Benign Prostatic Hyperplasia:

Traditionally, urologists have cared for patients with benign prostatic hyperplasia (BPH). However, because of demographic fluctuations, changes in the health care system, and the development of effective pharmacologic therapy for BPH, primary care physicians are increasingly involved not only in initial patient evaluation but also in continuing management.^1-3 Here we provide guidelines for treatment of uncomplicated BPH-with special emphasis on medical therapies.

OVERVIEW

BPH is the most prevalent urologic disease in men, and it will become more common as the population ages.⁴ The key risk factors are advancing age and the presence of androgens. Clinically significant BPH that requires treatment will develop in only 50% of all men with an enlarged prostate⁵; however,more than half of men older than 60 years show histologic signs of BPH, and 1 in 4 are treated for symptomatic BPH by age 80.⁶

Practice guidelines issued by the Agency for Health Care Policy and Research in 1994 describe BPH as "primarily a quality-of-life disease" and urge that it be viewed largely in terms of the degree of "bothersomeness" experienced by patients and the impact of the disease on their lives.⁶ However, the protracted course of BPH can result in complications, including acute urinary retention, recurrent urinary tract infection, recurrent gross hematuria, bladder stones, and renal insufficiency.

Discuss these issues with the patient, educate him about therapeutic options, and involve him in treatment decisions.^6,7 If the patient requests advice or "surrenders" his decision-making ability, it is appropriate to recommend the optimal treatment or act as the patient's proxy.⁶

SYMPTOMS

BPH symptoms occur most commonly in patients older than 40 years and develop gradually. Men of all races and cultures are affected.⁸ The most common reason patients seek treatment is that symptoms such as increased urinary frequency and nocturia become bothersome. Symptoms are commonly classified as "obstructive" (eg, hesitancy, straining, diminished and/or interrupted urinary stream, postmicturition dribbling, or sensation of incomplete emptying) or "irritative" (eg, increased frequency, nocturia, urgency, or urge incontinence). Most patients have a mix of both kinds of symptoms.

Differential diagnosis. Although BPH is the most common source of lower urinary tract symptoms (LUTS) in men older than 50 years, such symptoms have a variety of causes. Many patients may not have true BPH or prostatic enlargement; therefore, conditions that cause similar symptoms must be ruled out (Table 1).²

Other signs and symptoms to consider in generating the differential diagnosis include dysuria, polyuria, hematuria, and manifestations of malignancy; historical factors to consider include urethral syndromes (eg, sexually transmitted diseases, instrumentation, trauma); comorbid illness (eg, diabetes, congestive heart failure); and neurologic disease (eg, multiple sclerosis, Parkinson disease, spinal cord disease). In other disease processes, including malignancies, LUTS may develop more rapidly than in BPH; irritative symptoms predominate in these settings. In men younger than 50 years, symptoms are usually attributable to conditions other than BPH.²

Mechanisms that underlie symptoms. The obstructive symptoms of BPH appear to be caused by 2 different mechanisms: one is a static, mechanical obstruction resulting from the enlargement of the glandular tissue; the other is dynamic, the product of altered tone in the adrenergically innervated smooth muscle in the prostatic capsule and stroma as well as the bladder neck and trigone. Both components produce LUTS; fluctuations in symptoms result from changes in sympathetic nerve activity.^2,9,10

CLINICAL EVALUATION

Although the International Prostate Symptom Score (IPSS) questionnaire was not intended primarily as a diagnostic tool, this instrument is central to the initial evaluation. It is used to assess the severity of the condition and the extent to which symptoms impair quality of life (QOL); it can also be used to track symptoms quantitatively over time (Table 2). Symptoms are classified as mild (0 to 7), moderate (8 to 19), or severe (20 to 35).^6,11

The impact on QOL is assessed by a single question that helps in determining which therapeutic option to pursue. BPH can cause loss of sleep and anxiety and interfere with mobility, daily activities, leisure activities, and sexual relationships.

A general approach to the initial evaluation is outlined in Table 3. Be sure to take a careful medication history. Prescription or nonprescription anticholinergics or calcium channel blockers can impair bladder contractility. Sympathomimetics can increase outflow resistance. Diuretics may increase frequency and cause nocturia.^2,6

Physical examination. Perform a digital rectal examination (DRE) to confirm the characteristic enlarged, firm prostate gland and help rule out more serious conditions. Other findings of note, such as asymmetric consistency, hard areas, or discrete nodules, are often associated with prostate cancer and require further evaluation.² Cancer is diagnosed in approximately 26% to 34% of men with abnormal examination findings on DRE.^12-14 Fo- cus the neurologic examination on strength, sensation, and reflexes in the lower extremities, as well as sensation in the saddle area, to exclude conditions associated with bladder function abnormalities.³

Laboratory testing. Urinalysis via dipstick or examination of spun sediment can reveal abnormalities such as red and/or white cells or bacteria; these indicate possible urinary tract infection or genitourinary cancer, both of which may mimic BPH by causing symptoms such as frequency and urgency. A serum creatinine measurement is also recommended, because renal function may be abnormal in as many as 10% of patients with BPH symptoms. A serum glucose measurement is useful in excluding other causes of polyuria.

It is also important to identify and treat any complications of BPH (eg, acute urinary retention, hematuria, urolithiasis, infection), although the risk of serious complications in patients with untreated symptomatic BPH is thought to be low.^2,6 One study reported that the incidence of major complications was minimal in patients with moderate symptoms of BPH who elected watchful waiting.¹⁵

The measurement of prostate-specific antigen (PSA) levels to screen for prostate cancer is considered optional in the initial evaluation of the symptoms of lower urinary tract disorders because of the complexity of test result interpretation in the setting of BPH and uncertainty about the test's efficacy in reducing morbidity or mortality.⁶

Although some advocates recommend routine PSA screening of all men older than 50 years-and, in some cases, older than 40 years-BPH itself can elevate serum PSA levels, and the overlap of levels among men with BPH and men with prostate cancer is significant. Moreover, because of the slow progression of prostate cancer, PSA screening is controversial in patients older than 70 years and should not be performed routinely; the number of men older than 70 years who present with symptoms of BPH is substantial.⁶ Use of PSA screening is at the clinician's discretion; obstructive urinary symptoms do not predict malignancy. Discuss the risks and benefits of PSA screening with the patient as part of the informed consent process.

TREATMENT OPTIONS

The goal of treatment has changed from reduction of prostate size and relief of outlet obstruction to symptom control.¹⁶ A general approach to treatment is outlined in the Algorithm.

Any treatment plan for patients with uncomplicated but symptomatic BPH should include regular monitoring of symptoms and QOL concerns, as well as periodic prostate evaluation when appropriate. Among the options are watchful waiting, medical therapy, and surgery.

Patients with BPH may require assessment by a urologist. Situations where referral is indicated include:

• Development of complications (eg, urinary retention).
• Symptoms that do not respond to medical treatment.
• Uncertainty about the diagnosis.

Watchful waiting. For patients with an IPSS score below 8 or with more severe symptoms that are not very bothersome, watchful waiting may be the most appropriate strategy. Monitor symptoms and QOL concerns at least annually, and instruct patients to report symptom changes and potential BPH complications. Alert patients about LUTS-precipitating factors.⁶ These include:

• Incomplete voiding.
• Late-night fluid consumption.
• Alcohol and caffeine.
• Medications such as anticholinergic agents.

Regular monitoring and reassurance regarding the absence of cancer and obstruction further improve QOL.¹⁶

Herbal therapy. Many patients with mild symptoms try over-the-counter remedies, particularly plant extracts; the American dwarf saw palmetto plant, Serenoa repens, is the most widely used. A meta-analysis of evidence on the efficacy and safety of this agent in patients with BPH found improvements in symptoms and flow measures similar to those of finasteride, with fewer adverse effects. However, there are no data regarding the long-term efficacy and safety of saw palmetto or whether its use can prevent complications.¹⁷ Although plant extracts are widely used in Europe for symptomatic treatment of BPH, they have not been approved by the FDA for this indication. Because the manufacturing process has not been standardized, concerns about purity remain.¹⁸

Pharmacotherapy. Many patients can be treated with medication alone with less risk than that associated with invasive treatment.^6,7Table 4 lists the approved medical therapies for BPH-related symptoms. α-Adrenergic blockade is considered first-line therapy, regardless of symptom severity or baseline prostate volume.⁵

α₁-Adrenergic antagonists. Pharmacotherapy for BPH was initiated in the mid-1970s with the introduction of the nonselective α-adrenergic blocker phenoxybenzamine. The benefits of the newer nonselective agents terazosin and doxazosin and the selective agent tamsulosin include simpler dosing regimens and fewer side effects. These long-acting agents block α₁-adrenergic receptors in the urinary tract and prostate, which, in turn, produces relaxation of the smooth muscle of the prostatic stroma, prostatic capsule, periurethral area, and bladder neck.^19-22

Terazosin and doxazosin treatment must be initiated at low dosages to prevent side effects such as postural hypotension and first-dose syncope that can result from the effects of adrenergic blockade on nonprostatic tissues.^2,23 The dose is titrated upward until a therapeutic response is obtained. Although patients accommodate to the hypotensive effects, interruption of therapy for several days requires retitration.

In hypertensive patients, blood pressure reduction may be regarded as a benefit of therapy with α₁-blockers, although there is a somewhat greater risk of adverse events with these agents than with agents specific for the α_1A-receptor subtype.²² Evidence from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) suggests that it may be best to avoid α-blockers in hypertensive patients with BPH, especially those who have congestive heart failure.²⁴

A number of subtypes of the α₁-adrenergic receptor have been identified; α_1A-receptors have been established as the dominant type in the human prostate. (α_1B-Receptors are responsible for the contraction of human internal iliac artery branches.²⁵) Agents selective for α_1A-receptors have minimal effects on blood vessels and therefore are unlikely to produce unwanted blood pressure reduction.²¹

Tamsulosin, an agent with substantial α_1A selectivity, reduces symptoms of BPH almost immediately.²⁶ In a phase 3 placebo-controlled study, a single dose of tamsulosin significantly improved peak urinary flow (Q_max) within 4 to 8 hours compared with placebo.²⁶ After 1 week of therapy patients showed significant improvement in IPSS and QOL score. Because tamsulosin is unlikely to reduce blood pressure or produce first-dose syncope, it can be administered at the therapeutic dose from the outset, thus obviating the need for titration.

Terazosin and doxazosin have a slower onset of action than tamsulosin because of the need for titration, which can require 4 to 8 weeks. In a small double-blind study of normotensive elderly patients treated for LUTS suggestive of benign prostatic obstruction, a single daily dose of 0.4 mg of tamsulosin produced less nocturnal orthostatic hypotension than a single daily dose of 1, 2, or 5 mg of terazosin.²⁷ A study of 19,365 patients with LUTS suggestive of benign prostatic obstruction found that tamsulosin had minimal effects on blood pressure and no significant drug interactions in patients who had comorbid conditions (diabetes, hypertension, or other cardiovascular disease) or were taking concomitant antihypertensive medication (diuretics, β-blockers, calcium channel blockers, or angiotensin-converting enzyme inhibitors).²⁸

Androgen deprivation.

The principal pharmacologic alternative to adrenergic blockade is androgen deprivation. The only agents of this kind approved by the FDA for BPH are finasteride and dutasteride, which are both 5α-reductase inhibitors. These agents work by decreasing the conversion of testosterone to dihydrotestosterone through selective inhibition of 5α-reductase activity in the lower genitourinary tract. Finasteride and dutasteride are well tolerated and do not require dose titration, but it may take 6 to 12 months of therapy to attain full effectiveness.

^2,7

Androgen deprivation is effective in patients with larger prostates who cannot tolerate or who do not benefit from α-adrenergic blockers. In one study, men with moderate to severe symptoms at baseline and an enlarged prostate on DRE who were treated with finasteride for 4 years were less likely to undergo surgery than those who took a placebo (5% vs 10%) and also had a lower incidence of acute urinary retention (3% vs 7%).²⁹

5α-Reductase inhibitors are probably best reserved for men with moderate to severe symptoms who have experienced treatment failure with α₁-adrenergic blockers and/or who have a prostate volume greater than 40 cc.^7,30 Obtain a baseline PSA measurement before initiating therapy, since 5α-reductase inhibitors reduce PSA values.⁷ A second measurement may be obtained at 6 months to reestablish the baseline PSA. Increasing values will thereafter warrant appropriate monitoring and evaluation.

Surgical and minimally invasive options. Surgery is an appropriate initial treatment for the fully informed patient with moderate to severe symptoms. Surgery is also indicated for patients with refractory urinary retention, in whom an attempt at catheter removal has failed at least once and who have normal bladder contractility, and for patients with recurrent urinary tract infections, recurrent gross hematuria, bladder stones, or renal insufficiency clearly attributable to BPH.

Failure to respond to medical or minimally invasive therapy is not an absolute indication for surgery. The patient may choose to return to watchful waiting rather than risk the side effects of surgery, which include retrograde ejaculation (reported in 70% to 75% of patients who undergo transurethral prostatic resection [TURP]), impotence (5% to 10%), or urinary tract infection (5% to 10%).^4,6

Moderate (IPSS, 8 to 19) to severe (IPSS, 20 to 35) symptoms necessitate detailed discussion of therapeutic options with the patient, during which he should be informed about the benefits and risks associated with all the available treatments.³¹ Surgery (eg, TURP or open prostatectomy) has the highest rates of significant complications but also the highest rate of symptomatic improvement.⁶ Other options include minimally invasive therapies, such as transurethral incision of the prostate, transurethral needle ablation, laser prostatectomy, microwave hyperthermia, and electrovaporization, which carry a lower risk of complications. Although these procedures offer an alternative to surgery, medical therapy has become the first-line choice when-as is often the case-surgery is not absolutely indicated and the patient prefers less radical therapy.^6,32

References:

REFERENCES:1. Collins MM, Barry MJ, Bin L, et al. Diagnosis and treatment of benign prostatic hyperplasia: practice patterns of primary care physicians. J Gen Intern Med. 1997;12:224-229.
2. Barry M, Roehrborn C. Management of benign prostatic hyperplasia. Annu Rev Med. 1997;48:177-189.
3. Guthrie R. Benign prostatic hyperplasia in elderly men: what are the special issues in treatment? Postgrad Med. 1997;101:141-162.
4. Tammela T. Benign prostatic hyperplasia: practical treatment guidelines. Drugs Aging. 1997;10:349-366.
5. Oesterling JE. Benign prostatic hyperplasia: a review of its histogenesis and natural history. Prostate Suppl. 1996;6:67-73.
6. McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign Prostatic Hyperplasia: Diagnosis and Treatment. Clinical Practice Guideline Number 8. Rockville, Md: US Dept of Health and Human Services, Agency for Health Care Policy and Research; 1994. AHCPR publication 94-0582.
7. Medical Advisory Panel for the Pharmacy Benefits Management Strategic Health Group. The pharmacologic management of benign prostatic hyperplasia. VHA PBM-SHG publication 97-0008. Hines, Ill: Pharmacy Benefits Management Strategic Health Group, Veterans Health Administration, Department of Veterans Affairs; September 1997.
8. Oesterling JE. Benign prostatic hyperplasia: its natural history, epidemiological characteristics, and surgical treatment. Arch Fam Med. 1992;1:257-266.
9. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol. 1975;47:193-202.
10. Furuya S, Kumamoto Y, Yokoyama E, et al. Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J Urol. 1982;128:836-839.
11. Cockett AT, Aso Y, Denis L, et al. Recommendations of the International Consensus Committee concerning: 1. Prostate Symptom Score (I-PSS) and Quality of Life Assessment 2. Diagnostic work-up of patients presenting with symptoms suggestive of prostatism 3. Standardization of the evaluation of treatment modalities 4. BPH treatment recommendations. In: Cockett AT, Khoury S, Aso Y, et al, eds. The Second International Consultation on Benign Prostatic Hyperplasia (BPH); Paris, June 27-30, 1993. Paris: Jersey Scientific Communication International; 1994:553-564.
12. Lee F, Littrup PJ, Torp-Pedersen ST, et al. Prostate cancer: comparison of transrectal US and digital rectal examination for screening. Radiology. 1988;168:389-394.
13. Chodak GW, Keller P, Schoenberg H. Routine screening for prostate cancer using the digital rectal examination. Prog Clin Biol Res. 1988;269(HD):87-98.
14. Thompson IM, Ernst JJ, Gangai MP, Spence CR. Adenocarcinoma of the prostate: results of routine urological screening. J Urol. 1984;132:690-692.
15. Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med. 1995;332:75-79.
16. Teillac P.Relief of BPO or improvement in quality of life? Eur Urol. 1998;34(suppl 2):3-9.
17. Wilt TJ, Ishani A, Stark G, et al.Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA. 1998;280:1604-1609.
18. McKinney DE.Saw palmetto for benign prostatic hyperplasia. JAMA. 1999;281:1699.
19. Caine M, Perlberg S, Meretyk S. A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction. Br J Urol. 1978;50:551-554.
20. Abrams PH, Shah PJR, Stone R, Choa RG. Bladder outflow obstruction treated with phenoxybenzamine. Br J Urol. 1982;54:527-530.
21. Guthrie R. Terazosin in the treatment of hypertension and symptomatic benign prostatic hyperplasia: a primary care trial. J Fam Pract. 1994;39:129-133.
22. Chapple CR. Selective α₁-adrenoceptor antagonists in benign prostatic hyperplasia: rationale and clinical experience. Eur Urol. 1996;29:129-144.
23. Carruthers SG. Adverse effects of α₁-adrenergic blocking drugs. Drug Saf. 1994;11:12-20.
24. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;283:1967-1975.
25. Hatano A, Takahashi H, Tamaki M, et al. Pharmacological evidence of distinct α₁-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery. Br J Pharmacol. 1994;113:723-728.
26. Lepor H, for the Tamsulosin Investigator Group. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology. 1998;51:892-900.
27. de Mey C, Michel MC, McEwen J, Moreland T. A double-blind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and nocturnal orthostatic stress testing. Eur Urol. 1998;33:481-488.
28. Michel MC, Mehlburger L, Bressel HU, et al. Tamsulosin treatment of 19,365 patients with lower urinary tract symptoms: does co-morbidity alter tolerability? J Urol. 1998;160:784-791.
29. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998;338:557-563.
30. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology. 1996;48:398-405.
31. McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign Prostatic Hyperplasia: Diagnosis and Treatment. Quick Reference Guide for Clinicians Number 8. Rockville, Md: US Dept of Health and Human Services, Agency for Health Care Policy and Research; 1994. AHCPR publication 94-0583.
32. Narayan P, Tewari A. Overview of α-blocker therapy for benign prostatic hyperplasia. Urology. 1998;51(suppl 4A):38-45.