The Most Common Urinary Diseases in Men: Urethritis, Epididymitis, and Prostatitis
Clinician Reviews, March 2005 by Carl Diaz-Parker, Gennady Bratslavsky

Urethritis, epididymitis, and prostatitis are the most common genitourinary complaints in men, accounting for millions of office visits in the United States each year.

For urethritis that is sexually transmitted, treatment is based on identifying the responsible pathogen (usually Chlamydia trachomatis or Neisseria gonorrhoeae, although other organisms must he considered in the differential diagnosis).

Epididymitis can be present in a sexually transmitted form or one associated with urinary tract infections and prostatitis; testicular torsion must be ruled out.

Prostatitis can be acute or chronic, bacterial or abacterial; because its pathophysiology and pathogenesis are not well understood, it is difficult to treat. Several new therapeutic options are being investigated.

Among men with genitourinary complaints, the three most common conditions are urethritis (which accounts for some 200,000 initial office visits each year), epididymitis (600,000 office visits), and prostatitis (approximately two million office visits for genitourinary symptoms--or one fourth of all such visits for men). This article is a review of diagnostic and management strategies for these commonly seen conditions.

URETHRITIS
Urethritis is an inflammation of the urethra, usually associated with dysuria and urethral discharge. Before urethritis can be diagnosed, it is important to exclude cystitis and genital herpes infection, whose symptoms may mimic those of urethritis.

Generally, urethritis may be classified as sexually transmitted urethritis or urethral syndrome. Urethral syndrome is usually attributed to noninfectious factors (traumatic, psychologic, allergic, or chemical) and most recently to epithelial dysfunction and potassium recycling on the cellular level.
Sexually transmitted urethritis should always be considered in symptomatic patients, and all identified cases must be reported to state health departments. This form of urethritis can be further divided into two subgroups: gonococcal urethritis (GU, or gonorrhea), typically caused by Neisseria gonorrhoeae infection; and nongonococcal urethritis (NGU), most commonly associated with Chlamydia trachomatis. Other NGU-causing organisms that must be considered in the differential diagnosis include Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium, and Trichomonas vaginalis.

Transmission and Risk Factors
Genital infection with C trachomatis is the most common bacterial sexually transmitted disease (STD) in the US. In 2001, approximately 780,000 cases of genital chlamydia were reported to the CDC--about twice the number of cases of gonorrhea.

Although the incidence of C trachomatis infection is far greater, gonorrhea remains common in teenagers and in racial and ethnic minorities. Patients should be made aware that gonorrhea can be transmitted via vaginal secretions without vaginal penetration and through oral sex with a partner whose pharynx is infected. African-Americans may be more susceptible than other patients to strains of gonorrhea that cause systemic disease. In men who have sex with men (MSM), GU is more common than NGU. Uncircumcised men may be at greater risk of contracting gonorrhea than are circumcised men.

Varied Presentation
Classically, GU produces urethral discharge and burning on urination, but urethral itching may be the only symptom; GU may be asymptomatic in 40% to 60% of the contacts of persons with known gonorrhea.

Clinical clues to chlamydial infection include gradual onset of internal dysuria, recent sexual activity with a new partner, and absence of hematuria. Symptoms of frequency, urgency, and dysuria may be suggestive, but the causes of these symptoms can be difficult to distinguish.

Thus, NGU cannot be differentiated from GU on the basis of signs and symptoms alone. As with GU, the NGU patient may complain only of urethral itching. The variation in incubation periods is important to note. Some gonococcal strains produce symptoms in as little as 12 hours; others, not for three months.

Diagnosis
The patient is preferably examined three to four hours after the last void, so that discharge (which may vary in appearance from what is considered typical) is not washed away. In both GU and NGU, the meatus may be erythematous and tender.
During the examination, a calcium alginate swab (not a cotton swab, which may have a bactericidal effect) is inserted 2 to 3 cm into the urethra and gently rotated; such a specimen must be obtained from within the urethra, not simply from a drop of discharge. A "clean-catch" (or "midstream") urine sample is not appropriate.

Nucleic acid amplification tests make it possible to detect N gonorrhoeae and C trachomatis on any specimen. A Gram stain is positive for gonococcal urethritis if it reveals neutrophils and intracellular gram-negative diplococci; failure to detect these, along with a negative gonococcal culture, rules out gonorrhea.

Among NGU cases, about half are caused by C trachomatis. In symptomatic patients, the Gram-stained urethral smear has high sensitivity and negative predictive value for diagnosis of C trachomatis infection (96.7% and 97.4%, respectively) but low specificity (68.0%). (13) Pyuria, bacterial levels lower than 105/mL in urine, and a negative gonococcal culture should suggest C trachomatis urethritis.

In patients with a history of oral-genital contact, pharyngeal specimens should be collected, as should rectal swabs in MSM. The Gram stain is performed immediately and the specimen plated onto a modified Thayer-Martin agar and New York City medium or placed in a transport medium before processing.

Urethral syndrome, it should be noted, is often a diagnosis of exclusion.

Treatment
Current CDC recommendations call for treatment of both N gonorrhoeae and C trachomatis if diagnostic tools to distinguish between them are not available. While ceftriaxone administered intramuscularly is currently recommended for treatment of all uncomplicated gonococcal infections of the pharynx, anorectum, cervix, and urethra, it does not effectively treat C trachomatis. Thus, since men with GU are frequently infected with C trachomatis as well, it may be advisable to include a tetracycline derivative (eg, azithromycin, ofloxacin) in the regimen. Additionally, patients may require a less expensive alternative to ceftriaxone; several other treatment choices, in addition to those for NGU, are included in Table 1 (below).

Patients with sexually transmitted urethritis should be instructed to refer their sex partners for evaluation, testing, and treatment if they had sexual contact during the 60 days preceding onset of the patient's symptoms or diagnosis. The most recent sex partner should be evaluated, even if the last sexual contact occurred longer than 60 days before onset or diagnosis. Sexual intercourse should be avoided until seven days after treatment has begun.

Without treatment, urethritis persists for three to seven weeks, with 95% of men becoming asymptomatic after three months.

In many cases of urethral syndrome, pharmacologic therapy is not helpful. Patients may be referred to a urologic specialist for investigation of the causative factors and for appropriate treatment.

EPIDIDYMITIS
Epididymitis is an inflammatory reaction of the epididymis to one of several infectious agents or to local trauma. Acute epididymitis is a clinical syndrome consisting of pain, swelling, and inflammation of the epididymis, lasting less than six weeks. It should not be confused with chronic epididymitis, ie, long-standing pain in the epididymis and testicle, usually without swelling. Scrotal/testicular pain can have numerous causes, including inguinal hernia, fractured testis, hematoma, scrotal cellulitis, epididymal head cyst, varicocele, trauma, and various neoplasms. Most of these can be ruled out by a thorough history and physical examination.
Epididymitis can present in a sexually transmitted form or one associated with urinary tract infections and prostatitis. Thus, eliciting a specific history of sexual exposure or of prior genitourinary tract disease is crucial for diagnosis and appropriate treatment. (Infrequently, epididymitis may also be caused by a reflux of sterile urine into the epididymis, causing a local sterile chemical inflammation.)

Etiology
The patient's age suggests the most likely etiology of epididymitis. Within each age-group, the cause appears to be the same as the most common cause of genitourinary infection in that group. For example, in heterosexual men younger than 35, urethritis caused by N gonorrhoeae or C trachomatis is more common than bacteriuria. Thus, in this patient population, epididymitis is most commonly caused by these same organisms. In fact, C trachomatis causes about two thirds of the cases of noncoliform, nongonococcal epididymitis in these patients.

By contrast, in men older than 35, sexually transmitted urethritis is uncommon; thus, a non-sexually transmitted form of epididymitis is more likely, most commonly caused by Enterobacteriaceae or Pseudomonas.

Epididymitis that develops in children (which is rare) is most commonly caused by the coliform organisms that cause bacteriuria. It is important, however, to rule out anatomic abnormalities in children with epididymitis. In infants, epididymitis is more likely to result from genitourinary abnormalities (eg, abnormal ureteral insertion) or systemic hematogenous dissemination than it is in older boys.
In immunosuppressed males of any age, a very small percentage may have epididymitis resulting from systemic disease, eg, tuberculosis, cryptococcus, or brucella.

Presentation
While some men may have only a nonspecific finding of fever or other signs of infection, patients with acute epididymitis usually complain of sudden-onset, severely painful swelling of the scrotum. Pain may radiate along the spermatic cord and reach the abdomen, or possibly even the flank. Onset may be acute over one or two days, or more gradual; it is often accompanied by dysuria or irritative lower urinary tract symptoms. Erythema of the scrotum may develop, and the epididymis may double in size in as little as three to four hours. Many patients also have urethral discharge.

In acute epididymitis, inflammation and swelling usually begin in the tail of the epididymis and may spread to involve the rest of the epididymis and testicle. The spermatic cord is usually tender and swollen. Epididymitis is frequently accompanied by erythema, generally unilateral and primarily in the posterior aspect of the scrotum.

Examination and Diagnosis
If the patient is examined early in the course of the disease, the swelling may be localized to one portion of the epididymis. Later, the ipsilateral testis is often involved, producing epididymo-orchitis and making it difficult to distinguish the testicle from the epididymis within the inflammatory mass. Scrotal examination often reveals the presence of a hydrocele, caused by the secretion of inflammatory fluid between the layers of the tunica vaginalis testis.

Usually, the microbial etiology of epididymitis can be determined by examining a Gram-stained urethral smear and Gram stain of a midstream urine specimen for gram-negative bacteriuria. The presence of intracellular gram-negative diplococci on the smear correlates with the presence of N gonorrhoeae, whereas the presence of only white blood cells on the urethral smear indicates the presence of NGU. C trachomatis will be isolated in approximately two thirds of these patients. In older men, the presence of coliform bacteria often leads to diagnosis.

Treatment
For most patients with bacterial epididymitis, appropriate medical management depends on the age and history of the patient. In young, sexually active men, suspected sexually transmitted epididymitis should be treated with a single dose of ceftriaxone (250 mg IM) followed by tetracycline (500 mg PO (gid) or doxycycline (100 mg PO bid) for 21 days. This regimen covers both C trachomatis and N gonorrhoeae, the most common causes of epididymitis in this group.

In older patients, empiric treatment with agents appropriate for both gram-negative rods and gram-positive cocci should be initiated, pending urine culture and sensitivity results. Usually, treatment with a fluoroquinolone (levofloxacin 500 mg/d PO or ciprofloxacin 500 mg PO bid for at least two weeks) and an anti-inflammatory should be started. Bed rest, scrotal elevation, analgesics, and local ice packs are helpful. Surgery may be necessary to manage complications of acute epididymal infections but has no role in treating tuberculous or fungal epididymitis.

Special Considerations
Making the differential diagnosis between epididymitis and testicular torsion is imperative, particularly in men younger than 35. Delayed diagnosis of torsion can result in testicular infarction and loss of a testicle. Generally, Prehn's sign (triggered by elevating the scrotum toward the abdomen) manifests as relief of testicular discomfort in the patient with epididymitis, and worsening discomfort in the patient with torsion.

Although Prehn's sign is clinically useful, it is not absolute. In cases of suspected testicular torsion, ultrasonography of the scrotum, preferably with color flow Doppler imaging, should be performed to evaluate blood flow to the testicle.

In any scrotal mass, tuberculous epididymitis (the most common form of urogenital tuberculosis) must be considered. Although this condition is more likely to be confused with a malignancy than a cause of an acute scrotal mass, it can be an important cause of epididymitis in patients from areas where tuberculosis is endemic. Testicular malignancy must also be suspected, since as many as 30% of patients with testicular masses may present with epididymitis.

PROSTATITIS
About half of all men will experience symptoms of prostatitis at some time. Ubiquitous and difficult to treat, this inflammatory condition of the prostate has been divided into four classifications by the National Institute of Diabetes and Digestive and Kidney Diseases, NIH; see Table 2 (below). Despite much research, the pathophysiology and pathogenesis of prostatitis are not completely understood.

Presentation
Acute prostatitis may involve rapid onset of dysuria, frequency, urgency, nocturia, difficulty voiding, perineal and low back pain, fever, and chills.

In chronic prostatitis, onset is typically more insidious; many patients report development of symptoms over weeks or months. Fever and chills are usually absent; patients more often complain of irritative voiding problems and perineal and back discomfort. Patients may also report penile or testicular discomfort or pain during or after ejaculation.

Diagnosis
Diagnosis of acute prostatitis should be considered early, based on the history alone. Although physical examination may reveal an enlarged, boggy, and tender prostate, the digital rectal exam should be avoided to minimize the risk of bacteremia and sepsis. The white blood cell count is often elevated and urinalysis reveals pyuria and bacteriuria. Urine culture usually grows Escherichia coli (the responsible pathogen in 80% of cases). Other possible causative organisms include Klebsiella spp, Proteus spp, Enterobacter spp, and Staphylococcus aureus.

A diagnosis of chronic bacterial prostatitis is made after sterilization of the bladder urine with antibiotics, such as nitrofurantoin or amoxicillin. If, after prostatic massage, the expressed prostatic secretions and voided urine reveal 10 white blood cells per high-power field and there is a positive urine culture, a diagnosis of chronic bacterial prostatitis is made. Abacterial prostatitis, on the other hand, may be detected by inflammatory cells on expressed secretions or postmassage urine. No bacterial growth can be documented.
As is possible with any class of prostatitis, asymptomatic inflammatory prostatitis (class IV) is associated with elevated levels of prostate-specific antigen (PSA); thus, patients with elevated PSA levels should be screened for class IV prostatitis before biopsy. Biopsies that are negative for prostate cancer often reveal evidence of this benign condition; antibiotic therapy has been shown to normalize PSA levels in these patients.

Treatment
Ill patients with acute bacterial prostatitis may require hospitalization with broad-spectrum intravenous antibiotics (ampicillin and gentamicin), antipyretics, and bed rest. In case of retention, urinary diversion is best accomplished with suprapubic cystotomy. Afebrile patients are often managed as outpatients with trimethoprim-sulfamethoxazole or fluoroquinolone antibiotics for four weeks.

Chronic bacterial prostatitis requires these same medications, but for four to six weeks. Any patient who has frequent recurrent bouts of symptomatic chronic bacterial prostatitis may be considered for suppressive antibiotic therapy.
Chronic abacterial prostatitis is best treated with NSAIDs, hot sitz baths, and/or tricyclic antidepressants for pain control. Recently, the use of [alpha]-blockers has been examined, but with modest benefit. Two treatment options for benign prostatic hyperplasia (transurethral microwave therapy with urethral cooling and transurethral needle ablation) have also been investigated. These may be promising, but long-term data are not yet available.

CONCLUSION
In infectious genitourinary conditions, including sexually transmitted urethritis and epididymitis, an understanding of transmission and pathophysiology will help the clinician arrive at a correct diagnosis; history taking that reveals risk factors for an STD or previous urinary tract infections is often key. Knowledge of pathogenesis and pharmacotherapy will facilitate appropriate treatment choices for men who present with symptoms of these conditions

TABLE 1
Characteristics of Gonococcal and Nongonococcal Urethritis (5,7,11)
Classic name	Gonococcal urethritis	Nongonococcal urethritis
Common name	Gonorrhea	Chlamydia
Organism	Neisseria gonorrhoeae	Chlamydia trachomatis
Organism type	Gram-negative diplococci	Intracellular facultative anaerobe
Incubation period	3-10 days (may vary)	1-3 weeks
Urethral discharge	Usually profuse, purulent	Usually scant
Discharge color	Yellow or brown	Whitish or clear
Diagnostic tests	Nucleic acid amplification	Nucleic acid amplification
Other tests	Gram stain/culture	Culture/immunoassay
Recommended treatment	Ceftriaxone 125 mg 1M once or ciprofloxacin 500 mg PO once or ofloxacin 400 mg PO once or levofloxacin 250 mg PO once	Azithromycin 1000 mg PO once or doxycycline 100 mg PO gid x 7 d or erythromycin 500 mg PO bid x 7 d or ofloxacin 300 mg bid x 7 d
Sources: Campbell et al. Campbell's Urology. 2002; CDC. MMWR Recomm Rep. 2002; CDC. www.cdc.gov/STD/treatment/Cefixime.htm. 2004.