Benign Prostatic Hyperplasia: New Concepts for the Millennium€¦ · Burkhardt Zorn, MD; John J. Bauer, MD; and Judd W. Moul, MD. . .CONTINUING MEDICAL EDUCATION . . . VOL. 5, NO

Benign prostatic hyperplasia (BPH) is themost common benign neoplasm in men.Before the advent of medical therapy for

BPH in the early 1990s, the estimated number ofsurgical procedures for BPH was more than400,000 per year at an estimated annual cost of$4.5 billion.1 Transurethral surgery of the prostate(TURP) accounted for the majority of these pro-cedures, but there has been a 52% decrease in itsperformance since 1990.2 This decrease in theperformance of TURP is not only a reflection ofmedical therapy but also of the emergence of min-imally invasive techniques to treat BPH. Previousestimates in the early 1990s were that 1 in 4 menis treated in his lifetime for symptoms resultingfrom BPH and that this treatment accounts formore than 1.7 million office visits per year. Theaging population, public awareness of the condi-tion, and the availability of nonsurgical optionshave increased the percentage of men seeking andreceiving treatment.3 The high prevalence ofsymptomatic BPH has a substantial impact on thequality of life for elderly men and represents anincreasing significant financial burden.

The large number of men with BPH and the lackof objective indications for intervention haveresulted in the formulation of the clinical practiceguidelines for BPH, which was released in February1994.4 These guidelines represent recommendationsnot only to the urologist but also to the primary carephysician, who will be playing an increasinglymajor role in the treatment of this disease process.This brief review of BPH and the related diagnosticand treatment modalities is intended to provide theprimary care physician with an overview of this rap-idly changing field.

Benign Prostatic Hyperplasia: New Concepts for the Millennium

Burkhardt Zorn, MD; John J. Bauer, MD; and Judd W. Moul, MD

. . .CONTINUING MEDICAL EDUCATION . . .

VOL. 5, NO. 7 THE AMERICAN JOURNAL OF MANAGED CARE 911

CME ARTICLE

AUDIENCEThis article is designed for primary care physicianswho may be responsible for patients with benignprostatic hyperplasia (BPH).

GOALTo provide the reader with a basic understanding ofthe pathophysiology of BPH, its evaluation, and itstreatment.

OBJECTIVES1. To describe the prevalence, definitions, andsymptoms of BPH.2. To describe how BPH is evaluated in patientspresenting with lower urinary tract symptoms.3. To describe available treatment options and theexpected results.

From Walter Reed Army Medical Center, Washington, DC (B.Z.,J.J.B, and J.W.M), and the Center for Prostate Disease Research,Uniformed Services University of the Health Sciences Bethesda, MD(J.J.B and J.W.M).

The opinions and assertions contained herein are the privateviews of the authors and are not to be construed as reflecting theviews of the US Army and the Department of Defense.

Address correspondence to: Judd W. Moul, MD, Center forProstate Disease Research, 1530 East Jefferson St, Rockville, MD20852. E-mail: [email protected].

CONTINUING MEDICAL EDUCATION ACCREDITATIONJohns Hopkins University School of Medicine designates this

continuing medical educaton activity for 1 credit hour inCategory 1 of the Physician’s Recognition Award of theAmerican Medical Association.

Johns Hopkins University School of Medicine is accreditedby the Accreditation Council for Continuing MedicalEducation (ACCME) to sponsor continuing medical educationfor physicians.

This CME activity was planned and produced in accordancewith the ACCME Essentials.

912 THE AMERICAN JOURNAL OF MANAGED CARE JULY 1999

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. . . DEFINITIONS AND PATHOPHYSIOLOGY OF BENIGN PROSTATIC HYPERPLASIA . . .

In the past, a causal relationship between thepresence of BPH and the development of lower uri-nary tract symptoms was accepted. We now realizethat the lower urinary tract symptoms previouslyattributed to the histologic changes in the prostateconsistent with BPH are multifactorial in nature. Itis estimated that more than 50% of men at age 60years and nearly 90% at age 85 years will have his-tologic evidence of BPH. Of these men, however,only 50% will have clinical enlargement of theprostate and only 50% of these will become sympto-matic.3,4 This demonstrates that BPH does notalways result in benign prostatic enlargement orbenign prostatic obstruction. In addition, lower uri-nary tract symptoms are very common in men inthe absence of BPH and are as common and severein age-matched women.5-7 The preferred term todescribe the development of lower urinary tractcomplaints previously attributable to BPH in themale is now “lower urinary tract symptoms.” Moststudies still refer to these symptoms of BPH as thefocus of study; therefore, BPH will continue to beused throughout this paper.

The pathophysiology of the overactive bladderand its contribution to lower urinary tract symp-toms are beyond the scope of this paper. Therefore,only changes in the prostate associated with agingwill be discussed, thereby elucidating the rationalefor current medical therapy. Once again we mustemphasize that not all patients presenting with lowerurinary tract symptoms will have BPH, benign pro-static enlargement, or benign prostatic obstruction.

Determinants of prostate growth include aging,circulating androgens, 5α-reductase, and androgenreceptors. The prostate requires adequate levels oftestosterone and the ability to convert testosteroneto dihydrotestosterone to develop and grow.8 Forthis conversion of testosterone to dihydrotestos-terone, an enzyme called 5α-reductase is required.Genetic lack of this enzyme results in male pseudo-hermaphroditism and absence of prostatic develop-ment. Blockade of the testosterone to dihy-drotestosterone conversion has been shown todecrease prostatic epithelial growth, eventuallycausing shrinkage of the gland. Beyond this andro-genic control of growth, the exact mechanismwhereby BPH develops is unknown. Intenseresearch is under way to determine the molecularevents underlying BPH. Undoubtedly this knowl-

edge will improve our understanding of the mecha-nism involved and will direct future prevention.

BPH is primarily a stromal process. Earlyresearch has demonstrated that the stromal toepithelial ratio is increased as hypertrophy develops(normal = 2:1; BPH = 5:1).9 This stromal enlarge-ment is implicated in the mechanical obstruction(static component) of BPH. A significant componentof the prostatic adenoma is smooth muscle. Thesmooth muscle in the adenoma, prostatic urethra,and the bladder neck is innervated by α-adrenergicnerve fibers.10 Smooth muscle tone in these tissuesis responsible for the dynamic component ofobstruction seen in patients with BPH.

. . . SYMPTOMS OF BPH . . .

The symptoms associated with BPH have beenclassified as obstructive or irritative. Obstructivevoiding symptoms include hesitancy, intermittency,weak forceless stream, straining to void, and uri-nary dribbling. Irritative voiding symptoms includefrequency, urgency, nocturia, and sensation ofincomplete voiding. To better quantify these symp-toms, the American Urological Association (AUA)formed a Measurement Committee, which devel-oped a symptom and quality-of-life questionnaire. Itis called the International Prostate Symptom Scoreand has been translated into a number of languages(Table 1). Although the AUA score is validated todetermine symptom severity and response to treat-ment, a lack of specificity is apparent, as there aresimilar scores between elderly women and men anda general increase with age. Factors such as bladderaging, changes in physiologic production of urine,and other factors associated with aging are nottaken into consideration with this measurementtool. An additional tool to assess the degree towhich symptoms affect activities of daily living isthe BPH Impact Index.11 Health-seeking behaviorcorrelates better with bother than symptom scores.Therefore, patients seek treatment not necessarilyfor BPH symptoms but for the bother associatedwith those symptoms.

. . . EVALUATION . . .

In this era of cost containment, careful analysisof diagnostic testing methods to determine the pres-ence or severity of a disease is necessary. In 1994,the Agency for Health Care Policy and Research


recommended medical history, physical exam (toinclude digital rectal exam), urinalysis, serum crea-tinine, and the AUA symptom score as a baselineworkup for BPH. Optional tests include urodynamicstudies, voiding pressure flow studies, uroflow rates,postvoid residual determinations, and prostate-spe-cific antigen (PSA). Tests not recommended includeroutine intravenous pyelogram, renal ultrasonogra-phy, or cystoscopy unless otherwise clinically indi-cated. The savings that result from not performingan intravenous pyelogram and cystoscopy are atleast $300 dollars per patient evaluated.2 Althoughthe majority of patients can be started on medicaltherapy without further testing, additional testing

can provide direction for therapy in patients withmore complex presentations.

Urinalysis and urine cultures are useful for deter-mining whether urinary tract infection or asympto-matic bacteriuria is present. In addition, urinalysiscan determine whether microscopic hematuria ispresent. If hematuria is present, a full urologic eval-uation of the urinary tract is indicated regardless ofthe symptoms of BPH. Elevated creatinine levelsmay indicate renal deterioration from obstructionand mandate further testing and possibly moreaggressive treatment (ie, surgical relief of obstruc-tion). A full discussion of the PSA blood test isbeyond the scope of this article; however, PSA has

. . . BENIGN PROSTATIC HYPERPLASIA . . .

Table 1. Table1. American Urologic Association Symptom Score and International Prostate Symptom Score

IPSS = International Prostate Symptom Score.

Less than Not One Time Less than About More than Almostat All in Five Half the Time Half the Time Half the Time Always

Over the past month, how often have 0 1 2 3 4 5you had a sensation of not emptying your bladder completely after you have finished urinating?

Over the past month, how often have you 0 1 2 3 4 5had to urinate again less than 2 hoursafter you finished urinating?

Over the past month, how often have you 0 1 2 3 4 5found you stopped and started again several times when you urinated?

Over the past month, how often have you 0 1 2 3 4 5found it difficult to postpone urination?

Over the past month, how often have you 0 1 2 3 4 5had a weak urinary stream?

Over the past month, how often have you 0 1 2 3 4 5had to push or strain to begin urination?

Over the past month, how many times did 0 1 2 3 4 5you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?

Total I-PSS Score: _____________

Delighted Pleased Satisfied Mostly mixed Disatisfied Mostly unhappy Terrible

If you were to spend the rest 0 1 2 3 4 5 6of your life with your urinary condition just the way it is now, how would you feel about it?


. . . CME . . .

become very useful as a potential screening test forthe presence of prostate carcinoma.12 Interestedreaders are referred to a prior article on prostatecancer screening and the use of the PSA test thatappeared in this journal.13 Occult prostate cancermay be present in up to 20% of patients who pres-ent with symptoms of BPH. Clearly for mostpatients, it will be beneficial to know whetherprostate cancer exists, especially if surgical inter-vention is planned.

Uroflowmetry has been used frequently to deter-mine the presence of obstruction. The flow rate isdefined as fluid expelled via the urethra in millilitersper second. Peak flow rates of less than 12-15 mL/sare suggestive of obstruction. Patients with low uri-nary flow rates respond better to surgical therapy,but this may not be true of medical therapy.14,15

Uroflow is limited by its ability to distinguishobstruction from impaired detrusor contractility.16

Although almost all urologists have mechanicalflowmeters, home urinary flow testing also can beperformed by the patient at home and recorded forphysician evaluation. Basically, the patient is issueda specimen cup with cubic centimeter measure-ments and at midstream voids into the cup for 5seconds. Patients can record these flow rates at var-ious times. This simple test can be used to monitorBPH or measure the response to therapy withoutexpensive equipment.

Postvoid residual determinations have been sim-plified with office-based ultrasound units, eliminat-ing the need for catheterization. Many primary careoffices now have this technology available to them.Data from a Veterans Administration (VA) trialdemonstrated that a postvoid residual volume of morethan 100 mL increased the risk of urinary retention inBPH patients receiving watchful waiting.17

Pressure flow studies are the most accurate toolto define obstruction, but they are hindered by lackof consensus about the values that indicate obstruc-tion, as well as by the invasiveness of the procedure.Indications for pressure flow urodynamic studiesare shown below:

• Young age (<50 years) or lifelong symptoms• High residual urine volume• Known or suspected neurologic disease• Persistent symptoms after invasive procedure• New or investigative treatment

In summary, the majority of patients can bestarted on medical therapy after the evaluation sug-gested by the Agency for Health Care Policy and

Research. It is also our opinion that a PSA test shouldbe performed to screen for prostate cancer before thestart of BPH treatments. In the following sections weattempt to familiarize the primary care provider withthe myriad of treatment options present.

. . . TREATMENT OPTIONS . . .

Watchful WaitingWatchful waiting usually is recommended for

men with mild symptom severity, as reflected by anAUA score of 8 or less and little bother. Patientswith moderate to severe symptoms are also candi-dates for watchful waiting, but will often choosealternative therapies to include medical, minimallyinvasive, or surgical options. In a study comparingTURP with watchful waiting in patients with moder-ate symptoms, TURP was found to be more effectivein reducing treatment failure and improving geni-tourinary symptoms.17 In patients with low symp-tom scores and little bother, the patient and doctormust weigh the risks and benefits of treatment ver-sus watchful waiting.

Medical TherapiesAlthough the most widely used medical therapy

for BPH includes 2 classes of medications, α-adren-ergic blocking agents and 5α-reductase inhibitors,the use of alternative agents has increased recently.The term alternative implies that the drug is notcurrently approved for product labeling by the USFood and Drug Administration (FDA). These agentsaccount for 90% of prescriptions for BPH inGermany and almost 50% of prescriptions in Italy.18

The class of compounds, phytoestrogens, have beentouted to have estrogen-like activity and therebythe ability to inhibit luteinizing hormone, causingshrinkage of the prostate with a resultant decreasein symptoms. The following are alternative agentsfor treatment of BPH:

• Alfalfa: estrogen-like compound• Forage crops: estrogen-like compound• Stinging nettle: neurotoxin• Serenoa repens (saw palmetto): 5α-reductase

inhibitor (?)• Pumpkin seed• Rye pollen: 5α-reductase inhibitor (?)

The most frequently used alternative agent is sawpalmetto. Differing extraction methods account forits variable ability to inhibit 5α-reductase and itsdiffering effects in various clinical trials. Of 8 studies


evaluating saw palmetto, 7 reported a decrease insymptoms, 6 reported an increase in flow rates, and 4reported a decrease in postvoid residual volume.19 Allof these studies were short term, and in the largesttrial patients did not have a change in PSA values at6 months, bringing into question the 5α-reductaseactivity of this agent. Many patients are trying alter-native therapies or adding these agents to more con-ventional therapy; however, well-designed, controlledstudies are lacking, thereby clouding the issue ofthese agents effectiveness or utility.

The rationale for α-blocker use in patients withBPH is relaxation of prostate smooth muscle. However,there is increasing evidence that symptom improve-ment is not directly related to relaxation and relief ofobstruction. Numerous studies demonstrate a lack ofcorrelation between improvements in flow ratesand symptom changes.20 Therefore, α-blockersalso may affect sensory afferents or central nerv-ous system pathways in addition to their action onthe prostate. There are currently 3 FDA-approvedα-blockers to treat BPH: tamsulosin, terazosin, anddoxazosin.

Molecular cloning has allowed the identificationof three subtypes of α1-receptors; α1a, α1b, and α1d.Tamsulosin has partial selectivity for α1a and α1d,thereby avoiding the vascular effects attributable toα1b.21 Highly selective α1a-blockers are being devel-oped by the pharmaceutical industry and are current-ly in clinical trials. In addition, nonselective and short-acting α-blockers are occasionally used (Table 2).

Terazosin, the first α-blocker approved for BPH,has been the one most extensively investigated.Doxazosin has been similarly studied, and theresults of the clinical trials of these two long-actingα1-blockers are similar. In a multicenter, random-ized, double-blind study comparing once-daily dos-ing of placebo with once-daily dosing of terazosin 2mg, 5 mg, or 10 mg, the greatest symptom improve-ment was found with terazosin 10 mg.21 Seventypercent of patients realized a 30% improvement insymptom scores on the 10-mg dose. Peak flow ratesincreased 2.3 mL/s and the AUA score decreased7.6 points with terazosin. Table 3 shows the mostfrequently reported side effects. Fawzy and col-leagues reported on a 16-week, multicenter, ran-domized trial in which doxazosin doses were titrat-ed according to response; 88% of the patients wentto the maximal dose of 8 mg.22 Peak flow rates andchanges in flow rate were similar to those seen withterazosin, but adverse events were slightly morefrequent (Table 3). The Hytrin CommunityAssessment Trial randomized 2804 patients to

receive placebo or terazosin and allowed the physi-cian to titrate the terazosin dose according topatient response.23 Of those in the terazosin arm,70% had their doses titrated to 10 mg, demonstrat-ing that terazosin 10 mg is well tolerated. In an openlabel extension trial of terazosin with 494 patients,symptom improvements were maintained from 3 to42 months.24 Of the 213 patients (43.1%) who with-drew prematurely, 55 had therapeutic failure, 96had adverse effects, and 62 were lost for administra-tive reasons. It must be recognized that extensiontrials overestimate improvements by reporting onresponders. In an open label extension study of dox-azosin, symptom and flow rate improvements alsowere maintained up to 42 months. Until data areavailable from the Medical Therapy of ProstaticSymptoms (MTOPS) trial sponsored by the NationalInstitutes of Health, which is comparing placebo,doxazosin, finasteride, and both active medicationsover a 5-year period, the long-term efficacy of α-blockers will not be known.

Although the longer half-life of doxazosin (22hours) compared with that of terazosin (12 hours)makes doxazosin more appropriate for once-dailydosing, this difference did not affect clinical out-comes. Both terazosin and doxazosin cause minimalchanges in blood pressure in normotensive patients.The addition of these α-blockers in patients alreadyreceiving other antihypertensive agents is well toler-ated. In an attempt to assess the cost effectiveness ofpill-splitting an 8-mg tablet to provide two 4-mgdoses, McDairmid and colleagues studied the effect


Table 2. α-Blocker Class and Dosage

Class Dosage

Nonselective■ Phenoxybenzamine 10 mg twice daily

α1-Blocker Short Acting■ Prazosin 2 mg twice daily

α1-Blocker Long Acting■ Terazosin 5–10 mg every day■ Doxazosin 4–8 mg every day

Partially Selective α1a-Blocker Long Acting■ Tamsulosin 0.4–0.8 mg every day


of 4 mg versus 8 mg of doxazosin. He found a signif-icant difference in symptom improvement with the8-mg dose.25 The difference in symptom scoresbetween 4 mg and 8 mg of doxazosin is greater thanthe difference in symptom scores between 5 mg and10 mg of terazosin, thereby bringing into questionthe cost-effectiveness of pill-splitting. Although bothterazosin and doxazosin are recommended asevening medications, recent studies of doxazosinhave shown morning dosages are as well tolerated.26

Tamsulosin, a partially selective α1a-blocker, hasbeen investigated in 3 multicenter, randomized,double-blind studies. This agent was formulated toavoid the vascular effects of α1b blockade. Leporstudied 756 American men with BPH and foundchanges in AUA symptom score and peak flow rates(Table 4).27 Symptom score differences between the0.4-mg and 0.8-mg doses did reach statistical signif-icance. Changes in blood pressure were not signifi-cantly different between hypertensive and nor-motensive patients. As with the nonselective α1-blockers, symptom score and flow rate improve-ments were maintained in a 40-week extension trialwith 418 patients (55%) participating. A lower inci-dence of asthenia was noted with tamsulosin com-pared with other long-acting α1blockers, but anunexplained increase in retrograde ejaculation alsowas noted.

Comparing 2 nonconcurrent, randomized, multi-center trials shows that terazosin produces greaterimprovements in symptom scores and flow ratesthan tamsulosin. These findings must be confirmedwith a double-blind, randomized, placebo-controlledtrial comparing terazosin with tamsulosin. Theadvantages of uroselectivity with tamsulosin may be

at the cost of beneficial effects on sensory afferentsor central nervous system pathways. Furthermore,the lack of titration and the quicker effects on symp-tom scores and flow rates may be at the cost of over-all efficacy.

Medications also can be used to shrink the size ofthe prostate gland and ultimately improve symptomsrelated to the static component of BPH. In the firstlarge placebo-controlled multicenter trial with mentreated with 5 mg of finasteride per day, a significantdecrease in AUA scores, increase in maximum uri-nary flow rate, and decrease in prostate volume wereseen (Table 5).28 Adverse events and dropout rateswere related to changes noted in sexual functionsuch as decreased ejaculate and impotence. Theopen label extension trial demonstrated durableresponse to 48 months.29 The Proscar Long-termEfficacy and Safety Study trial is a randomized,double-blind study with 1503 patients randomizedto receive placebo and 1513 randomized to receivefinasteride. This study demonstrated reducedsymptoms and prostate volume, increases in uri-nary flow rates, reduced need for surgery, and alower incidence of acute urinary retention in thefinasteride arm.30

One of the concerns with finasteride is the lower-ing of serum PSA levels. Patients should have a 50%reduction of the PSA level over a 6-month periodwhile they are on finasteride. If this reduction doesnot occur, a urologic consultation is indicated to ruleout the possibility of occult prostate cancer. On theother hand, some feel that finasteride could actuallybe a chemopreventive agent for prostate cancer; anongoing NIH study, the Prostate Cancer PreventionTrial is evaluating this possibility.

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Table 3. Comparison of the Efficacy and Side Effects of Doxazosin and Terazosin

AUA = American Urologic Association.

Change Changein in FlowAUA Rate Hypotension

Agent Score (cc/s) Dizziness (%) Headache (%) Asthenia (%) (Postural) (%) Tachycardia (%) Impotence (%)

Doxazosin -5.7 +2.9 15.6 9.8 8.0 2.0 1.2 0.9

Terazosin -7.6 +2.3 9.1 7.0 7.4 3.9 1.1 1.6


Comparison of α-blocker therapy with 5α-reduc-tase inhibitor therapy was first reported in a 12-month VA cooperative trial. Terazosin was com-pared with placebo, finasteride, or a combination offinasteride and terazosin in 1200 men.31 In thisstudy, finasteride was found to be no more effectivethan placebo. On further analysis, patients in thisstudy had smaller prostates on average than thosedescribed in other published studies. A meta-analy-sis of finasteride studies found a statistical improve-ment over placebo in symptom scores and flow ratesif the prostate volume was 40 g or greater at base-line.32 The MTOPS trial has enrolled more than 3200patients in the same 4 treatment arms as the VAstudy, beginning in December 1995. This study iscontrolling for prostatesize and may give addi-tional evidence of effica-cy and duration ofresponse over a 5-yearperiod. Slight improve-ment in symptoms andflow rates was seen in thecombination arm of theVA study, and this findingalso will be addressedwith the MTOPS trial.

Summary of MedicalTherapy. The use of α-blockers is usually rec-ommended as first-linetherapy for mild to mod-erate BPH symptomsbecause of the relativeefficacy, rapid onset ofaction, and low cost. Thevalue of a more selectiveα-blocker such as tamsu-losin must be weighedagainst cost and efficacy.The Proscar Long-termEfficacy and Safety Studytrial has demonstratedthe long-term value offinasteride to decreasethe need for surgery andprogression to urinaryretention. The effect ofα-blockers on the naturalhistory of BPH will not beknown until the comple-tion of the MTOPS trial.The value of combination

therapy (α-blockers and 5α-reductase inhibitors)also must be determined. Research to predict whichpatients are destined to fail to respond to medicaltherapy may result in cost savings, because moreappropriate therapies can be instituted earlier in thecourse of this disease process.

Surgical Therapy for BPHTransurethral surgery of the prostate is still con-

sidered the gold standard by which other treatmentmodalities are measured. Patients with very largeprostate glands (greater than 80-100 g) may be bestserved by open prostatectomy. Over the last fewyears, newer procedures that are less invasive andcause less morbidity have been developed (Table 6).


Table 4. Efficacy and Side Effects of Tamsulosin

AUA = American Urologic Association.Adapted from reference 27.

Change Change in in Flow

AUA Rate Dosage Score (cc/s) Asthenia (%) Dizziness (%) Rhinitis (%) Ejaculation (%)

0.4 mg -8.3 +1.75 5 10 12 6

0.8 mg -9.6 +1.78 5 11 15 18

Table 5. Efficacy and Side Effects of Finasteride

AUA = American Urologic Association.

ChangeDecrease in Changein Prostate Peak in Decreased Decreased Impotence

Time of Volume Urinary Flow AUA Libido Ejaculate RateEvaluation (%) (cc/s) Score (%) Volume (%)

12 m -19.2 +1.6 -2.6 3.3 2.6 3.7

36 m -26.6 +2.4 -3.6 1.6 0.9 2.1

48 m -23.8 +2.2 -3.6 1.5 0.3 2.1


The use of these newer procedures results in out-comes somewhere between those of traditional sur-gical and medical therapy. However, absolute andrelative indications for surgery remain (Table 7).

The more traditional therapies of open prostatec-tomy and TURP are the most effective treatments,yet cause the most morbidity. These operations arethe best studied and have the greatest proven uro-dynamic improvements. TURP is associated with an18% perioperative morbidity rate. These complica-tions include transfusions in 5% to 15%, electrolytedisturbances in 2%, and stress incontinence in 1.5%

to 2.0%, as seen in combined series of Medicarepatients in the late 1980s.1 The impotence ratereported by the Agency for Health Care Policy andResearch is 13%, but newer randomized trials withspecific investigations of erectile function show a 1%to 8% incidence.33 In general, TURP and openprostatectomy are still the procedures that createthe greatest improvement in objective and subjec-tive improvement and currently have acceptablemorbidity.

Transurethral incision of the prostate is a proce-dure that was popularized by Orandi in the 1970s asa less invasive alternative to TURP.34 Rather thanresecting the tissue, one or two incisions are madein the prostate from the bladder neck to just proxi-mal to the external sphincter, allowing the prostateto spring open. In properly selected patients(patients with smaller prostates with less than 20 gof adenoma), the results of transurethral incision ofthe prostate are similar to those of TURP with lessmorbidity. Transurethral incision of the prostate isone of the most underused but effective treatmentsfor BPH.

Originally described by Bush in the 1960s todecrease the morbidity associated with TURP,transurethral electrovaporization of the prostatewas not widely accepted until recently.35 Ratherthan being resected, the tissue is vaporized with abroad-surfaced electrode that has a high cutting cur-rent. Early results are similar to those with TURP forsmaller glands, with less need for transfusion. Thecombination of TURP and transurethral electrova-porization of the prostate is being studied and usedfor patients with larger prostate glands.

Laser prostatectomy was introduced in the early1990s, but its use has diminished recently with theemergence of competing technologies. Types of laserprostatectomy include visual laser ablation of theprostate, contact laser ablation of the prostate, andinterstitial laser therapy. Visual laser ablation of theprostate uses a specialized laser fiber that reflectsthe laser energy at 90-degree angles; it is appliedunder direct vision through a cystoscope, causingcoagulative necrosis of the prostate tissue overtime.36 The most extensively studied laser energy isNd:YAG (neodymium: yttrium-aluminum-garnet),which in controlled studies showed efficacy compa-rable to that of TURP (Table 8). The biggest draw-back of visual laser ablation of the prostate is pro-longed postoperative catheterization and a delay ofweeks to months before recognizing an improve-ment in symptoms. Contact laser ablation of theprostate uses a quartz or silicon tip heated by laser

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Table 6. Surgical and Minimally Invasive Therapiesfor Benign Prostatic Hyperplasia

Minimally Invasive Devices■ Transurethral Microwave Thermotherapy■ Transurethral Balloon Dilation■ Transurethral Needle Ablation■ Prostatic Stents■ Intersitial Laser Coagulation

Surgical Therapies■ Transurethral Resection of the Prostate

• By electrocautery• By laser coagulation

■ Transurethral Vaporization of the Prostate• By electrocautery• By laser

■ Transurethral Incision of the Prostate■ Open Surgical Enucleation

Table 7. Indications for Surgery for Benign ProstaticHyperplasia

Absolute■ Urinary retention unresponsive to medical therapy■ Detrusor decompensation

Relative■ Repeat episodes of hematuria■ Repeat or persistent urinary tract infection■ Severe symptoms■ Bladder stones


energy to vaporize prostatic tissue. Vaporization ofthe prostatic tissue is a slow process, and contactlaser ablation of the prostate has proven best suitedfor small prostates. It has been used sparingly.Interstitial laser therapy could be included in thediscussion of minimally invasive techniques, but willbe mentioned here. Laser energy can be applieddirectly into the substance of the prostate with aspecially designed fiber that emits laser energy at360 degrees. This fiber is placed into the adenomatransurethrally with a cystoscope. Because the fiberis placed into the adenoma, damage to the urethrallining and the subsequent irritative symptoms areavoided. Catheterization for 5 or more days is stillrequired because of prostatic swelling. This tech-nique can be performed with local or regional anes-thesia and has favorable short-term results.37

Summary of Surgical Procedures. Only TURP,transurethral incision of the prostate, and openprostatectomy have long-term results. TURPremains the gold standard with which to compareother treatment modalities. Use of visual laser abla-tion of the prostate and contact laser ablation of theprostate has declined with the evolution oftransurethral electrovaporization of the prostateand resurgence of transurethral incision of theprostate. Interstitial laser therapy is a minimallyinvasive technique performed under local anesthe-sia with good short-term results, but it requires fur-ther evaluation before its role in the treatment ofBPH is defined.

Minimally Invasive Therapies for BPHIn an attempt to achieve less morbidity than that

associated with TURP but to achieve better out-comes than those associated with medical therapy,minimally invasive techniques have been devel-oped. These include transurethral microwave ther-motherapy, transurethral balloon dilation,transurethral needle ablation, and prostatic stents.

Transurethral balloon dilation is a procedurewhereby a deflated balloon is placed through theurethra into the prostate gland under direct visionor ultrasound guidance. The balloon is then inflatedto stretch the prostatic urethra until the prostaticcapsule is fractured. Results suggest that more than50% of patients have recurrence of original symp-toms and durable results were few.38 Few urologistscurrently use this technique because of these sub-optimal results.

In transurethral microwave thermotherapy,microwave heating of the prostate is performedthrough a transurethral microwave probe with a

rectal temperature-sensing probe. The urethralprobe also contains a cooling mechanism so the ure-thral lining is not damaged. The thermotherapycauses coagulative necrosis over time with an aver-age 12% to 18% loss of prostate volume, which cor-responds with symptomatic and objective improve-ment. Recent studies have shown the amount ofenergy delivered correlates with shrinkage andsymptom improvement.39 The addition of an α-blocker perioperatively decreases the number ofpatients requiring catheterization past 1 week from12% to 2%.40 No difference was noted in symptomscores at 12 weeks in these studies. The α-blockerwas stopped at 6 weeks. A comparison oftransurethral microwave thermotherapy and α-blocker therapy showed transurethral microwavethermotherapy to be superior with respect to symp-tomatic and objective improvement at 6 months(Table 9).41 Refine-ments in the physics and amountof thermal energy to be delivered are currently beinginvestigated.

Transurethral needle ablation uses radiofrequen-cy as a source of energy to heat the prostatic tissuewith subsequent coagulative necrosis. A specialdevice with 2 radio antenna are placed into the pro-static adenoma at various locations under cysto-scopic guidance to provide the thermal energy forcoagulative necrosis to occur. Treatment effect isdelayed because of swelling, and the best results arewith smaller prostates. A recent trial comparingtransurethral needle ablation with TURP shows sim-


Table 8. VLAP vs TURP in a Double-Blind,Randomized Trial

AUA = American Urologic Association; VLAP = visual laser assist-ed ablation of the prostate; TURP = transurethral surgery of theprostate.Adapted from reference 33.

Change in Change inAUA Score Mean Flow Rate

Treatment at 6 Months at 6 Months (mL/s)

VLAP (n = 19) -11.4 +2.9

TURP (n =23) -8.3 +9.9


. . . CME . . .

ilar improvement in symptoms but lesser improve-ments in urodynamic parameters with transurethralneedle ablation at 6 months.42 Additional studieshave demonstrated destruction of adrenergicnerves, which may be contributory to symptomimprovement with this and other forms of ther-motherapy.43 The improvement realized short termis durable to at least 3 years (Table 10).44

A therapy recently approved by the FDA that isappropriate for select patients with BPH is the pro-static stent.45 These stents are expandable titaniummetal mesh cylindrical tubes, which are placed intothe prostatic urethra. Once these stents are in place,the prostatic mucosa overgrows the metal stentmaterial, protecting the stent from exposure tourine. These stents can be placed under local anes-thesia and could obviate the need for chronic Foleyor suprapubic catheterization. The greatest utilityfor these stents may be in patients with urinaryretention who are unable to tolerate other therapies.

Summary of Minimally Invasive Therapies.With refinements in treatment delivery and a betterunderstanding of their effects, minimally invasivetherapies are becoming an increasingly used modal-ity in the treatment of BPH. The ultimate role ofthese therapies will be defined by longer termresults and clinical trials comparing them with exist-ing treatment modalities.

. . . CONCLUSIONS . . .

BPH therapies are multiple and diverse. Manynewer, yet unproved, techniques to treat BPH arenow being proposed. Intense research will lead to aclearer understanding of the molecular biologicevents leading to the development of BPH. Althoughthe exact etiology is unknown, BPH growth is underandrogenic and neurogenic control. The 5α-reduc-tase inhibitor finasteride and the α-adrenergicblockers terazosin, doxazosin, and tamsulosin areFDA-approved medical treatments. Alternative med-ical treatments (eg, saw palmetto) are also widelyused. The gold standard of surgical therapy remainsTURP or open prostatectomy, but less invasiveoptions including transurethral incision of theprostate and coagulation procedures are available.Minimally invasive treatments based on laserand radio-frequency administration of heat toshrink the gland and the prostatic stent are alsoavailable. The next decade will see continuedimprovements in our understanding of BPH, andoutcome research will further clarify the most effec-tive therapies for this condition.

AcknowledgementsThe authors thank Joanne De Ausen, Renee

Mooneyhan, and Michelle Hohensee from theCenter for Prostate Disease Research for making thefigure and typing the manuscript.

Table 10. Summary of World Literature forTransurethral Needle Ablation

AUA = American Urologic AssociationAdapted from reference 44.

Transurethral Change in Change in MaximumNeedle Ablation AUA Score Flow Rate (mL/s)

At 12 mo (n = 546) -13.1 +6.0

At 24 mo (n = 176) -14.3 +6.3

At 36 mo (n = 88) -14.7 +7.0

Table 9. Terazosin vs Transurethral MicrowaveThermotherapy at 2 Weeks and 6 Months

AUA = American Urologic Association; TUMT = transurethralmicrowave theramotherapy.Adapted from reference 41.

Mean MaximumTreatment AUA Score Flow Rate (mL/s)

Terazosin2 wk 14.0 10.9

6 mo 11.0 11.6

TUMT2 wk 15.8 7.7

6 mo 6.8 13.9



. . . REFERENCES . . .

1. Holtgrewe HL, Mebust WK, Dowd JB. Transurethralprostatectomy: Practice aspects of the dominant operation inAmerican urology. J Urol 1989;141:248-253.2. Holtgrewe HL, Bay-Nielsen H, Carlsson P. The economicsof the management of lower urinary tract symptoms andbenign prostatic hyperplasia. In: Proceedings of the 4thInternational Consultation on Benign Prostatic Hyperplasia(BPH).1997:4;63-80. 3. Barry MJ. The epidemiology and natural history of benignprostatic hyperplasia. Curr Opin Urol 1994;4:3-6.4. Benign Prostatic Hyperplasia Guideline Panel. ClinicalPractice Guideline: Benign Prostatic Hyperplasia. Rockville,MD: US Dept of Health and Human Services, Agency forHealth Care Policy and Research; 1994. AHCPR publicationno. 94-05825. Diokno AC, Brock BM, Brown BM. Prevalence of urinaryincontinence and other urological symptoms in the noninsti-tutionalized elderly. J Urol 1986;136:1022-1025.6. Lepor H, Machi G. Comparison of AUA symptom index inunselected males and females between fifty-five and seventy-nine years of age. Urology 1993;42:36-40.7. Chai TC, Belville WD, Mcguire EJ. Specificity of theAmerican Urological Association voiding symptom index:Comparison of unselected and selected samples of bothsexes. J Urol 1993;150:1710-1713.8. Thiypen AE, Silver RI, Guileyardo JM. Tissue distribution ofsteroid 5 alpha-reductase isozyme expression. J Clin Invest1993;92:903-910.9. Bartsch G, Muller HR, Oberholzer M. Electron microscop-ic stereological analysis of the human prostate and of benignprostatic hyperplasia. J Urol 1979;122:487-491.10. Lepor H, Tang R, Meretyk S. The alpha-adrenoreceptorsubtype mediating tension of the human prostate smoothmuscle. Prostate 1993;22:640-642.11. Barry MJ, Fowler FJ, O’Leary MP. Measuring disease-spe-cific health status in men with benign prostatic hyperplasia.Med Care 1995;33:145-155.12. Osterling JE. Prostate-specific antigen: Improving its abilityto diagnose early prostate cancer. JAMA 1992;267:2236-2238.13. Moul JW. Epidemiology and screening for prostate cancer.Am J Manag Care 1997;8:1200-1205. 14. Jensen KM, Jorgensen JB, Mogensen P. Urodynamics inprostatism, I: Prognostic value of uroflowmetry. Scand J UrolNephrol 1988;22:109-117.15. Witjes WP, Rosier FW, Wildt MJ. Urodynamic and clini-cal effects of terazosin therapy in patients with symptomaticbenign prostatic hyperplasia. J Urol 1996;155:1317-1323.16. Chancellor MB, Blaivas JG, Kaplan SA. Bladder outletobstruction versus impaired detrusor contractility: The role ofuroflow. J Urol 1991;145:810-812.17. Wasson JH, Reda DJ, Bruskewitz RC. A comparison oftransurethral surgery with watchful waiting for moderatesymptoms of benign prostatic hyperplasia. The VeteransAffairs Cooperative Study Group on Transurethral Resection ofthe Prostate. N Engl J Med 1995;322:75-79.

18. Buck AC. Phytotherapy for the prostate. Br J Urol1996;78:325-336.19. Carraro JC, Raynaund JB, Koch G. Comparison of phy-totherapy (Permixon) with finasteride in the treatment ofbenign prostatic hyperplasia: A randomized internationalstudy of 1098 patients. Prostate 1996;29:231-240.20. Lepor H, Williford WO, Barry MJ. The impact of medicaltherapy on bother due to symptoms, quality of life, and globaloutcome and factors predicting response. Veterans AffairsCooperative Studies Benign Prostatic Hyperplasia Study Group. JUrol 1998;160:1358-1367.21. Lepor H. Prostate selectivity of alpha blockers: From receptorbiology to clinical medicine. Eur Urol 1996;29(suppl):S12-S16.22. Fawzy A, Braun K, Lewis GP. Doxazosin in the treatmentof benign prostatic hyperplasia in normotensive patients: Amulticenter study. J Urol 1995;154:105-109.23. Roehrborn CG, Oesterling JE, Lloyd K. HytrinCommunity Assessment Trial. Evaluation of the clinical effec-tiveness of terazosin vs placebo in the treatment of patientswith symptomatic benign prostatic hyperplasia. J Urol1995;153:272A.24. Lepor H. Long-term efficacy and safety of terazosin inpatients with benign prostatic hyperplasia. Urology1995;45:406-413.25. McDiarmid SA, Mcguirt R, Emery RT. A randomized dou-ble-blind study assessing the optimal dosage of doxazosin intreating patients with benign prostatic hyperplasia. J Urol1998;159(suppl):S330. 26. Kaplan SA, Meade D, Alisera P. Doxazosin in physiologi-cally and pharmacologically normotensive men with benignprostatic hyperplasia. Urology 1995;46:512-517.27. Lepor H. Alpha-adrenergic blockers: A promising medicalalternative to prostatectomy? Rev Urol 1999;1:45-54. 28. Gormley GJ, Stoner E, Bruskewitz RC. The effect of finas-teride in men with benign prostatic hyperplasia. N Engl J Med1992;327:1185-1191.29. Moore E, Bracken B, Bremner W. Proscar: Five yearexperience. Eur Urol 1995;28:304-309.30. McConnell JD, Bruskewitz R, Walsh P. The effect of finas-teride on the risk of acute urinary retention and the need forsurgical treatment among men with benign prostatic hyperpla-sia. Finasteride Long-Term efficacy and Safety Study group. NEngl J Med 1998;338:557-563.31. Lepor H, Williford WO, Barry MJ. The efficacy of tera-zosin, finasteride, or both in benign prostatic hyperplasia. NEngl J Med 1996;335:533-539.32. Boyle P, Gould AL, Roehrborn CG. Prostate volume pre-dicts outcome of treatment of benign prostatic hyperplasiawith finasteride: Meta-analysis of randomized clinical trials.Urology 1996;48:398-405.33. Kabalin JN. Invasive therapies for benign prostatic hyper-plasia, part I. 1997 Monographs in Urology 1997;18:19-4734. Orandi A. Transurethral incision of the prostate comparedwith transurethral resection of the prostate in 132 matchingcases. J Urol 1987;138:810-815.35. Gallucci M. Transurethral electrovaporization of theprostate (TVP) vs TURP. A multicentric randomized compara-tive study. Eur Urol 1996;30:116-119.


. . . CME . . .

36. Cowles RS, Kabalin JN, Childs S. A prospective random-ized comparison of transurethral resection to visual laser abla-tion of the prostate for treatment of benign prostatic hyperpla-sia. Urology 1995;46:155-160.37. Whitfield HN. Interstitial laser (Indigo) in BPH: A random-ized controlled, prospective study. J Urol 1996;155:318A.38. Chiou RK, Lynch B. Randomized comparison of balloondilation and transurethral incision for symptomatic benignprostatic hyperplasia: Long-term follow-up. J Urol1993;149:464A.39. D’Ancona B, Van der Bij AK, Francisca EA. High energyTUMT in patients categorized according to the AmericanSociety of Anesthesiologists operative risk classification.Urology 1999;53:322-328.40. Djavan B, Shariat S, Fakhari M. Neoadjuvant and adju-vant alpha-blockade improves early results of high-energyTUMT for lower urinary tract symptoms of BPH. Urology1999;53:251-259.

41. Shariat S, Ghadwidel K, Marberger M. High-energytransurethral microwave thermotherapy (TUMT) versus alpha-blockade treatment for benign prostatic hyperplasia (BPH): Aprospective randomized clinical trial. J Urol 1999;161:139-143.42. Roehrborn CG, Burkhard FC, Brushewitz RC. The effectsof TUNA and TURP on pressure-flow urodynamic parameters:analysis of the US randomized study. J Urol 1999;162:92-97.43. Williams JC. Interstitial laser coagulation of the prostate:Effects on intraprostatic nerve fibers. Tech Urol 1996;2(3):130-135.44. Issa MM, Myrick SE, Symbas NP. The TUNA procedurefor BPH: Basic procedure and clinical results. Infect Urol1998;11:148-155. 45. Kletscher BA, Oesterling JE. Prostatic stents. Current per-spectives for the management of benign prostatic hyperplasia.Urol Clin North Am 1995;22:423-430.


CME TEST FORMAJMC Test #059907

Benign Prostatic Hyperplasia: New Concepts for theMillennium

(Test valid through July 31, 2000.No credit will be given after this date.)

CME QUESTIONS: TEST #059907

Please circle your answers:1. a b c d

2. a b c d

3. a b c d e

4. a b c d

5. a b c d e

6. a b c

7. a b c d

8. a b c d

9. a b c d

10. a b c d

(PLEASE PRINT CLEARLY)

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Please enclose a check for $10, payable toAmerican Medical Publishing, and mail with this form to:

The AJMC CME TestAmerican Medical Publishing

Suite 102241 Forsgate Drive

Jamesburg, NJ 08831

1. Regarding benign prostatic hyperplasia (BPH), whichof the following is true?

a) almost 50% of patients over age 80 years willhave histologic evidence of BPH

b) all patients with BPH have urinary symptomsc) the amount of enlargement correlates with symp-

tom severityd) “lower urinary tract symptoms” is now the term

preferred rather than BPH to describe changesin the lower urinary tract in the aging male

2. The American Urologic Association (AUA) symptomindex:

a) is only appropriate in white malesb) is validated to determine symptom severity and

response to therapyc) determines the best treatment for an individual

patientd) determines health-seeking behavior

3. All of the following are recommended in the patientwith BPH symptoms except:

a) historyb) digital rectal examc) serum creatinine leveld) prostate-specific antigen (PSA) teste) AUA symptom score

4. The most appropriate treatment of patients withmild BPH symptoms (AUA score of <8) is:

a) watchful waitingb) medical therapyc) minimally invasive therapyd) surgical therapy

5. Which of the following statements are true of med-ical therapy for BPH?

a) α-Blockers relax the dynamic component ofobstruction

b) 5α-Reductase inhibitors decrease the static com-ponent of obstruction

c) alternative medicines have no proven efficacyd) Highly selective α c-receptor antagonists have

fewer side effects than nonselective α1-receptorantagonists.

e) nonselective α1-blockers are normally taken atbedtime to avoid side effects

6. The Veterans Administration Trial comparing tera-zosin (Hytrin) with finasteride (Proscar) reached all ofthe following conclusions except:

a) terazosin therapy resulted in greater symptomimprovement than finasteride therapy

b) finasteride was no more effective than placebo inthis trial

c) the results were skewed because patients in thisstudy on average had larger prostates

. . .CME QUIZ . . .

Johns Hopkins University School of Medicine is accred-ited by the Accreditation Council for Continuing MedicalEducation (ACCME) to sponsor continuing medical educa-tion for physicians. Johns Hopkins University School ofMedicine designates this continuing medical educationactivity for 1.0 credit hour in Category 1 of the Physician’sRecognition Award of the American Medical Association.This CME activity was planned and produced in accordancewith the ACCME Essentials and Standards for CommercialSupport.

InstructionsAfter reading the article “Benign Prostatic Hyperplasia:

New Concepts for the Millenium,” select the best answer toeach of the following questions. In order to receive 1 CMEcredit, at least 7 of the 10 answers must be correct.Estimated time for this activity is 1 hour. CME credits aredistributed on a yearly basis.

(CME QUESTIONS CONTINUED FROM PREVIOUS PAGE)


. . .CME QUIZ . . .

7. Which of the following statements are true regard-ing the rationale for using more selective α1-receptorantagonists?

a) there is less orthostatic hypotensionb) there is less astheniac) there is no need for titration to the maximal dosed) there is decreased retrograde ejaculation

8. Which of the following were findings in The ProscarLong-Term Efficacy and Safety Trial?

a) reduction in need for surgery with Proscar versuswatchful waiting

b) reduction in the incidence of urinary retentionwith Proscar versus watchful waiting

c) confirmed 50% reduction of serum PSA level at 6months

d) a decreased chance of prostate cancer

9. Absolute and relative indications for surgery for BPHinclude:

a) hematuriab) bladder stonesc) repeat or persistent urinary tract infectiond) urinary incontinence

10. Comparing open prostatectomy with transurethralsurgery of the prostate (TURP) with transurethral incisionof the prostate (TUIP), efficacy can be described as:

a) open prostatectomy > TURP > TUIPb) open prostatectomy = TURP > TUIPc) open prostatectomy = TURP = TUIPd) open prostatectomy > TURP = TUIP

11. Which of the following use thermotherapy toachieve improvements in BPH symptoms?

a) transurethral microwave therapyb) transurethral needle ablationc) transurethral balloon dilationd) prostatic stents

12. Possible reasons for choosing nonselectiveα1-blockers rather than more selective agents include:

a) costb) beneficial effects on nonprostate smooth muscle

sites to include sensory afferents and centralnervous system pathways

c) lack of correlation between improvement in flowrates and symptom changes

d) ability of these agents to help in control of hyper-tension

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Benign Prostatic Hyperplasia: New Concepts for the Millennium€¦ · Burkhardt Zorn, MD; John J. Bauer, MD; and Judd W. Moul, MD. . .CONTINUING MEDICAL EDUCATION . . . VOL. 5, NO