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MODULE 1 1/46 Module 1: BPH – The Disease Mostafa M. Elhilali MD, PhD, FRCSC Professor and Chair, Department of Surgery McGill University Royal Victoria.

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Presentation on theme: "MODULE 1 1/46 Module 1: BPH – The Disease Mostafa M. Elhilali MD, PhD, FRCSC Professor and Chair, Department of Surgery McGill University Royal Victoria."— Presentation transcript:

1 MODULE 1 1/46 Module 1: BPH – The Disease Mostafa M. Elhilali MD, PhD, FRCSC Professor and Chair, Department of Surgery McGill University Royal Victoria Hospital Montréal, Québec

2 MODULE 1 2/46  To understand the difference between histologic and symptomatic BPH and the prevalence of each.  To learn the meaning of the different acronyms describing the symptoms of BPH and how they manifest in the condition.  To understand the progression of BPH and how it affects the function of the lower urinary tract.  To understand the micro- and macrophysiology of BPH and the role of androgens in the growth of the prostate.  To learn how BPH affects health-related quality of life (HRQoL). 1.1 Learning Objectives BPH = Benign Prostatic Hyperplasia, HRQoL= Health-Related Quality of Life

3 MODULE 1 3/46 1.2 Introduction  BPH is a progressive, non-malignant condition that affects men worldwide  All aging males develop BPH  Few experience symptoms  Fewer seek treatment BPH = Benign Prostatic Hyperplasia

4 MODULE 1 4/46  BPH is associated with:  Bothersome LUTS  Can affect quality of life (e.g. interference with daily activity & sleep)  Histological definition of BPH:  Stromal and epithelial cell hyperplasia beginning in the periurethral zone of the prostate LUTS = Lower Urinary Tract Symptoms

5 MODULE 1 5/46 Figure 1.1: Prevalence of BPH Adapted from Oesterling JE. Arch Fam Med 1992;1(2):257-66 100 15 25 35 45 55 65 75 85 0 20 40 60 80 Age (years) % Prevalence Microscopic BPH Countries Sampled JapanIndiaAustria DenmarkEngland USA

6 MODULE 1 6/46 Figure 1.2: Natural History of BPH: Relationship Between Symptoms and Prostate Volume Adapted from Girman CJ et al. J Urol 1995;153:1510-1515. 40–4950–5960–6970–79 Age (years) 30 20 10 0 Mild symptoms Moderate/ severe symptoms % of men with prostate volume >50 ml (N=2115)

7 MODULE 1 7/46  As with histologic evidence of BPH, the prevalence of bothersome symptoms also increases with age.  Approximately one half of all men who have a histologic diagnosis have moderate to severe LUTS 4 4. McDonald H et al. Can J Urol 2004;11:2327-2340. (p2327, intro) BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms

8 MODULE 1 8/46  About 50% of Canadian men 50 years of age and over display mild to severe symptoms of BPH, which worsen with age 5  If left untreated, LUTS can progress to AUR:  AUR is a distressing condition requiring urgent catheterization and hospitalization 6 5. McDonald H et al. Can J Urol 2004;11:2327-2340. (p2327, intro) 6. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5 th ed. Oxford: Health Press; 2005:7-8. BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms; AUR = Acute Urinary Symptoms

9 MODULE 1 9/46  The defining characteristic of BPH:  Histological evidence of hyperplastic prostatic tissue  As the condition progresses, it leads to urinary tract symptoms such as:  Urinary hesitancy  Weak urinary stream  Increased urinary frequency and urgency 7  Further discussed in Module 2 7. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5 th ed. Oxford: Health Press; 2005:22. BPH = Benign Prostatic Hyperplasia

10 MODULE 1 10/46 Table 1.1: Definition of Terms  LUTS Lower Urinary Tract Symptoms  BPE Benign Prostatic Enlargement (macroscopic)  BOO Bladder Outlet Obstruction  BPH Benign Prostatic Hyperplasia (microscopic/histologic)  BPO Benign Prostatic Obstruction (BOO caused by BPE)  Clinical BPH LUTS + BPE + BOO

11 MODULE 1 11/46 1.3 Symptoms  The symptoms that most characterize BPH are lower urinary tract symptoms (LUTS)  These are so typical of BPH that they are often referred to as “prostatism” or “symptoms of benign prostatic hyperplasia ” 9 9. Abrams P. BMJ 1994;308:929-930.

12 MODULE 1 12/46 Table 1.2: Problems and Consequences Histological BPH (Stromoglandular) By itself may not cause any problems LUTS Bother, Impact on QoL, interference with daily living, sexual dysfunction(?) BPE Acute Urinary Retention (AUR), Surgical Intervention, Secondary Changes of bladder anatomy and function, other outcomes (UTI, stones, renal failure, incontinence, etc.) BOO LUTS = Lower Urinary Tract Symptoms; BOO = Bladder Outlet Obstruction; BPE = Benign Prostatic Enlargement

13 MODULE 1 13/46 Adapted from Nordling J et al. In: Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:107-166. Aging Anoxia Obstruction High nocturnal diuresis Age-related diseases Neurologic diseases Local disease Bladder LUTS Figure 1.3: Conditions Potentially Leading to LUTS

14 MODULE 1 14/46  Many experts group LUTS into voiding or obstructive symptoms and storage or irritative symptoms 12,13  However, as the BPH progresses, LUTS becomes increasingly evident and severe 12. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5 th ed. Oxford: Health Press; 2005:21. 13. Ramsey EW, McSherry J. A community care program on benign prostatic hyperplasia: a primary-care physician’s guide. Mississauga, ON: Astra Pharma Inc.; 1996:19. LUTS = Lower Urinary Tract Symptoms; BPH = Benign Prostatic Hyperplasia

15 MODULE 1 15/46 1.4 Natural History of BPH  A difficult assessment  Biopsy results on large male populations are not readily available, and are impractical to obtain 14  Currently achieved through: 15  Surgical findings  Autopsy studies  Symptom assessments  Measures of urinary flow rates, prostatic volume, bladder wall thickness  Prostate Specific Antigen levels [PSA] 14. Jacobsen SJ et al. Urology 2001;58(Suppl 6A):5-16. p6 15. Jacobsen SJ et al. Urology 2001;58(Suppl 6A):5-16.

16 MODULE 1 16/46  BPH begins with an asymptomatic preclinical stage and progresses into the clinical stage with signs of voiding dysfunction  Clinical BPH takes years to develop, and only a small portion of men with preclinical BPH develop the clinical disease BPH = Benign Prostatic Hyperplasia

17 MODULE 1 17/46 BPE All Men > 40 yrs BOO LUTS / Bother Histologic BPH Figure 1.4: The Problem Adapted from Roerhborn CG. AUA 2005. LUTS = Lower Urinary Tract Symptoms; BPE = Benign Prostatic Enlargement; BOO = Benign Outlet Obstruction

18 MODULE 1 18/46 Figure 1.5: Early BPH - BPH Progression Bladder Prostatic Urethra Detrusor Muscle Developing benign hyperplastic tissue in transition zone Further enlargement of transition zone caused by proliferation of cells Diminished flow of urine from bladder Peripheral zone Transition zone Central zone Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005.

19 MODULE 1 19/46 Figure 1.6: Advanced BPH-Complications and the Need for Surgery Obstructed prostatic urethra Hypertrophied detrusor muscle Considerable BPH tissue presence Progressive impairment of bladder emptying Peripheral zone Transition zone Central zone Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005.

20 MODULE 1 20/46 Potential Complications of BPH  Bladder stones  Bladder damage (Trabeculations, Cellules, Diverticula)  Urinary tract infection  Urinary retention  Renal impairment  Gross Hematuria  Overflow incontinence

21 MODULE 1 21/46 Figure 1.7: Relative Risk of AUR in Relation to Prostate Volume A cohort of 2115 men, aged 50-79, was randomly selected from an enumeration of the Olmsted County. A 25% random subsample (n=537) were selected for a detailed clinical examination which included PSA determination, digital rectal examination and transrectal sonograpic examination of the prostate (73 men [13%] refused to participate or did not complete all diagnostic tests and 4 men [1.3%] were found to have prostate cancer and were excluded from the analysis). Follow-up was performed through a retrospective review of community medical records to determine the occurrence of AUR in the subsequent 4 years. Adjusted estimates were not calculated due to the small sample size. Reference category * ** *** Prostate volume (ml) 95% CI*** (1.0 – 9.0) < 30*** >30 Jacobsen, SJ et al. J Urol 1997;158:481-7 AUR = Acute Urinary Retention; PSA = Prostate-Specific Antigen; CI = Confidence Interval

22 MODULE 1 22/46 Figure 1.8: MTOPS Subanalysis: Prostate Volume and Risk of BPH Progression McConnell JD et al. J Urol. 2003;169(suppl):332. < 31 ng/ml ≥ 31ng/ml 3.4 3 0.3 0.6 5.6 4.3 1 2 0 1 2 3 4 5 6 7 Overall Progression Symptom Progression AURInvasive Therapy Rate per 100 PYR P=0.0031 P=0.001 P=0.004 P=0.0003 MTOPS = Medical Therapy of Prostatic Symptoms

23 MODULE 1 23/46 Figure 1.9: MTOPS Subanalysis – PSA and Risk of BPH Progression < 1.6ng/ml ≥ 1.6ng/ml 3.1 2.8 0.3 0.8 5.9 4.5 1 1.8 0 1 2 3 4 5 6 7 Overall Progression Symptom Progression AUR Invasive Therapy Rate per 100 PYR Adapted from McConnell JD et al. J Urol. 2003;169(suppl):332 PSA = Prostate Specific Antigen P=0.0008 P=0.0251 P=0.0029 P=0.018

24 MODULE 1 Figure 1.10: PLESS Cumulative Incidence of AUR, Surgery and Either One for Placebo Treated Patients by Increasing PSA 0 5 10 15 20 25 30 >0.0>0.5>1.0>1.5>2.0>2.5>3.0>3.5>4.0>4.5>5.0>5.5>6.0>6.5>7.0>7.5>8.0 Cumulative Incidence (%) Either Surgery AUR Adapted from Roerhborn CG. AUA 2005.; AUR = Acute Urinary Retention; PSA = Prostate Specific Antigen 24/49

25 MODULE 1 25/46  The precise causes of BPH are unknown, but the disease is clearly mediated by the androgen testosterone, and its more active metabolite dihydrotestosterone (DHT) 20  Other extrinsic factors (i.e. systemic, genetic, environmental) are also involved 20 20. Lee C, Cockett, A, Cussenot O, et al. Regulation of prostate growth. In: Chatelain C, Denis L, Foo KT, et al. eds. Benign prostatic hyperplasia. Plymouth, UK: Health Publication; 2001:81. BPH = Benign Prostatic Hyperplasia 1.5 Pathology and Pathogenesis

26 MODULE 1 26/46 Figure 1.11: Regulation of Prostate Growth: The Role of Androgens TestosteroneDihydrotestosterone O OH O H 5α-reductase Adapted from Bartsch G et al. Eur Urol 2000;37(4):367-380.

27 MODULE 1 27/46 Figure 1.12: Relative Roles of Type I and Type II 5α-reductase Tissues in which type I and type II 5α-reductase are predominant Skin (sebaceous glands) Type I Prostate gland Type II Liver Adrenal glands Internal/external genital tissues Seminal vesicles Epidiymis Hair follicles Liver Russell DW et al. Annu Rev Biochem 1994;63:25-61. Norman RW et al. J Urol 1993;150(5, pt 2):1736-9. Rittmaster RS. J Androl 1997;18(6):583-7. Gnanapragasam VJ et al. BJU Int 2000;86:1001-13. Bartsch G et al. Eur Urol 2000;37((4):367-80. Yokoi H et al. Histochem Cell Biol 1998;109(2):127-34. Thigpen AE. J Clin Invest 1993;92(2):903-10.

28 MODULE 1 28/46  DHT enters the nucleus and stimulates the translation and transcription of growth factors such as:  EGF – Epidermal Growth Factors  PDGF – Platelet Derived Growth Factors  FGF – Fibroblast Growth Factors  Other intrinsic factors that promote hyperplasia in the stromal and epithelial prostatic compartments DHT = Dihydrotestosterone

29 MODULE 1 29/46  Additional mechanisms that promote prostate growth include inhibition of apoptosis by factors such as Transforming Growth Factor  (TGF  )  Inhibition of apoptosis creates an imbalance between cell proliferation and death  This leads to progressive growth in the prostate’s transition zone 21 21. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5 th ed. Oxford: Health Press; 2005:10.

30 MODULE 1 30/46 Figure 1.13: Dynamic and Static Obstruction in BPH Dynamic Obstruction: Obstruction due to smooth muscle tone Static Obstruction: Obstruction due to enlargement of the prostate BPH = Benign Prostatic Hyperplasia Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5 th ed. Oxford: Health Press; 2005.

31 MODULE 1 31/46  Static Obstruction is caused by enlargement of the prostate as previously described  Dynamic Obstruction is caused by an increase in smooth muscle tone in the prostate and surrounding organs  Up to 60% of hyperplastic tissue is composed of smooth muscle cells and connective tissue

32 MODULE 1 32/46  Sympathetic nerve stimulation causes the release of norepinephrine, which binds to α 1 -andrenoreceptors located on the membrane of the smooth muscle cells  This triggers the influx of calcium and increases prostatic smooth muscle tone  There are several α 1 -receptor subtypes:  α 1A – predominant in the prostate  α 1B – involved in peripheral vasoconstriction  α 1D – abundant in the liver, spleen, and bladder

33 MODULE 1 33/46  The two mechanisms described above form the basis for the two major pharmacological approaches to treating BPH:  Inhibition of 5α-reductase to reduce the conversion of testosterone to DHT, resulting in prostate volume reduction  Inhibition of α 1 -adrenoreceptors to relax the smooth muscle contractions in the bladder neck and the prostatic urethra BPH = Benign Prostatic Hyperplasia; DHT = Dihydrotestosterone

34 MODULE 1 34/46 Pathology of BPH  Histologically, the first sign of BPH is the appearance of stromal nodules ranging in size from a few millimeters, to a few centimeters in diameter  The nodules are located in the peripheral area of the transition zone  This is followed by glandular hyperplasia and enlargement of the prostate BPH = Benign Prostatic Hyperplasia

35 MODULE 1 35/46  No correlation between prostate size and the degree of outflow obstruction.  This may be due to: 22  Relative proportions of stromal and glandular tissue  Variations in sympathetic nerve stimulation in the smooth muscle  Variable enlargement of the prostate’s middle lobe, resulting in a “ball-valve” obstruction without overall enlargement of the gland  Prostate enlargement is still correlated with risk of progression and complications such as AUR and the need for surgery 23 22. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5 th ed. Oxford: Health Press; 2005:11. 23. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5 th ed. Oxford: Health Press; 2005:12. AUR = Acute Urinary Retention

36 MODULE 1 36/46 1.6 BPH and Quality of Life (QoL)  In most men, BPH is a quality-of-life disease  Histologically, most men are symptom free especially in the early stages  Significant number go on to experience bothersome LUTS BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms

37 MODULE 1 37/46 10 8 6 4 2 0 6.1 9.0 3.6 5.6 2.3 Symptom score (p<0.0001) Bother score (p<0.005) Activity score (NS) Health-related quality-of-life score 3.1 ( n=471) Prostate  40 ml Prostate > 40 ml Higher Score  Worse Status Adapted from Girman CJ et al. Eur Urol 1999;35:277- 284. Figure 1.14: BPH and Quality of Life

38 MODULE 1 38/46  HRQoL studies performed in Scotland and the United States in the early 1990’s revealed similar findings 25  Of the 410 men with BPH in the Scottish study, 51% reported interference with at least one of a selected number of daily living activities as a result of urinary dysfunction  This was compared to 28% of men who did not have the condition 26 25. Garraway WM et al. Urology 1994;44:629-36. p629 26. Garraway WM et al. Br J Gen Pract. 1993;43:318-21. HRQoL=Health-Related Quality of Life; BPH = Benign Prostatic Hyperplasia

39 MODULE 1 39/46  In 17% of (working-aged) men aged 40-64 with BPH, this interference occurred most or all of the time for at least one activity of daily living, compared with about 3% of men in the same age group who did not have this condition  These men were more likely to be bothered by:  Nocturia  Hesitancy  Straining, Intermittency  Weak stream force  Dribbling and Urgency (most bothersome) BPH = Benign Prostatic Hyperplasia

40 MODULE 1 40/46 US Study (1993)  In a US study (n=707), men with BPH reported the most bothersome problems to be urgency, frequency and nocturia  Obstructive symptoms, peak urinary flow rates, and post-void urine estimates were unrelated to diminished QoL 27  These men complained of having to limit fluid intake before sleep or travel, and avoid outdoor sports or places without toilets 27  Considering the evidence, it is clear that HRQoL needs to be considered in any treatment plan 27. A comparison of quality of life with patient reported symptoms and objective findings in men with benign prostatic hyperplasia. The Department of Veterans Affairs Cooperative Study of transurethral resection for benign prostatic hyperplasia. J Urol. 1993;150(5 Pt 2):1696-700. BPH = Benign Prostatic Hyperplasia; QoL = Quality of Life; HRQoL = Health Related Quality of Life

41 MODULE 1 41/46 1.7 Conclusion  This module helped us differentiate between histologic and symptomatic BPH as well as the prevalence of each.  It clarified the different acronyms used for describing BPH symptoms.  It addressed the progression of BPH and how this affects the function of the lower urinary tract.  We specifically covered the micro- and macro-physiology of BPH with the role of androgens and α 1 -adrenoreceptors in the prostate as far as growth and dynamic changes.  Considering how BPH affects health-related quality of life (HRQoL) issues, it is very important that we include this component in any treatment plan. BPH = Benign Prostatic Hyperplasia; HRQoL=Health-Related Quality of Life

42 MODULE 1 42/46 1.8 Quiz 1.What percentage of men 60 years or older have symptomatic BPH? a)20% b)30% c)40% d)50% e)>50% (correct) BPH = Benign Prostatic Hyperplasia

43 MODULE 1 43/46 2.What is the defining characteristic of BPH? a)An enlarged prostate b)Symptoms of urinary obstruction (weak flow, hesitancy, and straining ) c)Elevated PSA d)Symptoms related to storage (frequency,urgency,incontinence) e)Histological evidence of hyperplastic prostatic tissue, obtained by biopsy (correct) PSA = Prostate Specific Antigen; BPH = Benign Prostatic Hyperplasia

44 MODULE 1 44/46 3.Which of the following is NOT a risk factor for acute urinary retention? a)advanced age b)large prostate c)family history (correct) d)previous history of AUR e)severe LUTS AUR = Acute Urinary Retention; LUTS = Lower Urinary Tract Symptoms

45 MODULE 1 45/46 4.Which type of 5α-reductase is most prominent in the prostate? a)Type 1 b)Type 2 (correct) c)Both types d)It varies from individual to individual

46 MODULE 1 46/46 5.What does the term “dynamic obstruction” refer to? a)Symptoms suggestive of acute urinary retention b)Urinary obstruction due to increased smooth muscle tone in the prostate and surrounding tissues (correct) c)Enlargement of the prostate resulting in urinary obstruction d)Progressive LUTS e)LUTS resistant to medical treatment LUTS = Lower Urinary Tract Symptoms


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