Benign Prostatic Hyperplasia · –Recognize and diagnose LUTS secondary to benign prostatic hyperplasia (BPH) ... –Upper urinary tract compromise –obstructive uropathy & renal

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

LUTS – Lower Urinary Tract Symptoms

Hypertrophied detrusor muscle

Obstructed urinary flow

Natural History of BPH: Symptoms Worsen

Kirby RS et al. Benign prostatic hyperplasia. Health Press, 1995.

14

30%

55%

15%

Remain Stable ImproveWorsen

Richard F et al., Prog Urol 2001; 11(2):250-63.

0

10

20

30

40

50

60

7%9%

11%

27%

50-59 years

9%

15%17%

21%

60-69 years

30%

35%33%

48%

70-79 years

0 1-7 8-19 20-35 pointsIPSS

2,372 French menIIEF

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%

ED(n=853)

No ED(n=3581)

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;349:23872398. Roehrborn CG et al. Urology.1999;53:473480.

Clinical Outcomes in BPH vs. Other Diseases

Condition Clinical Outcome Incidence (%)*

Osteoporosis Vertebral fracture 1.5Hip fracture 18

Atherosclerosis Fatal/nonfatal MI 2.1

Superficial bladder cancer Recurrence 30–88

Kidney stones Recurrence 2–47

BPH AUR 7Surgical 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

Hesitancy

Weak stream

Straining to pass urine

Prolonged micturition

Post-void dribbling

Sensation of incomplete bladder emptying

Acute or chronic urinary retention

Overflow incontinence

Irritative Symptoms

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

dutasteride

dutasteride

finasteride

Prostate Size Reduced

DHTTestosterone

5-α Reductase Inhibitors (5ARI’s)

Steers WD. Urology. 2001;58(suppl 6A):17–24.Bartsch G et al. Eur Urol. 2000;37:367380.

x x

x

5-AR = 5-alpha reductase; DHT = dihydrotestosterone

Type I 5AR

Type II 5AR

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 TherapyModerate-Severe Symptoms and Enlarged Prostate

✓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

-blocker Combination 5-ARI

COMBINATION THERAPY

McConnell JD, et al. N Engl J Med 2003;349:2387-98.

Combination therapy is better than monotherapy at reducing risk of clinical progression

Cu

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of

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Years

Roehrborn CG, et al. Eur Urol. 2010 Jan;57(1):123-31.

Combination therapy is better than monotherapy at improving symptoms

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What to do with the α-Blocker?

• With combination therapy, removal of the α-blocker after 6-9 months of therapy is reasonable1,4

• Majority of men will continue to enjoy good symptom control2,3,4

• More severe baseline symptoms may require that the α-blocker be continued longer-term2

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

McVary KT, et al. J Urol. 2007 Apr;177(4):1401-7.

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WeeksEfficacy of Tadalafil

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Tadalafil 20 mg

Efficacy of Vardenafil

Weeks

Efficacy of Sildenafil

-9

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PLA Run InWeek - 4

BaselineWeek 0 Week 4 Week 8 Week 12

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Placebo

Tad 2.5

Tad 5.0

Tad 10.0

Tad 20

Tadalafil Dosing For BPH

Compared to placebo (Ancova analysis)

* 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

Clinical meaningfulimprovement

*

*P < .05 versus placebo-7

-6

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Baseline Week 4 Week 8 Week 12

Placebo

Tadalafil

Tamsulosin

* *

***

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Study LVID

Tadalafil vs Placebo and Tamusolsin vs Placebo

• Some plant extracts have shown some efficacy in small clinical trials

• Serenoa repens (saw palmetto berry extract)

• Pygeum africanum (African plum)

Bent S, et al. N Engl J Med 2006;354:557-66.

No statistically significant difference between treatment with saw palmetto and placebo

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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