Module 1: BPH – The Disease

Module 1: BPH – The Disease
Mostafa M. Elhilali MD, PhD, FRCSC Professor and Chair, Department of Surgery McGill University Royal Victoria Hospital Montréal, Québec Module 1: Benign Prostatic Hyperplasia (BPH) – The Disease The principle author for this module is Dr. Mostafa Elhilali, Professor and Chair of the Department of Surgery at the McGill University in Montreal, Quebec. Understanding BPH: From the Science to the Clinical Setting

1.1 Learning Objectives 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 The Learning Objectives for this Module are: 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). BPH = Benign Prostatic Hyperplasia, HRQoL= Health-Related Quality of Life Understanding BPH: From the Science to the Clinical Setting

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 1.2 Introduction Benign prostatic hyperplasia (BPH) is a progressive, non-malignant condition that affects men worldwide. Although all aging males develop BPH, only a percentage of them experience symptoms, and an even smaller percentage will seek treatment. BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

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 BPH is one of the most common diseases affecting aging men. It can be associated with bothersome lower urinary tract symptoms (LUTS) that affect quality of life by interfering with normal daily activities and sleep patterns. BPH is defined histologically by stromal and epithelial cell hyperplasia beginning in the periurethral zone of the prostate. LUTS = Lower Urinary Tract Symptoms Understanding BPH: From the Science to the Clinical Setting

Figure 1.1: Prevalence of BPH
Module 1: BPH – The Disease Figure 1.1: Prevalence of BPH 100 80 % Prevalence Microscopic BPH 60 Countries Sampled 40 USA England Denmark Austria India Japan Figure 1.1: Prevalence of BPH Adapted from Oesterling JE. Arch Fam Med 1992;1(2):257-66 Beginning around the age of 25 to 30 years of age, histological BPH becomes evident on microscopic examination. Men however experience few if any signs or symptoms until middle age. In fact, histological BPH exists mostly in men over the age of 40 years.1 By 60 years of age, its prevalence is greater than 50% and by age 85, it is as high as 90%. 2 1. Roehrborn CG. BPH: From treatment to prevention: A change in paradigm prevention. Presentation at AUA 2005. 2. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol 2003;170: p530 20 15 25 35 45 55 65 75 85 Age (years) Adapted from Oesterling JE. Arch Fam Med 1992;1(2):257-66 Understanding BPH: From the Science to the Clinical Setting

Figure 1.2: Natural History of BPH: Relationship Between Symptoms and Prostate Volume 30 20 10 (N=2115) Mild symptoms Moderate/ severe symptoms Figure 1.2: Natural History of BPH: Relationship Between Symptoms and Prostate Volume Adapted from Girman CJ et al. J Urol 1995;153: Epidemiologic data have shown that BPH symptoms are more severe in patients with enlarged prostates. In a population-based study of 2115 men aged 40 to 79 years, the risk of having moderate to severe BPH symptoms was five times higher in men with larger prostates (>50 mL) compared to men with smaller prostates. The slide depicts the results of this study according to patient age, also demonstrating the impact of age on the prevalence of BPH. 3 3. Girman CJ, Jacobsen SJ, Guess HA, et al. Natural history of prostatism: relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 1995;153: *Study of relationships among prostate volume, urinary symptoms, and flow rates in 2115 men 40 to 79 years of age participating in a community-based study % of men with prostate volume >50 ml 40–49 50–59 60–69 70–79 Age (years) Adapted from Girman CJ et al. J Urol 1995;153: Understanding BPH: From the Science to the Clinical Setting

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 LUTS4 As with histologic evidence, the prevalence of bothersome symptoms also increases with age. Approximately one half of all men who have a histologic diagnosis have moderate to severe lower urinary tract symptoms (LUTS). 4 4. McDonald H, Hux M, Brisson M, Bernard L, Nickel JC. An economic evaluation of doxazosin, finasteride and combination therapy in the treatment of benign prostatic hyperplasia. Can J Urol 2004;11: (p2327, intro) 4. McDonald H et al. Can J Urol 2004;11: (p2327, intro) BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms Understanding BPH: From the Science to the Clinical Setting

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 Approximately one half of Canadian men 50 years of age or older have mild to severe symptoms of BPH, the prevalence of which increases with age. 5 If left untreated, LUTS can progress to acute urinary retention (AUR), a distressing condition requiring urgent catheterization and hospitalization. 6 5. McDonald H et al. Can J Urol 2004;11: (p2327, intro) 6. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:7-8. 5. McDonald H et al. Can J Urol 2004;11: (p2327, intro) 6. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:7-8. BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms; AUR = Acute Urinary Symptoms Understanding BPH: From the Science to the Clinical Setting

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 The defining characteristic of BPH is histological evidence of hyperplastic prostatic tissue, obtained by biopsy. As the condition progresses, it eventually leads to a number of lower urinary tract symptoms such as urinary hesitancy, a weak urinary stream, increased urinary frequency and urgency (this is discussed further in Module 2). 7 7. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press;2005:22. 7. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:22. BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

Table 1.1: Definition of Terms
Module 1: BPH – The Disease 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 Table 1.1: Definition of Terms The signs and symptoms of BPH are described using a veritable alphabet of acronyms:8 LUTS is the acronym for Lower Urinary Tract Symptoms. BPE stands for Benign Prostatic Enlargement. BOO is for Bladder Outlet Obstruction. BPH has already been mentioned. BPO is an acronym for Benign Prostatic Obstruction. Clinical BPH is defined as the combination of LUTS, BPE and BOO. 8. Silverman W. Alphabet soup and the prostate: LUTS, BPH, BPE, and BOO. JAOA 2004;104(Suppl 2):S1-S4. Understanding BPH: From the Science to the Clinical Setting

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 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. New words for old: lower urinary tract symptoms for “prostatism.” BMJ 1994;308: 9. Abrams P. BMJ 1994;308: Understanding BPH: From the Science to the Clinical Setting

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 Table 1.2: Problems and Consequences The terminology of BPH can vary and different aspects of the condition are related to different problems. Histological BPH may not cause any problems by itself. LUTS can cause considerable bother and impact on quality of life. BPE and BOO can lead to acute urinary retention (AUR), changes in bladder anatomy and function, and other outcomes which may necessitate surgical intervention. LUTS = Lower Urinary Tract Symptoms; BOO = Bladder Outlet Obstruction; BPE = Benign Prostatic Enlargement Understanding BPH: From the Science to the Clinical Setting

Figure 1.3: Conditions Potentially Leading to LUTS Aging Anoxia Obstruction High nocturnal diuresis Age-related diseases Neurologic diseases Local disease Bladder LUTS Figure 1.3: Conditions Potentially Leading to LUTS Adapted from Nordling J et al. In: Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Other conditions could present with LUTS and these include: bladder cancer, prostate cancer, urinary tract infection, prostatitis, and several causes of disturbed fluid balance. 10, 11 10. Reynard J. All possible causes of lower urinary tract symptoms must be investigated. [letter] BMJ 2001;323;750. 11. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:21. Adapted from Nordling J et al. In: Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Understanding BPH: From the Science to the Clinical Setting

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 Many experts group LUTS into voiding or obstructive symptoms and storage or irritative symptoms. 12, 13 However, as the BPH progresses, LUTS become increasingly evident and severe. (Module 2 will provide a detailed list of LUTS.) 12. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th 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. 12. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th 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 Understanding BPH: From the Science to the Clinical Setting

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] 1.4 Natural History of BPH Assessing the natural history of BPH is difficult, primarily because biopsies on large numbers of men in any given population are not readily available, nor is it practical to obtain them. 14 Therefore, surgical findings, autopsy studies and surrogate measures such as symptom assessments, urinary flow rates, prostatic volume, bladder-wall thickness, prostate specific antigen [PSA] levels, and correlations among them are currently the best means by which natural history of BPH can be estimated at the population level. 15 14. Jacobsen SJ, Girman CJ, Lieber MM. Natural history of benign prostatic hyperplasia. Urology 2001;58(Suppl 6A):5-16. p6 15. Jacobsen SJ, Girman CJ, Lieber MM. Natural history of benign prostatic hyperplasia. Urology 2001;58(Suppl 6A):5-16. 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. Understanding BPH: From the Science to the Clinical Setting

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 begins with an asymptomatic preclinical stage which progresses into a clinical stage with signs or symptoms of voiding dysfunction. Only a small proportion of men with preclinical BPH go on to develop clinical disease, which takes years to develop. BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

Figure 1.4: The Problem All Men > 40 yrs Histologic BPH BPE Figure 1.4: The Problem Adapted from Roerhborn CG. AUA 2005. The problem can be described in terms of overlapping symptoms, as is shown in this slide. Of men over 40 years of age, most develop histological BPH. However, progressively smaller percentages will develop LUTS, prostate enlargement, and obstruction. Some men will have one, two, or even three sets of symptoms, all due to BPH. But as shown, some men can develop obstruction or LUTS without histologic BPH. BOO LUTS / Bother Adapted from Roerhborn CG. AUA 2005. LUTS = Lower Urinary Tract Symptoms; BPE = Benign Prostatic Enlargement; BOO = Benign Outlet Obstruction Understanding BPH: From the Science to the Clinical Setting

Figure 1.5: Early BPH - BPH Progression
Module 1: BPH – The Disease Figure 1.5: Early BPH - BPH Progression Bladder Prostatic Urethra Detrusor Muscle Figure 1.5: Early BPH – BPH Progression Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005. As BPH progresses, the prostate enlarges and increasingly obstructs the urethra, leading to interference with normal urine flow. This results in pressure on the prostatic urethra which becomes less distensible, causing progressive obstruction of urine flow. The detrusor muscle responds to this obstruction by smooth muscle hypertrophy and connective tissue infiltration, resulting in increased voiding pressure, decreased bladder compliance and involuntary bladder contractions (detrusor overactivity) encountered in up to 70% of patients. 16 16. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:16-17. Further enlargement of transition zone caused by proliferation of cells Developing benign hyperplastic tissue in transition zone Peripheral zone Transition zone Central zone Diminished flow of urine from bladder Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005. Understanding BPH: From the Science to the Clinical Setting

Figure 1.6: Advanced BPH-Complications and the Need for Surgery
Module 1: BPH – The Disease Figure 1.6: Advanced BPH-Complications and the Need for Surgery Obstructed prostatic urethra Hypertrophied detrusor muscle Considerable BPH tissue presence Figure 1.6: Advanced BPH-Complications and the Need for Surgery Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005 If left untreated, BPH progresses to the point where bladder emptying may become completely impaired, culminating in acute urinary retention (AUR). If gradual overdistension occurs, painless retention may result in overflow incontinence, in addition to LUTS. The risk factors for AUR include advanced age, large hyperplastic prostate, high PSA values, increased post-void residual urine, reduced peak urine flow rate (Qmax < 10 mL/s), previous history of AUR, and severe LUTS. 17 17. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:16. Peripheral zone Transition zone Central zone Progressive impairment of bladder emptying Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005. Understanding BPH: From the Science to the Clinical Setting

Potential Complications of BPH
Module 1: BPH – The Disease Potential Complications of BPH Bladder stones Bladder damage (Trabeculations, Cellules, Diverticula) Urinary tract infection Urinary retention Renal impairment Gross Hematuria Overflow incontinence Potential Complications of BPH Although uncommon, prolonged outflow obstruction can also cause bladder stones, bladder diverticula, recurrent urinary tract infections (UTIs), chronic urinary retention, and, rarely, deterioration of renal function. 18 18. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:16. Understanding BPH: From the Science to the Clinical Setting

Figure 1.7: Relative Risk of AUR in Relation to Prostate Volume 95% CI*** (1.0 – 9.0) Figure 1.7: Relative Risk of AUR in Relation to Prostate Volume Jacobsen SJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997;158:481-7. BPH is clearly a progressive disease and recent studies have yielded data on how to predict which men will go on to have symptomatic progression. For example, the Olmsted County Study found that men with an enlarged prostate (greater than 30 cc) experienced a 3-fold increase in risk (95% CI , p = 0.04). < 30*** >30 Prostate volume (ml) 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 * ** *** Jacobsen, SJ et al. J Urol 1997;158:481-7 AUR = Acute Urinary Retention; PSA = Prostate-Specific Antigen; CI = Confidence Interval Understanding BPH: From the Science to the Clinical Setting

Figure 1.8: MTOPS Subanalysis: Prostate Volume and Risk of BPH Progression 7 P=0.0031 6 5.6 < 31 ng/ml ≥ 31ng/ml 5 P=0.001 4.3 4 Rate per 100 PYR 3.4 3 3 P=0.0003 2 2 Figure 1.8: MTOPS Subanalysis: Prostate Volume and Risk of BPH Progression McConnell JD et al. J Urol. 2003;169(suppl):332. As shown on this and the following slide, a subanalysis of the study named Medical Therapy of Prostatic Symptoms or MTOPS showed that prostate volume (as determined by transurethral ultrasound of the prostate or TRUS) and higher levels of PSA were correlated with a higher risk of BPH progression, including overall progression, symptom progression, AUR, and the need for invasive therapy. P=0.004 1 1 0.6 0.3 Overall Symptom AUR Invasive Therapy Progression Progression McConnell JD et al. J Urol. 2003;169(suppl):332. MTOPS = Medical Therapy of Prostatic Symptoms Understanding BPH: From the Science to the Clinical Setting

Figure 1.9: MTOPS Subanalysis – PSA and Risk of BPH Progression
Module 1: BPH – The Disease Figure 1.9: MTOPS Subanalysis – PSA and Risk of BPH Progression 7 P=0.0008 5.9 6 P=0.0251 < 1.6ng/ml ≥ 1.6ng/ml 5 4.5 4 Rate per 100 PYR 3.1 3 2.8 P=0.018 P=0.0029 2 1.8 Figure 1.9: MTOPS Subanalysis – PSA and Risk of BPH Progression Adapted from McConnell JD et al. J Urol. 2003;169(suppl):332. This slide shows the impact of PSA level on overall progression, symptom progression, AUR or invasive therapy. These studies have had an enormous impact on treatment and shifted the approach dramatically from surgical to medical treatment with 5α-reductase inhibitors, often in combination with α1-blockers (as you will see in Module 3). 1 1 0.8 0.3 Overall Symptom AUR Invasive Therapy Progression Progression Adapted from McConnell JD et al. J Urol. 2003;169(suppl):332 PSA = Prostate Specific Antigen Understanding BPH: From the Science to the Clinical Setting

Figure 1.10: PLESS Cumulative Incidence of AUR, Surgery and Either One for Placebo Treated Patients by Increasing PSA 30 Either 25 Surgery AUR 20 15 Cumulative Incidence (%) Figure 1.10: PLESS Adapted from Roerhborn CG. AUA 2005. In the PLESS trial, patients with higher baseline PSA were shown to have a higher incidence of either AUR, the need for surgery, or both. 10 5 >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 Adapted from Roerhborn CG. AUA 2005.; AUR = Acute Urinary Retention; PSA = Prostate Specific Antigen 24/49 Understanding BPH: From the Science to the Clinical Setting

1.5 Pathology and Pathogenesis
Module 1: BPH – The Disease 1.5 Pathology and Pathogenesis 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 Pathogenesis of BPH The precise causes of BPH are unknown, but it is clear that the disease is mediated by the androgens testosterone and its more active metabolite, dihydrotestosterone (DHT) as well as other extrinsic factors (i.e. systemic, genetic, and environmental factors). 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: p81 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 Understanding BPH: From the Science to the Clinical Setting

Figure 1.11: Regulation of Prostate Growth: The Role of Androgens
Module 1: BPH – The Disease Figure 1.11: Regulation of Prostate Growth: The Role of Androgens OH OH 5α-reductase O O Figure 1.11: Regulation of Prostate Growth: The Role of Androgens Adapted from Bartsch G et al. Eur Urol 2000;37(4): DHT is the principal androgen responsible for prostatic growth and BPH. 5-reductase enzyme mediates the conversion of testosterone to dihydrotestosterone or DHT. H Testosterone Dihydrotestosterone Adapted from Bartsch G et al. Eur Urol 2000;37(4): Understanding BPH: From the Science to the Clinical Setting

Figure 1.12: Relative Roles of Type I and Type II 5α-reductase
Module 1: BPH – The Disease 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 Figure 1.12: Relative Roles of Type I and Type II 5-reductase Russell DW et al. Annu Rev Biochem 1994;63: Norman RW et al. J Urol 1993;150(5, pt 2): Rittmaster RS. J Androl 1997;18(6): Gnanapragasam VJ et al. BJU Int 2000;86: Bartsch G et al. Eur Urol 2000;37((4): Yokoi H et al. Histochem Cell Biol 1998;109(2): Thigpen AE. J Clin Invest 1993;92(2): Type II 5-reductase enzyme is predominant in the prostate and other genital tissues, while both types I and II are common in tissues outside the prostate. Russell DW et al. Annu Rev Biochem 1994;63: Norman RW et al. J Urol 1993;150(5, pt 2): Rittmaster RS. J Androl 1997;18(6): Gnanapragasam VJ et al. BJU Int 2000;86: Bartsch G et al. Eur Urol 2000;37((4): Yokoi H et al. Histochem Cell Biol 1998;109(2): Thigpen AE. J Clin Invest 1993;92(2): Understanding BPH: From the Science to the Clinical Setting

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 This reiterates what was shown in the enzyme whereby dihydrotestosterone (DHT) enters the nucleus and stimulates the translation and transcription of growth factors, such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), fibroblast growth factors (FGF) and other intrinsic factors that promote hyperplasia in the stromal and epithelial prostatic compartments. DHT = Dihydrotestosterone Understanding BPH: From the Science to the Clinical Setting

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 Additional mechanisms that promote prostate growth include inhibition of apoptosis by factors such as transforming growth factor β (TGFβ). This creates an imbalance between cell proliferation and cell death, leading to progressive growth in the transition zone of the prostate. 21 21. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:10. 21. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:10. Understanding BPH: From the Science to the Clinical Setting

Figure 1.13: Dynamic and Static Obstruction in BPH
Module 1: BPH – The Disease 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 Figure 1.13: Dynamic and Static Obstruction in BPH Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005. Bladder outlet obstruction or BOO due to BPH is often described in terms of static and dynamic obstruction. BPH = Benign Prostatic Hyperplasia Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005. Understanding BPH: From the Science to the Clinical Setting

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 Static obstruction is due to the enlargement of the prostate as a result of mechanisms described before, whereas dynamic obstruction is due to 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. Understanding BPH: From the Science to the Clinical Setting

Sympathetic nerve stimulation causes the release of norepinephrine, which binds to α1-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 α1-receptor subtypes: α1A – predominant in the prostate α1B – involved in peripheral vasoconstriction α1D – abundant in the liver, spleen, and bladder Sympathetic nerve stimulation causes the release of norepinephrine which binds to α1-adrenoreceptors located on the membrane of smooth muscle cells. This triggers the influx of calcium and increases prostatic smooth muscle tone. There are several α1-receptor subtypes, including α1A, which is predominant in the prostate, α1B, which is involved in peripheral vasoconstriction, and α1D, which is abundant in the liver, spleen, and bladder. Understanding BPH: From the Science to the Clinical Setting

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 α1-adrenoreceptors to relax the smooth muscle contractions in the bladder neck and the prostatic urethra The two mechanisms described here form the basis for the two major pharmacological approaches to treating BPH: (1) inhibition of 5α-reductase to decrease the conversion of testosterone to DHT, resulting in prostate volume reduction, and (2) inhibition of α1-adrenoreceptors to relax the contraction of smooth muscle in the bladder neck and prostatic urethra. These are discussed more fully in Module 3 (Treatment of BPH). BPH = Benign Prostatic Hyperplasia; DHT = Dihydrotestosterone Understanding BPH: From the Science to the Clinical Setting

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 Histologically, the first sign of BPH is the appearance of stromal nodules, varying in size from a few millimeters to a few centimeters in diameter, predominantly in the peripheral area of the transition zone. This is followed by glandular hyperplasia and enlargement of the prostate. BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

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 Interestingly, there is no close correlation between the size of the prostate and the degree of outflow obstruction. This may be due to factors such as (1) the relative proportions of stromal and glandular tissue in the prostate, (2) variations in sympathetic nerve stimulation in the smooth muscle of the prostate, (3) variable enlargement of the middle lobe of the prostate, leading to a “ball-valve” obstruction without overall enlargement of the gland. 22 However, prostate enlargement is still correlated with the risk of progression and complications such as acute urinary retention and the need for surgery. 23 22. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:11. 23. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:12. 22. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:11. 23. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005:12. AUR = Acute Urinary Retention Understanding BPH: From the Science to the Clinical Setting

1.6 BPH and Quality of Life (QoL)
Module 1: BPH – The Disease 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 1.6 BPH and Quality of Life (QoL) In most men, BPH is primarily a quality-of-life disease. Although most men with histological BPH are relatively symptom-free, especially in the early stages, a significant number go on to experience bothersome lower urinary tract symptoms or LUTS. BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms Understanding BPH: From the Science to the Clinical Setting

Figure 1.14: BPH and Quality of Life
Module 1: BPH – The Disease Figure 1.14: BPH and Quality of Life 10 8 6 4 2 (n=471) Prostate  40 ml Prostate > 40 ml 9.0 Higher Score  Worse Status 6.1 5.6 Health-related quality-of-life score 3.6 3.1 2.3 Figure 1.14: BPH and Quality of Life Adapted from Girman CJ et al. Eur Urol 1999;35: To assess the effect of LUTS on health-related quality of life (HRQoL) Girman and colleagues examined 471 men (aged years) from Olmsted County, Minnesota, and subjected them to a full urological workup, including transrectal ultrasonography. 24 The men were asked to fill out questionnaires soliciting information about urinary symptom frequency, bother, degree of interference with daily activities and other measures of HRQoL. Results showed that HRQoL scores were worse for older men and men with more severe LUTS. Age-adjusted mean scores for symptom severity, bother and activity interference were about 50% worse for men with enlarged prostates (volume > 40 mL). After adjusting for age, men with enlarged prostates were nearly three times as likely to have moderate to severe symptoms, and about twice as likely to have bother or activity interference relative to men with smaller prostates. 24. Girman CJ, Jacobsen SJ, Rhodes T, Guess HA, Roberts RO, Lieber MM. Association of health-related quality of life and benign prostatic enlargement. Eur Urol. 1999;35: Symptom score (p<0.0001) Bother score (p<0.005) Activity score (NS) Adapted from Girman CJ et al. Eur Urol 1999;35: Understanding BPH: From the Science to the Clinical Setting

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 HRQoL studies conducted in the early 1990s in Scotland and the United States revealed similar findings. 25 Of 410 men with BPH in the Scottish study, 51% reported interference with at least one of a number of selected activities of daily living as a result of urinary dysfunction, compared with 28% of men who did not have this condition. 26 25. Garraway WM, Kirby RS. Benign prostatic hyperplasia: effects on quality of life and impact on treatment decisions. Urology 1994;44: p629 26. Garraway WM, Russell EB, Lee RJ, et al. Impact of previously unrecognized benign prostatic hyperplasia on the daily activities of middle-aged and elderly men. Br J Gen Pract. 1993;43: 25. Garraway WM et al. Urology 1994;44: p629 26. Garraway WM et al. Br J Gen Pract. 1993;43: HRQoL=Health-Related Quality of Life; BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

In 17% of (working-aged) men aged 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) In 17% of men of working age (40-64 years) with BPH, this interference occurred most or all of the time for at least one activity of daily living compared with only 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, and weak stream force, but the most bothersome symptoms were dribbling and urgency. BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

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 A US study of 707, men with BPH reported the most bothersome problems to be urgency, frequency and nocturia, whereas obstructive symptoms, peak urinary flow rates and post-void urine estimates were unrelated to diminished quality of life. 27 These men complained of having to limit their intake of fluid before going to bed or before travelling, and avoiding outdoor sports or places without toilets. 27 Considering this evidence, it is clear that health-related quality of life (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): 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): BPH = Benign Prostatic Hyperplasia; QoL = Quality of Life; HRQoL = Health Related Quality of Life Understanding BPH: From the Science to the Clinical Setting

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 α1-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. 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 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 Understanding BPH: From the Science to the Clinical Setting

1.8 Quiz What percentage of men 60 years or older have symptomatic BPH? 20% 30% 40% 50% >50% (correct) 1.8 Quiz 1. What percentage of men 60 years or older have symptomatic BPH? 20% 30% 40% 50% >50% (correct) BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

What is the defining characteristic of BPH? An enlarged prostate Symptoms of urinary obstruction (weak flow, hesitancy, and straining ) Elevated PSA Symptoms related to storage (frequency,urgency,incontinence) Histological evidence of hyperplastic prostatic tissue, obtained by biopsy (correct) 1.8 Quiz 2. What is the defining characteristic of BPH? An enlarged prostate Symptoms of urinary obstruction (weak flow, hesitancy, and straining ) Elevated PSA Symptoms related to storage (frequency,urgency,incontinence) Histological evidence of hyperplastic prostatic tissue, obtained by biopsy (correct) PSA = Prostate Specific Antigen; BPH = Benign Prostatic Hyperplasia Understanding BPH: From the Science to the Clinical Setting

Which of the following is NOT a risk factor for acute urinary retention? advanced age large prostate family history (correct) previous history of AUR severe LUTS 1.8 Quiz 3. Which of the following is NOT a risk factor for acute urinary retention? advanced age large prostate family history (correct) previous history of AUR severe LUTS AUR = Acute Urinary Retention; LUTS = Lower Urinary Tract Symptoms Understanding BPH: From the Science to the Clinical Setting

Which type of 5α-reductase is most prominent in the prostate? Type 1 Type 2 (correct) Both types It varies from individual to individual 1.8 Quiz Which type of 5α-reductase is most prominent in the prostate? Type 1 Type 2 (correct) Both types It varies from individual to individual Understanding BPH: From the Science to the Clinical Setting

What does the term “dynamic obstruction” refer to? Symptoms suggestive of acute urinary retention Urinary obstruction due to increased smooth muscle tone in the prostate and surrounding tissues (correct) Enlargement of the prostate resulting in urinary obstruction Progressive LUTS LUTS resistant to medical treatment 1.8 Quiz 5. What does the term “dynamic obstruction” refer to? Symptoms suggestive of acute urinary retention Urinary obstruction due to increased smooth muscle tone in the prostate and surrounding tissues (correct) Enlargement of the prostate resulting in urinary obstruction Progressive LUTS LUTS resistant to medical treatment LUTS = Lower Urinary Tract Symptoms Understanding BPH: From the Science to the Clinical Setting

Module 1: BPH – The Disease

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