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Practical Urology: EssEntial PrinciPlEs and PracticE

frequently performed. Uroflowmetry has a good

A good number of patients will never progress

positive predictive value for the diagnosis of

to pharmacological or surgical treatment.

BPO and Qmax values <10 mL/s have a 70% spec-

ificity.14,15 A weak stream is generally due to BPO

although detrusor underactivity cannot be ruled

Drug Therapy

unless pressure-flow study is performed.Voided

volumes of 150 mL or higher are associated with

If surgery was the first revolution in the manage-

a lower variability within the same patient; the

ment of BPH, pharmacotherapy was the second

test should always be performed in triplicate.

one. Four categories of drugs should be consid-

Pressure-flow study has the unique capacity to

ered: plant extracts, alpha1 adrenoceptor (AR)

diagnose BPO (although no consensus has been

antagonists, 5a- reductase inhibitors (5ARIs),

reached yet as to the relation between BPO and

and antimuscarinics.

the outcome of surgery), detrusor overactivity

Phytotherapy is a popular remedy for LUTS

and detrusor underactivity. Detrusor disorders

due to BPH that falls within the framework

are considered to be associated with unfavor-

of complimentary medicine in most countries

able outcome following TURP.

although some products are registered as drugs,

Diagnostic tests performed in the assess-

particularly in Europe. Plant extracts suffer dif-

ment of BPH can also be used to predict the

ferences in the pharmaceutical preparation as

outcome of treatment. Patients with elevated

the extraction procedures may differ among dif-

PSA and BPO levels have a higher chance to fail

ferent commercial products, so the activity (effi-

watchful waiting.16 Prostate volume and higher

cacy, bioavailability, and pharmacodynamics) of

IPSS values are associated with a higher risk of

individual components is not comparable; fur-

invasive therapy in patients receiving pharma-

thermore, some preparations contain mixture of

cological treatment.16,17 Prostate volume was

different extracts. The origin of phytotherapeu-

found to influence the success of a trial without

tic agents include: American dwarf palm, Saw

catheter in patients suffering acute urinary

palmetto, African plum tree, South African star

retention.18

grass,Pine Spruce,Stinging nettle,Rye,Pumpkin,

Physical examination of the BPH patient is of

and Cactus flower extracts. Active components

importance as it allows to rule out conditions

comprise: phytosterols (alpha-sitosterol), phy-

such as chronic retention that may require

toestrogens, fatty acids (lauric and myristica

immediate treatment and occult neurological

cid), lectins, flavonoids, plant oils, and polysac-

disorders that may be responsible for LUTS.

charides. Serenoa repens, extracted from the

Digital rectal examination of the prostate now

American dwarf palm is one of the most fre-

plays a minor role compared to the pre-PSA and

quently used products commercialized world-

pre-ultrasound era, but it remains a valid test to

wide under the name of Permixon. The drug is

diagnose BPE and rule out acute inflammatory

considered to have antiandrogen, antiprolifera-

disorders of the prostate, locally advanced pros-

tive, and anti-inflammatory activities. Six of

tate cancer, neurological conditions that may

seven randomized studies showed superiority

affect anal sphincter tone, and cancer of the low-

over placebo in reducing LUTS and improving

ermost part of the rectum.

flow rate, and two large comparative trials sug-

gested a similar efficacy among Permixon, finas-

teride, and tamsulosin. Two meta analyses of

Permixon studies performed by P. Boyle sug-

Treatment of BPH

gested a significant improvement of IPSS (−4.7),

nocturia (1.0 over placebo), and maximum flow

Watchful Waiting

rate (2.2 mL/s over placebo).22 A different con-

clusion was reached by a recent meta-analysis

The simple diagnosis of LUTS due to BPH does

published by the Cochrane Library suggesting

that Serenoa repens is not more effective than

necessarily trigger treatment. Most national and

placebo for the treatment of symptoms consis-

international guidelines suggest that patients

tent with BPH.23 Clinical trials performed using

with mild symptoms and no bother can be safely

other phytotherapeutics such as Pygeum

managed in a watchful waiting program.19-21

Africanum (Tadenan) or synthetic polyenes

(Mepartricin) are considered to be insufficient

Since a-1 AR antagonists are not first-line

and further research is needed before any rec-

treatment for arterial hypertension, the use of

ommendation can be made.

nonselective antagonists to control hyperten-

AR antagonists are the first-line treatment in

sion and LUTS at the same time is not encour-

the management of BPH because of their speed

aged and each condition should be treated

of action, safety, tolerability, and efficacy. They

independently.13 Adverse events most frequently

are considered to act on smooth muscle fibers

involve orthostatic hypotension, dizziness, and

tone (the so-called dynamic component of BPO).

asthenia suggesting that AR receptors expres-

Although most clinical trials were limited to 3-

sed in blood vessels and CNS are of import-

or 6-month treatment, more recent studies such

ance. Multiple, placebo-controlled, randomized,

as MTOPS and Combat trials provided 4-year

double-blind study of adequate size and dura-

data and CombAT trial will do the same in due

tion confirmed the positive effect of a-1 AR

time.9,24 a -AR and a

-Ar subtypes expressed

antagonists on LUTS.31-34 Alfuzosin and tamsu-

1A

1D

losin are known to be equally effective with sim-

in the prostate, urinary bladder, and spinal cord

are considered to be more important than a1B-

ilar tolerability although tamsulosin is known to

AR that are more involved in the blood pressure

cause ejaculatory dysfunction in <10% of

regulation. Diffusion of a1-AR antagonists into

patients. Tamsulosin proved to be better toler-

the central nervous system (CNS) is considered

ated than terazosin.35-37 Because of the possible

to be responsible for dizziness and asthenia

additive effect of a-1 AR antagonists and phos-

although there is no proof of it.

phodiesterase inhibitors in lowering blood pres-

a-1 AR antagonists are known to improve

sure, the FDA suggested to avoid using sildenafil

LUTS and flow rate by acting on the receptors

within 4h of taking an a- AR antagonist.38

expressed in smooth muscle fibers of the pros-

1

The issue of patient compliance to prescribed

tatic stroma,bladder neck,and urethra.Possible

medications is of importance as market data

mechanisms of action outside the LUT involv-

suggest that most BPH patients remain on treat-

ing ganglia, spinal, and/or supraspinal struc-

ment for a few months only. Outcome measures

tures in the CNS have been hypothesized.25,26

used in clinical trials of drug treatment of BPH

The positive effect of these drugs on LUTS can-

are validated parameters that proved to be sen-

not be explained by the moderate improvement

sitive to change, but the problem of statistical

of BPO.27 The concept of uroselectivity (desired

significance versus clinical one remains open.

effects on obstruction and LUTS related to

In particular, little information is available as to

adverse effects) was proposed to highlight the

the clinical outcome and disease progression in

low rate of adverse events observed with mod-

real-life practice.

ern molecules having minimal effect on blood

After the use of antiandrogens and androgen

pressure and the CNS.28 There is no consensus

ablation was discontinued, hormonal therapy of

as to the ideal profile of AR subtype selectivity;

BPH is nowadays based on 5a-reductase inhibi-

modern molecules have a high affinity for a-1A

tors (5ARIs).39-42 The introduction of 5ARIs

and a-1D AR subtype and low affinity for a-1B

opens a new perspective because of the signifi-

that seems involved in blood pressure regula-

cant effect of these drugs on prostate volume

tion. Slow release, once daily formulations of

suggesting that the progression of the disease

a1-AR antagonists were developed to increase

could be somehow halted.43 The slow onset of

patient compliance and tolerability although

the therapeutic effect on LUTS prevented these

none of the clinical trials was able to show

drugs from being used as first-line treatment for

superiority of the slow release formulation ver-

many years. Short-term randomized studies

sus the immediate release one so that the clini-

failed to prove advantage of 5ARIs versus pla-

cal relevance of such development remains

cebo.44-46 A paradigm shift was caused by the

unclear.29,30 Distribution of a-1 AR antagonists

results of an independent, long-term study that

in the human body is of importance as penetra-

randomized patients among placebo, doxazosin,

tion of the blood–brain barrier may be respon-

finasteride, and their combination using overall

sible for some of the side effects. Neither slow

disease progression as the primary endpoint.9

release formulation nor difference in lypophi-

After an average 4.5 years of follow-up, combi-

licity among different molecules appeared to

nation treatment proved to be superior to either

provide a clinical advantage to any drug.

monotherapy treatments in reducing overall

368

Practical Urology: EssEntial PrinciPlEs and PracticE

disease progression. Preliminary. Data from the

and antimuscarinics can be prescribed in com-

CombAT study, confirm the long-term efficacy

bination at treatment start, alternatively anti-

and safety of combination treatment with tam-

muscarinics can be added only in those patients

sulosin and dutasteride. Post hoc analyses of

who do not improve sufficiently on a-1 AR

randomized trials suggest that 5ARIs are more

antagonists.

efficacious in patients with enlarged prostates,

which are also at a higher risk of disease pro-

Interventional Therapies

gression.47,48 Open label extensions of random-

ized trials and long-term studies such as the

The challenge of BPH surgery is in the manage-

MTOPS provided convincing evidence of a sus-

ment of very large prostates as complications of

tained therapeutic effect over time. The aim of

Trans-Urethral Resection of the Prostate (TURP)

5ARIs treatment is twofold: to reduce parame-

are known to increase in larger prostates.54 Open

ters of disease severity that are usually associ-

surgery is rapidly fading away from the urologist

ated with a decreased quality of life such as

armamentarium because the outstanding out-

LUTS, and to prevent disease progression. Long-

come is associated with increased morbidity and

term treatment with 5ARIs as monotherapy or

high cost compared to TURP. The small number

in combination with a-AR antagonists provides

of open prostatectomies performed in urological

a significant improvement of LUTS, maximum

centers does no longer allow proper training of

flow rate, and post-void residual. Evaluation of

our residents.Transurethral resection of the pros-

5ARIs arms (monotherapy or combination) of

tate TURP evolved significantly over the last

randomized trials show a significant reduction

decades and the transfusion rate dropped from

in the overall disease progression and particu-

the two-digit to the single-digit range.55 Technical

larly in terms of symptom progression, prostate

improvement in electrocautery units and the

volume increase, acute urinary retention epi-

availability of bipolar surgery were instrumental

sodes, and need for surgery compared to pla-

in making TURP safer.56 Although transurethral

cebo. 5ARIs are known to reduce total PSA

resection of the prostate remains the gold stan-

values by roughly 50%, but accuracy of this

dard treatment for BPO, several alternative treat-

marker for early diagnosis of prostate cancer is

ments have been developed over the last decade

maintained.49 Long-term use of 5ARIs proved to

to provide durable improvement with reduced

be safe and adverse events mainly consist in

morbidity and side effects. The term “minimally

decreased libido, diminished ejaculation, and

invasive” is a frequently abused one, particularly

impotence. Contrary to a-AR antagonists, the

in BPH treatment and comprises totally different

therapeutic effect of 5ARIs takes time to develop

treatments.

and patients should not be reassessed before

Transurethral microwave thermotherapy

3 months of treatment. Randomized trials of

(TUMT) and transurethral needle ablation of

5ARIs in monotherapy or combination show

the prostate (TUNA) may be performed as

that patients should initiate treatment if they do

office-based procedures with no anesthesia.57,58

not commit long-term as clinical benefit over a-

Long-term data of TUMT series suggest how one

AR antagonists needs at least 1 year to develop.

in four patients with moderate degree of bladder

Patients with LUTS associated with proven BPE

obstruction and one in three patients with severe

are candidates for combination treatment as

BPO required surgery in the long term (8 years).59

post hoc analyses suggest that every male patient

Long-term data on TUNA are not yet available

with a total PSA of 1.5 ng/mL or greater and a

although a large European registry database will

prostate volume of 30 mL or larger is at risk for

provide an answer by 2012. Both techniques pro-

disease progression.50

vide clinical outcome that is certainly inferior to

The use of antimuscarinics in the manage-

that produced by surgery although the morbid-

ment of patients with LUTS due to BPH has

ity is certainly lower.60

been recently proposed to manage storage

Laser treatments of BPH are often called

symptoms that may remain following treat-

“minimally invasive” although both Holmium

ment with a-AR antagonists.51 Evidence from

Laser Enucleation of the Prostate (HoLEP) and

randomized trials confirms that the use of anti-

Photo Vaporization of the Prostate (PVP) differ

muscarinics. In patients with LUTS and symp-

from TURP only in terms of reduced bleeding

toms of overactive bladder, a-1 AR antagonists

and shorter hospital stay.61 Each technique has