Health and Prostate

Definition

Benign prostatic hyperplasia, a nearly ubiquitous condition, is the most common benign neoplasm of American men and occurs as a result of hormone-driven prostate growth.

Pathophysiology

• The prostate gland comprises three types of tissue: epithelial or glandular, stromal or smooth muscle, and capsule. Both stromal tissue and capsule are embedded with О±₁-adrenergic receptors.
• The precise pathophysiologic mechanisms that cause Benign prostatic hyperplasia are not clear. However, both intraprostatic dihydrotestosterone and type II 5 О±-reductase are thought to be involved.
• Benign prostatic hyperplasia commonly results from both static (gradual enlargement of the prostate) and dynamic (agents or situations that increase О±-adrenergic tone and constrict the gland’s smooth muscle) factors. Examples of drugs that can exacerbate symptoms include testosterone, О±-adrenergic agonists (e.g., decongestants), anticholinergics (e.g., antihistamines, phenothiazines, tricyclic antidepressants, anticholinergic antispasmodics, and anticholinergics for Parkinson’s disease).

Clinical presentation

• Patients with Benign prostatic hyperplasia can present with a variety of signs and symptoms. Symptoms vary over time and can improve, remain stable, or worsen spontaneously.
• Obstructive signs and symptoms result when dynamic and/or static factors reduce bladder emptying. Patients experience urinary hesitancy; urine dribbles out of the penis, and the bladder feels full even after voiding.
• Irritative signs and symptoms result from long-standing obstruction at the bladder neck. Patients experience frequency, urgency, and nocturia.
• Complications include chronic kidney disease, gross hematuria, urinary incontinence, recurrent urinary tract infection, bladder diverticula, and bladder stones.

Diagnosis

• Diagnosis of Benign prostatic hyperplasia requires a careful medical history, physical examination, objective measures of bladder emptying (e.g., peak and average urinary flow rate, postvoid residual urine volume), and laboratory tests (e.g., blood urea nitrogen and prostate-specific antigen).
• Medication history should include all prescription and nonprescription medications as well as dietary supplements.
• On digital rectal examination, the prostate is usually, but not always, enlarged (more than 20 g), soft, smooth, and symmetric.

Desired outcome

Benign prostatic hyperplasia treatment is aimed primarily at relieving manifestations of the disease that are bothersome for the patient. A secondary, but controversial, aim is to prevent serious complications in selected patients.

Treatment

• Management options for Benign prostatic hyperplasia include watchful waiting, drug therapy, and surgical intervention.
• The choice depends on the severity of signs and symptoms (Table Categories of Benign Prostatic Hyperplasia Disease Severity Based on Symptoms and Signs), with an emphasis on the patient’s perception.

Watchful waiting

• Watchful waiting is appropriate for patients with mild disease, and for those with moderate disease with only mildly bothersome symptoms and without complications.
• Watchful waiting involves reassessment at regular 6- to 12-month intervals. Patients should be educated about behavior modification such as fluid restriction before bedtime, avoiding caffeine and alcohol, frequent emptying of the bladder, and avoiding drugs that exacerbate symptoms.

Pharmacologic therapy

• Pharmacologic therapy is appropriate for patients with moderately severe Benign prostatic hyperplasia and as an interim measure for patients with severe Benign prostatic hyperplasia.
• Pharmacologic therapy interferes with the stimulatory effect of testosterone on prostate gland enlargement (reduces the static factor) or relaxes prostatic smooth muscle (reduces the dynamic factor) (Table Summary of Medical Treatment Options for Benign Prostatic).
• Two approaches are frequently used in the United States and merit separate consideration in this chapter. In general, 5О±-reductase inhibitors have the advantage of decreasing prostate volume. О±-Adrenergic antagonists have faster onset and are more likely to relieve symptoms. Combination therapy with both approaches is ideal for patients with severe symptoms and a prostate gland of 40 to 50 g or more.
• Agents that interfere with androgen stimulation of the prostate are not popular in the United States because of adverse effects. The luteinizing hormone-releasing hormone agonists leuprolide and goserelin cause decreased libido, erectile dysfunction, gynecomastia, and hot flashes. The antiandrogens bicalutamide and flutamide cause nausea, diarrhea, and hepatotoxicity.

5О±-Reductase Inhibitors

• 5О±-Reductase inhibitors are the only agents approved for Benign prostatic hyperplasia by the Food and Drug Administration (FDA) that interfere with the stimulatory effect of testosterone. These agents slow disease progression and decrease the risk of complications.
• Compared with О±-adrenergic antagonists, 5О±-reductase inhibitors have the disadvantages of requiring 6 months to maximally shrink an enlarged prostate, being less likely to induce objective improvement, and causing more sexual dysfunction.
• Whether the pharmacodynamic advantages of dutasteride confer clinical advantages over finasteride is unknown. Dutasteride inhibits types I and II 5 О±-reductase, whereas finasteride inhibits only type II. Dutasteride more quickly and completely suppresses intraprostatic dihydrotestosterone (versus 80% to 90% for finasteride) and decreases serum dihydrotestosterone by 90% (versus 70%).
• The ideal candidate has a prostate gland of 50 g or more. 5О±-reductase inhibitors might also be preferred in patients with uncontrolled arrhythmias, poorly controlled angina, use of multiple antihypertensives, or inability to tolerate hypotensive effects of О±-adrenergic antagonists.
• 5О±-Reductase inhibitors reduce serum prostate-specific antigen levels by 50%. Therefore, prostate-specific antigen should be measured at baseline and, for monitoring purposes, subsequent measurements should be doubled.
• 5О±-Reductase inhibitors are in FDA pregnancy category X and are therefore contraindicated in pregnant females. Pregnant and potentially pregnant women should not have contact with semen from men receiving 5О±-reductase inhibitors.

О±-Adrenergic Antagonists

• О±-Adrenergic antagonists relax the smooth muscle in the prostate and bladder neck, thereby increasing urinary flow rates by 2 to 3 mL/s in 60% to 70% of patients and reducing postvoid residual urine volumes. Terazosin and tamsulosin produce durable responses for 3 to 4 years.
• О±-Adrenergic antagonists do not decrease prostate volume or prostate-specific antigen levels.
• Terazosin, doxazosin, and alfuzosin are second-generation О±-adrenergic antagonists. They antagonize peripheral vascular О±₁-adrenergic receptors in addition to those in the prostate. Therefore, their adverse effects include first-dose syncope, orthostatic hypotension, and dizziness. Alfuzosin is less likely to cause cardiovascular adverse effects than other second-generation agents.
• To minimize orthostatic hypotension and first-dose syncope with terazosin and doxazosin, patients should be slowly titrated to a maintenance dose and should take these drugs at bedtime.

• Tamsulosin, the only third-generation О±-adrenergic antagonist, is selective for prostatic О±_1A receptors. Therefore, tamsulosin does not cause peripheral vascular smooth muscle relaxation.
• Tamsulosin is a good choice for patients who cannot tolerate hypotension; have severe coronary artery disease, volume depletion, cardiac arrhythmias, severe orthostasis, or liver failure; or are taking multiple antihypertensives. Tamsulosin is also suitable for patients who want to avoid the delay of dose titration or to avoid dosing only at bedtime.
• Caution is needed to avoid potential drug interactions. Tamsulosin decreases metabolism of cimetidine and diltiazem. Carbamazepine and phenytoin increase catabolism of О±-adrenergic antagonists.

Surgical intervention

• Prostatectomy, performed transurethrally or suprapubically, is the gold standard for treatment of patients with moderate or severe symptoms of Benign prostatic hyperplasia and for all patients with complications.
• Prostatectomy does not relieve irritative voiding symptoms of Benign prostatic hyperplasia. These patients may benefit from anticholinergic agents.

Phytotherapy

Although widely used in Europe for Benign prostatic hyperplasia, phytotherapy with products such as saw palmetto berry (Serenoa repens), stinging nettle (Urtica dioica), and African plum (Pygeum africanum) should be avoided. Studies of these herbal medicines are inconclusive, and the purity of available products is questionable.

Evaluation of therapeutic outcomes

• The primary therapeutic outcome of Benign prostatic hyperplasia therapy is restoring adequate urinary flow without causing adverse effects.
• Outcome depends on the patient’s perception of effectiveness and acceptability of therapy. The American Urological Association Symptom Index and International Prostate Symptom Score are validated standardized instruments that can be use to assess patient quality of life.
• Objective measures of bladder emptying (e.g., uroflowmeter and postvoid residual urine volumes) are also useful after 6 to 12 months of 5О±-reductase inhibitor therapy or 3 to 4 weeks of О±-adrenergic antagonist therapy.
• Laboratory tests (e.g., blood urea nitrogen, creatinine, prostate-specific antigen) and urinalysis should be monitored regularly. In addition, patients should have an annual digital rectal examination. If prostate-specific antigen does not decrease by 50% after 6 months of 5О±-reductase inhibitor therapy, the patient should be evaluated for prostate cancer.

Benign prostatic hyperplasia is one of the most common benign tumors affecting men over 40 years of age. The mean age at which patients develop symptoms is between 60 to 65 years. Ninety percent of men in their eighties exhibit histologic evidence of disease, 81% will experience symptoms due to benign prostatic hyperplasia, and 10% will develop acute urinary retention. The aging of the population also increases the number of men at risk for benign prostatic hyperplasia. In the past year, more than 1.7 million men have made an office visit to the urologist and these numbers continue to increase.

In the last 10 years, there has been a major shift in both the physician’s and patient’s perception of benign prostatic hyperplasia. From being considered a disease of aging, requiring intervention only to prevent potential complications, an emphasis shift has occurred. Today, benign prostatic hyperplasia is considered more a disease that affects quality of life; therefore, both evaluations and treatments are currently designed to relieve symptoms and reduce side effects. In this context, the use of medical therapies has become the primary first-line management option for patients initially presenting with symptoms. It has also been well established that patients with mild symptoms (International Prostate Symptom Score [IPSS < 7]) do not need therapy since a majority of the normal population older than 50 years will have mild symptoms. Secondly, there is currently adequate clinical data that medical management options can alleviate symptoms for up to 5 years in long-term trials, with excellent patient satisfaction and low incidence of long-term complications. Finally, there has been a perceptible shift from urologists to primary care physicians as the front-line managers in treating benign prostatic hyperplasia.

Alpha-blockers as a class are the most commonly used first line of agents in managing symptomatic benign prostatic hyperplasia. Approximately 80% of the patients receiving medical management are prescribed alpha-blockers by their primary care physician. This chapter will focus on the evaluation of alpha-blockers in treating symptoms of benign prostatic hyperplasia and the current status of their utility in the United States.

Pharmacophysiologic Rationale for the use of Alpha-Blocker Drugs

Alpha-Adrenergic Receptors: Structure and Classification

Adrenergic receptors are classified as alpha and beta receptors on the basis of their distribution, structure, mechanism of action, and effect on the target organ. Beta receptors are found in the heart, juxtaglomerular renal cells, pancreatic beta cells, smooth muscle cells of vascular, respiratory, and uterine organs, hepatic cells, and somatic motor nerve terminals for voluntary skeletal muscle contraction. Alpha receptors are found in most vascular smooth muscle cells, especially the eye and the prostate gland. Essentially, all of these receptors are transmem-brane proteins made up of seven helices that are structurally arranged to form an extracellular domain (the site of the norepinephrine-receptor complex) and an intracellular domain (the site of the G protein).

The alpha receptors are subdivided into two subgroups — alpha-1 and alpha-2. Alpha-1 receptors are post-synaptic in location and mediate contractions of smooth muscle in the prostate. Alpha-2 receptors are presynaptic in location and serve to regulate the amount of neurotrans-mitter transmission across the synaptic cleft. Stimulation of the alpha-2 receptors causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron; this inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neuro-transmission across the synaptic cleft. Blockage of these alpha-2 receptors results in a variety of systemic and cardiovascular effects due to their wide distribution. Similar to alpha-1 receptors, alpha-2 receptors are transmembrane proteins linked to a G-inhibitory protein on the intracellu-lar surface. Activation of the alpha-2 receptor causes activation of the Gs protein which, in turn, leads to deactiva-tion of the adenyl cyclase system and decreased production of cyclic adenosine monophosphate production.

The alpha-1 receptors are mediated primarily by the coupling protein Gq; this leads to activation of the phos-phoinositide cascade and liberates inositol-l,4,5-triphos-phate (IP-3) and diacylglycerol (DAG). The former opens the gated calcium channels in the cell membrane to increase the intracellular concentration of calcium while the latter activates the protein kinase enzyme to bring about an intracellular response, leading to smooth muscle relaxation.

Various studies have demonstrated that alpha-1 receptors predominate in the normal prostate. Other than in smooth muscles, they are also present on the prostatic blood vessels. The prostatic-specific subtype is alpha-la, an adrenergic receptor that constitutes 70% of all prostatic alpha-1 receptors. Since alpha-1 receptors are also present at various nonprostatic smooth muscles, they are not entirely uroselective. Blockade of these receptors causes few additional unwanted systemic side effects. Recently, however, a prostate-specific subtype of alpha-1 receptor has been identified by radioligand binding studies. Alpha receptors can either be native (denoted by capital suffix) or cloned (denoted by small case suffix). The true native alpha-receptors are called alpha-lA, alpha-IB, and alpha-ID in a recent classification proposed by the international union of pharmacology (IUPHAR). Their cloned counterparts are called alpha-la, alpha-lb, and alpha-Id. In an older classification, the cloned alpha-1A was called alpha-lc, alpha-lb was called alpha-lb, and alpha-ID was called alpha-la/d. Recently, a new alpha-1 receptor subtype was identified that has affinity for prazosin (alpha-1L); the importance of this receptor is still unexplained. Recognition of cloned prostate-specific smooth muscle adrenergic receptors (alpha-la, previously called alpha-lc) have major therapeutic implications since blockade spares all other kinds of adrenergic receptors.

Alpha-1 Adrenoceptor Antagonists

Long-Acting Antagonists

Alpha-1A Subtype Selective Alpha-Adrenergic Antagonist

Sexual Dysfunction

Few studies have investigated the prevalence of sexual dysfunction among patients with symptomatic benign prostatic hyperplasia. Preliminary analysis of baseline data obtained from the Prospective European Doxazosin and Combination Trial (PRFDIGT), however, suggests that there is a large burden of sexual dysfunction in patients with benign prostatic hyperplasia. In addition, the Treatment of Mild Hypertension Study (TOMHS) provided an opportunity to examine the prevalence of sexual problems in a population of hypertensive men. At initial screening, 14% of men reported sexual problems, mostly erectile dysfunction (12%). The proportion of men experiencing problems in obtaining and/or maintaining erection increased substantially after 60 years of age. Since benign prostatic hyperplasia and sexual dysfunction are both age-related disorders, it might be expected that a large proportion of elderly men with symptomatic benign prostatic hyperplasia will also experience sexual problems.

Although sexual dysfunction is traditionally thought to be related to antihypertensive agents, favorable effects were seen with doxazosin in the 24-month data from the TOMHS study. Doxazosin was significantly less likely to cause erectile dysfunction compared to the placebo and other antihypertensive therapy (p = -.01 among all groups). In the 505 men treated with antihypertensive therapy, difficulties in maintaining erections occurred in only 1.3% of the doxazosin group, compared to 3.8% in the placebo, 4.6% in the beta-blocker, 6.1% in the ACE-inhibitor, 9.0% in the calcium antagonist, and 14.1% in the diuretic groups.

In the U.S. tamsulosin study, the incidence of abnormal ejaculation was greater in patients receiving tamsulosin than in those receiving placebo (0.8 mg, 18%; 0.4 mg, 11%; and placebo, < 1%; p < .05). The abnormal ejaculation could be a combination of retrograde ejaculation secondary to bladder neck incompetence or could be due to anejaculation as a result of blockade of receptors on the vas deferens, seminal vesicles, and prostate. This hypothesis needs further study.

Cardiovascular Effects

Conclusion

To be an effective treatment for benign prostatic hyperplasia, medical therapy must not only improve the patient’s ability to urinate but must also have minimal side effects. It should be noted that currently available medical therapies must be continued indefinitely to maintain a therapeutic response. Medical therapies must also be cost-effective. The man who develops benign prostatic hyperplasia at 50 years of age may need therapy for 20 to 40 years. The total cost of such treatment could be significant. As with any medication or treatment regimen, it is important to determine which patients are candidates for a trial of medical therapy for benign prostatic hyperplasia. Any patient who is suffering from clinically significant benign prostatic hyperplasia symptoms and is not in urinary retention is a potential beneficiary from treatment with an alpha-1 adrenergic blocker or 5 a-reductase inhibitor (discussed elsewhere in the book). These therapies are not limited to the poor surgical candidate but can be useful for any patient with bothersome symptoms. Even in patients with moderate to severe symptoms, 85% remain satisfied with alpha-blocker therapy for a period of up to 1 year after treatment. Symptoms of a more severe nature and urinary retention, however, are contraindications to medical therapy. Patients with a history of orthostatic hypotension should not be treated with alpha-blockers.

In the decision to use an alpha-1 adrenergic antagonist, the preferences of both the physician and the individual patient are important. To help with this decision, the advantages and disadvantages of each medication must be understood. The alpha-1 adrenergic antagonists have several advantages. The long-acting drugs allow for once-a-day dosing. The therapeutic effect, as indicated by a > 30% increase in peak urinary flow rate, is realized in > 50% of patients receiving this therapy. The beneficial effect from treatment is realized as soon as 1 week with tamsulosin or 2 to 3 weeks after reaching the maximum dose with other agents. The major disadvantage of these medications in treating benign prostatic hyperplasia is the 10% incidence of untoward effects related to the cardiovascular system as well as titration to achieve maximum benefit. Some of these disadvantages have been solved by the use of subtype selective alpha-blockers.

The prostate gland is often referred to as being composed of five distinct lobes during fetal development — anterior, posterior, median, and two lateral lobes. In the adult prostate, this distinction is usually abolished and the prostate is considered to be composed of three concentric layers: the outer layer (the external prostate gland proper) and the two inner layers (the periurethral glands). Prostate cancer tends to arise in the outer layers of the glands while benign prostatic hyperplasia starts in the inner periurethral glands.

Benign prostatic hyperplasia is believed to arise from fibrostromal proliferation in the periurethral glands. As the gland progresses in size, patients will present with lateral and/or median prostatic lobe(s) enlargement. This latter will result in (a) compression, narrowing, and elongation of the prostatic urethra; (b) growth of the median lobe into the bladder, causing a ball-valve effect and possibly an increase in irritative symptoms; (c) a bladder response to obstruction that may result initially in hypertrophy and subsequently in decompensation, stasis of urine, and upper tract damage; and (d) a host of related complications, including hematuria, urinary tract infections, and calculi formation.

Pathophysiology of this common disease is far from clear. There is no direct cause and effect relationship between presence of glandular enlargement, physiologic presence of obstruction on urodynamic studies, and symptoms of “prostatism” experienced by the patient. Prostatism encompasses both obstructive and irritative symptoms. The obstructive symptoms cause a weak force of urine stream and are believed to be due to increased outflow resistance in the urethra (especially near the prostatic segment) while the irritative symptoms, such as frequency, hesitancy, urgency, and nocturia, are secondary to bladder response to obstruction as well as median lobe hyperplasia. The exact cause of symptoms in benign prostatic hyperplasia is far from clear, and no one hypothesis can explain all of the symptoms.

While obstructive features are the key to the cause of benign prostatic hyperplasia symptoms, irritative symptoms can occur without them. Also, diseases other than benign prostatic hyperplasia can result in symptoms identical to that produced by benign prostatic hyperplasia. The realization of this relationship has resulted in recent re-evaluations of the term “prostatism.”

Many urologists now prefer to use the designation “lower urinary tract symptoms” rather than prostatism. This designation comprises not only patients with benign prostatic hyperplasia but also those with chronic nonbacterial pro-statitis, bladder dysfunction, sphincter dysfunction, symptoms due to age-related changes, and symptoms related to multiple medications, among others. Recent data showing that women have IPSS scores similar to men also suggest that the bladder and urethra may be the cause of symptoms, rather than benign prostatic hyperplasia.

The scientific rationale for using alpha-blocker therapy for benign prostatic hyperplasia is based on the following observations: (1) prostatic smooth muscle contraction is the result of alpha-receptor mediated sympathetic stimulation; (2) contraction of smooth muscles in the prostatic capsule, adenoma, and bladder neck results in decreased bladder outflow; (3) several drugs are now available which can block alpha-receptor activity and cause relaxation of the prostatic smooth muscle; and (4) there is also evidence that alpha-receptors present in the anterior horn of the spinal cord may modulate both autonomic and somatic nerve response in the lower urinary tract.

Evidence for predominant alpha-receptor activity in the prostate comes from the studies of Caine and Raz published in 1975. They used isometric measurements on tissue strips to demonstrate that human prostatic smooth muscles contract under the influence of sympathetic innervation and that their effects were mediated through the alpha-adrenergic receptors. It has further been reported by several authors that benign prostatic hyperplasia patients with a predominant stromal component have a greater degree of dynamic obstruction.

Dynamic closure due to contraction of smooth muscles of adenoma, capsule, stroma, and bladder neck has been confirmed by the urodynamic studies of intraurethral pressure. In these in vivo studies, it has been revealed that approximately 40% of bladder outlet obstruction may be the result of smooth muscle contraction.

Alpha-blocking drugs have been shown to both bind and relax the prostatic smooth muscle. Drugs such as phenoxybenzamine, prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin, which are known alpha-receptor antagonists, bind extensively to prostatic alpha-receptors and relieve smooth muscle contractions.

Short-Acting Antagonists

Phenoxybenzamine

Phenoxybenzamine was the initial alpha-adrenergic blocking drug used for management of benign prostatic hyperplasia; however, it was a nonselective alpha-1 and alpha-2 receptor irreversible antagonist that produced many side effects. It did improve prostatic symptoms but had significant cardiovascular side effects in 30% of patients. It has also been shown to have mutagenic properties in animal studies. This drug is therefore no longer used in managing benign prostatic hyperplasia.

Prazosin Prazosin was the next selective alpha-1-blocker used to manage benign prostatic hyperplasia, at which time it was already being used for treating hypertension. Prazosin had fewer side effects and responded better than phenoxybenzamine. This drug, however, did have its setbacks; it was dispensed twice daily, which caused significant first-dose effect and vascular side effects during the morning dosage. In long-term studies, > 32% of patients discontinued use of prazosin due to various adverse effects.

Prazosin must be given three times per day to be effective for benign prostatic hyperplasia. In 1983, Hedlund and co-workers published results of a double-blind, placebo-controlled, crossover study with prazosin for the treatment of benign prostatic hyperplasia in 20 patients. The maximum and mean urinary flow rates were improved significantly with prazosin. Postvoid residual urine volumes decreased significantly during treatment as well. Although obstructive symptoms improved during treatment, there was no effect on irritative symptoms. The investigators concluded that prazosin was an effective treatment for patients with symptomatic benign prostatic hyperplasia.

In 1987, Kirby and associates described 80 patients who were evaluated in a double-blind, placebo-controlled study using prazosin. The peak urinary flow rates increased significantly from a mean of 8 mL per second to 13 mL per second. There was no observed increase for the placebo cohort. The investigators also showed a decrease in the patients’ urinary frequency in the treatment group compared to the placebo cohort. Although the study was flawed by a high drop-out rate of 25 patients, the investigators concluded that prazosin could be useful for treating benign prostatic hyperplasia. Other double-blind, placebo-controlled studies evaluating prazosin also showed statistically significant increases in urinary flow rate as well as improved “prostatism” symptoms.

Alfuzosin

Alfuzosin has been studied extensively in Europe. In 1985, Ramsay and co-workers evaluated 31 patients in a double-blind, placebo-controlled clinical trial; of the 31 patients, 20 were randomized to receive treatment. Although there was a significant improvement in frequency, there was no significant increase in peak urinary flow rates. Jardin and associates reported a large, randomized, double-blind controlled study of 518 men treated with alfuzosin for benign prostatic hyperplasia. There was a significant decrease in obstructive and irritative symptoms, a significant increase in mean urinary flow rate, and a decrease in postvoid residual urine volume. This study had several weaknesses, however, including the fact that 55% of the men entered the study without a urinary flow rate evaluation and only 39% of the patients were evaluated with measurement of postvoid urine volume. There was also variation among the treatment centers in terms of dose titration and outcome measures.

Current literature advocates continued use of alfuzosin for its effectiveness to be maintained in treating benign prostatic hyperplasia symptoms. In a recent study, however, Kaplan et al. examined the potential of intermittent dosing of alfuzosin. This study was a prospective open-label, parallel, randomized trial involving two phases. The first phase of the study involved 111 men taking 2.5 mg three times daily for 3 months. After this 3-month period, patients who responded to alfuzosin (defined as a 40% decrease in the IPSS and a 30% increase in measurement of uroflow [Qmax]) were enrolled into the 6-month dosing/phase II of the study; a total of 79 men were enrolled. These phase II participants were then randomized into one of three groups; group 1 continued alfuzosin 2.5 mg three times daily every day, group 2 received alfuzosin 2.5 mg three times daily every other day, and group 3 discontinued alfuzosin. Measurement of uroflow (Qmax) and completion of the IPSS were used to evaluate efficacy. Results during the phase II trial were interesting; the IPSS was 7.1 and 6.5 for group 1; 6.5 and 6.7 for the group taking alfuzosin every other day (group 2); and 11.4 and 12.3 for group 3, at 3 months and 6 months, respectively. The Qmax was 12.7 mL per second and 11.7 mL per second for group 1; 12.2 mL per second and 11.9 mL per second for group 2; and 9.7 mL per second and 9.3 mL per second for group 3 at 3 months and 6 months, respectively. There were no differences among group 1, patients taking alfuzosin every day, and group 2, patients taking alfuzosin every other day (p = .43). However, groups 1 and 2 performed better than group 3 (p < .02 and p < .015, respectively). The data clearly indicate that patients who took alfuzosin daily (group 1) did not have better results than men who took alfuzosin every other day. The authors further stated that complete cessation of alfuzosin resulted in recurrence of symptoms and impaired urinary flow. These data provide evidence that intermittent alfuzosin therapy may be a reasonable therapeutic regimen in responding patients.

Terazosin

Terazosin, an antihypertensive drug, is a selective alpha-1 adrenergic antagonist that has been studied extensively and is currently approved by the FDA for treatment of benign prostatic hyperplasia. This long-acting agent allows a once-a-day dosing schedule. Lepor and associates published the first randomized, placebo-controlled, phase II trial of terazosin, the largest experience to date with terazosin in the treatment of benign prostatic hyperplasia.  This multicenter study included 285 men with symptomatic benign prostatic hyperplasia who were randomly assigned in equal proportions to receive placebo or 2, 5, or 10 mg of terazosin administered once daily. Of the 285 men, 237 patients completed the 4-week, single-blind, placebo lead-in period and the 12-week, double-blind treatment period. All terazosin treatment groups exhibited a significantly greater decrease in total Boyarsky symptom scores compared with the placebo cohort (p < .001). The increase in peak urinary flow rate for the 10 mg group was 3.0 mL per second, a significant change compared to baseline (p < .001). This change was also significantly larger than the placebo group (p = .009). The improvements in symptom scores and urinary flow rates did not reach a plateau within the dose ranges evaluated, suggesting that further efficacy may be achieved with doses of terazosin exceeding 10 mg. The investigators concluded that these findings demonstrated that terazosin is efficacious in treating symptomatic benign prostatic hyperplasia. Further, Lepor and colleagues reported that the adverse effects of using terazosin were minimal.” In the 2,5, and 10 mg study groups, the incidence of postural hypotension was 2.7%, 8.3%, and 5.7%, respectively. The 8.3% for the 5 mg group was the only measurement statistically different from the placebo cohort. Other reported adverse events include headache (5.8%), asthenia (2.9%), dizziness (2.9%), flu syndrome (1.4%), urinary tract infection (1.4%), and syncope (1.4%). No other side effects were reported.

Other phase II studies have shown similar results to those obtained by Lepor. One such study was conducted by Fabricius and Hannaford. They collected data from a randomized, placebo-controlled, double-blind study of once-a-day dosing of terazosin (10 mg per day) in 57 patients with symptomatic benign prostatic hyperplasia. The study began with a 4-week placebo lead-in period followed by a single-blind 24-week treatment period. At the conclusion of the treatment period, 30 patients who responded to terazosin were randomly assigned to receive either terazosin or placebo (the double-blind study period). During the single-blind treatment period, peak urinary flow rate increased 54%, mean flow rate increased 55%, and residual volume decreased 56%. The mean obstructive symptom score, irritative symptom score, and physician global assessment score improved by 68%, 34%, and 27%, respectively. All of these changes were significant when compared with the baseline placebo group. Further, during the 12-week double-blind treatment period, the improvement in all efficacy variables was sustained in the terazosin group. Fabricius and Hannaford reported that the most frequent adverse events experienced by the patients in this study were headache, asthenia, and hypotension. When Lepor combined the data from this study with that of other terazosin studies, he found a 50% increase in peak urinary flow rates (p < .001), a 46% increase in the mean urinary flow rate (p < .001), a 67% decrease in obstructive symptoms (p < .001), and a 35% decrease in irritative-symptom scores (p < .00l).

Even though there are many successful clinical trial studies regarding terazosin in the United States, the same cannot be said about European clinical trials. Two studies in particular in Europe have not shown results from the terazosin group that are superior statistically or clinically to those in the placebo-treated groups. One study, conducted by Di Silverio from Italy, was a clinical trial using terazosin in 137 patients who were randomized to receive placebo or 2, 5, or 10 mg of terazosin. There were statistically significant differences between the placebo and active treatment groups when using the least square method (p = .012) but there were no statistically significant differences when percent changes from baseline were compared.

In another study conducted in the United Kingdom, 86 patients with symptomatic bladder outflow obstruction were randomized to receive terazosin or placebo. All terazosin-treated men showed improvement in obstructive symptoms when compared with placebo-controlled patients but these differences were not statistically significant because of the small number of patients enrolled in the study. Further, improvements in uroflowmetry measurements were seen in both placebo-treated and terazosin-treated groups.

Of the total of 163 patients from four investigations, 14% complained of dizziness, 10% suffered headaches, 7% had asthenia, 4% had hypotension, and 4% complained of impotence. Less than 1% complained of syncope or decreased libido. These symptoms may be exaggerated as these studies included titration to maximum doses. No placebo group data were available for comparison.

Doxazosin

Holme and associates presented early results on the use of doxazosin in treating patients with symptomatic benign prostatic hyperplasia. This double-blind, placebo-controlled study involved 47 patients who received 4 mg of doxazosin daily for 9 weeks and 44 patients who received placebo. The results of treatment were monitored by a symptom questionnaire, uro-dynamic studies, and voiding charts. The reduction in the degree of irritative symptoms was 80% for the treatment group and 45% for the placebo group (p < .05). Obstructive symptoms decreased by 63% for the treatment group and 31% for the placebo group (p < .05). Subjectively, 81% of the treatment group felt considerably much better, compared to 39% of the placebo group. The peak urinary flow rate increased by 25% in the doxazosin group but there was no change in the placebo cohort (p = .07). Very few side effects occurred in both groups, and no patient dropped out because of untoward events.

Chappie and associates presented the results of a 3-month, double-blind, placebo-controlled study of doxazosin for the treatment of benign prostatic bladder outlet obstruction. In this study, 67 patients received doxazosin 4 mg daily and 68 patients received a placebo. Patients were monitored throughout the study for symptoms, flow rates, incidence of adverse events, and blood pressure when supine and erect. Patients treated with doxazosin experienced a statistically significant improvement in nearly all symptoms compared to placebo-treated patients: frequency, 44% versus 27% (p = .06); nocturia, 39% versus 19% (p = .02); urgency, 60% versus 38% [p = .004); and premicturition delay, 56% versus 26% [p = .003). The increase in peak urinary flow rate was 2.6 mL per second in the treatment group, compared with 1.1 mL per second for the placebo cohort. This improvement was not statistically significant (p = .09). There was, however, a statistically significant improvement in the mean urinary flow rate (1 mL per second for the treatment group versus 0.2 mL per second for the placebo cohort [p = .04]). Chappie and associates reported only 1 patient who withdrew from the study secondary to drug-related events. They reported no clinically significant changes in sexual function or blood pressure.

In 1995, Fawzy and associates conducted a 16-week, double-blind, placebo-controlled study of 100 normoten-sive men to evaluate the role of doxazosin in the treatment of benign prostatic hyperplasia. In this study, the subjects were titrated to a maximally efficacious or tolerated dose of 8 mg; 87.8% of the participants tolerated up to 8 mg. In the mean analysis, patients taking doxazosin showed a significant improvement in maximum urinary flow rate compared to patients taking placebo. According to Fawzy et al.’s report, this significant effect of doxazosin was noted as early as week two and was sustained throughout the study. The proportion of patients with a clinically meaningful increase in peak flow rate of at least 3 mL per second was significantly greater in the doxazosin group (39%) than in the placebo group (17%). The severity of obstructive symptoms, irritative symptoms, and total symptoms decreased significantly with doxazosin compared to placebo; this change was evident within 4 weeks of initiation of therapy and was sustained for the duration of the study.

The second United States study was conducted by Gillenwater et al. and was also a multicenter, double-blind, placebo-controlled, dose-response study in 248 hypertensive men who had benign prostatic hyperplasia; 161 of these patients completed the study and were randomized to receive placebo or 2, 4, 8, or 12 mg of doxazosin. This study revealed that the maximum flow rate increased significantly in the doxazosin groups, by up to 3.6 mL per second, compared to an increase of 0.1 mL per second in the placebo group. The proportion of patients with a > 3 mL per second increase in peak flow rate was significantly larger in the 8 mg and 12 mg doxazosin groups compared to the placebo group; there was less of a change in peak flow rate in patients taking 2 mg or 4 mg of doxazosin compared to placebo but a rate of at least 3 mL per second was noted. In the endpoint analysis of symptoms, 4 mg of doxazosin was superior to placebo in decreasing the severity of obstructive symptoms, irritative symptoms, and total symptoms. The severity of total and obstructive symptoms also decreased significantly with 8 mg of doxazosin. Adverse events were reported by 48% of the men taking doxazosin and 35% of the placebo-treated patients. The side effects most frequently reported were dizziness, headache, and fatigue. Only 2.5% of the doxazosin-treated men experienced hypotension. The authors noted that the incidence of adverse events did not increase with increasing dose or duration of treatment.

Tamsulosin

Tamsulosin is a newly developed member of this class of drugs, is suitable for once-a-day dosing schedule, and is currently being studied extensively in the treatment of benign prostatic hyperplasia. Tamsulosin is a (-)-S-[2-[[2-(o-ethoxyphenoxy) ethylamino] propyl]-2-methoxybenzenesulfonamide HC1, a sulphamoylphenethylamine derivative which possesses potent and selective alpha-1A receptor antagonism. In preclinical trials, tamsulosin has been shown to have 13  times more efficacy for prostatic smooth muscle as compared to urethral smooth muscles. Other studies have revealed a 10 to 12 times higher affinity for prostatic receptors as opposed to vascular and extraprostatic tissue. Recent changes in nomenclature of alpha-blockers reveal the alpha-1A receptors to predominate in the prostate while alpha-IB and alpha-ID receptors predominate in the vascular smooth muscle. Tamsulosin belongs to a class of alpha-lA-receptor antagonists that have preferred selectivity for prostatic smooth muscle although it does have some binding to vascular smooth muscle receptors as well. Tamsulosin binding is remarkable for its significantly lower degree of nonspecific binding compared to other alpha-receptor antagonists.

Two 12-week, double-blind, placebo-controlled studies of tamsulosin 0.4 mg once daily have been conducted in Europe.’ More than 300 patients with symptomatic benign prostatic hyperplasia were enrolled in each study. In a recent meta-analysis of data from 575 patients (tamsulosin 382, placebo 193), a small improvement in peak flow rate was shown with tamsulosin (+1.6 mL per second) that was statistically significant when compared with placebo (+0.6 mL per second; p = .002). Tamsulosin also significantly improved the mean total Boyarsky symptom score compared with placebo (-3.3 and -2.2 points; p = .002). Long-term, open-label follow-up of these studies showed that about 70% of the patients receiving tamsulosin achieved a clinically significant improvement in benign prostatic hyperplasia symptoms and that the benefits were maintained over 12 months. Although tamsulosin is reported to have modest uroselectivity, dizziness considered to be possibly or probably related to study medication was experienced by 5% of the patients in this long-term study.

Tamsulosin was recently approved in the U.S. as Flo-max (by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield [Computed tomography]) for treatment of patients with symptomatic benign prostatic hyperplasia. The drug is available at a dosage of 0.4 mg given once per day, one-half hour after breakfast. The reasons for administering after food are that this administration allows a smoothing of the plasma levels and prevents rapid peaks in the blood, which may be beneficial in avoiding side effects. In a recent multicenter, randomized, double-blind, placebo-controlled, parallel group phase III clinical trial in the United States, Narayan and Tewari reporting for the Tamsulosin Investigator Group analyzed 735 patients randomized to double-blind therapy. Results revealed that tamsulosin at doses of 0.4 mg and 0.8 mg was clinically and statistically superior to placebo in relieving symptoms of benign prostatic hyperplasia in men with baseline moderate to severe symptoms. Secondly, tamsulosin had a safety profile that was superior to other currently available alpha-receptor antagonists with no evidence of first dose effects and no clinically significant orthostatic hypotension. The only two side effects noted with the 0.4 mg dose were a higher incidence of dizziness and abnormal ejaculation. In this study, tamsulosin (0.4 mg and 0.8 mg) resulted in a reduction in total American Urological Association (AUA) symptom score compared to placebo (p < .05). The percentage and number of patients who showed an improvement or reduction in the total AUA symptom score that was > 25% from baseline to endpoint was 56% (134 of 238), 55% (133 of 244), and 40% (95 of 235) in the groups of 0.8 mg once daily, 0.4 mg once daily, and placebo, respectively (p < .05).

In another pivotal study, Lepor reporting for the Tam-sulosin Investigator Group analyzed a multicenter phase III, randomized, parallel-designed, double-blind clinical comparison of three treatment groups: tamsulosin 0.4 mg per day, tamsulosin 0.8 mg per day, and placebo. All patients were evaluated prior to the study for eligibility on the basis of the AUA symptom score, uroflowmetry and prostate-specific antigen levels. Patients were evaluated for study eligibility during a 4-week single-blind placebo lead-in period before entry into the double-blind treatment period; 618 patients qualified for the study. The double-blind treatment phase lasted a total of 13 weeks. The results of this study confirmed the effectiveness of tamsulosin in treating benign prostatic hyperplasia at both the 0.4mg per day and 0.8 mg per day dosages. The effects of tamsulosin treatment were observed soon after initiation of therapy. Significant differences versus placebo in the total AUA symptom score were apparent after 1 week of treatment with tamsulosin 0.4 mg per day. Changes in uroflow demonstrated that tamsulosin has rapid onset of action, according to Lepor’s study. There was a statistically significant difference relative to baseline observed after the first dose of 0.4 mg per day tamsulosin versus placebo (p < .001). Further, the mean change from baseline to end-point was significantly greater in both tamsulosin treatment groups than in the placebo group (p < .001). Additionally, statistically significant differences in uroflow compared with placebo occurred within 4 to 8 hours after a single dose of tamsulosin 0.4 mg.

Overall, tamsulosin was well tolerated at dosages of 0.4 and 0.8 mg per day. Adverse events occurring more frequently in tamsulosin-treated patients included rhinitis, abnormal ejaculation, infection, and dizziness. Asthenia was minimal with tamsulosin. The incidence and severity of abnormal ejaculation were shown to be dose dependent. There was a higher overall incidence of discontinuation due to adverse events in the 0.8 mg per day tamsulosin group (13%) compared to the 0.4 mg per day tamsulosin group and placebo group (7% and 9%, respectively, p = . 115) . The higher incidence of discontinuation in the 0.8 mg per day tamsulosin group was reflected by a higher incidence of abnormal ejaculation, dizziness, chest pain, and hypotension than in the other two groups.

On completion of the previously discussed 13-week double-blind phase, the investigators continued the study by giving the patients an option to continue the double-blind treatment for up to 40 additional weeks. This extension study was designed to determine the long-term safety of tamsulosin and to identify whether response to tamsulosin is sustained, increased, or decreased during maintenance therapy. Of the 618 patients from the 13-week initial study, 418 (68%) continued into the extension phase of the same double-blind medication and dose. The parameters measured in this study were the AUA symptom score and maximum urinary flow rate. Statistically significant improvements were observed in all treatment groups (p < .001), even the placebo group. The improvements in the AUA symptom scores, however, were greater in each of the tamsulosin groups (0.4 and 0.8 mg per day) than in the placebo group and were comparable in the two tamsulosin treatment groups. Seventy-eight percent (103 of 132) of the patients treated with tamsulosin 0.8 mg per day demonstrated a decrease in total AUA symptom score of > 25% from baseline; 81% (111 of 137) of patients in the 0.4 mg per day tamsulosin group responded similarly; and 59% (72 of 123) of the patients in the placebo group responded similarly. Further, the mean changes in maximum urinary flow relative to baseline within the two tamsulosin groups were statistically significant (p < .001); the placebo group did not achieve a change of statistical significance. In the 0.8 mg per day tamsulosin group, 38% of the patients had a > 30% increase in Qmax from baseline; 40% achieved the same in the 0.4 mg per day tamsulosin group; and 22% achieved the same in the placebo group.

It is interesting to note that when comparing efficacy parameters obtained at the end of the total 53 weeks to that of the first 13 weeks of the study, the results showed a greater reduction in the tamsulosin groups than in the placebo group at all visits. At the end of the extension phase, the mean change in Qmax relative to baseline was 0.43 mL per second in the placebo group, 1.69 mL per second in the tamsulosin 0.4 mL per day group, and 2.10 mL per second in the tamsulosin 0.8 mL per day group. This increase from baseline was statistically significant for both of the tamsulosin groups but the change was not significant for the placebo group. Further, in the tamsulosin 0.4 mg per day group, the percentage of nonresponders (patients who had less than a 25% decrease in the total AUA symptom score from baseline) who became respon-ders (patients who had demonstrated a decrease in the total AUA symptom score of 25% or more from baseline) was 43%; this was significantly higher than that for respon-ders who became nonresponders (6%). In contrast, in the placebo group the percentage of nonresponders at the end of the phase III trial who became responders (21%) at the end of the extension phase was lower than the percentage of responders who became nonresponders (23%).

In this same study, over the combined 53 weeks of the double-blind treatment, there was an overall higher incidence of adverse events in the tamsulosin 0.8 mg per day group than in the 0.4 mg per day tamsulosin and placebo groups. The overall incidence of adverse events in the 0.4 mg per day tamsulosin and placebo groups was similar. The most commonly reported treatment-emergent side effect for all three groups was infection (colds and upper respiratory infections). The overall incidence of cardiovascular side effects was indistinguishable between the three groups; 14%, 10%, and 14% for the placebo group, 0.4 mg per day tamsulosin group, and 0.8 mg per day tamsulosin group, respectively. Another adverse event, abnormal ejaculation, occurred in 26% of the 0.8 mg per day tamsulosin group compared to 10% and 0% in the 0.4 mg per day tamsulosin and placebo group, respectively. From these data, it can be concluded that continued exposure to tamsulosin beyond the initial 13 weeks is not accompanied by enhanced risk for adverse events; the adverse events seen at the end of the 53-week trial period were similar to those seen at the end of the initial 13-week trial period.

Adverse Events of Alpha-1 Adrenergic Antagonists

The most important side effects of the alpha-1 blocking drugs are simply reflections of their alpha-blocking effects. The main manifestations are cardiovascular effects, which may cause orthostatic hypotension leading to dizziness, reflex tachycardia, and angina in patients with coronary artery disease. Another common side effect seen with the use of alpha-blockers is sexual dysfunction, mainly erectile dysfunction and retrograde ejaculation.

By blocking the alpha-1 adrenoceptor, these drugs cause peripheral vasodilation, which reduces total peripheral vascular resistance and thereby lowers high blood pressure. Indeed, reduction in blood pressure was the primary indication for which alpha-1 adrenoceptor antagonists were developed. The effects of selective alpha-1 blockade on the blood pressure of patients with benign prostatic hyperplasia are important in terms of the risk of adverse effects related to hypotension, both in normotensive patients and in those treated with other anti-hypertensives. Given that both benign prostatic hyperplasia and hypertension become more prevalent with increasing age, and that one would expect to find that a large proportion of older men have both conditions, these are very real concerns.

Clinicians are often faced with the dilemma of what to do when treating a patient with benign prostatic hyperplasia who already has hypertension controlled by an agent other than alpha-blockers. Should the existing antihypertensive agent be withdrawn or the alpha-blockers be given in addition to existing medication? In a small pilot study, Kaplan et al. investigated the effects of doxazosin on the blood pressures of 32 pharmacologically normotensive patients (patients in whom blood pressure was controlled by antihypertensive medication) with benign prostatic hyperplasia and 31 physiologically normotensive patients with benign prostatic hyperplasia. The results showed that doxazosin-induced reductions in blood pressure were small and clinically insignificant in both groups (no differences between groups). Further evidence is available from the Hytrin Community Assessment Trial (HYCAT), a community-based, double-blind, randomized trial of the treatment of symptomatic benign prostatic hyperplasia with ter-azosin versus placebo; 524 of the patients enrolled (274 were given terazosin and 250 were given placebo) were also treated with concurrent single or combination antihypertensive therapy. There were no significant differences between the terazosin and placebo patients in the incidence of blood pressure-related adverse events. These studies indicate that doxazosin or terazosin may be introduced for treating benign prostatic hyperplasia in hypertensive men whose blood pressure is already adequately controlled by other antihypertensive agents, without fear of a further clinical reduction in blood pressure. Monitoring of blood pressure is recommended, at least initially, however, when alpha-blockers are given in addition to any other existing antihypertensive medication.

In terms of cost-effectiveness, the most logical approach in patients with concomitant hypertension and benign prostatic hyperplasia is to replace the existing antihypertensive medication with an alpha-1 adrenoceptor antagonist. There is controversy over this approach, however. Hypertension often coexists with other risk factors for coronary heart disease, for example abnormal lipid profile and insulin resistance/glucose intolerance. Proponents of alpha-blockers for treatment of both diseases cite favorable effects of drugs such as doxazosin on these metabolic variables. Benefits include reduction in high blood pressure and serum lipids, an increase in fibri-nolysis, inhibition of platelet aggregation, attenuation of the adverse hemodynamic and homeostatic effects of smoking, and regression of cardiac hypertrophy. Alpha-blockers are also reported to improve insulin sensitivity and glucose intolerance, both in hypertensive patients with insulin resistance and in noninsulin-dependent diabetic patients. Such benefits provide further rationale for choosing alpha-1 adrenoceptor blockade for treating men with benign prostatic hyperplasia who have one or more of these risk factors.

Those opposed to the use of alpha-blockers for hypertension have equally powerful arguments. The Joint National Commission on Hypertension recommends lifestyle modifications, diuretics, calcium-channel Mockers, ACE (angiotension converting enzyme) inhibitors, and beta-blockers as first-line management for hypertension. The rationale for this is the fact that these agents have proven efficacy in reducing the risk of myocardial infarction, cerebrovascular accidents, and transient ischemic attack (TIA) in such patients. Alpha-blockers for hypertension are used mostly as additional rather than primary agents for treatment of hypertension.

The second major objection to using alpha-blockers is the spontaneous incidence of postural hypotension with aging. The Shep Study, for example, reported the incidence of spontaneous postural hypotension (a fall in systolic BP of > 20 mm Hg after 1 minute of quiet standing); it was reported that 20% of patients older than 65 years have postural hypotension, of which one-half are symptomatic. This study concluded further that the incidence of postural hypotension among the elderly increases with prolonged standing; 10.4% experienced hypotension after 1 minute of standing, 12% at 1 to 3 minutes of standing, and 17.3% at 3 minutes. One major cause of morbidity in elderly patients is falling due to spontaneous postural hypotension, resulting in hip fracture. Adding an alpha-blocker exacerbates this problem. Conversely, this does not happen when elderly patients are given calcium-channel blockers or ACE inhibitors. Finally, patients already on antihypertensives may need to be watched more carefully when alpha-blockers are added. With time constraints, the physician may prefer to simply use an alpha-1 receptor subtype selective agent to eliminate the need to counsel patients periodically about postural hypotension and its sequelae.

TABLE. Summary of Alpha-Blockers

TABLE. Cardiovascular Side Effects of Terazosin, Doxazosin, and Tamsulosin

In the American tamsulosin studies, dizziness occurred in a small percentage of patients (8-mg dose caused dizziness in 23% of patients; 4 mg, 20%; and placebo, 15%; p = .039 between 0.8 mg and placebo). Since dizziness was not associated with postural hypotension, it could be due to the binding of the drug to baroreceptors in the central or peripheral nervous system. This incidence of dizziness, however, is comparable to terazosin and doxazosin studies.”’ The lack of significant cardiovascular effects and hypotension with tamsulosin was also noted in the European studies. In the meta-analysis of the European trial, treatment-emergent adverse effects occurred in 36% of the tamsulosin group and in 32% of the placebo group (p = .802). During the 60 weeks of tamsulosin treatment, 60% of the patients experienced at least one treatment-emergent adverse event. Fifty-one (21%) of the patients experienced adverse events considered by the investigator to be probably or possibly related to tamsulosin.

Benign prostatic hyperplasia is a common condition in men, second only to cataract surgery as the most common reason for a surgical procedure among elderly men. In 1995, over 5.5 million men in the United States above the age of 50 years were estimated to meet criteria proposed for discussing therapy for benign prostatic hyperplasia according to treatment and diagnostic guidelines. The lifetime risk for medical or surgical intervention for benign prostatic hyperplasia in a 50-year-old man has been estimated at 40%. Benign prostatic hyperplasia represents a significant burden on health care, particularly in light of the aging of the general population.

The three components of benign prostatic hyperplasia, namely palpable enlargement of the prostate, lower urinary tract symptoms (lower urinary tract symptoms), and obstruction, overlap to varying degrees in individual patients. Despite the high prevalence of benign prostatic hyperplasia, standard clinical diagnostic criteria are yet to be developed. This limits the ability to characterize the natural history in untreated patients, and to identify risk factors for the disease or its progression. Since urinary symptoms can stem from other disease entities such as bladder disorders, the terms “lower urinary tract dysfunction” and lower urinary tract symptoms have been proposed to describe symptoms that are not necessarily prostate-specific. Likewise, benign prostatic enlargement refers to glandular enlargement, whether or not accompanied by lower urinary tract symptoms. In this chapter, benign prostatic hyperplasia refers to benign prostatic enlargement with associated lower urinary tract symptoms.

Although the high prevalence and chronic nature of benign prostatic hyperplasia are established, therapeutic decision-making has previously been difficult because of the lack of documentation from well-designed long-term studies on the progression of benign prostatic hyperplasia and its associated long-term risks if left untreated. This chapter reviews available data from community studies and clinical trials that document the long-term progressive nature of the disease. Recent evidence that progression and long-term complications of the disease may be preventable will be discussed.

Progression of Benign Prostatic Hyperplasia in Untreated Men

Cross-sectional studies based on community samples have consistently shown age-dependent increases in symptom severity associated with benign prostatic hyperplasia‘ and declines in peak flow rate. Such studies have also documented an increase in prostatic volume with age. However, cross-sectional relationships with age do not necessarily characterize aging effects that occur over time in individual patients. Long-term longitudinal studies following individual patients over time provide better estimates of the progression of the disease. Until recently, few studies of this nature had been conducted and such information was lacking in the urologic literature. Recent longitudinal community studies have provided documentation of the progression of untreated benign prostatic hyperplasia over periods of up to 7 years. In addition, data from long-term controlled clinical trials of medical therapy can also be examined for progression of benign prostatic hyperplasia in placebo-treated men.

Data from clinical trials, however, should be interpreted cautiously, given the selective nature of the trial population and the documented placebo effects which often occur in such studies. It is well known that clinical trial populations constitute a select population of men with the disease in question; rates of progression may depend on the entry criteria for the particular trial. In addition, the protocol-driven schedule of clinic visits and procedures may not always follow what might occur with the natural history of the disease. Placebo effects in blinded randomized clinical trials of benign prostatic hyperplasia can be strong, in part due to psychologic factors in the blinded setting, positive expectations and anticipation of patients, providers, and caregivers toward treatment, clinic effects, compliance, and regression to the mean. This is particularly applicable to measures such as symptoms and urinary flow rate but is less so for measures of prostate volume and occurrence of spontaneous acute urinary retention. Placebo arms of clinical trials may therefore not be generalizable to all men,’ reflecting only part of the natural history disease process.

Randomized controlled clinical trials are the “gold standard,” however, by which to judge evidence regarding therapeutic effects on clinical measurements and long-term complications of untreated disease. In this chapter, cross-sectional data from community and urologic studies as well as longitudinal data from both community-based studies and clinical trials will be examined to evaluate evidence for progression of benign prostatic hyperplasia and the potential for its prevention.

Findings from Community Studies and Clinical Trials

Long-Term Complications

Pharmacologic Strategies for Prevention

Discussion

Progression of urinary symptoms, prostate volume growth, and deterioration of urinary flow rate over time have been documented in a number of studies. Both cross-sectional and longitudinal community studies have consistently demonstrated worsening of urinary symptoms and flow rate, as well as prostatic growth, in men over 50 years of age. In addition, newly available data from placebo groups of men with benign prostatic hyperplasia in controlled clinical trials have documented measurable prostatic growth in individual selected patients over time.

With the accumulation of knowledge about benign prostatic hyperplasia in recent years, the International Consultation on benign prostatic hyperplasia Committee for Regulation of Prostatic Growth has recommended greater emphasis on possible intervention initiatives that could lead to the prevention of benign prostatic hyperplasia. Clinical trials have now documented that disease progression can be altered. This is supported by findings from long-term studies demonstrating that finasteride leads to durable improvements in urinary symptoms and flow rates as well as a reduction of prostate gland size and prevention of further growth over time in men with symptomatic benign prostatic hyperplasia. Multiple studies provided even stronger evidence in showing that finasteride reduces the risk of long-term outcomes of benign prostatic hyperplasia, including development of acute urinary retention and the need for benign prostatic hyperplasia-related surgery. No therapeutic agents other than finasteride have been shown to affect long-term complications or sequelae of benign prostatic hyperplasia.

The men recruited into most of the finasteride benign prostatic hyperplasia trials were older (generally in their sixties) with moderate to severe benign prostatic hyperplasia symptoms and an enlarged prostate on digital rectal examination. It is unknown what effect introduction of finasteride earlier in the disease process would have had. To study such effects and the effects on rarer complications, a much larger patient population and even longer-term follow-up is necessary. The 7-year trial of finasteride, doxazosin, their combination, and placebo currently being conducted by the National Institutes of Health will hopefully answer some of these questions. Likewise, the National Cancer Institute trial being conducted in 18,000 men to assess finasteride as a potential prostate cancer chemopreventive agent will also greatly supplement the available long-term evidence on prevention of benign prostatic hyperplasia upon its completion in 2003. Finally, long-term follow-up of young men currently being treated with finasteride 1 mg for male pattern hair loss may also shed light on this area.

Conclusion

The past decade has introduced many new alternatives for treating benign prostatic hyperplasia through minimally invasive procedures and medical therapy. Surgery and minimally invasive procedures may be employed later in the disease process and produce symptomatic relief but may have associated reoperative rates, while alpha-blockers rapidly alleviate symptoms. None of these strategies, however, have been shown to definitively alter the long-term progression of the actual disease process. The 5 a-reductase inhibitor finasteride has been shown to provide modest but durable symptomatic relief. It is the only available medical therapy which may prevent progression of benign prostatic hyperplasia by shrinking the prostate gland and reducing the risk of long-term complications such as acute urinary retention and benign prostatic hyperplasia-related surgical intervention.

Symptoms

It is well known that the prevalence of urinary symptoms increases with age. Based on cross-sectional community-based studies, age-related increases in the prevalence of lower urinary tract symptoms have been consistently found in numerous countries in studies using similar questionnaires, despite cross-cultural differences in the prevalence of moderate to severe symptoms.

Few longitudinal studies have explored the progression of lower urinary tract symptoms by following untreated men over time. Recent longitudinal findings from the community-based Olmsted County Study of Urinary Symptoms and Health Status Among Men suggest a measurable progression in symptom severity, on average, over 3.5 to 4 years accompanied by high intraindividual variability The age-related changes found in this study were consistent with autopsy prevalence studies relating prostate volume to age. Another community study has also documented symptom progression over 3 years. Continued follow-up of such community-based cohorts of men should better characterize the rate of progression of urinary symptoms over longer time periods among untreated men in the community.

In addition to the longitudinal community data from Olmsted County, 4-year longitudinal data are also available from a selected population of 500 patients with benign prostatic hyperplasia who were considered candidates for elective prostatectomy or watchful waiting at five North American urology practices. Although variability in symptoms within individuals was high, progression was dependent on initial symptom severity. Of those with mild symptoms at baseline, a high proportion had progressed to moderate (50%), severe (7%), or had undergone surgery (10%) at 4 years. For those with moderate baseline symptoms, 17% had progressed to severe symptoms by 4 years and 24% had undergone surgery. The majority of patients with severe symptoms at baseline either still had severe symptoms (38%) by 4 years or had undergone surgery (39%) .

There have been long-term, placebo-controlled trials conducted in men with benign prostatic hyperplasia that evaluated symptoms over periods of 1 to 4 years. Heterogeneity in the populations studied, entry criteria, number and frequency of clinic visits, symptom questionnaires used, and, especially, the magnitude of the placebo effects, however, limit the interpretation of such data from placebo arms of clinical trials in terms of natural progression of symptom frequency and severity.

Placebo-controlled finasteride, terazosin, and tamsu-losin studies in men with symptomatic benign prostatic hyperplasia have shown symptom-score improvements varying from 1 to 6 units in placebo-treated patients treated for 1 or more years. The magnitude of placebo effect appears to diminish somewhat with longer-term controlled follow-up.’ In general, the degree of symptomatic improvement with placebo in this type of clinical trial setting is related to baseline symptom severity and may involve a regression to the mean phenomenon. In the 4-year placebo-controlled clinical trial known as the Proscar Long-term Efficacy and Safety Study (PLESS) , however, a predefined slope analysis, which purposely evaluated the change in symptom score with placebo after the first year of the study, did show slight worsening (approximately 0.25 units per year) over years 2 through 4 of the study, consistent with the longitudinal data in untreated men.

Urinary Flow Rate

In cross-sectional studies, peak urinary flow rate has been shown to decline with age although intraindividual variability is high. Based on cross-sectional data collected from men randomly selected from the community, median peak flow rate declined from 20.3 mL per second for men aged 40 to 44 years to about 11.5 mL per second for men aged 75 to 79 years. Peak flow rate is dependent on voided volume and age, typically in a nonlinear manner; there have been various techniques proposed to construct nomograms. Single void peak flow rates have relatively low test-retest reliability in the same patients, and can be affected by medication and other extraneous factors, including diurnal variability and learning effects.’

Relatively little longitudinal data are available on the rate of deterioration in peak flow rates over time in representative cohorts of men. The longitudinal aspect of the Olmsted County community study recently reported that the decline in peak flow rate with age is supported by longitudinal data in individual untreated patients followed for approximately 5 years. The estimated rate of decline over 5 years in randomly selected men was approximately 2.4% per year. The rate of decline was greater in older men and in men with prostatic enlargement.

Although urinary flow rates are often thought to be objective measurements, placebo effects in clinical trials, even beyond the initial “learning” effects, are common with such measurements. In general, placebo-treated patients have typically shown slight improvement or no deterioration over time, depending on the study. Most alpha-blocker trials have been of limited duration, ranging from 3 weeks to 3 months of double-blind therapy, and have shown mean improvements for peak urinary flow rate as high as 2.2 mL per second in placebo groups at the end of study. In two trials of 1-year duration involving terazosin, the mean change for the placebo group ranged from 0.8 to 1.4 mL per second for peak urinary flow rate. Longer term finasteride trials have shown minimal change for peak urinary flow rates in placebo-treated patients over 1 to 4 years, and a 2-year study showed slight worsening for the placebo group.

Prostate Size

Autopsy studies, which by their very nature are cross-sectional, have documented a steady increase in prostate volume with increasing age. Community-based cross-sectional studies using transrectal ultrasonography or magnetic resonance imaging in men also suggest a steady increase in prostate size with increasing age. Jakobsen studied 115 men randomly selected from a population registry and another 60 men about to have a vasectomy. He noted slight increases in prostate volume with age but most of the men in his sample were aged 30 to 50 years. Bosch studied men aged 55 to 75 years recruited from a Rotterdam community to participate in a randomized trial of prostate cancer screening. He found much steeper age-dependent increases in overall prostate size and an age-related increase in the central hypoechoic volume. Garraway and Collins reported on prostate volume in men in a community setting selected on the basis of symptoms and low flow rate. Although the sample may not be representative of the general community, the age-related increase in prostate volume corresponded well with that found in the autopsy series by Berry.

Community-based longitudinal data are now available from the Olmsted County study, based on 5-year follow-up of randomly selected men aged 40 to 79 years. Prostate volume, as measured by ultrasound, increased an average of 1.6% per year consistently across all age groups. Interestingly, the rate of growth for individual patients was highly dependent on baseline prostate volume. Men with larger prostate volumes at baseline had larger growth rates than men with smaller prostates at baseline. The growth spurt around the sixth decade of life which had been postulated based on a small longitudinal study of 16 men followed for up to 7 years could be reflective of the typically larger prostate size for men in their sixties. Further research should confirm these findings.

Although earlier clinical trials suggested potential placebo effects on prostate volume measurements, careful methodologic attention and blinding procedures can reduce or eliminate such effects in clinical studies. Long-term prostate growth has been documented in placebo-treated patients from the PLESS trial.’ In this 4-year study of 3040 men with symptomatic benign prostatic hyperplasia and enlarged prostates (determined by digital rectal examination), prostate volume was obtained annually by magnetic resonance imaging in a subset of 155 men treated with placebo. All films were read at the end of the trial by a single radiologist blinded to treatment group as well as to patient identifiers, age, and year of measurement. Placebo-treated men experienced an average increase in prostate volume of approximately 3% per year. By the end of the study, men treated with placebo had a 14% increase in prostate volume over 4 years. Increases in prostate volume were documented in 80% of the placebo-treated men. The growth rates estimated in PLESS placebo patients are supported by estimates from 2-year trials.’ As it is known that men with increased prostate volume are at increased risk of benign prostatic hyperplasia-related outcomes (e.g., developing acute urinary retention, benign prostatic hyperplasia-related surgery),prostate volume growth over time may put untreated men with symptomatic benign prostatic hyperplasia at increased risk of long-term complications.

Untreated, benign prostatic hyperplasia may lead to complications such as acute or chronic urinary retention, renal failure, serious or recurrent urinary tract infections, bladder decompensation, hydronephrosis, and calculi, particularly bladder calculi. Few studies, however, have quantified the long-term risk of these complications. Several authors have reviewed the available literature on the incidence and risk of such complications in detail.

Acute Urinary Retention and Associated Risk Factors

Bladder outlet obstruction may progress to acute urinary retention, a painful, sudden inability to urinate. Many patients consider this to be the most serious outcome of untreated benign prostatic hyperplasia, and it often requires emergency medical attention. Some clinicians considered acute urinary retention to be an absolute indication for surgical intervention while others have proposed catheterization and a voiding trial.’ The recurrence of acute urinary retention within 1 week of catheterization is high, however. The etiology of acute urinary retention is not well understood. Based on previous studies, it has been thought to occur unpredictably.

The incidence-rate estimates for acute urinary retention vary dramatically by study. Estimates of acute urinary retention occurrence have ranged from 4 to 130 per 1000 person-years.” More recently, Barry estimated the incidence of acute urinary retention at 2.5% per year of men with clinically diagnosed benign prostatic hyperplasia followed for 4 years in North American urology practices.

In a recent analysis based on a review of 3- to 4-year data from men participating in the Olmsted County longitudinal community study, age, symptoms, urinary flow rate, and prostate volume were significant risk factors for the occurrence of acute urinary retention. Incidence rates of acute urinary retention in symptomatic men varied by age, ranging from 3.0 per 1000 person-years for men 40 to 49 years to 34.7 per 1000 person-years for men aged 70 to 79 years. Approximately half of the cases of retention were spontaneous while the rest were precipitated by factors such as preceding surgery, anesthesia, or medication. The risk of retention for men with prostates above 30 mL was elevated three-fold (95% CI: 1.0, 9.0) relative to men with smaller prostates and fourfold for men with low peak flow rate (< 12 mL per second).

Rates of acute urinary retention in placebo-controlled patients have varied across clinical trial settings with different entry criteria, particularly when follow-up data were not diligently collected or there was a high discontinuation rate. Since men who deteriorate often discontinue clinical trials and are not followed up, adequate information on those most at risk is lost if detailed follow-up on discontinued patients is not obtained. In addition, short studies, especially those that enrolled men with smaller prostate volumes, have typically not had high enough rates of acute urinary retention for reliable analysis.

Estimates have been surprisingly consistent, however, from four studies of sufficient duration (at least 1 year) and with adequate follow-up of discontinued patients, with data collected in a systematic fashion based on predefined criteria. The first, a randomized trial of transurethral resection of the prostate (transurethral resection of the prostate) versus watchful waiting in men over 54 years of age with moderate to severe symptoms and average baseline peak flow rate of approximately 12 mL per second, had a rate of “intractable urinary retention” of 2.9% for the watchful waiting group over 3 years. In the multinational, randomized, placebo-controlled Hytrin Community Assessment Trial (HYCAT) study, which evaluated patients over 55 years with AUA symptom index above 12 who were bothered and had a peak flow rate of 15 mL per second or below, the rate of spontaneous acute urinary retention in the placebo group was 1.3% in 1 year. In the pooled analysis of three multinational 2-year finasteride trials, the incidence of acute urinary retention was 2.7% over 2 years for placebo-treated patients with moderate to severe symptoms and prostatic enlargement. Finally, in the 4-year PLESS study, based in the United States, the incidence of spontaneous acute urinary retention in men with moderately to severely symptomatic benign prostatic hyperplasia was 4% over 4 years. Thus, in the clinical trial setting, the incidence of spontaneous acute urinary retention in placebo-treated men is approximately 1% per year. The incidence of precipitated acute urinary retention was also documented in PLESS and was found to be 3% over 4 years. As in the community-based Olmsted County longitudinal study, the incidence of spontaneous and precipitated retention appears to be approximately equivalent.

Surgical Intervention and Minimally Invasive Procedures

The most common surgical procedure for benign prostatic hyperplasia is transurethral resection of the prostate, with open prostatectomy typically reserved for men with very large prostates or for those in whom the lithotomy position is problematic or who require additional procedures. Minimally invasive procedures have been introduced more recently although long-term data on efficacy, complications, and recurrence are only recently accumulating. The indications for surgery vary widely and are not universally accepted. Older patients and those with renal insufficiency are at higher operative risk for complications and mortality due to increased comorbidity and may not be good candidates for surgical intervention.

Based on the Normative Aging Study, a man aged 50 years has been estimated to have a one in three chance of prostatectomy if he survives to the age of 80 years. Characterizing the risk for surgery is complex, however, due to the changing incidence of surgical intervention with time, the introduction of new surgical and medical alternatives, cost containment strategies, widely varying referral and geographic patterns, and lack of consensus on indications for surgery. The decision to proceed to surgery relies heavily on patient attitudes and values, which in turn can be influenced by the surgeon. Some patients avoid the trauma of surgery despite severe and bothersome symptomatology while others seek surgery for the mildest of symptoms. Although these factors make characterization of surgical risk complex, several epidemiologic studies and clinical trials have shed light on the rate of surgery and associated risk factors.

Several studies have found that severity of urinary symptoms was predictive of surgical intervention although individual symptoms found to be predictive have varied by study. Other factors include prior clinical diagnosis of benign prostatic hyperplasia, higher socioeconomic status, low body mass, Jewish religion, and nonsmoking status.” One study based on up to 30 years of follow-up of over 1000 men found that increased age, prostate size (as estimated by digital rectal examination), and urinary symptoms were predictive of prostatectomy. This is consistent with the finding that men with prostatic enlargement, moderate to severe symptoms, or low peak flow rate are more likely to seek medical care.

In the Veterans Administration trial of transurethral resection of the prostate versus watchful waiting, 24% of the men assigned to the watchful waiting group underwent surgery within 3 years and 2.9% had urinary retention. In the study mentioned above of 500 men with benign prostatic hyperplasia who were followed in five North American urology practices, 10% of those with mild symptoms at baseline underwent prostatectomy during the 4-year follow-up. The percentage of men proceeding to surgery was higher for men with moderate (24.1%) and severe (39.4%) symptoms at baseline.

Placebo-treated patients from alpha-blocker trials provide little information on the rate of surgery in untreated men due to the typically brief duration of the controlled portion of the study and the lack of adequate follow-up, as mentioned above. The HYCAT study, however, which recruited men aged 55 years or older with moderate to severe symptoms (AUA symptom index greater than 12) who were bothered and had reduced urinary flow rate (peak flow rate < 15 mL per second), reported a prostatectomy rate of 5% for placebo-treated patients during the 1-year study.

Placebo-controlled data from clinical trials of 5 a-reductase inhibitors ranging in duration from 2 to 4 years are available and provide data from the clinical trial setting. In a combined analysis of three 2-year multinational studies, Andersen et al. reported that 6.5% of the placebo patients with moderate to severe symptoms and prostatic enlargement underwent prostatectomy over the 2-year follow-up. Similarly, in the 4-year PLESS trial, approximately 10% of placebo-treated patients with moderately to severely symptomatic benign prostatic hyperplasia underwent surgical intervention over the 4-year period. Because participants in clinical trials may be encouraged to stay in the study and the studies were designed to be long-term, these rates may reflect an underestimate of rates of surgery in men with symptomatic benign prostatic hyperplasia. It is therefore not surprising that the rates are lower than those reported over a similar period in the urologic practice setting.

Rates for repeat prostatectomy following transurethral resection of the prostate or minimally invasive procedures have been reported but range in magnitude depending on the study. The Veterans Administration Cooperative trial of transurethral resection of the prostate versus watchful waiting had an estimated re-transurethral resection of the prostate rate for benign prostatic hyperplasia of 2% over 3 years although earlier studies suggested a rate as high as 10%. One French study of transurethral resection of the prostate showed a 6.3% reoperation rate at less than 1 year and 6.5% of patients experiencing urethral stricture. The likelihood of reoperation within 6 years from 1980 to 1987 was 15.1% in a study of 330 Rochester, Minnesota men who were undergoing their first prostatectomy for benign prostatic hyperplasia. In a recent study by Lu-Yao et al., based on a 20% random sample of Medicare claims, a recurrence rate of transurethral resection of the prostate for benign prostatic hyperplasia of approximately 2.9% over 3 years and 5.5% over 7 years was reported, with the risk of recurrence dependent on age.

Avoidance of surgery is important from a public health standpoint, partly because of the associated morbidity that occasionally occurs, and also because of the potential need for reoperation. Rare complications associated with surgical intervention include dilutional hyponatremia, perioperative infection such as epididymitis and urinary tract infection, fever, urinary retention, hemorrhage requiring transfusion, myocardial infarction, stroke, incisional complications, retrograde ejaculation, impotence, and urinary incontinence. The need for recatheterization, and hyponatremia presumably associated with fluid absorption, have also been reported.

Minimally invasive procedures such as laser prostatectomy, transurethral incision of the prostate, prostatic stents, and transurethral microwave thermotherapy have been purportedly associated with lower morbidity than transurethral resection of the prostate or open prostatectomy but have potentially higher reoperative rates. Sufficiently long-term data in large samples of men from multiple institutions are lacking, however. Effects of thermotherapy have been studied for periods as long as 3 to 4 years and appear to be durable in patients consenting to continued follow-up although various studies report high rates of complications such as urinary retention requiring catheterization. Retreatment rates vary from 0.6 to 14%.