A d o l e s c e n t Var i c o c e l e s an d

Infertility
Jessica T. Casey, MS, MD*, Rosalia Misseri, MD

KEYWORDS
 Varicocele  Infertility  Adolescent  Semen analysis  Varicocelectomy

KEY POINTS
 Varicoceles are associated with testicular atrophy and abnormal spermatogenesis, and
varicocele-related testicular damage is thought to be progressive in nature.
 The main indications for varicocele repair include male infertility, adolescents with ipsilat-
eral reduced testicular size or abnormal semen parameters, pain, and low testosterone.
 It is unknown whether adolescent varicoceles are associated with adult infertility and
benefit from early repair, because 80% of adult men with varicoceles are fertile.
 Adolescents likely demonstrate asynchronous testicular growth and multiple ultrasound
evaluations should be used to demonstrate stable, worsening or improving asymmetry
before proceeding with varicocelectomy.
 A meta-analysis demonstrated that sperm density, motility, and morphology were
decreased in adolescents with varicoceles; varicocele repair led to improvement in sperm
density and motility.

INTRODUCTION

A varicocele is a tortuous dilation of the testicular veins of the spermatic cord (plexus
pampiniform) palpable within the scrotum owing to high venous back pressure. The
majority of varicoceles occur on the left side given the insertion of the left gonadal
vein into the left renal vein and its associated higher venous pressure than the inferior
vena cava.
Although varicoceles are rare in prepubertal children (3% in <10 years old), the inci-
dence approaches 15% in those 10 to 19 years old, similar to the incidence in
adults.1,2 Varicoceles are the most common cause of male factor infertility, found in
up to 40% of men with infertility.3 Although the treatment of a varicocele in a man
desiring paternity is warranted, the treatment of varicoceles in adolescent males is
controversial.

The authors have nothing to disclose.

Department of Pediatric Urology, Riley Hospital for Children, 705 Riley Hospital Drive, Suite
4230, Indianapolis, IN 46202, USA
* Corresponding author.
E-mail address: jetcasey@iupui.edu

Endocrinol Metab Clin N Am - (2015) -–-

http://dx.doi.org/10.1016/j.ecl.2015.07.007 endo.theclinics.com
0889-8529/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2 Casey & Misseri

Varicoceles are associated with testicular atrophy and abnormal spermatogenesis,

and varicocele-related testicular damage is thought to be progressive in nature.4 Infer-
tile adult men with varicoceles have been found to have decreased sperm density,
decreased spermatic motility, and abnormal sperm morphology. Additionally, varico-
celes are associated with low testosterone and high follicle-stimulating hormone levels
in adult men.5 In the adolescent population, varicoceles are worrisome given the
concern for progressive effects on testicular growth, ongoing spermatogenesis, and
future fertility.
Varicoceles can be associated with a feeling of “heaviness” after a prolonged period
of standing. However, most varicoceles are asymptomatic, and fewer than 5% of ad-
olescents present with symptoms of scrotal or testicular pain.1 Adult varicoceles are
often detected on an evaluation for infertility. In adolescents, they are most often
detected during a well-child visit or by self-examination, possibly related to asymme-
try in testicular size or the mass itself.
Physical examination to identify varicocele should be performed in both the supine
and standing positions. Palpable varicoceles feel like a “bag of worms” in the upper
scrotum. When supine, the size of the varicocele should reduce. For a thorough exam-
ination or when a varicocele is not obvious, the clinician should have the patient stand
and perform a Valsalva maneuver.
Varicoceles are graded on a scale described by Dubin and Amelar.6 Grade I/III var-
icoceles are palpable only during or after a Valsalva maneuver. Grade II/III varicoceles
are palpable on routine physical examination without the need for a Valsalva maneu-
ver. Grade III/III varicoceles are visible to the eye and palpable on routine physical ex-
amination. Subclinical varicoceles are not detected on physical examination and
found by radiologic examination, most commonly scrotal ultrasonography. Subclinical
varicoceles have been shown to have no impact on fertility, and repair of subclinical
varicoceles has not been shown to improve fertility rates.7 However, subclinical vari-
coceles in the pediatric population have been shown to progress over time and may
require long-term follow-up.8
If a unilateral, right-sided varicocele that does not decompress while supine is
palpated, one should suspect a retroperitoneal mass and undergo cross-sectional
imaging.
In the adolescent population, relative testicular size should be assessed by physical
examination using an orchidometer and verified by ultrasound. Ultrasound has been
shown to be superior for assessment of volume differentials, a necessary component
for evaluation of the adolescent varicocele.9

PATHOPHYSIOLOGY OF VARICOCELES

The theories behind varicocele-associated abnormal spermatogenesis and impaired

fertility include elevated temperature effects on spermatogenesis and increased levels
of oxidants/gonadotoxins.10 The prevailing theory is that poor venous drainage asso-
ciated with varicoceles leads to disruption of the countercurrent heat exchange along
the spermatic cord, leading to elevated scrotal temperatures, which leads to impaired
spermatogenesis.10 Higher scrotal temperatures have been associated with
decreased production of testosterone by Leydig cells, altered Sertoli cell function
and morphology, injury to the germinal cell membrane, as well as decreased protein
synthesis and decreased amino acid transport.11–15
Other theories include oxygen deprivation leading to impaired spermatogenesis,
increased levels of gonadotropins owing to impaired drainage from poor venous
drainage, and increased levels of oxidants within the semen.10 Seminal reactive
 Adolescent Varicoceles and Infertility 3

oxygen species levels have been shown to be higher in the semen of patients with
higher grade varicoceles (grades II and III compared with grade I)16 and in patients
with infertility compared with fertile men.17 Additionally varicocele repair has been
shown to reduce seminal reactive oxygen species levels.17

INDICATIONS FOR TREATMENT OF VARICOCELES

There are 4 main possible indications for the treatment of varicoceles: (1) scrotal pain
related to the varicocele, (2) low testosterone levels in adult men, (3) adult male factor
infertility, and (4) adolescents with ipsilateral reduced testicular size and/or abnormal
semen analyses.

Varicocele-Associated Pain
Men and adolescents who present with painful clinical varicoceles should first attempt
conservative treatment consisting of scrotal support, oral nonsteroidal antiinflamma-
tory medications, and limitation of strenuous activity. In those who do not respond to
conservative treatment and have clinically palpable varicoceles with the associated
characteristic pain (chronic dull ache, dragging pain, or throbbing pain that worsens
with prolonged standing or physical activity), varicocele repair is an option. However,
pain may not resolve despite resolution of the palpable varicocele.18

Varicocele-Associated Hypogonadism
Additionally, varicocele repair has been shown to lead to significant testosterone level
improvements in adult men who are hypogonadal.19–21

Varicocele and Adult Male Infertility

The Male Infertility Best Practice Policy Committee of the American Urologic Associ-
ation recommends that varicocele repair be considered for the male partner of a
couple trying to conceive if the following 4 conditions are met: (1) the couple has docu-
mented infertility based on regular intercourse for more than 12 months, (2) the female
partner has normal fertility or a correctable cause of infertility, (3) the varicocele is clin-
ically palpable on physical examination, and (4) the male partner has 1 or more
abnormal semen parameters or sperm function tests.22 Additionally, men who have
a palpable varicocele and abnormal semen analyses who are not currently attempting
conception but desire future fertility are candidates for varicocele repair. Men with
palpable varicoceles but normal semen analyses who desire future fertility should
be offered semen analysis every 1 to 2 years to detect early signs of abnormal sper-
matogenesis from progressive testicular dysfunction.22
Varicocele repair in adult men has been show to improve not only sperm motility,
density, and morphology, but also specific functional sperm defects (sperm penetra-
tion assay, oxidant determination, and DNA fragmentation).5,23–26 In addition, varico-
cele repair has been show to improve serum follicle-stimulating hormone and
testosterone levels.5,27
Although there remains some controversy as to whether varicocele repair truly im-
proves semen parameters and paternity rates in adult men, meta-analyses limited to
studies of men with clinical varicoceles with abnormal semen parameters (and
excluding men with subclinical varicoceles or normal semen analyses) demonstrate
a benefit to varicocele repair.28,29 In the age of assisted reproductive techniques, vari-
cocele repair can allow couples to “downgrade” the level of complexity of assisted
reproductive techniques needed and allow for the potential for spontaneous preg-
nancy for those with nonobstructive azospermia.30
4 Casey & Misseri

Adolescent Varicoceles
Given the association between adult male varicoceles and infertility, and the known
progressive nature of varicoceles on spermatogenesis, adolescents with varicoceles
are a cause for concern. However, it is unknown whether varicoceles that present in
adolescence will lead to adult infertility and benefit from early repair, because 80%
of adult men with varicoceles do not have associated infertility. Many studies have
attempted to identify criteria by which to determine which adolescents would benefit
from varicocele repair. Criteria have included varicocele grade, testicular size discrep-
ancy, total testicular volume, and semen parameters.
Initial studies demonstrated a correlation between testicular asymmetry and higher
varicocele grade. More recent studies have shown no correlation between testicular
asymmetry and varicocele grade31 or semen parameters and varicocele grade.32
Historically, testicular asymmetry has been the main indication for varicocele repair
in the adolescent population, because there have been no objective measures of
impaired spermatogenesis, for example, semen analysis and paternity. Kass and Bel-
man33 demonstrated increases in testicular volume after varicocele repair. However,
debate remains regarding the precise volume difference to be used, the duration of
follow-up before intervention, and the significance of spontaneous catch-up growth.
Various studies use different testicular size discrepancy measurements to indicate
clinically relevant asymmetry as an indication for varicocele repair. These measure-
ments include 10%, 15%, or 20% relative volume differences or a 2- to 3-mL
absolute volume difference between the affected and unaffected testicle.31,34–36 In a
recent survey of pediatric urologists’ clinical practice, 85% reported greater than
20% testicular size discrepancy to be their criteria for a “significant” difference;
2.5% reported they used the definition of 2 mL absolute volume difference.37
Once significant asymmetry is found (using whichever definition is preferred), the
next question is how long to follow these patients before intervening with varicocele
repair. Investigators have shown that a large percentage of patients with initial asym-
metry become more symmetric with time.38 Conversely, some found that a large per-
centage of patients with initial symmetry become more asymmetric with time.39,40
Kolon and colleagues38 followed 71 boys with varicoceles and a history of 3 or more
ultrasounds and no intervening varicocele repair. They found that 71% of those with an
initial asymmetry of greater than 15% demonstrated spontaneous testicular growth
and no longer met the criteria for surgical intervention (<15% asymmetry) over a
3-year period. Therefore, the authors recommend at least 2, preferably 3, testicular
volume measurements 1 year apart to establish stability of testicular asymmetry.
Poon and colleagues40 followed 181 patients expectantly and found that 35% of those
with initial asymmetry of less than 20% asymmetry developed greater than 20%
asymmetry. Of those with initial asymmetry of less than 20%, 53% remained in that
range over a 12-month period. Korets and colleagues39 followed 89 patients with
initially less than 15% asymmetry and demonstrated that 42% had progression of their
asymmetry over an 18-month period. Adolescents likely demonstrate asynchronous
testicular growth and multiple ultrasound evaluations should be used to demonstrate
stable, worsening or improving asymmetry before proceeding with varicocele repair.
In a recent survey of pediatric urologists, after seeing a patient with “significant” (per-
sonal definition) testicular size discrepancy, 33% would proceed with varicocele repair
and the remainder would schedule a follow-up ultrasound at 6 or 12 months.37
Because using testicular asymmetry as a surrogate marker for abnormal spermato-
genesis may not be ideal, recent research has attempted to correlate adolescent
semen parameters with testicular asymmetry. In a study of 57 Tanner stage V
 Adolescent Varicoceles and Infertility 5

adolescent males aged 14 to 20 with clinically apparent varicoceles (grades I-III),

those with greater than 20% asymmetry had significantly lower sperm concentration,
total motile sperm count, and percent motile sperm.41 In a more recent study, Christ-
man and colleagues42 found that total testicular volume at the end of adolescence
correlated more with total motile sperm count than either prior total testicular volumes
or testicular volume differentials. Additionally, the overall suboptimal semen parame-
ters (66% with low total motile sperm counts) in this population of adolescents with
varicocele on active surveillance made these authors call into question the use of serial
monitoring of testicular volume differential to identify surgical candidates. They now
rely more heavily on semen analysis parameters to determine the need for varicocele
repair. Other studies by this group have demonstrated that the semen analysis param-
eters of youths (median age, 18.5 years) with uncorrected varicoceles more closely
resemble those of treated bilateral cryptorchidism than unilateral cryptorchidism,
possibly reflecting poorer future fertility outcomes than previously thought.43
A recent meta-analysis evaluated the effect of varicoceles and varicocele repair on
semen analysis of youths (defined as 15–24 years old).44 After an analysis of 10 studies
including 357 varicocele and 427 control patients, they demonstrated that sperm den-
sity, motility, and morphology were decreased significantly in patients with varico-
celes. Additionally, an analysis of another 10 studies including 379 treated and 270
untreated patients demonstrated significant improvement in sperm density and
motility after varicocele repair. Therefore, without the advantage of a large, random-
ized trial, there is good evidence that varicoceles affect spermatogenesis in adoles-
cents and some improvement can be seen with varicocele repair.
Despite the use of semen analyses in research to stratify the effect of varicoceles on
adolescent spermatogenesis, it does not seem to have crossed the line into clinical
use. In a survey of 74 pediatric urologists, 57% reported having never sent a patient
for a semen analysis.37 In another survey of 131 pediatric urologists, only 39% report
having used altered semen parameters as an indication for varicocele repair.45
The ultimate predictor of the benefit of varicocele repair in adolescents is eventual
paternity. Salzhauer and colleagues46 surveyed 50 patients who underwent varicocele
repair and were now more than 21 years old. Of the 18 patients who had attempted
paternity, all 18 were successful, demonstrating a lack of harm from varicocele repair.
However, this study does not demonstrate evidence for infertility in the unrepaired
adolescent varicocele. Bogaert and colleagues47 demonstrated no improvement in
paternity after varicocelectomy versus observation in a cohort of adolescents
screened for varicoceles. In this group, only 8% of those undergoing varicocelectomy
had testicular asymmetry. These studies shed some light onto the effect of adolescent
varicoceles on eventual paternity, but are incomplete studies with mixed populations.
Given the controversy surrounding adolescent varicocele management, it is not sur-
prising that surveys of pediatric urologists have revealed a lack of consensus on diag-
nostic approaches, treatment decisions and operative approaches.37,45

APPROACH TO VARICOCELE REPAIR

Surgical treatments for varicocele repair include open retroperitoneal (Palomo), laparo-
scopic retroperitoneal (artery-sparing or non–artery-sparing), inguinal approach (Ivanis-
sevich), and the subinguinal approach. The addition of the surgical microscope and
intraoperative Doppler ultrasonography has led to a decrease in postoperative complica-
tions (testicular artery injury, hydrocele formation, and varicocele recurrence). Addition-
ally, interventional radiology varicocele repair procedures include percutaneous
6 Casey & Misseri

embolization and sclerotherapy. In a recent survey of pediatric urologists, 38% per-

formed laparoscopic retroperitoneal varicocelectomies, 28% subinguinal microsurgical,
14% inguinal, 13% open retroperitoneal, 5% embolization, and 3% sclerotherapy.45

SUMMARY

Adult varicoceles are common in men with infertility and varicocele repair in this pop-
ulation has demonstrated improved semen parameters and paternity outcomes. How-
ever, without solid objective endpoints (reproducible semen analyses, paternity), the
indications for adolescent varicocele repair remain controversial.

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