homma et al-2011-international jou rnal of urology

Guidelinesiju_2861 1..33

JUA clinical guidelines for benign prostatic hyperplasiaYukio Homma,1 Momokazu Gotoh,2 Osamu Yokoyama,3 Naoya Masumori,4 Akihiro Kawauchi,5

Tomonori Yamanishi,6 Osamu Ishizuka,7 Narihito Seki,8 Toshiyuki Kamoto,9 Atsushi Nagai10 andSeiichiro Ozono11

Department of Urology, 1Graduate School of Medicine, The University of Tokyo, Tokyo, 2Nagoya University Graduate School ofMedicine, Nagoya, 3University of Fukui, Fukui, 4Sapporo Medical University School of Medicine, Sapporo, 5Graduate School ofMedical Science, Kyoto Prefectural University of Medicine, Kyoto, 6Dokkyo Medical University, Tochigi, 7Shinshu University Schoolof Medicine, Matsumoto, 8Graduate School of Medicine Sciences, Kyushu University, Fukuoka, 9Faculty of Medicine, University ofMiyazaki, Miyazaki, 10Kawasaki Medical School, Kurashiki, and 11Hamamatsu University School of Medicine, Hamamatsu, Japan

Abstract: The Japanese Urological Association has developed Clinical Guidelines for Benign Prostatic Hyperplasia (BPH)for men with suspected BPH. This article is an English translation of the abridged version of the Guidelines. The Guidelineswere formulated on the basis of evidence retrieved from the PubMed database between 1995 and 2009, as well as otherrelevant sources. The target patients of these Guidelines are men with suspected BPH, and the target users are urologists.Amandatory assessment should include amedical history, a physical examination, the completion of symptom and qualityof life questionnaires, a urinalysis, a prostate ultrasonography, measurement of serum prostate specic antigen andpostvoid residual urine, and uroowmetry. Optional tests include keeping a bladder diary, the measurement of serumcreatinine, and upper urinary tract ultrasonography. Care should be taken to not overlook coexisting diseases such asinfections or malignancies that may obscure the diagnosis. Treatment should consist of conservative therapy or the use ofmedications such as a1-adrenoceptor antagonists, or both. The use of 5a-reductase inhibitors or anticholinergic agentsshould be considered in patients with an enlarged prostate (>30 mL) or overactive bladder symptoms (Overactive BladderSymptom Score6), respectively. Surgical intervention is indicated when non-surgical treatments fail to provide sufcientsymptomatic relief, and when bladder outlet obstruction is highly suspected.

Key words: BPH, guidelines, male LUTS.

Introduction

A number of clinical guidelines have been formulated inJapan for lower urinary tract disorders such as benign pro-static hyperplasia (BPH),1 urinary incontinence,2 overactivebladder (OAB),3 male lower urinary tract symptoms(LUTS),4 interstitial cystitis and hypersensitive bladder syn-drome,5 nocturia,6 and neuropathic conditions. The clinicalguidelines for BPH have recently been revised extensively,and this article is an English translation of the abridgedversion of the revised guidelines. The target patients andusers of these Guidelines are men suspected of having BPHand urologists, respectively. In the case of the male LUTS

Guidelines,4 the target patients and users are men withLUTS and non-urologist physicians, respectively. Readersshould be aware of the earlier guidelines, particularly formale LUTS,4 when adopting the BPH Guidelines to clinicalpractice.

Methodology

The Guidelines were developed by committee members rec-ommended by the Japanese Urological Association (JUA).The members meticulously reviewed relevant references,retrieved via the PubMed and Japana Centra RevuoMedicina databases, and published between 1995 and 2009.Other sources of information included Japanese guidelinesfor other conditions, the BPH guidelines published by theAmerican Urological Association (AUA)7 and the EuropeanAssociation of Urology (EAU),8 and the meeting reports ofthe International Consultation on Urological Diseases onmale lower urinary tract disorders.9 A draft of the revisedguidelines was peer-reviewed by JUA executive membersbefore the guidelines were finalized. Funding was providedby the JUA.

Correspondence: Yukio Homma M.D., Department of Urology,Graduate School of Medicine, The University of Tokyo, 7-3-1Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected] is a translated summary of a full guideline first published asa book in Japanese by The Japanese Urological Association,Clinical guidelines for benign prostatic hyperplasia, 2011. Rich-Hill Medical, Tokyo.

Received 31 July 2011; accepted 28 August 2011.

International Journal of Urology (2011) 18, e1e33 doi: 10.1111/j.1442-2042.2011.02861.x

2011 The Japanese Urological Association e1

Algorithm

The algorithm (Fig. 1) is applicable to men who aresuspected of having BPH. Factors suggestive of BPHinclude age >50 years, LUTS (increased urinary fre-quency, voiding difficulties, urgency), and associatedcomplications, such as urinary retention and urinary tractinfection (UTI), or both.

The basic assessment of these men, mandatory in allcases, comprises their present and past history, thecompletion of symptom and quality of life (QOL) ques-tionnaires, a physical examination, urinalysis, uroflow-metry, postvoid residual urine measurement, a prostateultrasonography, and the determination of prostate-specific antigen (PSA) serum concentrations. Optionalassessments, selected on an individual basis, includekeeping a bladder diary, advanced urodynamic studies,the measurement of serum creatinine levels, and anupper urinary tract ultrasonography. Additional tests,such as urine cytology, urine culture, endoscopy, andradiological examinations may be indicated when otherdisorders are suspected. Other disorders include pros-tatic cancer, prostatitis, OAB, underactive bladder, bac-terial cystitis, interstitial cystitis, bladder cancer, bladderstones, urethritis, urethral stricture, neurogenic bladder,hydronephrosis, polyuria, and nocturnal polyuria.

When the patients history, symptoms, or test resultssuggest the presence of other disorders, further assess-ments need to be performed. Findings suggestive of otherdisorders are a history of urinary retention, urinary tractinfection, macroscopic hematuria, pelvic surgery orradiotherapy, and neuropathic diseases; symptoms ofbladder pain, perineal pain, monosymptomatic nocturia,and overt OAB symptoms; and test results revealingabnormal findings on rectal examinations, urinalysis, andultrasonography, elevated PSA levels, positive urinarycytology, increased residual urine, bladder stones, renaldysfunction, polyuria, and nocturnal polyuria.

When lower urinary tract dysfunctions, including symp-toms, can be attributed to BPH, both the patients desire

for treatment and the medical need for treatment shouldbe assessed. Medical need includes the event of severesymptoms, a highly enlarged prostate, or complications,such as urinary retention, hematuria, bladder stones,renal insufficiency, and UTI.

When there is no desire on the part of the patient fortreatment and no medical need for treatment, watchfulwaiting is indicated.

In most cases, conservative or medical therapy, or both,such as the use of a1-adrenoceptor antagonists, are firstindicated. When there is an indication for surgery,further assessments prior to surgery should beundertaken. Surgery is the preferred treatment in cases inwhich there are BPH-related complications, when it isanticipated that medical treatment will be insufficient, orif the patient prefers to undergo surgical therapy.

The baseline for medical treatment is the use of a1-adrenoceptor antagonists. When the prostate is enlarged(>30 mL) and when OAB symptoms are evident (over-active bladder symptom score [OABSS] 6), consider-ation should be given to changing the medical treatmentto 5a-reducatase inhibitors or anticholinergics or both(either instead of or in addition to a1-adrenoceptorantagonists), respectively. If these measures are not fullysuccessful, surgical indications should be evaluated.

Evaluation of surgical indications includes confirmingthe patients desire for surgery, making a systemicreview of the surgical risks, and an urodynamic evalua-tion of bladder outlet obstruction (BOO). BOO is to beassessed by pressure-flow studies or it may be feasible byother studies, such as uroflowmetry or bladder wallthickness, or both.

If a patients condition does not improve or worsens, thepatient should be reassessed, as described under thebasic assessment section, for the presence of other dis-orders. If a patients condition improves with treatment,regular reassessments should be undertaken to detect anypossible changes in the patients status, with therapeuticmeasures adjusted accordingly.

Denition of BPH

Summary

BPH is defined as a disease that manifests as a lower urinarytract dysfunction due to benign hyperplasia of the prostate,usually associated with enlargement of the prostate andLUTS suggestive of lower urinary tract obstruction.

There is no uniform definition for BPH.9,10 The Interna-tional Continence Society proposed the use of BPH exclu-sively as a histopathological term to refer to non-malignanthyperplasia of prostatic tissue, and coined the terms benignprostatic enlargement (BPE) for an enlarged prostate andbenign prostatic obstruction (BPO) for lower urinary tract

Conservative or medical treatmentwith -blockers etc.

Men suspected of BPH

Basic assessmentOptional assessmentFurther assessment

Surgicaltreatment

Yes

Watchfulwaiting

BPH most probable

Assessmentfor surgery

History/symptoms/testresults suggestive of

other disorders

No

Treat thedisorder/s

Assessment forother disorders

Symptoms ofoveractive bladder

Not improved

Enlargedprostate

5-reductaseinhibitor

Anticholinergics

Desire or needfor treatment

Fig. 1 Algorithm for benign prostatic hyperplasia (BPH).

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e2 2011 The Japanese Urological Association

obstruction.11 This strict terminology results in the redun-dant expression LUTS suggestive of BOO being used fora condition that is commonly referred to as BPH in clinicalpractice. In the present Guidelines, BPH needs to be definedin a way that is suitable for use in clinical practice.

Thus, in the present Guidelines, the term BPH is usedto refer to conditions in which there is benign hyperplasiaof the prostate. There are three characteristic pathophysi-ological features: (i) BPE; (ii) BPO; and (iii) LUTS.12

However, in a clinical setting, it is not necessarily feasibleto make an accurate assessment of all three factors. Spe-cifically, the pressure-flow studies that are mandatory forthe accurate evaluation of BPO are invasive and are thusnot performed routinely, even during urological consulta-tions. Less invasive tests, such as uroflowmetry, the mea-surement of postvoid residual urine (PVR), and anultrasonographic assessment of bladder wall thickness,cannot fully replace pressure-flow studies. However, inreality, men with LUTS and lower urinary tract dysfunc-tions are diagnosed as having BPH when BPE is present,BPO is suggested, and other pathologies are ruled out.Thus, in the present Guidelines, BPH is regarded as adisease with lower urinary tract dysfunction due to benignhyperplasia of the prostate, which is usually associatedwith enlargement of the prostate and LUTS that are sug-gestive of lower urinary tract obstruction.

Epidemiology and natural historyof BPH

Summary

BPH is a progressive disease that is common in elderly men.Although prevalence varies based on the definition of BPHused, 6 and 12% of Japanese men in their sixties and sev-enties, respectively, meet all three of the following criteriafor BPH: (i) an international prostate symptom score (IPSS)>7; (ii) prostate volume (PV) >20 mL; and (iii) peak urinaryflow rate (Qmax) 7, PV >20 mL, and Qmax 7 (%) PV >20 mL (%) Qmax

Factors affecting health-care seeking behavior

A population-based study in Olmsted County revealed thathealth-care seeking behavior was influenced by the severityof symptoms, particularly if they were bothersome and inter-fered with an individuals daily activities.35 In Japan there isa marginal overlap in the distribution of QOL scoresbetween the general population and patients with BPH.36

Prediction of disease progression

When acute urinary retention is regarded as an indicator ofdisease progression, the incidence in a US population hasbeen calculated to be 6.8 per 1000 person-years.37 Older age,a higher IPSS, Qmax 30 mL are all riskfactors for urinary retention. Surgical treatment would beanother indicator of disease progression, and the risk isrelated to age, the severity of the symptoms, an impairedQOL, decreased urinary flow rate, degree of prostateenlargement, and increased serum PSA levels.30,38

Natural history of BPH after diagnosis

The natural history of BPH can be monitored in men inwhom the watchful waiting approach is being taken or inthose on a placebo in Phase III clinical trials of medicaltreatments. The baseline PV and the rate of growth of theprostate during follow-up are greater in men with BPH thanin men in the general population.39,40 TheMedicalTherapy ofProstatic Symptoms study,41 which observedmen on placeboor doxazosin for 4.5 years, reported that prostate growthcould be predicted by baseline PV and serum PSA levels.Although LUTSworsened progressively in menwith BPH asa whole, in some patients improved or stable LUTS wasnoted.42 Symptomatic deterioration, development of acuteurinary retention, and conversion to BPH-related surgerytended to occur in men with severe LUTS, a large PV, andhigh PSA levels at baseline.4345 Fortunately, a recent studyhas found that BPH-related deaths or comorbidities, such ashydronephrosis, renal failure, UTI, and bladder stones, arerare. In a study of 737 patients treated with placebo, over4.5 years of follow-up only one patient developed recurrentUTI and none developed renal insufficiency.46

Pathophysiology

Summary

BPH is composed of stromal elements made up of smoothmuscle and connective tissue, as well as glandular andluminal epithelial cells, and arises in the periurethral regionof the prostrate. An interaction is seen between stromal andepithelial cells, mediated by proliferative factors, includingsex hormones, inflammation, and stimulation of adrenergic

nerves. Urethral compression associated with prostaticenlargement causes voiding symptoms. However, age-related DU is also an important cause of voiding symptoms.Urethral compression causes distension, ischemia, inflam-mation, and oxidative stress to the bladder, followed bychanges to the bladder nerves and smooth muscle and therelease of urothelial-derived mediators, causing storagesymptoms. Even without compression, stimulation of theurethral sensory nerves can cause storage symptoms. Impor-tant complications of BPH include recurrent urinary reten-tion, macroscopic hematuria, bladder calculi, recurrent UTI,and postrenal renal failure.

Prostate growth factors

Histologically, prostatic hypertrophic nodules (adenomas)consist of increased numbers of cells, so the term hyper-plasia is more appropriate than hypertrophy. Prostaticadenomas arise in the transitional zone and the periurethralregion of the prostate,47 with nodules initially consisting ofstromal elements only.48

An interaction is seen between prostatic stromal and epi-thelial cells, mediated by various growth factors, and thehyperplasia is thought to be caused by an imbalancebetween cellular proliferation and cell death. Although theimportance of male sex hormones to the development ofprostatic hyperplasia is undisputed,49 female sex hormonesalso contribute to its formation. Furthermore, inflammationplays an important role in the onset of hyperplasia andurinary retention.50 A clinical trial of 5a-reductase inhibitortherapy found that prostatic volumes were bigger, andsymptom scores higher, in patients with pathological evi-dence of inflammation.51 Cytokines derived from inflamma-tory cells also induce epithelial growth factors.52 In addition,the promotion of glandular proliferation in spontaneouslyhypertensive rats53 and the induction of apoptosis bya1-adrenoceptor antagonists54 suggest the involvement ofadrenergic nerves in prostatic hyperplasia.

Prostatic adrenergic receptors

a1-adrenergic receptors (AR) are the main AR in prostaticsmooth muscle, and three subtypes have been identified:a1A, a1B, and a1D. In the normal human prostate, the mRNAcontent of each of the a1A-, a1D-, and a1B-AR subtypes hasbeen reported to be 63, 31, and 6%, respectively, comparedwith 85, 14, and 1%, respectively, in prostatic hyperplasia.55

In both cases, a1A-AR is the predominant subtype. Con-versely, there have been reports of patients in whom thereare similar levels of a1A- and a1D-AR (41 and 49%, respec-tively), and in whom a1A-AR is no longer the predominantsubtype.56 A recent study found that the a1A-AR geneexpresses two subtypes, a1A and a1 L, with the a1 L subtype

GUIDELINES


being mainly involved in the contraction of the prostate andurethra.57 Noradrenaline-induced contraction of the prostateis nearly absent in a1D-AR knockout mice,57 but observa-tions of reduced urinary frequency and increased bladdervolumes58 indicate that a1D-AR are involved in bladder func-tion, not prostatic contractions. Detrusor overactivity (DO)induced by stimulation of the rat urethra is inhibited bya1-adrenoceptor antagonists with a high specificity for a1A-AR,59,60 indicating that storage symptoms in BPH are medi-ated by urethral a1A- and a1 L-AR.

BPE, LUTS, and BPO

The pathology of BPH consists of three elements: BPE,LUTS, and BPO.4 Because LUTS can result from a varietyof different diseases and conditions (Table 2), there is noclear correlation between LUTS and BPE or BPO.61,62

Whether there is a correlation between BPO and LUTSsometimes depends on the site of origin of prostaticnodules. For example, in the case of middle lobe hyperpla-sia, intravesical prostatic protrusion, rather than BPE, iscorrelated with LUTS and BPO.63 Urodynamic studiesshow a weak correlation between BPO and LUTS, whereasDO is correlated with the degree of BPO.64 Storage symp-toms, in particular urge incontinence, strongly suggestDO.6567

Voiding dysfunction associated with BPO: Voidingsymptoms in patients with BPH associated with BPO occuras a result of resistance to urine flow. Specifically, inresponse to BPO, the bladder smooth muscle hypertrophiesto maintain urine flow. When it can no longer compensate,a reduced expression of connexin 43, the structural proteinin the gap junctions between smooth muscle cells, impairsthe synchronization of contractions, resulting in contractiledysfunction.68 Even after any obstruction has been

removed, such as by surgery, voiding symptoms persist inone-third of patients.69 In particular, voiding symptoms areoften caused by bladder contractile dysfunction in patients>70 years of age (48%) and are even more common inthose with a history of urinary retention.70 BPO cannot bedemonstrated in 60% of patients >80 years of age withvoiding dysfunction.71,72 This is likely to be due to an age-associated decrease in bladder contractility and increase incollagen.Storage dysfunction associated with BPO: With BPH,the cycle of urine storage and voiding causes repeatedbladder distension, raised intravesical pressure, ischemia,and reperfusion, eventually resulting in various changes inthe urothelium, nerves, and smooth muscle. Impairedvesical blood flow results in oxidative stress, with free radi-cals causing damage to the urothelium, nerves, and smoothmuscle.73 Patients with persistent DO following transure-thral resection of the prostate (TURP) have ongoing impair-ment of perfusion of the lower urinary tract,74 suggestinga correlation between impaired perfusion and storagedysfunction.1 Changes in nerves: the nerves in the bladder wall (pelvic

nerve post-ganglionic fibers) are particularly vulnerableto ischemia and undergo partial denervation. With thisdenervation, the bladder smooth muscle becomes super-sensitive to acetylcholine (ACh).75 Furthermore, insensory nerves subjected to ischemia, the number ofneurokinin receptors increases,76 resulting in increasedsensory sensitivity.

2 Changes in bladder smooth muscle: in the normalbladder, adjacent smooth muscle cells are coupled andundergo autonomous contractions. However, in patientswith BPO, the increased expression of the gap junctionprotein connexin 43 induces synchronization of smoothmuscle cells, increasing the strength of contractions.77

Table 2 Diseases and conditions that cause male lower urinary tract symptoms

1. Prostate and lower urinary tractProstate: BPH, prostatitis, prostate cancerBladder: bacterial cystitis, interstitial cystitis, bladder cancer, bladder stones, bladder diverticulum, OAB, other (age-related

detrusor underactivity)Urethra: urethritis, urethral stricture

2. Nervous systemCerebral: cerebrovascular disorder, dementia, Parkinsons disease, multiple system atrophy, brain tumorSpinal cord: spinal cord injury, multiple sclerosis, spinal cord tumor, spinal infarction, spinal degenerative disease, spina

bidaPeripheral nerves: diabetic neuropathy, post-pelvic surgeryOther: aging, autonomic hyperactivity

3. MiscellaneousDrug related, polyuria, sleep disorders, psychogenic

BPH, benign prostatic hyperplasia; OAB, overactive bladder.

Guidelines


The increase in the strength of autonomous contractionsis also thought to be mediated by changes in the inter-stitial cell networks in the suburothelial and muscle lay-ers,78 the release of various urothelial mediators,supersensitivity to ACh,79 and/or the activation of theRhoA/Rho-kinase pathway.80

3 Urothelial-derived mediators: urothelial cells not onlyrelease neurotransmitters, but also have various recep-tors and ion channels on their surface, thereby influenc-ing bladder function.81 Important mediators released bythe urothelium include adenosine triphosphate, nitricoxide, prostaglandin, and ACh. These mediators arereleased in response to distension, ischemia, inflamma-tion, and/or oxidative stress, mediated by transientreceptor potential vanilloid 1,82 epithelial sodium chan-nel,83 acid-sensing ion channels,84 muscarinic, and otherpurinergic receptors,85 or AR on the bladder urothelium.These bladder urothelial cells, as well as C fibers in thebladder suburothelium, respond to these stimuli byincreasing their afferent input, thereby influencingstorage function.86

4 Afferent stimuli from the urethra: enlargement of theprostate leads to distension and irritability of the urethra,with storage symptoms mediated by the stimulation ofafferent nerves to the urethra. The induction of the mic-turition reflex by intraurethral prostaglandin E2 is inhib-ited by a-AR antagonists,59 suggesting that urethralsensory nerves play an important role in the onset ofstorage symptoms.

Conditions other than BPO: It is not uncommon formiddle-aged to elderly men with LUTS to have BPE butnot BPO.62 In particular, voiding symptoms in elderly menare caused by bladder contractile dysfunction rather thanobstruction.7072 Anesthesia of the prostatic urethra hasbeen reported to increase bladder volume,87 suggestingthat urethral sensory nerves are responsible for storagesymptoms.

Complications of BPH

Recurrent urinary retention

The incidence of acute urinary retention is significantlyhigher in patients with BPH who have a prostatic volume31 mL or serum PSA levels 1.6 ng/mL. These patientsare more likely to progress to invasive treatment.45 The riskof acute urinary retention increases with age and it is oftenassociated with DU.70

Macroscopic hematuria

Macroscopic hematuria is present in 12% of patients inwhom surgery is indicated for BPH.88 A possible cause ofthe macroscopic hematuria is increased microvessel density

due to the increased expression of vascular endothelialgrowth factor associated with the enlargement of theprostate.89,90

Bladder calculi

Bladder calculi associated with BPH are thought to becaused by urinary stasis,91 although the underlying mecha-nism is unclear.

Recurrent UTI

Increased PVR volumes and endoscopic manipulation in thelower urinary tract are thought to contribute to UTI.

Postrenal renal failure

Although renal failure is a rare complication of BPH (

Physical examinations of the lower abdomen may detecturinary retention, as evidenced by the distension of theabdominal wall. A digital rectal examination of the prostateenables the size and indurations of the prostate to be evalu-ated.Anal tonus and perineal sensation may be attenuated bycoexisting neurogenic deficits.

Urinalysis should be negative in BPH. The presence ofhematuria or pyuria, or both, should be evaluated further.Uroflowmetry is a non-invasive quantitative evaluation ofvoiding conditions, with a reduced flow rate indicating theobstruction of the bladder outlet or DU. A PVR measure-ment can be made using transabdominal ultrasonographyrather than by inserting a catheter.

The determination of serum PSA levels is useful topredict PV or the clinical progression of BPH, or both.99

However, it should be kept in mind that serum PSA valuesare also increased in cases of prostate cancer, acute urinaryretention, and prostatitis. Anti-androgens and 5a-reductaseinhibitors can reduce serum PSA values by approximatelyhalf.100

Prostate ultrasonography is recommended for the accu-rate evaluation of the volume and shape of the prostate.101

Trans-abdominal ultrasonography using a general ultra-sound instrument is less invasive and can simultaneouslydetect PVR and bladder pathology. Transrectal ultrasonog-raphy, which requires specialized equipment, evaluates thedetailed internal structure of the prostate. PV is usuallycalculated by an approximation of the ellipsoid formula andis predictive of BPH progression.102

Elective tests

The bladder diary records micturition times and thevolume voided over a period of 24 h. It is particularlyuseful for men with daytime and nocturnal frequency toidentify a reduction in the volume voided and (nocturnal)polyuria. Pressure-flow studies are standard urodynamictests that accurately evaluate both BOO and detrusor con-tractility. Because this test requires the insertion of a cath-eter, it is recommended only when the test results mayaffect therapeutic outcomes. Serum creatinine concentra-tions may be elevated in men with urinary retention orincidental renal dysfunction. An upper urinary tract ultra-sonography is recommended for men with abnormal uri-nalysis, large PVR, renal insufficiency, or a history ofother urological diseases.

Other tests

Endoscopy of the urethra and bladder is helpful for theevaluation of morphological changes, such as adenoma pro-trusion into the bladder and bladder trabeculations. It isrecommended for men with planned surgery and suspicionof other diseases, such as urethral stricture, bladder stones,

and cancer. Retrograde urethrography is able to detect aurethral stricture. Further evaluations are indicated whenother diseases and conditions are suspected.

Treatment

The treatment for BPH is basically an amelioration ofimpaired QOL by improving LUTS.

Grades of recommendation

The grades of recommendation for treatments (Table 3)were determined via committee discussion and consensus,based on the level of evidence (Table 4), as well as variabil-ity of conclusions, the magnitude of effect, clinical applica-bility, adverse events, and cost. Grades of recommendationfor individual treatments are shown in Table 5.

Pharmacotherapy

1 a1-adrenoceptor antagonists

a1-adrenoceptor antagonists relieve outlet obstruction byinhibiting contractions mediated by prostatic a1-AR,thereby ameliorating LUTS of BPH.4,103 a1-adrenoceptor

Table 3 Grade of recommendation

Grade Nature of recommendation

A Highly recommended to doB Recommended to doC No rm evidence for recommendation

C1 Can be consideredC2 Not recommended

D Recommended not to doReserved Unable to decide grade of recommendation

Table 4 Level of evidence

Level ofevidence

Type of evidence

1 Evidence obtained from multiple large-scalerandomized controlled trials (RCT)

2 Evidence obtained from a single RCT or lowquality RCT

3 Evidence obtained from non-randomizedcontrolled studies

4 Evidence obtained from observational studies5 Evidence obtained from case studies or expert

opinions

Guidelines


antagonists, also referred to as a1-blockers, can result in therapid relief of LUTS. The use of a1-adrenoceptor antago-nists can result in a 1625% (2.02.5 mL/s) increase inmaximum flow rate and a 3040% (46 point) reduction inthe average IPSS.4,7,8,103,104 Adverse reactions to alfuzosinand tamsulosin, such as postural hypotension and asthenia,have been reported to be as low as that reported for placebo(410%). Other adverse events include ejaculatory dysfunc-tion and intraoperative floppy iris syndrome. Alla1-adrenoceptor antagonists have a similar efficacy inappropriate doses, with the effects being dose depen-dent.7,8,104 In Japan, tamsulosin, naftopidil, silodosin, tera-zosin, urapidil, and prazosin have been approved for use.103

Note that the recommended doses of some drugs are differ-ent in Japan to those in Europe and the USA.

TamsulosinRecommendation grade: AThere is adequate evidence to support its efficacy for BPH(Level 1).Tamsulosin is an a1A/a1D-AR subtype-selective antagonist,with an affinity for a1A- and a1D-AR 15.3-, and 4.6-foldhigher, respectively, than for a1B-AR.105A Japanese random-ized clinical trial (RCT) of tamsulosin in the treatment ofBPH demonstrated its superiority to placebo, and reportedthat the optimal dosage was 0.2 mg/day.106 Studies inWestern countries have reported optimal doses of 0.4 mg/day.104,107 Adverse reactions to tamsulosin, including pos-tural hypotension (0.19%), were uncommon in the Japanesestudy (2.87%).

NaftopidilRecommendation grade: AThere is adequate evidence to support its efficacy for BPH(Level 1).Naftopidil is an a1D/a1A-AR subtype-selective antagonist,with an affinity for a1D-, and a1A-AR 16.7- and 5.4-foldhigher, respectively, than for a1B-AR.105 The efficacy ofnaftopidil in the treatment of BPH has been demonstratedin RCT comparing it with both placebo and otheragents.108,109

SilodosinRecommendation grade: AThere is adequate evidence to support its efficacy for BPH(Level 1).Silodosin is a selective a1A-adrenoceptor antagonist, withan affinity for a1A-, and a1D-AR 583- and 10.5-fold higher,respectively, than for a1B-AR.110 An RCT in Japan indi-cated significantly larger decreases in IPSS and QOLscores following treatment with silodosin compared withplacebo.111 Pooled results from two Phase III studies ofsilodosin for the treatment of BPH have been reported inthe USA.112

Table 5 Grade of recommendation pharmacotherapy;surgical interventions and other treatments

Treatment Grade

Pharmacotherapya1-adrenoceptor antagonists (a1-blockers)

Tamsulosin, naftopidil, silodosin,terazosin, urapidil

A

Prazosin C15a-reductase inhibitors

Dutasteride AFinasteride Reserved (not

approved)Anti-androgens

Chlormadinone, allylestrenol C1Others

Eviprostat, Cernilton, Paraprost,Chinese herbal medicines(Hachimi-jio-gan, Gosha-jinki-gan)

C1

Flavoxate, antidepressants,cholinergics, phosphodiesterase 5inhibitors

Reserved (notapproved)

Surgical interventionsOpen prostatectomy (sub-capsular

enucleation)B

Transurethral resection of the prostate ATransurethral incision of the prostate Bbipolar-TURP AHolmium laser enucleation of the

prostateA

Photoselective vaporization of theprostate by KTP laser

B

Holmium laser ablation of the prostate BTransurethral detachment of the prostate,

transurethral enucleation with bipolarsystem

C1

Interstitial laser coagulation of theprostate

C1

High-intensity focused ultrasound C1Transurethral needle ablation C1Transurethral microwave thermotherapy BUrethral stent C1Transurethral ethanol ablation of the

prostateReserved (not

approved)Botulinum toxin injection Reserved (not

approved)Other treatments

Lifestyle modication BWatchful waiting BSupplements C2Indwelling catheter ReservedIntermittent catheterization B

See Guidelines for Management of Male Lower UrinaryTract Symptoms.8

GUIDELINES


2 5a-reductase inhibitors

DutasterideRecommendation grade: AThere is adequate evidence to support its efficacy for definiteBPH (30 mL) (Level 1). Caution is required in evaluatingthe PSA value, since dutasteride affects PSA levels.Dutasteride inhibits both isoforms (type 1 and type 2) of5a-reductase and suppresses the production of dihydrotest-osterone (DHT). In Japan, a Phase II RCT was conductedwith 284 BPH patients aged 50 years, a prostaticvolume 30 mL, an IPSS 8, and a maximal urine flow15 mL/s.113 They were administered dutasteride 0 mg(placebo), 0.05 mg, 0.5 mg, or 2.5 mg daily for 24 weeks.An approximately 90% decrease in serum DHT levels wasobserved after 2 weeks treatment in the 0.5 and 2.5 mggroups, as was seen in overseas trials.114 A Japanese PhaseIII RCT allocated participants to receive dutasteride 0.5 mgdaily (n = 193) or placebo (n = 185) for 52 weeks.100 In thedutasteride group, a significant decrease in prostatic volumewas seen after 24 weeks treatment, and significantdecreases were seen in IPSS and maximal urine flow after36 weeks treatment. After 52 weeks treatment, IPSS hadimproved by 5.3 points, maximal urine flow by 2.2 mL/s,and prostatic volume by 22% over baseline. Althoughuncommon, adverse events related to sexual function wererather more common in the dutasteride group and PSAlevels decreased to an average 46.1%. These results are verysimilar to those from an overseas study.115

FinasterideRecommendation grade: reserved (not approved)There is adequate evidence to support its efficacy (Level 1).116

However, in Japan finasteride is indicated only for the treat-ment of androgenic alopecia and is not approved for BPH.

3 Anti-androgens

These drugs inhibit the pituitary function and the testicularproduction of testosterone, as well as testosterone uptakeand DHT binding to androgen receptors in the prostate.Although covered by insurance, the evidence to supporttheir efficacy for BPH is far from adequate and the incidenceof sexual dysfunction is high. Careful patient selection andfollow-up are necessary when prescribing these agents.

ChlormadinoneRecommendation grade: C1There is insufficient evidence to support its efficacy in BPH(Level 3). It is, however, thought to have a similar clinicaleffect to finasteride (not approved in Japan for BPH), whoseefficacy has been confirmed in overseas studies. Variousadverse reactions can occur, including sexual dysfunction.In a comparative trial of chlormadinone 50 mg/day versusEviprostat, symptomatic improvement was reported by 90%

of patients and the prostatic volume decreased by 50% in thechlormadinone group (n = 20), while symptomatic improve-ment was reported for 70% of patients and the prostaticvolume decreased by 30% in the Eviprostat group (n =20).117 Double-blind comparative trials of chlormadinoneand finasteride (not approved in Japan for BPH) foundsimilar clinical efficacy for both agents, including prostateshrinking effects.118,119

Important adverse reactions include congestive heartfailure, thrombosis, hepatic dysfunction or diabetes mellitusoccur, so treatment should not be continued indefinitely.

AllylestrenolRecommendation grade: C1There is insufficient evidence to support its efficacy (Level3). Sexual dysfunction can occur.Allylestrenol is considered to have a similar efficacy tochlormadinone. In randomized comparative studies of chlo-rmadinone versus allylestrenol, there were no significantdifferences between the two in terms of efficacy, butallylestrenol had less effect on sexual function.120122

Important adverse reactions include the loss of libido andsexual dysfunction, so treatment should not be continuedindefinitely.

4 Other oral medications

Eviprostat

Recommendation grade: C1There is some evidence to support its efficacy, although thestudies are old and its efficacy is inferior to that ofa1-adrenoceptor antagonists (Level 2). Recent studies havereported its usefulness in combination therapy witha1-adrenoceptor antagonist. Adverse reactions are rare andminor.Although the studies were conducted in 1975, there is evi-dence to support its efficacy from double-blind trials123,124

and a retrospective study suggesting its efficacy in the treat-ment of BPH.125 RCT conducted with Eviprostat anda1-adrenoceptor antagonists such as naftopidil109 and tam-sulosin126 have demonstrated the inferior efficacy ofEviprostat. However, symptomatic improvement has beenreported with the addition of Eviprostat to patients on tam-sulosin with persistent pelvic discomfort,127 and patientsrefractory to naftopidil.128

Cernilton (cernitine pollen extract)Recommendation grade: C1Efficacy is suggested for symptoms such as nocturia, butthere is no evidence of improvement in objective findings(Level 1). There are few adverse reactions.Comparison with placebo and Paraprost it is suggested thatcernilton is efficacious in relieving nocturia, but noimprovement was seen in the urinary flow rate or PVR

Guidelines


volume (I, II).129131 One study found cernilton useful in thetreatment of chronic abacterial prostatitis and chronicpelvic pain syndrome.132

Paraprost

Recommendation grade: C1There is insufficient evidence to support its efficacy (Level2). There are few adverse reactions.An RCT comparing Paraprost and prazosin found no sig-nificant difference in the degree of improvement in symp-toms or PVR volume, although Paraprost was inferior inimproving urinary flow rate.133

Chinese herbal medicines (Hachimi-jio-gan, Gosha-jinki-gan)Recommendation grade: C1There is insufficient evidence to support their efficacy,although some studies have reported the usefulness ofgosha-jinki-gan in combination with other agents (Level 2).Hachimi-jio-gan has been indicated for the treatment ofBPH, despite any clear supporting evidence. Gosha-jinki-gan is also a Chinese herbal drug that consists of hachimi-jio-gan with additional herbal ingredients. A crossover,non-blinded RCT in which gosha-jinki-gan was added whenOAB symptoms persisted despite treatment with tamsulosin,found a significant improvement in QOL in the combinationtherapy group.134 A study in which gosha-jinki-gan wasadministered to patients with prostate disease such as BPH,with an inadequate response to a1-adrenoceptor antagonisttherapy, found significant improvements in urinary flow rate,IPSS, and QOL scores.135

FlavoxateRecommendation grade: reserved (not approved)There is insufficient evidence to support its efficacy (Level2). Flavoxate is not approved in Japan for BPH.Although flavoxate has only weak anticholinergic activity, italso acts as a calcium channel blocker and to inhibit thecentral micturition reflex. A placebo-controlled RCT (n =70) found no significant difference between flavoxate andthe placebo in efficacy.136 Another study found a significantdecrease in nocturnal frequency after flavoxate was admin-istered to patients with BPH whose nocturia had notimproved with a1-adrenoceptor antagonist therapy.137 Therewere almost no adverse events.

AntidepressantsRecommendation grade: reserved (not approved)Tricyclic antidepressants have not yet been approved for thetreatment of BPH. There is scant evidence supporting theirefficacy (Level 5). Adverse events include arrhythmia anddrowsiness.Theoretically, imipramine should be effective for the treat-ment of various forms of urinary incontinence, but no

studies to date have demonstrated its efficacy in the treat-ment of BPH.

AnticholinergicsRecommendation grade: reserved (not approved)There is evidence to support the efficacy and safety of anti-cholinergic monotherapy for the treatment of BPH with OABsymptoms (Level 1). However, anticholinergic agents caninduce voiding difficulty and acute urinary retention, socaution is required in patients with BPH complicated byBOO or voiding difficulties. Anticholinergic agents are notcovered by medical insurance for BPH in Japan. They maybe used in combination with a1-adrenoceptor antagonists(see clinical question CQ 6 below).Of two placebo-controlled RCT of anticholinergics in malepatients without obvious symptoms of BOO, one reportedtheir superiority to placebo, and the other failed to show anysuch superiority. The frequency of acute urinary retentionwas less than 1% in the treatment group, however; similar tothat in the placebo group (I, II).138,139 A trial of anticholin-ergic monotherapy in the treatment of male patients withLUTS and DO confirmed their superiority to placebo, withno cases of acute urinary retention.140

However, anticholinergic agents can induce voiding dif-ficulty and acute urinary retention, so caution is requiredwhen considering anticholinergic monotherapy in malepatients, particularly those with obvious BOO.4 Anticholin-ergic agents are not covered by medical insurance for thetreatment of BPH, and should be administered with cautionto patients with BPH complicated by BOO or voidingdifficulties.

The Japan Neurogenic Bladder Society Practice guide-lines for overactive bladder recommend the use of anticho-linergic agents.3 The Guideline for management of malelower urinary tract symptoms recommends that anticholin-ergic therapy should be given under the supervision of aurologist.4Accordingly, anticholinergic monotherapy shouldonly be considered in male patients with OAB symptomswith no (or only mild) BPH, under strict urological super-vision. In patients with BPH accompanied by OAB symp-toms, however, a1-adrenoceptor antagonists should beadministered first, and an anticholinergic agent can be addedif the symptoms are refractory to adrenoceptor antagonistmonotherapy.

Cholinergic agentsRecommendation grade: reserved (not approved)The efficacy of these agents is suggested for patients whosesymptoms fail to respond to TURP, or with neurogenicbladder (Level 5), despite other contradictory studies (Level2). There is no evidence to support their efficacy for BPH orno approval of their use by medial insurance in Japan.Serious adverse events such as cholinergic crises, anginapectoris, and arrhythmias, have been reported.

GUIDELINES


Cholinergic agents are thought to enhance detrusor contrac-tility. They are not covered by medical insurance for thetreatment of BPH and their use is restricted to urinary reten-tion and underactive bladder. A meta-analysis of the use ofcholinergic agents in the treatment of underactive bladder,including male and female patients, found they were supe-rior to placebo in three of 10 RCT, and not superior inseven.141 In two RCT conducted with healthy male adultsand post-prostatectomy patients, these agents superiority toplacebo was not demonstrated.142,143 In Japanese studiesconducted with patients without BOO, a study with smallnumbers of participants found distigmine effective inpatients with difficulty voiding following TURP144 andanother study reported that combination cholinergic anda1-adrenoceptor antagonist therapy was more effective thanmonotherapy in the treatment of underactive bladder.145

Adverse events include abdominal pain and diarrhoea, andcholinergic crises, with sweating, miosis and respiratoryfailure, have also been reported.141

Phosphodiesterase-type 5 inhibitorsRecommendation grade: reserved (not approved)There is adequate evidence to support the efficacy ofsildenafil and tadalafil (Level 1). However, they are notapproved for BPH in Japan.Phosphodiesterase-type 5 (PDE5) inhibitors block degrada-tion of cGMP and increase nitric oxide activity. Relaxationof the smooth muscle of the urethra and prostate is alsomediated by nitric oxide,146 so we can expect PDE5 inhibi-tors to ameliorate LUTS.

In a placebo-controlled RCT in men with ED and LUTS,sildenafil (n = 189) significantly improved IPSS, QOLscores and the BPH impact index in comparison to placebo(n = 180).147 No significant change was seen in urinary flowrates, however. Another small-scale RCT did see a signifi-cant improvement in urinary flow rates.148 An RCT withthree treatment arms, alfuzosin 10 mg daily, sildenafil25 mg daily, and combination therapy, found significantimprovements in IPSS and ED in the combination therapygroup in comparison with the monotherapy groups.149 Alarge-scale RCT was undertaken in which patients with BPHand LUTS were allocated to placebo (n = 211), tadalafil2.5 mg daily (n = 208), tadalafil 5 mg daily (n = 212),tadalafil 10 mg daily (n = 216), or tadalafil 20 mg daily (n =209). Significant improvement in the IPSS was seen at alldosages in comparison to placebo, and the optimum dosageof tadalafil was determined to be 5 mg daily.150 Urinary flowrates improved, although the difference was not significant.Another RCT confirmed the efficacy of tadalafil, with sig-nificant improvement in symptoms in patients with ED andmoderate to severe symptoms of BPH.151,152 In a crossovertrial with 27 patients comparing tamsulosin (0.4 mg/day)monotherapy with tamsulosin plus tadalafil (20 mg/day)combination therapy (both for 45 days), significant improve-

ment in the IPSS and QOL score was seen in the combina-tion therapy group. However, no difference was seenbetween the groups in maximal urine flow or PVR vol-ume.153 Safety was excellent in both trials. These agents arenot approved for BPH in Japan.

5 Conservative therapies

Conservative therapies include lifestyle modification,watchful waiting, and supplements.

Lifestyle modificationRecommendation grade: BThere is adequate evidence supporting the efficacy of thistreatment (Level 2). Invasiveness is almost completelyabsent and the financial burden is low.Recommended lifestyle modifications include: (i) the provi-sion of education and reassurance (e.g. an explanation ofbladder and prostate physiology, reinforcing the fact that it isnot malignant, inviting patients to attend educational ser-vices); (ii) the restriction of excessive fluid intake (avoidingover-consumption of water, limiting intake of coffee andalcohol);154 (iii) bladder training, prompted voiding; and (iv)other (avoiding spicy foods, keeping bowels regular, regularexercise, avoiding sitting for extended periods and chills ofthe lower body, provision of information about medicationsthat affect micturition).4,155

Watchful waitingRecommendation grade: BThe evidence to support the usefulness of this approach isinadequate (Level 3). However, treatment may be unneces-sary for patients with BPH with no symptoms or complica-tions, and there are few disadvantages to not interveningearly with appropriate follow-up.Although there have been no studies providing clear evi-dence for this approach, even if BPH is present but thesymptoms are mild , there are no complications, and pros-tatic cancer has been excluded, then aggressive treatmentmay not be indicated. Some form of lifestyle modification isprovided when watchful waiting is the approach taken withpatients with mild symptoms.156,157 Annual assessment usingthe IPSS is recommended during the period of watchfulwaiting.8 With long durations of watchful waiting, 85% ofpatients remain stable after 1 year, dropping to 65% after5 years.7,8 The degree of bothersomeness of symptoms andPVR volume have been identified as predictive factors forthe cessation of watchful waiting.43,158

SupplementsRecommendation grade: C2Evidence to support this approach is lacking (Level 5), andinconsistent (Level 1). Safety is uncertain, and the cost topatients is high.

Guidelines


Most health foods and alternative remedies are handled asover-the-counter medications. Most are sold as combina-tions of multiple active ingredients, and the influence of thecombinations on efficacy and safety is unknown. Costs areborne by patients, as these medications are not covered bymedical insurance.

6 Other treatments

Indwelling catheterizationRecommendation grade: reservedAlthough an indwelling catheter allows urine to pass out ofthe bladder, complications and impairment of QOL arecommon. Indwelling catheterization is indicated only ifother treatments are impractical (Level 5).Indwelling catheterization is performed in cases of urinaryretention or severe difficulty with urination,70 or when othertreatments for BPH are impractical. Indwelling catheteriza-tion is associated with an increased risk of urethral trauma,decreased QOL, UTI and bladder stones.159 An alternative isinsertion of a suprapubic catheter (cystostomy).4

Intermittent catheterizationRecommendation grade: BThere is evidence for the superiority for intermittent cath-eterization compared with indwelling catheterization interms of preventing UTI and the early recovery of bladderfunction following surgery for urinary retention (Level 2).With intermittent catheterization QOL is considered to besuperior to indwelling catheterization.4 In an RCT controlledagainst an indwelling catheter group (n= 40), the incidence ofsymptomatic UTI was significantly lower in the intermittentcatheterization group (n = 40).160 In a study conducted withpatients with an indwelling catheter due to chronic urinaryretention, compared with a group who underwent TURP assoon as their renal function recovered (n = 17) and a groupwho underwent the same procedure after changing over tointermittent catheterization (n = 24), the bladder functionrecovered significantly earlier in the latter group.161

Surgical treatment (surgical therapy)

Summary

Surgical treatment for BPH is indicated in cases of: (i)insufficient response to medical therapy; (ii) the presence ofmoderate to severe symptoms; and (iii) the presence of (orconcern about) comorbidities, such as urinary retention,UTI, hematuria, and bladder stones. Surgical modalities aredivided into three groups: (i) resection/ablation or vaporiza-tion; (ii) thermal coagulation; and (iii) other techniques.Resection/ablation or vaporization is generally more effec-tive, but may be more often associated with perioperativecomplications. Although its precise definition is ambiguous,

minimally invasive surgical treatment appears to refer totechniques that are less invasive than an open prostatectomyand TURP. The selection of surgical techniques depends onthe features of BPH as well as patients characteristics, theavailability of equipment, and the surgeons experience. Therecommendation grade for each of the techniques describedwas determined in comparison with TURP, the standardsurgical procedure for BPH.

Open surgery (enucleation of the adenoma)

Recommendation grade: BThis classic technique may be associated with a high inci-dence of perioperative complications, but provides sus-tained efficacy, especially for large prostates.The enlarged adenoma is detached manually from the sur-rounding prostatic tissue (surgical capsule) via an incisionmade on the bladder or directly on the prostate capsule. Thisprocedure is used as a reliable and effective treatment, espe-cially for large BPH.8,162 The technique is associated with arelatively high incidence of complications, including hem-orrhage requiring blood transfusion (8.225.6%), reopera-tion (1.1%),163 surgical wound infection (26.9%), UTI(2.68.6%), and sepsis (8.6%).164 The postoperativere-treatment rate is generally low.165

TURP

Recommendation grade: ATURP is the standard, most extensively performed surgicaltechnique for the treatment of BPH. It is usually applicableto BPH of up to moderate size (

urethra. It is applicable to relatively small-sized prostates(80 mL showed that although PVP required a longer opera-tion time (80 vs 50 min, respectively), it was superior to opensurgerywith respect to the blood transfusion rate (0 vs 13.3%,respectively) and duration of catheterization and hospitaliza-tion, with no significant differences between the two tech-niques with regard to any other complications.227With regardto long-term outcome, PVP may be associated with a rela-tively high reoperation rate: 10.4% for prostates 80 mL.219 A histological examination isnot feasible because the prostate tissue is vaporized.

Transurethral enucleation with bipolar system

Recommendation grade: C1This technique consists of the transurethral detachment andenucleation of the adenoma without a laser. It may be effec-tive regardless of PV, but has not been evaluated sufficientlyin comparison with other treatment options or in terms oflong-term outcomes.Adenoma detachment is achieved with a resectoscope or aspecial loop through the bipolar system,228 or with a specialdetachment device through conventional TURP.229,230 Thedetached adenoma is either resected without enucleation, asin TURP, or enucleated and then minced and collected witha morcellator, as in HoLEP. A 3-year RCT comparing this

Guidelines


technique with TURP reported comparable efficacy inboth.231

Interstitial laser coagulation of theprostate (ILCP)

Recommendation grade: C1This treatment is as effective as TURP and is feasible, withrare serious adverse reactions. Benefits are not sustained,however, with further treatment or re-intervention requiredin almost half of all patients in long-term follow-up.ILCP delivers laser energy (from a neodymium : yttriumaluminum garnet or diode laser), via an applicator, into theprostate to produce coagulation necrosis within theadenoma, sparing its urethral surface. Although TURPresults in greater improvements in Qmax, RCT have foundthat ILCP and TURP are comparable in terms of improve-ments in LUTS and QOL.232,233 Good, long-term clinicaloutcomes following ILCP have also been reported.234,235 Themost common post-treatment adverse events are transienturinary retention and irritative symptoms. ILCP had aminimal impact on sexual function. Subsequent surgicalinterventions occurred at a rate of 316% within 1 year afterthe primary treatment.232,236 Over longer follow-up periods,reported rates of re-interventions, including drugs andsurgery, are 3050%.234,235

Transrectal high-intensity focusedultrasound (HIFU)

Recommendation grade: C1There have been few reports of the efficacy and safety ofHIFU. Although the safety profile is relatively favorable,further treatment or re-intervention is required in roughlyhalf of patients in long-term follow-up.HIFU irradiates highly focused ultrasound transrectally intothe prostate to create coagulation necrosis. Several clinicalstudies have reported that HIFU significantly improvessymptoms, QOL, and Qmax.237239 HIFU was comparable totransurethral microwave thermotherapy (TUMT) and tran-surethral needle ablation (TUNA) in improving LUTS overa 2-year follow-up period.240 Common post-treatmentadverse events following HIFU include transient urinaryretention, hematuria, and hematospermia.8 Thermoinjury ofthe rectum requiring surgical repair is an uncommon severeadverse event.8 The re-intervention rate ranged between 44and 58% 24 years after HIFU.241,242

Transurethral needle ablation (TUNA)

Recommendation grade: C1Symptomatic improvement is achievable withTUNA as muchas with TURP in the short to medium term with an increased

risk of postoperative irritability and urinary retention.Re-treatment, including surgery, is required in nearly half ofcases.TUNA therapy uses low-level radiofrequency energy deliv-ered via needles into the prostate to induce necrotic lesionsin the adenoma, thereby reducing BOO. Several clinicalstudies have reported significant improvements in thesymptom scores (an average reduction rate of 4070%) andQmax (26126%) over both short-term243245 and long-term246

follow-up periods. In RCT with 1218 months follow-upcomparing TUNA and TURP, no significant differenceswere found between the two in terms of improvements insymptom and bother scores.246,247 Another RCT comparingTUNA and TURP demonstrated stable treatment outcomesover a 5-year follow-up period.248 Common post-treatmentadverse events associated with TUNA include transienturinary retention and worsening storage symptoms in theearly post-treatment period.249,250 Reported treatment failurerates requiring subsequent further treatment, including phar-macotherapy and surgical intervention, are of the order of2139% over 25 years.241,246

Transurethral microwave therapy (TUMT)

Recommendation grade: BThis is the most extensively verified minimally invasive sur-gical treatment. Medium-term efficacy has been demon-strated with a high-energy deliver system, even for patientswith large prostatic volumes or urinary retention. Periop-erative and postoperative safety is superior to TURP,although less than a half of patients require re-intervention.TUMT uses a special transurethral catheter with a micro-wave antenna to deliver microwaves into the prostate toproduce coagulation necrosis and subsequent improvementin BOO. Numerous studies have been published on TUMTusing various devices or technical specifications under dif-ferent treatment protocols. In one clinical trial, TUMTtherapy using the first-generation device Prostasoft 2.0 wasless effective than TURP in reducing LUTS.251 However,TUMT, performed with high-energy delivery systems,including Prostatron (Prostasoft 2.5 and 3.5),252254 Ther-Matrx, Targis system, and CoreTherm,255257 was compa-rable to TURP in terms of improving LUTS and QOL overshort-term and long-term follow-up periods, althoughTURPresulted in a greater improvement in Qmax than TUMT.252

Arguments against TUMT as an alternative to TURP includethe morbidity associated withTUMT,256 including prolongedcatheterization periods,258 a higher incidence of dysuria orurgency,259 and urinary retention.260 Conversely, the inci-dences of hematuria or clot retention,261 blood transfusions,hyponatremia, ED, retrograde ejaculation,261263 and urethralstricture are less forTUMT thanTURP.The re-treatment rate(surgery or pharmacotherapy) after high-energy TUMT is

GUIDELINES


reported to be 36% within 1 year.264,265 Over longerfollow-up periods (up to 5 years), 1040% of patientsrequired re-intervention.257,266268

Urethral stent

Recommendation grade: C1Although the procedure is quickly efficacious with minimalinvasiveness, urethral stenting may be associated with com-plications that require stent removal. It is indicated in high-risk patients, in whom surgical interventions or otherinvasive therapies are contraindicated.Prostatic stents are placed in the prostatic urethra underendoscopic control to dilate the obstructed urethra. Tempo-rary or permanent stents can be used. Long-term data areavailable regarding the safety and efficacy of permanenturethral stents.269 As their name suggests, temporary stentsare used for the treatment of urinary retention after TUMTfor short periods.270,271 The clinical use of permanent stentsis limited by significant complications, including encrusta-tion (calcification), discomfort or urethral pain, bleeding,and the migration of the stents.272275

Transurethral ethanol ablation of theprostate (TEAP)

Recommendation grade: reserved (not approved)The efficacy of TEAP has been demonstrated for symptomsand urinary flow rates, although few long-term studies withlarge numbers of participants and no RCT comparing withstandard therapies are available. It is not covered bymedical insurance in Japan.As part of the TEAP procedure, anhydrous ethanol isinjected under urethroscopic control into the prostate. Theinjected ethanol induces coagulation necrosis and a reduc-tion in tissue volume. Several clinical studies have demon-strated significant improvements in symptom scores, QOL,and Qmax over both short-term and long-term follow-upperiods.276278 Common post-treatment adverse events asso-ciated with TEAP include urinary retention, hematuria, andirritative symptoms.276,278280 Bladder necrosis requiringurinary diversion has been reported in two cases.276 There-intervention rate ranges from 7% after 1 year276 to 40%after 3 years.277 RCT comparing TEAP with standardsurgery are required before this procedure can be considereda reasonable alternative treatment for BPH.

Botulinum toxin injection

Recommendation grade: reserved (not approved)There is adequate evidence to support its efficacy, althoughits long-term efficacy is uncertain. Botulinum toxin is notapproved in Japan for BPH.

Botulinum toxin inhibits ACh release at the neuromuscularjunction, causing the paralysis and atrophy of striated andsmooth muscles. It also inhibits ganglionic and postgangli-onic fibers of the autonomic nervous system, inducing tissueatrophy and apoptosis.281 Through the latter mechanism,direct intra-prostatic injections of botulinum toxin can beexpected to be beneficial in patients with BPH.

The usefulness of intra-prostatic botulinum toxin injec-tions is suggested in studies with patients with BPH in apoor general condition,282,283 and in an open labelled studywith 77 patients.284 Their results showed 2 months post-injection a 63.9% decrease in the IPSS, a 51.6% decrease inPSA, a 42.8% decrease in prostatic volume, a 55.9%decrease in PVR volume, and a significant improvement inurinary flow rates. An RCT that allocated patients refractoryto pharmacotherapy to a continued pharmacotherapy (n =30) or botulinum toxin therapy (n = 30) reported decreasedprostatic volumes and improvements.285

BPH treatment and sexual function

Summary

Treatments for BPH may impact adversely on sexual func-tion. Surgical interventions often result in ejaculatory dys-function; a1-adrenoceptor antagonists sometimes causeejaculatory dysfunction; and the use of 5a-reductase inhibi-tors and anti-androgens is associated with multiple sexualdysfunctions, with the frequency being higher for the latter.

Sexual dysfunction related to surgery

Ejaculatory dysfunction is the most common sexuallyrelated adverse event following surgery. The frequency ofejaculatory dysfunction has been reported to be 80% fol-lowing open surgery, 6570% following TURP,7,286 7080%following HoLEP or holmium laser ablation of the pros-tate,8,287 and 40% following TUIP.8 The frequency of ejacu-latory dysfunction following thermotherapy has beenreported to range between 6.1 and 51.4%.288,289 In contrast,ED following surgery is relatively rare, with rates of 12.5,210, and 0% reported for open surgery, TURP, and HoLEP,respectively.7,286,287,290

Sexual dysfunction related tomedical treatment

Erectile dysfunction (ED)

RCT have shown that ED is not caused by a1-adrenoceptorantagonists7 and that these antagonists may even reduce therisk of ED.291,292 The rates of ED have been reported to be8.130.9% for patients on finasteride8,293 and the rate of EDwas significantly greater for men on dutasteride than onplacebo (4.7 vs 1.7%, respectively) during the first 6 months

Guidelines


of treatment.294 In a Japanese RCT evaluating dutasteride,the frequency of ED was 2% compared with

strongly recommend the use of the Japanese criteria.301

Briefly, the efficacy of treatment for BPH is also evaluated infour domains: (i) symptoms; (ii) QOL; (iii) function; and(iv) anatomy. The efficacy of treatment is determined asexcellent, good, fair, or poor and is assessed using clinicalmeasures for: (i) symptoms (ratio of post-treatment : pre-treatment IPSS); (ii) QOL (ratio of post-treatment :pre-treatment QOL); (iii) function (ratio of post-treatment :pre-treatment Qmax); and (iv) anatomy (ratio of post-treatment : pre-treatment PV [see Table 8]). The overall effi-cacy is determined as the median of efficacy for threedomains, symptoms, QOL, and function.

In addition, to evaluate the efficacy of treatment on symp-toms of BPH, changes in the OABSS and CLSS after treat-ment can be used, with particular emphasis on one of thesymptoms of BPH (e.g. nocturia).302 The efficacy of treat-ment on QOL can be assessed using changes in the BPHimpact index, Kings health questionnaire, and SF-36,although the criteria for efficacy using these scales have notyet been standardized.

Other recommendations

The points listed below should be attended to in Phase 3studies of the efficacy of medical treatments for BPH: Double-blind RCT using placebos or standard treatments

as the control group are recommended. Although the primary endpoints should be evaluated at

3 months, patients should be monitored for efficacy andsafety for up to 12 months to assess the duration of theclinical effect of the drugs (the objective of which is todecrease PV).

CQ 1: When is a bladder diary recommended as part ofthe assessment of BPH?A bladder diary is recommended for men with daytime ornocturnal frequency (Grade B). The diary records individualvoiding prospectively, enabling the accurate evaluation ofvoiding time, individual volumes voided, and total urinaryvolume. This information is useful for the differential diag-nosis of urinary frequency, which can be classified as adecrease in the volume voided, polyuria, or both.4,300 Ideally,

the diary should be kept over a period of 37 days, althoughkeeping the diary over 1 or 2 days may be sufficient.8

CQ 2: What examination is recommended for the ana-tomical evaluation of the prostate?Ultrasonography is recommended for the anatomical evalu-ation of the prostate (Grade A). Compared with a digitalrectal examination and other imaging tests, ultrasonographyis more accurate and minimally invasive.4,101,303 Trans-abdominal ultrasonography is easily performed and isreadily able to detect bladder pathology, whereas trans-rectalultrasonography permits the detailed imaging of the innerstructures. The type of ultrasonography performed dependson the equipment available, as well as on the objective of theexamination. PV is predictive of both clinical progressionand the therapeutic outcomes of surgical and medicaltreatment.303,304

CQ 3: When and how is evaluation of the upper urinarytract recommended?Evaluation of the upper urinary tract is not to be performedroutinely. It is recommended for men with abnormal uri-nalysis, a large amount of PVR, renal insufficiency, or ahistory of other urological diseases (Grade B). In thesecases, ultrasonography is recommended as the initialmethod of assessment.4,303 Renal ultrasonography in 556men with BPH detected hydronephrosis, renal cystsand renal cancer in 2.5, 11.7% and 0.18% of men,respectively.305

CQ 4: What considerations are recommended whenassessing serum PSA values?Serum PSA concentrations should be determined becausehigher PSA concentrations are indicative of prostatic canceror enlarged PV.4,303,306 Serum PSA concentrations areincreased in men with enlarged adenoma, prostate cancer,urinary retention, and prostatitis,4,303,306 but can be reducedto approximately 50% by long-term treatment with anti-androgens or 5a-reductase inhibitors100,294,303 (Grade A).

CQ 5: Is long-term therapy with a1-adrenoceptorantagonists recommended?The efficacy and safety of a1-adrenoceptor antagonists up to1 year has been reported in many studies. However, there isa relative paucity of long-term data over 3 years regardingthe maintained efficacy of these drugs (Grade B). Mostlong-term studies into the efficacy of a1-adrenoceptorantagonists are open-label extensions of previous short-termtrials or retrospective studies in real-life clinical practice.The study designs are not consistent.

There are eight long-term studies (over 3 years; range410 years) for the treatment of a1-adrenoceptor antagonistsin the literature.307314 During follow-up, approximately 18,64, and 3680% of patients withdrew from the studies after

Table 7 Standard criteria for overall severity of benign pro-static hyperplasia

Overallseverity

No. of domains in Table 6 evaluated as:

Mild Moderate Severe

Mild 4, 3 0, 1 0Moderate Other combinationsSevere Any Any 2, 3, 4

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2, 3, and >4 years, respectively. The reasons for their with-drawal included an insufficient therapeutic response (1454%), loss to follow-up for unknown reasons (1648%),satisfaction with their condition (18%), the detection ofprostate cancer (454%), adverse effects (117%) andurinary retention (3%).307,308,310313 Eight percent of patientswith treatment failure stopped medication or changed toother drugs, and 825% underwent surgery. The risk factorsfor treatment failure were severe LUTS, low urinary flowrate, large prostate (>3040 mL), large PVR or a history ofurinary retention, concomitant OAB symptoms, urodynami-cally proven BOO, and insufficient effects after using short-term therapy.311314 Recently, the results of two long-term(4-year) RCT comparing the effects of 5a-reductase, ana1-adrenoceptor antagonist, and combination therapy onclinical progression in BPH/LUTS and prostatic enlarge-ment have been reported (see CQ 7).46,315

CQ 6: Is combination therapy with a1-adrenoceptorantagonists and anticholinergics recommended for menwith OAB?There is adequate evidence supporting the efficacy andsafety of combination therapy with a1-adrenoceptor antago-nists and anticholinergics for BPH associated with OAB(BPH/OAB; Grade A).

For male OAB symptoms, monotherapy witha1-adrenoceptor antagonists is effective and may be a first-line treatment,4 although the efficacy of a1-adrenoceptorantagonists is limited for patients with DO.316 The efficacyand safety of anticholinergic monotherapy have also beenconfirmed in the treatment of BPH/OAB.140 In a placebo-controlled RCT comparing tamsulosin, tolterodine ER, andtheir combination in men with BPH or OAB, the benefitswere significantly greater in the combination therapy group,with only a mild increase in PVR volumes and a 1%incidence of urinary retention.139 Combined therapies withanticholinergics and a1-adrenoceptor antagonists can beeffective in cases in which a1-adrenoceptor antagonists were

ineffective in improving storage symptoms, with urinaryretention being rare.317320 However, it should be noted thatmost of these studies were conducted in Caucasian men,with strict exclusion criteria, specialist supervision, andrelatively short-term observational periods. There remains aconcern about exacerbation of voiding difficulties and pos-sible urinary retention with a more widespread and longeruse of anticholinergics with or without a1-adrenoceptorantagonists in the practical setting.4

Note: Recently two Japanese studies reported that com-bination therapies with tamsulosin plus anticholinergics aremore effective for BPH and OAB than tamsulosin mono-therapy, with lower doses of anticholinergics associated withbetter outcomes.321,322

CQ 7: Is combination therapy with an a1-adrenoceptorantagonist and a 5a-reductase inhibitor recommended?Combination therapy is recommended for relatively severedisease, e.g. prostatic volume 30 mL (Grade B). TheCombAT study randomly assigned 4844 patients with BPH(prostatic volume 30 mL, 1.5 PSA 10 ng/mL, 5 maximal urine flow 15 mL/s) to three groups and admin-istered them with either dutasteride, tamsulosin or combi-nation therapy for 4 years.315 The average change in the IPSSscore was -6.3 points in the combination therapy group,which was significantly greater than that of -3.8 points inthe tamsulosin group and -5.3 points in the dutasteridegroup (both P < 0.001). The increase in maximal urine flowof 2.4 mL/s seen in the combination therapy group was alsosignificantly greater than that in the tamsulosin group(0.7 mL/s, P < 0.001) and the dutasteride group (2.0 mL/s,P < 0.05). The cumulative incidence of clinical progressionwas 12.6% in the combination therapy group, 21.5% in thetamsulosin group and 17.8% in the dutasteride group (bothP < 0.01 for time until progression). The cumulative inci-dence of acute urinary retention or surgical intervention forBPH was 4.2% in the combination therapy group, 11.9% inthe tamsulosin group and 5.2% in the dutasteride group,

Table 8 Standard criteria to determine the efcacy of treatment for BPH across individual domains

Measure Domains used to assess efcacy with respect to

Symptoms QOL Function Anatomy

IPSS post/pre QOL pre-post Qmax(mL/s) post-pre PV post/pre

EfcacyExcellent 0.25 4 10 0.5Good 0.50 3 5 0.75Fair 0.75 2, 1 2.5 0.9Poor >0.75 0 0.9

Standard criteria for therapeutic efcacy. The overall efcacy is determined as themedian of efcacy for three domains: symptoms,quality of life (QOL) and function. PV, prostate volume; Qmax peak urinary ow rate.

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with a significant difference between the combinationtherapy group and the tamsulosin group for time until inter-vention (P < 0.001), but with no significant differencebetween the combination therapy and dutasteride groups(P = 0.18).

A study with 327 patients with BPH (using criteriasimilar to the above study) administered tamsulosin plusdutasteride combination therapy to all patients for 24 weeks,then randomly assigned patients either to continue combi-nation therapy or to cease tamsulosin (replacing it withplacebo) and take dutasteride monotherapy for 36 weeks.323

As a result, for the 82 patients with a pre-treatment IPSS20, the aggravation of symptoms was reported by 14% ofthe continued combination therapy group (n = 42), and42.5% of the dutasteride monotherapy group (n = 40)(P-value unknown).

A study of the 5a-reductase inhibitor, finasteride (notindicated for BPH in Japan), the Medical Therapy of Pros-tatic Symptoms study randomly assigned 3047 patients withBPH (IPSS 8 points, 4maximal urine flow 15 mL/s)to one of four groups: placebo, doxazosin (a1-adrenoceptorantagonist), finasteride or combination therapy. They moni-tored clinical progression (IPSS, urinary retention, impairedrenal function, recurrent UTI) over a mean follow-up periodof 4.5 years.46 In comparison with the placebo group, therisk of clinical progression in the doxazosin, finasteride andcombination therapy groups was reduced by 39% (P 30 g/day) and BPH symptoms.345A study comparing 1369patients with BPH resistant to pharmacotherapy, with amaximal urine flow15 mL/s, and 1451 controls also founda negative correlation between alcohol consumption and theonset of BPH symptoms. As a possible mechanism, theauthors suggested that the hormonal status of consumers ofalcohol (e.g. decreased androgen levels) may play a part.346Astudy comparing 1813 patients with surgically treated BPH,1786 patients with IPSS 15 points, and 20 840controls (IPSS 7 points) found a negative correlationbetween moderate alcohol consumption (30.150 g/day) andthe severity of BPH symptoms, and a weaker negative corre-lation with high alcohol consumption (>50 g/day).347A Japa-nese study with 432 patients found no correlation betweenprostatic volume and alcohol intake.348 Urinary retention canbe triggered by alcohol consumption in patients with BPH.

CQ 12: What treatments are recommended for urinaryretention by BPH?Either the insertion of an indwelling catheter or intermittentcatheterization should be indicated. Subsequently catheterremoval may be attempted after the administration of ana1-adrenoceptor antagonist. Surgical intervention is likely tobe necessary for a large prostate (Grade B). In the shortterm, catheterization or the insertion of an indwelling cath-eter will be required in cases of urinary retention. Usingintermittent catheterization is recommended only forurinary retention due to transient causes (e.g. the use ofanaesthetic or a-sympathomimetic agents), and ana1-adrenoceptor antagonist at the attempt to remove theindwelling catheter.7

A retrospective survey of long-term results in 248patients in whom indwelling catheters were successfullyremoved after treatment with an a1-adrenoceptor antagonistfollowing acute urinary retention, with a mean follow-upperiod of 33 months, reported a failure rate of 11.6, 14.3,28.4, and 50.5% at 6, 12, 24 and 60 months, respectively.349

Multivariate analysis revealed a prostatic volume 50 mLand a PSA level 10 ng/mL at the time of acute urinaryretention, as predictive factors for surgical intervention.

In a study comparing surgery and pharmacotherapy astreatments to allow catheter removal in 72 patients with anindwelling catheter, multivariate analysis showed thatpatients with PSA >2.9 ng/mL, a large prostate size ondigital rectal examination, and a volume drained at the timeof catheterization >1000 mL, were best managed by surgicalintervention.350

CQ 13: What measures are recommended for men withsymptomatic BPH in whom usual treatments are not tobe indicated due to their deteriorating activities ofdaily life?Urethral stents, intermittent catheterizaion, and indwellingurethral or suprapubic catheters should be considered asmanagement options for such men (Grade B). The manage-ment for BPH is challenging in men with severe symptomsthat are resistant to medical therapy or with conditions suchas recurrent urinary retention, bladder stones, intractableUTI, and hematuria. Metallic stents can be placed in theprostatic urethra under endoscopic control. Although this isan effective, less invasive procedure for improving symptomsand objective parameters,269271 the clinical use of permanentstents is limited owing to the associated complications,including encrustation, discomfort or urethral pain, infec-tion, bleeding, and stent migration.8,272,273,351355 Intermittentself-catheterization is safe and useful with minimal compli-cations.160 It is therefore a reasonable management option formen at high risk of surgical intervention when the voidingdifficulties are resistant to medical treatment. However, itrequires manual dexterity and may not be a good option formen with severe mental disabilities or disabilities in theirupper limbs. Urethral indwelling catheters are useful forprompt management, yet they are associated with inevitableinfection, urethral erosion, strictures, and fistula formation.Suprapubic cystostomy is an alternative measure that avoidsthe complications caused by indwelling urethral catheters.

CQ 14: What therapeutic strategies are recommended toavoid sexual dysfunction as an adverse event?Surgical treatment or a1-adrenoceptor antagonists are rec-ommended to avoid ED. To prevent ejaculatory dysfunction,surgical treatment, a1A-adrenoceptor antagonists,5a-reductase inhibitors or anti-androgens should beavoided. To retain libido, 5a-reductase inhibitors or anti-androgens especially should be avoided (Grade B). ED as anadverse event is rare for surgery (012.5%),7,287,290 and com-parable with placebo for a1-adrenoceptor antagonists.7

Ejaculatory dysfunction has been reported to be 5080%post-surgery,7,8,286,287 and 1.6% to 22.3% in Japanese menusing a1-adrenoceptor antagonists, particularly a1A-adrenoceptor antagonists.111,356 Decreased libido and ejacu-latory dysfunction are observed in men taking 5a-reductaseinhibitors or anti-androgens,122,294 and are more pronouncedin the latter.122

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Conict of interest

Yukio Homma received research grants from Astellas,Asuka, DaiichiSankyo, Ono, Pfizer, and Takeda, andreceived lecture fees from Astellas and GlaxoSmithKline;Momokazu Gotoh received research grants from Astellas,DaiichiSankyo, GlaxoSmithKline and Takeda, and receivedlecture fees from Astellas; Osamu Yokoyama receivedresearch grants from AsahiKasei, Astellas, GlaxoSmith-Kline, Ono and Pfizer, and received lecture fees fromAstel-las, Kissei and Ono; Naoya Masumori received lecture feesfrom GlaxoSmithKline;Akihiro Kawauchi has no conflict ofinterest; Tomonori Yamanishi has no conflict of interest;Osamu Ishizuka received research grants fromAsahi Kasei;Narihito Seki received research grants from Astellas andKyorin, and received lecture fees from Astellas; ToshiykiKamoto has no conflict of interest; Atsushi Nagai receivedresearch grants from Kissei and Pfizer; Seiichiro Ozonoreceived lecture fees from Astellas. Funding of the commit-tee was provided by The Japanese Urological Association.

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