JUA clinical guidelines for benign prostatic hyperplasia

Risk factors for BPH

The principal risk factors for BPH are aging and normally functioning testicles. Although no definitive genes responsible for BPH have been identified, a family history of BPH and molecular abnormalities may increase the likelihood of its development. Dietary factors, such as isoflavonoids and lignans in vegetables, grains, and soy, may have a negative impact on the development of BPH.¹³ In addition, a recent study has reported a relationship between BPH and metabolic syndrome.¹⁴ The correlation between erectile dysfunction (ED) and LUTS suggests a common etiology for these conditions, such as changes in sympathetic nerve tone induced by insulin resistance.¹⁵

Natural history

BPH is a physiological process that occurs with aging, regardless of race, ethnicity or region.^16,17 Longitudinal studies have confirmed age-related increases in PV,^18,19 although in a small proportion of men PV has been noted to decrease with aging.²⁰ Recent studies indicate that PV is likely to increase in men in whom the prostate has a visible transition zone with a clear border^21,22 and with a large transition zone volume on transrectal ultrasound at baseline.²³ The prevalence of LUTS in the general population is age-related.^24–27 Longitudinal studies have shown an increase in IPSS with advancing age as a whole,^19,28,29 but with simultaneous decreases in IPSS in certain subgroups.^28,30 Q_max decrease with aging^31,32 and this may be attributable to BPO as well as detrusor underactivity (DU). The relationship between PV, LUTS, and urinary flow rate is generally poor in men presenting at hospital, but it is modest among men in the general population. Prostate enlargement is likely to be involved in the progression of symptoms.^19,33

The prevalence of BPH, which varies depending on the definition of BPH used,³⁴ has been estimated on the basis of results of community-based studies in Japan (Table 1).^25,31 Specifically, only 2% of men in their forties met the criteria of IPSS >7, PV >20 mL, and Q_max <10 mL/s. However, the proportion of men in their sixties and seventies who meet these criteria increases to 6 and 12%, respectively.

Factors affecting health-care seeking behavior

A population-based study in Olmsted County revealed that health-care seeking behavior was influenced by the severity of symptoms, particularly if they were bothersome and interfered with an individual's daily activities.³⁵ In Japan there is a marginal overlap in the distribution of QOL scores between the general population and patients with BPH.³⁶

Prediction of disease progression

When acute urinary retention is regarded as an indicator of disease progression, the incidence in a US population has been calculated to be 6.8 per 1000 person-years.³⁷ Older age, a higher IPSS, Q_max <12 mL/s, and PV >30 mL are all risk factors for urinary retention. Surgical treatment would be another indicator of disease progression, and the risk is related to age, the severity of the symptoms, an impaired QOL, decreased urinary flow rate, degree of prostate enlargement, and increased serum PSA levels.^30,38

Natural history of BPH after diagnosis

The natural history of BPH can be monitored in men in whom the “watchful waiting” approach is being taken or in those on a placebo in Phase III clinical trials of medical treatments. The baseline PV and the rate of growth of the prostate during follow-up are greater in men with BPH than in men in the general population.^39,40 The Medical Therapy of Prostatic Symptoms study,⁴¹ which observed men on placebo or doxazosin for 4.5 years, reported that prostate growth could be predicted by baseline PV and serum PSA levels. Although LUTS worsened progressively in men with BPH as a whole, in some patients improved or stable LUTS was noted.⁴² Symptomatic deterioration, development of acute urinary retention, and conversion to BPH-related surgery tended to occur in men with severe LUTS, a large PV, and high PSA levels at baseline.^43–45 Fortunately, a recent study has found that BPH-related deaths or comorbidities, such as hydronephrosis, renal failure, UTI, and bladder stones, are rare. In a study of 737 patients treated with placebo, over 4.5 years of follow-up only one patient developed recurrent UTI and none developed renal insufficiency.⁴⁶

Prostate growth factors

Histologically, prostatic hypertrophic nodules (adenomas) consist of increased numbers of cells, so the term “hyperplasia” is more appropriate than “hypertrophy”. Prostatic adenomas arise in the transitional zone and the periurethral region of the prostate,⁴⁷ with nodules initially consisting of stromal elements only.⁴⁸

An interaction is seen between prostatic stromal and epithelial cells, mediated by various growth factors, and the hyperplasia is thought to be caused by an imbalance between cellular proliferation and cell death. Although the importance of male sex hormones to the development of prostatic hyperplasia is undisputed,⁴⁹ female sex hormones also contribute to its formation. Furthermore, inflammation plays an important role in the onset of hyperplasia and urinary retention.⁵⁰ A clinical trial of 5α-reductase inhibitor therapy found that prostatic volumes were bigger, and symptom scores higher, in patients with pathological evidence of inflammation.⁵¹ Cytokines derived from inflammatory cells also induce epithelial growth factors.⁵² In addition, the promotion of glandular proliferation in spontaneously hypertensive rats⁵³ and the induction of apoptosis by α₁-adrenoceptor antagonists⁵⁴ suggest the involvement of adrenergic nerves in prostatic hyperplasia.

Prostatic adrenergic receptors

α₁-adrenergic receptors (AR) are the main AR in prostatic smooth muscle, and three subtypes have been identified: α_1A, α_1B, and α_1D. In the normal human prostate, the mRNA content of each of the α_1A-, α_1D-, and α_1B-AR subtypes has been reported to be 63, 31, and 6%, respectively, compared with 85, 14, and 1%, respectively, in prostatic hyperplasia.⁵⁵ In both cases, α_1A-AR is the predominant subtype. Conversely, there have been reports of patients in whom there are similar levels of α_1A- and α_1D-AR (41 and 49%, respectively), and in whom α_1A-AR is no longer the predominant subtype.⁵⁶ A recent study found that the α_1A-AR gene expresses two subtypes, α_1A and α_1 L, with the α_1 L subtype being mainly involved in the contraction of the prostate and urethra.⁵⁷ Noradrenaline-induced contraction of the prostate is nearly absent in α_1D-AR knockout mice,⁵⁷ but observations of reduced urinary frequency and increased bladder volumes⁵⁸ indicate that α_1D-AR are involved in bladder function, not prostatic contractions. Detrusor overactivity (DO) induced by stimulation of the rat urethra is inhibited by α₁-adrenoceptor antagonists with a high specificity for α_1A-AR,^59,60 indicating that storage symptoms in BPH are mediated by urethral α_1A- and α_1 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 variety of different diseases and conditions (Table 2), there is no clear correlation between LUTS and BPE or BPO.^61,62 Whether there is a correlation between BPO and LUTS sometimes depends on the site of origin of prostatic nodules. For example, in the case of middle lobe hyperplasia, intravesical prostatic protrusion, rather than BPE, is correlated with LUTS and BPO.⁶³ Urodynamic studies show a weak correlation between BPO and LUTS, whereas DO is correlated with the degree of BPO.⁶⁴ Storage symptoms, in particular urge incontinence, strongly suggest DO.^65–67

Recurrent urinary retention

The incidence of acute urinary retention is significantly higher in patients with BPH who have a prostatic volume ≥31 mL or serum PSA levels ≥1.6 ng/mL. These patients are more likely to progress to invasive treatment.⁴⁵ The risk of acute urinary retention increases with age and it is often associated with DU.⁷⁰

Macroscopic hematuria

Macroscopic hematuria is present in 12% of patients in whom surgery is indicated for BPH.⁸⁸ A possible cause of the macroscopic hematuria is increased microvessel density due to the increased expression of vascular endothelial growth factor associated with the enlargement of the prostate.^89,90

Bladder calculi

Bladder calculi associated with BPH are thought to be caused by urinary stasis,⁹¹ although the underlying mechanism is unclear.

Recurrent UTI

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

Postrenal renal failure

Although renal failure is a rare complication of BPH (<1%), the Japanese Clinical Guidelines for male LUTS and the EAU BPH Guidelines both recommend the measurement of serum creatinine levels as part of the initial assessment.^4,8 Diabetes mellitus and hypertension are common causes of kidney failure in patients with BPH.⁹²

1 α1-adrenoceptor antagonists

α₁-adrenoceptor antagonists relieve outlet obstruction by inhibiting contractions mediated by prostatic α₁-AR, thereby ameliorating LUTS of BPH.^4,103α₁-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.^{4,7,8,103,104} 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.^7,8,104 In Japan, tamsulosin, naftopidil, silodosin, terazosin, urapidil, and prazosin have been approved for use.¹⁰³ Note that the recommended doses of some drugs are different in Japan to those in Europe and the USA.

Tamsulosin

Recommendation grade: A

There is adequate evidence to support its efficacy for BPH (Level 1).

Tamsulosin is an α_1A/α_1D-AR subtype-selective antagonist, with an affinity for α_1A- and α_1D-AR 15.3-, and 4.6-fold higher, respectively, than for α_1B-AR.¹⁰⁵ A Japanese randomized clinical trial (RCT) of tamsulosin in the treatment of BPH demonstrated its superiority to placebo, and reported that the optimal dosage was 0.2 mg/day.¹⁰⁶ Studies in Western countries have reported optimal doses of 0.4 mg/day.^104,107 Adverse reactions to tamsulosin, including postural hypotension (0.19%), were uncommon in the Japanese study (2.87%).

Naftopidil

Recommendation grade: A

There is adequate evidence to support its efficacy for BPH (Level 1).

Naftopidil is an α_1D/α_1A-AR subtype-selective antagonist, with an affinity for α_1D-, and α_1A-AR 16.7- and 5.4-fold higher, respectively, than for α_1B-AR.¹⁰⁵ The efficacy of naftopidil in the treatment of BPH has been demonstrated in RCT comparing it with both placebo and other agents.^108,109

Silodosin

Recommendation grade: A

There is adequate evidence to support its efficacy for BPH (Level 1).

Silodosin is a selective α_1A-adrenoceptor antagonist, with an affinity for α_1A-, and α_1D-AR 583- and 10.5-fold higher, respectively, than for α_1B-AR.¹¹⁰ An RCT in Japan indicated significantly larger decreases in IPSS and QOL scores following treatment with silodosin compared with placebo.¹¹¹ Pooled results from two Phase III studies of silodosin for the treatment of BPH have been reported in the USA.¹¹²

2 5α-reductase inhibitors

Dutasteride

Recommendation grade: A

There is adequate evidence to support its efficacy for definite BPH (≥30 mL) (Level 1). Caution is required in evaluating the PSA value, since dutasteride affects PSA levels.

Dutasteride inhibits both isoforms (type 1 and type 2) of 5α-reductase and suppresses the production of dihydrotestosterone (DHT). In Japan, a Phase II RCT was conducted with 284 BPH patients aged ≥50 years, a prostatic volume ≥30 mL, an IPSS ≥8, and a maximal urine flow ≤15 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 was observed after 2 weeks' treatment in the 0.5 and 2.5 mg groups, as was seen in overseas trials.¹¹⁴ A Japanese Phase III RCT allocated participants to receive dutasteride 0.5 mg daily (n= 193) or placebo (n= 185) for 52 weeks.¹⁰⁰ In the dutasteride group, a significant decrease in prostatic volume was seen after 24 weeks' treatment, and significant decreases were seen in IPSS and maximal urine flow after 36 weeks' treatment. After 52 weeks' treatment, IPSS had improved by 5.3 points, maximal urine flow by 2.2 mL/s, and prostatic volume by 22% over baseline. Although uncommon, adverse events related to sexual function were rather more common in the dutasteride group and PSA levels decreased to an average 46.1%. These results are very similar to those from an overseas study.¹¹⁵

Finasteride

Recommendation grade: reserved (not approved)

There is adequate evidence to support its efficacy (Level 1). ¹¹⁶ However, in Japan finasteride is indicated only for the treatment of androgenic alopecia and is not approved for BPH.

3 Anti-androgens

These drugs inhibit the pituitary function and the testicular production of testosterone, as well as testosterone uptake and DHT binding to androgen receptors in the prostate. Although covered by insurance, the evidence to support their efficacy for BPH is far from adequate and the incidence of sexual dysfunction is high. Careful patient selection and follow-up are necessary when prescribing these agents.

Chlormadinone

Recommendation grade: C1

There is insufficient evidence to support its efficacy in BPH (Level 3). It is, however, thought to have a similar clinical effect to finasteride (not approved in Japan for BPH), whose efficacy has been confirmed in overseas studies. Various adverse reactions can occur, including sexual dysfunction.

In a comparative trial of chlormadinone 50 mg/day versus Eviprostat, symptomatic improvement was reported by 90% of patients and the prostatic volume decreased by 50% in the chlormadinone group (n= 20), while symptomatic improvement was reported for 70% of patients and the prostatic volume decreased by 30% in the Eviprostat group (n= 20).¹¹⁷ Double-blind comparative trials of chlormadinone and finasteride (not approved in Japan for BPH) found similar clinical efficacy for both agents, including prostate shrinking effects.^118,119

Important adverse reactions include congestive heart failure, thrombosis, hepatic dysfunction or diabetes mellitus occur, so treatment should not be continued indefinitely.

Allylestrenol

Recommendation grade: C1

There is insufficient evidence to support its efficacy (Level 3). Sexual dysfunction can occur.

Allylestrenol is considered to have a similar efficacy to chlormadinone. In randomized comparative studies of chlormadinone versus allylestrenol, there were no significant differences between the two in terms of efficacy, but allylestrenol had less effect on sexual function.^120–122 Important adverse reactions include the loss of libido and sexual dysfunction, so treatment should not be continued indefinitely.

4 Other oral medications

Eviprostat^®

Recommendation grade: C1

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

Although the studies were conducted in 1975, there is evidence to support its efficacy from double-blind trials^123,124 and a retrospective study suggesting its efficacy in the treatment of BPH.¹²⁵ RCT conducted with Eviprostat and α₁-adrenoceptor antagonists such as naftopidil¹⁰⁹ and tamsulosin¹²⁶ have demonstrated the inferior efficacy of Eviprostat. However, symptomatic improvement has been reported with the addition of Eviprostat to patients on tamsulosin with persistent pelvic discomfort,¹²⁷ and patients refractory to naftopidil.¹²⁸

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). There are few adverse reactions.

Comparison with placebo and Paraprost it is suggested that cernilton is efficacious in relieving nocturia, but no improvement was seen in the urinary flow rate or PVR volume (I, II).^129–131 One study found cernilton useful in the treatment of chronic abacterial prostatitis and chronic pelvic pain syndrome.¹³²

Paraprost^®

Recommendation grade: C1

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

An RCT comparing Paraprost and prazosin found no significant difference in the degree of improvement in symptoms or PVR volume, although Paraprost was inferior in improving urinary flow rate.¹³³

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

Recommendation grade: C1

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

Hachimi-jio-gan has been indicated for the treatment of BPH, 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 when OAB symptoms persisted despite treatment with tamsulosin, found a significant improvement in QOL in the combination therapy group.¹³⁴ A study in which gosha-jinki-gan was administered to patients with prostate disease such as BPH, with an inadequate response to α₁-adrenoceptor antagonist therapy, found significant improvements in urinary flow rate, IPSS, and QOL scores.¹³⁵

Flavoxate

Recommendation grade: reserved (not approved)

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

Although flavoxate has only weak anticholinergic activity, it also acts as a calcium channel blocker and to inhibit the central micturition reflex. A placebo-controlled RCT (n= 70) found no significant difference between flavoxate and the placebo in efficacy.¹³⁶ Another study found a significant decrease in nocturnal frequency after flavoxate was administered to patients with BPH whose nocturia had not improved with α₁-adrenoceptor antagonist therapy.¹³⁷ There were almost no adverse events.

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). Adverse events include arrhythmia and drowsiness.

Theoretically, imipramine should be effective for the treatment of various forms of urinary incontinence, but no studies to date have demonstrated its efficacy in the treatment of BPH.

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). However, anticholinergic agents can induce voiding difficulty and acute urinary retention, so caution is required in patients with BPH complicated by BOO or voiding difficulties. Anticholinergic agents are not covered by medical insurance for BPH in Japan. They may be used in combination with α₁-adrenoceptor antagonists (see clinical question CQ 6 below).

Of two placebo-controlled RCT of anticholinergics in male patients without obvious symptoms of BOO, one reported their superiority to placebo, and the other failed to show any such superiority. The frequency of acute urinary retention was less than 1% in the treatment group, however; similar to that in the placebo group (I, II).^138,139 A trial of anticholinergic monotherapy in the treatment of male patients with LUTS and DO confirmed their superiority to placebo, with no cases of acute urinary retention.¹⁴⁰

However, anticholinergic agents can induce voiding difficulty and acute urinary retention, so caution is required when considering anticholinergic monotherapy in male patients, particularly those with obvious BOO.⁴ Anticholinergic agents are not covered by medical insurance for the treatment of BPH, and should be administered with caution to patients with BPH complicated by BOO or voiding difficulties.

The Japan Neurogenic Bladder Society “Practice guidelines for overactive bladder” recommend the use of anticholinergic agents.³ The “Guideline for management of male lower urinary tract symptoms” recommends that anticholinergic therapy should be given under the supervision of a urologist.⁴ Accordingly, anticholinergic monotherapy should only be considered in male patients with OAB symptoms with no (or only mild) BPH, under strict urological supervision. In patients with BPH accompanied by OAB symptoms, however, α₁-adrenoceptor antagonists should be administered first, and an anticholinergic agent can be added if the symptoms are refractory to adrenoceptor antagonist monotherapy.

Cholinergic agents

Recommendation grade: reserved (not approved)

The efficacy of these agents is suggested for patients whose symptoms fail to respond to TURP, or with neurogenic bladder (Level 5), despite other contradictory studies (Level 2). There is no evidence to support their efficacy for BPH or no approval of their use by medial insurance in Japan. Serious adverse events such as cholinergic crises, angina pectoris, and arrhythmias, have been reported.

Cholinergic agents are thought to enhance detrusor contractility. They are not covered by medical insurance for the treatment of BPH and their use is restricted to urinary retention and underactive bladder. A meta-analysis of the use of cholinergic agents in the treatment of underactive bladder, including male and female patients, found they were superior to placebo in three of 10 RCT, and not superior in seven.¹⁴¹ In two RCT conducted with healthy male adults and post-prostatectomy patients, these agents' superiority to placebo was not demonstrated.^142,143 In Japanese studies conducted with patients without BOO, a study with small numbers of participants found distigmine effective in patients with difficulty voiding following TURP¹⁴⁴ and another study reported that combination cholinergic and α₁-adrenoceptor antagonist therapy was more effective than monotherapy in the treatment of underactive bladder.¹⁴⁵ Adverse events include abdominal pain and diarrhoea, and cholinergic crises, with sweating, miosis and respiratory failure, have also been reported.¹⁴¹

Phosphodiesterase-type 5 inhibitors

Recommendation grade: reserved (not approved)

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

Phosphodiesterase-type 5 (PDE5) inhibitors block degradation of cGMP and increase nitric oxide activity. Relaxation of the smooth muscle of the urethra and prostate is also mediated by nitric oxide,¹⁴⁶ so we can expect PDE5 inhibitors to ameliorate LUTS.

In a placebo-controlled RCT in men with ED and LUTS, sildenafil (n= 189) significantly improved IPSS, QOL scores and the BPH impact index in comparison to placebo (n= 180).¹⁴⁷ No significant change was seen in urinary flow rates, however. Another small-scale RCT did see a significant improvement in urinary flow rates.¹⁴⁸ An RCT with three treatment arms, alfuzosin 10 mg daily, sildenafil 25 mg daily, and combination therapy, found significant improvements in IPSS and ED in the combination therapy group in comparison with the monotherapy groups.¹⁴⁹ A large-scale RCT was undertaken in which patients with BPH and LUTS were allocated to placebo (n= 211), tadalafil 2.5 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 all dosages in comparison to placebo, and the optimum dosage of tadalafil was determined to be 5 mg daily.¹⁵⁰ Urinary flow rates improved, although the difference was not significant. Another RCT confirmed the efficacy of tadalafil, with significant improvement in symptoms in patients with ED and moderate to severe symptoms of BPH.^151,152 In a crossover trial with 27 patients comparing tamsulosin (0.4 mg/day) monotherapy with tamsulosin plus tadalafil (20 mg/day) combination therapy (both for 45 days), significant improvement in the IPSS and QOL score was seen in the combination therapy group. However, no difference was seen between the groups in maximal urine flow or PVR volume.¹⁵³ Safety was excellent in both trials. These agents are not approved for BPH in Japan.

5 Conservative therapies

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

Lifestyle modification

Recommendation grade: B

There is adequate evidence supporting the efficacy of this treatment (Level 2). Invasiveness is almost completely absent and the financial burden is low.

Recommended lifestyle modifications include: (i) the provision of education and reassurance (e.g. an explanation of bladder and prostate physiology, reinforcing the fact that it is not malignant, inviting patients to attend educational services); (ii) the restriction of excessive fluid intake (avoiding over-consumption of water, limiting intake of coffee and alcohol);¹⁵⁴ (iii) bladder training, prompted voiding; and (iv) other (avoiding spicy foods, keeping bowels regular, regular exercise, avoiding sitting for extended periods and chills of the lower body, provision of information about medications that affect micturition).^4,155

Watchful waiting

Recommendation grade: B

The evidence to support the usefulness of this approach is inadequate (Level 3). 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.

Although there have been no studies providing clear evidence for this approach, even if BPH is present but the symptoms are mild, there are no complications, and prostatic cancer has been excluded, then aggressive treatment may not be indicated. Some form of lifestyle modification is provided when watchful waiting is the approach taken with patients with mild symptoms.^156,157 Annual assessment using the IPSS is recommended during the period of watchful waiting.⁸ With long durations of watchful waiting, 85% of patients remain stable after 1 year, dropping to 65% after 5 years.^7,8 The degree of bothersomeness of symptoms and PVR volume have been identified as predictive factors for the cessation of watchful waiting.^43,158

Supplements

Recommendation grade: C2

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

Most health foods and alternative remedies are handled as over-the-counter medications. Most are sold as combinations of multiple active ingredients, and the influence of the combinations on efficacy and safety is unknown. Costs are borne by patients, as these medications are not covered by medical insurance.

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).

Indwelling catheterization is performed in cases of urinary retention or severe difficulty with urination,⁷⁰ or when other treatments for BPH are impractical. Indwelling catheterization is associated with an increased risk of urethral trauma, decreased QOL, UTI and bladder stones.¹⁵⁹ An alternative is insertion of a suprapubic catheter (cystostomy).⁴

Intermittent catheterization

Recommendation grade: B

There is evidence for the superiority for intermittent catheterization compared with indwelling catheterization in terms of preventing UTI and the early recovery of bladder function following surgery for urinary retention (Level 2).

With intermittent catheterization QOL is considered to be superior to indwelling catheterization.⁴ In an RCT controlled against an indwelling catheter group (n= 40), the incidence of symptomatic UTI was significantly lower in the intermittent catheterization group (n= 40).¹⁶⁰ In a study conducted with patients with an indwelling catheter due to chronic urinary retention, compared with a group who underwent TURP as soon as their renal function recovered (n= 17) and a group who underwent the same procedure after changing over to intermittent catheterization (n= 24), the bladder function recovered significantly earlier in the latter group.¹⁶¹

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.

The enlarged adenoma is detached manually from the surrounding prostatic tissue (surgical capsule) via an incision made on the bladder or directly on the prostate capsule. This procedure is used as a reliable and effective treatment, especially for large BPH.^8,162 The technique is associated with a relatively high incidence of complications, including hemorrhage requiring blood transfusion (8.2–25.6%), reoperation (1.1%),¹⁶³ surgical wound infection (2–6.9%), UTI (2.6–8.6%), and sepsis (8.6%).¹⁶⁴ The postoperative re-treatment rate is generally low.¹⁶⁵

TURP

Recommendation grade: A

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

With a transurethrally inserted endoscope, the adenoma is resected by a loop electrode with a high-frequency current. Electrolyte-free irrigation fluids are used to secure a clear view. This procedure is technically established and is regarded as the standard for BPH of moderate size (<50–80 mL) with a high efficacy and superiority to any of the transurethral surgical techniques developed up until the 1990s.^8,162,166 Complications of TURP include hemorrhage requiring blood transfusion (2.0–4.8%) and hyponatremia resulting from the absorption of irrigation fluid (0–1.1%).¹⁶⁷ The efficacy is sustained over the long term: in an 8-year follow-up survey on more than 20 000 men, the re-resection rate was only 7.4%.¹⁶⁸

Transurethral incision of the prostate (TUIP)

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 applicable to relatively small-sized prostates (<20–30 mL).

The bladder wall and the prostate are cut from the ureteral orifice to the verumontanum with a depth reaching the prostatic capsule.^169,170 An RCT has demonstrated that TUIP is as effective as TURP for relatively small BPH (<20–30 mL) without middle lobe hyperplasia.^171–173 TUIP has been associated with a shorter operation time, comparable short-term (up to 12 months) efficacy, and a lower incidence of complications, such as hemorrhage requiring blood transfusion and retrograde ejaculation.¹⁷² However, sustainability is inferior to that following TURP, with a reported reoperation rate for TUIP of 7.6–9.6% over 4–5 years.^166,172

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

Recommendation grade: A

This technique is as effective as conventional TURP, with a lower incidence of hyponatremia.

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 (i.e. a bipolar electrode).^174–179 Numerous RCT of BPH of 40–55 mL have shown there is a comparable operation time and efficacy between bipolar TURP and conventional TURP,^180–189 with a significantly lower incidence of hyponatremia for the former.^{180,183,185,188} Long-term follow-up results, including the duration of effect, are still awaited.^190,191

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 any aspect, including complications.

A holmium laser is irradiated through an endoscopic channel to either resect a prostatic adenoma or to detach an adenoma from the surgical capsule for enucleation (HoLEP). The holmium laser is readily absorbed by water and is capable of cutting, coagulating, and producing shock waves depending on the distance to the target tissue. Normal saline can be used as the irrigation fluid.^192–201

Numerous RCT have compared HoLEP and TURP^202–209 and have demonstrated that HoLEP is associated with a longer operation time (62.1–94.6 vs 33.1–73.8 min for HoLEP vs TURP, respectively),^204,206,208 less hemorrhage, and significantly a shorter duration of catheterization and hospitalization.^203,204 In four RCT of HoLEP compared with open surgery for large prostates (113–124 mL),^210–213 HoLEP exhibited comparable efficacy and significant superiority to open surgery in terms of blood transfusion rate and the duration of catheterization and hospitalization. The long-term re-treatment rate following HoLEP did not differ significantly compared with TURP or open surgery.^192,203 HoLEP can be performed safely in men with a large prostate (>100 mL) and those that are on anticoagulants.^193–195 Some reports suggest a high incidence of postoperative urinary incontinence, ejaculation disorders, and urethral stenosis following HoLEP.^193,214

Photoselective vaporization of the prostate by KTP laser (PVP)

Recommendation grade: B

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

A KTP or holmium laser is delivered endoscopically to vaporize the adenoma.^215–223 Three RCT investigating the effects of PVP compared with TURP have demonstrated that PVP is as effective as TURP and is associated with less hemorrhaging and a shorter duration of catheterization and hospitalization.^224–226 PVP may require a longer operation time than TURP when applied to large prostates.²²⁵ An RCT comparing PVP with open surgery in men with prostates >80 mL showed that although PVP required a longer operation time (80 vs 50 min, respectively), it was superior to open surgery with respect to the blood transfusion rate (0 vs 13.3%, respectively) and duration of catheterization and hospitalization, with no significant differences between the two techniques with regard to any other complications.²²⁷ With regard to long-term outcome, PVP may be associated with a relatively high reoperation rate: 10.4% for prostates <80 mL and 23% for prostates >80 mL.²¹⁹ A histological examination is not feasible because the prostate tissue is vaporized.

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 long-term outcomes.

Adenoma detachment is achieved with a resectoscope or a special loop through the bipolar system,²²⁸ or with a special detachment device through conventional TURP.^229,230 The detached adenoma is either resected without enucleation, as in TURP, or enucleated and then minced and collected with a morcellator, as in HoLEP. A 3-year RCT comparing this technique with TURP reported comparable efficacy in both.²³¹

Interstitial laser coagulation of the prostate (ILCP)

Recommendation grade: C1

This treatment is as effective as TURP and is feasible, with rare serious adverse reactions. Benefits are not sustained, however, with further treatment or re-intervention required in almost half of all patients in long-term follow-up.

ILCP delivers laser energy (from a neodymium : yttrium aluminum garnet or diode laser), via an applicator, into the prostate to produce coagulation necrosis within the adenoma, sparing its urethral surface. Although TURP results in greater improvements in Q_max, RCT have found that ILCP and TURP are comparable in terms of improvements in LUTS and QOL.^232,233 Good, long-term clinical outcomes following ILCP have also been reported.^234,235 The most common post-treatment adverse events are transient urinary retention and irritative symptoms. ILCP had a minimal impact on sexual function. Subsequent surgical interventions occurred at a rate of 3–16% within 1 year after the primary treatment.^232,236 Over longer follow-up periods, reported rates of re-interventions, including drugs and surgery, are 30–50%.^234,235

Transrectal high-intensity focused ultrasound (HIFU)

Recommendation grade: C1

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

HIFU irradiates highly focused ultrasound transrectally into the prostate to create coagulation necrosis. Several clinical studies have reported that HIFU significantly improves symptoms, QOL, and Q_max.^237–239 HIFU was comparable to transurethral microwave thermotherapy (TUMT) and transurethral needle ablation (TUNA) in improving LUTS over a 2-year follow-up period.²⁴⁰ Common post-treatment adverse events following HIFU include transient urinary retention, hematuria, and hematospermia.⁸ Thermoinjury of the rectum requiring surgical repair is an uncommon severe adverse event.⁸ The re-intervention rate ranged between 44 and 58% 2–4 years after HIFU.^241,242

Transurethral needle ablation (TUNA®)

Recommendation grade: C1

Symptomatic improvement is achievable with TUNA as much as 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 of cases.

TUNA therapy uses low-level radiofrequency energy delivered via needles into the prostate to induce necrotic lesions in the adenoma, thereby reducing BOO. Several clinical studies have reported significant improvements in the symptom scores (an average reduction rate of 40–70%) and Q_max (26–126%) over both short-term^243–245 and long-term²⁴⁶ follow-up periods. In RCT with 12–18 months follow-up comparing TUNA and TURP, no significant differences were found between the two in terms of improvements in symptom and bother scores.^246,247 Another RCT comparing TUNA and TURP demonstrated stable treatment outcomes over a 5-year follow-up period.²⁴⁸ Common post-treatment adverse events associated with TUNA include transient urinary retention and worsening storage symptoms in the early post-treatment period.^249,250 Reported treatment failure rates requiring subsequent further treatment, including pharmacotherapy and surgical intervention, are of the order of 21–39% over 2–5 years.^241,246

Transurethral microwave therapy (TUMT)

Recommendation grade: B

This is the most extensively verified minimally invasive surgical treatment. Medium-term efficacy has been demonstrated with a high-energy deliver system, even for patients with large prostatic volumes or urinary retention. Perioperative 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 microwave antenna to deliver microwaves into the prostate to produce coagulation necrosis and subsequent improvement in BOO. Numerous studies have been published on TUMT using various devices or technical specifications under different treatment protocols. In one clinical trial, TUMT therapy using the first-generation device Prostasoft^® 2.0 was less effective than TURP in reducing LUTS.²⁵¹ However, TUMT, performed with high-energy delivery systems, including Prostatron^® (Prostasoft 2.5 and 3.5),^252–254 TherMatrx^®, Targis system^®, and CoreTherm^®,^255–257 was comparable to TURP in terms of improving LUTS and QOL over short-term and long-term follow-up periods, although TURP resulted in a greater improvement in Q_max than TUMT.²⁵² Arguments against TUMT as an alternative to TURP include the morbidity associated with TUMT,²⁵⁶ including prolonged catheterization periods,²⁵⁸ a higher incidence of dysuria or urgency,²⁵⁹ and urinary retention.²⁶⁰ Conversely, the incidences of hematuria or clot retention,²⁶¹ blood transfusions, hyponatremia, ED, retrograde ejaculation,^261–263 and urethral stricture are less for TUMT than TURP. The re-treatment rate (surgery or pharmacotherapy) after high-energy TUMT is reported to be 3–6% within 1 year.^264,265 Over longer follow-up periods (up to 5 years), 10–40% of patients required re-intervention.^{257,266–268}

Urethral stent

Recommendation grade: C1

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

Prostatic stents are placed in the prostatic urethra under endoscopic control to dilate the obstructed urethra. Temporary or permanent stents can be used. Long-term data are available regarding the safety and efficacy of permanent urethral stents.²⁶⁹ As their name suggests, temporary stents are used for the treatment of urinary retention after TUMT for short periods.^270,271 The clinical use of permanent stents is limited by significant complications, including encrustation (calcification), discomfort or urethral pain, bleeding, and the migration of the stents.^272–275

Transurethral ethanol ablation of the prostate (TEAP)

Recommendation grade: reserved (not approved)

The efficacy of TEAP has been demonstrated for symptoms and urinary flow rates, although few long-term studies with large numbers of participants and no RCT comparing with standard therapies are available. It is not covered by medical insurance in Japan.

As part of the TEAP procedure, anhydrous ethanol is injected under urethroscopic control into the prostate. The injected ethanol induces coagulation necrosis and a reduction in tissue volume. Several clinical studies have demonstrated significant improvements in symptom scores, QOL, and Q_max over both short-term and long-term follow-up periods.^276–278 Common post-treatment adverse events associated with TEAP include urinary retention, hematuria, and irritative symptoms.^{276,278–280} Bladder necrosis requiring urinary diversion has been reported in two cases.²⁷⁶ The re-intervention rate ranges from 7% after 1 year²⁷⁶ to 40% after 3 years.²⁷⁷ RCT comparing TEAP with standard surgery are required before this procedure can be considered a reasonable alternative treatment for BPH.

Botulinum toxin injection

Recommendation grade: reserved (not approved)

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

Botulinum toxin inhibits ACh release at the neuromuscular junction, causing the paralysis and atrophy of striated and smooth muscles. It also inhibits ganglionic and postganglionic fibers of the autonomic nervous system, inducing tissue atrophy and apoptosis.²⁸¹ Through the latter mechanism, direct intra-prostatic injections of botulinum toxin can be expected to be beneficial in patients with BPH.

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

Erectile dysfunction (ED)

RCT have shown that ED is not caused by α₁-adrenoceptor antagonists⁷ and that these antagonists may even reduce the risk of ED.^291,292 The rates of ED have been reported to be 8.1–30.9% for patients on finasteride^8,293 and the rate of ED was significantly greater for men on dutasteride than on placebo (4.7 vs 1.7%, respectively) during the first 6 months of treatment.²⁹⁴ In a Japanese RCT evaluating dutasteride, the frequency of ED was 2% compared with <1% in the placebo group.²⁸⁶ Other studies have reported rates of ED of 6.96–53.7% in Japanese men on anti-androgens.^121,295

Ejaculatory dysfunction

The rate of ejaculatory dysfunction in men on α₁-adrenoceptor antagonists has been reported to be 0.4–30%,^{7,111,296,297} with the frequency higher in men using α_1A-adrenoceptor antagonists. In men on 5α-reductase inhibitors, the rate of ejaculatory dysfunction has been reported to range between 2.1 and 4.4%^39,116 and anti-androgens have been reported to cause ejaculatory dysfunction in as many as 50% of Japanese men using these drugs.¹¹⁸

Decreased libido

Decreased libido is associated with 5α-reductase inhibitors, with reported rates of 1.0–7.7%,^7,293,298 but not with α₁-adrenoceptor antagonists.⁷ Anti-androgens have been reported to decrease libido in 1.5% of Japanese patients with BPH.¹¹⁸

Inclusion criteria

Exclusion criteria

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 antagonist should be excluded.

Efficacy of treatments in BPH

Standard international criteria to determine the efficacy of treatments for BPH have not been established. Again, we strongly recommend the use of the Japanese criteria.³⁰¹ Briefly, the efficacy of treatment for BPH is also evaluated in four domains: (i) symptoms; (ii) QOL; (iii) function; and (iv) anatomy. The efficacy of treatment is determined as excellent, good, fair, or poor and is assessed using clinical measures 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 Q_max); and (iv) anatomy (ratio of post-treatment : pre-treatment PV [see Table 8]). The overall efficacy is determined as the median of efficacy for three domains, symptoms, QOL, and function.

In addition, to evaluate the efficacy of treatment on symptoms of BPH, changes in the OABSS and CLSS after treatment can be used, with particular emphasis on one of the symptoms of BPH (e.g. nocturia).³⁰² The efficacy of treatment on QOL can be assessed using changes in the BPH impact index, King's health questionnaire, and SF-36, although the criteria for efficacy using these scales have not yet been standardized.