study is recommended in order to rule out detrusor
underactivity and overactivity. IPP should be correctly evaluated when
surgery is planned.
Recurrent spontaneous urinary retention after failure of trials without catheter is
an indication of surgical intervention (see CQ13). Similarly, surgery would be
better to be considered in patients with hydronephrosis and/or renal function
impairment due to chronic bladder outlet obstruction (BOO) from BPH, gross
hematuria, bladder stone and recurrent urinary tract infection, whereas these
indications are empirical and not supported by clinical evidences [1].
Patients resistant to medical treatment are relative symptom-based indication of
surgery. However, male lower urinary tract symptoms are not always associated
with BOO or BPH [2]. Approximately 15% of patients undergoing surgery do not
profit in improvement of symptoms [3, 4]. Pressure-flow study (PFS) is an
important examination to provide objective information [4–6], and BOO, detrusor
underactivity (DU) and detrusor overactivity (DO) are key conditions to predict
outcome of surgery. However, it is still under debate whether this examination is
essential for judge of surgery [7, 8]. Although BOO is not an essential condition
for TURP, the degree of symptom improvement in patients without BOO is
approximately 70% of that in patients with BOO [6, 9]. DU, DO and absence of
BOO are independent risk factors for poor outcome of surgery [10].
- 38 -
Nocturia is the symptom least sensitive to treatment for BPH [11, 12]. When
nocturia remains as a main symptom after medical treatment for BPH, conditions
other than BPH, such as lowering functional bladder capacity, polyuria, nocturnal
polyuria and sleep disturbance, should be ruled out before decision of surgical
intervention. Frequency volume charts are recommended to use to detect such
conditions.
References of CQ11
1. Jang DG, Yoo C, Oh Y et al. Current status of transurethral prostatectomy: a
Korean multicenter study. Korean J. Urol. 2011; 52: 406–9. (4)
2. Hald T. Urodynamics in benign prostatic hyperplasia: a survey. Prostate
1989; 2 (Suppl): 69–77. (review)
3. Emberton M, Fordham M, Harrison M et al. The effect of prostatectomy on
symptom severity and quality of life. Br. J. Urol. 1996; 77: 233–47. (4)
4. Hakenberg OW, Pinnock CB, Marshall VR. The follow-up of patients with
unfavourable early results of transurethral prostatectomy. BJU Int. 1999; 84:
799–804. (4)
5. Javle P, Jenkins SA, Machin DG, Parsons KF. Grading of benign prostatic
obstruction can predict the outcome of transurethral prostatectomy. J. Urol.
1998; 160: 1713–7. (4)
6. Robertson AS, Griffiths C, Neal DE. Conventional urodyamics and
ambulatory monitoring in the definition and management of bladder outlet
obstruction. J. Urol. 1996; 155: 506–11. (4)
7. Homma Y. Pressure-flow studies in benign prostatic hyperplasia: to do or not
to do for the patient? BJU Int. 2001; 87: 19–23. (review)
8. McConnell JD. Why pressure-flow studies should be optional and not
mandatory studies for evaluating men with benign prostatic hyperplasia.
Urology 1994; 44: 156–8. (editorial)
9. Van Venrooij GEPM, Van Melick HHE, Boon TA. Comparison of outcomes of
transurethral prostate resection in urodynamically obstructed versus selected
urodynamically unobstructed or equivocal men. Urology 2003; 62: 672–6. (4)
10. Seki N, Takei M, Yamaguchi A, Naito S. Analysis of prognostic factors
regarding the outcome after a transurethral resection for symptomatic benign
prostatic enlargement. Neurourol. Urodyn. 2006; 25: 428–32. (4)
- 39 -
11. Homma Y, Yamaguchi T, Kondo Y, Horie S, Takahashi S, Kitamura T.
Significance of nocturia in the International Prostate Symptoms Score for
benign prostatic hyperplasia. J. Urol. 2002; 167: 172–6. (4)
12. Yoshimura K, Ohara H, Ichioka K et al. Nocturia and benign prostatic
hyperplasia. Urology 2003; 61: 786–90. (4)
- 40 -
CQ12
Which interventions are recommended for urinary retention in BPH patients ?
Answer:
Initially, immediate bladder decompression by catheterization should be
performed. Treatment with 1 blockers before a trial without catheter
(TWOC) is recommended after that. Surgical intervention for BPH is
required for patients with a TWOC failure. Duration of catheterization
should be shortened to reduce the comorbidity.
(Recommendation Grade B)
Acute urinary retention (AUR) due to BPH should be initially managed by
immediate bladder decompression. Urethral catheterization is exclusively more
chosen by urologists or emergency room physicians than suprapubic
catheterization world widely [1], and suprapubic catheterization is associated
with significantly high rate of hematuria, impossible catheterization and catheter
obstruction [2].
A trial without catheter (TWOC) is the next step. Treatment with 1 blockers for
2-3 days before catheter removal should be strongly recommended, since it
significantly increases success rate of TWOC [1, 3, 4]. Duration of
catheterization should be shortened, since catheterization for 4 days or longer is
associated with significantly higher rate of asymptomatic bacteriuria, lower
urinary tract infection, urine leak, catheter obstruction and prolongation of
hospitalization for adverse events [1]. After failure of first TWOC, second and
third TWOC can succeed. However, the rate of success of second and third
TWOC is not high and most patients with TWOC failure require surgical
intervention [1]. Even after success of TWOC, half patients require surgical
intervention during long-term follow-up [5].
Risk factors for failure of TWOC are older age (≥70y, OR 1.4), spontaneous AUR
(OR 1.4), large amount of drained volume (≥1000mL, OR 1.6), severe LUTS
before AUR (OR 1.6) and large prostate volume (>50mL, OR 1.6) [1].
References of CQ12
1. Fitzpatrick JM, Desgrandchamps F, Adjali K et al. Management of acute
urinary retention: a worldwide survey of 6074 men with benign prostatic
hyperplasia. BJU Int. 2012; 109: 88–95. (4)
- 41 -
2. Desgrandchamps F, De la Taille A, Doublet JD. The management of acute
urinary retention in France: a cross-sectional survey in 2618 men with benign
prostatic hyperplasia. BJU Int. 2006; 97: 727–33. (4)
3. Lucas MG, Stephenson TP, Nargund V. Tamsulosin in the management of
patients with acute urinary retention from benign prostatic hyperplasia. BJU
Int. 2005; 95: 354–7. (2)
4. McNeill SA, Hargreave TB, Roehrborn CG. Alfuzosin 10mg once daily in the
management of acute urinary retention: results of a double-blind
placebo-controlled study. Urology 2005; 65: 83–9. (1)
5. Lo KL, Chan MC, Wong A, Hou SM, Ng CF. Long-term outcome of patients
with a successful trial without catheter after treatment with an
alpha-adrenergic receptor blocker for acute urinary retention caused by
benign prostatic hyperplasia. Int. Urol. Nephrol. 2009; 42: 7–12. (4)
- 42 -
CQ13
Which therapies are recommended for BPH patients who are not fit for surgery
due to severe comorbidities ?
Answer:
For surgery-unfit patients, alternative therapies are recommended
according to individual medical and social conditions of patients. Each
option, such as urethral stent placement, intermittent catheterization,
urethral catheter placement, suprapubic cystostomy placement, and other
minimal invasive surgical therapies (TUMT, TUNA), have their respective
benefits and drawbacks. (Recommendation Grade C1)
There are patients with severe LUTS or complications of BPH in whom medical
therapy fails and for whom surgery is deemed a high risk. Alternative options for
such unfit patients include urethral stent placement, intermittent catheterization,
intra-prostatic ethanol injection, intra-prostatic botulinum toxin injection, urethral
catheter placement and suprapubic cystostomy placement.
Various types of urethral stent are available, and they can be used temporarily
(such as ProstakathTM, ProstaCoilTM and MemokathTM) or permanently (such as
MemokathTM , UroLumeTM and MemothermTM). Placement of stents is generally
safe and significantly improves obstructive symptoms [1]. However, the rate of
complications including removal due to stent malposition/migration, gross
hematuria, vesical irritability, symptomatic urinary tract infection, and stone
formation is not low during follow-up [2–5].
Clean intermittent catheterization is another option for surgery-unfit BPH. There
are few evidences of superiority of intermittent catheterization to continuous
catheterization for BPH patients. However, there are several RCTs showing
superiority of intermittent catheterization with regard to bacteriuria and urinary
tract infection in other diseases [6, 7]. Therefore, if possible, this technique
should be considered. Dementia, motor paralysis of upper limbs and visual
impairment do not allow patients to perform self-catheterization.
When medical and/or social condition cannot afford intermittent catheterization,
continuous indwelling of urethral catheter could be considered, while this method
is liable to various complications, including acquired hypospadias,
cutaneourethral fistula, and vesical stone formation [8]. Suprapubic cystostomy
has a further higher rate of stone formation than urethral catheterization [9].
- 43 -
Intraprostatic ethanol injection [10] and botulinum toxin injection [11] are
promising alternatives for surgery-unfit patients, while they are considered still
experimental. Transurethral microwave thermotherapy (TUMT) and transurethral
needle ablation (TUNA) are indicated in high risk patients especially having
bleeding tendency and volume overload [12]. These kinds of treatment can be
performed without anesthesia. Due to less improvement of symptoms [13], when
compared to standard treatment and introduction of any kind of laser therapy,
TUMP is performed less frequent during the last decade. TUNA is considered
contraindicated in prior radiation to pelvic organ due to higher risk of rectal fistula
[14].
References of CQ13
1. Vander Brink BA, Rastinehad AR, Badlani GH. Prostatic stents for the
treatment of benign prostatic hyperplasia. Curr. Opin. Urol. 2007; 17: 1–6.
(review)
2. Braf Z, Chen J, Sofer M, Matzkin H. Intraprostatic metal stents (Prostakath®
and Urospiral®): more than 6 years’ clinical experience with 110 patients. J.
Endourol. 1996; 10: 555–8. (4)
3. Gesenberg A, Sintermann R. Management of benign prostatic hyperplasia in
high risk patients: long-term experience with the Memotherm stent. J. Urol.
1998; 160: 72–6. (4)
4. Perry MJA, Roodhouse AJ, Gidlow AB, Spicer TG, Ellis BW.
Thermo-expandable intraprostatic stents in bladder outlet obstruction: an
8-year study. BJU Int. 2002; 90: 216–23. (4)
5. Masood S, Djaladat H, Kouriefs C, Keen M, Palmer JH: The 12-year outcome
analysis of an endourethral wallstent for treating benign prostatic hyperplasia.
BJU Int 2004; 94: 1271–4 (4)
6. Van den Brand IC, Castelein RM. Total joint arthroplasty and incidence of
postoperative bacteriuria with an indwelling catheter or intermittent
catheterization with one-dose antibiotic prophylaxis: a prospective
randomized trial. J. Arthroplasty 2001; 16: 850–5. (2)
7. Hakvoort RA, Thijs SD, Bouwmeester FW et al. Comparing clean intermittent
catheterisation and transurethral indwelling catheterisation for incomplete
voiding after vaginal prolapse surgery: a multicentre randomized trial. BJOG
2011; 118: 1055–60. (1)
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8. Igawa Y, Wyndaele JJ, Nishizawa O. Catheterization: possible complications
and their prevention and treatment. Int. J. Urol. 2008; 15; 481–5. (review)
9. Mitsui T, Minami K, Furuno T, Morita H, Koyanagi T. Is suprapubic cystostomy
an optimal urinary management in high quadriplegics? A comparative study
of suprapubic cystostomy and clean intermittent catheterization. Eur. Urol.
2000; 38: 434–8. (3)
10. Grise P, Plante M, Palmer J, Martinez-Sagarra J, Hernandez C, Schettini M.
Evaluation of the transurethral ethanol ablation of the prostate (TEAP) for
symptomatic benign prostatic hyperplasia (BPH): a European multi-center
evaluation. Eur. Urol. 2004; 46: 496–501. (4)
11. Brisinda G, Cadeddu F, Vanella S, Mazzeo P, Marniga G, Maria G. Relief by
botulinum toxin of lower urinary tract symptoms owing to benign prostatic
hyperplasia: early and long-term results. Urology 2009; 73: 90–4. (4)
12. De la Rosette J, Laguna MP, Gravas S, De Wildt MJ. Transurethral
microwave thermotherapy: the gold standard for minimally invasive therapies
for patients with benign prostatic hyperplasia ? J. Endourol. 2003; 7: 245–51.
(survey)
13. Zlotta AR, Giannakopoulos X, Machlum O, Ostrem T, Schulman CC.
Long-term evaluation of transurethral needle ablation of the prostate (TUNA)
for the treatment of symptomatic benign prostatic hyperplasia: clinical
outcome up to 5 years from 3 centers. Eur. Urol. 2003; 44: 89–93. (4)
14. Gravas S, Laguna MP, De la Rosette JJ. Efficacy and safety of intraprostatic
temperature controlled microwave thermotherapy in patients with benign
prostatic hyperplasia: results of a prospective, open-label, single-center
study with 1-year follow-up. J. Endourol. 2003; 17: 425–30. (4)
- 45 -
CQ14
What therapeutic strategies are recommended to avoid sexual dysfunction as an
adverse event?
Answer:
Watchful waiting (active surveillance) could be considered for avoidance
of any sexual dysfunction. Alpha 1 blockers could be recommended for
patients who care erectile dysfunction. Tamsulosin and silodosin are liable
to ejaculation dysfunction. 5 alpha-reductase inhibitors could cause
erectile dysfunction and decrease of libido.
Phosphodiesterase type 5 inhibitor, Tadalafil, has been approved for
BPH/Male LUTS in USA and some Asian countries in 2011. Tadalafil is
effective in both LUTS and ED, but has not been approved in most Asian
countries.
Surgical therapy can induce ED, and it generally result in ejaculation
dysfunction. Although the incidence of sexual adverse events by
minimally invasive treatments, such as transurethral microwave therapy
(TUMT) and transurethral needle ablation (TUNA), is lower, these types of
treatment cannot always avoid adverse events on sexual function.
(Recommendation Grade B)
If a patient has only mild lower urinary tract symptoms owing to BPH and cares
sexual dysfunction due to interventional therapy, watchful waiting is a potential
option.
Alpha 1 blockers, such as alfuzosin and doxazosin, have generally beneficial
effects on erectile function [1–4]. Further, the incidence of erectile dysfunction
(ED) induced by 1 blockers is not so high (0.6-12%) and similar to that by
placebo [4]. Therefore, 1 blockers can be recommended to use for patients
who care ED. Although non-selective A1Bs, such as alfuzosin and doxazosin,
have no increased risk of ejaculation dysfunction (EjD) (0-1.3%) [5], 1 blockers
selective for alpha-1A adrenoreceptor, including tamsulosin (~30%) [5] and
silodosin (~28%) [6] are associated with increased risk of EjD. 5 alpha-reductase
inhibitors (5ARIs), finasteride and dutasteride, can induce several types of
sexual dysfunction, i.e. ED, EjD, and decrease of libido [7, 8]. The incidence of
drug-related sexual adverse events decreases with longer duration of therapy [9,
10]. Phosphodiesterase type 5 inhibitors, such as sildenafil, vardenafil and
- 46 -
tadalafil, have promising effects both on lower urinary tract symptoms due to
BPH and erectile function [11, 12]. However, this type of drugs is approved for
treatment for LUTS in no Asian countries.
The incidence of ED by open prostatectomy and transurethral resection of the
prostate (TURP) is reported 3 to 20% [13, 14]. However, similar percentages of
patients could experience the improvement of erectile function by TURP
[14] .These standard surgical treatments inevitably result in EjD (~80%) [14].
Surgeries using holmium: YAG-laser (ablation; HoLAP, resection: HoLRP,
enucleation: HoLEP) or KTP-laser (vaporization; PVP) have similar effect on
sexual function to TURP [13].On the other hand, several minimally invasive
methods, such as transurethral microwave therapy (TUMT) and transurethral
needle ablation (TUNA), have lower incidence of adverse events on sexual
function [14].
References of CQ14
1. Rosen R, Seftel A, Roehrborn CG. Effects of alfuzosin 10mg once daily on
sexual function in men treated for symptomatic benign prostatic hyperplasia.
Int. J. Impot. Res. 2007; 19: 480–5. (1)
2. Kim MK, Cheon J, Lee KS et al. An open, non-comparative, multicentre study
on the impact of alfuzosin on sexual function using the Male Sexual Health
Questionnaire in patients with benign prostatic hyperplasia. Int. J. Clin. Pract.
2010; 64: 345–50. (4)
3. Kirby RS, O’Leary MP, Carson C. Efficacy of extended-release doxazosin
and doxazosin standard in patients with concomitant benign prostatic
hyperplasia and sexual dysfunction. BJU Int. 2005; 95: 103–9. (1)
4. Demir O, Ozdemir I, Bozkurt O, Asian G, Esen AA. The effect of
alpha-blocker therapy on erectile functions in patients with lower urinary tract
symptoms due to benign prostatic hyperplasia. Asian J. Andol. 2009; 11:
716–22. (4)
5. AUA Clinical Guidance, Management of BPH (Revised 2010), Final
Appendices
(http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.
cfm?sub=bph) (Guideline)
6. Marks LS, Gittelman MC, Hill LA, Volinn W, Hoel G. Rapid efficacy of highly
selective alpha 1A-adrenoreceptor antagonist silodosin in men with signs
and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3
- 47 -
studies. J. Urol. 2009; 181: 2634–40. (1)
7. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL.
The effect of finasteride on the risk of acute urinary retention and the need for
surgical treatment among men with benign prostatic hyperplasia. N. Engl. J.
Med. 1998; 338: 557–63. (1)
8. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and
safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in
men with benign prostatic hyperplasia. Urology 2002; 60: 434–41. (1)
9. Wessells H, Roy J, Bannow J, Grayhack J, Matsumoto AM, Tenover L.
Incidence and severity of sexual adverse experiences in finasteride and
placebo-treated men with benign prostatic hyperplasia. Urology 2003; 61:
579–84. (1)
10. Schulman C, Pommerville P, Hofner K, Wachs B. Long-term therapy with the
dual 5alpha-reductase inhibitor dutasteride is well tolerated in men with
symptomatic benign prostatic hyperplasia. BJU Int. 2005; 97: 73–80. (1)
11. Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A,
Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to
benign prostatic hyperplasia in men with or without erectile dysfunction.
Urology 2010; 75: 1452–8. (1)
12. Porst H, Kim ED, Casabe AR et al. Efficacy and safety of tadalafil once daily
in the treatment of men with lower urinary tract symptoms suggestive of
benign prostatic hyperplasia: results of an international randomized,
double-blind, placebo-controlled trial. Eur. Urol. 2011; 60: 1105–13. (1)
13. Larson TR. Current treatment options for benign prostatic hyperplasia and
their impact on sexual function. Urology 2003; 61: 692–8. (review)
14. Frieben RW, Lin HC, Hinh PP, Berardinelli F, Canfield SE, Wang R. The
impact of minimally invasive surgeries for the treatment of symptomatic
benign prostatic hyperplasia on male sexual function: a systematic review.
Asian J. Androl. 2010; 12: 500–8. (review)
- 48 -
3. Introduction
Masayuki Takeda, M.D., Ph.D., Hideki Kobayashi, M.D., Ph.D.,
Norifumi Sawada, M.D., Ph.D., Masaki Yoshida, M.D., Ph.D., Koji
Yoshimura, M.D., Ph.D., Momokazu Gotoh, M.D., Ph.D., Japan.
An increase in the prevalence of lower urinary tract symptoms (LUTS) with age
in men [1] is seen, and which is important given the increase in the aging
population [2]. Because of the great prevalence of benign prostatic hyperplasia
(BPH) in elderly men, which is as high as 40% in men in their fifth decade and
90% in men in their ninth decade [3], the most important and prevalent cause of
LUTS in men over 40 years is generally believed to be the enlarging
prostate/BPH. Although BPH is a histologic diagnosis that refers to the
proliferation of smooth muscle and epithelial cells within the prostatic transition
zone [4, 5], benign prostatic enlargement (BPE), or benign prostatic obstruction
(BPO) are often used in the same way as BPH in the clinical setting. Recently,
the causes of aging male LUTS are known to be multifactorial, and LUTS may
be linked to the prostate (BPH-LUTS), bladder (detrusor overactivity-overactive
bladder syndrome [OAB], detrusor underactivity), kidney/heart (nocturnal
polyuria), or brain (sleep disorder) [6]. Usually, more than one of those factors is
present, in a patient complaining of LUTS. According to such situation, the title of
the 1st UAA Guideline has been determined as “BPH/Male LUTS”, not solely
“BPH”, and the Purposes of this guideline is to summarize Practical Consensus
Statement on the Management of BPH/Male LUTS from UAA. Target doctors are
both Urologists and non-Urologists/General Practitioners, and target patients are
40 years or older male patients with BPH/LUTS. Traditionally in Asian countries,
socio-cultural atmosphere of accepting lower urinary tract symptoms (LUTS) as
a natural part of aging process has been dominant. However, far Eastern
countries like Japan, Korea and Taiwan have already become an “aging society”
and the ever-growing public interest in their health and well-being, public
awareness towards BPH has been increasing rapidly along with the number of
patients who visit hospitals seeking medical care for LUTS. Thus, it can be
expected that BPH will soon become a major issue with regard to public health
and welfare in all Asian countries, as is already the situation for many Western
countries. The UAA Guideline on Male LUTS mainly covers LUTS secondary to
benign prostatic enlargement (BPE) or benign prostatic obstruction (BPO),
detrusor overactivity or overactive bladder (OAB), and nocturia due to nocturnal
polyuria. Other causes of male LUTS are covered by separate EAU Guidelines.
- 49 -
3.1 Multifactorial Etiology of LUTS
3.2 Multifactorial conditions for LUTS
- 50 -
References
1. Platz EA, Joshu CE, Mondul AM, Peskoe SB, Willett WC, Giovannucci E.
Incidence and Progression of Lower Urinary Tract Symptoms in a Large
Prospective Cohort of United States Men. J. Urol. 2012; 186: 496–501.
2. World Population Ageing 1950–2050. 2002 [cited May 2012]; United Nations
Department of Economic and Social Affairs Population Division]. Available
from: http://www.un.org/esa/population/publications/worldageing
19502050/
3. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human
benign prostatic hyperplasia with age. J. Urol. 1984; 132: 474–9.
4. Lee C, Kozlowski J, Grayhack J. Intrinsic and extrinsic factors controlling
benign prostatic growth. Prostate 1997; 31: 131–8.
5. Auffenberg G, Helfand B, McVary K. Established medical therapy for benign
prostatic hyperplasia. Urol. Clin. North. Am. 2009; 36: 443–59.
6. Chapple CR, Roehrborn CG. A shifted paradigm for the further
understanding, evaluation, and treatment of lower urinary tract symptoms in
men: focus on the bladder. Eur. Urol. 2006; 49: 651–8.
7. Oelke M, Bachmann A, Descazeaud A et al. EAU Guideline Male LUTS
2012. Guidelines on Management of Male Lower Urinary Tract Symptoms
(LUTS) LUTS: lower urinary tract symptoms, incl. Benign Prostatic
Obstruction (BPO) BPO: benign prostatic obstruction.
(http://www.uroweb.org/guidelines/online-guidelines/)
- 51 -
4. Definition, and terminology of benign prostatic hyperplasia
(BPH) and related disorders
Salam, M.A., MD, Md Afiquor Rahman, MD
In the past, a number of terms such as prostatism, symptomatic benign prostatic
hyperplasia (BPH), and clinical BPH have been used to describe symptoms
related to micturition in older men. Currently, the traditional belief that urinary
symptoms in elderly men were always assumed to be directly or indirectly
related to prostate has been challenged. The term lower urinary tract symptoms
(LUTS) has been adopted and several consensus and guidelines committees
have attempted to define the appropriate terminology for categorizing the
pathophysiological conditions underlying male LUTS [1–5].
4.1 The term lower urinary tract symptoms (LUTS; as defined by the
International Continence Society) are the subjective indicator of a disease or
change in condition as perceived by the patient, caregiver or partner and may
lead him/her to seek help from health care professionals. LUTS can be classified
as storage, voiding, and post micturition symptoms.
4,2 Bladder storage (irritative) symptoms are experienced during the
storage phase of the bladder and include: increased daytime frequency, nocturia,
urgency, and urinary incontinence.
4.3 Voiding (obstructive) urinary symptoms are experienced during the
voiding phase and include: slow urinary stream, splitting or spraying of the
urinary stream, intermittent urinary stream, hesitancy, straining to void, and
terminal dribbling.
4.4 Post micturition symptoms include feeling of incomplete emptying and
postmicturition dribbling.
4.5 Benign prostatic hyperplasia (BPH) represents a histologic diagnosis
that refers to the proliferation of smooth muscle and epithelial cells within the
prostatic transition zone. Benign prostatic hyperplasia or BPH is a term used
(and reserved for) the typical histological pattern, which defines the disease.
BPH progression is a dynamic process that includes deterioration of LUTS and
- 52 -
health related quality of life, increased prostatic size, acute urinary retention
(AUR), and BPH-related surgery. Renal insufficiency and recurrent urinary tract
infections as additional measures of BPH progression have also been
considered. However, these outcomes are rarely observed [6–9].
4.6 Benign prostatic enlargement (BPE) is defined as prostatic enlargement
due to histologic benign prostatic hyperplasia. The term “prostatic enlargement”
should be used in the absence of typical prostatic histology
4.7 Bladder outlet obstruction (BOO) is the generic term for obstruction
during voiding and is characterized by increased detrusor pressure and reduced
urine flow rate. Therefore, the term BOO requires urodynamic confirmation
4.8 Benign prostatic obstruction (BPO) is bladder outlet obstruction (needs
urodynamic evaluation) and may be diagnosed when the cause of outlet
obstruction is known to be benign prostatic enlargement, due to histologic
benign prostatic hyperplasia.
The relationship between LUTS, BPH, BPE, BOO and BPO is complex and not
fully understood. Because the prevalence of histological BPH and LUTS is
age-related, it was often assumed that they were causally related, but recent
evidence indicate that male LUTS may result from a complex interplay of
pathophysiological influences, including prostatic pathology and bladder
dysfunction. However, BPH is the primary cause of LUTS in older men.
Most men with enlarged prostates may not have any symptoms at all. BPO may
occur in some but not all men with BPH and LUTS. The elderly men with BPH
may not develop BOO which is characterized by increased detrusor pressure
and reduced urine flow rate. Many men develop BPO without evidence of
histologically proven BPH. BOO due to BPE may have both static (increased
tissue mass) and dynamic (increased smooth muscle tone) components in the
prostate leading to variable lower urinary tract symptoms. BOO due to BPE or
BPH may lead to overactivity of the detrusor muscle leading to irritative
symptoms predominantly. This situation may not be clarified with conventional
investigations of BPH. An urodynamic studies will settles the issue by confirming
the overactivity of the bladder is due to benign prostatic obstruction [10, 11].
- 53 -
References
1. Abrams P, Cardozo L, Fall M et al. Standardisation Sub- Committee of the
International Continence Society. The standardisation of terminology in
lower urinary tract function: report from the standardisation sub-committee of
the International Continence Society. Urology 2003; 61: 37–49.
2. Arrighi HM, Metter EJ, Guess HA, Fozzard JL. Natural history of benign
prostatic hyperplasia and risk of prostatectomy, the Baltimore Longitudinal
Study of Aging. Urology 1991; 35 (Suppl): 4–8.
3. Chapple CR, Roehrborn CG. A shifted paradigm for the further
understanding, evaluation, and treatment of lower urinary tract symptoms in
men: focus on the bladder. Eur. Urol. 2006; 49: 651–8.
4. Chute CG, Panser LA, Girman CJ et al. The prevalence of prostatism: a
population based survey of urinary symptoms. J. Urol. 1993; 150: 85–9.
5. Emberton M, Andriole GL, De la Rosette J et al. Benign prostatic
hyperplasia: a progressive disease of aging men. Urology 2003; 61: 267–73.
6. Issa MM, Fenter TC, Black L, Grogg AL, Kruep EJ. An assessment of the
diagnosed prevalence of diseases in men 50 years of age or older. Am. J.
Manag. Care 2006; 12: S83–9.
7. Jacobsen SJ, Girman CJ, Guess HA, Rhodes, T, Oesterling JE, Lieber MM.
Natural history of prostatism: longitudinal changes in voiding symptoms in
community dwelling men. J. Urol. 1996; 155: 595–600.
8. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of
doxazosin, finasteride, and combination therapy on the clinical progression
of benign prostatic hyperplasia. N. Engl. J. Med. 2003; 349: 2387–98.
9. Roberts RO, Jacobsen SJ, Jacobsen D, Rhodes T, Girman CJ, Lieber MM.
Longitudinal changes in Roehrborn CG: Benign prostatic hyperplasia: an
overview. Rev. Urol. 2000; 7: S3–14.
10. Guidelines on the Management of Male Lower Urinary Tract Symptoms
(LUTS), incl. Benign Prostatic Obstruction (BPO), European Association of
Urology, 2012.
11. 2010 Update: Guidelines for the management of benign prostatic
hyperplasia. Can. Urol. Assoc. J. 2010; 4: 310–31.
- 54 -
5 Risk Factors for BPH
Jose Albert C. Reyes III, MD, DPBU, FPUA, FPCS
Evidence suggests that modifiable factors such as obesity, diet, dyslipidemia,
hormonal imbalance, hypertension, metabolic syndrome, alcohol and smoking
contribute to the development of BPH and/or LUTS other than aging and
androgens [1].
5.1 Genetic Factors:
Partin and colleagues demonstrated a concordance for benign prostate disease
in monozygotic (MZ) and dizygotic (DZ) twins who served in the United States
military in World War II [2]. Genetic factors not only determine risk for
development of BPH but also affect its presentation and severity. Also, Meikle
and colleagues demonstrated that heritability appears to account for 82.6% of
the variability in symptom score in men older than 50 years in a study conducted
on twins. Table 1 summarizes Family History of Early-Onset BPH Increases Risk
of Clinical Significant BPH (Table 1) [3].
5,2 Dietary Factors:
Those with high intake of protein and polyunsaturated fatty acid appear to be at
greater risk of developing BPH [4].
Marchard et al evaluated the relation between consumption of high animal fat
products to BPH and prostate cancer. It was proposed that certain aspects of
western diet, low amount of fruits and vegetables and a higher proportion of
energy from animal fats, explain the epidemiologic evidence linking western
dietary patterns to a higher BPH risk [5, 6].
Daily fruit consumption was later then found out to be inversely related to risk of
BPH [7]. Furthermore, Galuzzi et al found that Southeast Asian men have a
lower prevalence and severity of autopsy-diagnosed BPH than age-matched
North American men [8], implying that ethnicity and geographical factors, such
as migration, can influence the growth of the normal human prostate during
midlife [9]. Chyou examined 33 food items in relationship to prostatectomy rates
and found only beef intake significantly associated [10].
Araki and associates reported increased clinical diagnosis of BPH in men with
higher milk consumption and lower consumption of green and yellow vegetables
[11]. Overall there is no convincing evidence for any individual diet factor to play
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a major role in the development of LUTS/BPH.
5,3 Obesity, Hypertension, DM, Hypercholesterolemia and Sexual
Dysfunction:
The relationships between LUTS/BPH and obesity, BMI, and the metabolic
syndrome have recently been of great interest [12–15]. Autonomic hyperactivity
has been implicated in the development of both LUTS and ED in the aging male,
but conclusive clinical data are lacking [16]. In the EpiLUTS study both heart
diseases and hypertension were associated with more severe LUTS
constellations [17]. Dyslipidemia has also been associated with an increased risk
of BPH [18] (See Appendix- Table II). In a cohort in 1998 involving Swedish men
with BPH lower HDL, higher LDL, and higher triglycerides were associated with
increased prostate volume [19]. A pilot case-control study showed that higher
triglyceride levels, high waist-to-hip ratio, and lower HDL levels were associated
with BPH in North Indian population [20]. Hammarsten and Hogstedt examined
250 patients with LUTS and found non–insulin-dependent diabetes mellitus,
hypertension, tallness, obesity, high insulin level, and low high-density
lipoprotein cholesterol levels to be risk factors for the development of BPH and
suggested a causal relationship between high insulin levels and the
development of BPH and hypothesize increased sympathetic nerve activity in
men with BPH [21].
5.4 Other risk factors:
Physical activity thus appears to reduce the risks of BPH and LUTS. Similar
findings of increased likelihood of LUTS with increasing BMI and decreasing
likelihood with greater physical activity were also reported from the EpiLUTS
study [17]. Alcohol intake may lower incidence of BPH by decreasing plasma
testosterone production and increasing testosterone clearance. In an analysis of
the Prostate Cancer Prevention Trial, alcohol appears to have a somewhat
protective effect against BPH [22]. Studies on the relationship of liver cirrhosis
and BPH, revealed a lower incidence of BPH in men with cirrhosis [22–25].
However, multivariate analysis show and increase surgical risk for BPH in
patients taking in more than three glasses of alcohol per day [26, 27].
Cigarette smoking appears to have a protective effect on prostatism at certain
smoking intensities, but no effect or a deleterious effect at other intensities [28–
30]. Light or moderate smokers are less likely to have moderate to severe
- 56 -
prostatism, whereas heavy smokers are at least as likely to have moderate to
severe prostatism compared with never-smokers [31]. Cold medications
containing α-sympathomimetic drugs exacerbate LUTS by the expected effect
on the smooth muscles of the bladder outlet. Recently a careful analysis of the
data from the Olmsted County study demonstrated that daily use of
antidepressants, antihistamines, or bronchodilators is associated with a 2- to
3-point increase in the IPSS compared with age-matched nonusers and daily
use of antidepressants is associated with a decrease in the age-adjusted flow
rate [32].
It was reported that there is 49% reduction in risk for prostatectomy in widowed
versus single men [33]. Cross-sectional data from the Olmsted County study
suggest that the frequency of ejaculation has no effect on LUTS, peak urinary
flow rates, or prostate volume; the apparent protective association appears to be
an artifact caused by the confounding effects of age [34]. Impact of some
socioeconomic factors on LUTS and BPH had deepened with the help of two
studies, the European Prospective Investigation into Cancer and Nutrition
(EPIC) and the Epidemiology of Lower Urinary Tract Symptoms (EpiLUTS), and
the Boston Area Community Health (BACH) studies [35, 36]. Araki and
associates found higher rates of BPH in higher income groups [10], whereas, in
contrast, Glynn and coworkers reported higher rates of surgery in lower income
groups which could be because higher income groups might have better access
to health care whereas lower income groups might submit more readily to the
suggestion of a surgical procedure [37].
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APPENDIX
Table I. Family History of Early-Onset BPH Increases Risk of Clinical
Significant BPH
Relatives with history of prostatectomy (open or transurethral)
RELATIVE RISK of
for BPH
CLINICAL BPH
All first-degree male relatives
4.4
Fathers of proband
3.5
Brothers of proband
6.1
[3]
Table II. Modifiable Risk Factor Associated with Decreased or Increased
Risk of LUTS and/or BPH
STUDY
Health
Professiona
ls Follow-up
Massachus
etts Male
Aging Study
PLCO
NHANES III
DECREASED RISK OF BPH AND LUTS
RISK FACTOR
REFERENCE
CATEGORY
Clinical BPH:
Alcohol intake 0 g/day
Alcohol intake 30.1-50 g/day
Walking 0 hr/wk
Walking ≥ 2 hr/wk
Clinical BPH (physical
Physical activity 140
activity 862 kcal/day or
kcal/day
greater
Clinical BPH (alcohol intake Alcohol intake <5 g/day
60 g/day or greater)
Alcohol intake <5 g/day
TURP likelihood (alcohol
Alcohol intake <5 g/day
intake ≥60 g/day) Nocturia
(alcohol intake ≥60 g/day)
LUTS: Alcohol intake ≥1
Never
drink/day
Physical activity >6
Physical activity 0
times/wk
times/wk
- 58 -
OR (95% CI)
0.59 (0.51-0.70)
0.73 (0.63-0.84)
0.50 (0.3-0.9)
0.60 (0.5-0.7)
0.40 (0.3-0.7)
0.80 (0.7-1.0)
0.59 (0.36-0.97)
0.49 (0.29-0.84)
INCREASED RISK OF BPH AND LUTS
RISK FACTOR
REFERENCE
CATEGORY
Hunt-2
LUTS: BMI 40 mg/kg2 or
BMI less than 25
less/
Diabetes
No diabetes
Waist/hip ratio 0.94 or less Waist/hip ratio 0.85 or
less
NHANES III
LUTS: Diabetes
No diabetes
Hypertension
No hypertension
Increase in BMI between
No increase
age 25 yr + highest BMI ever
Waist circumference >102 Waist circumference
cm
<94cm
BLSA
LUTS: Diabetes
No diabetes
STUDY
Fasting glucose >110 ng/dL
Prostate ≥40 mL:
BMI >35 mg/kg2
Diabetes
Fasting glucose ≤110
ng/dL
BMI <25 kg/m2
No diabetes
Fasting glucose ≤110
ng/dL
OR (95% CI)
1.79 (0.90-3.56)
1.25 (1.04-1.49)
1.32 (1.15-1.50)
1.67 (0.72-3.86)
1.76 (1.20-2.59)
1.90 (0.89-4.05)
1.48 (0.87-2.54)
2.80 (1.10-7.10)
2.60 (1.01-6.70)
3.52 (1.45-8.56)
2.25 (1.25-4.11)
2.98 (1.70-5.23)
Fasting glucose >110 ng/dL
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6. Epidemiology & Natural history
Shing-Hwa Lu, M.D., Ph.D., and Edward Chen, M.D., Ph.D.
The following 4 categories are discussed in this chapter.
6.1 Natural history before diagnosis
6.2 Factors affecting health-care seeking behavior
6.3 Prediction of symptomatic progression
6.4 Natural history after diagnosis
6.1 Natural history before diagnosis
Benign prostatic hyperplasia (BPH) is the most common nonmalignant condition
of the prostate occurring in ageing men. Even though BPH is a major public
health problem, causing high morbidity and substantial worsening in men's
quality of life [1]. The prevalence rates of BPH, depend very much on the
parameters used in a case definition [2], has been estimated on the basis of
results of community-based studies in Japan [3–5]. Six and 12% of Japanese
men in their sixties and seventies, respectively, meet all three of the following
criteria for BPH: (i) an international prostate symptom score (IPSS) >7; (ii)
prostate volume (PV) >20 mL; and (iii) peak urinary flow rate (Qmax) <10 mL/s.
Only 2% of men in their forties and fifties met the above criteria.
The principal risk factors for BPH are aging and normally functioning testicles.
Although no definitive genes responsible for BPH have been identified, a family
history of BPH and molecular abnormalities may increase the likelihood of its
development. Dietary factors, such as isoflavonoids and lignans in vegetables,
grains, and soy, may have a negative impact on the development of BPH [1].
Furthermore, recent studies have claimed a relationship between metabolic
syndrome and BPH [6–8].
The normal prostate reaches 20 plus or minus 6 g in men between 21 and 30
years old, and this weight remains essentially constant with increasing age
unless benign prostatic hyperplasia develops. The prevalence of pathological
benign prostatic hyperplasia is only 8 % at the fourth decade; however, 50 % of
the male population has pathological benign prostatic hyperplasia when they are
51 to 60 years old. The average weight of a prostate that is recognized at
autopsy to contain benign prostatic hyperplasia is 33 plus or minus 16 g. Only 4
% of the prostates in men more than 70 years old reach sizes greater than 100 g.
- 63 -
An analysis of a logistic growth curve of benign prostatic hyperplasia lesions
removed at prostatectomy indicates that the growth of benign prostatic
hyperplasia is initiated probably before the patient is 30 years old. The early
phase of benign prostatic hyperplasia growth (men between 31 and 50 years old)
is characterized by a doubling time for the tumor weight of 4.5 years. In the mid
phase of benign prostatic hyperplasia growth (men between 51 and 70 years old)
the doubling time is 10 years, and increases to more than 100 years in patients
beyond 70 years old [9]. BPH is a physiological process that occurs with aging,
regardless of race, ethnicity or region [9, 10].
Estimated prostate growth rates increased with increasing age. However, the
estimated average annual change was 1.6% across all age groups. Estimated
prostate growth rates were high depending on baseline prostate volume with
higher growth rates for men with larger prostates [11].
BPH can be characterized as a progressive disease in a certain proportion of
men older than 50 yr. Men with growing prostates are at a greater risk of
symptomatic deterioration. Men who have prostates that do not grow
significantly are more likely to improve symptomatically [12]. The prevalence of
LUTS in the general population is age-related [4, 13, 15]. Longitudinal studies
have shown an increase in IPSS with advancing age as a whole [12, 16, 17], but
with simultaneous decreases in IPSS in certain subgroups [16, 18], Qmax
decrease with aging [5, 19], and this may be attributable to BPO as well as
detrusor underactivity (DU). Longitudinal studies have confirmed age-related
increases in PV [11, 12], although in a small proportion of men PV has been
noted to decrease with aging [20]. Recent studies indicate that PV is likely to
increase in men in whom the prostate has a visible transition zone with a clear
border [21, 22]. and with a large transition zone volume on transrectal ultrasound
at baseline [23]. The relationship between LUTS, urinary flow rate and PV is
generally poor in men presenting at hospital, but it is modest among men in the
general population. Prostate enlargement is likely to be involved in the
progression of symptoms [12, 24].
6.2 Factors affecting health-care seeking behavior
A cross-sectional, population-based cohort study in Olmsted County revealed
that health-care seeking behavior was influenced by the severity of symptoms,
particularly if they were bothersome and interfered with an individual's daily
- 64 -
activities. While symptom severity is an important determinant of health
care-seeking behavior for men with urinary symptoms, some additional factor or
factors associated with age remain that may drive men to seek care for urinary
symptoms. These factors may prove important in understanding the small-area
variations in treatment of benign prostatic hyperplasia that have been noted by
others. Men aged 70 to 79 years were 4.6 times as likely (95% confidence
interval, 2.1 to 10.1) as men aged 40 to 49 years to have sought health care
because of urinary symptoms [25]. Seventy-six% of men who had sought
medical care had prostatic enlargement, depressed peak urine flow rates, or
moderate-severe symptoms (sensitivity). In contrast, only 55% of men who did
not seek health care for urinary symptoms had mild symptoms, normal prostatic
volume, and normal peak urine flow rates (specificity). Clinical, physiologic, and
anatomic measures of prostatism do not adequately distinguish the men who
seek medical care for their urinary symptoms from those who do not. There
remain some factor(s) that apparently lead some men with minor disease to
seek care and that prevent men with measurable disease from seeking care
[26 ].
Voiding symptoms may have impact on medical care-seeking behavior through
QOL impairment in Japanese men. The QOL score appeared to reveal more
pronounced differences between men in clinic and community setting than the
IPSS category [27]. Core Lower Urinary Tract Symptom Score (CLSS)
questionnaire is more comprehensive than IPSS questionnaire for symptom
assessment of men with various diseases/conditions, although both
questionnaires can capture LUTS with possible negative impact on QOL [28].
The IPSS alone does not appropriately evaluate female LUTS. The CLSS
questionnaire could provide a comprehensive and simple assessment of female
LUTS [29].
6.3 Prediction of symptomatic progression
From a systemic review of placebo arm of clinical trials on benign prostatic
hyperplasia (BPH), the disease progression was observed in terms of increasing
prostate volume and decreased maximal urinary flow rate (Qmax). In addition,
the progression increases the risk of acute urinary retention (AUR) and surgery
[30]. The community-based and randomized controlled studies identified some
clinical parameters which may be associated with clinical progression,
complications such as AUR and related surgeries [31–35].
- 65 -
Progression may be associated with higher International Prostate Symptom
Score (IPSS), lower Qmax, increased post void residual urine (PVR) and
enlarged prostate volume. From the Medical Therapy of Prostatic Symptoms
study (MTOPS), the clinical progression of placebo arm (n=737) is 17%, the
AUR is 2%, and invasive therapy due to benign prostatic hyperplasia is 5% [36].
The risks for clinical progression in the study may include age ≥62 years old,
prostate volume ≥31 mL, prostate specific antigen (PSA) ≥1.6 ng/mL, Qmax
<10.6 mL/s and PVR ≥39 mL [37]. However, practicing doctors are faced with
patients often representing with several unfavorable conditions not only a single
risk. On a systemic analysis of expert opinions, the considerable PVR (>150 mL),
poor Qmax (<10 mL/s) and severe symptoms (total IPSS: 20–35) are the most
dominant factors predicting an elevated risk of disease progression [38].
Enlarged prostate and high PSA was found to be good clinical predictor of AUR
and BPH related surgery [39]. In addition, the high PVR should be reconsidered
as a predictor of BPH progression through the interpretation of longitudinal
population-based and placebo arm of controlled studies.
6.4 Natural history of BPH after diagnosis
The best way to see the natural history of BPH after diagnosis is to understand
the fate of watchful-waiting or placebo treatment group. In a community based
longitudinal study which was followed for 12 years showed an average
increased IPSS of 0.18 points per year (0.05 for men at 50s to 0.44 at 70s).
There was also a decreased Qmax 2% per year and median prostate growth of
1.9% per year. In addition, the accumulative incidence of AUR was 2.7% over 4
years monitoring [40, 41]. In the placebo controlled arm of MTOPS study, the
evidence revealed that symptom deterioration (IPSS ≥4 points) was the most
prevalent progression event (79.5%), with an accumulative incidence of 14%
over a mean follow-up of 4.5 years [36].
From a cohort study in North America, the outcome of men with BPH depends
on the initial symptom severity. However, the course of symptoms may vary
among patients even with same initial symptom severity [42, 43]. In those who
with severe symptoms usually did not have improvement to only mild symptoms.
Almost half of patients with moderate symptoms still had moderate symptoms at
4 years follow-up, and eventually a quarter of them underwent surgery.
After the diagnosis of BPH, self-management intervention including lifestyle
modification and specific behavioral changes such as decreasing fluid intake at
- 66 -
bed time, avoiding caffeine and alcohol consumption may be the choices of
management strategy, and which offer a better clinical response. However, the
failure rate at 3, 6 and 12 months is higher in watchful-waiting patients (40.3% vs.
9.6%; 58.2% vs. 17.8%; 65.7% vs. 24.6%) as compared with active
management [44]. This evidence indicates the BPH possesses a deteriorated
clinical or symptomatic natural history itself and early treatment may be better if
patients have bothersome symptoms.
The PROWESS study group revealed that their patients with moderate
symptoms have significant greater improvement with finasteride as compared
with placebo group. The prostate volume decreased 15.3% in treatment group
as compared with placebo group which increased their prostate volume about
8.9% at 24 months [45]. From a nationally representative databases study, in
additional to the α blockers therapy, each 30-day delay treatment with
5α-reductase inhibitors may result in an increased overall clinical progression
(21.1%), AUR (18.6%) and prostate related surgery (26.7%) within 6 months of
follow-up [46]. This means, even under early treatment with α blocker, patients
still have a relative higher risk of symptomatic progression if they did not reduce
the prostate size. In the Veterans Affairs Cooperative Study, 24%
watchful-waiting group patients will undergo surgery within three years waiting
assignment [47]. Based on the natural history after diagnosis of BPH either with
or without medical treatment, the fact of clinical progression should raise the
alertness of clinicians and theses patients should be informed with these facts,
especially those who under watchful-waiting treatment.
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16. Jacobsen SJ, Girman CJ, Guess HA, Rhodes T, Oesterling JE, Lieber MM.
Natural history of prostatism: longitudinal changes in voiding symptoms in
community dwelling men. J. Urol. 1996; 155: 595–600.
17. Lee AJ, Garraway WM, Simpson RJ, Fisher W, King D. The natural history
of untreated lower urinary tract symptoms in middle-aged and elderly men
over a period of five years. Eur. Urol. 1998; 34: 325–32.
18. Masumori N, Tsukamoto T, Rhodes T, Girman CJ. Natural history of lower
urinary tract symptoms in men: results of a longitudinal community-based
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19. Roberts RO, Jacobsen SJ, Jacobson DJ, Rhodes T, Girman CJ, Lieber MM.
Longitudinal changes in peak urinary flow rates in a community-based
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7. Pathophysiology of BPH
Keong Tatt Foo, M.D., Cheuk Fan Shum, M.D., and Colin Teo,
M.D.
BPH is a common disease affecting males above the age of 50 years. It was
reported that on autopsy study, 60% of patients above the age of 60 has BPH [1].
It is associated with a significant health impact, either as bothersome lower
urinary tract symptoms (LUTS) to patients, or less commonly as potentially
serious complications resulting from obstruction to urinary outflow.
It may not be easy to distinguish BPH from other lower urinary tract conditions in
aging males, since many of their symptoms overlap. Urgency symptoms from
detrusor overactivity after chronic obstruction may occur in many BPH patients,
but there are just as many BPH patients with bladder decompensation and
hypocontractility [2, 3].
The common belief that BPH is a diffused and generalized disease of the
prostate, resulting from some form of hormonal derangement that leads to
prostatic hyperplasia, enlargement of the overall prostatic size, compression of
the prostatic urethra, and a progressive obstruction to the bladder outlet, does
not reflect the entire pathophysiology of BPH.
7.1 Pathogenesis
Androgens must be present for prostate cells to grow. While androgens may not
directly cause BPH, they play an important permissive role. The observation that
castrated pre-pubertal boys do not develop BPH when they age illustrates the
presence of androgens is essential for BPH development. The main androgen,
testosterone, is converted by 5α reductase to dihydrotestosterone.
Dihydrotestosterone is 10-times more potent than testosterone due to its slower
dissociation from androgen receptors. Five-alpha reductase inhibitors suppress
this enzymatic conversion, resulting in decreased prostatic dihydrotestosterone
level, decreased prostatic volume, and symptomatic improvement.
Within the prostate, androgens bind to androgen receptors and initiate the
transcription of growth factors that are mitogenic to prostatic epithelial and
stromal cells. Such androgenic action can be both autocrine and paracrine in
stimulating stromal and epithelial cell growth and differentiation [4–6]. The
stromal to epithelial cell ratio is believed to be deranged in BPH. Normally, the
ratio is about 2:1, but this increases to more than 3:1 in BPH [7]. The altered
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stromal to epithelial interaction leads to the formation of microscopic nodules of
fibromuscular hyperplasia. These nodules are first formed in the transition zone
just below the smooth muscle collar of the preprostatic sphincter [8]. There are
also nodules forming within the periurethral glandular tissue in the smooth
muscle collar of the preprostatic sphincter. Within these nodules, fibroblasts
transform into smooth muscle cells within a matrix of connective tissues [9]. As
these nodules increase in number and size, they coalesce to form larger
adenoma. The lateral lobes of BPH are formed from the coalescence of
micronodules within the transition zone, whereas the middle lobe of BPH is
formed from micronodules within the periurethral sleeve of glandular tissue
posteriorly. The remainder of the prostate is then compressed outward to form a
false capsule posteriorly [10]. Therefore, BPH is a focal, stromal-induced
disease affecting the transition and periurethral zones with formation of
fibromuscular micronodules, which increase in size and number and coalesce
into the lateral and middle lobes [11].
Being nodular in nature, BPH adenoma can cause obstruction at the bladder
outlet and prostatic urethra depending on location, rather than size. A small
adenoma sited at the strategic bladder outlet, in the submucosal region can
cause significant obstruction, whereas one situated deeper in the stroma of the
gland would need to grow to a bigger size before it causes obstruction and
symptoms. As in the analogy of the garden hose, it is the distortion which is more
important factor that the compression of the prostatic urethra in BPH. Therefore,
if the term BPH is reserved for only histological diagnosis, for clinical BPH, it is
suggested that the term prostate adenomata (PA) which cause various degree of
obstruction would be appropriate. The term benign prostatic enlargement (BPE)
to indicate clinical BPH may not be appropriate, for often even when the gland is
small and not enlarged by definition, it can still cause significant obstruction
when the adenoma is sited at the strategic position causing distortion to urinary
flow.
7.2 Histopathology
On histological examination, benign prostatic hyperplasia (BPH) contains three
main components: 1. Epithelial cells (glandular tissue); it contains acini and
ducts. There are three major types of cells: Secretory epithelial cells, basal cells
and neuroendocrine cells. Epithelial cells surround the periphery of the acini and
secrete into the acini, and then secretions are drained into ducti and urethra. In
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the ablation of androgen, there occur a 90 % decrease in the number of
secretory cells, and an 80 % lessening in the volume of cells, 2. Luminal
surfaces in acini (glandular lumen), 3. Stroma; stromal tissue composed of
smooth muscle, connective tissue, fibroblasts, nerves, Iymphatic and blood
vessels [12]. The normal adult prostate contains about 20% epithelium, 30%
acinar lumens, and 50% stroma according to morphometric studies. As
mentioned above, the stromal to epithelial cell ratio is deranged in BPH.
Interestingly, it seems that men with symptomatic BPH have a significantly
higher proportion of stroma compared to men with asymptomatic BPH. The
nature of the predominant nodule in BPH may play a role in determining the
patients’ response to treatment. Smooth muscle predominant nodules respond
better to alpha antagonists, epithelial nodules to 5α reductase inhibitors, and
fibrous nodules to surgery.
The altered stromal to epithelial interaction seems to be mediated by various
growth factors. Androgen appears to act via transforming growth factor-alpha
(TGF-α) expression to regulate other growth factors, which in turn alter the
balance between cell growth and apoptosis within the micronodules. There are
five isoforms of TGF-α, of which three are found in mammals (α-1 to α-3), and
α-1 and α-2 have been investigated in BPH. TGFα-1 is under a negative
feedback by androgen, so a fall in androgen will lead to an increase in TGFα-1
expression [13]. Together with TGFα-2, they are inhibitory on epithelial and
stromal cell growth. On the other hand, basic fibroblast growth factor (bFGF) and
keratinocyte growth factor (KGF), both are mediated by transforming growth
factor-beta (TGF-β) stimulates epithelial and stromal cell growth [14]. Normally,
there is a fine balance between the actions of these growth factors. In BPH, the
fibroblast growth factors seem to override the transforming growth factors
[15]. The eventual formation of the lateral and median lobes distorts the prostatic
urethra, and produce bladder outlet obstruction.
7.3 Clinical Pathology
In the clinic, the prostatic adenomata (PA) and the distortion of the bladder neck
can be seen with trans-abdominal ultrasound (TAUS) of the prostate and bladder,
as intravesical prostatic protrusion (IPP). IPP is the distance measured from the
tip of the protruding lobes to the base of the prostate at the circumference of the
bladder, seen in the sagittal view on TAUS. A grading system for IPP is well
established. Grade 1 IPP is 5mm or less, grade 2 IPP is more than 5mm to
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10mm, grade 3 IPP is more than 10mm [16]. Recent studies have shown good
correlation between IPP grade and urodynamic evidence of obstruction. It had
been found that among patients with grade 1 IPP, only 21% were obstructed;
while up to 94% were obstructed among patients with grade 3 IPP [17]. The
positive predictive value was 94% and negative predictive value was 79%. In a
study comparing IPP and non-invasive Doppler ultrasound urodynamics in
diagnosing bladder outlet obstruction noninvasively, IPP was validated to be
strongly correlated to obstruction [18]. The sensitivity of the IPP grading was
90% for those with grade 3 IPP and a bladder obstructive Index (BOOI) of more
than 40. The specificity for those with grades 1 or 2 IPP, and a BOOI of 40 or
less was 60%. Rather than just the overall prostatic volume causing urethral
compression and obstruction, IPP also contributes to the degree of obstruction
due to urethral distortion by the PA.
Several studies have illustrated the natural history of clinical progression in BPH.
The placebo arm of the MTOPS study showed that the risk of clinical
progression was 4.5 per 100 man-years, representing a total risk of 17% at 4
years, including symptom deterioration in 14%, retention in 2%, and surgery in
5% [19]. Based on the Olmsted County Study and the Health Professionals
Follow-up study, the risk of retention was 6.8/1000 and of surgery was 4.5/1000
respectively [20, 21]. While the natural history of BPH is well established, the
challenge is to identify those patients that are likely to deteriorate. In this aspect,
IPP grading is a very useful clinical tool. Patients with grade 3 IPP are 7 times
more likely to progress than those with grade 1 IPP [22]. IPP also correlates well
with other parameters of obstruction in BPH, namely peak urinary flow rate, and
prostatic volume [23]. Therefore IPP is a good predictor of disease progression
in BPH.
7.4 Clinical Physiology
As the prostate is situated around the bladder neck, PA affect the functions of the
bladder first and then the kidneys.
The two basic functions of the bladder are storage and voiding.
The storage function can be suspected clinically to be affected if patients
developed frequency and urgency with small voided volumes. This can be
detected and measured with IPSS, and the voiding dairy, looking at frequency
and maximum voided volume (MVV). Storage function can be considered
significantly affected if MVV is less than 100ml and deterioration of IPSS by 4 or
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more points [24].
The voiding function can be assessed by simple TAUS measurement of the
post-void residue urine (PVR). PVR can vary depending on the fluid consumed
and the timing of the measurement. However, it can easily be re-measured by
asking the patient to pass urine again at the same visit. If necessary, the patient
can be asked to return for a subsequent test without the need to drink before the
test. Only persistently high PVR would be considered significant.
Obstruction can range from mild to severe. The degree of obstruction can be
easily measured by uroflowmetry. Maximum flow rate (Qmax) less than 10mL/s
has a 90% correlation with pressure-flow study (PFS) proven obstruction [25].
Poor flow rate can also be due to detrusor dysfunction secondary to a
neurogenic cause, diabetes or aging. This can be differentiated by measuring
the IPP. Only patients with low grade and poor flow would need to be further
investigated with PFS or flexible cystoscopy. For grade 3 IPP, even though the
uroflow may be good, more than 12mL/s, 65% were found to be still obstructed
on PFS [26].
When would obstruction be considered severe or significant for the clinician to
take more active measures? Obstruction would be significant if the functions of
the bladder are affected. Thus, when there is persistently high PVR, or poor MVV,
then obstruction can be considered clinically significant.
Normal PVR is less than 10mL, what would the cut off for PVR to be considered
clinically significant?
7.5 PVR and UTI:
A study in 2009 found that among 225 asymptomatic patients, thirty-one percent
had a positive urine culture, and they have higher mean PVR of 113mL,
compared to 41mL in those without infection (p<0.001) [27].
Another study in 2008 found that among 196 patients without UTI symptoms,
27% had positive urine culture, and their mean PVR was 257mL compared with
133mL in patients with negative cultures. The positive predictive value for
bacterial growth at PVR of 180mL or more, was 87% and the negative predictive
value was 94.7% [28]
7.6 PVR and AUR:
In a community based study of 477 men, it was found that patients with PVR of
more than 50mL were 2.5times more common in patient with prostate volume
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more than 30mL than those less than 30mL, and also 3 times more likely to have
acute urinary retention within 2 to 3 years [29].
In a study of 953 patients from pooled analysis of 11 alfusozin trials, it found that
PVR >100mL is statistically related to uroflow, at 60%, 47% and 39% with flow
rate of 8mL/s, 8 to 11mL/s and >11mL/s. In the follow up of 1 to 6 months, 7
patients developed acute urinary retention, and 6 out of these 7 patients had
PVR of more than 100mL at initial evaluation [30].
There is increasing evidence that dynamic variables such as PVR is important in
predicting complication of BPH in community studies and MTOPS. Patients who
had AUR had PVR above 100mL in all treatment groups, while those with no
AUR their PVR were below 100mL [31].
From the above studies, there is evidence that PVR is an important parameter to
assess in patients with BPH, and complications can result from PVR varying
from 50 to 180mL. A good cut off of PVR 100mL or more would be appropriate
and balanced in our assessment of BPH for further management.
PVR, which is a consequence of infravesical obstruction, is an important
predictor of complication of prostatic obstruction. Unlike IPP which is the cause
of bladder outlet obstruction, PVR is the consequence of obstruction, and
therefore it is inappropriate to use it to predict obstruction. However, it can be
used to predict complications from obstruction, like UTI, acute or chronic
retention of urine.
7.7 PVR and Chronic Retention of Urine:
A more serious complication is chronic retention of urine (CRU). CRU can be
defined as a distended painless palpable bladder associated with residual urine
>500mL and is often associated with bilateral hydronephrosis. Patients often
present with adult onset enuresis and chronic renal failure [32]. Typically,
patients do not have lower urinary tract symptoms, and therefore this group of
patients would be missed if only IPSS or QOL index are used during
management of BPH. A study in 2001 found that among 3277 patients
presenting with LUTS, only 0.02% had chronic retention [33]. This may not
reflect the true incidence as chronic retention usually do not present with
LUTS. As another study from Sri Lanka in Asia in 2004 found 30 patients with
chronic retention, within a period of 12 months, presenting with nocturnal
enuresis with or without hydronephrosis [34].
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7.8 Assessing Symptoms:
Thus, there are strong evidences that many BPH patients can have significant
obstruction with minimum urinary symptoms, and yet, suffer from serious
complications such as high pressure chronic retention, bilateral hydronephrosis
and renal impairment.
The International Prostate symptoms Score (IPSS) and the quality of life score
(QOL) has only weak correlation with the degree of obstruction and therefore
should not be used alone in the management of BPH.
7.9 Symptoms and Obstruction
Siris et al 1996 in a study of 75 men with “prostatism” and correlating with Qmax,
PVR and PFS found 33 men with severe symptoms and 42 men with mild or
moderate symptoms, 40 men had obstruction and 35 had equivocal or no
obstruction. The sensitivity and specificity of AUA symptoms index (precursor of
IPSS) for PFS definition of obstruction was 42.5% and 54.3%, the conclusion
was that symptoms score should not be used to gauge the degree of obstruction
[35].
Bosch JL et al 1995, in a study of community based subjects found 12% with
zero IPSS but 82% claimed to have “no voiding complain”. There was weak
co-relation between IPSS with PV (r=0.19), Qmax (r=-0, 18) and PVR
(r=0.25).The study concluded that the parameters in BPH should be considered
independently and that IPSS should not be used as a pre-selection criterion in
the determination of the prevalence of clinical BPH [36].
Wadie BS et al 2001 studied 460 men, and correlated the IPSS with PV, Qmax,
PVR and PFS and found no correlation with the total, obstructive or irritative
symptoms. They concluded that symptoms scores are qualitative and to use
them to quantify the degree of obstruction or evaluate therapy was questionable
[37].
Rosier PFWM et al 1996, in a study of 707 with LUTS, also found no co-relation
of IPSS with obstruction, patients with mild symptoms (0–7), 51% were still
obstructed, while those with severe symptoms 37% were not obstructed [38].
Chia SJ et al (2003) in a study of 200 patients with LUTS found that severe IPSS
(21–35), 57% were obstructed, while those with IPP more than 10mm (Grade3),
94% of patients were obstructed [17]. Lim LS et al (2010) also showed that there
is no correlation between severity of IPSS and IPP [22].
Using IPSS and QOL solely to decide on further management is too simplistic
- 78 -
and this would lead to overtreatment and under treatment in some patients. BPH
as a clinical entity (clinical BPH) is a composite of the gland causing obstruction
and symptoms (Hald Diagram) [39]. Therefore all three components should be
included in the total holistic assessment of the patient with clinical BPH.
The global QOL is more important than the total IPSS. This is because if the
patient is not bothered by his symptoms, there may not be a need to treat him,
unless he has significant obstruction by the prostate gland.
Deterioration of IPSS by 4 or more points may be important in the follow up of
patients as it may suggest the development of detrusor instability or over active
bladder (OAB) as a result of progression of BPO.
7.10 Application of Pathophysiology to clinical Practice in Real Life
Therefore for further management of BPH, significant obstruction as defined
above with persistent PVR of >100mL, should be ruled out first before
considering symptoms. Basic principle is that treatment should be according to
the severity of the disease. The cause of the obstruction and symptoms is the
prostate adenoma (PA). However, it is not necessary to treat all patients just
because the adenoma is there. IPP is useful in diagnosing the adenoma and the
degree of IPP predicts obstruction and progression of the disease. Though IPP
predicts that 49% of patients with grade 3 IPP will deteriorate, 51% still do not
deteriorate with a mean follow up of 30 months [22]. Treating patients just
because he has a grade 3 IPP would lead to over treatment of this cohort of
patient. Therefore, treatment should take into account whether the PA has
resulted in significant obstruction and bothersome symptoms, that is according
to the severity of the disease.
7.11 Staging of BPH
The severity of the disease BPH can be classified according to the stage,
combining the presence or absence of significant obstruction or bothersome
symptoms [40]. As discussed above, persistent PVR >100mL can be used as a
cut off to define significant obstruction, which should prompt the clinician to take
more active action in the management of BPH. In real life practice, PVR varies
according to the amount of pre-micturition volume and the timing of performing
the measurement; therefore it is emphasized that the PVR must be persistent.
Thus if patient has PVR >100mL, he is asked to void again and measurement
retaken. Also the PVR is interpreted together with the Qmax which is generally
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below 10mL/s and high grade IPP. Thus clinical BPH can be classified as;
Stage I: patients with No Significant Obstruction and No Bothersome symptoms
Stage II: patients with No Significant Obstruction but has Bothersome symptoms
(Defined as QOL 3)
Stage III: patients with Significant Obstruction defined as persistent PVR>100mL
or MVV (maximum voided volume) less than 100mL, irrespective of symptoms.
Patients may have more irritative symptoms because of inability to store, or no
bothersome symptoms in spite of large residue urine which would lead to chronic
retention of Urine and UTI.
Stage IV: patients with acute retention of urine, chronic retention, bladder stones,
recurrent UTI and hematuria.
As in malignant disease, further management of clinical BPH would be
according to the grade and stage of the disease.
Stage I ,Grade 1 can generally be watch, Stage III, grade3 would need more
aggressive treatment with pharmacotherapy such as combined α blocker with
5α-reductase inhibitors, or option for surgery, depending on the patients general
well-being, age and preferences. Stage IV high grade prostate would need
surgery. Generally there is good concordance between the grade and stage, but
if there is discordance with high stage low grade prostate as seen in about 16%
(7/44) of our patients then further more invasive investigations with urodynamic
studies and or flexible cystoscopy are indicated.
With this classification, of 406 patients 59% of patients can be watched, 32%
treated with pharmacotherapy and 9% had surgery at initial evaluation [41]. In an
Asian study by MK Li, of 892 patients, 17% were watch, 72.8% had
pharmacotherapy and 10.2% had surgery [42].
Conclusion
With better understanding of the pathophysiology of clinical BPH, patients can
be diagnosed clinically with non-invasive ultrasound and classified according to
grade and stage. The grade predicts the obstruction and progression, while the
stage guide the treatment. This staging system for BPH disease severity is
proposed in the initial UAA Guideline, but is not widely accepted, nor
recommended in the Guidelines of EAU, or AUA, or JUA, yet.
The final choice would take into account patients age, co-morbidity and his
preferences. Treating the patients as a whole would lead to a more balanced
and cost effective management and this is especially so in our Asian region.
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13. Roberts AB, Sporn MB. Physiological actions and clinical applications of
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transforming growth factor beta 1 and other growth factors on basic
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15. Sporn MB, Roberts AB. Interactions of retinoids and transforming growth
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16. Foo KT. Decision making in the management of benign prostatic
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17. Chia SJ, Heng CT, Chan S, Foo KT. Correlation of intravesical prostatic
protrusion with bladder outlet obstruction. BJU Int. 2003; 91: 371–4.
18. Nose H, Foo KT, Lim KB, Yokoyama T, Ozawa H, Kumon H. Accuracy of two
noninvasive methods of diagnosing bladder outlet obstruction using
ultrasonography: intravesical prostatic protrusion and velocity-flow video
urodynamics. Urology 2005; 65: 493–7.
19. Crawford ED, Wilson SS, McConnell JD et al. Baseline factors as predictors
of clinical progression of benign prostatic hyperplasia in men treated with
placebo. J. Urol. 2006; 174: 1422–6.
20. Jacobsen SJ, Jacobsen DJ, Girman CJ et al. Natural history of prostatism:
risk factors for acute urinary retention. J. Urol. 1997; 158: 481–7.
21. Meigs JB, Barry MJ, Giovannucci E, Rimm EB, Stampfer MJ, Kawachi I.
Incidence rates and risk factors for acute urinary retention: the health
professionals followup study. J. Urol. 1999; 162: 376–82.
22. Lee LS, Sim HG, Lim KB, Wang D, Foo KT. Intravesical prostatic protrusion
predicts clinical progression of benign prostatic enlargement in patients on
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8. Complications of BPH
Masayuki Takeda, M.D., Ph.D., Hideki Kobayashi, M.D., Ph.D.,
Masaki Yoshida, M.D., Ph.D., Koji Yoshimura, M.D., Ph.D., and
Momokazu Gotoh, M.D., Ph.D.
Many of the complications of progressive BPH are rare, and much of the
knowledge comes from studies of men presenting with such complications for
treatment (i.e., cases) rather than observing cohorts of men for the development
of complications. Severe symptoms, urinary retention, gross hematuria,
recurrent urinary tract infections, bladder calculi, and hydronephrosis or renal
insufficiency warrant transurethral incision, resection, vaporization, or open
prostatectomy (for very large neoplasms).
8.1 Mortality
Levi et al. have considered trends in mortality from BPH over the last decades in
Europe and, for comparative purposes, the USA and Japan. Between the early
1950s and the late 1990s, overall mortality from BPH in the European Union
(EU) fell from 5.9 to 3.5 per million, and the decline since the late 1950s was
over 96%. Comparable falls were observed in the USA and Japan, and BPH
mortality rates in the late 1990s were lower than in the EU (1.8/106 in the USA,
1.4 in Japan) [1, 2]. In the 1950s, death rates from BPH in the few Asian
countries that provided data were low on a worldwide scale (3-6/100 000 in
Hong Kong, 1-2 in Japan, and 1-7 in Singapore). Substantial reductions were
observed nonetheless over the last few decades, and rates in the late 1980s or
early 1990s were around 0-2/100 000 in these countries (three of the lowest
rates in the world). The reductions were observed in various age groups, but
were larger at younger ages [2, 3]. If the mortality rates from 1950 were applied
to 1990, 13,681 fewer deaths occurred in the United States alone than expected,
a major but unheralded health care achievement. The most probable
interpretation of these trends is that therapeutic improvements–including more
widespread and timely surgery, introduction of less invasive techniques, such as
transurethral prostatectomy, and possibly the development of medical
treatments–have had a favorable and substantial impact on BPH mortality.
There are, however, areas of the world, including several countries of Western
Europe and South America, where rates are still very high [4].
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8.2 Acute Urinary Retention
Acute urinary retention (AUR) is, for several reasons, one of the most significant
complications or long-term outcomes resulting from BPH.
The epidemiology of AUR is better understood in recent years and it has even
been demonstrated from randomized trials that, probably, a portion of AURs can
be prevented [5]. An AUR can occur spontaneously (that is without any external
triggering event) or can be provoked by triggers like general or regional
anesthesia, non-prostate-related surgery, transurethral instrumentation, certain
medications that have an effect on lower urinary tract function, excessive fluid
(particularly alcohol) intake and sexual activity. In older studies of the occurrence
of AUR the range of the incidence rates has varied widely between 4 and 130
per 1000 person-years [6]. In more recent studies, rates range from about 2 to
18 per 1000 person-years. It has in the past represented an immediate indication
for surgery. For this reason alone, AUR is both from an economic viewpoint as
well as from the viewpoint of the patient, an important and feared event, but, the
etiology of AUR is poorly understood. From a clinical and prognostic point of
view, spontaneous AUR should be separated from precipitated AUR, latter of
which refers to the inability to urinate after a triggering event such as non–
prostate-related surgery, catheterization, anesthesia, ingestion of medications
with sympathomimetic or anticholinergic effects or antihistamines, or others. All
other AUR episodes are classified as spontaneous [7]. The importance of
differentiating the two types of AUR becomes clear when evaluating the ultimate
outcomes of patients. After spontaneous AUR, 15% of patients had another
episode of spontaneous AUR and a total of 75% underwent surgery, whereas
after precipitated AUR only 9% had an episode of spontaneous AUR, and 26%
underwent surgery [7]. Since 49% of AUR cases amongst the LUTS/BPH
patients presented with AUR as the first symptom, i.e. without previous contacts
with a health care provider, it is clear that earlier patient identification is needed if
we aim to reduce the incidence of AUR by means of pharmacological treatment
[8]. Presently this type of risk assessment is only possible in men who have seen
a health care provider for an assessment.
8.3 Bladder Stones
The mechanism for bladder stone formation with BPH may the congestion of
urine (post-void residual urine). In a large autopsy study the prevalence of
bladder stones was 8 times higher in men with a histologic diagnosis of BPH
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(3.4%) compared with controls (0.4%) but no increased incidence of ureteral or
kidney stones were found [9]. Recurrence rate of stones after removal without
BPH surgery has been reported as 17.4% [10].
In a study comparing watchful waiting and TURP in men with moderate
symptoms, only 1 of 276 patients assigned to watchful waiting developed a
bladder stone in 3 years of follow-up [11]. The self-reported rate of a bladder
stone in a cross-sectional study in 2002 Spanish men was 0.7% [12] In clinical
practice the risk of bladder stone development is small and screening only
indicated if clinical circumstances warrant it (e.g., hematuria, stuttering of
urination).
8.4 Recurrent Urinary Tract Infections
The mechanisms of recurrent UTI in BPH are believed to be increased post-void
urine volume, and in case of urinary retention, urethral catheterization, however,
clear evidence is lacking. As the previous statement, surgical treatment is
generally reserved for those patients [13]. In older surgical series UTIs constitute
the main indication for surgical intervention in about 12% [14, 15]. The incidence
of UTIs in the placebo-treated patients was only 0.1/100 patient-years in the
MTOPs study [16].
8.5 Decompensated bladder
Irreversible loss of bladder (voiding) function sometimes occur in BPH patients.
However, when the process starts, whether it really is related to BPH and
obstruction, and when an intervention is necessary to prevent decompensating
with resultant inability to void is unclear. Decompensated bladder, or impaired
detrusor contractility may also occur as normal consequence of aging [17].
The critical question is whether delayed intervention might lead to progressive
irreversible loss of bladder function and misses a window for cure. There is no
direct evidence for this from longitudinal population or clinic patient studies.
However, one report with randomized comparison between initial TURP and
delayed TURP with initial conservative treatment showed that the conservative
arm to TURP later in the trial had not as significant an improvement in symptoms
and flow rate compared with those who underwent TURP at the beginning after
randomization [18].
8.6 Upper Urinary Tract Deterioration and Azotemia
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In general, the incidence of end stage renal failure in patients with BPH is rare
(lower than 1%), however, several guidelines recommend measurement of
serum creatinine as an initial evaluation [19]. BPH patients with renal impairment
often are complicated with DM or hypertension [20]. The Agency for Health Care
Policy and Research BPH guidelines reported a mean of 13.6% (range 0.3% to
30%) of patients presenting for TURP with evidence of renal failure based on
predominantly older studies. In the large database of patients who had upper
tract imaging before surgery, 7.6% of 6102 patients in 25 series had evidence of
hydronephrosis, of whom one third had renal insufficiency [21].
8.7 Hematuria
In BPH patients who have been indicated to surgery, 12 % showed macroscopic
hematuria [22]. It has always been recognized that patients with BPH might
develop gross hematuria and form clots with no other cause being identifiable.
One of the reasons may be upregulation of vascular endothelial growth factor
(VEGF) and increase in the density of microvessel density [23–25].
Precise population estimates and incidence rates are not available, and the
clinical management is dictated by the circumstances.
References
1. Washecka R, Rumancik, WM. Prostatic abscess evaluated by serial
computed tomography. Urol. Radiol. 1985; 7: 54–6.
2. Boyle P, Maisonneuve P, Steg A. Decrease in mortality from benign prostatic
hyperplasia: a major unheralded health triumph. J. Urol.1996; 155: 176–80.
3. Levi F, Lucchini F, Negri E, Boyle P, La Vecchia C. Recent trends in mortality
from benign prostatic hyperplasia. Prostate 2003; 56: 207–11.
4. La Vecchia C, Levi F, Lucchini F. Mortality from benign prostatic hyperplasia:
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5. Blanker MH, Groeneveld FP, Prins A, Bernsen RM, Bohnen AM, Bosch JL.
Strong effects of definition and nonresponse bias on prevalence rates of
clinical benign prostatic hyperplasia: the Krimpen study of male urogenital
tract problems and general health status. BJU Int. 2000; 85: 665–71.
6. Jacobsen S, Jacobson D, Girman C et al. Natural history of prostatism: risk
factors for acute urinary retention. J. Urol. 1997; 158: 481–7.
7. Roehrborn CG, Bruskewitz R, Nickel GC et al. Urinary retention in patients
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with BPH treated with finasteride or placebo over 4 years: characterization of
patients and ultimate outcomes. The PLESS Study Group. Eur. Urol. 2000;
37: 528–36.
8. Verhamme KM, Bosch RJ, Sturkenboom MC. Finasteride in benign prostatic
hyperplasia. N. Engl. J. Med. 2004; 350: 1359-1361; author reply 1359–61.
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469–74.
10. O’Connor RC, Laven BA, Bales GT, Gerber GS. Nonsurgical management of
benign prostatic hyperplasia in men with bladder calculi. Urology 2002; 60:
288–91.
11. Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM Henderson WG.
A comparison of transurethral surgery with watchful waiting for moderate
symptoms of benign prostatic hyperplasia. N. Engl. J. Med. 1995; 332: 75–9.
12. Hunter DJ, Berra-Unamuno A, Martin-Gordo A. Prevalence of urinary
symptoms and other urological conditions in Spanish men 50 years old or
older. J. Urol. 1996; 155: 1965–70.
13. Gerber GS. Benign prostatic hyperplasia in older men. Clin. Geriatr. Med.
1998; 14: 317–31.
14. Holtgrewe HL, Mebust WK, Dowd JB, Cockett AT, Peters PC, Proctor C.
Transurethral prostatectomy: practice aspects of the dominant operation in
American urology. J. Urol. 1989; 141: 248–53.
15. Mebust WK, Holtgrewe HL, Cockett AT, Peters PC. Transurethral
prostatectomy: immediate and postoperative complications: a cooperative
study of 13 participating institutions evaluating 3,885 patients. J. Urol. 1989;
141: 243–7.
16. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effects of
doxazosin, finasteride and the combination on the clinical progression of
benign prostatic hyperplasia. N. Engl. J. Med. 2003; 349: 2385–96.
17. Lepor H, Sunaryadi I, H, Sunaryadi I, Hartanto V, Shapiro E. Quantitative
morphometry of the adult human bladder. J. Urol. 1992; 148: 414–7.
18. Flanigan RC, Reda DJ, Wasson JH, Anderson RJ, Abdellatif M, Bruskewitz
RC. 5-Year outcome of surgical resection and watchful waiting for men with
moderately symptomatic benign prostatic hyperplasia: a Department of
Veterans Affairs cooperative study. J. Urol. 1998; 160: 12–6. discussion 16–
7.
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19. Homma Y, Gotoh M, Yokoyama O et al. Outline of JUA clinical guidelines for
benign prostatic hyperplasia. Int. J. Urol. 2011; 18: 741–56.
20. Gerber GS, Goldfischer ER, Karrison TG, Bales GT. Serum creatinine
measurements in men with lower urinary tract symptoms secondary to
benign prostatic hyperplasia. Urology 1997; 49: 697–702.
21. McConnell JD, Barry MJ, Bruskewitz RC. Benign prostatic hyperplasia:
diagnosis and treatment. Clinical practice guideline no. 8. Rockville, MD, U.S.
Department of Health and Human Services, Agency for Health Care Policy
and Research, Public Health Service, 1994. p. 1–17.
22. Mebust WK, Holtgrewe HL, Cockett AT, Peters PC. Transurethral
prostatectomy: immediate and postoperative complications. A 41.
cooperative study of 13 participating institutions evaluating 3885 patients. J.
Urol. 1989; 141: 243–7.
23. Foley SJ, Bailey DM. Microvessel disease in prostatic hyperplasia. BJU Int.
2000; 85: 70–3.
24. Pareek G, Shevchuk M, Armenakas NA et al. The effect of finasteride on the
expression of vascular endothelial growth factor and microvessel density: a
possible mechanism for decreased prostatic bleeding in treated patients. J.
Urol. 2003; 169: 20–3.
25. DiPaola RS, Kumar P, Hait WN, Weiss RE. State-of-the-art prostate cancer
treatment and research. a report from the Cancer Institute of New Jersey. N.
Engl. J. Med. 2001; 98: 23–33.
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9. Diagnosis & Investigation for BPH/Male LUTS
Rohan Malek, M.D., and Selvalingam Sothilingam, M.D.
Diagnosis of LUTS due to BPH should be considered in males above the age of
45 years presenting with lower urinary symptoms especially in the presence of
demonstrable enlargement of the prostate (BPE). Patients with lower urinary
tract symptoms suggestive of BPH seek medical advice because they are
bothered by their urinary symptoms [1, 2]. Patients may also present with
bladder outlet obstruction (BOO) at the first presentation. In Asia where
symptomatic patients may present late in the course of their disease, many of
them may present with complications from BPH such as hematuria, urinary tract
infection, urinary stones, renal failure and acute or chronic urinary retention.
Difficulties in translation of BPH guidelines into clinical practice are related to
lack of knowledge, differences in routine practices, beliefs, cost, availability and
reimbursement policies [3, 4]. Therefore the diagnosis and investigation of BPH
in Asia should take into account the wide variability of the socio economic
situation and the differing medical practices in Asian countries. It is
understandable that not all patients with LUTS would have access to urologists
or to centers with urological facilities, therefore these guidelines have been
formulated taking into account the minimum investigations that should be done
even at the level of the primary healthcare provider or general practitioner. There
are significant differences in the practice patterns between primary care
physicians and urologist in the evaluation of BPH [5].
9.1 Conditions not suitable for general physicians
It is recommended that patients seen by primary care physicians should be
referred to the urologist in the presence of the following: (Level IV evidence,
Grade C recommendation) [3, 6].
9.1.1 Urinary Retention
9.1.2 Palpable bladder
9.1.3 Urinary Incontinence
9.1.4 Hematuria
9.1.5 Proven urinary tract infection
9.1.6 Persistent bothersomeness
9.1.7 Bladder Stones
9.1.8 Hard Prostate
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9.1.9 PSA> 4 ng/mL(> 2 ng/mL , pts on 5ARI [7])
We propose that for Asia, investigations should be categorized as
9.2 Highly recommended (All Medical Practitioners)
9.3 Recommended in special settings (Urologist, Urological Centers)
9.4 Optional
All tests included in the highly recommended category are also recommended
by AUA, EUA, BAUS, 5th International Consultation on BPH, Australian NHMRC
and JUA [8–13].
9.2 Highly Recommended Tests
9.2.1 Medical history should be thorough taking into account duration,
severity of lower urinary tract symptoms and mandatory to include history of
incontinence and hematuria [14]. History should also take into consideration
patients’ general condition including neurologic and, psychiatric disorders,
diabetes mellitus and cardiac diseases. History of bowel habit is relevant and so
is patient’s mobility and social support. Important drug history should include use
of diuretics, antiplatelet /anticoagulants and antihypertensives. Previous urinary
tract intervention or urethral trauma should also be questioned. Family history is
equally important especially of prostate disease or prostate cancer. Patients
should also be questioned on erectile dysfunction.
9.2.2 Physical Examination includes general examination including
assessment of blood pressure and must include digital rectal examination [15],
neurological examination especially of the lower extremities and anal sphincter
tone. The digital rectal examination should comment on estimated prostate
volume, prostate surface and consistency. Lower abdominal examination to look
for palpable bladder should also be performed. Examination of genitalia is
equally important.
9.2.3 Symptoms Scores would be useful and the International Prostate
Symptom Score (IPSS) is most commonly used [14]. However it should be
validated according to the spoken and written language(s) of the respective
Asian countries. Using the IPSS symptom score, patients can be categorized as
having predominant voiding, storage or post micturition symptoms [16]. This can
guide in choosing therapeutic options and in follow up of patients after treatment.
QOL symptom score is useful to assess the bothersomeness of the LUTS. In
patients with significant storage symptoms, additional symptoms scores such as
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the OAB symptom score (OABSS) may be useful [12].
9.2.4 Urinalysis is recommended [17] to detect microscopic hematuria and
pyuria to exclude other urological conditions that can cause LUTS such as
urinary infection, urological malignancies and urinary stones [18].
9.2.5 Serum Creatinine, although not recommended in AUA, is
recommended here as initial assessment. In the context of the high incidence of
diabetes mellitus and stone disease in Asia, the rate of silent renal insufficiency
is expected to be high. This is more so in countries where access to medical
facilities is not readily available.
9.2.6 PSA is recommended in patients with more than 10 years life
expectancy or in patients in whom PSA will make a difference in management of
the prostate disease [4, 13]. Patients should be counseled adequately prior to
performing the PSA test. A baseline PSA would be useful in predicting patient’s
10 or 15 year risk of prostate cancer based on evidence from current literature.
There is evidently a relationship between PSA and prostate volume [19, 20].
Therefore PSA can also be used as a guide on identifying patients at risk for
BPH progression [21, 15].
9.2.7 Bladder diary is recommended in patients with predominantly storage
symptoms and in patients where nocturia appears to be most bothersome [22,
23], to exclude nocturnal polyuria.
9.3 Recommended in Special Settings
9.3.1 Uroflowmetry, where facilities are available can be done to assess
Qmax where a Qmax <10 mL/s may indicate a stronger need for surgical
intervention [24]. At least two readings would be preferable and the voided
volume should be more than 150 mL [25]. Furthermore a flat pattern on
uroflowmetry may alert the physician on the possibility of urethral stricture
disease.
9.3.2 Post Void Residual (PVR) urine is recommended after having done a
uroflowmetry. Although there is intra individual variations in the values and
problems in reproducibility, a high PVR may indicate bladder dysfunction and
poorer response to medical therapy [26] although there is no consensus on the
cutoff point [27].
9.3.3 Prostate Ultrasound either transabdominal or transrectal, is
recommended where facilities are available, in symptomatic patients to assess
prostate size and presence of Intravesical Prostatic Protrusion (IPP) to help
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decide on the most appropriate management for the patient [28, 29]. Patients
with IPP Grade 3 would be suitable candidates for surgical intervention [29].
It may also be useful to assess very large prostates when considering open
prostatectomy.
9.4 Optional
9.4.1 Upper Tract Imaging is recommended when there is microscopic or
macroscopic hematuria, renal insufficiency, in patients with chronic retention or
in patients with stone disease [18]. KUB X ray may routinely be done in countries
where stone disease is endemic.
9.4.2 Urodynamics can be performed for specific indication, i.e. in the very
young (< 50yrs) or old (> 80 yrs.) patients with LUTS [18], symptomatic patients
with Qmax >15 mL/s, patients with large PVR with no significant IPP, patients
suspected of having neurogenic bladder or after radical pelvic surgery and in
patients who have had surgery for BPH but are still symptomatic.
9.4.3 Transrectal Ultrasound biopsy of prostate is recommended for
indicated patients with PSA> 4ng/ml and or in those with suspicious DRE
findings where prostate cancer is suspected.
9.4.4. Cystoscopy is recommended in patients with hematuria, suspected
urethral stricture, before surgery, in patients who had prior lower tract surgery or
in BPH patients not responding to medical treatment [18].
Urine cytology is recommended in patients with hematuria or in BPH patients
not responding to medical treatment.
9.4.5 Retrograde Cystourethrography may be done in patients with history
and uroflow assessment suggestive of urethral stricture to provide further
information on length and site of urethral stricture.
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13. Madersbacher S, Alivizatos G, Nordling J, Sanz CR, Emberton M, De la
Rosette JJ. EAU 2004 guidelines on assessment, therapy and follow-up of
men with lower urinary tract symptoms suggestive of benign prostatic
obstruction (BPH Guidelines). Eur. Urol. 2004; 46: 547–54.
14. Bhargava S, Canda AE, Chapple CR. A rational approach to benign
prostatic hyperplasia evaluation: recent advances. Curr. Opin. Urol. 2004;
14: 1–6.
15. Kijvikai K. Digital rectal examination, serum prostatic specific antigen or
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transrectal ultrasonography: the best tool to guide the treatment of men
with benign prostatic hyperplasia. Curr. Opin. Urol. 2009; 19: 44–8.
16. Naughton MJ, Donovan J, Badi X et al. Symptom severity and QOL scales
for urinary incontinence. Gastroenterology 2004; 126: S114–S123.
17. Maruschke M, Protzel C, Hakenberg OW. How to make the diagnosis of
benign prostatic disease. Eur. Urol. 2009; Suppl 8: 490–5.
18. Abrams P, Chapple C, Khoury S, Roehrborn C, De la Rosette J.
International Scientific Committee. Evaluation and treatment of lower
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Lagunaa P, Alivizatosb G. Prostate specific antigen and benign prostatic
hyperplasia. Curr. Opin. Urol. 2000; 10: 3–8.
Chang YL, Lin ATL, Chen KK et al. Correlation between serum prostate
specific antigen and prostate volume in Taiwanese men with biopsy proven
benign prostatic hyperplasia. J. Urol. 2006; 175: 196–9.
Rosette JDL. Optimising assessment and treatment decisions for men with
BPH. Eur. Urol. 2006; Suppl 5: 710–5.
Van Venrooij GE, Van Melick HH, Eckhardt MD, Boon TA. Diagnostic and
predictive value of voiding diary data versus prostate volume, maximal free
urinary flow rate, and Abrams-Griffiths number in men with lower urinary
tract symptoms suggestive of benign prostatic hyperplasia. Urology 2008;
71: 469–74.
23. Batista JE, Berges R, Kastler EC et al. Future directions in evaluating
nocturia and its impact in patients with LUTS/BPH. Eur. Urol. 2006; Suppl
5: 19–21.
24. Belal M, Abrams P. Noninvasive methods of diagnosing bladder outlet
obstruction in men. part 2: noninvasive urodynamics. J. Urol. 2006; 176:
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10. Recommended grade for treatment: Pharmacotherapy and
Conservative Management
Kyu-Sung Lee, M.D., Joon Chul Kim, M.D.
10.1 Pharmacotherapy
The recommendations of this guideline are based on a structured literature
search using articles in English language published in the PubMed/Medline
databases, published between 1966 through Dec 31st, 2011. Databases
between 1966 and 1st January 2010, is based on EAU database
(http://www.uroweb.org/gls/pdf/12_Male_LUTS_LR%20May%209th%202012.
pdf).
Drugs used for the treatment of various forms of male LUTS are listed in Table 1.
The level of evidence and the grade of recommendation (according to the
current classification) for the each drug treatment are summarized in Table 2.
Table 1. Key pharmacokinetic properties and standard doses of drugs in Asia
for the treatment of male LUTS.
α1 adrenoceptor antagonists (for treating symptoms of BPH)
Drug
tmax
t½
Recommended daily dose
(hours)
(hours)
Alfuzosin IR
1.5
4–6
3 x 2.5 mg
Alfuzosin SR
3
8
2 x 5 mg
Alfuzosin XL
9
11
1 x 10 mg
Doxazosin IR
2–3
20
1 x 2–8 mg
Doxazosin GITS
8–12
20
1 x 4–8 mg
Naftopidil
2.2
13.2
1 x 25–75 mg
Silodosin
2.5
11–18
2 x 4mg, 1 x 8 mg
Tamsulosin MR
6
10–13
1 x 0.2–0.4 mg
Tamsulosin OCAS
4–6
14–15
1 x 0.4 mg (1x0.2mg in Japan)
Terazosin
1–2
8–14
1x 2, 5, 10 mg
5α-reductase inhibitors (for treating benign prostatic enlargement due to BPH)
Dutasteride
1–3
3–5 weeks
1 x 0.5mg
Finasteride
2
6–8 hours
1 x 5 mg
Anticholinergic drugs (for treating overactive bladder/storage symptoms)
Drug
tmax
t½
(hours)
(hours)
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Recommended daily dose
Darifenacin ERa
7
12
1 x 7.5–15 mg
Fesoterodine
5
7
1 x 4–8 mg
Oxybutynin IR
1
2-5
2-3 x 5 mg
Oxybutynin ER
4–6
13
1 x 5–30 mg
Propiverine IR
2
14–22
1–2 x 10–20 mg
Propiverine ER
10
20
1 x 30 mg
Solifenacin
3–8
45–68
1 x 5–10 mg
1.5
2.9
2 x 0.1-0.2 mg
1–2
2
2 x 2 mg
Tolterodine ER
4
7–10
1 x 4 mg
Trospium IR
5
18
2 x 20 mg
Trospium ER
5
36
1 x 60 mg
a,b
Imidafenacin
a
Tolterodine IR
a
PDE5 inhibitors (for treating male LUTS ± erectile dysfunction)
Sildenafil
1*
3–5
1 x 25–100 mg
17.5
1 x 2.5–20 mg
4–5
2 x 10 mg
(0.5–2)
Tadalafil
2
(0.5–12)
Vardenafil
1*
(0.5–2)
Udenafil
0.8–1.3
7.3–12
1 x 100 mg
Mirodenafil
1.3
2.5
1 x 50 mg
Botulinum toxin(for treating symptoms of BPH)
BotoxTM
Dysport
TM
Not detected
Not detected
100–300 U
Not detected
Not detected
300–600 U
Antidiuretics (for treating nocturia due to nocturnal polyuria
Desmopressin
1–2
3
1 x 0.1 – 0.4 mg orally before
sleeping
Table 2. Level of Evidence (LE) and Grade of Recommendation (GR) of drug
treatments of male LUTS
Drug treatment
1.
α1 blockers should be offered to men with moderate-to-severe lower
LE
GR
1
A
1
A
urinary tract symptoms.
Long-term treatment with α1 blockers for BPH patients is effective bot
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h subjectively and objectively.
2.
5α-reductase inhibitors are appropriate and effective treatment
1
A
2
B
1
B
4
C
alternatives for men with LUTS secondary to BPH who have
demonstrable prostate enlargement. 5α-reductase inhibitors can
prevent disease progression with regard to acute urinary retention and
need for surgery. The treatment is not recommended for short-term
therapy (<1 year).
Long-term treatment with 5α-reductase inhibitors is effective and well
tolerated.
3
Anticholinergics might be considered in men with moderate to severe
lower urinary tract symptoms who have predominantly bladder
storage symptoms with or without α1 blockers.
Caution is advised in men with increased postvoid residual urine
volume.
4.
PDE5 inhibitors reduce moderate to severe male lower urinary tract
1
A
1
A
3
C2
1
A
1
B
symptoms.
5.
Desmopressin can be used for the treatment of nocturia secondary to
nocturnal polyuria. Caution is advised in old men with hyponatremia
and impaired renal function. Serum sodium concentration level should
be monitored periodically.
6
Plant extracts reduce moderate to severe male lower urinary tract
symptoms. Although plant extracts agents show some promise for
symptom relief, their use remains controversial due to the lack of
established mechanisms of action, efficacy, and safety. Clinical trials
are often flawed, as most studies of small scale and short duration
are; they are not blinded or controlled, and most have no placebo
group.
7
Combination treatment with α1 blocker together with 5α-reductase
inhibitor should be offered to men with moderate-to-severe lower
urinary tract symptoms, enlarged prostates (≥30 mL or ≥40 mL), and
reduced Qmax (men likely to develop disease progression).
Combination treatment is not recommended for short-term therapy
(<1 year).
8.
Combination treatment with α1 blocker and anticholinergic might be
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considered in patients with moderate to severe lower urinary tract
symptoms if symptom relief has been insufficient with the
monotherapy of either drug.
Combination treatment should cautiously be prescribed in men who
2
B
2
A
3
C
are suspicious of having bladder outlet obstruction with increased
postvoid residual urine volume.
9
The combination of α1 blocker and PDE 5 inhibitor is well tolerated
and effective in improving lower urinary tract symptoms. However
caution is advised in men with hypotention.
10.
Intra-prostatic botulinum toxin injections for lower urinary tract
symptoms due to benign prostatic obstruction or urinary retention are
still experimental. Intra-prostatic botulinum toxin injections should be
performed only in clinical trials.
10.1.1 α1 adrenergic receptor antagonists (α1 blocker）
Alpha1-blockers produce a significant symptom improvement compared to
placebo, which the average patient will appreciate as a moderate improvement
from baseline [1-4]. The minor differences in efficacy noted between
the different α1 blockers are not statistically (when tested) or clinically significant
[5]. Prostate size does not affect α1 blocker efficacy but patients with smaller
prostates (<40 mL) seem to have better efficacy compared to those with larger
glands [6]. α1 blockers do not reduce prostate size and do not prevent acute
urinary retention, so that eventually some patients will have to be surgically
treated [7]. Nevertheless, the efficacy of α1 blockers appears to be
maintained over at least4 years [8]. The most frequent side-effects of
α1 blockers are asthenia, dizziness and (orthostatic) hypotension [9].
Although a reduction in blood pressure may benefit hypertensive patients,
at least some of the observed asthenia and dizziness can be attributed to a
decrease in blood pressure [10,11].
A systematic review concluded that α1 blockers do not adversely affect libido,
have a small beneficial effect on erectile function, but sometimes cause
abnormal ejaculation [12].
Originally, the abnormal ejaculation was thought to be retrograde, but more
recent data demonstrate that it is due to emission failure [13-20].
Although abnormal ejaculation has been observed more frequently with
- 101 -
tamsulosin [21-25], the apparently greater risk for abnormal ejaculation with
tamsulosin is intriguing as even more α1A-selective drugs, silodosin, carry a
greater risk [26-28].
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Urodynamic effects of alpha-adrenoceptor blockers: a review of clinical trials.
Urology 2003; 62:1–9.
3. Barendrecht MM, Abrams P, Schumacher H, De la Rosette JJ, Michel MC.
Do α1-adrenoceptor antagonists improve lower urinary tract symptoms by
reducing bladder outlet resistance? Neurourol. Urodyn. 2008; 27: 226–30.
4. Djavan B, Chapple C, Milani S, Marberger M. State of the art on the efficacy
and tolerability of alpha1-adrenoceptor antagonists in patients with lower
urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology
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5. Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular-related
safety profile and efficacy of α-adrenergic blockers for symptoms related to
benign prostatic hyperplasia. Int. J. Clin. Pract. 2008; 62: 1547–59.
6. Michel MC, Mehlburger L, Bressel HU, Goepel M. Comparison of tamsulosin
efficacy in subgroups of patients with lower urinary tract symptoms. Prostate
Cancer Prostatic. Dis. 1998; 1: 332–5.
7. Roehrborn CG. Three months’ treatment with the α1-blocker alfuzosin does
not affect total or transition zone volume of the prostate. Prostate Cancer
Prostatic. Dis. 2006; 9: 121–5.
8. McConnell JD, Roehrborn CG, Bautista O et al. The long-term effect of
doxazosin, finasteride, and combination therapy on the clinical progression
of benign prostatic hyperplasia. N. Engl. J. Med. 2003; 349: 2387–98.
9. Barendrecht MM, Koopmans RP, De la Rosette JJ, Michel MC. Treatment for
lower urinary tract symptoms suggestive of benign prostatic hyperplasia: the
cardiovascular system. BJU Int. 2005; 95 (Suppl 4): 19–28.
10. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with
tamsulosin. J. Cataract Refract. Surg. 2005; 31: 664–73.
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11. Michel MC, Okutsu H, Noguchi Y et al. In vivo studies on the effects of
α1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits.
Naunyn-Schmiedeberg’s Arch. Pharmacol. 2006; 372: 346–53.
12. Van Dijk MM, De la Rosette JJ, Michel MC. Effects of α1-adrenoceptor
antagonists on male sexual function. Drugs 2006; 66: 287–301.
13. Brawer MK, Adams G, Epstein H. Terazosin in the treatment of benign
prostatic hyperplasia. Terazosin Benign Prostatic Hyperplasia Study Group.
Arch. Fam. Med. 1993; 2: 929–35.
14. Roehrborn CG, Oesterling JE, Auerbach S et al. The Hytrin Community
Assessment Trial study: a one-year study of terazosin versus placebo in the
treatment of men with symptomatic benign prostatic hyperplasia. HYCAT
Investigator Group. Urology 1996; 47: 159–68.
15. Wilt TJ, Howe RW, Rutks I et al. Terazosin for benign prostatic hyperplasia.
Cochrane Database Syst. Rev. 2002; (4):CD003851.
16. Jardin A, Bensadoun H, Delauche-Cavallier MC, Attali P. Alfuzosin for
treatment of benign prostatic hypertrophy. The BPH-ALF Group. Lancet
1991; 337: 1457–61.
17. Buzelin JM, Roth S, Geffriaud-Ricouard C, Delauche-Cavallier MC. Efficacy
and safety of sustained-release alfuzosin 5 mg in patients with benign
prostatic hyperplasia. ALGEBI Study Group. Eur. Urol. 1997; 31: 190–8.
18. Van Kerrebroeck P, Jardin A, Laval KU, Van Cangh P. Efficacy and safety of
a new prolonged release formulation of alfuzosin 10 mg once daily versus
alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic
benign prostatic hyperplasia. ALFORTI Study Group. Eur. Urol. 2000; 37:
306–13.
19. MacDonald R, Wilt TJ. Alfuzosin for treatment of lower urinary tract
symptoms compatible with benign prostatic hyperplasia: a systematic review
of efficacy and adverse effects. Urology 2005; 66: 780–8.
20. Kirby RS, Andersen M, Gratzke P, Dahlstrand C, Hoye K. A combined
analysis of double-blind trials of the efficacy and tolerability of
doxazosin-gastrointestinal therapeutic system, doxazosin standard and
placebo in patients with benign prostatic hyperplasia. BJU Int. 2001; 87:
192–200.
21. Chapple CR, Wyndaele JJ, Nordling J, Boeminghaus F, Ypma AF, Abrams P.
Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A
meta-analysis of two randomised, placebo-controlled, multicenter studies in
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patients with benign prostatic obstruction (symptomatic BPH). European
Tamsulosin Study Group. Eur. Urol. 1996; 29: 155–67.
22. Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in
benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 1998;
51: 892–900.
23. Chapple CR, Al-Shukri SH, Gattegno B et al. Tamsulosin oral controlled
absorption system (OCAS) in patients with lower urinary tract symptoms
suggestive of benign prostatic hyperplasia (LUTS/BPH): efficacy and
tolerability in a placebo and active comparator controlled phase 3a study.
Eur. Urol. 2005; Suppl 4 (issue 2): 33–44.
24. Wilt TJ, MacDonold R, Rutks I. Tamsulosin for benign prostatic hyperplasia.
Cochrane Database Syst. Rev. 2003; (1): CD002081.
25. Gotoh M, Kamihira O, Kinukawa T et al. Comparison of tamsulosin and
naftopidil for efficacy and safety in the treatment of benign prostatic
hyperplasia: a randomized controlled trial. BJU Int. 2005; 96: 581–6.
26. Kawabe K, Yoshida M, Homma Y, Silodosin Clinical Study Group. Silodosin,
a new α1A-adrenoceptor-selective antagonist for treating benign prostatic
hyperplasia: a results of a phase III randomized, placebo-controlled,
double-blind study in Japanese men. BJU Int. 2006; 98: 1019–24.
27. Marks LS, Gittelman MC, Hill LA, Volinn W, Hoel G. Rapid efficacy of the
highly selective alpha1A-adrenoceptor antagonist silodosin in men with
signs and symptoms of benign prostatic hyperplasia: pooled results of 2
phase 3 studies. J. Urol. 2009; 181: 2634–40.
28. Chapple CR, Montorsi F, Tammela TL et al. Silodosin therapy for lower
urinary tract symptoms in men with suspected benign prostatic hyperplasia:
results of an international, randomized, double-blind, placebo- and
active-controlled clinical trial performed in Europe. Eur. Urol. 2011; 59: 342–
52.
10.1.2 5α-reductase inhibitor (5ARI)
5α-reductase inhibitors (Finasteride inhibits type 1 only, Dutasteride inhibits both
type 1 and 2) reduce LUTS (IPSS; moderate to severe) by approximately 15–
30%, decrease prostate volume by approximately 18–28% and increase Qmax
of free uroflowmetry by approximately 1.5–2.0 mL/s in patients with LUTS due to
prostate enlargement [1-8]. 5ARIs, but not α1 blockers, reduce the long-term
- 104 -
(>1 year) risk of acute urinary retention or need for surgery [9-12].
The most relevant adverse effects of 5ARIs are related to sexual function and
include reduced libido, erectile dysfunction and, less frequently, ejaculation
disorders. The incidence of sexual dysfunction and other adverse events is low
and even decreased with trial duration [3].
5ARIs should not be used in men with LUTS secondary to BPH without prostatic
enlargement. Due to the slow onset of action, 5ARIs are only suitable for
long-term treatment (many years) [13-15].
Their effect on the serum PSA concentration needs to be considered for prostate
cancer screening.
Of interest, 5ARIs might reduce blood loss during transurethral prostate surgery,
probably due to their effects on prostatic vascularization [16].
Long-time use of 5ARIs can improve urodynamic parametes [17-18].
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Andriole G, Bruchovsky N, Chung LW et al. Dihydrotestosterone and the
prostate: the scientific rationale for 5α-reductase inhibitors in the treatment
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Rittmaster RS, Norman RW, Thomas LN, Rowden G. Evidence for atrophy
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Naslund MJ, Miner M. A review of the clinical efficacy and safety of
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Andersen JT, Ekman P, Wolf H et al. Can finasteride reverse the progress
of benign prostatic hyperplasia? A two-year placebo-controlled study. The
Scandinavian BPH Study Group. Urology 1995; 46: 631–7.
Nickel JC, Fradet Y, Boake RC et al. Efficacy and safety of finasteride
therapy for benign prostatic hyperplasia: results of a 2-year randomised
controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy
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Marberger MJ, on behalf of the PROWESS Study Group. Long-term effects
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Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G l. Efficacy and
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Roehrborn CG, Lukkarinen O, Mark S, Siami P, Ramsdell J, Zinner N.
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4-year studies. BJU Int. 2005; 96: 572–7.
McConnell JD, Bruskewitz R, Walsh P et al. The effect of finasteride on the
risk of acute urinary retention and the need for surgical treatment among
men with benign prostatic hyperplasia. N. Engl. J. Med.1998; 338: 557–63.
10. Roehrborn CG. BPH progression: concept and key learning from MTOPS,
ALTESS, COMBAT, and ALF-ONE. BJU Int. 2008; 101 (Suppl 3): 17–21.
11. McConnell JD, Roehrborn CG, Bautista O et al. Medical Therapy of
Prostatic Symptoms (MTOPS) Research Group. The long-term effect of
doxazosin, finasteride, and combination therapy on the clinical progression
of benign prostatic hyperplasia. N. Engl. J. Med. 2003; 349: 2387–98.
12. Roehrborn CG, Siami P, Barkin J et al. The effects of combination therapy
with dutasteride and tamsulosin on clinical outcomes in men with
symptomatic benign prostatic hyperplasia: 4-year results from the
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14. Roehrborn CG, Siami P, Barkin J et al. The influence of baseline
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symptomatic benign prostatic hyperplasia and enlarged prostate: 2-year
data from the CombAT Study. Eur. Urol. 2009; 55: 461–71.
15. Gittelman M, Ramsdell J, Young J, McNicholas T. Dutasteride improves
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10.1.3 Anticholinergics
Muscarinic freceptor subtypes, especially M3 is the most important for
urinary bladder detrusor function [1-5], and muscarinic receptor antagonists
are valuable treatment modality for overactive bladder [6,7]. For elderly
population, there are higher incidence of adverse evens than younger [8].
Anticholinergics might be considered in men with moderate to severe lower
urinary tract symptoms who have predominantly bladder storage symptoms,
however, potential risk for urinary retention is a concern withoutα1 blockers
[9-16]. Hence, combination treatments or α1 blocker add-on treatments
have been evaluated [17-20]. Especially it may benefit men with lower
PSA levels (smaller prostates) [21].
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Chapple CR, Roehrborn CG. A shifted paradigm for the further
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10. Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates
lower urinary tract symptoms in men with benign prostatic hyperplasia. J.
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11. Höfner K, Burkart M, Jacob G, Jonas U. Safety and efficacy of tolertodine
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12. Kaplan SA, Roehrborn CG, Dmochowski R, Rovner ES, Wang JT, Guan Z.
Tolterodine extended release improves overactive bladder symptoms in
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13. Dmochowski R, Abrams P, Marschall-Kehrel D, Wang JT, Guan Z. Efficacy
and tolerability of tolterodine extended release in male and female patients
with overactive bladder. Eur. Urol. 2007; 51: 1054–64.
14. Herschorn S, Jones JS, Oelke M, MacDiarmid S, Wang JT, Guan Z.
Efficacy and tolerability of fesoterodine in men with overactive bladder: a
pooled analysis of 2 phase III studies. Urology 2010; 75: 1149–55.
15. Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability
of tolterodine for the treatment of overactive bladder in men with bladder
outlet obstruction. J. Urol. 2006; 175: 999–1004.
16. Roehrborn CG, Abrams P, Rovner ES, Kaplan SA, Herschorn S, Guan Z
Efficacy and tolerability of tolterodine extended-release in men with
overactive bladder and urgency incontinence. BJU Int. 2006; 97: 1003–6.
17. Kaplan SA, Roehrborn CG, Chancellor M, Carlsson M, Bavendam T, Guan
Z. Extended-release tolterodine with or without tamsulosin in men with
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lower urinary tract symptoms and overactive bladder: effects on Urinary
symptoms assessed by the International Prostate Symptom Score. BJU Int.
2008; 102: 1133–9.
18. Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z.
Tolterodine and tamsulosin for treatment of men with lower urinary tract
symptoms and overactive bladder. JAMA 2006; 296: 2319–28.
19. Nishizawa O, Yamaguchi O, Takeda M, Osamu Yokoyama for the TAABO
Study Group: Randomized Controlled Trial to Treat Benign Prostatic
Hyperplasia with Overactive Bladder Using an Alpha-blocker Combined
with Anticholinergics, LUTS 2011; 3:39-40.
20. Yamaguchi O, Kakizaki H, Homma Y, et al. on behalf of the ASSIT Study
Group: Solifenacin as add-on therapy for overactive bladder symptomsASSIST, randomized controlled study – Urology 2011; 78:126-33.
21. Roehrborn CG, Kaplan SA, Kraus SR, Wang JT, Bavendam T, Guan Z.
Effects of serum PSA on efficacy of tolterodine extended release with or
without tamsulosin in men with LUTS, including OAB. Urology 2008; 72:
1061–7.
10.1.4 PDE5 inhibitor
Nitric oxide/cyclic GMP pathway is an important functional implication not
only in penile erectile function, but in prostate/bladder neck smooth muscle
function [1-5]. Further study revealed that phosphodiesterase (PDE) isoenz
ymes are present in the lower urinary tract and prostate in human [6, 7].
PDE5 inhibitors may well have a role in therapy for BPH/LUTS, for either of
LUTS or uroflow [8-14]. Among PDE5 inhibotors initially developed for
erectile dysfuntion, tadalafil has been shown to be effective for Male/LUTS
in USA, European countries, and Asia [15-21].
It is likely that PDE5 inhibitor treatment will be of value, especially for men with
LUTS and significant ED [22-24]. Other PDE5 inhibitors have been tried for
Male LUTS/BPH [25].
References
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Burnett AL, Maguire MP, Chang TS, Ricker DD, Takeda M, Lepor H
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the human prostate. Urology, 45:435-439 (1995)
Takeda M, Tang R, Shapiro E, Burnett, A L, and Lepor H : Effects of nitric
oxide on human and canine prostates. Urology, 45:440-446 (1995)
Kedia GT, Ückert S, Jonas U, Kuczyk MA, Burchardt M. The nitric oxide
pathway in the human prostate: clinical implications in men with lower
urinary tract symptoms. World J. Urol. 2008; 26: 603–9.
Ückert S, Küthe A, Jonas U, Stief CG. Characterization and functional
relevance of cyclic nucleotide phosphodiesterase isoenzymes of the
human prostate. J. Urol. 2001; 166: 2484–90.
Ückert S, Oelke M, Stief CG, Andersson KE, Jonas U, Hedlund P.
Immunohistochemical distribution of cAMP- and cGMP phosphodiesterase
(PDE) isoenzymes in the human prostate. Eur. Urol. 2006; 49: 740–5.
Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int.
J. Clin. Pract. 2006; 60: 967–75.
Sairam K, Kulinskaya E, McNicholas TA , Boustead GB, Hanbury DC.
Sildenafil influences lower urinary tract symptoms. BJU Int. 2002; 90:
836-9.
9.
Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of
sildenafil citrate on lower urinary tract symptoms in men with erectile
dysfunction. J. Sex. Med. 2006; 3: 662–7.
10. McVary KT, Monnig W, Camps JL Jr., Young JM, Tseng LJ, Van den Ende
G. Sildenafil citrate improves erectile function and urinary symptoms in
men with erectile dysfunction and lower urinary tract symptoms associated
with benign prostatic hyperplasia: a randomised, double-blind trial. J. Urol.
2007; 177: 1071–7.
11. Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin and sildenafil is
superior to monotherapy in treating lower urinary tract symptoms and
erectile dysfunction. Eur. Urol. 2007; 51: 1717–23.
12. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich R. A randomised,
placebo-controlled study to assess the efficacy of twice-daily vardenafil in
the treatment of lower urinary tract symptoms secondary to benign
prostatic hyperplasia. Eur. Urol. 2008; 53: 1236–44.
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13. Güler C, Tüzel E, Dogantekin E, Kiziltepe G. Does sildenafil affect
uroflowmetry values in men with lower urinary tract symptoms suggestive
of benign prostatic enlargement? Urol. Int. 2008; 80: 181–5.
14. Guven EO, Balbay MD, Mete K, Serefoglu EC. Uroflowmetric assessment
of acute effects of sildenafil on the voiding of men with erectile dysfunction
and symptomatic benign prostatic hyperplasia. Int. Urol. Nephrol. 2009; 41:
287–92.
15. McVary KT, Roehrborn CG, Kaminetsky JC et al. Tadalafil relieves lower
urinary tract symptoms secondary to benign prostatic hyperplasia. J. Urol.
2007; 177: 1401–7.
16. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil
administered once daily for lower urinary tract symptoms secondary to
benign prostatic hyperplasia: a dose finding study. J. Urol. 2008; 180:
1228–34.
17. Bechara A, Romano S, Casabé A et al. Comparative efficacy assessment
of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH.
Pilot study. J. Sex. Med. 2008; 5: 2170–8.
18. Liquori G, Trombetta C, De Giorgi G et al. Efficacy and safety of combined
oral therapy with tadalafil and alfuzosin: an integrated approach to the
management of patients with lower urinary tract symptoms and erectile
dysfunction. preliminary report. J. Sex. Med. 2009; 6: 544–52.
19. Porst H, McVary KT, Montorsi F et al. Effects of once-daily tadalafil on
erectile function in men with erectile dysfunction and sign and symptoms of
benign prostatic hyperplasia. Eur. Urol. 2009; 56: 727–35.
20. Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM,
Elion-Mboussa A, Viktrup L. Changes in peak urinary flow and voiding
efficiency in men with signs and symptoms of benign prostatic hyperplasia
during once daily tadalafil treatment. BJU Int. 2010; 105: 502–7.
21. Takeda M, Nishizawa O, Imaoka T, Morisaki Y, Viktrup L. Tadalafil for the
Treatment of Lower Urinary Tract Symptoms in Japanese Men with Benign
Prostatic Hyperplasia: Results from a 12-week Placebo-controlled
Dose-finding Study with a 42-week Open-label Extension. LUTS 2012; 4:
110–9.
22. Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A,
Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to
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benign prostatic hyperplasia in men with or without erectile dysfunction.
Urology 2010; 75: 1452–8.
23. Porst H, Kim ED, Casabe AR et al. Efficacy and safety of tadalafil once
daily in the treatment of men with lower urinary tract symptoms suggestive
of benign prostatic hyperplasia: results of an international randomized,
double-blind, placebo-controlled trial. Eur. Urol. 2011; 60: 1105–13.
24. Liu L, Zheng S, Han P, Wei Q. Phosphodiesterase-5 inhibitors for lower
urinary tract symptoms secondary to benign prostatic hyperplasia: a
systematic review and meta-analysis. Urology 2011; 77: 123–9.
25. Chung BH, Lee JY, Lee SH, Yoo SJ, Lee SW, Oh CY. Safety and efficacy of
the simultaneous administration of udenafil and an alpha-blocker in men
with erectile dysfunction concomitant with BPH/LUTS. Int. J. Impot. Res.
2009; 21: 122–8.
10.1.5 Desmopressin
Desmopressin acetate (desmopressin) is a synthetic analogue of AVP (AVP:
arginine vasopressin) with high V2 receptor affinity and antidiuretic properties.
It is the only registered drug for antidiuretic treatment. In contrast to AVP,
desmopressin has no relevant V1 receptor affinity and hypertensive effects [1,2].
The clinical effects - in terms of urine volume decrease and an increase in urine
osmolality - last for approximately 8-12 hours[2]. Desmopressin may be used by
intravenous infusion, nasal spray, tablet, or MELT formulation [3,4].
Desmopressin significantly reduced nocturnal diuresis, decreased the number of
nocturnal voids, and extended the time until the first nocturnal void [5-7].
The 24-hour diuresis remained unchanged during desmopressin treatment.
Desmopressin should be taken once daily before sleeping [8].
As the optimal dose differs between patients, desmopressin treatment should be
initiated at a low dose (0.1 mg/day) and may be gradually increased every week
until maximum efficacy is reached [9]. For elderly patients, efficacy and safety
have been shown [9-12], however, the most frequent adverse events were
headache, nausea, diarrhea, abdominal pain, dizziness, dry mouth, and
hyponatremia. Hyponatremia was observed mainly in patients aged 65
years[13-16].
Caution is advised in old men with hyponatremia and impaired renal function.
Serum sodium concentration level should be monitored periodically.
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Rembratt A, Graugaard-Jensen C, Senderovitz, Norgaard JP, Djurhuus JC.
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placebo-controlled study. Eur. Urol. 2007; 52: 221–9.
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nocturnal polyuria in patients with benign prostatic hyperplasia: a
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treatment of nocturnal polyuria in the male. BJU Int. 1999; 84: 20–4.
Chancellor MB, Atan A, Rivas DA, Watanabe T, Tai HL, Kumon H.
Beneficial effect of intranasal desmopressin for men with benign prostatic
hyperplasia and nocturia: preliminary results. Tech. Urol. 1999; 5: 191–4.
Mattiasson A, Abrams P, Van Kerrebroeck P, Walter S, Weiss J. Efficacy of
desmopressin in the treatment of nocturia: a double-blind
placebo-controlled study in men. BJU Int. 2002; 89: 855–62.
Hvistendahl GM, Riis A, Norgaard JP, Djurhuus JC. The pharmacokinetics
of 400 µg of oral desmopressin in elderly patients with nocturia, and the
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Asplund R, Sundberg B, Bengtsson P. Desmopressin for the treatment of
nocturnal polyuria in the elderly: a dose titration study. Br. J. Urol. 1998; 82:
642–6.
10. Asplund R, Sundberg B, Bengtsson P. Oral desmopressin for nocturnal
polyuria in elderly subjects: a double-blind, placebo-controlled randomised
exploratory study. BJU Int. 1999; 83: 591–5.
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patients older than 65 years. Urology 2002; 59: 485–9.
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12. Rembratt A, Norgaard JP, Andersson KE. Desmopressin in elderly patients
with nocturia: short-term safety and effects on urine output, sleep and
voiding patterns. BJU Int. 2003; 91: 642–6.
13. Lose G, Mattiasson A, Walter S et al. Clinical experiences with
desmopressin for long-term treatment of nocturia. J. Urol. 2004; 172:
1021–5.
14. Bae JH, Oh MM, Shim KS et al. The effects of long-term administration of
oral desmopressin on the baseline secretion of antidiuretic hormone and
serum sodium concentration for the treatment of nocturia: a circadian study.
J. Urol. 2007; 178: 200–3.
15. Weatherall M. The risk of hyponatremia in older adults using desmopressin
for nocturia: a systematic review and meta-analysis. Neurourol. Urodyn.
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16. Rembratt A, Riis A, Norgaard JP. Desmopressin treatment in nocturia; an
analysis of risk factors for hyponatremia. Neurourol. Urodyn. 2006; 25:
105–9.
10.1.6 Plant extract/Herbal medicine
Phytotherapy comprises the medical use of various extracts of different
plants. The most important compounds are believed to be phytosterols,
ß-sitosterol, fatty acids, and lectins[1]. In vitro studies have shown that
plant extracts have so many functions. They have anti-inflammatory, antiandrogenic, oestrogenic effects, decrease sexual hormone binding globulin
(SHBG), inhibit aromatase, lipoxy-genase, growth-factor stimulated
proliferation of prostatic cells, 1-adrenoceptors, 5-reductase, muscarinic
cholinoceptors, dihydropyridine receptors, or vanilloid receptors,
and improve detrusor function, neutralise free radicals [1-3]. In spite of
a lot of mechanisms of action, phytotherapy remains problematic to use be
cause of different concentrations of the active ingredient(s) in different
brands of the same phytotherapeutic agent [4,5].
Although plant extracts agents show some promise for symptom relief, their use
remains controversial due to the lack of established mechanisms of action,
efficacy, and safety [6-13].
Clinical trials are often flawed, as most studies are of small scale and short
Duration. They are not blinded or controlled, and most have no placebo group.
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Hence, meta-analyses of extracts of the same plant do not seem to be justified
and results of these analyses have to be interpreted with caution.
References
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Madersbacher S, Berger I, Ponholzer A, et al. Plant extracts: sense or
nonsense? Current Opin Urol 2008;18:16-20.
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Levin RM, Das AK. A scientific basis for the therapeutic effects of
Pygeum africanum and Serenoa repens. Urol Res 2000 ;28:201-9.
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selected compounds of different brands of Serenoa repens extract.
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Scaglione F, Lucini V, Pannacci M, Caronno A, Leone C. Comparison of
the potency of different brands of Serenoa repens extract on
5alpha-reductase types I and II in prostatic co-cultured epithelial and
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Wilt T, Ishani A, MacDonald R, Stark G, Mulrow C, Lau J.
Beta-sitosterols for benign prostatic hyperplasia. Cochrane Database of
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Berges RR, Windeler J, Trampisch HJ, Senge T. Randomised,
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Klippel KF, Hiltl DM, Schipp B. A multicentric, placebo-controlled,
double-blind clinical trial of beta-sitosterol (phytosterol) for the treatment
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Wilt T, Ishani A, MacDonald R, Rutks I, Stark G. Pygeum africanum for
benign prostatic hyperplasia. Cochrane Database Syst. Rev. 2002; (1):
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Tacklind J, Mac Donald R, Rutks I, Wilt TJ. Serenoa repens for benign
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hyperplasia. Cochrane Database Syst. Rev. 2002; Issue 4: CD002081.
Barry MJ, Meleth S, Lee JY et al. Effect of increasing doses of saw
palmetto extract on lower urinary tract symptoms: a randomized trial.
JAMA 2011; 306: 1344–51.
10.1.7 Combination treatment with α1 blocker and 5α-reductase
inhibitor
Several studies have investigated the efficacy of combination therapy against
the efficacy of an 1-blockers and 5-reductase inhibitors, or placebo alone.
Initial studies with follow-up periods between 6 and 12 months used symptom
(IPSS) change as their primary endpoint [1-3]. All of these trials demonstrated
that the 1-blocker was superior to finasteride in symptom reduction, whereas
the combination treatment was not superior to the 1-blocker alone. More
recently, 4-year data analysis from MTOPS(medical therapy of prostatic
symptoms) as well as the 2- and 4-year results from the CombAT (Combination
of Avodart® and Tamsulosin) trials, have been reported [4-6].
In contrast to earlier studies with only 6 to 12 months follow-up, long-term data
have demonstrated that combination treatment is superior to either monotherapy
with regard to symptom reduction and Qmax (maximum urinary flow rate during
free uroflowmetry) improvement and superior to  1-blocker in reducing the risk
of acute urinary retention and the need for surgery [4-6].
Regarding discontinuation of 1 blockes after long-term combination
therapy, almost three-quarters of patients reported no worsening of symptoms.
However, patients with severe symptoms (IPSS > 20) at baseline may benefit
from longer combination therapy [7]. LUTS after discontinuation of 1 blocker
was sustained at 3 months (IPSS difference 1.24) and 9 months (IPSS
difference -0.44) [8]. Dutasteride patients discontinued  1-blocker therapy 64%
faster than finasteride patients at any time point [9].
Combination therapy should only be used when long-term treatment
(more than 12 months) is intended. Combination therapy with α1 blocker and
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5α-reductase inhibitor should be used primarily in men who have moderate
to severe LUTS and are at risk of disease progression (higher prostate volume,
higher PSA concentration, advanced age, etc.).
The adverse events observed during combination treatment were typical of
an α1 blocker and 5ARI. The frequencies of adverse events were significantly
higher for combination therapy for most adverse events
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Lepor H, Williford WO, Barry MJ et al. The efficacy of terazosin, finasteride,
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Debruyne FM, Jardin A, Colloi D et al. Sustained release alfuzosin,
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Kirby R, Roehrborn CG, Boyle P et al. Efficacy and tolerability of doxazosin
and finasteride, alone or in combination, in treatment of symptomatic
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McConnell JD, Roehrborn CG, Bautista O et al. The long-term effect of
doxazosin, finasteride, and combination therapy on the clinical progression
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Roehrborn CG, Siami P, Barkin J et al. The effects of dutasteride,
tamsulosin and combination therapy on lower urinary tract symptoms in
men with benign prostatic hyperplasia and prostatic enlargement: 2-year
results from the CombAT study. J. Urol. 2008; 179: 616–21.
Roehrborn CG, Siami P, Barkin J et al. The effects of combination therapy
with dutasteride and tamsulosin on clinical outcomes in men with
symptomatic benign prostatic hyperplasia: 4-year results from the CombAT
study. Eur. Urol. 2010; 57: 123–31.
Barkin J, Guimarães M, Jacobi G, Pushkar D, Taylor S, Van Vierssen Trip
OB. Alpha-blocker therapy can be withdrawn in the majority of men
following initial combination therapy with the dual 5alpha-reductase
inhibitor dutasteride. Eur. Urol. 2003; 44: 461–6.
Nickel JC, Barkin J, Koch C, Dupont C, Elhilali M. Finasteride monotherapy
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Issa MM, Lin PJ, Eaddy MT, Shah MB, Davis EA. Comparative analysis of
alpha-blocker utilization in combination with 5-alpha reductase inhibitors for
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Am. J. Manag. Care 2008; 14 (5 Suppl 2): S160–6.
10.1.8 Combination treatment with α1 blocker and anticholinergic
Combination treatment with α1 blocker and anticholinergic might be
considered in patients with moderate to severe LUTS if symptom relief has
been insufficient with the monotherapy of either drug.
At least nine trials have been published investigating the efficacy of the
combination treatment with 1-blockers and muscarinic receptor antagonists in
adult male patients with LUTS LUTS: lower urinary tract symptoms [1-8].
These trials demonstrated that persistent LUTS can be significantly reduced by
the additional use of a muscarinic receptor antagonist especially if detrusor
overactivity had been demonstrated [1-8]. Patient reported QoL, treatment
benefit, symptom bother, or patient perception of bladder condition was
significantly improved in the combination treatment arm [9-13]. The combination
treatment significantly reduced urgency urinary incontinence episodes as well as
urgency and significantly increased QoL compared to α1 blockers or placebo
alone. Combination treatment should cautiously be prescribed in men who are
suspicious of having bladder outlet obstruction with increased postvoid residual
urine volume [13-15].
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Saito H, Yamada T, Oshima H et al. A comparative study of the efficacy and
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Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of
doxazosin with or without tolterodine in men with symptomatic bladder
outlet obstruction and an overactive detrusor. BJU Int. 2004; 94: 817–20.
Lee KS, Choo MS, Kim DY et al. Combination treatment with propiverine
hydrochloride plus doxazosin controlled release gastrointestinal
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prostatic obstruction: a prospective, randomised, controlled multicenter
study. J. Urol. 2005; 174: 1334–8.
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Tolterodine and tamsulosin for treatment of men with lower urinary tract
symptoms and overactive bladder. JAMA 2006; 296: 2319–28.
MacDiarmid SA, Peters KM, Chen A et al. Efficacy and safety of
extended-release Oxybutynin in combination with tamsulosin for treatment
of lower urinary tract symptoms in men: randomised, double-blind,
placebo-controlled study. Mayo Clin. Proc. 2008; 83: 1002–10.
Athanasopoulols A, Gyftopoulos K, Giannitsas K, Fisfis J, Perimenis P,
Barbalias G. Combination treatment with an a-blocker plus an
anticholinergic for bladder outlet obstruction: a prospective, randomised,
controlled study. J. Urol. 2003; 169: 2253–6.
Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates
lower urinary tract symptoms in men with benign prostatic hyperplasia. J.
Urol.2005; 174: 2273–5.
Yang Y, Zhao SF, Li HZ et al. Efficacy and safety of combined therapy with
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9.
Maruyama O, Kawachi Y, Hanazawa K et al. Naftopidil monotherapy vs
naftopidil and an anticholinergic agent combined therapy for storage
symptoms associated with benign prostatic hyperplasia: A prospective
randomised controlled study. Int. J. Urol. 2006; 13: 1280–5.
10. Roehrborn CG, Kaplan SA, Kraus SR, Wang JT, Bavendam T, Guan Z.
Effects of serum PSA on efficacy of tolterodine extended release with or
without tamsulosin in men with LUTS, including OAB. Urology 2008; 72:
1061–7.
11. Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W. Safety and
tolerability of solifenacin add-on therapy to alpha-blocker treated men with
residual urgency and frequency. J. Urol. 2009; 182: 2825–3.
12. NishizawaO, Yamaguchi O, Takeda M, Yokoyama O, for the TAABO Study
Group: Randomized Controlled Trial to Treat Benign Prostatic Hyperplasia
with Overactive Bladder Using an Alpha-blocker Combined with
Anticholinergics, LUTS, 2011; 3:39-40.
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13. Yamaguchi O, Kakizaki H, Homma Y et al. Solifenacin as add-on therapy
for overactive bladder symptoms in men treated for lower urinary tract
symptoms--ASSIST, randomized controlled study. Urology 2011; 78: 126–
33.
14. Chapple C, Herschorn S, Abrams P, Sun F, Brodsky M, Guan Z. Tolterodine
treatment improves storage symptoms suggestive of overactive bladder in
men treated with α-blockers. Eur. Urol. 2009; 56: 534–41.
15. Takeda M, Nishizawa O, Gotoh M, Yoshida M, Takahashi S, Masumori N:
Clinical Efficacy and Safety of Imidafenacin as Add-on Treatment for
Persistent Overactive Bladder Symptoms Despite a-Blocker Treatment in
Patients with BPH: the ADDITION STUDY. Urology; 82:887-93, 2013.
10.1.9 Combination treatment with α1 blocker and PDE 5 inhibitor
The combination of α1 blocker and PDE 5 inhibitor is well tolerated and
effective in improving lower urinary tract symptoms [1-4].
However caution is advised in men with hypotention. Further data on safety
and cost-effectiveness, especially for combination therapy, will be needed.
References
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Bechara A, Romano S, Casabe A et al. Comparative efficacy assessment
of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH.
pilot study. J. Sex. Med. 2008; 5: 2170–8.
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3.
4.
Martinez-Salamanca JI, Carballido J, Eardley I et al. Phosphodiesteras
e type 5 inhibitors in the management of non-neurogenic male lower
urinary tract symptoms: critical analysis of current evidence. Eur. Urol.
2011; 60: 527–35.
Giuliano F, Oelke M, Jungwirth A et al. Tadalafil once daily improves
ejaculatory function, erectile function, and sexual satisfaction in men
with lower urinary tract symptoms suggestive of benign prostatic hype
rplasia and erectile dysfunction: results from a randomized, placebo- a
nd tamsulosin-controlled, 12-week double-blind study. J. Sex. Med.
2013; 10: 857–65.
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10.1.10
Botulinum toxin (BTX-A)
BTX-A inhibits vesicular neurotransmitter transport from nerve terminal via
inhibition of SNAIR/SNAP proteins [1]. Two commercially available products
(BotoxTM, DysportTM) of type A Botulinum toxin are now available in USA
and European countries (Table 1). The possible mechanisms of the effect
of intraprostatic injection of BTX-A may be variable including apoptosis
[2-5]. In addition to initla short term effects on the small prostate [6-8],
long-termeffects on LUTS, prostate volume, and QOL, were evaluated
[9-14]. There are some evidences to support its efficacy [9-14], large volu
me RCTdata is lacking [15,16].
Intra-prostatic BTX injections for LUTSdue to benign prostatic obstruction
or urinary retention are still experimental.
References
1.
Smith CP, Franks ME, McNeil BK et al. Effect of botulinum toxin A on the
2.
3.
4.
5.
6.
7.
autonomic nervous system of the rat lower urinary tract. J. Urol. 2003; 169:
1896–900.
Doggweiler R, Zermann DH, Ishigooka M, Schmidt RA. Botox-induced
prostatic involution. Prostate 1998; 37: 44–50.
Chuang YC, Huang CC, Kang HY et al. Novel action of botulinum toxin on
the stromal and epithelial components of the prostate gland. J. Urol. 2006;
175: 1158–63.
Chuang YC, Tu CH, Huang CC et al. Intraprostatic injection of botulinum
toxin type-A relieves bladder outlet obstruction in human and induces
prostate apoptosis in dogs. BMC Urology 2006; 6: 12.
Lin AT, Yang AH, Chen KK. Effects of botulinum toxin A on the contractile
function of dog prostate. Eur. Urol. 2007; 52: 582–9.
Kuo HC. Prostate botulinum A toxin injection – an alternative treatment for
benign prostatic obstruction in poor surgical candidates. Urology 2005; 65:
670–4.
Chuang YC, Chiang PH, Huang CC, Yoshimura N, Chancellor MB.
Botulinum toxin type A improves benign prostatic hyperplasia symptoms in
patients with small prostates. Urology 2005; 66: 775–9.
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8.
9.
Park DS, Cho TW, Lee YK, Lee YT, Hong YK, Jang WK. Evaluation of short
term clinical effects and presumptive mechanism of botulinum toxin type A
as a treatment modality of benign prostatic hyperplasia. Yonsei Med. J.
2006; 47: 706–14.
Chuang YC, Chiang PH, Yoshimura N, De Miguel F, Chancellor MB.
Sustained beneficial effects of intraprostatic botulinum toxin type A on
lower urinary tract symptoms and quality of life in men with benign prostatic
hyperplasia. BJU Int. 2006; 98: 1033–7.
10. Brisinda G, Cadeddu F, Vanella S, Mazzeo P, Marniga G, Maria G. Relief
by botulinum toxin of lower urinary tract symptoms owing to benign
prostatic hyperplasia: early and long-term results. Urology 2009; 73: 90–4.
11. Kuo HC, Liu HT. Therapeutic effects of add-on botulinum toxin A on
patients with large benign prostatic hyperplasia and unsatisfactory
response to combined medical therapy. Scand. J. Urol. Nephrol. 2009; 43:
206–11.
12. Nikoobakht M, Daneshpajooh A, Ahmadi H et al. Intraprostatic botulinum
toxin type A injection for the treatment of benign prostatic hyperplasia: initial
experience with Dysport. Scand. J. Urol. Nephrol. 2010; 44: 151–7.
13. Silva J, Silva C, Saraiva L et al. Intraprostatic botulinum toxin type A
injection in patients unfit for surgery presenting with refractory urinary
retention and benign prostatic enlargement. effect on prostate volume and
micturition resumption. Eur. Urol. 2008; 53: 153–9.
14. Silva J, Pinto R, Carvalho T et al. Intraprostatic botulinum toxin type A
injection in patients with benign prostatic enlargement: duration of the
effect of a single treatment. BMC Urology 2009; 9: 9.
15. Maria G, Brisinda G, Civello IM, Bentivoglio AR, Sganga G, Albanese A.
Relief by botulinum toxin of voiding dysfunction due to benign prostatic
hyperplasia: results of a randomised, placebo-controlled study. Urology
2003; 62: 259–64.
16. Crawford ED, Hirst K, Kusek JW et al. Effects of 100 and 300 units of
onabotulinum toxin A on lower urinary tract symptoms of benign prostatic
hyperplasia: a phase II randomized clinical trial. J. Urol. 2011; 186: 965–70.
10.1.11 β3-Adrenoceptor agonist, Mirabegron
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A β3-Adrenoceptor agonist, Mirabegron, alleviates symptoms of OAB while
having a mechanism of action that provides an alternative for patients who are
intolerant of or who have contraindications to anticholinergic agents [1]. The
place in therapy of mirabegron relative to anticholinergics in the treatment of
OAB secondary to BPH has not yet been established[ 2], however, urodynamic
safety for BPH/BOO has been confirmed[ 3].
References
1. Bridgeman MB, Friia NJ, Taft C, Shah M: Mirabegron: β3-adrenergic
receptor agonist for the treatment of overactive bladder, Ann Pharmacother,
2013;47:1029-38.
2. Otsuki H, Kosaka T, Nakamura K, Mishima J, Kuwahara Y, Tsukamoto T:
β3-Adrenoceptor agonist mirabegron is effective for overactive bladder that
is unresponsive to antimuscarinic treatment or is related to benign prostatic
hyperplasia in men, 2013;45:53-60.
3. Nitti V W, Rosenberg S, Mitceson D H, He W, Fakhoury A, Martin N:
Urodynamic safety of the 3-adrenoceptor agonist Mirabegron in males with
lower urinary tract symptomsa and bladder outlet obstruction, J Urol, 2013,
190:1320-7.
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10.2 Conservative Therapy
In this chapter, conservative therapies including lifestyle advises, watchful
waiting, indwelling catheter, and intermittent catheterization are discussed.
Transurethral microwave thermotherapy (TUMT), Transurethral needle ablation
(TUNA) and Prostate stent are discussed in the next chapter (Chapter 10:
Surgery.)
Table. Level of Evidence and Grade of Recommendations for Conservative
therapies
Level
Grade
2
B
Men with mild symptoms are suitable for watchful waiting.
2
B
The use of chronic indwelling catheter is necessary for patients who
5
C1
2
B
Lifestyle advises prior to or concurrent with treatment can provide the
opportunity for treatment of BPH and LUTS.
have refractory retention and high surgical risk.
Intermittent catheterization is associated with less UTI compared to
indwelling catheter and early recovery of bladder function following
surgery for urinary retention.
10.2.1 Life style advises/modifications
Lifestyle factors play some part in the pathogenesis of BPH and LUTS. Lifestyle
factors associated with increased risks of BPH and LUTS include obesity,
diabetes, and meat and fat consumption [1]. In contrast, factors associated with
decreased risks include exercise, and vegetable consumption. Modification of
these factors can provide the opportunity for treatment of BPH and LUTS. This
approach has noninvasiveness and low financial burden. Lifestyle advises and
recommended modifications for BPH and LUTS should probably include the
following [2, 3].
Modifications of fluid intake; Reduction of fluid intake at specific times is
necessary for patients with storage symptoms, and the recommended total daily
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fluid intake for an average man with LUTS should be 1500–2000mL. For
nocturia, evening fluid restriction 2 hours prior to sleeping is appropriate.
Avoidance or moderation of certain dietary factors which may have a diuretic
and irritant effect such as caffeine, alcohol, and spices.
Use of relaxed voiding, double-voiding techniques and urethral milking to
prevent post micturition dribble.
Distraction techniques, such as penile squeeze, breathing exercises, perineal
pressure and mental ‘tricks’ to take the mind off the bladder and toilet, to help
control irritative symptoms.
Bladder re-training, by which men are encouraged to ‘hold on’ when they have
sensory urgency to increase their bladder capacity (to around 400mL) and the
time between voids.
Optimizing the time of administration medication or substituting drugs for others
that have fewer urinary effects.
Providing necessary assistance when there is impairment of dexterity, mobility or
mental state.
Avoid constipation.
Education and reassurance
(Level of evidence 2, grade recommendation B)
10.2.2 Watchful waiting
There is some evidence to support the efficacy of watchful waiting [4, 5]. Men
who have not bothersome or mild uncomplicated LUTS are suitable for watchful
waiting which is not medical or surgical treatment but include education,
reassurance, periodic monitoring, and lifestyle advice. Progression of symptoms
is rare [6] and delayed treatment intervention is still effective in those patients. A
large study comparing watchful waiting and transurethral resection of the
prostate in men with moderate symptoms showed that those who had
undergone surgery had improved bladder function over the watchful waiting
group. Thirty six percent of patients crossed over to surgery in 5 years, leaving
64% doing well in the watchful waiting group [7]. For adequate patient selection,
physicians have to consider clinical findings because prostate-specific antigen,
obstructive symptom score, and transitional zone volume were identified as
important risk factors of clinical progression [8]. Watchful waiting patients usually
are recommended reexamination every 12 months.
(Level of evidence 2, Grade of recommendation B)
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10.2.3 Complementary/alternative medicine (CAM)
Most complementary and alternative medicines for BPH are extracts of the roots,
the seeds, the bark, or the fruits of the various plants. Among these, the most
commonly used and investigated product is an extract of the berry of the saw
palmetto (Serenoa repens). However, recent clinical trials have questioned their
efficacy and increasing doses of a saw palmetto extract did not improve LUTS
more than placebo [9, 10]. Other products include extracts of the African plum
tree (Pygeum africanum), stinging nettle (Urtica dioica), pumpkin seed
(Curcubita pepo), South African star grass (Hypoxis rooperi) and rye pollen
(Secale cereal). Complementary and alternative medicines other than saw
palmetto and Urtica dioica do not have evidence to support efficacy and safety.
(Level of evidence 2, grade of recommendation D)
10.2.4 Urethral indwelling catheter/Suprapubic catheter
The use of chronic indwelling catheter is necessary for patients who have
refractory retention and high surgical risk. However, it is associated with several
complications and significant impairment of quality of life. Urethral indwelling
catheter is technically easier, less morbid compared to suprapubic
catheterization, but its disadvantages are higher risk of injury to the urethra and
bladder neck [11]. Selection of management for patients with chronic indwelling
catheter should depend on the long term comfort for the patient and a physician
mind-set.
Patients who are on the waiting for definitive surgery after acute urinary retention
(AUR) need to indwell catheter too. In prospective cross-sectional survey, the
initial management of AUR consisted of urethral indwelling catheter and
suprapubic catheter in 83% and 17% respectively [12].
(Level of evidence 5, grade recommendation C1)
10.2.5 Intermittent catheterization
Intermittent catheterization is an alternative to an indwelling catheter in patients
who are capable of catheterizing themselves. It is associated with less urinary
tract infection compared to indwelling catheter [13]. There is evidence for early
recovery of bladder function following surgery for urinary retention [14]. It can
have a good effect of quality of life, especially sexual life.
However it is not appropriate in advanced old aged patients who may lack the
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mobility, visual acuity, or cognitive ability to manage self-catheterization. In
addition, patients with severe prostate enlargement have difficulty in urethral
catheterization if they do not have special skills or equipments.
(Level of evidence 2, grade of recommendation B)
References
1.
Parsons JK. Lifestyle factors, benign prostatic hyperplasia, and lower
urinary tract symptoms. Curr. Opin. Urol. 2011; 21: 1–4.
2.
Brown CT, van der Meulen J, Mundy AR, O'Flynn E, Emberton M.
3.
4.
5.
6.
7.
8.
9.
Defining the components of a self-management programme for men with
uncomplicated lower urinary tract symptoms: a consensus approach.
Eur. Urol. 2004; 46: 254–62; discussion 63.
Brown CT, Van Der Meulen J, Mundy AR, Emberton M. Lifestyle and
behavioural interventions for men on watchful waiting with
uncomplicated lower urinary tract symptoms: a national multidisciplinary
survey. BJU Int. 2003; 92: 53–7.
Netto NR Jr, De Lima ML, Netto MR, D'Ancona CA. Evaluation of
patients with bladder outlet obstruction and mild international prostate
symptom score followed up by watchful waiting. Urology 1999; 53: 314–
6.
Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson
WG. A comparison of transurethral surgery with watchful waiting for
moderate symptoms of benign prostatic hyperplasia. The Veterans
Affairs Cooperative Study Group on Transurethral Resection of the
Prostate. N. Engl. J. Med. 1995; 332: 75–9.
Fitzpatrick JM. The natural history of benign prostatic hyperplasia. BJU
Int. 2006; 97 (Suppl 2): 3–6; discussion 21–2.
Flanigan RC, Reda DJ, Wasson JH, Anderson RJ, Abdellatif M,
Bruskewitz RC. 5-year outcome of surgical resection and watchful
waiting for men with moderately symptomatic benign prostatic
hyperplasia: a Department of Veterans Affairs cooperative study. J. Urol.
1998; 160: 12–6; discussion 6–7.
Djavan B, Fong YK, Harik M et al. Longitudinal study of men with mild
symptoms of bladder outlet obstruction treated with watchful waiting for
four years. Urology 2004; 64: 1144–8.
Barry MJ, Meleth S, Lee JY et al. Effect of increasing doses of saw
palmetto extract on lower urinary tract symptoms: a randomized trial.
- 127 -
10.
11.
12.
13.
14.
JAMA 2011; 306: 1344–51.
MacDonald R, Tacklind JW, Rutks I, Wilt TJ. Serenoa repens
monotherapy for benign prostatic hyperplasia (BPH): an updated
Cochrane systematic review. BJU Int. 2012; 109: 1756–61.
Katsumi HK, Kalisvaart JF, Ronningen LD, Hovey RM. Urethral versus
suprapubic catheter: choosing the best bladder management for male
spinal cord injury patients with indwelling catheters. Spinal Cord 2010;
48: 325–9.
Desgrandchamps F, De La Taille A, Doublet JD. The management of
acute urinary retention in France: a cross-sectional survey in 2618 men
with benign prostatic hyperplasia. BJU Int. 2006; 97: 727–33.
Patel MI, Watts W, Grant A. The optimal form of urinary drainage after
acute retention of urine. BJU Int. 2001; 88: 26–9.
Ghalayini IF, Al-Ghazo MA, Pickard RS. A prospective randomized trial
comparing transurethral prostatic resection and clean intermittent
self-catheterization in men with chronic urinary retention. BJU Int. 2005;
96: 93–7.
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11. Recommended grade for treatment : Surgery
Wachira Kochakarn, M.D., Ph.D.
Absolute indications for surgery in patients with BPH/LUTS/BPE/BOO are
refractory urinary retention, recurrent urinary tract infection from BOO, refractory
hematuria due to BPH, renal insufficiency from chronic BOO, vesical calculi or
diverticulum. According to aging not only in Western countries but Asian
countries, such BPH patients are often at high risk for surgical interventions.
According to Treatment Algorithm (Chapter 1. Algorithm, d.Treatment Algorithm
of Bothersome Male LUTS Refractory to Medical/Conservative Treatment or
Absolute Surgical Indications for Urologist), American Society of
Anesthesiologists Operative Risk Assessment of Physical Status Class,
treatment recommendation are summarized in the following Table.
Table. Treatment recommendation according to operative risk assessment, and
prostate volume.
Operative Risk
Prostate Volume
Remark
Assessment
Recommended
treatments
ASA PS class IV
Conservative
CIC , Indwelling
Catheterization etc.
ASA PS class III, on
Laser
anti-coagulation drug
ASA PS class I or
PVP, Thulium laser,
HoLAP, HoLEP
>80 ml
class II
Classical/
TURP, TUEB
Laser
PVP, Thulium laser,
HoLEP
ASA PS class I
30-80 ml
or class II
Classical/
TURP, TUEB, PVP,
Laser /MIST
Thulium laser, HoLEP,
TUMT, TUNA
ASA PS class I
<30 ml
or class II
Classical/
TURP,
MIST
TUIP
ASA: American Society of Anesthesia, PS; Performance Status,
MIST; Minimal invasive therapy
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11.1 Transurethral resection of prostate (TURP)
TURP is the gold standard of surgical treatment of symptomatic BPH. An
indication that is accepted for TURP is for moderate to severe symptoms and for
those who fail to respond to medical treatment or don’t accept to medical
therapy. Many changes have undergone to improve outcome of TURP and incur
less complications such as optic quality, light sources, surgical and anesthetic
technique [1].
The current indications for TURP are moderate to severe bothersome
symptoms, recurrent urinary retention, bladder stones, obstructive renal failure
and hematuria due to prostate gland enlargement. Due to improvement of
instrument and technique including continuous sheath, TURP can be performed
in bigger gland than prior reported. In fact, prostate gland of 120 g can be done
with a minimal complication [2].
Complications of TURP [3] are TURP syndrome (1.4%), bleeding need for blood
transfusion (<20%), urethral stricture (10%). Mortality is less than 1 %. Bipolar
TURP is believed for fewer complications, especially TURP syndrome and
urethral stricture but there are data giving support of less complications as well
as a cost-analysis [4-7].
(Level 1 Evidence, Grade A Recommendation)
11.2 Transurethral incision of prostate (TUIP)
TUIP is indicated for men who have moderate to severe symptoms but reveal
small prostate gland. The accepted indication for TUIP is less than 30 g.
Long-term symptomatic improvement in TUIP is similar to TURP but with less
incidence of retrograde ejaculation [8].
(Level 2 Evidence, Grade B Recommendation)
11.3 KTP (greenlight)
Laser vaporization is associated with a low risk of hemorrhage and can be
performed safely even on large prostates [9-11]. Photoselective vaporization
prostatectomy (PVP) or greenlight laser ia another optional treatment in men
with symptomatic BPH who might have bleeding tendency. RCT comparing to
TURP shows camparable shortterm outcome but higher in reoperation in PVP
[11]. There is significant blood loss and shorten catherterization in PVP group
when compared to standard TURP. High voltage PVP (120 watts) is
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recommended for use in a very large galnd due to less time consumed in using
80 watts PVP [12].
There is sufficient evidence for the effectiveness and sustainability of laser
vaporization of the prostate, although tissue sampling is impossible, unlike
TURP.
(Level 2 Evidence, Grade B Recommendation)
11.4
HoLEP
Holmium laser enucleation ( HoLEP) is recommended for large prostate gland of
more than 50 g with bleeding tendency, including patients who take
anticoagulant [13-16]. RCT comparing HoLEP to TURP has demonstrated
impressive outcomes, especially in term of Qmax at 12 months after treatment.
But HoLEP has overall complication less than TURP (8.1% v.s.16.2%) [13].
(Level 1 Evidence, Grade B Recommendation)
11.5 Open prostatectomy
Open prostatectomy remains indicated as one of the optional treatments of BPH,
especially too large for TURP for fear of incomplete resection, massive bleeding
and dilutional hyponatremia [17]. Open prostatectomy is also indicated for
concomitant pathologies needing a surgical approach such as vesical stones
and diverticula.
(Level 3 Evidence, Grade C1 Recommendation)
Special situations
We categorize patients into 2 groups; patients, who can’t stop
anti-coagulation and who are not fit for surgery/general anesthesia.
1) Patient, who can’t stop anti-coagulation
a. KTP (greenlight)
(Level 2 Evidence, Grade B Recommendation)
b. HoLEP
(Level 1 Evidence, Grade B Recommendation)
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2) Patient, who are not fit for surgery/general anesthesia
a. Transurethral microwave thermotherapy (TUMT) and Transurethral
needle ablation (TUNA)
Transurethral microwave thermotherapy (TUMT) and transurethral needle
ablation (TUNA) are indicated in high risk patients especially having bleeding
tendency and volume overload [18]. This kind of treatment can be performed
without anesthesia. Due to less improvement of symptoms [18] when compared
to standard treatment and introduction of any kind of laser therapy, TUMT is
performed less frequent during the last decade. TUNA is considered
contraindicated in prior radiation to pelvic organ due to higher risk of rectal fistula
[19].
(Level 1 Evidence, Grade C Recommendation)
b. Prostate stent
Prostate stents have been indicated in elderly men with significant comorbidities
which are therefore unfit for surgery [20,21]. Two types of stent are introduced
as temporary and permanent stent.
(Level 3 Evidence, Grade D Recommendation)
Reference
1. Koshiba K, Egawa S, Ohori M, Uchida T, Yokoyama E, Shoji K. Does
transurethral resection of the prostate pose a risk to life? 22-year outcome.
J. Urol.1995; 153: 1506–9
2. Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of transurethral
resection of the prostate (TURP) – incidence, management and prevention.
Eur. Urol. 2006; 50: 969–80.
3. Reich O, Gratzke C, Bachmann A et al. Morbidity, mortality and early
outcome of transurethral resection of the prostate: a prospective multicenter
evaluation of 10,654 patients. J. Urol. 2008; 180: 246–9.
4. Michielsen DP, Debacker T, De Boe V et al. Bipolar transurethral in saline an
alternative surgical treatment for bladder outlet obstruction? J. Urol. 2007;
178: 2035–9.
5. Ho HSS, Cheng CWS. Bipolar transurethral resection of prostate: a new
reference standard? Curr. Opin. Urol. 2008; 18: 50–5.
6. Issa MM. Technological advances in transurethral resection of the prostate:
bipolar versus monopolar TURP. J. Endourol. 2008; 22: 1578–95.
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7. Singh H, Desai MR, Shrivastav P, Vani K. Bipolar versus monopolar
transurethral resection of prostate: randomized controlled study. J.
Endourol. 2005; 19: 333–8.
8. Lourenco T, Shaw M, Fraser C, MacLennan G, N'Dow J, Pickard R. The
clinical effectiveness of transurethral incision of the prostate: a systematic
review of randomised controlled trials. World J. Urol. 2010; 28: 23–32.
9. Horasanli K, Silay MS, Altay B, Tanriverdi O, Sarica K, Miroglu C.
Photoselective potassium titanyl phosphate (KTP) laser vaporization versus
transurethral resection of the prostate for prostates larger than 70 mL: a
short-term prospective randomized trial. Urology 2008; 71: 247-51.
10. Tasci AI, Tugcu V, Sahin S, Zorluoglu F. Rapid communication:
photoselective vaporization of the prostate versus transurethral
resection of the prostate for the large prostate: a prospective
nonrandomized bicenter trial with 2-year follow-up. J. Endourol. 2008;
22:347-53.
11. Skolarikos A, Papachristou C, Athanasiadis G, Chalikopoulos D,
Deliveliotis C, Alivizatos G. Eighteen-month results of a randomized
prospective
study
comparing
transurethral
photoselective
vaporization with transvesical open enucleation for prostatic
adenomas greater than 80 cc. J. Endourol. 2008; 22: 2333-40.
12. Lourenco T, Pickard R, Vale L et al. Alternative approaches to endoscopic
ablation for benign enlargement of the prostate: systematic review of
randomized controlled trials. BMJ 2008; 337: a449.
13. Kuntz RM, Ahyai S, Lehrich K, Fayad A. Transurethral holmium laser
enucleation of the prostate versus transurethral electrocautery resection of
the prostate: a randomized prospective trial in 200 patients. J. Urol. 2004;
172: 1012–6.
14. Ahyai SA, Gilling P, Kaplan SA et al. Meta-analysis of functional outcomes
and complications following transurethral procedures for lower urinary tract
symptoms resulting from benign prostatic enlargement. Eur. Urol. 2010; 58:
384–97.
15. Iwamoto K, Hiraoka Y, Shimizu Y. Transurethral detachment
prostatectomy using a tissue morcellator for large benign prostatic
hyperplasia. J. Nippon Med. Sch. 2008; 75: 77–84.
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16. Hiraoka Y, Shimizu Y, Iwamoto K, Takahashi H, Abe H. Trial of complete
detachment of the whole prostate lobes in benign prostate hyperplasia by
transurethral enucleation of the prostate. Urol. Int. 2007; 79: 50–4.
17. Serretta V, Morgia G, Fondacaro L et al. Open prostatectomy for benign
prostatic enlargement in southern Europe in the late 1990s: a contemporary
series of 1800 interventions. Urology 2002; 60: 623–7.
18. De la Rosette J, Laguna MP, Gravas S et al. Transurethral microwave
thermotherapy: the gold standard for minimally invasive therapies for
patients with benign prostatic hyperplasia? J. Endourol. 2003; 17: 245–51.
19. Zlotta AR, Giannakopoulos X, Machlum O, Ostrem T, Schulman CC.
Long-term evaluation of transurethral needle ablation of the prostate (TUNA)
for the treatment of symptomatic benign prostatic hyperplasia: clinical
outcome up to 5 years from 3 centers. Eur. Urol. 2003; 44: 89–93.
20. Gravas S, Laguna MP, De la Rosette JJ. Efficacy and safety of intraprostatic
temperature controlled microwave thermotherapy in patients with benign
prostatic hyperplasia: results of a prospective, open-label, single-center
study with 1-year follow-up. J. Endourol. 2003; 17: 425–30.
21. Vanderbrink BA, Rastinehad AR, Badlani GH. Prostatic stents for the
treatment of benign prostatic hyperplasia. Curr. Opin. Urol. 2007; 17: 1–6.
- 134 -
12. Abbreviations used in the text
This list is not comprehensive for the most common abbreviations.
ASA
AVP
AUA
BOO(I)
BPE
American Society of Anesthesia
Arginine vasopressin
American Urological Association
Bladder outlet obstruction (index)
Benign prostatic enlargement
BPH
BPO
cGMP
CIC
CombAT
DHT
DRE
EAU
EBM
Benign prostatic hyperplasia
Benign prostatic obstruction
Cyclic guanosine monophosphate
Clean intermittent catheterization
Combination of avodart® and tamsulosin
Dihydrotestosterone
Digital rectal examination
European Association of Urology
Evidence-based medicine
ED
EjD
eNOS
ER
FVC
GITS
GP
HoLAP
HoLEP
Erectile dysfunction
Ejaculation dysfunction
Endothelial nitric oxide synthase
Extended release
Frequency volume chart
Gastrointestinal therapeutic system
General practitioner
Holmium laser ablation of the prostate
Holmium laser enucleation of the prostate
IFIS
IPP
IPSS
IR
KTP
LUTS
MIST
MR
MTOPS
Intra-operative floppy iris syndrome
Intravesical protrusion of prostate
International prostate symptom score
Immediate release
Potassium titanyl phosphate
Lower urinary tract symptoms
Minimal invasive therapy
Modified release
Medical therapy of prostatic symptoms
NAION
Non-arteritic anterior ischemic optic neuropathy
- 135 -
NO
NOS
nNOS
n.s.
OAB
OCAS
PA
PDE
Nitric oxide
NO synthases
Neuronal nitric oxide synthase
Not significant
Overactive bladder
Oral controlled absorption system
Prostatic adenoma
Phosphodiesterase
PFS
PS
PSA
PV
PVP
PVR
Qmax
QoL
RR
Pressure-flow study
Performance Status
Prostate specific antigen
Prostate volume
Photoselective vaporization of the prostate
Post-void residual urine
Maximum urinary flow rate during free uroflowmetry
Quality of life
Relative risk
SHBG
SR
tmax
t½
TUEB
TUERP
TUIP
TUMT
Sexual hormone binding globulin
Sustained release
Time to maximum plasma concentration
Elimination half-life
Transurethral enucleation of prostate using bipolar electrode
Transurethral enucleation and resection of the prostate
(either using bipolar or monopolar electrode)
Transurethral incision of the prostate
Transurethral microwave therapy
TUNA
TURP
TUVP
UTI
WW
Transurethral needle ablation
Transurethral resection of the prostate
Transurethral vaporization of the prostate
Urinary tract infection
Watchful waiting
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