A. Characteristics

1. Occurs in >30% men >50 yrs old; >80% men over 70 years old
2. Hyperplasia of normal tissue - both glandular and stromal cells
   1. Enlargement of prostate comprises static component of BPH
   2. Smooth muscle surrounding prostate may increase contraction and comprises dynamic component
3. Frequently contains foci of frankly neoplastic tissue (discovered only at autopsy)
4. Occurs in central portion of gland, whereas 2/3 of cancers are found in periphery
5. Accompanied by small increase in PSA levels (>95% have levels <10)
6. In USA, 300,000 prostatectomies done annually for BPH

B. Symptoms

1. Generally referred to as lower urinary tract symptoms (LUTS)
   1. Obstruction
   2. Reduced urinary flow
   3. Prostatitis
   4. Urinary infections
   5. Increased risk of bladder symptoms including detrusor instability
   6. Sexual dysfunction due to BPH is unusual [2]
2. Obstruction
   1. Mild to Moderate Urinary Retention - sense of fullness, discomfort
   2. Severe Urinary Retention - frank pain; obstructive nephropathy
   3. Urinary hesitancy and terminal dribbling
   4. Straining on urination
3. Slow urinary flow
   1. Normal >20cc/sec
   2. Mild 15-20cc/sec
   3. Moderate 10-15cc/sec
   4. Severe <10cc/sec
4. Increased risk of prostatic and urinary infection ± stricture formation

C. Evaluation

1. Residual urinary volume - mild ~150-300cc; moderate >350cc
2. Urinalysis - evidence for infection
3. Renal Function
4. Determination of Prostate Volume
   1. Useful for determination of PSA density and for response to finasteride therapy
   2. Ultrasound evaluation is most common
   3. Magnetic resonance imaging (MRI) may also be used
5. Prostate Specific Antigen (PSA) Testing [3]
   1. Usually slightly elevated, often 4-10 range in BPH
   2. Relatively low PSA density found in BPH
   3. PSA density is usually high in prostate cancer
   4. PSA is less useful for detecting prostate cancer in men with clinically obvious BPH
   5. PSA should not generally be tested in men with <10 years to live
6. Prostate Biopsy
   1. Generally required in ALL BPH patients to rule out prostatic adenocarcinoma
   2. Sextant biopsy is usally performed
   3. Elevated alphamethyl-coenzyme A racemase levels on biopsy can distinguish between carcinoma and BPH/normal tissue [4]
7. Differential Diagnosis of Urinary Retention
   1. Diabetes mellitus - poorly controlled disease with poor bladder contraction
   2. Neurogenic Bladder
   3. Bladder Cancer - often with hematuria
   4. Anti-cholinergic Medications
   5. Urethral Stricture

D. Treatment [1]

1. Medical Therapy
   1. Peripheral alpha1-adrenergic blocking agents
   2. Finasteride (Proscar®) - 5-alpha-reductase inhibitor
   3. Combination of alpha1-adrenergic blocker and finasteride [19]
   4. Saw Palmetto Extract
   5. Pygeum africanum (derived from African prune tree bark) has mild activity [6]
   6. Gonadotropin Releasing Hormone Agonists (such as Nafarelin acetate)
   7. Anti-androgens - not generally used
2. Peripheral Alpha-Adrenergic Blocking Agents [7,8,20]
   1. Alpha-adrenergic blockers relax trigone muscle around bladder head
   2. This improves urinary stream with rapid onset of action
   3. Agents also generally reduce blood pressure, can cause hypotension, orthostasis
   4. Alpha blockers do not prevent progression to invasive treatment of BPH [19]
   5. Terazosin (Hytrin®) is approved (1-2mg po qhs) for BPH symptoms
   6. Doxazosin (Cardura®) 1-2mg qhs may also be used
   7. Tamsulosin (Flomax®) 0.4-0.8mg/qhs, with minimal hypotension (alpha1a specific) [7]
   8. Alfuzosin (Uroxatral®) 10mg qd taken after same meal each day [20]
   9. Side effects include hypotension, including orthostatic hypotension, mainly in >70year old
   10. Given mainly at night, this side effect is minimized
   11. Alfuzosin has less hypotension than doxazosin and terazosin and less ejaculatory dysfunction than tamsulosin [20]
   12. In men with BPH and overactive bladder, combination of tolterodine extended release with tamsulosin (an alpha1-adrenergic blocker) superior to either alone or placebo [21]
   13. Doxazosin combined with finasteride more effective than either alone at preventing clinical progression [19]
   14. Prazosin causes significant orthostatic hypotension and is not recommended
3. Finasteride (Proscar®) [9,10]
   1. Competitive type 2 5-alpha-reductase inhibitor
   2. Mild to moderately effective in 30-50% of persons after 3-6 months of therapy
   3. Prostatic volume showed 19% reduction after 6 months [2]
   4. Most effective in patients with very large prostate volumes (>40mL) [11]
   5. In the 4-year PLESS Trial, reduced need for surgery by ~50% (from 10% to 5%) [11]
   6. Confirmed in longer trials, alone and in combination with doxazosin [19]
   7. Reduced serum dihydrotestosterone (DHT) by 70%
   8. Overall, minimal improvements in symptom scores over 4 years
   9. Over 5 years, combination with alpha-blockers in men with very large prostates produces benefits greater than either agent alone [12,19]
   10. Slight increase in sexual dysfunction including impotence, decreased libedo
   11. Dose is 5mg po qd
4. Finasteride for Chemoprevention of Prostate Cancer [9]
   1. Finasteride studied in 18,000 men over 7 years
   2. Finasteride in 4368 men reduced overall prostate Ca from 24.4% to 18.4%
   3. High Grade Gleason (>6) tumors increased 5.1% in finasteride treated group (P=0.005)
   4. Finasteride reduced overall but increased high grade prostate cancers
   5. Finasteride reduced obstructive symptoms but caused frequent sexual side effects
5. Dutasteride (Avodart®) [13]
   1. Competitive inhibitor of both types 1 and 2 5-alpha-reductase
   2. Increases urinary flow within 1 month
   3. Reduces obstructive symptoms within 6 months
   4. Reduced prostate size 25% and need for surgery 55% over 2 years
   5. Reduced serum dihydrotestosterone (DHT) by 70%
   6. Impotence 4.7% versus 1.7% with placebo
   7. Gynecomastia 0.5-1.0%
   8. Dose is 0.5mg po qd
6. Saw Palmetto Extracts [14,15]
   1. Derived from American dwarf saw palmetto plant
   2. Serenoa repens or Sabal serrulata
   3. Typical extracts contain hundreds of compounds
   4. In randomized 1 year study versus placebo, no symptomatic or objective benefits [5]
   5. No improvement in symptoms, urinary flow rate, residual urinary volume, prostate volume [5]
   6. Dose is usually 160mg po bid liposterolic extract daily (equivalent to ~20gm crude berries)
   7. In general, only mild and infrequent adverse effects occurred;. long term safety not known
7. Surgery [1]
   1. Transurethral prostatectomy or TURP is most common
   2. Other types of proceedures have been developed
   3. Complete prostate resection - usually only for patients with cancer or resistant BPH
   4. Laser Prostatectomy - 50% improvement in symptoms, temporary urinary retention
   5. Laser has improved early symptoms but requires requires revision surgery in 38% versus those who received TURP initially [18]
   6. Thermal ablation
   7. Transurethral needle ablation
   8. Ultrasound ablation
   9. Microwave Therapy [9] - ~60% improvement in symptoms; less effective than TURP
8. TURP
   1. Nearly 400,000 TURPs are performed per year
   2. Generaly well tolerated, clearly effective in reducing symptoms
   3. Overall ~20% return to baseline function
   4. Comparison of TURP verus watchful waiting in moderate BPH showed TURP better [16]
   5. Many side effects: impotence (short term <20%), retrograde ejaculation [17]
   6. No change in overall sexual function at 3 years compared with no-surgery controls [16]
9. Indications for TURP in Reasonable Risk Surgical Candidates (Panel 4, Ref [1])
   1. Risk of urinary retention caused by prostatic obstruction
   2. Intractable symptoms caused by prostatic obstruction
   3. Recurrent or persistant LUTS caused by prostatic obstruction
   4. Two or more of the following:
   5. Documented post-voiding residual volume
      1. Pathophysiological changes of kidney, ureter or bladder caused by prostatic obstruction
      2. Abnormally low urinary flow rate OR normal flow rate with very high pressures
10. Other Therapy
    1. Balloon Dilation - ~50% recurrence at one year
    2. Indwelling prostatic stents - 70% improvement, 25% with retention

E. Prognosis [1,17]

1. Following initial evaluation, many patients will remain stable with BPH Sypmtoms
2. In moderate BPH, ~40% of patients will improve (45% no change) without therapy in 5 years
3. Only ~15% of men will deteriorate, and these should probably be selected for therapy

References

1. Thorpe A and Neal D. 2003. Lancet. 361(9366):1359
2. Kassabian VS. 2003. Lancet. 961(9351):60
3. Meigs JB, Barry MJ, Giovannucci E, et al. 1998. Am J Med. 104(6):517
4. Rubin MA, Zhou M, Dhanasekaran SM, et al. 2002. JAMA. 287(13):1662
5. Bent S, Kane C, Shinohara K, et al. 2006. NEJM. 354(6):557
6. Ishani A, MacDonald R, Nelson D, et al. 2000. Am J Med. 109(8):654
7. Tamsulosin. 1997. Med Let. 39(1011):96
8. Terazosin. 1994. Med Let. 36(916):15
9. Rittmaster RS. 1994. NEJM. 330(2):120
10. Finasteride. 1992. Med Let. 34(878):83
11. McConnell JD, Bruskewitz R, Walsh P, et al. 1998. NEJM. 338(9):557
12. McConnell JD. 2002. J Urol.
13. Dutasteride. 2002. Med Let. 44(1146):109
14. Saw Palmetto. 1999. Med Let. 41(1046):18
15. Ernst E. 2002. Ann Intern Med. 136(1):42
16. Wasson JH, et al. 1995. NEJM. 332(2):75
17. Oesterling JE. 1995. NEJM. 332(2):99
18. Fitzpatrick JM. 2000. Lancet. 356(9227):357
19. McConnell JD, Roehrborn CG, Bautista OM, et al. 2003. NEJM. 349(25):2387
20. Alfuzosin. 2004. Med Let. 46(1173):1
21. Kaplan SA, Roehrborn CG, Rovner ES, et al. 2006. JAMA. 296(19):2319