Benign Prostatic hyperplasia

Physiology of Prostate Gland

Fibromuscular Organ

• Androgen is trophic to the prostate gland.
• DHT, which is the most potent androgen, is from the conversion of testosterone by 5-alpha reductase enzyme.

Smooth Muscle Composition:

• Internal sphincter has alpha receptors that are sympathetic.

• Stimulation of these receptors increases the tone of the prostate around the prostatic urethra.
• Blockage of the reception leads to relaxation around the prostate gland.

BPH (Benign Prostatic Hyperplasia)

Benign prostatic hyperplasia (BPH) is a histological diagnosis associated with unregulated proliferation of connective tissue, smooth muscle, and glandular epithelium within the prostatic transition zone.

The bladder obstruction has symptoms due to physical increase in size of the prostate and dynamic factors as a result of the disproportional increase in the fibromuscular element and the alpha 1 receptors.

Symptoms are a mixture of storage/irritative and emptying/obstructive symptoms.

Clinical benign prostatic hyperplasia (BPH) is often identified as the worsening ability of a male to pass urine.

BPH is both extremely common and can cause significant harm.

• Increase in the volume of prostate occurs because of increase in the number of stromal smooth muscle cells.
• Ratio of stroma to epithelium rises to 5:1 in BPH, while it is 2:1 in normal prostate.
• The effect of androgens:
• Genetic factors - expression of genes for 5-AR2 enzyme receptors and pathway.
• Inflammation.
• Stromal-epithelial interactions.
• Sex steroid hormones: Testosterone, dihydrotestosterone, and estrogen.
• Metabolic syndrome.
• Diabetes & impairment of glucose metabolism.
• Level of activity.
• Inflammation.

• Age: The prevalence of BPH rises markedly with age. Autopsy studies have observed a histological prevalence of 8%, 50%, and 80% in the 4th, 6th, and 9th decades of life, respectively.
• Geography: International studies have also demonstrated geographic heterogeneity in prostate volume and LUTS prevalence. Significantly lower prostate volumes have been observed in men from Southeast Asia compared to western populations.
• Genetics: 4 to 6 fold increase in brothers, usually occur at earlier age (60 years), bigger prostate, more incidence of operation. Autosomal dominant. Deletions of Glutathione S-transferase enzyme genes, thought to confer cellular resistance to oxidative stress, were significantly associated with an increased risk of symptomatic BPH.

• History.
• Clinical examination: Abdomen and DRE.
• Serum PSA.
• Prostate biopsy.
• Renal function test.
• Cardiovascular Evaluation.
• Metabolic Evaluation.
• rPSS / AUA-SI.

Aims of Treatment: EAU Guidelines

The aim of therapy is to improve LUTS (Lower Urinary Tract Symptoms) and QoL (Quality of Life) and to prevent BPE/BPO-related complications such as urinary retention or upper urinary tract dilatation.

• EAU = European Association of Urology
• LUTS = Lower Urinary Tract Symptoms
• QoL = Quality of Life
• BPE = Benign Prostatic Enlargement
• BPO = Benign Prostatic Obstruction

• Treatment options for men with prostate obstruction have existed for centuries.
• It used to be one treatment fits all.
• Now, era of personalized medicine which is also applicable to the management of BPH.
• Better understanding of the pathology and advancement of technology using these two key principles, we will show the changing nature of the treatment of BPH.

• Based on published data on consequences and complications of the disease, BPH can be considered a progressive disease.
• The identification of specific risk factors for disease progression provides a basis for a risk profile-oriented therapy, not the same treatment for every patient.
• Patients at increased risk of progression can be identified based on specific risk factors, i.e. age, serum PSA, prostate volume, and LUTS. In such patients, it may be appropriate to initiate early preventive treatment.

Initial Management

• Initial management of men with LUTS suggestive of BPH can be categorized into:
• Watchful Waiting (WW)
• Medical Therapy
• Surgical Management
• Non-surgical Intervention

Watchful Waiting (WW)

• WW is a viable option to many men as the risk of progression is small.
• Regular monitoring allows physicians and patients to assess whether symptoms improve or deteriorate.
• WW is often more suitable for those with low symptom scores which are less bothersome and who have a low risk of progression.
• Small prostates <30mL.
• Lower PSA levels 1.5 ng/mL or less.

Medication in BPH

The availability of effective drugs for BPH has helped revolutionize the treatment of this condition.

• A significant proportion of urologists now spend less time performing surgery and often treat conditions such as BPH and erectile dysfunction with pharmacotherapy.
• There will be patients for whom surgery is the most suitable treatment option.

Medical Therapy

The following medical treatments are currently available for LUTS due to BPH:

• Alpha-blockers
• 5αRIs (5-alpha reductase inhibitors)

Combination Therapy

• Phytotherapy
• Antimuscarinics

Goals of Medical Therapy in Men with LUTS and BPH

Short-term:

• Improve LUTS and reduce bother.
• Improve urinary flow rate.
• Improve Quality of Life (QoL).

Long-term:

• Maintain symptom relief.
• Prevent symptomatic progression.
• Maintain urinary flow rate.
• Reduce prostate volume.
• Reduce risk of Acute Urinary Retention (AUR) and need for BPH-related surgery.

Alpha-blockers

• There are five currently available alpha-blockers:
• Tamsulosin
• Terazosin
• Alfuzosin
• Doxazosin
• Silodosin*
• Until efficacy differences are demonstrated, the choice of alpha-blocker will depend on safety and convenience.

Mode of Action

• Alpha-blockers relieve symptoms of BPH by causing smooth muscle relaxation through blockade of alpha-1 adrenoceptors in the prostate.
• Alpha-1 adrenoceptor is the predominant subtype localized in the prostate.

Alpha-blockers: Impact on Progression

• MTOPS demonstrated that alpha-blocker over 4 years had no effect on:
• Prostate Volume
• Natural history of the disease
• Despite improved symptom relief, alpha-blockers have no demonstrable effect on:
• Lowering long-term risk of AUR
• Lowering risk of BPH-related surgery

Alpha-blocker Tolerability

Common alpha-blocker adverse events include:

• Dizziness
• Ejaculatory dysfunction
• Asthenia
• Postural hypotension

Guideline recommendations for alpha-blockers:

Alpha-blockers are an acceptable medical therapy for men with moderate-to-severe LUTS.

Alpha-blockers: Summary

• Alpha-blockers rapidly improve symptoms and urinary flow but do not reduce prostate volume (PV).
• Men with a PV >40mL may have a higher treatment failure rate.
• Generally, tolerability is good.
• Alpha-blockers do not reduce the overall long-term risk of Acute Urinary Retention (AUR) or surgery.
• Alpha-blockers are an acceptable treatment option for patients with moderate/severe Lower Urinary Tract Symptoms (LUTS) and PV <40mL.

5αRIs

• Two 5αRIs:
• Finasteride inhibits 5αR type II.
• Dutasteride inhibits 5αR type I and II.
• Dutasteride is 2.5x more potent against type II isoenzyme than finasteride.
• Increased potency and dual inhibition may be warranted to enhance suppression of DHT.

5αRIs: Mode of Action

• 5αRIs suppress the conversion of testosterone to DHT through inhibition of the 5α-reductase isoenzymes.
• Reduction in androgenic drive of prostate.
• Reduction in prostate volume resulting in diminished outflow obstruction.

Two 5αRIs are currently available:

• Finasteride, a type II-selective 5ɑRI.
• Dutasteride, a dual (type I and type II) 5αRI.

5αR Enzymes

	Type I	Type II
Chromosome Location	5	2
Tissue Distribution	Primarily liver, skin, and scalp	Primarily genital tissue
Found in Prostate?	Yes	Yes
pH Optimum	Neutral to basic	Acidic
Inhibition by Finasteride	Not at clinical dose	Yes
Inhibition by Dutasteride	Yes	Yes

5αRI Tolerability

Common 5αRI adverse events include:

• Erectile dysfunction
• Decreased libido
• Gynecomastia
• Ejaculation disorders

Guideline recommendations for 5αRIs:

• 5αRIs are an acceptable treatment option for patients with moderate to severe Lower Urinary Tract Symptoms (LUTS) and an enlarged prostate (>30-40mL).
• 5αRIs can prevent BPH progression with regard to Acute Urinary Retention (AUR) and need for surgery.

5αRI Summary

Data from extensive, robust, controlled studies have confirmed that in men with enlarged prostates, both dutasteride and finasteride have a significant effect compared with placebo on:

• Reducing symptoms and impact of BPH.
• Reducing prostate volume (PV).
• Improving maximum urinary flow rate (Qmax).
• Reducing risk of Acute Urinary Retention (AUR) and surgery.

PSA and its Role in Therapeutic Decision Making

• PSA and PV are powerful predictors of the risk of BPH progression.
• PSA values of >1.6ng/mL predict a PV >40mL.
• PSA values of >1.4ng/mL predict a greater risk of BPH progression.
• PSA can be used to identify candidates for intervention with appropriate therapy in order to reduce an increased risk of BPH progression and improve their Quality of Life (QoL).

An elevated pretreatment PSA or an enlarged prostate gland may predict a poor long-term prognosis with alpha-blocker monotherapy.

Alpha-blockers have their highest probability of long-term symptom relief in patients who present with Lower Urinary Tract Symptoms (LUTS) and a small prostate and a low PSA value.

5αRIs have their highest probability of symptom relief in patients who present with LUTS and an enlarged prostate and a high PSA value.

Combination treatment of 5-alpha reductase inhibitor and alpha-1 blocker should be considered in patients with:

• High prostate volume, ≥40 grams.
• High PSA levels.
• Moderate to severe Lower Urinary Tract Symptoms (LUTS).
• Monotherapy likely to fail on long term.

Two Drug Classes Used in the Medical Management of BPH

5αRIs

• Decrease in DHT synthesis.
• Reduced androgenic drive of prostate.
• Reduction in prostate volume (PV) resulting in diminished outflow obstruction.

Alpha 1-Adrenergic Receptor Blockers

• Blockade of alpha 1-adrenergic receptors in prostate, urethra, bladder neck, and detrusor.
• Relaxation of smooth muscle resulting in improved urinary flow.
• Possible mechanisms beyond reduction in bladder outlet resistance may contribute to symptomatic benefit.

Tadalafil in the Treatment of BPH

PDE5

Other Therapies

• Intraprostatic injection of Botox (Allergan, Dublin, Ireland) treatment in the bladder.
• Prostatic urethral lift. This is a novel mechanical implant placed into the prostate that pulls the encroaching lobes of the prostate out of the way to improve men's flow.

Surgical Therapy - Indications

• Failure of medical therapy.
• Large glands.
• Associated large stones.
• Symptomatic diverticulum.
• Refractory urinary tract infections from BPH.
• Recurrent gross hematuria.
• Bladder calculi.

Surgical Therapy

Minimally Invasive Procedures

• TURP (Transurethral Resection of the Prostate)
• TUIP (Transurethral Incision of the Prostate)
• TULAP (Transurethral Laser Ablation of the Prostate)
• Laparoscopic prostatectomy

Open Procedures

• Retropubic and transvesical

TURP (Transurethral Resection of the Prostate)

"Gold Standard" of care for BPH

• Uses an electrical "knife" to surgically cut and remove excess prostate tissue
• Effective in relieving symptoms and restoring urine flow

The "gold standard" - TURP

Benefits

• Widely available
• Effective
• Long-lasting

Disadvantages

• Greater risk of side effects and complications
• 1-4 days hospital stay
• 1-3 days catheter
• 4-6 week recovery

Possible side effects of TURP

• Impotence
• Incontinence
• Bleeding
• Electrolyte imbalance (TUR Syndrome)
• May result in ICU (Intensive Care Unit)

Modifications of TURP

• TUIP
• SALINE TURP
• Uses Collins knife incision
• Uses bipolar electrodes at 5 & 7 o'clock
• Incisions just below ureteric orifices and just before Verumontanum
• Small fibrotic prostates < 30 grams
• Less incidence of retrograde ejaculation and Normal Saline
• Large Prostate: Reduced incidence of TUR syndrome

Open Operations

• Transvesical
• Retropubic
• Transperineal

Complications of Open Prostatectomy

Early

• Haemorrhage
• Sepsis
• DVT/PE (Deep Vein Thrombosis/Pulmonary Embolism)
• Atelectasis
• Acute Epididymorchitis
• Surgical Site Infection
• Bladder neck stenosis
• Urethral stricture

Persistent

• Vesicocutaneous fistula
• Osteitis pubis
• Urinary incontinence