1. Diagnosis and Management of Benign Prostatic Hyperplasia (BPH)
Michael Naslund M.D.
Medical Treatment Options for BPH Symptoms

2. Anatomy of BPH Normal BPH BLADDER Hypertrophied detrusor muscle
The model on the right (BPH) shows a distended bladder, enlarged prostate, and constricted urethra, as contrasted with the normal model on the left
BPH increases urethral resistance, resulting in compensatory changes in bladder function
Obstruction-induced changes in detrusor function, including smooth muscle hypertrophy, compounded by age-related changes in the functioning of the bladder, lead to urinary frequency, urgency, and nocturia, the most bothersome BPH-related complaints
Reference
Roehrborn CG, McConnell JD. Etiology, pathophysiology, epidemiology, and natural history of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein Alan J, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:
Hypertrophied detrusor muscle
PROSTATE
URETHRA
Obstructed urinary flow
Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:

3. Top 10 Diagnosed Diseases in Men Age ≥ 50 Years
Rank
Disease
1-year prevalence (%)
(n = 963,452 person-years) 1
Coronary Artery Disease/Hyperlipidemia
51.3 2
Hypertension
45.2 3
Diabetes Mellitus Type 2
17.5 4
Enlarged Prostate
13.5 5
Osteoarthritis
13.3 6
Arrhythmias
8.8 7
Cataract
8.6 8
Gastroesophogeal reflux disease
8.4 9
Bursitis
8.0 10
Prostate Cancer
7.8
A managed-care database analysis of all men 50 or older in 2003 (n = 963,452 person years) in the nationally representative Integrated Health Care Information Services National Managed Care Benchmark database was undertaken to determine the prevalence of Enlarged Prostate relative to other diseases. The Thomson Medstat Disease Staging Coding Criteria were used to map ICD-9 diagnosis codes (ICD-9 codes: 600 – benign prostatic hyperplasia, – benign neoplasm of the prostate), obtained from all inpatient and outpatient claims, to disease states. Enlarged Prostate (in the absence of detected prostate cancer) had the 4th highest 1-year prevalence in this population at 13.5%.
References
Issa MM, Fenter TC, Black L, Grogg AL, Kruep EJ. An assessment of the diagnosed prevalence of diseases in men 50 years of age or older. Am J Manag Care. 2006;12(suppl):S83–89.
Issa MM et al. Am J Manag Care. 2006;12(suppl):S83–S89.

4. Diagnosis of Bladder Outlet Obstruction

5. Lower Urinary Tract Symptoms (LUTS)
Obstructive Symptoms
Hesitancy
Weak stream
Straining to pass urine
Prolonged micturition
Feeling of incomplete bladder emptying
Urinary retention
Irritative Symptoms
Urgency
Frequency
Nocturia
Urge incontinence
Kirby RS et al. Benign prostatic hyperplasia. Health Press, 1995.

6. Problems Consequences
LUTS1,2
Bothersome
Interference with daily activities and sexual function
BPH
(Benign Prostatic
Hyperplasia)
AUR
Surgery
Nonfunctioning bladder
UTI
Stones
Renal failure
Problems and Consequences
The chief complaint of the patient with BPH is bothersome LUTS, which affects the patient’s quality of life (QOL)1
BPH is defined histologically as a disease process of stromal and epithelial cell hyperplasia beginning in the periurethral zone of the prostate1
An enlarged prostate gland with no clinical evidence of cancer, causing varying degrees of bladder outlet obstruction (BOO), is the most common pathology among the many conditions that can cause LUTS. Thus, the most common underlying pathology is referred to as BPH.1
LUTS can result in bothersome symptoms and may affect daily activities and sexual function1,2
Benign prostatic enlargement (BPE) and BOO are more closely linked with anatomic (mechanical) obstruction1
BPH may be associated with LUTS, poor bladder emptying, urinary retention, detrusor instability, UTI, hematuria, and renal insufficiency3
References
1. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170:
2. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44:
3. Lepor H, Lowe FC. Evaluation and nonsurgical management of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan, Ed Jr, Wein Alan J, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:
BOO3 (Bladder Outlet
Obstruction)
1. AUA Practice Guidelines Committee. J Urol. 2003;170:
2. Rosen R et al. Eur Urol. 2003;44:
3. Lepor H, Lowe FC. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:

7. Multinational Survey of the Aging Male (MSAM-7)
Objectives
Evaluate sexual function and prevalence of LUTS in a representative population of men aged years
Patients
14,254 men aged years in 7 countries: United States, United Kingdom, France, Germany, Italy, Spain, Netherlands
Methods
Postal questionnaire (validated scales)
IPSS, Dan-PSSsex, IIEF, demographic characteristics, comorbidity factors
The Multinational Survey of the Aging Male (MSAM-7) is the first large-scale, multinational investigation of LUTS and sexual function in older men.
Detailed questionnaires were completed by more than 14,000 men aged 50 to 80 years in 7 countries, including the United States. The sample in each country was representative of the target population in terms of age and social characteristics.
The US sample consisted of 2,253 men representative for the US population aged 50 to 80.
Rosen R. LUTS and male sexual dysfunction: Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the American Urological Association; May 26, 2002; Orlando, Fla.
Rosen R. Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the American Urological Association; May 26, 2002; Orlando, Fla.

8. MSAM-7 Older Men Are Still Sexually Active
92%
83%
83%
100%
65%
80%
60%
% of men with sexual activity in the last 4 weeks
40%
20%
Against common believe, older Men are still sexually very active, even in the older age group 70-79
Sexual activity here was defined as intercourse, masturbation and any activity that the participant considered “sexual”. 0%
Total
50-59
60-69
70-79
Age
Sexually activity = Any activity that the participant considered “sexual”
Rosen R. Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the American Urological Association; May 26, 2002; Orlando, Fla.

9. Average Number of Sexual Activities per Month*
MSAM-7: Sexual Activity Declines With Increasing Severity of LUTS Independent of Age
Age Effect 10
LUTS Effect 9
4.0
5.7
8.6 8
7.6
6.6
4.9
5.7
3.5
4.6
2.6
3.7
1.7
None
Mild
Moderate
Severe
LUTS 7 6
Average Number of Sexual Activities per Month* 5 4
Animated Slide, first: Shows average number of sexual activities per month in each age group among men without LUTS (blue bars). As expected, a clear decline in sexual activity with increasing age can be observed (AGE EFFECT).
At “click”: Within each age group, the number of sexual activities per month decreases significantly with increasing severity of LUTS (LUTS EFFECT)
In all age groups, men with severe LUTS reported sexual intercourse or activity per month that was about half as frequent as that reported by men with no LUTS.
Rosen R. LUTS and male sexual dysfunction: Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the American Urological Association; May 26, 2002; Orlando, Fla. 3 2 1
50-59 y
60-69 y
70-79 y
*Among total sample.
Rosen R. Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the American Urological Association; May 26, 2002; Orlando, Fla.

10. Average Erectile Function Score (IIEF)*
MSAM-7: Erectile Function Declines With Increasing Severity of LUTS Independent of Age
Age Effect
Average score on a scale from 1 to 30 (6 questions) measured by IIEF
Per question: 1 = Negative to 5 = Positive 30
LUTS Effect
15.2
19.3
22.3
LUTS
21.0
18.9
15.0 20
7.5
13.2
18.3
10.3
15.9
12.6
None
Average Erectile Function Score (IIEF)*
Mild
Moderate
[Dr. Nuckolls, transcript page 14]
[Note: data do not appear in abstract. Reference as Raymond Rosen, personal communication, or has this data been published?]
This slide shows the decline in erectile function (assessed by mean scores on the IIEF questionnaire) among men who reported sexual intercourse in the past 4 weeks, stratified by age group and severity of LUTS.
Within each age group, erectile function declined with increasing severity of LUTS, independent of other comorbidities.
Rosen R. LUTS and male sexual dysfunction: Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the American Urological Association; May 26, 2002; Orlando, Fla.
Animated Slide, first: Shows average score for Erectile Function (as measured by IIEF) in each age group among men without LUTS (blue bars). As expected, a clear decline in Erectile Function with increasing age can be observed (AGE EFFECT).
At “click”: Within each age group, the average score for Erectile Function (as measured by IIEF) decreases significantly with increasing severity of LUTS (LUTS EFFECT) 10
Severe
50-59 y
60-69 y
70-79 y
Base: Men sexually active/sexual intercourse during past 4 weeks, *as measured by IIEF.
Rosen R. Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the American Urological Association; May 26, 2002; Orlando, Fla.

11. Why Does BPH Progress In Some But Not All Men?

12. Risk Factors for BPH Progression
Age 50 years or older
AUA-SI score > 7
Enlarged prostate (≥ ml.)
PSA ≥ 1.5
It is important to identify which patients are at risk for BPH progression so appropriate treatment can be initiated. Risk factors for BPH progression include age > 50 years, an enlarged prostate,1-2 moderate-to-severe urinary symptoms (AUA-SI > 7),2 a weak urinary stream,2 and a PSA  1.4 ng/mL.1-2
References
1. Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology. 1999;53:473480.
2. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:23872398.
McConnell JD et al. N Engl J Med. 2003;349:2387 Roehrborn CG et al. Urology.1999;53:473480.

13. Prevalence of Histologic BPH Increases With Age10 20 30 40 50 60 70 80 90
100
20-29
30-39
40-49
50-59
60-69
70-79
80-89
Prevalence (%)
Pradhan (1975)
Swyer (1944)
Franks (1954)
Moore (1943)
Harbitz (1972)
Holund (1980)
Baron (1941)
Fang-Liu (1991)
Karube (1961)
Age (yr)
Prevalence of Histologic BPH Increases With Age
This slide shows age-stratified prevalence of BPH from 9 autopsy studies in the United States, England, Austria, Norway, Denmark, China, Japan, and India, with the smoothed line showing the average
Prevalence increases rapidly in the 4th decade of life, reaching nearly 100% in the 9th decade
Age-specific autopsy prevalence is strikingly similar in all populations studied, regardless of ethnic and geographic origin
Reference
Roehrborn CG, McConnell JD. Etiology, pathophysiology, epidemiology, and natural history of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein Alan J, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:
Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:

14. Risk Factors for BPH Progression
Age 50 years or older
AUA-SI score > 7
Enlarged prostate (≥ ml.)
PSA ≥ 1.5
It is important to identify which patients are at risk for BPH progression so appropriate treatment can be initiated. Risk factors for BPH progression include age > 50 years, an enlarged prostate,1-2 moderate-to-severe urinary symptoms (AUA-SI > 7),2 a weak urinary stream,2 and a PSA  1.4 ng/mL.1-2
References
1. Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology. 1999;53:473480.
2. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:23872398.
McConnell JD et al. N Engl J Med. 2003;349:2387 Roehrborn CG et al. Urology.1999;53:473480.

15. Relationship Between Prostate Volume and Serum PSA in Men with BPH65 75 60 70 65 55 60 50 55
Prostate volume (mL) 50 45
Age (years)
Progression of BPH does not occur to the same extent or at the same rate in all men.
Studies show that, besides age, 2 parameters can predict the progression of LUTS and BPH: prostate volume and serum PSA levels. In a study of 4627 men with BPH and no evidence of prostate cancer, prostate volume was strongly and age-dependently related to serum PSA. As prostate volume increased, so did serum PSA levels; and values for both of these variables were directly related to age. Given that response to treatment as well as risks of long-term complications of BPH depend on prostate volume, these data show that serum PSA has utility in therapeutic decision-making for patients with BPH.
Reference
Roehrborn CG, Boyle P, Gould AL, et al. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology. 1999;53:581–589. 40 35 30 1 2 3 4 5 6 7
Serum PSA (ng/mL)
Roehrborn CG et al. Urology. 1999;53:581–589.

16. Cumulative Incidence of Progression by Baseline PSA6
PSA (ng/mL)
P <
< 1.4 5
1.43.9
P =
 4.0 4
Rate per 100 person-years 3 2
A similar relationship between baseline PSA and risk of clinical progression of BPH was observed in the Medical Therapy of Prostatic Symptoms (MTOPS) study. The higher the PSA, the greater the risk of clinical progression, symptom deterioration (> 4-point rise in AUA-SI), and AUR. In this study, clinical progression was defined as the first occurrence of a 4-point increase from baseline in AUA-SI score, AUR, renal insufficiency, recurrent urinary tract infection, or urinary incontinence.
Reference
McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:23872398.
P < 1
Progression
> 4-point rise
in AUA-SI score
AUR
McConnell JD et al. N Engl J Med. 2003;349:23872398.

17. Treatment Options for BPH
Watchful waiting
Pharmacologic therapy
alpha-adrenergic blockers (for BPH symptoms)
5-ARIs
combinations of the above
Minimally invasive therapy
TUMT
TUNA
ILC
Less invasive surgery
Laser vaporization
Major surgery
TURP (gold standard)
TUIP
Open surgery (prostatectomy)
Treatment Options for BPH
Today, there is a wide variety of accepted treatments for BPH
In 2003, the AUA published the recommended guidelines for various types of treatments, ranging from the more conservative to the more invasive office-based and hospital-based treatments, including watchful waiting, medical therapies, various interventional therapies, such as transurethral resection of prostate, transurethral microwave thermotherapy, water-induced thermotherapy, and transurethral needle ablation
Other less-invasive therapies included visual laser ablation of prostate, interstitial laser coagulation, and transurethral electroevaporation of the prostate
Reference
AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170:
5-ARIs=5-alpha-reductase inhibitors
ILC=interstitial laser coagulation (also known as LITT)
TUIP=transurethral incision of prostate
TUMT=transurethral microwave thermotherapy
TUNA=transurethral needle ablation
TURP=transurethral resection of prostate
AUA Practice Guidelines Committee. J Urol. 2003;170:

18. Watchful Waiting/Active Surveillance
Patient is followed annually but receives no active intervention for symptoms1
Appropriate option for patients with mild symptoms, and for many with moderate to severe symptoms if they are not bothered1
Watchful Waiting/Active Surveillance
Treatment options for BPH include watchful waiting, medical therapy, and various surgical procedures1
Watchful waiting is the most conservative approach for patients with mild symptoms or those with moderate symptoms without bother1
The level of symptom distress that individual men are able to tolerate is variable. Watchful waiting may be a patient’s treatment of choice even if he has a high AUA Symptom Index or IPSS score1
Watchful waiting may require yearly follow-up by a physician for evaluation during which any changes that have occurred over the past year may be detected, specifically if symptoms have progressed or become more bothersome or if a complication has developed1
Population surveys have shown sexual dysfunction, LUTS, and prostate enlargement to be common in older men and the symptoms in individual men are highly variable2
References
1. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170:
2. Brookes ST, Donovan JL, Peters TJ, Abrams P, Neal DE. Sexual dysfunction in men after treatment for lower urinary tract symptoms: evidence from randomised controlled trial. BMJ. 2002;324:
AUA Practice Guidelines Committee. J Urol. 2003;170:
Brookes ST et al. BMJ. 2002;34:

19. Pharmacologic Therapy For BPH
-adrenergic blockers
5-reductase inhibitors
Combination therapy
Treatment options for BPH include watchful waiting, medical therapy, and various surgical procedures.1-3
Symptom improvement with medical treatment is less than that with surgical procedures. The mean probability of symptomatic improvement is 74% with an -adrenergic blocker versus 98% with an open prostatectomy.2 However, disadvantages of surgery include invasiveness, a period of recuperation and, in the case of open surgery, a comparatively prolonged hospitalization.3
Today, -adrenergic blockers, which inhibit contraction of prostatic smooth muscle, are first-line treatment for LUTS/BPH. Another pharmacologic option is the 5ARI, finasteride, which lowers prostatic androgen levels and can result in some decrease in prostate size.
Chatelain C, Denis L, Foo JKT, et al. 5th International Consultation on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001:
McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign Prostatic Hyperplasia: Diagnosis and Treatment. Clinical Practice Guideline, Number 8. AHCPR Publication No Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. February 1994.
Columbia University website. Therapies for the treatment of benign prostatic hyperplasia (BPH). Available at Accessed 8/23/01.
Dreikorn K, Lowe I, Borkowski A, et al. Other medical therapies. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001;

20. Distribution of Alpha Receptors in the Prostate and Bladder
Pelvic Floor
External Sphincter
Internal Sphincter
Trigone
Detrusor
Prostate Gland

21. Treatment Options: Alpha Blockers
Mechanism1,2:
Relax smooth muscle in bladder neck and prostate
Improve urinary flow (Qmax) and bothersome symptoms
Agents indicated for symptomatic BPH include1:
Alfuzosin
Doxazosin
Silodosin
Tamsulosin
Terazosin
There are two different prescription medication classes to treat Enlarged Prostate.1,2 The first, alpha blockers, relax smooth muscles in the prostate and bladder. This eases the pressure on the urethra and bladder and improves urine flow and reduces bothersome symptoms.1
References
1. Kaplan SA. Benign prostatic hyperplasia and enlarged prostate guidelines: how they can be useful to primary care. Weill Medical College of Cornell University Reports on Men’s Urologic Health. 2006;1(1):1-8.
2. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349(25):
BPH = Benign Prostatic Hyperplasia
1. Kaplan S. Weill Medical College of Cornell University Reports on Men’s Urologic Health. 2006;1(1): McConnell J, et al. N Engl J Med. 2003;349:

22. AUA Guidelines
“Alfuzosin,* doxazosin, tamsulosin and terazosin are appropriate treatment options for patients with LUTS secondary to BPH.”
“The adverse event profile appears slightly different between the four alpha-blocking agents”
AUA Guidelines
Alpha-blocker therapy is based on the hypothesis that clinical BPH is partly caused by alpha1-adrenergic–mediated contraction of prostatic smooth muscle, resulting in BOO. Alpha1-adrenergic–receptor antagonists (blockers), such as doxazosin, tamsulosin, alfuzosin, and terazosin inhibit this process and thus relieve the BOO.
The degree to which BPH patients are bothered by LUTS varies among individual
patients with the same level of symptoms, although in general the level of bother and interference will increase with the level of symptom severity
Reference
American Urological Association Research and Education Inc. BPH Guidelines. April 2003.
American Urological Association Research and Education Inc. BPH Guidelines. April *Please see accompanying Uroxatral® full prescribing information.

23. Differential Effects of -Blockers on Blood Pressure
Doxazosin1 and Terazosin2
Indicated for the treatment of hypertension
Initiated at a low dose to avoid a first-dose phenomenon (ie, syncope)3
Alfuzosin4, Tamsulosin5 and Silodosin
Not indicated for the treatment of hypertension
Initial dose titration not required
Doxazosin and terazosin, two of the -adrenergic blockers now being used for the treatment of BPH, were originally studied for the treatment of hypertension and, in fact, are still being used to treat high blood pressure.1,2 Treatment with these agents must be initiated at a low dose to avoid a first-dose phenomenon.3
By contrast, alfuzosin and tamsulosin are not indicated for the treatment of hypertension, they are uroselective and only indicated for BPH. Initial dose titration is not required for alfuzosin and is optional for tamsulosin.4,5
Cardura (doxazosin) Product Information.  Pfizer Inc.
Hytrin (terazosin) Product Information.  Abbott Laboratories.
Vallencien G. Alpha-blockers in benign prostatic hyperplasia. Urology. 1999;54:
Uroxatral (alfuzosin) Product Information.  Sanofi-Synthelabo Inc.
Flomax (tamsulosin) Product Information.  Boehringer Ingelheim Pharmaceuticals, Inc.
1. CarduraR (doxazosin mesylate tablets) Prescribing Information, Pfizer Inc.
2 HytrinR (terazosin hydrochloride) Prescribing information, Abbott Laboratories.
3. Vallencien G. Urology. 1999;54:
4. UroxatralR (alfuzosin HCl extended release tablets) Prescribing Information, Sanofi-Synthelabo Inc.
5. FlomaxR (tamsulosin hydrochloride) Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc.

24. 5-Reductase Inhibitors

25. Two 5-Reductase (5AR) Isoenzymes Convert Testosterone to DHT
Prostate
enlargement
DHT
Testosterone
Type II 5AR
Type I 5AR
Although the etiology of BPH is multifactorial and not yet definitively established, prostate growth is regulated by androgens, particularly dihydrotestosterone (DHT).
DHT and other androgens bind to androgen receptors in the stromal and epithelial cells of the prostate. When DHT binds to the androgen receptor, this causes a cascade of intracellular events that leads to the expression of genes and production of growth factors that regulate cell division and proliferation in the prostate.1 DHT has approximately 5 times greater affinity for the androgen receptor than testosterone.2
Testosterone is converted to the more potent androgen DHT by the enzyme 5-reductase (5AR). Two isoenzymes, or isoforms, of 5AR exist in the body: type I and type II. Both type I and type II 5AR isoenzymes are found in the prostate and affect stromal and epithelial cells in the prostate.1 In BPH, both isoenzymes of 5AR are elevated.3
References
1. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia. Eur Urol. 2000;37:367–380.
2. Grino BB, Griffen JE, Wilson JD. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology ;126:11651172.
3. Ielhe C, Radvanyi F, Gil Diez de Medina S, et al. Differences in steroid 5-reductase iso-enzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol. 1999;68:189195.
Bartsch G et al. Eur Urol. 2000;37:367380.

26. Near Complete DHT Suppression Requires Inhibiting Both 5AR Isoenzymes
Dutasteride
Finasteride
Type II 5AR
Testosterone
DHT
Near complete DHT suppression requires inhibition of both type I and type II 5AR isoenzymes. The 5ARIs suppress DHT by inhibiting the conversion of testosterone to DHT. AVODART® (dutasteride) is the only dual 5ARI  it selectively inhibits both type I and type II 5AR isoenzymes. In comparison, finasteride only inhibits the type II 5AR isoenzyme.
Reference
Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia. Eur Urol. 2000;37:367–380.
Type I 5AR
Prostate volume
reduced
Dutasteride
Bartsch G et al. Eur Urol. 2000;37:367380.

27. PSA Is Reduced in a Predictable Manner with Dutasteride
15.8
10.7
6.8
5.5
2.8
2.2
Placebo
–9.2
Mean change in serum PSA (%)
–35.7
Dutasteride
–43.5
AVODART® (dutasteride) reduces total serum PSA concentration by approximately 40% following 3 months of treatment and approximately 50% following 6, 12, and 24 months of treatment. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Therefore, for interpretation of serial PSAs in a man taking AVODART, a new baseline PSA concentration should be established after 3 to 6 months of treatment, and this new value should be used to assess potentially cancer-related changes in PSA. To interpret an isolated PSA value in a man treated with AVODART for 6 months or more, the PSA value should be doubled for comparison with normal values in untreated men.
The free-to-total PSA ratio (percent free PSA) remains constant at month 12, even under the influence of AVODART. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving AVODART, no adjustment to its value appears necessary.
Reference
Data on file, GlaxoSmithKline.
–48.6
–50.5
–52.4 1 3 6 9 12 15 18 21 24
Baseline
Month
Data on file, GlaxoSmithKline.

28. Using PSA To Detect Cancer-Related PSA Changes In Patients On 5-ARI’s
Establish new baseline PSA after 12 months of %-ARI treatment
Subsequent increases in PSA may indicate noncompliance, prostate cancer, or other prostate-related conditions that may need evaluation
In order to use PSA to detect potentially cancer-related changes in PSA in patients taking AVODART® (dutasteride), establish a new baseline PSA after 3 to 6 months of treatment. Subsequent increases in PSA may indicate noncompliance, prostate cancer, or other prostate-related conditions that may need evaluation. To interpret an isolated PSA value in men treated with a 5ARI for 6 months or more, double the PSA value for comparison with normal values in untreated men.

29. Rises in PSA after 6 Months on 5-ARI May Be Indicative of Prostate Cancer
Graph depicts 5-ARI treated patients only
Data on File GlaxoSmithKline

30. REDUCE Trial Study Design♦
Randomization
(Visit 2)
2-year biopsy*
(Visit 6)
4-year biopsy*
(Visit 10)
Study Entry
(Screen Visit 1)
Month: -7 -1 24 48 52
6-month eligibility window
4-year treatment period with
dutasteride 0.5 mg daily or placebo
REDUCE Trial Study Design
The use of AVODART for prevention or reduction of the risk of prostate cancer is not an approved indication, therefore, GSK may not offer any recommendations regarding its use in this manner.
Androgens, including testosterone and dihydrotestosterone (DHT) have a well established role in the etiology and progression of cancer.1 The enzyme 5-alpha-reductase (5AR) is responsible for the conversion of testosterone to DHT and is expressed in both androgen dependant and nonandrogen dependent cell lines of prostate cancer.2
A total of 8231 men with negative biopsies at baseline were randomized to receive AVODART 0.5 mg daily or placebo.3 Mandated biopsies were performed at 2 and 4 years, and rates of prostate cancer in each treatment group were determined. For-cause biopsies could occur at any time. Additionally, patients will have clinic visits every 6 months after randomization and will have phone contacts between visits and 4 months after the last dose.
Inclusion Criteria
For age years, PSA: ng/mL, for age years, PSA: 3-10 ng/mL, negative prostate biopsy (6-12 core) within 6 months of enrollment, free PSA ≤25%, IPSS <25 or <20 (if on alpha blocker for BPH), prostate volume ≤80 mL
Exclusion Criteria:
History of prostate cancer, prostate surgery, or acute urinary retention, peak urine flow rate <5 mL/sec, post-void residual volume >200 mL, severe prostatism (to reduce the number of men undergoing BPH-related surgeries and men with high grade precancerous lesions were excluded to minimize the number of for-cause biopsies), high grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) to minimize number of for-cause (interim) biopsies within first two years
References:
1. Lieberman R. Androgen deprivation therapy for prostate cancer chemoprevention: current status and future directions for agent development. Urology. 2001;58(Suppl 2A):83-90.
2. Negri-Cesi P, Colciago A, Poletti A, et al. 5α-reductase isozymes and aromatase are differentially expressed and active in the androgen independent human prostate cancer cell lines DU145 and PC3. Prostate. 1999;41:
3. Andriole G, Bostwick D, Brawley O, et al, for the REDUCE Study Group. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol. 2004;172:1314–1317.
Entry
biopsy
4-wk Placebo
run-in
For-cause biopsies may occur here
4-month Follow-up
NOTE: All biopsies centrally evaluated
* Mandatory Transrectal Ultrasound (TRUS)-guided 10 core biopsies
Andriole G et al. J Urol. 2004;172:1314–1317.

31. Preliminary Results from the REDUCE Trial (Analysis Ongoing)♦
Primary Endpoint: 23% reduction in biopsy-detectable prostate cancer with dutasteride vs. placebo over 4 years (P<0.0001)
Secondary Endpoint: Incidence of high grade tumors over 4 years
Gleason score 7-10: 6.7% for dutasteride vs. 6.8% for placebo (P=0.81)
Gleason score 8-10: 0.9% for dutasteride vs. 0.6% for placebo (P=0.15)
Data on file, GlaxoSmithKline

32. Minimally Invasive/Surgical Treatment Options For BPH

33. Principles of Thermotherapy
Blood supply of BPH adenoma more fragile than prostate capsule
Adenoma can be heated to cause necrosis
Capsule protected by better blood flow
Tissue necrosis, nerve damage/destruction lead to improved voiding symptoms

34. Anatomy of BPH Normal BPH BLADDER Hypertrophied detrusor muscle
The model on the right (BPH) shows a distended bladder, enlarged prostate, and constricted urethra, as contrasted with the normal model on the left
BPH increases urethral resistance, resulting in compensatory changes in bladder function
Obstruction-induced changes in detrusor function, including smooth muscle hypertrophy, compounded by age-related changes in the functioning of the bladder, lead to urinary frequency, urgency, and nocturia, the most bothersome BPH-related complaints
Reference
Roehrborn CG, McConnell JD. Etiology, pathophysiology, epidemiology, and natural history of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein Alan J, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:
Hypertrophied detrusor muscle
PROSTATE
URETHRA
Obstructed urinary flow
Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:

35. Radio Frequency Generator
Monitors temperature of urethra and prostate 50 times per second with Precision Reassurance Technology
Computerized graphics allow physician to view treatment in real time

36. Cartridge and Needle Deployment
Disposable Cartridge and Reusable Handle
Dual Deployment of Needles and Shields

37. Schematic of TUNA Procedure
Completed Procedure
with 8 Lesions
Creation of a Lesion

38. Transurethral Microwave Therapy
Microwave energy causes tissue necrosis
Cooling channels in catheter cool urethra

39. Interstitial Laser Therapy
Lesions created throughout prostate
Laser fiber alignment critical
Median lobe can be treated

40. Anesthesia Options Local (lidocaine jelly) Oral narcotics
Prostate block
I.V. sedation

41. Treatment Results After Thermotherapy
Most patients see improvement in symptoms
Results not as consistent as TURP
Bladder function important
Long term results of TUNA, TUMT and ILT are similar

43. PVP Laser Prostatectomy
Vaporizes tissue
Minimal bleeding
No catheter post-op

44. PVP Laser Removes Tissue
Opens bladder neck
Cavity similar to TURP
Improvement in symptoms similar to TURP
Less impotence than TURP, other morbidity similar

46. Should PSA Testing Be Done? If So, How Should it Be Done?

47. How Often Should PSA Be Tested?
All men should get PSA age 40
If PSA >1.0, check annually
If PSA <1.0, check annually at age 50
Annually at age 40 for A.A. or fam. hx.
Stop testing in mid to late 70’s
Don’t test if life expectancy < 10 yrs.

48. PSA and the Risk of Prostate Cancer
42-64%
20-30%
20-30%
J Urol 1992; 147:
J Urol 1998; 160:
Intern Med 1997; 126:480-4

49. Prevalence of PCa in Men With PSA < 4.0
NEJM 350: 2259, 2004

50. Is It Necessary/Desirable to Detect on-Palpable Cancer When PSA is < 4.0?
15-25% of men >50 have autopsy PCa
90% of men have PSA < 4.0
More occult PCa at lower PSA levels
Outcomes no better for PSA < 4 vs 4-10
With regular PSA testing, non-curable dx. uncommon

51. Age-Specific PSA for Different Races
*JAMA 270: 860, 1993
# NEJM 335: 304, 1996
++ BJU 75: 347, 1995

52. Causes of Elevated PSA

53. Causes of Elevated PSA
Cancer
BPH
Prostatitis
Infarct, retention

54. Prostatitis Can Elevate PSA
Assess voiding symptoms
Analyze previous PSA results
Consider antibiotic/anti-inflammatory trial
If still abnormal, do biopsy

55. Prostate Infarct Elevates PSA
Common in enlarged glands
Asymptomatic
Infarct can cause retention
Retention increases risk of carcinoma

56. Effect of Ejaculation on PSA
PSA does rise after ejaculation
Usually not clinically significant
Ideally, should abstain 72 hrs.
Consider for slight elevations

57. Causes of Elevated PSA: Iatrogenic
DRE- vs - prostate massage
Colonoscopy, catheterization
Prostate ultrasound/biopsy
Bx x in 5 min, 7.9 ng/ml in 24 hr.

58. Follow-up Time for PSA Elevation
Half-life days
PSA is baseline days after bx.
PSA is baseline 4- 6 wks. after acute prostatitis
In general, repeat PSA after 30 days

59. Detection of Cancer with PSA

60. Elevated PSA Is Not Specific for Cancer
BPH
Prostatitis
Infarct, retention

61. PSA Velocity Need 3 PSA values over 2 yrs. Results not specific
Increase > 0.75 suspicious for men >60
Increase > 0.50 suspicious for men < 60

63. Usefulness of Free-Total PSA
Improves specificity if PSA 4-10
Improves sensitivity if PSA < 4.0
Ratio ≥ 25% suggests benign disease
Ratio ≤ 12% suggests malignancy

64. uPM3: Genetic Urine Test For PCa
uPM3 detects PCA3 gene in voided urine
Requires vigorous prostate massage
Sensitivity 67%, specificity 89%
Accuracy: 443 tx.- uPM3- 81%, PSA 38%

65. EPCA-2 for PCa Detection
Measures nuclear matrix protein which is elevated in Pca
Sensitivity/specificity > 90%
Well defined cutpoint between PCa and BPH
Not yet FDA approved

66. Does PSA Testing Lower Cancer-Specific Mortality?

67. Increased Risk of Death From Prostate Cancer
NEJM 360:1320, 2009

68. Number of Prostate Cancers and Prostate Cancer Deaths
NEJM 360: 1310, 2009

69. Dying With PCa is Not Pleasant
Incontinence
Sexual dysfunction
Bone pain, fractures
Metabolic syndrome
Hormone Rx – induced dementia
Urinary symptoms, bleeding
Cachexia

70. PSA Testing Makes Sense For Relatively Young, Healthy Men