{ AUA

November 2012
AUA
2012 ANNUAL
MEETING HIGHLIGHTS
The Medical Management
of BPH
Course #09IC
BPH Medical Management
Course #31PG
Urologic Diseases for the Allied Health
Professional
The Science of Male Health Forum
Stress Response and BPH
Our knowledge.
{
Our patients’ lives.
Plenary Session
Take Home Message: Benign Prostatic
Hyperplasia and Lower Urinary Tract
Symptoms
Abstract Highlights
AUANews Editor
Gopal H. Badlani, MD
Publisher
American Urological Association
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Copyright © 2012 by American Urological Association
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AUA 2012 ANNUAL MEETING
HIGHLIGHTS
The Medical Management
of BPH
This CME activity is supported through an educational grant from Lilly USA, LLC.
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AUANews AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
1
CME INFORMATION
Highlights on the Medical Management of BPH
Method of Participation
This CME activity consists of a printed
overview of the content presented at a live
course at the 2012 AUA Annual Meeting
and an online posttest and evaluation.
the provider any relevant financial relationships they have with any commercial
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with regard to exposition or conclusion,
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To receive CME credit/hours of participation, participants must read the overview of courses 09IC and 31PG, complete the online posttest, passing with
a score of at least 80%, and submit the
evaluation and the credit request form by
visiting www.AUANet.org/BPH2012.
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Estimated Time to complete this
Activity: 1.5 hours
Release Date: November 2012
Expiration Date: November 30, 2013
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& Research Inc. (AUAER) must ensure
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Course #09IC BPH Medical
Management
Faculty
Claus G. Roehrborn, MD, Course
Director
Professor and Chair, Department of
Urology
UT Southwestern Medical Center
at Dallas
Dallas, TX
Disclosures: GlaxoSmithKline: Consultant or Advisor
Christopher Chapple, BSc, MD,
FRCS (Urol)
Honorary Senior Lecturer of Urology,
University of Sheffield
Consultant Urological Surgeon, Royal
Hallamshire Hospital
Sheffield, United Kingdom
Disclosures: Pfizer: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Recordati: Consultant or Advisor, Meeting Participant
or Lecturer, Scientific Study or Trial;
Astellas: Consultant or Advisor, Meeting
Participant or Lecturer, Scientific Study
or Trial; Allergan: Consultant or Advisor,
Meeting Participant or Lecturer, Scientific Study or Trial; American Medical
Systems: Consultant or Advisor, Scientific Study or Trial; Lilly: Consultant or
Advisor
Learning Objectives
At the conclusion of this CME activity,
participants should be able to:
•describe the natural history, etiology
and pathophysiology of male lower
urinary tract symptoms (LUTS) and
benign prostatic hyperplasia (BPH)
•apply deepened understanding of the
natural history of LUTS and BPH to
the treatment of men in their practice
•realize the benefit of and need for differentiated medical therapy for men
with LUTS and BPH
•distinguish mechanisms of action of
commonly used drugs for LUTS and
BPH
Course #31PG Urologic Diseases
for the Allied Health Professional:
Review of BPH Guidelines and Treatment Options
Faculty
Allen D. Seftel, MD, Course Director
Head of Urology, Cooper University
Hospital
Professor, Robert Wood Johnson School
of Medicine
Camden, NJ
Disclosures: Endo Pharma: Consultant or Advisor, Meeting Participant or
Lecturer; Pfizer: Consultant or Advisor;
Auxilium: Consultant or Advisor, Scientific Study or Trial; Abbott: Consultant
or Advisor
Jeffrey A. Albaugh, PhD, APRN-BC,
CUCNS
Advanced Practice Urology Clinical
Nurse Specialist
Jesse Brown VA Medical Center
Northwestern Memorial Wellness Insti▼ Continued on page 2
2
AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
CME Information
▼ Continued from page 1
tute Sexual Health Program
Chicago, IL
Disclosures: TIMM Medical: Meeting
Participant or Lecturer; Coloplast: Meeting Participant or Lecturer
Donald Bodner, MD
Professor of Urology
UH Case Medical Center
Cleveland, OH
Disclosures: Allergan: Scientific Study
or Trial; Medtronics: Investment Interest
Gina Fries, RPAC
Physician Assistant
University of Rochester Medical Center
Rochester, NY
Disclosures: Astellas pharma us: Scientific Study or Trial
Lindsey Kerr, MD
Urologic Wellness Center
Eastern Maine Medical Center
Bangor, ME
Disclosures: Novasys Medical: Investment Interest; American Medical Systems: Consultant or Advisor
Learning Objective
At the conclusion of this CME activity,
participants should be able to describe
the treatment options for men with minimally symptomatic BPH.
Statement of Need
There is a need to enhance urologists’
knowledge and improve their performance by providing them with the most
up-to-date developments and techniques
in urology to ensure the highest standard
of patient care and safety. This CME
activity will provide an overview of the
etiology, pathophysiology and natural
history of male LUTS and associated
benign prostatic hyperplasia. The faculty
will address the currently used nomenclature in this field and provide participants with an in-depth understanding of
the benefits of differentiated guideline
driven medical treatment of this common condition based on an enhanced
understanding of the mechanism of
action of the currently available drugs.
Target Audience
Urologists, urologists in training and nonphysician providers involved in urology.
Accreditation
The American Urological Association
Education & Research, Inc. is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education for
physicians.
Credit Designation
The American Urological Association
Education & Research, Inc. designates
this enduring material for a maximum
of 1.5 AMA PRA Category 1 Credit™.
Physicians should claim only the credit
commensurate with the extent of their
participation in the activity.
This enduring material credit is valid
only for content reformatted from courses 09IC and 31PG.
The AUA takes responsibility for the
content, quality and scientific integrity of
this CME activity.
Planners
Gopal Badlani, MD
Professor and Vice Chair, Department
of Urology
AUA Secretary
Wake Forest Baptist Medical Center
Winston Salem, NC
Disclosures: Olympus: Scientific Study
or Trial; Allergan: Scientific Study or
Trial; Lithotripsy group: Piedmont stone
& Physician Discovery: Investment
Interest
Elspeth M. McDougall, MD, FRCSC,
MHPE
Professor of Urology
Director, Surgery Education Center,
Associate Dean of Simulation & Continuing Medical Education
Chair, AUA Education Council
University of California, Irvine
School of Medicine
Irvine, CA
Disclosures: Endocare: Other - Unrestricted Grant; Ethicon Endo-Surgery:
Other - Equip Support-MIS Educ Center @ UCI; Intuitive Surgical: Other
- Equip Support-MIS Educ Center @
UCI; Karl Storz Endoscopy America:
Other - Equip Support-MIS Educ Center @ UCI; Simbionix: Other - Equip
Support-MIS Educ Center @ UCI
Commercial Support
This CME activity is supported by an
educational grant from Lilly USA, LLC.
Statement of Evidence-Based Content
As a provider of continuing medical
education accredited by the ACCME,
it is the policy of the AUAER to review
and certify that the content contained in
this CME activity is valid, fair, balanced,
scientifically rigorous and free of commercial bias.
Off-label or Unapproved Use of
Drugs or Devices
It is the policy of the AUAER to require
the disclosure of all references to off-label
or unapproved uses of drugs or devices
prior to the presentation of educational
content. The audience is advised that
this continuing medical education activity may contain reference(s) to off-label
or unapproved uses of drugs or devices.
Please consult the prescribing information for full disclosure of approved uses.
Copyright © 2012 by the American
Urological Association
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Access the AUA Privacy and Confidentiality Policy at http://www.auanet.org/
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AUANews AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
3
COURSE #09IC
BPH Medical Management
Claus G. Roehrborn, MD, Course Director; Christopher Chapple, BSc, MD FRCS (Urol), Faculty
Lower urinary tract symptoms (LUTS)
are common in men, particularly with
advancing age. These symptoms encompass storage, voiding and post-micturition symptoms. It must be remembered
that symptoms are not disease specific,
patients often have difficulty clearly
describing their symptoms accurately
and as clinicians we have our own mindset in terms of how to interpret these
symptoms. It is now recognized that storage symptoms are the most bothersome, particularly if incontinence is present. Recent
epidemiological studies have revealed the
prevalence of these symptoms.1 A misnomer exists in the literature in that storage
symptoms in men are often labeled as
“voiding dysfunction,” when in fact the
term filling dysfunction should be used
instead. In this context it must be borne
in mind that even in symptomatic men
nearly 100% of bladder time is spent
storing urine and the act of voiding is
transient.
Benign prostatic hyperplasia (BPH)
is commonly used as a diagnostic term
when referring to LUTS experienced
by men from the fifth decade of life
onwards. It is important to recognize that
the term BPH is a histological diagnosis
and cannot be made on the basis of
symptoms alone. The literature clearly
demonstrates the lack of consensus relating to the term BPH as it is interpreted in
many different ways. The International
Prostate Symptom Score (I-PSS) is commonly used in the evaluation of men presenting with symptoms. Of 7 questions
on the I-PSS 4 deal with voiding and 3
with storage dysfunction with an additional quality of life question. The I-PSS
cannot be used as a diagnostic criterion.
Flow rates are often used as a proxy
for obstruction combined with measurement of post-void residual, which relates
not to obstruction per say but to the ability of the bladder to empty, and hence
provides insight into bladder function.
In approximately 50% of men with BPH
the prostate is enlarged, and half of them
have some degree of bladder outflow
obstruction. Clearly there is considerable variation in the way symptoms are
described by patients at presentation.
The term overactive bladder (OAB)
was introduced more than a decade ago
and a review of the literature demonstrates that in men and women there is a
similar increased prevalence of the storage symptoms of OAB with age (defined
based on the symptoms of urgency associated with frequency, nocturia and urgency incontinence). It is well recognized
that OAB symptoms are prevalent in
men presenting to clinicians. In the past
it was suggested that these OAB symptoms were often associated with detrusor
overactivity and, therefore, by inference
believed to be a direct consequence of
bladder outlet obstruction, particularly
as they improved after surgical relief of
obstruction.
The current consensus among
researchers is that OAB and associated
detrusor overactivity may well be an agerelated phenomenon rather than a direct
consequence of outlet obstruction. In
this context sensory mechanisms have
been implicated as being important. The
effect of prostatic surgery may also be
related to a local deafferentation within
the prostatic urethra due to resection or
ablation of the urothelium within the
prostatic urethra.
It is now known that LUTS are not
disease specific and have a multifactorial cause. In particular, this fact is
confirmed when symptoms of nocturia
(sleep disturbing voiding) are considered. All recent guidelines suggest that a
voiding diary (frequency volume chart)
should be used in the evaluation of
all men with LUTS in addition to an
I-PSS, and flow rate and residual urine
measures. Using a voiding diary it is
possible to define the potential etiology
of nocturia, specifically with regard to
the volume of urine produced at night. If
the volume of urine produced after retiring to bed with the intention of going to
sleep is more than 33% of the 24-hour
urinary production, then the patient has
nocturnal polyuria. This volume would
suggest a pathophysiological cause for
the nocturia, which lies outside the lower
urinary tract, e.g. fluid retention, cardiac
dysfunction, sleep apnea etc.
In addition, lower urinary tract dysfunction is often associated with other medical conditions, particularly in the context
of the metabolic syndrome. Therefore,
the appropriate and effective treatment
of male patients presenting with symptoms needs to consider other potential
comorbid conditions, such as hypertension, erectile dysfunction, coronary artery
disease, diabetes, peripheral arterial disease and neurological disorders. With
recognition of the importance of these
associated factors has come an increased
emphasis in recent years on a “tailored”
approach to the effective treatment of
male patients with LUTS.
Alpha antagonist therapy has been the
mainstay of pharmacotherapy for the
management of male LUTS for more
than 3 decades. Alpha-1 antagonists act
rapidly on prostates of all sizes, and contemporary agents in common use are
effective and well tolerated. The most
commonly used agents that have the best
balance between efficacy and tolerability
are tamsulosin and alfuzosin. These are
available in once a day formulations and
have similar efficacy. While tamsulosin
has some increased activity for the alpha1a receptor, this has not resulted in any
greater efficacy or safety than seen with
alfuzosin. In addition, the development
of much higher subtype selectivity for
the alpha-1a receptor seen with silodosin
has not resulted in any greater efficacy
as evidenced by a direct comparison of
tamsulosin and silodosin.2
The use of 5-alpha-reductase therapy is
now well established and was discussed
▼ Continued on page 4
4
AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
Course #09IC
▼ Continued from page 3
in great detail by Dr. Roehrborn during
our course. In particular, in recent years
there has been increased emphasis on
the potential for combination therapy of
a 5-alpha-reductase inhibitor and alpha
blockers for the management of LUTS,
particularly in patients with prostates
larger than 30 gm with a proxy for this
being increased prostate specific antigen
(malignancy having been excluded).
There has been recent increased interest in the potential use of antimuscarinic therapy for many male patients
presenting with LUTS. If the predominant problem is storage dysfunction,
then antimuscarinic therapy will be as
effective in male as in female patients as
clearly established from a review of the
literature. In many male patients storage symptoms persist despite appropriate
pharmacotherapy for voiding symptoms.
Recent studies have shown the potential benefit accruing from the addition
of antimuscarinic therapy to an alpha1-antagonist in patients with a post-void
residual of less than 200 ml.
A major concern has been the potential risk of retention in male patients,
particularly when voiding dysfunction is
also present. With the appropriate dose
of antimuscarinic therapy in the absence
of increased post-void residual, retention
does not occur to any greater extent than
that seen with placebo in randomized
control trials.3 Research continues into
the potential for combination therapy for
voiding dysfunction.
Recent studies have suggested a beneficial effect with phosphodiesterase-5
(PDE5) inhibitors for the management
of male LUTS, albeit the PDE5 inhibitors do not appear to alter urodynamic
parameters to any significant extent. The
potential for these agents in therapeutic
practice was reviewed in detail by Dr.
Roehrborn.
It is clear from the literature that conventional concepts relating to the genesis of symptoms have been challenged
in recent years. There is an increasing
pharmacotherapeutic armamentarium
available for the treatment of BPH. It
is essential, as emphasized in all existing guidelines, that patients are evaluated appropriately with judicious use of
a targeted history coupled with an I-PSS
including the 7 questions within the
score and a quality of life score, flow rate,
post-void residual and a voiding diary. In
this context, assessment of prostate size is
also useful for identifying patients with
larger prostates who may benefit from
PDE5 inhibitors.
The mainstay of treatment for presumed BPH in male patients from the
fifth decade of life onward relies on
initial use of an alpha antagonist, potentially in larger prostates, combined with a
PDE5 inhibitor. Judicious use of antidiuretic therapy in male patients with
nocturia can be helpful after appropriate
evaluation to exclude significant nocturnal polyuria. In male patients with OAB
antimuscarinic therapy can be helpful,
potentially in combination with either
an alpha-1 antagonist or PDE5 inhibitor
following appropriate evaluation. Use
of PDE5 inhibitors is a new development for the management of LUTS
particularly in the male with coexisting
erectile dysfunction, albeit the literature would suggest a beneficial effect of
PDE5 inhibitors occurs whether there is
underlying erectile dysfunction or not.
Thus, the effective contemporary treatment of male patients presenting with
LUTS relies on comprehensive knowledge of the therapeutic options available
and a tailored approach to therapy. ♦
1. Irwin DE, Milsom I, Hunskaar S et al: Populationbased survey of urinary incontinence, overactive
bladder, and other lower urinary tract symptoms in
five countries: results of the EPIC study. Eur Urol
2006; 50: 1306.
2. 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, doubleblind, placebo- and active-controlled clinical trial
performed in Europe. Eur Urol 2011; 59: 342.
3. Athanasopoulos A, Chapple C, Fowler C et al: The
role of antimuscarinics in the management of men
with symptoms of overactive bladder associated
with concomitant bladder outlet obstruction: an
update. Eur Urol 2011; 60: 94.
AUANews AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
5
COURSE #31 PG
Urologic Diseases for the Allied Health Professional
Allen Seftel, MD, Course Director; Jeffrey Albaugh, PhD, APRN-BC,CUCNS, Donald Bodner, MD, Gina Fries, RPAC and Lindsey Kerr, MD, Faculty
The AUA guideline on the “Management of Benign Prostatic Hyperplasia
(BPH)” (Benign Prostatic Hyperplasia
(BPH) (2010) was reviewed in this course.
The index patient is a male 45 years old
or older consulting a health care provider
for lower urinary tract symptoms. BPH is
among the most common conditions of
aging men and can have a large impact
on the quality of life.
Central to the evaluation of an individual with BPH/LUTS along with a
detailed medical history and directed
physical examination is the AUA symptom score (AUASS) or the International
Prostate Symptom Score. This validated
questionnaire can be used to quantify
symptoms as mild (score less than 8),
moderate (8 to 19) or severe (20 to 35)
and help direct treatment. As a standard,
information on the benefits and harms of
treatment for LUTS secondary to BPH
should be explained to the patient with
moderate to severe symptoms (scores
8 or higher). Laboratory testing for
BPH/LUTS does not routinely include
creatinine measurement. The controversy regarding prostate specific antigen
screening and the recent U.S. Preventive
Services Task Force recommendations
were discussed.
Patient satisfaction is important to the
treatment of clinical BPH. Treatment
options include watchful waiting (active
surveillance), which is appropriate for
patients with mild symptoms (AUASS
less than 8) and those with moderate
symptoms that are not bothered by them.
For individuals with moderate symptoms
that are bothersome, treatment options
include pharmacologic as well as surgical therapies.
Approved medications for symptomatic BPH/LUTS include alpha blockers, daily Tadalafil, 5–alpha-reductase
inhibitors (5ARIs), anticholinergics and
combination of two or more of these
medications. Tadalafil 5 mg daily was
recently approved by the Food and Drug
Administration (FDA) for symptomatic
BPH/LUTS. Anticholinergic agents are
appropriate when the symptoms are primarily irritative. When considering anticholinergics, a baseline post-void residual is recommended and caution should
be exercised if the residual is greater than
250 to 300 cc. The combination of alpha
blockers with 5ARIs for larger prostates
has been shown to reduce the incidence
of urinary retention or the ultimate need
for surgical intervention.
No dietary supplement or phytotherapy agent is recommended for the management of LUTS/BPH. 5ARIs were not
approved by the FDA for the prevention of prostate cancer. When suggesting medical management, consideration
should be given to improve symptoms
and minimize adverse effects of the treatment.
Accepted surgical therapies for
BPH/LUTS include transurethral incision of the prostate, transurethral microwave thermotherapy, transurethral needle ablation, laser prostatectomy (vaporization, enucleation etc using a variety of
different lasers), transurethral resection
of the prostate (bipolar, monopolar or
vaporization), open prostatectomy and
laparoscopic or robotic simple prostatectomy. The advantages and risks of each
should be reviewed with the patient so
that he can make the best informed decision.
In conclusion, LUTS are often associated with other conditions and not just
BPH. The AUASS is central in helping
to decide treatment algorithms. It is
important to treat those individuals with
moderate to severe symptoms who are
bothered by the symptoms. Pharmacologic therapy is effective and a variety
of approaches are available. Minimally
invasive therapies and surgical options
are effective and continue to evolve.
Patients should be advised of treatment
alternatives. ♦
Donald Bodner, MD
Professor of Urology
UH Case Medical Center
Cleveland, Ohio
6
AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
THE SCIENCE OF MALE HEALTH FORUM
Stress Response and BPH
Robert H. Getzenberg, PhD and Prakash Kulkarni, PhD
Benign prostatic hyperplasia is a term
used to describe enlargement of the
prostate associated with lower urinary
tract symptoms. Although BPH refers
to the prostate, it is known that other
organs, including the bladder, are centrally involved in many of the symptoms associated with the disease. Despite
the fact that BPH is among the most
common urological conditions affecting
aging men, we still know little about its
etiology, and the frequently used medical therapies are focused on symptom
improvement rather than the biology of
the disease(s).
It is clear that not all BPH is created
the same. Some men present with large
prostates and others with prostates within
the normal size range. Furthermore,
BPH is currently treated differently than
most diseases as a result of its symptomatic description. As opposed to diseases like
cancer, BPH is not diagnosed pathologically but diagnosis is based on description of the reported symptoms and their
severity. Typically a disease presents and
the earlier the treatment the better. As
opposed to the approach of catching and
treating a disease early, BPH treatment
is usually reserved for men with some
of the most severe symptoms rather than
those with histological disease. Therefore, there is a dire need to improve our
molecular understanding of BPH so that
we can discern novel biomarkers that
could identify early in the disease course,
men with severe disease who could have
or may go into urinary retention.
No such biomarkers exist or are currently being used. Furthermore, biomarkers are needed that can stratify patients
into categories of response to therapies,
i.e. which patient may respond better to a
particular therapy. This type of approach
would allow us to focus potentially efficacious therapies on men with the disease
type known to be most responsive rather
than our current strategy of treating and
seeing if symptoms improve.
Among the biomarkers that have been
evaluated those associated with inflammation appear to have taken center
stage.1 It seems that a form of inflammation may be activated in more highly
symptomatic BPH. In an effort to characterize molecular changes associated
with symptomatic BPH, we performed
an analysis of patterns of gene expression associated with highly symptomatic
disease as defined by the AUA symptom
score.2 We identified a series of proteins
encoded by the differentially expressed
genes that were associated with severe
symptoms. Among these proteins was a
Cancer/Testis Antigen known as PAGE4,
alternatively called JM-27.
PAGE4 was relatively specific to the
prostate and approximately 18-fold higher in expression in BPH associated with
significant symptoms.2 PAGE4 protein
levels were found to be associated, not
with the prostatic epithelium like most
prostatic biomarkers, but with the prostatic stroma. The relatively high level
of expression within the stromal cells of
the prostate associated with symptomatic
BPH makes PAGE4 a unique protein.
In preliminary studies PAGE4 appears
to be expressed within the fetal prostate
but then turned off in the normal adult
prostate and reactivated in the stroma
of the men with symptomatic but not
asymptomatic BPH. When we artificially
over expressed, we found that the PAGE4
over expressing cells were able to protect
themselves from stresses including glucose deprivation, tumor necrosis factor-a
and doxorubicin challenge (Zeng Y, personal communication). Thus, it appears
that PAGE4 may represent a marker of
the stress associated changes that accompany symptomatic BPH. This stress reaction may include inflammation, which
as described above, has been associated
with more highly symptomatic disease.
The stress response not only involves
the epithelial components of the prostate, but the stromal elements as well. In
fact, it may be the stromal components
that are the key regulators of the prostatic
changes associated with BPH regardless of whether the disease presents as
more epithelial or stromal predominant.
The stress response may be a driver or a
passenger in the process that results in
the prostatic changes corresponding with
the observed symptoms but regardless, it
seems to be an important contributor.
Since most BPH is diagnosed not
pathologically, but as part of a spectrum
of symptoms, it would seem that a tool to
aid in the personalization of BPH treatment would be relatively noninvasive.
In an effort to identify noninvasive biomarkers of BPH, we have been measuring PAGE4 in the blood as a potential
indicator of disease type. These studies
should reveal whether PAGE4 has the
potential to serve as a serum based biomarker of symptomatic BPH.
We need to move beyond the currently used model in which we treat
BPH as merely a collection of symptoms
rather than focusing on the biology that
underlies them. Personalization is necessary to use the currently available treatments more wisely as well as understand
the potential of novel therapies to treat
patient subgroups. While we do not yet
have the biomarkers to discern personalization, our increased understanding of
the genetics, epidemiology and microenvironmental stress associated with BPH
should provide us with valuable tools to
begin down this road. ♦
1. Schenk JM, Kristal AR, Neuhouser ML et al:
Biomarkers of systemic inflammation and risk of
incident, symptomatic benign prostatic hyperplasia:
results from the prostate cancer prevention trial.
Am J Epidemiol 2010; 171: 571.
2. Prakash K, Pirozzi G, Elashoff M et al: Symptomatic and asymptomatic benign prostatic hyperplasia: molecular differentiation by using microarrays.
Proc Natl Acad Sci U S A 2002; 99: 7598.
AUANews AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
7
PLENARY SESSION
Take Home Message: Benign Prostatic Hyperplasia
and Lower Urinary Tract Symptoms
Dr. Ricardo R. Gonzalez,* Houston, Texas, provided the audience with highlights of the AUA meeting on BPH. The abstract numbers are indicated in
parentheses.
(Reprinted from AUANews 2012; Vol.
15, No. 7, pp 15-16)
Surgical Updates
Monopolar transurethral resection of the
prostate (TURP), postoperative urinary
infection and retention predicted urethral stricture after surgery for transurethral benign prostatic hyperplasia (BPH)
(2). The adoption of laser technology
is associated with an increase in surgical therapy for BPH (1974). Men who
underwent holmium laser enucleation
(HoLEP) reported improved sexual
parameters and decreased lower urinary
tract symptoms (LUTS) (1866).
In a small, randomized, controlled
trial (RCT) 200 units of intradetrusor
Botox® improved maximum urine flow
but not frequency in men with refractory
overactive bladder after surgical treatment for BPH (1971). Bipolar TURP
and HoLEP effectively treated bladder
outlet obstruction (BOO) in an RCT but
HoLEP resulted in less blood loss, catheterization time and hospital stay (1976).
Bipolar transurethral prostate enucleation effectively treats BOO compared
to open prostatectomy with less blood
loss, transfusion risk and hospital stay
(1977). Photoselective vaporization of
the prostate (PVP) before radiation was
safe and improved voiding symptoms
in men with concomitant symptomatic
BPH and prostate cancer (1979).
Ejaculatory preserving techniques
were feasible with modified TURP
(2013). Ejaculatory preserving modifications to PVP did not decrease the voiding
benefits associated with prostate debulking (2016). Thulium vapor resection of
the prostate was associated with erectile
dysfunction (ED) in 20% of men and
retrograde ejaculation in 56% of 54 of
113 men sexually active before surgery
(2014). At a single tertiary care center the
rate of incidental prostate cancer in 554
consecutive TURP specimens was 1.1%,
all of which were low grade, low volume
disease (2018).
Prostatic arterial embolization (PAE)
is a novel therapy for symptomatic BPH
with improvement in 73 of 92 men
(82%) at 3 months (2026). Other than 1
serious complication (bladder ischemia),
adverse events were limited.
PAE resulted in improved urodynamic parameters, including a decreased
obstruction index, in 76% of men treated
(2027). PVP with the 180 W 532 nm
GreenLight XPS™ laser was as effective as the 120 W GreenLight HPS®
laser with shorter operative time, less
fiber need and a greater prostate specific
antigen decrease, implying more tissue
removal (2175). Vapor incision of the
prostate with the GreenLight laser was
more time efficient with superior shortterm outcomes compared to traditional
PVP with the 120 W HPS laser in prostates greater than 80 cc (2176). An RCT
of PVP with the 120 W GreenLight HPS
laser vs TURP revealed similar LUTS
improvement 1 year postoperatively with
a shorter hospital stay in the PVP group
(2177).
Validated LUTS questionnaires
before renal transplantation may predict
patients who will have significant LUTS
after transplantation (2265). Early identification and management of urological
symptoms may help avoid complications
that can compromise renal allografts.
Laboratory Studies
A rat model of partial BOO resulted in
nerve damage to the bladder neck with
secondary changes to corpus cavernosal
smooth muscle, which mediates contraction/relaxation (1006). This study may
help explain the comorbid relationship
of ED with BOO. Testosterone positively regulated phosphodiesterase type 5
(PDE5) expression in rat prostatic stroma
(1565). Castration reduced not only prostate size, but also prostatic smooth muscle contractility via multiple pathways.
Tadalafil attenuated cell growth in BPH
xenografts in super-SCID mice (1570).
Laboratory/Epidemiology Update
Urinary nerve growth factor/creatinine
levels correlated with lower serum NOx
in men (1740). Serum high density
lipoprotein correlated with increasing
histological inflammation on prostate
specimens in men with BPH-LUTS who
underwent surgery (1734). Obesity was
associated with increasing prostate volume and an attenuated prostate volume
reduction with dutasteride on post hoc
analysis of the 4-year REDUCE (Reduction by Dutasteride of Prostate Cancer
Events) RCT of dutasteride vs placebo
(1736).
Medical Therapy for BPH/LUTS
Update
In the 4-year randomized CombAT
(Combination of Avodart® and Tamsulosin) trial only 5.9% of men on dutasteride initiated use of a PDE5 inhibitor
(PDE5i) (1248). A double-blind, placebo
controlled trial revealed that tadalafil and
tamsulosin decreased International Prostate Symptom Score but only tadalafil
improved quality of life and ED scores
over placebo (1245). A meta-analysis
of 7 RCTs comparing PDE5i vs placebo revealed that PDE5i significantly
improved LUTS and ED in men with
BPH with or without ED (1253).
An RCT showed that tamsulosin/
tadalafil was safe and more effective
for LUTS than tamsulosin/placebo in
▼ Continued on page 8
8
AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
Plenary Session
▼ Continued from page 7
men with LUTS associated with BPH
(1254). Five mg tadalafil daily improved
BPH-LUTS independent of ED severity
and prostate size on post hoc analysis
of 3 RCTs (1257). Doses of 50 and
100 mg mirabegron, a novel ß3 agonist
that mediates bladder relaxation, did
not adversely affect the flow rate, detrusor pressure at maximum flow rate or
bladder contractile index, and was well
tolerated in men with LUTS and BOO
(1869). ♦
*Financial interest and/or other relationship with American Medical Systems, Astellas, Allergan, GlaxoSmithKline and Watson Pharmaceuticals.
AUANews AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
9
ABSTRACT HIGHLIGHTS
1245: EFFECTS OF TADALAFIL OR TAMSULOSIN ON LOWER URINARY
TRACT SYMPTOMS SUGGESTIVE OF BENIGN PROSTATIC HYPERPLASIA AND ON ERECTILE DYSFUNCTION: RESULTS FROM AN INTERNATIONAL, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL*
Matthias Oelke, Francois Giuliano, Vicenzo Mirone, Lei Xu, David Cox, Lars Viktrup
(Reprinted from J Urol., suppl., 2012;
187: e503.
Introduction and Objectives
Tadalafil 5 mg once daily (TAD) can
improve lower urinary tract symptoms
suggestive of benign prostatic hyperplasia
(LUTS/BPH) and erectile dysfunction
(ED), which often coexist. This study
evaluated effects of TAD or tamsulosin
0.4 mg (TAM) compared with placebo
(PLA) on LUTS/BPH, and also on ED
in those men who were sexually active
and had ED
Methods
Men had moderate to severe LUTS/
BPH (International Prostate Symptom
Score [IPSS]≥13 and maximum flow rate
[Qmax] 4-15 mL/s). Patients received
PLA for 4 weeks (single-blind), then were
randomized to PLA (N=172), TAD 5 mg
(N=171) or TAM 0.4 mg (N=168) once
daily for 12 weeks. The primary comparison was between TAD and PLA; the study
was not powered for direct comparison
between active treatments. The primary
efficacy outcome was IPSS change at
endpoint (12 weeks or last measurement),
assessed by analysis of covariance. Other
measures included BPH Impact Index
(BII), IPSS Quality of Life (QoL) index,
the BPH-Treatment Satisfaction Scale
(TSS-BPH), Patient and Clinician Global
Impression of Improvement scales (PGII and CGI-I), the International Index
of Erectile Function-Erectile Function
domain (IIEF-EF), Qmax, and treatmentemergent adverse events (TEAEs).
Results
TAD and TAM significantly improved
total IPSS at endpoint (least squares mean
PLA-adjusted treatment difference: TAD,
-2.1 [p=0.001]; TAM, -1.5 [p=0.023]) and
1- and 4-weeks, and significantly improved
BII at 4 weeks and endpoint (Table). Only
TAD also significantly improved the IPSS
QoL index, TSS-BPH scores, and PGI-I
and CGI-I compared with PLA (Table).
TAD significantly improved ED at endpoint compared with PLA; TAM did
not (Table). Qmax increased significantly
at endpoint with both TAD (2.4 ml/s,
p=0.009) and TAM (2.2 ml/s, p=0.014)
compared with PLA (1.2 ml/s). TEAE
incidence was numerically higher with
TAD (23.4%) and TAM (23.8%) compared with PLA (20.3%).
Conclusions
Both TAD and TAM significantly
improved LUTS/BPH measured by IPSS
at endpoint and as early as 1 week, and
both improved Qmax at endpoint. Only
TAD significantly improved secondary
LUTS/BPH measures of QoL, global
improvement, and treatment satisfaction,
and only TAD improved ED. ♦
Awarded best poster in the Benign
Prostatic Hyperplasia: Medical and
Hormonal Therapy Session at annual
meeting of the American Urological
Association, Atlanta, Georgia, May
19-23, 2012.
*Eli Lilly and Company funded this
study.
PLA
TAD 5 mg
TAM 0.4 mg
P value
P-value TAM
TAD vs PLA vs PLA
Endpoint
-4.2 +/- 0.5
-6.3 +/- 0.5
-5.7 +/- 0.5
0.001
0.023
1-week
-2.5 +/- 0.4
-4.0 +/- 0.4
-4.0 +/- 0.4
0.003
0.005
4-weeks
-3.3 +/- 0.4
-5.5 +/- 0.4
-5.7 +/- 0.4
< 0.001
< 0.001
Endpoint
-0.9 +/- 0.2
-1.7 +/- 0.2
-1.5 +/- 0.2
0.003
0.026
4-weeks
-0.4 +/- 0.2
-1.2 +/- 0.2
-1.3 +/- 0.2
< 0.001
< 0.001
IPSS-QoL*
-1.0 +/- 0.1
-1.3 +/- 0.1
-1.1 +/- 0.1
0.022
0.546
0.013
0.216
IPSS*
BII*
CGI-I**
Better
62.5%
76.1%
69.4%
-
-
No change
31.9%
19.6%
26.1%
-
-
Worse
5.6%
4.3%
5.1%
-
-
0.005
0.116
PGI-I**
Better
62.9%
78.1%
72.6%
-
-
No change
32.1%
17.5%
22.9%
-
-
Worse
5.0%
4.4%
5.1%
-
-
TSS-BPH^
28.9
22.2
28.9
0.005
0.457
IIEF-EF*
2.1 +/- 0.8
6.0 +/- 0.8
1.7 +/- 0.8
< 0.001
0.699
PLA, placebo; TAD, tadalafil; TAM, tamsulosin; IPSS, International Prostate Symptom Score; QoL, quality of
life; BII, BPH Impact Index; CGI-I, Clinician Global Impression of Improvement; PGI-I, Patient Global Impression of Improvement; TSS-BPH, Treatment Satisfaction Scale-BPH; IIEF-EF, International Index of Erectile
Function-Erectile Function. *Least-squares mean change from baseline +/- standard error; p-value is from analysis of covariance for treatment difference in LS means. **Percentage of subjects in each response category at endpoint; p-value from Cochran-Mantel-Haenszel test for distribution of response across categories. ^Median score at
endpoint, lower scores indicate higher satisfaction; p-value from Van Elteren test comparing medians.
10
AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
1253: SYSTEMATIC REVIEW AND META-ANALYSIS OF
THE USE OF PHOSPHODIESTERASE TYPE 5 INHIBITORS (PDE5-Is) FOR LOWER URINARY TRACT SYMPTOMS (LUTS) SECONDARY TO BENIGN PROSTATIC
HYPERPLASIA (BPH)
Mauro Gacci, Florence, Italy; Giovanni Corona, Bologna Italy; Matteo Salvi, Linda Vignozzi, Florence Italy; Kevin T. McVary, Chicago IL; Steven A.
Kaplan, New York, NY; Claus G. Roehrborn, Dallas, TX; Sergio Serni, Florence Italy; Vincenzo Mirone, Naples, Italy; Marco Carini, Mario Maggi, Florence, Italy
(Reprinted from J Urol, suppl., 2012;
187: e506)
Introduction and Objectives
Aim of present study is to perform a
systematic review and meta-analyses of
available prospective and cross-sectional
studies on the use of phosphodiesterase
type 5 inhibitors (PDE5-Is) alone and/or
in combination with alpha1-adrenergic
blockers in LUTS/BPH patients.
Methods
An extensive Medline search was performed including the combination of
following words: LUTS, BPH, PDE5-Is,
sildenafil, tadalafil, vardenafil, udenafil,
alpha blockers, alpha1-adrenergic blocker.
Out of 107 retrieved articles, 12 were
included in the present meta-analysis.
The remaining 95 were excluded for
missing or incomplete data (baseline
data, standard deviation), deficiency in
methodology (lack of a placebo group,
several biases not included), assessment
of clinical outcomes without validated
instruments (IPSS, IIEF, Qmax).
Among the RCTs 12 published studies
were included (with 3492 patients): 7
comparing PDE5-Is vs placebo and 5 the
combination of PDE5-Is with alpha1adrenergic blockers vs alpha1-adrenergic
blockers alone.
IIEF-5 (International Index of Erectile
Function), IPSS (International Prostate
Symptom Score) and Maximum urinary
flow rate (Qmax) were the outcomes
included in the meta analyses.
Results
The 7 RCTs comparing PDE5i vs placebo enrolled 3214 patients with mean
age of 61.3 years (2250 PDE5-Is and 964
placebo), while the 5 comparing combination vs alpha-blockers alone enrolled
216 patients with mean age of 63.4 (109
combination and 107 alpha-blockers).
Median follow-up of all RCTs was 12
weeks.
Combining the results of those trials,
the use of PDE5-Is alone was associated
with a significant improvement of IIEF
score (5.5; p<0.0001), IPSS score (-2.8;
p<0.0001), but not Qmax (-0.00; p:N.S.)
at the end of the study, as compared
with placebo. Similarly the association of
PDE5-Is and alpha1-adrenergic blockers
improved IIEF score (3.60; p<0.0001),
IPSS score (-1.85; p=0.05), Qmax (1.53;
p<0.0001) at the end of the study, as
compared with alpha blockers alone.
Conclusions
The meta-analysis of the available crosssectional data suggests that PDE5-Is can
significantly improve LUTS and erectile
function in BPH men. PDE5-Is can be
considered as an alternative treatment for
patients with LUTS secondary to BPH
with or without erectile dysfunction. ♦
AUANews AUA 2012 ATLANTA, GA ANNUAL MEETING HIGHLIGHTS
11
1727: THE ASSOCIATION OF POSTTRAUMATIC
STRESS DISORDER WITH LOWER URINARY TRACT
SYMPTOMS IN MALE IRAQ AND AFGHANISTAN
VETERANS *
Benjamin Breyer, Beth Cohen, Daniel Berterthal, Raymond Rosen, Thomas Neylan, Karen Seal, San Francisco, CA
(Reprinted from J Urol, suppl., 2012;
187: e696)
es, and the prescription of medications
for LUTS.
Introduction and Objectives
Results
The main aim of this study was to
examine the association between posttraumatic stress disorder (PTSD) and
Lower Urinary Tract Symptoms (LUTS)
in male Iraq and Afghanistan veterans.
The median age of 643,599 Iraq and
Afghanistan veterans in VA healthcare
was 26 years; the prevalence of PTSD
and LUTS during the study period was
28.5% and 1.6%, respectively. Male veterans with PTSD compared to those
without PTSD were more likely to suffer
from LUTS (2.9% versus 1.1%, p<.001).
Veterans with PTSD compared to those
without PTSD were also more likely
to receive prescriptions for an alpha
blocker or 5 alpha-reductase inhibitor
(1.7% versus 0.7%, p<.001) and they
were more likely to have attended a urology clinic (8.1% versus 3.6%, p<.001). In
a generalized linear model adjusted for
sociodemographic, military service characteristics, and spinal cord injury, PTSD
independently increased the relative risk
of LUTS by nearly three times [adjusted
relative risk (ARR)=2.81, 95% Confidence Interval (CI) = 2.7-2.92]. After
additional adjustment for medications
Methods
This retrospective study used a Department of Veteran Affairs (VA) administrative database of Iraq and Afghanistan veterans enrolled in VA healthcare following military service separation between
10/07/01 through 09/30/11. ICD-9 diagnostic codes were used to identify PTSD
and LUTS. Health services utilization
and prescription medication data were
also obtained. Descriptive statistics were
used to compare the prevalence of LUTS
in veterans with and without PTSD and
generalized linear models were used
to examine associations between PTSD
and LUTS, utilization of urology servic-
used to treated PTSD (e.g. selective serotonin uptake inhibitors and other psychoactive medication) and urology clinic
visit history, the relative risk of LUTS
decreased, but was still significantly associated with PTSD (ARR=1.19, 95% CI=
1.12-1.26).
Conclusions
LUTS is prevalent among Iraq and
Afghanistan veterans enrolled in VA
healthcare who have received PTSD
diagnoses. While medications used in
the treatment of PTSD may contribute
to LUTS, PTSD and/or autonomic dysregulation associated with PTSD also
appears to independently increase the
likelihood of LUTS. Awareness of the
significant association between PTSD
and LUTS may stimulate more research
and improved treatments for this important quality of life issue. ♦
*BNB was supported by NIH grant
K12DK083021.