AUA Guidelines

www.auajournals.org/journal/juro

Management of Lower Urinary Tract Symptoms Attributed to

Benign Prostatic Hyperplasia: AUA GUIDELINE PART IdInitial
Work-up and Medical Management
Lori B. Lerner, MD,1,* Kevin T. McVary, MD, Michael J. Barry, MD, Brooke R. Bixler, MPH,
Philipp Dahm, MD, Anurag Kumar Das, MD, Manhar C. Gandhi, MD, Steven A. Kaplan, MD,
Tobias S. Kohler, MD, Leslie Martin, MD, J. Kellogg Parsons, MD, Claus G. Roehrborn, MD,
John T. Stoffel, MD, Charles Welliver, MD and Timothy J. Wilt, MD
1
VA Boston Healthcare System, Department of Surgery, West Roxbury, Massachusetts

Purpose: Benign prostatic hyperplasia (BPH) is a histologic diagnosis

Abbreviations
describing proliferation of smooth muscle and epithelial cells within the
and Acronyms
5-ARI [ 5-alpha reductase inhibitor
prostatic transition zone. The prevalence and severity of lower urinary tract
AUR [ acute urinary retention
symptoms (LUTS) in aging men are progressive and impact the health and
AUA [ American Urological Association welfare of society. This revised Guideline provides a useful reference on
BPE [ benign prostatic enlargement effective evidence-based management of male LUTS/BPH. See the accompa-
BPH [ benign prostatic hyperplasia nying algorithm for a summary of the procedures detailed in the Guideline
BPO [ benign prostatic obstruction (figures 1 and 2).
CT [ computerized tomography
Materials and Methods: The Minnesota Evidence Review Team searched Ovid
DO [ detrusor overactivity
ED [ erectile dysfunction
MEDLINE, Embase, Cochrane Library, and AHRQ databases to identify
EF [ erectile function eligible English language studies published between January 2008 and April
EjD [ ejaculatory dysfunction 2019, then updated through December 2020. Search terms included Medical
IFIS [ intraoperative floppy iris syndrome Subject Headings (MeSH) and keywords for pharmacological therapies, drug
IPSS [ International Prostate Symptom Score classes, and terms related to LUTS or BPH. When sufficient evidence existed,
LUTS [ lower urinary tract symptoms the body of evidence was assigned a strength rating of A (high), B (moderate), or
LUTS/BPH [ male lower urinary tract symp- C (low) for support of Strong, Moderate, or Conditional Recommendations. In
toms secondary/attributed to BPH
MRI [ magnetic resonance imaging
the absence of sufficient evidence, information is provided as Clinical Principles
PDE5 [ phosphodiesterase-5 and Expert Opinions (table 1).
PDE5i [ phosphodiesterase-5 inhibitor Results: Nineteen guideline statements pertinent to evaluation, work-up, and
PVR [ post-void residual medical management were developed. Appropriate levels of evidence and sup-
PSA [ prostate specific antigen
porting text were created to direct both primary care and urologic providers to-
QoL [ quality of life
wards streamlined and suitable practices.
TURP [ transurethral resection of the prostate
TWOC [ trial without catheter Conclusions: The work up and medical management of BPH requires attention to
UTI [ urinary tract infection individual patient characteristics, while also respecting common principles. Cli-
nicians should adhere to recommendations and familiarize themselves with
standards of BPH management.

Key Words: LUTS, BPH, alpha blocker, 5ARI, PDE5, IPSS, anticholinergic,
beta 3 agonist, prostate

Accepted for publication August 6, 2021.

The complete unabridged version of the guideline is available at https://www.jurology.com.
This document is being printed as submitted, independent of standard editorial or peer review by the editors of The Journal of Urology.
* Correspondence: VA Boston Healthcare System, Department of Surgery, 1400 VFW Parkway, West Roxbury, Massachusetts 02132 (tele-
phone: 603.252.5847; FAX: 781.749.5319; email: [email protected]).

0022-5347/21/2064-0806/0 https://doi.org/10.1097/JU.0000000000002183
THE JOURNAL OF UROLOGY® Vol. 206, 806-817, October 2021
Ó 2021 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A.

806 j www.auajournals.org/jurology
Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I 807

Figure 1. Basic Management of LUTS in Men Algorithm

BACKGROUND by age 60, and 80% by age 80. BPH can lead to
BPH is a histologic diagnosis that refers to the pro- benign prostatic enlargement (BPE), which can
liferation of glandular epithelial tissue, smooth mus- cause obstruction at the level of the bladder neck,
cle, and connective tissue within the prostatic termed benign prostatic obstruction (BPO).
transition zone. BPH is likely a multifactorial process, Parallel to the development of BPH, lower uri-
the exact etiology of which is unknown, but requires nary tract symptoms (LUTS) increase in frequency
testosterone. 5a-reductase (5AR), with its two iso- and severity with age and are divided into those
enzymes - type I and type II, converts testosterone to associated with storage of urine, and/or voiding/
its active metabolite, dihydrotestosterone (DHT). emptying. Male LUTS may be caused by a variety
DHT, which has a higher affinity for the androgen of conditions, including BPE and BPO. BPE con-
receptor and is considered the more potent androgenic tributes to LUTS via at least two routes: 1. Direct
steroid hormone, forms a complex that is then trans- BOO/BPO from enlarged tissue (static component);
ported to the nucleus. and 2. Increased smooth muscle tone and resistance
The T/DHT-androgen receptor complex within within the enlarged gland (dynamic component). In
the nucleus of the prostate cells initiates tran- men, overactive bladder (OAB) storage symptoms
scription of DNA and translation, with subsequent may be the result of primary detrusor overactivity
normal development, growth, and hyperplasia of the (DO), underactivity, or from obstruction induced by
prostate. BPH develops due to an imbalance be- BPE and BPO.3 It is important that healthcare
tween growth and apoptosis (cellular death) in favor providers recognize the complex dynamics of the
of growth, subsequently causing an increase in bladder, bladder neck, prostate, and urethra.
cellular mass.1,2 BPH and LUTS in the aging male can be pro-
BPH is nearly ubiquitous in the aging male with gressive, as seen in the Olmsted County Study. The
increases starting at age 40-45 years, reaching 60% prevalence of moderate-to-severe LUTS rose to

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
808 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I

BPH, clinicians should obtain a medical his-

tory, conduct a physical examination, utilize
the International Prostate Symptom Score
(IPSS), and perform a urinalysis. (Clinical
Principle)
2. Patients should be counselled on options for
intervention, which can include behavioral/
lifestyle modifications, medical therapy and/
or referral for discussion of procedural op-
tions. (Expert Opinion)
Patients with bothersome LUTS may present to
either primary care or urology. A complete medical
history, including prior procedures that could explain
presence of symptoms, sexual history, use of medica-
tions, overall fitness and health, IPSS and a urinalysis
(attention to presence/absence of glucosuria, protein-
uria, hematuria, and infection) should be performed.
Optional studies in initial management include
post void residual (PVR) measurement and uro-
flowmetry. A PVR can help determine a baseline
ability of the bladder to empty, identify severe urinary
retention that may not be amenable to medical ther-
apy, and/or indicate detrusor dysfunction. With no
Figure 2. Trial of Medical Therapy Algorithm
universally accepted definition of a clinically signifi-
cant PVR, following a trend over time is suggested.
Uroflowmetry is simple, risk-free, office-based, and
nearly 50% by age 80, with the development of acute can be an important adjunct. Flow rates of <10 mL/s
urinary retention (AUR) increasing from an inci- have shown a specificity of 70%, a positive predictive
dence of 6.8 episodes per 1,000 patient years of value of 70%, and a sensitivity of 47% for BOO.6 For
follow-up in the overall population, to a high of 34.7 more complex voiding scenarios with clinical uncer-
episodes in men aged 70 and older. Another study tainty, urodynamics should be considered.
has estimated that 90% of men between 45 and 80 In general, first line management includes behav-
years of age suffer some type of LUTS. The most ioral modification and/or medications. Advancing
important motivations for men seeking treatment directly to a procedural intervention without trialing
are severity and degree of bother associated with medications may also be discussed. Many supplements
symptoms.4 While LUTS/BPH is rarely life- and nutraceuticals containing ingredients such as saw
threatening, the impact on QoL is significant and palmetto, Pygeum africanum, stinging nettle, zinc, se-
should not be underestimated.5 The most prevalent lenium, and others are popular and have been marketed
and generally first line approach is behavioral and studied.7 Overall the results have been variable, as
and lifestyle modifications followed by medical ther- have study methods and quality, thus positive recom-
apy, including alpha-adrenergic antagonists (alpha mendations regarding their use are not warranted.
blockers), 5-alpha reductase inhibitors (5ARIs), Shared decision making and understanding the
phosphodiesterase 5 selective inhibitors (PDE5s), patients’ desires and risks for specific therapies can
anticholinergics, and beta-3 agonists - which may be help guide treatment strategies.
utilized alone, or in combination to take advantage of
their different mechanisms of action. Follow-up Evaluation.
The following summary presents effective 3. Patients should be evaluated by their pro-
evidence-based supported recommendations for the viders 4-12 weeks after initiating treatment
initial work-up and medical management of male (provided adverse events do not require
LUTS/BPH. earlier consultation) to assess response to
therapy. Revaluation should include the
IPSS. Further evaluation may include a
GUIDELINE STATEMENTS
post-void residual (PVR) and uroflowmetry.
Evaluation (Clinical Principle)
Initial Evaluation. 4. Patients with bothersome LUTS/BPH who
1. In the initial evaluation of patients presenting elect initial medical management and do not
with bothersome LUTS possibly attributed to have symptom improvement and/or experience

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I 809

intolerable side effects should undergo further

evidence is likely to change confidence (rarely used to support a

A statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature
evaluation and consideration of change in
Applies to most patients in most circumstances but better

Applies to most patients in most circumstances but better Applies to most patients in most circumstances but better
medical management or surgical intervention.

A statement, achieved by consensus of the Panel, that is based on members clinical training, experience, knowledge, and judgment for which there is no evidence
(Expert Opinion)

Balance between Benefits & Risks/Burdens unclear

Evidence Strength C (Low Certainty)

Alternative strategies may be equally reasonable

Recommendations for follow-up after initiating
Net benefit (or net harm) appears substantial

Net benefit (or net harm) appears moderate medical therapy remain undefined. Time intervals,

Better evidence likely to change confidence

Benefits > Risks/Burdens (or vice versa)

Benefits > Risks/Burdens (or vice versa)

evidence is likely to change confidence

tests to be conducted, and consequences of changes
in parameters such as the IPSS, QoL score, flowrate
recordings, or PVR have not been systematically
studied in the literature. For faster onset drugs
Strong Recommendation)

(alpha blockers, beta-3 agonists, PDE5s and anti-

Table 1. AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength

cholinergics), the first follow-up visit can be as early

as four weeks. For longer onset drugs (5-ARIs),
waiting 3-6 months is advised. At follow-up,
important elements include adverse medication ef-
fects, IPSS, QoL, and when available, uroflowmetry/
PVR. That said, there are no published thresholds
Applies to most patients in most circumstances but better

for monitoring changes in PVR, Imax or IPSS/QOL

Best action appears to depend on individual patient

to help guide therapy. Qmax changes after non-

Evidence Strength B (Moderate Certainty)

surgical therapies may be subtle and not neces-

sarily correlate with IPSS, but trends over time may
Better evidence could change confidence
Benefits > Risks/Burdens (or vice versa)

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is substantial

encourage a change in treatment strategy. IPSS/

Net benefit (or net harm) is moderate

QOL changes can be used to discuss patient expec-

evidence could change confidence

evidence could change confidence

tations, perceived response, and goals of treatment.

Increasing PVR may require additional in-
Benefits [ Risks/Burdens

vestigations and/or a change in therapy. When

medical management fails to address symptoms, or
intolerable drug-related side effects occur, urologic
circumstances

referral for additional workup (eg, urodynamics,

cystoscopy, prostate volume assessment) and/or
alternate treatments is recommended (figure 3).
Preoperative Testing (Statements 5-9 are
Applies to most patients in most circumstances and future

Applies to most patients in most circumstances and future

included and discussed in Management of Lower

Best action depends on individual patient circumstances

Urinary Tract Symptoms Attributed to Benign

Prostatic Hyperplasia: AUA GUIDELINE PART II
Evidence Strength A (High Certainty)

Future research unlikely to change confidence

e Surgical Evaluation and Treatment)

research is unlikely to change confidence

research is unlikely to change confidence

Strong Recommendation (Net benefit or Benefits > Risks/Burdens (or vice versa)

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is substantial

Medical Therapy
Net benefit (or net harm) is moderate

Alpha Blockers.
10. Clinicians should offer one of the following
alpha blockers as a treatment option for pa-
Benefits [ Risks/Burdens

tients with bothersome, moderate to severe

LUTS/BPH: alfuzosin, doxazosin, silodosin,
tamsulosin, or terazosin. (Moderate Recom-
mendation; Evidence Level: Grade A)
11. When prescribing an alpha blocker for the
treatment of LUTS/BPH, the choice of alpha
blocker should be based on patient age and
comorbidities, and different adverse event
Conditional Recommendation (No
apparent net benefit or harm)
Moderate Recommendation (Net

profiles (eg, ejaculatory dysfunction [EjD],

benefit or harm moderate)

changes in blood pressure). (Moderate

Recommendation; Evidence Level: Grade A)
harm substantial)

Multiple phase III randomized control trials,

Clinical Principle

Phase IV studies, systematic reviews, and meta-

Expert Opinion

analyses have demonstrated efficacy of alpha

blockers for LUTS and BPH since the 1980’s. They
are all relatively equally effective in terms of IPSS

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
810 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I

improvement, ranging from 4 -7 points as compared Alpha Blockers and Intraoperative Floppy Iris
to placebo (2-4 points).8 One of the most recent Syndrome (IFIS).
exhaustive network meta-analyses verifies this 12. When initiating alpha blocker therapy, pa-
observation (table 2).8 Attempts to identify sub- tients with planned cataract surgery should
groups of patients who may respond better to one be informed of the associated risks and be
alpha blocker or another have not shown differences advised to discuss these risks with their
in efficacy.9 Given that medication type and patient ophthalmologists. (Expert Opinion)
characteristics do not impact effectiveness, it is not Urologists initiating alpha blocker therapy should
recommended to switch between various options for inquire about plans for future cataract surgery and
insufficient response.10 However, changing from one inform them of IFIS risk, with delay of medication
alpha blocker to another on the basis of a side effect initiation until after planned procedures. Fortu-
is worthwhile. nately, increased awareness of IFIS has resulted in a
Terazosin and doxazosin are non-specific alpha-1 year by year decreased complication rate.15
receptor blockers approved for hypertension, as well
as BPH. Tamsulosin, alfuzosin, and silodosin have 5- Alpha Reductase inhibitor (5-ARI).
lower potential for orthostatic hypotension and 13. For the purpose of symptom improvement, 5-
syncope.11-13 When treating patients on several ARI monotherapy should be used as a treat-
antihypertensives, or with orthostatic hypotension, ment option in patients with LUTS/BPH with
it is best to select an alpha blocker that exhibits prostatic enlargement as judged by a prostate
minimal impact on blood pressure (eg, the highly volume of >30cc on imaging, a prostate spe-
selective alpha 1a blocker silodosin). cific antigen (PSA) > 1.5ng/dL, or palpable
Contrary to decreased hypotensive effects of the prostate enlargement on digital rectal exam
selective drugs, ejaculatory dysfunction (EjD), a long- (DRE). (Moderate Recommendation; Evidence
understood side effect of alpha-blockers, is more com- Level: Grade B)
mon with activity at the alpha 1a (silodosin and tam- 14. 5-ARIs alone or in combination with alpha
sulosin) versus alpha 1b receptor. Hellstrom blockers are recommended as a treatment
demonstrated that the EjD associated with selective option to prevent progression of LUTS/BPH
alpha 1a blockers is correctly called “anejaculation” and/or reduce the risks of urinary retention
and found that tamsulosin resulted in significantly and need for future prostate-related surgery.
decreased ejaculate volume (-2.4 D/- 0.17 mL) (Strong Recommendation; Evidence Level:
compared to alfuzosin (D0.3 D/- 0.18 mL) or placebo.14 Grade A)
Younger sexually active men are more likely to dis- 15. Before starting a 5-ARI, clinicians should
continue due to EjD; therefore, it would be prudent to inform patients of the risks of sexual side ef-
select alpha blockers with a low incidence of EjD fects, certain uncommon physical side effects,
(alfuzosin).

Figure 3. Algorithm for follow-up visits using IPSS and/or Global Subjective Assessment (GSA) question(s).

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I 811

Table 2. Effectiveness of Drug Therapies in Improving IPSS

and the low risk of prostate cancer. (Moderate differences. Finasteride selectively inhibits the 5-
Recommendation; Evidence Level: Grade C) AR type II isoenzyme, while dutasteride inhibits
16. Clinicians may consider 5-ARIs as a treat- both types I and II. This difference in activity re-
ment option to reduce intraoperative bleeding duces serum levels of DHT by approximately 70%
and peri- or postoperative need for blood with finasteride, compared to 95% with dutasteride.
transfusion after transurethral resection of However, in BPH tissue, type II 5AR is far more
the prostate (TURP) or other surgical inter- common than type I. Therefore, the reduction of
vention for BPH. (Expert Opinion) DHT in prostate tissues has been measured at
5-ARIs affect the influence of androgenic steroids approximately 80% (finasteride) and 94% (dutas-
on prostate growth via inhibition of 5AR, reducing teride). Due to the slow onset of action of these
DHT in the prostate. This leads to a reduction in medications as compared to alpha blockers, patients
androgenic growth and an increase in apoptosis and should be counseled on a slower symptom
atrophy, shrinking the organ from 15-25% at six improvement if treated with 5-ARI alone.
months. Atrophy is most pronounced in the glandular Numerous robust analyses of randomized,
epithelial component of the prostate, the source of placebo-controlled trials with finasteride have
production and release of serum PSA, reducing levels shown an improvement in standardized symptom
by approximately 50% (and a concomitant decrease in scores (eg, IPSS) superior to placebo. Numerically,
free PSA by 50%, which means that the ratio of free/ improvements of 3 to 4 points have been observed
total PSA remains constant).16,17 When providers and maintained for 6 to 10 years of follow-up.19,20 In
are screening men for prostate cancer who are on 5- the REDUCE trial, clinical progression (as defined
ARIs, patients should be informed of alterations in by increase in IPSS of 4, AUR, UTI, or BPH-
PSA due to the medication. After 1 year of 5-ARI related surgery) was less common in men on
therapy, the measured serum PSA value should be dutasteride compared to placebo (21% versus 36%;
doubled to accurately gauge disease progression.18 p <0.001).21 Only one study has directly compared
Treatment with 5-ARIs and combination therapy the outcomes of men randomized to either finaste-
hinges on prostate volume and PSA threshold ride or dutasteride. Amongst men randomized to
therefore, obtaining imaging with TRUS (or either medication over 12 months, no differences
reviewing existing cross-sectional imaging) to were noted with regards to prostate volume, AUA-SI
objectively assess prostate size is reasonable, with and Qmax.22
reservation of 5-ARIs for those with appropriately LUTS/BPH can have a progressive natural his-
enlarged glands. A minimum prostate volume of tory that is more profound in men with larger
>30cc or PSA >1.5ng/dL is necessary for a reliable glands and/or higher PSA values. The PLESS study
5-ARI response, but the larger the gland, the more suggested that 5-ARI therapy can be utilized in
pronounced the effects.17 appropriately enlarged prostates as prevention for
Finasteride and dutasteride, the only approved BPH as it alters the natural history thereof.
medications, have two important pharmacological Amongst men randomized to 5-ARI instead of alpha

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
812 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I

blocker alone or placebo groups, a lower risk of AUR mechanism of action of this PDE5 effect is only
and BPH related surgery was seen.23 partially understood. Ten key reports from 10 trials
Gynecomastia and sexual side effects can occur compared tadalafil 5 mg to placebo (n[5,129).29-38
with 5-ARI therapy. As part of MTOPS, in- The mean change in tadalafil (-5.4 points) compared
vestigators prospectively measured erectile and to controls (-3.6 points) was -1.74 (figure 4). Tada-
ejaculatory function, as well as libido, utilizing lafil resulted in little to no difference in IPSS as
questionnaire data.24 Declines in overall sexual compared to placebo. However, the percentage of
function were more pronounced with finasteride. In treatment responders, defined as 3 points change,
addition, there has also been discussion regarding showed a relative effect (1.13 to 1.80), suggesting
post-finasteride syndrome (PFS), a controversial and that tadalafil probably increases response to the
poorly-defined constellation of sexual, physical, and IPSS compared to placebo. Tadalafil is a reasonable
psychological symptoms that putatively persist after option to trial in selected men, ideally those with
discontinuation of the drug.25,26 Concerns regarding concomitant erectile dysfunction.
PFS prompted the FDA to amend the labels for 5-
Combination Therapy.
ARI with a warning of its risks. However, the
18. 5-ARI in combination with an alpha
robustness of the data justifying this change, which
blocker should be offered as a treatment op-
is based on anecdotal patient-reported outcomes
tion only to patients with LUTS associated
rather than prospective trials, remains unclear.27
with demonstrable prostatic enlargement
Finally, 5-ARI therapy and risk for prostate
as judged by a prostate volume of >30cc
cancer has resulted in publication of numerous
on imaging, a PSA >1.5ng/dL, or palpable
studies attempting to confirm or refute concerns.
prostate enlargement on DRE. (Strong
Sarkar et al.28 used the Veterans Affairs Infor-
Recommendation; Evidence Level: Grade A)
matics and Computing Infrastructure and National
19. Anticholinergic agents, alone or in combi-
Death Index to obtain patient records for 80,875
nation with an alpha blocker, may be
men with American Joint Committee on Cancer
offered as a treatment option to patients
stage I-IV prostate cancer diagnosed from January
with moderate to severe predominant stor-
1, 2001, to December 31, 2015. The primary outcome
age LUTS. (Conditional Recommendation;
was prostate cancer-specific mortality (PCSM).
Evidence Level: Grade C)
Secondary outcomes included time from first
20. Beta-3-agonists in combination with an
elevated PSA (defined as PSA4 ng/mL) to diag-
alpha blocker may be offered as a treatment
nostic prostate biopsy, cancer grade and stage at
option to patients with moderate to severe
time of diagnosis, and all-cause mortality (ACM).
predominate storage LUTS. (Conditional
PSA levels for 5-ARI users were adjusted by
Recommendation; Evidence Level: Grade C)
doubling the value. Median adjusted PSA at time of
21. Clinicians should not offer the combination
biopsy was significantly higher for 5-ARI users than
of low-dose daily 5mg tadalafil with alpha
5-ARI non-users (13.5 ng/mL versus 6.4 ng/mL; p
blockers for the treatment of LUTS/BPH as
<.001). These patients were more likely to have
it offers no advantages in symptom improve-
Gleason grade 8 or higher (25.2% versus 17.0%; p
ment over either agent alone. (Moderate
<.001), clinical stage T3 or higher (4.7% versus
Recommendation; Evidence Level: Grade C)
2.9%; p <.001), node-positive (3.0% versus 1.7%; p
Combination therapy is a common approach to
<.001), and metastatic (6.7% versus 2.9%; p <.001)
symptomatic LUTS, working on the premise that each
disease. In a multivariable regression, patients who
medication targets a different site in the lower urinary
took 5-ARIs had higher prostate cancer-specific and
tract. Together, they presumably maximize symptom
all-cause mortality. The important outcome of this
control. Standard combinations include alpha
study was the delayed diagnosis, presumably
blockers D 5-ARI; alpha-blocker D anticholinergic/
related to lack of awareness and/or correction of
antimuscarinic therapy, or alpha blockers D beta-3-
PSA values (doubling of the PSA value), and worse
agonists.
cancer-specific outcomes.
Two large studies evaluated alpha blocker and 5ARI
Phosphodiesterase-5 Inhibitor (PDE5). combinations: Medical Therapy of Prostatic Symptoms
17. For patients with LUTS/BPH irrespective (MTOPS) and Combination of Avodart and Tamsulosin
of comorbid erectile dysfunction (ED), 5mg (CombAT). Both studies showed statistically signifi-
daily tadalafil should be discussed as a cant reductions in parameters of clinical progression
treatment option. (Moderate Recommenda- with combination approaches over monotherapy.
tion; Evidence Level: Grade B) MTOPS enrolled over 3,000 men with at or below
The majority of studies that address the impact of average sized prostates and randomized them to
PDE5s on LUTS/BPH used tadalafil. The placebo versus doxazosin versus finasteride versus

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I 813

Figure 4. Mean Change from Baseline in IPSS in 10 RCTs

combination of doxazosin D finasteride. Men were results showed mild increase in PVR (25 mL versus
treated and followed for up to 5.5 years. The risk of 0 mL) and mild decrease in bladder contractility
overall clinical progression, defined as an increase index, with no urinary retention in the treatment
above baseline of at least 4 points in the IPSS, AUR, group.40 Other studies have confirmed similar
urinary incontinence, renal insufficiency, or recur- findings and as such, use in appropriately selected
rent UTI, was significantly greater with combina- patients is reasonable. That said, a PVR should be
tion therapy than that associated with doxazosin or obtained pre-treatment and monitored at follow-up.
finasteride alone. The risks of AUR and need for Combination therapy with alpha blockers and
invasive therapy were significantly reduced by anticholinergics makes intuitive sense in selected
combination therapy and finasteride, but not by patients with storage predominant LUTS/BPH.
doxazosin. Symptom and flow rate improvement Numerous studies of at least 5 anticholinergics
were superior in the combination therapy arm have been conducted, but largely with short dura-
compared to both monotherapies. tions (ie 12 week endpoints). IPSS improvement in
CombAT enrolled men with prostate volumes combination arms compared to alpha blockers alone
>30 mL by TRUS and PSA >1.5 ng/mL.39 Qmax is variable, making it challenging to derive conclu-
improvement was seen in combination therapy sions regarding efficacy. With the increase of drug
compared to placebo, but not dutasteride mono- related adverse events, a reasonable approach is to
therapy. At 4 years, Qmax improvements were more start with alpha blockers alone and add anticholin-
profound with increasing prostate volume and PSA ergics in selected cases.
levels in combination subjects. Not surprisingly, Unlike anticholinergic agents, monotherapy with
however, these patients had more drug related a beta-3-agonist has, thus far, not been shown to
adverse events over monotherapies. lead to significant differences in LUTS secondary to
Although the exact cause may be varied, both BPH. While not yet extensively studied, combina-
storage LUTS and OAB have similar symptoms, tion therapy with an alpha blocker, however, may
prompting use of anticholinergic, antimuscarinic, lead to improvement in symptoms similar to those
and beta-3-agonists therapy to help alleviate bother. seen with anticholinergics.
A safety trial was conducted in patients with Finally, the combination of low-dose daily tada-
urodynamically-proven obstruction and over- lafil with alpha blockers has not been shown to offer
activity, comparing tolterodine 2 mg to placebo. The greater symptom improvement over alpha blockers

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
814 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I

or low-dose daily tadalafil, alone. Therefore, this drivers of BPH and prostate growth and target
combination is not recommended, particularly given therapeutic agents.
the higher side effect risk.  Further defining differentially bothersome LUTS
and using enhanced metrics that include bother,
Acute Urinary Retention (AUR) Outcomes.
pain, and incontinence.
22. Physicians should prescribe an oral alpha
 Addressing healthcare disparities and cultural
blocker prior to a voiding trial to treat pa-
competency to better deliver care across all mem-
tients with AUR related to BPH. (Moderate
bers of society irrespective of race, ethnicity, so-
Recommendation; Evidence Level: Grade B).
cioeconomic and health status, and environment.
23. Patients newly treated for AUR with alpha
 The most prevalent and bothersome symptom of
blockers should complete at least three days
LUTS is nocturia, which is a unique symptom
of medical therapy prior to attempting trial
complex requiring special concern and judicious
without a catheter (TWOC). (Expert Opinion)
evaluation, including the role of sleep apnea. Noc-
24. Clinicians should inform patients who pass
turia is associated with increases in overall mor-
a successful TWOC for AUR from BPH that
tality and a lack of effective management
they remain at increased risk for recurrent
options merits deeper understanding and investi-
urinary retention. (Moderate Recommenda-
gation with more funded research.
tion; Evidence Level: Grade C).
 Determining predictive ability of various urody-
Numerous clinical trials have investigated
namic measures, with the subsequent clinical
pharmacologic treatment of AUR in men.41-49 The
and economic consequences of the findings, to
studies differ by definition of AUR (500- 1,500
impact overall outcomes and financial burden.
mL), inclusion criteria, treatment length, and
 Using imaging and tests to identify morphological
follow-up (1 day to 24 months). Men prescribed
aspects such as bladder wall thickness, trabecula-
alfuzosin or tamsulosin demonstrated improve-
tion, prostatic urethral angle, and intravesical
ment in AUR signs and symptoms, as measured by
prostatic protrusion to learn how they affect nat-
TWOC. In the alfuzosin studies, follow-up ranged
ural history, treatment response, and treatment
from 2 days to 2 years, or time to surgery. Pooled
options.
results showed successful TWOC with alfuzosin
 Creating studies that compare efficacy of behav-
compared to placebo, 60% versus 39%. The tam-
ioral and lifestyle intervention versus medication,
sulosin studies had similar follow-up limitations
and medication versus minimally invasive thera-
(5 days to 6 months) but similar efficacy (47%
pies, to determine ideal approaches and timing
versus 29% for placebo).
for individual patients.
Given the lack of standardized follow-up, long-
 Development of registries and analysis of elec-
term efficacy of alpha blocker therapy in treating
tronic medical records and insurance databases
AUR is unclear. All trials report a significant
to better improve our understanding of the
number of patients with subsequent urinary reten-
burden and cost of BPH/LUTS and identify
tion and LUTS after treatment occurring days to
areas for improvement and study.
months later, necessitating catheterization or sur-
 Development of a calculator with patient parame-
gical procedures.
ters to obtain a treatment algorithm, or set of
appropriate options, to streamline and define
care.
FUTURE DIRECTIONS In summary, BPH and LUTS are rich with op-
BPH and ensuing LUTS is a significant health issue portunities for research and development for those
affecting millions of men. There are enormous gaps seeking to improve the lives of generations of men.
in knowledge; therefore, there are also significant
opportunities for discovery. Many unanswered
questions exist including the role of inflammation, DISCLAIMER
metabolic dysfunction, obesity, and environmental This document was written by the Benign Prostatic
factors in etiology; as well as the role of behavior Hyperplasia Panel of the American Urological As-
modification, self-management, and evolving ther- sociation Education and Research, Inc., which was
apeutic algorithms in both the prevention and pro- created in 2016. The Practice Guidelines Committee
gression of disease. (PGC) of the AUA selected the committee chair.
Areas of particular interest that could further Panel members were selected by the chair. Mem-
define aspects of BPH/LUTS include, but are not bership of the Panel included specialists in urology
limited to, the following: and primary care with specific expertise on this
 Investigating disease etiology using computa- disorder. The mission of the panel was to develop
tional biology and genomic factors to understand recommendations that are analysis based or

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I 815

consensus-based, depending on panel processes they are necessarily time-limited. Guidelines

and available data, for optimal clinical practices cannot include evaluation of all data on emerging
in the treatment of early stage testicular cancer. technologies or management, including those that
Funding of the panel was provided by the AUA. are FDA-approved, which may immediately come
Panel members received no remuneration for to represent accepted clinical practices. For this
their work. Each member of the panel provides an reason, the AUA does not regard technologies or
ongoing conflict of interest disclosure to the AUA, management which are too new to be addressed by
and the Panel Chair, with the support of AUA this guideline as necessarily experimental or
Guidelines staff and the PGC, reviews all disclo- investigational.
sures and addresses any potential conflicts per
AUA’s Principles, Policies and Procedures for Man-
DISCLOSURES
aging Conflicts of Interest. While these guidelines do
All panel members completed COI disclosures.
not necessarily establish the standard of care, AUA
Disclosures listed include both topice and non-
seeks to recommend and to encourage compliance by
topic-related relationships. Consultant/Advisor:
practitioners with current best practices related to
Michael J. Barry, MD: US Preventive Services
the condition being treated. As medical knowledge
Task Force; Anurag Kumar Das, MD: Teledoc;
expands and technology advances, the guidelines will
Tobias S. Kohler, MD: Coloplast, American Medical
change. Today these evidence-based guidelines
Systems; Kevin T. McVary, MD: Merck, Olympus;
statements represent not absolute mandates but
Claus G. Roehrborn, MD: Glaxo Smith Kline, Neo-
provisional proposals for treatment under the spe-
tract, Procept Biorobotics, Boston Scientific, Zen-
cific conditions described in each document. For all
Flow, Teleflex; Charles Welliver, MD: Medscape.
these reasons, the guidelines do not pre-empt
Scientific Study or Trial: Michael J. Barry, MD:
physician judgment in individual cases. Treating
Healthwise; Steven A. Kaplan, MD: Urotronics;
physicians must take into account variations in
Kevin T. McVary, MD: NIDDK, NxThera, Olympus,
resources, and patient tolerances, needs, and
MedeonBio, Urotronic, Francis Medical; John T.
preferences. Conformance with any clinical guide-
Stoffel, MD: Department of Defense. Leadership
line does not guarantee a successful outcome. The
Position: Anurag Kumar Das, MD: Indian American
guideline text may include information or recom-
Urological Association; Kevin T. McVary, MD:
mendations about certain drug uses (‘off label‘)
UroNext; John T. Stoffel, MD: Journal of Urology,
that are not approved by the Food and Drug
Neurogenic Bladder Research Group. Health Pub-
Administration (FDA), or about medications or
lishing: Kevin T. McVary, MD: SRS Medical Sys-
substances not subject to the FDA approval pro-
tems; Claus G. Roehrborn, MD: NIDDK; Charles
cess. AUA urges strict compliance with all gov-
Welliver, MD: Oakstone Publishing. Other: Anurag
ernment regulations and protocols for prescription
Kumar Das, MD: Novartis, Sanofi-Aventis, Astellas,
and use of these substances. The physician is
Johnson and Johnson, Novo Nordisk, Schwabcare;
encouraged to carefully follow all available pre-
Charles Welliver, MD: ALX Oncology
scribing information about indications, contrain-
dications, precautions and warnings. These
guidelines and best practice statements are not ACKNOWLEDGEMENTS
intended to provide legal advice about use and AUA would like to thank the Minnesota Evidence
misuse of these substances. Although guidelines Review Team (Timothy J. Wilt, MD and Philipp
are intended to encourage best practices and Dahm, MD) for the development of the evidence
potentially encompass available technologies with report that was used to aid in the creation of this
sufficient data as of close of the literature review, guideline.

REFERENCES
1. Andriole G, Bruchovsky N, Chung L et al: Dihy- 3. Reynard J: Does anticholinergic medication have 5. Wei J, Calhoun E and Jacobsen S: Urologic
drotestosterone and the prostate: the scientific a role for men with lower urinary tract diseases in America project: benign prostatic
rationale for 5alpha-reductase inhibitors in the symptoms/benign prostatic hyperplasia either hyperplasia. J Urol 2005; 173: 1256.
treatment of benign prostatic hyperplasia. J Urol alone or in combination with other agents? Curr
2004; 172: 1399. Opin Urol 2004; 14: 13.
6. Reynard JM, Yang Q, Donovan JL et al: The ICS-
2. Russell D and Wilson J: Steroid 5alpha- 'BPH' Study: uroflowmetry, lower urinary tract
reductase: two genes/two enzymes. Annu Rev 4. McVary K: BPH: Epidemiology and Comorbidities. symptoms and bladder outlet obstruction. Br J
Biochem 1994; 63: 25. Am J Manag Care 12 2006; (5 Suppl): S122. Urol 1998; 82: 619.

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
816 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I

7. Bent S, Kane C, Shinohara K et al: Saw palmetto 20. Lam J, Romas N and Lowe F: Long-term treat- 33. Porst H, Kim ED, Casabe AR et al: Efficacy and
for benign prostatic hyperplasia. N Engl J Med ment with finasteride in men with symptomatic safety of tadalafil once daily in the treatment of
2006; 354: 557. benign prostatic hyperplasia: 10-year follow-up. men with lower urinary tract symptoms suggestive
Urology 2003; 61: 354. of benign prostatic hyperplasia: results of an in-
8. Yuan JQ, Mao C, Wong SY et al: Comparative ternational randomized, double-blind, placebo-
effectiveness and safety of monodrug therapies for 21. Toren P, Margel D, Kulkarni G, et al: Effect of controlled trial. Euro Urol 2011; 60: 1105.
lower urinary tract symptoms associated with benign dutasteride on clinical progression of benign
prostatic hyperplasia: a network meta-analysis prostatic hyperplasia in asymptomatic men with 34. Roehrborn CG, McVary KT, Elion-Mboussa A
version 2. Medicine (Baltimore) 2015; 94: 974. enlarged prostate: a post hoc analysis of the et al: Tadalafil administered once daily for lower
REDUCE study. BMJ 2013; 346: 1. urinary tract symptoms secondary to benign
9. Dahm P, Brasure M, MacDonald R et al: prostatic hyperplasia: a dose finding study.
22. Nickel JC, Gilling P and Tammela TL: Comparison
Comparative effectiveness of newer medications J Urol 2008; 180: 1228.
for lower urinary tract symptoms attributed to of dutasteride and finasteride for treating benign
benign prostatic hyperplasia: a systematic re- prostatic hyperplasia: the Enlarged Prostate In- 35. Takeda M, Nishizawa O, Imaoka T et al: Tadalafil
view and meta-analysis. Eur Urol 2017; 71: 570. ternational Comparator Study (EPICS). BJU Int. for the treatment of lower urinary tract symp-
2011; 108: 388. toms in japanese men with benign prostatic
10. Dahm P, Brasure M, MacDonald R et al: hyperplasia: results from a 12-week placebo-
23. Boyle P, Gould AL and Roehrborn CG: Prostate
Comparative effectiveness of newer medications controlled dose-finding study with a 42-week
volume predicts outcome of treatment of benign
for lower urinary tract symptoms attributed to open-label extension. LUTS 2012; 4: 110.
prostatic hyperplasia with finasteride: meta-
benign prostatic hyperplasia: a systematic re-
analysis of randomized clinical trials. Urology 36. Takeda M, Yokoyama O, Lee S et al: Tadalafil
view and meta-analysis. Eur Urol 2017; 71: 570.
1996; 48: 398. 5 mg once-daily therapy for men with lower
11. Lee M: Tamsulosin for the treatment of benign urinary tract symptoms suggestive of benign
24. Fwu CW, Eggers PW, Kirkali Z et al: Change in
prostatic hypertrophy. Ann Pharmacother 2000; prostatic hyperplasia: results from a randomized,
sexual function in men with lower urinary tract
34: 188. double-blind, placebo-controlled trial carried out
symptoms/benign prostatic hyperplasia associated
in Japan and Korea. Int J Urol 2014 ;21: 670.
with long-term treatment with doxazosin, finas-
12. Roehrborn CG, Van Kerrebroeck P, Nordling J
teride and combined therapy. 2014; 191: 1828. 37. Yokoyama O, Yoshida M, Kim SC et al: Tadalafil
et al: Safety and efficacy of alfuzosin 10 mg
once-daily in the treatment of lower urinary tract once daily for lower urinary tract symptoms
25. Irwig MS: Persistent sexual side effects of fi-
symptoms and clinical benign prostatic hyper- suggestive of benign prostatic hyperplasia: A
nasteride: Could they be permanent? J Sex Med
randomized placebo- and tamsulosin-controlled
plasia: a pooled analysis of three double-blind, 2012; 9: 2927.
placebo-controlled studies. BJU Int 2003; 92: 12-week study in Asian men. Int J Urol 2013;
257. 26. Fertig RM, Gamret AC, Darwin E et al: Sexual 20: 193.
side effects of 5-a-reductase inhibitors finaste-
38. Zhang Z, Li H, Zhang X et al: Efficacy and safety
13. Marks LS, Gittelman MC, Hill LA, et al: Rapid ride and dutasteride: A comprehensive review.
of tadalafil 5 mg once-daily in Asian men with
efficacy of the highly selective alpha1A- Dermatol Online J 2017; 23: 13030/qt24k8q743.
both lower urinary tract symptoms associated
adrenoceptor antagonist silodosin in men with
27. Harrell MB, Ho K, Te AE et al: An evaluation of with benign prostatic hyperplasia and erectile
signs and symptoms of benign prostatic hyper-
the federal adverse events reporting system data dysfunction: A phase 3, randomized, double-
plasia: pooled results of 2 phase 3 studies.
on adverse effects of 5-alpha reductase in- blind, parallel, placebo- and tamsulosin-
J Urol 2009; 181: 2634.
hibitors. World J Urol 2020; controlled study. Int J Urol 2019; 26: 192.
14. Hellstrom WJ and Sikka SC: Effects of acute 39. Roehrborn CG, Siami P, Barkin J et al: The effects
28. Sarkar RR, Parsons JK, Bryant AK et al: Associ-
treatment with tamsulosin versus alfuzosin on of dutasteride, tamsulosin and combination
ation of treatment with 5a-reductase inhibitors
ejaculatory function in normal volunteers. J Urol therapy on lower urinary tract symptoms in men
with time to diagnosis and mortality in prostate
2006; 176: 1529.
cancer. JAMA Intern Med 2019; 179: 812. with benign prostatic hyperplasia and prostatic
enlargement: 2-year results from the CombAT
15. Campbell RJ, El-Defrawy SR, Gill SS et al: Evo- 29. McVary KT, Roehrborn CG, Kaminetsky JC et al: study. J Urol 2008; 179: 616.
lution in the risk of cataract surgical complica- Tadalafil relieves lower urinary tract symptoms
tions among patients exposed to tamsulosin: a secondary to benign prostatic hyperplasia. J Urol 40. Kim TH, Jung W, Suh YS et al: Comparison of
population-based study. Ophthalmology 2019; 2007; 177: 1401. the efficacy and safety of tolterodine 2 mg and
126: 490. 4 mg combined with an a-blocker in men with
30. Egerdie RB, Auerbach S, Roehrborn CG et al: lower urinary tract symptoms (luts) and over-
16. Bruskewitz R, Girman C, Fowler J et al: Effect of Tadalafil 2.5 or 5 mg Administered Once Daily for active bladder: A randomized controlled trial.
finasteride on bother and other health-related 12 Weeks in Men with Both Erectile Dysfunction BJU Int 2016; 117: 307.
quality of life aspects associated with benign and Signs and Symptoms of Benign Prostatic
prostatic hyperplasia. PLESS Study Group. Pro- Hyperplasia: Results of a Randomized, Placebo- 41. Agrawal MS, Yadav A, Yadav H et al: A pro-
scar Long-term Efficacy and Safety Study. Urol- Controlled, Double-Blind Study. JSM 2012; 9: 271. spective randomized study comparing alfuzosin
ogy 1999; 54: 670 and tamsulosin in the management of patients
31. Kim SC, Park JK, Kim SW et al: Tadalafil suffering from acute urinary retention caused by
17. Kaplan S: 5alpha-reductase inhibitors: what role Administered Once Daily for Treatment of Lower benign prostatic hyperplasia. Indian J Urol 2009;
should they play? Urology 2001; 58: 65 Urinary Tract Symptoms in Korean men with 25: 474.
Benign Prostatic Hyperplasia: Results from a
18. Etzioni RD, Howlader N, Shaw PA et al: Long- Placebo-Controlled Pilot Study Using Tamsulosin 42. Salem Mohamed SH, El Ebiary MF and Badr
term effects of finasteride on prostate specific as an Active Control. LUTS 2011; 3: 86. MM: Early versus late trial of catheter removal
antigen levels: results from the prostate cancer in patients with urinary retention secondary to
prevention trial. J Urol 2005; 174: 877. 32. Oelke M, Giuliano F, Mirone V et al: Mono- benign prostatic hyperplasia under tamsulosin
therapy with Tadalafil or Tamsulosin Similarly treatment. Urol Sci 2018; 29: 288.
19. Vaughan D, Imperato-McGinley J, McConnell J Improved Lower Urinary Tract Symptoms Sug-
et al: Long-term (7 to 8-year) experience with gestive of Benign Prostatic Hyperplasia in an 43. Kumar S, Tiwari DP, Ganesamoni R et al: Pro-
finasteride in men with benign prostatic hyper- International, Randomised, Parallel, Placebo- spective randomized placebo-controlled study to
plasia. Urology 2002; 60: 1040. Controlled Clinical Trial. Euro Urol 2012; 61: 917. assess the safety and efficacy of silodosin in the

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 MANAGEMENT OF LUTS ATTRIBUTED TO BPH: AUA GUIDELINE PART I 817

management of acute urinary retention. Urology 46. McNeill SA, Hargreave TB, Roehrborn CG et al: 48. Shah T, Palit V, Biyani S et al: Randomised,
2013; 82: 171. Alfuzosin 10 mg once daily in the management placebo controlled, double blind study of alfu-
of acute urinary retention: results of a double- zosin SR in patients undergoing trial without
44. Maldonado-Avila M, Manzanilla-Garcia HA, blind placebo-controlled study. Urology 2005; catheter following acute urinary retention. Eur
Sierra-Ramirez JA et al: A comparative study on 65: 83. Urol 2002; 42: 329.
the use of tamsulosin versus alfuzosin in spon-
taneous micturition recovery after transurethral
catheter removal in patients with benign pros- 47. Patil SB, Ranka K, Kundargi VS et al: Comparison 49. Tiong HY, Tibung MJB, Macalalag M et al:
tatic growth. Int Urol Nephrol 2014; 46: 687. of tamsulosin and silodosin in the management Alfuzosin 10 mg once daily increases the chan-
of acute urinary retention secondary to benign ces of successful trial without catheter after
45. McNeill SA, Hargreave TB et al: Alfuzosin once prostatic hyperplasia in patients planned for trial acute urinary retention secondary to benign
daily facilitates return to voiding in patients in without catheter. A prospective randomized prostate hyperplasia. Urologia Internationalis
acute urinary retention. Urology 2004; 171: 2316. study. Cent European J Urol 2017; 70: 259. 2009; 83: 44.

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.