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| CECIL |
| TEXT BOOK of MEDICINE |
Section XI Renal and Genitourinary Diseases
| 130 BENIGN PROSTATE DISEASE AND PROSTATITIS Michael J. Barry • Mary McNaughton-Collins • |
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The prostate gland, the largest accessory gland in the male reproductive system, surrounds the prostatic urethra below the bladder. Superiorly, its base is contiguous with the bladder neck; inferiorly, its apex adjoins the urogenital diaphragm. The prostatic urethra is angulated at the verumontanum, the union with the two ejaculatory ducts. In younger men, the prostate weighs about 20 g. As men age, the prostate enlarges and develops a characteristic zonal anatomy (Fig. 130-1). Its acini communicate with the urethra via prostatic ducts, and it supplies about 20% of the semen volume. Prostatic fluid is rich in citrate, zinc, and polyamines, although their roles in reproduction are poorly defined.
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| FIGURE 130-1 Sagittal diagram of the distal prostatic urethral segment (UD), proximal urethral segment (UP), and ejaculatory ducts (E) showing their relationships to a sagittal section of the anteromedial nonglandular tissues (bladder neck [BN], anterior fibromuscular stroma [FM], preprostatic sphincter [PS], and distal striated sphincter [DS]). These structures are shown in relation to a three-dimensional representation of the glandular prostate: central zone (CZ), peripheral zone (PZ), and transitional zone (TZ). (From McNeal J: Normal histology of the prostate. Am J Surg Pathol 1988;12:619–633, with permission.) |
▪ BENIGN PROSTATIC HYPERPLASIA
Definition
Benign prostatic hyperplasia (BPH) is defined histologically by hyperplasia of both epithelial and stromal cells, beginning in the periurethral area. The hyperplasia can be symmetrical or asymmetrical and is generally progressive over time. With aging, multiple small hyperplastic nodules grow, coalesce, and compress normal tissue outward against the true prostatic capsule and create a surgical capsule bounding the expanding adenoma.
Epidemiology
The hyperplastic process often begins in the 30s; by 80 years of age, 85% of men have BPH. The age-specific prevalence of BPH at autopsy is remarkably similar among men of different ethnicities. Aging and functioning testes are the dominant risk factors. The onset of clinical manifestations of BPH before age 65 in a first-degree relative is also a risk factor. The prevalence of clinical manifestations is uncertain because of lack of consensus on a working definition. Nevertheless, about a third of U.S. men aged 40 to 79 years have moderate to severe lower urinary tract symptoms, a majority of which are attributable to BPH.
Pathobiology
Testosterone is converted by the 5α-reductase enzyme to dihydrotestosterone (DHT), the major intraprostatic androgen. BPH does not develop in men who are castrated before puberty or have 5α-reductase deficiency. Although the type 2 isoenzyme predominates in the prostate, the type 1 isoenzyme predominates elsewhere. An array of peptide growth factors, along with DHT, mediate stromal-epithelial interactions that alter the balance of cell proliferation and apoptosis and thereby lead to BPH. The mechanisms are poorly understood.
The genetics of BPH are also unclear. There may be an autosomal dominant hereditary form accounting for less than 10% of cases.
Clinical Manifestations
The morbidity of BPH is conferred through bothersome lower urinary tract symptoms. Traditionally, voiding symptoms, such as hesitancy, straining, a sense of incomplete emptying, intermittency, a weak stream, and postvoid dribbling, were considered to be a consequence of mechanical bladder outlet obstruction. Filling symptoms, such as frequency, nocturia, urgency, and urge incontinence, were thought to be due to secondary uninhibited detrusor contractions. However, poor correlations among symptom severity, prostate size, degree of obstruction, and detrusor instability suggest that their origin is more complex. The key lower urinary tract symptoms of BPH can be quantified by using the seven symptom questions in the International Prostate Symptom Score (IPSS) (Fig. 130-2).
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| FIGURE 130-2 International Prostate Symptom Score (IPSS). The seven symptom questions are part of a scale initially developed as the American Urological Association Symptom Index. The eighth question about symptom inconvenience is scored separately. (From Barry MJ, Fowler FJ Jr, O'Leary MP, et al: The American Urological Association symptom index for benign prostatic hyperplasia: The Measurement Committee of the American Urological Association. J Urol 1992;148:1549.) |
Bladder outlet obstruction as a result of BPH has both static and dynamic components. The static component is due to the enlarged prostate, whereas the dynamic component is due to increased adrenergic tone in the prostate, where α2-adrenoreceptors predominate.
In the setting of obstruction, increased detrusor pressure can result in detrusor hypertrophy and, eventually, fibrosis. Complications of BPH include acute urinary retention, which may result from prostatic infarction. Postvoid residual urine probably increases the risk for urinary tract infection or stone formation. With long-standing obstruction, hydroureter and hydronephrosis may develop and, eventually, renal failure. Men with BPH may have hematuria because there is often a complex of veins stretched over the enlarged prostate; however, other causes, especially malignancy, need to be considered.
Diagnosis
History
Usually, a working diagnosis of symptomatic BPH is made when an older man is evaluated for lower urinary tract symptoms. These symptoms should be quantified with the IPSS (see Fig. 130-2). Scores of 0 to 7 represent mild symptoms; 8 to 19, moderate symptoms; and 20 to 35, severe symptoms. The pattern of individual responses should be noted. When frequency and nocturia are the dominant symptoms, a voiding diary, in which the patient records the times and amounts of each void over a period of several days, may be helpful. For example, if the diary documents nocturnal polyuria alone, causes other than BPH should be strongly considered. Men with BPH tend to have a balance of voiding and filling symptoms that slowly progress with age. Rapid onset, manifestation before age 50, or filling symptoms without voiding symptoms are “red flags” suggesting alternative causes. A complete list of medications should be obtained because many, especially over-the-counter antihistamines, sympathomimetics, and anticholinergics, can affect the urinary tract.
Differential Diagnosis
Although lower urinary tract symptoms in older men are often due to BPH, the differential includes systemic diseases causing frequency and nocturia, such as diabetes and hypercalcemia, bladder outlet obstruction secondary to urethral strictures, and neurologic diseases affecting the bladder. A general medical history and the pattern of symptoms should provide clues to systemic diseases. Men with strictures have usually undergone genitourinary instrumentation or have had sexually transmitted diseases. Primary bladder problems should be suspected in men with previous stroke, Parkinson's disease, or diabetic neuropathy.
Physical Examination
The physical examination should include a digital rectal examination (DRE) and a focused neurologic examination to look for evidence of peripheral neuropathy or saddle-area anesthesia (the S2-4 segments innervate the bladder), which might suggest an underlying neuropathic bladder. The DRE should assess the size and consistency of the prostate. Classically, BPH causes a symmetrically enlarged, firm prostate, the consistency of the tip of the nose. Asymmetry or frank nodules suggest prostate cancer; however, prostate cancer can be present even when the prostate feels normal. Clinicians tend to underestimate prostate size; if the prostate feels enlarged, it usually is.
Laboratory Findings
Urinalysis should be performed for evidence of pyuria or hematuria. Optional studies include creatinine measurements, uroflow rates, and prostate-specific antigen (PSA) levels. Peak uroflow is often measured in urologists' offices, but it is unreliable with low voided volumes (<150 mL). Peak flows of less than 10 mL/sec are more suggestive of outlet obstruction, whereas flows greater than 15 mL/sec are less suggestive; unfortunately, men can have good flow with obstruction and forceful bladder contractions and poor flow without obstruction with weak bladder contractions.
PSA tests are used for early detection of prostate cancer; however, PSA has relatively poor specificity in this situation. Moreover, early detection of prostate cancer with PSA has not as yet been shown to reduce prostate cancer mortality in randomized trials. If a PSA assay is ordered, generally a level greater than 4 ng/mL should trigger an ultrasonography-guided prostate biopsy. Although about 50% of men with PSA levels greater than 10 ng/mL have prostate cancer at biopsy, about 25% with levels of 4.1 to 10.0 ng/mL have cancer, and 15% with levels of 4.0 ng/mL or less have cancer. Most authorities doubt the value of early detection of nonpalpable prostate cancer in men with a life expectancy of less than 10 years or after about the age of 75 in men with average comorbidity. Many men with BPH are older. However, for medical-legal reasons, it is wise to discuss the possibility of an underlying prostate cancer with any older man being evaluated for lower urinary tract symptoms. A PSA level, probably by serving as a proxy for prostate size, can also help stratify the future risk of progression to surgery or acute urinary retention, with higher values predicting greater risk.
The “gold standard” test for the diagnosis of bladder outlet obstruction is the documentation of increased bladder pressure relative to uroflow. The role of pressure-flow studies in the evaluation of men with lower urinary tract symptoms is debated. These tests should be considered in men who have atypical manifestations or diseases that increase their risk for primary bladder problems or in men who fail invasive therapy. Because findings at pressure-flow studies can predict responses to invasive therapy, albeit imperfectly, some authorities also consider them for men in whom medical therapy fails.
Prevention
As yet, there are no documented effective preventive strategies for BPH.
Treatment
Men with IPSS scores in the mild range are rarely bothered enough to treat. Similarly, an enlarged prostate alone is not an indication for treatment. The key step in decision making for men with moderate or severe symptoms is to assess the degree to which they are bothering the patient. The last IPSS question (see Fig. 130-2) can serve as an entree into this discussion.
For men with little inconvenience, “watchful waiting” is appropriate. The patient's situation should be periodically reassessed. Avoidance of offending medications is also wise.
Medical Therapy
Most men with bothersome symptoms initially choose medical therapy. α1-Adrenergic blockers and 5α-reductase inhibitors are the available prescription options. α-Blockers (Table 130-1) attack the dynamic component of BPH and have been shown to reduce symptoms in multiple clinical trials of up to 4 years' duration.1 The response to α-blockers is independent of prostate size. In general, doses should be increased toward the maximum until the therapeutic effect is optimal, unless side effects are limiting. Doxazosin and terazosin are effective for the treatment of both BPH and hypertension; however, α-blocker monotherapy can no longer be considered optimal for hypertension. The effect of α-blockers on the risk of acute retention or progression to surgery over a period of 4 years is not significant.
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In general, side effects of α-blockers include orthostatic hypotension, dizziness, and asthenia. Tamsulosin and alfuzosin appear to be more specific for the α1a-receptor subtype, which dominates in the prostate. Both agents appear to have little or no effect on blood pressure. However, because the dizziness and asthenia seen with α-blockers are not primarily mediated through hypotension, a lack of head-to-head comparisons makes it unclear whether these agents have advantages other than a lower risk for orthostatic hypotension.
Finasteride and dutasteride are the 5α-reductase inhibitors available to date (see Table 130-1). These agents block conversion of testosterone to DHT by the type 2 isoenzyme (finasteride) or both isoenzymes (dutasteride). Prostate size decreases by 15 to 20% over a 1-year period of treatment with either agent. Finasteride and dutasteride reduce lower urinary tract symptoms more than placebo does in trials of 2 to 4 years in duration, although symptom relief is more modest than that seen with α-blockers. 2,3 In addition, these agents reduce the rate of progression to surgery and acute urinary retention in men with larger prostates. PSA levels can be used to stratify the preventive benefit of finasteride. The “number needed to treat” for 4 years to prevent an episode of acute retention or surgery is about 30 for men with PSA levels less than 1.4 ng/mL, about 20 for PSA levels of 1.4 to 3.2 ng/mL, and about 10 for PSA levels greater than 3.2 ng/mL.
The main side effect of finasteride and dutasteride is sexual or ejaculatory dysfunction in about 5% of men. Both agents lower PSA levels by about 50%. Although they do not appear to interfere with the detection of prostate cancer, PSA levels must be interpreted differently. The simplest strategy is to double the measured PSA and interpret it as usual. In a recent randomized trial, finasteride reduced the 7-year cumulative incidence of prostate cancer from 24 to 18% in a group of men who were heavily screened, including routine end-of-study biopsies.4 However, because finasteride increased the risk for high-grade cancer from 5 to 6%, the ultimate impact of 5α-reductase inhibitors on prostate cancer mortality is uncertain.
Given the different mechanisms of α-blockers and 5α-reductase inhibitors, combination therapy is attractive. In a trial of 1 year's duration, finasteride offered no additional symptomatic benefit over α-blockers in terms of symptom reduction.5 However, combination therapy was more effective than monotherapy with either doxazosin or finasteride in preventing disease progression, including symptom progression, over a period of 4 years.2 When men have symptomatic BPH, an α-blocker is a reasonable first choice for medical therapy. Finasteride or dutasteride can be offered as well to men with palpably enlarged prostates or higher PSA levels for added preventive benefit.
Future directions in medical therapy include larger trials of various plant extracts, such as saw palmetto, which men widely use for lower urinary tract symptoms.
Surgical Therapy
Transurethral prostatectomy (TURP) is still considered the “gold standard” for treating BPH because it offers symptom reduction substantially greater than that achieved with medical therapy. TURP generally requires a brief hospital stay and an indwelling catheter at first. In a randomized trial comparing TURP with watchful waiting, both symptoms and BPH complications were substantially reduced with surgery.6 Moreover, the risks of sexual dysfunction and incontinence were no greater with TURP. Standard TURP uses a wire electrode to resect obstructing tissue. Newer variations use a rolling electrode or laser energy to vaporize or resect prostate tissue. These procedures appear to result in less short-term bleeding and good short-term symptom improvement, but their long-term effectiveness is undefined.
Newer, less invasive surgical therapies, including ethanol injections, high-intensity focused ultrasound, and water-induced thermal therapy, are being developed in an attempt to marry the durable symptom relief of TURP with the ease and minimal side effects of medical therapy.
Ancillary Treatments
Minimally invasive techniques have been developed to relieve symptoms without hospitalization. Transurethral microwave thermotherapy (TUMT) heats and coagulates prostate tissue by using a microwave antenna surrounded by a cooling jacket to protect the urethra. Transurethral needle ablation (TUNA) uses radiofrequency needles placed directly in the prostate to generate heat and cause coagulation. The mechanisms by which these treatments work are poorly understood. However, they appear to produce an initial level of symptom relief intermediate between drug therapy and TURP. Their long-term effectiveness remains unclear.
Prognosis
Lower urinary tract symptoms attributable to BPH generally progress slowly over time, but individuals vary. For example, in one study of men with symptom scores in the moderate range who elected watchful waiting, after 4 years of follow-up, 13% had only mild symptoms, 46% still had moderate symptoms, 17% had severe symptoms, and 24% had opted for surgery. The risk of acute urinary retention in such men is 1 to 2% per year. More serious complications appear to be exceedingly rare.
▪ PROSTATITIS
Definition
The validity of the traditional etiology-based classification of prostatitis has never been confirmed. The current National Institutes of Health (NIH) prostatitis classification system incorporates the terminology “chronic pelvic pain syndrome” to reflect uncertainty over whether chronic nonbacterial prostatitis and prostatodynia are in fact even related to the prostate (Table 130-2).
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Epidemiology
Two million outpatient visits for prostatitis are made annually in the United States. The histologic prevalence ranges widely from 6 to 98%. The prevalence of current prostatitis-like symptoms or a previous physician's diagnosis of prostatitis is about 10%.
Pathobiology
Both type I (acute bacterial) and type II (chronic bacterial) prostatitis account for 5 to 10% of cases. Like urinary tract infections, 80% are due to strains of Escherichia coli; 10 to 15% are due to Pseudomonas aeruginosa, Serratia, Klebsiella, and Proteus species; and 5 to 10% are due to enterococci.
The remainder (>90%) of prostatitis cases are type III (chronic abacterial/chronic pelvic pain syndrome) prostatitis, but the pathogenesis of this type remains uncertain. Type III prostatitis is further divided into inflammatory (type IIIA) and noninflammatory (type IIIB) subtypes based on the presence of leukocytes in expressed prostatic secretions and prostatic urine. Given that there appears to be no correlation between the presence of leukocytes and symptoms, the subdivision into types IIIA and IIIB is controversial; many experts believe that both inflammatory and noninflammatory chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are the same noninfectious condition, which may or may not be related to the prostate gland.
Theories for the etiology of type III prostatitis include infectious agents, such as Mycoplasma hominis, Ureaplasma urealyticum, Trichomonas vaginalis, Chlamydia trachomatis, viruses, anaerobic bacteria, and coagulase-negative staphylococci; pro-inflammatory cytokines; autoimmune mechanisms; neurogenic processes; increased prostate tissue pressure; chemical irritation; and increased tension in the muscles of the bladder neck and prostatic urethra or from tension myalgia of the pelvic floor. Psychological factors have also been implicated.
Clinical Manifestations
Type I prostatitis is characterized by the acute onset of fever, chills, and malaise; low back or perineal pain; and urinary symptoms, particularly dysuria, frequency, and urgency. The manifestation is generally dramatic, and the patient may appear toxic. DRE often reveals a markedly tender gland.
Type II prostatitis generally occurs in older men in association with recurrent urinary tract infections. The findings are less dramatic but involve similar lower urinary tract symptoms, pelvic pain, and sexual dysfunction. On DRE, the prostate may be normal, swollen, firm, or tender.
Type III prostatitis is characterized by pelvic pain, often associated with lower urinary tract symptoms and pain during or after ejaculation. DRE findings also vary.
Type IV prostatitis is, by definition, asymptomatic.
Because the hallmark of chronic prostatitis is a complex of symptoms that wax and wane, a brief, self-administered index has been developed and validated (NIH Chronic Prostatitis Symptom Index) to quantify them.
Diagnosis
Whereas acute prostatitis is relatively straightforward to diagnose, chronic prostatitis is more challenging. The symptom complexes of chronic prostatitis and BPH overlap such that BPH may be misdiagnosed in older men with chronic prostatitis. Although men can and do get both conditions, pain generally distinguishes chronic prostatitis from BPH. A PSA test is not indicated for the evaluation of chronic prostatitis; however, if a PSA test is performed and found to be elevated, the elevation should not be ascribed to CP/CPPS. In addition to BPH and prostate cancer, the differential diagnosis for chronic prostatitis includes sexually transmitted disease, urethritis, epididymitis, orchitis, urethral stricture, urinary tract infection, kidney stone, bladder cancer, hernia, pudendal artery insufficiency, sphincter dyssynergy, and neurogenic bladder.
Type I prostatitis is diagnosed primarily by clinical findings and a positive urine culture. Prostate massage is not recommended because of concern for bacteremia.
Type II and type III prostatitis are traditionally diagnosed with the four-glass test. This segmented, quantitative culture technique involves culturing initial-stream urine, midstream urine, expressed prostatic secretions after massage, and post–prostate massage urine. The simplified two-glass test involves culture and microscopic examination of urine obtained before and after prostatic massage; it is easier for all concerned, with similar operating characteristics. Although type II prostatitis is characterized by the presence of uropathogenic bacteria, it is the absence of uropathogens in the setting of genitourinary pain that defines type III prostatitis.
Type IV prostatitis is usually diagnosed incidentally by prostate biopsy or by finding leukocytes in prostatic secretions collected for infertility evaluation.
Prevention
There is no proven preventive strategy for any type of prostatitis.
Treatment
Type I prostatitis is relatively easy to treat. Antibacterial agents that normally diffuse poorly into prostatic fluid work well, probably because intense inflammation enhances penetration. The choice of antimicrobial is driven by culture results. Parenteral antibiotics are necessary for sicker patients, but oral fluoroquinolones or trimethoprim-sulfamethoxazole is adequate for outpatients. Treatment for 4 weeks is generally recommended.
Type II prostatitis is more difficult to treat because prostatic fluid becomes alkaline with chronic inflammation, thereby reducing antibiotic penetration. The fluoroquinolones and trimethoprim-sulfamethoxazole penetrate the prostate, but the penicillins, cephalosporins, aminoglycosides, and nitrofurantoin do not. Recommendations for the duration of therapy range from 6 to 12 weeks. The addition of an α-blocker may improve symptoms and reduce recurrences.
Type III prostatitis often engenders frustration on the part of the physician and confusion and dissatisfaction on the part of the patient. Because the cause is unknown, affected men receive various empirical therapies. The common practice of using antibiotics for chronic abacterial prostatitis is not supported by the existing evidence. 7,8 The effectiveness of α-blocker therapy, another common empirical treatment, remains uncertain. A 6-week trial of tamsulosin did not show symptom improvement 7; however, previous trials had shown a benefit 9,10; longer courses of therapy may be more beneficial. Further research is needed to test longer durations of α-blocker therapy, as well as α-blocker therapy in men naïve to previous treatments. In small trials, quercetin, finasteride, 11 pentosan polysulfate sodium, 12 tadalafil, 13 and pelvic floor electromagnetic therapy 14 appear to show possible benefit; further evaluation is merited.
For type IV prostatitis, no treatment is recommended.
Prognosis
The untreated natural history of all types of prostatitis is poorly defined. Most patients with type I prostatitis respond well to antibiotics, but some may progress to chronic prostatitis. Complications of type I prostatitis include prostatic abscess, acute urinary retention, septicemia, and rarely, vertebral osteomyelitis. Type II prostatitis can cause repeated urinary tract infections. Both type II and type III prostatitis have been associated with decreased fertility, although this relationship is not certain.
Future Directions
The Chronic Prostatitis Collaborative Research Network, funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases, is a multidisciplinary, multi-institutional effort to provide more information about the etiology, diagnosis, and treatment of prostatitis. Future directions in therapy include trials of medications, such as pregabalin, for treatment of the possible neuropathic pain associated with CP/CPPS. The Urologic Pelvic Pain Collaborative Research Network represents the overarching organization for collaborative research in chronic prostatitis, chronic pelvic pain syndrome, and interstitial cystitis and should serve to provide newer perspectives on chronic pelvic pain of urologic origin.
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