Benign Prostatic Hyperplasia Jay Lee, MD, FRCSC Clinical Associate Professor University of Calgary
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At the end of this program, participants will be able to: Define terminology related to lower urinary tract symptoms (LUTS) Recognize and diagnose LUTS secondary to benign prostatic hyperplasia (BPH) Predict progression in terms of symptoms, acute urinary retention and need for surgery Determine the appropriate care path for each patient
Definition of Terms BPH Benign Prostatic Hyperplasia BOO Bladder Outlet Obstruction Hypertrophied detrusor muscle LUTS Lower Urinary Tract Symptoms Obstructed urinary flow
Natural History of BPH: Symptoms Worsen 30% 55% Worsen Remain Stable Improve 15% Kirby RS et al. Benign prostatic hyperplasia. Health Press, 1995. 14
60 50 2,372 French men IIEF 48% 40 35% 33% 30 20 10 7% 9% 11% 27% 9% 15% 17% 21% 30% 0 50-59 years 60-69 years 70-79 years IPSS 0 1-7 8-19 20-35 points Richard F et al., Prog Urol 2001; 11(2):250-63.
ED (n=853) No ED (n=3581) Diabetes 20.2% 3.2% Hypertension 32.0% 13.6% Pelvic surgery 18.8% 2.4% LUTS 72.2% 37.7% Smoker 29.6% 34.6% Regular alcohol 37.5% 42.4% Braun M et al., Int J Impot Res 2000; 12:305-311
Risk Factors for BPH Progression Age 50 years or older Enlarged prostate ( 30 ml) PSA 1.4 ng/ml as a marker for prostate volume Moderate-to-severe urinary symptoms (AUA-SI score > 7) McConnell JD et al. N Engl J Med. 2003;349:2387 2398. Roehrborn CG et al. Urology.1999;53:473 480.
Clinical Outcomes in BPH vs. Other Diseases Condition Clinical Outcome Incidence (%)* Osteoporosis Vertebral fracture 1.5 Hip fracture 18 Atherosclerosis Fatal/nonfatal MI 2.1 Superficial bladder cancer Recurrence 30 88 Kidney stones Recurrence 2 47 BPH AUR 7 Surgical Intervention 10 *Annual incidence or rate per person-years Adapted from Roehrborn CG et al. Urology 2000;56:9-18; McConnell JD et al. N Engl J Med 1998; 338:557-563.
BPH Key Components of Diagnosis: History General medical history LUTS/severity/bother; hematuria, UTI, retention, incontinence Review of nervous system (evidence of neurogenic bladder) MS, spinal cord injury DM Family history of prostate cancer Past surgical history APR, spinal surgery Urethral Surgery/instrumentation Medications Note use of diuretics, antihypertensives, psychotropics, anticholinergics, hormones, some OTC cold medications Current BPH treatment Smoking, caffeine, EtOH intake
BPH / LUTS Symptoms Obstructive Symptoms Irritative Symptoms Hesitancy Weak stream Straining to pass urine Prolonged micturition Post-void dribbling Sensation of incomplete bladder emptying Acute or chronic urinary retention Overflow incontinence Frequency Urgency Nocturia Urge incontinence Dysuria Hematuria *Now: Storage and voiding
BPH Key Components of Diagnosis: Focused Physical Exam Digital rectal examination (DRE) Assess prostate size, consistency, symmetry, presence of nodules or indurations Size does not predict severity of symptoms or obstruction Also Check for suprapubic fullness (i.e., retention) Neurologic Exam
BPH Key Components of Diagnosis Urinalysis Abnormalities could suggest other problems hematuria, UTI, proteinuria Discuss PSA measurement if: Age > 50, life expectancy > 10 years (diagnosis of prostate cancer would change management) Family history of prostate cancer (age 40) African American (age 40) *** Serum creatinine High creatinine necessitates imaging of upper tract
A Word On PSA DO NOT DO PSA IF: ACUTE RETENTION INFECTION LIFE EXPECTANCY < 10 YEARS
BPH - Complications If untreated, can progress to serious complications including: Acute Urinary Retention (AUR) Bladder decompensation Upper urinary tract compromise obstructive uropathy & renal failure Recurrent UTI Bleeding Stones Bladder diverticuli Decreased quality of life Anderson JB et al. Eur Urol 2001;39:390-399.
Treatment Options - Overview Watchful Waiting Lifestyle Modifications hs fluids, limit alcohol/caffeine, timing of diuretic use Medical Therapy - -blockers, 5- -reductase inhibitors. Surgery TURP, minimally invasive strategies
- Blockers
Alpha Blockers: General Established Mechanism of Action Blockade of sympathetic activity Relaxation of prostatic and bladder-neck smooth muscle Effects Have rapid onset of action and are well tolerated Improve urinary flow and reduce LUTS Flow rates by ~ 25% Sx Scores by 20-40% (4-6 points) Do not affect prostate enlargement or PSA *** Little effect on disease progression wrt rate of AUR/surgery Adapted from Kirby RS. Eur Urol 1999;36(suppl 1):48-53.
Common -Blocker Side Effects Orthostatic hypotension Dizziness (central versus vascular phenomenon) Nasal Congestion Fatigue Head-ache GI Upset RETROGRADE EJACULATION
1A Blockers Long-acting, Subtype Selective Tamsulosin (Flomax CR) - 0.4 mg 0.8mg/day Alfuzosin (Xatral) 10mg po qd Silodosin (Rapaflo) 8 mg po qd Exhibits greater uro-selectivity Selective antagonist of 1A -receptor subtype Subtype makes up ~70% of all 1 -receptors in the prostate Once daily dosing No antihypertensive properties therefore no dose adjustments are necessary
5- -Reductase Inhibitors
5-α Reductase Inhibitors (5ARI s) Type II 5AR dutasteride finasteride x x Testosterone DHT Type I 5AR x dutasteride 5-AR = 5-alpha reductase; DHT = dihydrotestosterone Prostate Size Reduced Steers WD. Urology. 2001;58(suppl 6A):17 24. Bartsch G et al. Eur Urol. 2000;37:367 380.
5- -Reductase Inhibitors Mechanism of action Regulates conversion of Tt to DHT Prostatic levels of DHT by 80-90% Slows rate of prostate enlargement Effects (may take 6-9mo) Decreases prostate volume by ~ 20% Reduces the risk of AUR and the need for BPH-related surgery not appropriate for men with LUTS who do not have prostatic enlargement *** Will lower PSA by 50% over 12 months
Indications for 5- Reductase Inhibitors Monotherapy or Combination therapy with -blocker Large prostate - men with larger prostates (> 40 g) respond more favorably (Response can be predicted by PSA - poor response if < 1.3 ng/ml) Hematuria 2 BPH
5ARI Efficacy: Summary Data from robust randomized placebo-controlled studies has confirmed that both dutasteride and finasteride have a significant effect in men with enlarged prostates: Reducing symptoms (30% from baseline) and impact of BPH Reducing prostate size (20-30%) Improving urinary stream (1-2 ml/sec) Reducing risk of urinary retention and surgery (>50%) Improvements are generally seen after ~6 months or more and continue to build beyond 2 years of therapy McConnell JD et al. N Engl J Med 1998;338:557 63 Roehrborn CG et al. Urology 2002; 60: 434-441
PSA Testing in Patients on Medical Therapy for LUTS/BPH α-blocker therapy has no effect on PSA 5α-Reductase Inhibitors lower PSA by 40-50% in 6 months Critical to have baseline PSA Refer for biopsy if elevated Repeat PSA after 6 months treatment If does not fall, indicates non-compliance or cancer risk Double PSA value to determine cancer risk Progressively rising PSA on treatment is indication for referral and biopsy
Combination Therapy Moderate-Severe Symptoms and Enlarged Prostate -blocker Combination 5-ARI Rapid onset Improvements in symptoms and stream Further improvement in symptoms and stream Long-lasting symptom benefit Prevent disease progression Reduce risk of AUR and surgery
COMBINATION THERAPY
Cumulative incidence of progression (%) Combination therapy is better than monotherapy at reducing risk of clinical progression McConnell JD, et al. N Engl J Med 2003;349:2387-98.
Adjusted mean change in IPSS Combination therapy is better than monotherapy at improving symptoms Month Roehrborn CG, et al. Eur Urol. 2010 Jan;57(1):123-31.
What to do with the α-blocker? With combination therapy, removal of the α- blocker after 6-9 months of therapy is reasonable 1,4 Majority of men will continue to enjoy good symptom control 2,3,4 More severe baseline symptoms may require that the α-blocker be continued longer-term 2 1) Nickel CJ et al. Can J Urol; 2005;12(3);2677-2683 2) J Barkin et al. European Urology (2003): 44; 461-466. 3) Baldwin KC et al: Urology 58(2), 2001 3) Nickel et al. CUAJ 2008;2(1):16-21.
Tadalafil 5mg currently indicated for men with BPH-related LUTS Recent clinical studies investigating PDE5- inhibitors in BPH
Mean change in symptom score Mean change in symptom score Mean change in symptom score Efficacy of Tadalafil Weeks Efficacy of Vardenafil Weeks Tadalafil 20 mg Efficacy of Sildenafil Weeks McVary KT, et al. J Urol. 2007 Apr;177(4):1401-7.
Mean Change in Total IPSS Score from Baseline to Endpoint Tadalafil Dosing For BPH PLA Run In Week - 4 0-1 -2-3 -4-5 -6-7 -8 Baseline Week 0 Week 4 Week 8 Week 12 Placebo Tad 2.5 Tad 5.0 Tad 10.0 Tad 20 Clinical meaningful improvement -9 * Tadalafil 2.5mg p<.05 at week 4, and Tadalafil 5, 10, and 20 mg p<.01 for Weeks 4, 8, and 12 compared to placebo Compared to placebo (Ancova analysis)
LS Mean Change from Baseline Tadalafil vs Placebo and Tamusolsin vs Placebo Baseline Week 4 Week 8 Week 12 0 Placebo -1 Tadalafil -2 Tamsulosin -3-4 -5-6 * * * * * * -7 *P <.05 versus placebo Study LVID
Some plant extracts have shown some efficacy in small clinical trials Serenoa repens (saw palmetto berry extract) Pygeum africanum (African plum)
Mean change in symptom score No statistically significant difference between treatment with saw palmetto and placebo Month Bent S, et al. N Engl J Med 2006;354:557-66.
Absolute Indications for Surgery Refractory retention Renal failure obstructive uropathy Recurrent infections Recurrent Bleeding Stones
BPH - When to Refer Referral warranted in patients with: IPSS > 20 (severe) Urinary retention Recurrent UTI Hematuria Bladder stones Renal insufficiency Failure of medical treatment Abnormal DRE or Elevated PSA
Key Messages BPH is very common in men BPH is progressive Multiple medications are available for treatment Some men will require intervention past medical therapy