Efficacy of Varicocelectomy in Improving Semen Parameters: New Meta-analytical Approach

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Adult Urology

fficacy of Varicocelectomy inmproving Semen Parameters:ew Meta-analytical Approach

shok Agarwal, Fnu Deepinder, Marcello Cocuzza, Rishi Agarwal, Robert A. Short,dmund Sabanegh, and Joel L. Marmar

BJECTIVES To determine the efficacy of varicocelectomy in improving semen parameters.ETHODS A meta-analysis was performed to evaluate both randomized controlled trials and observational

studies using a new scoring system. This scoring system was developed to adjust and quantify forvarious potential sources of bias, including selection bias, follow-up bias, confounding bias,information or detection bias, and other types of bias, such as misclassification. Of 136 studiesidentified through the electronic and hand search of references, only 17 studies met our inclusioncriteria. The study population was infertile men with clinically palpable unilateral or bilateralvaricocele and at least one abnormal semen parameter who had undergone surgical varicoce-lectomy (high ligation or inguinal microsurgery). Only those studies that had at least three semenanalyses (ie, sperm count, motility, and morphology) per patient, before and after surgicalvaricocelectomy, were included.

ESULTS The combined analysis demonstrated that the sperm concentration increased by 9.71 � 106/mL(95% confidence interval [CI] 7.34 to 12.08, P �0.00001) and motility increased by 9.92% (95%CI 4.90 to 14.95, P � 0.0001) after microsurgical varicocelectomy. Similarly, the spermconcentration increased by 12.03 � 106/mL (95% CI 5.71 to 18.35, P � 0.0002) and motilityincreased by 11.72% (95% CI 4.33 to 19.12, P � 0.002) after high ligation varicocelectomy. Theimprovement in World Health Organization sperm morphology was 3.16% (95% CI 0.72 to 5.60,P � 0.01) after both microsurgery and high ligation varicocelectomy.

ONCLUSIONS Surgical varicocelectomy significantly improves semen parameters in infertile men with palpable
varicocele and abnormal semen parameters. UROLOGY 70: 532–538, 2007. © 2007 Elsevier Inc.
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aricoceles are the most frequent abnormal phys-ical finding in men who present for an infertilityevaluation and represent the most common

reatable cause of male factor infertility.1,2 The preva-ence of varicocele is approximately 15% in the generalopulation, 19% to 41% in men with primary infertility,nd 45% to 81% in men with secondary infertility.3 Inurrent medical practice, impairment of semen parame-ers, particularly sperm count, motility, and morphology,uggest that a varicocele might be present.4,5 Despitextensive research, the exact cause of infertility in menaving varicocele is still not known.

his meta-analysis was supported by funds from the Reproductive Research Center andhe Glickman Urological Institute, Cleveland Clinic.

From the Reproductive Research Center, Glickman Urological Institute, Departmentf Obstetrics Gynecology, Cleveland Clinic, Cleveland, Ohio; Health Research andducation Center, Washington State University, Spokane, Washington; and Division ofrology, Robert Wood Johnson Medical School, Camden, New JerseyReprint requests: Ashok Agarwal, Ph.D., H.C.L.D., Center for Advanced Research

n Human Reproduction, Infertility and Sexual Function, Glickman Urological Insti-ute, Department of Obstetrics Gynecology, Cleveland Clinic, 9500 Euclid Avenue,

aesk A19.1, Cleveland, OH 44195. E-mail: [email protected]: October 20, 2006; accepted (with revisions): April 16, 2007

32 © 2007 Elsevier Inc.All Rights Reserved

Although varicocele repair is widely used as a treat-ent of male infertility, the effectiveness of varicocelec-

omy with respect to fertility remain to be clarified.6

aricoceles have been traditionally treated with surgicaligation of the internal spermatic vein, although radio-ogic embolization has also been used as an alternativeherapy. Although a large number of reports have shownmprovement in the semen parameters after correction ofaricocele,3,7–10 other studies have suggested no bene-t.11–13 To resolve the issue, a few investigators havettempted to perform a meta-analysis to assess the effi-acy of varicocelectomy in improvement of fertility.owever, these studies did not discuss the benefit of

aricocelectomy on semen parameters.2,14 It is importanto highlight that even the couples who had failed tochieve a natural pregnancy after varicocele treatmentight have achieved better results with assisted repro-

uctive techniques because of the increase in seminaluality.15

Therefore, we conducted a new meta-analysis to assesshe effect of varicocelectomy on the semen parameters by
nalyzing reports that included men with clinically pal-
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able varicoceles who had preoperative and postopera-ive semen data. Our aim was to determine the efficacy ofaricocele repair in terms of improvement in the semenarameters in subfertile men planning to father a child.

ATERIAL AND METHODS

n the present meta-analysis, we analyzed randomized con-rolled trials (RCTs) and observational studies. Although RCTsemain the reference standard, some investigators have recom-ended inclusion of case-control and observational studies in aeta-analysis, as long as the studies have been carefully evalu-

ted for potential bias.16,17 The studies were selected by per-orming an extensive electronic and hand search using BIOSIS,MBASE, and Medline from 1985 to the present with the helpf a professional librarian. The key words, used in differentombinations, were varicocelectomy, microsurgery, high liga-ion, infertility, semen parameters, and pregnancy outcome. Noxclusions were made on the basis of language. Only thosetudies that had at least three semen analyses (sperm count,otility, and morphology) per patient, before and after surgical

aricocelectomy (high ligation or inguinal microsurgery), werencluded. We did not consider the results of embolization orelective catheterization of the internal spermatic vein on se-en parameters. The subjects were infertile men who under-ent varicocelectomy for unilateral or bilateral palpable vari-ocele with at least one abnormal semen parameter. Theatients served as their own controls, and we compared theffect change over time. The studies did not include a controlroup in the sense of a “no treatment” control, and the naturef the comparison groups varied across the studies. The bestolicies practice groups of both the American Urological As-ociation and the American Society for Reproductive Medicineave recommended varicocele treatment for infertile men withlinical varicocele and at least one abnormal semen parameterr sperm function test.18 Therefore, the studies of subjects withubclinical varicoceles were excluded. We did not include thetudies evaluating the role of varicocelectomy in improving theemen parameters in adolescents.

To enable unbiased scoring of the studies, we adhered to therinciples of the Potsdam guidelines19 and blinded all articlesnd reviewers. The methods, results, tables, and figures fromach study were extracted, and each report was assigned andentification number by an individual other than the twocorers. The results were blacked out in each report. Only thexes and captions of the figures were included in the evaluation,lacking out the actual graphs and data values. Summary sta-istics and P values were blacked out of the tables and the labelsnd parameters measured were left. Two evaluators who werenaware of the results, authors, journal, and year of publicationvaluated each study on its methodologic merits using our newcoring system (Table 1).

Instead of a simple checklist that might have produced bias, wesed a new scoring system to analyze the studies.19,20 This scoringystem was developed to adjust and quantify for various potentialources of bias, including selection bias, follow-up bias, confound-ng bias, information or detection bias, and other types of bias, suchs misclassification (Table 1). The point ranges for inclusion orxclusion were determined by the epidemiologic importance ofach study, its scientific quality, and the possibility of the reporteaching a biased conclusion. A greater score indicated that the
tudy met most of the criteria required to avoid introducing bias o
ROLOGY 70 (3), 2007

nto the study. If the total points for more than one category of biasere less than the acceptable range, the study was excluded from

he final analysis. If the total points for only one category were lesshan the acceptable range, the study was reexamined to determinehether the overall study was likely to be biased, and, if not,hether it could be included in the meta-analysis. Two reviewers

cored each study independently, and the final decision onhether to include a study was determined by a discussion between

he two reviewers. On a preformatted data extraction sheet, theutcomes of interest for continuous variables (ie, sperm concen-ration, motility, and morphology data) were extracted, and aeighted mean was calculated. The semen data were segregatedccording to the type of surgical procedure used on these patients.

Because the semen data can vary in sequential analyses orrom one measurement to the next and can serve as a source ofias, a random effects model was used to adjust for the hetero-eneity among the studies. Statistical significance was set atlpha � 0.05. The statistical analysis was done using RevManoftware (version 4.2.8) developed by the Cochrane Collabo-ative for the purpose of meta-analysis (www.cochrane.org).

ESULTStotal of 136 studies were identified through the elec-

ronic search and hand search of references. Of these, 113ere judged to be relevant according to the review of thebstracts and titles. More studies were eliminated becausef use of inadequate study designs and relevance of mea-ured outcomes, yielding 68 studies to be blinded. Aftercoring, 42 studies qualified for inclusion; however, 25 ofhese studies were excluded after additional evaluation ofhe study design. For example, analyses of studies thatompared outcomes before and after laparoscopy wereot included because this procedure was used in onlyhree studies, and this technique was mainly used ondolescents or men with subclinical varicoceles. At theonclusion of the evaluation period, only 17 studies werencluded in the meta-analysis that pertained to the semenarameters.Of the 17 studies, a total of 10 examined the concen-

ration and motility of sperm before and after interven-ion by microsurgery. The sperm concentration increasedy 9.71 � 106/mL (95% confidence interval [CI] 7.34 to2.08, P �0.00001) in these 10 studies (Fig. 1A). Theverage motility increased by 9.92% (95% CI 4.90 to4.95, P � 0.0001) in the studies that used microsurgeryFig. 1B).

The results for high ligation were similar after applyingweighted average over seven or eight studies (depend-

ng on the outcomes measured). The sperm concentra-ion increased by 12.03 � 106/mL (95% CI 5.71 to 18.35,

� 0.0002) as calculated from the reported results inight studies (Fig. 2A). Motility increased by 11.72%95% CI 4.33 to 19.12, P � 0.002) as averaged over theeported results in seven studies (Fig. 2B).

Morphology was only reported in 7 of the 17 studiesFig. 3). These studies were analyzed together and in-luded three studies that used microsurgery and threehat used high ligation. One study had data on morphol-
gy using both of these techniques. The combined results
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or both types of surgery were included in the analysis.he change in the World Health Organization spermorphology36 was statistically significant, with an esti-ated change of 3.16% (95% CI 0.72 to 5.60, P � 0.01;

ig. 3).

OMMENTe examined the efficacy of surgical varicocelectomy in

he improvement of semen parameters by conducting aeta-analysis involving both RCTs and observational

Table 1. Scoring sheet used for evaluating preoperativevaricocelectomy on semen parameters

Selection/Follow-up Confounding

From what, if any, underlyingcohort is the studypopulation derived?

(3) From a geographic cohort(3) From a community(2) From a clinic population(1) Unable to answer

Was the time between thetwo follow-up periodsshort enough to allowfor no confounding byage within subjects(�2 years)?

(3) Yes(1) No(1) Unable to answer

How were subjectsrecruited?

(3) All cases in the populationwere included

(2) Cases were recruitedconsecutively over aperiod of time

(3) Cases were randomlyselected

(1) Unable to answer

Do they evaluate andaccount for potentialconfounders that mayvary over time (eg,amount of follow-uptime, season, smoking,alcohol consumption,original sperm count,time-varying exposures)

(1) No(2) Yes, but they do not

adjust(3) Yes, and they adjust

for them when necess(1) Unable to answer

Did the investigators restrictagainst participants basedon infection, previoustreatment, and femalefactor infertility orconditions related to ARToutcome and spermparameters?


Did the investigatorsprespecify the sameprocedures for analysisfor before and after theintervention?

(2) Yes(2) Not applicable(1) No(1) Unable to answer

Was there loss of follow-upor lack of participationgreater than 10% of thosesampled initially?

(1) Yes(2) No(1) Unable to answerTotal � Total �

The exclusion criteria were as follows: selection/follow-up—maxim4–6; confounding—maximal score, 8; minimal score, 3; includeminimal score, 3; include range, 8–10; exclude range, 3–7; otherrange, 3–7; any studies with two or more categories scoring in the escoring in exclude range would be included.

tudies. The previous meta-analyses of varicocele studies c

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id not evaluate the semen parameters and concludedhat varicocele repair does not improve the fertility out-ome.2,14 However, several investigators have foundethodologic flaws in these meta-analyses that mightave biased the results.37–40 The studies selected in theseeta-analyses were clinically heterogeneous, the number

f patients analyzed was few, and the patient dropout oross to follow-up rates was significantly great. Neither ofhese meta-analyses included a large unpublished Worldealth Organization study that had suggested that vari-

postoperative repeated measures studies on effect of

Information/Detection Bias Other

Was the method of follow-upthe same before and aftertreatment?


Does the study combineoutcomes acrossgroups with veryheterogeneoushistories/durations ofinfertility and acrossdifferentinterventions?


Was the measurement ofoutcome(s) objective?Objective meaning medicalrecords or diagnostic test,not objective/subjectivemeaning recall, etc.


Was severity/grade ofvaricocele evaluatedbefore theintervention?


Was ascertainment ofoutcome performed at thesame location both beforeand after treatment?


Did investigators use anestablished set ofguidelines for semenanalysis?


Total � Total �

core, 11; minimal score, 4; include range, 7–11; exclude range,ge, 5–8; exclude range, 3–4; information—maximal score, 10;ximal score, 10; minimal score, 3; include range, 8–10; excludee range would be excluded and any studies with only one category

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utcome. Three of the eight studies included in the meta-nalyses of Evers and Collins14 included men with subclin-cal varicoceles and two trials involved men with a normalemen analysis. Similarly, Kamischke and Nieschlag2 in-luded studies with subclinical varicoceles and normal se-en analysis findings in their meta-analysis. In addition,

oth of these meta-analyses included data from therapy withadiologic embolization of the internal spermatic vein.

In the present meta-analysis, we included both RCTs and

igure 1. (A) Postoperative sperm concentration increasedB) Postoperative sperm motility increased significantly afteean difference; SD � standard deviation.

bservational studies, which could be controversial to some. w

ROLOGY 70 (3), 2007

owever, we firmly believe that it is sound for the currentubject matter because we compared the effect change overime among the patients undergoing varicocelectomy ratherhan comparing against the “no treatment” controls. Theotsdam Consultation has also recommended against aban-oning the observational studies if the methodologic designsf these studies are critically evaluated.19 Moreover, becausenly a few existing RCTs met our inclusion criteria, com-ining the data from the observational studies and RCTs

ificantly after microsurgical varicocelectomy (P �0.00001).rosurgical varicocelectomy (P � 0.0001). WMD � weighed

signr mic

as considered the only means of reaching a logical con-

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lusion. Another source of bias in our study results from theariability of semen data in sequential analyses, referred tos regression to the mean.9 Although we could not elimi-ate this statistical phenomenon, we tried to minimize it byelecting only those studies that had at least three semennalyses per patient, before and after varicocelectomy, andsing a random effects model to adjust for the heterogeneitymong the studies.

Although pregnancy outcomes are crucial, sperm den-ity may be an important measurement to evaluate theertility status of the male partner among varicocele pa-ients, especially after several studies have been publishedinking sperm density to fertility. Ombelet et al.41 pro-osed cutoff values of semen parameters for fertile popu-ation using the 10th percentile as 14.3 � 106/mL for

igure 2. (A) Postoperative sperm concentration increasedB) Postoperative sperm motility increased significantly afteean difference; SD � standard deviation.

perm concentration, 28% for progressive motility, and t

36

% for sperm morphology. More recently, in a prospec-ive study, Guzick et al.42 suggested subfertility for semenharacteristics such as a sperm concentration of less than3.5 � 106/mL, motility less than 32%, and normalorphology less than 9%. In addition, they found that

he percentage of normal sperm morphology was the mostowerful discriminator between the fertile and infertileopulations. In contrast, Nallella et al.43 reported thatperm motility and concentration are superior indicatorso the percentage of normal morphology for differentiat-ng between fertile and infertile men. In a Danish study,onde et al.44 found that the probability of conception

ncreased with an increasing sperm concentration up to0 � 106/mL. Despite the different ranges proposed forarious sperm characteristics to distinguish between fer-

ficantly after varicocelectomy by high ligation (P � 0.0002).icocelectomy by high ligation (P � 0.002). WMD � weighed

signir var

ile and infertile men, a common observation in all the

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bove-mentioned studies was that better pregnancy out-omes were associated with better semen parameters.

In clinical practice, the main treatment options fornfertile men with varicoceles have been varicocelectomynd assisted reproductive techniques; however, Schle-el45 reported significantly greater costs per born childith in vitro fertilization versus varicocelectomy.hese results suggest economic and pregnancy out-ome advantages for varicocelectomy versus in vitroertilization, and these findings should be reportedhen counseling patients. In addition, according to

he data from this meta-analysis, couples should benformed that varicocelectomy could improve the se-

en parameters.

ONCLUSIONSe have concluded from our meta-analysis that surgical

aricocelectomy is an effective treatment for improvinghe semen parameters of infertile men with a clinicallyalpable varicocele.21–35

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Efficacy of Varicocelectomy in Improving Semen Parameters: New Meta-analytical Approach

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