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Varicoceles in the pediatric and

adolescent population: threat to


future fertility?
Deborah L. Jacobson, M.D.a,b and Emilie K. Johnson, M.D., M.P.H.a,b
a b
Division of Pediatric Urology, Ann & Robert H. Lurie Children's Hospital of Chicago; and Department of Urology,
Northwestern University Feinberg School of Medicine, Chicago, Illinois

Determining the effect of varicoceles on future fertility is challenging owing to multiple issues in children/adolescents, including: lim-
itations in obtaining and interpreting semen analyses; potential for unequal differential testicular growth during puberty regardless of
varicocele presence; and the potential for a lengthy interval between surgical intervention for varicocele in adolescence and attempts at
paternity. This review presents a summary and evaluation of the available evidence relating to future fertility among children and ad-
olescents with varicoceles. Data relating to proxy fertility measures in children/adolescents, including testicular size asymmetry and
semen analysis abnormalities, demonstrate that these proxy measures are imperfect predictors of future fertility. Two large, recently
published series of adolescents undergoing varicocele treatment showed conflicting paternity outcomes. Pediatric and adolescent vari-
cocele will remain a clinical conundrum, subject to both over- and under-treatment, until more definitive prospective data are available.
(Fertil SterilÒ 2017;108:370–7. Ó2017 by American Society for Reproductive Medicine.)
Key Words: Fertility, pediatrics, varicocele

Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/
16110-fertility-and-sterility/posts/18172-24312

selected for final inclusion in this re-

V
aricoceles in the pediatric and evidence relating to the effects of vari-
adolescent population pose a coceles in children and adolescents on view on the basis of relevance to the
clinical challenge because of future fertility. For context, an over- subtopics detailed below.
uncertain effects on future fertility, view of pediatric/adolescent varicocele
and there are currently no guidelines presentation, epidemiology, pathogen-
in place for management of pediatric esis, clinical evaluation, and treatment
PRESENTATION AND
patients with varicoceles. Determining options is also presented. To conduct EPIDEMIOLOGY
the effect of varicoceles on future this review, searches of PubMed, Web The definition and grading system used
fertility is challenging owing to multiple of Science, EMBASE, and Scopus were to characterize varicoceles is identical
issues in children/adolescents, performed. Search terms were entered in children/adolescents and adults. A
including: limitations in obtaining and to identify primary literature related varicocele is defined as an abnormal
interpreting semen analyses (SA); po- to varicoceles, pediatrics, semen anal- dilation of the pampiniform plexus in
tential for unequal differential testicular ysis, testicular hypotrophy, and the scrotum, and children/adolescents
growth during puberty regardless of fertility/infertility. Abstracts were re- with varicocele most often present to
varicocele presence; and the potential viewed by both authors and subcatego- a urologist after an incidental diagnosis
for a lengthy interval between surgical rized. Book chapters and non–English by their pediatrician. Varicoceles in
intervention for varicocele in adoles- language articles were excluded, and children/adolescents are clinically
cence and attempts at paternity. additional articles were selected after graded according to the classification
The purpose of this review is to review of the references from the initial system originally described by Dubin
summarize and evaluate the available articles identified. Articles were and Amelar in 1970 (1), in which grade
1 indicates that the varicocele is
palpable with Valsalva, grade 2 indi-
Received May 8, 2017; revised June 21, 2017; accepted July 13, 2017; published online August 10, 2017.
cates palpability with standing only,
D.L.J. has nothing to disclose. E.K.J. has nothing to disclose. and grade 3 indicates visibility with
Reprint requests: Emilie K. Johnson, M.D., M.P.H., Ann & Robert H. Lurie Children's Hospital, Division standing.
of Urology, 225 E. Chicago Avenue, Box 24, Chicago, Illinois 60611 (E-mail: ekjohnson@
luriechildrens.org). In children/adolescents the preva-
lence and grade distribution of varico-
Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282/$36.00
Copyright ©2017 American Society for Reproductive Medicine, Published by Elsevier Inc.
celes varies according to whether
http://dx.doi.org/10.1016/j.fertnstert.2017.07.014 epidemiologic or clinical-level studies

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are evaluated. Multiple European studies have reported popu- Although not studied as comprehensively as in adults,
lation prevalence estimates of pediatric/adolescent varico- several theories about the relationship between varicoceles
cele, which are largely derived from school screening and future infertility have been evaluated among adolescents.
protocols. Overall prevalence estimates range from 4.1% to For example, one study found elevated levels of nitric oxide
35.1%, and prevalence seems to increase with increasing pa- and nitrotyrosine (a marker of nitric oxide damage) in the
tient age (2–7). For example, one Turkish study found a 0.8% spermatic veins of adolescent patients with varicocele (21).
varicocele prevalence in boys aged 2–6 years, with an In another study, Bertolla et al. (22) compared SA parameters
increase to 11% by age 11–19 years (2). The authors also and DNA fragmentation in adolescent boys with and without
noted a sharp rise in prevalence in boys aged 10–14 years varicocele. Although no difference was noted between varico-
(2). In these population-level studies, grade 1 varicoceles cele patients and normal controls with respect to SA param-
tended to be most common, followed by grade 2 and then eters, including concentration, motility, and morphology, a
grade 3. In a cohort of 960 boys from Montenegro, overall higher rate of DNA fragmentation was noted in adolescents
varicocele prevalence was found to be 9.7%. In this study, with a varicocele. The authors postulate that DNA fragmenta-
51% of 94 boys with a varicocele had grade 1, 33% grade 2, tion may be an early marker of apoptosis and/or oxidative
and 16% grade 3 on screening evaluation (7). Interestingly, stress, even when SA parameters are normal (22). These find-
Niedzielski et al. (4) found a stable prevalence of grade 1 vari- ings were corroborated in a 2014 study by Lacerda et al. (23),
cocele in Polish school boys with increasing age but noted in which adolescent patients with significant preoperative
that grades 2 and 3 became more common as boys began DNA fragmentation demonstrated post-varicocelectomy
progress through adolescence. The prevalence of palpable improvement in DNA fragmentation rates.
bilateral varicoceles in adolescents with varicocele ranges
from 10.8% to 59.1%, with subclinical right varicoceles in
an additional 8.7%–17.6% of patients (8–12). Varicoceles CLINICAL EVALUATION AND RELIABILITY OF
are more common in boys who are taller, have lower body SIZE ESTIMATION METHODS
mass index, and have larger phalluses, although the reasons Clinical evaluation of the pediatric/adolescent varicocele fo-
for these associations are unclear (3, 13). cuses on the perceived potential for future infertility, which is
Similar to population-level screening studies, clinical largely based on testicular size estimation and SA (when
studies of pediatric/adolescent varicocele conducted in urol- feasible). Although large testicular size discrepancies can be de-
ogy clinics demonstrate that patients with varicoceles tend tected via physical examination, adjunctive strategies for more
to present during mid- to late adolescence. One such study, accurate estimation of testicular size are recommended. Multi-
spanning a 17-year period, found a mean (SD) age at pre- ple different orchidometers have been developed for measuring
sentation of 15.2  3.5 years (14). In contrast to the larger testicular size (Table 1) (24, 25), and several formulas for
epidemiologic studies, children/adolescents evaluated in estimating testicular volume according to ultrasound
urology clinics tend to have a vastly different grade distribu- measurements have been utilized in relevant publications
tion than boys with varicocele who are identified through (Table 2) (24, 26). The Lambert formula (27) (length  width
population-based screening. It is rare for boys presenting to  height  0.71) for measurement of testicular volume is the
a urology clinic to have a grade 1 varicocele, with rates most commonly used formula in recently published pediatric/
ranging from 0 to 15% (15–18). In these studies of patients adolescent varicocele literature. A recent survey of pediatric
evaluated in urology clinics, at least a plurality of patients urologists found that 49% of respondents reported
tends to present with a grade 3 varicocele. In one study monitoring testicular size by ultrasound, 38% by
patients with grade 3 varicocele comprised 68% of the study orchidometer, and 11% by physical examination alone (28).
sample (18). This difference in grade at presentation in In general, ultrasound measurements are considered
epidemiologic studies vs. studies of patients presenting to somewhat more accurate for estimating true testicular volume
urology clinics is likely due to referral bias. when compared with orchidometers. This finding is supported
by comparisons made in two recent studies. In the first, or-
chidometer measurements and ultrasonograhic volume cal-
PATHOGENESIS culations were compared with measured testicular volume
There are multiple proposed pathologic mechanisms for the among euthanized dogs (24). In the second, orchiectomy
relationship between varicoceles and infertility, a full discus-
sion of which is outside the scope of this review. In general it
is not understood why some men with varicocele develop TABLE 1
infertility and some do not. It is postulated that multiple fac-
tors, including poor testicular perfusion, heat stress, oxidative Orchidometers for testicular volume measurement.
stress, and endocrine abnormalities, contribute to the devel- Name of device Shape
opment of varicocele-associated infertility (19, 20). The
Prader Solid ellipse
uncertainty about which individuals with a varicocele will Rochester Cutout to surround testis
develop infertility is especially vexing for clinicians trying Seager Caliper to measure, then calculate volume
determine whether treatment for pediatric/adolescent according to a formula
varicocele is indicated, because any attempts at paternity Takihara Cutout to surround testis
Jacobson. Varicoceles in pediatrics. Fertil Steril 2017.
will occur many years in the future.

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SA parameters (32). In another contemporary survey of pedi-


TABLE 2
atric urologists, 59% reported following adolescents for
Formulas for calculating testicular volume.
persistent size discrepancy over time, whereas 32% reported
intervening after a size discrepancy has been documented
Name Formula once (28). Recently it has been suggested that an abnormally
Behre (p/6)  L  D2 low total testicular volume may be a more accurate reflection
Ellipsoid L  W  H  0.52 of the negative effects of a varicocele on testicular function
Lambert L  W  H  0.71
Prolate spheroid L  W2  0.52
(14, 33), thus this parameter may replace size differential as
Note: D ¼ diameter; H ¼ height; L ¼ length; W ¼ width.
an indication for pediatric/adolescent varicocelectomy in
Jacobson. Varicoceles in pediatrics. Fertil Steril 2017.
the future.
When treatment is recommended on the basis of the indica-
tions discussed above, options for repair of pediatric/adolescent
specimens from prostate cancer patients were compared with varicocele are similar to adult treatment options. These include
several ultrasound-based volume measurements (29). Both embolization/sclerotherapy, laparoscopic varicocelectomy
studies concluded that measurements utilizing the Lambert (with or without artery sparing), Palomo retroperitoneal varico-
formula most closely correlated with measured testicular vol- celectomy, inguinal varicocelectomy, and subinguinal micro-
umes. In a clinical study of men presenting to an infertility surgical repair. Recent reports have indicated increasing
clinic, Prader orchidometer measurements were highly corre- utilization of laparoscopic repairs and decreased utilization of
lated with testicular volumes measured via ultrasound, but retroperitoneal repairs when compared with surgical ap-
accuracy varied with provider experience. In this study, Behre proaches reported more than a decade ago (31, 32, 34).
et al. (26) found that Prader orchidometer measurements Presently laparoscopic varicocelectomy is the most common
taken by a more experienced andrologist were more highly approach in the pediatric/adolescent population, with 38%–
correlated with volumes measured by ultrasound. 44% of pediatric urologists selecting this approach (31, 32).
For patients who can provide a semen specimen, SA pro- Subinguinal microsurgical varicocelectomy rates have
vides a useful adjunct to history, physical examination, and remained relatively stable over time, with approximately 25%
testicular size measurements as determined by orchidometer of urologists reporting this as their preferred approach in both
or ultrasound. However, use of SA is somewhat limited by older and more contemporary reports (31, 32, 34). In a recent
multiple factors, including [1] lack of standardized SA values review of 15 adolescent series a bilateral procedure was
for adolescent patients, [2] inability to obtain a specimen from performed 0%–85.7% of the time (median 5%) among boys
some patients due to physical or emotional maturity con- undergoing varicocelectomy (8). Reported recurrence rates for
straints, and [3] provider reluctance or discomfort with SA. adolescent varicocele treatment modalities include 13% for
Fortunately, the concordance between key parameters (total percutaneous embolization (35), 3% for sclerotherapy (36),
count, total motile sperm count [TMC]) obtained on consecu- 3%–5% for laparoscopic varicocelectomy (37, 38), and 6%–
tive SA seems to be high; thus, even one SA can provide valu- 7% for inguinal and subinguinal approaches (37, 39, 40).
able information in adolescents (30). Though not validated in
an adolescent population, the World Health Organization
RELATIONSHIP BETWEEN ADOLESCENT
reference values are generally used to interpret SA among ad-
olescents. A recent survey of pediatric urologists indicated
VARICOCELE AND ENFERTILITY
that most (53% of the 168 who responded to the survey) never Traditional indications for treatment of pediatric/adolescent
ask for an SA in their practice, whereas only 13% routinely do varicocele, including asymmetric growth and SA abnormal-
so (31). In this survey Fine et al. also noted that 25% of pedi- ities, assume that these indications serve as a reliable proxy
atric urologists felt uncomfortable discussing SA with adoles- for future fertility potential. There is an inherent assumption
cents in general, and 22% felt discomfort depending on the that varicocelectomy will result in improvement of such pa-
patient/family (31). Even when barriers to SA are overcome rameters, and ultimately future fertility, whereas observation
and a SA is obtained, a ‘‘normal’’ SA may not reveal more sub- will result in deterioration of fertility potential over time.
tle damage, such as sperm DNA fragmentation, associated Many investigators have sought to clarify the relationship be-
with future fertility challenges (22). tween proxy measures of future testicular function (testicular
volume, SA abnormalities, hormonal abnormalities) and
fertility, as detailed below. Emerging data have also begun
TREATMENT to examine the relationship between treatment of varicocele
Common indications for surgical treatment of pediatric/ during childhood/adolescence and paternity outcomes.
adolescent varicocele include testicular size discrepancy, SA
abnormality, and patient discomfort. Variability in urologists'
interpretation of these indications exists, and not all urolo- Testicular Consistency, Asymmetry, and Total
gists recommend varicocelectomy for every indication. In Testis Volume
one recent survey of pediatric urologists, 96% reported rec- Historically, testicular consistency was considered a reliable
ommending varicocelectomy for decreased ipsilateral testic- indicator of the quality of spermatogenesis (41), and changes
ular size, 79% recommended varicocelectomy for testicular in testicular consistency were considered an indication for
pain, and only 39% recommended the procedure for altered surgical intervention in adolescents with varicocele (42).

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Although testicular consistency is occasionally reported in postoperative volume gain among 16 of 20 adolescents under-
more contemporary literature, it is not generally the outcome going microsurgical varicocelectomy for grade 2–3 varicocele
of interest. A 2013 cross-sectional cohort of more than 4,000 who were followed for a mean of 3.3 years. Since that time,
Turkish schoolboys used testicular consistency as an indicator randomized controlled trials have demonstrated significant ab-
of testicular atrophy, but consistency-specific outcomes were solute increases in bilateral testis volumes (56, 57) and
not reported (2). Studies by Gershbein et al. (43) and Ku et al. improved differential volumes (58) among adolescents
(44) considered palpably soft testes an indication for surgical treated for varicocele without concomitant improvements
intervention, but postoperative testicular consistency was not among control patients. A recent meta-analysis of 14 studies
discussed. A 2002 study by Cayan et al. (45) reported on 15 involving 1,475 patients also demonstrated significant postop-
boys with a clinically palpable varicocele and associated erative reductions in testicular asymmetry, with an overall
soft testicle, all of whom normalized postoperatively. average testicular catch-up growth rate of 76.4% (59). Rates
The use of testicular asymmetry (also referred to as hypo- of catch-up growth in retrospective series range from 69% to
trophy, or testicular volume differential) as a surrogate for 86% (11, 17, 43, 54, 60). Catch-up growth begins as early as
testicular dysfunction among adolescents with varicocele is 9 months after surgical repair, with the most significant in-
controversial. Part of the debate stems from lack of consensus creases noted at 12 to 24 months (61). Factors including vari-
on what constitutes asymmetry, with authors reporting on ab- cocele grade, duration of follow-up, and presence of unilateral
solute size differentials of 2–3 mL (46), relative size differentials vs. bilateral varicocele have not been associated with catch-up
ranging from 10% to 25% (47), or some combination of these growth (11, 17, 45, 62). Ipsilateral testicular hypertrophy after
values. A 2016 survey of 168 Society for Pediatric Urology surgical intervention has also been reported in some series,
members (53% response rate) found that 58.7% of respondents with up to 38% of patients affected (43, 45, 60).
defined asymmetry as a >20% size differential, whereas 6.6% Similar to the clinical interpretation of catch-up growth,
used a >10% criterion, and 31% of respondents considered the implications of testicular asymmetry itself are also un-
longitudinal changes only (31). In large population-based co- clear. A study by Diamond et al. (63) demonstrated signifi-
horts, the estimated prevalence of adolescent testicular asym- cantly lower sperm concentration and TMC in patients with
metry in the setting of varicocele is between 6.5% and 9.3%, testicular asymmetry >10%, with increasingly dramatic dif-
depending on the use of a 10% vs. 20% threshold, whereas there ferences for larger volume differentials. Among patients
is no evidence of asymmetry among pre pubertal patients (6, with 10% vs. 15% vs. 20% asymmetry, median sperm concen-
10). In adolescent cohorts referred for clinical follow-up, prev- trations were 70 106/mL vs. 35 106/mL vs. 15 106/mL,
alence estimates range from 33% to 70% for >10% asymmetry respectively, and TMC were 64 106 vs. 32 106 vs. 10
(18, 45, 48, 49), 17% to 55% for >15% asymmetry (43, 49, 50), 106 (63). Similarly, Keene et al. (64) found that sperm con-
and 7% to 48% for >20% asymmetry (14, 17, 23, 48, 49, 51–53) centration and quality were lower in adolescent patients with
In addition to varying definitions of asymmetry, measurements >20% asymmetrical testes. However, Christman et al. (49)
may be obtained via various orchidometers (Table 1) or via demonstrated that the presence of >20% testicular asymme-
ultrasound measurements using one of several volume try was not predictive of abnormal semen analysis; instead,
formulas (Table 2). These discrepancies make it difficult to the total testicular volume at the time of final ultrasound
compare values between studies. was associated with low TMC (<20 106/mL). In a recent
Even if one assumes that consistent methods for deter- report, Kurtz et al. (14) found an association between testic-
mining testis volume and standard definitions of asymmetry ular volume differentials >20% and low TMC (odds ratio
exist, the natural history of testicular asymmetry remains un- [OR] 2.1, 95% confidence interval [CI] 1.0–4.1), with a signif-
clear. A 2009 study by Kozakowski et al. (18) found that 71% icantly stronger association between total testis volume
of 24 patients with >20% asymmetry had persistent or wors- <30 mL and low motile sperm counts (OR 4.2, 95% CI 1.8–
ened asymmetry at a mean 13.2 months' follow-up. An addi- 9.7) (14). The studies by Christman and Kurtz suggest that to-
tional 36% of the 53 patients without initial asymmetry tal testis volume may be more important than testicular
developed >20% asymmetry during that same period. How- asymmetry for predicting of future fertility.
ever, Kolon et al. (54) followed 133 adolescents for a mean
3.5 years and noted resolution of size asymmetry among
71% of conservatively managed patients. The group deter- Semen Analysis Abnormalities
mined that asynchronous growth often normalizes over Semen analysis has the potential to serve as a useful adjunct
time and recommended extended follow-up before interven- to testicular size estimation in determining who may benefit
tion. A retrospective review by Van Batavia et al. (50) shows from treatment of pediatric/adolescent varicocele. However,
more mixed results, with 33% resolution vs. 24% stability vs. as mentioned earlier, there are multiple barriers to obtaining
43% progression at a mean 11.7 months of observation. These SA in the pediatric/adolescent population. In patients for
variable reports of changes in testicular asymmetry make whom an SA is obtained, this measurement can provide
studies of testicular growth after varicocelectomy somewhat potentially valuable insight into fertility potential and can
difficult to interpret, because it is unknown exactly how be used to assess the success of varicocelectomy (similar to
many boys would have experienced a resolution in size asym- adults). However, controversy exists about the utility of SA
metry without intervention. as a proxy measure of future fertility, and it is not completely
The concept of postoperative testicular catch-up growth clear that improvements in SA parameters will translate into
was first introduced in 1987, when Kass et al. (55) noted improved fertility outcomes for adolescents with varicocele.

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Among infertile adults with a varicocele, SA parameters (in Hormonal Abnormalities


addition to paternity rates) are an important component of the Along with evaluations for testicular asymmetry and SA ab-
patient assessment and one of the key outcome measures as- normalities, a hormonal evaluation may help to determine
sessed after varicocelectomy. Adults with varicocele frequently whether a varicocele is affecting testicular function. Multiple
have abnormal SA findings (46, 65), with a large cross- hormonal abnormalities have been noted among adult men
sectional study demonstrating a negative association between with varicocele. A large cross-sectional study of European
sperm concentration and increasing varicocele grade. Sub- men undergoing compulsory evaluation before military ser-
group analysis of patients with bilateral varicoceles demon- vice demonstrated that varicoceles are associated with signif-
strated sperm concentrations in between those of men with icant elevations in FSH and inhibin B; there was no
grade 2 and grade 3 varicoceles (65). Multiple studies have association between serum T and varicocele status (65). A pro-
demonstrated improvement in TMC and other SA parameters spective, nonrandomized, comparison study of men with a
after varicocelectomy (66, 67). In one retrospective study, history of infertility, clinical varicocele, and hypogonadism
Zorba et al. (67) reported a mean TMC increase from 10.7  who underwent either microscopic varicocelectomy or assis-
106/mL to 30.2  106/mL among adult men undergoing ted reproduction demonstrated that the mean total T rose
varicocelectomy. Steckel et al. (68) examined the relationship from 1.77 ng/mL to 3.01 ng/mL in the varicocelectomy
between varicocele size and response to varicocelectomy in cohort, whereas it declined from 1.85 ng/mL to 1.77 ng/mL
86 men, finding that SA among men with a grade 3 in the assisted reproduction cohort. The authors conclude
varicocele improved more than in those with lower-grade var- that varicocelectomy significantly improves serum T among
icoceles. A 1996 study by Takahara et al. (69) corroborated infertile, hypogonadal men with varicocele (74). These find-
these findings, though there were no grade-associated differ- ings were corroborated by Hsiao et al. (75), who found
ences noted in a subsequent study by Ishikawa et al. (70). increased serum T values in 65 of 78 men with treated varico-
As seen in adults, varicoceles also seem to negatively affect celes, with a mean 109.1-ng/mL elevation. Zalata et al. (76)
SA parameters in adolescents. As previously mentioned, Dia- found that androgen receptor expression was significantly
mond et al. (63) demonstrated a dramatic decrease in TMC with diminished in 125 infertile men with varicocele when
increasing degrees of testicular asymmetry. In another prospec- compared with 107 infertile men without varicocele and 67
tive study by Mori et al. (71), sperm concentration and progres- fertile controls.
sive motility were lower in boys with varicocele vs. those without. Studies of hormonal abnormalities among adolescents
However, both SA parameters were within normal limits accord- with varicocele have shown mixed results. Abnormalities
ing to 1999 World Health Organization reference values. in GnRH stimulation (77), LH response (78), FSH levels
The natural history of SA parameters among adolescents (62), inhibin B levels (79), and T (12) have been reported
with varicocele is still being elucidated. A recent study by Chu in small retrospective series. Fideleff et al. (80) performed
et al. (16) indicates that abnormal SA findings among many a larger, prospective study of 93 adolescents aged
adolescents with varicocele will normalize without interven- 8–16 years (mean 12.8 years) with left varicoceles who un-
tion. In this retrospective review, 47% of adolescent boys with derwent baseline and stimulated hormonal testing
an abnormal initial TMC (<20  106/mL) normalized without including GnRH, LH, FSH, and T. Laboratory results were
surgical correction of the varicocele. compared with those from 29 normal controls, and the au-
As in adults, varicocelectomy in adolescents seems to thors found no correlation between presence of a varicocele
improve SA parameters, including sperm concentration and and hormonal findings when controlling for Tanner stage.
motility (44, 72). Yamamoto et al. (57) conducted a randomized Twenty-eight adolescents ultimately underwent varicoce-
trial of Palomo varicocelectomy vs. observation in adolescents lectomy, and postoperative laboratory testing was
and found that sperm concentration increased significantly in completed in 14 patients. There were no statistically signif-
patients undergoing varicocelectomy vs. observation. Sperm icant differences in pre- vs. postoperative hormonal pa-
concentrations were also higher in the varicocelectomy group rameters, leading the authors to conclude that there is
compared with normal controls (57). However, all values (even not a reliable biomarker for predicting testicular function
preoperative) were within normal limits, indicating uncertainty in adolescents (80). To date, hormonal abnormalities have
as to whether the observed increase after varicocelectomy not been frequently utilized in the evaluation and follow-
would be clinically significant in terms of future paternity. In a up of children/adolescents with varicocele.
retrospective review of adolescents and adults undergoing
varicocelectomy, Ku et al. (44) reported a significant
improvement in both sperm concentration (31.7  106/mL to Effect of Varicocele Treatment in Childhood/
40.7  106/mL) and motility (41.8% to 52.1%) after Adolescence on Paternity
varicocelectomy. In this study, the increase in motility was not Although proxy measures of future fertility are used by ne-
significant among adults, and the authors suggest that this cessity to determine which children/adolescents with vari-
provides an argument in favor of prophylactic varicocelectomy cocele may benefit from treatment, the ultimate outcome
for adolescents. A recent retrospective analysis of adolescents measure is paternity. Varicoceles are present in approxi-
undergoing varicocelectomy demonstrated improvement in mately 31% of men evaluated for infertility (81), and re-
TMC in 82% and normalization of TMC in 55% of patients sults from studies of infertile adults with varicocele are
whose only indication for surgery was abnormal findings on used, in part, to justify treatment of varicocele in child-
SA (73). hood/adolescence. Spontaneous paternity rates among

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men with a history of infertility and subsequent varicoce- the control group (OR 3.6, 95% CI 2.3–5.7), leading the au-
lectomy range from 33% to 48% (66, 82, 83). Abdel- thors to conclude that adolescent varicocele repair is bene-
Meguid et al. (83) reported on a prospective, nonmasked, ficial for paternity (12). However, Bogaert et al. (86)
randomized controlled trial of 145 men aged 20–39 years reported contradictory results among patients participating
with a history of infertility, varicocele, and at least one in a Belgian adolescent screening program. The authors
impaired semen parameter who underwent microscopic surveyed 361 men diagnosed with varicocele following
varicocelectomy vs. observation. Spontaneous pregnancy adolescent screening, 58% of whom underwent sclerother-
was achieved in 33% of treated patients vs. 14% of controls apy at age 11–18 years and 42% of whom were conserva-
over 1 year of follow-up (OR 3.04, 95% CI 1.3–7.0). The tively followed. The two groups had similar age at
authors posited that varicocelectomy was superior to diagnosis, prevalence of testicular asymmetry, varicocele
observation in this population and calculated that the grade, and desire for paternity. Overall, 158 men desired
number needed to treat to allow one extra pregnancy was paternity. At a median follow-up of 14 years, paternity
5.27 men (83). was documented in 67 of 86 (78%) of the active treatment
Retrospective cohort studies demonstrate comparable group and 61 of 72 (85%) of the conservative managed
outcomes. A 1994 review of 13 infertile patients with a his- group. Between-group outcomes were not significantly
tory of varicocele and prior unsuccessful IVF cycle demon- different, leading the authors to conclude that there is no
strated improvements in oocyte fertilization rates after benefit to treatment for adolescent varicocele (86). Other
Palomo varicocelectomy and subsequent IVF. Whereas small surveys report paternity rates of 75%–100% but are
only 8 of 82 oocytes (10%) were successfully fertilized pre- limited by small sample sizes (12–18 patients) and rela-
operatively, 31 of 76 (41%) were fertilized postoperatively, tively youthful cohorts (87, 88).
for a 31% overall pregnancy rate (84). Similarly, Kamal
et al. (66) reviewed pregnancy outcomes among 159 infer-
tile couples at a mean 30 months after microsurgical vari-
cocelectomy. The authors found an association between RECOMMENDATIONS FOR PEDIATRIC/
preoperative sperm concentration and spontaneous preg- ADOLESCENT VARICOCELE
nancy rates, with an 8% pregnancy rate for men with con- On the basis of the data presented in the previous sections,
centrations <5  106/mL, a 42% rate for men with summary recommendations for evaluation based on size esti-
concentrations 5–10  106/mL, and a 74% rate for mation and SA were developed and are displayed in Table 3.
men with concentrations >20  106/mL (66). A recent Also included are key targets for future research related to pe-
meta-analysis by Kirby et al. (85) also demonstrated diatric and adolescent varicocele.
improvement in live birth rates among oligospermic and To conclude, varicoceles are a common entity in adoles-
azoospermic men with undergoing varicocele repair (OR cents, and concern exists that they may negatively affect
1.76, 95% CI 1.2–2.5). Although these cohorts were limited future fertility potential. Testicular asymmetry and SA abnor-
to infertile adults, improvements in postoperative paternity malitity are the traditional proxy measures of future fertility
rates are often used to justify adolescent procedures. that have been used as indications for varicocelectomy in
Several studies of paternity among men who under- children/adolescents. Although multiple series have shown
went adolescent varicocele repair have recently been pub- improvement in these proxy parameters after varicocelec-
lished. The largest of these compared paternity rates and tomy, these measures are limited by uncertain natural history
time to conception among 286 men who underwent micro- and lack of a direct relationship between improvement in
scopic varicocelectomy at age 12–19 years with paternity these parameters and future paternity. Two large, recently
among 122 men who were managed conservatively in published series of adolescents undergoing varicocele treat-
that same time period. Overall paternity rates were 221 of ment showed conflicting paternity outcomes. Pediatric/
286 (77%) in the treatment group vs. 59 of 122 (48%) in adolescent varicocele will remain a clinical conundrum,

TABLE 3

Pediatric/adolescent varicocele: summary recommendations and targets for future research.


Topic Summary recommendations Targets for future research
Size estimation Testicular size should be followed with serial Determining whether testicular size discrepancy or total
measurements via either orchidometer or testicular testicular volume is a better proxy for future fertility
ultrasound. Physical examination alone is not
recommended.
Semen analysis A single SA should be offered to all peri- or postpubertal Creating SA parameters to account for adolescent semen
boys. analyses and expanding parameters outside the
traditional SA (i.e., DNA fragmentation) to determine
the efficacy of varicocelectomy
Future paternity Increase the number of longitudinal studies of paternity
among adolescents with a history of varicocele
Jacobson. Varicoceles in pediatrics. Fertil Steril 2017.

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VIEWS AND REVIEWS

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varicocele. Hum Reprod 2003;18:26–9.
Acknowledgments: The authors thank Peggy Murphy, 22. Bertolla RP, Cedenho AP, Hassun Filho PA, Lima SB, Ortiz V, Srougi M. Sperm
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24. Paltiel HJ, Diamond DA, Di Canzio J, Zurakowski D, Borer JG, Atala A. Testic-
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