This article is rather long ... but very informative for anyone suffering from BPH.




Benign Prostatic Hypertrophy
Which Nonoperative Strategies Are Best?


Michael J. Wehle, MD
Scott W. Lisson, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO. 4 - APRIL 2002

----------------------------------------------------------------------

In Brief:
Benign prostatic hypertrophy is one of the common complaints of older men who visit their primary care physicians. Nonoperative therapy, such as drug therapy or lifestyle modification, is aimed primarily at reducing bothersome lower urinary tract symptoms and preventing serious morbidity such as urinary retention and renal function impairment. As more men reach advanced age, it becomes crucial for the primary care physician to be aware of the epidemiology, pathophysiology, natural history, clinical presentation, and therapeutic modalities available for the treatment of clinically significant cases.

Benign prostatic hypertrophy (BPH) is the nonmalignant enlargement of the prostate gland from an increase in cellular growth. BPH is the most common benign neoplasm among men, and its incidence increases steadily with age. Clinical BPH is well defined and quite prevalent: Up to 20% of men between 40 and 64--and 40% of men older than 65--are afflicted.1 Histologic BPH is found in 50% of men older than 60 and up to 88% of men older than 80.2 Multiple studies1-3 have shown that 80% of 80-year-old men have BPH-related symptoms, and 10% of them will experience urinary retention.

Not surprisingly, development of BPH parallels patients' complaints. Decreased urinary flow is noted in 25% of 55-year-old men, and as many as 50% will notice it by age 75.4 Studies indicate that a 40- to 50-year-old man has approximately a 20% to 30% lifetime risk of requiring surgical intervention for prostatism.3 An estimated 8 million men are potential candidates for medical intervention to alleviate BPH-related symptoms. BPH-related morbidity costs the US healthcare system several billion dollars annually.5

The Three-Component Model
The mechanism responsible for BPH-induced lower urinary tract symptoms (LUTS) is poorly understood; however, a three-component model is currently favored by urologists. This model involves the static, dynamic, and detrusor-related contributions to BPH-induced symptomatology.

Static.
The static component consists of increased prostatic tissue mass caused by cellular proliferation that results in clinically significant BPH. Androgens, including testosterone and dihydrotestosterone, stimulate cell growth and are crucial to this process. Both stromal and epithelial elements proliferate; however, stromal tissue in the prostatic transition zone constitutes most of a hyperplastic gland. The normal stroma-to-epithelial ratio of 2:1 in a healthy prostate increases to 5:1 in a hyperplastic prostate. Enlargement of the transition zone that surrounds the prostatic urethra is recognized endoscopically by lateral or medial lobe hypertrophy. Periurethral hyperplastic tissue expansion compromises the urethral lumen and produces symptoms of bladder outlet obstruction.6

Dynamic.
Increased prostatic smooth muscle tone constitutes the dynamic component of BPH. The prostate capsule and bladder neck are rich in smooth muscle and alpha receptors. Stimulation of the alpha receptor causes smooth muscle contraction that increases the resistance to flow at the bladder neck and prostatic urethra. Alpha-receptor blockade will decrease bladder and prostatic muscle tone, improving urine flow. This explains the clinical efficacy of alpha antagonists in treating symptoms.

Detrusor related.
Fifty percent of patients who have BPH will also experience involuntary detrusor contractions that eventually lead to histologic alterations in bladder musculature, decreased bladder compliance, and compromised detrusor contractile strength.7 These changes can cause incomplete emptying, urgency, and frequency.


Natural History
Although the true natural history of BPH remains elusive because of study limitations, one thing is clear: BPH is generally a slow and protracted disease process. In addition, it appears that LUTS secondary to BPH do not necessarily progress to complete bladder-outlet obstruction. One study8 noted that 50% of patients with symptomatic BPH remained stable, 10% required surgery, and 33% improved spontaneously within 5 years. Acute urinary retention was seen in 5% to 30% of patients in this study but was difficult to predict based on history and physical exams. Another study9 showed that up to 40% of patients who had symptomatic BPH improved with conservative management, including watchful waiting and even placebo usage.

Serious morbidity, including urosepsis and renal insufficiency from obstructive uropathy, is seen in a very small percentage of patients. Although prostate size does not consistently correlate with symptom severity, the Olmsted County study10 showed that patients who have large prostates are at increased risk for serious complications. Prostate volume of 30 mL or greater was associated with a threefold increase in the risk of urinary retention. Further study and long-term follow-up is needed to help patients who have BPH understand their prognosis and treatment options.

Clinical Presentation and Evaluation
A complete history and physical examination is vital because not all LUTS are caused by BPH. A complete differential diagnosis should include neurogenic bladder, urethral stricture, bladder neck contracture, stone disease, urinary tract infection, prostatitis, bladder cancer, and prostate cancer.

History.
The terms LUTS and prostatism describe the various BPH-related symptoms that are traditionally classified as either obstructive or irritative. Obstructive symptoms include a decreased force of stream, hesitancy, strangury, terminal dribbling, incomplete bladder emptying, and intermittency. Irritative symptoms include nocturia, frequency, urgency, dysuria, and urge incontinence.

To better quantify patient complaints, several questionnaires have been developed. The American Urological Association (AUA) symptom index is often used for diagnosis and for monitoring symptom progression. Each question on this seven-item, self-administered questionnaire yields 0 to 5 points. Patients who score 0 to 7 points are deemed mildly symptomatic; 8 to 19 points, moderately symptomatic; and 20 to 35 points, severely symptomatic.

Physical exam.
A digital rectal examination should always be performed to assess prostate size and architecture. While gland size does not consistently correlate with symptomatology, a rectal exam is essential to rule out irregularities suggestive of malignancy and prostatitis. Any patient who has an abnormal rectal exam warrants further evaluation by a urologist.

Laboratory tests.
For patients who have marked irritative symptoms, urinalysis and urine cytology may help rule out in situ carcinoma of the bladder and urinary tract infection. Hematuria in infected urine helps differentiate these conditions. Annual serum creatinine level monitoring is also useful in patients with prostatism; an elevated level may indicate chronic renal insufficiency. Less than 10% of patients seek treatment for BPH-related upper tract obstruction. An elevated creatinine level may indicate this often asymptomatic condition.

Measurement of serum prostate-specific antigen (PSA) is the final optional laboratory test that can be ordered for a patient who has BPH symptoms. Data suggest that PSA level alone is not a reliable marker to distinguish BPH from prostate cancer; however, additional information such as age, percent-free PSA, PSA density, and PSA sedimentation velocity can help the physician develop a reasonable treatment algorithm.5 About 20% of patients who have normal PSA levels will have occult malignancy. In patients who have PSA levels greater than 10 ng/mL, the likelihood of prostate cancer is as high as 50%.

Additional tests, including cystourethroscopy, uroflometry, and urodynamic evaluation, are sometimes required to make a correct diagnosis for a patient with symptoms suggestive of prostatism. A urologist can initiate and perform these tests in the office.

Treatment Indications
Even after a comprehensive evaluation for BPH-related symptoms, the decision to treat is sometimes nebulous. There is no debate for men who have obstructive uropathy (eg, refractory urinary retention, hydronephrosis, recurrent urinary tract infections, recurrent gross hematuria, or chronic renal insufficiency). These patients should be considered for definitive surgical correction of their BPH. (Surgical modalities, both traditional and minimally invasive, are beyond the scope of this article.) Most patients seen by the primary care physician, however, do not fall into this category; they are merely seeking relief from LUTS that affect their lifestyle. Symptomatic relief can be accomplished by a myriad of nonoperative techniques (figure 1). Therapeutic modalities, whether medical or surgical, all share similar goals: to decrease bladder outlet obstruction, improve quality of life, reduce symptoms, decrease residual urine volume, and reduce the incidence of acute urinary retention and renal insufficiency.11



Nonoperative Treatment Options
The physician's armamentarium is complex, with many medical and surgical options available for the patient who has LUTS secondary to BPH.

Watchful waiting. Patients who have mild BPH may be managed by careful monitoring without intervention. Patients should be advised that symptoms may be eased by avoiding certain medications, such as over-the-counter cold medications and some antihistamines, and by modifying behavior, such as avoiding coffee and alcohol after dinner. Follow-up and symptom reassessment is vital for these patients and should include an annual physical examination, AUA symptom score, and laboratory testing. Symptom progression with or without changes in laboratory values (eg, creatinine elevation, hematuria) should prompt consideration for a change in management.

Drug therapy.
Several drugs are currently available for BPH. The major pharmacologic groupings include alpha-receptor blockers, 5alpha-reductase inhibitors, and phytotherapy. More than one drug may be used.

Alpha-receptor blockers are indicated when proliferation of smooth muscle cells in the prostatic stroma lead to blockage in the bladder outlet. These drugs induce the smooth muscles in the bladder neck and prostate to relax, thereby reducing the blockage, increasing the urine flow, and reducing BPH symptoms. Alpha-adrenergic blockers have been used since the 1970s when phenoxybenzamine hydrochloride was shown to improve urine flow rates and symptom severity in men with bladder outlet obstruction.12 Unfortunately, postural hypotension and other unacceptable side effects limit its widespread use as an effective treatment option for BPH.

By the early 1990s, pharmacologic advances had generated alpha1-selective adrenoceptor blockers with gentler side effects. Widely accepted by urologists and primary care providers, mainstays of the alpha-blocker therapy include the long-acting agents terazosin hydrochloride, doxazosin mesylate, and tamsulosin hydrochloride.

Terazosin is a long-acting, selective alpha1-blocker originally developed as an antihypertensive agent. It was approved for the treatment of BPH in 1993, and its 12-hour half-life facilitates once-a-day dosing. The Hytrin Community Assessment Trial13 confirmed its efficacy in relieving symptoms of BPH, reducing AUA symptom scores, and improving peak flow rates. These improvements were shown to persist over time. Terazosin must be titrated, and its efficacy is dose related. The usual starting therapy is 1 mg for 3 days, 2 mg for 12 days, and 5 mg at bedtime thereafter. (A dose of 10 mg at bedtime may be necessary in a minority of patients.) Side effects result from alpha-adrenergic-receptor blockade of nonprostatic tissue. The incidence of side effects is low and includes dizziness (6.7%), asthenia (3.8%), somnolence (2.0%), and syncope (0.5%).11 The patient's sexual function is preserved, and terazosin will not alter PSA levels.

Doxazosin is another long-acting, selective alpha-adrenergic receptor antagonist that is equally effective in treating symptomatic BPH. Like terazosin, once-a-day dosing is facilitated by a 9- to 13-hour half-life. Long-term studies have shown doxazosin to be effective in decreasing obstructive and irritative symptoms, improving peak urinary flow rates, and decreasing mean systolic blood pressure.14 Like terazosin, side effects are minimal, and doxazosin should be titrated over several weeks.

Tamsulosin is a sulfamoylphenethylamine derivative with prostate-specific alpha1A-receptor-antagonist properties. Presumably, fewer side effects will result because tamsulosin has greater uroselectivity and less activity in vascular smooth muscle than other alpha-receptor antagonists. Abrams et al15 showed that tamsulosin is roughly 12 times more selective for prostatic smooth muscle than for vascular smooth muscle, and that 0.4-mg/day dosing is effective in relieving symptoms of prostatism. Another multicenter, placebo-controlled study16 showed reduced AUA symptom scores, increased peak flow rates, and faster onset of action with tamsulosin versus placebo. Side effects were uncommon and included rhinitis, abnormal ejaculation, and dizziness. Tamsulosin does not require dose titration.

When choosing an alpha-receptor blocker, primary care physicians should consider patients' other comorbidities. No single alpha-antagonist has been shown to be more effective than another in any well-controlled prospective study; each drug has its own advantages and disadvantages. Despite the proven efficacy of these drugs, up to 50% of BPH patients discontinue these medications over time.

5alpha-reductase inhibitors, such as finasteride, impede the prostatic conversion of testosterone to dihydrotestosterone, a potent promoter of prostate gland growth. One randomized controlled study17 demonstrated that 5 mg/day of finasteride improved AUA symptom scores and peak flows, reduced prostate volumes by 24% to 27%, and prevented disease progression in men with significantly enlarged prostates.

Another study18 indicated that finasteride may not only ameliorate symptoms of BPH, but may also decrease the risk for complications and surgery. The Proscar Long Term Efficacy and Safety Study enrolled more than 3,000 men with symptomatic prostatism and enlarged prostates (gland volume >40 mL), and reported not only decreased symptoms of BPH and prostatic volume, but also a decreased probability of surgery and acute urinary retention.

While some data support finasteride's efficacy, other studies are not so promising. A study by Lepor et al19 compared combined therapy with finasteride and terazosin with each as monotherapy. Terazosin alone was shown to be more efficacious than finasteride alone, and finasteride did not add any additional therapeutic benefit to alpha-blocker therapy. The ineffectiveness of finasteride in this study may be partly because the cohorts had relatively modest-sized prostates.

Clinicians can expect to see a 50% decrease in the baseline PSA levels of BPH patients who use finasteride, but the full decrease may take 3 to 6 months to become evident. Prostate cancer or patient noncompliance should be suspected if the PSA level does not fall with finasteride treatment. Side effects are typically related to sexual function, including ejaculatory dysfunction, decreased libido, and impotence. While urologists do not agree on finasteride's role in treating symptomatic BPH, this modality appears to be best for men who have prostatism and a documented prostate volume of at least 40 mL.

Phytotherapy.
Plant extracts, such as saw palmetto, have been used for centuries to nurture good prostate health. These agents contain mostly free fatty acids, free fat alcohols, and triterpenes. Their pathophysiologic mechanisms are unknown, but multiple hypotheses include 5alpha-reductase inhibition and antiestrogenic effects. Studies thus far have been inconclusive. No conclusive scientific data support that these phytochemicals reduce outflow obstruction, prostate volume, or PSA level.20 Additional investigation is required to convince the urologic community of the efficacy of this popular modality.

Lifestyle Factors
Interest lies in the association between BPH and lifestyle factors such as smoking, alcohol consumption, exercise, and sexual activity. Two studies21,22 have demonstrated an inverse relationship between smoking, alcohol consumption, and the development of BPH. Data indicate that moderate cigarette smoking and alcohol consumption may decrease symptoms of prostatism as well as the risk of BPH-related surgery. Exercise has also been shown to protect against the development of LUTS.23 Men who walk regularly had fewer symptoms and required less BPH-related surgery. Scant reliable data associate sexual activity with BPH. While we do not advocate cigarette smoking, it is worth noting that lifestyle factor modification has been shown in some studies21-23 to alter BPH symptoms and outcomes.

Vigilant Care
BPH symptoms vary from annoying LUTS to acute urinary retention and renal failure. A complete differential diagnosis should be explored, and therapy should be dictated by symptom severity. Watchful waiting is very reasonable for patients who have mild symptoms. Moderate symptoms can be managed with an array of pharmacologic agents. Continued research will undoubtedly yield further medical and surgical advances.


References
Garraway WM, Russell EB, Lee RJ, et al: Impact of previously unrecognized benign prostatic hyperplasia on the daily activities of middle-aged and elderly men. Br J Gen Pract 1993;43(373):318-321
Berry SJ, Coffey DS, Walsh PC, et al: The development of human benign prostatic hyperplasia with age. J Urol 1984;132(3):474-479
Birkhoff JD, Wiederhorn AR, Hamilton ML, et al: Natural history of benign prostatic hypertrophy and acute urinary retention. Urology 1976;7(1):48-52
Arrighi HM, Guess HA, Metter EJ, et al: Symptoms and signs of prostatism as risk factors for prostatectomy. Prostate 1990;16(3):253-261
McConnell JD, Barry MJ, Bruskewitz RC: Benign prostatic hyperplasia: diagnosis and treatment. Agency for Health Care Policy and Research. Clin Pract Guidel Quick Ref Guide Clin 1994;Feb(8):1-17
Ziada A, Rosenblum M, Crawford ED: Benign prostatic hyperplasia: an overview. Urology 1999;53(3 suppl 3a):1-6
Hald T: Urodynamics in benign prostatic hyperplasia: a survey. Prostate Suppl 1989;2:69-77
Ball AJ, Feneley RC, Abrams PH: The natural history of untreated 'prostatism.' Br J Urol 1981;53(6):613-616
Roberts RG: BPH: new guidelines based on symptoms and patient preference. The Agency for Health Care Policy and Research. Geriatrics 1994;49(7):24-31
Jacobsen SJ, Jacobson DJ, Girman CJ, et al: Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997;158(2):481-487
Medina JJ, Parra RO, Moore RG: Benign prostatic hyperplasia (the aging prostate). Med Clin North Am 1999;83(5):1213-1229
Caine M, Perlberg S, Shapiro A: Phenoxybenzamine for benign prostatic obstruction: review of 200 cases. Urology 1981;17(6):542-546
Roehrborn CG, Oesterling JE, Auerbach S, et al: The Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. HYCAT Investigator Group. Urology 1996;47(2):159-168
Lepor H, Kaplan SA, Klimberg I, et al: Doxazosin for benign prostatic hyperplasia: long-term efficacy and safety in hypertensive and normotensive patients. The Multicenter Study Group. J Urol 1997;157(2):525-530
Abrams P, Schulman CC, Vaage S: Tamsulosin, a selective alpha 1c-adrenoceptor antagonist: a randomized, controlled trial in patients with benign prostatic 'obstruction' (symptomatic BPH). The European Tamsulosin Study Group. Br J Urol 1995;76(3):325-336
Lepor H: Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 1998;51(6):892-900
Nickel JC, Fradet Y, Boake RC, et al: Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two Year Study. CMAJ 1996;155(9):1251-1259
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. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998;338(9):557-563
Lepor H, Williford WO, Barry MJ, et al: The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996;335(8):533-539
Fitzpatrick JM, Lynch TH: Phytotherapeutic agents in the management of symptomatic benign prostatic hyperplasia. Urol Clin North Am 1995;22(2):407-412
Roberts RO, Jacobsen SJ, Rhodes T, et al: Cigarette smoking and prostatism: a biphasic association? Urology 1994;43(6):797-801
Platz EA, Rimm EB, Kawachi I, et al: Alcohol consumption, cigarette smoking, and risk of benign prostatic hyperplasia. Am J Epidemiol 1999;149(2):106-115
Platz EA, Kawachi I, Rimm EB, et al: Physical activity and benign prostatic hyperplasia. Arch Intern Med 1998;158(21):2349-2356


----------------------------------------------------------------------

Dr Wehle is an assistant professor and Dr Lisson is a resident in the department of urology at Mayo Medical School in Jacksonville, Florida. Address correspondence to Michael J. Wehle, MD, Dept of Urology, Mayo Medical School, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail to wehle.michael@mayo.edu.

Disclosure information: Dr Wehle discloses no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.