Benign Prostatic Hypertrophy (BPH) is the most

Medical treatment of benign prostatic hypertrophy There is little doubt that medical therapy has transformed the treatment of benign prostatic hypertrophy (BPH). The medical treatment of BPH continues to be based on two main classes of drugs, alpha adrenergic blockers and 5-alpha reductase inhibitors. Dr Yeung Ng Specialist Registrar, Department of Urology, Queen Margaret Hospital, Dunfermline, Scotland Mr David Gordon Brown Consultant Urological Surgeon,Department of Urology, Queen Margaret Hospital, Dunfermline, Scotland email yeungng@nhs.net Benign Prostatic Hypertrophy (BPH) is the most common reason for men over the age of 50 years to consult a urologist. Strictly speaking, BPH is a histological diagnosis defined by the presence of stromoglandular hyperplasia in prostate tissue. Autopsy data has shown that there is a sigmoid distribution of BPH with age. 1 There is an 8% prevalence in the 31 40 years age group, rising to 50% in the 51 60 years group and 88% in those aged over 80 years. Prostate volume also shows a linear increase with age. BPH is intimately linked to the clinical symptoms collectively known as lower urinary tract symptoms (LUTS), in particular reduced urinary flow. Clinically reported LUTS has been reported in 17% of men aged 50 59, 27% aged 60 69 and in 35% of men over the age of 70 years. 2 Diagnosis LUTS are a collective group of symptoms characterised by poor flow, frequency, nocturia, urgency, post micturition dribbling and incomplete emptying. The IPSS/AUA questionnaires are universally used scoring systems to calculate the patients perceived severity of symptoms. 3 There are six symptom domains scored from 0 5 plus a quality of life score. A score of less than 8 signifies mild symptoms, 8 19 moderate symptoms and 20 35 severe symptoms. The most commonly used objective measurement of outflow obstruction is uroflowmetry. The patient is asked to void into a flow machine that plots a trace of urinary flow rate against time. A maximum flow rate of less than 10ml/s signifies a high probability of obstruction whilst a flow rate of greater than 15ml/s generally suggests obstruction is unlikely although results can be confounded by weak detrusor muscle contraction. 4 The shape of the graph and voiding time are important as prolonged voiding times and a flattening of the graph may indicate obstruction. Generally uroflowmetry is undertaken in conjunction with a post void scan of bladder residual volume to assess incomplete emptying. Clinical assessment of prostatic volume by digital rectal examination is necessary. It is difficult for the non specialist to accurately assess prostate size, but a non enlarged gland should be less than 25cc or classically described as the size of a walnut. A benign gland is smooth, symmetrical, regular and with a median sulcus. Any variation from this may represent a prostate cancer and should be referred for a urological opinion. Other baseline investigations are urinalysis and culture and baseline serum creatinine. The use of routine prostatespecific antigen (PSA) testing remains controversial with relation to screening for prostate cancer and is beyond the scope of this article. With regard to BPH and LUTS, a PSA of greater than 1. 4 has been associated with symptom progression. 5 It is common practice to check PSA as a baseline investigation. BPH has a number of clinical complications. Urinary retention must be considered to be the disease endpoint. It is the most recognised but not most common sequelae of BPH and occurs with an incidence of between 0. 6 and 1. 8 times/100 patient years. 5,6,7 Poor urinary flow (<12ml/s), larger prostate volume (>30ml), age and IPSS score are all risk factors. A PSA of >1. 4 also increases risk of retention. Bladder stones may occur with an incidence of up to 3. 4% or eight times greater than non bladder outflow obstruction patients 8 due to urinary stasis. Frank haematuria is self reported in 2. 5% of BPH patients. 9 Urinary tract infection 14

is actually comparatively rare (0. 1 times/100 patient years) as is post renal failure. Bladder decompensation can occur and this results in a chronic painless urinary retention with a large residual bladder volume of greater than 750ml. Placebo BPH and LUTS is unusual in that both natural history and the placebo arms of treatment studies have shown that around 40% of patients with LUTS will report improvement of symptoms without treatment. 4,10 However, this effect appears to be temporary and long term studies show a reversal of placebo effect after one year and progression of symptoms after this time. Pharmaceutical treatment The medical treatment of BPH continues to be based on two main classes of drugs, alpha adrenergic blockers and 5-alpha reductase inhibitors. Alpha adrenergic blockers Human prostate contains smooth muscle that contracts in the presence of alpha adrenergic agonist such as norepinephrine. The majority of smooth muscle is located in a ring around the base of the bladder and failure of this to relax with voiding may be the principle factor in the reduction in urinary flow rate. Alpha 1 adrenergic receptors mediate this contraction and indeed the human prostate contains 98% of these receptors in the body. Alpha-1 a subtypes predominate in the prostate and urethra, d subtypes in the bladder and sacral cord and b subtypes in vascular smooth muscles. The a subtype increases in vascular muscle in proportion with ageing. 11 There are numerous alpha blockers on the market though once daily preparations now prevail. They remain the most commonly prescribed medication for BPH. Although many placebo controlled studies exist, most are six months or less in duration and there are very few head to head studies between different drugs. Tamsulosin MR/XL is the most potent alpha blocker and has some selectivity for alpha 1 a and d receptor subtypes as opposed to b. However, this does not appear to translate to any clinical advantage. A Cochrane review looking at 4,122 patients in 14 studies (six placebo controlled) found that tamsulosin treatment resulted in a mean reduction in IPSS score of 2. 1 versus placebo, improved quality of life and a mean improvement in peak flow of 1.05ml/s over placebo. 12 Only two small head to head studies have been conducted versus terazosin and alfuzosin and showed similar efficacy. Alfuzosin XL shows similar improvements in flow and symptoms to other alpha blockers with extension studies up to 30 months. 13 It is notable in that it is the only drug that has been shown to result in increased success of trial removal of catheter (TROC) post urinary retention. A placebo controlled study showed a 55% versus 29% significant successful TROC rate after 24 hours of catheterisation with two days of alfuzosin treatment. 14 A six month extension trial did show a lower percentage of patients proceeding to TURP (17% versus 24%). Doxazosin is a long acting alpha blocker with a half life of over 22 hours. However, it exhibits blood pressure lowering properties and needs to be titrated up from 2mg to 8mg. 15 These properties have limited its use. Its symptom relieving efficacy has been shown to be maintained in 42 month extension studies. 16 In addition the MTOPS study 7 has shown that it works synergistically with finasteride in reducing symptom progression and this has lead to its more widespread use. In summary, there appears to be little to choose between the various alpha blockers and they are probably of similar efficacy. It may be worth noting that only alfuzosin XL has been shown to increase the success of TROC after retention and to date, only doxazosin has been shown to have a synergistic effect with finasteride in combination therapy. Alpha blocker therapy is associated with dropout rates of 10 15%. The most commonly reported side effect is orthostatic hypotension, especially after the first dose and it is generally recommended that the first dose is taken at bedtime. Gastrointestinal disturbance is reported, as are hypersensitivity reactions and retrograde ejaculation. Severe hepatic and renal impairment are contraindications to taking this medication. 5-alpha reductase inhibitors 5-alpha reductase inhibitors (5 ARI) block the conversion of testosterone to dihydrotestosterone in the prostate by inhibition of the responsible enzyme. The latter is the main androgen in the prostate and has a potency 1. 5 2. 5 times greater than testosterone. Androgens are required for normal embryonic development of the prostate and their withdrawal in adults results in a reduction in prostatic volume due to regression of epithelial elements. 17 Finasteride was the first 5ARI and is the most studied. Studies have shown that this is effective in reducing prostatic volume by up to 18% at one year, rising to GM2 Midlife and Beyond 2010 June 15

32% after four years of treatment. 5 It reduces both IPSS scores by 1 2 points and improves peak flow by 1 2ml/s. However, in contrast to alpha blockers, finasteride takes six months to produce a significant clinical effect. Its effect on the incidence of acute urinary retention is shown in a number of studies. Both the PLESS 5 and PROWESS 18 studies, which studied finasteride 5mg versus placebo, showed 57% relative reductions in urinary retention in the study group over placebo at four and two years points respectively. However, this reduction in retention rates is volume dependent. Large scale studies where the mean prostate volume is less than 40mg have shown no significant reduction in urinary retention rates with finasteride over placebo 10,19 whilst subset analyses of prostate volumes of greater than 50ml show greater relative reductions in urinary retention rates with 5ARI treatment. It should be noted that urinary retention is a comparatively rare event and that an absolute reduction in retention incidence from 7 to 3% in PLESS translates to the need to treat 25 men for four years to prevent one episode of retention. Finasteride is the medical treatment of choice in treating frank haematuria secondary to BPH. Frank haematuria secondary to BPH resolves in 91% of patients treated with at least six months of finasteride. 20 Dutasteride is a new 5ARI that unlike finasteride inhibits both isoforms of 5-alpha reductase and has a greater impact on serum DHT levels. Dutasteride reduces the IPSS score by 4. 5 points and improves flow by 2. 2ml/s at 24 months and appears to act quicker than finasteride with significant symptom reduction versus placebo by four months. 21,22,23 More recent data has pointed to a continued reduction in symptom scores with longer durations of treatment. Prostate volume reduction is 13. 8% by three months, 23. 6% at one year and 27. 3% by four years. The effect on urinary retention and progression was studied in a four year study of 4,844 men (COMBAT) 24 and results found that combination therapy of dutasteride and tamsulosin was significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression. Side effects of 5ARIs are retrograde ejaculation, impotence and decreased libido in up to 5% of patients, hypersensitivity reactions especially rash and breast tenderness. Both ARIs lower PSA by around 50% with large interpatient variability so baseline PSA should be checked prior to starting therapy. Phytotherapy The use of natural plant products for the treatment of BPH has gained some interest particularly amongst patients. The most well known are Saw Palmetto Berry (Seronea Repens), South African Star Grass (Hypoxis Rooperi) and African Plum (Pygeum africanum). The mechanism of action of these plants is poorly understood but may be due to alteration of growth factor induced prostatic hypertrophy, especially EGF and bfgf. The literature supporting the use of these extracts is comparatively weak and there are few placebo controlled trials. A small meta-analysis on Saw Palmetto 25 has been completed that showed modest improvements in urinary flow and IPSS scores together with a small reduction in nocturia. A double blind placebo controlled trial using Hypoxi Rooperi showed quite significant improvements in flow, IPSS and quality of life but these results have not been replicated in over a decade. 26 No studies have ever looked at progression rates or long-term safety and so phytotherapy cannot generally 16

be recommended as an alternative to conventional medical therapy. Combination therapy The interest in the concomitant use of 5ARIs and alpha adrenergic blockers has been prompted by the MTOPS study of 3047 men over the age of 50 years with moderate to severe LUTS. 7 Doxazosin 8mg, finasteride 5mg, combination, or placebo groups were followed up after four years of treatment with primary endpoints centring around progression of symptoms (rise in IPSS of 4) or complications including retention, UTI, renal function deterioration and incontinence. A deterioration in IPSS scores (ie. symptoms) was the most common event (14%) whilst urinary retention occurred in 2% and BPH surgery was carried out in 5% of patients. The reduction in risk of progression (in any form) was 39% for doxazosin alone, 34% for finasteride and 67% for combination treatment compared to placebo. However, when only urinary retention was taken into consideration, doxazosin was not significantly beneficial over placebo and only finasteride or combination groups showed relative reductions of 69 and 64% respectively versus placebo. It should be pointed out that several previous studies on combination therapy (Veterans, PREDICT and ALFIN) 10,13,19 did not show benefit of finasteride although mean prostate volumes were all less than 40cc in these studies. A new fixed-dose combination therapy (dutasteride 0. 5mg/tamsulosin hydrochloride 0. 4mg) is the first single capsule, fixed-dose combination therapy to be approved in Europe for the treatment of moderate-to-severe symptoms of BPH. The impact of medical therapy There is little doubt that medical therapy has transformed the treatment of BPH. Prior to the 1980s, open prostatectomy was the only real option for the treatment of BPH. Despite this procedure being superseded by transurethral prostatectomy, the prostatectomy rate has fallen by around 50% in both the USA and the UK. 27 Over the same period the incidence of reported LUTS has increased by around 40%. Medical therapy is increasingly used particularly in primary care, where the UK use of these drugs increased five fold from 1992 to 2000. 2 Indications for referral to a urologist and treatment guidelines Medical therapy can be started by a non urologist for symptomatic patients. This is usually in the form of an alpha blocker given their rapid onset of action. Referral to a urologist is warranted if symptoms remain troublesome despite medical therapy. Obviously, urinary retention, obstructive renal failure and frank haematuria warrant urgent referral. Other indications include persistent dipstick haematuria recurrent urinary infection and bladder stones. Guidelines on referral have been published by the British Association of Urological Surgeons 28 (www. eguidelines.co.uk) and the European Association of Urology 29 has guidelines on investigation and treatment (www.uroweb.org/professional-resources/guidelines). Conclusion Men presenting to their physician complaining of LUTS require a careful history and symptom assessment. The clinician should always perform a digital rectal examination to assess the size and nature of the prostate gland as malignancy may present in the same way as BPH. Assessment of the flow rate and residual scan are often available through nurse-led clinics. The assessment of these can influence the treatment given and determine whether the involvement of the local urology department is necessary. Larger prostates respond better to 5ARI drugs though the mainstay of treatment is the use of alpha blockers. Alpha adrenergic blockers are rapidly effective in terms of symptom relief and improve the success rates of spontaneous passage of urine post catheter removal. 5ARIs reduce prostatic volume and improve symptoms after six months. Combination therapy has benefits over monotherapy with either of the above classes of drug and is worth considering particularly in symptomatic patients who are already on one drug. We have no conflict of interest References 1. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132(3): 474 49 2. Logie J, Clifford GM, Farmer RD. Incidence, prevalence and management of lower urinary tract symptoms in men in the UK. BJU Int 2005; 95(4): 557 62 3. Barry MJ, Fowler FJ Jr, O Leary MP, et al. The American Urological Association symptom index for benign 18

prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148(5): 1549 57 4. Reynard JM, Yang Q, Donovan JL, et al. The ICS- BPH Study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. Br J Urol 1998; 82(5): 619 23 5. Roehrborn CG, Bruskewitz R, Nickel GC, et al. Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37(5): 528 36 6. Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. Urology 1999; 53(3): 473 80 7. McConell JD, Roehrburn CG, Bautista OM, et al. The MTOPS research group. The long term effect of doxazosin, finasteride and combination therapy on the clinical progression of benign prosatic hyperplasia. N Engl J Med 2003; 349: 2387 98 8. Grosse H. Frequency, localization and associated disorders in urinary calculi. Analysis of 1671 autopsies in urolithiasis. Z Urol Nephrol 1990; 83(9): 469 74 9. Hunter DJ, Berra-Unamuno A, Martin-Gordo A. Prevalence of urinary symptoms and other urological conditions in Spanish men 50 years old or older. J Urol 1996; 155(6): 1965 70 10. Lepor H, Williford WO, Barry MJ, et al.the impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. J Urol 1998; 160(4): 1358 67 11. Schwinn DA. The role of a1-adrenergic receptor subtypes in lower urinary tract symptoms. BJU International 2001; 88(2): 27 34 12. Wilt T, MacDonald R, Rutks I. Tamsulosin for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews 2002, Issue 4. 13. Debruyne FM, Jardin A, Colloi D, et al. Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol 1998; 34(3):169 75 14. Sustained-release alfuzosin and trial without catheter after acute urinary retention: a prospective, placebocontrolled trial. BJU Int 1999; 84(6): 622 7 15. Fawzy A, Braun K, Lewis GP, et al. Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study. J Urol 1995; 154(1): 105 9 16. Lepor H, Kaplan SA, Klimberg I, et al. Doxazosin for benign prostatic hyperplasia: long-term efficacy and safety in hypertensive and normotensive patients. The Multicenter Study Group. J Urol 1997; 157(2): 525 30 17. McConnell JD. Prostatic growth: new insights into hormonal regulation Br J Urol 1995; 76(1): 5 10 18. Marberger MJ. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a doubleblind, placebo-controlled, multicenter study. PROWESS Study Group. Urology 1998; 51(5): 677 86 19. Kirby RS, Roehrborn C, Boyle P, Prospective European Doxazosin and Combination Therapy Study InvestigatorsEfficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003; 61(1):119 26 20. Sieber PR, Rommel FM, Huffnagle HW, et al. The treatment of gross hematuria secondary to prostatic bleeding with finasteride. J Urol 1998; 159(4): 1232 33 21. Debruyne F, Barkin J, van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004; 46(4): 488 94 22. Roehrborn CG, Boyle P, Nickel JC, et al Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60(3): 434 41 23. Roehrborn CG, Lukkarinen O, Mark S, et al. Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies. BJU Int 2005; 96(4): 572 27 24. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol 2010; 57(1):123 31 25. Wilt T, Ishani A, MacDonald R. Serenoa repens for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews 2002, Issue 3 26. Berges RR, Windeler J, Trampisch HJ, Senge T. Randomised, placebo-controlled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group. Lancet 1995 ; 345(8964): 1529 32 27. Lu-Yao GL, Barry MJ, Chang CH, et al. Transurethral resection of the prostate among Medicare beneficiaries in the United States: time trends and outcomes. Prostate Patient Outcomes Research Team (PORT). Urology 1994; 44(5): 692 8 28. Speakman MJ, Kirby RS, Joyce A, et al. The British Association of Urological Surgeons. Guideline for the primary care management of male lower urinary tract symptoms. BJU Int 2004; 93(7): 985 90 29. EAU Guidelines on Benign Prostate Hypertrophy: www.uroweb.org/professional-resources/guidelines GM2 Midlife and Beyond 2010 June 19