Urethritis is an inflammatory condition of the urethra, the tube that carries urine from the bladder out of the body.  This inflammation is often caused by infection, although non-infectious causes also exist. Urethritis is a common condition, particularly in sexually active individuals, and is a significant component of the spectrum of sexually transmitted infections (STIs).

Symptoms can include pain or burning during urination, itching or irritation in the urethra, and discharge. Prompt diagnosis and treatment are essential to relieve symptoms, prevent complications, and reduce transmission, especially when the cause is infectious.

Definition and Classification

Urethritis is defined as inflammation of the urethra. It is primarily classified based on the causative agent, particularly whether or not Neisseria gonorrhoeae is identified.

1. Gonococcal Urethritis (GU):

   • Caused by infection with the bacterium Neisseria gonorrhoeae.

   • Historically the most common cause of urethritis.

   • Tends to cause more abrupt onset and often more severe symptoms (copious purulent discharge) compared to non-gonococcal urethritis.

2. Non-Gonococcal Urethritis (NGU):

   • Urethritis caused by pathogens other than Neisseria gonorrhoeae.

   • The most common cause of urethritis in many regions today.

   • Etiology is diverse.

NGU is further classified based on the identified pathogen:

• Chlamydial Urethritis: Caused by Chlamydia trachomatis. This is the most common identifiable cause of NGU.

• Mycoplasmal Urethritis: Caused by Mycoplasma genitalium. Increasingly recognized as a significant cause of NGU and persistent/recurrent urethritis.

• Ureaplasmal Urethritis: Caused by Ureaplasma urealyticum or Ureaplasma parvum. Their role in NGU is debated, but U. urealyticum is considered a potential pathogen.

• Trichomonal Urethritis: Caused by the parasite Trichomonas vaginalis. More common in women but can occur in men, often causing NGU.

• Herpetic Urethritis: Caused by Herpes Simplex Virus (HSV). Can occur as part of primary genital herpes infection.

• Adenoviral Urethritis: Caused by adenoviruses, often associated with pharyngoconjunctival fever.

• Other Bacterial Causes: Less common, but can include enteric bacteria (e.g., Escherichia coli), especially in individuals who practice receptive anal intercourse or have urinary tract abnormalities.

3. Non-Infectious Urethritis:

   • Urethritis not caused by an infectious agent.

   • Can be due to:

     • Trauma: Insertion of foreign bodies, catheterization, vigorous sexual activity.

     • Chemical Irritation: Spermicides, soaps, detergents, lubricants.

     • Allergic Reactions: To latex condoms, spermicides, or other substances.

     • Reactive Arthritis (formerly Reiter’s Syndrome): A systemic inflammatory condition that can follow certain infections (commonly Chlamydia or gastrointestinal infections) and includes urethritis, arthritis, and conjunctivitis.

     • Foreign Bodies or Strictures: Can cause chronic irritation and inflammation.

Etiology and Risk Factors

The primary etiology of urethritis is infection, predominantly sexually transmitted pathogens.

Infectious Causes and Transmission:

• Sexually Transmitted Infections (STIs): The vast majority of infectious urethritis cases are acquired through sexual contact. Risk factors for infectious urethritis include:

  • Unprotected sexual intercourse (vaginal, anal, or oral).

  • Multiple sexual partners.

  • New sexual partners.

  • History of STIs.

  • Having a partner with urethritis or an STI.

• Neisseria gonorrhoeae: Transmitted through vaginal, anal, or oral sex.

• Chlamydia trachomatis: Transmitted through vaginal, anal, or oral sex. Can also be transmitted from an infected mother to her infant during childbirth, causing neonatal conjunctivitis and pneumonia.

• Mycoplasma genitalium: Transmitted through sexual contact.

• Ureaplasma species: Can be sexually transmitted.

• Trichomonas vaginalis: Transmitted through sexual contact.

• Herpes Simplex Virus (HSV): Transmitted through direct contact with herpes lesions, often during sexual activity.

Non-Infectious Causes:

• Trauma: Mechanical injury to the urethra.

• Chemical Irritation: Exposure to irritant substances.

• Allergies: Hypersensitivity reactions.

• Systemic Conditions: Reactive arthritis.

Risk factors for non-infectious urethritis are related to exposure to the causative irritant or underlying medical conditions.

Pathophysiology

The pathophysiology of urethritis involves the inflammatory response of the urethral mucosa to an insult, most commonly infection.

1. Infectious Agents: Pathogens (bacteria, viruses, parasites) adhere to and invade the epithelial cells lining the urethra.

2. Inflammatory Response: The presence of the pathogen triggers an inflammatory response. Immune cells (neutrophils, lymphocytes) are recruited to the site of infection.

3. Mucosal Damage: The inflammatory process and sometimes direct effects of the pathogen (e.g., toxins) cause damage to the urethral epithelial cells.

4. Edema and Erythema: Inflammation leads to swelling (edema) and redness (erythema) of the urethral mucosa.

5. Increased Vascular Permeability: Inflammatory mediators increase the permeability of blood vessels, leading to leakage of fluid and inflammatory cells into the urethral lumen.

6. Exudate Formation: The accumulation of inflammatory cells, fluid, and sloughed epithelial cells forms an exudate, which is often seen as urethral discharge.

7. Sensory Nerve Stimulation: Inflammation and irritation of the nerve endings in the urethral wall cause pain and burning sensations, particularly during the passage of urine.

8. Fibrosis and Stricture Formation (Chronic/Severe Cases): In chronic or severe cases, particularly with certain infections or trauma, the repeated inflammation and healing process can lead to the deposition of fibrous tissue in the urethral wall. This can result in urethral strictures, which are narrowings of the urethra that obstruct urine flow.

In non-infectious urethritis, the inflammatory process is triggered by the non-infectious irritant or immune response, leading to similar inflammatory changes in the urethral mucosa, but without the presence of an invading pathogen.

Clinical Manifestations

The clinical presentation of urethritis varies depending on the cause, but common symptoms include:

• Dysuria: Pain or burning sensation during urination. This is a very common symptom.

• Urethral Discharge: Exudate from the urethra. The character of the discharge can vary:

  • Gonococcal Urethritis: Often copious, purulent (thick, yellowish-green), and sometimes bloody. Onset is often abrupt (within days of exposure).

  • Non-Gonococcal Urethritis: Typically less copious and less purulent than gonococcal discharge. May be clear, white, or mucoid. Onset is often more gradual (days to weeks after exposure).

• Urethral Itching or Irritation: A tickling or uncomfortable sensation within the urethra.

• Frequency and Urgency: Increased need to urinate and a sudden, strong urge to urinate (less common than dysuria and discharge, may suggest involvement of the bladder or prostate).

• Meatal Tenderness and Erythema: Redness and tenderness around the urethral opening.

• Painful Swelling of the Testicles (Epididymitis): A potential complication, particularly of gonococcal and chlamydial urethritis, where the infection spreads to the epididymis.

It is important to note that many individuals with urethritis, particularly NGU caused by Chlamydia or Mycoplasma, may be asymptomatic or have very mild symptoms. This contributes to the silent spread of these infections.

In women, urethritis can occur, often as part of a lower urinary tract infection or in association with cervicitis. Symptoms may include dysuria, frequency, and urgency, which can overlap with symptoms of cystitis (bladder infection). Urethral discharge may be less noticeable than in men.

Diagnosis

Diagnosing urethritis involves a combination of clinical assessment and laboratory testing to identify the causative agent.

1. Medical History:

   • Detailed history of symptoms (onset, duration, character of pain and discharge).

   • Sexual history: Number of partners, timing of last sexual contact, type of sexual practices (vaginal, anal, oral), use of condoms, history of STIs in the patient or partners.

   • History of urinary tract infections.

   • History of trauma or exposure to chemical irritants.

   • Review of medications.

2. Physical Examination:

   • Examination of the urethral meatus for redness, swelling, and discharge.

   • If discharge is not spontaneously present, the urethra may be “milked” from the base of the penis towards the tip to express any exudate.

   • Examination of the scrotum to assess for epididymitis.

   • In women, a pelvic examination may be performed to assess for vaginal or cervical discharge and signs of cervicitis.

3. Laboratory Tests:

   • Urethral Swab: A small swab is inserted a few centimeters into the urethra to collect a sample of exudate and epithelial cells. This is the preferred sample type for many tests.

   • First-Catch Urine: The first portion (10-20 mL) of a voided urine sample is collected. This sample contains cells and exudate from the urethra and is a less invasive alternative to urethral swabs, particularly for nucleic acid amplification tests (NAATs).

   • Microscopy of Urethral Discharge: A Gram stain of urethral discharge can be examined under a microscope:

     • Gonococcal Urethritis: Presence of Gram-negative intracellular diplococci (bacteria within neutrophils) is highly suggestive of gonorrhea.

     • Non-Gonococcal Urethritis: Presence of increased numbers of polymorphonuclear leukocytes (PMNs or neutrophils) in the absence of Gram-negative intracellular diplococci. A threshold of $\ge 5$ PMNs per high-power field on a Gram-stained urethral smear is often used.

   • Nucleic Acid Amplification Tests (NAATs): Highly sensitive and specific tests that detect the genetic material of pathogens. NAATs are the preferred method for detecting Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium from urethral swabs or first-catch urine. They can also be used for Ureaplasma species and Trichomonas vaginalis.

   • Cultures: Bacterial cultures can be performed for Neisseria gonorrhoeae (on specific media) or other bacteria, but NAATs are generally preferred due to higher sensitivity. Viral cultures may be performed if herpetic urethritis is suspected.

   • Tests for other STIs: Depending on the patient’s risk factors and clinical presentation, testing for other STIs (e.g., HIV, syphilis) may be indicated.

Diagnosis often involves performing NAATs for N. gonorrhoeae and C. trachomatis on a urethral swab or first-catch urine. Microscopy of a urethral smear can provide rapid presumptive diagnosis, especially for gonorrhea.

Management

Management of urethritis aims to treat the underlying cause (especially if infectious), relieve symptoms, prevent complications, and prevent transmission.

1. Treatment of Infectious Urethritis:

   • Treatment is based on the suspected or confirmed causative agent.

   • Gonococcal Urethritis: Treated with antibiotics. Due to increasing antibiotic resistance, current recommendations often involve combination therapy, such as a single dose of ceftriaxone intramuscularly plus a single dose of azithromycin orally or a 7-day course of doxycycline orally. Treatment regimens are regularly updated based on resistance patterns.

   • Chlamydial Urethritis: Treated with antibiotics. Recommended regimens include a single dose of azithromycin orally or a 7-day course of doxycycline orally. Alternative regimens are available.

   • Non-Gonococcal Urethritis (Empirical Treatment): If the cause of NGU is not immediately identified (e.g., based on microscopy), empirical treatment is often initiated to cover the most common causes, particularly Chlamydia trachomatis and Mycoplasma genitalium. A common empirical regimen is a 7-day course of doxycycline orally. If M. genitalium is suspected or detected, treatment with azithromycin (longer course than for Chlamydia) or moxifloxacin may be necessary, depending on macrolide resistance.

   • Mycoplasmal Urethritis: Treatment can be challenging due to antibiotic resistance. Azithromycin (specific regimen) or moxifloxacin are commonly used, guided by susceptibility testing if possible.

   • Trichomonal Urethritis: Treated with metronidazole or tinidazole orally.

   • Herpetic Urethritis: Treated with antiviral medications (e.g., acyclovir, valacyclovir, famciclovir).

   • Other Causes: Treated with appropriate antimicrobial agents based on identification and susceptibility.

2. Partner Notification and Treatment:

   • For infectious urethritis (especially STIs), it is crucial to inform and treat sexual partners to prevent reinfection and further transmission. Expedited partner therapy (EPT), where partners are treated without a clinical examination, may be an option in some settings for chlamydial infection.

3. Symptomatic Treatment:

   • Pain relievers (e.g., acetaminophen, ibuprofen) can help manage dysuria.

   • Increased fluid intake may help dilute urine and reduce burning.

4. Management of Non-Infectious Urethritis:

   • Treatment involves identifying and removing the causative irritant or managing the underlying condition (e.g., treating reactive arthritis).

5. Prevention of Complications:

   • Prompt and effective treatment reduces the risk of complications such as epididymitis, prostatitis, and urethral strictures in men, and pelvic inflammatory disease (PID) in women.

6. Prevention of Recurrence and Transmission:

   • Education on safer sexual practices, including consistent and correct condom use.

   • Regular STI screening for individuals at high risk.

Complications

If left untreated or inadequately treated, urethritis can lead to several complications:

• Epididymitis: Inflammation of the epididymis, a coiled tube located at the back of the testicle. Causes pain, swelling, and tenderness in the scrotum. A common complication of gonococcal and chlamydial urethritis.

• Prostatitis: Inflammation of the prostate gland. Can cause pain in the groin, pelvic area, or genitals, as well as urinary symptoms.

• Urethral Strictures: Narrowing of the urethra due to scarring from chronic or severe inflammation. Can cause difficulty urinating, weak stream, and incomplete bladder emptying. More common with gonococcal urethritis in the pre-antibiotic era, but can still occur.

• Reactive Arthritis: A systemic inflammatory condition that can be triggered by certain infections, including Chlamydia trachomatis and some gastrointestinal bacteria. Characterized by a triad of arthritis, urethritis, and conjunctivitis (“can’t see, can’t pee, can’t climb a tree”).

• Infertility: Chronic or recurrent infections, particularly epididymitis, can potentially affect sperm production and transport, leading to infertility.

• Pelvic Inflammatory Disease (PID) in Women: While urethritis is primarily a male diagnosis, the same pathogens can cause cervicitis and ascend to the upper reproductive tract in women, leading to PID, which can cause chronic pelvic pain, ectopic pregnancy, and infertility.

• Disseminated Gonococcal Infection: In rare cases, Neisseria gonorrhoeae can spread to other parts of the body, causing arthritis, tenosynovitis, dermatitis, and rarely endocarditis or meningitis.