1. BENIGN PROSTATIC HYPERPLASIA (Module 2 of Renal/Prostate Disease)
Bill Lyons, M.D.
UNMC Geriatrics & Gerontology
Hello, my name is Bill Lyons with the Geriatrics Section at the University of Nebraska Medical Center. I would like to welcome you to Module 2 of the unit on Renal and Prostate Disease. This module will cover the subject of BPH, or benign prostatic hyperplasia. As with other modules, this one will employ PowerPoint with voice overlay. After this module, you will try your hand at a case-based question, and we will provide you with the right answer and an explanation. At that time you will have the option to continue with the next module in the series, covering prostate cancer, or you can take a break. We recommend that you complete this module before disengaging. When this module and question are completed, please click on “Mark Reviewed” on the main page of the minifellowship to indicate your completion.

2. BPH: LEARNING OBJECTIVES
Pathophysiology and Epidemiology
Workup
Differential Diagnosis
Medical Treatment
Surgical Treatment
This slide lists the learning objectives for this module. By the time you have completed the module, you should be able to outline the pathophysiology and brief epidemiology of BPH, and you should be able to describe the workup, differential diagnosis, and available treatment modalities as well.

3. BACKGROUND Incidence age-related Autopsy studies, BPH prevalence:
20% men in their 40s
90% men over 80
Two ingredients for BPH
Androgens (dihydrotestosterone): castration shrinks established BPH, improves symptoms
Aging (aging prostate more androgen-sensitive)
First, a little background on the subject of BPH. As you probably know, the incidence of this disorder is very age-related. Autopsy studies bear this out, and have shown that the prevalence of BPH is about 20% for men in their 40s, and rises to 90% for men over 80! Experts in prostate disease tell us that you need two ingredients for BPH. First, you need androgens, primarily dihydrotestosterone, which is the more biologically active form of testosterone. As evidence of the importance of androgens, it is well-known that chemical or surgical castration will shrink established prostatic enlargement, and it improves BPH symptoms. The second key ingredient for the development of BPH is age. Although very young men have androgen levels at least as high as those of elderly men, they very seldom have BPH. Presumably time is required to develop a hypertrophied gland, but there is also evidence that the aging prostate is more androgen-sensitive.

4. BACKGROUND, cont. Prostate: stromal +epithelial tissues
BPH from either alone or in combination
Stroma has abundant adrenergic innervation
Increased tone  increased resistance to urine flow through prostatic urethra
Histologically, the two dominant tissue types in the prostate are stroma and epithelium. Clinical BPH can result from hyperplasia of either or both components. Another contributor to symptomatic BPH – probably underappreciated – relates to the fact that the stromal component of the prostate contains abundant adrenergic innervation. Increases in sympathetic nerve tone cause smooth muscle contraction in the prostate, which leads directly to an increased resistance to the flow of urine through the prostatic portion of the urethra.

5. BPH: PATIENT HISTORY Symptoms: Obstructive & Irritative Obstructive
Increased resistance to flow
Neck of bladder, prostatic urethra
Static and dynamic components
Irritative
From bladder’s response to flow resistance
Hypertrophy + collagen deposition
Detrusor instability, less passive compliance
The symptoms of BPH are generally classified as being either ‘obstructive’ or ‘irritative’ in nature. Obstructive symptoms arise from the increased resistance to the flow of urine out of the bladder. Points of increased flow resistance include the bladder neck and the prostatic segment of the urethra. The overall resistance to flow is made up of two components, a static (or fixed) component and a dynamic component. The dynamic component of resistance is that part which varies as a function of the sympathetic nerve tone activating the smooth muscle in the prostatic stroma. Irritative symptoms of BPH are those that arise from the response of the urinary bladder to having to empty against a high resistance to flow. Over time, the wall of a the bladder of a patient with BPH shows hypertrophy and collagen deposition. These changes result in detrusor instability, meaning that the detrusor muscle contracts more readily and at lower filling volumes. The bladder also shows less passive compliance, meaning that more-than-expected pressure in the bladder is required to hold each added milliliter of urine.

6. OBSTRUCTIVE VOIDING SYMPTOMS
Hesitancy
Reduced force of stream
Sense of incomplete emptying
Intermittent flow
Strain to urinate
Post-void dribbling
Obstructive voiding symptoms in men with BPH are those shown in this slide. Hesitancy means it takes longer to start emptying the bladder; this is often associated with a sense of straining to urinate. Reduced force of stream might be evident when a patient is asked to compare the force to that when he was a teenager. Patients with a sense of incomplete emptying feel that their bladders still hold a lot of residual fluid at the end of urination. Intermittent flow means that the urine stream isn’t continuous during the time of bladder voiding, but stops and starts during the process. The last obstructive symptom, post-void dribbling, can be a cause of minor incontinence in men with prostatism.

7. IRRITATIVE VOIDING SYMPTOMS
Urgency
Frequency
Nocturia
This fellow in a fedora is dashing to the men’s room; he may be experiencing the first of the irritative voiding symptoms, or urgency. The others are frequency (such as having to go to the bathroom less than 2 hours from last time), and nocturia, or having to arise from bed at night to use the toilet.

8. AUA QUESTIONNAIRE Seven questions, each 0-5, total 0-35
Evaluate before start therapy, and to assess results of therapy. Over the last month:
1 Incomplete Emptying?
2 Frequency – go again less than 2 hr later?
3 Intermittency stop/start several times?
4 Urgency – difficult to postpone urinating?
5 Weak Stream?
6 Straining – push/strain to begin?
7 Nocturia – how many times on typical night?
The American Urological Association has developed a questionnaire that has found use even outside of research settings. It contains seven questions, and each question is scored from zero to five, so that the questionnaire’s grand total varies from 0 to 35. Higher scores indicate more troublesome symptoms. The patient is asked to consider his urinary symptoms over the preceding month. The seven questions cover: sense of incomplete emptying; urinary frequency; intermittent urinary stream; urinary urgency; sense of weak stream; straining to begin urination; and nocturia. The full AUA questionnaire can be obtained by visiting the AUA’s patient information website at

9. DIFFERENTIAL DIAGNOSIS
Prostate cancer
Bladder cancer
Bladder stone
UTI (also BPH complication)
Urethral stricture (trauma, instrumentation, urethritis)
Contracture of bladder neck (instrumentation)
Neurogenic bladder (CVA, MS, trauma, DM)
Of course, every man with obstructive or irritative voiding symptoms does not necessarily have BPH. What else needs to be considered in the differential diagnosis? This slide lists the other conditions that should come to mind. Cancer in either the prostate or the urinary bladder can cause voiding difficulties resembling BPH. So, too, can bladder calculi. Urinary tract infections, such as cystitis or prostatitis, are often associated with irritative voiding symptoms or dysuria. Of course, a man can have both BPH and a urinary tract infection, as UTIs are a common complication of BPH. Urethral strictures can cause obstructive or irritative symptoms; they typically arise in the setting of previous trauma, instrumentation (like bladder catheterization), or urethritis from a sexually transmitted disease. Symptomatically, a contracture in the bladder neck may be indistinguishable from BPH or urethral stricture; and again, patients with a previous history of instrumentation are those at greater risk. Finally, patients with a neurogenic bladder may complain of voiding symptoms reminiscent of BPH. Neurogenic bladders commonly arise in the setting of strokes, multiple sclerosis, trauma, and diabetic neuropathy.

10. PHYSICAL EXAMINATION DRE – size, consistency, tenderness
Size of gland correlates poorly with symptoms
Turning now to the physical examination, a digital rectal exam is often helpful, not so much for establishing BPH as the diagnosis, but for ruling out competing diagnoses. This is because the size of the palpated prostate gland tends to correlate very poorly with the severity of a given patient’s symptoms.

11. PHYSICAL EXAM, cont. Abdomen – palpation, percussion Neurological
Enlarged bladder?
Normal = well below umbilicus
Neurological
Perineal sensation
Sphincter tone
Anal wink
Bulbocavernosus reflex
A quick check of the abdomen, with palpation and percussion, should be done to uncover an enlarged bladder. If you encounter a urinary bladder reaching anywhere close to the umbilicus, that is abnormal. When performing the neurological exam, you should check the items listed in this slide. Verify that the skin on the perineum has intact sensation to touch. Check anal sphincter tone, and verify that the bulbocavernosus reflex is present. In patients with an intact reflex, squeezing the head of the penis produces a transient increase in anal sphincter tone. Lastly, the anal wink is checked by gently scratching the skin near the anal verge, and observing for puckering of the sphincter.

12. ADDITIONAL STUDIES Urinalysis and urine culture Serum creatinine
PSA controversial (BPH, cancer overlap)
Upper tract imaging for hematuria, renal insufficiency
Post-void residual
Urodynamic studies
Suspected neurologic disease
Failed surgery
Some additional studies are needed in most or all patients with symptoms of apparent BPH. Still other studies are ordered on a case-by-case basis. Urinalysis, urine culture, and serum creatinine should be sent for most patients. These may help rule out infection, bleeding lesions in the urinary tract, and renal impairment. Sending a PSA is not obviously helpful, particularly since elevations in PSA won’t help you to easily distinguish BPH from cancer. BPH is a common cause of PSA elevations. Patients with hematuria or renal insufficiency need some form of upper urinary tract imaging, such as ultrasound or CT. Measurements of post-void urinary residuals can help to identify patients at risk of overflow incontinence or urinary retention. Prescribing bladder relaxants is risky for men with BPH in general, but particularly so for men with high post-void residuals. Finally, urodynamic studies, conducted by a urologist, may help in the evaluation of men with suspected neurologic disease or men who have undergone urologic surgery but who still have very bothersome symptoms.

13. MEDICAL TREATMENT
Alpha blockers perhaps better if significant component of stromal smooth muscle
5-alpha-reductase inhibitors for BPH from primarily excess epithelial tissue
Therapy for BPH can be either medical or surgical. Let’s start with a couple of what may be theoretical points regarding medical treatment. First, because stromal smooth muscle is made to contract by increased sympathetic nerve tone, alpha blockers -- which tend to block this transmission – may be better if a man has BPH primarily from substantial stromal tissue. And second, since the epithelial component of prostatic tissue will shrink in the setting of androgen deprivation, 5-alpha-reductase inhibitors should help men with excess epithelial tissue.

14. MEDICAL TREATMENT, cont.
Cannot predict response to a particular therapy
Having said all that, it is very difficult to predict how a particular patient will respond to a particular therapy.

15. MEDICAL TREATMENT, cont.
Mild BPH: watchful waiting
Prostate and bladder neck contraction mediated via alpha-1a receptors
Alpha Blockers:
Alpha-1: prazosin, terazosin, doxazosin
Alpha-1a: tamsulosin
Patients with mild BPH should probably managed without medications at all, that is, with watchful waiting. Treated this way, some one third to one half will actually show improvement in their symptoms. But if drug treatment is needed, it is generally best to start with alpha blockers, such as prazosin, terazosin, doxazosin, and tamsulosin. Contraction in the prostate and bladder neck is mediated by adrenergic alpha-1a receptors. Of the alpha blockers, only tamsulosin is selective for the 1a receptor subtype. The less-selective agents prazosin, terazosin, and doxazosin are alpha-1 receptor blockers. The four agents probably do not differ in their effectiveness. Rather, the three less-selective drugs are more likely to cause side effects, particularly orthostatic hypotension. This is not a small matter for the geriatric age group, of course. I remember well a patient I was taking care of when I was a resident. He was an 80-year-old with newly diagnosed BPH, and I started him on prazosin. The next time I saw him, about a week later, he had a big bandage on his forehead. He explained that, shortly after starting the medicine, he arose one night to use the toilet, and while standing and starting to void, he blacked out, cutting his head on the towel rack.

16. MEDICAL TREATMENT, cont.
Alpha Blockers, cont.
Dosed daily: terazosin, doxazosin, tamsulosin
Dosed bid: prazosin
Slow dose escalation required (perhaps less so with tamsulosin)
Side Effects: orthostatic hypotension and dizziness, headache, rhinitis and nasal congestion, retrograde ejaculation, fatigue
Of the alpha blockers, only prazosin requires twice-daily dosing. Terazosin, doxazosin, and tamsulosin all can be dosed once a day, preferably at night, to minimize the risk of orthostatic misadventures. The doses of all these drugs require very slow dose escalation to reduce the risk of serious side effects, especially postural blood pressure changes. I always warn patients to expect orthostatic symptoms when one of these drugs is first started. This early-onset postural dizziness is known as alpha blockers’ first-dose effect. Besides orthostatic changes, other side effects of alpha blockers include dizziness, headache, runny nose and nasal congestion, retrograde ejaculation, and fatigue.

17. MEDICAL TREATMENT, cont.
5-alpha-reductase inhibitor: finasteride
Blocks conversion of testosterone  DHT
Reduces epithelial component of prostate, shrinks gland, decreases PSA
Months (>6) of treatment before improvement
Symptoms better only if large prostate?
Side Effects: reduced libido, erectile dysfunction
Beside alpha blockers, the other medical option for treatment of BPH is finasteride, a 5-alpha-reductase inhibitor. This medication acts by interfering with the conversion of testosterone to the more biologically active hormone dihydrotestosterone. Finasteride use reduces the epithelial component of the prostate, thereby shrinking the gland. One consequence of this is a reduced serum level of PSA, a fact worth remembering if you check serum PSA levels to screen for prostate cancer. If used to treat BPH, it will take many months of use – probably at least 6 months – before finasteride produces clinical improvement in men, so patients should be counseled not to expect immediate results. Data from some studies suggest that only men with large prostates (bigger than 40g) will see symptomatic improvement with finasteride. Side effects of the drug are those that might be expected for an agent that causes androgen deprivation, namely, reduced libido and erectile dysfunction.

18. MEDICAL TREATMENT, cont.
Combine alpha blockade and finasteride?
RCT over 3000 men (McConnell et al, NEJM 2003)
Mean age 63, mean f/u 4.5 years
Doxazosin vs. finasteride vs. combo vs. placebo
Clinical progression: combo > either drug > placebo
You may be wondering if combining alpha blockers and finasteride is beneficial in BPH treatment. This has been studied, and a report was published in the New England Journal of Medicine in In this study McConnell and coworkers randomized over 3000 men to the alpha blocker doxazosin, to finasteride, to the combination of both drugs, or to placebo. Men in the study had an average age of 63, and were followed up for a mean of 4 and a half years. The authors found that measures of clinical progression of BPH were most favorable with the combination of the two drugs, and that either drug alone was better than placebo.

19. MEDICAL TREATMENT, cont.
Combination Therapy, continued
Placebo-controlled Prostate Cancer Prevention Trial:
Finasteride reduced overall prevalence of prostate cancer
But increased proportion of poorly-differentiated cases
Experts debating whether true harm
But adding finasteride to an alpha blocker may not be without its risk. The placebo-controlled Prostate Cancer Prevention Trial found that, although finasteride reduced the overall prevalence of prostate cancer, it increased the proportion of poorly-differentiated cases in the men who received the drug. At this point experts are debating whether this represented a true harm or not.

20. MEDICAL TREATMENT, cont.
Consider adding finasteride
Men with large prostate
Progressing symptoms
Discuss risk
So at this point, the best approach in terms of using finasteride, is probably the following. For those men with BPH who are suffering worsening symptoms, despite use of the highest tolerated dose of alpha blockade, and who have large prostates, consider the addition of finasteride. But it is important to discuss with the patient or his surrogate that there may be an increased risk of higher-grade prostate malignancies with use of the drug.

21. SURGERY Who to refer for interventions?
Because not every man with BPH does well with medical management, the question arises: Who should be referred to a urologist for a more invasive approach to treatment?

22. SURGERY, cont. Consider for referral: Refractory retention
Failed attempt at d/c of catheter
Overflow incontinence
Large bladder diverticula
Recurrent UTI
Recurrent/persistent gross hematuria
Bladder stones
Renal insufficiency
This slide lists the situations and conditions that should prompt consideration of urologic referral. First, men with refractory urinary retention should probably see a urologist. Examples of this would be men who have indwelling Foley catheters because of bladder outlet obstruction, and who have failed attempts at passing urine without the catheter. Men with overflow incontinence due to bladder outlet obstruction should also see a urologist. Patients with large bladder diverticula, which can be complications of longstanding BPH, should be referred for surgical management. Finally, men with other serious BPH complications should be referred; these complications include: recurrent urinary tract infections, recurrent or persistent gross hematuria, bladder stones, and renal insufficiency.

23. SURGERY, cont. Transurethral Resection of the Prostate
Spinal anesthesia
1-2 day hospital stay
Better symptom scores than minimally- invasive methods
Risks: ED, incontinence, retrograde ejaculation, urethral stricture/bladder neck contracture
Urgency/frequency may persist
What interventional treatment options are available for the older man with BPH? TURP, or transurethral resection of the prostate, is well-established and fairly widely available. This procedure is generally done under spinal anesthesia, and typically requires a one or two-day hospital stay. Patients who undergo TURP usually demonstrate better symptom scores than those who receive the minimally-invasive treatments I will discuss in a minute. Risks of TURP include erectile dysfunction, urinary incontinence, retrograde ejaculation (which is more the rule than the exception), and the development of urethral strictures or bladder neck contractures. Unfortunately, some men who have developed bladder hypertrophy and detrusor instability before they undergo their TURP find that urgency and frequency persist afterwards. With time, the symptoms typically improve.

24. SURGERY, cont. Transurethral Incision of the Prostate
Faster, less morbid than TURP
Requires right prostate anatomy (small gland)
Higher rate of reoperation vs. TURP
But less incidence of stricture, incontinence, retrograde ejaculation
An alternative to the TURP is the Transurethral Incision of the Prostate. This procedure is faster than the TURP and has less associated morbidity. Also, to be considered for this treatment, a man must have a certain kind of prostatic anatomy, particularly a smaller gland. Men who undergo transurethral incision of the prostate generally show a higher rate of subsequent re-operation for BPH than men who get a TURP. But in its favor, men who receive transurethral incision of the prostate show a lower incidence of stricture, urinary incontinence, and retrograde ejaculation than men who get a TURP.

25. SURGERY, cont. Open Prostatectomy Minimally Invasive Procedures
When gland too large to treat otherwise
Bladder stones, diverticula
Minimally Invasive Procedures
Laser, needle ablation, electrovaporization, hyperthermia, ultrasound
Need RCT, long-term follow-up
Intraurethral stents
Patients with short life expectancy, high risk
Occasionally, an older man with BPH requires an open prostatectomy for treatment of his disease. This usually occurs either because his gland was too large for less invasive methods, or because he had co-existing complications or problems (like bladder stones or bladder diverticula) that called for an open surgical approach. At the other end of the treatment spectrum, there are a number of so-called minimally invasive procedures that have been employed to treat men with BPH. The modalities in this category include use of lasers, needle ablation methods, electrovaporization, hyperthermia, and ultrasound. Unfortunately, there is not an abundance of high-quality literature that allows us to make confident conclusions about the benefits of these procedures. In particular, there is a great need for randomized, controlled trials with long-term follow-up in this area. Finally, placement of intraurethral stents remains an option for some elderly men with advanced BPH. Patients who might be good candidates for this treatment are those with a short life expectancy, and those who are felt to have an otherwise high surgical risk.

26. REFERENCES AND READINGS
Lieber MM. Mayo Clin Proc 1998;73:
McConnell JD et al. NEJM 2003;349:
Stoller ML, Carroll PR. Urology. Chapter 23 in: Tierney LM Jr, McPhee SJ, Papadakis MA, Current Medical Diagnosis & Treatment, 2004, McGraw-Hill.
Thompson IM et al. NEJM 2003;349:
This slide lists some of the major references used to create this presentation. If you are interested in learning more about the subject of benign prostatic hyperplasia, these sources make excellent reading, and their bibliographies are helpful as well.
This completes Module 2 of kidney and prostate disease, covering BPH. To proceed to the question, close this window, advance to page two in this learning unit and click on “Module 2 question.” Then proceed to Module 3 on prostate cancer, or take a break if you’d like.

27. Post-test 1
You assume the care of a 75-year-old man who was recently discharged from the hospital, where he had undergone treatment for diverticulitis. In reviewing his hospital discharge summary, you find that an abdominal and pelvic CT was performed, showing sigmoid diverticulitis, a simple right renal cyst, a large urinary bladder diverticulum, and pronounced prostatomegaly. Clinically, his diverticulitis has resolved, but he complains of chronic nocturia, urinary frequency, sense of incomplete emptying, and straining to initiate his urinary stream. Symptoms are modestly improved on a regimen of terazosin 5 mg qhs and finasteride 5 mg qd. Other past medical history includes knee osteoarthritis, diet-controlled diabetes mellitus, recurrent urinary tract infections, and depression. The best approach to treating this man’s urinary complaints is to:

28. The best approach to treating this man’s urinary complaints is to:
Check his PSA, and consider referral for prostate biopsy, depending on the result.
(b) Increase the dose of his terazosin.
(c) Refer him to a urologist for consideration of TURP.
(d) Refer him to a urologist for consideration of an open procedure.
(e) Prescribe a bladder relaxant, such as oxybutynin.

29. Correct Answer:    (d) Refer him to a urologist for consideration of an open procedure.
Feedback:(d) This patient’s recurrent urinary tract infections and bladder diverticulum suggest that he is more appropriately managed by surgical intervention than by medications alone. The presence of the large diverticulum makes it likely that he will need an open procedure prostatectomy and diverticulectomy/bladder repair. Checking his PSA is not likely to be helpful, as a high PSA is nonspecific and may represent BPH, prostate cancer, or urinary tract infection. Increasing the dose of terazosin might be the right choice, if not for the recurrent UTIs and bladder diverticulum. TURP may help with the obstructive symptoms, but won’t solve the diverticulum problem. And prescribing a bladder relaxant would likely make matters worse by increasing the risk of urinary retention.