EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99

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Mysteries, Facts, and Fiction in Varicocele Pathophysiology

and Treatment

Nikolaos Sofikitis a,*, Sotirios Stavrou a, Sotirios Skouros a, Fotios Dimitriadis a,

Panagiota Tsounapi b, Atsushi Takenaka b
a
Laboratory of Molecular Urology and Genetics of Human Reproduction, Department of Urology, Ioannina University School of Medicine, Ioannina, Greece
b
Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, 36 Nishimachi, Yonago, Japan

Article info Abstract

Keywords: Development of varicocele in the human has been associated with reduced male
Azoospermia reproductive potential. Induction of left experimental varicoceles in the rat, rabbit,
Spermatozoa and monkey results in a bilateral detrimental effect on testicular endocrine and
Testis exocrine function. This review discusses mechanisms mediating the consequences
Varicocele of varicocele on male reproductive potential, indications for the treatment of
Varicocelectomy varicocele, and techniques for varicocelectomy and reviews the difficulties in
the interpretation of studies evaluating the effect of varicocele reversal on semen
parameters and male reproductive potential.
# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Ioannina University School of Medicine, Ioannina

45110, Greece. Tel. +30 69443 63428; Fax: +30 26510 07069.
E-mail address: akrosnin@hotmail.com (N. Sofikitis).

1. Introduction
Varicocele, a vascular abnormality of the testicular venous
drainage system is manifested by a mass of abnormally
dilated, tortuous veins of the pampiniform and/or the
cremasteric venous plexus. Varicocele represents the most
common cause of primary and secondary infertility in men
[1]. Although the prevalence of a clinical varicocele in the
male general population is approximately 15%, it has been
implicated as a factor responsible for infertility in 35% of
infertile men [2,3] and in 81% of men with secondary
infertility [4]. Furthermore, it has been demonstrated that
clinical varicocele is diagnosed in 11.7% of infertile men
with normal semen analysis and 25.4% of infertile men with
abnormal semen analysis [5].
2. Etiology of varicocele
The cause for the high incidence of unilateral varicocele on
the left side is that the left testicular vein (LTV) runs
vertically when the man is standing up and inserts into the
left renal vein at a right angle [6]. The right testicular vein, in
contrast, runs tangentially to insert into the inferior vena
cava. This results in less flow turbulence and back pressure
in the right testicular vein and consequently leads to a lower
incidence of venous dilation in the right spermatic cord. In
addition, incompetent or absent venous valves in the
spermatic veins, which have been documented in previous
studies [7,8], may be an important contributing factor in the
development of varicocele, since man’s upright posture may
cause an increase in LTV pressure when the valves are
incompetent, thus leading to venous distension and
dilatation. We have demonstrated the absence of valves
within the LTV at the pelvic or lumbar level in 33% and 37%
of patients, respectively [9].
Vascular contractions of the LTV caused by catechola-
mines from the left adrenal gland and drained into the left
renal vein via the left adrenal vein and then into the LTV
have been proposed as a another factor for the development
of left varicocele [10]. Such contractions of the LTV
may increase the pressure in the LTV and might cause
retrograde blood flow in the LTV. However, these supposed

http://dx.doi.org/10.1016/j.eursup.2014.07.002
1569-9056/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
90 EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99
contractions of the LTV have never been demonstrated on
venography and, therefore, this remains a hypothesis.
In a few cases, compression of the left renal vein between
the superior mesenteric artery and the aorta (the nutcracker
phenomenon) increases intravenous pressure in the left
renal vein and the LTV, leading to dilation of the LTV and
establishment of varicocele [6]. Finally, on rare occasions,
renal or retroperitoneal tumors exerting pressure on the
LTV or on the renal vein may lead to varicocele develop-
ment.
3. Pathophysiology of varicocele
3.1. Effects of left varicocele on the ipsilateral testis
The pathophysiologic mechanism responsible for the
detrimental effects of a left varicocele on the ipsilateral
testicular function has not really been elucidated [11–17].
However, several theories have been proposed.
3.1.1. The theory of an increased testicular temperature
Varicoceles are thought to induce their noxious effect by
elevating scrotal temperature via reflux of warm abdomi-
nal blood through incompetent valves of the spermatic
veins [18–20] and there is good evidence to support this
theory.
The elevated intrascrotal temperature results in reduc-
tions in testosterone synthesis by Leydig cells and reduced
Sertoli cell secretory function [21]. In fact, Rajfer and
coworkers [22] have demonstrated a decrease in intra-
testicular testosterone content in varicocelized rats
attributable to a functional defect in testicular 17,20-
desmolase. In addition, varicocele ligation has been
demonstrated to be associated with reductions in intras-
crotal temperature in infertile men [23]. Similarly, the
induction of left varicocele in rats [24,25], in rabbits
[26,27], and in nonhuman primates [28] resulted in a
significant elevation of testicular temperature. Surgical
repair of experimentally induced varicoceles in the rat
model [29] and in the rabbit model [26] significantly
reduced testicular temperatures.
The increases in left testicular temperature in varicoce-
lized rats have been shown to result in a decrease in
intratesticular testosterone content [22,24] and in varico-
celized rabbits have been considered to result in Sertoli cell
secretory dysfunction [26]. Similarly, in a subpopulation of
men with varicocele, a cause-and-effect mechanism has
been established between Leydig cell secretory dysfunction
and varicocele [30].
3.1.2. The theory of insufficiency of the hypothalamo-pituitary-
gonadal axis
The observation that the serum levels and spermatic vein
levels of luteinizing hormone, follicle-stimulating hormone,
and testosterone do not vary predictably from normal in the
majority of patients with varicocele has resulted in the
hypothesis that the hypothalamo-pituitary-gonadal axis
is not affected by a varicocele [31]. In contrast, Hudson and
coworkers [32] described an excessive gonadotropin
response to gonadotropin-releasing hormone (GnRH) stim-
ulation in a group of infertile men with varicocele.
Furthermore, they found that following varicocele ligation,
only individuals who demonstrated a normalization of
their gonadotropin response to GnRH stimulation improved
their sperm concentration. Thus it may be speculated that
there is a certain subpopulation of men with varicoceles
who demonstrate an imbalance in the sensitivity of
hypothalamo-pituitary-testicular axis.
3.1.3. The theory of retrograde flow of adrenal or renal metabolites
down the left spermatic vein
Javert and Clark [33] suggested that retrograde blood flow
occurs in men with varicoceles. Mazo and colleagues [34]
provided initial evidence for a functional interrelationship
between adrenals and testes in the pathogenesis of
infertility in men with a left varicocele. Cohen and
coworkers [35] suggested that in patients with varicoceles,
a retrograde flow of adrenal catecholamines through the
testicular vein results in damage to spermatogenesis. Ito
and coworkers [36] reported that reflux of renal venous
blood down the spermatic vein resulted in elevated
concentrations of prostaglandin E and prostaglandin F in
spermatic venous blood in varicocele patients, which may
impair spermatogenesis by various mechanisms. The same
group found no increase in spermatic vein cortisol
concentrations and, therefore, they hypothesized that
adrenal metabolites do not reflux but renal metabolites
do. On the other hand, renin concentrations might be
expected to be elevated if renal vein blood was refluxing
down the LTV to any significant degree, yet Lindholmer and
et al. [37] found no difference in renin concentrations in
peripheral blood and LTV blood in men with varicocele.
The literature does not allow the unequivocal acceptance
of the theory that retrograde blood flow through the LTV is
an important aspect of varicocele. For instance, Sofikitis and
Miyagawa [38] have shown that left adrenalectomy in
varicocelized rats does not inhibit the development of
varicocele-related physiologic changes in the testis, sug-
gesting that retrograde flow of adrenal metabolites via the
LTV cannot be important in varicocele pathophysiology.
Furthermore, studies in an experimental rabbit varicocele
model confirmed the varicocele-related alterations that
have been established in the human [26,27]. However, in
the rabbit, the LTV does not drain into the renal vein but
into the left lumbotesticular trunk, which collects blood
mainly from the retroperitoneal wall. This is strong
evidence that the role of adrenal or renal metabolites in
the development of testicular damage in the varicocelized
rabbit is disputable.
3.1.4. The theory of testicular hypoxia and alterations in the
testicular extracellular fluid dynamics: Is there a metabolic defect in
the varicocelized testis?
Studies in experimental varicocele models in the rat have
documented that vascular endothelial growth factor
expression is associated with angiogenesis in the varico-
celized testis, and this suggests that varicocele can lead to
tissue hypoxia and induce angiogenesis [39]. Hsu and
 EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99
coworkers [40] demonstrated that decreased arterial blood
flow and defective energy metabolism in the varicocele-
bearing testicles are important components of varicocele
pathophysiology. In addition, further studies in experimen-
tal varicocele models have suggested increased testicular
vascular permeability, which then decreases gradually with
time [28,41–43]. It has been hypothesized that changes in
testicular interstitial fluid dynamics may occur in parallel
[44] and that microvascular fluid exchange may be
dramatically altered in varicocele [28,41,45] (Fig. 1). The
results of a study by Wang and colleagues [46] have shown
that a left-sided experimental varicocele could cause
bilateral testicular hypoxia and increased germ-cell apo-
ptosis, both of which play an important role in testicular
dysfunction. On the other hand, two studies—one in men
with varicoceles [47] and one in the rabbit varicocele model
[48]—have demonstrated that lactate concentrations in LTV
blood are significantly lower than in respective control
groups. In both studies, mean lactate and pyruvate
concentrations in the LTV were significantly correlated.
These two studies do not allow the unequivocal acceptance
of the testicular hypoxia theory in subjects with varicocele
and rather suggest that there is defective glycolysis
preceding the stage of pyruvate formation in the varicoce-
lized testis.
3.1.5. The theory of cadmium accumulation
Benoff and coworkers [49] reported significantly elevated
cadmium levels in testicular biopsy samples in infertile men
with varicoceles; these values were inversely related to the
increase in sperm concentration after varicocelectomy.
Also, the same group reported that deletions in L-type
calcium channel a-1 subunit testicular transcripts correlat-
ed with testicular cadmium content and apoptosis in
infertile men with varicocele [50]. Thus, these authors
hypothesized that an infertile man with a varicocele has a
specific genetic or environmentally induced defect that
causes infertility and that varicoceles interact with these
defects to exacerbate the already reduced fertility potential.
3.2. Effects of left varicocele on the contralateral testis
Using animal models, numerous investigators demonstrat-
ed that unilateral varicoceles are accompanied by a bilateral
detrimental effect on testicular temperature, blood flow,
and histology [22,24,42,51]. These adverse effects did not
appear to be immunologically mediated [52].
To explain the detrimental effect of left varicocele on the
contralateral, right-sided testis, various theories have been
proposed, including that of the existence of anastomoses
between the left and right testicular venous systems,
allowing the transfer of noxious substances from the left
varicocelized testis to the contralateral right one. However,
it has been demonstrated that the effects of unilateral
varicocele on the contralateral testis are not mediated
through the ipsilateral testis [51]. Thus, vascular commu-
nications between the left and the right testicle could not
explain the detrimental effect of a left varicocele on the
right testis in rats with a left varicocele [51]. Two other
91
Fig. 1 – Varicocele results in an increase in the hydrostatic pressure in
the testicular venules and, subsequently, at the venous ends of the
capillaries (point A). Points B and D represent the extracellular
testicular space. Thus, the pressure difference (pressure in point B
minus pressure in point A) decreases with an overall impaired capacity
of the venous ends of testicular capillaries to reabsorb the extracellular
fluid. Point C represents the pressure at the arterial end of the capillary.
Thus, the pressure difference (pressure in point C minus pressure in
point D) decreases, resulting in impaired exit of nutrients from the
arterial end of the capillaries.
popular theories have been expressed: One is that of a
dilatation of the right testicular vein in subjects with left
varicocele [53] and the other that of the role of the
sympathetic nervous system [54].
It has been demonstrated that induction of a left
varicocele in rats results in secondary right varicocele in
60% of the animals [53]. Interestingly, surgical repair of the
secondary right varicocele in rats with primary left
varicocele restores right testicular and epididymal function
[53]. Also, an induced unilateral varicocele significantly
increases the biochemical indicators of tissue hypoxia in
both testes. As this increase is prevented by chemical
sympathectomy, the sympathetic nervous system may play
a role in the bilateral testicular degeneration associated
with varicocele [54].
3.3. Effects of varicocele on sperm physiology
3.3.1. Varicocele and sperm oxidative stress
Hendin and coworkers [55] suggested that increased levels
of reactive oxygen species and decreased antioxidant
capacity levels in the semen are associated with varicocele.
These changes may be related to functional sperm
abnormalities and the infertility often seen in these
patients. Similarly, Pasqualotto and colleagues [56] have
suggested that the fertility potential in fertile varicocele
patients can decline due to oxidative stress attributable to
higher reactive oxygen-species levels but low total antioxi-
dant capacity. Nallella and colleagues [57] have shown that
infertile patients with varicocele have elevated levels of
interleukin-6 and reactive oxygen species as well as
decreased levels of total antioxidant capacity, which have
a detrimental role in the pathophysiology of infertility in
these patients. Agarwal and coworkers [58] have concluded
92 EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99
that oxidative stress-induced injury appears to be one of the
main mechanisms mediating the detrimental effects of left
varicocele on spermatozoa. Yesilli et al. [59] suggested that
spermatozoal malondialdehyde levels (a marker of oxida-
tive stress) are significantly higher in infertile men with
varicoceles compared to healthy men. A meta-analysis by
Agarwal and coworkers [60] also suggested that reduced
total antioxidant capacity and increased oxidative stress
may be a component in the etiology of infertility in men
with varicocele. However, administration of antioxidants
should be regarded with some caution because appropriate
levels of reactive oxygen species represent a prerequisite for
sperm capacitation processes (see Aitken and Baker [61] for
review).
3.3.2. Varicocele and sperm total-acrosin profiles
The acrosin activity of spermatozoa cannot be predicted by
the standard parameters of semen analysis, suggesting that
acrosin represents a different parameter of spermatozoal
function [62]. We have demonstrated that total acrosin
activity is significantly less in the spermatozoa of infertile
men with varicoceles [63]. Similar findings have been
presented for smokers with varicoceles [64].
3.3.3. Varicocele effects on sperm DNA
Several groups have reported that left varicocele is
associated with increased sperm DNA damage [65,66].
Smit et al. [67] have provided evidence that decreased
sperm DNA fragmentation after varicocelectomy is associ-
ated with increased pregnancy rate. Thus, an intranuclear
effect of left varicocele may be associated with the
diminished male reproductive potential in individuals with
left varicoceles.
3.3.4. Varicocele and abnormal retention of cytoplasmic droplets
Zini and coworkers [68] have demonstrated that varicocele
is associated with abnormal retention of cytoplasmic
droplets by human spermatozoa. Considering that Zini
et al. [69] have also demonstrated that the retention of
sperm cytoplasmic droplets is negatively correlated with
sperm motility, it appears that the liberation of spermato-
zoa that have not undergone the normal epididymal
maturation process may contribute to the diminished
sperm function in individuals with varicoceles.
3.3.5. Postfertilization effects of left varicocele
Dimitriadis et al. [70] have provided strong evidence that
embryos derived from the fertilization of oocytes by
spermatozoa from varicocelized subjects have a lower
potential for cleavage, blastocyst development, and overall
implantation capacity.
3.4. Effects of varicocele on male fertility potential
The development of a unilateral varicocele affecting
bilateral Leydig cell secretory function [22] results in a
significant reduction in bilateral intratesticular testoster-
one content, which, in turn, affects the Sertoli cell secretory
function [26]. The decreased intratesticular testosterone
profiles and androgen-binding protein activity (a marker of
Sertoli cell secretory function) may result in other defects
besides those occurring in spermatogenesis. The epididy-
mal sperm maturation process is also affected, since the
main source of intraepididymal testosterone is testicular
testosterone straight from the ipsilateral testis and, within
the epididymal lumen, testosterone is bound to the
androgen-binding protein secreted by Sertoli cells and
not to the sex hormone-binding globulin produced by the
liver. Thus, the development of a left varicocele results in
bilateral defects in testicular spermatogenetic activity and
the epididymal spermatozoa maturation process (Fig. 2).
These defects, together with other contributory factors
already mentioned (eg, decreased total acrosin profiles,
sperm oxidative stress, or sperm DNA fragmentation) may
represent the connective links between the varicocele
phenotype and reduced male reproductive potential.
Varicocele repair reducing testicular temperature reverses
the cascade of biochemical effects of left varicocele on both
testes and on sperm physiology (Fig. 3).
4. The mysteries of varicocele
Some observations about varicocele are not completely
understood. For example, the contralateral testicular
effect of a unilateral left varicocele has been extensively
discussed; however, additional mechanisms may exist.
Additionally, some varicocele patients demonstrate one,
two, or three abnormal parameters in their spermiograms
and are infertile. However, there are many men with
varicocele who have normal semen parameters and normal
fertility. To explain this enigma, Harrison and coworkers
[28,41] have suggested that the testicular consequences of
left varicocele are mediated through an increase in the
extracellular testicular fluid (testicular extracellular ede-
ma). Thus, if a subpopulation of men with left varicoceles
has an adequate testicular lymphatic drainage system,
these men may not develop extracellular edema (Fig. 1) and
testicular function may be unimpaired [6]. Also, it can be
hypothesized that the fertility potential of some men with
varicoceles who have already fathered children may be
temporary and, at a later age, these men may become
infertile without being aware of it.
It has also been noted that some men with varicocele and
with low quantitative and qualitative sperm parameters
improve in one, two, or three parameters of their spermio-
grams after varicocele repair, whereas others do not show
any changes in semen quality. Snydle and Cameron [71] have
provided strong evidence that the development of varicocele
is accompanied by an ultrastructural defect in Sertoli cells.
In addition, Sofikitis and Miyagawa [38] have suggested
that left varicocele is accompanied by Sertoli cell secretory
dysfunction. Thus, if the development and the duration of
left varicocele results in irreversible damage to Sertoli cell
secretory function, sperm concentration is not anticipated
to improve after varicocele repair.
Last, obesity appears to protect against varicocele
development. The mechanism is unknown. It may be
suggested that the presence of retroperitoneal fat may
 EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99
VARICOCELE
Testicular
temperature
Leyding cell
secretory
function
ROS
Intratesticular
testosterone
Spermatogenesis
Sperm DNA fragrnentation
or oxidation
Sperm concentration
Male reproductive potential
Fig. 2 – The cascade of biochemical and cellular events responsible for the development of the detrimental effect of varicocele on male reproductive
potential.
ABP = androgen-binding protein; ROS = reactive oxygen species.
impede the retrograde flow of blood from the renal vein
towards the testis through the left spermatic vein.
5. Treatment of a varicocele
5.1. When to treat varicoceles
According to the European Association of Urology (EAU)
2014 guidelines, varicocele repair should be considered in
cases of a clinical varicocele, oligospermia, duration of
infertility of 2 yr, and otherwise unexplained infertility
[72,73]. However, in three randomized controlled studies,
varicocele repair in men with a subclinical varicocele had no
beneficial effect on fertility potential [74–76]. Furthermore,
studies of men with a varicocele and normal semen
parameters did not demonstrate a clear benefit of varicocele
repair over observation [77,78].
5.2. Varicocelectomy in azoospermic men
Patients with nonobstructive azoospermia and varico-
celes have shown a probability for reappearance of
spermatozoa in their semen after varicocele repair
[16,79–81], although these studies have been relatively
small and with low pregnancy rates after intercourse.
Kadioglu et al. [82] have shown that microsurgical
inguinal varicocele repair enabled 21% of azoospermic
men to provide motile sperm via ejaculate. However, for
the best results of varicocele repair, the authors acknowl-
edge that a certain threshold of spermatogenesis should
93
Sertoli cell
secretory function
Intratesticular/
intraepididymal ABP
Defect in epididymal
sperm maturation
Sperm membrane
lipid peroxidation
Sperm motility
Sperm with abnormal
retention of cytoplasmic
droplets
exist requiring the presence of at least spermatids [82]. In
addition, Giannakis et al. [81] demonstrated that in
azoospermic men with varicoceles who were negative for
testicular spermatozoa, a cut-off value of telomerase
assay outcome equal to 28 units of total product
generated per microgram of protein had 84.2% overall
diagnostic accuracy to identify those men with varico-
celes (without testicular spermatozoa) who will become
positive/negative for spermatozoa after varicocelectomy.
Likewise, in another study [83], it was seen that varicocele
repair can result in the appearance of spermatozoa in the
ejaculate of azoospermic men when severe hyposperma-
togenesis or maturation arrest at the spermatid stage was
present in the testicular biopsy. It must be emphasized
that the appearance of spermatozoa in semen of
azoospermic men with varicocele after varicocelectomy
is temporary [81] and, therefore, sperm cryopreservation
should be performed.
5.3. Varicocele repair in adolescence
Although the treatment of varicoceles in adolescents may
be effective, there is a significant risk of overtreatment
(level of evidence: 2a). Kass and Belman [84] suggested
that with varicocelectomy in adolescents, a catch-up
growth of the varicocelized testis may be anticipated.
Okuyama and coworkers [85] have demonstrated an
increase in testicular volume after varicocele repair in
adolescents. Decastro et al. [86] demonstrated that
among adolescents with preoperative left hypotrophy
94 EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99

Varicocelectomy

Reduction in testicular venous hydrostatic pressure

Reduction in the pressure at the venous ends of testicular capillaries

Subsequent improvement in extracellular fluid reabsorption and

alleviation of testicular extracellular edema

Better nutrition of the testis and improvement in the functionality

of the testicular countercurrent heat exchange system

Improvement in leydig Decrease in ros

Decrease in testicular temperature synthesis
cells secretory function
(Increase in ITT)
Improvement in sertoli cellular
secretory function
(Enhancement in ABP)
Improvement in spermatogenesis

Improvement in ESMP

Improvement in fertility potential

Fig. 3 – Mechanisms responsible for improvement in male fertility potential after varicocelectomy.
ABP = androgen-binding protein; ESMP = epididymal sperm maturation process; ITT = intratesticular testosterone; ROS = reactive oxygen species.

who underwent varicocelectomy, 69% achieved catch-up
growth within 28 mo.
5.4. Techniques of varicocelectomy
5.4.1. Scrotal surgery
These techniques have been abandoned because they are
accompanied by a high risk of injury to the internal
spermatic artery.
5.4.2. Retroperitoneal varicocelectomy
The retroperitoneal approach is still commonly used.
According to a recent meta-analysis, the overall spontaneous
pregnancy rate after retroperitoneal varicocelectomy is
37.7% [87]. The main advantage of this method is that only
a limited number of veins will be ligated. Therefore, this
technique also has a high incidence of varicocele recurrence
(15%) [87], especially when the testicular artery is preserved.
According to Goldstein [88], varicocele recurrence is usually
due to preservation of the periarterial plexus of fine veins
surrounding the artery (venae comitantes). These veins have
been shown to communicate with larger internal spermatic
veins. An additional reason for varicocele recurrence after the
Palomo procedure is that in the lumbar and pelvic
retroperitoneal space, a large number of branches of the
internal spermatic veins are found. If some of these veins
remain intact after a Palomo procedure, there may be a higher
likelihood of varicocele recurrence [9].
Another cause of recurrence after retroperitoneal vari-
cocelectomy is that sometimes a left varicocele involves the
cremasteric-external spermatic-testicular venous drainage
system rather than the pampiniform-internal spermatic-
testicular venous drainage system. This second venous
system cannot be identified by the retroperitoneal approach
[88,89]. Also, varicocele recurrence may be due to the
presence of a collateral veins, which may bypass the ligated
retroperitoneal veins, rejoining the internal spermatic vein
proximal to the site of ligation [90].
Meta-analytic data demonstrate an overall postoperative
hydrocele formation rate of 8.24% [87] as result of the
difficulty in positively identifying and preserving lympha-
tics using the Palomo technique [91]. Matsuda et al. [92]
have demonstrated that there was no significant difference
in postoperative fertility between varicocelectomy with
ligation of the artery versus an artery-sparing procedure.
Sofikitis et al. [93] emphasized that after ligation of the
internal spermatic artery, the development of testicular
ischemia will depend on the diameters of the cremasteric
and the deferential arteries. If these latter arteries are
adequate, no damage to the ipsilateral testis will occur.
However, ligation of the internal spermatic artery may
result in ipsilateral testicular damage in those varicocele
patients with small or absent cremasteric and deferential
arteries; this is especially important in patients with prior
scrotal surgery. It has been shown that only in one-third of
these men, the sum of the diameters of the cremasteric and
the deferential arteries would be adequate to maintain the
necessary blood flow to the testicle [93].
5.4.3. Laparoscopic varicocelectomy
Laparoscopic repair resembles the Palomo technique.
Postoperative complications of the laparoscopic approach
are similar to those of the Palomo technique [94–99]. A
meta-analysis of 36 studies reported that the overall
spontaneous pregnancy rate after laparoscopic varicocelec-
tomy was 30%, the overall recurrence rate was 4.3%, and
the overall hydrocele formation rate was 2.84% [87].
The lymphatic-sparing and artery ligation laparoscopic
 EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99
technique described by Glassberg et al. was accompanied by
a lower incidence of hydrocele formation in adolescents
[100]. Potential additional complications of the laparoscop-
ic technique include hemorrhage, air embolism, and injury
to bowel or other viscera.
5.4.4. Conventional nonmagnified inguinal and subinguinal surgery
The main advantage of these approaches is that they offer
the ability to deliver the spermatic cord out of the wound,
which makes it easier to identify the testicular artery,
lymphatics, and small periarterial veins [88]. With this
approach, ligation of external spermatic and gubernacular
veins is possible. Meta-analysis results indicated that the
overall spontaneous pregnancy rate after macroscopic
inguinal varicocelectomy series was 36%, the overall
recurrence rate in the macroscopic inguinal or subinguinal
varicocelectomy series was 2.6%, and the overall hydrocele
formation rate was 7.3% [87]. A significant disadvantage of
the subinguinal approach is that at this level, the number of
veins increases dramatically and the artery is often divided
into two or three branches, making arterial identification
and preservation more difficult [101].
5.4.5. Microsurgical inguinal and subinguinal surgery
Microsurgical inguinal and subinguinal repair has resulted
in a reduction in the incidence of hydrocele formation
[80,102–104]. Meta-analytic data report an overall sponta-
neous pregnancy rate after microsurgical varicocelectomy
of 42%, an overall recurrence rate of 1.05%, and a hydrocele
formation rate of 0.44% [87]. The main advantage of the
microsurgical inguinal or subinguinal approaches is the
possibility of preserving the internal spermatic artery and
the lymphatics, since damage to the lymphatics may result
in testicular dysfunction [41], and the potential to ligate the
external spermatic and the gubernacular veins, as well.
Goldstein et al. [88] compared microsurgical inguinal
varicocelectomy and conventional inguinal varicocelecto-
my and claimed that the former procedure resulted in a
significantly lower incidence of hydrocele formation,
testicular artery injury, and varicocele recurrence. Al-
Kandari et al. [105] demonstrated that compared with
open inguinal and laparoscopic varicocelectomy, the sub-
inguinal microsurgical varicocelectomy offers the best
outcome. Similarly, Al-Said et al. [106] reported that
compared to open and laparoscopic varicocele repair,
microsurgical varicocelectomy had the advantages of no
hydrocele formation, a lower incidence of recurrence, and
better positive effects in sperm count and motility. In
addition, Boman et al. [107] demonstrated that in infertile
men with clinical varicocele and isolated asthenospermia,
sperm motility and total motile sperm count improved
significantly after microsurgical varicocelectomy. Hydro-
cele formation, testicular artery injury, and varicocele
recurrence are the most frequent complications following
varicocele repair.
5.4.6. Radiographic occlusion techniques
Radiographic occlusion techniques of the LTVs have been
used extensively [108,109]. Meta-analytic data show that
95
the overall spontaneous pregnancy rate after radiologic
embolization was 33.2% and the recurrence rate was 12.7%
[87]. The main reason for varicocele recurrence after
radiographic occlusion is believed to be the failure to
successfully cannulate small collaterals and external
spermatic veins [88]. The occlusion of the internal
spermatic veins using balloons or coils has a success rate
ranging from only 75% to 90% [110–112]. For this reason, a
significant number of patients undergoing radiographic
occlusion will require an additional surgical procedure. The
complications following radiographic occlusion, such as coil
migration, pulmonary embolus [113], vein perforation, and
allergic reactions, occasionally can be serious. Radiographic
occlusion techniques may also be performed using ante-
grade scrotal sclerotherapy via cannulation of a scrotal vein
[114–116].
6. Does varicocele repair really improve semen
quality or male reproductive potential?
There are substantial difficulties in interpreting the results
of different clinical trials that used different techniques of
varicocelectomy when looking at the effect of varicocelec-
tomy on fertility. For example, a large number of published
studies did not include a control group. Thus, an observation
group or a group of patients who received only a
pharmaceutical treatment was not included, and a positive
effect on fertility potential after varicocelectomy was not
necessarily attributable to varicocele reversal per se but
may have been a consequence of a natural improvement of
testicular function of the patient with time. However, some
studies did include a control group. For instance, Nillson
et al. [78] found no statistically significant improvement in
semen parameters, morphology, or progressive motility in a
series of men submitted to surgery compared with an
untreated control group during an observation period of
53 mo. Similarly, Nieschlag et al. [117] have suggested
that regular counseling of infertile couples is as effective as
interventional treatment of varicoceles in achieving preg-
nancies. In contrast, Madgar and coworkers [118], who
performed a randomized controlled trial of high spermatic-
vein ligation, found that in a population of infertile men
with varicocele as the only demonstrable factor of
infertility, varicocele repair improved sperm parameters
and fertility rate. Abdel-Meguid et al. [119] also performed a
randomized controlled trial providing level 1b evidence for
the superiority of varicocelectomy over observation in
infertile men with palpable varicoceles and impaired semen
quality. In their trial, significantly increased odds of
spontaneous pregnancy and improvements in semen
characteristics after surgery were seen within 1 yr of
follow-up. In another elegant, controlled trial [120], it was
suggested that although varicocelectomy should always be
performed before assisted reproduction is pursued, varico-
cele surgery does not increase pregnancy rates when
combined with intracytoplasmic sperm injection. However,
contrasting results have been published by Gokce et al.
[121], also from a controlled trial. In that study, it was
suggested that performing varicocelectomy improved the
96 EUROPEAN UROLOGY SUPPLEMENTS 13 (2014) 89–99
pregnancy rates of intracytoplasmic sperm injection in
otherwise fertile couples with clinical varicoceles.
Another obstacle is that the vast majority of studies on the
consequences of varicocele repair include different types of
techniques with surgery on different anatomic components.
For instance, some surgeons preserve the testicular artery
during varicocelectomy, whereas others routinely ligate it.
Furthermore, some surgeons routinely ligate the lymphatic
vessels, while others routinely perform lymph vessel-sparing
operations. Thus, the term varicocelectomy does not refer to a
well-standardized procedure, and thus the consequences
will rather depend on the type of technique used. In a meta-
analysis, Evers and Collins [122], including only controlled
studies of nonmagnified varicocele reversal techniques,
concluded that varicocele repair does not seem to be an
effective treatment for male infertility or unexplained
subfertility. However, the conclusions of this meta-analysis
cannot be accepted, since studies recruiting men with
subclinical varicoceles were included and there was not a
single study included that used microsurgical varicocelecto-
my, the gold standard of varicocele reversal.
According to the EAU 2014 guidelines, repair of a
subclinical varicocele for improving fertility potential does
not appear to be beneficial. However, the same group of
authors, performing a meta-analysis published in the
Cochrane Library [123], suggested the opposite conclusion:
that there is evidence suggesting treatment of a varicocele in
men from couples with otherwise unexplained subfertility
may improve the chance of pregnancy. In an updated 2013
version of this Cochrane review, the same authors [124]
suggested that surgical or radiologic treatment of varicocele
may benefit subfertile men with a clinical varicocele and poor
semen quality. An estimate of the number needed to treat
arrived at the ratio of seven to one (ie, for seven men treated,
one additional pregnancy will result).
A great number of studies on the effects of varicocele
reversal evaluated the numbers, quantitative and qualita-
tive motility, and morphology of sperm. However, one of the
most perplexing problems in the evaluation of the infertile
men is the inability of the standard parameters of semen
analysis to predict the outcome of in vitro fertilization
[125,126]. Thus, even if a study demonstrates statistically
significant improvements in some semen parameters after
varicocelectomy, it cannot be concluded that the surgical
procedure improved the man’s reproductive potential.
Likewise, a large number of studies have evaluated the
effect of varicocele reversal on pregnancy rates. In such
studies, however, it is impossible to reliably control the
maternal reproductive potential. Even if a woman is
considered fertile after having undergone the most thor-
ough and up-to-date investigations, it is never possible to
definitely exclude the possibility that the infertility of a
couple is due to an undetermined female factor.
7. Conclusions
We can draw three conclusions from our review of the
literature. First, a unilateral varicocele causes bilateral
Leydig cell and Sertoli cell secretory dysfunction resulting in
bilateral impairment in spermatogenesis and epididymal
sperm maturation, which, together with other factors such as
excessive production of reactive oxygen species or abnormal
retention of cytoplasmic droplets, decrease the male repro-
ductive potential overall. Second, microsurgical varicocelec-
tomy facilitating the preservation of the testicular artery and
the surrounding lymph vessels represents the gold standard
for varicocele repair. And third, surgical or radiologic
treatment of varicocele may benefit subfertile men with
clinically manifest varicocele and poor semen quality.
Conflicts of interest
The authors have nothing to disclose.
Funding support
None.
Acknowledgments
The authors would like to thank S. Adreadakis for the
secretarial support in the preparation of this review.
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