Journal of Endocrinological Investigation

https://doi.org/10.1007/s40618-018-0952-7

REVIEW

Treating varicocele in 2018: current knowledge and treatment options

M. Zavattaro1 · C. Ceruti2 · G. Motta1 · S. Allasia1 · L. Marinelli1 · C. Di Bisceglie1 · M. P. Tagliabue1 · M. Sibona2 ·
L. Rolle2 · F. Lanfranco1 

Received: 18 May 2018 / Accepted: 11 September 2018

© Italian Society of Endocrinology (SIE) 2018

Abstract
Purpose  Varicocele is defined as a state of varicosity and tortuosity of the pampiniform plexus around the testis caused by
retrograde blood flow through the internal spermatic vein. The prevalence of clinically relevant varicocele ranges from 5 to
20% in the male population and is often associated with infertility and reduction of sperm quality. In this review, the patho-
physiology and clinical aspects of varicocele are reviewed along with therapeutic options and treatment effects on sperm
parameters and fertility both in adult and in pediatric/adolescent subjects.
Methods  We conducted a Medline and a PubMed search from 1965 to 2018 to identify publications related to varicocele
clinical aspects, treatment procedures and treatment outcomes. Keywords used for the search were: “varicocele”, “varico-
celectomy”, “sclerotherapy”, “male infertility”, “subfertility”, and “semen abnormalities”.
Results  Data from a large number of studies in adolescent and adult males indicate that varicocele correction improves
semen parameters in the majority of patients, reducing oxidative stress and improving sperm nuclear DNA integrity either
with surgical or percutaneous approach.
Conclusions  Varicocele repair seems to represent a cost-effective therapeutic option for all males (both adolescent and
adults) with a clinical varicocele in the presence of testicular hypotrophy, worsening sperm alterations or infertility. On the
other hand, some investigators questioned the role of varicocelectomy in the era of assisted reproduction. Thus, a better
understanding of the pathophysiology of varicocele-associated male subfertility is of paramount importance to elucidating
the deleterious effects of varicocele on spermatogenesis and possibly formulating new treatment strategies.

Keywords  Varicocele · Male infertility · Sperm · Varicocelectomy

Introduction is often associated with valvular insufficiency, but venous

Varicocele is defined as a state of varicosity and tortuosity
of the pampiniform plexus (PP) around the testis caused by
retrograde blood flow through the internal spermatic vein
(ISV). The PP is a venous plexus located in the spermatic
cord whose veins gradually come together to drain into the
ISV. Varicocele is more frequent on the left side for anatomi-
cal reasons (mainly perpendicular drainage into the left renal
vein) and is favored by congenitally weak vessel walls. It
* F. Lanfranco
fabio.lanfranco@unito.it
1
Division of Endocrinology, Diabetology and Metabolism,
Department of Medical Sciences, University of Turin, Corso
Dogliotti 14, 10126 Turin, Italy
2
Division of Urology, Department of Surgical Sciences,
University of Turin, Turin, Italy
reflux can also occur when collateral retrograde flow through
aberrant communicating veins joins the internal spermatic
vein caudally; these vessels may arise from lumbar or iliac
veins [1].
Primary varicocele (unraveled etiology) should be distin-
guished from secondary forms caused by external compres-
sion [2].
The prevalence of clinically relevant varicocele ranges
from 5 to 20% in the male population and is often associ-
ated with infertility and reduction of sperm quality. Varico-
cele represents the most common correctable cause of male
infertility, affecting from 19 to 41% of men with primary
infertility, 45 to 81% of men with secondary infertility and
30–45% of males with dyspermia [1–3].
Varicocele usually presents between the ages of 15 and
25 years and is unilateral on the left in 78–93% of cases,
bilateral in 2–20% and unilateral on the right in 1–7% [4].

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Vol.:(0123456789)
 Journal of Endocrinological Investigation

In this review, the pathophysiology and clinical aspects
of varicocele are reviewed along with therapeutic options
and treatment effects on sperm parameters and fertility
both in adult and in pediatric/adolescent subjects. We con-
ducted a Medline and a Pubmed search from 1965 to 2018
to identify publications related to varicocele clinical aspects,
treatment procedures and treatment outcomes. Keywords
used for the search were: “varicocele”, “varicocelectomy”,
“sclerotherapy”, “male infertility”, “subfertility”, “semen
abnormalities”.
exceeds venous capacity of the PP, resulting in venous dila-
tation and varicocele [8]. Moreover, some authors demon-
strated that patients with varicocele had significant higher
concentration of nitric oxide (a potent vasodilator) in PP
veins [9]. Lastly, an old but intriguing theory suggested that
an altered function of the fasciomuscular tube around ISV
and qualitative defects in the wall of the spermatic cord (i.e.,
an atrophy of collagen fibers) may result in venous dilatation
and stasis, inducing varicocele formation [10].
Symptoms, diagnosis and treatment

Pathophysiology Although some men may refer scrotal discomfort, varicocele

The dilation and reflux in primary varicocele are thought to
occur because of several reasons. First, several venography
and cadaver studies confirm that the left, and sometimes
right, ISV drains into the renal vein, or a suprarenal vein, in
a perpendicular fashion. This drainage pattern, along with
observations that the left spermatic vein has a longer overall
drainage tract and experiences greater venous differences in
pressure, may explain the preponderance of left-sided vari-
coceles [5].
Second, some authors affirmed that missing or insuffi-
cient valves in the ISV allow reflux of blood, as pointed
out by venography studies that demonstrated the presence
of incompetent outflow valve in 75% of left varicocele [6].
In contrast with the theory of missing valves, other authors
proposed the “ontogenetic etiology”, according to which the
major cause of varicocele is an involution of veins forming a
collateral draining network, leading to poor blood drainage
and increased risk of reflux. Actually, the presence of sig-
nificant differences in the number of collateral veins between
adults and adolescents seems to suggest that embryological
abnormalities may have a limited effect in the genesis of
varicocele and other pathogenetic mechanisms should play
a role as well [2].
A third theory, known as the “nutcracker phenomenon”,
supports the hypothesis that varicocele may be caused by
the compression of the left renal vein between the superior
mesenteric artery and the aorta, leading to an increase in the
hydrostatic pressure in the ISV with decreased blood drain-
age and subsequent venous reflux and dilation of the PP [7].
Furthermore, the increasing prevalence of varicocele
from childhood through adolescence led to hypothesize a
transient increase in arterial blood flow to the testis that
is typically asymptomatic. Adults are often diagnosed dur-
ing evaluation for infertility, while in adolescence varicocele
is usually discovered incidentally on physical examination
[11]. Only about 2% to 10% of men with varicocele com-
plain of pain, mainly in the scrotum or in the inguinal area
[12].
As part of the initial evaluation, a complete reproductive
and sexual history should be obtained. Physical examination
of the scrotum is still the most commonly used technique to
diagnose varicocele (sensitivity 50–70%) and should be per-
formed in a relaxed patient in standing position, in a warm
room and carried out by a well-trained physician [2, 13].
A subclinical varicocele is diagnosed when a non-pal-
pable reflux or dilatation in the internal spermatic vein is
observed by radiologic imaging studies, most commonly by
scrotal Doppler ultrasonography [14, 15]. Scrotal ultrasound
(sensitivity 97%; specificity 94%), in addition to being the
main used technique either for confirming the presence of
clinically palpable varicocele or to diagnose subclinical
ones, can be helpful when the physical examination is diffi-
cult or indeterminate, such as in patients with obesity, previ-
ous scrotal surgery, small scrotum or thick scrotal skin [11].
During ultrasonography, varicocele appears as an anechoic
structure of enlarged veins, increasing in diameter during
Valsalva maneuver. The presence of venous reflux lasting
for more than 1 s after Valsalva maneuver or spontaneously
has a very high sensitivity and specificity in diagnosing vari-
cocele (97% and 94%, respectively), which can be classified
according to Dubin’s criteria (Table 1) [2].
Venography of the ISV is considered to be the gold stand-
ard for varicocele diagnosis. This technique consists in cath-
eterization of the ISV or one of its branches and is employed
almost exclusively during sclerotherapy or embolization,

Table 1  Dubin’s grading in
Doppler evaluation Source:
Adapted from Di Bisceglie
et al. [1]
Grade 0 Modest and transitory reflux during Valsalva maneuver sometimes also present in the healthy
subject (normal report)
Grade 1 The reflux persists longer than the previous one but finishes before the end of Valsalva maneuver
Grade 2 The reflux persists the full time of Valsalva maneuver
Grade 3 Basal reflux which does not change during Valsalva maneuver (hypertensive forms)

13
Journal of Endocrinological Investigation
either by an antegrade or a retrograde approach; after the
injection of the contrast agent, a Valsalva maneuver is
required to correctly detecting the reflux [2].
Despite becoming clinically apparent during adolescence,
the bulk of health implications related to varicocele is gen-
erally not perceived until adult age when sperm alteration
induced by varicocele can reduce fertility and probability of
successfully reaching paternity. Varicocele repair is aimed
at eliminating the dilatation of the PP and the blood reflux.
Several approaches have been proposed for varicocele repair,
including ligation and section of the dilated venous vessels
by an open surgical (with inguinal, subinguinal or retrop-
eritoneal access), microsurgical (inguinal or subinguinal) or
laparoscopic approach; on the other hand, embolization or
sclerotherapy, either by a surgical antegrade or a retrograde
percutaneous approach represent valid therapeutic options.
Both surgical and endovascular procedures are based on the
interruption of retrograde flow into the PP from the ISV or
from collateral veins [2].
Nowadays, the laparoscopic approach and retroperito-
neal ligation techniques are considered as second-choice
options; surgical procedures, based on either an inguinal or
a subinguinal incision with identification and ligation of the
veins within the spermatic cord as the cord passes through
the inguinal canal and subinguinal area, are usually the first
approach. These techniques can be performed with the aid
of an operating microscope to facilitate the visualization
of anatomical structures as arteries, veins, and lymphatics
[16]. On the other hand, due to its vascular pathophysiol-
ogy, varicocele is amenable to sclerotization with or without
embolization, either by a percutaneous retrograde or scrotal
antegrade approach, and these procedures represent a valid
option for many patients. However, percutaneous retrograde
embolization does not offer the possibility of correcting
defects in collateral vessels supplying varicocele, leading to
post-procedural persistence of disease [16].
Ultimately, the optimal procedure is the one that allows
at the same time the ligation of veins contributing to the
varicosity (or that could lead to a recurrence in the future)
and the preservation of veins responsible for testicular blood
drainage (preventing vascular engorgement). In addition, the
procedure should leave the testicular arteries, lymphatics,
and vas deferens intact [14].
According to current guidelines and best practice state-
ments, correction of varicocele should be offered in all
symptomatic patients (complaining of pain, discomfort)
or in males of infertile couple when clinically palpable
varicocele is present, when the female has normal fertility
or potentially correctable infertility or when one or more
semen abnormalities are present [17]. However, despite the
clear association between varicocele and male subfertility,
skepticism persists. Some investigators questioned the role
of varicocelectomy in the era of assisted reproduction. A
better understanding of the pathophysiology of varicocele-
associated male subfertility is of paramount importance to
elucidating the deleterious effects of varicocele on spermato-
genesis and possibly formulating new treatment strategies.
It also helps the selection of appropriate patients who will
benefit from the treatment of varicocele [18].
Sperm alterations
The effects of varicocele on semen parameters were firstly
described in 1965, when MacLeod noted a decrease in sperm
motility and density [19]. Nowadays, it is known that varico-
cele can be associated with testicle hypotrophy, alteration in
gonadotropin levels and impaired spermatogenesis leading
to reduced fertility [20].
In particular, data from studies and recent meta-analyses
involving a great number of patients showed that varicocele
is associated with reduced sperm count, motility and mor-
phology but not with reduced semen volume [21–24].
Studies on a large number of patients with clinical varico-
cele and infertility showed a great prevalence of oligoasthe-
noteratozoospermia (14.2%), asthenozoospermia (17.9%),
oligozoospermia (13.2%) with significant inverse correlation
between sperm density and grade of varicocele [25].
In particular, Vivas-Acevedo et al. [26], reported that in
patients with grade I varicocele, the most affected parameter
was sperm motility, followed by morphology. In grade II,
both morphology and motility were affected, with a higher
percentage of oligoasthenoteratozoospermia (15.3%).
Finally, in men with bilateral varicocele and in particular in
men with grade III left varicocele, the most affected param-
eter was sperm morphology. Moreover, a negative correla-
tion between age increase and sperm motility was observed.
In addition, a “stress pattern” of morphologic changes, not
specific to varicocele but including increased numbers of
immature forms, amorphous cells, and tapered forms, was
also described [27].
Witt and Lipshultz demonstrated a greater frequency of
varicocele in men with secondary infertility than in those
with primary infertility. This suggested that varicocele might
be a progressive rather than static pathological condition,
with possible structural and functional damage to the testi-
cle [28]. Confirmation of this hypothesis was provided by
Lenzi et al. [29] who found a significantly different testicular
volume and semen quality in a group of adolescents with
un-operated varicocele than in both a group of adolescents
who had undergone varicocelectomy and a control group.
Furthermore, several studies demonstrated that even in
patients with normal semen parameters, varicocele is cor-
related with an impaired sperm DNA integrity and with a
higher prevalence of DNA fragmentation than in healthy
controls [30].
13

In particular, a systematic review, including case–control
studies on fertile and infertile men with clinical varicocele
compared with fertile controls, reported that patients with
varicocele had a higher sperm DNA fragmentation, support-
ing the hypothesis that varicocele may lead to DNA damage
even when fertility is not impaired [31].
Many studies tried to elucidate the mechanisms under-
lying the relationship between varicocele and impaired
spermatogenesis, testicular atrophy and infertility (Fig. 1).
Most of these investigations proposed a mechanism of
impaired testicular blood flow leading to increased scro-
tal temperature as well as oxidative stress. Moreover, sex
hormone changes, reflux of warm blood, adrenal hor-
mones and autoimmunity have also been cited as possi-
ble causal factors [14]. For example, the reflux of renal
warm blood caused by varicocele has been hypothesized
to cause increased testicular temperature, as demonstrated
by many studies showing that males with varicocele and
reduced sperm quality have significantly warmer testicles
than men with normal sperm parameters [20, 32, 33]. The
link between hyperthermia and impaired spermatogenesis
is still unclear: increased testicular temperature may cause
DNA fragmentation and damage nuclear proteins in the
seminiferous tubules and germinal cells causing apoptosis
and resulting in testicular hypotrophy and altered sper-
matogenesis [20]. A recent study in rats has identified a
Fig. 1  Proposed pathophysiological mechanisms of varicocele on fertility potential
13
Journal of Endocrinological Investigation
number of thermo-sensitive genes in spermatocytes and
round spermatids [34]. The ability of scrotal heating to
induce alterations of testicular germ cell apoptosis or
death and to impair semen quality has been also confirmed
in humans by Zhang et al. [35] in a clinical study aimed
to identify the use of testicular hyperthermia as a possible
contraceptive treatment.
Another hypothesis is based on an excessive production
of reactive oxygen species (ROS), which has been associated
with reduced sperm motility, abnormal sperm morphology
and decreased sperm adenosine triphosphate (ATP) produc-
tion [5, 18]. The oxidative damage to DNA and chromatin
structure may also affect immature spermatogonia, poten-
tially leading to germ cell apoptosis [36]. Altogether, com-
promised DNA integrity can cause a reduction in the fertility
potential and might represent the link between varicocele
and impaired semen quality [22, 37].
The relationship between varicocele and sperm altera-
tions could be due to the increased venous pressure in the
ISV and the PP, reducing arterial inflow, causing chronic
vasoconstriction of the testicular arterioles, with subsequent
hypoperfusion, stasis and hypoxia, and interfering also with
the regulation of metabolic products and accumulation of
toxins with detrimental effect on the tubular epithelium [38].
Moreover, the role of hypoxia was confirmed at the molecu-
lar level as well, with one study noting a higher expression
Journal of Endocrinological Investigation
of hypoxia-inducible factor 1a (HIF-1a) in ISV blood sam-
ples [39].
Some authors suggested that high concentrations of adre-
nal cortical hormones in refluxing blood might damage the
seminiferous epithelium through arteriolar vasoconstriction
causing testicular hypoxia [19]. Other authors proposed a
potential role of toxic agents present in refluxing blood, such
as cadmium or reactive oxygen species (ROS) [38, 40].
Varicocele has also been associated with possible
breaches in the blood–testis barrier and subsequent forma-
tion of antisperm antibodies inducing macrophage reaction
(with sperm phagocytosis and immobilization) and a dys-
function in the acrosome reaction [41].
Finally, alterations in the hypothalamic–pituitary–gonadal
axis with decreased testosterone levels were described in
some patients with varicocele, possibly contributing to the
impairment in sperm production and quality [42]. Litera-
ture data are controversial: some authors described improve-
ments in sperm quality following normalization of testoster-
one levels after varicocelectomy, while other studies showed
no differences in testosterone concentrations between infer-
tile patients with varicocele and healthy controls with no
evidence of correlation between a postsurgical increase in
testosterone levels and improvement of sperm quality [42,
43]. Noteworthy, in all those studies, testosterone levels were
measured in peripheral blood; however, circulating levels
may be normal in the face of reduced intra-testicular testos-
terone concentrations [14].
Regardless of the actual impact of each of these factors,
the observation that men with varicocele aged more than
30 years have worse semen quality and reduced testoster-
one production suggests that the harmful effects are age
dependent [14]. Pallotti et al. [24] have recently assessed
the impairment of spermatogenesis induced by varicocele in
a large single-center caseload (with all semen examinations
carried out in the same laboratory by the same seminologist,
thus assuring the utmost standardization and uniformity of
the findings): these authors showed that nearly 80% of vari-
cocele patients present semen quality within the WHO refer-
ence limits. Semen quality is further worsened by increased
age, underlining that varicocele has a progressive impact
on spermatogenesis: the longer the time since its onset, the
greater its effects.
Effects of varicocele treatment on sperm
and hormone parameters
Varicocele treatment may be associated with improve-
ments in semen quality. Several studies and meta-analy-
ses reported a significant correlation between varicocele
correction and improvement in sperm motility and con-
centration, while data on sperm morphology are contro-
versial [14, 18]. Data from a recent randomized control
trial (RCT) demonstrated an improvement of 15% in both
sperm count and motility in men with palpable varicocele
and at least one abnormal semen parameter in comparison
to control subjects [44]. Similarly Di Bisceglie et al. [1]
described a significant improvement in sperm concentra-
tion and progressive motility but not in sperm morphology
after retrograde sclerotherapy. It is possible that the latter
parameter needs more time for normalization, especially
when a negative noxa is present for a long period of time
[1]. Improvement in sperm parameters occurs with both
surgical and percutaneous radiologic techniques [45, 46].
Interestingly, Condorelli et al. [47] have recently shown
that more than half of the patients with varicocele have a
dilation of the periprostatic venous plexus (DPVP). This
is associated with reduced sperm motility and increased
seminal fluid viscosity compared to patients with vari-
cocele, but without DPVP. After varicocelectomy, only
patients without DPVP showed a significant improvement
of sperm progressive motility and seminal fluid viscosity
compared to patients with varicocele and DPVP.
Concerning hormonal profile, males with varicocele
may present elevated FSH and low testosterone levels;
this hormonal pattern seems to be reversible after varico-
celectomy in about 50–75% of patients [42]. A study by
our group demonstrated a significant increase in inhibin
B and a decrease in FSH levels 6 months after varico-
cele repair in a group of 38 patients, while no hormone
changes were observed over time in a group of patients
with uncorrected left varicocele; no significant change in
serum testosterone levels was observed. Semen analysis
showed a significant improvement in sperm concentration
and progressive motility after treatment [48].
Furthermore, data from small case studies suggest that
inhibin B levels in varicocele patients, which can be lower
than in normal subjects, are positively correlated with tes-
ticular volume and improve after varicocelectomy, suggest-
ing a reversible Sertoli cell defect [49, 50]. These data were
confirmed in a small prospective trial on 36 infertile males
with high-grade unilateral or bilateral varicocele undergo-
ing surgical correction, where a significant correlation was
found between inhibin B levels and the improvement in
sperm count and morphology, leading the authors to state
that serum inhibin B levels can be used as a reliable preop-
erative marker of testicular potential activity and can predict
the chances of improving spermatogenesis after treatment
[51]. Kondo et al. [52] also showed that low-serum FSH and
high testosterone can represent significant factors predicting
the improvement of semen characteristics before varicocele
repair in a retrospective study of 97 patients.
On the contrary, Rodriguez Pena et al. [53] did not find
any predictive factors in the seminal fluid in a retrospective
study of 202 patients, even if the post-operative sperm con-
centration increased significantly in patients with normal
13

sperm count or moderate oligozoospermia, while it did not
in those with mild and severe oligozoospermia.
Kimura et  al. [54] found a greater improvement in
sperm concentration and motility among younger males
(< 37 years), suggesting that early varicocele repair could
result in better outcomes regarding semen parameters.
A recent single-center retrospective study by D’Andrea
et al. [55] showed that sperm quality improved after varico-
cele repair in subfertile men with altered sperm parameters
and this was more relevant in the case of disappearance of
left spermatic vein reflux at the Doppler sonographic deter-
mination, resulting in a higher total motile sperm count after
repair compared to the group with a reduced left spermatic
vein reflux.
In conclusion, despite further data from high-quality pro-
spective studies are needed, meta-analyses and randomized
controlled trials (RCTs) showed a significant improvement
in semen parameters after varicocele correction, although
these changes do not allow to draw any conclusions about
fertility, which still remains the “focal point”.
Varicocele treatment and sperm DNA fragmentation
Conventional semen analysis (semen volume, sperm count,
motility and morphology) is almost routinely performed in
the evaluation of varicocele, but it does not provide informa-
tion about putative varicocele-associated sperm dysfunctions
such as chromatin alterations or DNA fragmentation, that
can be detected even when semen analysis results are within
the reference ranges [56, 57]. Consequently, additional tests
are needed to discover further aspects of sperm function that
cannot be identified by conventional semen analysis and may
represent useful tools to assess the fertility potential in men
with varicocele.
Several studies revealed that varicocele is associated
with higher proportion of spermatic DNA abnormalities,
immature chromatin and reduction in mitochondrial activ-
ity leading to morphological and functional alterations [22,
58, 59]. According to those evidences, a recent meta-anal-
ysis by Wang et al. [60] on 240 patients and 176 healthy
controls confirmed that males with varicocele had signifi-
cantly higher sperm DNA damage than controls (evaluated
using TUNEL or sperm chromatin structure assay), with a
significant improvement in DNA integrity after varicocele
correction.
Data from small case studies suggest that varicocele repair
may induce: (1) a significant improvement in DNA packing,
(2) a reduced oxidative stress (as indicated by increased con-
centrations of antioxidant agents and a decrease in oxidative
stress markers), (3) a reduced apoptosis (phosphatidylserine
externalization), and (4) an improvement in sperm binding
capacity to the “zona pellucida” [61–64]. Additional data
reported an improvement in sperm motility, global DNA
13
Journal of Endocrinological Investigation
methylation and intensity of DNA methylation after surgery,
although the differences were not significant when compared
with pre-surgical values [65].
Moreover, Reichart et al. [66] examined sperm subcellu-
lar organelles in men with treated and untreated varicocele,
finding a significant increase in normal acrosome structure,
chromatin condensation and sperm head appearance in
treated subjects.
Finally, new emerging data pointed out the role of mast
cells and their products (ex. tryptase, histamine); in fact,
seminal mast cells significantly decreased post-varicocelec-
tomy with an inverse correlation with sperm parameters,
suggesting a potential causal role in the genesis of infertility.
In this context, reactive oxygen species, which have been
associated with sperm alterations in terms of motility, mor-
phology, DNA integrity and accelerated apoptosis, may act
as modulators of mast cell degranulation through the release
of mediators [67].
In conclusion, although several studies have shown that
varicocele repair results in a significant reduction in sperm
DNA fragmentation, suggesting to consider it as an inde-
pendent measure of semen analysis, the clinical significance
of this parameter is still unclear and further data are needed
to prove a correlation with pregnancy rate increase [17].
Varicocele treatment and fertility
Varicocelectomy is often combined with assisted repro-
ductive techniques (ART) such as intrauterine insemina-
tion (IUI), in vitro fertilization (IVF), or intracytoplasmic
sperm injection (ICSI) and several studies in recent years
have demonstrated tangible benefits in terms of pregnancy
and live birth rates when the male partner had undergone
varicocele correction versus no treatment [68].
Furthermore, multiple studies showed that varicocele
correction may eliminate or reduce the degree of ART
required, with one study reporting spontaneous pregnancy
rates of 37% following repair [69]. Samplaski et al. [70]
performed a retrospective study on prospectively collected
data on total motility sperm count (TMSC) of 373 infertile
men who underwent varicocele repair: men with TMSC < 5
million were considered candidates for IVF, 5–9 million for
IUI, and > 9 million for natural pregnancy (NP). Varicoce-
lectomy was significantly associated with a beneficial effect
in TMSC: 58.8% of males who were candidate to IVF were
‘‘upgraded’’ to IUI or NP and the most pronounced increase
was seen in patients with basal TMSC < 5 million; similarly,
when considering men with a baseline sperm TMSC of 5–9
million, 64.9% became candidate to NP.
Several data from studies on ART in infertile couples
with the male partner with varicocele are reported in lit-
erature. Both retrospective and prospective studies demon-
strated that higher pregnancy and live birth rates and lower
Journal of Endocrinological Investigation
miscarriage rates were recorded only in men who underwent
varicocele correction before ART techniques, independently
from sperm parameter improvements, suggesting the pres-
ence of a “functional factor” that can impact on reproduc-
tive outcomes and which is not routinely measured in con-
ventional semen analysis [71–73]. On the other hand, other
studies reported no differences in pregnancy rates after ART
for men with corrected varicocele but did not use a control
group with untreated varicocele for comparison [74, 75].
A large amount of literature data evaluated the impact of
varicocele correction on natural pregnancy rates [76–79].
In 2012, the Cochrane Institute published a revised meta-
analysis on the effects of varicocele treatment (surgery or
embolization) in men from couples with otherwise unex-
plained subfertility. It was showed that treatment could
improve a couple’s chance of pregnancy. However, findings
were inconclusive as the quality of the available evidence
was very low. The authors stated that more research was
needed with live birth or pregnancy rate as the primary out-
come [80].
A RCT evaluating the effects of varicocelectomy on preg-
nancy and live birth rates in couples with first-term recur-
rent miscarriage, whose male partners had normal semen
parameters but a clinically palpable varicocele, showed that
the pregnancy rate was significantly higher in the group in
which men underwent varicocelectomy than in couples who
underwent expectant protocol (44.1% vs 19%) [81]. Simi-
larly, when considering males with infertility lasting more
than 2 years, couples receiving a varicocele repair had a
significantly higher pregnancy rate than patients with uncor-
rected varicocele (26 vs. 13.4%) and a lower percentage of
spontaneous first-trimester miscarriage (13.3 vs. 69.2%)
[82].
A meta-analysis by Kirby et al. [83] including seven arti-
cles with a total of 1241 patients showed that varicocele
repair before assisted reproduction leads to improved preg-
nancy and live birth rates even in oligospermic/azoospermic
subjects; sperm retrieval rates were also higher, especially
in persistently azoospermic men. Another systematic review
by Esteves et al. [84] including eighteen studies and 468
patients with non-obstructive azoospermia and varicocele
undergoing either surgical or percutaneous correction, con-
firmed an increase in sperm retrieval rate (43.9% of patients)
and pregnancy rate (13.6%) after treatment (with no signifi-
cant differences between the two techniques).
In conclusion, available meta-analyses evaluating the
impact of varicocelectomy on pregnancy rate in infertile
couples continue to be influenced by previous heterogene-
ous and methodologically poor RCTs. However, recent RCTs
and nonrandomized controlled studies have proved signifi-
cant advantages in terms of pregnancy rate in patients who
underwent treatment instead of observation [85]. Moreo-
ver, current literature suggests that varicocele repair could
improve a couple’s chance for pregnancy by increasing natu-
ral pregnancy rate or live birth rate after intra-cytoplasmic
sperm injection. Nevertheless, since many statements in
favor of varicocele correction are based on low-quality evi-
dence, further studies on pregnancy and/or live birth rates
rather than changes in semen parameters are needed. On the
other hand, with the growing rise of ART, questions have
been raised about the utility of varicocele repair [86].
Varicocele treatment in pediatric and adolescent
patients
The prevalence of varicocele in pediatric patients is low
(< 1% under 10 years) and increases during puberty up to
15%, suggesting that adolescent varicocele persists in adult-
hood since the prevalence remains similar [87]. Interestingly,
the prevalence of varicocele in males undergoing clinical
evaluation because of infertility is about 20–40% [88],
whereas 80% of men with a varicocele diagnosed during
adolescence are fertile [89].
Varicocele repair in pediatric and adolescent patients
represents a clinical challenge because of uncertain effects
on fertility and lack of guidelines; furthermore, it should
be intended as a preventative treatment, whose beneficial
effects require a valid level of evidence.
At the current state of knowledge varicocele repair in
adolescents is recommended in case of pain, reduced tes-
ticular volume or alteration in sperm parameters. Apart from
pain, which is probably the most accepted indication, all
others criteria for varicocele correction still remain debat-
able, since no tests or exams are available to identify patients
who would benefit from therapy in adolescence, avoiding
overtreatment [90]. Moreover, current guidelines and best
practice statements are based on low-quality evidence (i.e.,
non-randomized trials, retrospective reviews or expert opin-
ion) and provide general recommendations for intervention
mainly based on the presence of testicular hypotrophy and
abnormal semen parameters [91]. More in details, guidelines
from the European Society of Paediatric Urology suggest
varicocele correction when the difference in testicular vol-
ume is greater than 2 ml or 20%, but comparison of testis
volume is difficult because of variations of testis volume
occurring through adolescence, regardless of varicocele
presence [92]. Likewise, interpretation of sperm parame-
ters is often challenging, because current normal values are
derived from normal adult males. Hence, when considering
indications for varicocele repair in pediatric or adolescent
population, many issues should be considered such as limi-
tations in obtaining and interpreting semen analyses and
the time-lapse between varicocele correction and concep-
tion attempts. The real utility of semen analysis as a proxy
measure of future fertility is still unknown and it is not clear
13

whether improvements in seminal parameters induced by
varicocele repair will translate into improved fertility [93].
Similarly to what is seen in adults, in pediatric/adoles-
cent patients varicocele seems to negatively affect seminal
parameters (sperm concentration and motility), and these
effects may revert after varicocele repair [94, 95]. Unfortu-
nately, data on this topic are still controversial. A large study
by Cayan et al. [96] comparing paternity rates among boys
who underwent surgical varicocelectomy at age 12–19 years
and men who were managed conservatively, reported a
higher paternity rate in the group of treated patients (77%
vs 48%; OR 3.6, 95% CI 2.3–5.7), suggesting a favorable
effect of varicocele repair on paternity. On the other hand,
Bogaert et al. [89] reported no differences in paternity rates
among patients participating to a Belgian adolescent screen-
ing program when comparing treated (at age 11–18 years)
vs untreated subjects. This discrepancy may suggest the
existence of a subgroup of patients who could benefit from
an early repair, although no proper tools to identify these
patients are currently available [90].
In conclusion, even though multiple series have shown
an improvement in testicular volume and sperm parameters
after varicocelectomy in adolescent patients, these measures
are still limited by an uncertain natural history and by the
lack of a direct relationship between improvement in these
parameters and future paternity.
Conclusions
Despite the first description by the Roman physician Aulus
Cornelius Celsus dates back over 2000 years, varicocele still
remains a controversial pathology. The presence of varico-
cele can lead to alterations in seminal parameters (sperm
count, motility or morphology) and integrity of sperm DNA,
contributing to infertility, reduced pregnancy/live birth rate
and possible increased risk of miscarriage during the first
trimester.
Data from a large number of studies in adolescent and
adult males suggest that varicocele correction improves
semen parameters in the majority of patients, reducing oxi-
dative stress and improving sperm nuclear DNA integrity
either with surgical or percutaneous approach [97]. In cou-
ples undergoing ART, varicocele correction may improve
semen parameters and sperm health and increase the likeli-
hood of successful fertilization using IVF or ICSI and could
decrease the level of ART needed to achieve successful preg-
nancy [69].
Keeping this in mind, varicocele repair seems to represent
an effective therapeutic option for all males (both adoles-
cent and adults) with a clinical varicocele in the presence
of symptoms, sperm alterations or infertility. However,
since many evidences in favor of varicocele correction are
13
Journal of Endocrinological Investigation
based on low-quality investigation protocols, further data
from high-quality prospective studies are needed to draw
ultimate conclusions about the efficacy and appropriateness
of varicocele repair.
Acknowledgements  This work was supported by University of Turin
(“Ricerca locale ex-60%”).
Compliance with ethical standards 
Conflict of interest  On behalf of all authors, the corresponding author
states that there is no conflict of interest.
Ethical approval  This article does not contain any studies with human
participants or animals performed by any of the authors.
Informed consent  No informed consent.
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