Urinary Obstruction & Benign Prostatic Hyperplasia (BPH)

1. Urinary Obstruction & Benign Prostatic Hyperplasia (BPH) Xiao Huang, MD; PhD Department of Urology,1st Affiliated Hospital of Zhejiang University, School of Medicine

2. Urinary Obstruction • Urinary Tract Anatomy • Urinary Obstruction • Reason of Urinary Obstruction • Hydronephrosis

3. Urinary Tract Anatomy

4. Urinary Obstruction

5. Reason of Urinary Obstruction

6. Obstruction Reason Classification • Dynamic and structural • Congenital and aquired • Populations • Child: congenital • Adults: stone, injury, tumor ,TB • Women: pelvic disease • Old men: BPH • Locations • Kidney: calculus, tumor, infection, TB, UPJ stricture, congenital deformity • Ureter: stone, tumor, iatrogenic injury, ureteritis,TB , Metastatic carcinoma • Bladder: BPH, bladder neck contracture, tumor, calculus, Neurogenic bladder • Urethral: urethral stricture, Phimosis ,Congenital Posterior urethral valve ,stone.

7. Hydronephrosis • What is hydronephrosis? • Hydronephrosis is a "stretching" or dilation of the inside, or collecting part, of the kidney. • It often results from a blockage in the ureter where it joins the kidney that prevents urine from draining into the bladder. • Urine is trapped in the kidney and causes it to stretch. • Hydronephrosis may also be due to abnormal backwash or "reflux" of urine into the bladder.

8. Degrees of Hydronephrosis Kidney function: Minimally affected compensation damage

9. Benign Prostatic Hyperplasia (BPH)

10. Objectives • What is a BPH • How to approach a patient with LUTS (lower urinary tract symptoms) • Treatment of BPH

11. Outline 1. Definition of BPH 2. Anatomy and Physiology 3. Microscopic Appearance 4. Prevalence of BPH 5. Etiology 6. Natural History of BPH 7. LUTS 8. Approach to a patient with BPH 9. IPSS 10. Differential Diagnosis 11. Management of BPH 12. Treatment of BPH

12. 1.Definition • BPH is a nonmalignant enlargement of the prostate gland caused by cellular hyperplasia of both glandular and stromal elements that leads to troublesome lower urinary tract symptoms (LUTS) in some men • It is the most common benign tumor in men and is not a precancerous condition

13. The prostate is a compound tubuloalveolar exocrine gland of the male mammalian reproductive system Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen Secret is composed of simple sugars and proteins (proteolytic enzymes, acid phosphatase, prostate-specific antigen);zinc and citric acid 2.Anatomy and physiology

14. Lower urinary tract

15. A healthy human prostate is slightly larger than a walnut (4cm by 3cm). It surrounds the urethra just below the urinary bladder and can be felt during a rectal exam. It has anterior, median, posterior and two lateral lobes Relations: Posterior: rectal ampulla (Denonvilliers’ fascia);Superior: bladder neck ; Anterior:pubic symphysis (retropubic space of Retzius); Inferior: urogenital diaphragm It’s work is regulated by androgens which are responsible for male sex characteristics 2. Anatomy and physiology

16. Glandular cells produce milky fluid that liquefies semen Smooth muscle cells, which contract during sex and squeeze the fluid from the glandular cells into the urethra, where it mixes with sperm and other fluids to make semen. The muscle cells are stimulated by alpha adrenergic receptors Stromal cells (which form the structure of the prostate) The prostate gland also contains an enzyme - 5 alpha-reductase that converts testosterone to dihydrotestosterone 2.Anatomy and physiology

17. 2.1. Zonal Anatomy(McNeal-1972) • Peripheral Zone 70% of the young adult (60-70% of CaP) • Central Zone 25% (5-10% CaP) • Transition Zone 5% ( 10-20% CaP) BPH

18. Zonal Anatomy

19. Prostate consists of a thin fibrous capsule under which are circulary oriented smooth muscle fibres and collagenous tissue. Prostatic stroma lies deep to this layer and is composed of connective and ellastic tissue and smooth muscle where epithelial cells are embeded As a male ages, there are more likely to be small concretions within the glandular lumina, called corpora amylacea, that represent laminated concretions of prostatic secretions. The glands are normally separated by stroma The thin layer of connective tissue that surrounds the prostate merges with surrounding soft tissues, including nerves 3.Microscopic Appearance

20. 4.Prevalence of BPH • In men 20 to 30 years of age, the prostate weighs about 20 g; • however, the mean prostatic weight increases after the age of 50.

21. 4.Prevalence of BPH 20% of men age 41-50 50% of men age 51-60 65% of men age 61-70 80% of men age 71-80 90% of men age 81-90 lower urinary tract symptoms associated with BPH increase with age.

22. Pathophysiology of Clinical BPH: Predictive Risk Factors • Increasing age • Prostatic enlargement • Lower-urinary-tract symptoms (LUTS) • Decreased urinary flow rate • Elevated prostate-specific antigen (PSA) Slide I.4

23. 5.Etiology of BPH • Androgens • Estrogens • Lifestyle • Hereditary(genetic)/Race

24. 5.1 Androgens • Testosterone and related hormones play a permissive role in BPH • Androgens have to be present for BPH to occur • Administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms • Didhydrotestosterone (DHT), a metabolite of testosterone is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. This enzyme is localized principally in the stromal cells; hence, these cells are the main site for the synthesis of DHT • DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. DHT is 10 times more potent than testosterone because it dissociates from the androgen receptor more slowly • the active androgen, DHT, is important in promoting growth of prostate that would eventually lead to symptomatic BPH.

25. Regulation of Prostate Growth: Intrinsic and Extrinsic Factors Extrinsic factors Testicular • Androgens • Estrogens • Nonandrogenic Intrinsic factors(prostate) Stroma • Fibroblast • Smooth muscle • Extracellular matrix Epithelium • Luminal • Basal • Neuroendocrine Nontesticular • Endocrine organs • Neurotransmitters • Immunologic Genetic • Homeobox genes • Hereditary diseases Urethra • Urine • Testis-epididymal fluid Environmental • Dietary • Micro-organisms (immune response) Extrinsic factors Adapted from Lee C et al. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:79-106. Slide III.1

26. Regulation of Prostate Growth:Role of Androgens • DHT is the principal androgen responsible for prostatic growth and BPH • 5-reductase mediates the conversion of testosterone to DHT OH OH 5-reductase O O H Testosterone Dihydrotestosterone Adapted from Bartsch G et al Eur Urol 2000;37(4):367-380. Slide III.2

27. 5.2 Estrogen • BPH occurs when men generally have elevated estrogen levels and relatively reduced free testosterone levels • Prostate tissue becomes more sensitive to estrogens and less responsive to DHT • Cells taken from the prostates of men who have BPH have been shown to grow in response to high estradiol levels with low androgens present • Estrogens may render cells more susceptible to the action of DHT • Androgen/estrogen ratio change

28. 5.3 Lifestyle • On a microscopic level, BPH can be seen in the vast majority of men over the age of 70 years, around the world • Men who lead a western lifestyle have a much higher incidence of symptomatic BPH than men who lead a traditional or rural lifestyle

29. Pathological or first phase of BPH -asymptomatic and involves a progression from microscopic to macroscopic BPH Clinical or second phase of BPH - progression from pathological to ‘clinical BPH’ =development of LUTS Mechanical and dynamic components are responsible for the progression from pathological to clinical BPH In clinical BPH, the ratio of stroma to epithelium is 5: 1 Asymptomatic hyperplasia the ratio is 2.7:1 6.Natural History of BPH

30. Enlarged prostate LUTS BOO Pathophysiology of Clinical BPH: Overlapping but Independent Features Adapted from Nordling J et al. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:107-166. Slide I.2

31. 7.1.Voiding/Obstructive symptoms: Hesitancy Intermittency Incomplete voiding Weak urinary stream Straining to pass urine Prolonged micturition Terminal dribbling 7.2.Storage/Irritative symptoms: Frequency of urination Nocturia Urgency (compelling need to void that can not be deferred) Urge incontinence 7. Lower Urinary Tract Symtoms-LUTS

32. 7. Obstructive and irritative symptoms origin • Obstructive symptoms-mechanical obstruction due to glandular enlargement as well as dynamic obstruction secondary to contraction of the smooth muscle of the prostate, urethra and bladder neck. This dynamic obstruction is a result of sympathetic nervous system mediated stimulation of alpha-1adrenoceptors • Irritative symptoms - detrusor instability related to detrusor muscle changes in response to obstruction, such as bladder wall hypertrophy and collagen deposition in the bladder • Adrenoceptors may be further sub-divided into alpha1A and alpha1D subtypes, with alpha1A predominant in the prostate and alpha 1D in the bladder. Thus blockade of alpha1A may be necessary for reduction of obstruction whereas the blockade of alpha1D may be required to relieve storage symptoms

33. 10.1. Pre-prostatic Urethral stricture Bladder neck contracture Bladder tumors Neurogenic bladder Bladder calculi Urinary tract infections 10.2. Prostatic Prostatitis Prostate Cancer 8. Differential Diagnosis

34. 9. Approach to a patient with BPH • History: (LUTS, previous surgery in the GU tract, STD and Hx of urethral stricture, prescription meds and over the counter meds). Use IPSS • Physical Examination :digital rectal exam ( R/O Ca:nodules, asymmetry, hardened ridges, induration; R/O prostatitis: tenderness, bogginess; R/O anal malignancy and detect undiagnosed neurologic conditions by evaluating the sphincter tone and perianal sensation;Abdomianl exam-distended bladder) • Urinalysis- by dipstick and routine microscopy, urine culture and sensitivity to R/O infections and hematuria • Serum PSA-optional to R/O Prostate Cancer

35. 9. Approach to a patient with BPH (cont’d) • Upper tract imaging (IVP,CT, U/S) only in presence of concomitant urinary tract disease or complications-hematuria, UTI, renal insufficiency, Hx of stone disease • Cystoscopy- only for patients who don’t respond to medical Trx to determine the need for surgical approach • Cystometrograms and urodynamic profile -for patients with suspected neurologic disease or those who failed prostate surgery • Flow rate, post-void residual urine determination and pressure flow- optional

36. Mild (score 0-7) Moderate (score 8-19) Severe (score 20-35) 10. IPSS

37. 11. Management of BPH • Goal- rapid and sustained relief of symptoms: • Decrease bladder outlet obstruction • Improve bladder emptying • Lower detrusor instability • Reverse renal insufficiency • Prevent future episodes of gross hematuria, UTI and urinary retention • Quality of life and sexuality • Management depends on severity

38. 12. Treatment of BPH • Lifestyle modification • Watchful Waiting • Medical Therapy • Phytotherapy (alternative) • Surgical Treatment : Conventional Surgical or Minimally Invasive Treatment

39. 12. Treatment Algorithm

40. 12.1. Lifestyle Changes • Enriched diet with ample amounts of fresh fish, fruits and vegetables • Reduce stress • Exercise on a regular basis • Weight within normal limits • Limit fluid intake, decrease bladder irritants-caffeine, alcohol; avoid anticholinergic drugs, narcotics and skeletal muscle relaxants • See your doctor if you develop nocturia • Be aware of interaction of botanical and medical treatment

41. 12.2. Watchful Waiting • The risk of progression or complications is uncertain • In men with symptomatic BPH, progression is not inevitable and some men undergo spontaneous improvement or resolution of their symptoms • Retrospective studies on the natural history of BPH are inherently subject to bias, related to patient selection and the type and extent of follow-up. Very few prospective studies addressing the natural history of BPH have been reported. A large randomized study compared finasteride with placebo in men with moderately to severely symptomatic BPH and enlarged prostates on DRE (McConnell et al, 1998). Patients in the placebo arm of the study had a 7% risk of developing urinary retention over 4 years • Appropriate management of men with mild symptom scores (0-7) • Men with moderate or severe symptoms can also be managed in this fashion if they so choose • Neither the optimal interval for follow-up nor specific endpoints for intervention have been defined

42. 12.3. Medical Treatment • Alpha blockers • 5α-Reductase inhibitors • Combination Therapy

43. Initially used for treatment of high blood pressure The human prostate and bladder base contain alpha-1-adrenoreceptors and the prostate contracts to corresponding agonists. The contractile properties of the prostate and bladder neck are mediated primarily by the subtype α1a receptors Alpha blockade improves both objective and subjective symptoms and signs of BPH in some patients Alpha blockers can be classified according to their receptor selectivity as well as their half-life Alpha Blockers Oral Dosage Alpha-1 short-acting: Prazosin 2mg BID Alpha-1, long-acting: Terazosin 5 or 10 OD Doxazosin 4 or 8 OD Alpha-1a selective: Tamsulosin 0.4 or 0.8 OD 12.3. Medical Treatment Alpha blockers

44. 12.3. Medical Treatment,Alpha blockers(cont’d) • Short Acting: Prazosin • Long-acting: Alfuzosin, Doxazosin mesylate, Tamsulosin, Terazosin • Side Effects: dizziness, postural hypotension, fatigue, retrograde ejaculation, rhinitis, and headaches. May potentiate other antihypertensive medications • Studies have shown that all of them have comparable effectiveness and the future research is focussed on improving convenience and tolerability • Terazosin and doxazosin may decrease the total cholesterol as well as LDL fraction. Both may cause first-dose syncope so titration is required • Alfuzosin and tamsulosin -have alpha 1A selectivity and dose titration is not required

45. 12.3. Medical Treatment,Alpha blockers(cont’d) • A study performed at the University of Maryland, Baltimore, USA, published in Jan. 2007, Title:”A review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the enlarged prostate” • Conclusion: alpha-blockers in men with enlarged prostate have reported improvementsin total symptom scores of 10% to 20% compared with placebo • Do not reduce the risk of long-term complications nor disease progression

46. 12.3. Medical Treatment5α-Reductase inhibitors • Finasteride is a 5α-reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone. It affects the epithelial component of the prostate, resulting in a reduction in the size of the gland and improvement in symptoms • Six months of therapy are required to see the maximum effects on prostate size (20% reduction) and symptomatic improvement • Several randomized, double-blind, placebo-controlled trials have compared finasteride with placebo. Efficacy, safety, and durability are well established • Symptomatic improvement is seen only in men with enlarged prostates (> 40 mL) • Side effects include decreased libido, decreased ejaculate volume, and impotence. Serum PSA is reduced by approximately 50% in patients being treated with finasteride, but individual values may vary, thus complicating cancer detection • Cost: $ 73 for 30 day supp.

47. 12.3. Medical Treatment5α-Reductase inhibitors (cont’d) • Dutasteride: not enough data! In 3 double-blind trials it reduced acute urinary retention (1.8% versus 4.2%- placebo) and need for surgery (2.2% vs 4.1%) but increased impotence ( 7.3% vs 4.0%), ejaculation disorder, and gynecomastia and lowered libido • Cost: $84 for 30 day supp.

48. 12.3. Medical Treatment5α-Reductase inhibitors (cont’d) • Summary: • Significantly reduced the relative risk for acute urinary retention(AUR) and enlarged prostate-related surgery, slowed the disease progression, and showed greater relief of symptoms compared to placebo • Dutasteride, improved symptom scores greater after 4 years of therapy compared with 2 years (-6.4 vs -4.3 points, respectively) and flow rates were better (2.6 vs 2.3 mL/sec). • Finasteride showed maintenance of the decreased risk for AUR and enlarged prostate-related surgery over 4 year period • Generally well tolerated, with sexual dysfunction the most frequently reported adverse effect (1%-8%)

49. 12.3. Medical TreatmentCombination therapy • Short term • Veterans Affairs Cooperative Study, 1229 men with BPH randomly assigned to placebo, finasteride, terazosin or bothfor one year. Results as follow: • Terazosin lowered the symptom score and increased the peak urinary flow rate when compared with placebo • Finasteride alone was no better than placebo • The combination of finasteride and terazosin was no better than terazosin alone

50. 12.3. Medical TreatmentCombination therapy (cont’d) • Short term • PREDICT trial in which 1095 men were randomly assigned to doxazosin, finasterid or bothfor one year. Resluts as follow: • Doxazosin more effective than finasteride or placebo for urinary symptoms and flow rate • Combination no more effective than doxazosine alone • Conclusion:Combination treatment with an alpha-blocker and a 5ARI is beneficial for immediate relief of symptoms ( with discontinuation of the alpha-blocker after several months of therapy)