1. health and fitness
2. disease
3. infertility

andrologia 35, 325–330 (2003)
Accepted: April 22, 2003
Chronic prostatitis and male accessory gland infection – is
there an impact on male infertility (diagnosis and therapy)?
K. Everaert1, A. Mahmoud2, C. Depuydt2, M. Maeyaert1 and F. Comhaire2
Departments of 1Urology and 2Internal Medicine, Section of Endocrinology and Metabolic Diseases, Ghent University
Hospital, Ghent, Belgium
Key words. Cytokines—Infertility—leucocytes, genital tract inflammation—prostatitis
Summary. The aim of this article was to discuss
by means of a review of the literature and own study
material the multifactorial aetiology of male infertility, extrapolate this hypothesis to male accessory
gland infection (MAGI) and relate it to chronic
prostatitis and its treatment. Infertility is a multifactorial disease and diagnosis and therapy must be
oriented as such. Although the relationship between
prostatitis and infertility remains unclear, bacteria,
viruses, leucocytes, reactive oxygen species, cytokines, obstruction and immunological abnormalities
must be seen as cofactors in the development of
infertility in patients with MAGI and prostatitis.
Infection, trauma, allergy, neurogenic damage,
chemical or mechanical factors can lead to a longlasting inflammation of the prostate or pelvic organs
even after eradication of the aetiological agent, and
is potentially related to infertility through cytokines.
In relation to treatment of infertility, antibiotics play
a role in bacterial prostatitis whereas in abacterial
prostatitis other treatments like antioxidants, sacral
nerve stimulation and anti-inflammatory treatment
are worth to be studied in the future.
Introduction
Using the criteria for male accessory gland infection
(MAGI) defined by the WHO (Rowe et al., 2000), a
variable portion of infertile men were diagnosed with
this disease in different regions of the world. Several
diseases like varicocele, MAGI, etc. are linked to
infertility without strong proof of causality or efficacy
of their treatment. Male (sub)infertility should be
considered a multifactorial disease in whom genetic
Correspondence: Prof. Dr K. Everaert, P6 Department of
Urology, Ghent University Hospital, De Pintelaan 185, B9000
Ghent, Belgium. Tel.: 32-9-2402276; Fax: 32-9-2403889;
e-mail: [email protected]
factors coincide with lifestyle factors, environmental
or occupational factors and diseases like varicoceles
and MAGI (Comhaire et al., 1999). MAGI itself is
suggested to be multifactorial in relation to the
causality of infertility. Factors that influence infertility in patients with MAGI are bacteria, viruses,
leucocytes, inflammation, obstruction, site of infection and immunological factors. All these factors are
suggested to play an aetiopathological role in
infertility but many lack proof of causality (Wolff,
1998). The aim of this article is to discuss by means of
a review of the literature and own study material the
multifactorial aetiology of male infertility in patients
with MAGI and relate it to chronic prostatitis and its
treatment.
Results
Multifactorial aetiology of male infertility
Our data suggest that 12% of male partners of
infertile couples, with abnormal semen quality to
present MAGI, either as only diagnosis or in
combination with other diseases such as varicocele
or immunological infertility. Evaluating this population by means of the sperm production index (sperm
concentration · ejaculatory volume/total testicular
volume ¼ 4.9 million spermatozoa per total testis
volume in normal men; Elliasson, 1968; Van
Waeleghem et al., 1996) demonstrates a cumulative
distribution (Fig. 1) suggesting a multifactorial causality in male infertility (Comhaire et al., 1999). In
Fig. 2 is indicated that varicoceles and smoking have
an additive effect in decreasing the sperm production
index. Varicoceles associated with genetic defects
also increase significantly genetic damage in the
DNA of spermatozoa compared with patients without varicoceles suggesting synergism of different factors that disturb testicular function (Chen et al., 2002).
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326
K. Everaert et al.
Figure 1. Retrospective study of factors affecting sperm production
in 486 non azoospermic men (mean values). Diagnostic criteria and
semen analysis according to WHO guidelines. Sperm production index
(Mean values) = Sperm concentration million ml)1) · semen volume
(ml)/ bilateral testicular volume in ml (measured by Prader orchidometer). The figure shows that a combination of factors that are
insignificant individually may have a significant effect on sperm
production when combined. Difference between all patients and the
group with no V, E, C or S is statistically significant (P < 0.01, t-test).
Figure 2. Retrospective study of 36 patients with varicocele
diagnostic criteria and semen analysis according to WHO guidelines.
In the vertical axis the frequency distribution (percent) of sperm
production index categories in patients with varicocele (n = 14) and
nonsmokers (n = 22) is shown (sperm production index = sperm
concentration (million ml) 1) · semen volume (ml)/ bilateral testicular
volume in ml (measured by Prader orchidometer). In the horizontal
axis, the sperm production index is classified by intervals. The figure
indicates that smoking has a negative effect on sperm production in
patients with varicocele. In contrast to nonsmokers, all smokers had a
sperm production index that is clearly below the normal value for the
reference population (4.9 million sperm (ml testis))1; Van Walleghem
et al., 1996).
Bacteria and viruses
For both pathogens, including mycoplasma and
chlamydia species, there is very conflicting evidence
in the literature that they have a causal relationship
with male infertility (Purvis & Christiansen, 1993;
Huwe et al., 1998). Semen is characterized by low
bacteria counts, asymptomatic men having positive
cultures, there is no correlation with leucocytes in
the semen, there is urethral contamination, 80% of
prostatitis patients have no bacteria and the contact
time between the infectious agent and the spermatozoa is rather short in patients with prostatitis
Figure 3. Retrospective study. Box and Whisker dot plot of
chlamydia complement binding reaction in male serum (inverted titer)
is significantly lower in couples with successful (IUI pregnant, n = 8)
compared to unsuccessful intrauterine insemination (IUI nonpregnant,
n = 21). (Wilcoxon test, P < 0.05).
(Weidner et al., 1999 a,b). All the above listed
considerations make it very unlikely that bacteria,
viruses, chlamydia or mycoplasma have a causal
relationship with male infertility in patients with
chronic prostatitis. However, during exacerbation of
infection higher counts of infectious agents are more
likely to influence infertility and there is evidence
that bacteria might produce interleukin 8 which is a
potential harmful for spermatozoa (Buch et al., 1994;
Depuydt et al., 1998). In addition, some evidence
exists that Escherichia coli, mycoplasma and Chlamydia
trachomatis can decrease acrosome reaction (Köhn
et al., 1998; Jungwirth et al., 2002) but a review of the
literature fails to demonstrate a decrease in fertilizing capacity in vivo. We found a decrease
in conception following intra-uterine insemination
in patients with C. trachomatis infection (Fig. 3). In
conclusion, the impact of infectious agents in
chronic prostatitis remains unclear and debatable.
Leucocytes
Although clinical MAGI coincides with leucocytospermia, asymptomatic MAGI does not, the concentrations of leucocytes differ significantly among
countries, there is high spontaneous resolution rate
and sometimes leucocytes have a positive effect on
fertilization (Aitken & Baker, 1995; Wolff, 1995;
Yanushpolsky et al., 1995; Ludwig et al., 1998).
Again, these conflicting data might suggest that
leucocytes do not have a negative effect on male
fertility.
Reflux in the internal spermatic vein induces
forced efflux of testicular venous blood through the
deferential vein, into the plexus of Santorini. This
seems to increase the risk of prostatovesiculitis
particularly among men who smoke. The latter
were reported to carry a higher risk of genitoANDROLOGIA 35, 325–330 (2003)
Infertility and prostatitis
(a)
WBCs (ROC) differentiate between varicocele patients with
abnormal (+ve, ≤4.9, n =75) or normal sperm production index
(–ve, >4.9 million ml–1, n =10)
WBC: criterion >0.3 million ml–1, AURC = 0.69
Sensitivity
100
80
60
40
20
0
0
20
40
60
80
100
100-Specificity
(b)
Sperm production index
(million per ml testis)
Correlation between WBCs & sperm production in subfertile men with
varicocele and abnormal epididymis
10
8
6
4
2
0
–2
–4
0.01
0.1
0.3
1
10
WBCs (million ml–1)
Normal: up to 1 million ml–1
(n = 22, r = –0.55, P= 0.012)
Figure 4. Retrospective study on 85 patients with varicocele (Fig.
4a) and 22 with varicocele and abnormal epididymis (Fig. 4b). The
figures illustrate how varicocele patients have a lower sperm production
index if they have concomitant leucocytospermia and that the cut-off
point decreased significantly compared to the WHO-definition. So the
number of peroxidase positive cells in the ejaculate that interferes with
the sperm production capacity depends on the presence or absence of
complementary factors that can disturb testicular function.
urethral infections (Pavone et al., 2000). Figures 4a
and b illustrates how varicocele patients have a
lower sperm production index if they have concomitant leucocytospermia and that the cut-off
point decreased significantly compared to the
WHO definition. Therefore the number of peroxidase positive cells in the ejaculate that interferes
with the sperm production capacity depends on the
presence or absence of complementary factors that
can disturb testicular function.
Inflammation
Interleukin 1 is produced by many cells in response
to infection, inflammation or tissue damage
(Depuydt et al., 1998). Interleukin 1 activates
interleukin 6 from the B cells that differentiate into
ANDROLOGIA 35, 325–330 (2003)
327
antibody-forming cells leading to elimination of the
pathogen and perhaps to male infertility. Interleukin 1 also activates proliferation of neutrophils and
macrophages, both producing reactive oxygen
species (ROS) and may as such have a deleterious
effect on fertility through a decrease in polyunsaturated fatty acids in the membrane of the spermatozoa, transverse mutations in the DNA of the
spermatozoa and a decrease in acrosome reaction
(Depuydt et al., 1998; Zalata et al., 1998). Bacteria
itself can produce interleukin 8 which is suggested
to have a deleterious effect on fertility (Buch et al.,
1994; Depuydt et al., 1998). It became clear that
noxe might produce long lasting inflammation even
after eradication of, i.e. bacteria distinguishing an
infection of the male accessory glands and the
syndrome MAGI. Interleukin 1–6 and ROS are
diagnostic for MAGI and interleukin 6 is found to
be most specific (Depuydt et al., 1998).
The hepatocyte growth factor and scatter factor
are different names for the same cytokine produced
by mesodermally derived cells (epithelium of
prostate and seminal vesicles) and macrophages
(Depuydt et al., 1996). Its expression is triggered by
interleukin 1 and it contributes to tissue repair or
regeneration of injured tissues indirectly explaining
why leucocytes might also be Ôgood SamaritansÕ
(Aitken & Baker, 1995; Depuydt et al., 1998).
Physiopathologically the inflammation described
above in MAGI can also be triggered by other noxe
than bacteria or viruses like trauma, chemical
irritation, neurogenic damage, allergy, mechanical
factors, etc. (Depuydt et al., 1998; Miller et al., 2002).
Chronic prostatitis type 3 or chronic pelvic pain
syndrome is characterized by inflammation (John
et al., 2001; Ludwig et al., 2002), dysfunction of the
pelvic floor (Zermann et al., 1999; Everaert et al.,
2001) and pelvic congestion (Beard et al., 1984;
Thomas et al., 1992). Chronic pelvic pain syndromes
are also seen in women and therefore it is obsolete to
refer to the prostate as the responsible organ for the
disease (Beard et al., 1984). A neurogenic origin for
vascular congestion as for the pain syndrome as such
has been suggested (Stones et al., 1992). Even in
absence of leucocytes (prostatitis type 3b) the
symptoms are related to the serum and semen
interleukin 6 and nerve growth factor suggesting a
neurogenic inflammation as physiopathological
mechanism (John et al., 2001; Miller et al., 2002).
The secondary dysfunctions of the pelvic floor are
caused by muscle spasms for which we refer to the
Ôpain cycle theoryÕ (Birklein et al., 2000) resulting in
voiding dysfunction, dyschezia, dyspareunia and
have been extensively described by several authors
(Zermann et al., 1999; Everaert et al., 2001). Both
the pain cycle theory and the vascular hypothesis
can easily be integrated into a disorder known as
328
K. Everaert et al.
Ôcomplex regional pain syndromeÕ which is a specific
type of neuropathic pain accompanied by muscle
spasm, vasodilatation and vasoconstriction (Veldman et al., 1993). The reported incidence varies
from 1 to 35% depending on the type of trauma
(fracture, nerve damage, infarction, etc.) following
which the syndrome developed. Theoretically a
primary neurogenic damage causes neurogenic
inflammation (Stones et al., 1992; Miller et al.,
2002) which is responsible for typical neurogenic
pain (100%), muscle spasms (49%), vascular congestion (47% increase and 47% decrease in skin
temperature) and dysfunctions (95%) (Veldman
et al., 1993). Other examples of complex regional
pain syndromes are Sudeck’s atrophy and frozen
shoulder or shoulder–hand syndrome. In conclusion, a primarily infectious cause can lead to
neurogenic inflammation and secondary to a longlasting pain syndrome and perhaps infertility linked
to inflammation (cytokines).
Obstruction
It is clear from the literature that infection can
cause obstruction of the male genital tract. Azoospermia is seen following gonorrhoea and bilateral
epididymitis (Weidner et al., 1999 a,b). Anatomically it is easy to link obstruction with male infertility,
however it is unclear what impact partial or
unilateral obstruction has on fertility. Complete
obstruction is diagnosed by a very low semen
plasma alpha-glucosidase activity but the exact
value of this diagnostic marker in partial obstruction remains unclear (Mahmoud et al., 1998a).
From the literature it is clear that vasectomized
patients have a long-lasting elevation of the semen
plasma interleukin 6 concentration (Depuydt et al.,
1996) and following reversal of the vasectomy, huge
concentration of ROS are found in the semen plasma
(Shapiro et al., 1998) suggesting that obstruction
causes inflammation as well proximally (prostate?) as
distally of the obstruction. This inflammation might
be a co-factor in the aetiopathogenesis of the
infertility. As in chronic prostatitis type 3b, elevated
semen and serum interleukin 6 concentrations, that
are related to the symptoms of the patients are found.
It would be interesting to study the potential
relationship between obstruction and prostatitis in a
vasectomy model. Hypothetically vasectomy blocks
the transport of antioxidants of epididymal origin to
the prostate, while causing a long-lasting excess in the
local production of inflammatory cytokines.
spermatozoa making it unlikely that there is direct
causality between prostatitis and infertility (Wolff,
1995). Besides differences in the contact time, there
are also secretory changes in prostatitis (decrease in
muramidase, gamma glutamyl transferase, citric
acid, reducing capacity and increase in viscosity)
compared with infection of the seminal vesicles
(decrease in ejaculatory volume, fructose) or epididymitis (decrease in alpha-glucosidase) because of
impaired function of these organs (Mahmoud et al.,
1998b; Ludwig et al., 2002). How these different
factors interfere with infertility has not been proven
but the changes in secretory function can be used
for diagnostic purposes.
According to the WHO, the diagnosis of MAGI
as a cause of infertility is given if the patient has
abnormal spermatozoa and certain characteristics
that are present in the history, physical examination, urine and/or the ejaculate are met (Rowe
et al., 2000). Every effort should be made to localize
the site of MAGI. Altered physical characteristics of
the ejaculate, decreased seminal markers such as
citric acid and gamma glutamyl transferase (prostate) and alpha-glucosidase (epididymis) and
ultrasonography are useful. This has therapeutic
implications, for example, the use a fluorinated
quinolone that passes the blood–prostate barrier of
the diseased prostate (Comhaire, 1987). The female
partner has also to be treated concomitantly when
infectious organisms are found, e.g. Chlamydia.
Vicari (2000) found that antibiotic treatment of
both partners did not improve the pregnancy rates
in cases with MAGI when the epididymis was also
involved (prostato–vesiculo–epididymitis). This failure has been attributed to the effect of MAGI on
the antioxidant function of the epididymis (Vicari,
2000). Supplementary antioxidant treatment of the
male may be effective in some of these cases,
especially in (ex-)smokers (Comhaire et al., 2000;
Vicari & Calogero, 2001).
A recent cross-sectional study suggests that sperm
quality declines with age in subfertile men with
MAGI (Rolf et al., 2002), one more reason to treat
MAGI.
Immunology
There is no causal relationship found between
immunological factors, prostatitis, MAGI and
infertility in the literature (Eggert-Kruse et al.,
1996).
Site of infection
Therapy of chronic prostatitis, MAGI and the link
to infertility
In bacterial prostatitis, there is a rather short
contact time between bacteria, leucocytes and
In bacterial prostatitis, it is proved that antibiotics
can eradicate bacteria and decrease inflammation
ANDROLOGIA 35, 325–330 (2003)
Infertility and prostatitis
but it is less clear that in prostatitis patients sperm
quality improves and there is no proof that
conception increases following antibiotic therapy
(Comhaire, 1987; Weidner et al., 1999 a,b).
As ROS production is related to infertility, it
is suggested that imbalance by an excess of prooxidants can be treated by supplements of
antioxidants. The potential beneficial effect of
antioxidants on infertility is suggested by several
authors (Mahmoud et al., 1999; Comhaire et al.,
2000) but so far no precise data are available to
state that these therapies improve infertility and
conception.
Electrical neuromodulation like sacral nerve
stimulation [neurostimulator (IPG3) and a quadripolar electrode (3080) from Medtronic Interstim,
Lausanne, Switzerland] has been shown to be
effective in decreasing neurogenic inflammation
(Shaker et al., 2000) and pain (Everaert et al., 2001)
in patients with chronic pelvic pain syndrome.
There is however no proof of effect on fertility or
conception. In addition, anti-epileptic drugs, antidepressive drugs and anti-inflammatory drugs
might decrease neurogenic inflammation but there
is no relationship with fertility as such in the
literature.
In addition cytokines, novel markers of inflammation in chronic pelvic pain syndromes are
potential targets for therapy in symptoms and
infertility (John et al., 2001).
Conclusion
Infertility is a multifactorial disease, and diagnosis
and therapy must be oriented as such. Although the
relationship between prostatitis and infertility
remains unclear, bacteria, viruses, leucocytes,
ROS, cytokines, obstruction and immunological
abnormalities must be seen as cofactors in the
development of infertility in patients with MAGI
and prostatitis. Infection, trauma, allergy, neurogenic damage, chemical or mechanical factors lead
to a long-lasting inflammation even after eradication
of the aetiological agent. Antibiotics play a role in
bacterial prostatitis in relation to the treatment of
infertility whereas in abacterial prostatitis other
treatments like antioxidants, neuromodulation,
anti-inflammatory treatment are worth to be studied
in the future.
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