Infertility

VaricoceleA Dilemma for the Urologist

Current Concepts
a report by

M a rc e l l o C o c u z z a , M D , E d m u n d S a b a n e g h , M D and A s h o k A g a r w a l , P h D
Reproductive Research Center, Glickman Urological Institute, Cleveland Clinic

Although varicocele repair is widely used as a treatment for male infertility,

the effectiveness of varicocelectomy has been a focus of intense debate for
nearly 50 years. A number of conflicting reports in the literature has resulted
in divergent guidelines by various professional groups. The American
Urological Association (AUA) and the American Society for Reproductive
Medicine (ASRM) recommend treatment for clinical varicoceles when a male
partner has abnormal semen parameters. The National Collaborating
Center for Womens Health of 2005 suggests not offering surgery for men
with varicocele as a fertility treatment, while the European Association of
Urology (EUA) still considers it controversial.
There is significant evidence in the literature to support the theory that
varicocele has a harmful effect on the testis and that varicocelectomy can
prevent the progressive decline in testicular function, as well as reverse the
damage. However, there are few adequately controlled prospective trials
concerning the effect of varicocele repair on fertility.
The development of intracytoplasmatic sperm injection (ICSI) as an effective
therapy for cases of male infertility has become a valid means of overcoming
multiple sperm deficiencies. ICSI has been suggested by some to represent
the solution for all cases of male factor infertility, regardless of etiology. Even

Marcello Cocuzza, MD, is a Fellow in Andrology in the Glickman

Urological Institute at the Cleveland Clinic. Since 2004, he has
been a staff member in the Urology Department of Hospital das
Clinicas, Sao Paulo, Brazil. His research interests are in the
surgical treatment of male infertility and in unraveling the role of
oxidants in sperm dysfunction.

Edmund S Sabanegh Jr, MD, is Chief of the Section of Male

Infertility for the Glickman Urological Institute. His research
interests include complex reconstructions for obstruction of the
reproductive tract, testicular blood flow, varicoceles, and
environmental influences on fertility. He heads one of the few
Male Infertility Fellowship programs in the US, which combines
basic research with extensive clinical experience.

Ashok Agarwal, PhD, is the Director of the Reproductive

Research Center, and the Director of the Clinical Andrology
Laboratory and Reproductive Tissue Bank at the Cleveland
Clinics Glickman Urological and Kidney Institute. Professor
Agarwal is recognized internationally for his innovative research
into the pathophysiology of male infertility.

men with potentially treatable causes of infertility might be treated with

assisted reproductive techniques instead of specific therapy.
The following review discusses current concepts in varicoceles and
summarizes the leading theories on the mechanisms for varicoceleinduced testicular damage. It reviews existing literature on the efficacy
of varicocelectomy for the treatment of infertility. It discusses the role of
varicocelectomy in the management of varicoceles in the adolescent as
well as in nonobstructive azoospermic patients. Finally, the authors
critically review the cost-effectiveness of the surgical treatment of a
varicocele compared with assisted reproductive techniques.
Varicocele and Male Infertility
Over the past decade, the association of varicocele with male subfertility has
been repeatedly demonstrated and the beneficial effect of varicocele repair
in infertile men with oligoasthenospermia has been reported.1 Varicocele is
implicated as a factor in 3550% of men with primary infertility and up to
81% of men with secondary infertility.2,3 The higher incidence in secondary
infertility implicates varicoceles in producing a progressive decline in
testicular function over time.
An association of abnormal semen parameters in infertile patients with the
presence of varicocele during physical examination has been reported by
several studies. In 1965, MacLeod first reported that the majority of semen
samples obtained from 200 infertile men with varicocele had decreased
sperm count, decreased motility, and increased abnormal forms.4 A study
conducted by the World Health Organization (WHO) on varicocele found its
presence in 25.4% of infertile men with abnormal semen, noting that it is
accompanied by decreased testicular volume, lower total sperm count, and
a decline in Leydig cell secretion.5
Large numbers of uncontrolled studies have suggested that varicocele
ligation can improve sperm count, motility, and morphology. Overall,
varicocelectomy studies reported significant improvements in one or more
semen parameters in 65% of men, and pregnancy rates of 40% in couples.6
However, the effectiveness of varicocele repair in terms of pregnancy rate
improvement is a controversial matter in the literature due to the large
number of poorly designed and uncontrolled studies.
Various mechanisms have been proposed for infertility in men with
varicocele. The etiology remains to be proved, but suggested mechanisms
include hypoxia and stasis, testicular venous hypertension, elevated
testicular temperature, increase in spermatic vein catecholamine, and
increased oxidative stress.712 However, the exact cause is still unknown.

TOUCH BRIEFINGS 2007

VaricoceleA Dilemma for the Urologist

Oxidative Stress and Varicocele

In the context of human reproduction, a balance normally exists between
reactive oxygen species (ROS) production and antioxidant scavenging activities
in the male reproductive system. Minimal amounts of ROS remain in the
system since they are needed for the regulation of normal sperm functions
such as sperm capacitation, the acrosome reaction, and spermoocyte
fusion.13 The production of excessive amounts of ROS in semen can
overwhelm the antioxidant defense mechanisms of spermatozoa and seminal
plasma, causing oxidative stress. Recent studies report that increased ROS
levels are detected in the semen of 2540% of infertile men.14,15 Aitken et al.
reported that men with elevated ROS levels in semen have a seven-fold
reduction in conception rates compared with men with low ROS.16 Moreover,
high levels of DNA damage and oxidative stress have been associated with a
decrease in the fertilizing capacity of spermatozoa.17
The relationship between ROS and varicocele has been documented by our
center.12 Studies in subfertile men with varicocele demonstrate the existence
of an excessive release of nitric oxide within dilated spermatic veins, which
might be responsible for spermatozoa dysfunction.18,19 Seminal ROS levels
show a positive correlation with varicocele grade. Men with varicocele grade
2 and 3 have significantly higher seminal ROS levels compared with men with
varicocele grade 1.20 A recent meta-analysis reported that oxidative stress
parameters (such as ROS and lipid peroxidation) are significantly increased
and antioxidant concentrations significantly decreased in varicocele patients
compared with normal sperm donors.21 Mostafa et al. was the first to show
that varicocelectomy reduces ROS levels and increases concentrations of
antioxidants such as superoxide dismutase, catalase, glutathione peroxidase,
and vitamin C of seminal plasma from infertile men.22
DNA Damage and Varicocele
Excessive generation of ROS in the reproductive tract attacks not only the
fluidity of the sperm plasma membrane, but also the integrity of DNA in
the sperm nucleus. DNA bases are susceptible to oxidative damage,
resulting in base modification, strand breaks, and chromatin cross-linking.
Infertile men with varicoceles have high levels of spermatozoal DNA
damage, which also appear to be related to increased levels of reactive
oxygen species.23 Chen et al. reported that patients with varicocele have
increased 8-hydroxy-2-deoxyguanosine, an indicator of oxidative DNA
damage.24 Zini and Libman reviewed the reports of 37 men who
underwent microsurgical varicocelectomy and showed decreased sperm
DNA denaturation six months after varicocelectomy compared with preoperatively, suggesting a mechanism for semen parameter improvements
noted post-ligation (27.7 versus 24.6%, respectively, p <0.05).25
Predicting Improvement in Semen Parameters and Pregnancy
Rates Following Varicocelectomy
The etiology underlying infertility is uncertain in men whose seminal
parameters do not significantly improve or whose partners do not achieve
pregnancy following varicocele surgery. A key to resolving this problem is to
identify patients who could benefit from treatment by evaluating variables
of favorable prognosis. Fretz and Sandlow summarized these variables and
they are shown in Table 1.
Recently, the impact of varicocele grade on the magnitude of improvement
in semen quality after varicocele repair has been discussed. Early reports
suggested that varicocele size had no relation to outcome following

US GENITO-URINARY DISEASE 2007

varicocele repair in infertile men.26,27 These findings led to the conclusion that
non-palpable varicoceles detected by radiological image studies should be
candidates for treatment as well. The majority of infertile men and other
males of the general population would be candidates for varicocele repair, as
subclinical varicocele is detected in approximately 44% of fertile men and up
to 60% of infertile patients.28,29 However, subsequent studies have suggested
that subclinical varicocelectomy is of questionable benefit. While there are
mild improvements in post-operative semen parameters, pregnancy rates
were not improved with ligation of these subclinical varicoceles.3033 This was
also confirmed by the only randomized prospective study.34 Additionally,
surgical repair of subclinical varicoceles did not result in statistically significant
differences in seminal parameters or pregnancy rate compared with
treatments using clomiphene citrate.35 The debate over repair for subclinical
varicoceles can be resolved only by performing randomized trials with treated
and untreated groups of patients. In the mean time, patients with subclinical
varicocele should be aware that surgery is highly questionable and no longer
recommended based on the existing literature.1
Steckel et al. reported that men with grade III varicocele have lower motile
sperm counts and show a greater relative improvement in semen quality
after varicocelectomy than those with grades I and II varicoceles who
present with higher mean sperm densities.36 However, since large
varicoceles are associated with the lowest pre-operative semen quality and
thus compensate for greater initial testicular impairment, overall pregnancy
rates are similar regardless of size.30 The current evidence supports that
varicocele size does matter and that infertile patients receiving varicocele
repair for large varicoceles are more likely to show seminal parameter
improvement than patients with smaller varicoceles.
Patients with higher pre-repair sperm counts have significantly greater
absolute improvement in semen parameters than those with more severe
oligospermia.6 Moreover, men who achieved a post-operative total motile
sperm count greater than 20 million were more likely to initiate a pregnancy
by less invasive techniques: natural and intrauterine insemination (IUI).37
Marks et al. described that pre-ligation sperm motility of 60% or more is
associated with an improved post-ligation pregnancy rate. Also, reduced
presurgical testicular volume or elevated follicle-stimulating hormone (FSH)
concentrations were identified as negative predictors for post-ligation
outcome. The lack of testicular atrophy was found to indicate higher postoperative pregnancy rates, and testicular volume greater than 30ml was
identified as an independent predictor of fertility after varicocelectomy.38,39
Varicocele repair is more likely to improve fertility in patients with serum FSH
concentrations lower than 11.7mIU/ml or lower than 300ng/ml.38,39
The gonadotropin response to exogenous gonadotropin-releasing hormone
(GnRH) test has been suggested by some as a means to identify patients
who would benefit from varicocele ligation. Atikeler et al. showed that a
significant elevation in FSH (approximately 1.52.0 times baseline) and
luteinizing hormone (LH) (approximately 2.02.5 times baseline) 3060
minutes after an intranasal bolus of GnRH (100mg) was a predictor in
identifying patients whose semen parameters would improve after
varicocelectomy.40 Similarly, Segenreich et al. reported that 81% of men
with an exaggerated GnRH test response had a post-operative improvement
in their sperm variables, whereas only 19% of men lacking an exaggerated
response showed improvement. Corresponding pregnancy rates at 18

Infertility

Table 1: Pre-operative Predictors of Seminal Improvement

after Varicocelectomy 47
High-grade varicocele (grade III)
Lack of testicular atrophy
Normal serum FSH
Total motility >60%
Total motile sperm count >5x106
Positive GnRH stimulation test
FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone.

months in the two groups were 67.4 and 9.3%, respectively. The authors
concluded that a positive pre-operative GnRH test is a good predictor of
improvement in semen parameters and pregnancy after varicocele surgery.41
Y chromosome microdeletions are another factor that portends little or no
improvement after varicocele ligation. The Y chromosome plays a critical
role in the control of spermatogenesis. Y chromosome microdeletions can
be detected in as many as 414.3% of oligospermic men and in up to 18%
of azoospermic men.41,42 Moro et al. reported that Y chromosome deletions
were observed in seven out of 40 infertile patients (17.5%) presenting with
severe oligospermia (fewer than 5x106 sperm/ml), bilateral testicular
volume loss, and varicocele. Interestingly, no deletions were found in 80
patients with varicocele and mild oligozoospermia (sperm count
1020x106/ml).43 Pryor et al. examined the incidence of Y chromosome
microdeletion in 200 consecutive infertile men and found that 3% of those
with varicocele had microdeletions.44 Cayan et al. reported results after
varicocelectomy in five patients who had co-existing Y chromosome
deletions and found no significant improvement in seminal parameters or
pregnancy rates.45 These findings suggest that men with poor seminal
parameters and Y chromosome microdeletions might have an incidental
varicocele for which surgical repair is unlikely to improve fertility.46
These prognostic indicators can facilitate the identification of patients with
a better prognosis for varicocele repair, or the choice of those couples more
likely to be initial candidates for assisted reproductive techniques.
Varicocelectomy or Assisted Reproductive Technology
What Is Better?
In the era of intracytoplasmic sperm injection, the role of andrologists has
been transformed. The relative pregnancy rates achieved by this modality
have led to a troubling decrease in efforts to establish a correct diagnosis of
infertility cause.
Although assisted reproduction technology (ART) provides an opportunity
to families with infertility, the potential medical risks entailed by multiplegestation pregnancies and the associated costs cannot go unnoticed.
Therefore, couples considering assisted reproductive techniques should be
aware of the risks of these procedures. Medical risks include ovarian
hyperstimulation and multiple-gestations.4850
In addition to the safety concerns, which procedure is more cost-effective
for infertile couples with male varicocele in this era of cost-containment
awareness: ICSI or varicocele repair? Schlegel first reported a comparison of
ICSI and varicocele repair using a cost per delivery analysis and concluded
that primary treatment with varicocelectomy was more cost-effective than
sperm retrieval/ICSI, while providing comparable delivery rates.51 Total
hospital delivery costs, as well as costs attributable to multiple gestations

and complications, were analyzed. The average US reported delivery rate

after one attempt of ICSI was 28% compared with 30% found after
varicocele repair. The average cost per delivery for varicocelectomy was
$26,268, whereas for ICSI it was estimated at $89,091.
Recently, Meng et al. applied a decision-analyses model to compare the cost
of pregnancy for varicocelectomy versus ART treatment in varicocele
patients.52 Decision models are constructed with pre-defined assumptions
and are used to estimate outcomes once several options for treatment are
available. The authors concluded that initial varicocele repair was more costeffective than ART treatment for infertile couples.
After varicocele repair, a couple can proceed with assisted reproduction if
pregnancy is not achieved. Varicocele repair may allow some couples to
proceed with IUI prior to proceeding with more advanced assisted
reproductive techniques, since studies suggest that varicocelectomy
improves the effectiveness of subsequent IUI.53,54
While ICSI provides a viable alternative for the treatment of infertile couples
with varicocele, current evidence supports that the treatment of varicocele
is a more cost-effective therapy for infertility.5153
Managing Varicocele in Adolescents
Although varicocele is cited as one of the leading causes of male infertility,
it is essential to recognize that varicocele does not typically begin in
adulthood, but rather in the peri-pubertal period. Epidemiological studies
reveal that varicocele is not generally present in children under 10 years of
age, and its incidence gradually increases at the beginning of the second life
decade.55,56 The incidence of varicocele in adolescents is approximately 15%
by the late teenage years, a rate similar to the general population, and with
the same distribution of grades. Varicocele incidence peaks at the age of 15
years and remains relatively stable thereafter.55,56
Awareness of the potential damage associated with long-standing
varicoceles has motivated urologists to become more conscientious in their
pursuit of adolescent varicoceles. The decision of when to treat adolescents
with varicocele is controversial, since 80% of adults with varicocele are
fertile.57 Routine surgery is inappropriate for all adolescents since it is not
cost-effective and fertility will not necessarily be affected by the varicoceles.
Non-selective surgical intervention would submit a large population of boys
to unnecessary surgery. On the other hand, it is unacceptable to allow
potentially irreversible testicular damage to manifest with infertility as
adults. Adolescent varicoceles are often associated with testicular volume
loss, endocrine abnormalities, and abnormal seminal parameters.58 After
varicocele diagnosis, patients should be evaluated for testicular volume and
consistency. Varicocelectomy is indicated when a palpable varicocele is
associated with ispilateral testicular growth retardation greater than 2ml or
two standard deviations compared with the normal testicular curve.
Additionally, it should be considered in boys with bilateral varicoceles or a
solitary testis, since testicular growth retardation may not be evident in this
population. Physicians may discuss the possibility of seminal analysis for
older adolescents to help with the decision to treat although few studies
have evaluated the normality of seminal parameters in adolescents with
varicocele, most likely because of ethical concerns related to the
procurement of semen specimens in young boys.59,60 If seminal parameters
are abnormal and high-grade varicocele is present, surgery should be

US GENITO-URINARY DISEASE 2007

VaricoceleA Dilemma for the Urologist

considered even with bilateral normal testicular volume.

Figure 1: Algorithm of Indications and Benefits of Varicocele Repair

As in adults, exaggerated GnRH response to stimulation has been detected in

adolescents with varicocele.61 Adolescents with a palpable varicocele and
abnormal gonadotropin stimulation test responses may benefit from varicocele
surgery.62 In addition, in adolescents large varicoceles that are associated with
debilitating ispilateral testicular pain should be considered for repair.63
A rapid catch-up growth of the affected testis after varicocelectomy has
been consistently reported in 5080% of adolescents and suggests that
early intervention is effective as well as defensible.59,6467 In addition, semen
quality improvement has been demonstrated.6870 Recently, in an
uncontrolled study Salzhauer et al. showed high paternity rates among men
who underwent a varicocele repair during adolescence.71
In some boys, a varicocele develops immediately before puberty when the
testis is immature and vulnerable. Based on testicular size, evidence
suggests that the time of development of a varicocele in relation to puberty
may be the critical factor in the subsequent development of infertility.72 The
recognition and treatment of an early-developing varicocele may help to
reduce the infertility associated with this condition. In the absence of
prospective controlled studies concerning the optimal management
of asymptomatic varicocele in adolescents, parents should be made aware
of the possibility of subsequent infertility.
Induction of Spermatogenesis after Varicocelectomy in
Azoospermic Men
Nonobstructive azoospermia in association with a varicocele is estimated to
range between 5 and 10% in adults.7375 Tulloch, in 1955, reported the
return of spermatogenesis and subsequent pregnancy after varicocele repair
in an initially azoospermic patient, renewing attention on varicocele
treatment.76 After varicocele repair, motile sperm are found in the ejaculate
of azoospermic men in 2155% of the cases, although spontaneous
pregnancies are rare.74,75,77 Varicocele repair in this population may avoid the
need for subsequent testicular sperm retrieval procedures because they can
provide sperm via ejaculation.
Even though an improvement in spermatogenesis is seen in up to half of
the patients, assisted reproductive techniques will be necessary for the
majority of these couples to initiate pregnancy.78 Fertilizing ability and ICSI
success rates are superior when fresh motile ejaculated sperm is used
compared with sperm provided by testicular biopsy or microsurgical
testicular sperm extraction.79,80
Although azoospermic patients may exhibit an improvement in
spermatogenesis after varicocelectomy, a gradual decline in
spermatogenesis and return to azoospermia has been reported in up to
55.5% of the patients 12 months after surgery.78 These patients may
experience intermittent sperm production, and varicocele repair may have
solely a temporary effect, resulting in the induction of spermatogenesis for
a short period of time. Since these patients may not be able to maintain
spermatogenesis, semen cryopreservation is strongly recommended
following the initial improvement after surgery.
As mentioned previously, a high prevalence of Y chromosome
microdeletions in azoospermic infertile men exists. Karyotype and Y

US GENITO-URINARY DISEASE 2007

Subclinical

Varicocele

Treatment not
recommended
Palpable lesion

Adolescents

Infertile couples
Normal female partner

Reduced ipsilateral
testicular size

Abnormal seminal
parameters

Preserve testicular
growth and fertility

Improve semen quality

May improve fertility
Down stage or shift the
level of ART needed

Adult men
not attempting
to concieve

Azoospermia

Abnormal
semen analysis

May avoid invasive

testicular sperm
retrieval procedures

Varicocele repair
may be offered to
preserve fertility

chromosome mapping is crucial in the evaluation of men with varicocele

and azoospermia. These patients should be aware of chromosomal
abnormalities so that they can obtain genetic counseling to stratify their risk
of transmission to offspring.
Varicocele Treatment in the Light of
Evidence-based Medicine
In this age of evidence-based medicine, it is interesting that few randomized
controlled studies have been performed to clarify the cost-effective benefit
of varicocelectomy. Reviews concerning efficacy of varicocelectomy in
subfertile couples are heterogeneous and include studies with suboptimal
methodology.81 Comparison among these reported trials is confounded by
substantial differences in important factors such as varicocele size, infertility
cause, seminal parameter criteria for study inclusion, concurrent female
fertility factors, and short follow-up time after varicocelectomy.82
The results of a systematic review by Evers and Collins in 2003 had a
negative influence on the varicocele treatment recommendations of the
EUA Working Group on Male Infertility.83 Only randomized, controlled
trials were included that addressed varicocele repair for male subfertility,
and the conclusion was that surgery or radiological treatment of
varicocele does not seem to be an effective treatment for male or
unexplained subfertility.
A recent review challenged the meta-analysis by Evers and Collins, carrying
out their own critical analysis of all available randomized, clinical trials.81 As
the AUA and ASRM did not recommend varicocele repair in patients with
normal semen analyses or subclinical varicoceles, five out of eight studies
selected in the previous meta-analysis were excluded to allow a critical
assessment of current treatment guidelines.34,35,8486 Based on this review,
Ficarra et al. concluded that the meta-analysis by Evans and Collins would
support varicocele treatment in the context of only examining studies in the
literature that were consistent with current guideline recommendations. It
suggested supporting continuing varicocele treatment for improvement of
fertility instead.81
The two most important randomized, controlled studies reported an

Infertility

improvement in seminal parameters following varicocele repair, but they are

discordant regarding pregnancy outcomes and maintain the controversy
concerning varicocele treatment effects upon fertility.87,88

varicoceles produce a progressive harmful effect upon the testis resulting in

the decline of seminal parameters. Figure 1 summarizes the most common
indications and the expected benefits from the varicocele repair.

Recently, our center tried to resolve this controversy by conducting a metaanalysis that examined the effect of varicocelectomy on semen parameters
and pregnancy rates for infertile couples in which the male partner had
abnormal semen parameters and clinical varicocele. We analyzed both
randomized, controlled trials and observational studies. Although this data is
not published yet, we concluded from our meta-analysis that surgical
varicocelectomy is an effective treatment for improving semen parameters of
infertile males with clinically palpable varicocele. Based on the data from
current literature and contrary to previous meta-analyses, our study suggests
that varicocelectomy does indeed have a beneficial effect on fertility status
by improving the odds of spontaneous pregnancy in female partners.

The main goal of varicocelectomy is to preserve testicular function and

initiate pregnancy in infertile couples. However, even when pregnancy is not
achieved, improved seminal quality after surgery can obviate or downstage
the need for assisted reproductive techniques. Identifying those individuals
with varicocele who will present better benefit from varicocele treatment is
always a challenge for andrologists.

Our results further support that the improvement in semen parameters

achieved with varicocelectomy may help infertile couples achieve pregnancy
spontaneously or with less invasive and inexpensive techniques such as IUI.
Conclusion
Varicocele remains a common finding in infertile men and is often the sole
identifiable cause of infertility in couples. There is convincing evidence that

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Current data support the assertion that varicocelectomy is successful in

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