Sample Chapter

October 2007

Section 10

Benign prostatic hyperplasia (BPH) is a common cause of morbidity in older men in developed countries. BPH causes lower urinary tract symptoms (LUTS) and occasionally results in such complications as acute urinary retention, urinary tract infection, and obstructive uropathy. Although increasing appreciation of the relatively benign natural history of this condition and the development of medical treatments have reduced the role of surgery, prostatectomy remains a widely performed procedure. The sheer prevalence of LUTS attributable to BPH, their impact on patients' quality of life, and the availability of effective medications make BPH important in primary care as well as urologic practice.

Figure 1. Prevalence of BPH Histology

Autopsy studies indicate that the prevalence of histologic BPH ranges from about 25% for men in their 40s to about 85% for men older than 80 years [see Figure 1].¹ The average prostate volume in young men without histologic evidence of BPH is about 20 ml. A community-based study of men from Olmsted County, Minnesota, has indicated that mean prostate volume increases with age: 23 ml at 40 to 49 years of age, 27 ml at 50 to 59 years, 32 ml at 60 to 69 years, and 39 ml at 70 to 79 years.² In a community-based study from the Netherlands, the prevalence of a prostate volume greater than 40 ml ranged from 15% in men 55 to 59 years of age to 28% for those 60 to 64 years, 36% for those 65 to 69 years, and 55% for those 70 to 74 years.³

Other epidemiologic studies have examined the relationship of peak urinary flow (uroflow) rates (Qmax) and age. In the Olmsted County study, mean Qmax decreased from about 20 ml/sec in men 40 to 44 years of age to about 12 ml/sec at 75 to 79 years of age.⁴ The proportion of men with a flow rate less than 10 ml/sec ranged from 5% at 40 to 44 years of age to 25% at 70 to 74 years of age. Another parameter linked to BPH, postvoid residual volume (PVR), does not appear to be age-related.

Of course, BPH without symptoms is more a histologic curiosity than a disease, and not all LUTS are attributable to BPH. What is the prevalence of symptomatic BPH in older men? The answer depends on how BPH is defined. A Dutch study of a community-based sample of men 55 to 74 years of age found that the prevalence of BPH varied from 4.3% to 19%, depending on which of eight case definitions of clinically important disease was applied.⁵ By any definition, however, BPH is a common cause of symptoms in older men, at least in Western countries.

Although the prevalence of histologic BPH is remarkably similar across countries with populations of varying races and ethnicities, Asian men appear to have smaller prostates at any given age and undergo less surgery for BPH. Whites and African Americans appear to have similar risks, although their patterns of disease presentation may differ to some degree.⁶ Studies conflict as to whether there may be a positive or negative association between BPH and cigarette smoking. Recent evidence suggests a relationship between prostatic enlargement and central obesity, an important component of the metabolic syndrome.⁷ Cirrhosis of the liver appears to be negatively associated with BPH, probably because of higher circulating levels of estrogens relative to androgens. Older men with moderate to severe lower urinary tract symptoms also appear to be at higher risk for erectile dysfunction, even after accounting for age and the use of medications that may affect erectile function.⁸ Finally, men with a family history of BPH may be at increased risk for BPH, especially if the affected relative was diagnosed before 60 years of age, and twin studies indicate a 3.3-fold higher risk in monozygotic twins with affected siblings. Despite the apparent contribution of family history as a risk factor, the genetic aspects of BPH remain poorly understood.⁹

Figure 2. Diagram of the Prostate

The normal prostate consists of epithelial glandular components in a stroma of connective tissue and smooth muscle [see Figure 2]. BPH involves hyperplasia of both the epithelial and stromal compartments. The hyperplastic process begins in the periurethral and transition zones of the prostate; in contrast, prostate cancer preferentially develops in the peripheral zones.¹⁰ Over time, multiple small hyperplastic nodules grow and coalesce into a large central adenoma, compressing the more peripheral tissue against the fibrous prostatic capsule. This compressed tissue can create a surgical capsule that bounds the central adenoma. The surgical capsule serves as the plane of resection for an open prostatectomy.

Eventually, prostatic enlargement from hyperplasia can result in bladder outlet obstruction, which is defined as increased detrusor pressure relative to the rate of urine flow. Bladder outlet obstruction has both a static component (from luminal narrowing secondary to prostate tissue growth) and a dynamic component (from increased neuromuscular tone in the hyperplastic prostate). Neuromuscular tone in the bladder neck, prostatic capsule, and prostatic stroma is attributable to their relatively high density of alpha₂-adrenergic receptors. At least three types of alpha₂-adrenergic receptors have been identified in the lower urinary tract. Epithelial and vascular tissues, on the other hand, are more richly supplied with alpha₁-adrenergic receptors. The bladder may respond to outlet obstruction with hypertrophy, uninhibited contractions, and fibrosis.

These histologic, anatomic, and pathophysiologic processes may result in LUTS. Traditionally, such symptoms have been grouped into two categories: bladder emptying symptoms, which presumably result primarily from mechanical obstruction, and bladder filling symptoms, which presumably result primarily from detrusor overactivity (see below).¹¹

Although this model of the link between BPH and LUTS is convenient, it is undoubtedly simplistic. Researchers have documented that the severity of LUTS correlates poorly with prostate size, the degree of bladder outlet obstruction, and the severity of uninhibited detrusor contractions. Moreover, improvement in symptoms with treatment does not correlate well with improvements in these ostensibly objective parameters; for some treatment modalities, symptoms may improve despite the absence of changes in these other measures. Recently, histologic evidence of inflammation has been documented in many men with histologic BPH, even in the absence of cardinal symptoms of prostatitis, such as painful ejaculation. Moreover, it appears that the degree of inflammation is predictive of progression in symptom severity; in particular, the degree of inflammation correlates with the risk of acute urinary retention.¹² The scientific uncertainty over the mechanisms that link the histologic process of BPH with symptoms contributes to clinical uncertainty over how to treat older men who present with bothersome LUTS.

The pathophysiologic mechanisms underlying the development and progression of BPH are also incompletely understood. Aging and the presence of functioning testes through puberty into adulthood are absolute requirements. Clearly, BPH involves prolonged exposure of the prostate gland to androgens. The conversion of testosterone to dihydrotestosterone (DHT), which is the major intraprostatic androgen, is accomplished by the type 2 5a-reductase isoenzyme; this isoenzyme occurs largely in prostatic stromal cells, although it is also found in some peripheral tissues. In contrast, the type 1 5a-reductase isoenzyme has low activity in the prostate and is expressed predominantly in the skin and liver. DHT serves as a powerful mitogen for prostatic cells. Men who were castrated before puberty do not develop BPH, and medical or surgical castration later in life causes apoptosis of prostatic epithelial cells. Other factors extrinsic to the prostate also appear to be important in prostate growth, including estrogens, possibly a nonandrogenic testicular factor, and factors such as diet and genetics. In the prostate, interactions between epithelial and stromal cells and the extracellular matrix, mediated primarily by locally produced (intrinsic) growth factors, appear important. These peptide growth factors, including fibroblast growth factors, insulinlike growth factors, and epidermal growth factors, may be the local determinants of prostate growth.¹³

The extent of the medical evaluation necessary to establish a working clinical diagnosis of LUTS attributable to BPH is controversial. In most men older than 50 years, a characteristic history alone may be sufficient. However, not all older men with a typical history will have either prostatic enlargement or evidence of bladder outlet obstruction on pressure-flow studies. In some of these men, environmental factors or systemic diseases may be causing or exacerbating their symptoms. Others may have disorders of the lower urinary tract that are not associated with bladder outlet obstruction, or they may have bladder outlet obstruction that is not caused by BPH. There is a growing appreciation of the importance of bladder dysfunction in older men with LUTS, particularly detrusor overactivity, which commonly occurs in association with bladder outlet obstruction, and sometimes independently.¹⁴

Clinical Features

Slowly progressive difficulties with bladder emptying and filling are characteristic of BPH. Symptoms related to bladder emptying in men with BPH include straining, hesitancy, intermittency, a weak stream, terminal dribbling, and a sensation of incomplete emptying. Symptoms related to bladder filling include daytime frequency, nocturia, urgency, and urge incontinence. These filling symptoms are also consistent with detrusor overactivity.

History

When older men present with LUTS, a careful history will uncover most alternative causes. The physician should look for evidence of systemic diseases that can present as LUTS, particularly urinary frequency and nocturia. Examples of such diseases include diabetes, heart failure (which can cause a nocturnal diuresis distinct from the effect of diuretics), and hyperparathyroidism. Neurologic diseases—including diabetic peripheral and autonomic neuropathy, stroke, and Parkinson disease—may be associated with neuropathic disorders of the bladder. A complete list of medications should be obtained, and the time at which the patient takes medications such as diuretics should be ascertained. Patients should be specifically questioned about the use of over-the-counter medications for cough, cold, and allergy, because the anticholinergic and sympathomimetic agents in these preparations may cause or exacerbate symptoms.

The urologic history should include any genitourinary malignancies (personal or family), hematuria, acute urinary retention, or urinary tract infection. Patients should be asked about urethral strictures, as well as genitourinary trauma, instrumentation, and sexually transmitted diseases, which may result in stricture.

Figure 3. International Prostate Symptom Score

LUTS in older men can be quantified using the American Urological Association Symptom Index (AUASI).¹⁵ This seven-item questionnaire, which is widely used in epidemiologic and clinical research, as well as clinical practice, assesses the frequency of seven lower urinary tract symptoms, each on a scale of 0 to 5. The individual item scores can be added to calculate an overall score ranging from 0 (best) to 35 (worst). Scores of less than 8 reflect mild symptoms; 8 to 18, moderate symptoms; and 19 to 35, severe symptoms. The International Prostate Symptom Score (IPSS) contains the same symptom question set as the AUASI and a separately scored quality-of-life question addressing the degree of bother caused by the respondent's symptoms¹⁶ [see Figure 3]. The IPSS is designed for self-administration, but visually impaired patients or patients who cannot read may have the questionnaire read to them. Quantifying symptom severity provides objective documentation of the patient's condition and serves as a baseline against which to judge change over time. Responses to individual items should be noted.

Men with symptoms attributable to BPH usually have a balance of filling and voiding symptoms; men with mostly filling symptoms, and particularly nocturia alone, are more likely to have a condition other than BPH as the cause of their symptoms. Patients should be asked about the time course of their symptoms. Rapid onset of symptoms is uncharacteristic of BPH and should be a red-flag warning of other potential causes, including genitourinary malignancy. Dysuria and pelvic pain are also uncommon in men with BPH; pelvic pain, and particularly pain on ejaculation, are more characteristic of prostatitis.

Finally, because BPH and its treatment can affect both sexual function and urinary continence, men should be asked about these issues before any treatment is begun. Urge incontinence may be seen with BPH as a result of detrusor overactivity; other types of incontinence may be engendered by treatment.

Some clinicians ask patients with LUTS to keep a voiding diary over a few days to a week.¹⁷ Voiding diaries contribute information independent of but complementary to symptom scores.¹⁸ Patients should measure and record the volume of each voiding, noting any episodes of incontinence. The pattern of voiding reflected in the diary may provide valuable clues to the cause of symptoms, particularly when it reveals nocturnal polyuria.

Perhaps the most important aspect of assessing LUTS is to ask the patient how much he is bothered by them. Although the level of botheration is generally related to symptom severity, some patients tolerate severe symptoms quite well, whereas other patients are aggravated by moderate symptoms. Intervention may make more sense for the latter patients than the former, regardless of symptom score. The question about botheration on the IPSS may serve as a good entry into this discussion [see Figure 3].

Physical Examination

Patients considering alpha-blocker treatment should have their blood pressure determined, both supine and standing. Patients considering operative treatment should undergo a general evaluation for risks of complications from anesthesia and surgery.

The physician should perform a targeted physical examination that includes palpation of the lower abdomen for evidence of a grossly enlarged bladder, assessment of the extremities for peripheral neuropathy, and assessment of the perineal area and inner thighs for saddle anesthesia. A patient with neuropathy or saddle anesthesia is more likely to have a neurologic disorder affecting the bladder.

A digital rectal examination (DRE) should be done, and the examiner should note the size, symmetry, and texture of the prostate. BPH characteristically produces a symmetrically enlarged, firm prostate of the consistency of the tip of the nose. Asymmetry in consistency or the presence of hard nodules suggests prostate cancer, but these findings are neither sensitive nor specific.

With DRE, there is a tendency to underestimate prostate size.¹⁹ When a clinician thinks the prostate is enlarged, it usually is; however, the prostate may well be enlarged even if the clinician thinks it is not. This discrepancy may be important, because for some medical therapies, efficacy is related to prostate size. Moreover, agreement between clinicians, even urologists, on the presence or absence of palpable prostate abnormalities suggesting cancer has been only fair.²⁰

Laboratory Testing

Routine tests performed on men with LUTS should include a urinalysis to screen for hematuria and infection. Many clinicians order serum creatinine and prostate-specific antigen (PSA) tests, although the value of those is arguable for many patients. Less frequently performed tests in this setting include PVR measurement, uroflow measurement, and imaging of the upper urinary tract.

Urinalysis

Pyuria suggests infection, either primary or superimposed on bladder outlet obstruction. Microscopic hematuria may simply reflect the fact that the enlarged prostate is quite vascular, but it should prompt further evaluation for malignancy.

Serum Creatinine Measurement

An elevated creatinine level may be a clue to the occasional case of obstructive uropathy. However, the rarity of this condition has recently led to practice guidelines that recommend against routine measurements of creatinine in men with LUTS suggestive of BPH.²¹

Prostate-Specific Antigen Testing

The role of PSA measurement in men with LUTS is controversial. Screening studies do not confirm that patients with LUTS that are suggestive of BPH are more likely to have prostate cancer.²² However, BPH and prostate cancer may coexist. Therefore, looking for prostate cancer in men with LUTS and a nonsuspicious DRE is most appropriately considered screening, not diagnosis. The performance of PSA as a screening test deteriorates in the setting of BPH, primarily because of lower specificity. Although a PSA level higher than 10 ng/ml is relatively specific for prostate cancer, only about 25% of men with PSA levels in the range of 4.1 to 10 ng/ml have prostate cancer at biopsy; many of the rest have BPH.²³

Most urologists doubt the value of early detection of prostate cancer in men whose life expectancy is less than 10 years²⁴ or who are older than 75 years and are in average health. Clinicians should have a conversation about the possibility of coexisting prostate cancer with patients who present with LUTS, and they should decide together whether to pursue such a diagnosis.

A PSA level over 4 ng/ml has traditionally been considered an indication for biopsy. However, evidence from the Prostate Cancer Prevention Trial demonstrated that PSA levels were of little value in distinguishing men who were without prostate cancer from men who were found to have prostate cancer on biopsy; about 15% of men with PSA levels of 4.0 ng/ml or less have prostate cancer, and about 15% of those have high-grade (Gleason 7 or higher) cancers.²⁵

Many attempts have been made to find laboratory features that would indicate the likelihood of cancer in patients with an elevated PSA level, and so improve biopsy yield. In general, however, the performance of these so-called PSA derivatives has been disappointing. For example, measurement of the proportion of total PSA that is circulating in the free form has been proposed for men with total PSA levels of 4.1 to 10 ng/ml whose DRE results were negative, with a proportion above 25% considered to offer reassurance that cancer is absent. However, only about 20% of men with total PSA levels in this range will have a supposedly reassuring free PSA percentage; and even in those men, the probability of cancer at biopsy is still about 10%.²⁶ More recently, rates of change of PSA, rather than raw PSA values, have been proposed as derivatives that may better separate men with prostate cancers more likely to cause future morbidity and mortality from men with both BPH and less clinically important prostate cancers. Earlier research showed that men whose initial PSA level was between 4.1 and 10.0 ng/ml and whose PSA level rose by more than 0.75 ng/ml/year, as averaged over at least three annual measurements, were more likely to have prostate cancer than BPH.²⁷

Another reason to consider ordering a PSA test for a man with LUTS is that PSA values can be used to estimate prostate size and thus help stratify the risk of future problems attributable to BPH, such as progression of symptoms, acute urinary retention, or need for surgery.²⁸ The predicted likelihood of a prostate size greater than 40 ml is about 50% for a PSA of 1.5 ng/ml, 60% for a PSA of 2.5 ng/ml, and 75% for a PSA of 4.0 ng/ml.²⁹ A PSA level can also help predict the preventive effect of a 5a-reductase inhibitor on BPH complications (see below).

Residual Volume Measurement

An optional test for a patient with LUTS is the assessment of PVR by catheterization or ultrasonography. Obtaining such measurements is difficult in primary care, and substantial day-to-day variation limits their value. Probably only PVR values that are both consistently and excessively elevated (i.e., > 350 ml) constitute a reliable indication of the need for more aggressive treatment.

Urinary Flow Rate

Many urologists measure uroflow rates in their offices. About 90% of men with peak uroflow rates of less than 10 ml/sec have bladder outlet obstruction, compared with about 30% of men with peak flow rates greater than 15 ml/sec. Values between 10 and 15 ml/sec are associated with bladder outlet obstruction in about two thirds of cases.³⁰ Unfortunately, the utility of uroflow rates is limited by the fact that measured values vary within a given patient, and so multiple measurements are necessary to improve reliability. Also, a voided volume of at least 150 ml is needed for reliability, and some patients with LUTS cannot meet that requirement. Moreover, low flow rates can be seen in patients with weak detrusor contraction in the absence of obstruction, and strong contractions can maintain flow even in the presence of obstruction. For all of these reasons, uroflowmetry is an optional test.

The simultaneous measurement of bladder pressure and urine flow is considered the gold standard for the diagnosis of bladder outlet obstruction.³¹ There are a number of criteria for calling a pressure-flow study positive, all of which are based, in various ways, on documenting a high bladder pressure relative to the uroflow rate. More sophisticated videourodynamics can localize the site of obstruction. These tests require special equipment and training; are somewhat invasive, requiring a urethral catheter; can be expensive; and yield equivocal results in some men. They are usually recommended for patients with atypical presentations; for patients with neurologic diseases, in whom the probability of primary bladder disorders is higher; and for men with persistent symptoms after surgical therapy for symptoms presumed to be from BPH. Few urologists would recommend a pressure-flow study for a typical patient before a trial of medical therapy, but some would routinely recommend such a study before undertaking a prostatectomy after medical therapy fails. There is not universal agreement regarding this recommendation, however, because for a substantial proportion of men with LUTS who are without unequivocal evidence of obstruction, surgery results in a significant improvement in symptoms.³²

Upper Urinary Tract Imaging

Upper urinary tract imaging (i.e., by ultrasonography, computed tomography, or intravenous pyelography) and urethrocystoscopy are not indicated for routine cases of LUTS attributable to BPH.³³

Cystoscopic findings in particular have not correlated well with the severity of symptoms of bladder outlet obstruction. Such studies should be reserved for selected patients with findings such as microscopic hematuria.

Once the clinician has made a working diagnosis of LUTS attributable to BPH and when the patient is sufficiently bothered by his symptoms to at least consider therapy, the initial management choice is usually between watchful waiting and medical therapy. Traditionally, medical therapies for LUTS attributable to BPH include alpha blockers and 5a-reductase inhibitors. Many patients try complementary and alternative medical treatments of prostate problems, especially phytotherapies. Growing appreciation of the role of detrusor overactivity in men with particularly bothersome filling symptoms such as urgency and urge incontinence has led to trials of anticholinergic agents in such men, even when bladder outlet obstruction is suspected.

Watchful Waiting

When the bother of a patient's LUTS is not sufficient, in his mind, to justify the potential side effects, costs, and inconvenience of medication, watchful waiting is the optimal management strategy. Although virtually all patients with mild symptom scores (i.e., an IPSS from 0 to 7 points) choose this course, it is also a reasonable course for patients with moderate or severe symptoms who are not very bothered by them. Patients should be advised to take lifestyle measures to improve symptoms, such as avoiding fluids, particularly beverages containing caffeine, before bedtime. They should also avoid medications that might worsen LUTS, including nonprescription ones [see History, above]. A recent small trial of a self-management program that focused on lifestyle changes showed impressive effects in older men with LUTS; improvements in symptom scores over 1 year were similar to those seen in trials of medical therapies.³⁴

Figure 4. Four-year Outcomes in BPH

Men should report worsening symptoms, particularly if they are feeling more bothered by their symptoms. Although, on average, symptoms can be expected to gradually increase, individual courses are quite variable, and some men note improvement over time [see Figure 4].³⁵ A natural history study has shown little symptomatic or urodynamic deterioration in men with proven bladder outlet obstruction who were followed without active treatment for 10 years or longer.³⁶

Medical Treatment

Alpha Blockers

Alpha₁-adrenergic blockers work primarily through relaxation of prostatic smooth muscle and relief of the dynamic component of bladder outlet obstruction. However, additional mechanisms have been proposed, including increased apoptosis of prostatic cells. Alpha blockers neither reduce prostate size nor lower PSA levels. Their onset of action is relatively rapid, although some alpha blockers require dose titration to achieve a maximal therapeutic effect while minimizing side effects. Many patients have hypertension and BPH, and both problems may be treated with an alpha blocker; however, data strongly suggest that alpha-blocker monotherapy is not optimal treatment for hypertension.³⁷

Many randomized trials have documented the efficacy of alpha blockers over placebo in studies lasting up to 4 years.^38,39 For example, in a large trial, over 2,000 men were randomized to receive either placebo or terazosin in doses of up to 10 mg daily. IPSS scores dropped about 8 points with the alpha blocker and about 4 points with placebo.⁴⁰ Such data highlight the impressive magnitude of the placebo effect on LUTS. Some of this placebo effect is attributable to regression toward the mean, which is seen when men with particularly marked symptoms are recruited into trials. In clinical practice, patients perceive their change in symptoms from baseline, so their improvement results from a combination of the pharmacologic benefit of the intervention with these other effects. The therapeutic effect of the alpha blockers is independent of prostate size.⁴¹ As is true of all treatments for men with symptoms attributed to BPH, the men with the highest symptom scores can expect the greatest absolute decrease in their symptom scores with alpha blockers. Therefore, many men with symptom scores in the severe range benefit from a therapeutic trial of alpha blockers before consideration is given to more invasive treatment.

Various alpha blockers are used in the treatment of LUTS attributable to BPH. Although head-to-head trials of alpha blockers are relatively few, the therapeutic effects of different agents appear similar.⁴² There is currently great interest in developing alpha blockers with selectivity for the subtypes of the alpha₁-adrenergic receptor to maximize the therapeutic effect while minimizing side effects. Tamsulosin and alfuzosin indeed appear more selective than doxazosin and terazosin for the alpha₁-adrenergic receptor, which is the predominant subtype in prostatic smooth muscle. However, this difference in pharmacologic selectivity does not appear to translate into major differences in efficacy.^38,42

Side effects of alpha blockers include orthostatic hypotension, dizziness, and asthenia. The last two side effects are not primarily mediated by low blood pressure.⁴³ Tamsulosin and alfuzosin do not affect blood pressure, as do the other alpha blockers, but it is unclear whether the risk of side effects other than orthostatic hypotension is appreciably reduced with these agents.^21,38 Abnormal ejaculation has been reported in about 10% of men on tamsulosin.²¹ In short-term clinical trials, the proportion of men who withdraw from alpha blocker treatment because of side effects is generally low, but this proportion is likely to be higher in clinical practice, particularly over time. Caution must be exercised in combining alpha blockers with phosphodiesterase type 5 inhibitors used for the treatment of erectile dysfunction, which commonly coexists with BPH, for fear of inducing hypotension. Sildenafil at doses over 25 mg should not be taken within 4 hours of an alpha blocker; and vardenafil and tadalafil should be used cautiously, starting at the lowest dose by men on stable doses of alpha blockers, with careful monitoring of blood pressure.

Nonselective alpha₁-adrenergic blockers such as doxazosin and terazosin require dose titration [see Table 1]. Most clinicians start with a 1 mg dose at bedtime for several days to avoid so-called first-dose hypotension, although the clinical relevance of this phenomenon is poorly documented. In most patients, the dose should be pushed to the highest level if possible; the clinician should monitor supine and standing blood pressure, side effects, and the patient's global impressions of improvement before dose escalation. Follow-up administration of the IPSS may help objectify improvements and aid in the decision whether to proceed to the highest recommended dose. Both doxazosin and terazosin can be given once daily. Many clinicians recommend taking them at bedtime, although it is unclear whether this strategy reduces side effects.

Tamsulosin, extended-release doxazosin, and extended-release alfuzosin are designed for once-daily administration and do not require as many dose-titration steps as doxazosin and terazosin. Tamsulosin and extended-release doxazosin have two recommended dose levels; extended-release alfusosin has just one.

Although alpha blockers have repeatedly been shown to reduce LUTS, their ability to reduce the risk of BPH complications over the long term, particularly the development of acute urinary retention, appears weak.³⁹ A large 2-year trial of alfuzosin did demonstrate prevention of symptom progression and the need for surgery, but not prevention of acute retention.⁴⁴

5a-Reductase Inhibitors

The 5a-reductase inhibitors currently available for the treatment of BPH are finasteride and dutasteride. Finasteride selectively and irreversibly binds with the 5a-reductase isoenzyme type 2, which predominates in the prostate, and thereby blocks conversion of testosterone to DHT, the dominant intraprostatic androgen. This agent lowers serum DHT by about 70% and intraprostatic DHT to an even greater degree. Dutasteride is a dual 5a-reductase inhibitor; it blocks both type 1 and type 2 isoenzymes and lowers serum DHT by about 90%.⁴⁵ Whether this dual blockade offers any clinical advantage is uncertain.

Men who take finasteride at the recommended dose of 5 mg daily or dutasteride at 0.5 mg daily can expect a 20% to 25% reduction in prostate size over the first year of therapy,^45,46 accompanied by about a 50% reduction in PSA level.^45,47 Despite this effect on PSA, these drugs have not been shown to impair the ability to diagnose prostate cancer in controlled trials. However, PSA levels must be interpreted differently. The most common recommendation is simply to double the measured PSA levels for men on finasteride or dutasteride, then interpret the results as usual.

Like the alpha blockers, finasteride and dutasteride have been shown in a number of clinical trials to produce greater symptom reduction than placebo. However, the symptom reduction has generally been smaller than for the alpha blockers, averaging 2 to 4 points from baseline IPSS scores.^45,48 The efficacy of finasteride, reflected in the group mean difference between finasteride and placebo in these trials, depends on prostate size. For men with prostates less than 40 ml, the differences between finasteride and placebo are minimal, but the differences in IPSS scores between finasteride and placebo increase to 1.0 to 1.5 points for men with prostates greater than 40 ml in trials lasting up to 2 years.⁴⁸ Dutasteride's relative efficacy is also conditioned by prostate size, with about a 1 point improvement over placebo for men with prostates 30 to 40 ml and about 2 points for men with glands larger than 40 ml.⁴⁹

In a longer-term trial, finasteride resulted in about a 3 point decrease in symptom score from baseline over 4 years, roughly 2 points greater than the decrease shown with placebo.⁴⁶ The slow response of symptoms to finasteride was obvious, with nadir scores not reached for at least 2 years. Finasteride also significantly reduced the risk of acute urinary retention (from 6.6% to 2.8%) and of progression to prostatectomy (from 8.3% to 4.2%). In a 2-year trial, the effects of dutasteride on the relative risk of acute urinary retention and on progression to surgery were similar to those of finasteride.⁴⁵ Data from the finasteride trial indicated that about 15 patients would have to take finasteride for 4 years to prevent the development of acute retention or the progression to surgery in one of those patients. This trial also documented that this preventive benefit of finasteride depends on prostate size and, furthermore, that serum PSA level could be used as a proxy for prostate size to estimate the expected benefit.⁵⁰ The estimated number of men who would need to be treated for 4 years to prevent one episode of acute retention or progression to surgery is about 29 for baseline PSA levels less than 1.4 ng/ml, 18 for PSA levels of 1.4 to 3.2 ng/ml, and 9 for PSA levels greater than 3.2 ng/ml.⁵¹

Finasteride also seems effective at reducing the risk of recurrent bleeding in men presenting with BPH-related hematuria.⁵² This effect is probably attributable to finasteride-induced suppression of vascular endothelial growth factors.

Finasteride is relatively well tolerated. About 5% to 10% of men notice decreased libido or ejaculatory abnormalities over the first year of treatment; fewer than 1% of men have rashes, gynecomastia, or breast tenderness. After the first year of treatment, side effects with finasteride and placebo are essentially identical.⁴⁶ The side-effect profile of dutasteride is similar.⁴⁵

In a large cancer prevention trial, the 7-year cumulative likelihood of a prostate cancer diagnosis was 18.4% with finasteride and 24.4% with placebo.²⁵ The likelihood in both trial arms was higher than expected because of intensive surveillance for prostate cancer, including end-of-study biopsies (regardless of DRE findings or PSA levels) in most participants. However, the likelihood of a high-grade prostate cancer (defined as a cancer with a Gleason score of 7 to 10) increased from 5.1% with placebo to 6.4% with finasteride. These results raise doubt about whether finasteride would do more good than harm in terms of its effect on prostate cancer morbidity and mortality. However, use of finasteride appears to be associated with a modest improvement in the ability of PSA testing to distinguish patients with prostate cancer from those without; this effect may also explain the trial's findings.⁵³ The effect on prostate cancer incidence should be considered when prescribing finasteride (and, presumably, dutasteride, which works by the same mechanism) to men for LUTS attributable to BPH.

Combination Therapy

Given that alpha blockers and 5a-reductase inhibitors work through different mechanisms, combination therapy is an attractive concept. Nevertheless, in head-to-head comparative trials, both terazosin and alfuzosin used alone were found to be superior to finasteride for symptom relief over 6 to 12 months of therapy,^54,55 and the combination of finasteride with terazosin or alfuzosin was found to be no better than either alpha blocker alone in the short term. However, in a subsequent 4-year trial, doxazosin, finasteride, and combination therapy were compared with placebo in terms of their ability to reduce the rate of BPH progression, defined primarily as 4-point increases in IPSS. The risk of progression at 4 years was 17% with placebo, 10% with either doxazosin or finasteride, and 5% with both.³⁹ The advantage of combination therapy was most apparent among men with prostate volumes greater than 40 ml.⁵⁶ Patients who take combination therapy are exposed to the side effects of both agents.

Anticholinergics

Anticholinergics have historically been avoided in men with LUTS attributable to BPH, for fear of exacerbating bladder outlet obstruction and precipitating acute urinary retention. On the other hand, many men with bladder outlet obstruction also have uninhibited detrusor contractions and bothersome filling symptoms, such as frequency, nocturia, urgency, and urge incontinence, that might be helped by anticholinergics. A 2006 meta-analysis found five trials of anticholinergics in men with LUTS attributable to BPH in which the anticholinergics had no overall effect on the IPSS, though one trial did find a significant reduction in the subset of IPSS filling symptoms, with a fairly low risk of urinary retention of 0.3% over 12 weeks.⁵⁷ In a 2007 12-week trial, men 40 years of age or older who had bothersome LUTS, including prominent filling symptoms, were randomized to receive one of four regimens: tamsulosin, long-acting tolteridine, both agents, or placebo. Although the overall effect of combination therapy on the IPSS appeared no greater than the effect of tamsulosin alone, combination did appear to produce a greater reduction in urgency and frequency, as assessed on the basis of voiding diaries. The risk of acute retention was 0.5%.⁵⁸ The role of anticholinergics, alone or in combination with other agents, requires further study in older men with LUTS attributable to BPH, and no anticholinergic has yet been approved by the FDA for this purpose.

Phytotherapy

Many patients around the world take phytotherapies for LUTS. They may take these preparations on their own initiative or at the recommendation of a clinician. Meta-analyses suggest that a number of these phytotherapies, including extracts of the saw palmetto plant,⁵⁹b-sitosterol plant extracts,⁶⁰ rye grass pollen extract,⁶¹ and Pygeum africanum plant extracts,⁶² are effective for reducing some LUTS. The effects appear to be small, and the trials are generally limited by design problems, particularly short durations of follow-up and incomplete outcome assessments. In particular, few studies used validated symptom scores as outcome measures. A recent high-quality trial of saw palmetto extract, one of the most widely used phytotherapies for men with LUTS, showed no therapeutic effect.⁶³ The mechanisms of any effects are poorly defined. Moreover, preparations of these agents vary, so patients are not assured that any given preparation will afford the same benefits seen in trials.

Surgery and Minimally Invasive Treatment

Transurethral and Open Prostatectomy

Transurethral prostatectomy (TURP) remains the gold standard for relieving symptoms and reducing the risk of complications for men with BPH. TURP involves resecting the central adenoma of the hyperplastic prostate transurethrally under direct visualization using a resectoscope with an electrified cutting loop. General or spinal anesthesia is usually used. In the United States, patients may have as little as an overnight hospital stay after TURP and may require a urinary catheter for a short period until the initial hematuria induced by the resection begins to clear.

In a randomized trial comparing TURP and watchful waiting, mean IPSS scores fell by about 12 points from baseline with TURP by 7.5 months after randomization, as compared with a decrease of 1 point with expectant management over that period.⁶⁴ Although there are no randomized trials comparing medical therapy with TURP, the decreases in symptom scores with TURP are substantially greater than with any medication. In a randomized trial comparing TURP with expectant management that included almost 600 men with moderate symptoms, treatment failures (predominantly deterioration to severe symptoms, acute retention, or the development of a very large residual volume) were significantly reduced from about 20% to 10% over 3 years with TURP, as compared with watchful waiting.⁶⁵ However, these results must be interpreted in light of the fact that about a quarter of the patients initially assigned to expectant management crossed over to the surgery group within 3 years.

With the availability of other effective and less invasive treatment options, age-adjusted rates of TURP in Medicare beneficiaries fell by about half from 1984 to 1997.⁶⁶ However, the procedure became progressively safer over this period; currently, 30-day mortality is less than 1%. Moreover, TURP provides durable symptom relief, with a 5-year risk for reoperation of about 5%.⁶⁶ Although erectile dysfunction and incontinence have been traditionally considered potential side effects of TURP, the risks were similar for TURP and watchful waiting in the largest comparative trial.⁶⁵ Retrograde ejaculation is a common outcome of TURP, occurring in the majority of cases. Men should be warned to expect this result when considering TURP.

A prostatic adenoma can also be resected through an open incision using either a retropubic or a suprapubic approach. To avoid the incision, as well as potential complications such as wound infection, open prostatectomy is generally reserved for men with the largest prostates, in whom a transurethral resection may be especially challenging. An open prostatectomy can also be expected to provide excellent and durable symptom relief.

Transurethral Incision and Electrovaporization

Transurethral incision of the prostate (TUIP) involves making one or two longitudinal incisions in the prostate without resecting tissue. This procedure has been considered especially well suited to younger men with smaller prostates. In a meta-analysis of four small trials, symptom relief at 12 months with TUIP was similar to that with TURP.⁶⁷ However, long-term comparative results are not available. The risk of retrograde ejaculation was 73% with TURP but only 21% with TUIP.⁶⁷

Transurethral electrovaporization of the prostate (TUVP) is similar to TURP but uses a roller electrode to vaporize superficial layers of tissue while coagulating deeper layers. A meta-analysis of several small trials suggested that the primary benefit of TUVP is fewer bleeding complications, but this advantage is not definitive.⁶⁸ The longest trial (5 years) suggested that TURP and TUVP had similar effects on symptoms, but few patients completed 5 years of follow-up.⁶⁹

Laser Coagulation, Vaporization, and Enucleation

A number of treatment strategies using laser energy to coagulate, vaporize, or actually enucleate prostate tissue have been explored for men with LUTS attributable to BPH. An early technique of noncontact coagulation has been totally abandoned. In a meta-analysis, short-term symptom responses to a spectrum of laser procedures were somewhat less impressive than for TURP, with higher risks of reoperation, though with fewer transfusions and postoperative strictures.⁷⁰ Longer-term trials comparing visual laser ablation of the prostate (VLAP) and contact laser vaporization with TURP have also shown higher retreatment rates with the laser strategies over 3 to 5 years.^71,72 A holmium laser ablation technique appeared to have results comparable to those of TURP in a 1-year trial, and a holmium laser enucleation technique had similar results to TURP at 2 years.^73,74 A long learning curve and high equipment costs have inhibited wider use of holmium laser procedures. A high-powered KTP (so-called greenlight) laser can be used for vaporization, but, as yet, there are few long-term data comparing its effectiveness with that of TURP or holmium laser procedures.⁷⁵

Thermal Therapies

A number of minimally invasive treatments have been developed to coagulate prostate tissue with heat generated through various mechanisms. These office-based treatments are designed to reduce symptoms, with less sedation and fewer side effects than is seen with surgery. No tissue is resected, so their mechanism of action is uncertain. Transurethral microwave therapy (TUMT) uses a microwave antenna placed in the urethra to generate heat. The urethra, which is pain sensitive, is protected by a cooling jacket. TUMT reduced symptoms more than terazosin in an 18-month trial⁷⁶; however, in small trials comparing TUMT and TURP, symptomatic outcomes were somewhat less impressive with TUMT.⁶⁸ One long-term trial suggested that TUMT and TURP yielded similar results at 5 years, a conclusion limited by the dropout of a third of subjects.⁷⁷ TUMT produces fewer side effects related to bleeding than does TURP. Transurethral needle ablation (TUNA) uses two radiofrequency needles placed directly into the prostate via the urethra to heat and coagulate tissue. In one comparative trial, symptom reduction was somewhat less with TUNA than with TURP at 1 year. However, both bleeding and retrograde ejaculation were less common with TUNA.⁷⁸ Long-term outcomes are poorly defined for either of these heat-based treatments, and comparative studies between them are of generally poor quality.⁷⁹

Management of Acute Urinary Retention

Acute urinary retention occurs at a rate of 1% to 2% a year in men with LUTS attributable to BPH. The occurrence of acute urinary retention used to be considered an absolute indication for surgery. However, case series have documented that up to half of men with acute retention have a successful voiding trial after a period of catheter drainage, and most of the men who experience success will continue to void, at least over a 6 month period following the procedure. The optimal duration of catheter drainage is poorly defined, with recommended periods ranging from a few days to several weeks. Trials have generally shown that pretreatment with an alpha blocker before catheter removal modestly improves the probability of a successful voiding trial.^80,81

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

Figure 2 Tom Moore.

Figure 3 International Consultation on BPH.