Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

67. Benign Prostatic Hyperplasia

Mary Lee


KEY CONCEPTS

 Images Although symptomatic benign prostatic hyperplasia (BPH) is rare in men younger than 50 years of age, it is very common in men 60 years and older because of androgen-driven growth in the size of the prostate. Symptoms commonly result from both static and dynamic factors.

 Images BPH symptoms may be exacerbated by medications, including antihistamines, phenothiazines, tricyclic antidepressants, and anticholinergic agents. In these cases, discontinuing the causative agent can relieve symptoms.

 Images Specific treatments for BPH include watchful waiting, drug therapy, and surgery.

 Images For patients with mild disease who are asymptomatic or have mildly bothersome symptoms and no complications of BPH disease, no specific treatment is indicated. These patients can be managed with watchful waiting. Watchful waiting includes behavior modification and return visits to the physician at 6- or 12-month intervals for assessment of worsening symptoms or signs of BPH.

 Images If symptoms progress to a moderate or severe level, drug therapy or surgery is indicated. Drug therapy with an α1-adrenergic antagonist is an interim measure that relieves voiding symptoms. In select patients with prostates of at least 40 g, 5α-reductase inhibitors delay symptom progression and reduce the incidence of BPH-related complications.

 Images All α1-adrenergic antagonists are equally effective in relieving BPH symptoms, but do not halt disease progression or delay surgical intervention. Older second-generation immediate-release formulations of α1-adrenergic antagonists (e.g., terazosin, doxazosin) can cause adverse cardiovascular effects, mainly first-dose syncope, orthostatic hypotension, and dizziness. For patients who cannot tolerate hypotensive effects of the second-generation agents, the third-generation, pharmacologically uroselective agents (e.g., tamsulosin, silodosin) are good alternatives. An extended-release formulation of alfuzosin, a second-generation, functionally uroselective agent, and third-generation pharmacologically uroselective agents have fewer cardiovascular adverse effects than immediate-release formulations of terazosin or doxazosin. Generic formulations are less expensive than single-source agents and should be preferentially prescribed in patients with limited financial resources.

 Images 5α-Reductase inhibitors are useful primarily for patients with large prostates greater than 40 g who wish to avoid surgery and cannot tolerate the side effects of α1-adrenergic antagonists. 5α-Reductase inhibitors have a slow onset of action, taking up to 6 months to exert maximal clinical effects, which is a disadvantage of their use. In addition, decreased libido, erectile dysfunction, and ejaculation disorders are common adverse effects, which may be troublesome problems in sexually active patients.

 Images Phosphodiesterase inhibitors are indicated in patients with moderate-severe BPH and erectile dysfunction. They improve lower urinary tract symptoms (LUTS), but do not increase urinary flow rate or reduce postvoid residual (PVR) urine volume. For these reasons, phosphodiesterase monotherapy is considered less effective than an α-adrenergic antagonist for BPH. A phosphodiesterase inhibitor may be used alone or along with an α-adrenergic antagonist.

 Images Anticholinergic agents are indicated in patients with moderate to severe LUTS with a predominance of irritative voiding symptoms. Because older patients are at high risk of systemic anticholinergic adverse effects, uroselective anticholinergic agents may be preferentially prescribed. To minimize the risk of acute urinary retention, a patient’s PVR urine volume should be less than 250 mL before initiating treatment with an anticholinergic agent.

 Images Surgery is indicated for moderate to severe symptoms of BPH for patients who do not respond to or do not tolerate drug therapy or for patients with complications of BPH. It is the most effective mode of treatment in that it relieves symptoms in the greatest number of men with BPH. However, the two most widely used techniques, transurethral resection of the prostate and open prostatectomy, are associated with the highest rates of complications, including retrograde ejaculation and erectile dysfunction. Therefore, minimally invasive surgical procedures are often desired by patients. These relieve symptoms and are associated with a lower rate of adverse effects, but they have higher reoperation rates than the gold standard procedures.


Benign prostatic hyperplasia (BPH) is the most common benign neoplasm of American men. A nearly ubiquitous condition among elderly men, BPH is of major societal concern, given the large number of men affected, the progressive nature of the condition, and the healthcare costs associated with it.

This chapter discusses BPH and its available treatments: watchful waiting, α1-adrenergic antagonists, 5α-reductase inhibitors, phosphodiesterase inhibitors, anticholinergic agents, and surgery. The limitations of phytotherapy are described.

EPIDEMIOLOGY

Images According to the results of autopsy studies, approximately 80% of elderly men develop microscopic evidence of BPH. About half of the patients with microscopic changes develop an enlarged prostate gland, and as a result, they develop symptoms including difficulty emptying urine from the urinary bladder. Approximately half of symptomatic patients eventually require treatment.

The peak incidence of clinical BPH occurs at 63 to 65 years of age. Symptomatic disease is uncommon in men younger than 50 years, but some urinary voiding symptoms are present by the time men turn 60 years of age. The Boston Area Normative Aging Study estimated that the cumulative incidence of clinical BPH was 78% for patients at age 80 years.1 Similarly, the Baltimore Longitudinal Study of Aging projected that approximately 60% of men at least 60 years old develop clinical BPH.2

NORMAL PROSTATE PHYSIOLOGY

Located anterior to the rectum, the prostate is a small heart-shaped, chestnut-sized gland located below the urinary bladder. It surrounds the proximal urethra like a doughnut.

Soft, symmetric, and mobile on palpation, a normal prostate gland in an adult man weighs 15 to 20 g. Physical examination of the prostate must be done by digital rectal examination (i.e., the prostate is manually palpated by inserting a finger into the rectum). Thus, the prostate is examined through the rectal mucosa.

The prostate has two major functions: (a) to secrete fluids that make up a portion (20–40%) of the ejaculate volume and (b) to provide secretions with antibacterial effect possibly related to its high concentration of zinc.2

At birth, the prostate is the size of a pea and weighs approximately 1 g. The prostate remains that size until the boy reaches puberty. At that time, the prostate undergoes its first growth spurt, growing to its normal adult size of 15 to 20 g by the time the young man is 25 to 30 years of age. The prostate remains this size until the patient reaches age 40 years, when a second growth spurt begins and continues for the rest of his lifetime. During this period, the prostate can quadruple in size or grow even larger.

The prostate gland comprises three types of tissue: epithelial tissue, stromal tissue, and the capsule. Epithelial tissue, also known as glandular tissue, produces prostatic secretions. These secretions are delivered into the urethra during ejaculation and contribute to the total ejaculate volume. Androgens stimulate epithelial tissue growth. Stromal tissue, also known as smooth muscle tissue, is embedded with α1-adrenergic receptors. Stimulation of these receptors by norepinephrine causes smooth muscle contraction, which results in an extrinsic compression of the urethra, reduction of the urethral lumen, and decreased urinary bladder emptying. The normal prostate is composed of a higher amount of stromal tissue than epithelial tissue, as reflected by a stromal-to-epithelial tissue ratio of 2:1. This ratio is exaggerated to 5:1 for patients with BPH, which explains why α1-adrenergic antagonists are quickly effective in symptomatic management and why 5α-reductase inhibitors reduce an enlarged prostate gland by only 25%.2,3 The capsule, or outer shell of the prostate, is composed of fibrous connective tissue and smooth muscle, which also is embedded with α1-adrenergic receptors. When stimulated with norepinephrine, the capsule contracts around the urethra (Fig. 67-1).

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FIGURE 67-1 Representation of the anatomy of and α-adrenergic receptor distribution in the prostate, urethra, and bladder. (Western J Med 1994;161:501. Reproduced with permission from the BMJ Publishing Group.)

Testosterone is the principal testicular androgen in males, whereas androstenedione is the principal adrenal androgen. These two hormones are responsible for penile and scrotal enlargement, increased muscle mass, and maintenance of the normal male libido. These androgens are converted by 5α-reductase in target cells to dihydrotestosterone (DHT), an active metabolite. Two types of 5α-reductase exist. Type I enzyme is localized to sebaceous glands in the frontal scalp, liver, and skin, although a small amount is in the prostate. DHT produced at these target tissues causes acne and increased body and facial hair. Type II enzyme is localized to the prostate, genital tissue, and hair follicles of the scalp. In the prostate, DHT induces growth and enlargement of the gland.3

In prostate cells, DHT has greater affinity for intraprostatic androgen receptors than testosterone, and DHT forms a more stable complex with the androgen receptor. Thus, DHT is considered a more potent androgen than testosterone in the prostate. Of note, despite the decrease in testicular androgen production in the aging male, intracellular DHT levels in the prostate remain normal, probably due to increased activity of intraprostatic 5α-reductase.3

Estrogen, a product of peripheral metabolism of androgens, is believed to stimulate the growth of the stromal portion of the prostate gland. Estrogens are produced when testosterone and androstenedione are converted by aromatase enzymes in peripheral adipose tissues. In addition, estrogens may induce the androgen receptor.2 As men age, the ratio of serum levels of testosterone to estrogen decreases as a result of a decline in testosterone production by the testes and increased adipose tissue conversion of androgen to estrogen.

PATHOPHYSIOLOGY

Although the precise pathophysiologic mechanisms causing BPH remain unclear, the role of intraprostatic DHT and type II 5α-reductase in the development of BPH is evidenced by several observations:

   1. BPH does not develop in men who are castrated before puberty.

   2. Patients with type II 5α-reductase enzyme deficiency do not develop BPH.

   3. Castration causes an enlarged prostate to shrink.

   4. Administration of testosterone to orchiectomized dogs of advanced age produces BPH.

The pathogenesis of BPH is often described as resulting from both static and dynamic factors. Static factors relate to anatomic enlargement of the prostate gland, which produces a physical block at the bladder neck and thereby obstructs urinary outflow. Enlargement of the gland depends on androgen stimulation of epithelial tissue and estrogen stimulation of stromal tissue in the prostate. Dynamic factors relate to excessive α-adrenergic tone of the stromal component of the prostate gland, bladder neck, and posterior urethra, which results in contraction of the prostate gland around the urethra and narrowing of the urethral lumen.

Symptoms of BPH disease may result from static and/or dynamic factors, and this must be recognized when drug therapy is considered. For instance, some patients may present with obstructive voiding symptoms but have prostates of normal size. In these patients, dynamic factors likely are responsible for the symptoms. However, for patients with enlarged prostate glands, static and dynamic factors likely are working in concert to produce the observed symptoms. Moreover, the likelihood of developing moderate to severe voiding symptoms is directly related to the increasing size of the prostate gland.4

Static factors may be accentuated if the patient becomes stressed or is in pain. In these situations, increased α-adrenergic tone may precipitate excessive contraction of prostatic stromal tissue. When the stressful event resolves, voiding symptoms often improve.2

MEDICATION-RELATED SYMPTOMS

Images Medications in several pharmacologic categories should be avoided for patients with BPH because they may exacerbate symptoms.5 Testosterone replacement regimens, used to treat primary or secondary hypogonadism, deliver additional substrate that can be metabolized to DHT by the prostate. Although no cases of BPH have been reported because of exogenous testosterone administration, cautious use is advised for patients with prostatic enlargement. α-Adrenergic agonists, used as oral or intranasal decongestants (e.g., pseudoephedrine, ephedrine, or phenylephrine), can stimulate α-adrenergic receptors in the prostate, resulting in muscle contraction. By decreasing the caliber of the urethral lumen, bladder emptying may be compromised. β-Adrenergic agonists (e.g., terbutaline) may cause relaxation of the bladder detrusor muscle, which prevents bladder emptying.6 Drugs with significant anticholinergic adverse effects (e.g., antihistamines, phenothiazines, tricyclic antidepressants, or anticholinergic drugs used as antispasmodics or to treat Parkinson’s disease) may decrease contractility of the urinary bladder detrusor muscle. For patients with BPH who have a narrowed urethral lumen, loss of effective detrusor contraction could result in acute urinary retention, particularly for patients with significantly enlarged prostate glands. Diuretics, particularly in large doses, can produce polyuria, which may present as urinary frequency, similar to that experienced by patients with BPH.

CLINICAL PRESENTATION

Patients with BPH can present with a variety of symptoms and signs of disease. All symptoms of BPH can be divided into two categories: obstructive and irritative.

Obstructive symptoms, also known as prostatism or bladder outlet obstruction, result when dynamic and/or static factors reduce bladder emptying. The force of the urinary stream becomes diminished, urinary flow rate decreases, and bladder emptying is incomplete and slow. Patients report urinary hesitancy and straining and a weak urine stream. Urine dribbles out of the penis, and the urinary bladder always feels full, even after patients have voided. Some patients state that they need to press on their bladder to force out the urine. In severe cases, patients may go into urinary retention when bladder emptying is not possible. In these cases, suprapubic pain can result from bladder overdistension.

Approximately 50% to 80% of patients have irritative voiding symptoms, which typically occur late in the disease course. Irritative voiding symptoms result from long-standing obstruction at the bladder neck. To compensate, the bladder muscle undergoes hypertrophy so that it can generate a greater contractile force to empty urine past the anatomic obstruction at the bladder neck. Although initially helpful, decompensation eventually occurs, and the hypertrophied bladder muscle is no longer able to generate adequate contractile force as it becomes hypersensitive and ineffective in storing urine. As a result, small amounts of urine irritate the bladder and initiate a bladder emptying response. Patients complain of urinary frequency and urgency. Bedwetting or clothes wetting occurs. Patients report waking up every 1 to 2 hours at night to void (nocturia), which significantly reduces quality of life.

Symptoms of BPH vary over time. Symptoms may improve, remain stable, or worsen spontaneously. Thus, BPH is not necessarily a progressive disease; in fact, some patients experience symptom regression. Between one and two thirds of men with mild disease stabilize or improve without treatment over 2.5 to 5 years.2,4 However, other patients experience a slow progression of disease.


CLINICAL PRESENTATION Benign Prostatic Hyperplasia

General

    • A patient is in no acute distress unless he has moderate to severe symptoms or complications of BPH

Symptoms

    • Urinary frequency, urgency, intermittency, nocturia, decreased force of stream, hesitancy, and straining

Signs

    • Digital rectal examination reveals an enlarged prostate (<20 g) with no nodules or indurations; prostate is soft, symmetric, and mobile

Laboratory Tests

    • Increased blood urea nitrogen (BUN) and serum creatinine with long-standing, untreated bladder outlet obstruction, elevated PSA level

Other Diagnostic Tests

    • Increased American Urological Association (AUA) Symptom Score, decreased urinary flow rate (<10 mL/s), and increased postvoid residual (PVR) urine volume

Collectively, obstructive and irritative voiding symptoms and their impact on a patient’s quality of life are referred to as lower urinary tract symptoms (LUTS). However, LUTS is not pathognomonic for BPH and may be caused by other diseases, such as neurogenic bladder and urinary tract infection.2

Another presentation of BPH is silent prostatism. Patients have obstructive or irritative voiding symptoms, but adapt to them and do not voluntarily complain about them. Such patients do not present for medical treatment until complications of BPH disease arise or a spouse brings in the symptomatic patient for medical care.

BPH can be a progressive disease, although the rate of progression is variable among patients.2,5 When BPH progresses, it can produce complications that include the following:

   1. Acute, painful urinary retention, which can lead to acute renal failure

   2. Persistent gross hematuria when tissue growth exceeds its blood supply

   3. Overflow urinary incontinence or unstable bladder

   4. Recurrent urinary tract infection that results from urinary stasis

   5. Bladder diverticula

   6. Bladder stones

   7. Chronic renal failure from long-standing bladder outlet obstruction

Approximately 17% to 20% of patients with symptomatic BPH require treatment because of disease complications.7 Older men greater than 70 years of age with large prostates greater than 40 g and a postvoid residual (PVR) urine volume greater than 100 mL are three times more likely to have severe symptoms or suffer from acute urinary retention and to require prostatectomy than patients with smaller prostates.810 Thus, a serum prostate-specific antigen (PSA) level of 1.4 ng/mL (1.4 mcg/L) has been used as a surrogate marker for an enlarged prostate gland to identify patients at risk for developing complications of BPH disease6,10 and has been used to guide selection of the most appropriate treatment modality in some patients.11,12

DIAGNOSTIC EVALUATION

Because the obstructive and irritative voiding symptoms associated with BPH are not unique to the disease and can be presenting symptoms of other genitourinary tract disorders, including prostate or bladder cancer, neurogenic bladder, prostatic calculi, or urinary tract infection, the patient presenting with signs and symptoms of BPH must be thoroughly evaluated.

A careful medical history should be taken to ensure that a complete listing of symptoms is collected as well as to identify concomitant disorders that may be contributing to voiding symptoms. The medical history should be followed by a thorough medication history, including all prescription and nonprescription medications and dietary supplements that the patient is taking. Any drugs that could be causing or exacerbating the patient’s symptoms should be identified. If possible, the suspected drugs should be discontinued or the dosing regimen modified to ameliorate the voiding symptoms.

The patient should undergo a physical examination, including a digital rectal examination, although the size of the prostate gland may not correspond to symptoms. BPH usually presents as an enlarged, soft, smooth, symmetric gland, greater than 20 g in size. Some patients have only a slightly enlarged gland and yet have bothersome or even serious voiding difficulties. Other patients have intravesical enlargement of the prostate gland (i.e., the gland grows into the urinary bladder and produces a ball-valve blockage of the bladder neck). This type of prostate enlargement is not palpable on digital examination.

The patient’s perception of the severity of BPH symptoms guides selection of a particular treatment modality in a patient. To evaluate the patient’s perceptions objectively, validated instruments, such as the AUA Symptom Score (Table 67-1), are commonly used. Using the AUA Symptom Score, the patient rates the “bothersomeness” of seven obstructive and irritative voiding symptoms.2,13 Each item is rated for severity on a scale from 0 to 5, such that 35 is the maximum score and is consistent with the most severe symptoms. Patients usually are stratified into the three groups shown in the table based on disease severity for the purposes of deciding a treatment approach.

TABLE 67-1Categories of BPH Disease Severity Based on Symptoms and Signs

Images

In addition, the patient can complete a voiding diary in which he records the number of voids, the volume of each void, and voiding symptoms for several days. This information is used to evaluate symptom severity and tailor recommendations for lifestyle modifications that may ameliorate symptoms.

The only clinical laboratory test that must be performed is a urinalysis. Because many of the voiding symptoms of BPH could be caused by other urologic disorders, a urinalysis can help screen for bladder cancer, stones, and infection. To screen for prostate cancer, another common cause of glandular enlargement, a PSA test should be performed for patients aged 40 years or more, with at least a 10-year life expectancy in whom the cost of the test will be outweighed by the potential benefit of diagnosing the disorder.13,14

Additional objective measures of bladder emptying should be performed if surgical treatment is being considered. Measures include peak and average urinary flow rate (normal is at least 10 mL/s). These measures are determined using an uroflowmeter, which checks the rate of urine flow out of the bladder. This is a quick noninvasive outpatient procedure in which the patient is instructed to drink water until his bladder feels full and then the patient’s urinary flow is clocked during voiding. A low urinary flow rate (<10 to 12 mL/s) implies failure of bladder emptying or a functional disorder of the detrusor muscle. Thus, the degree of bladder outlet obstruction may not correlate with peak urinary flow rate.13

Another objective measure is PVR urine volume (normal is 0 mL), which is assessed using a transabdominal ultrasound. A high PVR urine volume (<25 to 30 mL) implies failure of bladder emptying and a predisposition for urinary tract infections. Because of a weak correlation among voiding symptoms, prostate size, and urinary flow rate, most physicians use a combination of measures, including the patient’s assessment of symptoms along with objective evaluation of urinary outflow and presence of complications of BPH to determine the need for treatment.

Many other tests can be performed if additional information is needed to assess the severity of BPH disease and its complications, to assist in the preoperative assessment of the patient, or to distinguish prostate enlargement due to BPH from that caused by prostate cancer. Tests include a serum blood urea nitrogen (BUN) and creatinine, voiding cystometrogram, transrectal ultrasound of the prostate, IV pyelogram, renal ultrasound, and prostate biopsy.

TREATMENT

Benign Prostatic Hyperplasia

The goals of treatment are to control symptoms, as evidenced by a minimum of a 3-point decrease in the AUA symptom index, prevent progression of complications of BPH disease, and delay the need for surgical intervention for BPH.

As a disease of symptoms, BPH is treated by relieving bothersome symptoms. However, selection of a single best treatment for a patient must consider the variable costs and adverse effects of treatment options, the inability to clearly distinguish patients who experience spontaneous regression or disease stabilization from those in whom symptoms progress, and the potential benefit that may occur in a comparatively small number of treated patients.

The AUA Guidelines on Management of Benign Prostatic Hyperplasia is the principal tool used in the United States,13 and the AUA recommendations are similar to the European15 and Canadian Practice Guidelines (Fig. 67-2).16

Images

FIGURE 67-2 Management algorithm for benign prostatic hyperplasia (BPH).

Images All patients should be encouraged to initiate and maintain a heart healthy lifestyle, including a low-fat diet, high intake of plenty of fresh fruits and vegetables, regular physical exercise, and no smoking.17 Specific treatment options include watchful waiting, pharmacologic therapy, and surgical intervention. Although phytotherapy is used by some patients alone or along with conventional medications for BPH, head-to-head comparisons with FDA-approved treatments are lacking; consequently, such herbals cannot be recommended at this time.

Images Patients with mild disease are asymptomatic or have mildly bothersome symptoms and have no complications of BPH disease. For these patients, no specific treatment is indicated. These patients can be managed with watchful waiting, which entails having the patient return for reassessment at intervals of 6 to 12 months. At each return visit, the patient should complete a standardized, validated survey tool to assess severity of symptoms. Watchful waiting should be accompanied by patient education about the disease and behavior modification to avoid practices that exacerbate voiding symptoms. Behavior modification includes restricting fluids close to bedtime, minimizing caffeine and alcohol intake, frequent emptying of the bladder during waking hours (to avoid overflow incontinence and urgency), and avoiding drugs that could exacerbate voiding symptoms.18 At each visit, physicians should assess the patient’s risk of developing acute urinary retention by evaluating the patient’s prostate size or using PSA as a surrogate marker of prostate enlargement.13

Images If symptoms progress to the moderate or severe level, or the patient perceives his symptoms to be bothersome, the patient should be offered specific treatment. In these patients, watchful waiting delays—but does not decrease—the need for prostatectomy. In symptomatic patients, watchful waiting can lead to intractable urinary retention, increased PVR urine volumes, and significant voiding symptoms.18,19Recommended treatment options include drug therapy with an α1-adrenergic antagonist or 5α-reductase inhibitor, a combination of an α1-adrenergic antagonist and a 5α-reductase inhibitor, a phosphodiesterase inhibitor or an anticholinergic agent; or surgery.

Patients with serious complications of BPH should be offered surgical correction (transurethral or open prostatectomy, or a minimally invasive surgical procedure). Drug therapy is considered an interim measure for such patients because it only delays worsening of complications and the need for surgical intervention.13,18,19

Desired Outcomes

The desired outcomes of treatment include reducing LUTS as evidenced by an improvement of AUA Symptom Score by at least three points, an increase in the peak urinary flow rate, and a normalization of PVR to less than 50 mL. In addition, treatment should prevent the development of disease complications and reduce the need for surgical intervention. Treatment should be well tolerated and be cost-effective.

Personalized Pharmacotherapy

In selecting the most appropriate treatment for an individual patient, consideration should be given to the severity and quality of the patient’s LUTS, the likelihood of developing complications of BPH (based on size of the patient’s prostate gland), and the patient’s preference for medical versus surgical intervention.

Concurrent medical illnesses of the patient should also be considered. For example, if the patient has erectile dysfunction and moderate BPH, then a phosphodiesterase inhibitor might be preferred over a 5α-reductase inhibitor. If medical treatment is initiated, the patient’s level of renal function should be assessed, as the daily dose of some α-adrenergic antagonists and some anticholinergics require modification to avoid accumulation.

Pharmacologic Therapy

Drug therapy for BPH can be categorized into three types: agents that relax prostatic smooth muscle (reducing the dynamic factor), agents that interfere with testosterone’s stimulatory effect on prostate gland enlargement (reducing the static factor), and agents that relax bladder detrusor muscle (Tables 67-2 and 67-3). Of the agents that relax prostatic smooth muscle, second- and third-generation α1-adrenergic antagonists have been most widely used. These agents relax the intrinsic urethral sphincter and prostatic smooth muscle, thereby enhancing urinary outflow from the bladder. Phosphodiesterase inhibitors also relax bladder neck and prostatic smooth muscle. α1-Adrenergic antagonists and phosphodiesterase inhibitors do not reduce prostate size. Of the agents that interfere with testosterone’s stimulatory effect on prostate gland size, the only agents approved by the FDA are 5α-reductase inhibitors (e.g., finasteride, dutasteride). Other agents that interfere with androgen stimulation of the prostate have not been popular in the United States because of the many adverse effects associated with their use. The luteinizing hormone-releasing hormone superagonists leuprolide and goserelin decrease libido and can cause erectile dysfunction, gynecomastia, and hot flashes. Antiandrogens (e.g., bicalutamide, flutamide) produce nausea, diarrhea, and hepatotoxicity. Finally, antimuscarinic agents relax detrusor muscle contraction, which reduces irritable voiding symptoms in some patients with BPH.

TABLE 67-2 Medical Treatment Options for Benign Prostatic Hyperplasia

Images

TABLE 67-3 Comparison of α1-Adrenergic Antagonists, 5α-Reductase Inhibitors, Phosphodiesterase Inhibitors, and Anticholinergic Agents for BPH

Images

Selection of a medical treatment for a patient should be determined on a case-by-case basis after the patient and provider discuss the risks, benefits, and costs of various treatments. With drug therapy for BPH, patients must understand that the benefits continue only as long as the medication is taken.

If possible, drug therapy should be initiated with a single agent, usually an α1-adrenergic antagonist, which is faster acting and more effective than a 5α-reductase inhibitor. In addition, α1-adrenergic antagonists are effective in reducing LUTS independent of prostate size, have no effect on PSA, and are associated with less sexual dysfunction than are 5α-reductase inhibitors. A 5α-reductase inhibitor is a good first-choice agent for symptomatic patients with a significantly enlarged prostate (<40 g) who cannot tolerate the cardiovascular adverse effects of α1-adrenergic antagonists.

For patients at risk for developing complications of BPH, specifically patients with an enlarged prostate gland greater than 40 g7 and an elevated PSA ≥1.4 ng/mL (1.4 mcg/L), combination drug therapy with an α1-adrenergic antagonist and a 5α-reductase inhibitor is more beneficial than single drug therapy. The pharmacologic rationale for such a combination is that using two drugs with different mechanisms of action can be more effective than either drug alone. The clinical benefit of combination therapy is that it quickly relieves symptoms, delays disease progression, and reduces the need for surgical intervention.

For patients with both erectile dysfunction and BPH, a phosphodiesterase inhibitor alone or in combination with an α-adrenergic antagonist may be used. However, it should be noted that a phosphodiesterase inhibitor alone will only relieve LUTS and will not improve urinary flow rate or decrease postvoid urine volume. Therefore, a phosphodiesterase inhibitor is generally considered less effective than an α-adrenergic antagonist.

For patients with LUTS with a predominance of irritative voiding symptoms, an anticholinergic agent could be added to an existing drug regimen for BPH. To reduce the risk of developing systemic anticholinergic adverse effects, an uroselective anticholinergic agent may be preferentially prescribed. To avoid the risk of developing acute urinary retention, the patient’s PVR volume should be less than 250 mL before starting an anticholinergic agent.

α-Adrenergic Antagonists

Three generations of α-adrenergic antagonists have been used to treat BPH. They all relax smooth muscle in the prostate and bladder neck. Because of their antagonism of presynaptic α2-adrenergic receptors that results in tachycardia and arrhythmias, first-generation agents such as phenoxybenzamine have been replaced by the second-generation postsynaptic α1-adrenergic antagonists and third-generation uroselective postsynaptic α1A-adrenergic antagonists.

Images The second- and third-generation α1-adrenergic antagonists are considered equally effective for treatment of BPH.13,20,21 These agents generally improve the AUA Symptom Score by 30% to 40%, decreasing the AUA Symptom Index by three to six points, within 2 to 6 weeks, depending on the need for up dose titration; increase urinary flow rate by 2 to 3 mL/s in 60% to 70% of treated patients; and reduce PVR urine volume. With continued use, durable clinical benefit has been demonstrated for years.21 They have no effect on prostate volume. α1-Adrenergic antagonists do not reduce PSA levels, preserving the utility of this prostate cancer marker in this high-risk population.13

Adrenergic agents differ in their causation of hypotensive adverse effects and ejaculation disorders. Modified- or extended-release formulations and third-generation α-adrenergic1A antagonists produce a lower prevalence of hypotension than immediate-release, second-generation agents. In addition, older, immediate-release, second-generation α-adrenergic antagonists are available as inexpensive generic formulations, which may be desirable in selected patients.13

Second-generation agents include prazosin, terazosin, doxazosin, and alfuzosin. At the usual doses used to treat BPH, prazosin, terazosin, and doxazosin antagonize peripheral vascular α1-adrenergic receptors in addition to those in the prostate. As a result, first-dose syncope, orthostatic hypotension, and dizziness are characteristic adverse effects. To improve tolerance to these adverse effects, therapy should start with a low dose of 1 mg daily and then should be slowly titrated up to a full therapeutic dose over several weeks.20,22 Additive blood-pressure-lowering effects commonly occur when these agents are used with antihypertensive agents, which limit the use of these agents for some patients.13 These agents differ in terms of duration of action and dosage formulation. Whereas prazosin requires dosing two to three times per day, terazosin, doxazosin, and alfuzosin offer more convenient once-daily dosing. Because prazosin requires twice- to thrice-daily dosing and has significant cardiovascular adverse effects, it is not recommended in the current AUA guidelines for treatment of BPH.13 Extended-release dosage formulations are available for doxazosin and alfuzosin. These offer the convenience of once-daily dosing, treatment initiation with a full therapeutic dose, and decreased dose-related hypotension as the formulation produces lower peak serum concentrations than immediate-release products.23,24 An α1-adrenergic antagonist is not preferred as single-drug therapy for treatment of both BPH and hypertension in a patient. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) of 24,000 patients with hypertension, doxazosin produced more congestive heart failure than amlodipine, lisinopril, or chlorthalidone.25 Thus, both the AUA and the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure13,26 recommend that patients with BPH and hypertension be treated with separate and appropriate drug treatment for each medical condition.27

Alfuzosin is considered functionally and clinically uroselective in that usual doses used to treat BPH are less likely than other second-generation agents to cause cardiovascular adverse effects in animal or human models.23 This clinical observation has been observed more often with the once-daily, extended-release formulation of alfuzosin, which is the only commercially available formulation in the United States, as compared with the immediate-release formulation that is dosed three times per day, which is available in Europe.28 Its clinical uroselectivity has been postulated to be due to higher concentrations of alfuzosin achieved in the prostate versus serum after usual doses,29decreased blood–brain barrier penetration of alfuzosin,30 absence of high peak serum levels with the extended-release formulation,31 and the fixed dosing schedule of the extended-release formulation. The extended-release alfuzosin dosing is FDA approved for 10 mg daily, with no dose titration increase. This formulation is particularly convenient for physician prescribers and patients who are starting to take the medication.

Tamsulosin and silodosin are the only third-generation α1-adrenergic antagonists available in the United States. They are an advance over second-generation agents in that they are pharmacologically selective for prostatic α1A-adrenergic receptors, which comprise approximately 70% to 75% of the adrenergic receptors in the prostate gland, prostatic urethra, and bladder neck.32,33 Blockade of these receptors results in smooth muscle relaxation of the prostate and bladder neck without causing peripheral vascular smooth muscle relaxation. Tamsulosin and silodosin have low affinity for vascular α1B-adrenergic receptors, which explains why hypotension is not a common adverse effect.34

Uroselectivity of these drugs for α1A-adrenergic receptors has multiple implications. Dose titration is minimal; therefore, patients can begin tamsulosin with the lowest effective maintenance dose. Patients can be instructed to take the dose anytime during the day, unlike immediate-release formulations of terazosin and doxazosin, which should be taken at bedtime so that patients can sleep through the time when peak cardiovascular adverse effects are most likely to occur. However, for best oral absorption, tamsulosin should be taken on an empty stomach because food decreases the drug’s bioavailability and reduces the peak serum concentration of the drug after dosing. The onset of peak action is quick, in the range of 1 week, and only a minority of patients will require uptitration to a higher daily dose. No decreases in blood pressure or increases in heart rate have been reported in normotensive patients, the elderly, subgroups of patients with well-controlled hypertension, or those with uncontrolled hypertension.35 Thus, tamsulosin allows initiation of treatment with a therapeutic dose that is not limited by cardiovascular adverse effects, unlike immediate-release formulations of terazosin and doxazosin.34 Finally, the addition of tamsulosin to select antihypertensive regimens of patients does not result in potentiation of the hypotensive effect of furosemide, enalapril, nifedipine, and atenolol.36,37 Therefore, tamsulosin is a good choice, particularly for patients who cannot tolerate hypotension; have severe coronary artery disease, volume depletion, cardiac arrhythmias, severe orthostasis, or liver failure; are taking multiple antihypertensives; or when the titration would be too complicated for the patient or produce an unacceptable delay in onset for a particular patient.

As compared with tamsulosin, silodosin requires dosage modification in patients with hepatic impairment and renal impairment (creatinine clearance less than 30 mL/min [0.5 mL/s]), and has the potential for more drug interactions with inhibitors of CYP 3A4 (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) and P-glycoprotein (e.g., cyclosporine). In addition, silodosin’s safety in patients with cardiovascular disease has been documented in fewer studies when compared with tamsulosin.33 Finally, silodosin is commercially available from only one source, whereas tamsulosin is available as a generic formulation. For these reasons, tamsulosin is the preferred third-generation α1-adrenergic antagonist in clinical practice.20,33,38

The usual doses of α1-adrenergic antagonists are summarized in Table 67-4.

TABLE 67-4 Dosing of Drugs Used in Treatment of Benign Prostatic Hyperplasia

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When using immediate-release formulations of the second-generation α1-adrenergic antagonists terazosin and doxazosin, slow titration up to a therapeutic maintenance dose is necessary to minimize orthostatic hypotension and first-dose syncope. Conservatively, dosages should be increased in an orderly stepwise process, at 2- to 7-day intervals, depending on the patient’s response to the medication. A faster titration schedule can be used as long as the patient does not develop orthostatic hypotension or dizziness. Two sample titration schedules for terazosin are as follows:

    • Schedule 1: Slow titration

Days 4 to 14: 2 mg at bedtime

Weeks 2 to 6: 5 mg at bedtime

Weeks 7 and on: 10 mg at bedtime

    • Schedule 2: Quicker titration

Days 1 to 3: 1 mg at bedtime

Days 4 to 14: 2 mg at bedtime

Weeks 2 to 3: 5 mg at bedtime

Weeks 4 and on: 10 mg at bedtime

Patients should continue taking the drug as long as they continue to respond to it. Durable responses for 6 and 10 years have been reported for tamsulosin39 and doxazosin,40 respectively. If BPH symptoms worsen despite maximum tolerable drug doses, surgery should be considered.

With the exception of silodosin, no dosage adjustments are recommended for α1-adrenergic antagonists for patients with renal failure. Because these drugs are hepatically catabolized, the lowest effective dose should be used for patients with hepatic dysfunction, and patients should be monitored carefully for adverse effects. With the exception of silodosin, no specific dosing guidelines for this patient population are available. For silodosin, a reduced daily dose of 4 mg is recommended for patients with moderate renal impairment or those with hepatic dysfunction.

Approximately 10% to 12% of patients discontinue taking second-generation α1-adrenergic antagonists because of adverse effects, especially those that affect the cardiovascular system (e.g., syncope, dizziness, hypotension).41Patients who tolerate hypotension poorly should avoid second-generation α1-adrenergic antagonists.42 This includes patients with poorly controlled angina, serious cardiac arrhythmias, patients with reduced circulating volume, patients with untreated hypertension, and patients taking multiple antihypertensives.22,41 These patients are candidates for a third-generation α1-adrenergic antagonist or finasteride, if drug therapy is deemed necessary. Whether extended-release alfuzosin or silodosin is a good choice remains to be elucidated in controlled comparison trials with tamsulosin.43,44

Tiredness and asthenia, anejaculation, flu-like symptoms, and nasal congestion are the most common dose-related adverse effects of tamsulosin and silodosin.45 These adverse effects are extensions of their α-adrenergic antagonist activity and are unavoidable, but with proper education patients likely will not discontinue treatment.

Floppy iris syndrome has been associated with doxazosin, silodosin, and tamsulosin use, although the number of reported cases is highest with tamsulosin.46 The mechanism for this adverse reaction is related to blockade of α1A-adrenergic receptors in iris dilator muscles. As a result, during cataract surgery, pupillary constriction occurs and the iris billows out (floppy iris), both of which complicate the procedure or can increase the likelihood of postoperative complications, including posterior capsular rupture, retinal detachment, residual retained lens material, or endophthalmitis.4648 Permanent loss of vision can result.

Patients who are taking α1-adrenergic antagonists and who plan to undergo cataract surgery should inform their ophthalmologist that they are taking this medication so that appropriate measures can be taken during eye surgery, for example, use of iris retractors, pupillary expansion rings, or potent mydriatic agents.4648 No benefit has been demonstrated with holding the α1-adrenergic antagonist preoperatively.

For patients who are scheduled to have cataract surgery, and who have not yet started an α1-adrenergic antagonist, they should be advised to delay the start of the α1-adrenergic antagonist until surgery has been completed.4648

Patients with severe sulfa allergy should avoid tamsulosin.

Caution is needed when CYP 3A4 inhibitors, for example cimetidine and diltiazem, are used with α1-adrenergic antagonists because a drug–drug interaction could lead to decreased metabolism of the latter agents. In contrast, concurrent use of potent CYP 3A4 stimulators, for example carbamazepine and phenytoin, may increase hepatic catabolism of α1-adrenergic antagonists.

Phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) may produce hypotension if used in large doses along with α1-adrenergic antagonists. The mechanisms for this interaction are related to the intrinsic vasodilatory effects of phosphodiesterase inhibitors and the higher susceptibility of elderly patients to venous pooling because of autonomic incompetence.28,49,50 The prevalence of hypotension depends on the specific phosphodiesterase inhibitor and α1-adrenergic antagonist agent, specifically the combination of tadalafil and tamsulosin is least likely to produce a clinically significant drug interaction, as compared with other combinations.50 Therefore, a patient’s blood pressure should be stabilized on the α1-adrenergic antagonist before starting a phosphodiesterase inhibitor. In addition, patients who are taking phosphodiesterase inhibitors with α1-adrenergic antagonists should have their blood pressure monitored closely when initiating combined drug use.


Clinical Controversy…

Among the α-adrenergic antagonists, agents that are uroselective appear to have a lower potential to cause hypotension than nonuroselective agents. However, it is unclear if there is any distinct advantage of using silodosin or alfuzosin, as opposed to tamsulosin.

α-Reductase Inhibitors

Images Finasteride competitively inhibits type II 5α-reductase, the predominant isoform of the enzyme in the prostate, suppresses intraprostatic DHT by 80% to 90%, and decreases serum DHT levels by 70%.11Dutasteride is a nonselective inhibitor of type I and II 5α-reductase. It more quickly and completely suppresses intraprostatic DHT production and decreases serum DHT levels by 90%.51 However, direct comparison clinical trials show no advantages of these pharmacodynamic actions of dutasteride when compared with finasteride.52 These agents are indicated for management of moderate to severe BPH disease for patients with enlarged prostate glands of at least 40 g.52 For such patients, 5α-reductase inhibitors may slow disease progression and decrease the risk of disease complications, thereby decreasing the ultimate need for surgical intervention. When taken continuously for 4 years or 6 years, dutasteride or finasteride, respectively, has been shown to decrease the risk of acute urinary retention and prostatectomy.53,54 For patients with severe disease, these agents generally can be used with a 6-month short course of an α1-adrenergic antagonist, which will provide fast symptom relief until the 5α-reductase inhibitor starts to work. 5α-Reductase inhibitors may be preferred for patients with BPH and an enlarged prostate gland who have uncontrolled arrhythmias, have poorly controlled angina, are taking multiple antihypertensive agents, or are unable to tolerate hypotensive adverse effects of α1-adrenergic antagonists.

5α-Reductase inhibitors reduce prostate size by 25%, increase peak urinary flow rate by 1.6 to 2.0 mL/s, improve voiding symptoms in approximately 30% of treated patients, and produce few serious adverse effects. Compared with α1-adrenergic antagonists, 5α-reductase inhibitors have several disadvantages. 5α-Reductase inhibitors have a delayed peak onset of clinical effect, which is undesirable for patients with bothersome symptoms, and an adequate clinical trial is 6 to 12 months. In addition, patients experience less objective improvement of the AUA Symptom Score and urinary flow rate with 5α-reductase inhibitors than with α1-adrenergic antagonists.13 5α-Reductase inhibitors cause more sexual dysfunction than α1-adrenergic receptor antagonists; therefore, physicians consider 5α-reductase inhibitors to be the second-line agents for treatment of BPH in sexually active males (Tables 67-3 and 67-5).13

TABLE 67-5 Monitoring of Drugs Used in Treatment of Benign Prostatic Hyperplasia

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Patients with BPH who have large prostate glands, PSA level less than 3 ng/mL (3 mcg/L) and are concerned about developing prostate cancer can be prescribed finasteride 5 mg daily for up to 7 years. In the Prostate Cancer Prevention Trial, finasteride reduced the 7-year prevalence of prostate cancer by 25%.55 However, in this study, finasteride was associated with a 27% increase in the number of patients who developed high-grade prostate cancer, which has a potential for invasiveness. Although originally thought to be an disadvantage of finasteride use, it is now thought that the higher incidence of prostate cancer is due to biopsy sampling bias. That is, since finasteride reduces the size of the prostate gland, this results in increased sensitivity of sampling biopsies to detect prostate cancer.

Another clinical trial produced similar results. The Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study compared the effect of 4 years of continuous use of dutasteride versus placebo on reducing the incidence of prostate cancer in more than 6,700 men at high risk for developing prostate cancer. At the end of the study, dutasteride-treated patients had a 22.8% decreased relative risk of prostate cancer. Of the patients with biopsy-positive prostate cancer, a similar number of patients in each treatment group developed high grade tumors of Gleason grade 7 to 10 with no statistical difference between the groups.56

Thus, when finasteride is administered to patients with BPH and is also being continued to prevent prostate cancer, it should be reserved for patients with a family history of prostate cancer or in men of African descent who have an increased risk of developing prostate cancer. The possibility of developing a high-grade prostate cancer should be discussed with the patient before he initiates treatment with a 5α-reductase inhibitor for prevention of prostate cancer.55

Finasteride is well absorbed from the GI tract (95%), and its absorption is unaffected by food. Peak serum concentrations are reached 1 to 2 hours after the dose. Finasteride is highly protein bound. The liver extensively metabolizes finasteride to inactive metabolites, which are largely excreted in stool. The plasma half-life is 4.7 to 7.1 hours, but its biologic half-life probably is longer, as decreased serum DHT levels persist for up to 2 weeks after finasteride dosing is stopped.

For BPH, finasteride is given in doses of 5 mg by mouth daily. The dose can be taken with meals or on an empty stomach. No dosage adjustment is needed for patients with renal dysfunction. Although no dosage reduction is recommended for patients with hepatic insufficiency, patients should be monitored carefully. Maximal reductions in prostate volume or symptom improvement may not be evident for 12 months, but noticeable changes from baseline should occur after 6 months of continuous treatment. No clinically relevant drug interactions have been reported with 5α-reductase inhibitors.

Patients must continue to take 5α-reductase inhibitors as long as they respond. Durable responses to finasteride and dutasteride have been reported with continued treatment for 6 years54 and 4 years,52respectively. Upon discontinuation of the drug, prostate size and voiding symptoms generally return to baseline.

5α-Reductase inhibitors can produce sexual dysfunction, and this has led to discontinuation of therapy in up to 12% of treated patients in one pooled analysis.52 Ejaculation disorders (dry sex or delayed ejaculation) have been reported in 3% to 8% of treated patients.57 These disorders, which are possible results of decreased prostatic secretion, are reversible with drug discontinuation.

Erectile dysfunction has been reported for 3% to 16% of patients.52 It may be secondary to ejaculation disorders or may be due to drug-induced inhibition of nitric oxide synthase (which is needed to produce nitric oxide, a vasodilatory substance) in cavernosal tissue.58 The role of 5α-reductase inhibitors in causing erectile dysfunction is not clear, as elderly men with BPH commonly develop erectile dysfunction as they age or have concurrent medical illnesses or concomitant drug therapies that may predispose to the development of sexual dysfunction. Decreased libido has been reported in 2% to 10% of treated patients.52

Other minor adverse effects include nausea, abdominal pain, asthenia, dizziness, flatulence, headache, rash, muscle weakness, and gynecomastia.

5α-Reductase inhibitors are in FDA pregnancy category X, which means that they are contraindicated in pregnant females. Exposure of the male fetus to finasteride may produce pseudohermaphroditic offspring with ambiguous genitalia, similar to those of patients with a rare genetic deficiency of type II 5α-reductase. Because of this teratogenic effect, women who are pregnant or seeking to become pregnant should not handle 5α-reductase inhibitor tablets and should not have contact with semen from men being treated with 5α-reductase inhibitors. Women health professionals of childbearing age should handle this product with rubber gloves if there is any chance that they are pregnant.

Usual doses of 5α-reductase inhibitors produce a median reduction of serum PSA levels by 50% at months 6 to 12 after the start of treatment. For this reason, PSA levels must be measured before treatment begins, and the patient should have a digital rectal examination. After 6 months of therapy, the patient should have a repeat PSA. If the level does not decline by 50% and the patient has been adherent to the 5α-reductase inhibitor regimen, he should be evaluated for prostate cancer. Annually thereafter, the patient should have a PSA assay and digital rectal examination. Patients with an increase in PSA level of 0.3 ng/L or more above the baseline nadir level should be evaluated for prostate cancer59 or noncompliance to the prescribed regimen. To interpret a PSA level in a patient being treated with a 5α-reductase inhibitor, it is generally recommended that the actual measured level be doubled to get an estimate of the true level.13,59


Clinical Controversy…

Dutasteride is a nonselective 5α-reductase inhibitor that more quickly and effectively lowers intraprostatic DHT production and lowers plasma DHE levels than finasteride. Whether these hormonal changes result in clinical advantages over finasteride remains to be elucidated.

Combination Therapy of 5α-Reductase Inhibitor and α-Adrenergic Antagonist

Combination therapy with an α1-adrenergic antagonist and a 5α-reductase inhibitor is ideal for patients with severe symptoms, who also have an enlarged prostate gland of at least 40 g and PSA of at least 1.4 ng/mL (1.4 μg/L), a surrogate marker for an enlarged prostate gland.7,13,60 Such patients appear to be at high risk for disease progression, as evidenced by symptom worsening and development of disease complications, including acute urinary retention, recurrent urinary tract infection, or need for surgical intervention.7

In the landmark Multiple Treatment of Prostate Symptoms Study (MTOPS), a regimen of finasteride and doxazosin for 5 years was shown to prevent symptom progression by 66%, decrease the risk of developing acute urinary retention by 81%, and decrease the need for prostate surgery by 67%. Moreover, urinary symptom improvement and higher urinary flow rates at 15–18 months were observed in patients treated with combination therapy, as compared with monotherapy with finasteride alone or doxazosin alone.7 In another key clinical trial, the Combination of Avodart and Tamsulosin (COMBAT) study, dutasteride versus tamsulosin versus a combination of dutasteride and tamsulosin were evaluated in patients with large prostate glands (i.e., mean prostate volume of 55 ± 23 cc [55 ± 23 mL] and a mean PSA of 4 ng/mL [4 mcg/L]). The combination regimen was more effective in reducing symptoms 9 months after the start of treatment than dutasteride alone or tamsulosin alone. Whether the combination of dutasteride and tamsulosin prevents disease progression after 4 years awaits long-term study results, although preliminary subgroup analysis has shown that combination therapy reduces the percentage of patients who develop disease progression.61,62

Although not proven by direct comparison trials, any combination of 5α-reductase inhibitor and α1-adrenergic antagonist probably is similarly effective for patients with the aforementioned characteristics.13The disadvantages of a combination regimen include increased medication cost to the patient and an increased incidence of adverse drug effects (i.e., 18% to 27% of patients discontinued treatment due to hypotension).


Clinical Controversy…

The combination of an α1-adrenergic antagonist and 5α-reductase inhibitor can relieve LUTS, slow progression of BPH, and reduce the need for prostate surgery for patients with moderate to severe symptoms and a prostate of 40 g or larger. It may be possible to discontinue the α1-adrenergic antagonist after the first several months; however, this potentially cost-saving measure requires further clinical study.

Phosphodiesterase Inhibitors

Images Several observations led to the use of phosphodiesterase inhibitors for management of BPH. BPH and erectile dysfunction are often present concurrently in the same patient.63 Adverse effects of α-adrenergic antagonists and 5α-reductase inhibitors include erectile dysfunction, which is likely to respond to a phosphodiesterase inhibitor.64 The pathophysiology of BPH and erectile dysfunction may be common in so far as both disorders may be associated with increased vascular smooth muscle tone and pelvic atherosclerosis.

Phosphodiesterase inhibitors are thought to relax smooth muscle in the prostate and bladder neck, probably by increasing cyclic GMP. By so doing, phosphodiesterase inhibitors inactivate the rho-kinase pathway, which normally regulates smooth muscle contraction mediated by endothelin and α-adrenergic stimulation and contributes to the presence of obstructive voiding symptoms.6466 In addition, phosphodiesterase inhibitors may cause direction relaxation of the detrusor muscle of the bladder, which could reduce irritative voiding symptoms.67

In multiple clinical trials of patients with moderate LUTS, tadalafil caused significant improvements in voiding symptoms as measured by the AUA Symptom Index score or IPSS, with the level of improvement similar to that observed with α-adrenergic antagonists.66,68 However, no increase in urinary flow rate or reduction in PVR urine volume occurred with tadalafil alone.69,70 Tadalafil 2.5 mg was inferior to 5 mg, and doses of 10 mg or 20 mg were not superior to 5 mg.65,71 This is the basis of the current product labeling dose of tadalafil 5 mg daily for BPH. The most common adverse effects observed are headache, flushing, gastroesophageal reflux, sinusitis, and back pain, which are generally reversible and do not require discontinuation of therapy. When tadalafil was combined with an α-adrenergic antagonist, patients experienced significant improvements in LUTS, increased urinary flow rates, and decreased PVR volume.70

A few other studies have included sildenafil 50 mg or 100 mg daily or vardenafil 10 mg twice a day.65,72 Most of the clinical trials have evaluated tadalafil for treatment of BPH. This is probably because BPH is viewed as a chronic disease and tadalafil has been FDA-approved for once-daily dosing, and has the longest half-life and duration of action among the phosphodiesterase inhibitors. The recommended tadalafil dose is 5 mg daily.

Based on the limited benefit, cost, and potential adverse effects of tadalafil, it would be prudent to reserve its use for patients with both BPH and erectile dysfunction.69,70,73 If used in combination with an α-adrenergic antagonist, precautions should be taken to minimize hypotension, specifically, stabilize the patient’s blood pressure on the α-adrenergic antagonist before adding tadalafil.

Anticholinergic Agents

Images Treatment with an α1-adrenergic antagonist, 5α-reductase inhibitor, or surgery may improve urinary flow rate and bladder emptying; however, the patient may still complain of irritative voiding symptoms (e.g., urinary frequency, urgency, and nocturia), which mimic those of overactive bladder syndrome. A variety of anticholinergic agents, including oxybutynin and tolterodine, have been added to α-adrenergic antagonist regimens to relieve these symptoms.7476

By blocking muscarinic receptors in the detrusor muscle, anticholinergic agents can reduce uninhibited detrusor contractions, a sequela of prolonged bladder outlet obstruction from BPH. Thus, they can reduce urinary frequency and urgency. Because older patients are sensitive to the drugs’ CNS adverse effects and dry mouth, patients should be started on the lowest effective dose and then slowly titrated up.7476

Uroselective anticholinergic agents, which preferentially inhibit M3 receptors (e.g., darifenacin or solifenacin), or transdermal (oxybutynin) or extended-release formulations of anticholinergic agents (e.g., tolterodine) are recommended for patients who poorly tolerate systemic anticholinergic adverse effects. In the presence of BPH, anticholinergic agents can rarely cause acute urinary retention. Therefore, before prescribing an anticholinergic agent, a PVR urine volume should be measured and should be less than 250 mL.13

Surgical Intervention

Images The gold standard for treatment of patients with complications of BPH is prostatectomy performed either transurethrally or as an open surgical procedure.13,18 Surgical intervention is also used for patients with moderate to severe symptoms, who are not responsive to drug therapy, who are noncompliant with drug therapy, or who prefer surgical intervention. Surgical intervention is always indicated for patients with complications of BPH, including acute urinary retention not responsive to drug treatment, chronic urinary retention associated with decreased renal function or overflow urinary incontinence, urolithiasis, or recurrent hematuria.77 Surgical removal of the prostate offers the highest rate of symptom improvement, but it also has the highest complication rate.

With transurethral resection of the prostate (TURP), an endoscopic resectoscope inserted through the urethra is used to remove the inside core of the prostate. This enlarges the urethral opening at the bladder neck. Often performed as outpatient surgery, this procedure produces on average a peak urinary flow rate increase of 125% and improvement of voiding symptoms by almost 90% in approximately 90% of patients.18 A common complication of TURP is retrograde ejaculation, occurring in up to 75% of patients. Significant bleeding, urinary incontinence, and erectile dysfunction occur in smaller, but significant numbers of patients (2% to 15%).78 Approximately 2% to 10% and 12% to 15% of patients require second surgeries within 5 and 8 years, respectively.78

Alternatively, an open surgical procedure (open prostatectomy) can be performed retropubically or suprapubically. This necessitates hospitalization for at least a few days, anesthesia, and a longer recuperation time. Adverse effects of open prostatectomy include bleeding, urinary and soft-tissue infection, retrograde ejaculation in 77% of patients, erectile dysfunction in 16% to 33% of patients, and urinary incontinence in 2% of patients. The reoperation rate is 3% to 5% at 10 years.13

Transurethral incision of the prostate (TUIP) is an alternative surgical procedure for patients with moderate to severe voiding symptoms who have an enlarged prostate gland less than 30 g in size. In the short term TUIP is as effective as TURP but requires less operation time, causes less blood loss, and produces fewer adverse effects.13 TUIP involves using an endoscopic resectoscope to make two or three incisions at the bladder neck to widen the opening. In limited long-term studies, the reoperation rate for TUIP is slightly higher than with TURP.

Minimally invasive surgical procedures are highly desirable by patients. The procedures are short (lasting minutes), have a lower potential to produce adverse effects, are less expensive than continuous drug therapy regimens lasting years, and they may be particularly useful in debilitated patients who are poor surgical candidates. The ideal candidates have moderate to severe voiding symptoms with smaller sized prostate glands. These procedures typically use heat energy from microwaves, water, or laser to destroy prostate tissue.13 Commonly used procedures include transurethral needle ablation of the prostate and transurethral microwave thermotherapy of the prostate.79,80A disadvantage of all minimally invasive surgical procedures is the high percentage of patients who may develop acute urinary retention in the immediate postoperative period. In addition, patients who undergo minimally invasive procedures generally experience smaller improvements in voiding symptoms and urinary flow rates, and are more likely to require reoperation after an initial improvement in symptoms than patients who undergo TURP or open prostatectomy.81,82

Phytotherapy

Although phytotherapy is widely used in Europe for the management of BPH, the published data on herbal agents are largely inconclusive and conflicting. Studies often lack placebo controls, which are essential for assessing treatments of BPH because spontaneous regression of symptoms can occur. Furthermore, because these agents are marketed under the Dietary Supplements Health and Education Act, their efficacy, safety, and quality are not regulated by the FDA. For these reasons, herbal products—including saw palmetto berry (Serenoa repens), stinging nettle (Urtica dioica), South African star grass (Hypoxis rooperi), pumpkin seed (Cucurbita pepo), and African plum (Pygeum africanum)—are not recommended for treatment of BPH.13,83 An excellent review on phytotherapy for BPH has been published.84

EVALUATION OF THERAPEUTIC OUTCOMES

The primary therapeutic outcome of BPH therapy is improvement of voiding symptoms with minimal treatment-related adverse effects. As a disease for which therapy is directed at the voiding symptoms that the patient finds most bothersome, assessment of outcomes depends on the patient’s perceptions of the effectiveness of therapy. Use of a validated, standardized instrument, such as the AUA Symptom Score, for assessing patient’s voiding symptoms is important in this process.13

For patients being considered for surgical treatment, objective measures of bladder emptying are useful and include the urinary flow rate and PVR urine volume (see Diagnostic Evaluation above).

Because this patient population is at high risk for prostate cancer, PSA should be measured and a digital rectal examination performed annually if the patient has a life expectancy of at least 10 years. For patients taking 5α-reductase inhibitors, a second PSA taken after 6 months of treatment should be compared with baseline measurements. If the patient is suspected of having developed renal impairment as a consequence of long-standing bladder outlet obstruction, then BUN and serum creatinine should be evaluated at regular intervals.

SUMMARY

A ubiquitous disease of aging men, symptomatic BPH requires medical attention to preserve the patient’s quality of life and to prevent disease complications, many of which can be life threatening in this patient population. In men who have no or mildly bothersome symptoms, watchful waiting and behavior modification are the best treatment approach, as BPH remains stable or even regresses in approximately half of these men.

For patients with voiding symptoms that are moderate to severely bothersome, pharmacotherapy is indicated. An α1-adrenergic antagonist is the agent of first choice. Second-generation agents include terazosin, doxazosin, and alfuzosin, and third-generation agents include tamsulosin and silodosin. Immediate-release formulations of terazosin and doxazosin cause more cardiovascular adverse effects than do extended-release formulations (e.g., doxazosin or alfuzosin), or uroselective α1A–adrenergic agents (e.g., tamsulosin or silodosin). 5α-Reductase inhibitors are preferred drug treatment for patients with enlarged prostates who poorly tolerate the hypotensive adverse effects of α1-adrenergic antagonists. However, 5α-reductase inhibitors have a slow onset of action. For patients who do not respond to monotherapy, combination drug therapy could be attempted. Such regimens have been found to be most effective for patients with enlarged prostates greater than 40 g. Alternatively, surgery is an option.

For patients with both moderate-severe BPH and erectile dysfunction, a phosphodiesterase inhibitor alone or combined with an α-adrenergic antagonist may be prescribed. For patients with moderate to severe BPH with a predominance of irritative voiding symptoms, an anticholinergic agent may be added to an existing drug treatment regimen for BPH provided that the patient has a PVR urine volume less than 250 mL.

For patients who have complications of BPH, surgery is required. Although it has more adverse complications than does pharmacotherapy or watchful waiting, TURP is considered the gold standard.

ABBREVIATIONS

Images

REFERENCES

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