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Journal of Endocrinological Investigation



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

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

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

Journal of Endocrinological Investigation

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

Pathophysiology Although some men may refer scrotal discomfort, varicocele

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

Table 1  Dubin’s grading in
Doppler evaluation Source: Grade 0 Modest and transitory reflux during Valsalva maneuver sometimes also present in the healthy
Adapted from Di Bisceglie subject (normal report)
et al. [1] 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)

Journal of Endocrinological Investigation

either by an antegrade or a retrograde approach; after the better understanding of the pathophysiology of varicocele-
injection of the contrast agent, a Valsalva maneuver is associated male subfertility is of paramount importance to
required to correctly detecting the reflux [2]. elucidating the deleterious effects of varicocele on spermato-
Despite becoming clinically apparent during adolescence, genesis and possibly formulating new treatment strategies.
the bulk of health implications related to varicocele is gen- It also helps the selection of appropriate patients who will
erally not perceived until adult age when sperm alteration benefit from the treatment of varicocele [18].
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. Sperm alterations
Several approaches have been proposed for varicocele repair,
including ligation and section of the dilated venous vessels The effects of varicocele on semen parameters were firstly
by an open surgical (with inguinal, subinguinal or retrop- described in 1965, when MacLeod noted a decrease in sperm
eritoneal access), microsurgical (inguinal or subinguinal) or motility and density [19]. Nowadays, it is known that varico-
laparoscopic approach; on the other hand, embolization or cele can be associated with testicle hypotrophy, alteration in
sclerotherapy, either by a surgical antegrade or a retrograde gonadotropin levels and impaired spermatogenesis leading
percutaneous approach represent valid therapeutic options. to reduced fertility [20].
Both surgical and endovascular procedures are based on the In particular, data from studies and recent meta-analyses
interruption of retrograde flow into the PP from the ISV or involving a great number of patients showed that varicocele
from collateral veins [2]. is associated with reduced sperm count, motility and mor-
Nowadays, the laparoscopic approach and retroperito- phology but not with reduced semen volume [21–24].
neal ligation techniques are considered as second-choice Studies on a large number of patients with clinical varico-
options; surgical procedures, based on either an inguinal or cele and infertility showed a great prevalence of oligoasthe-
a subinguinal incision with identification and ligation of the noteratozoospermia (14.2%), asthenozoospermia (17.9%),
veins within the spermatic cord as the cord passes through oligozoospermia (13.2%) with significant inverse correlation
the inguinal canal and subinguinal area, are usually the first between sperm density and grade of varicocele [25].
approach. These techniques can be performed with the aid In particular, Vivas-Acevedo et al. [26], reported that in
of an operating microscope to facilitate the visualization patients with grade I varicocele, the most affected parameter
of anatomical structures as arteries, veins, and lymphatics was sperm motility, followed by morphology. In grade II,
[16]. On the other hand, due to its vascular pathophysiol- both morphology and motility were affected, with a higher
ogy, varicocele is amenable to sclerotization with or without percentage of oligoasthenoteratozoospermia (15.3%).
embolization, either by a percutaneous retrograde or scrotal Finally, in men with bilateral varicocele and in particular in
antegrade approach, and these procedures represent a valid men with grade III left varicocele, the most affected param-
option for many patients. However, percutaneous retrograde eter was sperm morphology. Moreover, a negative correla-
embolization does not offer the possibility of correcting tion between age increase and sperm motility was observed.
defects in collateral vessels supplying varicocele, leading to In addition, a “stress pattern” of morphologic changes, not
post-procedural persistence of disease [16]. specific to varicocele but including increased numbers of
Ultimately, the optimal procedure is the one that allows immature forms, amorphous cells, and tapered forms, was
at the same time the ligation of veins contributing to the also described [27].
varicosity (or that could lead to a recurrence in the future) Witt and Lipshultz demonstrated a greater frequency of
and the preservation of veins responsible for testicular blood varicocele in men with secondary infertility than in those
drainage (preventing vascular engorgement). In addition, the with primary infertility. This suggested that varicocele might
procedure should leave the testicular arteries, lymphatics, be a progressive rather than static pathological condition,
and vas deferens intact [14]. with possible structural and functional damage to the testi-
According to current guidelines and best practice state- cle [28]. Confirmation of this hypothesis was provided by
ments, correction of varicocele should be offered in all Lenzi et al. [29] who found a significantly different testicular
symptomatic patients (complaining of pain, discomfort) volume and semen quality in a group of adolescents with
or in males of infertile couple when clinically palpable un-operated varicocele than in both a group of adolescents
varicocele is present, when the female has normal fertility who had undergone varicocelectomy and a control group.
or potentially correctable infertility or when one or more Furthermore, several studies demonstrated that even in
semen abnormalities are present [17]. However, despite the patients with normal semen parameters, varicocele is cor-
clear association between varicocele and male subfertility, related with an impaired sperm DNA integrity and with a
skepticism persists. Some investigators questioned the role higher prevalence of DNA fragmentation than in healthy
of varicocelectomy in the era of assisted reproduction. A controls [30].

Journal of Endocrinological Investigation

In particular, a systematic review, including case–control number of thermo-sensitive genes in spermatocytes and
studies on fertile and infertile men with clinical varicocele round spermatids [34]. The ability of scrotal heating to
compared with fertile controls, reported that patients with induce alterations of testicular germ cell apoptosis or
varicocele had a higher sperm DNA fragmentation, support- death and to impair semen quality has been also confirmed
ing the hypothesis that varicocele may lead to DNA damage in humans by Zhang et al. [35] in a clinical study aimed
even when fertility is not impaired [31]. to identify the use of testicular hyperthermia as a possible
Many studies tried to elucidate the mechanisms under- contraceptive treatment.
lying the relationship between varicocele and impaired Another hypothesis is based on an excessive production
spermatogenesis, testicular atrophy and infertility (Fig. 1). of reactive oxygen species (ROS), which has been associated
Most of these investigations proposed a mechanism of with reduced sperm motility, abnormal sperm morphology
impaired testicular blood flow leading to increased scro- and decreased sperm adenosine triphosphate (ATP) produc-
tal temperature as well as oxidative stress. Moreover, sex tion [5, 18]. The oxidative damage to DNA and chromatin
hormone changes, reflux of warm blood, adrenal hor- structure may also affect immature spermatogonia, poten-
mones and autoimmunity have also been cited as possi- tially leading to germ cell apoptosis [36]. Altogether, com-
ble causal factors [14]. For example, the reflux of renal promised DNA integrity can cause a reduction in the fertility
warm blood caused by varicocele has been hypothesized potential and might represent the link between varicocele
to cause increased testicular temperature, as demonstrated and impaired semen quality [22, 37].
by many studies showing that males with varicocele and The relationship between varicocele and sperm altera-
reduced sperm quality have significantly warmer testicles tions could be due to the increased venous pressure in the
than men with normal sperm parameters [20, 32, 33]. The ISV and the PP, reducing arterial inflow, causing chronic
link between hyperthermia and impaired spermatogenesis vasoconstriction of the testicular arterioles, with subsequent
is still unclear: increased testicular temperature may cause hypoperfusion, stasis and hypoxia, and interfering also with
DNA fragmentation and damage nuclear proteins in the the regulation of metabolic products and accumulation of
seminiferous tubules and germinal cells causing apoptosis toxins with detrimental effect on the tubular epithelium [38].
and resulting in testicular hypotrophy and altered sper- Moreover, the role of hypoxia was confirmed at the molecu-
matogenesis [20]. A recent study in rats has identified a lar level as well, with one study noting a higher expression

Fig. 1  Proposed pathophysiological mechanisms of varicocele on fertility potential

Journal of Endocrinological Investigation

of hypoxia-inducible factor 1a (HIF-1a) in ISV blood sam- trial (RCT) demonstrated an improvement of 15% in both
ples [39]. sperm count and motility in men with palpable varicocele
Some authors suggested that high concentrations of adre- and at least one abnormal semen parameter in comparison
nal cortical hormones in refluxing blood might damage the to control subjects [44]. Similarly Di Bisceglie et al. [1]
seminiferous epithelium through arteriolar vasoconstriction described a significant improvement in sperm concentra-
causing testicular hypoxia [19]. Other authors proposed a tion and progressive motility but not in sperm morphology
potential role of toxic agents present in refluxing blood, such after retrograde sclerotherapy. It is possible that the latter
as cadmium or reactive oxygen species (ROS) [38, 40]. parameter needs more time for normalization, especially
Varicocele has also been associated with possible when a negative noxa is present for a long period of time
breaches in the blood–testis barrier and subsequent forma- [1]. Improvement in sperm parameters occurs with both
tion of antisperm antibodies inducing macrophage reaction surgical and percutaneous radiologic techniques [45, 46].
(with sperm phagocytosis and immobilization) and a dys- Interestingly, Condorelli et al. [47] have recently shown
function in the acrosome reaction [41]. that more than half of the patients with varicocele have a
Finally, alterations in the hypothalamic–pituitary–gonadal dilation of the periprostatic venous plexus (DPVP). This
axis with decreased testosterone levels were described in is associated with reduced sperm motility and increased
some patients with varicocele, possibly contributing to the seminal fluid viscosity compared to patients with vari-
impairment in sperm production and quality [42]. Litera- cocele, but without DPVP. After varicocelectomy, only
ture data are controversial: some authors described improve- patients without DPVP showed a significant improvement
ments in sperm quality following normalization of testoster- of sperm progressive motility and seminal fluid viscosity
one levels after varicocelectomy, while other studies showed compared to patients with varicocele and DPVP.
no differences in testosterone concentrations between infer- Concerning hormonal profile, males with varicocele
tile patients with varicocele and healthy controls with no may present elevated FSH and low testosterone levels;
evidence of correlation between a postsurgical increase in this hormonal pattern seems to be reversible after varico-
testosterone levels and improvement of sperm quality [42, celectomy in about 50–75% of patients [42]. A study by
43]. Noteworthy, in all those studies, testosterone levels were our group demonstrated a significant increase in inhibin
measured in peripheral blood; however, circulating levels B and a decrease in FSH levels 6 months after varico-
may be normal in the face of reduced intra-testicular testos- cele repair in a group of 38 patients, while no hormone
terone concentrations [14]. changes were observed over time in a group of patients
Regardless of the actual impact of each of these factors, with uncorrected left varicocele; no significant change in
the observation that men with varicocele aged more than serum testosterone levels was observed. Semen analysis
30 years have worse semen quality and reduced testoster- showed a significant improvement in sperm concentration
one production suggests that the harmful effects are age and progressive motility after treatment [48].
dependent [14]. Pallotti et al. [24] have recently assessed Furthermore, data from small case studies suggest that
the impairment of spermatogenesis induced by varicocele in inhibin B levels in varicocele patients, which can be lower
a large single-center caseload (with all semen examinations than in normal subjects, are positively correlated with tes-
carried out in the same laboratory by the same seminologist, ticular volume and improve after varicocelectomy, suggest-
thus assuring the utmost standardization and uniformity of ing a reversible Sertoli cell defect [49, 50]. These data were
the findings): these authors showed that nearly 80% of vari- confirmed in a small prospective trial on 36 infertile males
cocele patients present semen quality within the WHO refer- with high-grade unilateral or bilateral varicocele undergo-
ence limits. Semen quality is further worsened by increased ing surgical correction, where a significant correlation was
age, underlining that varicocele has a progressive impact found between inhibin B levels and the improvement in
on spermatogenesis: the longer the time since its onset, the sperm count and morphology, leading the authors to state
greater its effects. that serum inhibin B levels can be used as a reliable preop-
erative marker of testicular potential activity and can predict
Effects of varicocele treatment on sperm the chances of improving spermatogenesis after treatment
and hormone parameters [51]. Kondo et al. [52] also showed that low-serum FSH and
high testosterone can represent significant factors predicting
Varicocele treatment may be associated with improve- the improvement of semen characteristics before varicocele
ments in semen quality. Several studies and meta-analy- repair in a retrospective study of 97 patients.
ses reported a significant correlation between varicocele On the contrary, Rodriguez Pena et al. [53] did not find
correction and improvement in sperm motility and con- any predictive factors in the seminal fluid in a retrospective
centration, while data on sperm morphology are contro- study of 202 patients, even if the post-operative sperm con-
versial [14, 18]. Data from a recent randomized control centration increased significantly in patients with normal

Journal of Endocrinological Investigation

sperm count or moderate oligozoospermia, while it did not methylation and intensity of DNA methylation after surgery,
in those with mild and severe oligozoospermia. although the differences were not significant when compared
Kimura et  al. [54] found a greater improvement in with pre-surgical values [65].
sperm concentration and motility among younger males Moreover, Reichart et al. [66] examined sperm subcellu-
(< 37 years), suggesting that early varicocele repair could lar organelles in men with treated and untreated varicocele,
result in better outcomes regarding semen parameters. finding a significant increase in normal acrosome structure,
A recent single-center retrospective study by D’Andrea chromatin condensation and sperm head appearance in
et al. [55] showed that sperm quality improved after varico- treated subjects.
cele repair in subfertile men with altered sperm parameters Finally, new emerging data pointed out the role of mast
and this was more relevant in the case of disappearance of cells and their products (ex. tryptase, histamine); in fact,
left spermatic vein reflux at the Doppler sonographic deter- seminal mast cells significantly decreased post-varicocelec-
mination, resulting in a higher total motile sperm count after tomy with an inverse correlation with sperm parameters,
repair compared to the group with a reduced left spermatic suggesting a potential causal role in the genesis of infertility.
vein reflux. In this context, reactive oxygen species, which have been
In conclusion, despite further data from high-quality pro- associated with sperm alterations in terms of motility, mor-
spective studies are needed, meta-analyses and randomized phology, DNA integrity and accelerated apoptosis, may act
controlled trials (RCTs) showed a significant improvement as modulators of mast cell degranulation through the release
in semen parameters after varicocele correction, although of mediators [67].
these changes do not allow to draw any conclusions about In conclusion, although several studies have shown that
fertility, which still remains the “focal point”. varicocele repair results in a significant reduction in sperm
DNA fragmentation, suggesting to consider it as an inde-
Varicocele treatment and sperm DNA fragmentation pendent measure of semen analysis, the clinical significance
of this parameter is still unclear and further data are needed
Conventional semen analysis (semen volume, sperm count, to prove a correlation with pregnancy rate increase [17].
motility and morphology) is almost routinely performed in
the evaluation of varicocele, but it does not provide informa- Varicocele treatment and fertility
tion about putative varicocele-associated sperm dysfunctions
such as chromatin alterations or DNA fragmentation, that Varicocelectomy is often combined with assisted repro-
can be detected even when semen analysis results are within ductive techniques (ART) such as intrauterine insemina-
the reference ranges [56, 57]. Consequently, additional tests tion (IUI), in vitro fertilization (IVF), or intracytoplasmic
are needed to discover further aspects of sperm function that sperm injection (ICSI) and several studies in recent years
cannot be identified by conventional semen analysis and may have demonstrated tangible benefits in terms of pregnancy
represent useful tools to assess the fertility potential in men and live birth rates when the male partner had undergone
with varicocele. varicocele correction versus no treatment [68].
Several studies revealed that varicocele is associated Furthermore, multiple studies showed that varicocele
with higher proportion of spermatic DNA abnormalities, correction may eliminate or reduce the degree of ART
immature chromatin and reduction in mitochondrial activ- required, with one study reporting spontaneous pregnancy
ity leading to morphological and functional alterations [22, rates of 37% following repair [69]. Samplaski et al. [70]
58, 59]. According to those evidences, a recent meta-anal- performed a retrospective study on prospectively collected
ysis by Wang et al. [60] on 240 patients and 176 healthy data on total motility sperm count (TMSC) of 373 infertile
controls confirmed that males with varicocele had signifi- men who underwent varicocele repair: men with TMSC < 5
cantly higher sperm DNA damage than controls (evaluated million were considered candidates for IVF, 5–9 million for
using TUNEL or sperm chromatin structure assay), with a IUI, and > 9 million for natural pregnancy (NP). Varicoce-
significant improvement in DNA integrity after varicocele lectomy was significantly associated with a beneficial effect
correction. in TMSC: 58.8% of males who were candidate to IVF were
Data from small case studies suggest that varicocele repair ‘‘upgraded’’ to IUI or NP and the most pronounced increase
may induce: (1) a significant improvement in DNA packing, was seen in patients with basal TMSC < 5 million; similarly,
(2) a reduced oxidative stress (as indicated by increased con- when considering men with a baseline sperm TMSC of 5–9
centrations of antioxidant agents and a decrease in oxidative million, 64.9% became candidate to NP.
stress markers), (3) a reduced apoptosis (phosphatidylserine Several data from studies on ART in infertile couples
externalization), and (4) an improvement in sperm binding with the male partner with varicocele are reported in lit-
capacity to the “zona pellucida” [61–64]. Additional data erature. Both retrospective and prospective studies demon-
reported an improvement in sperm motility, global DNA strated that higher pregnancy and live birth rates and lower

Journal of Endocrinological Investigation

miscarriage rates were recorded only in men who underwent improve a couple’s chance for pregnancy by increasing natu-
varicocele correction before ART techniques, independently ral pregnancy rate or live birth rate after intra-cytoplasmic
from sperm parameter improvements, suggesting the pres- sperm injection. Nevertheless, since many statements in
ence of a “functional factor” that can impact on reproduc- favor of varicocele correction are based on low-quality evi-
tive outcomes and which is not routinely measured in con- dence, further studies on pregnancy and/or live birth rates
ventional semen analysis [71–73]. On the other hand, other rather than changes in semen parameters are needed. On the
studies reported no differences in pregnancy rates after ART other hand, with the growing rise of ART, questions have
for men with corrected varicocele but did not use a control been raised about the utility of varicocele repair [86].
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]. Varicocele treatment in pediatric and adolescent
In 2012, the Cochrane Institute published a revised meta- patients
analysis on the effects of varicocele treatment (surgery or
embolization) in men from couples with otherwise unex- The prevalence of varicocele in pediatric patients is low
plained subfertility. It was showed that treatment could (< 1% under 10 years) and increases during puberty up to
improve a couple’s chance of pregnancy. However, findings 15%, suggesting that adolescent varicocele persists in adult-
were inconclusive as the quality of the available evidence hood since the prevalence remains similar [87]. Interestingly,
was very low. The authors stated that more research was the prevalence of varicocele in males undergoing clinical
needed with live birth or pregnancy rate as the primary out- evaluation because of infertility is about 20–40% [88],
come [80]. whereas 80% of men with a varicocele diagnosed during
A RCT evaluating the effects of varicocelectomy on preg- adolescence are fertile [89].
nancy and live birth rates in couples with first-term recur- Varicocele repair in pediatric and adolescent patients
rent miscarriage, whose male partners had normal semen represents a clinical challenge because of uncertain effects
parameters but a clinically palpable varicocele, showed that on fertility and lack of guidelines; furthermore, it should
the pregnancy rate was significantly higher in the group in be intended as a preventative treatment, whose beneficial
which men underwent varicocelectomy than in couples who effects require a valid level of evidence.
underwent expectant protocol (44.1% vs 19%) [81]. Simi- At the current state of knowledge varicocele repair in
larly, when considering males with infertility lasting more adolescents is recommended in case of pain, reduced tes-
than 2 years, couples receiving a varicocele repair had a ticular volume or alteration in sperm parameters. Apart from
significantly higher pregnancy rate than patients with uncor- pain, which is probably the most accepted indication, all
rected varicocele (26 vs. 13.4%) and a lower percentage of others criteria for varicocele correction still remain debat-
spontaneous first-trimester miscarriage (13.3 vs. 69.2%) able, since no tests or exams are available to identify patients
[82]. who would benefit from therapy in adolescence, avoiding
A meta-analysis by Kirby et al. [83] including seven arti- overtreatment [90]. Moreover, current guidelines and best
cles with a total of 1241 patients showed that varicocele practice statements are based on low-quality evidence (i.e.,
repair before assisted reproduction leads to improved preg- non-randomized trials, retrospective reviews or expert opin-
nancy and live birth rates even in oligospermic/azoospermic ion) and provide general recommendations for intervention
subjects; sperm retrieval rates were also higher, especially mainly based on the presence of testicular hypotrophy and
in persistently azoospermic men. Another systematic review abnormal semen parameters [91]. More in details, guidelines
by Esteves et al. [84] including eighteen studies and 468 from the European Society of Paediatric Urology suggest
patients with non-obstructive azoospermia and varicocele varicocele correction when the difference in testicular vol-
undergoing either surgical or percutaneous correction, con- ume is greater than 2 ml or 20%, but comparison of testis
firmed an increase in sperm retrieval rate (43.9% of patients) volume is difficult because of variations of testis volume
and pregnancy rate (13.6%) after treatment (with no signifi- occurring through adolescence, regardless of varicocele
cant differences between the two techniques). presence [92]. Likewise, interpretation of sperm parame-
In conclusion, available meta-analyses evaluating the ters is often challenging, because current normal values are
impact of varicocelectomy on pregnancy rate in infertile derived from normal adult males. Hence, when considering
couples continue to be influenced by previous heterogene- indications for varicocele repair in pediatric or adolescent
ous and methodologically poor RCTs. However, recent RCTs population, many issues should be considered such as limi-
and nonrandomized controlled studies have proved signifi- tations in obtaining and interpreting semen analyses and
cant advantages in terms of pregnancy rate in patients who the time-lapse between varicocele correction and concep-
underwent treatment instead of observation [85]. Moreo- tion attempts. The real utility of semen analysis as a proxy
ver, current literature suggests that varicocele repair could measure of future fertility is still unknown and it is not clear

Journal of Endocrinological Investigation

whether improvements in seminal parameters induced by based on low-quality investigation protocols, further data
varicocele repair will translate into improved fertility [93]. from high-quality prospective studies are needed to draw
Similarly to what is seen in adults, in pediatric/adoles- ultimate conclusions about the efficacy and appropriateness
cent patients varicocele seems to negatively affect seminal of varicocele repair.
parameters (sperm concentration and motility), and these
effects may revert after varicocele repair [94, 95]. Unfortu- Acknowledgements  This work was supported by University of Turin
(“Ricerca locale ex-60%”).
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
Compliance with ethical standards 
and men who were managed conservatively, reported a Conflict of interest  On behalf of all authors, the corresponding author
higher paternity rate in the group of treated patients (77% states that there is no conflict of interest.
vs 48%; OR 3.6, 95% CI 2.3–5.7), suggesting a favorable
effect of varicocele repair on paternity. On the other hand, Ethical approval  This article does not contain any studies with human
participants or animals performed by any of the authors.
Bogaert et al. [89] reported no differences in paternity rates
among patients participating to a Belgian adolescent screen- Informed consent  No informed consent.
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 References
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