Outline of JUA clinical guidelines for benign prostatic hyperplasia

Authors


  • This abstract is reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x.

  • The complete English version is available at http://onlinelibrary.wiley.com/doi/10.1111/iju.2011.18.issue-11/issuetoc

  • This is a translated summary of a full guideline first published as a book in Japanese by The Japanese Urological Association, Clinical guidelines for benign prostatic hyperplasia, 2011. RichHill Medical, Tokyo.

Yukio Homma M.D., Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: homma-uro@umin.ac.jp

Abstract

The Japanese Urological Association has developed Clinical Guidelines for Benign Prostatic Hyperplasia (BPH) for men with suspected BPH, which have been abridged and translated into English. This article is a shortened version of the English translation. The Guidelines were formulated on the basis of evidence retrieved from the PubMed database between 1995 and 2009, as well as other relevant sources. The target patients of these Guidelines are men with suspected BPH, and the target users are urologists. A mandatory assessment should include a medical history, a physical examination, the completion of symptom and quality of life questionnaires, urinalysis, prostate ultrasonography, measurement of serum prostate specific antigen and postvoid residual urine, and an uroflowmetry. Optional tests include a bladder diary, the measurement of serum creatinine, and upper urinary tract ultrasonography. Care should be taken to not overlook coexisting diseases such as an infection or malignancy that may obscure the diagnosis. Treatment should consist of conservative therapy or the use of medications such as α1-adrenoceptor antagonists, or both. The use of 5α-reductase inhibitors or anticholinergic agents should be considered in patients with an enlarged prostate (>30 mL) or overactive bladder symptoms (overactive bladder symptom score ≥6), respectively. Surgical intervention is indicated when non-surgical treatments fail to provide sufficient symptomatic relief and bladder outlet obstruction is highly suspected.

Introduction

A number of clinical guidelines have been formulated in Japan for lower urinary tract disorders such as benign prostatic hyperplasia (BPH),1 urinary incontinence, overactive bladder (OAB), male lower urinary tract symptoms (LUTS),2 interstitial cystitis and hypersensitive bladder syndrome, nocturia, and neuropathic conditions. This article is a shortened version of the English translation of these Guidelines. The target subjects and users are men suspected of having BPH and urologists, respectively. In the case of male LUTS Guidelines,2 the target subjects and users are men with LUTS and non-urologist physicians, respectively. Readers should be aware of the earlier guidelines, particularly for male LUTS,2 when adopting the BPH Guidelines into clinical practice.

Methodology

The BPH Guidelines were developed by committee members recommended by the Japanese Urological Association (JUA). The members meticulously reviewed relevant references, retrieved via the PubMed and Japana Centra Revuo Medicina databases, published between 1995 and 2009. Other sources of information included Japanese guidelines for other conditions, the BPH Guidelines published by the American Urological Association (AUA)3 and the European Association of Urology,4 and the meeting reports of the International Consultation on Urological Diseases on male lower urinary tract disorders.5 A draft of the revised guidelines was peer-reviewed by JUA executive members before the guidelines were finalized. Funding was provided by the JUA.

Algorithm

  • • The algorithm (Fig. 1) is applicable to men who are suspected of having BPH. Factors suggestive of BPH include age >50 years, LUTS, and associated complications, such as urinary retention and urinary tract infection (UTI), or both.
  • • The basic assessment of these men, mandatory in all cases, comprises their present and past history, the completion of symptom and quality of life (QOL) questionnaires, a physical examination, urinalysis, uroflowmetry, postvoid residual urine (PVR) measurement, prostate ultrasonography, and determination of serum prostate-specific antigen (PSA) concentrations. Optional assessments, selected on an individual basis, include keeping a bladder diary, advanced urodynamic studies, measurement of serum creatinine levels, and an upper urinary tract ultrasonography. Additional tests, such as urine cytology, urine culture, endoscopy, and radiological examinations, may be indicated when other disorders are suspected. Other disorders include prostatic cancer, prostatitis, overactive bladder, underactive bladder, bacterial cystitis, interstitial cystitis, bladder cancer, bladder stones, urethritis, urethral stricture, neurogenic bladder, hydronephrosis, polyuria, and nocturnal polyuria.
  • • When the patient's history, symptoms, or test results suggest the presence of other disorders, further assessments need to be performed. Findings suggestive of other disorders are a history of urinary retention, urinary tract infection, macroscopic hematuria, pelvic surgery or radiotherapy, and neuropathic diseases; symptoms of bladder pain, perineal pain, monosymptomatic nocturia, and overt overactive bladder symptoms; and test results revealing abnormal findings on rectal examinations, urinalysis, and ultrasonography, elevated prostate-specific antigen levels, positive urinary cytology, increased PVR, bladder stones, renal dysfunction, polyuria, and nocturnal polyuria.
  • • When lower urinary tract dysfunctions, including symptoms, can be attributed to BPH, both the patient's desire for treatment and the medical need for treatment should be assessed. Medical need includes the event of severe symptoms, a highly enlarged prostate, or complications, such as urinary retention, hematuria, bladder stones, renal insufficiency, and urinary tract infection.
  • • When there is no desire on the part of the patient for treatment and no medical need for treatment, watchful waiting is indicated.
  • • In most cases, conservative or medical therapy, or both, such as the use of α1-adrenoceptor antagonists, are first indicated. When there is an indication for surgery, further assessments prior to surgery should be undertaken. Surgery is the preferred treatment in cases in which there are benign prostatic hyperplasia-related complications, when it is anticipated that medical treatment will be insufficient, or if the patient prefers to undergo surgical therapy.
  • • The baseline for medical treatment is the use of α1-adrenoceptor antagonists. When the prostate is enlarged (>30 mL) and when OAB symptoms are evident (via an overactive bladder symptom score [OABSS]≥6), consideration should be given to changing the medical treatment to 5α-reductase inhibitors or anticholinergics (either instead of, or in addition to, α1-adrenoceptor antagonists), respectively. If these measures are not fully successful, surgical indications should be evaluated.
  • • An evaluation of surgical indications includes confirming the patient's desire for surgery, making a systemic review of the surgical risks, and a urodynamic evaluation of bladder outlet obstruction (BOO). BOO is to be assessed by pressure-flow studies or it may be feasible using other studies, such as uroflowmetry or bladder wall thickness, or both.
  • • If a patient's condition does not improve or worsens they should be reassessed, as described in the basic assessment section, for the presence of other disorders. If a patient's condition improves with treatment, regular reassessments should be undertaken to detect any possible changes in their status, with therapeutic measures adjusted accordingly.
Figure 1.

Algorithm for benign prostatic hyperplasia (BPH), reproduced from the original version of the JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x.

Definition of BPH

There is no uniform definition for BPH.5 The International Continence Society proposed using “BPH” exclusively as a histopathological term to refer to the non-malignant hyperplasia of prostatic tissue, and coined the term “benign prostatic enlargement” (BPE) for an enlarged prostate and “benign prostatic obstruction” (BPO) for lower urinary tract obstruction.6 However, in reality, men with LUTS or lower urinary tract dysfunctions, or both, are diagnosed as having BPH when BPE is present, and when BPO is suggested, and when other pathologies are ruled out. Thus, in the present Guidelines, BPH is defined as a disease with lower urinary tract dysfunction due to benign hyperplasia of the prostate, which is usually associated with the enlargement of the prostate and LUTS that are suggestive of lower urinary tract obstruction.

Epidemiology and natural history of BPH

The principal risk factors for BPH are aging and normally functioning testicles. BPH is a progressive disease that is common in elderly men regardless of race, ethnicity or region.7 Although prevalence varies based on the definition of BPH used, 6 and 12% of Japanese men in their sixties and seventies, respectively, meet all three of the following criteria for BPH: (i) an international prostate symptom score >7; (ii) prostate volume (PV) >20 mL; and (iii) peak urinary flow rate (Qmax) <10 mL/s (Table 1).8,9 Risk factors for the clinical progression of BPH are aging, prostate enlargement, elevated PSA, LUTS, impaired QOL, and decreased urinary flow rate.10–12 Lethal comorbidities related to BPH are rare.

Table 1.  Prevalence of benign prostatic hyperplasia in Japan8,9
Age (years)IPSS >7 (%) (1)PVR >20 mL (%) (2)Qmax <10 mL/s (%) (3)Prevalence (%) [(1) + (2) + (3)]
  1. This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x. IPSS, international prostate symptom score; Qmax, peak urinary flow rate; PVR, postvoid residual urine.

40–49472042
50–59443562
60–695239196
70–7963374212

Pathophysiology

BPH consists of stromal elements made up of smooth muscle and connective tissue, as well as glandular and luminal epithelial cells, and arises in the periurethral region of the prostrate.13 An interaction is seen between stromal and epithelial cells, mediated by proliferative factors, including sex hormones, inflammation, and the stimulation of adrenergic nerves.14,15 LUTS can result from a variety of different diseases and conditions (Table 2).2 In BPH patients, urethral compression associated with prostatic enlargement causes voiding symptoms. However, age-related detrusor underactivity (DU) is also an important cause of voiding symptoms.16 Urethral compression causes distension, ischemia, inflammation and oxidative stress to the bladder, followed by changes to the bladder nerves and smooth muscle and the release of urothelial-derived mediators, causing storage symptoms.17–19 Even without compression, the stimulation of the urethral sensory nerves can cause storage symptoms.20 Important complications of BPH include recurrent urinary retention, macroscopic hematuria, bladder calculi, recurrent UTI, and post-renal renal failure.

Table 2.  Diseases and conditions that cause male lower urinary tract symptoms
  1. This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x. BPH, benign prostatic hyperplasia; OAB, overactive bladder.

1. Prostate and lower urinary tract
 Prostate: BPH, prostatitis, prostate cancer
 Bladder: bacterial cystitis, interstitial cystitis, bladder cancer, bladder stones, bladder diverticulum, OAB, other (age-related detrusor underactivity)
 Urethra: urethritis, urethral stricture
2. Nervous system
 Cerebral: cerebrovascular disorder, dementia, Parkinson's disease, multiple system atrophy, brain tumor
 Spinal cord: spinal cord injury, multiple sclerosis, spinal cord tumor, spinal infarction, spinal degenerative disease, spina bifida
 Peripheral nerves: diabetic neuropathy, post-pelvic surgery
 Other: aging, autonomic hyperactivity
3. Miscellaneous
 Drug related, polyuria, sleep disorders, psychogenic

Diagnosis

Basic evaluation and tests for men suspected of BPH include a clinical history, the assessment of symptoms and QOL using validated questionnaires (i.e. the core lower urinary tract symptoms score,21 international prostate symptom score [IPSS],22 and OABSS23), a physical examination, urinalysis, uroflowmetry, PVR measurement, serum PSA determination, and a prostate ultrasonography. PSA levels predict PV and the clinical progression of BPH,24 and may increase in prostate cancer, acute urinary retention, and prostatitis. Anti-androgens and 5α-reductase inhibitors can reduce serum PSA values by approximately half.25 Case-sensitive or elective tests include keeping a bladder diary, pressure–flow studies, serum creatinine measurements, and ultrasonography of the upper urinary tract.

Treatment

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 the variability of conclusions, the magnitude of effect, clinical applicability, adverse events, and cost. Grades of recommendation for individual treatments are shown in Table 5.

Table 3.  Grade of recommendation
GradeNature of recommendation
  1. This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x.

AHighly recommended to do
BRecommended to do
CNo firm evidence for recommendation
 C1Can be considered
 C2Not recommended
DRecommended not to do
ReservedUnable to decide grade of recommendation
Table 4.  Level of evidence
Level of evidenceType of evidence
  1. This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x.

1Evidence obtained from multiple large-scale randomized controlled trials (RCT)
2Evidence obtained from a single RCT or low quality RCT
3Evidence obtained from non-randomized controlled studies
4Evidence obtained from observational studies
5Evidence obtained from case studies or expert opinions
Table 5.  Grade of recommendation – pharmacotherapy; surgical interventions and other treatments
TreatmentGrade
  • See “Guidelines for Management of Male Lower Urinary Tract Symptoms”.4 This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x.

Pharmacotherapy 
 α1-adrenoceptor antagonists (α1-blockers) 
  Tamsulosin, naftopidil, silodosin, terazosin, urapidilA
   PrazosinC1
 5α-reductase inhibitors 
  DutasterideA
  FinasterideReserved (not approved)
 Anti-androgens 
  Chlormadinone, allylestrenolC1
 Others 
  Eviprostat®, Cernilton®, Paraprost®, Chinese herbal medicines (Hachimi-jio-gan, Gosha-jinki-gan)C1
  Flavoxate, antidepressants, cholinergics, phosphodiesterase 5 inhibitorsReserved (not approved)
Surgical interventions 
 Open prostatectomy (sub-capsular enucleation)B
 Transurethral resection of the prostateA
 Transurethral incision of the prostateB
 bipolar-TURPA
 Holmium laser enucleation of the prostateA
 Photoselective vaporisation of the prostate by KTP laserB
 Holmium laser ablation of the prostateB
 Transurethral detachment of the prostate, transurethral enucleation with bipolar systemC1
 Interstitial laser coagulation of the prostateC1
 High-intensity focused ultrasoundC1
 Transurethral needle ablationC1
 Transurethral microwave thermotherapyB
 Urethral stentC1
 Transurethral ethanol ablation of the prostateReserved (not approved)
 Botulinum toxin injectionReserved (not approved)
Other treatments 
 Lifestyle modificationB
 Watchful waitingB
 SupplementsC2
 Indwelling catheterReserved
 Intermittent catheterizationB

Pharmacotherapy

1 α1-adrenoceptor antagonists

α1-adrenoceptor antagonists relieve outlet obstruction by inhibiting contractions mediated by prostatic α1-adrenoceptors, thereby ameliorating LUTS of BPH. α1-adrenoceptor antagonists, also referred to as α1-blockers, can result in the rapid relief of LUTS. The use of α1-adrenoceptor antagonists can result in a 16–25% (2.0–2.5 mL/s) increase in maximum flow rate and a 30–40% (4–6 point) reduction in the average IPSS.2–4,26 Adverse reactions to alfuzosin and tamsulosin, such as postural hypotension and asthenia, have been reported to be as low as that reported for placebo (4–10%). Other adverse events include ejaculatory dysfunction and intraoperative floppy iris syndrome. All α1-adrenoceptor antagonists have a similar efficacy in appropriate doses, with the effects being dose dependent. In Japan, tamsulosin, naftopidil, silodosin, terazosin, urapidil, and prazosin have been approved for use. Note that the recommended doses of some drugs are different in Japan than those recommended in Europe and the USA.

Tamsulosin, naftopidil, silodosin

Recommendation grade: A

There is adequate evidence to support efficacy of these three drugs for BPH (Level 1).27–29

2 5α-reductase inhibitors

These drugs inhibit both or either of the isoforms (type 1 and type 2) of 5α-reductase, suppressing production of dihydrotestosterone (DHT).

Dutasteride

Recommendation grade: A

There is adequate evidence to support efficacy for definite BPH (≥30 mL) (Level 1). Dutasteride inhibits both isoforms (type 1 and type 2) of 5α-reductase. A Japanese Phase III trial allocated patients with a prostatic volume ≥30 mL to dutasteride 0.5 mg daily (n = 193) or placebo (n = 185) for 52 weeks. Dutasteride improved IPSS by 5.3 points, maximal urine flow by 2.2 mL/s, and prostatic volume by 22% over the baseline. Although uncommon, adverse events related to sexual function were more common than placebo, and PSA levels decreased to an average 46.1%.25 These results are very similar to those in an overseas study.30

Finasteride

Recommendation grade: reserved (not approved)

There is adequate evidence to support efficacy (Level 1),31 although finasteride is not approved for BPH in Japan.

3 Anti-androgens

These drugs inhibit the pituitary function and testicular production of testosterone, as well as testosterone uptake and DHT binding to androgen receptors in the prostate. Various adverse reactions including sexual dysfunction can occur.

Chlormadinone

Recommendation grade: C1

There is insufficient evidence to support its efficacy in BPH (Level 3).32 It is, however, thought to have a clinical effect similar to finasteride (not approved in Japan for BPH),33,34 whose efficacy has been confirmed in overseas studies.31

Allylestrenol

Recommendation grade: C1

There is insufficient evidence to support the efficacy of this drug (Level 3). In randomized comparative studies there were no significant differences between chlormadinone and allylestrenol in terms of efficacy, but allylestrenol had less effect on sexual function.35–37

4 Other oral medications

Eviprostat®

Recommendation grade: C1

There is some evidence to support the efficacy of this drug, although the studies are old,38,39 and its efficacy is inferior to α1-adrenoceptor antagonists (Level 2). Recent studies have reported its usefulness in combination therapy with α1-adrenoceptor antagonist.40,41 Adverse reactions are rare and minor.

Cernilton® (cernitine pollen extract)

Recommendation grade: C1

Efficacy is suggested for symptoms such as nocturia, but there is no evidence of improvement in objective findings (Level 1).42 There are few adverse reactions.

Paraprost®

Recommendation grade: C1

There is insufficient evidence to support efficacy (Level 2).43 There are few adverse reactions.

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

Recommendation grade: C1

There is insufficient evidence to support efficacy, although some studies have reported the usefulness of gosha-jinki-gan in combination with other agents (Level 2).44,45

Flavoxate

Recommendation grade: reserved (not approved)

There is insufficient evidence to support efficacy (Level 2).46 Flavoxate is not approved in Japan for BPH.

Antidepressants

Recommendation grade: reserved (not approved)

Tricyclic antidepressants have not yet been approved for the treatment of BPH. There is scant evidence supporting their efficacy (Level 5).2 Adverse events include arrhythmia and drowsiness.

Anticholinergics

Recommendation grade: reserved (not approved)

There is evidence to support the efficacy and safety of anticholinergic monotherapy for the treatment of BPH with OAB symptoms (Level 1).47–49 However, anticholinergic agents are not covered by medical insurance for BPH in Japan, and can induce voiding difficulty or acute urinary retention in men with BPH.2 They may be used in combination with α1-adrenoceptor antagonists.

Cholinergic agents

Recommendation grade: reserved (not approved)

Efficacy is suggested for patients whose symptoms fail to respond to transurethral resection of the prostate (TURP), or with neurogenic bladder (Level 5),50,51 despite contradictory studies (Level 2).52 There is no evidence to support the efficacy for BPH and no approval for its use has been given by medial insurance in Japan. Serious adverse events such as cholinergic crises, angina pectoris, and arrhythmias have been reported.

Phosphodiesterase-type 5 inhibitors

Recommendation grade: reserved (not approved)

There is adequate evidence to support efficacy for sildenafil and tadalafil (Level 1).53–55 However, they are not approved for BPH in Japan.

5 Conservative therapies

Lifestyle modification

Recommendation grade: B

There is adequate evidence supporting the efficacy of this approach (Level 2).2 Invasiveness is almost completely absent, and the financial burden is low. Recommended lifestyles include the provision of education and reassurance, restriction of excessive fluid intake, bladder training, prompted voiding, and other measures.

Watchful waiting

Recommendation grade: B

The evidence to support the usefulness of this approach is inadequate (Level 3).13,56 However, treatment may be unnecessary for patients with BPH with no symptoms or complications, and there are few disadvantages to not intervening early with appropriate follow-up.4

Supplements

Recommendation grade: C2

Evidence to support supplements is lacking (Level 5), and inconsistent (Level 1).2 Safety is uncertain, and the cost to patients is high.

6 Other treatments

Indwelling catheterization

Recommendation grade: reserved

Although an indwelling catheter allows urine to pass out of the bladder, complications and impairment of QOL are common. Indwelling catheterization is indicated only if other treatments are impractical (Level 5).

Intermittent catheterization

Recommendation grade: B

There is evidence for the superiority for intermittent catheterization in comparison to indwelling catheterization in terms of preventing UTI57 and for early recovery of bladder function following surgery for urinary retention (Level 2).58

Surgical treatment

Surgical treatment for BPH is indicated in cases of: (i) insufficient response to medical therapy; (ii) the presence of moderate to severe symptoms; and (iii) in the presence of (or concern about) comorbidities, such as urinary retention, UTI, hematuria, and bladder stones. Surgical modalities are divided into three groups: (i) resection/ablation or vaporization; (ii) thermal coagulation; and (iii) other techniques. Resection/ablation or vaporization is generally more effective, but may be more often associated with perioperative complications. Although its definition is ambiguous, minimally invasive surgical treatment appears to refer to techniques that are less invasive than an open prostatectomy and TURP. The selection of surgical techniques depends on the features of BPH as well as the patient's characteristics, the availability of equipment, and the surgeon's experience. The recommendation grade for each of the techniques described was determined in comparison with TURP, the standard surgical procedure for BPH.

Open surgery (enucleation of the adenoma)

Recommendation grade: B

This classic technique may be associated with a high incidence of perioperative complications, but provides sustained efficacy, especially for large prostates.4,59,60

TURP

Recommendation grade: A

TURP is the standard, most extensively performed surgical technique for the treatment of BPH. It is usually applicable to a BPH of up to moderate size (<50–80 mL) and provides a sustained effect.4,59,61 Complications include hemorrhage and hyponatremia from irrigation fluids.

Transurethral incision of the prostate

Recommendation grade: B

This technique involves cutting the prostate at the 5 and 7 o'clock positions of the bladder neck to open the prostatic urethra. It is associated with a shorter operation time, comparable short-term (up to 12 months) efficacy, and a lower incidence of complications.62 It is applicable to relatively small-sized prostates (<20–30 mL).62,63

Bipolar transurethral resection of the prostate in saline (bipolar TURP)

Recommendation grade: A

Bipolar TURP is similar technically to conventional TURP, except that it uses saline as the irrigation fluid and the endoscope sheath as the return current collector. This technique is as effective as conventional TURP, with a lower incidence of hyponatremia.64,65

Holmium laser enucleation of the prostate (HoLEP)

Recommendation grade: A

HoLEP is applicable regardless of PV and there is sufficient evidence for its effectiveness and the sustainability of efficacy. It is comparable to open surgery or TURP in every respect, including complications.66–68

Laser vaporization of the prostate (photoselective vaporization of the prostate by KTP laser)

Recommendation grade: B

Laser vaporization is associated with a low risk of hemorrhage and can be performed safely even on large prostates.69–71 There is sufficient evidence for the effectiveness and sustainability of laser vaporization of the prostate, although tissue sampling is impossible, unlike TURP.

Transurethral enucleation with bipolar system

Recommendation grade: C1

This technique consists of the transurethral detachment and enucleation of the adenoma without a laser. It may be effective regardless of PV, but has not been evaluated sufficiently in comparison with other treatment options or in terms of its long-term outcomes.72–74

Interstitial laser coagulation of the prostate

Recommendation grade: C1

The treatment is as effective as TURP and is feasible with rare serious adverse reactions.75 Benefits are not sustained, however, with further treatment or reintervention required in almost half of patients in long-term follow-up.76,77

Transrectal high-intensity focused ultrasound

Recommendation grade: C1

There have been few reports of the efficacy and safety of high-intensity focused ultrasound. Although the safety profile is relatively favorable,78 further treatment or re-intervention is required in roughly half of patients in long-term follow-up.79

Transurethral needle ablation

Recommendation grade: C1

As much symptomatic improvement is achievable as with TURP in the short to medium term, with an increased risk of postoperative irritability and urinary retention.80–82 Re-treatment, including surgeries, is required in nearly half of cases.82

Transurethral microwave therapy

Recommendation grade: B

This is the most extensively verified, minimally invasive surgical treatment. Medium-term efficacy has been demonstrated, even for patients with large prostatic volumes or urinary retention by using a high-energy deliver system.83–85 Perioperative and postoperative safety is superior to TURP,85 although fewer than half the patients require re-intervention.86

Urethral stent

Recommendation grade: C1

Although this procedure is quickly efficacious with minimal invasiveness,87 urethral stenting may be associated with complications that require stent removal.88,89 It is indicated in high-risk patients in whom surgical interventions or other invasive therapies are contraindicated.

Transurethral ethanol ablation of the prostate

Recommendation grade: reserved (not approved)

Efficacy has been demonstrated for symptoms and urinary flow rates,90–92 although few long-term studies with large numbers of participants and no randomized controlled trials (RCT) comparing it with standard therapies are available. It is not covered by medical insurance in Japan.

Botulinum toxin injection

Recommendation grade: reserved (not approved)

There is adequate evidence to support its efficacy,93,94 although its long-term efficacy is uncertain. Botulinum toxin is not approved in Japan for BPH.

BPH treatment and sexual function

Treatments for BPH may impact adversely on sexual function.3 Surgical interventions often result in ejaculatory dysfunction;4,95,96α1-adrenoceptor antagonists sometimes cause ejaculatory dysfunction;29 and the use of 5α-reductase inhibitors and anti-androgens is associated with multiple sexual dysfunctions, with a higher frequency for the latter.33,36,97,98

Clinical study

This section details the standard criteria necessary for any clinical study on BPH.

Inclusion/exclusion criteria

Inclusion criteria

  • • Men aged ≥50 years (can be ≥40 years)
  • • Clinical signs and symptoms of BPH
  • • Moderate to severe LUTS (i.e. IPSS ≥8)
  • • QOL disturbance due to LUTS (i.e. QOL score ≥2)
  • • Prostate enlargement (i.e. PV ≥20 mL)
  • • Suspected lower urinary tract obstruction (i.e. Qmax <15 mL/s)

Exclusion criteria

  • • Suspicion or presence of diseases other than BPH
  • • Persisting effects of pretreatment for BPH
  • • A history of any diseases affecting lower urinary tract function
  • • Conflicts with the characteristic of the treatment

Note: patients on BPH medications should stop treatment before enrollment into a study (12 months for 5α-reductase inhibitors and anti-androgens, 4 weeks for α1-adrenoceptor antagonists and anticholinergics). Those using gonadotropin-releasing hormone agonists and antagonists should be excluded.

Criteria for severity and therapeutic efficacy

We recommend the Japanese criteria,99,100 since the standard criteria for severity and therapeutic efficacy are not available at present (Tables 6–8). The efficacy of treatment on symptoms and QOL can be assessed using changes in the symptom score, BPH impact index, King's health questionnaire, and Short Form-36, although the criteria for efficacy using these scales have not yet been standardized.

Table 6.  Standard criteria for the severity of individual domains in benign prostatic hyperplasia (BPH)
MeasureDomains used to assess severity of BPH
SymptomsQOLFunctionAnatomy
IPSSIPSS QOL indexQmax (mL/s)PVR volume (mL)Prostate volume (mL)
  1. This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x. IPSS, International Prostate Symptom Score; PVR, postvoid residual urine; Qmax peak urinary flow rate; QOL, quality of life index.

Severity of BPH     
 Mild0–70, 1≥15<50<20
 Moderate8–192–4≥5<100<50
 Severe20–355, 6<5≥100≥50
Table 7.  Standard criteria for overall severity of benign prostatic hyperplasia
Overall severityNo. of domains in Table 6 evaluated as:
MildModerateSevere
  1. This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x.

Mild4, 30, 10
ModerateOther combinations
SevereAnyAny2, 3, 4
Table 8.  Standard criteria for therapeutic efficacy
MeasureDomains used to assess efficacy with respect to
SymptomsQOLFunctionAnatomy
IPSS post/preQOL pre-postQmax(mL/s) post-prePV post/pre
  1. The overall efficacy is determined as the median of efficacy for three domains: symptoms, quality of life (QOL), and function. This table has been reproduced from the original version of JUA Clinical Guidelines for Benign Prostatic Hyperplasia: doi: 10.1111/j.1442-2042.2011.02861.x. IPSS, international prostate symptom score; PV, prostate volume; Qmax peak urinary flow rate.

Efficacy    
 Excellent≤0.25≥4≥10≤0.5
 Good≤0.503≥5≤0.75
 Fair≤0.752, 1≥2.5≤0.9
 Poor>0.75≤0<2.5>0.9

Other recommendations

Recommendations for Phase 3 clinical studies on medical treatments include; (i) double-blinded RCT using placebos or standard treatments as the control group; and (ii) monitoring of efficacy and safety for up to 12 months, with the primary end-points evaluated at 3 months.

Clinical question (CQ) 1: When is a bladder diary recommended as part of the assessment of BPH?

A bladder diary is recommended for men with daytime or nocturnal frequency (Grade B). The diary records individual voiding prospectively, enabling the accurate evaluation of voiding time, individual volumes voided, and total urinary volume. This information is useful for the differential diagnosis of urinary frequency, which can be classified as a decrease in the volume voided, polyuria, or both.2,101,102 Ideally, the diary should be kept over a period of 3–7 days, although keeping the diary for over 1 or 2 days may be sufficient.4

CQ 2: What examination is recommended for the anatomical evaluation of the prostate?

Ultrasonography is recommended for the anatomical evaluation of the prostate (Grade A). Compared with a digital rectal examination and other imaging tests, ultrasonography is more accurate and minimally invasive.2,100,102 Trans-abdominal ultrasonography is easily performed and readily able to detect bladder pathology, whereas trans-rectal ultrasonography permits the detailed imaging of the inner structures. The type of ultrasonography performed depends on the equipment available, as well as on the objective of the examination. PV is predictive of both clinical progression and the therapeutic outcomes of surgical or medical treatment.102,103

CQ 3: When and how is evaluation of the upper urinary tract recommended?

Evaluation of the upper urinary tract is not to be performed routinely. It is recommended for men with abnormal urinalysis, a large amount of PVR, renal insufficiency, or a history of other urological diseases (Grade B). In these cases, ultrasonography is recommended as the initial method of assessment.2,102 Renal ultrasonography in 556 men with BPH detected hydronephrosis, renal cysts, and renal cancer in 2.5, 11.7 and 0.18% of men, respectively.104

CQ 4: What considerations are recommended when assessing serum PSA values?

Serum PSA concentrations should be determined because higher PSA concentrations are indicative of prostatic cancer and enlarged PV.2,102 Serum PSA concentrations are increased in men with enlarged adenoma, prostate cancer, urinary retention, and prostatitis, but can be reduced approximately to 50% by long-term treatment with anti-androgens or 5α-reductase inhibitors25,97,102 (Grade A).

CQ 5: Is long-term therapy with α1-adrenoceptor antagonists recommended?

The efficacy and safety of α1-adrenoceptor antagonists up to 1 year has been reported in many studies. However, there is a relative paucity of long-term data over 3 years regarding the maintained efficacy of these drugs (Grade B). Most long-term studies into the efficacy of α1-adrenoceptor antagonists are open-label extensions of previous short-term trials or retrospective studies in real-life clinical practice. The study designs are not consistent. In long-term studies (over 3 years; range 4–10 years), approximately 18, 64, and 36–80% of patients withdrew from the studies after 2, 3, and >4 years, respectively. The risk factors for treatment failure were severe LUTS, low urinary flow rate, large prostate (>30–40 mL), large PVR or a history of urinary retention, concomitant OAB symptoms, urodynamically proven BOO, and insufficient effects with short-term therapy.105–108

CQ 6: Is combination therapy with α1-adrenoceptor antagonists and anticholinergics recommended for men with OAB?

There is adequate evidence supporting the efficacy and safety of combination therapy with α1-adrenoceptor antagonists and anticholinergics for BPH associated with OAB (BPH or OAB; Grade A).

For male OAB symptoms, monotherapy with α1-adrenoceptor antagonists is effective and may be a first-line treatment,2 although the efficacy of α1-adrenoceptor antagonists is limited for patients with detrusor overactivity (DO).109 The efficacy and safety of anticholinergic monotherapy have also been confirmed in the treatment of BPH and OAB.49 Combined therapies with anticholinergics and α1-adrenoceptor antagonists are more effective than monotherapy with α1-adrenoceptor antagonists in improving storage symptoms, with urinary retention being rare.48,110–112 However, it should be noted that most of these studies were conducted in Caucasian men, with strict exclusion criteria, specialist supervision, and relatively short-term observational periods. There remains a concern about the exacerbation of voiding difficulties and possible urinary retention in a practice setting.2

Note: two recent Japanese studies reported that combination therapies with tamsulosin plus anticholinergics are more effective for BPH and OAB than tamsulosin monotherapy, with lower doses of anticholinergics associated with better outcomes.113,114

CQ 7: Is combination therapy with an α1-adrenoceptor antagonist and a 5α-reductase inhibitor recommended?

Combination therapy is recommended for relatively severe disease, e.g. prostatic volume ≥30 mL (Grade B). The combination therapy with dutasteride and tamsulosin (CombAT) study randomly assigned men with BPH (N = 4844, prostatic volume ≥30 mL, 1.5 ≤ PSA ≤ 10 ng/mL, 5 ≤ maximal urine flow ≤ 15 mL/s) to either dutasteride, tamsulosin or combination therapy for 4 years.115 The average change in the IPSS and the cumulative incidence of clinical progression, −6.3 points and 12.6% in the combination therapy group, respectively, were significantly better than in other groups. Men on combination therapy for 24 weeks were randomly assigned to either continued combination therapy or dutasteride monotherapy for 36 weeks.116 Of 82 men with a pretreatment IPSS, ≥20 symptom aggravation was reported in 14% of the continued combination therapy group and 42.5% of the dutasteride monotherapy group. A study of finasteride (not indicated for BPH in Japan), the Medical Therapy of Prostatic Symptoms (MTOPS) study, randomly assigned 3047 men with BPH (IPSS ≥8 points, 4 ≤ maximal urine flow ≤ 15 mL/s) to placebo, doxazosin, finasteride or combination therapy.117 The risk of clinical progression during 4.5 years (5%) was significantly less in the combination therapy group. A similar additive effect of combination therapy is suggested in Japanese men,25,118 although trials on its efficacy and cost effectiveness in Japanese men are awaited.

CQ 8: What urodynamic test is recommended for men undergoing surgical treatment for BPH?

BOO, DU, and DO are all important prognostic variables for the surgical outcomes of BPH.119 Symptom improvement is less likely for men with no or equivocal BOO compared with men with evident BOO.120 Both DU without BOO and DO without BOO strongly predict treatment failure for TURP.121 A higher degree of BOO without DO or DU, or both, is associated with improvements in both symptoms and QOL.122 Thus, urodynamic examinations, including pressure-flow studies and cystometry, are recommended to delineate BOO, DU, and DO (Grade B). Predicting BOO using simpler parameters such as uroflowmetry and PV may be a viable alternative.123

CQ 9: What measures are recommended for persistent symptoms after surgical treatment (predominantly TURP)?

Appropriate treatments should be selected after evaluating possible causes other than BOO using urodynamic studies, including pressure-flow studies and recording a frequency and volume chart (Grade B). DO induced by BOO generally improves postoperatively, but DO without accompanying BOO often persists after surgery,121 or DO may arise independently as a result of the surgery.124 DU is present in 20–30% of men with LUTS,125 and the surgical outcome for these patients is poor.119 In a long-term postoperative study, BOO recurred in only 12.4% of patients treated with TURP, whereas DU was present in 36.5% of the men complaining of LUTS after surgery.124 Nocturia is a symptom with low specificity for BPH126 that is often caused by polyuria. Thus, the postoperative recurrence of LUTS is not necessarily attributable to BOO, but rather to overlooked or developing DO, DU, or polyuria.

CQ 10: What treatments are recommended for urinary retention by BPH?

Either insertion of an indwelling catheter or intermittent catheterization should be indicated. After this, catheter removal may be attempted after administration of an α1-adrenoceptor antagonist. Surgical intervention is likely to be necessary for a large prostate (Grade B). It is recommended to use intermittent catheterization only for urinary retention due to transient causes (e.g. the use of anaesthetic or α-sympathomimetic agents) and an α1-adrenoceptor antagonist at an attempt to remove the indwelling catheter.3 A retrospective survey on 248 patients in whom indwelling catheters were successfully removed after treatment with an α1-adrenoceptor antagonist, with a mean follow-up period 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.127 Multivariate analysis revealed a prostatic volume ≥50 mL, and a PSA level ≥10 ng/mL at the time of acute urinary retention, as predictive factors for surgical intervention. Another multivariate analysis of 72 patients showed that those with PSA >2.9 ng/mL, a large prostate size on digital rectal examination, and a volume drained at the time of catheterization >1000 mL, were best managed by surgical intervention.128

CQ 11: What measures are recommended for men with symptomatic BPH in whom usual treatments are not indicated due to deteriorating activities in daily life?

Urethral stents, intermittent catheterizaion, and indwelling urethral or suprapubic catheters should be considered as management options for such men (Grade B). Although stenting is an effective, less invasive procedure for improving symptoms,87 its utility is limited by the associated complications, including encrustation, discomfort or urethral pain, UTI, bleeding, and stent migration.4,88,89,129,130 Intermittent self-catheterization is safe and useful with minimal complications,57 although it requires manual dexterity. Urethral indwelling catheters are useful for prompt management, yet are associated with inevitable UTI, urethral erosion, strictures, and fistula formation. Suprapubic cystostomy is an alternative measure that avoids the complications caused by indwelling urethral catheters.

CQ 12: What therapeutic strategies are recommended to avoid sexual dysfunction as an adverse event?

Surgical treatment or α1-adrenoceptor antagonists are recommended to avoid erectile dysfunction (ED). To prevent ejaculatory dysfunction, surgical treatment, α1A-adrenoceptor antagonists, 5α-reductase inhibitors or anti-androgens should be avoided. To retain libido, 5α-reductase inhibitors or anti-androgens especially should be avoided (Grade B). ED as an adverse event is rare for surgery (0–12.5%),4,96 and is comparable with placebo for α1-adrenoceptor antagonists.4 Ejaculatory dysfunction has been reported to be 50–80% post-surgery,3,4,95,96 and 1.6 to 22.3% in Japanese men using α1-adrenoceptor antagonists, particularly α1A-adrenoceptor antagonists.29,131 Decreased libido and ejaculatory dysfunction are observed in men taking 5α-reductase inhibitors or anti-androgens,37,97 with more pronounced in the latter.122

Conflict of interest

Yukio Homma received research grants from Astellas, Asuka, DaiichiSankyo, Ono, Pfizer, and Takeda, and received lecture fees from Astellas and GlaxoSmithKline; Momokazu Gotoh received research grants from Astellas, DaiichiSankyo, GlaxoSmithKline and Takeda, and received lecture fees from Astellas; Osamu Yokoyama received research grants from AsahiKasei, Astellas, GlaxoSmithKline, Ono and Pfizer, and received lecture fees from Astellas, Kissei and Ono; Naoya Masumori received lecture fees from GlaxoSmithKline; Akihiro Kawauchi has no conflict of interest; Tomonori Yamanishi has no conflict of interest; Osamu Ishizuka received research grants from Asahi Kasei; Narihito Seki received research grants from Astellas and Kyorin, and received lecture fees from Astellas; Toshiyki Kamoto has no conflict of interest; Atsushi Nagai received research grants from Kissei and Pfizer; Seiichiro Ozono received lecture fees from Astellas. Funding of the committee was provided by The Japanese Urological Association.

Ancillary