1. Aetna considers the following approaches to the treatment of benign prostate hypertrophy (BPH) medically necessary for members with benign prostatic hypertrophy as alternatives to transurethral resection of the prostate (TURP):

    

   1. Alpha adrenergic blockers (alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin)
   2. Hormonal manipulation (including finasteride, dutasteride, and dutasteride plus tamsulosin)
   3. Interstitial laser coagulation of the prostate (ILCP)
   4. Laser prostatectomy
   5. Laser based procedures including contact laser ablation of the prostate (CLAP), holmium laser procedures of the prostate (HoLAP, HoLEP, HoLRP), photoselective laser vaporization of the prostate (PVP), transurethral ultrasound-guided laser induced prostatectomy (TULIP), and visually-guided laser ablation of the prostate (VLAP, also called non-contact laser ablation of the prostate)
   6. Tadalafil (5 mg daily dose) (Note: Some plans exclude coverage of tadalafil; please check benefit plan descriptions)
   7. Transurethral electrovaporization of the prostate (TUVP)
   8. Transurethral incision of the prostate (TUIP)
   9. Transurethral microwave thermotherapy (TUMT)
   10. Transurethral needle ablation (TUNA), also known as transurethral radiofrequency needle ablation (RFNA)
   11. Ultrasonic aspiration.

   See also CPB 0100 - Cryoablation.

2. Aetna considers the UroLume endourethral prosthesis (urethral stent) medically necessary to relieve prostatic obstruction secondary to BPH in men at least 60 years of age, or men under 60 years of age who are poor surgical candidates, and whose prostates are at least 2.5 cm in length.  (Note: UroLume is not intended for temporary use).

   UroLume endourethral prosthesis is also considered medically necessary for the treatment of recurrent bulbar urethral stenoses/strictures when previous therapeutic approaches such as dilation, urethrotomy or urethroplasty have failed (i.e., treatment was ineffective or there is recurrent stricture requiring additional treatment).

   Aetna considers the UroLume endourethral prosthesis experimental and investigational for other indications because its effectiveness for indications other than the ones listed above has not been established.

3. Aetna considers the following approaches for the treatment of BPH to be experimental and investigational because the effectiveness of these interventions has not been established by the peer-reviewed medical literature:
   
   
   1. Absolute ethanol injection (transurethral)
   2. Botulinum toxin
   3. Cryosurgical ablation
   4. Endoscopic balloon dilation of the prostate
   5. Lutenizing hormone-releasing hormone antagonists
   6. Plasma kinetic vaporization (PlasmaKinetic Tissue Management System, Gyrus, Maple Grove, MN)
   7. Prostatic urethral lift
   8. Temporary prostatic urethral stent
   9. Transrectal thermal therapy (including transrectal microwave hyperthermia, transrectal radiofrequency hyperthermia, transrectal electrothermal hyperthermia, and transrectal high-intensity focused ultrasound)
   10. Water-induced thermotherapy (also known as hot-water balloon thermoablation and thermourethral hot-water therapy).

This policy is based primarily on the practice guideline of management of benign prostatic hyperplasia (BPH) from the American Urological Association.  While a number of treatment modalities have been shown to be effective for BPH, it is not yet evident which of these techniques will prove to be superior or which will approach the effectiveness of transurethral resection of the prostate (TURP) in treating BPH.

Temporary stents are designed primarily for short-term use in the treatment of symptomatic BPH, for a duration of 6 months to 3 years (van Dijk and de la Rosette, 2003).  Temporary stents are made of non-absorbable material, which prevents epithelial ingrowth and therefore allows easy removal.  However, this may lead to unintended migration.  Some temporary stents are biodegradable, so that they break down into small fragments, which are excreted through the urethra over time.  Although no explantation of biodegradable stents is required, the excreted fragments may cause urethral obstruction.

According to the guidelines by the American Urological Association (AUA, 2003), "because prostatic stents are associated with significant complications, such as encrustation, infection and chronic pain, their placement should be considered only in high-risk patients, especially those with urinary retention".  AUA guidelines explain: "Clinical trials of temporary prostatic stents are ongoing, and some long-term efficacy and safety studies have been published.  It is unclear whether prostatic stents have applications in men with symptomatic BPH who have not developed urinary retention and whose medical conditions permit other forms of treatment."

One temporary prostatic urethral stent currently in development is the Spanner, which is designed for temporary use (30 days or less) in men with bladder outlet obstruction to reduce elevated post-void residual and improve voiding symptoms.  The stent design is very similar to the proximal 4 to 6 cm portion of a Foley catheter.  It includes a proximal balloon to prevent distal displacement, a urine port situated cephalad to the balloon, and a reinforced stent of various lengths to span most of the prostatic urethra.  There is also a distal anchor mechanism attached by sutures, and a retrieval suture which extends to the meatus and deflates the proximal balloon when pulled.

Corica et al (2004) reported that the Spanner significantly improved voiding function and quality of life among patients with prostatic urethral obstruction (n = 30).  However, in a review on recent developments in the management of symptomatic BPH, Ogiste and colleagues (2003) stated that the role of stents as an intermediary in cases of treatment failure, or as definitive therapy for BPH and its associated problems are still unclear, when compared with newer, minimally invasive options.  Current literature on stents is relatively sparse.  However, recent studies showed that permanent and temporary prostatic urethral stenting are effective in relieving obstruction and urinary retention.  Nevertheless larger controlled clinical studies are needed to demonstrate the real value of this intervention.

Azuyma and Chancellor (2004) commented that although the results of the use of bioabsorbable spiral stents are encouraging, "there are still too many failures."  The authors state that controlled studies are needed to compare bioabsorbable stents with other forms of therapy.

The California Technology Assessment Forum (2002) concluded that water-induced thermotherapy for BPH does not meet CTAF's technology assessment criteria.  The assessment concluded that "[e]xisting studies have not yet demonstrated that WIT results in better health outcomes as much as or more than the established alternative of TURP, TUNA, or microwave thermotherapy."  Furthermore, in a review on minimally invasive therapies for BPH, Naspro et al (2005) noted that "currently, transurethral microwave thermotherapy seems to offer the soundest basis for management of the condition, providing the longest term follow up and the largest numbers of studies completed to date.  Among surgical alternatives, holmium laser enucleation has gained ground as an encouraging new approach, being similar to standard transurethral resection of the prostate, but reducing perioperative morbidity with the same long-term results.  More randomized comparisons correctly conducted need to be undertaken before an accurate general picture is available for the urologist".

Transurethral electrovaporization of the prostate (TUVP) is another alternative, minimally invasive procedures to treat BPH.  This procedure combines electrosurgical vaporization and desiccation to remove obstructive hyperplastic prostatic tissue with minimal morbidity.  It entails a special electrosurgical modification involving a grooved roller electrode with a large surface area and multiple edges of contact; thus allowing high current density to be delivered to an extensive area of tissue to be vaporized.  The device fits standard resectoscopic equipment, and its use requires no special skills other than those needed for conventional TURP.

Fowler et al (2005) compared the clinical and cost-effectiveness of TUVP with TURP.  Men requiring surgery for lower urinary tract symptoms deemed to be due to BPH were recruited from 4 centers in south-east England.  Main outcome measures were the International Prostate Symptom Score (IPSS) and the IPSS quality of life (QOL) question.  Secondary outcome measures included urinary flow rate, post-void urinary volume, prostate volume and pressure-flow urodynamics.  TURP and TUVP were both effective in producing a clinically important reduction in IPSS and positive change in the IPSS QOL question.  The success rate for relief of symptoms was 85 % for TURP and 74 % for TUVP.  Neither the success of the treatment nor the change in aggregated IPSS was significantly different between the groups.  The improvement was sustained to 24 months after treatment with no significant difference between the groups.  The effectiveness of both treatments was also equivalent when assessed through improvement in objective measures of urinary tract function, reduction in prostate size and the change in health questions of SF-36.  The absolute incidence of adverse events was similar between the 2 groups.  The incidence of severe or prolonged bleeding was less with TUVP, as evidenced by the need for blood transfusion and the drop in hemoglobin level 24 hours post-operatively.  This study did not show any significant difference in inpatient stay or use of outpatient resources between the groups.  The authors concluded that TURP and TUVP are equivalently effective in improving the symptoms of benign prostatic enlargement over at least 2 years.  TUVP is associated with less morbidity due to hemorrhage than TURP.  This finding is in agreement with that of the National Institute for Health and Clinical Excellence (2003), which stated that there is adequate support for the use of TUVP, and that of Nohuglu et al (2005) who found that TUVP is as effective as TURP with similar morbidity.  The advantages of TUVP are that the urethral catheter is withdrawn earlier, hospitalization is shorter, and bleeding is less.

Thomas et al (2006) noted that botulinum neurotoxin (BoNT) application recently has been extended to prostate disorders.  While BoNT has shown promising preliminary results for male lower urinary tract symptoms, and translational research suggests novel mechanism of action of BoNT in the prostate, it is important to remember that the application of BoNT in the prostate is not approved by the regulatory agencies and caution should be applied until larger randomized clinical trials are completed.  This is in agreement with the observations of Azzouzi et al (2006) as well as Chuang and Chancellor (2006).

Kuo and Liu (2009) evaluated the effectiveness of BoNT-A in patients with large BPH with an unsatisfactory response to combined alpha-blocker and 5-alpha-reductase inhibitor therapy.  A total of 60 patients with total prostate volume (TPV) of greater than 60 ml with unsatisfactory response to combination medical therapy were randomly assigned to receive add-on intra-prostatic BoNT-A injection (n = 30) or continued medical therapy (control group).  Patients in the treatment group received 200 to 600 U of Botox injected into the prostate.  Outcome parameters including IPSS, quality of life index (QOL-I), TPV, maximum flow rate (Q(max)) and post-void residual (PVR) volume were compared between treatment and control groups at baseline, 6 months and 12 months.  Significant decreases in IPSS, QOL-I and TPV, and increase in Q(max) were observed at 6 months and remained stable at 12 months in the treatment group.  Improvements in IPSS and QOL-I were also observed at 6 months and a decrease in TPV at 12 months was noted in the control group.  However, no significant changes in any parameters except for QOL-I at 6 and 12 months were noted between the treatment and control groups.  Acute urinary retention developed in 3 patients receiving BoNT-A treatment.  Three BoNT-A and 2 medical treatment patients converted to trans-urethral surgery at the end of study.  The authors concluded that the findings of this study showed that add-on prostatic BoNT-A medical treatment can reduce prostate volume and improve lower urinary tract symptom score and QOL-I within 6 months in the treatment of large BPH.  However, the therapeutic effect at 12 months was similar to combination medical treatment.

Oeconomou and Madersbacher (2010) summarized the mechanisms through which BoNT-A could inhibit the progression of BPH and eliminate the lower urinary tract symptoms (LUTS) according to the findings of animal studies.  Furthermore, these researchers reviewed clinical studies to report the safety and effectiveness of intra-prostatic BoNT-A injection according to various injection protocols.  The experimental studies reported induced relaxation of the prostate, atrophy, and reduction in its size through inhibition of the trophic effect of the autonomic system on the prostate gland.  Also, a possible mechanism of reduction in LUTS might take place through inhibition of sensory afferents from the prostate to the spinal cord.  Clinical studies reported symptomatic relief and improvement in the measured parameters during the follow-up period, whereas local or systematic side-effects are rare.  The authors concluded that it should be recognized that, at present, this therapy is still experimental.  Although the results of the clinical studies are encouraging, the level of evidence is low.  Large-scale, clinical, placebo-controlled, randomized studies, including long-term surveillance to document the evidence of this therapy are needed.

In a phase II prospective study, Richter et al (2009) recorded the effectiveness and complications of holmium laser enucleation of the prostate (HoLEP) in the first post-operative year.  Eighty-six of 343 consecutive patients with benign prostatic obstruction (IPSS greater than 10] were treated with the VersaPulse 100-W laser (Lumenis), 2.0 J/50 Hz or 3.2 J/25 Hz.  Pre-operative and post-operative prostate-specific antigen (PSA), Q(max), IPSS, prostate gland volume, and PVR volume were prospectively measured.  The median follow-up time was 8 months (3 to 21).  Median patient age was 71 (50 to 83) years, and mean operating time was 77.5 (9 to 135) mins.  There was only 1 case of significant bleeding.  In 14 of 86 cases (16 %), HoLEP was combined with TURP.  Short-term voiding complaints were expressed by 26.7 % of the questioned patients.  The length of hospital stay was in most cases less than 48 hrs.  IPSS, Q(max), PSA, PVR volume, gland volumes, and QOL improved significantly after 3 months, and all parameters remained unchanged after 12 months.  The re-operation rate within 12 months was 6.8 %.  The authors concluded that the advantage of HoLEP over TURP is the very low bleeding rate and thus a shorter hospital stay and possible out-patient therapy.  In particular, patients with prostate gland volume less than 50 mls profit from HoLEP.  Post-operative voiding complaints are comparable to those with TURP.  Moreover, the authors stated that long-term results are needed to confirm the low re-operation rate.

Erol et al (2009) prospectively evaluated vaporization efficiency of the high-power, 980-nm diode laser for bladder outlet obstruction due to BPH.  A total of 47 consecutive patients were included in the study.  Inclusion criteria were maximal flow rate 12 ml per second or less with voided volume 150 ml or greater, IPSS of 12 or greater, and QOL score 3 or greater.  Patients with a history of neurogenic voiding dysfunction, chronic prostatitis, or prostate or bladder cancer were excluded from analysis.  Pre-operative maximal flow rate, post-void residual urine, IPSS, QOL, International Index of Erectile Function-5, PSA, and prostate volume were compared with values at 3 and 6 months.  Complications were assessed.  Month 3 assessment revealed that the mean (+/- SD) IPSS decreased significantly from 21.93 +/- 4.88 to 10.31 +/- 3.79 (p = 0.0001).  The mean maximal flow rate increased significantly from 8.87 +/- 2.18 to 17.51 +/- 4.09 ml per second (p = 0.0001).  Quality of life score changed considerably compared to baseline.  All of these values showed slight improvement at month 6.  There was no deterioration in erectile function according to the International Index of Erectile Function-5 short form.  Post-void residual urine decreased significantly; reductions in prostate volume and PSA were also significant.  The most common post-operative complications were retrograde ejaculation (13 of 41 patients or 31.7 %) and irritative symptoms (11 of 47 or 23.4 %), which subsided in the maximal flow rate at 2 weeks.  Re-catheterization was necessary in 2 patients due to urinary retention after catheter removal; 2 patients had temporary combined urge and stress incontinence for 2 weeks.  Late bleeding in 1 patient 4 weeks post-operatively resulted in catheterization and irrigation.  The authors concluded that the high-power diode laser provided significant improvements in IPSS and the maximal flow rate with low morbidity.  Thus, these results of prostate vaporization with the high-power diode laser, representing what is to the authors' knowledge the first clinical study in the literature, are encouraging.  The authors stated that further randomized clinical trials are needed to ascertain the role of high-power diode laser as an alternative to TURP or other laser techniques for BPH.

Van Cleynenbreugel et al (2009) presented recent clinical and urodynamic data on trans-urethral photo-selective vaporization of the prostate, and reported on the recent introduction of the 120-W GreenLight laser (GLL) high-performance system.  These researchers noted that recent studies confirm improved urodynamic findings following GLL treatment.  Moreover, it can be used safely in high-risk patients (e.g., those on anti-coagulant medication and patients with cardiopulmonary diseases), and has been proposed as an alternative to prostate enucleation for larger glands.  The introduction of the 120-W high-performance system GLL does, however, place distinct demands on training and operative schemes.  The authors concluded that the clinical results of GreenLight prostate vaporization are equivalent to those following TURP, with reduced operative risks, even for the high-risk patient.  These clinical benefits have been confirmed by improved urodynamic parameters.  Moreover, they noted that the potential advantages of the new 120-W high-performance system GLL have yet to be validated in larger randomized trials.

Ruszat et al (2008) evaluated the intermediate-term clinical effectiveness and the rate of complications in 80-W photo-selective vaporization of the prostate (PVP) with the potassium-titanyl-phosphate laser (GreenLight, Minnetonka, MN) compared with TURP in a prospective non-randomized 2-center study.  A total of 396 patients (PVP = 269, TURP = 127) with lower urinary tract symptoms secondary to BPH were included in the study.  There was a significant difference in mean age (72 years for PVP versus 68 for TURP, p = 0.001).  Patients were therefore stratified in age categories (less than 70, 70 to 80, greater than 80 years) and compared for peri-operative variables, functional outcome and complications, with a follow-up of up to 24 months.  The mean prostate size was greater (overall, 62 versus 48 mls, p < 0.001) and mean operative duration longer (overall 72 versus 53 mins; p = 0.001) for PVP in all age categories.  The rate of intra-operative bleeding (3 % versus 11 %), blood transfusions (0 % versus 5.5 %) and capsule perforations (0.4 % versus 6.3 %), and early post-operative clot retention (0.4 % versus 3.9 %) was significantly lower for PVP.  Hospitalization time was significantly shorter in the PVP group for patients aged less than 70 years (3.0 versus 4.7 days) and 70 to 80 years (4.0 versus 5.0 days; p = 0.001).  The improvement of peak urinary flow rate was higher after TURP for any age category.  The IPSS and PVR volume during the follow-up showed no significant difference.  After 12 months, the overall prostate size reduction was 63 % (-30 mls) after TURP and 44 % (-27 mls) after PVP.  The rate of repeat TURP/PVP was higher in the PVP group (6.7 % versus 3.9 %, not significant) within the follow-up of up to 2 years.  The incidence of urethral and bladder neck strictures was comparable.  The authors concluded that PVP was more favorable in terms of peri-operative safety.  Although patients assigned for PVP were older and had larger prostates, PVP resulted in a similar functional outcome.  They stated that further follow-up is needed to draw final conclusions about the long-term effectiveness of PVP.

Naspro and colleagues (2009) noted that HoLEP and 532-nm laser vaporization of the prostate (with potassium titanyl phosphate [KTP] or lithium borate [LBO]) are promising alternatives to TURP and open prostatectomy (OP).  These investigators evaluated the safety, effectiveness, and durability by analyzing the most recent evidence of both techniques, aiming to identify advantages, pitfalls, and unresolved issues.  A Medline search of recently published data (2006 to 2008) regarding both techniques over the last 2 years (January 2006 to September 2008) was performed using evidence obtained from randomized trials (level of evidence: 1b), well-designed controlled studies without randomization (level of evidence: 2a), individual cohort studies (level of evidence: 2b), individual case control studies (level of evidence: 3), and case series (level of evidence: 4).  In the last 2 years, several case-control and cohort studies have demonstrated reproducibility, safety, and effectiveness of HoLEP and 80-W KTP laser vaporization.  Four randomized controlled trials (RCTs) were available for HoLEP, 2 compared with TURP and 2 compared with OP, with follow-up greater than 24 months.  Results confirmed general effectiveness and durability of HoLEP, as compared with both standard techniques.  Only 2 RCTs were available comparing KTP laser vaporization with TURP with short-term follow-up, and only 1 RCT was available comparing KTP laser vaporization with OP.  The results confirmed the overall low peri-operative morbidity of KTP laser vaporization, although effectiveness was comparable to TURP in the short-term, despite a higher re-operation rate.  The authors concluded that although they are at different points of maturation, KTP or LBO laser vaporization and HoLEP are promising alternatives to both TURP and OP; KTP laser vaporization needs further evaluation to define the re-operation rate.  Increasing the number of quality prospective RCTs with adequate follow-up is mandatory to tailor each technique to the right patient.

Chung and Te (2009) stated that traditionally, the gold standard for treatment of BPH has been the electrocautery-based TURP.  However, the number of laser techniques being performed is rapidly increasing.  Potential advantages of laser therapy over traditional TURP include decreased morbidity and shorter hospital stay.  There are several techniques for laser prostatectomy that continue to evolve.  The main competing techniques are currently the HoLEP and the 80-W 532-nm laser prostatectomy.  The HoLEP, using the Holmium:YAG laser, has been shown to have clinical results similar to TURP and is suitable for patients on anti-coagulation as well as those with large prostates.  Disadvantages of this technique are the high learning curve and requirement of a morcellator.  When used to treat BPH, studies have demonstrated that, like the HoLEP, the 80-W KTP laser is safe and effective in patients with large prostates and in those taking oral anti-coagulation.  Several studies have compared these 2 techniques to TURP.  Frequently reported advantages of the HoLEP over the 80-W laser prostatectomy are the availability after the procedure of a pathology specimen and ability to remove a higher percentage of prostate tissue during resection.  However, the trans-urethral laser enucleation of the prostate addresses these concerns and has shown to have durable outcomes at 2-year follow-up.  Two new laser systems and techniques, the thulium laser and the 980-nm laser, have emerged recently.  However, clinical data from these procedures are in their infancy and large long-term studies are needed to ascertain their clinical effectiveness.

Lourenco and colleagues (2008) ascertained the clinical effectiveness and cost utility of procedures alternative to TURP for BPH unresponsive to expectant, non-surgical treatments.  Electronic searches of 13 databases to identify relevant RCTs were carried out.  Two reviewers independently assessed study quality and extracted data.  The International Prostate Symptom Score/American Urological Association (IPSS/AUA) symptom score was the primary outcome; others included QOL, peak urine flow rate and adverse effects.  Cost-effectiveness was assessed using a Markov model reflecting likely care pathways.  A total of 156 reports describing 88 RCTs were included.  Most had fewer than 100 participants (range of 12 to 234).  It was found that TURP provided consistent, high-level, long-term symptomatic improvement.  Minimally invasive procedures resulted in less marked improvement.  Ablative procedures gave improvements equivalent to TURP.  Furthermore, HoLEP resulted in greater improvement in flow rate.  Holmium laser enucleation of the prostate is unique amongst the newer technologies in offering an advantage in urodynamic outcomes over TURP, although long-term follow-up data are lacking.  Severe blood loss was more common following TURP.  Rates of incontinence were similar across all interventions other than TUNA and laser coagulation, for which lower rates were reported.  Acute retention and re-operation were commoner with newer technologies, especially minimally invasive interventions.  The economic model suggested that minimally invasive procedures were unlikely to be cost-effective compared with TURP.  Transurethral vaporization of the prostate was both less costly and less effective than TURP; whereas HoLEP was estimated to be more cost-effective than a single TURP but less effective than a strategy involving repeat TURP, if necessary.  The base-case analysis suggested an 80 % chance that TUVP, followed by HoLEP if required, would be cost-effective at a threshold of 20,000 pounds per quality-adjusted life-year.  At a 50,000 pounds threshold, TUVP, followed by TURP as required, would be cost-effective, although considerable uncertainty surrounds this finding.  The main limitations are the quantity and quality of the data available, in the context of multiple comparisons.   The authors concluded that in the absence of strong evidence in favor of newer methods, the standard -- TURP -- remains both clinically effective and cost-effective.  There is a need for further research to establish (i) how many years of medical treatment are necessary to offset the cost of treatment with a minimally invasive or ablative intervention; (ii) more cost-effective alternatives to TURP; and (iii) strategies to improve outcomes after TURP.

Hashim and Abrams (2010) noted that benign prostatic enlargement (BPE) leading to benign prostatic obstruction (BPO) affects an increasing number of men as they grow older.  They can affect QOL and cause LUTS including urinary retention.  The currently available pharmacotherapies are alpha-blockers and 5-alpha reductase inhibitors, which may be effective but can have adverse effects and long-term compliance problems.  Thus, it is important to find new medical treatments for LUTS/BPO and this review aimed to identify the potential future drugs undergoing clinical trials in this field.  Articles were identified by means of a computerized Google, PubMed and Cochrane Library search over the last 10 years (using the following keywords: benign prostate hyperplasia, enlargement and obstruction) and a search of the PharmaProjects database.  The exact etiology of BPH and its consequences, BPE and BPO, are not known; however, aging and functioning testes have been implicated.  Several classes of drugs are currently undergoing clinical trials such as phosphodiesterase-5 (PDE5) inhibitors and lutenizing hormone-releasing hormone antagonists.  Others include phytoestrogens, progestogens, NX1207 and PRX302.  Some of these work by affecting testosterone level and, therefore, on the static component of BPO, while it is not known how the rest work.  The authors stated that until the exact etiology of BPH/BPE/BPO is known, it is unlikely the cure for this disorder will be found.

Wang (2010) examined the use of PDE5 inhibitors for BPH/LUTS treatment and highlighted the clinical significance.  Pre-clinical and clinical studies have provided promising evidence that PDE5 inhibitors may be an effective and well-tolerated treatment option for BPH/LUTS.  Combination therapy using PDE5 inhibitors and alpha1-adrenergic blockers resulted in greater improvements in BPH/LUTS than did either drug alone.  There has been increasing interest in the use of PDE5 inhibitors to treat BPH/LUTS.  Combination of PDE5 inhibitors and alpha1-adrenergic blockers may have an additive beneficial effect on BPH/LUTS compared with monotherapy.  Mechanisms of action of nitric oxide/cyclic guanosine monophosphate/PDE5 pathway in the treatment of BPH/LUTS deserve further investigations.  The author concluded that larger-scale, well-designed clinical trials are needed to ascertain the safety, effectiveness and cost-effectiveness of PDE5 inhibitors in the treatment of LUTS secondary to BPH.

Andersson et al (2011) reviewed the published literature describing the pathophysiology of male LUTS, with an emphasis on mechanisms that may be modulated or improved by PDE5 inhibition.  Literature (through March 2010) was obtained via Medline searches and from the individual reviewers files.  Articles were selected for review based on describing in-vitro, pre-clinical, or clinical studies of pathological processes contributing to LUTS, or possible effects of PDE5 inhibition in the lower urinary tract.  Major mechanisms contributing to LUTS include: reduced nitric oxide/cyclic guanosine monophosphate signaling; increased RhoA kinase pathway activity; autonomic over-activity; increased bladder afferent activity; and pelvic ischemia.  Tadalafil and other PDE5 inhibitors have demonstrated beneficial effects on smooth muscle relaxation, smooth muscle and endothelial cell proliferation, nerve activity, and tissue perfusion that may impact LUTS in men.  The authors concluded that the pathophysiology of male LUTS is complex and not completely understood.  LUTS may occur independently of BPH or secondary to BPH but in both cases involve obstructive or irritative mechanisms with substantial pathophysiological overlap.  While the precise mechanism remains unclear, inhibition of PDE5 seems to have an effect on several pathways that may impact LUTS.

On October 6, 2011, the FDA approved tadalafil (Cialis) for the treatmentof of BPH, and for the treatment of BPH and erectile dysfunction (ED), when the conditions occur simultaneously.  Tadalafil should not be used in patients taking nitrates (e.g., nitroglycerin) because the combination can cause an unsafe decrease in blood pressure.   Also, the use of tadalafil in combination with alpha blockers for the treatment of BPH is not recommended because the combination has not been adequately studied for the treatment of BPH, and there is a risk of lowering blood pressure.  In 2 clinical trials, men with BPH who took 5 mg of tadalafil once-daily experienced a statistically significant improvement in their symptoms of BPH compared to men who were treated with placebo.  The trials based their findings on a reduction in total IPSS scores.  In a 3rd study, men who experienced both erectile dysfunction (ED) and BPH and who took 5 mg of tadalafil once-daily had improvement in both their symptoms of BPH and in their ED compared to men who were treated with placebo.  The improvement in ED was measured using the Erectile Function domain score of the International Index of Erectile Function.

Chin et al (2012) evaluated the effectiveness of the prostatic urethral lift in relieving LUTS secondary to BPH.  A total of 64 men, aged greater than or equal to 55 years, with moderate-to-severe symptomatic BPH were treated and followed-up at 6 Australian institutions.  The treatment consisted of transurethral delivery of small implants to secure the prostatic lobes in an open condition, thereby reducing obstruction of the urethral lumen.  The effectiveness, including International Prostate Symptom Score, quality of life, benign prostatic hyperplasia Impact Index, and peak urethral flow rate were assessed at 2 weeks and 3, 6, 12, and 24 months.  The effect of this treatment on erectile and ejaculatory function was assessed using the Sexual Health Inventory for Men and Male Sexual Health Questionnaire for Ejaculatory Dysfunction.  The prostatic urethral lift improved LUTS symptoms rapidly and durably.  The International Prostate Symptom Score was reduced 42 % at 2 weeks, 49 % at 6 months, and 42 % at 2 years in evaluable patients.  The peak flow rate improved by greater than or equal to 30 % (2.4 ml/s) at all intervals compared with baseline.  No compromise in sexual function was observed after this treatment.  The authors concluded that the present study demonstrated that LUTS and flow improvements without compromising sexual function.  They noted that although this was an early study with a small cohort, this therapy shows promise as a new option for patients with LUTS.