Surgery or embolization for varicoceles in subfertile men

(Review)

Kroese ACJ, de Lange NM, Collins J, Evers JLH

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 10
http://www.thecochranelibrary.com

Surgery or embolization for varicoceles in subfertile men (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 31
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Surgery or embolization for varicoceles in subfertile men (Review) i

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Surgery or embolization for varicoceles in subfertile men

Anja CJ Kroese1 , Natascha M de Lange2 , John Collins3 , Johannes LH Evers4

1
Maxima Medical Centre, Veldhoven, Netherlands. 2 Orbis Medical Centre, Sittard-Geleen, Netherlands. 3 Obstetrics and Gynaecology,
McMaster University, Mahone Bay, Canada. 4 Department of Obstetrics & Gynaecology, Centre for Reproductive Medicine and
Biology, Maastricht, Netherlands

Contact address: Johannes LH Evers, Department of Obstetrics & Gynaecology, Centre for Reproductive Medicine and Biology,
GROW, School for Oncology and Developmental Biology, Maastricht University Medical Centre P.O. Box 5800, Maastricht, 6202
AZ, Netherlands. jlh.evers@mumc.nl.

Editorial group: Cochrane Menstrual Disorders and Subfertility Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 10, 2012.
Review content assessed as up-to-date: 22 January 2012.

Citation: Kroese ACJ, de Lange NM, Collins J, Evers JLH. Surgery or embolization for varicoceles in subfertile men. Cochrane Database
of Systematic Reviews 2012, Issue 10. Art. No.: CD000479. DOI: 10.1002/14651858.CD000479.pub5.

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
A varicocele is a meshwork of distended blood vessels in the scrotum, usually left-sided, due to dilatation of the spermatic vein. Although
the concept that a varicocele causes male subfertility has been around for more than 50 years now, the mechanisms by which a varicocele
would affect fertility have not yet been satisfactorily explained. Neither is there sufficient evidence to explain the mechanisms by which
varicocelectomy would restore fertility. Furthermore, it has been questioned whether a causal relation exists at all between the distension
of the pampiniform plexus (a network of many small veins found in the human male spermatic cord) and impairment of fertility.
Objectives
To evaluate the effect of varicocele treatment on live birth and pregnancy rate in subfertile couples where the male has a varicocele.
Search methods
We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (12 September 2003 to January 2012), the
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library Issue 1, 2012), MEDLINE (January 1966 to
January 2012), EMBASE (January 1985 to January 2012), PsycINFO (to Week 1 2012) and reference lists of articles. In addition, we
handsearched specialist journals in the field from their first issue until 2012. We also checked cross-references, references from review
articles and contacted researchers in the field.
Selection criteria
Randomised controlled trials (RCTs) were included if they were relevant to the clinical question posed. If they reported pregnancy
rates or live birth rates as an outcome measure, and if they reported data in treated (surgical ligation or radiological embolization of
the internal spermatic vein) compared to untreated or placebo groups. Two authors independently screened potentially relevant trials.
Any differences of opinion were resolved by consensus (none occurred for this review).
Data collection and analysis
Ten studies met the inclusion criteria for the review. For one study we had only data from a published abstract. All ten studies only
included men from couples with subfertility problems; one excluded men with sperm counts less than 5 million per mL and one
excluded men with sperm counts less than 2 million per mL, with or without progressive motility of less than 10%. Two trials involving
Surgery or embolization for varicoceles in subfertile men (Review) 1
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
clinical varicoceles included some men with normal semen analysis. Three studies specifically addressed only men with subclinical
varicoceles. Studies were excluded from meta-analysis if they made comparisons other than those specified above.
Main results
The meta-analysis included 894 men. No studies reported live birth. The combined fixed-effect odds ratio (OR) of the 10 studies for
the outcome of pregnancy was 1.47 (95% confidence interval (CI) 1.05 to 2.05, very low quality evidence), favouring the intervention.
The number needed to treat for an additional beneficial outcome was 17, suggesting benefit of varicocele treatment over expectant
management for pregnancy rate in subfertile couples in whom varicocele in the man was the only abnormal finding. Omission of the
studies including men with normal semen analysis and subclinical varicocele, some of which had semen analysis improvement as the
primary outcome rather than live birth or pregnancy rate, was the subject of a planned subgroup analysis. The outcome of the subgroup
analysis (five studies) also favoured treatment, with a combined OR 2.39 (95% CI 1.56 to 3.66). The number needed to treat for an
additional beneficial outcome was 7. The evidence was suggestive rather than conclusive, as the main analysis was subject to fairly high
statistical heterogeneity (I2 = 67%) and findings were no longer significant when a random-effects model was used or when analysis
was restricted to higher quality studies.
Authors’ conclusions
There is evidence suggesting that treatment of a varicocele in men from couples with otherwise unexplained subfertility may improve a
couple’s chance of pregnancy. However, findings are inconclusive as the quality of the available evidence is very low and more research
is needed with live birth or pregnancy rate as the primary outcome.

PLAIN LANGUAGE SUMMARY

Surgery or embolization for varicoceles in subfertile men
Varicocele is a dilatation (enlargement) of the veins along the spermatic cord (the cord suspending the testis) in the scrotum. Dilatation
occurs when valves within the veins along the spermatic cord fail and allow retrograde blood flow, causing a backup of blood. The
mechanisms by which varicocele might affect fertility have not yet been explained, and neither have the mechanisms by which surgical
treatment of the varicocele might restore fertility. This review analysed 10 studies (894 participants) and found evidence (combined
odds ratio was 1.47 (95% CI 1.05 to 2.05) to suggest an increase in pregnancy rates after varicocele treatment compared to no treatment
in subfertile couples, in whom, apart from poor sperm quality, varicocele in the man was the only abnormal finding. This means that 17
men would need to be treated to achieve one additional pregnancy. However, findings were inconclusive as the quality of the available
evidence was very low and more research is needed with live birth or pregnancy rate as the primary outcome.

Surgery or embolization for varicoceles in subfertile men (Review) 2

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Surgery or embolization for varicoceles in subfertile men (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Varicocele occlusion versus no treatment for varicoceles in subfertile men

Patient or population: Patients with varicoceles in subfertile men

Settings:
Intervention: Varicocele occlusion versus no treatment

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Control Varicocele occlusion

versus no treatment

Pregnancy rate 173 per 1000 235 per 1000 OR 1.47 894 ⊕
(180 to 300) (1.05 to 2.05) (10 studies) very low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 All of the trials were open label due to very different interventions but there is no evidence that an attempt was made to blind outcome
assessors. There were insufficient details provided for allocation concealment, randomisation and selective reporting in almost all of
the trials.
2
I2 statistic was 67%
3
BACKGROUND internal spermatic vein with sclerosing solutions (sclerosation),
tissue adhesives, or detachable balloons or coils have been used as
alternatives. Laparoscopic ligation has also been proposed (Cayan
2009).
Description of the condition
A varicocele is a meshwork of distended blood vessels in the scro-
tum, usually left-sided, due to dilatation of the spermatic vein. How the intervention might work
There are different grades of varicocele as defined by the World
Health Organization (WHO): WHO 0: only demonstrable by The mechanisms by which a varicocele might affect fertility have
technical diagnostic methods; WHO I: only palpable/visible dur- not yet been explained, and neither have the mechanisms by which
ing Valsalva manoeuvre; WHO II: palpable when in upright po- surgical treatment of the varicocele might restore fertility. Im-
sition at room temperature; WHO III: visible when in upright paired blood drainage from the testis leading to increased scro-
position at room temperature. It has long been uncertain whether tal temperature, hypoxia, increased testicular pressure and reflux
it is true or not that a varicocele is “nature’s attempt to heal a dis- of adrenal metabolites and hormones, with deleterious effects on
eased testis rather than afflict an otherwise healthy one” (Nieschlag spermatogenesis have been proposed as the etiology (Dubin 1975;
1995/1998). Although the concept that a varicocele causes male Homonnai 1980; Pryor 1987; Segenreich 1986).
subfertility has been around for more than fifty years now, the
mechanisms by which varicoceles would affect fertility have not yet
been satisfactorily explained. Neither is there sufficient evidence to Why it is important to do this review
explain the mechanisms by which varicocelectomy might restore
Many men with varicocele have normal fertility and investiga-
fertility. Furthermore, it has been questioned whether a causal re-
tors have doubted the therapeutic value of treatment of varicocele
lationship exists at all between the distension of the pampiniform
(Rodriquez 1978; Vermeulen 1985). A review of 50 publications
plexus (a network of many small veins found in the human male
of observational studies including a total of 5471 couples with un-
spermatic cord) and impairment of fertility.
compromised female fertility and a varicocele in the man showed
In a multi-centre study on the investigation and diagnosis of the
widely varying pregnancy rates of 0% to 50% after treatment, with
subfertile couple, the incidence of varicocele in the male partners
a weighted mean of 36% (Mordel 1990). This is similar to the
of subfertile couples was 11.7%. On the other hand, in men with
33% spontaneous pregnancy rate in a 1992 review of 20 studies
abnormal semen analysis (SA) parameters the incidence of varic-
of 2026 couples with completely unexplained subfertility (Taylor
ocele was 25.4% (WHO 1992). Thus, varicocele is the most fre-
1992). Conclusions regarding the true effect of varicocelectomy on
quent single physical abnormality found in subfertile men and oc-
pregnancy rate can only be derived from prospective studies with
clusion of the left spermatic vein is accepted by many physicians as
an unbiased control group: randomised controlled trials (RCTs).
the treatment of choice for this condition (Nieschlag 1993). Esti-
mates of the incidence of varicocele in men from the general popu-
lation, however, arrive at a similar figure (15%) (ASRM 2008). Yet
varicocele for many years has been associated with abnormalities
in semen parameters and implicated as a cause of male subfertil- OBJECTIVES
ity (Dubin 1977). Impaired blood drainage from the testis lead- To evaluate the effect of varicocele treatment on live birth and
ing to increased scrotal temperature, hypoxia, increased testicular pregnancy rate in subfertile couples where the male has a varico-
pressure and reflux of adrenal metabolites and hormones, with cele.
deleterious effects on spermatogenesis have been proposed as the
etiology (Dubin 1975; Homonnai 1980; Pryor 1987; Segenreich
1986).
METHODS

Description of the intervention Criteria for considering studies for this review
Varicocelectomy is the surgical correction of a varicocele. There
are various methods, the traditional method of treatment being
surgical ligation of the internal spermatic vein. Several surgical Types of studies
techniques have been employed but retroperitoneal high ligation Published and unpublished randomised controlled trials were el-
(as initially described by Ivanissevitch and modified by Palomo) igible for inclusion. We excluded non-randomised trials as they
and trans inguinal ligation (as described by Bernardi) are the most are associated with a high risk of bias. Trials were eligible if they
frequently performed. More recently, selective embolization of the dealt with the treatment of varicocele in subfertile couples and

Surgery or embolization for varicoceles in subfertile men (Review) 4

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
contained a control group (no treatment) or placebo group and see the appendices Appendix 1; Appendix 2; Appendix 3; Ap-
had the outcome pregnancy rate or live birth rate. pendix 4; Appendix 5.

Types of participants Searching other resources

Men with a varicocele (any grade) and normal or abnormal se- We handsearched reference lists of articles retrieved by the search
men analysis, who were part of a couple with otherwise unex- and contacted experts in the field to obtain additional data. We
plained subfertility. We recorded the grades of varicocele accord- also handsearched any relevant journals and conference abstracts
ing to WHO criteria (WHO 0: only demonstrable by technical that were not covered in the MDSG register, in liaison with the
diagnostic methods; WHO I: only palpable/visible during Val- Trials Search Coordinator.
salva manoeuvre; WHO II: palpable when in upright position at
room temperature; WHO III: visible when in upright position at
room temperature). The clinical findings were confirmed by one Data collection and analysis
of the technical diagnostic methods (such as Doppler ultrasound,
phlebography, radioactive scanning or thermography).

Selection of studies
Types of interventions
Two review authors (JE and JC) independently scanned the ti-
Surgical ligation or embolization versus no treatment or delayed tles and abstracts of articles retrieved by the search and obtained
treatment or placebo. the full text of all potentially eligible studies for the 2009 review.
They independently examined the full text articles for compliance
Types of outcome measures with the inclusion criteria and selected studies for inclusion in the
previous reviews. Two other authors (AK and NL) updated the
search for this review in the same way; corresponding with study
Primary outcomes investigators, as required, to clarify study eligibility (e.g. with re-
1. Live birth. spect to participant eligibility criteria and allocation method), and
2. Pregnancy rate. resolving disagreements by consensus or by discussion with a third
author (JE).

Secondary outcomes
Data extraction and management
Adverse events: complications due to varicocelectomy.
Two review authors (AK and NL) independently extracted data
Semen quality was specified in the original review as a secondary
from eligible studies using a data extraction form designed and
outcome, but later seemed irrelevant in the presence of more clini-
pilot-tested by the authors. Any disagreements were resolved by
cally meaningful outcomes, and, therefore, was omitted when up-
consensus or by discussion with a third author (JE). Data extracted
dating this review.
included study characteristics and outcome data (Characteristics
of included studies): method of randomisation; number of men
randomised, excluded and analysed; whether they were single cen-
Search methods for identification of studies tre or multi-centre studies; employed parallel or cross-over design;
We searched for all published and unpublished RCTs, without nature of interventions; the participants (age range, eligibility cri-
language restriction, and in consultation with the Cochrane Men- teria). We listed details of duration of subfertility, method of in-
strual Disorders and Subfertility Group (MDSG) Trials Search vestigation of the varicocele, sperm analysis and previous treat-
Coordinator. ment(s) whenever given; blinding of treatment (virtually impossi-
ble in studies involving surgery); the use of sequential analysis or
factorial design; the performance of a power calculation; duration
Electronic searches of follow-up; whether pregnancy was an outcome measure and, if
We searched the following electronic databases, trial registers and so, how it was diagnosed; how pregnancy results were presented
web sites: the Cochrane Menstrual Disorders and Subfertility (particularly whether cumulative conception curves with the use of
Group Trials Register (from 12 September 2003 to January 2012), life table analysis were employed); and the source of any funding.
the Cochrane Central Register of Controlled Trials (CENTRAL, We recorded the grades of varicoceles according to WHO criteria
The Cochrane Library Issue 1, 2012), MEDLINE (January 1966 (WHO 0: only demonstrable by technical diagnostic methods;
to January 2012), EMBASE (January 1985 to January 2012), WHO I: only palpable/visible during Valsalva manoeuvre; WHO
PsycINFO (to Week 1 2012) and reference lists of articles. Please II: palpable when in upright position at room temperature; WHO

Surgery or embolization for varicoceles in subfertile men (Review) 5

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
III: visible when in upright position at room temperature). For Assessment of heterogeneity
females we recorded age and factors of female infertility (when ap- We examined heterogeneity (variations) between the results of
plicable). Where studies had multiple publications, the main trial different studies by inspecting the scatter in the data points on
report was used as the reference and additional details were derived the graphs and the overlap in their confidence intervals and, more
from secondary papers. We corresponded with study investigators formally, by checking the results of the Chi2 tests.
for further data on methods and/or results, as required.
In the preparation of the previous review additional information
was obtained from Dr Nieschlag on the randomisation procedure Assessment of reporting biases
in his study. In view of the difficulty of detecting and correcting for publica-
tion bias and other reporting biases, we aimed to minimise their
potential impact by ensuring a comprehensive search for eligible
Assessment of risk of bias in included studies studies and by being alert for duplication of data. There is always
the risk of publication bias; however, to our knowledge there are
Two review authors (AK and NL) independently assessed the in-
no ongoing trials except the trial included by Dohle (Dohle 2010).
cluded studies for risk of bias using the Cochrane risk of bias as-
If there were 10 or more studies in a primary analysis, we planned
sessment tool (www.cochrane-handbook.org) for: allocation (ran-
to produce a funnel plot to explore the possibility of small study
dom sequence generation and allocation concealment); blinding
effects (a tendency for estimates of the intervention effect to be
of participants and personnel, blinding of outcome assessors; in-
more beneficial in smaller studies).
complete outcome data; selective reporting; and other bias. Dis-
agreements were resolved by discussion or by a third review author
(JE). We have described all judgements fully and presented the Data synthesis
conclusions in the Risk of Bias table, which has been incorporated Where the studies were sufficiently similar, we planned to combine
into the interpretation of review findings by means of sensitivity the data using fixed-effect models in the following comparison:
analyses (see below). varicocelectomy versus no treatment, not further stratified.
In the meta-analysis graphs, an increase in the odds of a particu-
lar outcome, which may have been beneficial (e.g. pregnancy/live
Measures of treatment effect birth) or detrimental (e.g. adverse events), was displayed to the
For dichotomous data, we used the numbers of events in the con- right of the centre line and a decrease in the odds of an outcome
trol and intervention groups of each study to calculate the Mantel- to the left of the centre line.
Haenszel odds ratios (ORs). We presented 95% confidence inter-
vals (CI) for all outcomes. If data to calculate ORs were not avail- Subgroup analysis and investigation of heterogeneity
able, we utilised the most detailed numerical data available that
Where data were available, we conducted a subgroup analysis with
facilitated similar analysis of included studies (e.g. test statistics,
more strictly defined inclusion criteria: studies that included men
P values). We compared the magnitude and direction of effect
with abnormal semen, clinical varicocele and studies that reported
reported by studies with how they were presented in the review,
live birth/pregnancy as a primary outcome.
taking account of legitimate differences.
If we detected substantial heterogeneity, we planned to explore
possible explanations via sensitivity analyses. We planned to take
any statistical heterogeneity into account when interpreting the
Unit of analysis issues results, especially if there was any variation in the direction of
The primary analysis was per man (from a couple) randomised. effect.
Multiple live births/pregnancies were counted as one live birth/
pregnancy. Sensitivity analysis
We planned to conduct sensitivity analyses for the primary out-
comes to determine whether the conclusions were robust to arbi-
Dealing with missing data
trary decisions made regarding the eligibility and analysis. These
The data were analysed on an intention-to-treat basis as far as analyses included consideration of whether the review conclusions
possible and attempts were made to obtain missing data from the would have differed if:
original investigators. Pregnancy was assumed not to have occurred 1. eligibility was restricted to studies without high risk of bias;
in couples without a reported outcome or couples who were lost 2. a random-effects model had been adopted;
to follow-up. For other outcomes, only the available data were 3. the summary effect measure was relative risk rather than odds
analysed. No imputation was undertaken. ratio.

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Overall quality of the body of evidence: Summary of varicocele only (Grasso 2000; Unal 2001; Yamamoto 1996). One
Findings Table study (Breznik 1993) included clinical as well as subclinical varic-
A Summary of Findings Table was generated using GRADEPRO ocele. Four studies excluded azoospermia (Abdel-Meguid 2011;
software. This table evaluated the overall quality of the body of ev- Dohle 2010; Krause 2002; Nilsson 1979). The mean of men age
idence for the main review outcome, using GRADE criteria (study was 28.4 to 38 years (range 21 to 52 years). Nine studies included
limitations (i.e. risk of bias), consistency of effect, imprecision, only couples with infertility persisting longer than one year. The
indirectness and publication bias). duration of infertility was not mentioned in one study (Breznik
1993). Seven studies mentioned no obvious causes of female in-
fertility, one included also couples with treatable female infertil-
ity (Krause 2002). Two studies did not mention female infertility
(Grasso 2000; Unal 2001).
Interventions
RESULTS
One of 10 studies compared embolization/surgical repair versus
no treatment (Breznik 1993).
Two of 10 studies compared embolization versus no treatment
Description of studies (Krause 2002) or counselling only (Nieschlag 1995/1998).
See: Characteristics of included studies; Characteristics of excluded One of 10 studies compared surgical repair (ligation) versus
studies. clomiphene citrate (Unal 2001).
Six of 10 studies compared surgical repair (ligation) versus no treat-
ment, and one compared surgical repair versus delayed treatment
Results of the search (Madgar 1995).
In previous versions of this review the search strategy had identified Studies comparing treatment with counselling only were in-
25 studies. Sixteen studies were excluded. Nine studies met the cluded and the outcome of the counselling-only group (Nieschlag
inclusion criteria. One study was an extension of a previously 1995/1998) was considered together with those of the no-treat-
published study. Therefore, eight studies were left. A further six ment groups from other trials. The study that compared varico-
studies were identified for the update of the review in 2012 (Abdel- cele treatment with clomiphene citrate (Unal 2001) was included
Meguid 2011; Al-Kandari 2007; Al-Said 2008; Dohle 2010; Fayez since for this indication clomiphene citrate was judged no more
2010; Zheng 2009). Four studies were excluded. A total of 10 effective than vitamin C (Abel 1982). In this study (Unal 2001),
studies (11 publications) were included for this update with a total the control group pregnancy rate was the lowest of all trials.
of 894 men retained. Outcomes
No studies reported live birth.
Included studies Five of 10 studies reported pregnancy rate as primary outcome
(Abdel-Meguid 2011; Breznik 1993; Dohle 2010; Madgar 1995;
Study design and setting
Nieschlag 1995/1998).
Ten studies (11 publications) were included in the review. One
Three of 10 studies reported pregnancy rate as secondary outcome
study (Nieschlag 1995/1998) was an extension of a previously
(Nilsson 1979; Unal 2001; Yamamoto 1996).
published study (Nieschlag 1995). All studies were randomised
One of 10 studies reported conception rate as primary outcome
controlled trials (RCTs). Seven (Abdel-Meguid 2011; Breznik
(Krause 2002).
1993; Dohle 2010; Madgar 1995; Nieschlag 1995/1998; Nilsson
One of 10 studies reported paternity as secondary outcome (Grasso
1979; Unal 2001) were single centre studies. One (Krause 2002)
2000).
was a multi-centre study. For two studies (Grasso 2000; Yamamoto
1996) it was unclear whether they were single centre or multi-
centre studies.
Excluded studies
Participants
Ten studies included 449 men with varicocele in the intervention Sixteen studies were excluded in previous reviews with a further
groups and 445 men with varicocele in the control groups. All four excluded in the present update. The predominant reason for
men were from couples with otherwise unexplained subfertility. exclusion was their comparing two or more technical procedures
Two studies of men with clinical varicocele also included normo- (different types of surgery and embolization) without the inclusion
spermic varicocele patients (Breznik 1993; Nilsson 1979). One of an untreated comparison group.
study excluded men with sperm counts of less than 5 million per
mL (Madgar 1995) and one study (Krause 2002) excluded men
with less than 2 million per mL, with or without less than 10%
progressive motility. Three studies included men with subclinical
Risk of bias in included studies

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
See additional table and figures ’Risk of bias of studies’ (Figure 1;
Figure 2). One trial (Madgar 1995) used a randomised postpone-
ment-of-treatment design, and only data from the period before
treatment in the controls have been included in the present review.
Only the corresponding data (from the first 12 months following
varicocelectomy) have been used for the immediate intervention
group of this study.

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.

Surgery or embolization for varicoceles in subfertile men (Review) 9

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 2. Methodological quality graph: review authors’ judgements about each methodological quality
item presented as percentages across all included studies.

Allocation
The number of drop-outs after randomisation and the losses to
Overall, although the included studies all contained a statement follow up were considerable (1.3% to 54%) in six of 10 studies
about random allocation, these were not high quality studies. Their (Abdel-Meguid 2011; Breznik 1993; Dohle 2010; Krause 2002;
poor methodological quality and their clinical and statistical het- Nieschlag 1995/1998; Yamamoto 1996), and went unmentioned
erogeneity should be taken into account. Three out of 10 stud- in four of 10 studies (Grasso 2000; Madgar 1995; Nilsson 1979;
ies (Abdel-Meguid 2011; Krause 2002; Nieschlag 1995/1998) de- Unal 2001).These studies were considered to be at high risk of
scribed a strategy for concealment of the allocation sequence. Two attrition bias.
out of 10 studies (Abdel-Meguid 2011; Krause 2002) included a
power calculation in the Methods section. Four out of 10 studies
used computer randomisation (Abdel-Meguid 2011; Dohle 2010; Selective reporting
Krause 2002; Nieschlag 1995/1998) and were at low risk of se- For infertility interventions, live birth and the surrogates preg-
lection bias. Six out of 10 studies did not state randomisation nancy rate and clinical pregnancy rate are by far the most impor-
(Breznik 1993; Grasso 2000; Madgar 1995; Nilsson 1979; Unal tant outcomes and no other outcomes were consistently reported.
2001; Yamamoto 1996). These studies were at unclear risk of se-
lection bias.
Other potential sources of bias

Blinding Five out of 10 studies reported no baseline differences (Abdel-

Meguid 2011; Dohle 2010; Krause 2002; Madgar 1995; Nieschlag
Ten out of 10 studies were partly surgical, none was (single or 1995/1998), one of the 10 studies reported no difference in
double) blinded. Blinding is virtually impossible in surgical trials, baseline age (Unal 2001), four out of 10 studies did not report
unless sham surgery is performed. Blinding is not likely to make if there were baseline differences (Breznik 1993; Grasso 2000;
a difference to the outcomes (pregnancy and live birth rate). All Nilsson 1979; Yamamoto 1996). These studies were at unclear
studies were at unclear risk of bias. risk of bias. The period of untreated follow-up was 12 to 40
months in one study (Unal 2001), 12 months in seven studies
(Abdel-Meguid 2011; Grasso 2000; Krause 2002; Madgar 1995;
Incomplete outcome data
Nieschlag 1995/1998; Yamamoto 1996) and > 36 months in the
Surgery or embolization for varicoceles in subfertile men (Review) 10
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
other two (Breznik 1993; Nilsson 1979). Studies with an untreated 1. Live birth
follow-up duration of more than 12 months can report unjustifi-
ably higher pregnancy rates, which is also a source of bias. Three of No studies reported the outcome live birth rate.
the 10 studies (Krause 2002; Madgar 1995; Nieschlag 1995/1998)
did not offer or allow for an intention-to-treat analysis. One of the
10 studies (Dohle 2010) performed an intention-to-treat analysis,
five of the 10 studies (Breznik 1993; Grasso 2000; Nilsson 1979; 2. Pregnancy
Unal 2001; Yamamoto 1996) did not describe their analysis in
sufficient detail to estimate the role of attrition. The OR comparing treatment (intervention) to no treatment (or
counselling/clomiphene citrate) for pregnancy rate was 1.47 (95%
CI 1.05 to 2.05, P = 0.03, 894 men, 181 pregnancies, I2 = 67%)
Effects of interventions
(Figure 3) which suggests a statistically significant benefit for treat-
See: Summary of findings for the main comparison Varicocele ment. The number needed to treat to benefit was 17. However,
occlusion versus no treatment for varicoceles in subfertile men the overall quality of the evidence was rated as very low (Summary
of findings for the main comparison) and there was substantial
heterogeneity (I2 = 67%). A funnel plot for this outcome was not
Primary outcomes
suggestive of publication bias (Figure 4).

Figure 3. Forest plot of comparison: 1 Varicocele occlusion versus no treatment, outcome: 1.1 Pregnancy
rate.

Surgery or embolization for varicoceles in subfertile men (Review) 11

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 4. Funnel plot of comparison: 1 Varicocele occlusion versus no treatment, outcome: 1.1 Pregnancy
rate.

The subgroup analysis consisted of five trials, which were re-

stricted to men with clinical varicoceles, an abnormal semen analy-
sis (azoospermia excluded) and pregnancy rate as the primary out-
come (Abdel-Meguid 2011; Dohle 2010; Krause 2002; Madgar
1995; Nieschlag 1995/1998). In the results of the subgroup anal-
ysis, the OR comparing treatment to no treatment was 2.39 (95%
CI 1.56 to 3.66, P = 0.03, 505 men, 121 pregnancies, I2 = 64%)
(Figure 5) which also significantly favoured treatment. The num-
ber needed to treat to benefit was 7. Excluding unpublished data
(Dohle 2010) the combined OR favouring treatment was 2.11
(95% CI 1.13 to 3.38), number needed to treat was 8.

Surgery or embolization for varicoceles in subfertile men (Review) 12

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 5. Forest plot of comparison: 2 Varicocele occlusion versus no treatment in men with abnormal
semen analysis, clinical varicocele and primary outcome pregnancy rate, outcome: 2.1 Pregnancy rate.

involved men with normal semen analysis (and azoospermia) and

Sensitivity analyses
subclinical varicocele, some of which had semen analysis improve-
1. When analysis was restricted to studies that reported ac- ment as the primary outcome rather than pregnancy rate (Breznik
ceptable methods of randomisation and allocation concealment 1993; Grasso 2000; Nilsson 1979; Unal 2001; Yamamoto 1996),
(Abdel-Meguid 2011; Krause 2002; Nieschlag 1995/1998) there and performed a subgroup analysis. So the subgroup consisted of
was no significant difference between the groups, though the lower five trials, which were restricted to men with clinical varicocele,
confidence interval was 1.00 (OR 1.67, 95% CI 1.00 to 2.78, P an abnormal semen analysis and pregnancy rate as the primary
= 0.05, 342 men, 79 pregnancies, I2 = 48%). outcome. This subgroup analysis also favoured treatment over no
2. When a random-effects model was used there was no significant treatment, with a combined OR of 2.39 (95% CI 1.56 to 3.66).
difference between the groups, though heterogeneity remained Statistical heterogeneity was fairly high for the primary analysis
substantial (OR 1.38, 95% CI 0.70 to 2.71, P = 0.36, I2 = 67%). (67%). Moreover, findings were sensitive to the choice of statisti-
3. When risk ratio rather than odds ratio was reported, the statis- cal model and a random-effects model found no significant differ-
tical significance of the findings did not change (RR 1.34, 95% ence between the groups. Restriction to higher quality studies also
CI 1.03 to 1.74, P = 0.03). found no significant difference between the groups, though this
analysis included only 79 men and results bordered on statistical
Secondary outcomes significance.
The present review suggests a benefit from treatment of varicocele
for subclinical and clinical varicocele in subfertile men with nor-
Adverse events mal and abnormal semen analysis and with otherwise unexplained
subfertility. However, our findings are not conclusive as the overall
One study included the outcome adverse events (Abdel-Meguid
quality of the evidence was very low.
2011). No events were reported.

DISCUSSION Overall completeness and applicability of

evidence
Summary of main results No studies reported live birth, but the included studies did report
The findings of the original review (2009) failed to offer evidence pregnancy rates. There was discussion in the review team about the
that treatment of a varicocele in men from couples with otherwise applicability of studies which included men with normal semen
unexplained subfertility improves the chance of spontaneous preg- analysis and subclinical varicocele and a primary outcome other
nancy. The findings of this updated review, supplemented by two than live birth or pregnancy. For this reason we performed a sub-
studies (Abdel-Meguid 2011; Dohle 2010) suggest that pregnancy group analysis of studies which were restricted to men with clinical
rates may improve after treatment of varicocele. The combined varicoceles, an abnormal semen analysis (azoospermia excluded)
OR of the 10 studies was 1.47 (95% CI 1.05 to 2.05, P < 0.03), and pregnancy rate as the primary outcome. This subgroup anal-
favouring treatment over no treatment. We excluded studies which ysis agreed with the findings of the main analysis.

Surgery or embolization for varicoceles in subfertile men (Review) 13

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Quality of the evidence Marmar 2007), the present updated review suggests that there
might be some value in varicocelectomy in selected patients.
The clinical and statistical heterogeneity of the studies and the
small numbers should be taken into account, and the overall qual-
ity of the evidence was rated as very low (Summary of findings
for the main comparison). Moreover, our findings were sensitive
to choice of statistical model, and were only of borderline signifi- AUTHORS’ CONCLUSIONS
cance when analysis was restricted to higher quality studies. This
suggests that the benefit found for treatment of varicocele should Implications for practice
be interpreted very cautiously. A funnel plot for the outcome of
Surgical or radiological treatment of varicocele in subfertile men
pregnancy rate (Figure 4) was not suggestive of publication bias.
with clinical varicocele and abnormal semen analysis may be of
benefit, but the evidence is not conclusive. The value of surgical or
radiological treatment in subfertile men with subclinical varicocele
Potential biases in the review process and normal semen analysis is disputable, as the number needed to
treat to benefit was 17.
The decision to include studies which included normozoospermic
men from infertile couples (Breznik 1993; Nilsson 1979; Unal
2001; Yamamoto 1996) was disputable, but was based on their ap-
Implications for research
parently representing a category of patients for whom varicocelec- The ideal trial design would be to compare, in a randomised fash-
tomy is deemed appropriate. Given their allocation by randomisa- ion, a sham operation with the actual procedure; any other design
tion these men were evenly distributed between the experimental is potentially biased by the placebo effect of having had the op-
group and the controls. Also, the decision to include studies which eration performed; and surgery is a strong placebo indeed. How-
accepted men with subclinical varicocele (Breznik 1993; Grasso ever, for such a trial design it would be difficult to obtain ethical
2000; Nilsson 1979; Unal 2001; Yamamoto 1996) is disputable. committee approval since it would put the control group at risk of
The Americal Urology Association (AUA) and the American Soci- surgical and anaesthetic complications without any possibility of
ety for Reproductive Medicine (ASRM) state that normospermia benefit (Hargreave 1997). Since all studies included in the present
and subclinical varicocele are no indication for surgical treatment. review essentially considered invasive treatment, in none had the
A literature search regarding the relationship between grade of investigator, patient, or assessor been blinded to the procedure per-
varicocele and the response to varicocelectomy showed different formed. However, the outcome measures of this review, live birth
outcomes, ranging from no improvement of semen analysis af- and pregnancy rate, were unambiguous. Therefore, apart from the
ter treatment of subclinical varicocele to significant improvement. placebo effect, no other negative factors of the lack of blinding
However, live birth or pregnancy rate were not outcomes in these were presumed to affect the conclusions drawn.
studies. This was a reason to perform a subgroup analysis with the
The studies included in the present review of varicocele treatment
exclusion of these studies (Breznik 1993; Grasso 2000; Nilsson
are heterogeneous. This indicates a need for a large, properly con-
1979; Unal 2001; Yamamoto 1996).
ducted RCT of varicocele treatment in men with varicocele and
We included two studies (Nieschlag 1995/1998; Unal 2001) com-
sperm defects, from couples with otherwise unexplained subfertil-
paring clomiphene citrate and counselling (respectively) to treat-
ity. The authors realise, however, that it will become increasingly
ment, since for the sake of this review both interventions may be
difficult to conduct such a study, since the introduction of in vitro
regarded as ‘placebo’ compared to surgery or embolization. The
fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) in
OR comparing counselling only or clomiphene citrate to no treat-
the fertility clinic will make many men reluctant to take the risk of
ment for pregnancy rate was 1.27 (95% CI 0.70 to 2.32, P = 0.43,
being allocated to the no-treatment arm of such a study, when at
445 men, 77 pregnancies), which was not significant.
the same time a robust treatment of proven effectiveness is read-
ily available in the form of IVF/ICSI. The issue will be further
compounded by the fact that many couples tend to delay their
Agreements and disagreements with other first pregnancy nowadays, and are likely to feel that they have not
studies or reviews much time left to spend on expectant management once they have
decided, in their mid- to late thirties, to seek professional help for
This review covers a long period of time. Especially in the early
their fertility problem.
years, study methodology was far from perfect. Addition of new,
better studies to the review has allowed for performing a sub-
group analysis of the higher quality studies. Although the find-
ings of our previous meta-analysis were consistent with those of
non-Cochrane reviews at the time (Cocuzza 2008; French 2008; ACKNOWLEDGEMENTS

Surgery or embolization for varicoceles in subfertile men (Review) 14

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Jane Clarke was involved in the 2008 and 2009 updates.
Patrick Vandekerckhoven was involved in preparing the 2001 ver-
sion of this review.

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Surgery or embolization for varicoceles in subfertile men (Review) 17

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Abdel-Meguid 2011

Methods Randomised clinical trial. 251 men eligible, 150 randomised, 75 to varicocelectomy, 75
to no treatment. All men received allocated intervention. 2 men lost to follow-up. 5
excluded from analysis

Participants Married, overall healthy men 20-39 years of age, who had had infertility for more than
1 year of unprotected intercourse. Clinical palpable unilateral or bilateral varicocele
(grades 1-3) and impaired semen quality (sperm concentration < 20 million/mL and/
or progressively motile sperm < 50% and/or morphologically normal sperm < 30%)
. Exclusion: normal semen parameters, azoospermia, an abnormal hormonal profile,
additional causes of infertility, significant medical diseases, smoking, occupational heat
exposure, associated female factor infertility, female age > 35 years, unstable marriage.
Mean age men 29.3 and 28.4 years in no treated and treated groups, respectively. Mean
age women not stated

Interventions Subinguinal microsurgical varicocelectomy VERSUS no treatment

Outcomes Pregnancy rate. Method of diagnosis not specified. Duration of follow-up 12 months

Notes Single centre trial

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random allocation sequence was computer
bias) generated

Allocation concealment (selection bias) Low risk An independent research assistant

Blinding (performance bias and detection High risk

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk 2 men lost to FU, 5 excluded from analysis
All outcomes

Selective reporting (reporting bias) Unclear risk Unclear

Other bias Unclear risk Method of diagnosis not specified

Surgery or embolization for varicoceles in subfertile men (Review) 18

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Breznik 1993

Methods Randomised clinical trial. 96 men (of an unspecified number of eligibles) were ran-
domised, 17 excluded (18%; all accounted for), 79 eventually analysed (38 treated, 41
controls). Five couples achieving pregnancy before surgery were transferred to the no
treatment group. This has been corrected for this review (see notes). More detailed in-
tention-to-treat analysis not possible

Participants Men with subclinical (thermography, phlebography) and clinical varicoceles (WHO I-
III). Definition and duration of subfertility not stated. Age and infertility work up not
stated. Female causes and previous treatment excluded. Men with azoospermia were
excluded, men with normospermia were included

Interventions High ligation of spermatic vein(s) (Palomo), sclerosation of spermatic vein, or Gianturco
spiral embolization VERSUS no treatment

Outcomes Pregnancy rate. Method of diagnosis not specified. Duration of follow-up 48 months
(12 months in 1 treated patient)

Notes 13 pregnancies in 38 women (34%) of treated men and 22 in 41 (54%) of non-treated

men; however, 5 couples with pregnancy before surgery had been transferred to no
treatment group. Correction results in 18/43 (42%) and 17/36 (47%) pregnancies,
respectively. 25 of 79 included men had normospermia

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given

bias)

Allocation concealment (selection bias) Unclear risk Unspecified

Blinding (performance bias and detection High risk Not blinded

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk 82 % FU complete

All outcomes

Selective reporting (reporting bias) Unclear risk No information given

Other bias Unclear risk Unclear description of inclusion and exclu-

sion criteria. Method of diagnosis of preg-
nancy not specified. No intention-to-treat
analysis

Surgery or embolization for varicoceles in subfertile men (Review) 19

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dohle 2010

Methods Randomised clinical trial. 416 men eligible,130 randomised, 65 men to treatment and
65 to no treatment. 12 (9%) lost to follow up, not accounted for. Number of exclusions
not noted. Intention-to-treat analysis was performed

Participants Men with no other abnormalities than clinical varicocele (confirmed by ultrasound)
and subnormal semen analysis. Duration of subfertility > 1 year. Definition subfertility
not stated. Age women < 36 years. Exclusion: azoospermia, obvious female subfertility
causes. Mean age men 32.9 and 32.7 years, mean age women 29.6 and 29.3 years in
treated and no treated groups, respectively. Baseline characteristics comparable

Interventions Surgical repair (not specified) VERSUS delayed treatment after 1 year (ART or varicocele
repair)

Outcomes Pregnancy rate. Method of diagnosis not specified

Notes Data of a published abstract completed by contact with the author. The study will be
published later this year. The study started as a multi-centre trial, but turned into a single
centre trial because of lack of included patients

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not assessable because of incomplete study
bias) data

Allocation concealment (selection bias) Unclear risk Not assessable because of incomplete study
data

Blinding (performance bias and detection High risk

bias)
All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not assessable because of incomplete study
All outcomes data

Selective reporting (reporting bias) Unclear risk Not assessable because of incomplete study
data

Other bias Unclear risk Not assessable because of incomplete study

data

Surgery or embolization for varicoceles in subfertile men (Review) 20

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Grasso 2000

Methods Randomised clinical trial. 68 men randomised of an unspecified number of eligibles. All
agreed not to resort to ART for 12 months

Participants Men with subclinical (Doppler ultrasound) varicocele (Hirsch grade I left varicocele)
and abnormal semen analysis: oligo- astheno- or teratozoospermia of varying degrees.
Clinical varicocele excluded. Definition of subfertility not stated. Duration > 1 year.
Female subfertility causes and previous treatment not stated

Interventions Left spermatic vein ligation (Palomo) VERSUS no treatment.

Outcomes Primary: Sperm analysis. Secondary: Paternity. Method of diagnosis not specified. Du-
ration of follow-up 12 months

Notes Only men aged > 30 years old (range 30 to 38) included. 1 pregnancy in 34 women (2.
9%) of treated men and 2 in 34 (5.9%) of non-treated men

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given

bias)

Allocation concealment (selection bias) Unclear risk No information given

Blinding (performance bias and detection High risk

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk No information given

All outcomes

Selective reporting (reporting bias) Unclear risk No information given

Other bias Unclear risk Only men aged > 30 years old (range 30 to
38) included. Unclear description of inclu-
sion and exclusion criteria

Krause 2002

Methods Randomised clinical trial. 67 men randomised, of an unspecified number of eligibles: 33

to sclerosation, 34 to no treatment. 36 (54%) lost to follow up, 2 dropped out directly
after randomisation. 31 completed study. Intention-to-treat analysis performed

Participants Men from couples with > 1 year subfertility, with clinical varicoceles only. Definition
subfertility not stated. Exclusion: subclinical varicoceles; symptomatic varicoceles; genital
disease (e.g. cryptorchidism); severe general disease; use of drugs with effects on sperm;
sperm count < 2 million per mL; progressive motility < 10%; > 1 million per mL
leucocytes; volume < 1 mL; untreated or untreatable female subfertility. Mean age men
Surgery or embolization for varicoceles in subfertile men (Review) 21
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Krause 2002 (Continued)

32.2 years; women 29.7 years. Loss to follow up 54%, unaccounted for

Interventions Retrograde or antegrade sclerosation VERSUS no treatment.

Outcomes Conception rate. Method of diagnosis: Ultrasound. Duration of follow-up 12 months

Notes Multi-centre trial, scheduled to include 460 men. Discontinued after 3 years because
of poor recruitment (70 men in 15 centres). Intention-to-treat analysis was performed;
however, only 42 out of 67 men (63%) were treated as randomised. Very poor follow-
up

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random number generator, provided by
bias) telephone after registration

Allocation concealment (selection bias) Low risk Conducted remotely

Blinding (performance bias and detection High risk Not blinded

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk 46% FU complete, loss to follow up not
All outcomes accounted for.

Selective reporting (reporting bias) Unclear risk No information given

Other bias Unclear risk Prospective, correction of power, selection

bias

Madgar 1995

Methods Randomised clinical trial, postponement-of-treatment study, part of unpublished WHO

study #84902. 210 new patients, 57 eligible, 45 men randomised, 25 to treatment group,
20 to no-treatment

Participants Inclusion: visible or palpable left varicocele, abnormal SA (< 20 million/mL, WHO)
. Exclusion: SA < 5 million/mL, accessory gland infection, abnormal FSH, LH or T.
Definition subfertility and work up according to WHO, duration > 12 months. Age 28.
7 years in either group. Female factors excluded. Previous treatment not mentioned

Interventions Surgical high ligation of spermatic vein(s) (modified Palomo) VERSUS delayed surgery
(for 12 months)

Outcomes Pregnancy rate. Method of diagnosis not specified. Duration of follow-up 12 months

Surgery or embolization for varicoceles in subfertile men (Review) 22

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Madgar 1995 (Continued)

Notes Only pre-treatment part in control patients taken into account for present review

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given

bias)

Allocation concealment (selection bias) Unclear risk Unspecified

Blinding (performance bias and detection High risk

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk As allocated, minus losses to FU (not
All outcomes noted)

Selective reporting (reporting bias) Unclear risk No information given

Other bias Unclear risk No information given

Nieschlag 1995/1998

Methods Randomised clinical trial. 226 eligible: 203 randomised, 23 opted for assisted reproduc-
tion. 125 completed study: 62 treated by ligation/embolization, 63 received counselling
only. 78 (38%) drop-outs after randomisation, all accounted for. Intention-to-treat anal-
ysis not performed

Participants Men from couples with > 1 year subfertility; regular, unprotected intercourse; Valsalva-
positive varicocele (WHO grade I: N = 66, grade II: N = 43, grade III: N = 16) and
subnormal (WHO) semen analysis. Exclusion: history of maldescended testes, infections,
anti-sperm antibodies, general disease, chronic medication, obvious female subfertility
causes (anovulation, endometriosis, tubal blockage). Mean age men 33, women 30.5 yrs
in counselling. Loss to follow up accounted for

Interventions Radiological embolization or surgical ligation VERSUS counselling only. Radiological

embolization: by Histacryl tissue adhesive. Surgical ligation: by high retroperitoneal
ligation according to Bernardi (1942). All men in the treatment and no-treatment groups
were re-investigated and counselled after 3, 6, 9 and 12 months

Outcomes Pregnancy rate. Method of diagnosis not specified. Duration of follow-up 12 months

Notes During study period WHO definition of normal morphology cut-off changed from 50%
to 30%. Since patient assignment was random all study groups affected equally (mean
date of entry into study not different)
The only significant difference for achieving pregnancy was the female age at admittance

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nieschlag 1995/1998 (Continued)

to the study regardless of treatment modality: 28.8 years (pregnant) versus 31.1 years
(not pregnant) (P < 0.05)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random number generator, before first pa-
bias) tient entered study, provided in opaque en-
velopes

Allocation concealment (selection bias) Low risk Adequate, by third party

Blinding (performance bias and detection High risk

bias)
All outcomes

Incomplete outcome data (attrition bias) Unclear risk No information given

All outcomes

Selective reporting (reporting bias) Unclear risk No information given

Other bias Unclear risk This study was first published in 1995
and then continued and published again in
1998 because of insufficient power

Nilsson 1979

Methods Randomised clinical trial. 96 men included of 165 eligible, excluded: 69 men. 51 men
treated by surgical ligation, 45 to control group. Loss to follow up and drop-outs not
mentioned

Participants Inclusion: men with unilateral varicocele of couples with primary subfertility. Exclusion:
previous genital or inguinal surgery, mumps orchitis during/after puberty, uni- or bilat-
eral cryptorchidism (treated or untreated), azoospermia, anti-sperm antibodies, raised
FSH, female subfertility factors (ovulatory inadequacy, tubal blockage, cervical hostility)
. Diagnosis of varicocele: clinical. Duration of subfertility 2-8 yrs. Mean age treated men
31 yrs, controls 30 yrs, age women not stated

Interventions Surgical ligation of internal spermatic vein(s) (modified Palomo) and cremasteric vein(s)
(if varicosity of that system as well) VERSUS no treatment. Co-interventions specifically
stated to have been avoided

Outcomes Primary outcome: sperm analysis. Secondary outcome: pregnancy rate. Method of diag-
nosis of pregnancy not specified. Duration follow-up: mean 53 months (range 36 to 74
months)

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nilsson 1979 (Continued)

Notes Varicocele patients from subfertile couples were included, irrespective of semen analysis
results. Normospermia was not an exclusion criterion, 26% men had sperm counts < 20
million/mL. Old study (more than 30 years)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given

bias)

Allocation concealment (selection bias) Unclear risk Unspecified

Blinding (performance bias and detection High risk

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk FU complete

All outcomes

Selective reporting (reporting bias) Unclear risk No information given

Other bias Low risk Duration of subfertility has a broad range

and is extensive (> 24 months): selection
bias. Follow-up period for pregnancy rate
is extensive (36-74 months)

Unal 2001

Methods Randomised clinical trial. 42 men randomised, 21 to surgery, 21 to clomiphene citrate.

Number eligible not stated. Method of randomisation not stated. Inclusion criteria well
described, exclusion criteria not stated

Participants Inclusion: men with left subclinical (Doppler ultrasound) varicocele and normal testicu-
lar size. Definition of subfertility not stated. Duration > 1 year. Fertility work up, female
fertility and age not stated. Oligoasthenospermia to normospermia are included

Interventions Surgical ligation of the spermatic vein VERSUS clomiphene citrate for 6 months (50
mg/day)

Outcomes Seminal improvement. Pregnancy rate was a secondary outcome. Duration of follow-up
12-40 months

Notes Men taking clomiphene citrate in control group. Normospermia was not an exclusion
criteria. Only left subclinical varicocele were included

Risk of bias

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Unal 2001 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given

bias)

Allocation concealment (selection bias) Unclear risk Unspecified

Blinding (performance bias and detection High risk

bias)
All outcomes

Incomplete outcome data (attrition bias) Unclear risk FU not mentioned

All outcomes

Selective reporting (reporting bias) Unclear risk No information given

Other bias Unclear risk Follow-up period for pregnancy rate is ex-
tensive (12-40 months). Small study pop-
ulation

Yamamoto 1996

Methods Randomised clinical trial. Method of randomisation not stated. 92 were randomised,
45 to treatment, 47 to no-treatment group. Intention-to-treat analysis not performed.
Inclusion criteria well described, exclusion criteria not stated

Participants Inclusion: left subclinical varicocele, defined as a thermographic difference of > 0.3
degree Celsius and no clinical varicocele. No patients reported previous cryptorchidism,
hydrocoele, testicular trauma, or surgery of the urogenital tract. Definition subfertility
not stated, duration 1-5 yrs. Mean age men 32 (range 24-37) yrs. Age women not stated.
Infertility work up included history, physical examination, BBT, endocrinology, and
HSG (in selected patients)

Interventions High ligation of the internal spermatic vein(s) VERSUS no treatment

Outcomes Sperm analysis. Secondary outcome was pregnancy rate. Method of diagnosis of preg-
nancy not specified. Duration follow-up 12 months

Notes Men with normospermia have been included in this study. Method of diagnoses of
varicocele is disputable

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Unclear

bias)

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Yamamoto 1996 (Continued)

Allocation concealment (selection bias) Unclear risk Unspecified

Blinding (performance bias and detection High risk Not used

bias)
All outcomes

Incomplete outcome data (attrition bias) Unclear risk As allocated, minus losses to FU.
All outcomes

Selective reporting (reporting bias) Unclear risk 91% FU complete

Other bias Unclear risk Method of diagnosis of pregnancy not spec-

ified. Duration of subfertility has a broad
range and is extensive

Dr Nieschlag provided additional information on the allocation concealment procedure in his study.
Abbreviations: ART = Assisted Reproductive Technology; BBT = Basal Body Temperature; FSH = Follicle Stimulating Hormone; FU
= Follow-Up; HSG = Hysterosalpingography; LH = Luteinising Hormone; SA = Semen Analysis; T = Testosterone; yrs = years

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Al-Kandari 2007 RCT with three arms: open inguinal, laparoscopic, and subinguinal microscopic surgery

Al-Said 2008 RCT with three arms: open inguinal, laparoscopic, and subinguinal microscopic surgery

Barbalias 1998 RCT of four different venous embolization approaches

Cavallini 2003 RCT with three arms: surgery, cinnoxicam, and placebo. Pregnancy rates not reported

Cayan 2000 RCT of high ligation surgery versus microsurgical high inguinal varicocelectomy

De Rose 2003 RCT with three arms: surgery, surgery and menotropin, or menotropin

Fayez 2010 RCT with three arms: compared outcome and complications of three simple varicocelectomy techniques

Grasso 1995 RCT of bilateral versus unilateral occlusion of spermatic veins in men with bilateral varicoceles

Khan 2003 RCT of high versus low ligation procedures

Laven 1992 RCT in adolescents. Follow-up of testicular volume, semen analysis. No pregnancy rates

Surgery or embolization for varicoceles in subfertile men (Review) 27

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Matsuda 1993 RCT of artery preservation versus ligation

Nieschlag 1993 RCT of surgical ligation versus embolization. Semen analysis, pregnancy rates

Paduch 1997 RCT in adolescents. Follow-up of testicular volume. No semen analysis, no pregnancy rates

Podkamenev 2002 RCT of laparoscopy versus open surgery

Sautter 2002 RCT of laparoscopy versus sclerotherapy

Sayfan 1992 RCT of three techniques of varicocele repair: percutaneous embolization, high ligation of the internal spermatic
vein(s), and trans inguinal ligation of the internal and external spermatic vein(s)

Yamamoto 1995a RCT in adolescents. Follow-up of testicular volume, semen analysis

Yamamoto 1995b RCT of spermatic artery preservation versus ligation

Yavetz 1992 RCT of embolization versus surgical ligation

Zheng 2009 RCT with two arms: bilateral varicocelectomy versus left varicocelectomy in patients with left clinical and right
subclinical varicocele

Surgery or embolization for varicoceles in subfertile men (Review) 28

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Varicocele occlusion versus no treatment

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Pregnancy rate 10 894 Odds Ratio (M-H, Fixed, 95% CI) 1.47 [1.05, 2.05]

Comparison 2. Varicocele occlusion versus no treatment in men with abnormal semen analysis, clinical varicocele
and primary outcome pregnancy rate

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Pregnancy rate 5 505 Odds Ratio (M-H, Fixed, 95% CI) 2.39 [1.56, 3.66]

WHAT’S NEW
Last assessed as up-to-date: 22 January 2012.

Date Event Description

12 September 2012 New citation required and conclusions have changed 2 studies added; results of updated review suggest ev-
idence of slight benefit from treatment

2 February 2012 New search has been performed Anja Kroese and Natascha de Lange added to author-
ing team

HISTORY
Protocol first published: Issue 2, 1995
Review first published: Issue 1, 2001

Surgery or embolization for varicoceles in subfertile men (Review) 29

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Date Event Description

21 October 2008 Amended ROB figures added

22 April 2008 Amended Converted to new review format.

22 April 2008 New citation required but conclusions have not Jane Clarke added to authoring team
changed

15 January 2008 New citation required and conclusions have changed Substantive amendment

22 November 2007 New search has been performed Two new studies found and excluded

25 October 2007 New search has been performed Search string revised and re run

CONTRIBUTIONS OF AUTHORS
Anja Kroese participated in the screening of the literature, the initial data abstraction and the data management, the analysis and
interpretation of the data, and the preparation of the manuscript.
Natascha de Lange participated in the screening of the literature, the initial data abstraction and data management, the analysis and
interpretation of the data, and the preparation of the manuscript.
John Collins participated in the initial review and all updates. He also participated in the preparation of the manuscript of this review
Johannes Evers participated in the screening of the literature, the initial data abstraction and data management, the analysis and
interpretation of the data, and the preparation of the manuscript of all previous reviews. He also participated in the preparation of the
manuscript of this review.

DECLARATIONS OF INTEREST
No conflicts of interest exist.

SOURCES OF SUPPORT

Internal sources
• Internal support, Not specified.
MDSG editorial base

Surgery or embolization for varicoceles in subfertile men (Review) 30

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
External sources
• New Source of support, Not specified.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Live birth was made a primary rather than a secondary outcome.

NOTES
In the 2004 update three new RCTs were added to the Included Studies section of the review, one ongoing study was added to the
Ongoing Studies section, and further detail was added to the narrative sections of the review.
In the 2008 update two new RCTs were considered for inclusion that were excluded.
In the 2009 update no new RCTs were included.

INDEX TERMS

Medical Subject Headings (MeSH)

∗
Embolization, Therapeutic; Infertility, Male [etiology; surgery; ∗ therapy]; Outcome Assessment (Health Care); Pregnancy Rate;
Randomized Controlled Trials as Topic; Sperm Count; Varicocele [complications; surgery; ∗ therapy]

MeSH check words

Female; Humans; Male; Pregnancy

Surgery or embolization for varicoceles in subfertile men (Review) 31

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.