Interactive Tutorial: BPH

Question 1

Prostate

Answer 1

Function (From ERS28):
- 15-30% ejaculate volume
- main source of
1. Citric acid —> antioxidant
2. **Zinc —> antioxidant + **sperm chromatin stabilisation
3. **Prostatic acid phosphatase, **Prostate-specific antigen (PSA)
—> **Semenogelins cleavage
—> allow sperm to **swim and capacitation

Anatomy:
- Base of bladder
- Problem: Obstruction / Cancer
- McNeal’s zonal anatomy
1. **Transitional zone (wraps around prostatic urethra) (10%): Common site of BPH
2. Central zone (25%)
3. **Peripheral zone (65%): Common site of prostate cancer
4. Anterior fibromuscular stroma
5. Peri-urethral zone

Question 2

Benign Prostatic Hyperplasia (BPH)

Answer 2

Epidemiology:
- Increase with age
- >50 yo: 50-75%
- >70 yo: 80%
- More prevalent in Western countries

Etiology / Risk factors:
1. Age (Altered balance between epithelial cell maturation / apoptosis)
2. Race (Western)
3. Diet (Fat / cholesterol intake, less dietary fibre)
4. Metabolic syndrome (?DM)
5. Genetics (role unclear)
6. Growth factors (basic fibroblastic GF, insulin-like GF etc.)
7. ?Hormonal status (Increased estrogen-androgen ratio)
- Increased estrogen (obese, hyperlipidaemia)
- Reduced androgen (age-related, hypogonadism, alcohol)

Pathophysiology (although benign but ~ cancer):
1. ***Increase proliferation
- reawakening of embryonic processes in prostatic stroma which induces epithelial cell proliferation

2. ***Decrease apoptosis
3. Mediated by ***Androgen dependent growth factors
   - TGF (transforming growth factor)
   - IGF (insulin-like growth factor)
   - EGF (epidermal growth factor)

Process:
Initial **micronodule formation in transitional zone
—> periurethral region
—> fuse up to become **macronodule (aka **BPH nodule / **Adenoma)
—> obstruct prostatic urethra

NB: Large prostate not necessarily cause symptoms —> it is the ***symptoms that matter!

Question 3

Symptoms of BPH

Answer 3

LUTS:
- **Non-specific term for symptoms which may be attributable to lower urinary tract **dysfunction
- Can be attributable to other diseases not just BPH
- FUN DISH

Storage LUTS (FUN):
- **Frequency
- **Urgency
- ***Nocturia

Voiding LUTS (DISH):
- Terminal **dribbling
- **Intermittency
- **Straining
- Slow stream
- **Hesitancy
- Sense of incomplete voiding

Question 4

International Continence Society (ICS) definition

Answer 4

Frequency: Complaint of increase frequency to void than usual
Urgency: Complaint of a **sudden, compelling desire to void which is difficult to defer
Urgency incontinence: Complaint of **involuntary leakage associated with urgency
Nocturia: Complaint of interruption of sleep **>=1 time because of the need to micturate. Even void is preceded and followed by sleep
Polyuria: **>3L / day
Nocturnal polyuria: ***>1/3 of total urine output

Question 5

History taking in BPH

Answer 5

1. Details of Voiding + Storage LUTS
2. ***Dysuria (signify UTI / complication of BPH (∵ stasis of urine))
3. ***Haematuria (gross haematuria is malignancy until proven otherwise)
4. Bedwetting (High pressure chronic retention)
5. ***Lifestyle: Amount + Nature of fluid intake (usually affect Storage LUTS: frequency / urgency)
6. ***Family history of prostate cancer
7. ***History of DM, neurological disease, spinal / pelvic surgery (∵ cause neurogenic bladder (mimic BPH symptoms))

Question 6

P/E in BPH

Answer 6

1. Abdominal examination
   - Palpable bladder
   (- Ballotable kidneys)
2. Digital rectal examination (DRE)
   - **Prostate: Size, Consistency, Symmetry, Nodule (signify cancer), Presence of median groove
   - **Anal tone (esp. in AROU)
   - **Blood on glove
   - **Rectal lesion (e.g. impacted faeces)
3. External genitalia
   - Meatal stenosis
   - Palpate for urethral stone
   (- Phimosis)

Question 7

Investigations in BPH

Answer 7

1. Blood test
   - CBC + Clotting profile —> prepare for surgery
   - RFT —> Obstructive uropathy
   - PSA:
   —> only for patients with life expectancy >10 years + after detail counselling
   —> do NOT check PSA during retention / UTI (falsely elevated)!
2. ***Urinalysis
   - Urine microscopy —> rule out UTI
   - Urine culture —> rule out UTI
3. KUB
   - Stone
4. ***Uroflowmetry + Post-void residual urine (PVR)
   - <10 ml/s: 90% of patients have BOO
   - 10-15 ml/s: 60%
   - >15 ml/s: 30%
5. **IPSS + **QOL scores
   - Assess severity (guide treatment)
   - Risk factor for progression

(6. Frequency-volume chart (esp. if Storage LUTS) —> 3 days record of fluid intake, urine output including night, incontinence issue)

Others:
7. ***Transrectal USG of prostate (TRUS)
- Measure size of prostate
- Before starting 5α-reductase inhibitor (only useful in large prostate >30-40cc)
- Before surgery to decide modality of surgical intervention

8. ***Flexible cystoscopy
   - Not necessarily unless haematuria
9. ***USG / CT urogram
   - Not necessarily unless haematuria
10. **Urodynamic study (Check **Detrusor contractility)
    - Specific indications to look for alternative diagnosis
    —> Atypical age (very young: 40s —> suspected other pathologies other than BPH)
    —> Suspected neurogenic bladder
    —> History of spinal / pelvic surgery
    —> Failed intervention for LUTS

Question 8

Obstructive uropathy

Answer 8

Deranged RFT during AROU —> after catheterisation RFT improve —> deranged RFT is due to Obstructive uropathy

Treatment implication:
- Obstructive uropathy —> ***Absolute indication for surgery (TURP) in BPH

Question 9

Uroflowmetry

Answer 9

• Electronic recording of urinary flow rate through course of micturition
• Provide visual image of “strength” of patient’s urine stream
• Interpret with caution: **non-diagnostic, **non-specific for causes of symptoms
• Must void >150ml to be representative

1. Drink 500-1000ml fluid and wait until the patient has a comfortably full bladder
2. Pass urine into machine
   - Avoid squeezing of penis
   - Avoid stream wandering around the funnel (give inaccurate result)
   - Avoid straining
3. Aim pass >=150ml (∵ voided volume too small —> flow will definitely weak —> inconclusive)
4. Repeat if voided volume <150ml

Interpretation:
1. Look at voided volume
- >=150ml —> Representative
- <150ml —> Inconclusive

2. Maximum flow (**Qmax)
   - **predict risk of Urodynamical bladder outlet obstruction (BOO)
   —> <10 ml/s: 90% of patients has BOO
   —> 10-15 ml/s: 60%
   —> >15 ml/s: 30%

(Normal values:
- Men <40: >=21 ml/s
- Men 40-60: >=18 ml/s
- Men >60: >=13 ml/s
- Women <50: >=25 ml/s
- Women >50: >=18 ml/s)

3. **Pattern
   - Normal: Bell shape
   - **Prolonged voiding + **Low Qmax: BPH
   - **Plateau shape (Fixed Qmax): Stricture (pathognomonic: peak flow limited by diameter of stricture)
   - Very high Qmax + Short voiding time: Detrusor overactivity (Dysfunctional voiding curve)
   - Intermittent flow curve: Neurogenic bladder
4. ***Post-void residual urine (PVR)
   - Normal: <50-100ml

Question 10

IPSS + QOL scores

Answer 10

IPSS: International Prostate Symptom Score
1. 7 questions on LUTS
- How often do you experience:
—> Storage (FUN): Frequency, Urgency, Nocturia (times)
—> Voiding (IISS): Intermittency, Straining, Slow stream, Sense of incomplete voiding
- Frequency: 0 (not at all) - 5 (all the time, except Nocturia)
- 0-7: Mild
- 8-19: Moderate
- 20-35: Severe

2. 1 question on QOL
   - 0 (delighted) - 6 (terrible)

Role:
1. Assess **severity (guide treatment)
2. **Monitor treatment response
3. ***Predict risk of progression of BPH (i.e. risk of future ROU, future need of surgery)

(Symptoms questionable when correlated with home uroflowmetry, only correlation with nocturia is good —> should do both together)

Question 11

***Treatment of BPH

Answer 11

1. Watchful waiting
2. Medical therapy
   - α blockers (1st line)
   - 5α-reductase inhibitors
   - Anticholinergics (for storage symptoms)
   - β3 agonists (for storage symptoms)
3. Surgery
   - Resection (TURP / TUIP)
   - Enucleation (HOLEP / BIPOLEP / Open)
   - Greenlight laser vaporisation (i.e. Photosensitive vaporisation of prostate (PVP))
   - Ablative techniques: Prostate artery embolisation (PAE), Water vapour energy ablation (REZUM), Aqua-ablation
   - Non-ablative techniques: Prostatic urethral lift (PU lift / Urolift)

Question 12

1. Watchful waiting

Answer 12

Indication:
- Mild symptoms (i.e. ***IPSS: 0-7)

Components:
1. Education + reassurance
2. Periodic monitoring
3. **Lifestyle modification
- Reduce fluid intake at night
- Avoid caffeine / alcohol
- Treat constipation
- Review medications (avoid cough mixtures etc.)
- **Double-voiding for sense of incomplete emptying
- **Urethral milking for post-micturition dribbling
- **Bladder retraining for urgency (esp. for Storage LUTS)

(- 66% stays the same at 5 years
Risk (but low) of:
- Symptom progression
- AROU
- UTI
- Bladder stone
- Renal insufficiency
- Incontinence
- Haematuria)

Question 13

2. Medical therapy: α blockers

Answer 13

Indication:
- Moderate to Severe LUTS (***IPSS: >=8)

α blockers:
- Improve **dynamic component of BOO
- Antagonise alpha 1A receptor in smooth muscle of prostate —> relaxation of smooth muscle —> **↓ in prostate tone —> ↓ in bladder outlet resistance (but **NO change in prostate size)
- Improve **symptoms + Qmax but **NOT progression, AROU, need for surgery (*risk remain the same)

SE (α1A+1B receptor in CNS system, α1+2 receptor in blood vessels):
- Asthenia (5%)
- **Dizziness (6%)
- Headache (2%)
- **Postural hypotension (1%)
- ***Retrograde ejaculation (8%) (∵ bladder neck relaxation —> semen go into bladder instead)
- Rhinitis (Tamsulosin) (rare)
- Intraoperative floppy iris syndrome (rare)
- Erectile dysfunction (controversial, 5%)

Types (unimportant):
1. α1 selective (short-acting) (issue with compliance)
- Prazosin
- Alfuzosin IR

2. α1 selective (long-acting)
   - ***Terazosin
   - Doxazosin
   - Alfuzosin SR
3. α1a selective (consider when SE prominent —> avoid dizziness, postural hypotension)
   - ***Tamsulosin
   - Silodosin

Question 14

2. Medical therapy: 5α-reductase inhibitors

Answer 14

Testosterone can bind directly to the AR / converted to DHT by 5AR (5α-reductase)
—> Testosterone diffuse into cell
—> Epithelial cell: bind to AR + induce growth factor
—> **Stromal cell: majority converted to **DHT by ***Type 2 5AR —> bind to AR / diffuse into nearby epithelial cell (Paracrine action)
—> Complex bind to specific binding site of nucleus
—> Induce transcription of androgen-dependent gene
—> Protein synthesis
—> Development of BPH

2 isoforms of 5AR:
- Type 1: Extra-prostatic (skin, liver)
- ***Type 2: Prostatic (nuclear membrane of stromal cell, but not epithelial cell)

5α-reductase inhibitors:
- Suppression of conversion of testosterone to **DHT —> prostate epithelial cells apoptosis —> ↓ prostate volume
- Improves **static component of BOO
- Use alone / **combination with α-blockers (for **large prostate >30-40cc)
—> Improve symptoms + Qmax + **Prevent progression, AROU, need for surgery
- Also suppress VEGF, reduce vascularity —> useful for **Bleeding BPH

Types:
1. Finasteride (Type 2 5ARI)
2. Dutasteride (Type 1+2 5ARI)
- similar efficacy
- max effect after 6 months (compliance counselling)
- durable effect
- ***reduce prostate volume + PSA level by ~50% after 6-12 months (need adjust PSA by x2 ∵ prostate volume is reduced by 50%)

SE:
- **Erectile dysfunction
- **Decreased libido
- Ejaculatory disorder
- Gynaecomastia

Question 15

2. Medical therapy: Anticholinergics

Answer 15

Muscarinic receptors:
- M1-5
- Bladder: 80% M2, 20% M3
- Bladder contractions involve mainly M3
- Role of M2 in bladder unclear
- Brain: M1-5
- Eye, salivary gland: M3
- Heart, intestine: M2-3

MOA:
- Competitive antagonist on post-synaptic M3 receptor
—> Inhibit opening of Ca channel by inhibiting Phospholipase C/IP3 pathway
—> Reduce smooth muscle contraction

Indication:
- Uncommon drug used in BPH
- Refractory ***Storage symptoms (improve frequency, urgency)

Types (most are non-selective):
Tertiary amine
1. ***Oxybutynin (M1-3)
2. Tolterodine (functional selectivity for bladder over salivary gland)
3. Solifenacin (M2-3)
4. Darifenacin (M3)
5. Fesoterodine (non-selective)
6. Propiverine (non-selective)

Quaternary amine (less lipophilic, not cross BBB, less CNS SE)
1. Trospium chloride

SE:
- Dry mouth
- Constipation
- Dizziness
- Glaucoma
- Cognitive impairment

CI:
- **Uncontrolled acute closure angle glaucoma
- Untreated ulcerative colitis (Toxic megacolon)
- Intestinal obstruction
- MG
- **Urinary retention / Large residual urine volume (PVRU) (>=200ml (SpC Revision))

Question 16

2. Medical therapy: β3 agonists

Answer 16

**Mirabegron
- Improve **Storage symptoms (frequency, urgency)

MOA:
- Different pathway than Antimuscarinics
- Activate adenylate cyclase, facilitate ATP to cAMP —> Protein kinase A —> Smooth muscle relaxation —> ↓ Detrusor contraction

Indication:
- Intolerance to antimuscarinic
- Suboptimal Storage LUTS despite antimuscarinic

Less SE (dry mouth / constipation) than antimuscarinic
- well tolerated
- more expensive

Question 17

3. Surgery

Answer 17

Indications (RUSHES)
**Absolute indication:
1. Recurrent / Refractory **retention of urine (>=2 times requiring catheterisation)
2. Recurrent **UTI due to obstruction
3. Bladder **stone
4. Recurrent haematuria due to bleeding BPH
5. **Obstructive uropathy (*elevated creatinine due to BOO)

Relative indication:
1. LUTS **suboptimal control with drugs
2. **Bothersome LUTS who does not want medical treatment (due to their lower reduction in SS)

Types:
1. Resection (**small-moderate prostate 30-80g)
- **TURP
- TUIP

2. Enucleation (**large prostate >80g)
   - **HOLEP (Holmium laser enucleation of prostate)
   - ***BIPOLEP (Transurethral bipolar endoscopic enucleation of prostate)
   - Open enucleation (Obsolete due to complications)
3. Vaporisation (reserved for patient on ***anticoagulant which cannot be stopped peri-operatively)
   - Greenlight laser vaporisation (i.e. Photosensitive vaporisation of prostate (PVP)) —> very good in haemostasis but not good in resection + cannot obtain cell for cytology

(New technology:
4. Ablative techniques: Prostate artery embolisation (PAE), Water vapour energy ablation (REZUM), Aqua-ablation
5. Non-ablative techniques: Prostatic urethral lift (PU lift / Urolift)
—> can be done in ***LA
—> less erectile dysfunction, ejaculatory dysfunction after surgery)

Question 18

Transurethral resection of prostate (TURP)

Answer 18

• ***Gold standard for prostate <80g
• Piecemeal resection of prostate from inside out (由中間開始切一舊舊 —> 切到出面 —> more bleeding + inadequate resection + tissue left behind)
• GA / Spinal anaesthesia
• No need further medication after surgery

Types:
1. Monopolar TURP
- **Glycine as irrigation fluid
- SE of **TUR syndrome: dilutional ***hyponatraemia due to systemic absorption of glycine

2. Bipolar TURP
   - ***Saline as irrigation fluid
   - No TUR syndrome

Complications:
Specific:
1. **Incontinence (2%)
2. **Erectile dysfunction (6.5%)
3. **Retrograde ejaculation (68%)
4. **Urethral stricture / bladder neck stenosis (4%)
5. ***TUR syndrome (0.5%)

General:
1. Bleeding (2%)
2. Sepsis (4%)
3. DVT / PE
(4. Re-operation
5. Death)

Question 19

Transurethral incision of prostate (TUIP)

Answer 19

• For ***small prostate <30g
• AS effective as TURP in small prostate in relieving obstruction

Advantage:
1. Less bleeding
2. Shorter operative time
3. Less retrograde ejaculation
4. Less bladder neck stenosis / stricture

Question 20

(Anatomical) Endoscopic enucleation of prostate (AEEP)

Answer 20

Standard for ***large prostate >80g

Mode of energy:
1. HOLEP (Holmium laser enucleation of prostate)
2. BIPOLEP (Transurethral bipolar endoscopic enucleation of prostate) (bipolar diathermy)

Procedure:
1. Laser enucleation (剝橙皮)
2. Haemostasis
3. Morcellation (打散攞出黎)

Advantage over TURP:
1. **Less bleeding (∵ enucleation plane: a natural plane between adenoma and prostate capsule with minimal blood (~剝橙皮) vs TURP: many raw surfaces created by surgery)
2. Shorter catheterisation time
3. **More radical resection of BPH nodule
4. Better improvement in Uroflowmetry parameters (Qmax + RU)
5. ***Lower chance of recurrence / need for repeat intervention
6. Similar complication rate

Disadvantage:
1. **More technically demanding
2. **Longer operative time

As effect as Open simple prostatectomy with lower morbidities

Question 21

Open simple prostatectomy

Answer 21

• Obsolete (∵ advancement in EEP produce similar effect with less morbidities, replaced by EEP now)
• Considered the most effective + durable procedure for BPH
• Large prostate >80-100g

Disadvantage:
- High bleeding risk, transfusion (>50%), incontinence (>10%)

Question 22

New technology: Convective Water vapour energy (WAVE) ablation (REZUM)

Answer 22

MOA:
- Radiofrequency power to create thermal energy in the form of water vapour
—> deposits the stored thermal energy when steam phase shifts to liquid upon cell contact
—> steam disperse through tissue interstices
—> release thermal energy onto prostatic tissue
—> cell necrosis

Advantage:
- Can be done under **LA
- Preserve erectile + ejaculatory function —> good for **young patients

Disadvantage:
- Lack long term data

Question 23

New technology: Prostate artery embolisation (PAE)

Answer 23

Interventional radiology —> Embolisation of both Left + Right prostate artery

Advantage:
- Can be done under ***LA
- Less bleeding
- Shorter catheterisation time (compared to TURP)

Disadvantage:
- Lack long term data

Question 24

New technology: Prostatic urethral lift (PU lift / Urolift)

Answer 24

MOA:
- Permanent anchor-like implants made of nitinol, stainless steel and sutures
—> deployed using a specifically designed delivery device
—> retracting the enlarged lateral prostate lobes (扯開prostate lobes)
—> restore a patent prostatic urethral channel

Advantage:
- Can be done under **LA
- Preserve erectile + ejaculatory function —> good for **young patients

Disadvantage:
- Lack long term data

Question 25

New technology: Aqua-ablation

Answer 25

Image guided robotic waterjet ablation: AquaBeam MOA: - A targeted high velocity saline stream ablates prostatic tissue without the generation of thermal energy under real-time transrectal ultrasound guidance Advantage: - Lower risk of retrograde ejaculation Disadvantage: - High transfusion rate - Risk of bleeding requiring emergency operation —> Less popular now - Ejaculatory dysfunction - Lack long term data

Question 26

TUR syndrome

Answer 26

- 1.5% Glycine is hypotonic (2.2% Glycine is isotonic but N+V) (cannot use saline —> ions within will dissipate energy of diathermy) - Multifactorial: —> Dilutional HypoNa + Osmotic natriuresis by Glycine + Bleeding etc. —> Common end point: HypoNa —> Risk factor: Long operation time Symptoms: - 30-60 mins post-op / during intra-op (patients can tell if only on Spinal anaesthesia) - HypoNa: <125 usually symptomatic - Low serum osmolality 1. Confused, restless 2. CVS symptoms - Typical: ***↑ ICP —> ***↑ BP + ***Bradycardia - If extensive bleeding —> ↓ BP, Tachycardia 3. Seizure, coma Prevention: 1. TURP <1 hour 2. Irrigation continuous, well controlled pressure (<1m) 3. Reduce intra-vesical press (clear outflow) 4. Keep body temp warm 5. Recognise problem early - ***Monitor U+E on table - Prompt TURP termination - ***Early IV furosemide / mannitol (diuresis) —> pass Na but pass more H2O - ***Methods to monitor: measure patient’s weight, 1% ethanol —> (absorb 20 ml/min - 1200 ml/hr) Treatment: 1. Supportive care 2. ***IV 0.9% Saline + Fluid restriction (CAUTIOUS fluid overload with saline) 3. ***IV furosemide / mannitol 4. Monitor clinical status 5. If Na <120 / unwell —> ICU —> 3-500 ml 3% saline (***hypertonic) / slowly over 4 hours —> Consider ***haemofiltration