I.3.13 Infection/Inflammation of the Accessory Sex Glands Key Messages

I.3 Male Factor Fertility Problems
I.3.13 Infection/Inflammation of the Accessory
Sex Glands
F. Comhaire, A. Mahmoud
Key Messages
Infection of the accessory sex glands is diagnosed in a variable proportion of cases with
abnormal semen quality depending on
regional differences.
The influence of infection/inflammation of the
epididymis on semen quality and fertility is
more important than that of infection/inflammation of the prostate or seminal vesicles.
Whereas bacteria themselves have little influence on the fertilizing capacity of spermatozoa, changes in the function of the affected
glands and reactive oxygen species generated
by white blood cells damage spermatozoa.
The diagnosis of male accessory sex gland
infection is based on a combination of
elements in the patient’s history, clinical signs,
and biological analysis of urine and semen.
Treatment uses antibiotics and antioxidants,
complemented with intrauterine insemination
and/or assisted reproduction, depending on
the severity and reversibility or irreversibility
of damage to sperm cells.
The diagnosis of male accessory gland infection is
given when semen classification is azoospermia or
abnormal spermatozoa and this is considered to result
from present or past infection of the accessory sex
glands, or inflammatory disease of the urogenital tract
(Rowe et al. 2000).
Aetiology and Physiopathology
Infection of the accessory sex glands includes epididymitis, vesiculitis and/or prostatitis, which are caused by
either pathogens transmitted by sexual contact or by
so-called trivial urological pathogens. Among the
former, Chlamydia trachomatis is the most common
pathogen (Keck et al. 1998), but gonococcus may also
occur. The urological pathogens commonly identified
are Escherichia coli, Streptococcus faecalis, Proteus
mirabilis and pseudomonas. The role of coagulasenegative staphylococcus is uncertain, while Staphylococcus aureus is usually a laboratory contaminant
(Rodin et al. 2003).
Infection causes inflammation characterized by the
classical symptoms such as pain, swelling, and impaired function. The latter is responsible for deficient
secretion of minerals, enzymes and fluids that are
needed for optimal function and transport of the spermatozoa. The abnormal biochemical make-up of the
seminal plasma results in decreased seminal volume,
abnormal viscosity and liquefaction, abnormal pH,
and impaired functional capacity of the spermatozoa.
These are commonly poorly motile and may have antisperm antibodies attached of the IgG and/or IgA class,
causing immunological infertility.
In addition, infection or inflammation increase the
number of peroxidase-positive white blood cells (pus
cells) generating reactive oxygen species that change
the lipid composition of the sperm membrane, reducing its fluidity and fusogenic capacity with impaired
acrosome reactivity and ability to fuse with the oolemma (Comhaire et al. 1999). Reactive oxygen species induce oxidative damage to sperm DNA, with excessive
production of a.o. 8-hydroxy-2-deoxyguanosin and
mutagenesis (Chen et al. 1997). Also, inflammation increases the production of a number of cytokines such
as interleukin 1 (alpha and beta), interleukin 6 and 8,
and tumour necrosis factor, which further impair
sperm function and fertilizing capacity (Depuydt et al.
1996; Gruschwitz et al. 1996).
Chronic inflammation of the epididymis may result
in (partial) obstruction of the sperm passage with oligo- or azoospermia (Dohle et al. 2003). Rupture of the
blood-testis barrier from obstruction causes antisperm antibodies (Hendry 1986).
Clinical and Laboratory Findings
History taking commonly reveals one or several episodes of dysuria and/or pollakisuria, which may have
disappeared spontaneously or after a short treatment
with an antibiotic or urinary antiseptic. However, the
patient may be unaware of any acute urinary symptoms
in the past. Sometimes, the patient mentions recurrent
episodes of intrascrotal pain that usually feels rather
dull and is exacerbated by pressure. Ejaculatory symptoms may occur such as reduced ejaculation force or
volume, painful sensation during or immediately after
ejaculation, or blood staining of the ejaculate. Finally,
sexual complaints may be mentioned, including decreased libido and orgasmic feeling, or even erectile
I.3.13 Infection/Inflammation of the Accessory Sex Glands
Clinical examination should focus on the careful
palpation of the scrotal content, particularly the epididymis and vas deferens. Any swelling or nodularity
should be noted, as well as pain during soft pressure.
Rectal examination can be performed, but transrectal
or transabdominal echography may reveal more relevant information.
General blood analysis may reveal signs of infection,
such as increased number of white blood cells, increased sedimentation rate or abnormal globulin proportions upon electrophoresis. Specific tests for circulating antibodies against Chlamydia should be included in the routine investigation for male infertility. The
laboratory may detect antisperm antibodies of the IgG
class in serum.
Urine analysis may reveal bacterial infection or an
increased number of white blood cells, but the analysis
of urine obtained after prostate massage should be
more relevant. However, the absence of urinary abnormality does not exclude male accessory gland infection, particularly epididymitis.
Semen analysis is of pivotal importance to the diagnosis. Semen must be collected as described in the section on semen analysis, in order to avoid contamination with cells and bacteria from the skin or urethra.
When semen culture is performed for the counting and
identification of bacteria, preparatory dilution of the
sample is required, reducing the bacteriostatic capacity
of seminal plasma, prostate fluid in particular. The
number of round cells must be counted, and these must
be differentiated into peroxidase-negative cells, mostly
spermatogenetic cells, and peroxidase-positive white
blood cells (WHO 1999). Also, it is mandatory to perform biochemical analysis of the seminal plasma in order to measure the markers of secretion of the sex
glands, including, for example, alpha-glucosidase for
the epididymides, citric acid or gamma glutamyl transferase (or calcium or zinc) for the prostate, and, possibly, fructose for the seminal vesicles.
Finally, the presence of antisperm antibodies on
spermatozoa must be traced by means of, for example,
the direct MAR test for both IgG and IgA (WHO 1999).
Diagnosis and Differential Diagnosis
The diagnosis is accepted in patients with abnormal semen quality – oligo- and/or asteno- and/or teratozoospermia, or azoospermia – who combine abnormalities
under the following headings (Comhaire et al. 1980;
Rowe et al. 2000):
A. A history of urinary infection, epididymitis, sexually transmitted disease, and/or physical signs: thickened or tender epididymis, thickened vas deferens,
abnormal rectal examination
B. Abnormal urine after prostatic massage and/or detection of Chlamydia trachomatis in urine
C. Ejaculate abnormalities:
– Elevated number of peroxidase-positive white
blood cells
– Culture with significant growth of pathogenic
– Abnormal viscosity and/or abnormal biochemical composition, and/or high levels of inflammatory markers or highly elevated reactive oxygen
The diagnosis requires either two signs from different
headings, or at least two ejaculate signs in each of two
subsequent semen samples. If bacteria are detected,
they should be identical in urine and in semen, or in the
two semen samples.
Male accessory sex gland infection may be combined with other diseases such as varicocele, in which
case a lower number of white blood cells may cause
complementary damage (Everaert et al. 2003), or an
immunological factor, or sexual or ejaculatory dysfunction. These diseases will require adequate management and may interfere with the fertility outcome after
treatment of the infection.
The treatment of the infection should be the same as for
urinary tract infections. However, abnormal secretion
of the prostate results in an alkaline environment in
this gland, by which antibiotics such as doxycycline are
not concentrated and are therefore inefficient. The
third-generation quinolones (e.g. ofloxacin and pefloxacin) are concentrated in both an alkaline and acidic
milieu, and therefore do penetrate well into the diseased prostate and the seminal vesicles (Comhaire
1987). In case of streptococcus infection, the quinolones are poorly active, and treatment with amoxicillin or
cephalosporins may be indicated.
Commonly, bacterial infestation is eradicated, but it
may return, sometimes with a different pathogen. It
may be necessary to add a second, longer-term treatment with another antibiotic.
Results of Treatment
Whereas bacteria can usually be eliminated from the
genitourinary region, white blood cells may persist for
several months, and functional impairment of the accessory glands is commonly irreversible. This implies
that the processes impairing the fertilizing capacity of
spermatozoa remain active, and that fertility is not restored. Complementary treatment with food supple-
I.3 Male Factor Fertility Problems
ments containing antioxidants may be required, and
treatment similar to that of idiopathic oligozoospermia
can be indicated.
In general, the success rate of antibiotic treatment of
male accessory gland infection in terms of spontaneous
conception is poor and not significantly better than
that of placebo. Treatment aiming at the elimination of
pathogens is, however, indicated for reasons of good
medical practice, and in order to reduce the risk of future complications, including prostate cancer (Roberts
et al. 2004).
Because oxygen damage to the sperm membrane
and, most of all, DNA may persist after antibiotic treatment, intrauterine insemination and in vitro fertilization may yield poor results, and intracytoplasmic
sperm injection, though generating pre-embryos, may
fail in creating an ongoing pregnancy (Zorn et al. 2004).
Therefore, careful complementary treatment and a holistic approach are indicated.
Depending on the localization of the infection or inflammation, the prognosis after treatment is variable.
Whereas the effects of prostatitis and vesiculitis are less
important, and the effect of treatment on fertility is
rather favourable, (chronic) epididymitis usually
causes substantial and irreversible damage to the quality and the fertilizing capacity of spermatozoa (Vicari
2000). Also, immunological infertility, resulting from
rupture of the blood–testis barrier, is irreversible.
In view of the poor prognosis regarding the repair of
fertility, prevention of infectious disease is of primordial importance.
On the one hand, prevention of sexually transmitted
disease, and its immediate treatment in positive cases,
will prevent infertility in a later stage. In particular, recurrent infections with Chlamydia were documented to
cause disastrous effects that are irreversible (Gonzales
et al. 2004).
Men who smoke run a four- to fivefold higher risk of
prostatitis and subsequent spread of infection to the other accessory sex glands. In addition, tobacco smoke generates surplus amounts of oxygen radicals and toxic
damage to spermatozoa. Avoiding tobacco is, therefore,
the most important factor in the prevention of male accessory gland infection by common urological pathogens. In addition, relatively symptom-poor episodes of
urinary infection, e.g. occurring after an episode of diarrhoea, may remain untreated and ultimately develop into chronic infection/inflammation that is hard to treat,
let alone cure. Therefore, any episode of urinary complaints suggestive for infection in the male must be treated adequately, in particular using quinolones, in order to
avoid pathogens being harboured in the prostate gland.
Chen CS, Chao HT, Pan RL, Wei YH (1997) Hydroxyl radicalinduced decline in motility and increase in lipid peroxidation and DNA modification in human sperm. Biochem Mol
Biol Int 43:291 – 303
Comhaire FH (1987) Concentration of pefloxacin in split ejaculates of patients with chronic male accessory gland infection. J Urol 138:828 – 830
Comhaire F, Verschraegen G, Vermeulen L (1980) Diagnosis of
accessory gland infection and its possible role in male infertility. Int J Androl 3:32 – 45
Comhaire FH, Mahmoud AM, Depuydt CE, Zalata AA, Christophe AB (1999) Mechanisms and effects of male genital
tract infection on sperm quality and fertilizing potential: the
andrologist’s viewpoint. Hum Reprod Update 5:393 – 398
Depuydt CE, Bosmans E, Zalata A, Schoonjans F, Comhaire FH
(1996) The relation between reactive oxygen species and cytokines in andrological patients with or without male accessory gland infection. J Androl 17:699 – 707
Dohle GR, van Roijen JH, Pierik FH, Vreeburg JT, Weber RF
(2003) Subtotal obstruction of the male reproductive tract.
Urol Res 31:22 – 24
Everaert K, Mahmoud A, Depuydt C, Maeyaert M, Comhaire F
(2003) Chronic prostatitis and male accessory gland infection–is there an impact on male infertility (diagnosis and
therapy)? Andrologia 35:325 – 330
Gonzales GF, Munoz G, Sanchez R, Henkel R, Gallegos-Avila G,
Diaz-Gutierrez O, Vigil P, Vasquez F, Kortebani G, Mazzolli A,
Bustos-Obregon E (2004) Update on the impact of Chlamydia
trachomatis infection on male fertility. Andrologia 36:1 – 23
Gruschwitz MS, Brezinschek R, Brezinschek HP (1996) Cytokine levels in the seminal plasma of infertile males. J Androl
17:158 – 163
Hendry WF (1986) Clinical significance of unilateral testicular
obstruction in subfertile males. Br J Urol 58:709 – 714
Keck C, Gerber-Schafer C, Clad A, Wilhelm C, Breckwoldt M
(1998) Seminal tract infections: impact on male fertility and
treatment options. Hum Reprod Update 4:891 – 903
Roberts RO, Bergstralh EJ, Bass SE, Lieber MM, Jacobsen SJ
(2004) Prostatitis as a risk factor for prostate cancer. Epidemiology 15:93 – 99
Rodin DM, Larone D, Goldstein M (2003) Relationship between semen cultures, leukospermia, and semen analysis in
men undergoing fertility evaluation. Fertil Steril 79 Suppl
3:1555 – 1558
Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA (2000)
WHO manual for the standardized investigation, diagnosis
and management of the infertile male. Cambridge University Press, Cambridge
Vicari E (2000) Effectiveness and limits of antimicrobial treatment on seminal leukocyte concentration and related reactive oxygen species production in patients with male accessory gland infection. Hum Reprod 15:2536 – 2544
WHO (1999) WHO laboratory manual of the examination of
human semen and sperm-cervical mucus interaction. Cambridge University Press, Cambridge
Zorn B, Virant-Klun I, Vidmar G, Sesek-Briski A, Kolbezen M,
Meden-Vrtovec H (2004) Seminal elastase-inhibitor complex, a marker of genital tract inflammation, and negative
IVF outcome measures: role for a silent inflammation? Int J
Androl 27:368 – 374