speakman

7/25/2019 Speakman

1/10

Lower Urinary Tract Symptoms Suggestive of Benign Prostatic

Hyperplasia (LUTS/BPH): More Than Treating Symptoms?

Mark J. Speakman *

Musgrove Park Hospital, Taunton & Somerset NHS Foundation Trust, Taunton, Somerset TA1 5DA, United Kingdom

e u r o p e a n u r o l o g y s u p p l e m e n t s 7 ( 2 0 0 8 ) 6 8 0 6 8 9

a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m

Article info

Keywords:Acute urinary retentionAetiologyBenign prostatic hyperplasiaPathogenesisProgressionQuality of lifeTreatment

Please visitwww.eu-acme.org/europeanurologyto read andanswer questions on-line.The EU-ACME credits willthen be attributedautomatically.

Abstract

Context: Duringthelasttwodecades,ithasbecomeclearthatthemanage-ment of lower urinary tract symptoms associated with benign prostatichyperplasia (LUTS/BPH) is much more than just treating symptoms.Objective: This review paper gives an overview of the main factorsinfluencing individual treatment decisions for LUTS/BPH patients.Evidence acquisition: This paper summarizes the content of an updatelecture held during a symposium on the management of LUTS/BPH at the2008 European Association of Urology meeting. During the presentation,the current decision drivers were discussed based upon recent literatureand illustrated with the results of a Web-based survey evaluating urol-ogists opinions on LUTS/BPH management.Evidence synthesis: The treatment of choice depends on the severity and

type of LUTS, which are nowadays believed to have a multifactorialaetiology. Consequently, treatment for LUTS/BPHshould not focus merelyon the prostate, but alsoon other organs involved in disease pathogenesis.In addition, the progressive character of LUTS/BPH is an important driverwhen taking treatment decisions. Patients at low risk of disease progres-sion require a fast and sustained symptom relief with minimal treatmentmorbidity, while patients at high risk of progression additionally requirecontinuous treatment delaying LUTS/BPH progression and the develop-mentof complications. Therefore,cliniciansshould be ableto determine apatients individual risk of progression. At present, seven baseline para-meters and three dynamic variables have been identified as predictors ofLUTS/BPH progression. Furthermore, as the quality of life (QoL) of both

patients and their partners is severely affected by LUTS/BPH, this aspectshould alsobe considered.Finally, treatment decisions arealsoinfluencedby existing comorbidities in the patient.Conclusions: Treatment for LUTS/BPH should aim at relieving the symp-toms and especially at improving the patients QoL with minimal treat-ment morbidity. Furthermore, LUTS/BPH treatment should be adapted tothe patients individual risk of disease progression.# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Tel. +44 1823 342 102; Fax: +44 1823 343 571.E-mail address:[email protected].

1569-9056/$ see front matter# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2008.08.003
http://www.eu-acme.org/europeanurologyhttp://www.eu-acme.org/europeanurologymailto:[email protected]://dx.doi.org/10.1016/j.eursup.2008.08.003http://dx.doi.org/10.1016/j.eursup.2008.08.003mailto:[email protected]://www.eu-acme.org/europeanurologyhttp://www.eu-acme.org/europeanurology

7/25/2019 Speakman

2/10

1. Introduction

Benign prostatic hyperplasia (BPH) is a disorder thatis macroscopically characterized by an enlargementof the prostate gland and histologically caused bythe progressive hyperplasia of stromal and glan-

dular prostatic cells. This nonmalignant overgrowthof prostatic tissue might ultimately lead to constric-tion of the urethral opening. Consequently, clinicalBPH is often associated with lower urinary tractsymptoms (LUTS). In fact, BPH is the main cause ofLUTS in ageing men. About half of the malepopulation over the age of 50 can be diagnosedwith histological BPH, and this prevalence increaseswith age to about 90% over the age of 80 [1].Clinically, about one-third of men in their sixthdecade of life suffer from moderate-to-severe LUTS,and this percentage rises to about 45% in men older

than 70[2].The classical treatment for LUTS/BPH mainlyfocused on symptom relief by surgical removalof the enlarged prostate, thereby relieving urinaryoutflow obstruction [3]. However, during thelast two decades, it has become clear that themanagement of LUTS/BPHeither by watchfulwaiting, by pharmacological treatment witha1-adrenoceptor (a1-AR) antagonists and/or 5a-reductase inhibitors, or by (minimally invasive)surgeryis much more than just treating symp-toms. To date, four modern drivers for taking

individual treatment decisions for LUTS/BPH canbe discerned.In this paper, the impact of the multifactorial

aetiology and the progressive character of LUTS/BPH on the management of this condition willbe discussed. In addition, the risk factors fordisease progression, as well as additional factorsinfluencing individual treatment decisions, will bereviewed.

2. Evidence acquisition

This paper summarizes the content of an updatelecture held during the symposium The future ofLUTS/BPH: management beyond the prostate atthe annual meeting of the European Association ofUrology in 2008. During the presentation, anoverview of the current drivers for taking indivi-dual treatment decisions on LUTS/BPH was givenbased on recent literature. Furthermore, theresults of a Web-based survey evaluating urolo-gists opinions on the management of LUTS/BPHwere used to illustrate the key points of thepresentation.

3. Evidence synthesis

3.1. Lower urinary tract symptoms suggestive of benign

prostatic hyperplasia have a multifactorial aetiology and a

progressive character

3.1.1. Multifactorial aetiology of lower urinary tractsymptoms suggestive of benign prostatic hyperplasia

Lower urinary tract symptoms secondary to BPH cangenerally be classified as voiding symptoms (pre-viously called obstructive), storage symptoms (pre-viously called irritative), and post-micturitionsymptoms[4].

Voiding symptoms such as slow stream, splittingor spraying of the urine stream, intermittentstream, hesitancy, straining, and terminal dribbleare believed to result from obstruction at the levelof the prostate. This obstruction can be caused by

an increase in prostate volume (mechanic orstatic component of obstruction) and/or by anincreased smooth muscle contraction in the pros-tate, bladder neck, and urethra (dynamic compo-nent of obstruction).

In contrast, storage symptoms such as nocturia,urgency, increased daytime frequency, and urinaryincontinence are thought to have a more complexaetiology [3,5]. For a long time, these symptoms werebelieved to result from obstruction- and/or age-induced detrusor instability (see 3.1.2.1.)[6,7].

However, it has now become clear that extrapro-

static mechanisms such as stimulation ofa1

-ARs inthe bladder, and especially the a1D-AR subtype,which predominates in the human detrusor, alsoplay a role in the development of storage symptoms[5,8,9]. However, further studies are needed to defineexactly the role of these receptors in humans.

In addition, a1-ARs located in peripheral gangliaand/or spinal cord segments are also thought tocontribute to the aetiology of LUTS/BPH. They mightfacilitate the release of acetylcholine, resulting inthe activation of muscarinic receptors in thedetrusor, increased bladder contractions, and the

concomitant development of storage symptoms[5].Furthermore, bladder muscarinic receptors andpurinergic receptors themselves might also play arole in the pathogenesis of LUTS, as witnessed by theeffectiveness of antimuscarinic agents in the treat-ment of overactive bladder (OAB) and by the changesin muscarinic and purinergic receptor expression inOAB (idiopathic or induced by bladder outletobstruction)[912].

Finally, several other factors have been suggestedto affect bladder function and to contribute to LUTS,such as the endocrine, renal, and cardiac systems[3,9].

e u r o p e a n u r o l o g y s u p p l e m e n t s 7 ( 2 0 0 8 ) 6 8 0 6 8 9 681

7/25/2019 Speakman

3/10

In conclusion, it is clear that not only obstructionat the level of the prostate, but many other, oftenoverlapping, factors are also involved in the aetiol-ogy of LUTS/BPH. Therefore, treatment should notonly focus on the prostate, but should also take theother players in the pathogenesis of the disease into

account.

3.1.2. Progressive character of lower urinary tract symptoms

suggestive of benign prostatic hyperplasia

3.1.2.1. Progressive cellular changes in the bladder

Although the bladder is one of the aetiological factorsin the development of LUTS/BPH, the organ itself alsosuffers from outlet obstruction. Indeed, followingpartial outlet obstruction, the bladder undergoesprogressive pathological changes in which threedistinct phases can be discerned[6,13,14].

As an initial response to the progressive increase

in urethral resistance, the bladder reacts withhypertrophy of smooth muscle cells, urothelialand interstitial fibroblast hyperplasia, and increasedcollagen synthesis and deposition. Together, theseevents result in a progressive increase in bladdermass during this initial stage. As soon as the bladdermass is sufficient to maintain detrusor contractilityand bladder emptying, the bladder enters thecompensated stage. In this phase, bladder massremains stable, but the progressive changes incellular structure and function still continue.Finally, these alterations interfere with the com-

pensatory mechanisms, resulting in destabilizationof bladder function and in the initiation of thedecompensated phase. This final stage is character-ized by a further increase in bladder mass and aprogressive decrease in smooth muscle in thebladder wall, leading to a deterioration of bladdercontractility. In addition, the increase of connectivetissue negatively affects bladder elasticity. There-fore, end-stage decompensated bladders have apoor contractile function and/or poor compliance.

These progressive pathological processes in thebladder might not only be evoked by chronic outlet

obstruction, but also by age-related changes in thelower urinary tract. Indeed, increasing age wasshown to be associated with a decrease in detrusorcontractility, bladder capacity, and ability to with-hold voiding and an increase in postvoid residual(PVR). Moreover, the prevalence of detrusor over-activity and nocturia increases with age [7].

In animal models, these pathological events havebeen shown to be reversible as long as the bladder isin the compensated stage [13]. However,as soonas itenters the decompensated stage, removal of partialoutlet obstruction only induces a partial recovery ofbladder function proportional to the level of decom-

pensation. Finally, when decompensation pro-gresses beyond a critical point, bladder damagebecomes irreversible, and bladder dysfunction pro-ceeds to end-stage decompensation.

In the long term, this obstruction- and/or age-induced bladder damage can result in the develop-

ment of serious complications in humans such asurinary tract infections, bladder stones, acuteurinary retention (AUR), or renal failure [14].

From the aforesaid, it is clear that LUTS/BPH havea progressive character, at least in some of ourpatients. Therefore, it is important to initiatetreatment at an early stage in those patients at risk,when pathological changes are still reversible. Onlyin this way can bladder function be maintained anddisease progression and the development of seriouscomplications be avoided.

3.1.2.2. Natural history of lower urinary tract symptoms

suggestive of benign prostatic hyperplasia: incidence of clinical

progression events

The importance of early treatment initiation forLUTS/BPH is further underscored by the substantialincidence of disease progression events in thegeneral population, which can be assessed eitherfrom longitudinal community-based studies or fromplacebo arms of controlled trials.

One of the longitudinal studies that provided thelargest body of evidence was the Olmsted Countystudy, in which a randomly selected cohort of 2115

middle-class North American Caucasian men aged4079 yr was followed. In this study, severity of LUTSwas significantly increased at follow-up, as illus-trated by the progression of 22% of men with mildsymptoms at baseline to moderate-to-severe symp-toms after 42 mo and by a mean annual increase inInternational Prostate Symptom Score (IPSS) of 0.18points [15]. Moreover, median peak urinary flow rate(Qmax) also decreased by 2.1% per year [16], whileprostate volume was significantly increased atfollow-up (average annual growth of 1.6%) [17].However, serious outcomes such as AUR and the

need for BPH-related surgery occurred rather infre-quently in the general population, as indicated by acumulative incidence of AUR of 2.7% over 4 yr[18].

Comparable results, showing a clear deteriorationof symptoms but a low incidence of serious compli-cations such as AUR, were also obtained from severalother longitudinal population-based studies[1921].

This progressive character of LUTS/BPH and themain contribution of symptom worsening to overallclinical progression was also confirmed in theplacebo arm of the Medical Therapy Of ProstaticSymptoms (MTOPS) study [22]. This double-blindcontrolled trial, following a total of 3047 men aged


7/25/2019 Speakman

4/10

50 yr with moderate-to-severe LUTS and a Qmaxof415 ml/s, was designed to assess the impact ofmedicaltherapies on the risk of BPH progression. Thecumulative incidence of overall clinical progression(definedas the first occurrence of a4-point increasein IPSS, AUR, urinary incontinence, renal insuffi-

ciency, or recurrent urinary tract infection) appearedto be 16.6% over 4 yr. Symptom deteriorationaccounted for the largest proportion (79.5%) of theseprogression events, while AUR (14.8%, correspondingto a cumulative incidence of 2.4% over 4 yr),incontinence (4.9%), and urinary tract infection orurosepsis (0.8%) occurred less frequently.

From the studies described above, it is clear thatdespite the low incidence of serious progressionevents such as AUR and BPH-related surgerydisease progression occurs significantly in patientswith LUTS/BPH when left untreated. Since reversion

of the pathological bladder changes underlying theseprogression events becomes impossible beyond acertain point, treatment should aim at preventingprogression of LUTS/BPH at an early disease stage.Consequently, medical physicians should be able todetermine a patients individual risk of diseaseprogression before taking treatment decisions. Thecurrently known risk factors for progression of LUTS/BPH, as well as other modern drivers for takingdecisions in the management of the disease, will bediscussed extensively in the next section.

3.2. Modern drivers for taking individual treatmentdecisions

3.2.1. Risk factors for the progression of lower urinary tract

symptoms suggestive of benign prostatic hyperplasia

Until now, seven parameters have been described tobe predictors of LUTS/BPH progression at baseline;that is, age, severity of LUTS at baseline, prostatevolume, prostate-specific antigen (PSA) levels, Qmax,

PVR, and prostatic inflammation. In addition, threedynamic variables have been recognized as pre-dictors of future disease-related events[23].

Convincing evidence that the baseline para-meters age, severity of symptoms, prostate volume,Qmax, and PVR have a predictive value for the risk of

LUTS/BPH progression was obtained from theOlmsted County Study. The relative risk of AURwas shown to be increased about eight times in menaged 7079 yr compared to men aged 4049 yr.Furthermore, a more than three times increasedrelative risk of AUR was observed for men withmoderate-to-severe symptoms compared to menwith mild LUTS, while men with a prostate volume>30 ml had a threefold increased relative risk ofAUR. In addition, a baseline Qmax12 ml/s increasedthe relative risk of AUR about fourfold [18],andaPVR>50 ml augmented this risk about three times[24].

The findings of this longitudinal community-based study were subsequently confirmed in theplacebo arms of several controlled studies, such asthe MTOPS study [22,25] and the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a finasteridestudy which enrolled 3040 men in the US withmoderate-to-severe LUTS, Qmax

7/25/2019 Speakman

5/10

Inflammation has been thought to be involved inthe pathogenesis of LUTS/BPH for over a decade.This idea was based on the observation thatprostatic inflammation and LUTS/BPH frequentlyoccur together [28,29]. However, only recently,inflammation was also suggested to be an independ-

ent risk factor for disease progression. The mostconvincing evidence for this hypothesis came fromthe MTOPS study [30]. Examination of baselineprostate biopsies in a subgroup of 1197 patientsshowed the presence of an acute and/or chronicinfiltrate in 45% of men. In the placebo group, thesemenwho also had larger prostate glands andhigher PSA valuesdisplayed a remarkably fasterprogression rate over time than men withoutinflammation, as witnessed especially by the sig-nificantly higher incidence of AUR in these patients(Fig. 2).

Further support for these data was provided byseveral recent studies. Analysis of the baseline datafrom the REduction by DUtasteride of prostateCancer Events (REDUCE) trial, a randomized dou-ble-blind placebo-controlled study in 8224 menevaluating the effects of 0.5 mg dutasteride oncedaily on reducing the risk of prostate cancer, showeda weak but statistically significant correlationbetween the degree of histological chronic inflam-mation and the degree of LUTS[31].

Furthermore, by examination of longitudinal datafrom the OlmstedCounty Study, it was demonstrated

that physician-diagnosed prostatitis is associated

with a more than twofold increased risk of laterdevelopment of BPH-associated events (prostatitis,enlarged prostate, or BPH) and a greater risk ofrequiring later treatment (medication or surgery) forBPH[32].

Finally, the role of inflammation in the pathogen-

esis and progression of BPH was confirmed in asingle-centre, retrospective study in 406 patientsundergoing transurethral resection of the prostatefor AUR or LUTS. Men with acute and/or chronicintraprostatic inflammation were shown to have agreater risk of AUR than men without inflammation[33].

Although all these data are in line with inflam-mation being a risk factor for disease progression,more studies are needed to confirm this hypothesis.In this regard, the longitudinal 4-yr follow-up in theREDUCE study might provide useful information. In

addition, as daily use of nonsteroidal anti-inflam-matory drugs has already been shown to beinversely related to the onset of moderate-to-severeLUTS, low Qmax, increased prostate volume, andelevated PSA levels in the Olmsted County Study[34], the potential of anti-inflammatory agents in theprevention of LUTS/BPH progression needs to befurther evaluated.

Next to these seven baseline variables, threedynamic variables have been identified as predic-tors of LUTS/BPH progression; that is, deteriorationof LUTS over time, increase in PVR over time, and

symptom deterioration and/or increasing botherwhile receiving treatment[23].Progressive deterioration of symptoms was first

recognized as a risk factor for LUTS/BPH progressionin the Health Professionals Follow-up study, aprospective cohort study analyzing the incidenceof AUR among 6100 male US health professionalsaged 4583 yr. In this study, the risk of AUR wasshown to be increased two- to threefold in men whohad a worsening of LUTS during the 2-yr follow-upperiod. Moreover, this risk seemed to be indepen-dent of baseline symptom severity[21].

Next, the role of changes in PVR over time as apredictor of future LUTS/BPH-related events becameclear from the placebo arm as well as from thetreatment arms of the MTOPS study. Indeed,patients who did not develop AUR during thefollow-up had a stable PVR throughout the study,while those who subsequently developed AURdisplayed a steady increase in PVR[35].

Finally, symptom deterioration during treat-mentand increasing bother during treatment, inparticularwere identified as dynamic variablespredicting LUTS/BPH progression in the ALFuzosinONcE daily (ALF-ONE) study, a large open-label

Fig. 2 Impact of acute and/or chronic inflammation on the

risk of clinical progression of benign prostatic hyperplasia

(BPH): results from the Medical Therapy Of Prostatic

Symptoms (MTOPS) study[30]. The percentage of patients

experiencing overall clinical progression, acute urinary

retention (AUR), or BPH-related surgery during follow-up

(mean duration 4.5 yr) is compared between patient

groups with (n = 544) and without inflammation (n = 653)

on baseline biopsies. The risk of AUR is significantly

increased in patients with baseline inflammation, while

overall clinical progression also tends to be increased in

these patients.


7/25/2019 Speakman

6/10

real-life study assessing the efficacy and safety ofalfuzosin at 10 mg once daily in real-life practice.Failure to respond to alfuzosin, defined as aworsening of IPSS 4 or a bother score >3 at thelast available assessment under treatment, wasshown to be a powerful predictor of AUR and BPH-

related surgery in the short term (6 mo)[36]as wellas in the long term (3 yr) [37].Based on these predictors of LUTS/BPH progres-

sion, nomograms can be developed. These modelsuse a mathematical algorithm to help physicianspredict a patients individual risk of disease pro-gression [38]. Currently, the MTOPS ProstaticSample Analysis (MPSA) Consortium is trying toidentify and validate new molecular markers thatmay identify risk of LUTS progression. Usingdifferent approaches, a high stromal-to-epithelialratio in the prostatic transition zone, as well as 19

unique autoantigens, were shown to be associated

with BPH progression. Moreover, detailed studies ofvarious PSA isoforms revealed that incorporationof baseline serum levels of BPH-A, a mature,enzymatically inactive, uncomplexed form of PSA,significantly enhances the accuracy of nomogramsin predicting AUR and BPH-related surgery[39].

Hence, it is clear that the baseline and dynamicpredictors of LUTS/BPH progression can help phy-sicians to tailor treatment to a patients individualrisk profile of progression. Patients who are at lowrisk of disease progression require only a fast andcontinued symptom relief with minimal morbidityassociated with treatment. However, for patients athigher risk of progression, symptom relief should becombined with continuous treatment aimed atdelaying the progression of the disease and thedevelopment of complications [40]. In this way,the management of LUTS/BPH can become more

cost-effective.

Fig. 3 Impact of lower urinary tract symptoms (LUTS) on the quality of life (QoL) of both patients and their partners: (a)

Comparison of impact on QoL of LUTS and different stages of prostate cancer (PCa) [42]. Total International Prostate

Symptom Score (IPSS) and total Functional Assessment of Cancer TherapyGeneral (FACTG) score (QoL questionnaire) are

compared among a control population, patients with moderate or severe LUTS (IPSS score in parentheses), and patients in

different clinical stages of prostate cancer (T1T2: organ-confined prostate cancer; T3T4: metastatic prostate cancer).

Severe LUTS cause a similar decrease in the QoL as 80% advanced prostate cancer. (b) Impact of symptomatic LUTS/BPH

(benign prostatic hyperplasia) on QoL of patients partners. The percentage of partners affected by several QoL-related

issues is depicted (n = 90). QoL is considerably affected in partners of LUTS/BPH patients[44].


7/25/2019 Speakman

7/10

3.2.2. Other modern drivers for taking individual treatment

decisionsNext to a patients current degree of symptomseverity and his risk of progression and futurecomplications, at least two additional factors alsoinfluence a medical physicians treatment decision;that is, the patients quality of life (QoL) and existingcomorbidities.

Although LUTS/BPH is not associated with painand does not involve a threat to life, the disease hasa significant impact on the QoL of patients. Men withLUTS, and especially nocturia and incompletebladder emptying, experience a higher degree of

bother and interference with daily activities and ahigher degree of worry and impact on psychologicalwell-being than men without symptoms [41,42].Severe LUTS have an even greater impact on the QoLthan do chronic illnesses such as diabetes, hyper-tension, angina, and gout [43] and advanced prostatecancer (Fig. 3a) [42]. Moreover, the QoL of bothpatients and their partners decreases as the severityof LUTS increases (Fig. 3b)[41,42,44]. Therefore, it isnot surprising that the fear of symptom deteriora-tion and concomitant QoL worsening is the mainreason for patients to consult a physician [45].Hence, it is clear that a patients QoL is one of the

most important aspects that should be taken into

account by clinicians when deciding upon LUTS/BPHmanagement, as illustrated by the outcomes of aWeb survey among urologists (Fig. 4).

Another factor influencing the management ofLUTS/BPH is the presence of comorbidities. Indeed,as this condition is quite common in ageing men, itoften occurs concomitantly with other commonage-related disorders such as cardiovascular dis-ease, hypertension, diabetes, metabolic syndrome,and erectile dysfunction[46]. Therefore, treatmentdecisions should also be guided by the existence ofthese comorbidities, since side-effects of medica-

tions might exacerbate the comorbid conditions.

4. Conclusions

From the above, it is clear that the management ofLUTS/BPH is more than just treating symptoms. Fourmain drivers for taking individual treatment deci-sions can be discerned (Fig. 5).

Firstly, the treatment of choice depends on theseverity and type of LUTS, which are known to havea multifactorial aetiology. Voiding symptoms arebelieved to be caused by obstruction at the level of

Fig. 4 Opinions of 382 urologists participating in a Web-based survey on the management of a patient with a first

presentation of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). The percentage of

respondents preferring a certain treatment option is depicted. The patients bother and quality of life (QoL) appear to be

important drivers in taking treatment decisions for LUTS/BPH.


7/25/2019 Speakman

8/10

the prostate, while many different mechanisms,

including detrusor overactivity and aberrant stimu-lation of receptors in the bladder or its innervatingstructures, can contribute to the development ofstorage symptoms. Therefore, treatment for LUTS/BPH should focus not merely on the prostate, butalso on other organs that play a role in diseasepathogenesis such as the bladder.

Secondly, the progressive character of LUTS/BPHis an important driver for taking treatment deci-sions. As progressive pathological changes in thebladder become irreversible beyond a certain stage,treatment should aim at preventing disease pro-

gression in an early disease phase. Only in this way,bladder function can be maintained and the devel-opment of serious complications such as AUR can beavoided.

Consequently, physicians should be able todetermine a patients individual risk of diseaseprogression before taking treatment decisions. Untilnow, seven parameters have been described to bepredictors of LUTS/BPH progression at baseline; thatis, age, baseline severity of LUTS, prostate volume,PSA levels, Qmax, PVR, and prostatic inflammation.In addition, three dynamic variables; ie deteriora-

tion of LUTS over time, increase in PVR over time,and symptom worsening and/or increasing botherduring treatment, have also been recognized aspredictors of future LUTS/BPH-related events. More-over, an extensive search for new biomarkers ofdisease progression is still going on and shouldresult in a more accurate prediction of a patientsrisk and, therefore, in a more cost-effective manage-ment of the disease.

Thirdly, as the QoL of both patients and theirpartners is severely affected by LUTS/BPH andis inversely correlated with the severity of LUTS,this parameter should be considered carefully

by clinicians when deciding upon LUTS/BPH

treatment.Finally, the treatment of choice for LUTS/BPH willalso depend on the existence of comorbidities in thepatient, since side-effects of several medicationsmight negatively affect these concomitant disor-ders.

All four factors should be taken into account inthe current management of LUTS/BPH. After asses-sing the causes of the disease and the risk factors forprogression, a differentiation should be madebetween patients at low or at high risk of diseaseprogression. Treatment of patients at low risk

should aim at relieving the symptoms and especiallyat improving the QoL, thereby causing minimalmorbidity or exacerbation of comorbid conditions.On the other hand, patients at higher risk of diseaseprogression require a combination of the previousstrategy with a continuous treatment that protectsthe bladder and avoids the development of compli-cations. This current approach is more cost-effec-tive and better adapted to a patients individualsymptoms, risks, and needs than the classicaltreatment approach focusing merely on symptomrelief.

Conflicts of interest

Mark Speakman received an honorarium for pre-senting the lecture at the EAU symposium on whichthis paper was based.

Funding support

The publication of this review was supported byAstellas Pharma Europe.

Fig. 5 Overview of four main drivers for taking individual treatment decisions in the management of lower urinary tract

symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH).


7/25/2019 Speakman

9/10

Acknowledgements

The author is grateful to Ismar Healthcare NV fortheir assistance in writing the manuscript.

References

[1] Berry SJ, Coffey DS, Walsh PC, Ewing LJ. The development

of human benign prostatic hyperplasia with age. J Urol

1984;132:4749.

[2] Chute CG, Panser LA, Girman CJ, et al. The prevalence of

prostatism: a population-based survey of urinary symp-

toms. J Urol 1993;150:859.

[3] Speakman MJ. The causes of lower urinary tract symp-

toms in patients. Drugs Today 2001;37(Suppl D):36.

[4] Abrams P, Cardozo L, Fall M, et al. The standardisation

of terminology of lower urinary tract function: report

from the Standardisation Sub-Committee of the Interna-

tional Continence Society. Neurourol Urodyn 2002;21:16778.

[5] Price D. Potential mechanisms of action of superselective

a1-adrenoceptor antagonists. Eur Urol 2001;40(Suppl 4):

511.

[6] Levin RM, Levin SS, Zhao Y, Buttyan R. Cellular and

molecular aspects of bladder hypertrophy. Eur Urol

1997;32(Suppl 1):1521.

[7] Elbadawi A, Diokno AC, Millard RJ. The aging bladder:

morphology and urodynamics. World J Urol 1998;16(Suppl

1):S1034.

[8] Schwinn DA, Michelotti GA. alpha1-adrenergic receptors

in the lower urinary tract and vascular bed: potential role

for the alpha1d subtype in filling symptoms and effects ofageing on vascular expression. BJU Int 2000;85(Suppl 2):

611.

[9] Andersson KE. Storage and voiding symptoms: pathophy-

siologic aspects. Urology 2003;62(Suppl 2):310.

[10] Kim JC, Yoo JS, Park EY, Hong SH, Seo SI, Hwang TK.

Muscarinic and purinergic receptor expression in the

urothelium of rats with detrusor overactivity induced

by bladder outlet obstruction. BJU Int 2008;101:3715.

[11] Mukerji G, Yiangou Y, Grogono J, et al. Localization of M2

and M3 muscarinic receptors in human bladder disorders

and their clinical correlations. J Urol 2006;176:36773.

[12] OReilly BA, Kosaka AH, Chang TK, Ford AP, Popert R,

McMahon SB. A quantitative analysis of purinoceptorexpression in the bladders of patients with symptomatic

outlet obstruction. BJU Int 2001;87:61722.

[13] Levin RM, Haugaard N, OConnor L, et al. Obstructive

response of human bladder to BPH vs. rabbit bladder

response to partial outlet obstruction: a direct compar-

ison. Neurourol Urodyn 2000;19:60929.

[14] Tubaro A, Miano L. Managing the consequences of

obstruction. Eur Urol Suppl 2002;1(9):217.

[15] Jacobsen SJ, Girman CJ, Guess HA, Rhodes T, Oesterling JE,

Lieber MM. Natural history of prostatism: longitudinal

changes in voiding symptoms in community dwelling

men. J Urol 1996;155:595600.

[16] Roberts RO,Jacobsen SJ,Jacobson DJ, RhodesT, GirmanCJ,

Lieber MM. Longitudinal changes in peak urinary flow

rates in a community based cohort. J Urol 2000;163:10713.

[17] Rhodes T, Girman CJ, Jacobsen SJ, Roberts RO, Guess HA,

Lieber MM. Longitudinal prostate growth rates during 5

years in randomly selected community men 40 to 79 years

old. J Urol 1999;161:11749.

[18] Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Natural historyof prostatism: risk factors for acute urinary retention. J

Urol 1997;158:4817.

[19] Lee AJ, Garraway WM, Simpson RJ, Fisher W, King D. The

natural history of untreated lower urinary tract symp-

toms in middle-aged and elderly men over a period of five

years. Eur Urol 1998;34:32532.

[20] Dobrovits M, Chaudry A, Anagnostou T, et al. A lon-

gitudinal prospective study of men with mild symptoms

of BOO treated with watchful waiting over 4 years. Eur

Urol Suppl 2003;2(1):26, abstract 96.

[21] Meigs JB, Barry MJ, Giovannucci E, Rimm EB, Stampfer MJ,

Kawachi I. Incidence rates and risk factors for acute

urinary retention: the health professionals followupstudy. J Urol 1999;162:37682.

[22] McConnell JD, Roehrborn CG, Bautista OM, et al. The long-

term effect of doxazosin, finasteride, and combination

therapy on the clinical progression of benign prostatic

hyperplasia. N Engl J Med 2003;349:238798.

[23] Khastgir J, Khan A, Speakman M. Acute urinary retention:

medical management and the identification of risk fac-

tors for prevention. Nat Clin Pract Urol 2007;4:42231.

[24] KolmanC, GirmanCJ, Jacobsen SJ,LieberMM. Distribution

of post-void residual urine volume in randomly selected

men. J Urol 1999;161:1227.

[25] Crawford ED, Wilson SS, McConnell JD, et al. Baseline

factors as predictors of clinical progression of benignprostatic hyperplasia in men treated with placebo. J Urol

2006;175:14226.

[26] Roehrborn CG, McConnell JD, Lieber MM, et al. Serum

prostate-specific antigen concentration is a powerful pre-

dictor of acute urinary retention and need for surgery in

men with clinical benign prostatic hyperplasia. PLESS

Study Group. Urology 1999;53:47380.

[27] Marberger MJ, Andersen JT, Nickel JC, et al. Prostate

volume and serum prostate-specific antigen as predictors

of acute urinary retention: combined experience from

three large multinational placebo-controlled trials. Eur

Urol 2000;38:5638.

[28] Nickel JC, Downey J, Young I, Boag S. Asymptomaticinflammation and/or infection in benign prostatic hyper-

plasia. BJU Int 1999;84:97681.

[29] Kramer G, Mitteregger D, Marberger M. Is benign prostatic

hyperplasia (BPH) an immune inflammatory disease? Eur

Urol 2007;51:120216.

[30] Roehrborn CG, Kaplan SA, Noble WD, et al. The impact of

acute or chronic inflammation in baseline biopsy on the

risk of clinical progression of BPH: results from the MTOPS

study. J Urol 2005;173(Suppl):346, abstract 1277.

[31] Nickel JC, Roehrborn CG, OLeary MP, Bostwick DG, Som-

erville MC, Rittmaster RS. The relationship between pros-

tate inflammation and lower urinary tract symptoms:


7/25/2019 Speakman

10/10

examination of baseline data from the REDUCE trial. Eur

Urol. In press.doi:10.1016/j.eururo.2007.11.026.

[32] St Sauver JL, Jacobson DJ, McGree ME, Girman CJ, Lieber

MM, Jacobsen SJ. Longitudinal association between pros-

tatitis and development of benign prostatic hyperplasia.

Urology 2008;71:4759.

[33] Mishra VC, Allen DJ, Nicolaou C, et al. Does intraprostatic

inflammation have a role in the pathogenesis andprogres-sion of benign prostatic hyperplasia? BJU Int 2007;100:

32731.

[34] St SauverJL, Jacobson DJ,McGreeME, Lieber MM,Jacobsen

SJ. Protective association between nonsteroidal antiin-

flammatory drug use and measures of benign prostatic

hyperplasia. Am J Epidemiol 2006;164:7608.

[35] Emberton M. Definition of at-risk patients: dynamic vari-

ables. BJU Int 2006;97(Suppl 2):125.

[36] Emberton M, Elhilali M, Matzkin H, et al. Symptom dete-

rioration during treatment and history of AUR are the

strongest predictors for AUR and BPH-related surgery in

men with LUTS treated with alfuzosin 10 mg once daily.

Urology 2005;66:31622.[37] Vallancien G, Emberton M, Alcaraz A, et al. Alfuzosin

10 mg once daily for treating benign prostatic hyperpla-

sia: a 3-year experience in real-life practice. BJU Int 2008;

101:84752.

[38] Slawin KM, Kattan MW. Theuse of nomograms for select-

ing BPH candidates for dutasteride therapy. Rev Urol

2004;6(Suppl 9):S405.

[39] Mullins C, Lucia MS, Hayward SW, et al. A comprehensive

approach toward novel serum biomarkers for benign

prostatic hyperplasia: the MPSA Consortium. J Urol

2008;179:124356.

[40] Chapple CR. The total approach in lower urinary tract

symptoms/benign prostatic hyperplasia (LUTS/BPH)

management: introduction and conclusions. Eur Urol

Suppl 2003;2(7):15.

[41] Girman CJ, EpsteinRS, Jacobsen SJ, et al. Natural history of

prostatism: impact of urinary symptoms on quality of lifein 2115 randomly selected community men. Urology

1994;44:82531.

[42] Batista-Miranda JE, Molinuevo B, Pardo Y. Impact of lower

urinary tract symptoms on quality of life using Functional

Assessment Cancer Therapy scale. Urology 2007;69:

2858.

[43] Welch G, Weinger K, Barry MJ. Quality-of-life impact of

lower urinary tract symptom severity: results from the

Health Professionals Follow-Up Study. Urology 2002;59:

24550.

[44] Sells H, Donovan J, Ewings P, MacDonagh RP. The devel-

opment and validation of a quality-of-life measure to

assess partner morbidity in benign prostatic enlarge-ment. BJU Int 2000;85:4405.

[45] Trueman P, Hood SC, Nayak US, Mrazek MF. Prevalence of

lower urinary tract symptoms and self-reported diag-

nosed benign prostatic hyperplasia, and their effect on

quality of life in a community-based survey of men in the

UK. BJU Int 1999;83:4105.

[46] McVary KT. BPH: epidemiology and comorbidities. Am J

Manag Care 2006;12:S1228.

http://dx.doi.org/10.1016/j.eururo.2007.11.026http://dx.doi.org/10.1016/j.eururo.2007.11.026

speakman

Documents