Benign Prostatic Hyperplasia in Primary Care: What You Need to Know Arthur L. Burnett*,† and Alan J. Wein‡ From the Hopkins University School of Medicine, Baltimore, Maryland, and University of Pennsylvania Health System (AJW), Philadelphia, Pennsylvania

Purpose: We reviewed recent literature and treatment guidelines regarding the prevalence, pathophysiology, and management of BPO related to BPH; and management of lower urinary tract symptoms secondary to BPH. Materials and Methods: Published literature and current treatment concepts were reviewed regarding the diagnosis and treatment options for BPO. Results: BPH is a histological diagnosis that can contribute to medical problems, including enlargement of the prostate and BPO. These conditions should be treated only if the symptoms are troublesome, there is considerable risk of progression, and/or cancer is suspected. Very effective medical and surgical options are available to treat BPO and improve patient quality of life. Conclusions: BPO is highly treatable, but should be managed in close collaboration with the patient. Pharmacological agents and minimally invasive procedures, when appropriate, are generally preferred to more invasive surgery. Patients with mild or moderate symptoms usually can be treated by a primary care physician; more complicated cases should be referred to a urologist for evaluation and management. Key Words: prostate, benign prostatic hyperplasia, bladder neck obstruction, urination disorders

without the others; however, BOO is uncommonly seen without BPE and BPH. Entities that can cause this include urethral structure, bladder neck contracture, bladder neck dysfunction, and striated sphincter dyssynergia. LUTS typically drive clinical management, and LUTS that may be related to BPO include urgency, frequency, nocturia, and possibly urge UI during the filling/storage stage of micturition. Emptying symptoms associated with BPO can include straining to void, weak urinary stream, feeling of incomplete emptying, and a perceived need for repeat voiding. With any of these symptoms, the patient should be considered for pharmacological or surgical treatment only if he has significant, troublesome LUTS associated with BPO, or if the situation has created a risk for lower or upper urinary tract dysfunction. Precise estimates of complications from BPO, such as damage of the lower and upper urinary tract, are unclear. However, it has been reported that a mean rate of 13.6% of patients presenting for surgical treatment of BPO have upper tract deterioration and azotemia.4 Potential complications of BPO can include urinary retention, renal impairment, urinary tract infection, gross hematuria, bladder stones, bladder decompensation, and overflow UI as a result of retention.5 Most of these are relatively uncommon. Detrusor overactivity (involuntary bladder contractions) occurs in approximately 50% of men with documented BPO. The pathophysiology of this association is uncertain, but the overactivity disappears in approximately 70% after outlet reduction.6 There are 2 mechanisms by which the prostate can cause bladder obstruction. One is by the narrowing of the urethral lumen due to the BPE associated tissue bulk. This is de-

PATHOPHYSIOLOGY, INCIDENCE AND DEMOGRAPHICS OF BPH here is considerable confusion as to the precise role of BPH as it relates to the LUT and the micturition process. It is known that BPH is extremely common in older men, but what many do not understand is that BPH is not a medical problem itself. It is a histological diagnosis, which can be the driver of medical problems related to micturition. The incidence of BPH increases greatly with age; it is clinically evident in 50% of the male population by age 50 years, and in 80% by age 80 years.1 The excessive cell proliferation associated with BPH causes the condition known as BPE, which is not necessarily problematic but may cause narrowing of the urethral lumen.2 BPH also can lead to BOO. BOO in the older male is almost always secondary to BPH. Moderate to severe LUTS are described to occur in 18%, 29%, 40%, and 56% of men in their 40s, 50s, 60s, and 70s, respectively.1 The term BPO often is used interchangeably with BOO; however, it actually refers to BOO that occurs concurrently with BPE.3 The Appendix lists these abbreviations for quick reference. While there is significant overlap in the prevalence of LUTS, BPH, and BOO, any of these conditions can exist

T

* Correspondence: 600 North Wolfe St., Marburg 407, Baltimore, Maryland 21287 (telephone: 410-614-3986; FAX: 410-614-3695; email: [email protected]). † Financial interest and/or other relationship with Pfizer, Guilford Pharmaceuticals, Bayer/GlaxoSmithKline and Lilly/ICOS. ‡ Financial interest and/or other relationship with ONO Pharmaceuticals, Pharmacia, Yamanouchi, Indevus, Theravance, Bard, Lilly, Pfizer, Novartis, BioXell and GlaxoSmithKline.

0022-5347/06/1753-0019/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION

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Vol. 175, S19-S24, March 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(05)00310-1

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FIG. 1. I-PSS score sheet

scribed as the static component of bladder obstruction, because it remains constant except for variation related to size. The dynamic component consists of prostatic smooth muscle tone, which is mediated by the noradrenergic effect on ␣-adrenergic receptors.7 Smooth muscle tone is found in the prostate stroma (which contains smooth muscle and connective tissue), prostatic capsule, and urethra; it is mediated primarily by ␣1 receptors. Prostatic smooth muscle tone can be increased by such agents as systemic decongestants containing an ␣-adrenergic agonist; increased tone may precipitate increased symptoms of BPO, urinary retention, or decreased flow rate. Smooth muscle tone can be decreased with ␣-adrenergic antagonists (also known as ␣-blockers); this is the basis of 1 type of pharmacological treatment of LUTS secondary to BOO. Commonly prescribed agents include terazosin, doxazosin, tamsulosin, and alfuzosin. There are 3 ␣-adrenergic receptor subtypes identified, but they also exist outside the LUT, which explains the range of side effects commonly seen with ␣-blockers.

tively diagnose BPO; however, it provides a baseline value for a parameter that can be rechecked during a course of pharmacological management, watchful waiting, or following surgery. An increase in the I-PSS from year to year indicates a condition that is worsening; a decrease indicates the patient is responding to treatment. The serum PSA test is a commonly performed laboratory test that has relevance for patients with BPH. As indicated in the AUA guidelines, “serum PSA has been demonstrated to have an excellent correlation with prostate size and predict the natural history of the condition. Men with higher PSA levels are at greater risk to have future prostate growth, develop deterioration of LUTS and urinary flow rate, experience acute urinary retention, and require BPHrelated surgery.”10 The PSA test also has ramifications with regard to risk for prostate cancer, which may impact on BPH treatment plans. In patients with a life expectancy of 10 years or less, it may not be appropriate to order a PSA test, since a diagnosis of prostate cancer would be unlikely to alter management in that person. The exception would be a patient in whom surgery for BOO is indicated, or if the prostate is greatly enlarged. For patients who indicate their symptoms to be especially troublesome, or in whom pharmacological management has produced suboptimal results, additional studies may be warranted, including uroflowmetry, PVR, pressure flow or videourodynamic studies, and US of the prostate. US also can be easily used to measure PVR. Urinary flow is measured by having the patient void into a flowmeter, which measures the change in the weight of the urine during the course of the void. A normal urinary flow for a healthy young man would peak at approximately 25 ml per second (fig. 2), whereas a patient affected by BPO might have a weaker but steady flow due to compression of the urethra. Clinicians would expect to see this latter condition in association with BPO, although it also may be due to decreased bladder contractility. If the uroflowmetry results for a patient with an otherwise healthy bladder show a peak urinary flow of approximately 12 ml per second or less, this generally is indicative of BPO.11 These patients should be treated according to how much their symptoms bother them, as illustrated in a suggested treatment algorithm (fig. 3). Mild and moderate, uncomplicated cases of BPO certainly can be well managed by a knowledgeable PCP, particularly if a comfortable physician-

DIAGNOSIS AND TREATMENT In an older male patient presenting with LUTS, with or without some degree of nonsuspicious BPE, BOO due to BPH should be suspected. The initial evaluation should include a thorough patient history, general physical examination, I-PSS, pelvic and DRE, urinalysis, and possibly a PSA test. A bladder diary is particularly useful in patients who experience nocturia.8 The I-PSS is a set of 7 questions regarding incomplete emptying, micturition frequency, intermittence, urgency episodes, weak urinary stream, straining at urination, and nocturia (fig. 1).9 An eighth question termed the “bother score” pertains to the patient perceived QOL related to LUTS. Total score for all 7 questions yields a classification ranging from “mildly symptomatic” (score 0 to 7) to “severely symptomatic” (score 20 to 35). The I-PSS does not defini-

FIG. 2. Effects of BPO on urinary flow (Q). ml/s, ml per second

BENIGN PROSTATIC HYPERPLASIA IN PRIMARY CARE

FIG. 3. Suggested PCP guide to BPO management. WW, watchful waiting.

patient relationship already exists. Referral to a urologist should be considered for LUTS associated with a suspicious DRE, hematuria, abnormal PSA, pelvic or rectal pain, infection, palpable bladder or large residual urine volume, bladder stones, renal failure, or neurological disease. Nonresponse to conservative treatment also warrants urological consultation, as does a pending significant change in treatment regimen. Above all, treatment should be goal directed from the patient perspective. His level of QOL impairment and his interest in pursuing a certain course of therapy should drive treatment decisions. Certainly, though, decisions on treatment may override the patient perspective in the face of clinical circumstances, such as urinary retention and renal failure. It is important to thoroughly discuss findings, treatment options, and potential outcomes/consequences to enable the patient to make an informed decision. It is equally important to have adequate followup to monitor for progression of disease in patients choosing watchful waiting or noninvasive therapy. Treatment options. Watchful waiting, pharmacological therapy, and surgery are the 3 courses of action available to patients with BPH. The simplest and least invasive option is watchful waiting, which could more accurately be termed active surveillance, as it involves regular monitoring for signs of disease progression that may be indicators for treatment.4 Watchful waiting is certainly appropriate for patients with mild LUTS and minimal BPE.12 Annual followup should include evaluation of symptoms, DRE, and a PSA if one was deemed advisable initially and life expectancy is still 10 years or greater. Urodynamics are not considered necessary for routine monitoring; however, uroflow and PVR assessments often are instructive. In general, patients at higher risk for future complications are those with PSA 1.5 ng/ml or greater, or increasing PSA levels, moderate to severe LUTS, and prostate size 30 cc or greater. These are patients who should probably be treated. First line therapy in most cases would be pharmacological agents that either decrease prostate smooth muscle tone or shrink the prostate. The agents can be combined in some cases. (Note that if the condition appears advanced and poses an imminent danger, invasive therapy may be appropriate as the first step.) Medical therapy is a long-term

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commitment for the patient, and surveys by pharmaceutical companies show that 20% to 40% of patients discontinue therapy within 12 months; in fact, up to 50% of patients discontinue therapy within 3 years,13 often because of perceived lack of efficacy and/or side effects. The 2 commonly used classes of drugs are ␣-blockers and 5AR inhibitors. The ␣-blockers provide the most rapid relief by decreasing the smooth muscle tone in the stroma and prostate capsule, thereby, addressing the dynamic component of prostatic obstruction. They are considered the most effective monotherapy for treatment of BPO. The 5AR inhibitors decrease prostatic bulk, thereby addressing the static component. The 2 often are combined in patients with moderate to severe LUTS, progression of BPO, and/or marked prostate enlargement (discussed in greater depth below). According to the AUA BPH Guidelines Committee,10 similar efficacy has been demonstrated for the 4 ␣-blockers, terazosin, doxazosin, tamsulosin, and alfuzosin. They all demonstrate rapid but modest improvement in urinary flow, as well as a decrease in LUTS; however, their side effect profiles and uroselectivity differ.14 –17 Side effects of these drugs can include fatigue, orthostatic hypotension, edema, rhinitis, dyspnea, headache, angina, arrhythmia, and impaired sexual function. All except tamsulosin have shown to have modest effects on sexual function, although tamsulosin has shown a higher incidence of ejaculatory dysfunction. Tamsulosin and alfuzosin have demonstrated relative uroselectivity. The mechanism of the 5AR inhibitors (finasteride and dutasteride) is related to the role that androgens have in the pathogenesis of BPH. DHT, which is converted from testosterone by 5AR, has a 10-fold greater affinity for androgen receptors compared with testosterone. DHT promotes prostate cell proliferation, suppresses prostate cell apoptosis, and increases prostate angiogenesis. The 5AR inhibitors reduce prostatic bulk by preventing the conversion of testosterone to DHT, which should lead to a smaller prostate, less proliferation, and less vasculature.18,19 Both 5AR agents have shown similar efficacy and side effect profiles according to the AUA BPH Guidelines Committee.10 Side effects include impotence, decreased libido, decreased semen quantity during ejaculation, and decreased serum PSA.18,19 Gynecomastia is also a possible side effect, although it is relatively rare. (The PSA decrease with both drugs is typically about 50%.20) Therefore, doubling the PSA value will yield an accurate test result. If the PSA score is not significantly decreased after 6 months of treatment with a 5AR inhibitor, this is a possible indicator of progression or cancer. The PCP should consider referring the patient to a urologist for possible biopsy. As noted, ␣-blockers and 5AR inhibitors may be prescribed concomitantly in the absence of troubling side effects. Combination therapy affects both mechanisms involved in the pathogenesis of BPO, ostensibly offering better outcomes. In the landmark Medical Therapy of Prostatic Symptoms study,21 combination therapy with doxazosin and finasteride was found to be more effective in decreasing the risk of overall clinical progression of BPH than either drug alone (p ⬍0.001). In placebo treated patients, the incidence of clinical progression during a 4-year period was 17%, compared with 10% in both the doxazosin monotherapy group and the finasteride monotherapy group (p ⬍0.001 and 0.002, respectively). The incidence of progression was 5% in the

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FIG. 4. QOL improvement in patients with BOO treated with tolterodine plus tamsulosin. QoL9, BPH QOL 9. UROLIFE, Urolife.®

patients on combination therapy. The Medical Therapy of Prostatic Symptoms group recommended that combination therapy be considered for patients with prostate size greater than 30 to 40 cc or PSA levels greater than 1.4 ng/ml to prevent clinical progression of BPH. In patients with BPH/BPO who are also experiencing significant symptoms of OAB, it has been previously suggested that the addition of an antimuscarinic to BPH therapy would lead to urinary retention.22 It is now believed that this is not the case unless the patient is already very close to being in retention. Abrams et al found that 2 mg tolterodine twice daily did not significantly affect maximum flow rate, detrusor pressure, or PVR in men with urodynamically proven BOO, OAB, and a PVR less than 40% maximum cystometric capacity.23 (The study population was not receiving concomitant ␣-blockers or 5AR inhibitors.) Athanasopoulos et al evaluated the addition of 2 mg tolterodine twice daily to 0.4 mg tamsulosin daily and found the combination therapy to significantly improve QOL in patients with OAB and BOO, compared to patients treated with tamsulosin monotherapy (p ⫽ 0.0003, fig. 4).24 No patients experienced acute urinary retention, and tolterodine did not affect urine flow or PVR. Based on these studies, it is considered safe to offer antimuscarinic therapy to those patients on ␣-blockers with or without 5AR inhibitors who are still experiencing troublesome symptoms of OAB. It should be noted, however, that patients with significant PVR (eg more than 350 ml) should not receive this therapy because there is potential for increased risk of infection, further bladder decompensation, or renal insufficiency. Close monitoring of the patient is recommended. One other noninvasive therapy that should be mentioned is CAM. This has become very popular in recent years, with many patients ingesting herbal or dietary supplements in hopes of improving a medical condition. The most common one used by patients with BPO is probably saw palmetto. There are anecdotal claims regarding improvement in symptoms, and small clinical trials have demonstrated some efficacy in decreasing LUTS,25 while other researchers claim there is no evidence of efficacy.26 No data regarding longterm use are available. Although these CAM supplements do not appear to be contraindicated in patients with BPO, the

AUA BPH Guidelines Committee has taken the position that none of these CAM treatments have been proven effective in patients with BPO.10 While noninvasive therapy is recommended whenever possible in patients with BPO, certain symptoms or conditions necessitate surgery. Surgical intervention is recommended in patients in whom BPO causes renal insufficiency, urinary retention, recurrent UTI, bladder calculi, hydronephrosis, or high PVR. A minimally invasive procedure is appropriate for moderate (and occasionally severe) LUTS in patients in whom the prostate is still relatively small (with no significant middle lobe). The physician should be experienced with the technology, and patient expectations should be moderate. While the risk of postoperative difficulties is lower with this type of procedure than with more invasive therapy, the effects may not be as long lasting. Surgery provides immediate subjective and objective improvement but carries certain postoperative risks. Impotence occurs in approximately 4% to 10% of patients treated surgically for benign disease. UI is seen in approximately 0.5% to 1.5% of patients. The 5-year recurrence rate is 2% to 10%.27 Minimally invasive options include transurethral needle ablation, transurethral microwave thermotherapy, water induced thermotherapy, and intraprostatic stents. Ethanol injection is experimental but would qualify as being minimally invasive. Surgery includes TURP, transurethral laser prostatectomy (resection/ablation/vaporization), transurethral incision of the prostate, and open prostatectomy. TURP is considered the gold standard in management of BPO, with 70% to 85% of patients experiencing improvement of symptoms. It is considerably less invasive than open prostatectomy. Potential complications include infection, bleeding, reoperation, UI and erectile dysfunction (6% or less). Open prostatectomy often is recommended in cases in which the prostate mass is greater than 100 gm. However, the efficacy rate goes up and the recurrence rate goes down with the more invasive procedures. Postoperative discomfort is of greater duration, but so is the relief of symptoms after recovery. The incidence of recurrence is very low. Such large prostates can now be managed with transurethral laser resection as well.10 CONCLUSIONS In evaluating patients for LUTS symptoms associated with BPO, the general rule should be “minimal treatment for minimal bother.” If patient symptoms are not very troublesome, and if there is no clinical indication of progressive disease or another condition warranting immediate therapy, there is no reason to prescribe treatment. Treatment decisions should be made with patient participation and with patient goals in mind. Outcomes of medical and surgical procedures, and the occurrence of adverse events must also be considered when making a treatment decisions. Medical therapies are effective when compared to placebo control,10 but both minimally invasive and surgical procedures provide better overall outcomes. However, each has the potential for adverse events. With medical intervention, the most likely adverse events to be encountered include asthenia, dizziness, dysfunction of gastrointestinal systems, headache, respiratory congestion, and sexual dysfunction, depending on

BENIGN PROSTATIC HYPERPLASIA IN PRIMARY CARE what medication is used and when compared to placebo controls. Minimally invasive therapies typically show adverse events related to urinary retention, infection, and post-procedure irritation when variously compared to TURP, sham operated controls, or watchful waiting, although 1 or more minimally invasive therapies may affect sexual function. Surgical therapies have a higher incidence of adverse events related to acute urinary retention, stricture, significant hematuria, infection, post-procedure irritation, and sexual dysfunction.10 While surgery is likely to have longer lasting results than less invasive procedures, most patients will prefer the minimally invasive options. PCPs can treat most patients with mild to moderate symptoms that do not warrant an invasive procedure. Referral to (or consultation with) a urologist should be considered when patient LUTS are accompanied by an abnormal DRE, pain, infection, palpable bladder, and/or neurological disease, if the patient is nonresponsive to first line therapy, or if there is a suspicion of cancer. APPENDIX Terminology and Abbreviations for Prostatic Conditions BPH BPE BOO BPO LUTS

Benign prostatic hyperplasia Proliferation of cells; a histological finding; may not create medical problem Benign prostatic enlargement Frequent outcome of BPH; may cause narrowing of urethral lumen Bladder outlet obstruction Interferes with urinary flow; almost always preceded by BPH Benign prostatic obstruction BOO occurring concurrently with BPE Lower urinary tract symptoms

Abbreviations and Acronyms 5AR AUA BOO BPE BPH BPO CAM DHT DRE I-PSS LUT LUTS OAB PCP PSA PVR QOL TURP UI US

⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽

5␣-reductase American Urological Association bladder outlet obstruction benign prostatic enlargement benign prostatic hyperplasia benign prostatic obstruction complementary alternative medicine dihydrotestosterone digital rectal examination International Prostate Symptom Score lower urinary tract LUT symptoms overactive bladder primary care physician prostate specific antigen post-void residual urine volume quality of life transurethral resection of the prostate urinary incontinence ultrasonography

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2. Nordling, J., Artibani, W., Hald, T., Horn, T., Keuppens, F., Levin, R. et al: Pathophysiology of the urinary bladder in obstruction and aging. In: Benign Prostatic Hyperplasia. Edited by C. Chatelain, L. Denis, K. T. Foo, S. Khoury and J. McConnell. Plymouth, United Kingdom: Health Publication Ltd., 2001 3. Roehrborn, C. G.: 5-␣-Reductase inhibitors prevent the progression of benign prostatic hyperplasia. Rev Urol, suppl., 5: S12, 2003 4. McConnell, J. D., Barry, M. J. and Bruskewitz, R. C.: Benign Prostatic Hyperplasia: Diagnosis and Treatment. Agency for Health Care Policy and Research Publication No. 94-0582. Rockville, Maryland: Agency for Health Care Policy and Research, 1994 5. Jepsen, J. V. and Bruskewitz, R. C.: Office evaluation of men with lower urinary tract symptoms. Urol Clin North Am, 25: 545, 1998 6. Abrams, P. H., Farrar, D. J., Turner-Warwick, R. T., Whiteside, C. G. and Feneley, R. C.: The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol, 121: 640, 1979 7. Schwinn, D. A.: Novel role for a1-adrenergic receptor subtypes in lower urinary tract symptoms. BJU Int, suppl., 86: 11, 2000 8. Chatelain, C., Denis, L., Foo, K. T., Khoury, S. and McConnell, J.: Recommendations of the International Scientific Committee. In: Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication Ltd., 2001 9. Leveillee, R. J., Patel, V. and Bird, V. G.: Prostate hyperplasia, benign. Available at http://www.emedicine.com/med/ topic1919.htm. Accessed February 17, 2005 10. AUA, Practice Guideline Committee: AUA guidelines on management of benign prostatic hyperplasia: (2003). Chapter 1: diagnosis and treatment recommendations. J Urol, 170: 530, 2003 11. McLoughlin, J., Gill, K. P., Abel, P. D. and Williams, G.: Symptoms versus flow rates versus urodynamics in the selection of patients for prostatectomy. Br J Urol, 66: 303, 1991 12. Roehrborn, C. G.: Focus on lower urinary tract symptoms: nomenclature, diagnosis, and treatment options. Rev Urol, 3: 139, 2001 13. De La Rosette, J. J., Kortmann, B. B., Rossi, C., Sonke, G. S. Floratos, D. L. and Kiemeney, L. A.: Lomg-term risk of retreatment of patients using alpha blockers for low urinary tract symptoms. J Urol, 167: 1734, 2002 14. Cardura® package insert. New York: Pfizer, 2002 15. Flomax® package insert. Ridgefield, Connecticut: Boehringer Ingelheim Pharmaceuticals, 2004 16. Hytrin® package insert. North Chicago: Abbott Laboratories, 2001 17. UroXatral® package insert. New York: Sanofi-Synthelabo, 2003 18. Avodart™ package insert. Research Triangle Park: GlaxoSmithKline, 2004 19. Proscar® package insert. Whitehouse Station, New Jersey: Merck and Co., 2004 20. Bartsch, G., McConnell, J. D., Mahler, C., Calais Da Silva, F., Klocker, H., Richard, F. et al: Endocrine treatment of benign prostatic hyperplasia. In: Benign Prostatic Hyperplasia. Edited by C. Chatelain, L. Denis, K. T. Foo, S. Khoury and J. McConnell. Plymouth, United Kingdom: Health Publication Ltd., 2001 21. McConnell, J. D., Roehrborn, C. G., Bautista, O. M., Andriole, G. L., Jr., Dixon, C. M., Kusek, J. W. et al: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med, 349: 2387, 2003

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22. Appell, R. A.: Overactive bladder in special patient populations. Rev Urol, suppl., 5: S37, 2003 23. Abrams, P., Kaplan, S. H. and Millard, R.: Tolterodine treatment is safe in men with bladder outlet obstruction (BOO) and symptomatic detrusor overactivity (DO). Neurourol Urodyn, 20: 547, 2001 24. Athanasopoulos, A., Gyftopoulos, K., Giannitsas, K., Fisfis, J., Perimenis, P. and Barbalias, G.: Combination treatment with an alpha-blocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomized, controlled study. J Urol, 169: 2253, 2003

25. Gerber, G. S., Kuznetsov, D., Johnson, B. C. and Burstein, J. D.: Randomized, double-blind, placebo-controlled trial of saw palmetto in men with lower urinary tract symptoms. Urology, 58: 960, 2001 26. Gordon, A. E. and Shaughnessy, A. F.: Saw palmetto for prostate disorders. Am Fam Physician, 67: 1281, 2003 27. Flanigan, R. C., Reda, D. J., Wasson, J. H., Anderson, R. J., Abdellatif, M. and Bruskesitz, R. C.: 5-Year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign hyperplasia: a Department of Veterans Affairs cooperative study. J Urol, 160: 12, 1998