Prostatic Disorders and Erectile Dysfunction
Virginia P. Arcangelo
Disorders of the prostate appear as part of the normal aging process and also as abnormalities distinct from normal aging. Often, it is not until age 40 that a man begins to show some form of noncancerous prostatic disorder, whereas prostate cancer usually is found after age 50. At 70, approximately 40% of men report lower urinary tract symptoms (LUTS), increasing to 50% at the age of 75, most often from benign prostatic hypertrophy (BPH).
Prostate cancer is the second most common type of cancer affecting men, with a lifetime prevalence of 15%. Black men have the highest incidence of prostate cancer. Asian and Hispanic men are at lower risk than White men. In addition to race, other risk factors for prostate cancer are age and family history. The disease rarely occurs before age 45, but the incidence rises exponentially thereafter; nearly 70% of cases are diagnosed in men age 65 and older. There are 147.8/100,000 cases of newly diagnosed prostate cancer per year.
Prostate disorders are diagnosed through clinical manifestations and screening procedures used to detect or rule out prostate cancer. Lack of knowledge about prostate cancer and lack of available screening procedures are the major deterrents to accurate and timely diagnosis of prostate cancer.
Treatment of prostatic disorders itself may result in some untoward side effects, which must then also be managed. Often, the man postpones seeking medical intervention and blames aging for many of the manifestations, thus delaying treatment. Some difficulties in seeking treatment can relate to the man’s culture; sexuality—specifically, masculinity—can be perceived as synonymous with virility. For this reason, a man may choose not to discuss (even with a health care worker) clinical manifestations.
Prostatic disorders and LUTS occur because of inflammation or infection (prostatitis), BPH, and prostate cancer; prostatitis can involve the bladder neck, thus becoming prostatocystitis. A bacterial infection is often the cause of prostatitis, although some nonbacterial forms of prostatitis do exist. Inflammation can be chronic or acute.
Adenocarcinoma is the most common type of prostate cancer. Metastasis can follow slowly or quickly, and often, the symptoms of metastasis are what lead the man to seek medical intervention.
Presenting manifestations of prostatic disorders are usually specific to the urinary tract and include difficulty in onset of urine flow with or without a low flow of urine, frequency or urgency in voiding, incontinence, distention of the bladder, and hematuria. Management of prostatic disorders is specific to the particular disorder (cancerous vs. noncancerous), with some overlap in treatment.
PROSTATITIS
CAUSES
Prostatitis is one of the most common urological infections afflicting adult men and has recently been divided into four different categories based on the National Institutes of Health (NIH) consensus classification (Weidner & Anderson, 2008). This category system includes category I (acute bacterial prostatitis); category II (chronic bacterial prostatitis); category III chronic nonbacterial prostatitis and pelvic pain syndrome, including inflammatory and noninflammatory types (CP/CPPS); and category IV (asymptomatic inflammatory prostatitis). Acute and chronic bacterial prostatitis affects less than 5% of men with prostatitis. Most patients with prostatitis are found to have either nonbacterial prostatitis or prostatodynia. This
disorder can be acute or chronic. With acute bacterial prostatitis, the chief organisms involved are Escherichia coli and Pseudomonas species, although strains of staphylococci or streptococci also are seen. Chronic bacterial prostatitis is associated with Pseudomonas, E. coli, Proteus mirabilis, Klebsiella pneumoniae, and Enterococcus species, particularly Enterococcus faecalis. Nonbacterial prostatitis is essentially an inflammatory disorder.
disorder can be acute or chronic. With acute bacterial prostatitis, the chief organisms involved are Escherichia coli and Pseudomonas species, although strains of staphylococci or streptococci also are seen. Chronic bacterial prostatitis is associated with Pseudomonas, E. coli, Proteus mirabilis, Klebsiella pneumoniae, and Enterococcus species, particularly Enterococcus faecalis. Nonbacterial prostatitis is essentially an inflammatory disorder.
PATHOPHYSIOLOGY
Often chronic, nonbacterial prostatitis is nonetheless problematic for the patient. Primary etiologies of this condition include two predominant patterns of inflammation. The first is that of an allergic condition and is associated with eosinophil infiltration. The second is a nonspecific form in which granulomatous inflammation by peculiar, large, pale macrophages is found.
In acute bacterial prostatitis, as with any type of bacterial invasion, the prostate becomes overwhelmed by the bacteria, leading to inflammatory response activation. Usually, acute bacterial prostatitis is seen as an infection ascending up the urinary tract, and younger men, ages 30 to 50, can be affected with this illness.
DIAGNOSTIC CRITERIA
Symptom manifestation revolves around urinary tract signs. There is pain in the lower abdomen, difficulty in bladder emptying with or without a small stream during urination, nocturia, and fever to 104°F (40°C). Along with the febrile state, as with other infections, general arthralgia and malaise can occur.
On examination and interview, the man often admits to painful ejaculation and pain in the rectal or perineal areas. All the symptoms are due to the edema associated with acute inflammation of the prostate. Because of the risk of generalized septicemia, pharmacotherapeutics are urgently warranted.
Culture isolation of prostatic urine is the most accurate method of diagnosis. Prostatic urine is defined as the third and fourth (urine) secretion specimens of four serial urine sample because prostatic fluid is at a significantly higher concentration in these last two of four serial voids. The four urine samples are obtained sequentially, beginning with the initial void, followed by a midstream urine specimen, prostatic massage secretion, and finally the urine voided after the prostatic massage. Standard laboratory culture techniques are applied to establish the causative organism.
Nonbacterial prostatitis is confirmed by negative prostatic urine cultures with a positive elevated white blood cell count and the presence of inflammatory cells in prostatic secretions. This condition and another nonbacterial type of prostatitis known as prostatodynia have the same symptoms as does bacterial prostatitis. Treatment of the nonbacterial forms usually consists of symptom management without the use of antibiotics.
INITIATING DRUG THERAPY
Antibiotics are the required pharmacotherapy. (See Chapter 8.) Given that causative organisms are usually gram negative and, less commonly, gram positive, appropriate antibiotics are needed. The overall course of antibiotic therapy is of longer duration than that used to treat other systemic infections. Usually, antibiotics are given for 4 to 6 weeks, but up to 12 weeks of therapy may be necessary due to poor penetration of prostate tissue. Because chronic bacterial prostatitis is a bacterial infection, an appropriate antibiotic with good tissue penetration in the prostate should be selected. Fluoroquinolones have demonstrated the best tissue concentration and are recommended as first-line agents. Although trimethoprim-sulfamethoxazole (TMP-SMZ) may be considered, the tissue penetration may not be as effective, and in many areas of the United States, there is evidence of increasing uropathogenic resistance.
Second-line drugs include doxycycline, azithromycin, and clarithromycin. A 4- to 6-week course of therapy is usually recommended; however, a 6- to 12-week course is often needed to eradicate the causative organism and to prevent recurrence, especially if symptoms persist after completion of the initial therapy. No guidelines exist for treating gram-positive organisms, but ciprofloxacin and levofloxacin have adequate gram-positive coverage as well as excellent gram-negative coverage, and both medications penetrate the prostate tissue well.
Adjunctive therapies that may be beneficial include the use of sitz baths, analgesics, stool softeners, and antipyretics, along with rest. Prostatic massage, voiding in a warm bath (to relax pelvic muscles), and discontinuation of alcohol and caffeinated beverages can also help to relieve symptoms. If possible, withdrawal from antidepressants, anticholinergics, or sedatives may also help bladder function.
Goals of Drug Therapy
The goal of pharmacotherapy for prostatitis is to eradicate the causative organism and restore the prostate to health. Prostatitis often becomes chronic, and therefore, repeated trials with antibiotics or prolonged dosage schedules may be warranted.
Anti-Infectives
Table 33.1 depicts dosage information, adverse events, contraindications, and special considerations for the anti-infective management of bacterial prostatitis.
Trimethoprim-Sulfamethoxazole
This drug is a bacteriostatic combination product and is considered to be more powerful than its two components given separately. Also, when given as the combined form, resistance on the part of the causative organism arises less frequently. This agent ultimately adversely affects the production of proteins and nucleic acids of bacteria at the target (prostate) site. TMP-SMZ further inhibits growth of bacteria because of its antimetabolite property toward PABA (para-aminobenzoic acid). Drug-drug interactions can present when the patient is also
taking phenytoin (Dilantin), oral hypoglycemics, or warfarin (Coumadin). Close monitoring of the seizure threshold, serum glucose level, or partial thromboplastin time is important in the patient on TMP-SMZ who is also taking these other agents.
taking phenytoin (Dilantin), oral hypoglycemics, or warfarin (Coumadin). Close monitoring of the seizure threshold, serum glucose level, or partial thromboplastin time is important in the patient on TMP-SMZ who is also taking these other agents.
TABLE 33.1 Overview of Selected Antibiotics Used to Treat Acute Bacterial Prostatitis | ||||||||||||||||||||||||||
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Fluoroquinolones
Fluoroquinolones are also effective for bacterial prostatitis. Effective against gram-negative anaerobes and some gram-positive bacteria, these agents decrease the growth and replication of bacteria by inhibiting bacterial deoxyribonucleic acid (DNA) during synthesis. These agents may be the first choice for someone sensitive or allergic to TMP-SMZ.
The absorption of fluoroquinolones is reduced by milk, antacids (aluminum or magnesium based), iron or zinc salts, and sucralfate. For the patient who is also taking any of these medications, the dose should be taken either 2 hours after or 4 hours before the other medication.
Fluoroquinolones also affect the use of theophylline and warfarin. Elevated levels can occur, and thus, a lower dosage of theophylline or warfarin may be necessary.
Doxycycline
A long-acting tetracycline, doxycycline (Vibramycin) acts by inhibiting protein synthesis: binding of peptidyl transfer ribonucleic acid (tRNA) is blocked at ribosomal mRNA.
Many of the metal ions—aluminum, calcium, iron, magnesium, and zinc—can interfere by creating chelates with doxycycline. Thus, if these metals are given (and they often are as components of antacids), at least 2 hours should separate their use from the ingestion of doxycycline.
Azithromycin and Clarithromycin
These are macrolide antibiotics. Macrolides inhibits RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunits of susceptible microorganisms. They induce dissociation of tRNA from the ribosome during the elongation phase. Thus, RNA-dependent protein synthesis is suppressed, and bacterial growth is inhibited. Macrolides are mainly bacteriostatic but can be bacteriocidal depending on bacterial sensitivity and antibiotic concentration.
Selecting the Most Appropriate Agent
Oral antibiotics are the treatment agents of choice.
First-Line Therapy
The primary choice for first-line antibiotic therapy is a fluoroquinolone (Table 33.2). Therapy lasts for 4 to 6 weeks. See Figure 33.1 for more information. TMP-SMZ may also be considered if treatment is in an area where there is not a high incidence of resistance.
Second-Line Therapy
Doxycycline, azithromycin, and clarithromycin are second-line agents. If the infection is not resolved with 4 to 6 weeks of drug treatment, therapy can be continued for up to 12 weeks.
Special Population Considerations
In older men who are taking fluoroquinolones, creatinine clearance must be monitored.
TABLE 33.2 Recommended Order of Treatment for Prostatitis | |||||||||
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MONITORING PATIENT RESPONSE
As a group, anti-infective agents should begin to elicit results after the first week of therapy. Subjective response from the patient indicating alleviation of symptoms is helpful in monitoring the effectiveness of these medications. Some patients may not notice symptom resolution until after 2 weeks; they should be told this and encouraged to continue taking the medication. Ultimately, 12 weeks of therapy may be required. Follow-up cultures may be obtained at the practitioner’s discretion. Further diagnostic criteria may also be recommended for ongoing symptom manifestation.
 FIGURE 33.1 Treatment algorithm for prostatitis. |
PATIENT EDUCATION
The patient should understand potential side effects, interactions, and appropriate use of the medications. Literature can provide patients with a guide for such potential concerns as well as dosing information. With a prepared and knowledgeable patient, these medications are effective against prostatitis. Cost also can be a factor of concern to the patient. The practitioner should be aware of any financial constraints the patient may have, because compliance with medication is important for effective treatment of bacterial prostatitis.
BENIGN PROSTATIC HYPERPLASIA
Benign prostatic hyperplasia (BPH) is the most common prostate problem in men older than age 50; the disease rarely causes symptoms before age 40. As life expectancy rises, so does the occurrence of BPH—an estimated 6.3 million men have BPH. In the United States alone, the disease accounts for 6.4 million doctor visits and more than 400,000 hospitalizations annually. Approximately 90% of men age 80 and older have histologic evidence of BPH, and more than 80% have BPH-related symptoms. Approximately 25% of men older than age 55 and 50% of men older than age 75 experience decreased urinary flow.
CAUSES
The cause of BPH is not well understood. It has been observed that BPH does not develop in men whose testes were removed before puberty. For this reason, some researchers believe that factors related to aging and the testes may spur the development of BPH. Men produce both testosterone and small amounts of estrogen. As men age, the amount of active testosterone in the blood decreases, leaving a higher proportion of estrogen. Studies performed on animals have suggested that BPH may occur because the higher amount of estrogen within the gland increases the activity of substances that promote cell growth. Another theory focuses on dihydrotestosterone (DHT), a substance derived from testosterone in the prostate, which may help control its growth. Some research has indicated that even with a drop in the blood’s testosterone level, older men continue to produce and accumulate high levels of DHT in the prostate. This accumulation of DHT may encourage the growth of cells. Researchers have also noted that men who do not produce DHT do not develop BPH.
PATHOPHYSIOLOGY
The dynamic component of BPH and LUTS is based on autonomic input to the smooth muscles in the lower urinary tract, including the bladder, prostate, and urethra. These areas have
a large concentration of α1-adrenergic receptors that, when stimulated by various stressors, cause increasing smooth muscle tone. This increased smooth muscle tone leads to increased urethral resistance and contributes to the bladder outlet obstructive symptoms of BPH. This physiology leads to the basis for a main class of drugs to treat BPH, the use of α1-adrenergic blockers.
a large concentration of α1-adrenergic receptors that, when stimulated by various stressors, cause increasing smooth muscle tone. This increased smooth muscle tone leads to increased urethral resistance and contributes to the bladder outlet obstructive symptoms of BPH. This physiology leads to the basis for a main class of drugs to treat BPH, the use of α1-adrenergic blockers.
An underlying pathophysiologic process of BPH is the formation of large, nonmalignant lesions at the periurethral region of the prostate gland. Prostatic hyperplasia is an overgrowth of normal cells in the stromal and epithelial tissues of the prostate gland. The hyperplasia originates in the transition zone of the prostate, which surrounds the prostatic urethra between the bladder and the anus. The etiology of the hyperplastic process is unknown, but it has been speculated that it is hormone related because it occurs only in older men. The male aging process involves a decrease in testosterone production with a concomitant increase in estrogen; estrogen may be a sensitizer for the escalating hyperplasia. Bladder control involves reflex activity of the peripheral autonomic nervous system (ANS). The reflex for normal micturition is housed in the brain stem and supported by descending and ascending pathways from the spinal cord. Both the external sphincter and the detrusor muscle are needed for bladder control. Reflex micturition is innervated at the S2 to S4 and T1 to L1 levels in the spinal cord. The cortical center of the brain appears to be important for inhibition or control of the micturition center to modulate contractile, filling, and expulsion activity.
Parasympathetic and sympathetic innervation is crucial to the role of the ANS in voiding. Parasympathetic interplay allows for the detrusor muscle to maintain tone and to contract, whereas sympathetic interplay allows for the bladder to expand and maintain a large filling capacity. The dynamic component of BPH and LUTS is based on autonomic input to the smooth muscles in the lower urinary tract, including the bladder, prostate, and urethra. These areas have a large concentration of α1-adrenergic receptors that, when stimulated by various stressors, cause increasing smooth muscle tone. This increased smooth muscle tone leads to increased urethral resistance and contributes to the bladder outlet obstructive symptoms of BPH. This physiology leads to the basis for a main class of drugs to treat BPH, the α1-adrenergic blockers.
BPH disease manifests as urinary tract symptoms. Obstructed urine outflow, the predominant pattern, includes diminished force of the urine stream, an urgent need for nocturnal voiding, residual urine with or without overflow incontinence, and even a feeling of pressure in the abdomen. These manifestations result from either partial or complete compression of the urethra by the hyperplastic prostate. Bladder wall hypertrophy occurs, and herniation into the bladder can occur. Ultimately, if treatment is not initiated, a postrenal cause of acute renal failure can develop because of back pressure on the renal system (i.e., the ureters) and the onset of hydronephrosis.
DIAGNOSTIC CRITERIA
Diagnosis of BPH usually begins with the patient seeking medical intervention because of the annoying symptoms. Along with a complete social history and physical examination, a digital rectal examination (DRE) is performed to palpate the prostate. The degree of prostate enlargement has not been found to correlate with the severity of symptoms; rather, the location of the enlargement is what leads to symptom manifestation.
BPH severity is assessed using validated, self-administered symptom questionnaires such as the American Urological Association Symptom Index (AUASI) (http://www.urology-health.org/_media/_pdf/AUA%20Symptom%20Score.pdf) (Table 33.3) or International Prostate Symptom Score (http://www.urospec.com/uro/Forms/ipss.pdf). Mild or nonbothersome symptoms do not require treatment. Bothersome symptoms are managed with lifestyle modifications, medications, and surgery.
In the AUASI, symptoms are scored as mild (0 to 7 points), moderate (8 to 19 points), or severe (20 to 35 points). The American Urological Association (AUA) recommends that this scale be used on initial assessment and then for following the course of illness by periodic ongoing assessment of the patient. Such follow-up management enables the practitioner to initiate more acute or intensive therapy when the score increases. Patients with severe BPH symptoms should not be managed by this scale.
Postvoid catheterization is performed to ascertain the degree of urine retention; any amount of residual urine beyond 100 mL is considered significant. Uroflowmetry provides information about the force of the urine stream. Urodynamics can also be assessed using noninvasive pneumatic technology. Other diagnostic tools include x-ray films, digital ultrasound, computed tomography (CT) scans, magnetic resonance imaging (MRI), and radionuclide scans. Biopsies can be added to the diagnostic workup for further clinical assessment of any hardened prostatic areas found by DRE. Laboratory monitoring of creatinine and blood urea nitrogen should be incorporated to determine whether renal involvement exists and, if so, to what degree. Prostate-specific antigen (PSA) levels can be elevated in patients with BPH.
Many symptoms of BPH stem from obstruction of the urethra and gradual loss of bladder function, which results in incomplete emptying of the bladder. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, including a hesitant, interrupted, or weak stream; urgency, dribbling, or urinary retention; more frequent urination, especially at night; painful urination; and incontinence.
It is extremely important to evaluate men at risk for these symptoms. In 8 out of 10 cases, these symptoms suggest BPH, but they also can signal more serious conditions, such as prostate cancer.
INITIATING DRUG THERAPY
There are three major classes of drugs used to treat BPH. One group is α-adrenergic antagonists or α-blockers (doxazosin, terazosin, tamsulosin, alfuzosin, and silodosin). Tamsulosin,
silodosin, and alfuzosin are selective α1-adrenoreceptor antagonists, selective for α1A-adrenergic receptor. While causing smooth muscle relaxation in the lower urinary tract, it minimizes blood pressure-related adverse effects. These relax the smooth muscle fibers of the bladder neck and prostate, thereby reducing the dynamic components of prostatic obstruction.
silodosin, and alfuzosin are selective α1-adrenoreceptor antagonists, selective for α1A-adrenergic receptor. While causing smooth muscle relaxation in the lower urinary tract, it minimizes blood pressure-related adverse effects. These relax the smooth muscle fibers of the bladder neck and prostate, thereby reducing the dynamic components of prostatic obstruction.
TABLE 33.3 AUA Symptom Index Scale | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Another group is 5-α-reductase inhibitors (finasteride and dutasteride). Five-α-reductase inhibitors decrease levels of intracellular DHT (the major growth-stimulatory hormone in prostate cells) without reducing testosterone levels. This leads to prostatic size reduction of 20% to 30%. Symptom relief occurs within 2 weeks of initiating α-blockers, compared with several months with finasteride.
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