Lower Urinary Tract Symptoms (LUTS) and Management of Benign Prostatic Obstruction

1. Lower Urinary Tract Symptoms (LUTS)andManagement of Benign Prostatic Obstruction Julian Mander

2. Old Terminology • “Prostatism” = any voiding symptoms • Rx TURP all men with LUTS • 80% successful outcome Mebust et al J Urol 1989;141: 24 • TURP - 1% incontinent (Mconnell 1994 USA Govt Clinical 13.6% impotent Practice Guidelines ) 73.4% retrograde ejaculation 3.1% urethral stricture 0.5 - 3.3% mortality <90 days

3. New Terminology • “Lower Urinary Tract Symptoms” = LUTS • Obstructive, Irritative or Mixed • Appropriate investigation leading to diagnosis and appropriate therapy! • Medical therapy: alpha blockers, 5 alpha reductase inhibitors, phytoestrogen • New surgical therapy: Laser, TUVP, Thermotherapy, HIFU • Successful outcomes? • Are we doing any better? Few randomized controlled trials assessing outcomes of new diagnostic terminology and therapeutic approaches.

4. Obstructive LUTS • Hesitancy • Poor flow • Terminal dribbling • Spraying stream • Feeling of incomplete emptying

5. Cause of Obstructive LUTS • Mechanical Benign prostatic obstruction Urethral stricture Malignant prostatic obstruction Stones and bladder cancer • Functional Bladder neck dyssynergia External sphincter dyssynergia (neuro)

6. Irritative LUTS • Frequency • Nocturia • Urgency • Strangury • Burning micturition • Bladder pain

7. Causes of Irritative LUTS • Primary bladder overactivity(“instability”) • Secondary bladder overactivity Primary bladder pathology Inflammatory - UTI and prostatitis “Interstitial cystitis” Neoplastic - Bladder cancer and CIS Bladder stones Secondary to extravesical influence Bladder outflow obstruction - (BOO)= BPO, Urethral stricture, MPO Stones upper urinary tract Extravesical neoplasm • Neuropathic - Detrusorhyperreflexia

8. New Terminology • LUTS - The standardisation of terminology of the lower urinary tract. Abrams et al World J Urol 1989; 6: 233 - 453 New words for old: lower urinary tract symptoms for “Prostatism” Abrams Br Medical J 1994; 308 929 - 30 • BOO - bladder outflow obstruction • BPO - benign prostatic obstruction • BPH - benign prostatic hyperplasia • MPO - malignant prostatic obstruction

9. MPO - Rare and late • Are men with lower urinary tract symptoms at increased risk of prostate cancer? A systematic review and critique of the available evidence. Young et al (Sydney) BJU International 2000; 85: 1037 • 11/179 potentially relevant studies on LUTS and prostate cancer 6/11 failed to account for age as confounding factor • All 5 remaining studies were flawed - “present literature found no compelling evidence of association between LUTS and prostate cancer.” • “Value of prostate cancer screening is as yet speculative. Hence, as the evidence to date of association between LUTS and early prostate cancer is weak, PSA testing of men with LUTS is similarly a grey area.”

10. MPO - Rare and late • “The paucity of rigorously acquired evidence with which to determine the relationship between LUTS and early prostate cancer is a cause for concern.” • NH&MRC Clinical Practice Guidelines : The management of uncomplicated LUTS in men. AGPS 1996 75% Australian GPs surveyed one year after guidelines published said patients expected PSA testing if they had LUTS c/f if they had no LUTS. 50% GPs surveyed in 1999 support PSA screening in men with LUTS. • Guidelines stated “ Men with uncomplicated LUTS should be advised that there are no data to suggest that they have increased risk of prostate cancer.” Young et al say: “Given conflicting results from poor quality studies, we see no reason to revise this guideline.”

11. BPO - Common • Definition - LUTS associated with BPH +/- BOO but BOO poorly defined except on urodynamic testing by Abrams - Griffith nomogram. Attempts to define BOO on flow rate<10 ml/sec max, post void resid volume>80ml and IPSS. • Incidence - Moderate to severe LUTS occur in about 25% of men aged 50 years and over and the prevalence increases with age. Chute et al J Urol 1993 150: 85 - 9 90% 80 year old men have BPH • Pathophysiology – Lepor “The Pathophysiologyof LUTS in the Aging Male Population” BJU 1998 81 Suppl 1 29-33 Involves smooth muscle activity, or other neurological elements affected by alpha- blockers ?sensory input ?bladder alpha1D receptor input 40% BPH is smooth muscle JUrol1982 - 40% alpha tone, 53% static obst. TURP helps symptoms from BPO = problem bladder neck, prostate

12. BPO - Costs • In the USA treatment for BPO costs $2 billion per year and results in 1.7 million physician visits per year (1997 data) • Currently the most common treatment in USA is Alpha blocker medical therapy • 100,000 Prostatectomies annually in USA (1997 data) • Phytoestrogen>90% of all drugs prescribed for BPO in Germany

13. BPO - Symptoms • Generally a mixture of irritative and obstructive lower urinary tract symptoms. • Note “normal” ranges for nocturia: Nocturia x1 50s from Abrams, Bristol x2 60s Note nocturnal polyuria = >35% total urine output during sleep look for x3 70s medical cause. Peak age for BPO symptoms is 63 years, with many spontaneously resolving over future years. Typically BPO symptoms are quite variable in severity, worse during the night and in cold weather Small group not responding or shortlived response to alpha blockers generally have middle lobe enlargement, representing true mechanical obstruction, generally leading to TURP surgery - recent BJU study SX correlate more with extent of intravesical prostate seen on U/S c/f size prostate or residual volume

14. IPSS International Prostate Symptom Score Over the past month Not at Less than Less than About half More than Almost Your how often have you.. All 1 time in 5 half the time the time half the time always score 1. had the sensation of not emptying your 0 1 2 3 4 5 bladder completely after you finished urinating? 2. had to urinate again less than two hours 0 1 2 3 4 5 after you finished urinating? 3. stopped and started again several times when 0 1 2 3 4 5 you urinated? 4. found it difficult to postpone urination? 0 1 2 3 4 5 5. had a weak urinary stream? 0 1 2 3 4 5 6. had to push or strain to begin urination? 0 1 2 3 4 5 And finally.. None Once Twice 3 times 4 times 5 times or more 7. Over the past month, how many times did you typically get 0 1 2 3 4 5 up to urinate from the time you went to bed at night until the time you got up in the morning? Add up your score and write it in the box TOTAL 0 -8 mild symptoms 8 - 19 moderate symptoms 20 - 35 severe symptoms

15. Investigation of BPO • Diagnostic tests MSU (or urinalysis) everyone with LUTS Baseline tests U/S urinary tract NB appearance/size prostate meaningless NB residual inaccurate if bladder is overdistended Flexible cystoscopy if significant irritativeLUTS and considering non surgical therapy, to rule out bladderneoplasm. Serum creatininenotuseful unless kidneys abnormal on U/S Optional tests Videourodynamics if considering surgery with possible neuropathic component e.g. Parkinsons disease or post stroke LUTS Bladder diary useful where problem may be polyuria, esp diabetics( > 3 li/24 hours) Urine flow rates unhelpful Useless tests IPSS unhelpful generally - research tool

16. Decision to Treat BPO • Absolute indications 1) Obstructive uropathy – hydronephrosis on U/S, usually bilateral with distended bladder usually 500 – 1,000 ml +/- impaired renal function. 2) Retention, usually after failed TOV on medical therapy. • Relative indications 1) Reason for presentation - generally fear of cancer related to media misrepresentation - DRE and informed consent for PSA test. 2) LUTS ? Obstructive or irritativeLUTS leading to correct investigation and diagnosis. 3) Diagnose BPO - MSU and U/S probably adequate unless frank haematuria or marked irritative symptoms = flexible cystoscopy. 4) Decision to treat is determined by the patient, given degree of “bother” vsrisk/benefit of treatment strategies. 5) Alpha blockers or Phytoestrgen trial of medical therapy is initially appropriate. 6) Failed medical therapy - refer for surgical management.

17. Pharmacological Treatment of BPO • Alpha Blockers • Beneficial effects for LUTS first reported by Caine in 1976 BJU 48:255-63. • Mechanism of action is unclear, but “theoretically” SM relaxation. • Alpha 1A receptors 75% of receptors in prostate + predominate in heart + predominate in splanchnic and coronary arteries. • Alpha 1D receptors predominate in bladder and spinal cord. • Suggests alpha 1A+D selectivity (Tamsulosin) may be a flawed concept as far as minimising blood pressure SE – suggestion that reduced SE due to slower absorption of tamsulosin. • Questioned whether dizziness SE is related to hypotension in the low doses of prazosin used for LUTS. • Prazosin0.5 mg bd with food, increase to 1mg bd after one week. • Tamsulosin400 microgm mane $50 - $80 per month.

18. Alpha Blockers • Do they work? • Two placebo controlled trials of prazosin 1987 and 1992 increased peak flow 2.0 - 4.8 ml/sec over baseline before the days of symptom scores, deemed effective treatment BPO • Review of 13 randomized trials of tamsulosin 5/6 studies showed benefit over placebo by symptom score 5/6 studies showed improved flow rates c/f placebo 1 study showing similar improvement in symptom score c/f prazosin Wilt et al J Urol 2002; 167: 177-183 • Many other studies on Terazosin, Doxazosin and Alfuzosin (now as slow release Xatral, once daily). • Note slow release probably primary reason for reduced SE vsprazosin (similar if prazosin with food).

19. Phytoestrogen - Saw Palmetto • Saw Palmetto is Derived from american dwarf palm tree - Sabalserrulata. Non competitive inhibitor of type I 5-alpha reductaseuncompetitively inhibits type II isoenzymeof 5-alpha reductase (c/f dutasteride- selective competitive inhibitor type II 5-alpha reductase). • Minimal effects on prostate volume and no effect on serum PSA. • No reduction in serum dihydrotestosterone. • 4 placebo controlled trials show significant improvement in symptoms and statistical improvement in flow rates but study duration 1 - 3 months. • 3 placebo controlled trials showed no significant improvement in symptoms, and although flow rates improved, said to not be statistically significant. • Suggested benefit but reliability of study conclusions in doubt. “Saw Palmetto for the Treatment of Men with Lower Urinary Tract Symptoms” Gerber J Urol 2000; 163: 1408 - 1412

20. Phytoestrogen - Beta-sitosterol • Worldwide sale plant extracts for treatment BPH is US$80 million annually. • Phytopharmacologicalagent from South African star grass, Hypoxisrooperi or from a species of Pinus or Picea = a mixture of phytosterols. • Exact mechanism of action unknown - may be related to cholesterol metabolism or antiinflammatory effects via interference prostaglandin synthesis. • 4 placebo controlled trials 519 total patients but with short study duration 4 -26 weeks. • IPPS improved 4.9 points over placebo. • Flow rate improved 3.91 ml over placebo. • Residual urine improved 28.62 ml over placebo. • Conclude that Beta sitosterols do improve symptoms and flow, but short duration of studies and problems with standardization of preparations. Beta sitosterol for the treatment of benign prostatic hyperplasia: a systematic review Wilt et al BJU 1999; 83: 976-983

21. 5 Alpha Reductase Inhibitors • Finasteride and Dutasteride • Selective, competitive inhibitor of type II 5 alpha reductase, resulting in reduced prostatic levels of dihydrotestosterone, with reduction in prostate size and reduction of benign prostatic obstructio.n • Finasteride - Improved urodynamic parameters of obstruction in placebo controlled trial using urodyamic assessment 8.1 cm reduction detrusor pressure at max flow 1.1 ml/sec improvement in max flow rate 22.8% reduction in prostate volume Improvement greater in prostates > 40 gm Abrams et al J Urol 1999; 161: 1513 • Finasteride problem is cost - $120 per month unless repatentitled. • Dutasteride now on PBS 500 microgm once daily dose “Treatment, in combination with an alpha-antagonist, of lower urinary tract symptoms due to benign prostatic hyperplasia where treatment is initiated by a urologist” • “Duodart” now on PBS Dutasteride 500microgm + Tamsulosin 400microgm single daily dose. “Treatment of lower urinary tract symptoms due to benign prostatic hyperplasia where treatment has been initiated by a urologist”. • Effect of finasteride on symptom scores is not seen until 6 - 9 months after starting treatment, maximum effect may take > one year. • Symptom imrovement in 25 - 33 % in long term studies • Reduces PSA readings in all men

22. BPH + Haematuria= Dutasteride • BPH is the most common cause of painless macroscopic haematuria in older males, generally precipitated by physical activity. • Finasteridecures 91% of bleeding associated with BPH - initially reported in 1995, first retrospective study published 1998. Seiberet al J Urol 1998; 159: 1232- 1233 • 12% TURPs performed for bleeding from BPH, but problem often recurs some time after TURP. • Prospective study on 57 patients 63% recurrence of haematuria in untreated control group within one year Vs 14% in finasteride treated group. Foley et al J Urol 2000; 163: 496 • Finasteride results in reduction in vascular endothelial growth factor and subsequent decrease in the microvessel density of prostatic suburethraltissue. Pareeket al J Urol 2003; 169(1): 20-23

23. Surgery for BPO - TURP • Open prostatectomy - still used for very large prostates. • TURP • 80% good outcome Risks: 1% incontinent , 13.6% impotent, 73.4% retrograde ejaculation, 3.1% urethral stricture, 2% blood transfusion, 0.5 – 3.3% mortality < 90 days (Mconnell 1994 USA GovtClinical Practice Guidelines). • Glycineirrigant and glycine toxicity with post op life threatening hyponatremia. • Absolute indication in men with obstructive uropathy. (Alternative long term IDC) • Absolute indication in patients with retention from BPO, not voiding on alpha blocker / Duodart. (Alternative IDC) • Absolute indication in patients with MPO, having escaped hormonal manipulation control but with a relatively high risk of incontinence, up to 20%. (Alternative IDC) • Relative indication in those with significant symptoms, not responding to or not wanting pharmacological therapy (significant improvement only if symptom score is “severe” pre op Fowler JAMA 1988; 259: 3018) • 10% require redo TURP within 8 years.

24. Resectoscope

25. Alternative Surgery for BPO • Other Surgical Procedures TUMT trans urethral microwave thermotherapy TUNA trans urethral needle ablation HIFU high intensity focused ultrasound Laser prostatectomy - Coagulation VLAP +/- contact vaporize Interstitial Laser Resection Holmium YAG (= TURP) Now “GreenLight” (KTP) and Thulium laser TUVP trans urethral vaporization = electrocautery 200W spiked rollerball • Rapidly moving field in 1990s, with many poor studies, difficult to analyse, but in the end, pharmacological therapy has overtaken TURP, with relatively few TURP procedures now being done. Above equipment expensive.

26. Laser Prostatectomy • AMS “GreenLight laser” originally Laserscope KTP in use 1991 with good outcomes London but power limited by fibre to 80W or 100W. KTP = potassium-titanyl-phosphate laser 532 nm wavelength AMS now refined with water-cooled MoXy side-fire fibre delivering 180W power from XPS laser machine. MoXywatercooled fibres expensive. Vaporise or resect. N Saline irrigant so no glycine toxicity risks. Relatively good haemostasis. • “Thulium laser” Quanta System “Cybr TM 150” 150W laser either reusable end-fire fibre or single use side-fire fibre. Holmium-chromium-thulium triple-doped Yttrium aluminium garnet (Ho:Cr:Tm:YAG, or Ho,Cr,Tm:YAG) is an active laser medium material with high efficiency. Single-element thulium-doped YAG (Tm:YAG) lasers operate between 1930 and 2040 nm. The wavelength of thulium-based lasers is very efficient for superficial ablation of tissue, with minimal coagulation depth in air or in water. This makes thulium lasers attractive for laser-based surgery.

27. GreenLight XPS

28. BND - Bladder Neck Dyssynergia • Important cause of chronic voiding dysfunction in young and middle aged men. • Commonly associated with perineal/testicular pain and commonly misdiagnosed as “chronic prostatitis”. • True incidence is unknown, but commonly seen in practice. • Etiology is unknown, but commonly seen after precipitating event, most commonly bacterial prostatitis, often inadequately treated. • Subgroup of men in mid - late 40s ? ” pre BPO” ? hormonal changes • Seven reported cases of renal failure in young men from this condition • Personal experience now of three cases of renal failure with BOO BND • One study on alpha blocker therapy for treatment of BND 24 patients as their own controls IPSS improvement 18.3 to 11.6 Max flow improved 11.8 to 15.9 ml/sec Residual improved 80.2 to 48.5 ml Yang et al J Urol 2002; 168: 571-574

29. Bladder Neck Incision • All studies in prostates <30 gm. 70.3% improvement in IPSS post TUIP vs 75% post TURP, no difference in improvement of flow rates. Less morbidity, esp less bleeding intra and post op, shorter stay Dorflingeret al Scand J UrolNephrol 1992; 26(4): 333-8 • Questionable long term efficacy - personal experience of high re - do rates in teaching hospitals. • Operation of choice for bladder neck stenosis which is a complication previous TURP or radical prostatectomy.

30. Chronic Prostatitisand Chronic Pelvic Pain Syndrome • Bacterial prostatitis occurs in all men with UTI and is associated with acute pain and LUTS. Do not do PSA tests in men with acute LUTS. Rx with antibiotics that work in the prostate – Trimethoprim or Fluoroquinolones (Norfloxacin). • “Chronic prostatitis” is generally abacterial, with negative MSUs. • Now recognized as “Chronic Pelvis Pain Syndrome” or CPPS. • Definition: CPPS is characterised by pelvic or perinealpain without evidence of urinary tract infection, lasting longer than 3 months. • Clinical features: Symptoms generally fluctuate in severity. Pain can be present in the perineum, testicles, tip of penis, pubic or bladder area. Pain may radiate to the back and rectum, making sitting uncomfortable. Pain can range from mild to debilitating. Post ejaculatory pain is common. LUTS commonly associated irritative +/- obstructive. Sexual dysfunction is common, along with fatigue and depression. • Said to be suffered by JFK, James Boswell, John Cleese and John Anderson ( former deputy PM Aus).

31. Chronic Prostatitis and Chronic Pelvic Pain Syndrome • Etiology Unknown Bacterial infection excluded in an important 2003 study by Lee and Berger Uni Washington. Wide range of theories: 1. Stress-driven hypothalamic-pituitary-adrenal axisdysfunction. 2. Neurogenic inflammation } 3. Myofascial pain syndrome } In the last 2 categories 2) and 3), dysregulationof the local nervous system due to past trauma, infection or an anxious disposition and chronic albeit unconscious pelvic tensing lead to inflammation that is mediated by substances released by nerve cells (such as substance P). The prostate (and other areas of the genitourinary tract: bladder, urethra, testicles) can become inflamed by the action of the chronically activated pelvic nerves on the mast cells at the end of the nerve pathways. Crossover with or differential diagnosis with “interstitial cystitis” is in play.

32. Chronic Prostatitis and Chronic Pelvic Pain Syndrome • Diagnosis “Problematic” No distinct objective test. Peak incidence in men 35 – 45 years age range. Categorization as “Inflammatory” or “Non-inflammatory” CPPS based on the levels of pus cells in expressed prostatic secretions (EPS), but these categories are of questionable clinical use. 1) Inflammatory (Category Ⅲa) EPS has WBC 2) Non-inflammatory (Category Ⅲb) EPS has no WBC Recent studies have questioned the distinction between categories Ⅲa and Ⅲb, since both categories show evidence of inflammation if pus cells are ignored and other more subtle signs of inflammation, like cytokines, are measured.

33. Chronic Prostatitis and Chronic Pelvic Pain Syndrome • Treatment Prostate massage - common treatment 30 or 40 years ago, no data. Alpha blockers - especially if LUTS or pain with ejaculation, suggesting BND causative. Amitriptyline - especially if bladder pain (interstitial cystitis), but do MSU and urine cytology. NSAIDs - mixed reports Psychological therapy - treat secondary depression “paradoxical relaxation” (Jacobsen) aerobic exercise ? “Neuromodulation”