The VaricocelePuneet Masson, MDa, Robert E. Brannigan, MDb,*

themselves out.2 Another popular modality in-volved the use of Andrew varicocele clamp, whichremoved the dilated vessels along with the scrotalskin covering these vessels.3 Several modifica-tions were made on these varicocelectomy tech-niques, but the main indication for surgery wasscrotal discomfort secondary to varicocele.The benefits of varicocelectomy with regards to

male reproduction were not recognized until thelate nineteenth century. In 1885, Barwell4 reportedon 100 men with varicoceles who underwentplacement of wire loops around dilated scrotalveins and observed an improvement in testicular

improvement in semen parameters in 26 patients,of which 10 had return to normal fertility with suc-cessful pregnancy.7 His conclusion that where avaricocele is associated with subfertility, the vari-cocele should be cured has become part ofthe backbone of reproductive medicine, and nu-merous studies have followed demonstrating animprovement in semen parameters and pregnancyrates in infertile men undergoing this procedure.These more contemporary series on varicocelesand treatment options, including outcomes data,are reviewed in further sections.

a Division of Urology, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, 3rdFloor, West Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA; b Department of Urology,

, Suite 20-150, 675 North Saint Clair

* Corresponding author.

KEYWORDS

Infertility Microsurgery Pampiniform plexus Sperm Testicle Varicocele Varicocelectomy

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.comUrol Clin N Am 41 (2014) 129144E-mail address: r-brannigan@northwestern.eduNorthwestern University, Feinberg School of Medicine, Galter PavilionStreet, Chicago, IL 60611, USApassing of wire loops around the scrotal vesselsand applying tension until they eventually cut

In his series of 30 patients undergoing unilateralor bilateral varicocelectomy, he demonstrated anwas the Woods operation, which consisted of the male infertility until the work of Tulloch in 1955.HISTORICAL PERSPECTIVE

The association of the varicocele with male infer-tility derives back to the first century AD whenCelsius reported a link between dilated scrotalveins and testicular atrophy.1 Besides supportiveclothing, no known intervention was offered forsymptomatic painful varicoceles until the nine-teenth century when various methods were estab-lished to ligate these dilated veins. Among them

KEY POINTS

Varicoceles are present in 35% to 40% of infertilinfertility.

Varicoceles can result in disordered spermatogtubules, testicular atrophy, and decreased testo

Microsurgical varicocelectomy results in improvwith low rates of recurrence and postoperative

Varicocelectomy is more cost-effective than bofor affected infertile couples.http://dx.doi.org/10.1016/j.ucl.2013.08.0010094-0143/14/$ see front matter 2014 Elsevier Inc. Allsize and consistency. Testicular function wasaugmented by Bennet5 in 1889, when he reportedan improvement in semen quality in a patient whounderwent bilateral varicocelectomy. In 1929,Macomber and Sanders6 further elucidated thereproductive benefit to varicocelectomy by report-ing normal semen parameters and fertility after theprocedure in an oligozoospermic subfertile pa-tient. Despite these early reports, varicocelectomydid not gain popularity as a surgical treatment of

en and represent a highly treatable form of male

sis, germ cell sloughing within the seminiferousrone secretion.

semen parameters and reproductive outcomesrbidity.

UI and in vitro fertilization as a treatment optionrights reserved. uro

into the left renal vein, whereas the right internal

Masson & Brannigan130spermatic vein drains obliquely into the venacava. This basic finding has 2 ramifications thatcontribute to the left-sided predisposition. Forone, the course of the left internal spermatic veinresults in a length of approximately 8 to 10 cmlonger than its right-sided counterpart. This addedlength, coupled with upright posture, results inincreased hydrostatic pressure, which can over-come valvular mechanisms in certain men andlead to dilatation and tortuosity of spermatic veins.Second, the perpendicular insertion of the leftinternal spermatic vein into the left renal vein ex-poses the left spermatic vein to pressure eleva-tions within the left renal vein. The obliqueinsertion of the right internal spermatic vein intothe vena cava, on the contrary, shields the right in-ternal spermatic vein from the increased pressureswithin the vena cava.13 The basis for increased hy-drostatic pressure and varicocele formation is bestelucidated by the work of Shafik and Bedeir,14 whostudied venous tension patterns in spermatic cordThe varicocele clamps and wire loops were dis-continued in the early twentieth century as the liga-tion or excision of the pampiniform plexustransformed to varicocelectomy through theinguinal or scrotal route. Because of the high fail-ure rate and the risk of injury to end arteriesthrough the scrotal approach, Ivanissevich advo-cated high ligation of the internal spermaticvein through either the high inguinal or retroperi-toneal approach.2 In 1960, he further documentedhis experience with 4470 operative cases, demon-strating both low complication and failure rates,and many surgeons continue to use some modifi-cation of this technique today.8 More advances invaricocelectomy came through the use of micro-surgery in the 1980s, when several publishedseries demonstrated not only greater efficacy butalso a reduction in morbidity through better pres-ervation of the internal spermatic artery andlymphatic channels with higher magnification.911

ANATOMY

A varicocele is defined as a dilatation or tortuosityof the veins of the pampiniform plexus. Clinically,they are found more commonly on the left side,although there is wide variation among the re-ported prevalence of bilateral varicoceles, whichrange from 30% to 80%.12 An isolated right-sided varicocele is extremely rare and raisesconcern about an underlying retroperitoneal mass.The reason for the prevalence of left varicoceles

can be clarified by retroperitoneal anatomy. Theleft internal spermatic vein drains perpendicularlyveins in 32 patients with a left varicocele and30 controls. They demonstrated that patientswith left varicoceles have a venous tension thatis considerably higher both during rest and duringValsalva maneuver compared with that in controlsubjects, with average increases of 19.7 mm Hgand 22 mm Hg, respectively.The predisposition to varicocele formation is

also related to abnormalities in valvular mecha-nisms among certain patients. In a well-quotedstudy, Ahlberg and colleagues15 performedanatomic examination of 30 normal men at au-topsy and revealed the complete absence ofvalves in 40% of the left spermatic veins and23% of the right spermatic veins. In a follow-upstudy, Ahlberg and colleagues16 performed selec-tive phlebography in patients with varicoceles andcontrol subjects in the erect position; they demon-strated retrograde left internal spermatic vein fillingin 22 patients with varicoceles and right internalspermatic vein filling in 10 patients. They reportedthat some of these patients had no valves andothers had incompetent valvular mechanics.Meanwhile, they did not observe any retrogradefilling in 9 control patients and 6 patients who un-derwent previous varicocelectomy. These studiesarticulate 2 important points: first, valvular mal-function or absence does exist in a certainsegment of the population, and second, theabsence of valves is more common in the left inter-nal spermatic vein.There may also be a genetic basis to the valvular

dysfunction leading to varicocele development.Raman and colleagues17 evaluated 62 first-degree relatives of patients with varicoceles andfound that 56.5% of them had a clinically palpablevaricocele on physical examination, comparedwith a prevalence of 6.8% in 263 controls. Specif-ically, among the first-degree relatives with varico-celes, 74% were brothers, 41% were fathers, and67%were sons. Although the genetic mechanismspredisposing to varicocele formation remain to beelucidated, these results suggest an inheritancepattern of this anatomic finding.Most anatomic research has been conducted

on the internal spermatic vein and varicocele for-mation; however, there are some data to suggestthat dilated external spermatic (cremasteric) veinscan also contribute to primary or recurrent varico-celes. In 1980, Coolsaet18 retrospectively re-viewed 67 patients with left varicoceles whounderwent preoperative venography and demon-strated that the cause of varicoceles stems fromdysfunction within the internal spermatic vein,obstruction of the common iliac vein (resulting indilated external spermatic veins), or both mecha-nisms. Murray and colleagues19 evaluated 44 vari-

cocele recurrences and reported that 58% of

he found hypospermatogenesis with decreased

The Varicocele 131thickness of germinal epithelium in both testes.24

Several others have confirmed his findings andhave also reported areas of spermatogenic arrest,sloughing of spermatogenic cells, and Sertoli cellonly histology associated with the presence ofunilateral varicoceles.25 Saleh and colleagues26

reported testicular biopsy results from 37 azoo-spermic men with varicoceles; these revealedcomplete spermatogenesis with disorganization,sloughing, and low to moderate sperm counts in30%, arrested spermatogenesis in 38%, and Ser-toli cell only histology in 32% of cases. Despitethe extensive testicular dysfunction in these azoo-spermic men, the authors showed that the degreeof histopathologic impairment is independent ofthe clinical grade of the varicocele. The same de-gree of testicular damage was equally associatedwith either grade I or grade III varicoceles.It remains unclear when an otherwise incidental

varicocele may become pathologic. Gorelick andGoldstein reported that varicoceles were palpablethese are due to inguinal (external spermatic) col-laterals. Using 4 mm as the threshold for vein dila-tion, Chehval and Purcell20 identified dilatedexternal spermatic veins in 49.5% of 93 varico-celes in 67 patients. It is generally acknowledgedthat these external spermatic veins can lead tovaricocele formation and recurrence, and stan-dard inguinal or subinguinal varicocelectomy callsfor routine inspection and ligation of these externalspermatic collaterals. In addition to demonstratingvaricocele recurrences due to venous collateralsthat bypass the inguinal portion of the spermaticcord, Kaufman and colleagues21 report that 7%of recurrences are due to scrotal collaterals. Thisfinding forms the basis for delivery of the testicleduring varicocelectomy and ligation of all guber-nacular veins exiting from the tunica vaginalis.Goldstein and colleagues22 report a lower recur-rence rate (0.6%) with delivery of the testis andadaption of the microsurgical technique.

PATHOPHYSIOLOGY

It is well acknowledged that varicoceles can causeprogressive testicular damage and infertility. Lip-shultz and Corriere demonstrated that varicocelesresult in testicular atrophy in both fertile and sub-fertile men.23 Multiple histologic studies haveexplored this phenomenon on the microscopiclevel. Not only is there the loss of testicular masswith varicoceles, but also there can be substantialareas of testicular dysfunction. Scott reported hisfindings after having performed bilateral testicularbiopsies in 17 patients with unilateral varicoceles;in 35% of men presenting with primary infertilityand in 81% of men with secondary infertility. Themen with secondary infertility had significantlylower mean sperm concentration, poorer mor-phology, and higher follicle-stimulating hormonelevels than did men with varicoceles and primaryinfertility.27 Their findings suggest that varicocelescause a progressive decline in fertility and cancontinue to induce impairment of spermatogen-esis, despite prior fertility. Chehval and Purcell28

followed men with varicoceles presenting forfertility evaluation at 9- to 96-month intervals andfound a statistically significant deterioration insperm density and motility, suggesting progres-sive testicular deterioration.There are several hypotheses that attempt to

explain the correlation between varicoceles andtesticular dysfunction. The most widely acknowl-edged mechanism is that of testicular hyperther-mia. Human testicles are approximately 1C to2C less than normal body temperature. Scrotalthermoregulation is maintained by thin scrotalskin, which lacks subcutaneous fat and a counter-current heat exchange system involving the pam-piniform plexus. This system, first proposed byDahl and Herrick,29 allows arterial blood to becooled as it is delivered to the testis and enablesthe lower temperatures ideal for testicular func-tion. In most men, scrotal temperatures are lowestduring the standing position; however, standingalso intensifies varicoceles and may prevent thereduction in testicular temperature.30 In 1973,Zorgniotti and Macleod31 reported that oligozoo-spermic patients with varicoceles had bilateral in-trascrotal temperatures that were significantlyhigher by 0.6C to 0.7C than those of normal con-trols. Goldstein and Eid32 used sensitive needlethermistors to measure intratesticular and bilateralscrotal surface temperatures in anesthetized infer-tile men with unilateral varicoceles and normalcontrols, and they demonstrated an average tem-perature increase of 2.5C inmen with varicoceles.Several other studies have demonstrated an in-crease in intrascrotal temperature in men with var-icoceles, although there is controversy on theamount of elevation.Animal and human studies show that this addi-

tional heat can be detrimental to spermatogenesis.Lue and colleagues33 exposed the scrota of rats to43C for 15 minutes, which resulted in increasedapoptosis for spermatocytes and spermatids. Yinand colleagues,34 using an adult mouse model ofexperimental unilateral cryptorchidism, showedthat exposure of the testis to abdominal tempera-ture results in increased DNA fragmentation, lossof testicular weight, histologic evidence of germcell loss, and widespread apoptosis of germ cells

(particularly primary spermatocytes and round

Masson & Brannigan132spermatids). Although human studies also confirmthe association between varicoceles, elevatedscrotal temperatures, and testicular dysfunction,not all men with varicoceles share this phenome-non. Lewis and Harrison35 demonstrated thatmen with varicoceles and abnormal spermatogen-esis had higher scrotal temperatures comparedwith men with varicoceles and normal results insemen analyses. To confound the picture further,Mieusset and colleagues36 demonstrated thatinfertile men with abnormal spermatogenesishave higher scrotal temperatures compared withfertile men, regardless of the presence of a varico-cele. Although the scrotal temperatures of infertilemen with varicoceles were significantly higher thanthose of fertile men, they did not differ significantlyfrom those of infertile men without varicoceles.The persistence of scrotal hyperthermia and

abnormal semen parameters in only some menwith varicoceles remains a clinical mystery. Nu-merous studies have investigated various molecu-lar markers in men with varicoceles to see whythese dilated tortuous veins have a harmful effecton spermatogenesis in only some men. One inter-esting theory involves the heat shock proteins(HSPs) and heat shock factors (HSFs), both ofwhich generally have a protective function. Acti-vated by increased temperature and stress,HSPs and HSFs serve as molecular chaperonesthat mitigate the stress-induced denaturation ofother proteins, allowing cells to survive in poten-tially lethal conditions.37 Lima and colleagues38

have shown that the gene expression of oneparticular HSP, HSPA2, is downregulated in ado-lescents with varicoceles and oligozoospermiacompared with both adolescents without varico-celes and adolescents with varicoceles andnormal sperm concentration. Yes illi and col-leagues39 confirmed that HSPA2 level is lower inpatients with varicoceles and abnormal semenparameters and that this expression increasessignificantly after varicocelectomy. These studiessuggest that HSPA2 expression may be a markerof thermal tolerance in men with varicoceles. Otherstudies have demonstrated additional HSPs andHSFs in ejaculated sperm of men with varicocelesand impaired spermatogenesis, although the clin-ical significance of these molecular markers re-quires further investigation.40

Hypoxia and oxidative stress also play a role invaricocele pathophysiology. In a rat varicocelemodel, Kilinc and colleagues41 demonstratedthat the levels of various markers for hypoxia andangiogenesis, namely, hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelialgrowth factor, were significantly elevated in rats

with surgically induced varicoceles comparedwith a sham operated cohort and a control group.In men with a grade 3 unilateral varicocele under-going varicocelectomy, Lee and colleagues42

demonstrated that HIF-1alpha expression is7-fold higher in the internal spermatic veincompared with control subjects. Both thesestudies confirm that varicoceles are associatedwith increased hypoxia, and this may contributeto testicular dysfunction. Further, increased oxida-tive stress has also been associated with varico-celes. Hendin and colleagues43 demonstratedthat patients with varicoceles had significantlyhigher reactive oxygen species (ROS) levelscompared with controls; however, these levelsdid not differ significantly between infertile menwith varicoceles and fertile men with varicoceles.Likewise, total antioxidant levels were significantlylower among men with varicoceles, regardless offertility status. Other markers for oxidative stress,namely, nitrotyrosine and 4-hydroxy-2-nonenalmodified proteins, have also been identified inmen with varicoceles.44,45 ROS production insemen has been associated with loss of spermmotility, decreased capacity for sperm-oocytefusion, and loss of fertility.46 Surgical correctionof the varicocele is associated with decreasedoxidative stress; Mostafa and colleagues47 re-ported that varicocelectomy results in a significantreduction in ROS levels and also an increase in theantioxidant capacity of semen in infertile men.The reflux of renal and adrenal metabolites into

the spermatic vein is also hypothesized to con-tribute to varicocele pathophysiology. Givenvenography studies, which demonstrate reflux ofblood from the renal vein to the spermatic vein,along with venous pooling secondary to the dila-tion and tortuosity of the varicocele, it is thoughtthat these renal and adrenal metabolites can betoxic to testicular function. However, there isconsiderable inconsistency among studies exam-ining the presence of these metabolites in repro-ductive tissues. Comhaire and Vermeulen48

reported increased catecholamine levels in the in-ternal spermatic vein of patients with varicoceles,but other investigators were unable to confirm thisfinding.4850 Elevated levels of prostaglandins Eand F, both of which are antispermatogenic in an-imal models, have been identified in the internalspermatic vein in patients with varicoceles.51,52

In addition, elevated levels of the potent vasodi-lator adrenomedullin have been identified in thespermatic vein of patients presenting for varico-cele repair; it is thought that this metabolite maydisturb the countercurrent heat exchange systemof the spermatic cord.53

Hormonal dysfunction has also been associated

with varicoceles and can contribute to their

The Varicocele 133pathophysiology. Animal studies using surgicallyinduced varicoceles show subsequent reductionsin serum and intratesticular testosteronelevels.54,55 Comhaire and Vermeulen56 havedemonstrated that decreased plasma testos-terone concentrations are found in men with vari-coceles. In one of the largest studies to date, theWorld Health Organization published data on9034 men presenting for an infertility evaluationand reported that men older than 30 years withvaricoceles had significantly lower testosteronelevels than younger men with varicoceles. Mean-while, this trend was not observed in men withoutvaricoceles, suggesting a progressive detrimentaleffect of the varicocele on Leydig cell function.57

However, other reputable series have not shownany significant differences in plasma testosteronein men with varicoceles compared with normalmen.58,59 Additional studies suggest Leydig celldysfunction and decreased testosterone synthesisin some men with varicoceles. Weiss and col-leagues60 reported that the testicular tissue ofmen with varicoceles and severe oligozoospermiahave suppression of in vitro testosterone synthesiscompared with normal controls. Sirvent and col-leagues61 studied testicular histology in men withvaricoceles and reported increased Leydig cellcytoplasmic vacuolization and atrophy and adecrease in the total number of Leydig cells; thiswas true of bilateral testicular tissue in men witha unilateral varicocele.The reversibility of Leydig cell dysfunction with

varicocele treatment remains controversial. Withretroperitoneal varicocelectomy, historical studiesby Hudson and colleagues49 and Segenriech andcolleagues62 report an insignificant increase intestosterone from preoperative levels, althoughboth study populations were small (14 and 24patients, respectively). Conversely, Su and col-leagues63 reported a statistically significant in-crease in serum testosterone levels in 53 infertilemen with varicoceles undergoing microsurgicalinguinal varicocelectomy. Mean serum testos-terone increased from a preoperative level of319 to 409 ng/dL, suggesting that varicocelec-tomy can improve Leydig cell function in menwith varicoceles. In addition, they found an in-verse correlation between preoperative testos-terone levels and change in testosterone levelsafter varicocelectomy, which suggests that pa-tients with lower preoperative serum testosteronelevels and potentially more testicular dysfunctionmight achieve the greatest benefit from varicoceletreatment. Tanrikut and colleagues64 reporteddata on 200 men undergoing varicocelectomyand reported a significant increase in serum

testosterone levels in 70% of patients; however,they did not find any association between changein testosterone level and age, laterality of varico-cele, or varicocele grade. These findings confirmthe benefit to varicocelectomy in improving testic-ular function in some men and also suggest thatthe improvement in testosterone biosynthesis isindependent of age and varicocele severity.Nonetheless, the reversibility of hormonal dys-function by varicocelectomy remains controver-sial, and, to date, no best practice policystatements or guidelines advocate varicocelec-tomy for isolated hypogonadism.

PRESENTATION

Varicoceles are present in 15% to 20% of the gen-eral population but in approximately 35% to 40%of men presenting for an infertility evaluation.30,65

Any man presenting with a known varicocelewho has a possible interest in future paternityshould be offered a thorough medical and repro-ductive history, a physical examination, a hormoneprofile, and semen analysis testing.

Diagnosis

A meticulous physical examination is paramountto accurately diagnosing a varicocele. Ideal condi-tions include a warm room, a comfortable andcooperative patient, and a skilled clinician. Tofacilitate examination of the scrotal contents, thescrotum should be warm and relaxed. A cold envi-ronment or uncomfortable patient may result inshrinkage or tightening of the scrotum, which canmake a varicocele more difficult to palpate.Some clinicians have even recommended a heat-ing pad to ensure the accuracy of the physical ex-amination.66 The patient should be examined inboth the recumbent and upright positions.These tortuous dilated veins have been

described as a bag of worms by Dubin and Ame-lar67 and may be significantly reduced or evendisappear when the patient is in the supine posi-tion. When a varicocele is suspected but notclearly palpable, the patient should perform a Val-salva maneuver in the standing position. This exer-cise will enable the dilated veins to become moreengorged, and the clinician may palpate a discretepulse when examining the cord. Typical findingsinclude dilated veins above the testis within thespermatic cord, most commonly on the left side,along with ipsilateral or bilateral testicular atrophy.Although isolated right varicoceles do occur, theyare extremely rare and should raise the questionof an underlying retroperitoneal process such aslymphadenopathy. Furthermore, varicoceles thatdo not reduce in the supine position should raise

the same concern and merit further investigation.

The varicocele grading system, as proposed byDubin and Amelar,67 as is follows:

lation with venography. Thus, in situations in whichphysical examination may be challenging due toscrotal size or skin thickness, CDUmay be a usefuladjunct to the diagnosis of varicocele.

Caution with scrotal ultrasonography persistsbecause of the detection of subclinical varicocelesand the controversy surrounding their manage-ment. Mihmanli and colleagues71 used CDU in208 testes units in infertile patients without clinicalvaricoceles on physical examination and detected94 subclinical varicoceles. However, correction ofsubclinical varicoceles has not been proved topositively affect fertility. Grasso and colleagues72

randomized 68 infertile patients with subclinicalvaricoceles to varicocelectomy versus observa-tion and found no improvement in sperm quality

ate

Grade 1, small Palpable only with thepatient standing andperforming a concurrentValsalva maneuver

Grade 2,moderate

Palpable with the patientstanding, without aValsalva maneuver

Grade 3, large Visible through the scrotal

Masson & Brannigan134Fig. 1. (A) Scrotal ultrasonography demonstrated dilClinical varicoceles are defined as varicocelesthat are palpable on physical examination, andonly these varicoceles have been associated withinfertility. Although there are several radiologicmodalities available, routine use of imagingstudies is not recommended for the detection ofsubclinical varicoceles in patients without apalpable abnormality.68

Ultrasonography

Scrotal ultrasonography is not indicated for routineevaluation of men with varicoceles. However, in asituation in which the physical examination isinconclusive, scrotal ultrasound examination canbe used for clarification. Chiou and colleagues69

demonstrated a sensitivity of 93% and specificityof 85% for color flow Doppler ultrasonography(CDU) when compared with physical examination(Fig. 1). All moderate to large varicoceles foundon physical examination were detected by CDUdiagnosis. Petros and colleagues70 demonstratedthat CDU detected 93% of varicoceles found onphysical examination and provided the best corre-

skin and palpable withthe patient standing(B) Doppler flow in patient with grade 3 varicocele.or paternity. Yamamoto and colleagues73 reportedsimilar findings in 85 infertile patients; they notedan improvement in sperm density, but there wereno significant differences in sperm motility,morphology, or pregnancy rate. Because of thedearth of data showing any reproducible benefitfor the treatment of subclinical varicoceles, wide-spread use of ultrasonography to screen fordilated spermatic veins is not advocated.Scrotal ultrasonography is useful in patients who

have undergone prior surgery and in whom recur-rence or persistence of varicocele is suspected. Inaddition, ultrasonography is more accurate thanphysical examination or orchidometer when as-sessing testicular size, especially when there isthe concern for progressive testicular atrophy.Thus, although ultrasonography is not routinelyused in the diagnosis of varicocele, it may supple-ment physical examination findings in some casesand should be used at the discretion of the treatingclinician.

Venography

Retrograde spermatic venography is generallyconsidered to be the most sensitive test for thedetection of varicoceles. However, it is fairly inva-sive and usually only performed in conjunctionwith therapeutic occlusion. Access is usually ob-tained via the right femoral vein or right internal ju-gular vein, as described by Seldinger, and acatheter is advanced to the testicular vein and a

d tortuous veins consistent with varicocele (arrows).

The Varicocele 135contrast agent injected.74 In patients with palpablevaricoceles, reflux has been reported in 100% ofpatients.16 However, the specificity of this modal-ity has been questioned, as there is a considerablefalse-positive rate. Netto Junior and colleagues75

demonstrated no statistically significant differ-ences in the presence of spermatic vein reflux insubfertile patients with varicoceles, fertile patientswith varicoceles, and normal controls.There is also considerable technical variability

with diagnosis,76 and thus venography is consid-ered an adjunct to physical examination and usu-ally reserved for situations where treatment canbe pursued in the same setting. An interestingconcept proposed by Hart and colleagues77 advo-cates intraoperative spermatic venography duringvaricocelectomy, with a reported 16% collateraldrainage rate that could have resulted in varico-cele persistence if those specific veins were notligated. Given the low recurrence rate and ad-vances with microsurgery, intraoperative sper-matic venography is not routinely performed;however, it can provide a more precise anatomicdefinition of venous anatomy in postsurgical pa-tients with varicocele persistence or recurrence.For this reason, a common indication for venog-raphy is a recurrent or persistent postsurgical vari-cocele; thus, difficult venous anatomy can be welldelineated and simultaneous treatment offered.Punekar and colleagues78 reported a successrate of 85% in patients with recurrent varicocelesusing stainless steel coil embolization.

TREATMENT INDICATIONSInfertility

As per the American Urological Association BestPractice Policy Report on Varicocele and Infer-tility, varicoceles should be treated when all thefollowing conditions are met:

1. Varicocele is palpable on physical examinationof the scrotum.

2. The couple has known infertility.3. The female partner has normal fertility or a

potentially treatable cause of infertility.4. The male partner has abnormal semen param-

eters or abnormal results from sperm functiontests.68

With regards to infertility, varicocele treatment isnot indicated if semen parameters are normal or ifthe varicocele is subclinical. Adult men who arenot actively trying to conceive but present withan incidental varicocele should be counseled onfertility risk and offered at least 1 semen analysisto evaluate their reproductive capacity. Although

not all men with varicoceles have abnormal semenparameters, a substantial proportion of them mayhave reduced counts, decreased motility, and/orabnormal morphology.13,25 Because they may tryto achieve conception sometime in the future,men with clinically palpable varicoceles and ab-normal semen parameters should be informed ofdefinitive varicocele treatment options.Men with clinically palpable varicoceles and

normal semen parameters may be at risk for futuretesticular dysfunction. Witt and Lipshultz79

demonstrated that varicoceles are capable ofcausing progressive fertility loss. In their date-matched retrospective analysis, they noted thatvaricoceles were identified as the cause of infer-tility in 69% of men with secondary infertilitycompared with 50% of men with primary infertility,suggesting that varicoceles are progressive le-sions resulting in the loss of previously establishedfertility. Gorelick and Goldsteins work, as previ-ously discussed, supported this finding.27 Forthis reason, young adult men with clinicallypalpable varicoceles, normal semen parameters,and a desire for future paternity should be offeredmonitoring with serial semen analyses every 1 to2 years. If abnormal results are obtained, semenanalyses should be repeated, and if progressivedysfunction persists, they can be offered definitivetreatment of varicocele. In addition, men with sec-ondary infertility and clinically palpable varicocelesshould be offered the same treatment as individ-uals presenting with primary infertility.Young men with clinically palpable varicoceles

and objective evidence of testicular atrophy mayalso be considered for varicocele treatment.Semen analyses can be offered to further clarifyreproductive potential in this population, althoughreduced ipsilateral testicular size may aloneindicate testicular dysfunction secondary to vari-cocele.80 Sigman and Jarow81 reported that pa-tients with unilateral left varicoceles andipsilateral testicular hypotrophy had significantlyreduced semen parameters compared with pa-tients without hypotrophy. Thus, adolescents andyoung men with varicocele-associated testiculargrowth retardation should be offered treatment.In patients with varicoceles but with normal (ipsilat-eral) testicular size, routine follow-up shouldinclude objective measurements of testicular sizeand/or semen analyses to detect the earliest signof testicular dysfunction.With the advent of advanced assisted reproduc-

tive technologies (ARTs), many couples with male-factor infertility secondary to varicocele mayultimately choose between varicocele treatmentand IUI or in vitro fertilization/intracytoplasmicsperm injection (IVF/ICSI). Although many factors

may influence this decision, couples should be

genesis andmaturation arrest spermatid stage had

grade or age.

Masson & Brannigan136improvement in sperm density (patients withSertoli-cell-only or maturation arrest spermatocytestage did not demonstrate a benefit). Although allcouples eventually required some form of ART toachieve a pregnancy, this study contends thatcertain patientswith spermatogenic failure and var-icoceles may be candidates for varicocele repair,instead of resorting to testicular sperm extractionin preparation for ICSI. Additional studies regardingthe benefit of varicocelectomy with ART are dis-cussed a subsequent section.

Hypogonadism

The progressive negative effect of varicoceles onLeydig cell function has been previously discussedalong with the association of varicoceles and lowserum testosterone in somemen.With greater pub-lic awareness of hypogonadism and concern forvaricoceles as a significant risk factor for androgendeficiency, there is an ongoing debate regardingthe benefit of varicocelectomy for improving serumtestosterone. Earlier studies did not show a statis-tically significant increase in serum testosteroneafter varicocelectomy; however, many of thesestudies were smaller scale49,62 and included pa-tientswith normal to above-normal baseline testos-terone levels.85,86 Meanwhile, studies by Su andcolleagues63 and Tanrikut and colleagues64 haveshown not only that varicocelectomy leads to animprovement in serum testosterone but also thatmen with lower preoperative testosterone levelsderived themost benefit. Hsiao and colleagues87,88

corroborated this finding in infertile men with base-routinely counseled that varicocele repair mightoffer a permanent solution to male-factor infertility,whereas IUI or IVF/ICSI must be used for eachpregnancy attempt. Moreover, there is consider-ably greater cost savings for varicocele treatmentversus IUI/IVF or IVF in patients with isolatedvaricocele-related infertility.82,83

Varicocele treatment is not routinely recommen-ded when IVF is necessary secondary to a femalefactor. However, in certain cases with both maleand female factor components, varicocelectomycan augment ART efforts. In some azoospermicor cryptozoospermic patients, varicocele repaircan lead to improvednumbers of ejaculated sperm,thereby sparing these men a testicular spermextraction. Kim and colleagues84 reported thatapproximately 43% of patients with azoospermiahad return of sperm in the ejaculate after unilateralor bilateral varicocelectomy. These patients alsounderwent simultaneous testicular biopsy, whichrevealed that only men with severe hypospermato-line lower testosterone values and confirmed thatAlthough this biochemical response in previ-ously hypogonadal men is interesting, it is worth-while to also assess the effects of varicoceletreatment on the signs and symptoms of hypogo-nadism. Many younger men with hypogonadismmay present with low energy, diminished libido,and erectile dysfunction (ED). Srini and Veera-chari89 evaluated 200 heterosexual, hypogonadalinfertile men with clinical varicoceles and dividedthem into 2 groups: those who underwent varico-celectomy and those who underwent ART. In thevaricocelectomy group, they observed a statisti-cally significant increase in serum testosteronelevels with 78% of patients becoming eugonadal.As expected, there was no change in serumtestosterone levels in the hypogonadal men withvaricoceles who underwent ART. However, theyobserved a reduction in ED among patients inthe varicocelectomy group; the prevalence of EDdecreased from 44% to 31%. Meanwhile, therewas a mild increase from 39% to 41% in EDamong those who were in the ART group and didnot have correction of their serum testosterone.Zohdy and colleagues90 performed a similar studywith 141 heterosexual infertile hypogonadal menwith clinical varicoceles divided into a varicocelec-tomy treatment arm and an ART arm. They also re-ported a significant increase in serum testosteronelevels in the varicocelectomy arm with normaliza-tion of testosterone levels in 75.5% of thesemen. Moreover, they reported a significant in-crease in the International Index of Erectile Func-tion 5 questionnaire results in hypogonadal menundergoing varicocelectomy, suggesting clinicalimprovement with regards to erectile function insymptomatic men.Varicocelectomy for men with low testosterone

levels is a controversial and an evolving concept;it is not at this time considered to be a standard ofcare. To date, the body of evidence regarding vari-cocele treatmentand low testosteronehasprimarilyfocused on populations of infertile men. Further-more, there are no studies on the long-termmainte-nance of higher testosterone levels after varicocelerepair. Nonetheless, there is emerging evidence tosuggest that microsurgical varicocelectomy maybe a promising alternative to the medical treatmentof hypogonadism and potentially prevent futureandrogen deficiency in some men.

Symptomatic Varicoceles

Varicoceles can also present with pain, which issignificant increases in serum testosterone post-varicocelectomy are independent of varicoceletypically a dull ache and localized to the scrotum

The Varicocele 137or inguinal area. There is tremendous variabilityin the frequency, character, and intensity of thisdiscomfort, and other potential causes of painmust be explored before the varicocele istreated. Common conservative measures includescrotal support/elevation, antiinflammatory med-ications, and analgesic agents. Patients may alsobenefit from a referral for pelvic floor physicaltherapy or consultation with a pain medicinespecialist.When conservative measures prove inade-

quate, definitive treatment of the varicocele canbe offered, although patients should be coun-seled that surgery may not relieve their discom-fort. There is considerable variability regardingsurgical outcomes for symptomatic varicoceles,but most reports show a high rate of success inrelieving discomfort. These studies include sub-jects ranging from 11 to 284 patients, althoughthe majority includes data on less than 100 pa-tients. Rates for resolution of pain and improve-ment of pain after varicocelectomy range from53% to 94% and 42% to 100%, respectively.91

Most contemporary studies use the microsurgicalsubinguinal approach,92 although all other op-tions such as laparoscopic and robotic tech-niques have also been used with respectableresults.93,94

TREATMENT OPTIONS

The cornerstone of varicocele treatment is disrup-tion of the internal spermatic venous drainage ofthe testicle while preserving the internal sper-matic artery, the vasal and deferential vessels,and the spermatic cord lymphatics. Definitivetreatments for varicocele include surgery andradiographic venous embolization. Although allapproaches have been shown to be effective,there is the general preference among many urol-ogists to favor surgery given their expertise withvarious surgical approaches to varicocelectomyand its minimal complication rate. There areseveral surgical options available, and they arediscussed later.

Inguinal and Subinguinal Approach

Most varicocele repairs are conducted using eitherof these 2 approaches. The inguinal approach,initially described by Ivanissevich,8 necessitatesexposure and incision of the external obliqueaponeurosis. Care should be taken to avoid injuryto the ilioinguinal nerve. The spermatic cord is thenidentified andmobilized at the level of the pubic tu-bercle, and it is carefully elevated and securedwith a Penrose drain. This exposure also facilitates

exposure of large external cremasteric vesselsthat can contribute to the varicocele.13 With Loupemagnification or microsurgery, the inguinal ap-proach allows excellent identification of theinternal spermatic artery and vein before consider-able branching transpires.The subinguinal approach does not involve inci-

sion of the external oblique fascia and has beenshown to minimize postoperative discomfort.95,96

This approach is preferred at our and many othercenters. After making a skin incision at the levelof the external inguinal ring, the spermatic cord ismobilized immediately below at the level of the pu-bic tubercle and secured with a Penrose drain. Anylarge external cremasteric vessels should be iden-tified and ligated. Because there is considerablebranching of the internal spermatic vein at the sub-inguinal level, most urologists use microsurgerywith this approach to effectively recognize andpreserve the testicular artery, vas deferens, andlymphatic vessels.Microsurgical varicocelectomy has been shown

to have a higher success rate and minimal compli-cation rates when compared with nonmicrosurgi-cal modalities.97,98 Large-scale retrospectivestudies have documented extremely low recur-rence and complication rates; these complicationscan include hydrocele formation, testicular atro-phy, recurrent pain, and infection.22,99 All patientsshould be counseled about the indications, risks,and benefits of surgery, including realistic assess-ments with regards to their outcome of interest(eg, fertility, pain). These procedures can beperformed under local, regional, or general anes-thesia, although we favor use of general anes-thesia with either a laryngeal mask airway orendotracheal tube. The patient is supine on theoperating room table with standard perioperativeprecautions such as padding, deep venous throm-boembolism prophylaxis, and intravenous antibi-otics for prophylaxis against gram-positive skinorganisms. We use an operating microscopewith a dual ocular system for our procedures.A 2.5- to 3-cm oblique incision is typically made

over the external inguinal ring and then deepenedthrough Camper and Scarpa fascias. UsingRichardson retractors, the spermatic cord isexposed and gently dissected by sliding a fingerlongitudinally from the external ring to the upperscrotum. The cord is then manipulated, placedover a 1-inch Penrose drain, and carefully deliv-ered to skin level. We typically expose and ma-neuver the cord using manual dissection, butsome favor use of a Babcock instrument to gentlygrasp the cord and aid in delivery.66 Throughmanual retraction of the spermatic cord with thePenrose drain, perforating external spermatic

vessels are identified and carefully ligated.

Masson & Brannigan138At this point, the operating microscope isbrought into the field and the cord is examined un-der 8 to 15 power magnification. Many differentapproaches to cord dissection have been de-scribed in the literature. We use Gerald pickupsand Bovie electrocautery to carefully dissectthrough the external and internal spermatic fas-cias. The spermatic cord is secured under theoperating surgeons index finger (usually standingon the contralateral side of the table), and the vasdeferens with associated vessels is maneuveredmedially. The edges of the external and internalspermatic fascia are secured medially and later-ally, thus exposing and flattening out the internalspermatic vessels. This exposure transforms thecord from a cylindrical, 3-dimensional structureto a more 2-dimensional configuration, facilitatingidentification of individual vessels. The dissectionis carried out as proximally as possible to theexternal inguinal ring.The micro-Doppler is introduced to help locate

the internal spermatic arteries before fine dissec-tion begins. We request that the anesthesiologistmaintain the patients systolic blood pressuregreater than 100 mm Hg to assist us in isolatingan arterial Doppler signal and also to help us visu-alize subtle pulsations that indicate arterial flow. Ifthere is the concern for vasospasm, we irrigate thefield with lidocaine 1% solution. Other surgeonsrecommend papaverine (30 mg/mL) diluted in a1:5 ratio with saline to help dilate the arteries.100

Once the artery is identified, care is taken to pro-tect it and reidentify it several times through thefine dissection to confirm preservation. All internalspermatic veins are ligated with 3-0 or 4-0 silk anddivided, although some surgeons use surgicalclips for venous occlusion. Any lymphatics arealso identified and preserved. Dissection is thencarried out through the cremasteric fibers, andany cremasteric arteries identified are also pre-served. All cremasteric veins are ligated anddivided. The cord is repeatedly examined toensure no other veins (other than those preservedin the vas deferens packet) are visualized. The in-ternal spermatic arteries are also reassessedwith Doppler to ensure flow.At the completion of the varicocelectomy, the

spermatic cord should have patency of only testic-ular and cremasteric arteries, lymphatics, and vasdeferens with its associated vessels. After con-firming adequate hemostasis, the wound is irri-gated and the cord is returned to its orthotopicposition. Scarpa and Camper fascia are closedwith absorbable sutures, and the incision is infil-trated with a local anesthetic. The skin is closedwith a running subcuticular closure and reinforced

with Steri-strips, followed by a dry sterile dressing.Alternative Surgical Approaches

The retroperitoneal approach, originally describedby Palomo,101 involves ligation of the internal sper-matic vein superior to the internal ring. The skinincision is made at the level of the internal ringmedial of the anterior superior iliac spine, anddissection is carried out through the external andinternal oblique fascia and muscles. The internalspermatic vein is visualized and then ligated anddivided. A principle advantage of this techniqueis that it enables identification of the internal sper-matic vein before it extensively branches; a signif-icant disadvantage of this approach is that it doesnot allow access to the external spermatic veins,which have been shown to contribute to varico-celes.18 Furthermore, some patients may havemore pain during the recovery period due todissection of the abdominal musculature.98

The scrotal approach, addressed here for histor-ical reasons, is no longer favored because of itssubstantial rate of injury to the spermatic arteriesand resultant testicular atrophy/loss.30 Althoughit can be performed under local anesthesia, thisapproach has an unacceptably high complicationrate, which includes a 40% incidence of hydro-celes.102 This technique is no longer considereda viable option for performing varicocelectomy.With advancements in minimally invasive sur-

gery and the increasing familiarity that manyurologists have with laparoscopy, laparoscopicvaricocelectomy provides another mode of treat-ment. It is an intraperitoneal procedure, whichhas its own inherent risks, and involves high liga-tion of the spermatic vein. The procedure is similarto the open retroperitoneal approach in thatexternal spermatic vessels are not identified andmay put the patient at risk for varicocele per-sistence or recurrence. However, there is lesspostoperative pain and faster return to normal ac-tivities following laparoscopic surgery comparedwith the retroperitoneal technique. One additionaladvantage of the laparoscopic approach is that itenables bilateral ligations in an efficient and expe-ditious manner. Unilateral or bilateral varicocelec-tomy can also be executed resourcefully if apatient is undergoing another laparoscopic proce-dure at the same time. Overall, laparoscopy hasbeen shown to be safe and efficacious when per-formed by experienced surgeons, although theincidence of postoperative hydrocele and varico-cele recurrences was higher than in microsurgicalvaricocelectomy.103

Percutaneous Venous Occlusion

Embolization is considered a nonoperative ap-

proach to varicocelectomy, and the technique

abnormal semen parameter who had undergoing

The Varicocele 139surgical varicocelectomy, and insisted on at least3 semen analyses per patient. Seventeen studieswere included, and the combined analysis demon-strated that sperm concentration increased by9.71 million/mL and motility increased by 9.92%after microsurgical varicocelectomy. After high-ligation varicocelectomy, the combined analysisrevealed that sperm concentration increased by12.03 million/mL and motility increased by11.72%. Morphology increased by 3.16% withboth approaches. In this thorough meta-analysis,these investigators have shown that surgicalhas been described earlier in this article. Theadvantage of radiological venous embolization isquicker recuperative time and less pain. Successrates of varicocele treatment are slightly lessthan that of open surgery, with most large seriesranging from 85% to 95%.104,105 Complicationscan include vascular perforation, coil or balloonmigration, and the risk of allergic contrast reac-tion.30 Furthermore, concern exists regarding radi-ation exposure and its potential effect onspermatogenesis in a population of subfertile men.

TREATMENT OUTCOMES

Most studies reporting efficacy data on varicoce-lectomy are nonrandomized retrospective ana-lyses and report improvements in semenparameters and fertility. Although their resultsare promising, they generally contain a diversepatient population with varied inclusion or exclu-sion criteria, inadequate study designs, andlimited data on preoperative and postoperativeparameters, all of which make a meta-analysisof the data challenging. Further, several studiessuggest no benefit, especially with regards topregnancy outcomes.106108 To clarify this issue,the National Institutes of Health supported amulticenter randomized controlled trial on varico-cele repair to obtain better data on pregnancyand live birth rates. However, this trial wasstopped after 2.5 years because of low recruit-ment (only 3 patients were randomized), reflectingthe general unwillingness of most fertility-desiringcouples to be placed in the placebo arm.109

A review of the earlier literature in 1994 bySchlesinger and colleagues110 demonstrated animprovement in semen parameters after varicoce-lectomy in subfertile men. A recent meta-analysisby Agarwal and colleagues111 confirms thisfinding. Their inclusion criteria was stricter thanprevious meta-analyses; they included onlystudies with infertile men with clinically palpableunilateral or bilateral varicoceles, and at least onevaricocelectomy is an effective treatment forimproving semen parameters of infertile men witha clinically palpable varicocele.Despite these improvements, treatment of vari-

coceles for fertility remains controversial. There isconsiderable variability with regards to pregnancyoutcomes after varicocele repair in infertile cou-ples. A recent Cochrane review concluded that,although there is evidence suggesting that varico-cele repairmay improve a couples chance of preg-nancy, the quality of available evidence is low.112

Marmar and colleagues113 explored the efficacyof varicocelectomy with regards to spontaneouspregnancy. In their meta-analysis, which focusedexclusively on pregnancy outcomes, they foundthat infertile men with a clinically palpable varico-cele were 2.63 to 2.87 times more likely to achievea spontaneous pregnancy following surgical vari-cocelectomy compared with observation.A recent randomized controlled trial by Abdel-

Meguid and colleagues114 corroborates thisfinding. A total of 145 infertile men with clinical var-icoceles were allocated in a one-to-one fashionto either an observation (control) arm or subingui-nal microsurgical varicocelectomy. There wereno changes in the semen analysis in the controlarm, but the treatment arm demonstrated signifi-cant improvements in sperm concentration,motility, and morphology. Moreover, patients inthe treatment arm were 3.04 times more likely toachieve a spontaneous pregnancy comparedwith their counterparts.For patients with nonobstructive azoospermia,

testicular sperm extraction coupled with in vitrofertilization and intracytoplasmic sperm injectionis typically required for conception. Clinicallypalpable varicoceles are found in 4.3% to13.3%of men with azoospermia or severe oligozoosper-mia, and the role of varicocelectomy in these menhas been controversial given the probability thatthese men may still be subfertile after the sur-gery.115 Weedin and colleagues116 conducted ameta-analysis on varicocele repair in this patientpopulation using 11 publications during the past20 years. Their total patient population was 233men with azoospermia undergoing varicocelec-tomy, and 39.1% of them had motile sperm inthe ejaculate after surgery. A total of 14 sponta-neous pregnancies were reported. However,testicular pathology was identified as a predictorof success; patients with maturation arrest(42.1%) or hypospermatogenesis (54.5%) weresignificantly more likely to benefit than patientswith Sertoli-cell-only histopathology (11.3%,P

ology caused by varicoceles and which patients

cord veins in normal and varicocele individuals.

Masson & Brannigan140will remain less adversely affected. As is the casein so many domains of medicine, there is likely agenetic component to these outcomes. Several in-vestigators are already working on sperm andseminal markers of susceptibility for damagewrought by varicoceles, and we suspect that in20 years we might be able to more effectivelystratify patients for this risk based the basis ofsuch clinical markers. Technically, further ad-vances in microsurgical optics and instrumenta-tion will surely come to pass. The incredibleadvances of the preceding 20 years have includedincreased precision in instrumentation, smallerDoppler probes with enhanced functionality, andmore optimized microsurgical optics. Althoughsome researchers are currently investigating therole of robotics in the setting of varicocelectomy,it is unclear how much, if any, technical advantagethis approach affords in performing the procedure.In 20 years, this question will surely have beenEven if the use of ART is inevitable, varicocelerepair can augment the chance of a successfulpregnancy. In a small series, the IUI success ratewas higher after varicocele repair.117 Estevesand colleagues118 evaluated the effect of varico-celectomy on intracytoplasmic sperm injectionand found that infertile men undergoing varicoce-lectomy have an improved number of motile spermand a decreased sperm defect score. In addition,they observed significantly higher clinical preg-nancy and live birth rates and a decreased miscar-riage rate in the varicocele-treated group. Thus,even in situations requiring some form of ART,treatment of clinical varicocele in men with mark-edly decreased semen quality increases the cou-ples ability to conceive. With improvement insemen parameters, varicocele repair may alsoenable some couples to undergo IUI before pro-ceeding to more advanced ART.

VARICOCELECTOMY IN 2034: WHAT DOESTHE FUTURE HOLD?

No one has a crystal ball or other tool to foreseethe future, but that should not preclude one fromconsidering the future and all of the possibilitiesthat it might provide diagnostically and therapeuti-cally. Varicoceles are a highly prevalent condition,and it is known that, although some men suffermarked reproductive or endocrine impairment asa result, other patients remain unscathed. Weenvision that an additional 20 years of academicinvestigation and technical advances will affordus more front end tools to determine which pa-tients will be more susceptible to the pathophysi-answered with greater clarity.J Urol 1980;123:3835.

15. Ahlberg NE, Bartley O, Chidekel N. Right and left

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Acta Radiol Diagn (Stockh) 1966;4:593601.

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17. Raman JD, Walmsley K, Goldstein M. InheritanceUltimately, the holy grail of varicocele treat-ment would be a reliable, safe, specific, and effec-tive treatment that does not involve a surgicalincision or percutaneous access of the great veins.These authors suspect that much more than20 years will need to pass for this holy grail treat-ment to be realized.

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Masson & Brannigan144

The VaricoceleKey pointsHistorical perspectiveAnatomyPathophysiologyPresentationDiagnosisUltrasonographyVenography

Treatment indicationsInfertilityHypogonadismSymptomatic Varicoceles

Treatment optionsInguinal and Subinguinal ApproachAlternative Surgical ApproachesPercutaneous Venous Occlusion

Treatment outcomesVaricocelectomy in 2034: what does the future hold?References