Review Article

Systematic Review of the Impact of Varicocele Grade on

Response to Surgical Management
Denise Asafu-Adjei,* Clark Judge, Christopher M. Deibert, Gen Li, Doron Stember and Peter J. Stahl
From the Departments of Urology, Columbia University Medical Center York (DA-A, PJS) and Mount Sinai Hospital (DS) and Department of Biostatistics, Mailman
School of Public Health (GL), New York, New York, Section of Urology, University of Chicago Medical Center (CJ), Chicago, Illinois, and Division of Urological Surgery,
University of Nebraska Medical Center (CMD), Omaha, Nebraska

Purpose: We evaluated the impact of varicocele grade on the response to vari-

Abbreviations
and Acronyms
ART [ assisted reproductive
technology
ASRM [ American Society for
Reproductive Medicine
AUA [ American Urological
Association
IVF [ in vitro fertilization
NOS [ Newcastle-Ottawa Scale
Accepted for publication February 12, 2019.
The corresponding author certifies that, when
applicable, a statement(s) has been included in
the manuscript documenting institutional review
board, ethics committee or ethical review board
study approval; principles of Helsinki Declaration
were followed in lieu of formal ethics committee
approval; institutional animal care and use
committee approval; all human subjects provided
written informed consent with guarantees of
confidentiality; IRB approved protocol number;
animal approved project number.
No direct or indirect commercial, personal,
academic, political, religious or ethical incentive
is associated with publishing this article.
* Correspondence: Department of Urology,
Columbia University Medical Center, 161 Fort
Washington Ave., 11th Floor, New York, New
York 10032 (e-mail: ps2192@cumc.columbia.edu).
cocelectomy or spermatic vein embolization.
Materials and Methods: We systematically reviewed the published English
language literature to identify studies on changes in semen quality and pregnancy
outcomes after varicocele treatment, stratified by varicocele grade. Descriptive
statistics and continuous random effects models were used to study the impact of
varicocele grade and the surgical approach on the response to treatment. Result
heterogeneity among studies was analyzed using the I2 statistic. Quality assess-
ment of nonrandomized studies was done with the Newcastle-Ottawa Scale.
Publication bias was analyzed using funnel plots and the Egger test.
Results: We identified 20 studies describing the outcome of varicocele treatment
stratified by varicocele grade in a total of 2,001 infertile men with varicocele. A
microsurgical approach (inguinal, subinguinal and/or Palomo) was used in 11 of
the 20 studies (55%). Varicocele treatment was associated with improvements in
sperm concentration and overall motility in patients with all grades of varicocele.
Semen quality improvements were directly related to varicocele grade. The mean
sperm concentration improvement in men with grades 1, 2, 2-3 and 3 varicoceles
were 5.5, 8.9, 12.7 and 16.0 million sperm per ml, respectively. The mean
improvement in the percent of overall motility in men with grades 1, 2, 2-3 and 3
varicoceles was 9.6%, 10.6%, 10.8% and 17.7%, respectively. Pregnancy outcomes
were assessed but could not be analyzed systematically due to the lack of
adequate published data.
Conclusions: Mean improvements in the sperm concentration and the percent of
overall motility after treatment of grade 1 varicocele were statistically significant
but small in magnitude. In contrast, mean improvements in the sperm concen-
tration and the percent of overall motility after treatment of grade 2-3 varicoceles
were greater and highly likely to be clinically significant. Incorporating varico-
cele grade into shared decision making discussions with affected couples may
improve the ability to select patients who are the best candidates for treatment.

Key Words: testis; infertility, male; spermatic cord; varicocele;

semen analysis

VARICOCELE, the most commonly iden- Varicocelectomy in properly selected

tified correctable cause of male infer- patients improves semen quality and
tility, is found in up to 35% to 50% of increases the probability of natural
men with primary infertility and 69% conception.3e5 However, it has been
to 81% with secondary infertility.1,2 shown that about 85% of adolescents

0022-5347/20/2031-0048/0 https://doi.org/10.1097/JU.0000000000000311
THE JOURNAL OF UROLOGY® Vol. 203, 48-56, January 2020
Ó 2020 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A.

48 j www.auajournals.org/jurology
Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 VARICOCELE GRADE AND SURGICAL MANAGEMENT
with uncorrected varicocele go on to achieve paternity
with potential improvement in semen parameters if
followed with time.6,7
The AUA and the ASRM recommend considering
varicocelectomy in men with documented infertility,
abnormal semen quality and minimal/no identified
female factor.8 However, couples affected by asso-
ciated male factor subfertility due to varicocele may
elect to defer varicocele surgery and instead select
treatment with ARTs such as intrauterine insemi-
nation or IVF. Kirby et al called the published AUA
and ASRM guidelines into question, having found
that varicocelectomy also improves ART.9 This has
led to the growing significance of varicocele man-
agement in infertility care.
Treatment selection of varicocelectomy or ART in
this extremely common clinical scenario is best
accomplished through shared, individualized deci-
sion making between the affected couple and the
physician. Such a discussion should include coun-
seling about the risks, costs, benefits and efficacy of
each approach. Factors often considered in this de-
cision process include the number of children
desired by the couple, the surgical risk profile of the
affected male, the age and medical status of the fe-
male partner, the personal feelings of each couple
about ART and resource availability. Varicocelec-
tomy may offer a permanent solution to male factor
infertility and it is considerably more cost-effective
than ART.10 However, ART circumvents the need
to correct abnormal semen parameters and it can be
associated with shorter time to pregnancy.
Dubin and Amelar introduced the varicocele
grading system in 1970 when they evaluated
whether preoperative varicocele size was related to
semen parameter changes.11 The grading system
classifies grade 1 varicocele as varicocele palpable
only by the Valsalva maneuver, grade 2 as palpable
at rest but not visible and grade 3 as easily visible.
The AUA and ASRM guidelines group all clinical
varicoceles together and do not distinguish by
grade.3e5,8 However, it is intuitive that the degree of
testicular impairment resulting from a varicocele
might be influenced by the grade of the varicocele.
Our objective was to systematically study the re-
lationships of varicocele grade to baseline semen
quality and the response to varicocelectomy using the
2010 WHO standards for the lower limit of normal for
the sperm concentration as 15 million/ml and 40% for
sperm motility. In so doing we wanted to explore
varicocele grade as a possible factor which could be
used to counsel affected couples about treatment op-
tions for varicocele associated subfertility.
MATERIALS AND METHODS
This study was initially performed according to the
PRISMA (Preferred Reporting Items for Systematic
Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
49
Reviews and Meta-Analyses) guidelines for systematic
reviews.12 However, due to the methodological and
clinical heterogeneity of the included studies a meta-
analysis was inappropriate and so a systematic review
was pursued.
Search Strategy
We searched the literature to identify randomized clinical
trials, cohort and case-control studies of the impact of
varicocele grade on the response to varicocele treatment.
We used certain databases, including PubMedÒ (1966 to
December 7, 2016), EmbaseÒ (1966 to December 7, 2016)
and MEDLINEÒ (1946 to December 7, 2016) with com-
binations of the terms “varicocele” AND “male infertility”
AND “grade” or “size” AND “varicocelectomy OR varicocele
ligation or varicocele repair.” The Cochrane CENTRAL
(Central Register of Controlled Trials) database was
searched and yielded 1 study, which was also obtained in a
prior search. We also searched references of included studies
to identify additional, potentially relevant studies.
Two of us (CJ and CMD) independently performed
identical literature searches with no discordance. The
searches were limited to human and adult studies. Un-
published studies were not sought and only English lan-
guage articles were included. If multiple studies were
identified with overlapping patients, only the most recent
study was selected for inclusion.
Study Selection
The described search strategy was used to obtain titles
and abstracts potentially relevant to the review. Studies
were screened based on titles and abstracts. All duplicates
were removed at this point and the full text of the articles
was obtained. The citations of these full text articles were
used to find additional studies which may have been
missed by the initial search.
Studies were included in analysis if they met all of
certain criteria, including 1) infertile men with at least a
unilateral varicocele who underwent varicocelectomy or
embolization, 2) the men were stratified by varicocele
grade and 3) the effects of varicocelectomy on fertility or
semen parameters were evaluated by grade. Studies were
excluded if they met any of certain criteria, including
1) they did not provide data stratified by individual grade
or a grouping of grades 2-3, excluding grade 1, 2) the
majority of the study population consisted of middle
and late adolescents, typically ages 15 to 21 years, or
3) fertility was not described by the pregnancy rate or at
least 1 standard semen analysis parameter. Studies were
excluded if varicocele repair was performed for indications
other than fertility purposes.
Data Extraction
Extracted data included baseline semen parameters
stratified by grade, posttreatment semen parameters
stratified by grade, pregnancy rates stratified by grade
and the surgical approach. Surgical approaches included
microsurgical (inguinal, subinguinal and Palomo) vs all
other varicocelectomy approaches (inguinal, subinguinal,
scrotal and Palomo). The first author, number of partici-
pants, study design, study participants and followup
duration were also extracted. Some studies referred to
grade 1, 2 and 3 varicoceles as small, medium and large,
 50 VARICOCELE GRADE AND SURGICAL MANAGEMENT
respectively. These studies described the classification
methodologies, which were identical or similar to the
varicocele grading system. Therefore, for the purpose of
this analysis small, medium and large varicoceles were
considered grade 1, 2 and 3, respectively.
The primary outcomes were associations of varicocele
grade with posttreatment improvement in semen param-
eters and the posttreatment pregnancy rate. Data were
collected from the study text and tables. Authors were not
contacted about missing data.
Quality Assessment
Nonrandomized studies were qualitatively assessed with
the NOS. The NOS evaluates 3 categories, including se-
lection, comparability and outcome, using a star system in
which yes answers to the scale criteria yield a star. Se-
lection, which has a maximum of 4 stars, is an evaluation
of how appropriate the study and control populations are
for evaluating the study hypothesis. Comparability with a
maximum of 2 stars evaluates the comparability of the
control and study groups. Outcome with a maximum of 3
stars assesses the time and methods of how outcomes
were gathered.13 A score of 7 or greater is considered to
indicate a high quality study.
Many studies examined different questions, including
other questions than in this systematic review. The 1
randomized control trial included in study was analyzed
with the 7-item Cochrane Collaboration tool to detect the
risk of bias.14
Data Synthesis
Attempts were made to perform a meta-analysis but the
heterogeneity of reported study populations was high,
limiting the statistical conclusions of a meta-analysis.
Due to the methodological and clinical heterogeneity of
the included studies a meta-analysis was inappropriate. A
narrative synthesis of the data was performed and ranges
are provided for data as applicable.
Semen quality and pregnancy outcomes were stratified
by grade for analysis. Because of different reporting
strategies in the included studies, we included a grade 2-3
cohort in addition to the grades 1, 2 and 3 cohorts. Patients
were grouped into the grade 2-3 cohort when it was not
possible to determine whether they had grade 2 or 3 vari-
cocele according to the relevant publication. The grade 2-3
cohort did not overlap with the grade 2 and 3 cohorts.
Posttreatment and pretreatment semen parameters
were compared. The mean differences in sperm concentration
and percent total motility were analyzed using a continuous
random effects model. Heterogeneity of results among studies
was analyzed using I2 statistics. Low, mid and high level
heterogeneity was considered I2 less than 25%, 25% to 75%
and greater than 75%, respectively.15 A meta-analysis was
performed using R (https://www.r-project.org/foundation/) to
create forest plots of each outcome. To evaluate publication
bias, we produced a funnel plot for each corresponding forest
plot. Additionally, we applied the Egger test to test the
asymmetry/bias of each funnel plot. Publication bias anal-
ysis was determined with R.
Changes in sperm morphology after treatment could
not be systematically analyzed due to high levels of vari-
ation in the classification systems used to report sperm
Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
morphology in the included studies and inconsistent
reporting of changes in sperm morphology after treatment.
RESULTS
Search Results
The initial database search identified 569 studies,
including 190 from MEDLINE, 245 from Embase
and 134 from PubMed. After screening and then
excluding duplicate studies 264 articles met the
criteria for further review. An additional 5 studies
were added after manually searching relevant ref-
erences. At that point 1 study was excluded because
an updated version had been published which
included many of the same patients from the prior
study. Therefore, 269 articles were assessed for
study eligibility, of which 247 were excluded after
reading the full text. The 20 studies which met the
criteria were included in the review (fig. 1).
Study Characteristics
The supplementary table (https://www.jurology.com)
shows characteristics of the included studies. All 20
studies were published, full text articles, 17 were
cohort studies evaluating semen parameters before
and after surgery and 3 compared pregnancy rates by
grade before and after surgery. The 20 selected
studies evaluated a total of 2,001 infertile men with
varicocele. Mean age of the pooled study populations
varied from 26.4 to 38 years (range 16 to 63). In 11
studies only the microsurgical approach (inguinal and
subinguinal) was used. The remaining 9 studies con-
sisted of various surgical approaches, including Pal-
omo (retroperitoneal), inguinal, subinguinal, scrotal
and embolization.
The supplementary table (https://www.jurology.com)
shows the post-procedure semen analysis time points
also obtained for each study. Postintervention followup
was most often done between 3 and 6 months but in 1
study followup ranged from 3 to about 77 months.
Quality Assessment
Nine of the 19 nonrandomized studies were high
quality and none had a score below 5 (see table).
Factors contributing most to poor quality assess-
ment were the lack of a good comparison cohort
(whether it was a nonsurgery group for pregnancy
data or a grade 1 vs 2/3 varicocele group) and
inadequate followup. One randomized study was at
high risk of performance and detection bias since
participants and personnel were not blinded. The
study was also at high risk for attrition bias in that
incomplete data were not disclosed. However, the
study was at low risk for reporting bias in that there
was no selective reporting. It had an uncertain risk
of selection bias in that it did not state how the
random sequence was generated or describe alloca-
tion concealment.
 VARICOCELE GRADE AND SURGICAL MANAGEMENT 51

Figure 1. Flowchart of screened, excluded and analyzed publications

Varicocele Grade Prevalence among Treated Men varicocele grade 1. The remaining 846 men (67.9%)
In the studies for this systematic review, which had grade 2 or 3 varicocele. As stated, studies were
included 1,299 men representing all 3 clinical varico- included if they provided data stratified by individual
cele grades, 417 (32.1%) were evaluated for clinical grade or a group of grades 2-3, excluding grade 1.

NOS quality assessment

Selection* Comparability† Outcome‡

1 2 3 4 5 6 7 8 9 Score
Baker et al: BMJ 1985; 291: 1678 Yes No Yes Yes Yes No Yes No No 5
Vermeulen et al: J Androl 1986; 7: 147 Yes No Yes Yes Yes Yes Yes Yes Yes 8
Steckel et al16 Yes Yes Yes Yes Yes No Yes Yes Yes 8
Scherr et al24 Yes No Yes Yes No No Yes No Yes 5
Jungwirth et al17 Yes Yes Yes Yes Yes No Yes Yes Yes 8
Onozawa et al18 Yes Yes Yes Yes Yes No No No Yes 6
Ishikawa and Fujisawa19 Yes No Yes Yes No No Yes Yes Yes 6
Ortapamuk et al20 No Yes Yes Yes Yes No Yes Yes Yes 7
Pasqualotto et al25 Yes No Yes Yes No No Yes Yes Yes 6
Mohamid21 Yes Yes Yes Yes Yes No Yes Yes No 7
Ozturk et al26 Yes Yes Yes Yes Yes No Yes Yes Yes 8
Tavalaee et al32 Yes No Yes Yes No No Yes No Yes 5
Leung et al27 Yes No Yes Yes No No Yes No Yes 5
Grasso et al30 Yes Yes Yes Yes Yes No Yes Yes Yes 8
Hosseinifar et al22 Yes No Yes Yes No No Yes Yes Yes 6
Lehtihet et al31 Yes No Yes Yes No No Yes No Yes 5
Guo et al29 Yes No Yes Yes No No Yes Yes Yes 6
Tavalaee et al28 Yes No Yes Yes No No Yes No No 7
Ni et al23 Yes Yes Yes Yes Yes No Yes Yes Yes 8

* Representation of exposed cohort (1), selection of nonexposed cohort (2), ascertainment of exposure (3) and demonstration that outcome of interest was not present at start of
study (4).
† Comparability of cohorts based on design or analysis (5, 6).
‡ Assessment of outcome (7), was followup long enough for outcomes to occur (8) and adequacy of followup cohorts (9).

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 52 VARICOCELE GRADE AND SURGICAL MANAGEMENT

Associations baseline motility of 30.8% (95% CI 13.37e48.17,

Varicocele Grade and Baseline Semen Parameters.
Baseline sperm concentration was directly related
to varicocele grade. Nine studies in a total of 294
men with grade 3 varicoceles showed a mean base-
line concentration of 32.79 million sperm per ml
(95% CI 15.75e49.83, I2 [ 73.7%).16e23 Seven
studies in a total of 381 men with grade 2-3 vari-
cocele showed a mean baseline of 20.3 million sperm
per ml (95% CI 7.18e33.34, I2 [ 30.8 %).21,24e29
Seven studies in a total of 213 men with grade 2
varicocele showed a mean baseline concentration
of 27.6 million sperm per ml (95% CI 10.52e44.73,
I2 [ 82.4%).16e21,23 Eight studies in a total of 211
men with grade 1 varicocele showed a mean baseline
of 30.1 million sperm per ml (95% CI 18.55e41.59,
I2 [ 85.6%)16e21,23,30 The generally high I2 values
further confirmed heterogeneity across all studies in
our analyses.
Mean baseline total motility was also directly
related to varicocele grade. Nine studies in a total of
156 men with grade 3 varicocele reported a mean
I2 [ 60.0%)16,19e23,31 Nine studies in a total of 445
men with grade 2/3 varicocele showed a mean base-
line motility of 29.4% (95% CI 19.33e39.39, I2 [
0%).21,24e29,32 Five studies in a total of 131 men with
grade 2 varicocele had a mean baseline of 33.5% (95%
CI 15.50e51.45, I2 [ 72.05 %).16,19e21,23,33 Seven
studies in a total of 101 men with grade 1 varicocele
showed a mean of 35.3% (95% CI 28.47e42.13, I2 [
0%).16,19e21,23,33 There was low heterogeneity among
patients with grade 1 and 2/3 varicoceles in terms of
baseline sperm motility. This had implications in the
observed outcomes of this parameter in the respective
groups.
Varicocele Grade and Improved Semen Quality after
Varicocelectomy. Systematic review demonstrated
statistically significant improvements in the mean
sperm concentration after varicocelectomy in men
with all grades of varicocele (fig. 2). The magnitude
of improvement was directly related to varicocele
grade. The mean improvement in the sperm

Figure 2. Forest plots of mean sperm concentration before vs after varicocelectomy in men with varicocele. A, grade 3.16-23 B, grade 2 or
3.12,24-29 b/l, bilateral varicocele group. Uni, unilateral varicocele group. MV, standard microsurgical varicocelectomy group. IVDU,
intraoperative Doppler group. C, grade 2.16,21,23 D, grade 1.16-21,23,30

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 VARICOCELE GRADE AND SURGICAL MANAGEMENT 53

concentration in men with grade 1, 2, 2-3 and 3
varicocele was 5.5, 8.9, 12.7 and 16.0 million sperm
per ml, respectively. High heterogeneity was
observed among studies included in sperm concen-
tration analyses for men with grade 1, 2 and 3
varicocele (I2[92.6%, 82.9% and 96.7%, respec-
tively). Mid level heterogeneity was observed among
included studies on sperm concentration analysis in
men with grade 2-3 varicoceles (I2[69.2%). The
Egger test performed for comparisons showed no
evidence of publication bias as no p value was sta-
tistically significant (fig. 2).
Systematic review also revealed statistically sig-
nificant improvement in the overall percent of
sperm motility after varicocelectomy in men with all
varicocele grades (fig. 3).34 The magnitude of
improvement was also directly related to varicocele
grade. Mean improvement in the percent of total
motility in men with grade 1, 2, 2-3 and 3 varicocele
was 9.6%, 10.6%, 10.8% and 17.7%, respectively.
High heterogeneity was observed among studies
included in sperm concentration analysis in men
with grade 1, 2-3 and 3 varicocele (I2[76.2%, 92.4%
and 96.0%, respectively). Mid level heterogeneity
was observed among included studies on sperm
concentration analysis in men with grade 2 varico-
cele (I2[71.4%).
Overall our findings showed some degree of
publication bias in 2 subgroup analyses. This bias
included a change in motility after varicocelectomy
of grade 1 varicocele (Egger p <0.001) and after vari-
cocelectomy in the grade 2 or 3 group (Egger p[0.048).
Improved Semen Quality after Varicocelectomy by
Surgical Approach. In 11 studies a microsurgical
approach (inguinal, subinguinal and Palomo) was
used for varicocele repair. The remaining 9 studies
described a combination of Palomo, inguinal, sub-
inguinal and scrotal approaches. Comparative sub-
analysis was done to assess differences in semen
concentration and overall sperm motility based on
surgical approach (microsurgical vs all others)
stratified by varicocele grade. There was no statis-
tically significant improvement in semen concen-
tration or overall sperm motility for any varicocele

Figure 3. Forest plots of mean percent total motility before vs after varicocelectomy in men with varicocele. A, grade 3.16,19-23,31,34
B, grade 2 or 3. b/l, bilateral varicocele group. Uni, unilateral varicocele group. MV, standard microsurgical varicocelectomy group.
IVDU, intraoperative Doppler group.21,24-29,32 C, grade 2.16,19-21,23 D, grade 1.16,19-21,23,34

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 54 VARICOCELE GRADE AND SURGICAL MANAGEMENT
grade when comparing a microsurgical approach to
all other approaches (Palomo, inguinal, subinguinal,
scrotal and embolization).
Varicocele Grade and Pregnancy Outcomes after
Varicocelectomy. There were insufficient pregnancy
data to stratify by grade for comparison in this
study.
DISCUSSION
The key findings of this study show improvement in
semen concentration and motility after varicocelec-
tomy with greater improvement in patients with
higher grade varicocele. This has major implications
for the management of infertility.
Despite some persistent controversy, the efficacy
of varicocelectomy as a treatment of varicocele
associated infertility is well established and sup-
ported by high quality clinical studies. Current AUA
and ASRM guidelines recommend treatment in
infertile men with a palpable varicocele, abnormal
semen analysis and a fertile partner.3e5,8 Nonethe-
less, many men who meet the recommended criteria
for varicocelectomy choose to defer treatment and
continue attempts at natural conception or pursue
reproduction via ART.
The underuse of varicocelectomy as a treatment
strategy is likely multifactorial. Some possible ex-
planations include a lack of knowledge among
reproductive endocrinologists and patients about the
demonstrated efficacy of varicocelectomy in properly
selected patients, financial incentives which may bias
reproductive endocrinologists toward performing ART
and reluctance of male patients to undergo what they
view as testicular surgery. In addition, the somewhat
unpredictable and quantitatively modest impact of
varicocelectomy on semen quality and the pregnancy
rate may also drive clinical care away from varicoce-
lectomy. This latter potential driver of the underuse of
varicocelectomy could be reduced by efforts to refine
patient selection to restrict treatment to those most
likely to derive substantive clinical benefit from
surgery.
Incorporating more specific clinical factors
beyond palpable varicocele and abnormal semen
parameters into shared decision making about
varicocelectomy has already begun. The most recent
guidelines of the ASRM have for the first time
qualified the treatment recommendation by sug-
gesting that men who meet criteria for treatment
but have isolated teratozoospermia may be less
likely to benefit from varicocelectomy than men
with oligozoospermia and/or asthenozoospermia.8
This qualifying amendment to the overall recom-
mendation is an acknowledgement of recent research
demonstrating a minimal morphology improvement
Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
after varicocelectomy in patients with isolated
teratozoospermia.35,36
There has been a recent focus in reproductive
medicine on the role of varicocele repair in the era of
ART and its significant clinical benefits in terms of
sperm parameters. Varicocele repairs may obviate
the need to proceed with IVF or other forms of ART.
In a retrospective review by Samplaski et al 373
men who underwent varicocele repair via a micro-
scopic subinguinal approach had statistically sig-
nificant improvement in the total motile sperm
count with the largest improvement in the lowest
baseline total motile sperm count group of less than
5 million.37 More notably, in that study almost 60%
of men who were initial IVF candidates were
upgraded to be candidates for natural conception or
intrauterine insemination. This has significant
psychosocial and financial implications, given the
emotional investment and direct cost of ART. In a
meta-analysis by Kirby et al varicocele repair was
associated with improved live birth and pregnancy
rates with IVF or intracytoplasmic sperm injection
in men with oligozoospermia or azoospermia.9
Furthermore, men with persistent azoospermia
after varicocele repair who required testicular
sperm extraction had an improved sperm retrieval
rate.
The current analysis was done to determine
whether varicocele grade could be incorporated into
shared decision making with patients considering
varicocelectomy. In particular, this analysis was
performed to further inform decision making in
patients with grade 1 varicocele, who comprise a
large subset of the population with varicocele.
Epidemiological data suggest that grade 1 varico-
cele accounts for 34.6% to 76.6% of varicoceles in
subfertile men.38-40 In this study patients with
grade 1 varicocele accounted for 33.9% of men who
underwent varicocele treatment.
Men with grade 1 varicocele may be at lower risk
for varicocele related testicular dysfunction than
men with larger varicoceles due to the less severe
physiological alterations which would be expected to
result from milder venous dilatation and congestion.
In some of these patients small varicoceles could be
incidental findings which occur in the setting of
infertility resulting from a different or an idiopathic
etiology. Recent data on a large, multinational,
population based study of semen quality in healthy
European men supports the notion that the testic-
ular injury resulting from varicocele does indeed
depend on varicocele grade.41 In that study the
proportion of men with low semen quality among
those with grade 1 varicocele did not differ from that
of men without varicocele (35.1% vs 31.4%). How-
ever, the proportion of men with grade 2 and 3
varicocele who had low semen quality was
 VARICOCELE GRADE AND SURGICAL MANAGEMENT 55

significantly higher than in men without varicocele
(40.4% and 54.9%, respectively vs 31.4%).
Our study is consistent with recently published,
population based data from Europe. It suggests that
men with larger varicoceles have a lower baseline
sperm concentration and a lower percent of overall
motility than men with smaller varicoceles. Addi-
tionally, our data demonstrate that the magnitude of
the treatment response to varicocelectomy is higher
among men with grade 2-3 than grade 1 varicocele.
There are several limitations to our analysis. The
first is that we found significant heterogeneity in
the systematic review with all forest plots revealing
an I2 of 69% or higher. However, it should be noted
that the I2 statistic was biased to provide exagger-
ated heterogeneity in our systematic review due to
the small number of studies included in each forest
plot and to the reporting style of the studies.42 The
studies provide a mean parameter before and after
surgery with the SD but not a SD on the mean
improvement itself. Therefore, we structured the
systematic review to analyze the mean before and
after surgery as if there were 2 independent groups.
Since the groups were not independent but rather
included the same patients, the variance was again
overestimated.
The retrospective nature of several of these studies
is also a limitation in this review. Another limitation
involves the subjectivity of varicocele grading and ac-
curacy among different physicians. A final limitation is
the limited number of randomized controlled trials.
Most varicocele studies have been self-controlled with
pre-intervention and postintervention parameters in
the same patient. Therefore, the dominance of cohort
study types could have limited significant findings.
Publication bias occurs when the outcome of a
research study influences the decision to publish
research findings. This can skew the available
original data to include only information with major
results and possibly eliminate null findings. Evalu-
ating for publication bias is important in the setting
of any literature review because generated conclu-
sions can be biased if the original literature is
contaminated by this bias. Overall our findings
showed some degree of publication bias on subgroup
analyses, including the change in motility after vari-
cocelectomy for grade 1 varicocele (Egger p <0.001)
and the change in motility after varicocelectomy in
the grade 2 or 3 group (Egger p[0.048). This lends
some confidence to the conclusions of our study.
Furthermore, many studies are outdated, small
and nonrandomized, and only 1 included study was
a randomized controlled trial. We could not include
data from the highest quality randomized, controlled
trial of varicocelectomy because that study did not
stratify the treatment response by varicocele grade.5
There was also significant heterogeneity in regard
to surgical approaches and techniques whether
the patient populations were restricted to unilat-
eral or bilateral varicocele and whether they were
screened for at least 1 abnormal semen analysis
parameter.
Despite the limitations of this study, to our
knowledge the current analysis is the largest one
reported to date in which the treatment response to
varicocelectomy stratified by varicocele grade was
evaluated. Our analyses offer definitive and robust
support that men with larger varicoceles benefit
more from treatment than men with smaller vari-
coceles. This has been posited for many years but it
has not been definitively demonstrated until now.
CONCLUSIONS
The improvement in semen quality which occurs
after varicocele treatment is directly related to
varicocele grade. Mean reported improvements in
sperm concentration and the percent of overall
motility after treatment of grade 1 varicocele are
statistically significant but small. In contrast, mean
reported improvements in the sperm concentration
and the percent of overall motility after treatment of
grade 2-3 varicocele are larger and highly likely to
be clinically significant. Incorporating varicocele
grade into shared decision making discussions with
affected couples may improve our ability to select
patients for varicocelectomy who are most likely to
benefit from surgery.

REFERENCES
1. Gorelick JI and Goldstein M: Loss of fertility in
men with varicocele. Fertil Steril 1993; 59: 613.
2. Witt MA and Lipshultz LI: Varicocele: a progressive
or static lesion? Urology 1993; 42: 541.
3. Kroese AC, de Lange NM, Collins J et al: Surgery
or embolization for varicoceles in subfertile men.
Cochrane Database Syst Rev 2012; 10: CD000479.
4. Marmar JL, Agarwal A, Prabakaran S et al:
Reassessing the value of varicocelectomy as a
treatment for male subfertility with a new meta-
analysis. Fertil Steril 2007; 88: 639.
5. Abdel-Meguid TA, Al-Sayyad A, Tayib A et al:
Does varicocele repair improve male infertility?
An evidence-based perspective from a random-
ized, controlled trial. Eur Urol 2011; 59: 455.
6. Bogaert G, Orye C and De Win G: Pubertal screening
and treatment for varicocele do not improve chance
of paternity as adult. J Urol 2013; 189: 2298.
7. Chu DI, Zderic SA, Shukla AR et al: The nat-
ural history of semen parameters in untreated
asymptomatic adolescent varicocele patients:
a retrospective cohort study. J Pediatr Urol
2017; 13: 77.
8. Report on varicocele and infertility: a committee
opinion. Practice Committee of the American
Society for Reproductive Medicine and Society
for Male Reproduction and Urology. Fertil Steril
2014; 102: 1556.

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 56 VARICOCELE GRADE AND SURGICAL MANAGEMENT
9. Kirby EW, Wiener LE, Rajanahally S et al: Un-
dergoing varicocele repair before assisted
reproduction improves pregnancy rate and live
birth rate in azoospermic and oligospermic men
with a varicocele: a systematic review and meta-
analysis. Fertil Steril 2016; 106: 1338.
10. Penson DF, Paltiel AD, Krumholz HM et al: The
cost-effectiveness of treatment for varicocele
related infertility. J Urol 2002; 168: 2490.
11. Dubin L and Amelar RD: Varicocele size and re-
sults of varicocelectomy in selected subfertile
men with varicocele. Fertil Steril 1970; 21: 606.
12. Panic N, Leoncini E, de Belvis G et al: Evaluation
of the endorsement of the Preferred Reporting
Items for Systematic Reviews and Meta-Analysis
(PRISMA) statement on the quality of published
systematic review and meta-analyses. PLoS One
2013; 8: e83138.
13. Stang A: Critical evaluation of the Newcastle-
Ottawa scale for the assessment of the quality
of nonrandomized studies in meta-analyses. Eur
J Epidemiol 2010; 25: 603.
14. Higgins JP, Altman DG, Gøtzsche PC et al: The
Cochrane Collaboration's tool for assessing risk
of bias in randomised trials. BMJ 2011; 343:
d5928.
15. Higgins JP, Thompson SG, Deeks JJ et al:
Measuring inconsistency in meta-analyses. BMJ
2003; 327: 557.
16. Steckel J, Dicker AP and Goldstein M: Rela-
tionship between varicocele size and response to
varicocelectomy. J Urol 1993; 149: 769.
17. Jungwirth A, G€og€us C, Hauser G et al: Clinical
outcome of microsurgical subinguinal varicoce-
lectomy in infertile men. Andrologia 2001; 33:
71.
18. Onozawa M, Endo F, Suetomi T et al: Clinical
study of varicocele: statistical analysis and the
results of long-term follow-up. Int J Urol 2002; 9:
455.
19. Ishikawa T and Fujisawa M: Effect of age and
grade on surgery for patients with varicocele.
Urology 2005; 65: 768.
20. Ortapamuk H, Tekdogan UY, Naldoken S et al:
Hemodynamic evaluation of varicocele: the role
of scrotal scintigraphy and Doppler ultrasonog-
raphy in the prediction of postoperative seminal
improvement. Ann Nucl Med 2005; 19: 529.
Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
21. Mohamid MA: The effect of magnified bilateral
varicocele ligation on semen quality and the
natural paternity rate in subfertile men, based on
the sum of varicocele grading. Arab J Urol 2012;
10: 434.
22. Hosseinifar H, Sabbaghian M, Nasrabadi D et al:
Study of the effect of varicocelectomy on sperm
proteins expression in patients with varicocele
and poor sperm quality by using two-dimensional
gel electrophoresis. J Assist Reprod Genet 2014;
31: 725.
23. Ni K, Steger K, Yang H et al: A comprehensive
investigation of sperm DNA damage and
oxidative stress injury in infertile patients with
subclinical, normozoospermic, and astheno/
oligozoospermic clinical varicocoele. Andrology
2016; 4: 816.
24. Scherr D and Goldstein M: Comparison of
bilateral versus unilateral varicocelectomy in
men with palpable bilateral varicoceles. J Urol
1999; 162: 85.
25. Pasqualotto FF, Lucon AM, de Goes PM et al: Is it
worthwhile to operate on subclinical right vari-
cocele in patients with grade II-III varicocele in
the left testicle? J Assist Reprod Genet 2005; 22:
227.
26. Ozturk U, Ozdemir E, Buyukkagnici U et al: Effect
of spermatic vein ligation on seminal total
antioxidant capacity in terms of varicocele
grading. Andrologia 2012; 44: 199.
27. Leung L, Ho KL, Tam PC et al: Subinguinal
microsurgical varicocelectomy for male factor
subfertility: ten-year experience. Hong Kong Med
J 2013; 19: 334.
28. Tavalaee M, Bahreinian M, Barekat F et al: Effect
of varicocelectomy on sperm functional charac-
teristics and DNA methylation. Andrologia 2015;
47: 904.
29. Guo L, Sun W, Shao G et al: Outcomes of
microscopic subinguinal varicocelectomy with
and without the assistance of Doppler ultra-
sound: a randomized clinical trial. Urology 2015;
86: 922.
30. Grasso M, Lania C, Castelli M et al: Low-grade
left varicocele in patients over 30 years old:
the effect of spermatic vein ligation on fertility.
BJU Int 2000; 85: 305.
31. Lehtihet M, Arver S, Kalin B et al: Left-sided
grade 3 varicocele may affect the biological
function of the epididymis. Scand J Urol 2014;
48: 284.
32. Tavalaee M, Abbasi H, Deemeh MR et al: Semen
parameters and chromatin packaging in micro-
surgical varicocelectomy patients. Int J Fertil
Steril 2012; 6: 165.
33. Takahara M, Ichikawa T, Shiseki Y et al: Rela-
tionship between grade of varicocele and the
response to varicocelectomy. Int J Urol 1996; 3:
282.
34. Tinga DJ, Jager S, Bruijnen CL et al: Factors
related to semen improvement and fertility after
varicocele operation. Fertil Steril 1984; 41: 404.
35. Okeke L, Ikuerowo O, Chiekwe I et al: Is vari-
cocelectomy indicated in subfertile men with
clinical varicoceles who have asthenospermia or
teratospermia and normal sperm density? Int J
Urol 2007; 14: 729.
36. Cakan M, Bakirtas H, Aldemir M et al: Results of
varicocelectomy in patients with isolated ter-
atozoospermia. Urol Int 2008; 80: 172.
37. Samplaski MK, Lo KC, Grober ED et al: Varico-
celectomy to “upgrade” semen quality to allow
couples to use less invasive forms of assisted
reproductive technology. Fertil Steril 2017; 108:
609.
38. The influence of varicocele on parameters of
fertility in a large group of men presenting to
infertility clinics. World Health Organization.
Fertil Steril 1992; 57: 1289.
39. Soylemez H, Atar M, Ali Sancaktutar A et al:
Varicocele among healthy young men in Turkey;
prevalence and relationship with body mass
index. Int Braz J Urol 2012; 38: 116.
40. Bozhedomov VA, Lipatova NA, Rokhlikov IM
et al: Male fertility and varicocoele: role of im-
mune factors. Andrology 2014; 2: 51.
41. Damsgaard J, Joensen UN, Carlsen E et al:
Varicocele is associated with impaired semen
quality and reproductive hormone levels: a study
of 7035 healthy young men from six European
countries. Eur Urol 2016; 70: 1019.
42. von Hippel PT: The heterogeneity statistic I2 can
be biased in small meta-analyses. BMC Med Res
Methodol 2015; 15: 35.