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Breyer_pap_1_A4_2011 27/06/2012 11:07 Page 81
Infection
Sexually Transmitted Infection and Long-term
Risk of Lower Urinary Tract Symptoms
Allison S Glass,1 Bogdana Kovshilovskaya2 and Benjamin N Breyer3
1. Junior Specialist; 2. Medical Student; 3. Assistant Professor, Department of Urology, University of California, San Francisco, California, US
Abstract
Lower urinary tract symptoms (LUTS) are prevalent. Clinical presentation is varied and often represents complex pathophysiological
processes. Sexually transmitted infection (STI), typically acquired during young adulthood, produces genital tract inflammation with
potentially systemic adverse outcomes. Clinical and basic science research suggests that sexually acquired pathogens may play a role
in development of LUTS later in life. A self-reported history of STI is correlated with moderate to severe LUTS in multiple studies.
Furthermore, analysis of tissue and other biological specimens demonstrate evidence of sexually transmitted pathogens in patients with
prostatitis or urinary tract symptoms in several reports. While evidence is limited, practitioners should consider risk of long-term urinary
morbidity when counselling patients about STI treatment and prevention.
Keywords
Sexually transmitted infection, lower urinary tract symptoms, ascending infection, chronic inflammation, benign prostatic hypertrophy,
gonorrhoea, chlamydia, human immunodeficiency virus, genital herpes, syphilis, pelvic inflammatory disease
Disclosure: The authors have no conflicts of interest to declare.
Received: 29 March 2012 Accepted: 30 April 2012 Citation: European Urological Review, 2012;7(1):81–4
Correspondence: Benjamin N Breyer, University of California, San Francisco, Department of Urology, 400 Parnassus A610, San Francisco, CA 94143, US.
E: [email protected]
Lower urinary tract symptoms (LUTS) include bothersome urinary
complaints such as frequency, urgency and nocturia. It is estimated
that half of people worldwide will experience some degree of LUTS in
their lifetime and the prevalence may be rising.1 Treatment-associated
costs are estimated to be billions of dollars.2,3 While a number of risk
factors exist for the development of LUTS such as advancing age,
diabetes and depression, among others, sexually transmitted infections
(STI) have been suggested to play a pathogenic role. STIs directly impact
the genito-urinary tract by local and systemic inflammation. This review
presents current literature on patient-reported history of sexually
acquired infections and the development of LUTS later in life. We also
describe pathways of STI-mediated inflammation and pathophysiology
of LUTS.
Sexually Transmitted Infections –
The Scope of the Problem
Despite implementation of widespread screening and improved
treatment practices, STIs remain a US healthcare concern. In 2010,
19 million new STIs were diagnosed, accounting for US$17 billion
healthcare dollars.4 Chlamydia (Chlamydia trachomatis) is the most
common STI reported, occurring in 6.8 % of girls ages 14–19 years.
Over 1.3 million cases were diagnosed in 2010, representing a
decrease in incidence for the first time in a decade. While screening
has resulted in a decrease in incidence, diagnosis and treatment is
complicated by the fact that the infection can be asymptomatic in men
and women. Gonorrhoea (Neisseria gonorrhoeae) accounted for over
300,000 STIs; antibiotic resistance, especially to fluoroquinolones, is
expected to produce a rise in incidence in the near future. The number
© TOUCH BRIEFINGS 2012
of cases of syphilis (Treponema pallidum) is increasing, especially
amongst black men who have sex with men.4 Other causes of
non-gonococcal urethritis include genital mycoplasms (i.e. Ureaplasma
urealyticum, Mycoplasma genitalium and M. hominis), Trichomonas
vaginalis and herpes simplex virus. The presence of ulcerating STIs,
such as syphilis and genital herpes, increases the likelihood of
transmitting and acquiring human immunodeficiency virus (HIV).
Upwards of 50,000 new cases of HIV are diagnosed annually and
as of 2008, 1.2 million people were HIV positive in the US.4
Clinical Evidence
Recent literature supports the hypothesis that inflammation
secondary to STIs plays an important role in LUTS pathogenesis. The
majority of studies reflect male-only populations with varying degrees
of demographic variables including race, age and specific sexual
orientation described. Table 1 presents specific studies that have
evaluated LUTS in men with history of STI.
Male Populations
Sutcliffe et al. describe the impact of STIs on LUTS in the large nested
Health professionals follow-up study (HPFS), an ongoing prospective
cohort.5 This study found that a history of gonorrhoea was associated
with any (odds ratio [OR] 1.76), moderate/severe (OR 1.89) and severe
(OR 2.69) LUTS. Further, this was the only study to address incident LUTS
as data was taken from surveys collected every two years from
1992–2000. History of gonorrhoea also correlated to any (OR 1.63)
and severe (OR 2.4) new-onset symptoms. Subsequently, Sutcliffe
et al. evaluated prevalence of viral STIs in male participants of the
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Infection
Table 1: Studies that Examine Sexually Transmitted Infection History and Patient-reported Lower Urinary Tract
Symptoms in Men
Study
Year
n
Per cent
>60
Years
LUTS
Measure
Prevalence
Moderate or
Severe LUTS
Sutcliffe et al.5
2005
30,123
NS
Modified
9.5 %
IPSS/AUA SI
Sutcliffe et al.6
2007
7,015
NS
Presence of nocturia,
NS
STI Prevalence
STI and Risk of Moderate
or Severe LUTS
Gonorrhoea, 3 %
Gonorrhoea 1.89 OR (CI 1.51–2.37)
Syphilis, 0.2 %
Syphilis 1.45 OR (CI 0.77–2.73)
HSV-1, 73.6 %*
Age 30–49:
incomplete emptying,
HSV-2, 59 %*
HHV-8 5.8 OR (CI 1.8–19.1)
hesitancy or
HPV-16, 10.8 %*
weak stream
CMV, 68.5 %*
Age 50–59:
HHV-8, 3.3 %*
HPV 5.6 OR (CI 2.1–14.9)
HBV, 8.6 %*
CMV 3.9 OR (CI 1.5–9.8)
HCV, 3.3 %*
HCV 11.7 OR (CI 2.9–46.7)
1.8 OR (CI 1.5–2.1)
Collins et al.7
2002
31,681
NS**
IPSS/AUA SI
16 %
NS, 3.1 %
Joseph et al.8
2003
708
28 %
IPSS/AUA SI
29.7 %
NS, 54 %
1.5 OR (CI 1.08–2.07)
Wallner et al.9
2009
703
43 %
IPSS/AUA SI
6.7 %
Gonorrhoea, 52 %
Gonorrhoea 1.42 OR (CI 0.77–2.62)
Breyer et al.11
2012
2,348
5.9 %
IPSS/AUA SI
33 %
Syphilis, 3.7 %
Syphilis 0.49 OR (CI 0.07–3.75)
Herpes, NS, 1.3 %
Herpes 2.09 OR (CI 0.25–17.3)
HIV, 14.1 %
HIV 2.03 OR (CI 1.15–3.59)
Gonorrhoea, 19 %
Gonorrhoea 1.43 OR (CI 1.08–1.88)
Syphilis, 9.4 %
Syphilis 1.4 OR (0.97–2.01)
Chlamydia,12.6 %
Herpes, 8.1 %
Breyer et al.12
2011
1,830
NS***
IPSS/AUA SI
35 %
HIV, 17.7 %
HIV, 1.07 (CI 0.74–1.5)±
Gonorrhoea, 25 %
HIV (+ADI), 1.52 (CI 1.09–2.12)±
Chlamydia, 14 %
Gonorrhoea 1.39 OR (CI 1.09–1.79)✝
*Varying proportions of total cohort were subjected to individual sexually transmitted infection (STI) analysis. **Mean age of those with lower urinary tract symptoms (LUTS) was 60.5 years.
***Mean age of HIV-infected group was 45 years. ✝Moderate LUTS only. ± = adjusted OR; ADI = AIDS-defining illness; AUA SI = American Urological Association symptom index;
CMV = cytomegalovirus; HIV = human immunodeficiency virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HHV-8 = human herpes virus 8; HPV = human papillomavirus;
HSV = herpes simplex virus; IPSS = international prostate symptom score; NS = non-specified; OR = odds ratio; Bold font reflects statistical significance.
Third national health and nutrition examination survey (NHANES).6
Positive associations were found between serological evidence of
several sexually acquired viruses and reporting two or more LUTS
symptoms in men age 30–59 years. Collins et al. examined a large,
nationwide sample of healthy men from the HPFS study.7 Of 31,681
men who were surveyed, 16 % reported a history of prostatitis or
LUTS. History of STI (pathogen not specified) resulted in 1.8-fold
increase in odds of these symptoms.
African-American Men
Several studies specifically address LUTS and STI history in African
American men.8,9 Joseph et al. describe a cohort in which over half
reported a history of any STI (including gonorrhoea, syphilis, genital
herpes or genital warts) and this conferred a 1.5-fold increased risk
of developing moderate to severe LUTS.8 Conversely, Wallner et al. in a
population-based sample of African-American men found no significant
association between LUTS and history of gonorrhoea, syphilis, genital
herpes or partner history of cervical cancer.9 Ejike et al. investigated
the role of STI and chronic prostatitis (CP) symptoms by performing a
cross-sectional survey of black undergraduate students in Nigeria.10
Presence and severity of symptoms was assessed by use of the
National Institutes of Health-Chronic Prostatitis Symptom Index
(NIH-CPSI). Of the 2,003 men who completed the survey, 73 % of
those with history of STI had CP symptoms. Presence of CP symptoms
correlated positively and significantly with self-reported history
of STI (p<0.05).
Homosexual Men
Breyer et al. report results of a cross-sectional, Internet-based survey
assessing the relationship of LUTS to urinary tract infection (UTI),
82
prostatitis, STI, lifetime sexual partner count and recreational drug use
in homosexual men.11 A relatively young population completed the
survey (mean age 39 years). One-third of the respondents reported
moderate to severe LUTS and 14.1 % reported history of HIV, 12.6 %
chlamydia and 19 % gonorrhoea. Multivariate analysis revealed a
significant association between positive lifetime history of HIV or
gonorrhoea and moderate to severe LUTS. In the same cohort, Breyer
et al. evaluated whether HIV/AIDS status was an independent risk
for LUTS.12 Men with HIV were more likely to report moderate to
severe LUTS. After adjusting for age, co-morbidities and history of
UTI, STI and prostatitis, AIDS-defining HIV positive men were 1.79-times
more likely to experience moderate to severe LUTS. Gonorrhoea was
also found to be an independent risk factor for moderate LUTS.
Women
There are very few studies that evaluate the impact of STI and
development of LUTS in women, likely due to varied presentation,
aetiology and classification of symptoms. Tchoudomirova et al.
describe a cohort of 217 who reported recurrent urinary symptoms
in spite of negative urinary culture.13 Symptomatic women had more
STIs compared to women without symptoms, in particular, history
of genital herpes (6.5 versus 2.5 %, p=0.01) and genital warts (11.1
versus 7.0 %, p=0.06). However, there was no difference in rates of
patient-reported history of chlamydia or gonorrhoea infection. Potts
et al. investigated incidence of Ureaplasma urealyticum in 48 women
with chronic LUTS.14 Half of these women were urine culture positive
and following antibiotic treatment, symptom severity and urinary
frequency improved. As Ureaplasma is a common component of
normal genital flora it can be sexually transmitted and as this study
found, eradication can lead to reduction in LUTS.
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Sexually Transmitted Infection and Long-term Risk of Lower Urinary Tract Symptoms
In addition to lack of literature addressing STI infection in women,
there are several limitations to the available literature. Most of the
studies described are survey-based, which are prone to subject
reporting bias and STI treatment information is generally unknown.
Furthermore, the majority of studies do not address the temporal
component of STI and onset of urinary symptoms.
Men
STI can lead to long-term development of LUTS by a variety of
mechanisms (see Figure 1). Initially, STI often presents as urethritis
(urethral discharge and/or dysuria), epididymitis, genital ulcers or
genital warts. Local inflammation can result in scar tissue deposition
and urethral stricture disease, which often manifests as LUTS. Largely
secondary to gonorrhoeal infection, this sequela is now very
uncommon because of antibiotic use.15 In men, ascending infection of
urogenital pathogens to the prostate can result in acute prostatitis
and potentially chronic infection.
By way of multiple biological parameters, investigators have assessed
presence of several sexually acquired pathogens in men with chronic
prostatitis (CP) symptoms. Cultures of prostate tissue specimens,
expressed prostatic secretions, urethral swabs and semen as well as
serum antibody titers have identified pathogens such as Chlamydia
trachomatis, Mycoplasma genitalium, Staphylococcus epidermidis,
Staphylococcus haemolyticus, Corynebacterium seminale and
Coryneform spp. in men with symptoms of CP or chronic pelvic
pain syndrome (CPPS).16–23 Importantly, these studies reveal positive
associations between sexually acquired pathogens and CP symptoms
in the absence of clinically active infection. Through a variety of
mechanisms, including production of chronic inflammation, STIs appear
to promote risk of long-term symptomatic prostatitis symptoms.
Several sexually acquired pathogens have been linked to chronic
histological inflammation within the prostate. Bacterial causes of STI,
including Neisseria gonorrhoeae, Chlamydiatrachomatis, Trichomonas
vaginalis and Treponema pallidum, have been found to produce
persistent inflammatory response within the gland’s parenchyma.24
Similarly, in vitro rat models have demonstrated prostate epithelial
cell upregulation of pro-inflammatory cytokines and chemokine genes
in response to Chlamydia murinarum exposure. Chlamydia was also
detected in numerous sites distant from prostate installation within
the urogenital tract including urethra, bladder, prostate and seminal
vesicles.25 Chlamydia was also shown to persist three months after
introduction into the prostate gland, accompanied by significant
histological changes and inflammatory cell infiltration.26
Chronic inflammationis a common histological finding in tissue
specimens of men with benign prostate hyperplasia (BPH), an
important cause of both irritative and obstructive urinary symptoms in
men. Several studies suggest chronic inflammation plays an important
role in the pathogenesis of BPH.5,6,27 Sutcliffe et al. postulate that
infection of these pathogens within the prostate results in high
amounts of inflammation-mediated secretion of growth factors that
promote stimulation of prostate epithelial cell growth.
Women
Research regarding the pathogenesis and possible mechanism for an
association between STI and LUTS is lacking. Acute STI presentation
EUROPEAN UROLOGICAL REVIEW
STI Rx
toxicity
Damage to
pelvic nerves
Systemic
effect
Lower urinary tract symptoms
Pathogenesis of Local and Ascending Infection
Figure 1: Pathophysiology of Sexually Transmitted
Infection-mediated Inflammation and Lower
Urinary Tract Symptoms
STI-mediated inflammation
Limitations
Prostatitis/
PID
Ascending
infection
prostate
or uterus/
fallopian
tubes
Chronic
inflammation
BPH
Local
effect
Chronic
inflammation
Scar
tissue/
stricture
BPH = benign prostatic hyperplasia; PID = pelvic inflammatory disease; Rx = treatment
prescription; STI = sexually transmitted infection.
in women is varied and can include non-specific irritative urinary
symptoms, urethritis, cervicitis or salpingitis. In women of reproductive
age, ascending infection results in pelvic inflammatory disease (PID)
and is estimated to occur in 8 % of women.28 Typically associated with
chlamydia or gonorrhoea infection, PID can increase risk of recurrent
PID, ectopic pregnancy, infertility and chronic pelvic pain.29 Cases of
chronic chlamydia infection and incontinence have been reported.30
Half of women infected with gonorrhoea and 90 % of those infected
with chlamydia are asymptomatic.4
Systemic Effects
Processes that result in systemic inflammation are postulated to
afflict the urinary tract and contribute to new or worsening LUTS.31,32
Late-stage syphilis or neuro-syphilis, now uncommon because of
widespread treatment efforts, has been associated with
incontinence and other lower tract symptoms.33,34 Similarly, end-organ
damage secondary to HIV and HIV-treatment are associated with a
variety of urological morbidities including stone disease, UTI, sexual
dysfunction and nephropathy. 35–38 Detrusor instability and
urodynamic abnormalities, thought to result from damage to pelvic
nerves that control the bladder, have also been observed in patients
with HIV.39,40
Conclusion and Future
STIs are prevalent, with over one million cases reported annually.
As there is much focus on the amount of healthcare dollars and
resources spent on screening and treatment of STIs, the long-term
cost to the patient is less recognised. Through a variety of
mechanisms, STI-mediated inflammation appears to play an
important role in the development of significant urinary tract
morbidity. Several clinical studies have found positive associations
between moderate or severe LUTS and history of gonorrhoea,
syphilis, HIV and other sexually acquired viruses. Other than
treatment of the causative pathogen, it is unknown if and how to
adjust treatment of urinary symptoms that occur in patients with
history of STI. While limitations to the available data must be
considered, providers can discuss risk of LUTS when counselling
patients about STI treatment and prevention. n
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