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Module 1: BPH – The Disease

Mostafa M. Elhilali MD, PhD, FRCSCProfessor and Chair, Department of SurgeryMcGill UniversityRoyal Victoria HospitalMontréal, Québec

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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

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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

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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

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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 75 850

20

40

60

80

Age (years)

% Prevalence MicroscopicBPH Countries Sampled

JapanIndiaAustria

DenmarkEnglandUSA

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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.

40–49 50–59 60–69 70–79

Age (years)

30

20

10

0

Mild symptoms

Moderate/severe symptoms

% o

f m

en w

ith

pro

stat

e vo

lum

e >

50 m

l

(N=2115)

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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

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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

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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

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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

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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.

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Table 1.2: Problems and Consequences

Histological BPH (Stromoglandular)

By itself may not cause any problems

LUTSBother, Impact on QoL,

interference with daily living, sexual dysfunction(?)

BPEAcute 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

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13/46Adapted from Nordling J et al. In: Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:107-166.

Aging

Anoxia

Obstruction

High nocturnaldiuresis

Age-relateddiseases

Neurologicdiseases

Localdisease

Bladder

LUTS

Figure 1.3: Conditions Potentially Leading to LUTS

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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

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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.

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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

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BPE

All Men> 40 yrs

BOOLUTS /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

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Figure 1.5: Early BPH - BPH Progression

Bladder

ProstaticUrethra

DetrusorMuscle

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.

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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.

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Potential Complications of BPH

Bladder stones

Bladder damage (Trabeculations, Cellules, Diverticula)

Urinary tract infection

Urinary retention

Renal impairment

Gross Hematuria

Overflow incontinence

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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

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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

3.43

0.3 0.6

5.6

4.3

1

2

0

1

2

3

4

5

6

7

OverallProgression

SymptomProgression

AUR Invasive Therapy

Rat

e p

er 1

00 P

YR

P=0.0031

P=0.001

P=0.004

P=0.0003

MTOPS = Medical Therapy of Prostatic Symptoms

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Figure 1.9: MTOPS Subanalysis – PSA and Risk of BPH Progression

< 1.6ng/ml

≥ 1.6ng/ml

3.12.8

0.30.8

5.9

4.5

1

1.8

0

1

2

3

4

5

6

7

OverallProgression

SymptomProgression

AUR Invasive Therapy

Rat

e p

er 1

00 P

YR

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

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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

Cu

mu

lati

ve I

nci

den

ce (

%) Either

Surgery

AUR

Adapted from Roerhborn CG. AUA 2005.; AUR = Acute Urinary Retention; PSA = Prostate Specific Antigen 24/49

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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

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Figure 1.11: Regulation of Prostate Growth: The Role of Androgens

Testosterone Dihydrotestosterone

O

OH

O

OH

H

5α-reductase

Adapted from Bartsch G et al. Eur Urol 2000;37(4):367-380.

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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.

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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

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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.

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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.

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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

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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

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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

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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

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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

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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

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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)

Hea

lth

-rel

ated

q

ual

ity-

of-

life

sco

re

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

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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

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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

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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

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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

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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

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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

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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

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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

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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