Agarwal.qxp 25/2/08 12:42 pm Page 55
Varicocele – A Dilemma for the Urologist
Oxidative Stress and Varicocele discussed. Early reports suggested that varicocele size had no relation
In the context of human reproduction, a balance normally exists to outcome following varicocele repair in infertile men.
26,27
These
between reactive oxygen species (ROS) production and antioxidant findings led to the conclusion that non-palpable varicoceles detected
scavenging activities in the male reproductive system. Minimal by radiological image studies should be candidates for treatment as
amounts of ROS remain in the system since they are needed for the well. The majority of infertile men and other males of the general
regulation of normal sperm functions such as sperm capacitation, the population would be candidates for varicocele repair, as subclinical
acrosome reaction and sperm–oocyte fusion.
13
The production of varicocele is detected in approximately 44% of fertile men and up to
excessive amounts of ROS in semen can overwhelm the antioxidant 60% of infertile patients.
28,29
However, subsequent studies have
defence mechanisms of spermatozoa and seminal plasma, causing suggested that subclinical varicocelectomy is of questionable benefit.
oxidative stress. Recent studies report that increased ROS levels are
detected in the semen of 25–40% of infertile men.
14,15
Aitken et al.
The majority of infertile men and other
reported that men with elevated ROS levels in semen have a seven-fold
reduction in conception rates compared with men with low ROS.
16
males of the general population would
Moreover, high levels of DNA damage and oxidative stress have been
be candidates for varicocele repair, as
associated with a decrease in the fertilising capacity of spermatozoa.
17
subclinical varicocele is detected in
The relationship between ROS and varicocele has been documented by approximately 44% of fertile men and
our centre.
12
Studies in subfertile men with varicocele demonstrate the
up to 60% of infertile patients.
existence of an excessive release of nitric oxide within dilated spermatic
veins, which might be responsible for spermatozoa dysfunction.
18,19
While there are mild improvements in post-operative semen
Seminal ROS levels show a positive correlation with varicocele grade. parameters, pregnancy rates were not improved with ligation of these
Men with varicocele grade 2 and 3 have significantly higher seminal subclinical varicoceles.
30–33
This was also confirmed by the only
ROS levels compared with men with varicocele grade 1.
20
A recent randomised prospective study.
34
Additionally, surgical repair of
meta-analysis reported that oxidative stress parameters (such as ROS subclinical varicoceles did not result in statistically significant
and lipid peroxidation) are significantly increased and antioxidant differences in seminal parameters or pregnancy rate compared with
concentrations significantly decreased in varicocele patients compared treatments using clomiphene citrate.
35
The debate over repair for
with normal sperm donors.
21
Mostafa et al. were the first to show that subclinical varicoceles can be resolved only by performing randomised
varicocelectomy reduces ROS levels and increases concentrations of trials with treated and untreated groups of patients. In the mean time,
antioxidants such as superoxide dismutase, catalase, glutathione patients with subclinical varicocele should be aware that surgery is
peroxidase and vitamin C of seminal plasma from infertile men.
22
highly questionable and no longer recommended based on the
existing literature.
1
DNA Damage and Varicocele
Excessive generation of ROS in the reproductive tract attacks not only Steckel et al. reported that men with grade III varicocele have lower
the fluidity of the sperm plasma membrane, but also the integrity of motile sperm counts and show a greater relative improvement in
DNA in the sperm nucleus. DNA bases are susceptible to oxidative semen quality after varicocelectomy than those with grades I and II
damage, resulting in base modification, strand breaks and chromatin varicoceles who present with higher mean sperm densities.
36
However,
cross-linking. Infertile men with varicoceles have high levels of since large varicoceles are associated with the lowest pre-operative
spermatozoal DNA damage, which appear to be related to increased semen quality and thus compensate for greater initial testicular
levels of reactive oxygen species.
23
Chen et al. reported that patients impairment, overall pregnancy rates are similar regardless of size.
30
The
with varicocele have increased 8-hydroxy-2’-deoxyguanosine, an current evidence supports that varicocele size does matter and that
indicator of oxidative DNA damage.
24
Zini and Libman reviewed the infertile patients receiving varicocele repair for large varicoceles are
reports of 37 men who underwent microsurgical varicocelectomy and more likely to show seminal parameter improvement than patients
showed decreased sperm DNA denaturation six months after with smaller varicoceles.
varicocelectomy compared with pre-operatively, suggesting a
mechanism for semen parameter improvements noted post-ligation Patients with higher pre-repair sperm counts have significantly greater
(27.7 versus 24.6%, respectively, p<0.05).
25
absolute improvement in semen parameters than those with more
severe oligospermia.
6
Moreover, men who achieved a post-operative
Predicting Improvement in Semen Parameters and total motile sperm count greater than 20 million were more likely to
Pregnancy Rates Following Varicocelectomy initiate a pregnancy by less invasive techniques: natural and
The aetiology underlying infertility is uncertain in men whose seminal intrauterine insemination (IUI).
37
parameters do not significantly improve or whose partners do not
achieve pregnancy following varicocele surgery. A key to resolving this Marks et al. described that pre-ligation sperm motility of 60% or more
problem is to identify patients who could benefit from treatment by is associated with an improved post-ligation pregnancy rate. Also,
evaluating variables of favourable prognosis. Fretz and Sandlow reduced pre-surgical testicular volume or elevated follicle-stimulating
summarised these variables (see Table 1). hormone (FSH) concentrations were identified as negative predictors
for post-ligation outcome. The lack of testicular atrophy was found to
Recently, the impact of varicocele grade on the magnitude of indicate higher post-operative pregnancy rates, and testicular volume
improvement in semen quality after varicocele repair has been greater than 30ml was identified as an independent predictor of
EUROPEAN GENITO-URINARY DISEASE 2007 55
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