Medical management of BPH

Introduction

Benign prostatic hyperplasia (BPH), also known as benign prostatic hypertrophy, is a histologic diagnosis characterized by proliferation of the prostatic cellular elements, and represents a chronic, progressive disease with important care implications to the healthcare system.¹Donnell RF. Curr Opin Urol. 2011;21(1):22-6.  

BPH becomes clinically relevant when it is associated with bothersome lower urinary tract symptoms (LUTS); nevertheless, the relationship between BPH and LUTS is complex, since not all men with histological BPH will develop significant LUTS, while other men who do not have histological BPH can develop LUTS. Studies have strengthened the relationship between bladder outlet obstruction and benign prostatic enlargement; and LUTS seem to have a wider range of etiologies.^2-42) McConnell JD, Bruskewitz R, et al. N Engl J Med 1998; 338: 557-63.
3) Roehrborn CG, Boyle P, Nickel JC et al. Urology 2002; 60: 434-41.
4) Kirby RS. Prostate Cancer and Prostatic Diseases 1999;2, 62-65.  

The relationship between BPH/LUTS and ageing is well established; the characteristic histological changes of BPH are increasingly more common as men get older. While by the age 50 years up to 50% of men may have histologically distinguished BPH, the reported prevalence increases up to 90% by age 90.⁵Speakman MJ, Kirby RS, Joyce A, et al. BJU Int 2004; 93: 985-90.  ^,6McVary KT. Am J Manag Care 2006; 12: S122-8.  

Mechanisms of BPH symptoms

Obstruction-induced bladder dysfunction contributes significantly to LUTS, and bladder obstruction occurs because of two main mechanisms. The prostate enlarges with prostatic tissue growth, resulting in narrowing of the urethral lumen.⁷Burnett AL, Wein AJ. J Urol. 2006;175:S19-S24.   The enlargement of prostatic tissue depends on the potent androgen dihydrotestosterone (DHT). In the prostate gland, type II 5-alpha-reductase metabolizes circulating testosterone into DHT, which works locally, and binds to androgen receptors in the cell nuclei, potentially resulting in BPH.

Another mechanism is related to the tone of smooth muscle, which encapsulates the prostate, urethra, and prostate stoma, mediated by alpha-adrenergic receptors. Large numbers of alpha-1-adrenergic receptors are located in the smooth muscle of the prostate, as well as in the bladder neck (Figure 1), and their stimulation causes an increase in smooth-muscle tone, thus, worsening symptoms

of obstruction and retention of urine and decreasing the urinary flow rate, and worsen LUTS. Conversely, blockade of these receptors can reversibly relax these muscles, with subsequent relief of LUTS, and this is the target of most commonly used drug classes for BPH (alpha-antagonists, 5-alpha-reductase inhibitors), which focus on reversing these mechanisms.⁸Available at: http://www.medscape.org/viewarticle/440787.  

BPH progression and prognosis

BPH progression is defined as worsening of symptoms, deterioration of urinary flow rate, increase in prostate volume, and outcomes such as acute urinary retention (AUR) and the need for surgery either for AUR or symptoms.⁹Emberton M, Andriole GL, et al. Urology 2003; 61: 267-73.  

In fact, numerous factors, such as age and prostate volume, have been linked with the risk of BPH progression events;^10-1210) Jacobsen SJ, Jacobson DJ, Girman CJ et al. J Urol 1997; 158: 481-7.
11) a. Roehrborn CG, McConnell JD, Lieba M, et al. Urology 1999; 53(3):473-80. b. Roehrborn CG, Boyle P, Bergner D et al. Urology 1999; 54: 662-9. c. Roehrborn CG. Rev. Urol. 2002; 4(Suppl 5):S29-S38. d. Roehrborn CG. Rev. Urol. 2003; 5(Suppl 4):518-27.
12) Pinto F, Racioppi M, Sacco E, et al. Arch Ital Urol Androl. 2009;81(1):1-8.      and, in particular, an increase in symptom severity with increasing age has also been reported in Asian men.¹³Li M-K, Garcia LA, Rosen R. BJU Int 2005; 96: 1339-54.  

Men with a prostate volume of ≥ 30 ml are more likely to suffer from moderate- to-severe symptoms, reduced flow rates, and AUR, compared with men with prostate volume < 30 ml.¹⁴Anderson JB, Roehrborn CG, Schalken JA et al. TEur Urol 2001; 39: 390-9.    Moreover, an enlarged prostate is also predictive of the need for BPH-related surgery; other predictors include reduced urinary flow, increased symptom score and increased bother.

Clinical approach considerations

Though bothersome LUTS are commonly the only determinant for a BPH diagnosis in clinical practice, simple investigations can be highly effective in accurately diagnosing LUTS due to BPH. The American Urological Association (AUA) and the European Association of Urology (EAU) guidelines recommend a series of initial evaluations for men with LUTS suggestive of bladder obstruction (Box 1.).¹⁵Madersbacher S, Alivizatos G, et al. Eur Urol 2004; 46:547-54.  ^,16American Urological Association. Guideline on the Management of Benign Prostatic Hyperplasia (BPH). http://www.auanet.org/guidelines/bph.cfm.   In 2011, AUA published a 2010 update to their Guideline on the Management of BPH.¹⁷McVary KT, Roehrborn CG, Avins AL, et al. J Urol. Mar 17 2011;  

IPSS scoring

AUA developed a tool known as the International Prostate Symptoms Score (IPSS) to measure the symptoms, which are related to both storage and voiding dysfunction (Box 2).¹⁸Barry MJ, Fowler FJ Jr, O’Leary MP, et al. J Urol. 1992;148:1549-1557.  

PSA for enlarged prostate

Serum prostate-specific antigen (PSA) level, closely correlated with prostatic volume, is another useful parameter for determining the risk of BPH progression.¹²Pinto F, Racioppi M, Sacco E, et al. Arch Ital Urol Androl. 2009;81(1):1-8.    Using prostate volume, uroflowmetry, serum PSA, one could estimate the risk of clinical progression.¹⁹Djavan B, Margreiter M, et al. Curr Opin Urol. 2011 Jan;21(1):5-12.  

Extensive data from the placebo arm of the Proscar Longterm Efficacy and Safety Study (PLESS) demonstrated PSA as a strong predictor of an enlarged prostate, or one that is likely to increase in size, in addition to the risk of developing LUTS, poor urinary flow, AUR and ⁄ or BPH related surgery.¹¹a. Roehrborn CG, McConnell JD, Lieba M, et al. Urology 1999; 53(3):473-80. b. Roehrborn CG, Boyle P, Bergner D et al. Urology 1999; 54: 662-9. c. Roehrborn CG. Rev. Urol. 2002; 4(Suppl 5):S29-S38. d. Roehrborn CG. Rev. Urol. 2003; 5(Suppl 4):518-27.  

• 12. Pinto F, Racioppi M, Sacco E, et al. Arch Ital Urol Androl. 2009;81(1):1-8.  

The risk of either needing BPH-related surgery or developing AUR ranged from 8.9% to 22.0% during the 4 years in placebotreated patients stratified by increasing prostate volume and from 7.8% to 19.9% when stratified by increasing serum PSA. Further, receiver operating characteristic curve analyses showed that serum PSA and prostate volume were the most powerful predictors of spontaneous AUR in placebo-treated patients (Figure 2).

The relationship between PSA and prostate growth may vary from one individual to another. A retrospective analysis of 1859 patients showed that 89% of those with a PSA ≥ 1.5 ng / ml had a prostate volume > 30 ml.²⁰Mochtar CA, Kiemeney LA, van Riemsdijk MM et al. Eur Urol 2003; 44: 695-700.   The correlation between PSA and prostate volume has also been demonstrated in Asian men.²¹Chang YL, Lin AT, Chen KK et al. J Urol 2006; 176: 196-9.  ^,22Shim HB, Lee JK, Jung TY et al. Prostate Cancer Prostatic Dis 2007;10:143-8.   Consequently, the data suggest that the correlation between PSA and prostate volume is close enough for serum PSA to be used to estimate the degree of prostatic enlargement.

Pharmacotherapy

There has been a considerable decline in the popularity of surgery in the past to manage symptoms associated with BPH, and this has made medical therapy the most frequently used treatment option in clinical practice.²³Sarma AV, Jacobson DJ, McGree ME et al. J Urol 2005; 173: 2048-53.   In fact, now medical therapy is the first and the most frequently used treatment for BPH; surgical treatments are a second-line option when medical therapy is non effective or when complications are associated.¹²Pinto F, Racioppi M, Sacco E, et al. Arch Ital Urol Androl. 2009;81(1):1-8.   Long et al evaluated an impact of pharmacotherapy on the incidence of transurethral prostatectomy for BPH, and found a decrease of about 51% in the TURPs performed annually.²⁴Long R, Connolly S, Sweeney P. Ir Med J. 2010 Oct;103(9):281-2.  

Goals of therapy in BPH include measurable improvement in quality of life (QOL; through use of the IPSS), amelioration of LUTS, and prevention of serious complications.²⁵Nickel JC. Am J Manag Care. 2006;12(suppl 5):S141-S148.   Drugs use is mainly dependent on the disease severity as well as on the underlying cause; the AUA’s IPSS can have a role here by staging a patient’s disease.

While watchful waiting is recommended in patients with low symptom severity scores, treatment is indicated in patients who have IPSS scores > 7 and are generally considered to have moderate-to-severe LUTS.²⁵Nickel JC. Am J Manag Care. 2006;12(suppl 5):S141-S148.   At this level the cost of the disease would outweigh the cost of treatment; symptom severity at this level is associated with significantly higher costs, more utilization of health care resources, and decreased QOL of patients.

The medical therapeutic options for BPH have evolved significantly over the last three decades, giving rise to the receptor-specific alpha-blockers that comprise the first line of therapy. Typically, alpha-antagonists are the first-line agents, because symptoms progress, owing to their efficacy and rapid response seen upon initiation.⁷Burnett AL, Wein AJ. J Urol. 2006;175:S19-S24.   If symptoms persist, 5-alpha-reductase inhibitors may be added to the regimen.

Alpha-antagonists

A significant component of LUTS secondary to BPH is believed to be related to the smooth-muscle tension, mediated by the alpha-1-adrenergic receptors, in the prostatic tissue. Therefore, alpha-adrenergic receptor-blocking agents should decrease resistance along the bladder neck, prostate, and urethra by relaxing the smooth muscle, and allowing passage of urine. These agents block effects of postganglionic synapses at the smooth muscle and exocrine glands.

Alpha-antagonists are in fact the most effective agents used to treat the moderate-to-severe and bothersome symptoms associated with bladder outlet obstruction secondary to BPH.⁷Burnett AL, Wein AJ. J Urol. 2006;175:S19-S24.   They reduce bladder outlet obstruction by decreasing the alpha-adrenergic tone of the smooth muscle within the prostate, and lessen the symptoms related to urinary storage including frequency, nocturia, urgency, and incontinence – symptoms that are generally reported as the most bothersome with the largest impact on QOL.

Receptor selectivity

Of the 3 subtypes of the alpha-1 receptor, i.e. 1a, 1b, and 1d, the alpha-1a receptor is most specifically concentrated in the bladder neck and prostate, and the alpha-1d in the bladder. About 70% of the subtypes belong to alpha-1a subtype.^26-2826) Yamada S, Ito Y. α(1)- Handb Exp Pharmacol. 2011;(202):283-306.
27) Caine M, Raz S, Zeigler M. Br J Urol. 1975;47:193-202.
28) Price DT, Schwinn DA, Lomasney JW, et al. J Urol. 1993;150:546-551.     Further, considering that the alpha-1a subtype is predominant in the prostate, bladder neck, and urethra, and alpha-1d in the bladder, drugs selective for these receptor subtypes (e.g., Tamsulosin) may have a potential therapeutic advantage of producing relatively less orthostatic hypotension and requiring no gradual uptitration from the initial dosage. Whereas agents which are not receptor subtype specific such as Alfuzosin have higher cardiovascular related side effects such as orthostatic hypotension, and dizziness.²⁹http://www.medscape.com/viewarticle/458899_10/   Another new subtype alpha- 1a receptor selective agent is Silodosin. In a study, patients were randomized to receive Silodosin 4 mg twice daily and Tamsulosin 0.2 mg once daily. The most common adverse event in the Silodosin group was abnormal ejaculation which occurred more often in the Silodosin than in the Tamsulosin group (22.3% vs. 1.6%).³⁰Kawabe K, Yoshida M, Homma Y; Silodosin Clinical Study Group. BJU Int. 2006;98(5):1019-24.  

Tamsulosin with ADS technology (Advanced Delivery System) is a new improved formulation/delivery system of Tamsulosin.

The Innovative ADS technology ensures continuous and consistent Tamsulosin release throughout the entire length of the gastrointestinal (GI) tract including the colon where water is poorly available, unlike conventional Tamsulosin formulations which are dependent on the presence of water in the GI tract to release the active ingredient. Consequently, drug release (and hence absorption) is impeded during the passage of the formulation through the colon where the amount of water is very limited.

This concept results in a more constant exposure to Tamsulosin over 24 hours with a smaller peak-to-trough fluctuation (PTF) than the conventional formulations. It also reduces/eliminates the dependency on food. Tamsulosin with ADS provides a safe once daily treatment of LUTS/BPH and can be given without dose titration, and with reduced risk of orthostatic hypotension.

Benefits of Tamsulosin with ADS technology are:

• 24 hours consistent drug release
• Improved control of nocturia and IPSS score
• Independent of food intake
• Reduced Cmax related side effects

5-alpha-reductase inhibitors

In patients with LUTS and enlarged prostates, 5-alphareductase inhibitors (5ARIs) are believed to be appropriate and effective treatment. EAU guidelines for the management of BPH recommend 5ARIs for the treatment of bothersome LUTS in men with a prostate volume > 30 ml, when there is no absolute indication for surgery.¹⁵Madersbacher S, Alivizatos G, et al. Eur Urol 2004; 46:547-54.   Additionally, 5ARIs should be considered as first line medical treatment in men with symptomatic, progressive BPH as indicated by a prostate volume ≥ 30 ml and / or PSA ≥ 1.5 ng / ml.³¹Bartsch G, Fitzpatrick JM, et al. BJU Int 2004; 93 (Suppl. 1): 27-9.  

5ARIs improve LUTS by decreasing prostate volumes in the presence of BPH.⁷Burnett AL, Wein AJ. J Urol. 2006;175:S19-S24.   Interestingly, they display their effectiveness at long distance decreasing prostate volume; accordingly, patients with larger prostates may achieve a greater benefit. This results in improved symptoms, urinary flow and QOL, and a reduced risk of AUR and BPH-related surgery.¹²Pinto F, Racioppi M, Sacco E, et al. Arch Ital Urol Androl. 2009;81(1):1-8.   Further, maximal reduction in prostate volume may require about six months of therapy.

Two drugs available within this class are Dutasteride and finasteride. The medications differ in their extent of being able to block the 5-alpha-reducatase conversion of testosterone to DHT within the body. While finasteride works only on the 5-alpha-reductase type II enzyme, inhibiting about 70% of the conversion of testosterone to DHT within the body, in contrast, Dutasteride has an affinity for both, type I and type II, 5-alpha-reductase receptors and inhibit both 5-alpha-reductase type I and type II, preventing about 95% conversion of testosterone to DHT.⁷Burnett AL, Wein AJ. J Urol. 2006;175:S19-S24.  

Treatment with Dutasteride results in a greater degree and consistency of DHT suppression than with finasteride. In a study of men with BPH, mean percent decrease in DHT was 98.4 ± 1.2% with 5.0 mg Dutasteride and 94.7 ± 3.3% with 0.5 mg Dutasteride, with less variability than the 70.8 ± 18.3% suppression observed with 5 mg finasteride.³²Clark RV, Hermann DJ, Cunningham GR et al. J Clin Endocrinol Metab 2004; 89:2179-84.  

Effects on symptom scores and symptomatic progression

Dutasteride is safe and effective in terms of the reduction of prostate volume and symptoms, and flow rate improvement during a 24-month study period. Data from phase III studies with Dutasteride showed a 4.5-point improvement in symptoms at 2 years, compared with 2.3 points in the placebo group (p < 0.001).³Roehrborn CG, Boyle P, Nickel JC et al. Urology 2002; 60: 434-41.   There were significant improvements in symptoms from 6 months in the majority of patients, and from 3 months in some subjects. The total prostate and transition zone volumes were reduced by a mean of 25.7% and 20.4%, respectively (Figure 3), and the maximal flow rate improved significantly from 1 month, with an increase of 2.2 ml/s reported at 24 months.

Improvements in symptom scores at the end of a 2-year open-label extension of these studies increased to 6.5 points (p < 0.001 vs. 2 years of Dutasteride treatment). In fact, continuous improvement in symptoms was seen with 4 years of Dutasteride treatment.³³Debruyne F, Barkin J, van Erps P et al. Eur Urol 2004; 46: 488-94.  

Effects on AUR and BPH-related surgery

A reduced relative risk of AUR (57%) and a surgical intervention (48%) was shown with Dutasteride treatment compared with placebo at 2 years (both p < 0.001 vs. placebo); the reduction was maintained to 4 years during the open-label phases of the studies.³Roehrborn CG, Boyle P, Nickel JC et al. Urology 2002; 60: 434-41.  ^,33Debruyne F, Barkin J, van Erps P et al. Eur Urol 2004; 46: 488-94.  

Consideration for patient selection: Effect on PSA

An improved IPSS and peak urinary flow rate was demonstrated in patients having prostate volumes ≥30 ml upon initiating therapy with 5ARIs.³⁴Chapple CR. BJU Int. 2004;94:738-744.   Furthermore, when using an agent in this class, it must be considered that 5ARIs typically decrease a patient’s PSA; the decrease in PSA is typically maximally achieved when the maximal decrease in prostatic volume is noted (about six months).

Nevertheless, even though they reduce serum PSA, this is predictable and more importantly does not jeopardize the diagnostic performance of PSA for detecting prostate cancer. Using doubled PSA values from six months onwards in 5ARI-treated men, and accordingly establishing a new baseline PSA level, would preserve the clinical utility of the PSA test in prostate cancer detection regardless of PSA level.³⁵Andriole GL, Marberger M, Roehrborn CG. J Urol 2006; 175: 1657-62.  ^,36Thompson IM, Chi C, Ankerst DP et al. J Natl Cancer Inst 2006; 98: 1128-33.   Further urologic workup is warranted if PSA levels increase or do not follow this trend.⁷Burnett AL, Wein AJ. J Urol. 2006;175:S19-S24.  

Combination therapy

Guidelines recommend alpha-blockers and 5ARIs, either alone or in combination, among appropriate medical treatment options for BPH/LUTS.³⁷Girman CJ, Jacobsen SJ, Guess HA et al. JUrol 1995; 153: 1510-5.  ^,38Oelke M, Bachmann A, Descazeaud A et al. European Urology Association, 2010.   While the alpha-1-receptor blockers provide rapid symptomatic relief, the 5ARIs target the underlying disease process and provide mid- and long-term symptom relief in addition to a reduction in the risk of progression events such as AUR and BPH-related surgery.³⁹Emberton M, Cornel EB, Bassi PF, et al. Int J Clin Pract. Jul 2008;62(7):1076-86.   Accordingly, the complementary effects provide a sound rationale for combination therapy with 5ARIs / alpha- blockers, which provides greater and more durable benefits.

Combination therapy of α-blocker and 5α-reductase inhibitor was found to result in great benefit for symptom improvement as well as risk reduction of disease progression and complications; the approach has also been demonstrated to be cost-effective owing to its efficacy in halting symptoms and progression of BPH.

In long-term studies in men with enlarged prostates, combination therapy with both alpha-antagonist and 5ARIs has demonstrated clear benefit in preventing disease progression and improving symptoms.⁴⁰Kirby RS, Roehrborn C, Boyle P, et al. Urology. 2003;61:119-126.  

Dutasteride and Tamsulosin

The combination of Dutasteride and Tamsulosin is indicated for BPH in men with an enlarged prostate. The CombAT trial, a 4-year, large-scale global, multicentric, randomized, double-blind, parallel-group study, was designed to investigate the benefits of combination therapy with the dual 5-ARI Dutasteride and the alpha-blocker Tamsulosin in improving symptoms and long-term outcomes in men with moderate-to-severe symptoms of BPH and prostate enlargement.

The investigators intended to assess the symptoms and long-term outcomes (AUR and surgery) as separate primary endpoints at 2 and 4 years, respectively.⁴¹Siami P, Roehrborn CG, et al. Contemp Clin Trials 2007; 28: 770-9.   The trial used additional entry thresholds for prostate volume (≥ 30 ml) and PSA (≥ 1.5 ng / ml) to select patients who are at higher risk of disease progression. Figure 4 shows the mean change IPSS score from baseline, primary endpoint in 4-year CombAT trial.⁴²Barkin J. Patient Prefer Adherence. 2011; 5: 483-490.  

The independent assessment of symptom relief at 2 years and risk of AUR and surgery at 4 years in the CombAT trial allow a more transparent examination of which parameter is contributing to the overall treatment effect. Consequently, the study allows assessment of those patients most likely to benefit from combination therapy, rather than evaluating the role of combination therapy across the entire disease spectrum, and appears contributing to the standard of care shifting towards combined drug therapy in appropriately selected patients, while better defining the role of the alpha-blockers.⁴³Montorsi F, Roehrborn C, Garcia-Penit J, et al. BJU Int. Feb 23 2011;   In 2010 USFDA approved the fixed dose combination of Tamsulosin 0.4 mg and Dutasteride 0.5 mg.

Recently, Haillot et al⁴⁴Haillot O, Fraga A, Maciukiewicz P, et al. Prostate Cancer Prostatic Dis. 2011 Dec;14(4):302-6.   conducted a post hoc analysis of data from a subgroup in the CombAT trial, and provided further evidence to support the use of long-term combination therapy (Dutasteride plus Tamsulosin) in men with moderate-to-severe LUTS because of BPH and prostatic enlargement.

Anticholinergics

Men presenting with LUTS should undergo comprehensive clinical evaluation before BPH is treated, if indicated. Should symptoms fail to resolve, addition of anticholinergic drugs may be considered in the absence of significant postvoid residual urine volumes.⁴⁵Armitage J, Emberton M. Curr Opin Urol. 2008 Jan;18(1):11-5.  

Nevertheless, the concerns that they may predispose to AUR, are associated with anticholinergic side effects and may cause drug-drug interactions (as elderly are on polytherapy) warrants their cautious use and careful patient selection. In fact, men on this therapy who are reporting increased hesitancy or showing signs of increasing postvoid residual urine or clinical evidence of retention should be warned to stop the anticholinergic element of the combination therapy immediately.

Flavoxate in BPH patients with nocturia

Flavoxate hydrochloride, free from the concerns associated with use of anticholinergics, can be used to alleviate the symptoms of LUTS and overactive bladder, in combination with an alpha-1 adrenoreceptor blocker. It is a flavone derivative with smooth muscle relaxing activity which is used for disorders caused by smooth muscle spasms.⁴⁶Ruffmann R, Sartani A. Drugs Exp Clin Res. 1987;13(1):57-62.   The presence of phosphodiestrase enzymes in the prostate and the detrusor muscle of the bladder implies that phosphodiestrase inhibitors like Flavoxate may be appropriate therapy for BPH related LUTS. Kato et al examined the effectiveness of supplemental administration of Flavoxate in patients with BPH whose nocturia was not adequately relieved by an alpha1-adrenoceptor blocker. Patients (n=52) who had ≥ 2 episodes of nocturnal micturition after administration of Tamsulosin hydrochloride or naftopidil for ≥ 4 weeks received 400-600 mg of Flavoxate hydrochloride in addition to an alpha1-adrenoceptor blocker for another 8-12 weeks.⁴⁷Kato S, Kusaka M, Shiroki R, et al. Hinyokika Kiyo. 2008 Mar;54(3):173-7.   The authors found that, with supplemental administration of Flavoxate hydrochloride, significant improvement was observed in the number of nocturnal micturition, total IPSS score, QOL score and BPH impact index. Therefore, supplemental administration of Flavoxate hydrochloride is effective for the improvement of nocturia and QOL in BPH patients having inadequate response with an alpha1-adrenoceptor blocker. In a study by Dash et al, a combination of Tamsulosin with Flavoxate improved IPSS, irritating symptoms and QOL significantly more than taking the alpha blocker alone in patients of LUTS associated with BPH.⁴⁸Dash A, Kumar T, Pandey BL, et al. UroToday Int J. 2010 Aug;3(4).  

Conclusion

BPH is a significant problem affecting the ageing men, and is often associated with bothersome LUTS. In many men the disease presents with a progressive course that can result in complications such as acute AUR and BPH-related surgery. In fact, these complications can be more direct concerns. Further, considering the significant pain, discomfort, and burden associated with AUR and surgery, there is a need for therapeutic approaches that reduce the risk of such progression events while also achieving symptom relief. The approach reflects in the growing medical management of the condition, and is also endorsed by the guidelines.

References

1. Donnell RF. Curr Opin Urol. 2011;21(1):22-6.
2. McConnell JD, Bruskewitz R, et al. N Engl J Med 1998; 338: 557-63.
3. Roehrborn CG, Boyle P, Nickel JC et al. Urology 2002; 60: 434-41.
4. Kirby RS. Prostate Cancer and Prostatic Diseases 1999;2, 62-65.
5. Speakman MJ, Kirby RS, Joyce A, et al. BJU Int 2004; 93: 985-90.
6. McVary KT. Am J Manag Care 2006; 12: S122-8.
7. Burnett AL, Wein AJ. J Urol. 2006;175:S19-S24.
8. Available at: http://www.medscape.org/viewarticle/440787.
9. Emberton M, Andriole GL, et al. Urology 2003; 61: 267-73.
10. Jacobsen SJ, Jacobson DJ, Girman CJ et al. J Urol 1997; 158: 481-7.
11. a. Roehrborn CG, McConnell JD, Lieba M, et al. Urology 1999; 53(3):473-80. b. Roehrborn CG, Boyle P, Bergner D et al. Urology 1999; 54: 662-9. c. Roehrborn CG. Rev. Urol. 2002; 4(Suppl 5):S29-S38. d. Roehrborn CG. Rev. Urol. 2003; 5(Suppl 4):518-27.
12. Pinto F, Racioppi M, Sacco E, et al. Arch Ital Urol Androl. 2009;81(1):1-8.
13. Li M-K, Garcia LA, Rosen R. BJU Int 2005; 96: 1339-54.
14. Anderson JB, Roehrborn CG, Schalken JA et al. TEur Urol 2001; 39: 390-9.
15. Madersbacher S, Alivizatos G, et al. Eur Urol 2004; 46:547-54.
16. American Urological Association. Guideline on the Management of Benign Prostatic Hyperplasia (BPH). http://www.auanet.org/guidelines/bph.cfm.
17. McVary KT, Roehrborn CG, Avins AL, et al. J Urol. Mar 17 2011;
18. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. J Urol. 1992;148:1549-1557.
19. Djavan B, Margreiter M, et al. Curr Opin Urol. 2011 Jan;21(1):5-12.
20. Mochtar CA, Kiemeney LA, van Riemsdijk MM et al. Eur Urol 2003; 44: 695-700.
21. Chang YL, Lin AT, Chen KK et al. J Urol 2006; 176: 196-9.
22. Shim HB, Lee JK, Jung TY et al. Prostate Cancer Prostatic Dis 2007;10:143-8.
23. Sarma AV, Jacobson DJ, McGree ME et al. J Urol 2005; 173: 2048-53.
24. Long R, Connolly S, Sweeney P. Ir Med J. 2010 Oct;103(9):281-2.
25. Nickel JC. Am J Manag Care. 2006;12(suppl 5):S141-S148.
26. Yamada S, Ito Y. α(1)- Handb Exp Pharmacol. 2011;(202):283-306.
27. Caine M, Raz S, Zeigler M. Br J Urol. 1975;47:193-202.
28. Price DT, Schwinn DA, Lomasney JW, et al. J Urol. 1993;150:546-551.
29. http://www.medscape.com/viewarticle/458899_10/
30. Kawabe K, Yoshida M, Homma Y; Silodosin Clinical Study Group. BJU Int. 2006;98(5):1019-24.
31. Bartsch G, Fitzpatrick JM, et al. BJU Int 2004; 93 (Suppl. 1): 27-9.
32. Clark RV, Hermann DJ, Cunningham GR et al. J Clin Endocrinol Metab 2004; 89:2179-84.
33. Debruyne F, Barkin J, van Erps P et al. Eur Urol 2004; 46: 488-94.
34. Chapple CR. BJU Int. 2004;94:738-744.
35. Andriole GL, Marberger M, Roehrborn CG. J Urol 2006; 175: 1657-62.
36. Thompson IM, Chi C, Ankerst DP et al. J Natl Cancer Inst 2006; 98: 1128-33.
37. Girman CJ, Jacobsen SJ, Guess HA et al. JUrol 1995; 153: 1510-5.
38. Oelke M, Bachmann A, Descazeaud A et al. European Urology Association, 2010.
39. Emberton M, Cornel EB, Bassi PF, et al. Int J Clin Pract. Jul 2008;62(7):1076-86.
40. Kirby RS, Roehrborn C, Boyle P, et al. Urology. 2003;61:119-126.
41. Siami P, Roehrborn CG, et al. Contemp Clin Trials 2007; 28: 770-9.
42. Barkin J. Patient Prefer Adherence. 2011; 5: 483-490.
43. Montorsi F, Roehrborn C, Garcia-Penit J, et al. BJU Int. Feb 23 2011;
44. Haillot O, Fraga A, Maciukiewicz P, et al. Prostate Cancer Prostatic Dis. 2011 Dec;14(4):302-6.
45. Armitage J, Emberton M. Curr Opin Urol. 2008 Jan;18(1):11-5.
46. Ruffmann R, Sartani A. Drugs Exp Clin Res. 1987;13(1):57-62.
47. Kato S, Kusaka M, Shiroki R, et al. Hinyokika Kiyo. 2008 Mar;54(3):173-7.
48. Dash A, Kumar T, Pandey BL, et al. UroToday Int J. 2010 Aug;3(4).