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Curr Bladder Dysfunct Rep (2014) 9:181–187

DOI 10.1007/s11884-014-0246-7

INFLAMMATORY/INFECTIOUS BLADDER CONDITIONS (S MOURAD, SECTION EDITOR)

Urethritis in Women—Considerations Beyond Urinary


Tract Infection
W. D. Ulmer & J. L. Gilbert & E. J. B. De

Published online: 15 July 2014


# Springer Science+Business Media New York 2014

Abstract Urethritis is a common condition affecting women urethritis secondary to common urinary tract infection (UTI).
in the USA. The symptoms, however, are not specific to a There is a ubiquity of information known and available on
unique cause and are shared among a wide variety of urogen- urethritis due to urinary pathogens: the American Academy of
ital diseases. This article evaluates the current literature and Family Physicians [1••] and the European Association of
provides tools to the practicing clinician. Infections, particu- Urology [2] have published excellent resources available both
larly urinary tract infection and vaginitis, are common causes. online and in print.
The sexually transmitted infection Chlamydia trachomatis We will focus on urethritis in women whose symptoms do
continues to be one of the most common etiologies for ure- not resolve with empiric antibiotics and/or whose urine culture
thritis. Newer research provides evidence for the importance is negative. In this context, causes of urethritis may be divided
of Ureaplasma and Mycoplasma genitalium. Mechanical trau- into several categories: sexually or non-sexually transmitted
ma, vaginal atrophy, chemical and mechanical exposure, and infections, vulvar and hormonal conditions, anatomic abnor-
Skene’s gland and other anatomical pathology will also be malities, chemical or mechanical trauma, and cancer. Sexually
reviewed. The diagnosis and treatment of urethritis often transmitted infections are common in the general population
require the practitioner to treat associated diseases such as and account for a large percentage of non-UTI urethritis.
chronic pelvic pain syndrome and dyspareunia. Urethritis is Much is known about gonococcal and chlamydial infections;
intensely symptomatic leading to a pressured office interac- however, organisms such as Mycoplasma genitalium and
tion, and it is our intent to provide the tools for a comprehen- Ureaplasma will likely gain importance as their pathogenicity
sive approach to female urethritis. are characterized. Vulvodynia is less common but may cause
enormous morbidity [3••]. Regardless of the cause, urethritis
is an important source of suffering for women.
Keywords Urethritis . Female . Dysuria . Vaginal . Atrophy .
The goal of this manuscript is to provide clinicians
Vaginitis . Vulvodynia . Non-chlamydial . Non-gonococcal .
throughout the chain of referral with the tools needed to treat
Mycoplasma
women presenting with urethral inflammation. Urologists of-
ten see these patients secondarily after initial work-up by the
primary medical doctor or emergency physician and the pa-
Introduction tient is often anxious at first meeting with documents from a
series of prior visits requiring review. We aim to map out how
Urethritis is a common condition affecting women of all ages these complex patients can be treated to satisfaction after
in the USA and globally. By definition, it is simply inflam- relatively straightforward investigations.
mation of the urethra—therefore, there is tremendous overlap
in etiology. For the purposes of this paper, we will omit

Sexually Transmitted Infections


W. D. Ulmer : E. J. B. De (*)
Albany Medical Center, Albany, NY 12208, USA Chlamydia and Gonococcus
e-mail: elisede@gmail.com

J. L. Gilbert Sexually transmitted infections (STIs) represent an important


BioReference Laboratories, Elmwood Park, NJ, USA etiology of urogenital pain and urethritis in women. Chlamydia
182 Curr Bladder Dysfunct Rep (2014) 9:181–187

is the most common, with over 1.4 million cases reported in Tuberculosis
2012 [4]. Furthermore, the actual incidence is at least twice this
stated amount at 2.8 million, as many cases proceed undiag- Genital tuberculosis incidence in the USA has been quoted at
nosed due to undertesting [4]. Although many may not have 0.07 % [6]. Rates are much higher in developing countries and
complaints, common signs and symptoms include painful uri- endemic areas. Specific risk factors for exposure may suggest
nation, frequency, vaginal burning and itching, mucopurulent indication for testing. Secondary genitourinary tuberculosis
cervicitis, abnormal vaginal discharge, and dyspareunia. A accounts for 10–14 % of extrapulmonary tuberculosis in some
thorough investigation of women presenting with dysuria areas [7]. Although rare, acute urethritis manifests as myco-
should include testing for STIs as the impact on women’s health bacterial discharge and can result in chronic stricture forma-
and the economic burden of the morbidities are significant. The tion [8]. Urine polymerase chain reaction testing may be
possible sequelae of untreated Chlamydia and Gonococcus positive for tuberculosis. Testing of a lesion itself with poly-
include pelvic inflammatory disease, chronic pelvic pain, ec- merase chain reaction also provides a relatively quick and
topic pregnancy, and infertility. In fact, the US Preventive accurate method of diagnosing the disease compared to cul-
Services Task Force recommends annual screening for chla- ture [9].
mydial infection in all sexually active, non-pregnant young
women ages 24 and younger and in older non-pregnant women M. genitalium
who are at increased risk [5]. Voided urine specimens or cervi-
cal swab should be obtained and sent for laboratory evaluation. M. genitalium is a small parasitic bacterium that lives on the
Specimens obtained for Chlamydia testing should routinely be ciliated epithelial cells of the genital tract. This bacterium may
tested for gonococcal infections as well, which are less com- be transmitted sexually. Its role and significance in genital
mon but are likely to be asymptomatic. The well-established infection is still being investigated. A recent review found that
treatment regimen of cephalosporin with macrolide or doxycy- M. genitalium may have a worldwide prevalence of 2 % even
cline should be prescribed for suspected cases of either disease in low-risk populations [10•]. Its presence has a positive
(specifically, ceftriaxone 250 mg in a single intramuscular dose association with urethritis, vaginal discharge, signs of cervi-
plus azithromycin 1 g orally in a single dose or doxycycline citis, and, importantly, pelvic inflammatory disease and infer-
100 mg orally twice daily for 7 days). In cases where the tility [10•, 11]. The bacterium is detected by nucleic acid
test results are available, if Chlamydia test is positive and amplification tests on urine sample or vaginal swab, which
the gonococcus test is negative, the patient can be treated may not be available in all locations. Persons found to be
for Chlamydia alone (azithromycin). In cases where the infected can be treated with azithromycin 1 g once. Failure
gonococcus test is positive and the Chlamydia test is rates of up to 28 % have been reported due to resistance [12].
negative, the patient should still be treated with dual Extended 5-day regimens of azithromycin therapy increase
therapy to counter gonococcal resistance to ceftriaxone cure rates to 96 % after doxycycline treatment failure [13]. If
(www.cdc.gov). treatment with azithromycin fails, prescribers should use
moxifloxacin 400 mg daily for 10–14 days.

Ureaplasma
Non-chlamydial and Non-gonococcal Urethritis
Ureaplasma urealyticum and Ureaplasma parvum are other
Herpes potential causes of urethritis. The bacteria are actually com-
mon colonizing species of the male and female genitourinary
Viral infection by the herpes simplex virus may be a cause of tract, and their role in pathologic infection is being investigat-
urethritis in women. Urethritis in association with herpes ed [14]. There is growing evidence for the role of particularly
simplex virus may be accompanied by painful, visible blisters; U. parvum in pathologic infections; however, current recom-
however, many women will have only intraurethral herpes mendations regarding the role of treatment are lacking [13].
simplex virus infection or small meatal ulcers without external The bacteria can be detected by a polymerase chain reaction
lesions. The gold standard for testing had been viral culture assay on voided urine or vaginal swab in women. Treatment
from the lesion, but the more recently available polymerase options follow regimens for Chlamydia, using azithromycin
chain reaction (PCR) testing of the lesion is more sensitive or doxycycline.
than culture for herpes simplex virus (HSV). Testing can also
be performed using direct fluorescent antibody testing of a Polymerase Chain Reaction Testing
lesion. Antiviral regimens of acyclovir, famciclovir, or
valacyclovir taken regularly are known to reduce frequency Most labs offer PCR testing for M. genitalium and
of episodes. Ureaplasma species on urine and vaginal swab. These are
Curr Bladder Dysfunct Rep (2014) 9:181–187 183

not FDA-approved at the present time but are laboratory- urinary tract infection randomized to treatment with
validated. PCR for Gonococcus, Chlamydia, Trichomonas, intravaginal estrogen, the estrogen decreased rates of recurrent
HSV-1 and HSV-2, and Mycobacterium tuberculosis is urinary tract infection to 0.5 episodes per patient-year com-
FDA-approved (www.fda.gov). pared to 5.9 episodes per patient-year in the control group
[20]. Possible mechanisms of action involve improvement of
the basal maturation index, altered pH [21], and improved
mucosal seal of the urethra [22].
Vulvar Conditions

Vaginal Atrophy Infectious Vulvovaginitis

Vaginal atrophy is a prevalent and underreported condition in Inflammation of the vagina is often secondary to bacte-
postmenopausal women [15]. Vaginal dryness is also possible rial vaginosis, candida infection, and/or Trichomonas. All
secondary to oral contraceptive use, and vaginal atrophy has can present with pain, itching, and discharge. Dysuria
been seen to some degree in young women on hormonal may be present as well and is characterized by pain from
contraceptives [16, 17]. Other causes of decreased estrogen contact of urine with the vulva externally [23]. Treatment
levels include decreased ovarian function due to radiation should be guided by the underlying cause [23]. Diagno-
therapy or chemotherapy, immune disorder, removal of the sis involves testing for the causative organism. Wet
ovaries, postpartum state, lactation, and the effects of various mount preparations from the vagina may reveal
medications, including tamoxifen (Nolvadex), danazol Trichomonas organisms on light microscopy; however,
(Danocrine), medroxyprogesterone (Provera), leuprolide this has a lower sensitivity as compared to culture and
(Lupron), and nafarelin (Synarel). Previous studies have dem- polymerase chain reaction at 65,78, and 99 %, respec-
onstrated the presence of estrogen receptors throughout the tively. KOH wet mount taken from the lateral walls of
genitourinary system including not only the vagina and vulva the vagina is useful for identifying yeast (pseudohyphae
but also the urethra and bladder [18]. Decreased estrogens can and buds). The vaginal pH measurement, taken from just
have a profound effect on the genitourinary system due to its inside the entrance to the vagina, can contribute to the
impact on cellular maturation, pH, blood flow, and nerve differential: bacterial vaginosis and Trichomonas infec-
stabilization. Atrophy and the resulting syndrome are typically tions tend to exhibit a pH above 4.5 (normal 3.8 to 4.5).
characterized by vaginal irritation, dryness, urinary frequency,
urgency, urge incontinence, and recurrent urinary tract infec-
tions [19]. Physical exam may reveal thinned, sometimes Contact Vulvovaginitis
erythematous tissues on physical exam. There can be a burn-
ing sensation with touching or manipulation. Age and hor- Contact vaginitis typically presents with erythema, irritation,
monal manipulation precedes the onset of symptoms. Vulvar and pruritus (more common in allergic reaction) [24]. Com-
atrophy can also be seen on biopsy; however, this would only mon causes include wipes, soap, cleansers/douches, filamen-
be performed to rule out malignancy or lichen sclerosus. tous toilet papers, condoms, spermicide, detergent, perfumes,
Treatment involves application of vaginal estrogens—creams lubricants, and semen. These patients can present with dysuria
are more likely to coat the vulva and urethra than pellets or from local irritative symptoms. A detailed history regarding
rings. The patient can be advised to apply with the finger in practices may reveal the source of irritation (for example,
addition to the internal applicator to ensure the urethra and residual bleach on the hands prior to onset of symptoms).
vulva are covered. The commercial products can have an Interestingly, interstitial cystitis and a history of recurrent
alcohol base. If the patient experiences burning with the urinary tract infection have been found to be more prev-
product, compound pharmacies can mix topical estrogen with alent among subjects with contact vulvitis [25]. In our
Aloe or VersaBase® to reduce irritation. Occasionally, a peri- practice, the patient with complaints of vulvar symptoms
menopausal or postmenopausal patient will present to the is provided a list of irritants that worsen and substances
clinic in extreme urethral pain. Once infection is ruled out, it that reduce vulvar irritation—this reduces the interview
is the author’s experience that anticholinergics and time in clinic and can be used as a resource at home. She
phenazopyridine and occasionally vaginal Valium supposito- reports her triggers for documentation after she has had
ries from a compound pharmacy can bridge the initiation of time to think on the subject. This list alone (Table 1)—
vaginal estrogens for later tapering. Treating patients for atro- particularly changing tissue products and ceasing wipes—
phy will not only improve symptoms but may also decrease has resolved or improved a significant proportion of our
risks for future causes of bacterial urethritis. Raz and col- clinical population. For extreme cases, vaginal steroids or
leagues demonstrated that in 93 women with postmenopausal wound care can be required.
184 Curr Bladder Dysfunct Rep (2014) 9:181–187

Table 1 Comprehensive list of vulvar irritants. Most importantly, the some patients. Further research and work is needed to
authors provide suggested first-line remedies that often provide relief to
find effective medical treatment, as treating with com-
the patient with minimal costs
mon pain medications and antidepressants has not shown
Vulvar exposures great success. A randomized control trial by Foster et al.
in 2010 did not show advantage in pain relief over
Irritants Calming agents or habits
placebo for desipramine and lidocaine treatment [29].
• Sanitary wipes • Aloe-based sensitive toilet paper Surgical excision of the involved vulvar tissue should
• Perfumed or harsh soaps • Blotting rather than wiping be considered in rare unresponsive cases and only by
• Filamentous toilet papers or pads • Hydrating hypoallergenic experienced hands. A second opinion is prudent. Success
(e.g., septic, safe, or recycled sensitive skin soap (if allergic to
brands) sodium laurel sulfate, African
from vestibulectomy is reported between 65 and 90 %
• Vigorous wiping black soap can be used) but long-term relief is uncertain [30]. Multidisciplinary
• Lace or other abrasive clothing • Cotton underwear: keep as dry as approaches to treatment, including pelvic floor physical
(tight jeans) possible therapy, have shown better results [31]—therefore, reduc-
• Horseback or bicycle riding • Sanitary napkins with a plastic
• Spermicidal lubricants or even rather than fibrous top
ing tension in high-tension pelvic floor muscles may be
particular condom materials • Olive oil for comfort or particularly helpful to reduce overall pain.
• Household cleaners on hands (self intercourse
or partner) • Coconut oil for comfort (can be
• Feminine perfumes chilled)
• Cologne or facial hair on partner’s • Petroleum jelly or other barrier
face after cleaning to protect from Anatomic Considerations
• KY Jelly irritation (urine, chlorine, etc.)
Diverticula

Vulvar Lichen Sclerosus There are anatomic etiologies to consider in women pre-
senting with symptoms of urethritis. Urethral diverticula
Vulvar lichen sclerosus presents as a thickening of the vulvar are rare and therefore not often considered in the differ-
skin with varying degrees of involvement. It is characterized ential. The overall incidence in females is between 1 and
by pruritus, pain, and tenderness with or without blisters and 6 % [32]. When present, they typically occur in the distal
ulcers [26]. Diagnosis is by biopsy. Topical corticosteroids are two thirds of the urethra. Symptoms classically include
the first-line treatment for vulvar lichen sclerosus, and topical dysuria, dyspareunia, and postvoid dribbling. Symptoms
calcineurin inhibitors remain the second-line agents in patients may also include a painful vaginal mass, chronic pelvic
for whom steroids provided incomplete resolution of symp- pain, refractory lower urinary tract symptoms, obstruction
toms or were not tolerated. or stress urinary incontinence, intermittent passage of
purulent or bloody material, and recurrent UTIs. Patients
Vulvodynia may also be asymptomatic with an incidentally detected
diverticulum. The diverticulum may be suspected on
Vulvodynia is a diagnosis of exclusion, and care must be taken physical exam by a palpable mass; urethral fluid may be
to rule out other etiologies (including neuropathy) for pain. expressed and cystoscopy may reveal an ostium. MRI is
Vulvodynia is generally divided into localized provoked pain the most sensitive imaging modality with most centers
(vestibulodynia) and generalized unprovoked vulvodynia having specific protocols, including postvoiding images,
[3••]. Vestibulodynia is defined as pain of the vestibule of to provide the best visualization of the urethra [33]. Some
the vulva and not explained by another condition for greater studies have found sensitivity to be up to 100 % [34]. The
than 3 months. The prevalence is estimated to be from 11 to use of transvaginal ultrasound in the diagnosis of diver-
16 % in a recent review by Andrews [3••]. Central and ticula has been investigated and can be useful in patients
peripheral sensitization seems to be responsible for perpetua- with contraindication to MRI. Furthermore, transvaginal
tion of the symptoms long after the initial inciting event has ultrasound may be a relatively easy and inexpensive
occurred. Possible inciting events could range from traumatic method of management and postsurgical follow-up [35].
injury (straddle injuries, overstretching of nerves to the pelvic Treatment is primarily surgical but observation is an op-
floor during pregnancy) to hormonal changes and to surgical tion in asymptomatic or compromised patients. It should
and medical side effects [27••, 28••]. Lifestyle changes may be be noted that prior transurethral bulking agents will be
attempted first. The simple measures of switching to cotton read by many radiologists as a diverticulum. Correlation
underwear, avoiding tight-fitting undergarments, using mild with history and comparison of the density within the
soaps, lubrication for sexual intercourse, and cooling gel structure to the urine in the bladder will help differentiate
packs to decrease painful sensation may provide relief for the bulking agents from a true diverticulum.
Curr Bladder Dysfunct Rep (2014) 9:181–187 185

Fig. 1 Rough diagnostic guide to


be used in the work-up of non-
UTI dysuria in females. This
should be used, in conjunction
with the paper, to aid the
physician in arriving at the
appropriate diagnosis and
treatment

Skene’s Duct Cyst Trauma

The Skene’s glands are paraurethral glands located along Urethritis is possible secondary to mechanical/chemical
the anterior vaginal wall. The ducts drain into the distal trauma, such as lace or tight clothing. Passage or rarely
urethra near the meatus. Cyst, irritation, or abscess may retention of calculi in the urethra or intramural ureter
uncommonly develop. When adjacent to the urethral (referred pain in the latter case) can lead to symptoms.
meatus and large enough, they may even cause urethral Trauma from normal or rough sexual intercourse may
obstruction and urinary retention. They can cause dysuria cause local inflammation and symptoms, especially as
or focal pain. Physical exam may reveal an erythematous menopause sets in, rendering the tissue more vulnerable.
irritation of a portion of the meatus or a small palpable History will usually yield a potential cause; however, there
cyst. MRI or ultrasound can be useful for diagnosis. may be situations the woman does not feel comfortable
Surgical excision may be required and is usually straight- disclosing. Trauma should be suspected when edema is
forward [36•]. observed and if the story seems inconsistent. The patient’s
limits of tolerance should not be crossed, and cystoscopy
and exam under anesthesia may be necessary.
Foreign Objects

Iatrogenic causes of urethritis should be kept in mind during Urethral Stricture


the evaluation. A thorough history and physical exam may
reveal an obstructing or eroded sling as a cause for the pa- Urethral stricture can cause dysuria due to turbulent flow.
tient’s dysuria (due to turbulence or mucosal irritation, respec- Although rare, urethral stricture in women may also present
tively). Rarely, self-insertion of foreign bodies will be the with frequency, urgency, and less commonly obstructive
cause. Physical examination of the vagina and vulvar region symptoms [37]. One of the authors evaluated a case of
after a thorough history will yield the most information. Lactobacillus urethritis in a 48-year-old woman proximal to
Iatrogenic injury secondary to implanted devices such as an underlying urethral stricture, the obstruction allowing for
sling, bulking agents, intrauterine devices, and pessaries growth of the usually non-pathogenic organism. Report of
should be sought. Imaging or cystoscopy may be performed weak or splayed stream or uroflow revealing low flow rates
to evaluate the extent of involvement and assess for damage to may be suggestive; however, the diagnosis is typically made
the urethra. by cystoscopy.
186 Curr Bladder Dysfunct Rep (2014) 9:181–187

Cancer Compliance with Ethics Guidelines

Conflict of Interest Jeffrey Gilbert and William Ulmer declare that


Unresolved urethritis can rarely reflect a neoplastic pro- they have no conflicts of interest. Elise De reports financial relationships
cess. Cystoscopy (and cytology where relevant) should outside of the submitted work with the following companies: Astellas,
be undertaken in patients who are not responding to the Allergan, American Medical Systems, AMGEN, Boston Scientific,
above interventions or who have microscopic hematuria Ferring, Welch’s Grape Juice, Capital Region Medical Research Founda-
tion, and United BioSource Corporation.
(≥3 rbc per ×40 high power field on urine microscopy) at
any point. Hematuria should prompt upper tract radio- Human and Animal Rights and Informed Consent This article does
logic evaluation as well [38]. not contain any studies with human or animal subjects performed by any
of the authors.

Conclusion References

Urethritis is a common and highly symptomatic condition


Papers of particular interest, published recently, have been
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highlighted as:
is facile with the above work-up will provide an efficient
• Of importance
diagnosis and well-chosen treatment plan.
•• Of major importance
In summary, a few basic considerations at presentation
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