Should Combination Therapy be Standard for Benign Prostatic Hyperplasia?

Benign Prostatic Hyperplasia and the ageing men

Nonmalignant enlargement of the prostate gland is referred to as Benign Prostatic Hyperplasia (BPH).¹Dhingra N, Bhagwat D. Benign prostatic hyperplasia: An overview of existing treatment. Indian Journal of Pharmacology. 2011;43(1):6-12.   It is considered a strictly age-related phenomenon that manifests in nearly all males over 40 years of age.A review of autopsy data suggests that almost 10% men develop histologic BPH in the third decade of their life, 20% in their fourth decade, 50-60% in their sixth decade, and 80-90% in their seventh and eighth decades of life.²Roehrborn CG. Benign Prostatic Hyperplasia: An Overview. Reviews in Urology. 2005;7(Suppl 9):S3-S14.   The prevalence of BPH still remains underestimated, attributable to its asymptomatic nature.³Costa P, Ben Naoum K, Boukaram M, Wagner L, Louis JF. Benign prostatic hyperplasia (BPH): prevalence in general practice and practical approach of French general practitioners. Results of a study based on 17,953 patients. Prog Urol. 2004 Feb;14(1):33-9.   However, upon the onset of subjective symptoms, the condition becomes a clinical entity.²Roehrborn CG. Benign Prostatic Hyperplasia: An Overview. Reviews in Urology. 2005;7(Suppl 9):S3-S14.   The development of these symptoms in part is related to the underlying pathophysiological processes, which also influence the degree of prostate enlargement.⁴Lepor H. Pathophysiology, Epidemiology, and Natural History of Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 9):S3-S10.  

Mechanisms contributing to development of Benign Prostatic Hyperplasia symptoms

Benign Prostatic Hyperplasia involves hyperplasia of stromal and glandular epithelium in the transition zone of the prostate surrounding the urethra.1 It is characterized by increase in prostate volume and stromal smooth muscle tone, termed as static and dynamic component, respectively. The resultant periurethral expansion exerts forces that may cause physical compression of the urethra, leading to anatomic bladder outlet obstruction (BOO).

Symptoms and their prevalence

Clinically, the condition may present as lower urinary tract symptoms (LUTS), urinary tract infections, acute urinary retention, renal failure hematuria, and bladder calculi.⁵Patel ND, Parsons JK. Epidemiology and etiology of benign prostatic hyperplasia and bladder outlet obstruction. Indian Journal of Urology: IJU: Journal of the Urological Society of India. 2014;30(2):170-176.   LUTS complex commonly affect around 15-60% of men older than 40 years of age, which may be categorized as obstructive and irritative symptoms.²Roehrborn CG. Benign Prostatic Hyperplasia: An Overview. Reviews in Urology. 2005;7(Suppl 9):S3-S14.  ⁶Parsons JK. Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: Epidemiology and Risk Factors. Current Bladder Dysfunction Reports. 2010;5(4):212-218.   Obstructive symptoms consist of hesitancy, straining,weak flow, prolonged voiding, partial or complete urinary retention, and overflow incontinence. The irritative symptoms are often more bothersome and include frequency, urgency with urge incontinence,nocturia, painful urination, and small voided volumes.As the age increases, prevalence rates of LUTS are also known to rise steadily. It is considered by many to be age-related and men usually learn to live with it. Besides, the elderly individuals also experience increase in size of the prostate, referred to as benign prostatic enlargement (BPE); ranging from 25-30 g for men in their 40s, 30-40 g for men in their 50s, to 35-45 g for men in their 60s, across various racial and ethnic groups. However, it may also be noted that men with histologic BPH may not necessarily develop BPE, as depicted in Figure 1. Similarly, LUTS or other annoying symptoms may not always be associated with concomitant BPE. Even individuals with normalized prostate may experience these symptoms, while those with enlarged one may complain of only few, if any, symptoms.²Roehrborn CG. Benign Prostatic Hyperplasia: An Overview. Reviews in Urology. 2005;7(Suppl 9):S3-S14.   These features impair the quality of life, and are associated with anxiety and depression, which warrants frequent clinical assessment in all men aged around 50 years.⁷Tanguay S, Awde M, Brock G, Casey R, Kozak J, Lee J, Nickel JC, Saad F. Diagnosis and management of benign prostatic hyperplasia in primary care. Canadian Urological Association Journal. 2009;3(3 Suppl2):S92-S100.  

Clinical approach to patients with Benign Prostatic Hyperplasia symptoms

Making an earlier and timely diagnosis of BPH facilitates implementation of effective management strategies. This is also critical in reassuring the patients that the condition is a treatable disorder,and not a precursor to prostate cancer, which is a common concern.⁷Tanguay S, Awde M, Brock G, Casey R, Kozak J, Lee J, Nickel JC, Saad F. Diagnosis and management of benign prostatic hyperplasia in primary care. Canadian Urological Association Journal. 2009;3(3 Suppl2):S92-S100.   During the diagnostic evaluation of men with LUTS, the primary objective is to rule out other associated causes of urological and nonurological origin that may mimic BPH (Table 1), while the secondary objective remains the assessment of symptom severity.⁸Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.   The evaluation of an affected patient comprises a careful history taking and physical examination, including digital rectal and neurological examinations, symptom scoring (including quality of life and sexual score), and measurement of serum prostate specific antigen (PSA).⁹Bhargava S, Canda AE, Chapple CR. A rational approach to benign prostatic hyperplasia evaluation: recent advances. Curr Opin Urol.2004 Jan;14(1):1-6.   The decision on whether the patient should be subjected to surgery or be put on medical therapy depends on severity of symptoms, ultrasound findings and severity of obstruction as indicated on uroflow studies.

History and examination

A thorough history is a crucial component of BPH evaluation as it throws light on associated illnesses,such as episodes of hematuria, urinary tract infections,tuberculosis, diabetes, nervous system and nervous disorders (Parkinson’s disease or stroke), prior radiation or pelvic surgery, urethral stricture disease,and urinary retention.⁸Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.   Moreover, medications may also aggravate the LUTS symptoms, such as cold or sinus medications, and should not be overlooked (Table 1).⁷Tanguay S, Awde M, Brock G, Casey R, Kozak J, Lee J, Nickel JC, Saad F. Diagnosis and management of benign prostatic hyperplasia in primary care. Canadian Urological Association Journal. 2009;3(3 Suppl2):S92-S100.  ⁸Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.   Symptom scoring instruments have been developed for the baseline assessment of symptom severity in men presenting with LUTS, judgment of treatment response or even disease progression.The two most commonly used instruments are the International Prostate Symptom Score (IPSS) and the American Urological Association (AUA) symptom score. Use of IPSS highlights the global impact of LUTS on quality of life by categorizing symptoms as mild (score 0-7), moderate (score 8-19), or severe (score 20-35). However, it cannot contribute to the diagnosis of BPH specifically, as a variety of lower urinary tract disorders (such as infection, tumor, neurogenic bladder disease) also demonstrate higher IPSSs.⁸Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.   The diagnostic value is however increased when detailed history is combined with meticulous examination.

Rectal examination is considered important in providing essential information in patients with voiding dysfunction. The anal area is inspected followed by assessment of rectal sphincter tone by insertion of the examining finger. This reveals the functional status of the somatic, sensory, and motor components of the sacral reflex arc and indirectly determines the parasympathetic input to the lower urinary tract.¹⁰McVary KT. Clinical Evaluation of Benign Prostatic Hyperplasia. Reviews in Urology. 2003;5(Suppl 4):S3-S11.   Moreover, the digital rectal and neurological examinations also aid in detecting prostate/rectal malignancy and the presence of any related neurological problems. Although digital rectal examination provides an approximate size of the prostate gland, it does not aid in deciding whether active treatment is required. However, an estimate of the prostate size does influence the selection of an appropriate therapeutic strategy, such as pharmacotherapy or transurethral/ open prostatectomy.⁸Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.   Besides, the symmetry and consistency of the prostate is also recorded along with presence of any nodules or induration.¹⁰McVary KT. Clinical Evaluation of Benign Prostatic Hyperplasia. Reviews in Urology. 2003;5(Suppl 4):S3-S11.  

Investigations

Laboratory investigations include tests that may add to the diagnostic accuracy and aid in formulating the final clinical impression. These broadly encompass blood and urine analyses, urodynamic evaluation,selected radiologic and ultrasound imaging studies,and cystourethroscopy.¹⁰McVary KT. Clinical Evaluation of Benign Prostatic Hyperplasia. Reviews in Urology. 2003;5(Suppl 4):S3-S11.   Urine should be analyzed for glucose, protein, occult blood, and pH with a multiparameter dipstick. This helps in screening of urinary tract infections, bladder cancer, and stones.⁷Tanguay S, Awde M, Brock G, Casey R, Kozak J, Lee J, Nickel JC, Saad F. Diagnosis and management of benign prostatic hyperplasia in primary care. Canadian Urological Association Journal. 2009;3(3 Suppl2):S92-S100.  ¹⁰McVary KT. Clinical Evaluation of Benign Prostatic Hyperplasia. Reviews in Urology. 2003;5(Suppl 4):S3-S11.   The AUA guideline recommends measurement of serum creatinine and PSA as important diagnostic parameters.¹⁰McVary KT. Clinical Evaluation of Benign Prostatic Hyperplasia. Reviews in Urology. 2003;5(Suppl 4):S3-S11.  

Measurement of PSA levels is preferred before rectal examination in men who have at least a 10-year life expectancy and who would be a candidate for prostate cancer treatment.¹⁰McVary KT. Clinical Evaluation of Benign Prostatic Hyperplasia. Reviews in Urology. 2003;5(Suppl 4):S3-S11.   ¹¹Edwards JL. Diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2008 May 15;77(10):1403-10.   PSA demonstrates near to accurate prostate volume that corresponds with the risk of symptom progression.⁷Tanguay S, Awde M, Brock G, Casey R, Kozak J, Lee J, Nickel JC, Saad F. Diagnosis and management of benign prostatic hyperplasia in primary care. Canadian Urological Association Journal. 2009;3(3 Suppl2):S92-S100.   It is estimated that greater PSA levels, such as >1.6 ng/mL,>2.0 ng/mL, and >2.3 ng/mL for men in their fifties, sixties, and seventies are 70% sensitive and 70% specific for a prostate volume >40 mL.¹¹Edwards JL. Diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2008 May 15;77(10):1403-10.   Assessment of prostate volume is imperative, as it is a risk factor for acute urinary retention, and may suggest the need for BPH-related surgery. Herein, the ability of PSA to strongly predict prostate growth contributes to selection of most appropriate therapy. This has shifted the focus towards a more comprehensive and prognostic approach, preventing the risk factors of BPH-related outcomes.¹²Roehrborn CG, McConnell J, Bonilla J, Rosenblatt S, Hudson PB, Malek GH, Schellhammer PF, Bruskewitz R, Matsumoto AM, Harrison LH,Fuselier HA, Walsh P, Roy J, Andriole G, Resnick M, Waldstreicher J.Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study. J Urol. 2000 Jan;163(1):13-20.   If results of urinalysis,digital rectal examination or PSA levels are abnormal,additional testing is warranted.⁸Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.  

A number of noninvasive tests have been developed, such as residual urine and urine flow rates.Assessment of residual urine through an ultrasound is a common urodynamic study. It aids in evaluation of bladder function, diagnostic inquiry, and assessment of treatment efforts. However, failure in measurement of the volume and use of this information makes the practice questionable. On the other hand,uroflowmetry (or uroflow) is an electronic recording of the urinary flow during 1 voiding episode that provides an average flow rate (Q_ave), maximum flow rate (Q_max), the maximum recorded flow rate, volume voided, time to maximum flow rate, total flow time, and urinary flow pattern (Figure 2). It offers a simple,noninvasive, and useful means of detecting BOO.

Despite this, the outcomes of this test have been variable for many causes, such as for an enlarged BPH-associated prostate, urethral stricture, meatal stenosis, and weakness of the detrusor muscle itself.The presence and effect of bladder neck obstruction from BPH can be confirmed by cystourethroscopy. It also identifies the configuration and site of obstructive tissue, but not its physiological effect. The latter can be examined by establishing residual urine and presence and degree of trabeculation and bladder pathology (such as diverticula and stones). Use of cystography and retrograde and voiding urethrography can at times prove critical in evaluation of bladder or urethral diverticula.¹⁰McVary KT. Clinical Evaluation of Benign Prostatic Hyperplasia. Reviews in Urology. 2003;5(Suppl 4):S3-S11.   Once the condition has been diagnosed,treatment is instituted based upon the severity of symptoms. Men presenting with mild symptoms are kept under observation and are assessed annually.As the symptoms worsen, treatment is initiated to effectively relieve the symptoms of BPH.¹¹Edwards JL. Diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2008 May 15;77(10):1403-10.  

Treatment approach to patients with Benign Prostatic Hyperplasia symptoms

The range of therapeutic interventions for treatment of BPH is as broad as the spectrum of its symptoms.Yet, the best individualized care is preferred, aiming to identify patients at risk of unfavorable outcomes and to ameliorate bothersome LUTS. The treatment goals for BPH also emphasize on relieving the patients of associated morbidities, such as urinary retention,persistent gross hematuria, recurrent infections,bladder stones, or renal insufficiency, and to optimize their management strategy.¹³Gonzalez RR, Kaplan SA. First-line treatment for symptomatic benign prostatic hyperplasia: is there a particular patient profile for a particular treatment? World J Urol. 2006 Sep;24(4):360-6.   ¹⁴Roehrborn CG. BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE. BJU Int. 2008 Mar;101 Suppl 3:17-21.  

An extensive review of LUTS symptoms, digital rectal examination, urinalysis, and serum PSA measurement guides therapeutic decision-making. Watchful waiting can be considered a reasonable option if the patient’s symptoms are not bothersome.In cases with distressing symptoms, medical therapy as first-line intervention [such as alpha-blockers and 5-alpha-reductase inhibitors (5ARIs)] is administered and annual observation is recommended (Table 2).If response to medical therapy is poor, the condition may be re-assessed through uroflowmetry, postvoid residual urine volume (PVR) measurement, and a urodynamic pressure-flow study. Anticholinergic therapy is preferred in cases with normal PVR and absence of BOO, especially when the findings are suggestive of an overactive bladder. On the other hand, if PVR is high, surgical intervention may be considered, even if there is no BOO (Figure 3).⁸Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.   However, in all cases, the patient must be informed of all the treatment alternatives available (Table 2) and the risks and benefits of each therapy should be weighed, promoting shared decision-making process.¹³Gonzalez RR, Kaplan SA. First-line treatment for symptomatic benign prostatic hyperplasia: is there a particular patient profile for a particular treatment? World J Urol. 2006 Sep;24(4):360-6.   ¹⁵American urological association guideline: management of benign prostatic hyperplasia (BPH). Available at: http://www.auanet.org/ education/guidelines/benign-prostatic-hyperplasia.cfm. Accessed on:19.9.16.  

Alpha-adrenergic receptor antagonists:Focus on efficacy of Tamsulosin

Alpha-adrenergic receptor antagonists or alphablockers remain the mainstay in the treatment of symptomatic BPH. These drugs are considered to block the alpha-adrenergic receptors, which regulate the tension of smooth muscles of prostate, responsible for BOO. Since BOO often causes enlarged prostate via dynamic (functional obstruction) and static mechanisms (bulk enlargement), these agents relax the prostate smooth muscles, thereby effectively improving the resultant symptoms. The US Food and Drug Administration (FDA) has approved 4 alphaadrenergic receptor antagonists for the treatment of LUTS, namely terazosin, doxazosin, tamsulosin, and alfuzosin. All these agents are long-acting alpha-1-blockers, well-tolerated, and demonstrate comparable dose-dependent effectiveness.¹⁶Sandhu JS. Therapeutic options in the treatment of benign prostatic hyperplasia. Patient preference and adherence. 2009;3:213-223.   ¹⁷Lepor H. Alpha Blockers for the Treatment of Benign Prostatic Hyperplasia. Reviews in Urology. 2007;9(4):181-190.  

Tamsulosin is a uroselective alpha-blocker and shows 20 to 38-fold greater ∝1A subtype adrenergic receptor selectivity in comparison to ∝1B receptors.This particular feature of tamsulosin explains its favorable tolerability profile as it exhibits lower cardiovascular side effects and lacks interaction with antihypertensives. It has been in use for over more than a decade and was amongst the first drugs developed specifically to treat BPH-associated LUTS.¹⁸Narayan P, Tunuguntla HSGR. Long-Term Efficacy and Safety of Tamsulosin for Benign Prostatic Hyperplasia. Reviews in Urology. 2005;7(Suppl 4):S42-S48.   It acts by relaxing smooth muscles in the prostate and bladder neck, which facilitates bladder emptying. As a result, the obstructive voiding symptoms improve by at least 25% in up to 80% of patients with symptomatic BPH. This not only reduces PVR, but also displays a beneficial effect on peak urinary flow rate.¹⁹Lee M. Tamsulosin for the treatment of benign prostatic hypertrophy.Ann Pharmacother. 2000 Feb;34(2):188-99.   Chapple and coworkers²⁰Chapple CR, Wyndaele JJ, Nordling J, Boeminghaus F, Ypma AF, Abrams P. Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A meta-analysis of two randomized, placebo-controlled,multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group. Eur Urol.1996;29(2):155-67.   have also demonstrated its efficacy in improving storage or irritative symptom scores,even in patients with benign prostatic obstruction.In comparison to placebo, use of tamsulosin was associated with improvement in other urological parameters as well, depicted in Figure 4. The usual dosage of tamsulosin in clinical practice is 0.4 or 0.8 mg, administered orally as a single daily dose.¹⁹Lee M. Tamsulosin for the treatment of benign prostatic hypertrophy.Ann Pharmacother. 2000 Feb;34(2):188-99.   Studies have revealed that at this usual dose, tamsulosin exhibits a rapid onset of action, and dose titration or modification is generally not required. Rather, it is suggested that it can be safely used for the long-term treatment of BPH.¹⁹Lee M. Tamsulosin for the treatment of benign prostatic hypertrophy.Ann Pharmacother. 2000 Feb;34(2):188-99.  ²¹Narayan P, Lepor H. Long-term, open-label, phase III multicenter study of tamsulosin in benign prostatic hyperplasia. Urology. 2001 Mar;57(3):466-70.   A long-term multicenter study21 showed that all primary efficacy parameters improved from baseline and were maintained throughout the study. In addition, the episodes of adverse events did not increase over the time, which clearly favored its long-term tolerability (even longer than 1 year) in treatment of BPH. Tamsulosin is also considered a more convenient alternative than its counterparts.¹⁹Lee M. Tamsulosin for the treatment of benign prostatic hypertrophy.Ann Pharmacother. 2000 Feb;34(2):188-99.   In one of the systematic literature reviews,²²Dong Z, Wang Z, Yang K, Liu Y, Gao W, Chen W. Tamsulosin versus terazosin for benign prostatic hyperplasia: a systematic review. Syst Biol Reprod Med. 2009 Aug;55(4):129-36.   it was revealed that patients on tamsulosin scored better on IPSS in comparison to those who received terazosin.Moreover, it is less likely to cause hypotension when used as a monotherapy or in combination with other antihypertensive agents, which makes it a choice of drug over other alpha-adrenergic antagonists for the management of symptomatic BPH.¹⁹Lee M. Tamsulosin for the treatment of benign prostatic hypertrophy.Ann Pharmacother. 2000 Feb;34(2):188-99.   However, it may not reduce the overall long-term risk of acute urinary retention or BPH-related surgery, which can be achieved by using 5ARIs.²³Emberton M, Cornel EB, Bassi PF, Fourcade RO, Gomez JMF, Castro R. Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. International Journal of Clinical Practice. 2008;62(7):1076-1086.  

5-Alpha-reductase inhibitors: Significant role of dutasteride

European Association of Urology (EAU) guidelines recommend the use of 5ARIs for the treatment of moderate-to-severe LUTS in men with either an enlarged prostate (>40 mL) or elevated PSA concentration (>1.4-1.6 ng/mL).²⁴EAU Guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS) – update April 2014. Available at:https://uroweb.org/wp-content/uploads/Non-Neurogenic-Male-LUTS_2705.pdf. Accessed on: 21.9.16.   These therapeutic gents inhibit the conversion of testosterone to dihydrotestosterone (DHT), which is the primary androgen responsible for prostate development.²³Emberton M, Cornel EB, Bassi PF, Fourcade RO, Gomez JMF, Castro R. Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. International Journal of Clinical Practice. 2008;62(7):1076-1086.   Their onset of action is slow, targeted to hinder the disease progression in terms of both acute urinary retention and the need for surgery.²⁴EAU Guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS) – update April 2014. Available at:https://uroweb.org/wp-content/uploads/Non-Neurogenic-Male-LUTS_2705.pdf. Accessed on: 21.9.16.   5ARIs are available in two forms, dutasteride and finasteride. These differ in their action on isoenzymes of 5AR; while finasteride inhibits only the 5AR type 2 isoenzyme, dutasteride is a dual inhibitor of both 5AR type 1 and type 2.As a result, serum DHT suppression is greater with dutasteride (95%) in contrast to finasteride (70%).²³Emberton M, Cornel EB, Bassi PF, Fourcade RO, Gomez JMF, Castro R. Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. International Journal of Clinical Practice. 2008;62(7):1076-1086.   ²⁴EAU Guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS) – update April 2014. Available at:https://uroweb.org/wp-content/uploads/Non-Neurogenic-Male-LUTS_2705.pdf. Accessed on: 21.9.16.   Besides, dutasteride exhibits longer elimination half-time (3-5 weeks), and its continuous treatment reduces prostate DHT concentration by 85-90%.²⁴EAU Guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS) – update April 2014. Available at:https://uroweb.org/wp-content/uploads/Non-Neurogenic-Male-LUTS_2705.pdf. Accessed on: 21.9.16.   Numerous studies attest to efficacy of dutasteride in improving prostate volume and symptoms, flow rate, and risk of acute urinary retention and surgery.In one such 24-month study,²⁵Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G; ARIA3001 ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002 Sep;60(3):434-41.   use of dutasteride was associated with reduction in serum DHT, total prostate volume, and transition zone volumes by a mean of 90.2%, 25.7%, and 20.4%, respectively. Improvement in symptom score was observed as early as 3 months.The maximal flow rate increased significantly by 2.2 mL/s at 24 months. Moreover, risk of acute urinary retention and surgery reduced by 57% and 48%,respectively (Figure 5). While well-tolerated, greater treatment satisfaction can be achieved by combining dutasteride with tamsulosin than by either drug used alone.²⁶Keating GM. Dutasteride/tamsulosin: in benign prostatic hyperplasia.Drugs Aging. 2012 May 1;29(5):405-19.  

Combination therapy of dutasteride and tamsulosin: An approach for optimal outcomes in most patients

It is clear from the above discussion that while alphablockers provide rapid symptomatic relief, it does not target the underlying pathological process.On the other hand, 5ARIs offer mid- and longterm symptomatic relief (due to their slow onset of action) and reduce the risk of disease progression (acute urinary retention and BPH-related surgery).Therefore, their combination can be used to achieve maximum benefits of their complementary effects, which seems a rational approach for the long-term management of bothersome BPH.²³Emberton M, Cornel EB, Bassi PF, Fourcade RO, Gomez JMF, Castro R. Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. International Journal of Clinical Practice. 2008;62(7):1076-1086.   Moreover, the EAU and the AUA guidelines recommend the use of combination therapy of an alpha-blocker and a 5ARI for treatment of moderate-to-severe BPH/BPE-related LUTS, enlarged prostate, reduced Qmax, and in men at high risk of disease progression.²⁷Dimitropoulos K, Gravas S. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia. Therapeutic Advances in Urology. 2016;8(1):19-28.  

Combination of dutasteride and tamsulosin is considered to be more effective than either monotherapy; provides superior long-term outcomes and symptomatic relief from bothersome BPH and LUTS. It is available as a fixed-dose combinationdutasteride 0.5 mg/day and tamsulosin 0.4 mg/day. Results of the randomized, double-blind, multinational CombAT trial²⁷Roehrborn CG, Siami P, Barkin J, Damiao R, Major-Walker K, Morrill B, Montorsi F; CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement:2-year results from the CombAT study. J Urol. 2008 Feb;179(2):616-21;discussion 621.   ²⁹Tan-Dy CRY, Ohlsson A. Lactase treated feeds to promote growth and feeding tolerance in preterm infants. Available from: https:// www.nichd.nih.gov/ cochrane_nd data/tandyc_01/tandyc_01.html [Accessed on 22 November 2016].   showed the benefits of using this combination therapy over a period of 2 (primary endpoint) and 4 years. It comprised improved LUTS,reduced risk of disease progression, and greater mean change in the total IPSS. After 4 years of study, it was observed that the time to first acute urinary retention or BPH-related surgery significantly favored men on dutasteride plus tamsulosin combination versus those receiving monotherapy. Furthermore, combination of dutasteride and tamsulosin demonstrates superior effects in reducing relative risk of BPH clinical progression in men with enlarged prostates, when compared to either monotherapy. Therefore, use of combination therapy is advised when long-term treatment (more than 12 months) is suggested.27 Overall, their concomitant use in treatment of BPH was generally well-tolerated and was associated with better health-related quality of life.²⁶Keating GM. Dutasteride/tamsulosin: in benign prostatic hyperplasia.Drugs Aging. 2012 May 1;29(5):405-19.   ²⁷Dimitropoulos K, Gravas S. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia. Therapeutic Advances in Urology. 2016;8(1):19-28.   ²⁷Roehrborn CG, Siami P, Barkin J, Damiao R, Major-Walker K, Morrill B, Montorsi F; CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement:2-year results from the CombAT study. J Urol. 2008 Feb;179(2):616-21;discussion 621.   ²⁹Tan-Dy CRY, Ohlsson A. Lactase treated feeds to promote growth and feeding tolerance in preterm infants. Available from: https:// www.nichd.nih.gov/ cochrane_nd data/tandyc_01/tandyc_01.html [Accessed on 22 November 2016].  

Conclusion

Benign prostatic hyperplasia, as the name suggests,is nonmalignant enlargement of the prostate gland.It is often associated with LUTS, BPE, and BOO, in a rather complex way and manifest as obstructive and irritative symptoms. The affected patients are clinically approached on the basis of their symptom score, DRE, PSA levels, and urological parameters.Pharmacological therapy is initiated only in cases presenting with bothersome symptoms. Tamsulosin is a commonly used therapeutic agent for treating symptomatic BPH. It is an alpha-adrenergic receptor antagonist and works by relaxing smooth muscles in the prostate and bladder neck, which facilitates bladder emptying, thereby providing rapid relief. It is well-tolerated and exhibits lower cardiovascular side effects. Dutasteride is a 5ARI that inhibits both 5AR type 1 and type 2 isoenzymes, thereby suppressing DHT concentrations. It not only gradually reduces the prostate volume and symptoms, but also reduces the risk of acute urinary retention and BPH-related surgery. Combination therapy of dutasteride and tamsulosin is considered to be more effective than either monotherapy alone. It displays dual benefit of rapid symptomatic relief and targeting underlying pathological process. It is generally well-tolerated and is associated with better health-related quality of life and treatment satisfaction.

References

1. Dhingra N, Bhagwat D. Benign prostatic hyperplasia: An overview of existing treatment. Indian Journal of Pharmacology. 2011;43(1):6-12.
2. Roehrborn CG. Benign Prostatic Hyperplasia: An Overview. Reviews in Urology. 2005;7(Suppl 9):S3-S14.
3. Costa P, Ben Naoum K, Boukaram M, Wagner L, Louis JF. Benign prostatic hyperplasia (BPH): prevalence in general practice and practical approach of French general practitioners. Results of a study based on 17,953 patients. Prog Urol. 2004 Feb;14(1):33-9.
4. Lepor H. Pathophysiology, Epidemiology, and Natural History of Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 9):S3-S10.
5. Patel ND, Parsons JK. Epidemiology and etiology of benign prostatic hyperplasia and bladder outlet obstruction. Indian Journal of Urology: IJU: Journal of the Urological Society of India. 2014;30(2):170-176.
6. Parsons JK. Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: Epidemiology and Risk Factors. Current Bladder Dysfunction Reports. 2010;5(4):212-218.
7. Tanguay S, Awde M, Brock G, Casey R, Kozak J, Lee J, Nickel JC, Saad F. Diagnosis and management of benign prostatic hyperplasia in primary care. Canadian Urological Association Journal. 2009;3(3 Suppl2):S92-S100.
8. Lepor H. Evaluating Men with Benign Prostatic Hyperplasia. Reviews in Urology. 2004;6(Suppl 1):S8-S15.
9. Bhargava S, Canda AE, Chapple CR. A rational approach to benign prostatic hyperplasia evaluation: recent advances. Curr Opin Urol.2004 Jan;14(1):1-6.
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