Varicoceles: prevalence and

pathogenesis in adult men

Raul I. Clavijo, M.D., Robert Carrasquillo, M.D., and Ranjith Ramasamy, M.D.
Department of Urology, University of Miami Miller School of Medicine, Miami, Florida

Varicocele, or dilation of the pampiniform venous plexus, affects up to 15% of men. However, few of these men encounter problems
with fertility. This discrepancy between men with varicocele and the number of adversely affected men has led to abundant research to
identify the mechanisms for formation of varicocele as well as the pathologic mechanisms by which varicoceles affect fertility potential.
In this review, we discuss the prevalence of varicocele in adults, the anatomic features of varicocele, the leading theories as to how vari-
cocele can negatively affect fertility potential, and finally, the current literature on the impact of varicocele on testosterone production.
(Fertil SterilÒ 2017;108:364–9. Ó2017 by American Society for Reproductive Medicine.)
Key Words: Infertility, varicocele, spermatic vein, reactive oxygen species, testosterone
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/
16110-fertility-and-sterility/posts/18168-24269

ANATOMY: DEFINING THE

V
aricocele is defined as dilation ipsilateral renal vein, or the spermatic
of the pampiniform venous VARICOCELE AND vein itself, impeding testicular venous
plexus draining the testicle. It MECHANISMS FOR ITS drainage.
is typically diagnosed during a physical The dilation and reflux in primary
FORMATION
exam of the scrotum and graded ac- varicocele is thought to occur because
cording to the following scale: grade I Blood from the testicle drains into a of several reasons. First, several venog-
varicocele (palpable only during Val- network of veins referred to as the pam- raphy and cadaver studies confirm that
salva maneuver), grade II (palpable in piniform plexus. With the use of cast the left, and sometimes right, internal
the standing position), and grade III preparations, light-microscopic exami- spermatic vein drain into the renal vein,
(visible without palpation) (1). In one nation, and computer-aided three- or a suprarenal vein, in a perpendicular
of the earliest reviews on varicoceles, dimensional reconstruction, Ergun fashion (7). This drainage pattern, along
written more than 30 years ago, the et al. demonstrated that the veins with observations that the left spermatic
incidence of varicoceles in healthy directly draining the testicle can be vein has a longer overall drainage tract
men ranged from 4.4% to 22.6%, with separated into two bundles, one of and experiences greater venous differ-
an average of 15% (2). Interestingly, which is a collection of veins tightly ences in pressure, may explain the pre-
the prevalence is similar (15.7%) in a wrapped around the testicular artery, ponderance of left-sided varicoceles and
contemporary study of 7,035 military and the other in the adjacent fatty tis- relative scarcity of clinically palpable
recruits (all over 18 years of age) from sue (Fig. 1) (6). These two bundles of bilateral and isolated right-sided varico-
six European countries. Among men veins eventually coalesce into the in- celes (3,8–10). With these anatomic
with varicocele, only 1.1% had bilateral ternal spermatic vein at the level of observations it is not surprising that the
disease and 0.2% had isolated right- the internal inguinal ring. Dilation of development of varicoceles has been
sided varicocele on physical exam (3). the internal spermatic vein with reflux associated with somatometric
On the other hand, the prevalence of of blood down into the pampiniform parameters that theoretically should
varicocele can be as high as 45% plexus, is thought to be the primary alter the length of venous drainage and
among men seeking care for primary pathologic process for varicocele for- hydrostatic pressures. In fact, several
infertility and 80% among men seeking mation. Rarely, varicoceles can be a studies have consistently associated
care for secondary infertility (4, 5). result of external compression of the increasing height as a factor associated
with the presence of varicoceles, with
taller men having a greater prevalence
Received April 30, 2017; accepted June 29, 2017. of varicoceles (11, 12). However, those
R.I.C. has nothing to disclose. R.C. has nothing to disclose. R.R. has nothing to disclose. studies did not define distinct height
Reprint requests: Ranjith Ramasamy, M.D., Department of Urology, University of Miami Miller School
of Medicine, 1120 NW 14th Street, Miami, Florida, 33136 (E-mail: ramasamy@miami.edu). cutoffs that could predict the presence
of varicocele.
Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282/$36.00
Copyright ©2017 American Society for Reproductive Medicine, Published by Elsevier Inc.
Second, incompetence of venous
http://dx.doi.org/10.1016/j.fertnstert.2017.06.036 valves and variation in internal

364 VOL. 108 NO. 3 / SEPTEMBER 2017


FIGURE 1
Testicular venous drainage. A: Testicular artery; C: cremasteric venous
drainage with artery; D: deferential venous drainage with artery; I:
testicular drainage veins tightly wrapped around testicular artery; II:
testicular drainage veins separate from testicular artery. Used with
permission from Ergu €n S, Bruns T, Soyka A, Tauber R. Cell Tissue
Res 1997;288:391–8 (6).
Clavijo. Varicocele prevalence and pathogenesis. Fertil Steril 2017.
spermatic vein drainage is postulated as a contributing factor
to the development of varicoceles. Early studies in men on
postmortem examinations revealed that there was incompe-
tence or absence of internal spermatic vein valves in one-
half of the men that were studied (13). More recent studies
have shown the complete absence or incompetence of valves
in patients with varicoceles (14), particularly adolescents (15).
Along these lines, it has been observed that varicoceles may
also be caused by the presence of accessory or alternate con-
nections between the internal spermatic vein and systemic
venous circulation that lack antirefluxing mechanisms (15,
16). This anatomic variety must be considered when
treating patients at a level far from where testicular veins
coalesce (17). In fact, this anatomic variety regarding
drainage of the internal spermatic vein may be a reason
why there is a significantly higher rate of varicocele
recurrence after procedures such as laparascopic selective
internal spermatic vein ligation and percutaneous venous
embolization of the internal spermatic vein (18, 19).
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Fertility and Sterility®
Third, a relatively rare mechanism for varicocele forma-
tion is compression of the left renal vein or internal spermatic
vein (20). Classically, the nutcracker syndrome, where the
renal vein is compressed between the aorta and superior
mesenteric artery, has been postulated as a possible source
of internal spermatic vein insufficiency, some studies associ-
ating this condition with the development of varicoceles more
in adolescents than in adults and those with lower body mass
indexes (15, 21). Importantly, given the possibility of a
varicocele being caused by external compression from a
tumor or anatomical malformation, such as situs inversus, it
is advised that isolated right-sided varicoceles, and poten-
tially new left-sided varicoceles in older men, be worked up
with the use of abdominal imaging (20, 22).
Anatomically distinct from testicular veins, extrafunicular
veins are made up of the cremasteric, external pudendal, gu-
bernacular, and deferential veins, all of which drain into the
iliac vein. Although it is advocated that one spare the deferen-
tial veins during varicocelectomy (23), ligation of the remain-
ing extrafunicular veins is controversial. Venography provides
evidence that makes it unlikely that the extrafunicular veins
contribute to pathologic (refluxing) primary or recurrent vari-
coceles (24). However, based on the theory that varicoceles
represent an example of a venous retrograde circuit where
venous blood flow starts at the incompetent internal spermatic
vein and then travels through the pampiniform plexus and out
to the pelvic veins, ligation of some these extrafunicular (eg
cremasteric) veins may aid in closing this pathologic venous
circuit (25). Clinically, it seems that attempting to ligate all ex-
trafunicular veins except for the deferential vein by delivering
the testicle provides no benefit in terms of improvement of hor-
monal and semen parameters (25).
PATHOLOGIC MECHANISMS OF THE
VARICOCELE
Despite the extensive literature on varicoceles, the precise
mechanism by which they can potentially affect spermato-
genesis remains elusive. It has been well established that var-
icoceles are associated with impaired semen parameters even
in those not seeking care for infertility (3). However, no single
theory conclusively explains how varicoceles directly affect
spermatogenesis, and most plausible mechanisms have been
extrapolated from nonhuman models (26).
Here we review the data on the pathologic mechanisms
that have been evaluated, including oxidative stress, local
hormonal imbalances, stasis of blood (toxin accumulation),
testicular hypoperfusion, and heat stress (Fig. 2).
Oxidative Stress
Reactive oxygen species (ROS) are highly reactive oxygen-
containing chemical species that are unavoidable byproducts
of metabolic pathways, such as mitochondrial respiration,
which have been observed to impair spermatogenesis (27).
Mitochondria are thought to be the main source of sperm-
produced ROS, particularly in the formation of superoxide
in the electron transport chain (28). Excessive ROS production
has been associated with reduced sperm motility, abnormal
365
VIEWS AND REVIEWS
FIGURE 2
Summary of the proposed molecular mechanisms for the pathologic impact of varicoceles on fertility potential. ATP ¼ adenosine triphosphate;
ROS ¼ reactive oxygen species.
Clavijo. Varicocele prevalence and pathogenesis. Fertil Steril 2017.
sperm morphology, and decreased sperm adenosine triphos-
phate (ATP) production (29). ROS may also affect less mature
spermatogonia by causing damage to DNA and chromatin
structure, potentially leading to germ cell apoptosis (30).
Varicoceles are associated with the presence of higher
oxidative stress in the semen of patients seeking care for
infertility (31). Abnormally high levels of ROS can increase
DNA fragmentation (30, 32). In turn, compromise in DNA
integrity can then lead to decreased fertility potential and
may serve as the link between varicoceles and impaired
semen quality (32, 33), especially given the evidence that
varicocelectomy can decrease sperm DNA fragmentation
and increase fertility potential (34, 35). Unfortunately, the
reference ranges for both ROS and DNA fragmentation can
vary widely depending on the assay used in the laboratory.
Testicular Hypoperfusion and Stasis of Blood
(Toxin Accumulation)
Testicular biopsies from men with varicoceles have provided his-
tologic evidence that this condition leads to stagnation of blood
in microcirculatory vessels, resulting in ischemic structural
changes at the cellular level (10, 36). Evidence of hypoxia in
men with varicoceles has been investigated at the molecular
level as well, with one study noting a higher expression of
hypoxia-inducible factor 1a, a key regulator in tissue response
366
to hypoxia, in internal spermatic vein samples (37). Another
source of support of the theory that varicoceles decrease local
blood flow in the testicle are studies demonstrating improved
testicular arterial hemodynamics after varicocelectomy (38, 39).
Heat Stress
There is significant evidence that scrotal hyperthermia leads to
impairment of spermatogenesis as evident from the literature
evaluating heat stress as contraception as well as the effect of fe-
vers on spermatogenesis (40). Several human and animal studies
have measured significantly increased intratesticular and scrotal
skin temperature associated with varicoceles (41, 42). Theories as
to how varicoceles increase testicular temperature mostly revolve
around the model of scrotal countercurrent heat exchange
proposed by Dahl et al. where heat is exchanged above the
testicle between vessels carrying blood to the testicle and
vessels exiting the testicle (43). Molecular mechanisms for how
heat stress leads to impairment in spermatogenesis includes
decreased production of proteins overall and specifically key
enzymes, such as topoisomerase I, DNA polymerase, and heat
shock proteins (44, 45).
VARICOCELE AND HYPOGONADISM
Given the importance of adequate serum levels of testosterone
to spermatogenesis and fertility, it has been hypothesized that
VOL. 108 NO. 3 / SEPTEMBER 2017

varicoceles impair normal Leydig cell function and number,
and in turn Sertoli cell function. Repair of varicoceles can
restore normal serum androgen levels with reversal of symp-
tomatic hypogonadism and impaired spermatogenesis. The
relationship between varicocele repair and serum testosterone
was documented as early as the 1970s (46). We now under-
stand testicular function to be temperature dependent, and
the aforementioned pathogenic mechanisms of varicoceles,
including toxin accumulation, heat stress, and oxidative
stress, may directly affect the Leydig cell population of the
testis responsible for the normal intratesticular testosterone
concentrations needed for spermatogenesis (47).
Leydig cells are the principal androgen-producing cells in
mammals, contributing 95% of total serum testosterone
secretion in adult men. Testosterone is the end-product of a
five-step enzymatic pathway under direct stimulation of LH
produced by the pituitary gland (48). LH stimulates intracel-
lular cyclic AMP–protein kinase A signaling, which promotes
trafficking of cholesterol precursor from the cytoplasm to
mitochondria by way of steroidogenic acute regulatory pro-
tein (StAR) (49, 50). Trafficking of cholesterol by StAR is a
rate-limiting step in testosterone biosynthesis, and in vitro
studies have demonstrated inhibition of StAR protein expres-
sion and activity during oxidative stress (51). In vivo studies
in mice have demonstrated a significant decrease in serum
and intratesticular levels of testosterone when challenged
with chronic hypoxia, which is known to cause elaboration
of ROS in gonadal tissue (52, 53). A similar phenomenon
has been described in human patients with obstructive sleep
apnea and long-term exposure to high altitude, which are
coincident with decreases in serum testosterone and oligo-
zoospermia (54, 55).
Heat stress to the testes as a result of varicocele affects
testicular function. Recent nonhuman studies demonstrate a
direct toxic effect on the viability of Leydig cells and testos-
terone production after heat stress. Normal heat stress re-
sponses on the cellular level are mediated by the
endoplasmic reticulum, an organelle essential to maintaining
cellular homeostasis under stress conditions, which activates
an intracellular cascade known as the unfolded protein
response (56). This stress response allows for detection of
heat-induced protein misfolding, and subsequent degradation
of these proteins with a halt to protein translation. When this
heat stress is chronic in nature, the unfolded protein response
cascade has been shown to also activate proapoptotic path-
ways leading to cell death (57). In 2016, investigators used tis-
sue culture and live mouse models to investigate the effect of
heat stress on Leydig cell function and viability (58). With the
use of a tissue culture cell line of mouse Leydig tumor cells
responsive to hCG, they demonstrated a clear increase in
stress response mediator proteins and a concordant decrease
in hCG-induced steroidogenic activity. Levels of hormone
product as well as key enzyme levels in the testosterone syn-
thetic pathway were diminished. With the use of a live mouse
model, this heat stress–mediated decrease in steroidogenesis
was recapitulated. Steroidogenic enzymes, including StAR,
and serum levels of testosterone were decreased in mice after
several cycles of heat exposure to 42 C for 15 minutes per
day. Decreased steroidogenic enzymes and serum testosterone
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Fertility and Sterility®
was reversible by the administration of tauroursodeoxycholic
acid (TUDCA), a known endoplasmic reticulum stress inhibi-
tor, injected intraperitoneally. At the histologic level, mice
undergoing repeated heat stress exhibited Leydig cell death
and activation of proapoptotic cellular cascades within Ley-
dig cells, again reversible with administration of the TUDCA
stress-inhibiting agent.
Multiple nonhuman animal models have been published
confirming a direct pathologic consequence of anatomic
varicoceles on Leydig cell viability. Luo et al. performed a
sham-controlled experiment in rats with surgically induced
left-sided varicoceles (59). Biochemical studies on these rats
at 4 and 8 weeks after induction of varicocele demonstrated
apoptosis of Leydig cells and decreased testosterone biosyn-
thesis, with intratesticular levels markedly reduced in the
varicocele group versus the sham group at 8 weeks (24.84
vs. 29.41 ng/g; P< .05). Immunohistochemical evaluation in
that study showed a statistically significant increase in Leydig
cell apoptotic index in the varicocele group compared with
sham control at 4 and 8 weeks (P< .01), and StAR mRNA
expression levels were significantly decreased in the varico-
cele group compared with sham control. Very interestingly,
a similar decrease in StAR mRNA expression was seen in
the right (normal) testis compared with the left (varicocele)
testis in the experimental group, suggestive of a systemic
consequence to surgically induced varicocele. Other enzy-
matic dysfunction has been demonstrated in rodent models;
experimental varicocele induction in one experiment was
shown to inhibit testosterone production by Leydig cells at
the 17,20-desmolase step in the biosynthetic pathway (60).
The utility of varicocelectomy also has been demonstrated
in nonhuman models. Ozturk et al. (61) conducted a study
involving rats with a surgically induced varicocele without
repair, and a surgically induced varicocele with repair at
4 weeks. Intratesticular testosterone levels were assessed at
8 weeks (4 weeks after repair) and there was a statistically sig-
nificant increase of serum testosterone in the repair group
compared with rats that did not have varicocelectomy, indi-
cating that repair allows for reversal of varicocele-related
hypogonadism.
In the context of adult humans, multiple studies have been
published demonstrating a clear effect of varicocele repair on
serum testosterone levels, beginning in 1995 with a retrospec-
tive study by Su et al. (62). Those investigators reported an in-
crease in total serum testosterone from 319  12 ng/dL
preoperatively to 409  23 ng/dL (P< .0004) after inguinal or
subinguinal microsurgical varicocele repair in 33 men present-
ing with infertility. Since that time, other studies corroborated
these findings (25,63–65) whereas others failed to
demonstrate an increase in serum testosterone after
varicocelectomy (66–68). It is worthwhile to note, however,
that in the studies suggesting no effect of varicocele repair, a
majority of patients had normal preoperative serum
testosterone levels, and change in serum testosterone was a
secondary outcome measure, perhaps undermining the ability
of those studies to detect a change owing to insufficient
statistical power and variability in measurement of serum
testosterone levels. Recent prospective studies appear to
confirm a statistically significant increase in serum
367
VIEWS AND REVIEWS
testosterone after varicocelectomy in hypogonadal men (69–
71), and a 2012 meta-analysis of nine studies with a total of
814 men showed a mean increase in serum testosterone of
97.48 ng/dL (95% confidence interval [CI] 43.73–151.22;
P¼ .0004) from preoperative levels (72). Whether this increase
in serum testosterone of 100 ng/dL translates into improvement
of clinically significant symptoms remains to be seen.
CONCLUSION
In reviewing what is known about varicoceles in adults, it is
clear varicoceles are not only prevalent but also pathologic,
leading to impairment of semen parameters and testosterone
production. It is important to understand the anatomy of var-
icoceles, particularly the variety of venous drainage paths,
because it can determine how effective treatment options
are, especially if one chooses embolization or high ligation
of the internal spermatic vein. Looking at molecular patho-
genic mechanisms as they relate to impairment of semen pa-
rameters and testosterone production, it is clear that there are
several plausible theories that still remain unproven. Never-
theless, it is important for clinicians to understand the anat-
omy and mechanism by which varicocele affects testicular
function, because it will help with choosing the ideal treat-
ment option and in the discussion of causes of recurrence
and complications when counseling patients.
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