MEDICAL MANAGEMENT OF BPH

DR ANCHAL,DNB RESIDENT UROLOGY

MMHRC

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What is the pathology of BPH?

• Hyperplastic process

• Earliest sign : micronodule formation in transitional zone – lateral lobes (mixture of stromal cell and epithelial component) and in periurethral region –median lobe within the smooth muscle collar of the preprostatic sphincter (mainly connective tissue)

• Further coalescence and growth of micronodule become macronodule

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Pathophysiology of BOO

• BOO cause thickening of bladder wall

• High intra-renal pressure hydronephrosis

• Impair renal function & even renal failure

• Microscopic: – Smooth muscle cell enlarged

– Increase in connective tissue (collagen and elastin) btw SM bundles

– Lead to poor compliance

• BOO also cause bladder overactivity– Prolong increase intravesicle pressure during voiding

– Ischemia of bladder wall

– Damage to neurons within the bladder (denervation)

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Some clinical definition• LUTS: Lower urinary tract symptom:

– Non-specific terms for symptom which may be attributable to lower urinary tract dysfunction

– Storage LUTS (Frequency, Urgency, Nocturia) – Voiding LUTS (Hesitancy, Straining, Slow stream, intermittency,

terminal dribbling, sense of incomplete voiding)

• BOO: Bladder outflow obstruction– Urodyanmical diagnosis of an obstruction to passage of urine

• BPE: Benign prostate enlargement: – Clinical finding of an enlarged prostate

• BPH: Benign prostatic hyperplasia: – Histological basis of BPE leading to BOO that result in LUTS

• BPO: Benign prostatic obstruction: – BOO cause by BPE

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Differential Diagnosis of LUTS

• Prostate1

– Obstruction (BPH, BPE, BOO) (30%)• Bladder1

– Detrusor overactivity (50%)– Impaired detrusor contractility (30%) – Sensory urgency– Sphincteric incontinence – Polyuria/nocturnal polyuria

• Medications2

– Antihistamines– Antidepressants

1. Chaikin DC, Blaivas JG. Curr Opin Urol. 2001;11:395-398. 2. Su L et al. J Clin Epidemiol. 1996;49:483-487.

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What are the different instrument for measurement of LUTS in men?

• DAN (Danish Prostate Symptom Score)

• Bristol Male LUTS

• AUA

• IPSS

– Derived from AUA + 1 more QOL question

– Most commonly used

– Valid , Reliable and reproducible

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IPSS• 7 Question + 1 QOL• How often do you experience:

– Voiding: Straining , intermittency, slow stream, sense of incomplete voiding– Storage: Nocturia (times), Frequency (<2 hr) , Urgency

• Frequency: – not at all 0 – <1/5 : 1– <1/2 2– ½ : 3– > ½ : 4– all the time : 5 (except nocturia)

• 0-7 mild; 8-19 moderate, 20-35 severe

• QOL: 0:delighted > 6:terrible

• Reliable, reproducible and valid

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Barry et al J Urol 1995

• A 3-point absolute drop in IPSS is required for the patient to perceive as improvement

• The required drop in score is greater in those with higher baseline IPSS

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Any drawbacks of IPSS?

• Drawbacks

– Does not make a diagnosis, just a symptom score

– Not prostate / BPH specific – females / patients with CPPS can have an IPSS score

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Treatments for LUTS, BPH, BOO

• Watchful waiting• Medical therapy

– 5-reductase inhibitors

– -blockers– Combination therapy– Phytotherapy

• Office-based treatment– TUMT– TUNA– WIT

• Surgicenter/hospital-based treatment– TURP (gold standard)– TUIP– Open surgery– TUVP– ILC– VLAP– Prostatic stents

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What are the important factors in treatment of LUTS/BPH??

Degree of bothersome

Risk of progression

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What is the treatment option of WW?• Mild to moderate LUTS• Moderate to severe symptoms without bothering • Components for WW

– Reassurance, education and explanation to patients– Lifestyle advice : esp for storage LUTS

• Reasonable fluid intake, timed voiding• Reduction of fluid before bedtime (nocturia)• Avoidance of caffeine and alcohol• Avoiding medications like antihistamine• Double voiding and urethral milking (sense of incomplete voiding

and post-micturition dribble)• Distraction technique for irritative LUTS• Avoid constipation

– Periodic reevaluation with SS, UFR and PVR to check for Progression

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What is the evidence of WW?

• Option for many men as few, if left untreated, will progress to acute urinary retention and complications

• Some men’s symptoms may improve spontaneously, while others’ symptoms remain stable for many years

• IPSS in Placebo group from PLESS study even decrease 1.3 after 4 years

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What is the evidence of WW?

• Ball study (AJ Ball, P Abrams et al, BJUI 1981)

• 100 men with LUTS FU 5 yrs

– 25% get better, 30% get worse, 40% same

• 2% AUR, 10% require surgery

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BPH – Medical Therapy

Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; National Cancer Institute. NIH Publication No. 99-4303, 1999.

Alpha blockers 5-Alpha reductase inhibitors

Improve symptoms and increase urinary flow rate by relaxing prostatic and bladder-neck smooth muscle through sympathetic activity blockade

Improve symptoms, increase urinary flow rate, and prevent BPH outcomes by reducing prostate enlargement through hormonal mechanisms

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• Mechanisms

– Relaxation of the dynamic smooth muscle component in the stroma of the prostate via competitive antagonism at the A1R

– Reduce prostate tone and bladder outlet obstruction

• It has been shown that α-blockers have little effect on urodynamically determined bladder outlet resistance

– For female bladder neck, not supplied by adrenergic nerves

• So other proposed mechanisms

– Induction of apoptosis

• Doxazosin and terazosin have been shown in vitro to induce apoptosis in prostate cells independent of the A1R (but contrary to this is the lack of change in size of the prostate seen clinically)

• By working at extraprostatic sites

– Detrusor (by increasing blood flow)

– Spinal cord ?

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Djavan

• Meta-analysis 1999 of AARB [EU]– Response rate : 30-40%

– Reduce SS by 30% (4pt)

– Improves Qmx by 16-25%

• All alpha·1-adrenoceptor antagonists (alfuzosin, terazosin, doxazosin and tamsulosin) produce comparable improvements in LUTS and urinary flow

• Max effect at ~4weeks

• No reason to prolong for more than 1 month if not efficacious

• 1/3 of men will not experience SS reduction

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Summary

Terazosin Doxazosin Alfuzosin Tamsulosin

Qmax rise 0.6-2 1.4-3.5 1.3 1.3-1.7

SS drop 1-2.3 2-4 1.6 2.3-3.2

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How many types of Alpha 1 receptors are you aware of?

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Alfa1-adrenoceptor (AR)• Mediate prostates smooth muscle contraction• Alpha 1 receptor (A1R) can be divided, based on molecular cloning and in

vitro studies– High affinity for prazosin :

• A1aR, A1bR and A1dR

– Low affinity for prazosin :• A1LR (may represent a functional phenotype of A1aR)

– A2R• All three high affinity types have been demonstrated in the prostate stroma

(influence of SM tone)– 70% predominance A1aR

• Inferred that dynamic component of the prostate smooth muscle is via activation of the A1aR but the contribution of the other subtypes are not clear

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• Rapid relief of symptoms and improvement of flow rate (days)

• Effective regardless of prostate size3

– Reduces symptoms equally well in patients with and without BOO

• Effective irrespective of patient symptom (mild , moderate or severe)

• Effective across all age group• Do not reduce prostate size• Do not prevent AROU

AARB : Summary

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Summary: -Blockers• All alpha-blockers seen to have similar efficacy in improving

symptoms and flow• Tamsulosin has less effect on blood pressure than alfuzosin

(especially in elderly patients) and causes less symptomatic orthostatic hypotension

• Tolerability of alfuzosin and tamsulosin is similar and better than other agent

• Benefit of alfa1-AR has shown to be better than placebo and finasteride in men with LUTS by RCT

• Low risk of morbidity2

• Differences between agents with regards to

– Cardiovascular side effects

– Sexual side effects: more retrograde Ejaculation in Tamsolusin

– More vasodilatory SE with alfulzosin

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What are the side effects of AAR?

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What are the side effects of AAR?

1. Asthenia, dizziness – 10%

2. Postural hypotension (1%)

– doxazosin and terazosin > alfuzosin and tamsulosin

3. Impotence (5-8%)

4. Retrograde ejaculation (8%)

– 1% with doxazosin, terazosin, alfuzosin (Djavan)

– 4% with tamsulosin 0.4mg (Djavan) – more

5. Rhinitis

– Tamsulosin

• In studies, up to 30% withdraw because

– Lack of efficacy

– Adverse effects

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What is IFIS?

• Intraoperative floppy iris syndrome

• First reported in 2005 in cataract surgery among patients taking tamsulosin

Chang DF, Campbell JR. Intraoperative floppy-iris syndrome associated with tamsulosin (Flomax). J Cataract Refract Surg 2005; 31:664–673

• Triad of intraoperative findings during cataract surgery

1. Poor preoperative pupil dilation

2. Iris billowing and prolapse

3. Progressive intraoperative myosis

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How does 5ARI work?

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Two types of 5AR (testosterone to DHT)

• Type 1 : predominance in extraprostatic tissue (skin, liver), role in BPH remains unclear

• Type 2 : predominance in prostate but also expressed in extraprostatic tissue, for prostatic growth, development and hyperplasia process

• Testosterone: DHT in prostate is 1:5 • Causes apoptosis and atrophy of the epithelial part

of the prostate• Reduce the “static” component of BPH• Prostate size reduction: 20-25%• PSA level: ½ after 6-12m of treatment

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What is the result of dutasteride VS finasteride?

• Finasteride: Type II inhibitor (5mg)

• Dutasterdie : Type I & II inhibitor (0.5mg))

• Both reduce prostate DHT concentration by 90%

• Indirect comparison between individual studies and one unpublished direct comparative trial indicate that dutasteride and finasteride are equally effective in the treatment of LUTS

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What are the indications of 5ARIs?

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Indications

• Men with LUTS and an enlarged prostate (> 40cc)

• Boyle meta-analysis of RCTs concluded that finasteride only be useful if prostate gland > 40cc

• Those with risk for progression – PLESS and MTOPS can reduce progression

• Effective treatment for refractory hematuria due to prostate bleeding– Suppression of VEGF

– Insufficient data to use 5AR before TURP to reduce bleeding

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What is the efficacy of 5ARIs?

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• PLESS [MaConnell NEJM 1998]

• 4 yrs of 5 AR Inhibitors vs placebo

– Increase of Qmax 1.9ml/s (placebo 0.2)

– Decrease in SS by ~3 (placebo 1.3)

– Reduce risk of AUR by ~60% (5% vs 10%)

– Reduce risk of BPHRS by ~60% (3% vs 7%)

– Reduce prostate size by 20% (vs 15% in placebo)

• AUA

– Less effective in improving LUTS than alpha-blocker

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EAU

• Only suitable for long term treatment• After 2-4 yr of treatment:

– Reduce symptom score by 15%– Reduce prostate volume: 20-25%– Increase Qmax: 2ml/s

• Symptom reduction not better than placebo if prostate size < 40cc

• Dutasteride reduce IPSS, prostate volume & AROU and increase Qmax even if prostate 30-40cc

• Reduce symptom slower than AARB• Reduce risk of AROU better than AARB• Reduce blood loss during TURP (decrease vascularization)

• High PSA & large prostate seems to be most beneficial

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What are the side effects

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PLESS

• Decreased libido 6%

• ED 8%

• Ejaculate disorder (retrograde, failure , decrease semen volume) 4%

• Rash, breast enlargement, tenderness1%

• Most of these occur during the 1st yr and does not increase over time

• But leads to withdrawal from PLESS in 30%

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How does 5ARI affect PSA and does that mask the early detection of

prostate cancer?

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EAU

• 5ARI lower the PSA by ~50% after 1 yr. • Both the PLESS Study Group & Finasteride PSA

study Group (Andriole Urology 1998 and Oesterling Urology 1997) have verified that :

• doubling the PSA value after taking finasteride allows appropriate interpretation of PSA and 5ARI does not mask the detection of prostate cancer.

• Histologically it has also been shown that 5ARI does not cause problems with interpretation of TRUS Bx (PLESS study Group Yang Urology 1999)

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What are the role of antimuscarinics?

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What are muscarinic receptors?

• Five muscarinic receptor subtypes (M1-M5) have been described in humans, of which the M2 and M3 subtypes are predominantly expressed in the detrusor

• Although approximately 80% of these muscarinic receptors are M2 and 20% M3 subtypes, only M3 seems to be involved in bladder contractions in healthy humans

• The role of M2 subtypes remains unclear. However, in men with neurogenic bladder dysfunction and in experimental animals with neurogenic bladders or bladder outlet obstruction M2 receptors seem to be involved in smooth muscle contractions as well

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How dose bladder contraction mediated?

• Scaral (S2-4) micturition centre connet to bladder via pelvic nerves

• Acetlcholine stimulate post-synaptic muscarinic receptor G-protein mediated Ca release opening of Ca channels SM contraction

• Anticholinergic inhibitsmuscarinic receptor stimuation reduce SM cell contraction

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What is the use of antimuscarinic in BPH?

• Muscarinic receptor antagonists might be considered in men with moderate to severe LUTS who have predominantly bladder storage symptoms

• This drug should be used precautiously if residual urine >250-300ml

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What is the evidence of Antimuscarinic vs Placebo?

• Randomized, placebo-controlled trials demonstrated that Tolterodine can significantly reduce: 1. Urgency incontinence

2. Daytime or 24-hour frequency

3. Urgency related voiding – Roehrborn et al, et al. Extended-release tolterodine with or without

tamsulosin in men with lower urinary tract symptoms and overactive bladder: effects on urinary symptoms assessed by the International Prostate Symptom Score. BJU Int. 2008 Nov;102(9):1133-9. Epub 2008 May 26.

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What is the evidence of antimuscarinic?

• If treatment outcome was stratified by PSA, tolterodine significantly reduced daytime frequency, 24h voiding frequency and IPSS storage symptoms in those men with PSA concentrations below 1.3 ng/mL, which was not the case in men with PSA of 1.3 ng/mL or more indicating that men with smaller prostates might profit more from antimuscarinic drugs– Roehrborn CG, Kaplan SA, et al. Effects of serum PSA on efficacy of tolterodine extended

release with or without tamsulosin in men with LUTS, including OAB. Urology 2008 Nov;72(5):1061-7

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Urodynamic effect of Antimuscurinic

• Larger bladder volume to first detrussorcontraction

• Decrease bladder contractility index

• Qmax is unchange

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What are the side-effects of antimuscarinic?

1. Dry mouth - 25%2. Constipation (4%) similar to placebo3. AROU and increase of postvoid residual urine in

men without bladder outlet obstruction is minimal and not significantly different compared to placebo

4. Nasopharyngitis (3%) 5. Dizziness (5%)6. Withdrawal rate – 10%

– Withdrawal due to side-effect <1% (no diff from placebo)

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Will it cause retention?

• Increase PVR is minimal and no different from placebo

• Fesoterodine 8mg show higher PVR than fesoterodine 4mg or placebo

• Incidence of AROU is comparable to placebo

• Men with BOO : not recommended due to theoretical risk

• Generally recommend that not for PVR > 200ml and Qmax < 5ml/s

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What are the studies : antimuscarinics + AARB?

TIMES JAMA2006• LUTS +OAB, no prior Rx

• Tolterodine SR (Tsr) + tamsulosin (T) ,either therapy, placebo

• Tsr +T in general more efficacious than either one

• Tsr = Tsr +T in low PSA and small prostate

• Tsr +T suggested for high PSA and high prostate vol

• Exclude PVR > 40% of CC

• Conclusion: Combination therapy is more efficacious then mono therapy , esp in pt with high PSA + prostate volume

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ADAM Pfizer data

• On alpha1 blockers with persistent OAB• Randomized to continue alpha-1-blockers with Tsr or placebo

• Conclusion: Pt on AARB with persistent OAB will have improved sym when adding Tsr

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What are the recommendations of combination therapy?

• Combination treatment with α-blocker and muscarinic receptor antagonist might be considered in patients

– with moderate to severe LUTS if symptom relief has been insufficient with the monotherapy of either drug

– More effacicious with pt with high PSA + prostate volume

• Combination treatment should cautiously be prescribed in men who are suspicious of having bladder outlet obstruction

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What phytotherapeutic agents are you aware of?

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Is there any role of phytotherapy?

• EAU Guidelines committee is unable to make specific recommendations about phytotherapy of male LUTS because of the heterogeneity of the products and the methodological problems associated with meta-analyses

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Phytotherapy

• Saw Palmetto berry (Seronoa Repens)– Anti-inflammatory , antiproliferative , oestrogenic drug

with 5ARI activity

– Previous Meta-analysis : 40% reduction in symptom score (same as finasteride) [ Wilt JAMA 1998]

– Recent study: no difference vs placebo (see below)

• South African Star Grass (Harzol) – Contain beta-sitosterol

– Cause apoptosis in prostate stromal cell

– RCT vs placebo: 5pt improvement of SS over placebo

• Others: African plum (Pygeum Africanum)

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What is the evidence of Saw Palmetto for BPH?

• Mode of action is unknown• Double-blind trial, randomly assigned 225 men > 49yo• Moderate-to-severe symptoms • One year of treatment : saw palmetto (160 mg BD) or placebo• Result: There was no significant difference in

1. Change in AUASI scores 2. Qmax3. Prostate size4. Residual volume after voiding5. Quality of life, or serum prostate-specific antigen levels 6. The incidence of side effects was similar in the two groups

• Conclusions: In this study, saw palmetto did not improve symptoms or objective measures of benign prostatic hyperplasia

N Engl J Med 2006;354: 557-66

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Desmopressin

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What is the role of desmopressin?• Indication: Nocturia with a polyuric background• MOA:

– Synthetic analogue of vasopressin– Anti-diuretic effect: increase water re-absorption & urine osmolality,

decrease water excretion & urine volume– Only V2 affinity: No V1 effect (HT , vasoconstriction) – Effect of reduce urine volume last 8-12 hour

• Form: IV, Nasal spray , tablet, MELT• Dosage:

– Initiated at a low dose (0.1 mg/day) PO nocte– Gradually increased every week until maximum efficacy is reached– The maximal daily dose recommended is 0.4 mg/day

• Usage: – Patients should avoid drinking fluids at least 1 hour before using

desmopressin until 8 hours thereafter

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• Effect: – Reduced nocturnal diuresis : 1ml/min

– Reduced number of nocturia: 2x /night

– Extend time to first nocturia by: 1.6 hour

– Reduce % of urine volume excreted at night

• Side effect: – Headache, naeusea, diarrhoea, abd pain , dizziness , dry mouth

– Hypo Na (< 130mmol/L) (5%)

– Peripheral edema & HT

• Cautions: – Risk of Hypo Na is 8x in pt > 65yo

– Men aged 65 years or older, desmopressin should not be used if the serum sodium concentration is below the normal value

– In all other men aged 65 years or older, serum sodium concentration should be measured at day 3 and 7 as well as after 1 month and, if serum sodium concentration has remained normal, every 3-6 months subsequently

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PDE5 inhibitor

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LUTs and ED

• ED and LUTs strongly linked

• both highly prevalent in aging men

• co-prescription of both drugs likely to increase• PED5-i: increase concentration of cGMP reduce

SM tone of detrussor , prostate and urethra

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• Risk of combination therapy:– Tadalafil : singificant drop of BP with doxazosin , hence to ↓ BP effect,

suggest alfuzosin/ tamsulosin to combine with PDE5i

– sildenafil should not be used in doses exceeding 25 mg within 4 h of taking an α1-AR antagonist

– Tamulosin → dose dependent anejaculation

• AARB on ED: – Would not worsen ED

– Cardura XL & Alfulzosin may improve IIEF

• Combination Tx– Pilot study n=62 with untreated LUTS and ED

– Randomized to alfuzosin 10mg QD, Viagra 25mg QD, or both for 12 weeks.

– IPSS improvement -24% for combination (-16% for alfuzosin/ -17% for Viagra)

– IIEF improvement +59% for combination (+17% for alfuzosin/ +50% for Viagra)

– Combination well tolerated with no serious adverse events

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What is the practical consideration of PDE5 inhibitor?

• PDE5 inhibitors reduce moderate to severe male LUTS but on effect on Qmax

• Officially licensed only for the treatment of erectile dysfunction and pulmonary arterial hypertension

• Treatment beyond this indication (e.g. male LUTS) is still experimental and should not be used routinely in the clinical setting

• Long-term experience in patients with LUTS is still lacking

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What is the evidence of combined therapy?

MTOPS

COMBAT

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Combination Therapy: Rationale

• 5ARIs and -blockers have complementary actions

–5ARIs act on the hormonal axis–-blockers act on the adrenergic receptors

• Main reported effects

–-blockers induce rapid symptom and flow rate improvement

–5ARIs reduce risk of progression to AUR or BPH-related surgery

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Indications

• Men with moderate to severe LUTS

• Risk of disease progression (large prostate, High PSA, Advance Age, etc)

• Only be used with long-term treatment (>12m) is intended

• Discontinuation of AARB after 6m might be consider in men with moderate LUTS

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Major combination therapy trials

1. VA study Lepor H et al. N Engl J Med. 1996 Aug 22;335(8):533-9.

2. PREDICT Kirby RS et al. Urology. 2003 Jan;61(1):119-26

3. MTOPS McConnell JD et al. N Engl J Med. 2003 Dec 18;349(25):2387-98

4. CombAT Roehrborn CG et al. J Urol 2008;179(2):616-21

• But 1. 2. only look at symptom improvement, no monitoring progression

• Both only 1 yr Fu

• Also smaller prostate size

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MTOPS: Conclusion

1. Doxazosin, Finasteride and the combination all reduce the risk of overall clinical progression. Combination more effective than either drug alone

2. In reducing symptom score rise, combination therapy more effective than monotherapy

3. In reducing risk of AUR and the need for BPH related surgery, combination and finasteride equally effective

4. Doxazosin slightly delays the the time to AUR and BPH related surgery but failed to reduce the risk of these of events over the duration of the study

5. Combination resulted in greater improvement in AUA-SS and Qmx than monotherapy alone

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Combination therapy (dutasteride + tamusulosin) can

• Reduce AUR /BPHRS: – Better than tamsulosin but not dutasteride

• Reduce BPH clinical progression/ IPSS: – Better than both monotherapy

• Improves patient-record , disease specific QoL & treatment satisfaction: – Better than both monotherapy

• Controlling both storage & voiding symptoms: – Better than both monotherapy– Dutasteride can improve voiding symptom as from effect

of prostate volume , but also as effective as alfa-blocker in the control of storage symptoms

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THANKS