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J Endocrinol Invest

DOI 10.1007/s40618-017-0713-z

ORIGINAL ARTICLE

Varicocele and semen quality: a retrospective case–control study


of 4230 patients from a single centre
F. Pallotti1 · D. Paoli1 · T. Carlini1 · A. R. Vestri2 · G. Martino3 · A. Lenzi1 ·
F. Lombardo1 

Received: 23 May 2017 / Accepted: 12 June 2017


© Italian Society of Endocrinology (SIE) 2017

Abstract  patients were divided into age classes (<17, 18–28, 29–39
Purpose  The aim of the present study is to assess impair- and  ≥40 years), and Group V patients were classified as
ment of spermatogenesis induced by varicocele in, to our “low” (I–II) or “high” (III–IV) grade.
knowledge, the largest single-centre caseload available to Results  Varicocele patients had a higher mean height than
date. controls, as well as lower BMI. There was also a statisti-
Materials and methods We conducted a retrospective cally significant reduction in the concentration/mL and the
study on 4230 consecutive patients attending our Depart- total sperm number in Group V against Group C. When
ment for andrological outpatient assessment and precon- stratified by age, values for all semen parameters were sig-
ception check-ups between 2011 and 2014. A total of 2113 nificantly worse in the older than in the younger age classes
patients had varicocele (Group V), while the remaining in both Group V and Group C, except for concentration/mL
2117 were selected as the control group (Group C). All and total sperm number in the 29–39 and ≥40 age classes
in both groups. A multivariable logistic regression analysis
showed that factors independently predicting the presence
* F. Lombardo of varicocele were older age, higher BMI and smoking for
francesco.lombardo@uniroma1.it more than 10 years.
F. Pallotti Conclusions  Varicocele patients show worse semen param-
francesco.pallotti@uniroma1.it eters compared to controls, although their values were still
D. Paoli within WHO reference limits. Semen quality is further
donatella.paoli@uniroma1.it worsened by increased age, grade and chronic smoking.
T. Carlini
tania.carlini@uniroma1.it Keywords  Varicocele · Spermatogenesis · Sperm
A. R. Vestri parameters · BMI
annarita.vestri@uniroma1.it
G. Martino
giovanni.martino@uniroma1.it Introduction
A. Lenzi
andrea.lenzi@uniroma1.it Varicocele is the abnormal enlargement and tortuousness of
1
the spermatic vein. It is a common finding in men under-
Laboratory of Seminology‑Sperm Bank “Loredana Gandini”,
going specialist examinations for infertility. Its incidence
Department of Experimental Medicine, “Sapienza”
University of Rome, Viale del Policlinico 155, 00161 Rome, is between 4.4 and 22.6% of the male population of fertile
Italy age, and it is found in 21–41% of patients examined for pri-
2
Department of Public Health and Infectious Diseases, mary fertility, peaking at 75–81% of patients with second-
“Sapienza” University of Rome, Rome, Italy ary infertility [1–3]. It usually presents between the ages
3
Department of Surgical Sciences “R. Paolucci”, “Sapienza” of 15 and 25 years and is unilateral on the left in 78–93%
University of Rome, Rome, Italy of cases, bilateral in 2–20% and unilateral on the right in

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J Endocrinol Invest

1–7% [4]. The correlation between impaired semen param- impairment of spermatogenesis induced by varicocele on,
eters and varicocele [2, 5] and the observation that infertile to our knowledge, the largest single-centre caseload avail-
patients have a greater incidence of this condition supports able to date, correlating it with the severity (grade) of the
the hypothesis that varicocele impairs spermatogenesis and disease and the patient’s age.
affects fertility [3].
However, the pathogenic mechanisms affecting sper-
matogenesis are still not completely clear, although they Materials and methods
may plausibly be attributed to hypoxia and haemostasis,
increased scrotal temperature, adrenal metabolite reflux, Patients
autoimmunity and increased oxidative stress [6]. A reflux-
induced increase in scrotal temperature, which is normally The study was approved by our University Hospital’s insti-
about 2 °C lower than body temperature, may be correlated tutional review board. We conducted a retrospective study
with reduced spermatogenesis, especially if associated with on a population of 4230 consecutive patients attending the
other external factors contributing to its further increase Department of Experimental Medicine—Medical Patho-
(exposure to high temperatures, duration of sitting posi- physiology Section, University of Rome “La Sapienza”—
tion) [7, 8]. Another factor associated with impaired semen for an andrological outpatient assessment and preconcep-
quality in the presence of varicocele is an increase in reac- tion check-ups between 2011 and 2014. The exclusion
tive oxygen species (ROS) levels, especially in association criteria were: cryptorchidism, testicular cancer or other
with other disorders (infections), environmental factors tumours, previous chemotherapy and/or radiotherapy,
(pollution, radiation) or lifestyle factors (smoking). The Klinefelter’s syndrome and other chromosomal conditions
oxidative stress caused by increased ROS production and and genetic syndromes, and any other andrological condi-
reduction in the sperm’s total antioxidant capacity leads to tion known to affect semen parameters. All patients under-
peroxidation of the membrane lipids, reduced plasma mem- went a careful medical history, general physical examina-
brane fluidity and impaired sperm–oocyte interaction. The tion and andrological examination. A total of 2113 patients
exact mechanism leading to the establishment of oxida- were found to have varicocele at physical examination
tive stress is not fully known, but ROS levels seem to be (Group V), while the remaining 2117 were selected as the
directly correlated with the severity of the varicocele and control group (Group C). A total of 1434 patients from
are significantly reduced after the repair procedure [9, 10]. Group V also performed testicular ultrasonography and
Induced oxidative stress can also cause sperm chromatin were subdivided on the basis of the location and severity of
abnormalities and sperm apoptosis and necrosis [11, 12]. the varicocele, expressed in grades from I to IV [18].
Recently, several authors pointed out that a simultaneous Patients were classified as “low” (I–II) or “high” (III–
dilation of the periprostatic venous plexus, often suggestive IV) grade. Finally, both cases and controls were divided
of a chronic (and asymptomatic) prostatitis, might further into age groups (<17 years, 18–28 years, 29–39 years
impair the quality of semen plasma and sperm parameters and ≥40 years).
[13–15].
Regardless of the actual impact of each of these factors, Semen analysis
the observation that men with varicocele aged more than
30 years have worse semen quality and reduced testoster- The seminal fluid of all patients and controls was exam-
one production suggests that the harmful effects are age ined. Semen samples were collected by masturbation
dependent [6]. directly into a sterile plastic container after 2–7 days of
There is a general agreement in the recent literature sexual abstinence. They were examined by light micro-
that varicocele is associated with impaired testicular func- scope according to World Health Organization 2010
tion and infertility. However, numerous studies have been ­criteria [19]. All seminal fluid examinations were carried
unable to establish the clinical importance of this correla- out by the same biologist (LG). The following variables
tion, as not all patients with varicocele prove to be infertile were taken into consideration: volume (mL), sperm con-
[16]. A recent meta-analysis by Agarwal et al. stressed the centration (n/mL), total sperm number (n × 106/ejaculate),
potential limitations of the published studies, such as the progressive motility (%) and morphology (% abnormal
high heterogeneity of the data and control groups, the fact forms).
that some confounding factors (age, smoking and obesity)
were not always taken into consideration and the use of dif- Statistical analysis
ferent versions of the WHO guidelines [17].
Given the heterogeneity of the literature evidence and Continuous variables are presented as mean ± SD, and dif-
the open debate on this argument, the present study assesses ferences were evaluated by the Student t or Mann–Whitney

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U test, depending on the shape of the distribution curve. measurements were available for 4044 subjects and showed
Categorical variables are summarized with counts and per- that the varicocele patients had a higher mean height
centages and were compared by Χ2 or Fisher’s exact tests. than the control group (178.4 ± 6.5 vs. 177.2 ± 6.5 cm,
One-way analysis of variance (ANOVA) followed by Bon- p < 0.001), while 31.7% (661) in Group V and 51.6%
ferroni as a post hoc test was performed to evaluate dif- (1073) in Group C had BMI ≥25 (Fig. 2) (mean BMI
ferences between groups and age classes. A multivariable 23.7 ± 2.9 vs. 25.3 ± 3.3 kg/m2, p < 0.001). Table 1 com-
logistic regression analysis was performed to calculate the pares the semen parameters of the two groups; there was a
adjusted ORs of factors associated with the varicocele. The statistically significant reduction in the number of sperm/
multivariate analysis was determined including all vari- mL and the total sperm number in Group V against Group
ables that could potentially affect the subjects with varico- C.
cele. The following variables were specifically included as All patients were divided into subgroups by total sperm
covariates: age class (18–28, 29–39, ≥40 years), BMI (nor- number and motility, using the 5th percentile of refer-
mal weight, overweight and obese), smoking (median years ence values [19] (cut-offs total sperm number <39 × 106/
of smoking: non-smokers, less than 10 years, more than ejaculate and sperm motility <32%) as indices of sperm
10 years). The probability values are two-sided; a probabil- testicular production and function. An arbitrary cut-off
ity of less than 0.05 was considered to indicate statistical value was chosen for abnormal forms (<80%). Analysis of
significance. All computations were carried out with Statis- total sperm number revealed that 12.9% (268) of patients
tical Package for the Social Sciences (SPSS) 22.0 (SPSS in Group V and 11.6% (241) in Group C presented <39 ×
Inc., Chicago, USA). ­106 sperm/ejaculate (p  = 0.21). Analysis of progressive
motility revealed that 21.5% (449) of patients in Group
V and 22.0% (457) in Group C presented <32% motility
Results (p  = 0.73). Finally, 54.0% (1126) of Group V patients and
52.9% (1101) of Group C patients had ≥80% abnormal
We examined 2113 varicocele patients with a mean age forms (p  = 0.48); these differences were not statistically
of 28.2 ± 8.0 years and 2117 controls with a mean age of significant (Fig. 3). It should be stressed that approximately
35.8 ± 7.4 years (p < 0.001). A total of 28 patients (1.3%) 80% of patients in both groups presented semen parameters
in Group V and 37 patients (1.8%) in Group C were azo- within the reference ranges [19].
ospermic. These patients were excluded from the statis- Groups V and C were divided by age (Group
tical analysis, which was therefore performed on 2085 V:  ≤17 years: 73 patients, 18–28 years: 1089 patients,
subjects from Group V and 2080 from Group C. 28.2% 29–39 years: 703 patients, ≥40 years: 220 patients; Group
(589 patients) in Group V and 30.9% (642) in Group C C:  ≤17 years: 9 patients, 18–28 years: 319 patients,
were smokers (p  = 0.064; Fig. 1). Height and weight 29–39 years: 1131 patients; ≥40 years: 621 patients).

Fig. 1  Percentage of smokers and non-smokers in varicocele and Fig. 2  Percentage of overweight patients (BMI ≥25) in varicocele
control groups and control groups

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Table 1  Mean, standard deviation and significance for varicocele group against control group
Age (years) Volume (mL) Sperm conc. Total sperm Progressive Abnormal
(N × ­106) number motility forms (%)
(N × ­106) (%)

Varicocele 2085 pts 28.2 ± 8.0 (27.0) 3.2 ± 1.5 (3.0) 66.6 ± 53.9 (55.0) 198.5 ± 162.1 (160.0) 43.9 ± 15.0 (50.0) 81.4 ± 6.8 (80.0)
Controls 2080 pts 35.8 ± 7.4 (36.0) 3.2 ± 1.5 (3.0) 76.7 ± 66.5 (62.0) 223.7 ± 195.1 (174.0) 44.5 ± 15.2 (50.0) 81.4 ± 7.0 (80.0)
p value <0.001 ns <0.001 <0.001 ns ns

Medians in brackets

Fig. 3  Percentage of patients with semen parameters below the cut-off (total sperm number <39 × ­106; progressive motility <32%; abnormal
forms ≥80%) in varicocele and control groups

Patients aged ≤17 years were excluded from the statisti- There was no significant difference in the height of the
cal analysis in both groups due to the small sample size. two subgroups (178.5 ± 6.6 vs. 178.5 ± 6.7 cm, low vs.
Within the groups stratified by age, values for all semen high grade), but there was a statistically significant dif-
parameters (concentration/mL, number/ejaculate, motility, ference in BMI (23.9 ± 3.0 vs. 23.4 ± 2.8 kg/m2, low
abnormal forms) except volume were significantly worse in vs. high grade, p < 0.001). All semen parameters except
the older than in the younger age classes in both Group V volume were significantly worse in high-grade patients
and Group C, except for concentration/mL and total sperm (Table  2). Table 3 shows the results of the multivariable
number in the 29–39 and ≥40 age classes in both groups. logistic regression analysis with the adjusted ORs of fac-
When comparing the same age classes between the two tors associated with development of varicocele. Age is a
groups, semen parameter values were significantly worse factor independently predicting the presence of varico-
in Group V than in Group C, with the exception of semen cele: age 18–28 years [OR 2.29, 95% CI (1.13–4.64)];
volume in the 18–28 and ≥40 classes and concentration/ age 29–39 years [OR 10.94, 95% CI (5.43–22.07)] and
mL and total sperm number in the 29–39 and ≥40 classes age  ≥40 years [OR 18.78, 95% CI (9.21–38.28). Addi-
(Fig. 4). tional predictive factors are: BMI ≥25.0 [OR 1.50, 95%
Group V patients were stratified by location and grade: CI (1.31–1.73)] vs. normal weight and median years of
81.1% (1668 patients) with left varicocele, 15.5% (320) smoking: more than 10 years [OR 1.38, 95% CI (1.13–
with bilateral varicocele and 3.4% (69) with right vari- 1.69)] vs. no smoking.
cocele. The statistical analysis was conducted on the
largest subgroup, namely patients with left varicocele.
A precise colour Doppler assessment of grade was avail- Discussion
able for 1434 of these, demonstrating that 735 of patients
(51%) with a mean age of 28.7 ± 8.2 years had a low (I There is a high incidence of varicocele in the male pop-
or II) grade and 699 patients (49%) with a mean age of ulation. It has been associated with impaired spermato-
26.9 ± 7.6 years had a high (III or IV) grade varicocele. genesis, even if the mechanisms for this damage are

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Fig. 4  Comparison and significance of varicocele vs. control groups divided by age class

still not fully clear. Furthermore, this association (even over 7000 patients, of whom 1253 had varicocele. This
if broadly accepted) is still somewhat controversial, as condition was found in 25% of patients with impaired
many patients with varicocele do not show any significant semen parameters and 12% of normozoospermic patients.
impairment of spermatogenesis and are fertile. In 1992, a However, there was a reduction in total sperm number
large multicentre study reported the semen parameters of and ipsilateral testicular volume in the varicocele group,

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Table 2  Mean, standard deviation and significance for varicocele grade I–II vs. varicocele grade III–IV
Age Volume (ml) Sperm conc. Total sperm number Progressive Abnormal
(×106) (N × ­106) motility (%) forms (%)

Low grade 735 pts 28.7 ± 8.2 (28.0) 3.2 ± 1.6 (3.0) 70.8 ± 53.5 (60.0) 212.7 ± 171.2 (173.4) 45.6 ± 13.8 (50.0) 81.0 ± 6.7 (80.0)
High grade 699 pts 26.9 ± 7.6 (25.0) 3.2 ± 1.6 (3.0) 63.2 ± 51.4 (48.0) 190.4 ± 154.5 (151.0) 43.2 ± 14.6 (50.0) 81.7 ± 6.4 (80.0)
p value <0.001 ns 0.006 0.01 0.001 0.02

Medians in brackets

Table 3  Multivariable-adjusted ORs of factors associated with devel- consecutive patients with varicocele. That study also found
opment of varicocele a lower incidence of varicocele in patients with a higher
p value OR 95% CI BMI [26]. This concords with other studies investigating
the same aspect: Chen et al. reported lower BMIs in vari-
Age 18–28 0.021 2.29 1.13 4.64
cocele patients than in controls, although they found no
Age 29–39 <0.0001 10.94 5.43 22.07
correlation with age class or differences in semen qual-
Age ≥40 <0.0001 18.78 9.21 38.28
ity [27], while Gokce et al. in a caseload of 1255 patients
Smoking <10 anni 0.773 1.03 0.84 1.25
including 587 with varicocele confirmed the greater effects
Smoking ≥10 anni 0.002 1.38 1.13 1.69 on semen parameters in varicocele patients against controls
Overweight and obese (BMI ≥25) <0.0001 1.50 1.31 1.73 and stressed the higher mean height and lower BMI found
CI Confidence interval in varicocele patients than in controls [28]. More recently,
in a multicentre study of more than 7000 north European
patients (median age 19 years) including 1102 with varico-
although there were no significant differences in the other cele, Damsgaard et al. found impaired semen parameters in
semen parameters considered, such as sperm motility and patients with grade III varicocele against those with a lower
abnormal forms [2]. grade and against controls. This study also found a higher
Witt and Lipshultz demonstrated a greater frequency of incidence of varicocele in patients with a lower BMI [29].
varicocele in men with secondary infertility than in those In a recent meta-analysis of ten studies published
with primary infertility. This suggested that varicocele might between 2010 and 2015, Agarwal et al. confirmed the
be a progressive rather than static pathological condition, impairment of semen parameters (total sperm number,
with possible structural and functional damage to the testicle motility and abnormal forms) in patients with varicocele.
[20]. Confirmation of this hypothesis was provided by Lenzi However, they noted that this study could be affected by the
et al. who found a significantly different testicular volume heterogeneity of the caseloads included in the meta-anal-
and semen quality in a group of adolescents with un-oper- ysis, as not all of the studies reported confounding factors
ated varicocele than in both a group of adolescents who had such as age, smoking and height and weight [17].
undergone varicocelectomy and a control group [21]. To our knowledge, the present study reports the largest
In a 2014 meta-analysis, Nork et al. confirmed these single-centre caseload of varicocele patients. Our results
data, finding impaired semen parameters (abnormal forms, concord with recent literature reports, finding a significant
concentration and motility) in 357 young varicocele reduction in sperm concentration and total sperm number in
patients in comparison with 427 controls [22]. the varicocele group against the control group, even though
Some authors have suggested a “dose-dependent” effect the mean semen parameters remained within the refer-
of varicocele on male reproductive potential, asserting that ence values [19]. We found a similar percentage of patients
subjects with a high-grade or bilateral varicocele would below the 5th percentile in both groups. The importance of
present progressively worse semen parameters [23, 24]. the single-centre nature of this study should be stressed;
Vivas-Acevedo et al. compared 155 normozoospermic whereas the semen analyses in multicentre studies were
men without and 363 men with varicocele, for the latter of carried out by different laboratories, in our study all semen
which both the site (left, right or bilateral) and grade (I, II examinations were carried out in the same laboratory by
or III) were specified. Abnormal forms and sperm motil- the same seminologist. This assures the utmost standardi-
ity were worse in the higher grades, whereas there was no zation and uniformity of the findings. The mean age of
significant difference in concentration among the various varicocele patients was lower than that of the controls, as
groups [25]. patients who were symptomatic and/or whose vascular dis-
Al-Ali et al. also found progressively worse semen ease was detectable on physical examination reached clini-
parameters with higher grades of varicocele in 716 cal observation earlier.

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However, logistic regression analysis revealed that age symptoms are more evident (high-grade varicocele). Sper-
was directly associated with the prevalence of varicocele; matogenesis was more greatly affected in patients with a
the risk of vascular disease rose with increasing age, reach- high-grade than a low-grade varicocele.
ing an OR of 18.78 in men aged ≥40 years. This shows that In light of all this, our data indicate that although vari-
the vascular deterioration underlying varicocele is a disease cocele is one of the most common findings in andrologi-
with a progressive impact. cal outpatient practice, in many patients it has only mod-
There was a similar percentage of smokers in both est effects on semen quality. It is possible that, even in the
groups, enabling the influence of smoking to be excluded presence of unaffected semen parameters, varicocele might
as the primary cause of the difference in semen parameters produce detrimental effects at the expense of different bio-
between the two groups. However, heavy smokers (≥10 functional parameters of the seminal fluid, but further stud-
cigarettes/day) had a greater risk of developing varicocele; ies are needed to verify this hypothesis. Finally, this study
this risk was 1.38 times higher than in non-smokers, con- did not aim to identify candidate patients for varicocelec-
sistent with the hypothesis that vascular damage may in tomy; however, our results indicate that spermatogenesis
some way be influenced or modulated by high exposure impairment progresses with age and varicocele grade, sug-
to the toxins and oxidative stress associated with smok- gesting that these patients should be monitored carefully.
ing. The greater height of the varicocele patients, as also
found in the cited studies, is in line with the hypothesis that Acknowledgements  This work is dedicated to the memory of Prof.
Loredana Gandini, who carried out the semen analyses in this study.
greater height might lead to greater hydrostatic pressure The authors wish to thank Marie-Hélène Hayles for her assistance in
in the pampiniform vascular plexus and therefore a higher the English translation of the manuscript.
probability of forming a varicocele due to detachment from
the vascular wall. However, as we found no significant dif- Compliance with ethical standards 
ference in height between patients with low and high-grade
varicocele, we can deduce that while greater height is asso- Conflict of interest  The authors have no conflicts of interest.
ciated with a greater incidence of varicocele, it alone is not
a factor influencing the severity of the vascular damage. Financial support This work was supported by a grant from the
Italian Ministry of Education and Research (MIUR-PRIN) and “Sapi-
Similarly, our data show a lower mean BMI in varico- enza” University of Rome, Faculty of Medicine.
cele patients than in controls, as well as a lower BMI in
the high-grade varicocele subgroup in comparison with the Ethical approval This retrospective research was approved by our
low-grade subgroup. However, logistic regression analysis University Hospital’s institutional review board (Protocol 419/16).
revealed that increased BMI is associated with an increased
risk of varicocele, with overweight or obese patients having Informed consent  Informed consent was obtained from all individual
a greater risk than those with a normal weight (OR 1.50; partecipants included in the study.
95% CI 1.31–1.73; p < 0.0001). This finding needs further
investigation.

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