Module 1: BPH – The Disease Mostafa M. Elhilali MD, PhD, FRCSCProfessor and Chair, Department of SurgeryMcGill UniversityRoyal Victoria HospitalMontréal, Québec
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). BPH = Benign Prostatic Hyperplasia, HRQoL= Health-Related Quality of Life
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
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
Figure 1.1: Prevalence of BPH 100 80 % Prevalence Microscopic BPH 60 Countries Sampled 40 USA England Denmark Austria India Japan 20 0 85 75 65 15 35 55 25 45 Age (years) Adapted from Oesterling JE. Arch Fam Med 1992;1(2):257-66
Figure 1.2: Natural History of BPH: Relationship Between Symptoms and Prostate Volume 30 20 10 0 (N=2115) Mild symptoms Moderate/severe symptoms % 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;153:1510-1515.
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 4. McDonald H et al. Can J Urol 2004;11:2327-2340. (p2327, intro) BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms
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. 5th ed. Oxford: Health Press; 2005:7-8. BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms; AUR = Acute Urinary Symptoms
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. 5th ed. Oxford: Health Press; 2005:22. BPH = Benign Prostatic Hyperplasia
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.
Table 1.2: Problems and Consequences LUTS = Lower Urinary Tract Symptoms; BOO = Bladder Outlet Obstruction; BPE = Benign Prostatic Enlargement
Anoxia High nocturnal diuresis Aging Bladder Age-relateddiseases Obstruction Localdisease Neurologicdiseases LUTS Figure 1.3: Conditions Potentially Leading to LUTS Adapted from Nordling J et al. In: Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:107-166.
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. 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
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.
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
Figure 1.4: The Problem All Men > 40 yrs Histologic BPH BPE BOO LUTS / Bother Adapted from Roerhborn CG. AUA 2005. LUTS = Lower Urinary Tract Symptoms; BPE = Benign Prostatic Enlargement; BOO = Benign Outlet Obstruction
Peripheral zone Transition zone Central zone Figure 1.5: Early BPH - BPH Progression Bladder ProstaticUrethra DetrusorMuscle Further enlargement of transition zone caused by proliferation of cells Developing benign hyperplastic tissue in transition zone Diminished flow of urine from bladder Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005.
Peripheral zone Transition zone Central zone 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 Adapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005.
Potential Complications of BPH • Bladder stones • Bladder damage (Trabeculations, Cellules, Diverticula) • Urinary tract infection • Urinary retention • Renal impairment • Gross Hematuria • Overflow incontinence
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 * ** *** Figure 1.7: Relative Risk of AUR in Relation to Prostate Volume 95% CI*** (1.0 – 9.0) < 30*** >30 Prostate volume (ml) AUR = Acute Urinary Retention; PSA = Prostate-Specific Antigen; CI = Confidence Interval Jacobsen, SJ et al. J Urol 1997;158:481-7
< 31 ng/ml ≥ 31ng/ml Figure 1.8: MTOPS Subanalysis: Prostate Volume and Risk of BPH Progression 7 P=0.0031 6 5.6 P=0.001 5 4.3 4 3.4 Rate per 100 PYR 3 3 P=0.0003 2 2 P=0.004 1 1 0.6 0.3 0 Overall Symptom AUR Invasive Therapy Progression Progression MTOPS = Medical Therapy of Prostatic Symptoms McConnell JD et al. J Urol. 2003;169(suppl):332.
< 1.6ng/ml ≥ 1.6ng/ml Figure 1.9: MTOPS Subanalysis – PSA and Risk of BPH Progression 7 P=0.0008 5.9 6 P=0.0251 5 4.5 4 3.1 Rate per 100 PYR 2.8 3 P=0.018 P=0.0029 1.8 2 1 1 0.8 0.3 0 Symptom Overall AUR Invasive Therapy Progression Progression Adapted from McConnell JD et al. J Urol. 2003;169(suppl):332 PSA = Prostate Specific Antigen
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 (%) 10 5 0 >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 24/49 Adapted from Roerhborn CG. AUA 2005.; AUR = Acute Urinary Retention; PSA = Prostate Specific Antigen
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 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
Figure 1.11: Regulation of Prostate Growth: The Role of Androgens OH OH 5α-reductase O O H Testosterone Dihydrotestosterone Adapted from Bartsch G et al. Eur Urol 2000;37(4):367-380.
Type I Type II Hair follicles Skin (sebaceous glands) Liver Liver Prostate gland Seminal vesicles Adrenal glands Epidiymis Internal/external genital tissues 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 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.
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
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. 5th ed. Oxford: Health Press; 2005:10.
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 HyperplasiaAdapted from Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press; 2005.
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
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
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 BPH = Benign Prostatic Hyperplasia; DHT = Dihydrotestosterone
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
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. 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
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
Symptom score(p<0.0001) Bother score(p<0.005) Activity score(NS) Figure 1.14: BPH and Quality of Life 10 8 6 4 2 0 (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 Adapted from Girman CJ et al. Eur Urol 1999;35:277-284.
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
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
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
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. BPH = Benign Prostatic Hyperplasia; HRQoL=Health-Related Quality of Life
1.8 Quiz • What percentage of men 60 years or older have symptomatic BPH? • 20% • 30% • 40% • 50% • >50% (correct) BPH = Benign Prostatic Hyperplasia
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
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
Which type of 5α-reductase is most prominent in the prostate? • Type 1 • Type 2 (correct) • Both types • It varies from individual to individual
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