# Effects of Varicocele Repair on Testicular Endocrine Function: A Systematic Review and Meta-Analysis

Rossella Cannarella, Rupin Shah, Edmund Ko, Parviz Kavoussi, Amarnath Rambhatla, Taha Abo-Almagd Abdel-Meguid Hamoda, Ramadan Saleh, Ahmed M Harraz, Aldo E Calogero, Damayanthi Durairajanayagam, et al.

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## To cite this version:

Rossella Cannarella, Rupin Shah, Edmund Ko, Parviz Kavoussi, Amarnath Rambhatla, et al. "Effects of Varicocele Repair on Testicular Endocrine Function: A Systematic Review and Meta-Analysis." The World Journal of Men's Health, 2024, 42, 10.5534/wjmh.240109. hal-04766032

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# Effects of Varicocele Repair on Testicular Endocrine Function: A Systematic Review and Meta-Analysis

Rossella Cannarella<sup>1,2,3 ID</sup>, Rupin Shah<sup>3,4 ID</sup>, Edmund Ko<sup>3,5 ID</sup>, Parviz Kavoussi<sup>3,6 ID</sup>, Amarnath Rambhatla<sup>3,7 ID</sup>, Taha Abo-Almagd Abdel-Meguid Hamoda<sup>3,8,9 ID</sup>, Ramadan Saleh<sup>3,10,11 ID</sup>, Ahmed M. Harraz<sup>3,12,13,14 ID</sup>, Aldo E. Calogero<sup>1,3 ID</sup>, Damayanthi Durairajanayagam<sup>3,15 ID</sup>, Tuncay Toprak<sup>3,16 ID</sup>, Gokhan Calik<sup>3,17 ID</sup>, Andrea Crafa<sup>1,3 ID</sup>, Sezgin Gunes<sup>3,18 ID</sup>, Nazim Gherabi<sup>3,19 ID</sup>, Shinnosuke Kuroda<sup>2,3 ID</sup>, Hussein Kandil<sup>3,20 ID</sup>, Murat Gül<sup>3,21 ID</sup>, Florence Boitrelle<sup>3,22,23 ID</sup>, Ramy Abou Ghayda<sup>3,24 ID</sup>, Raghavender Kosgi<sup>3,25 ID</sup>, Vilvapathy Senguttuvan Karthikeyan<sup>3,26 ID</sup>, Giorgio I. Russo<sup>3,27 ID</sup>, Selahittin Cayan<sup>3,28 ID</sup>, Rajender Singh<sup>3,29 ID</sup>, Eric Chung<sup>3,30 ID</sup>, Carlo Giulioni<sup>3,31 ID</sup>, Gian Maria Busetto<sup>3,32 ID</sup>, Ashok Agarwal<sup>3,33 ID</sup>

<sup>1</sup>Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy, <sup>2</sup>Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, <sup>3</sup>Global Andrology Forum, Moreland Hills, OH, USA, <sup>4</sup>Division of Andrology, Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India, <sup>5</sup>Department of Urology, Loma Linda University Health, Loma Linda, CA, USA, <sup>6</sup>Austin Fertility & Reproductive Medicine/Westlake IVF, Austin, TX, USA, <sup>7</sup>Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA, <sup>8</sup>Department of Urology, King Abdulaziz University, Jeddah, Saudi Arabia, <sup>9</sup>Department of Urology, Faculty of Medicine, Minia University, Minia, Egypt, <sup>10</sup>Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt, <sup>11</sup>Ajyal IVF Center, Ajyal Hospital, Sohag, Egypt, <sup>12</sup>Mansoura University Urology and Nephrology Center, Mansoura, Egypt, <sup>13</sup>Department of Surgery, Urology Unit, Farwaniya Hospital, Farwaniya, Kuwait, <sup>14</sup>Department of Urology, Sabah Al Ahmad Urology Center, Kuwait City, Kuwait, <sup>15</sup>Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia, <sup>16</sup>Department of Urology, University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Türkiye, <sup>17</sup>Department of Urology, Istanbul Medipol University, Istanbul, Türkiye, <sup>18</sup>Department of Medical Biology, Medical Faculty, Ondokuz Mayis University, Samsun, Türkiye, <sup>19</sup>Department of Medicine, University of Algiers 1, Algiers, Algeria, <sup>20</sup>Fakih IVF Fertility Center, Abu Dhabi, UAE, <sup>21</sup>Department of Urology, Selçuk University School of Medicine, Konya, Türkiye, <sup>22</sup>Reproductive Biology, Fertility Preservation, Andrology, CECOS, Poissy Hospital, Poissy, France, <sup>23</sup>Department of Biology, Reproduction, Epigenetics, Environment and Development, Paris Saclay University, UVSQ, INRAE, BREED, Jouy-en-Josas, France, <sup>24</sup>Urology Institute, University Hospitals, Case Western Reserve University, Cleveland, OH, USA, <sup>25</sup>Department of Andrology & Men's Health, Apollo Hospitals, Hyderabad, India, <sup>26</sup>Andrology Unit, Department of Urology, Apollo Hospitals, Chennai, India, <sup>27</sup>Urology Section, Department of Surgery, University of Catania, Catania, Italy, <sup>28</sup>Department of Urology, University of Mersin School of Medicine, Mersin, Türkiye, <sup>29</sup>Division of Endocrinology, Central Drug Research Institute, Lucknow, India, <sup>30</sup>Department of Urology, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia, <sup>31</sup>Department of Urology, Polytechnic University of Marche, Ancona, Italy, <sup>32</sup>Department of Urology and Organ Transplantation, University of Foggia, Foggia, Italy, <sup>33</sup>Cleveland Clinic, Cleveland, OH, USA

**Purpose:** The objective of this manuscript is to assess the effect of varicocele repair (VR) in patients with clinical varicoceles on serum total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin B serum levels.

**Materials and Methods:** The study was performed in compliance with the Meta-Analysis and Systematic Reviews of Observational Studies (MOOSE) guidelines and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). All eligible studies were selected following the PICOS (Population, Intervention, Comparison/Comparator, Outcomes, Study design) model. The values of each outcome measured after VR were compared to the before parameters and, when available, to the values on patients with unrepaired varicocele, and to those of healthy controls with no varicocele. For
total testosterone, the values were sub-analyzed based on the mean total testosterone levels before VR (<300 ng/dL or >300 ng/dL), the fertility status, the time of follow-up and the technique used for VR.

**Results:** From a total of 460 abstracts retrieved, 48 articles were included in our meta-analysis. Serum total testosterone levels were significantly higher after VR compared to both pre-treatment levels (mean difference [MD] 82.45 ng/dL, 95% confidence interval [CI]: 64.14–100.76; p<0.00001) and to the levels of patients with unrepaired varicocele (MD 91.64 ng/dL, 95% CI: 62.30–120.99; p<0.00001). They did not differ from the levels of healthy controls with no varicocele (MD -22.01 ng/dL, 95% CI: -68.59–24.58; p=0.35). The increase resulted to be independent from the mean total testosterone levels before VR, fertility status, time of follow-up and type of VR. After VR, a trend toward lower serum LH levels was found compared to before values (MD -0.37 IU/L, 95% CI: -0.74–0.01; p=0.06). When compared to the levels of patients with unrepaired VR, LH levels after VR were significantly lower (MD -0.96 IU/L, 95% CI: -1.56 to -0.35; p=0.002). LH levels were not significantly higher than healthy men without varicocele (MD 0.84 IU/L, 95% CI: -0.68–2.36; p=0.28). Patients with VR had significantly lower FSH levels compared to their pre-treatment values (MD -1.43 IU/L, 95% CI: -1.82 to -1.04; p<0.00001), and also to those of patients with non-repaired varicocele (MD -2.35 IU/L, 95% CI: -4.06 to -0.65; p=0.007). When compared to healthy controls with no varicocele, FSH levels were significantly higher (MD 2.71 IU/L, 95% CI: 1.12–4.31; p=0.0009). Lastly, after VR no significant change in inhibin B serum levels was seen compared to pre-treatment levels (MD 11.76 pg/mL, 95% CI: -3.83–27.35; p=0.14).

**Conclusions:** The present meta-analysis is the largest to date to assess the impact of VR on Leydig cell and Sertoli cell function using a before-after analysis for uncontrolled studies, and using data from patients with unrepaired varicoceles or healthy patients without varicocele as controls. VR was found to increase and restore to normality serum levels of total testosterone and LH. This evidence could be of value in considering the treatment of varicocele in patients with low testosterone or those who show a progressive decline in testosterone levels.

**Keywords:** Follicle stimulating hormone; Hormones; Inhibin B; Luteinizing hormone; Testosterone; Varicocele

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

## INTRODUCTION

Male hypogonadism is defined by a reduced production of testosterone by the testis, ascribed to a primary dysfunction of the gonad or to a lack of stimulation of the testes by the hypothalamic-pituitary axis. The latest guidelines of the Endocrine Society consider the value of 264 ng/dL (9.2 nmol/L) as the cut-off for the diagnosis of hypogonadism, in the presence of symptoms suggestive of the disease [1]. The 2022 position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS), however, set the cut-off at 346 ng/dL [2], highlighting the lack of consensus on the serum testosterone value below which diagnosis of hypogonadism can be made.

Hypogonadism may be observed in patients with male infertility [3,4]. This includes those with varicocele, which may impair Leydig cell function [5]. It is commonly reported in men with variable prevalence, depending on their age, fertility status, and the method to diagnose varicocele. In a large study of 7,035 young healthy men, median age 19 years, from the general

population of six European countries and do not selected for infertility, 15.7% had clinical varicoceles [6]. In this study, the presence of varicocele was associated with poorer semen quality, higher serum levels of follicle-stimulating hormone (FSH), lower inhibin B, and higher levels of luteinizing hormone (LH). However, in this study, testosterone and free testosterone were not significantly different between patients with and without varicocele and healthy men.

The link between varicocele and deterioration of spermatogenesis is well established. Nevertheless, varicocele could also impair Leydig cell function leading to reduced testosterone synthesis which is a significant risk factor for hypogonadism and spermatogenesis failure [7]. Although still controversial, evidence supporting positive effect of varicocele repair (VR) on serum testosterone levels has been demonstrated in experimental and clinical studies [8]. The proposed detrimental effects of varicocele are suggested to be related to oxidative stress, heat stress, local hormonal imbalances, testicular hypoperfusion, and stasis of blood with accumulation of toxins [9]. The evidence that varicocele
decreases Leydig cell production of testosterone is increased. Some studies indicate the presence of low testosterone levels in patients with varicocele [10] and their improvement after VR [8,11]. However, no definitive conclusion has been reached due to opposite results from other studies [12-14].

Given the controversial effects of VR on testicular steroidogenesis, the aim of this systematic review and meta-analysis was to investigate the impact of VR on serum total testosterone (TT), LH, FSH, and inhibin B levels in patients with clinical varicocele, whose varicocele was treated due to testicular pain or as part of infertility management. The results of the current review may allow the development of clear guidelines on the management of these varicocele-associated endocrine abnormalities.

## MATERIALS AND METHODS

### 1. Search strategy

This meta-analysis was performed in compliance with the Meta-Analysis and Systematic Reviews of Observational Studies (MOOSE) guidelines [15] and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines [16]. The data were extracted through extensive searches in the Scopus, PubMed, and Cochrane databases from 1970 to the present.

The search strategy included the combination of the following Medical Subjects Headings (MeSH) terms and keywords: varicoc*, management, embolization / embolisation, microsurg* / micro-surg*, varicocelectomy,

repair, correction, treatment, ligation, surg*, operation, radiolog*, sperm*, semen, seminal, ejaculate, asperm* / azoo* / azoosperm*, oligo* / oligosperm* / oligozoosperm*, astheno* / asthenosperm* / asthenozoosperm*, terato* / teratosperm* / teratozoosperm*, and necro* / necro sperm* / necrozoosperm* / testosterone / hypogonadism. The search was limited to original research in humans and no language restrictions were applied. Other relevant articles were manually extracted by searching the reference lists of the articles selected using the keywords listed above.

Studies were first evaluated for inclusion by reading their titles and abstracts. When the abstract did not allow detecting whether the study contained data in line with the outcomes of interest for the meta-analysis, the full text was read carefully. To ensure that the study evaluation was performed in a standardized manner, researchers were subject to methodical training exercises prior to the start of the study [17]. Each article was then independently assessed for eligibility by two different researchers. A third researcher resolved any disagreement and made the final decision.

### 2. Selection criteria

Our review included all uncontrolled and controlled studies on men with clinical varicocele until November, 2023 that measured TT serum levels in patients undergoing VR for infertility or hypogonadism. Data on LH, FSH and inhibin B were also extracted when present. Eligible studies were selected following the PICOS (Population, Intervention, Comparison/Comparator, Outcomes, Study type) model (Table 1) [18]. We however

<table><caption>**Table 1.** Selection criteria of the studies that were included in this systematic review and meta-analysis using the PICOS model</caption><thead><tr><td>PICOS</td><td>Inclusion criteria</td><td>Exclusion criteria</td></tr></thead><tbody><tr><td>Population</td><td>Patients with clinical varicocele</td><td>Adolescent, subclinical varicocele, hormonal treatment, testosterone replacement therapy, antioxidant supplementation, major comorbidities</td></tr><tr><td>Intervention</td><td>Varicocele repair</td><td>-</td></tr><tr><td>Comparison</td><td>Before-treatment parameters<br>Patients with untreated varicocele<br>Healthy subjects with no varicocele</td><td>-</td></tr><tr><td>Outcome</td><td>Total testosterone<br>LH<br>FSH<br>Inhibin B</td><td>-</td></tr><tr><td>Study type</td><td>Observational studies, controlled non-randomized trials, RCTs</td><td>In vitro, animal studies, case reports, case series, communications, proceedings, conference abstracts</td></tr></tbody></table>

LH: luteinizing hormone, FSH: follicle-stimulating hormone, RCT: randomized controlled trial.
excluded the following studies: studies on adolescents,
studies of subclinical varicocele, studies with no VR, in
vitro studies, animal studies, case reports, case series,
and communications (Table 1).

Abstracts of the retrieved articles were indepen-
dently screened using the PICOS filter and assessed to
confirm their eligibility. The full texts of the screened
articles were then examined against the exclusion cri-
teria listed in Table 1. Data were extracted and keyed
into a structured spreadsheet, after which the entries
were verified by the second researcher. Differences in
views were resolved by a third, more experienced re-
searcher whose judgment was considered final.

3. Data extraction

The following data were extracted: study design, pa-
tients' age, grade of varicocele and method of VR, time
to follow-up evaluation, number of patients in the ex-
perimental group and control group (if any), hormone
levels, presence of infertility, duration of infertility,
presence of hypogonadism. Data were extracted by one
researcher and then verified by a second researcher.
Any disagreements were resolved by a third senior re-
searcher.

4. Quality assessment

The quality of evidence (QoE) assessment of the
respective articles included was performed by inde-
pendent researchers working in pairs and further
reviewed by a third researcher to maintain uniform
standards and to highlight the risk of bias.

Quality assessment for observational studies was
done using the Cambridge Quality Checklist [19]. Vari-
ables were classified as correlates, risk factors, and
causal risk factors. Correlates were applied based on
construct and statistical conclusion validity and risk
factors (longitudinal studies) and causal risk factors
were assessed using the correlation between variables
that should have preceded the outcome. A total score
of 0–5 at the Cambridge Quality Checklist denoted
a low QoE, 6–10 a moderate QoE, 11–15 a high QoE.
Randomized controlled trials (RCTs) were assessed us-
ing the Consolidated Standards of Reporting Trials
(CONSORT) guidelines [20], the Jadad scale [21], and
the Revised Cochrane Risk of Bias Tool 2.0 (ROB-2)
[22]. The CONSORT checklist helped to determine how
well the parallel groups RCT were conducted. Based on
the Jadad scale, points were assigned for randomiza-

tion, blinding, and whether the trial included results
of all included patients. The ROB-2 was applied to
identify bias in the RCT results, based on randomiza-
tion, deviations, missing data, outcome measurement,
and reporting of results, whereby the studies were cat-
egorized into low risk, some concerns, and high risk of
bias. The scores from the Jadad, CONSORT and ROB-2
were taken into consideration to assign a low, moder-
ate or high QoE. In detail, the Jadad checklist allows
to assign a score from 1 to 5 (up to 2 was considered as
high risk, 3 as moderate risk, 4 and 5 as low risk), the
CONSORT uses a score up to 25 (0–8, high risk; 9–16,
moderate risk; 17–25, low risk). The ROB-2 does not
provide a score but automatically identifies a study as
with high, moderate or low risk of bias based on the
assessment process.

5. Statistical analysis

1) Quantitative data analysis

For the meta-analysis, Comprehensive Meta-Analysis
Software (Version 3) (Biostat Inc.) and the Review
Manager (RevMan) Version 5.4 (The Cochrane Col-
laboration, 2020) were used. The mean difference (MD)
was used as the measure of effect size for statistical
comparison between VR cases and controls. To check
the heterogeneity across pooled studies, Cochran's Q
test and heterogeneity index (I²) were used with p<0.10
considered statistically significant [23]. I² is the repre-
sentator of heterogeneity and it generally lies between
0% and 100%, where <50% represents low-to-moderate
heterogeneity and >50% suggests high heterogeneity
[24]. In the case of low heterogeneity, the fixed-effect
model was used to draw the statistical inference. In
the case of >50% heterogeneity, the random-effects
model was acquired. For generating high-resolution
forest plots, the MD and 95% confidence interval (95%
CI) were considered for both the “all studies” and the
pooled data respectively [25].

2) Sensitivity analysis

The method of one study removal at a time was used
for sensitivity analysis. One study was excluded at a
time and their pooled effect size and CI were calculated
to find if that study was sensitive. If the exclusion of a
particular study resulted in a change of the inference,
it was labeled as a 'sensitive study.'
### 3) Publication bias analysis

Asymmetrical funnel plots were taken to qualitatively suggest the presence of publication bias. The presence of publication bias represents the missing studies from one side of the graph. We further used Egger's intercept test, for representing publication bias quantitatively. If publication bias was present, imputed publication bias was drawn on forest plots using 'Duval and Tweedie's Trim and Fill' method [26].

### 4) Sub-analyses

Four sub-analyses were conducted to explore the effect of VR on TT based on: 1) the mean TT (values >300 ng/dL vs. values ≤300 ng/dL), 2) fertility status (infertile vs. fertile), 3) the follow-up duration, and 4) the technique used for VR.

## RESULTS

The initial search retrieved a total of 460 articles. After removing duplicates, non-original articles, *in vitro* or animal studies, or articles on a different topic, 206 full texts were screened. Of these, 158 were excluded and 48

original articles [10,12,13,27-71] were finally included in the present meta-analysis (Fig. 1).

Characteristics of included studies are shown in Table 2. The majority were observational studies, with only four RCTs [29,48,58,68]. Follow-up duration ranged from 3 to 24 months. Several articles provided information on patients' fertility status, with only a few describing the presence of hypotestosteronemia in the enrolled cohort (Table 2).

QoE of each article is provided in Table 3.

### 1. Total testosterone

A total of 48 studies with 4,191 patients have been included in the before-after analysis on the effect of VR on TT levels, finding a significant increase in its levels (MD 82.45 ng/dL, 95% CI: 64.14 to 100.76; p<0.00001) (Fig. 2). The analysis showed the presence of inter-study heterogeneity, as demonstrated by the Q-test (Q-value=1,692.2; p<0.001) and I²=96.0%. At the sensitivity analysis, no study was sensitive enough to change the conclusion that VR significantly increases TT level. Tests for funnel plot asymmetry were performed and provided no evident indication of publica-

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

2024

**Fig. 1.** Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow-chart.
<table><caption>Table 2. Main characteristics of included studies</caption><thead><tr><th>Author</th><th>Study type</th><th>Age (y)</th><th>Number of patients</th><th>Varicocele grade (I-III)</th><th>Follow-up (mo)</th><th>Type of varicocele repair</th><th>Presence of infertility</th><th>Duration of infertility (mo)</th><th>Presence of hypogonadism</th></tr></thead><tbody><tr><td>Abdel-Meguid et al, 2014 [27]</td><td>Non-randomized controlled study</td><td>n.s.</td><td>165</td><td>n.s.</td><td>6-12</td><td>Subinguinal microsurgical</td><td>Yes (99 patients)</td><td>n.s.</td><td>56 patients had TT &lt;300 ng/dL</td></tr><tr><td>Bolat et al, 2019 [28]</td><td>Retrospective</td><td>Group 1: 18.9±0.8<br>Group 2: 26.4±2.7<br>Group 3: 34.6±3.9</td><td>292</td><td>Group 1: I: 3;<br>II: 5;<br>III: 25</td><td>n.s.</td><td>Subinguinal microsurgical</td><td>Yes</td><td>Group 1: 21.6±20.6<br>Group 2: 20.8±24.6<br>Group 3: 35.6±40.3</td><td>n.s.</td></tr><tr><td>Bryniarski et al, 2017 [29]</td><td>Randomized controlled trial</td><td>Group 1: 31.6±3.3<br>Group 2: 33.6±2.7</td><td>74</td><td>n.s.</td><td>12</td><td>Laparoscopic Microscopic</td><td>Yes</td><td>&gt;1 year</td><td>n.s.</td></tr><tr><td>Cantoro et al, 2015a [30]</td><td>Prospective</td><td>Group 1: 29.4±5.1<br>Group 2: 31.3±4.2</td><td>337</td><td>n.s.</td><td>6</td><td>Percutaneous embolization</td><td>Yes</td><td>Group 1: 15.3±4.3<br>Group 2: 13.4±4.8</td><td>n.s.</td></tr><tr><td>Cantoro et al, 2015b [31]</td><td>Prospective</td><td>28.4±6.3</td><td>118</td><td>n.s.</td><td>n.s.</td><td>Sclero-embolization (n=97); Ligation (n=16); Bilateral ligation (n=5)</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Cayan et al, 1999 [32]</td><td>Retrospective</td><td>29.5 (21.0-40.0)</td><td>78</td><td>n.s.</td><td>Up to 12</td><td>Subinguinal</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Hurtado de Catalfo et al, 2007 [33]</td><td>Prospective</td><td>Group 1: 28.0±3.0<br>Group 2: 28.0±4.0</td><td>69</td><td>n.s.</td><td>8</td><td>n.s.</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Di Bisceglie et al, 2007 [34]</td><td>Retrospective</td><td>28.1 (16.0-43.0)</td><td>38</td><td>n.s.</td><td>Up to 6</td><td>Sclerotherapy</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Enatsu et al, 2014 [35]</td><td>Retrospective</td><td>34.2±5.6</td><td>102</td><td>I: 8; II: 39; III: 55</td><td>9</td><td>Subinguinal</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Fujiisawa et al, 2001 [36]</td><td>Retrospective</td><td>32.5±4.3</td><td>52</td><td>n.s.</td><td>n.s.</td><td>Subinguinal</td><td>Yes</td><td>33.1±25.5</td><td>n.s.</td></tr><tr><td>Gat et al, 2004 [37]</td><td>Retrospective</td><td>35.1±6.68</td><td>83</td><td>I: 22; II: 3; III: 22</td><td>n.s.</td><td>Embolization</td><td>Yes</td><td>&gt;12</td><td>n.s.</td></tr><tr><td>Ghanem et al, 2011 [38]</td><td>Prospective</td><td>32.7±1.1</td><td>59</td><td>I: 52; II: 7</td><td>6</td><td>Sclerotherapy</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr></tbody></table>
<table><caption>Table 2. Continued 1</caption><thead><tr><th>Author</th><th>Study type</th><th>Age (y)</th><th>Number of patients</th><th>Varicocele grade (I-III)</th><th>Follow-up (mo)</th><th>Type of varicocele repair</th><th>Presence of infertility</th><th>Duration of infertility (mo)</th><th>Presence of hypogonadism</th></tr></thead><tbody><tr><td>Ghanem et al, 2020 [39]</td><td>Prospective</td><td>Group 1: 34.2±2.1<br>Group 2: 33.9±3.1</td><td>109</td><td>II: 52; III: 12</td><td>6</td><td>High retroperitoneal ligation: 18<br>(28%); Inguinal ligation: 34<br>(53%); Subinguinal ligation: 3 (5%); Laparoscopic varicocelectomy: 9 (14%)</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Ghazi and Abdel-fattah 2011 [40]</td><td>Prospective</td><td>35.6±7.2</td><td>82</td><td>n.s.</td><td>6</td><td>Microscopic subinguinal</td><td>Yes</td><td>67.0±36.0</td><td>n.s.</td></tr><tr><td>Grober et al, 2004 [41]</td><td>Retrospective</td><td>31.5 (16.0–52.0)</td><td>54</td><td>n.s.</td><td>3</td><td>Subinguinal microsurgery with TD</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Gomaa et al, 2018 [10]</td><td>Prospective controlled</td><td>&gt;18</td><td>45</td><td>n.s.</td><td>6</td><td>Loup assisted subinguinal</td><td>67% out of 90 suffered from infertility</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Ito et al, 1993 [42]</td><td>Observational, controlled</td><td>Group 1: 33.0 (24.0–45.0)<br>Group 2: 23.0 (9.0–52.0)</td><td>56</td><td>I: 7; II: 7; III: 17</td><td>6</td><td>Microsurgical</td><td>Yes (31 out of 56)</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Iwasaki et al, 2003 [43]</td><td>Retrospective</td><td>33.1</td><td>26</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Jin et al, 2020 [44]</td><td>Non-randomized controlled study</td><td>Group 1: 27.75±4.74<br>Group 2: 27.30±3.69</td><td>181</td><td>Group 1: I: 11;<br>II: 47;<br>III: 56<br>Group 2: I: 8;<br>II: 23;<br>III: 36</td><td>6</td><td>Microsurgical subinguinal</td><td>Yes</td><td>&gt;12</td><td>n.s.</td></tr><tr><td>Kuroiwa et al, 1991 [45]</td><td>Retrospective</td><td>33.0 (26.0–44.0)</td><td>28</td><td>n.s.</td><td>6</td><td>Embolization</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Lee et al, 2007 [46]</td><td>Retrospective</td><td>39.6</td><td>18</td><td>16 left: II: 5; III: 11<br>12 right: I: 3; II: 8; III: 1</td><td>14 wk</td><td>Subinguinal</td><td>n.s.</td><td>n.s.</td><td>6 patients had TT &lt;300 ng/dL</td></tr><tr><td>Li et al, 2012 [47]</td><td>Retrospective</td><td>33.1 (15.0–42.0)</td><td>35</td><td>I: 2; II: 8; III: 11</td><td>3</td><td>Subinguinal</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr></tbody></table>
<table><caption>Table 2. Continued 2</caption><thead><tr><th>Author</th><th>Study type</th><th>Age (y)</th><th>Number of patients</th><th>Varicocele grade (I-III)</th><th>Follow-up (mo)</th><th>Type of varicocele repair</th><th>Presence of infertility</th><th>Duration of infertility (mo)</th><th>Presence of hypogonadism</th></tr></thead><tbody><tr><td>Lu et al, 2018 [48]</td><td>Placebo-controlled double-blind trial</td><td>32.76±3.24</td><td>27</td><td>n.s.</td><td>6</td><td>Subinguinal</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td rowspan="4">Lv et al, 2016 [49]</td><td rowspan="4">Prospective</td><td>Group 1: 23.7±3.7</td><td rowspan="4">345</td><td rowspan="4">n.s.</td><td rowspan="4">n.s.</td><td>Laparoscopic</td><td>Group 1: 38</td><td rowspan="4">n.s.</td><td rowspan="4">n.s.</td></tr><tr><td>Group 2: 25.1±4.6</td><td>Microscopic inguinal</td><td>Group 2: 40</td></tr><tr><td>Group 3: 24.2±7.5</td><td>Microscopic retroperitoneal</td><td>Group 3: 34</td></tr><tr><td>Group 4: 22.8±6.8</td><td>Microscopic subinguinal</td><td>Group 4: 41</td></tr><tr><td rowspan="2">Majzoub et al, 2021 [50]</td><td rowspan="2">Retrospective</td><td rowspan="2">37.14±7.86</td><td rowspan="2">85</td><td rowspan="2">Left: I: 3; II: 34; III: 48; Right: I: 18; II: 6; III: 2</td><td rowspan="2">n.s.</td><td>Subinguinal</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>microsurgical</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Nuhoğlu et al, 2004 [51]</td><td>Prospective</td><td>Group 1: 29.5±4.2</td><td rowspan="2">56</td><td rowspan="2">n.s.</td><td rowspan="2">n.s.</td><td>Subinguinal</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td></td><td>Group 2: 28.0±5.4</td><td>microsurgery</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Ozden et al, 2008 [52]</td><td>Prospective</td><td>24.1±3.6</td><td>30</td><td>II: 10; III: 20</td><td>Up to 6</td><td>Subinguinal</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Öztekin et al, 2020 [53]</td><td>Prospective</td><td>26.8 (18.0–41.0)</td><td>57</td><td>II: 3; III: 54</td><td>6</td><td>Microsurgical</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Pasqualotto et al, 2005a [54]</td><td>Prospective</td><td>n.s.</td><td>61</td><td>I-III</td><td>6</td><td>Microsurgical</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Pasqualotto et al, 2005b [55]</td><td>Retrospective</td><td>Group 1: 32.5±4.5</td><td rowspan="2">50</td><td rowspan="2">Group 1: Left II and III</td><td rowspan="2">18</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td></td><td>Group 2: 29.7±3.6</td><td>Group 2: Left II and III; Right subclinical</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Plerik et al, 2001 [56]</td><td>Retrospective</td><td>35.5±5.7</td><td>30</td><td></td><td>Up to 3</td><td>Palomo</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Prasivoravong et al, 2014 [57]</td><td>Prospective</td><td>30.43±5.16</td><td>47</td><td>III</td><td>6</td><td>Embolization</td><td>Yes</td><td>33.76±19.72</td><td>n.s.</td></tr><tr><td>Qu et al, 2017 [58] Randomized controlled study</td><td>Retrospective</td><td>26.8±5.9</td><td>44</td><td>I: 0; II: 25; III: 13</td><td>9</td><td>Ligation</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr></tbody></table>
<table><caption>Table 2. Continued 3</caption><thead><tr><th>Author</th><th>Study type</th><th>Age (y)</th><th>Number of patients</th><th>Varicocele grade (I-III)</th><th>Follow-up (mo)</th><th>Type of varicocele repair</th><th>Presence of infertility</th><th>Duration of infertility (mo)</th><th>Presence of hypogonadism</th></tr></thead><tbody><tr><td>Ramasamy and Schlegel 2006 [59]</td><td>Retrospective</td><td>n.s.</td><td>165</td><td>Group 1:<br>I: 14;<br>II: 18;<br>III: 14<br>Group 2:<br>I: 13;<br>II: 34;<br>III: 27</td><td>24</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Reşorlu et al, 2010 [13]</td><td>Retrospective</td><td>28.1 (18.0-48.0)</td><td>96</td><td>n.s.</td><td>6</td><td>Microsurgical subinguinal</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Rodriguez Pena et al, 2009 [12]</td><td>Retrospective</td><td>23.5 (15.0-35.0)</td><td>202</td><td>II (70%), III (30%)</td><td>n.s.</td><td>Inguinal</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Sathya Srini et al, 2011 [60]</td><td>Prospective</td><td>30.0±4.9<br>(24.0-49.0)</td><td>100</td><td>n.s.</td><td>6-12</td><td>Microsurgical</td><td>Yes</td><td>3.23±1.75 y</td><td>Yes (TT&lt;280 ng/dL)</td></tr><tr><td>Segenreich et al, 1986 [61]</td><td>Prospective</td><td>n.s.</td><td>50</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Senturk et al, 2020 [62]</td><td>Retrospective</td><td>29.88±6.86</td><td>250</td><td>n.s.</td><td>6</td><td>n.s.</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Shabana et al, 2015 [63]</td><td>Prospective, non-controlled, observational</td><td>28.3±7.4</td><td>123</td><td>I: 42; II or III: 81</td><td>6</td><td>Microscopic subinguinal</td><td>Yes</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Shinoda, 1985 [64]</td><td>Prospective</td><td>n.s.</td><td>46</td><td>n.s.</td><td>n.s.</td><td>High ligation</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Smit et al, 2010 [65]</td><td>Prospective</td><td>34.0±6.9</td><td>49</td><td>I: 16; II: 15; III: 13</td><td>3</td><td>Ligation: 36; microsurgical: 8</td><td>Yes</td><td>2.7±1.6 y</td><td>n.s.</td></tr><tr><td>Su et al, 1995 [66]</td><td>Retrospective</td><td>35.0 (22.0-57.0)</td><td>53</td><td>I (n=13); II (n=22); III (n=18)</td><td>3</td><td>Inguinal or subinguinal</td><td>Yes</td><td>21.0 (0-156.0)</td><td>n.s.</td></tr><tr><td>Tanrikut et al, 2011 [67]</td><td>Retrospective</td><td>35.0 (18.0-70.0)</td><td>325</td><td>n.s.</td><td>3-12</td><td>Subinguinal</td><td>n.s.</td><td>n.s.</td><td>38 patients had TT &lt;300 ng/dL</td></tr><tr><td>Vyas et al, 2017 [68]</td><td>Randomized controlled trial</td><td>Group 1:<br>23.63±4.53<br>Group 2:<br>26.11±5.12</td><td>69</td><td>Group 1:<br>II: 16;<br>III: 14<br>Group 2:<br>II: 15;<br>III: 15</td><td>3</td><td>Subinguinal</td><td>Yes (40 [66%])</td><td>n.s.</td><td>n.s.</td></tr><tr><td>Younes, 2003 [69]</td><td>Observational, controlled</td><td>37.0±5.9</td><td>48</td><td>II: 30; III: 18</td><td>3-6</td><td>Ligation</td><td>n.s.</td><td>n.s.</td><td>n.s.</td></tr></tbody></table>
<table><caption>Table 2. Continued 4</caption><thead><tr><th>Author</th><th>Study type</th><th>Age (y)</th><th>Number of patients</th><th>Varicocele grade (I-III)</th><th>Follow-up (mo)</th><th>Type of varicocele repair</th><th>Presence of infertility</th><th>Duration of infertility (mo)</th><th>Presence of hypogonadism</th></tr></thead><tbody><tr><td>Zheng et al, 2009 [70]</td><td>Prospective</td><td>Group 1: 31.8±1.57<br>Group 2: 32.2±1.49</td><td>Group 1: 53<br>Group 2: 51</td><td>Group 1: I: 2/53;<br>II: 19/53;<br>III: 32/53<br>Group 2: I: 2/51;<br>II: 18/51;<br>III: 31/51</td><td>12</td><td>Microsurgical</td><td>Yes</td><td>>12</td><td>n.s.</td></tr><tr><td>Zohdy et al, 2011 [71]</td><td>Retrospective</td><td>33.8±6.1<br>(23.0-48.0)</td><td>141</td><td>n.s.</td><td>6</td><td>Microsurgical</td><td>Yes</td><td>3.7±3.4 y</td><td>64 patients had TT<br>&lt;300 ng/dL</td></tr></tbody></table>

n.s: non-specified, TT: total testosterone, TD: testicular delivery.

<table><caption>Table 3. Results of Cambridge Quality Checklist, Cochrane risk of bias for RCTs, CONSORT, and Jadad tools for quality assessment</caption><thead><tr><th rowspan="2">Author</th><th colspan="3">Cambridge Quality Checklist score</th><th colspan="2">Cochrane</th><th colspan="2">Jadad</th><th rowspan="2">QoE</th></tr><tr><th>Checklist for correlates</th><th>Checklist for risk factors</th><th>Checklist for causal risk factors</th><th>Risk of bias for RCTs</th><th>Score</th><th>Score</th><th>Score</th></tr></thead><tbody><tr><td>Abdel-Meguid et al, 2014 [27]</td><td>3</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Bolat et al, 2019 [28]</td><td>2</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Bryniarski et al, 2017 [29]</td><td>2</td><td>3</td><td>7</td><td>1</td><td>18</td><td>1</td><td>High</td><td>High</td></tr><tr><td>Cantoro et al, 2015a [30]</td><td>3</td><td>3</td><td>6</td><td>-</td><td>-</td><td>-</td><td>-</td><td>High</td></tr><tr><td>Cantoro et al, 2015b [31]</td><td>3</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Cayan et al, 1999 [32]</td><td>3</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Hurtado de Catalfo et al, 2007 [33]</td><td>2</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Di Bisceglie et al, 2007 [34]</td><td>1</td><td>3</td><td>6</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Enatsu et al, 2014 [35]</td><td>2</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Fujisawa et al, 2001 [36]</td><td>3</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Gat et al, 2004 [37]</td><td>2</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Ghanem et al, 2011 [38]</td><td>1</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Ghanem et al, 2020 [39]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Ghazi and Abdelfattah 2011 [40]</td><td>2</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr><tr><td>Grober et al, 2004 [41]</td><td>2</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td></tr></tbody></table>
<table><caption>Table 3. Continued</caption><thead><tr><th rowspan="2">Author</th><th colspan="3">Cambridge Quality Checklist score</th><th colspan="2">Cochrane</th><th colspan="2">CONSORT</th><th rowspan="2">Jadad Score</th><th rowspan="2">QoE</th></tr><tr><th>Checklist for correlates</th><th>Checklist for risk factors</th><th>Checklist for causal risk factors</th><th>Risk of bias for RCTs</th><th>Score</th><th>Score</th><th>Score</th></tr></thead><tbody><tr><td>Gomaa et al, 2018 [10]</td><td>2</td><td>3</td><td>6</td><td>-</td><td>-</td><td>-</td><td>-</td><td>High</td><td></td></tr><tr><td>Ito et al, 1993 [42]</td><td>1</td><td>2</td><td>4</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Iwasaki et al, 2003 [43]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Jin et al, 2020 [44]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Kuroiwa et al, 1991 [45]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Lee et al, 2007 [46]</td><td>2</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Li et al, 2012 [47]</td><td>2</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Lu et al, 2018 [48]</td><td>2</td><td>3</td><td>3</td><td>7</td><td>3</td><td>9</td><td>Moderate</td><td>Moderate</td><td></td></tr><tr><td>Lv et al, 2016 [49]</td><td>2</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td>Moderate</td><td></td></tr><tr><td>Majzoub et al, 2021 [50]</td><td>0</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Nuhoğlu et al, 2004 [51]</td><td>2</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Ozden et al, 2008 [52]</td><td>3</td><td>2</td><td>4</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Öztekin et al, 2020 [53]</td><td>1</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Pasqualotto et al, 2005a [54]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Pasqualotto et al, 2005b [55]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Pierik et al, 2001 [56]</td><td>3</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Prasivoravong et al, 2014 [57]</td><td>3</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Qu et al, 2017 [58]</td><td>3</td><td>3</td><td>3</td><td>5</td><td>3</td><td>6</td><td>Moderate</td><td>Moderate</td><td></td></tr><tr><td>Ramasamy and Schlegel 2006 [59]</td><td>2</td><td>3</td><td>4</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Reşorlu et al, 2010 [13]</td><td>1</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Rodriguez Pena et al, 2009 [12]</td><td>1</td><td>1</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Low</td><td></td></tr><tr><td>Sathya Srini et al, 2011 [60]</td><td>2</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Segenreich et al, 1986 [61]</td><td>0</td><td>3</td><td>4</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Senturk et al, 2020 [62]</td><td>1</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Shabana et al, 2015 [63]</td><td>3</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Shinoda, 1985 [64]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Smit et al, 2010 [65]</td><td>3</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Su et al, 1995 [66]</td><td>3</td><td>2</td><td>1</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Tanrikut et al, 2011 [67]</td><td>1</td><td>2</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Vyas et al, 2017 [68]</td><td>2</td><td>3</td><td>7</td><td>1</td><td>16</td><td>3</td><td>High</td><td>Moderate</td><td></td></tr><tr><td>Younes, 2003 [69]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Zheng et al, 2009 [70]</td><td>3</td><td>3</td><td>4</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr><tr><td>Zohdy et al, 2011 [71]</td><td>1</td><td>3</td><td>3</td><td>-</td><td>-</td><td>-</td><td>-</td><td>Moderate</td><td></td></tr></tbody></table>

RCT: randomized controlled trial, QoE: quality of evidence.
tion bias (Egger's test: intercept 1.9; 95% CI: -0.4 to 4.1; p=0.1), as shown also by the symmetry of the funnel

plot (Supplement Fig. 1).

Patients were grouped according to the mean levels

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

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<caption>Fig. 2. Serum total testosterone levels in patients after varicocele repair compared to before treatment values. SD: standard deviation, IV: inverse variance, CI: confidence interval.</caption>
<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

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<caption>Fig. 2. Continued.</caption>

of TT before VR. No subgroup differences were found ($\chi^2=2.53$; $p=0.11$). Specifically, both the subgroup with mean TT <300 ng/dL at baseline and >300 ng/dL experienced a significant increase after VR (MD 108.47 ng/dL, 95% CI: 76.65 to 140.29; $p<0.00001$; and MD 78.47 ng/dL, 95% CI: 59.64 to 97.29; $p<0.00001$, respectively) (Supplement Fig. 2).

Subgroup analysis was also performed according to the fertility status, with no significant subgroup difference found. Though TT increased significantly in infertile patients after VR (MD 64.98 ng/dL, 95% CI: 43.89 to 86.07; $p<0.00001$) and no significant increase was found in the fertile group (MD 42.31 ng/dL, 95% CI: -66.75 to 151.36; $p=0.45$), the difference in increase between the two groups was not statistically significant ($\chi^2=0.16$; $p=0.69$), possibly due to small numbers in the fertile group (Supplement Fig. 3).

The sub-analysis performed according to the time of follow-up (3, 6, 9, 12, 24 months) resulted in the absence of significant subgroup difference ($\chi^2=2.78$; $p=0.60$),

with an already appreciable increase at 3 months (MD 75.76 ng/dL, 95% CI: 13.42 to 138.09; $p=0.02$), at 6 (MD 47.75 ng/dL, 95% CI: 28.43 to 67.06; $p<0.00001$) and at 24 months (MD 49.89 ng/dL, 95% CI: 8.49 to 91.30; $p=0.02$). Increase at 9 and 12 months, however, was not significant (MD 296.85 ng/dL, 95% CI: -41.61 to 635.30; $p=0.09$; and MD 59.66 ng/dL, 95% CI: -28.59 to 147.90; $p=0.19$, respectively), likely due to the low number of studies included in these two latter subgroups (Supplement Fig. 4).

With regard to the technique of VR, subgroup analysis did not show any significant difference ($\chi^2=4.44$; $p=0.22$), indicating that the increase in TT after VR was independent of the technique used. Particularly, the increase was significant in the non-microscopic ligation (MD 104.78 ng/dL, 95% CI: 72.30 to 137.26; $p<0.0001$), microscopic VR (MD 72.28 ng/dL, 95% CI: 45.94 to 98.61; $p<0.0001$), and percutaneous occlusion (MD 54.49 ng/dL, 95% CI: 16.22 to 92.75; $p=0.005$) subgroups. No significant increase was found in the lapa-
roscopic subgroup, probably because of the low number of studies included (MD 145.77 ng/dL, 95% CI: -154.06 to 445.59; p=0.34) (Supplement Fig. 5).

VR patients were compared to those with unrepaired controls. This analysis, which included 5 studies, for a total of 496 VR patients and 280 controls, showed significantly higher levels in VR patients than controls (MD 91.64 ng/dL, 95% CI: 62.30 to 120.99; p<0.00001) (Fig. 3). Inter-study heterogeneity was found, as indicated by the Q-test (Q-value: 22.9, p<001) and I²=74.0%. At the sensitivity analysis, no study was found sensitive enough to alter the conclusion that TT increases after

VR compared to patients with unrepaired varicocele. At the Egger's test, no publication bias was found (Egger's test: intercept 3.8, 95% CI: -3.8 to 11.5; p=0.25), as shown also by the symmetry of the funnel plot (Supplement Fig. 6).

Patients undergone VR were further compared to healthy men without varicocele, in an analysis including 5 studies, 150 operated patients and 139 controls. No difference in TT serum levels was found (MD -22.01 ng/dL, 95% CI: -68.59 to 24.58; p=0.35) (Fig. 4). This may indicate that VR allows not only an improvement in TT values after VR, but also a restoration to normal-

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

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<figure><img src="image_12.png" /><figcaption>**Fig. 3.** Serum total testosterone in patients after varicocele repair (VR), compared to patients with unrepaired varicocele. SD: standard deviation, IV: inverse variance, CI: confidence interval.</figcaption></figure>

<figure><img src="image_13.png" /></figure>

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<caption>**Fig. 4.** Serum total testosterone in patients after varicocele repair (VR), compared to patients with unrepaired varicocele. SD: standard deviation, IV: inverse variance, CI: confidence interval.</caption>
<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /><figcaption>**Fig. 5.** Serum luteinizing hormone levels in patients after varicocele repair (VR) compared to before treatment levels. SD: standard deviation, IV: inverse variance, CI: confidence interval.</figcaption></figure>

ity. The Q-test indicated a trend toward the presence of inter-study heterogeneity, but significance was not reached (Q-value: 8.7; p=0.07). I² statistics (54.0%) suggested the presence of inter-study heterogeneity. Only one study [47] resulted sensitive enough to alter the conclusion that testosterone levels are not significantly different in VR patients than healthy controls with no

varicocele. After its removal, TT was significantly lower in patients than controls (MD -42.63 ng/dL, 95% CI: -73.26 to -12.0; p=0.006). No publication bias was found at the Egger's test (Egger's test: intercept 4.7, 95% CI: -2.0 to 11.4; p=0.11), as derived also by the symmetry of the funnel plot (Supplement Fig. 7).
## 2. Luteinizing hormone

Serum levels of LH in patients after VR were compared with their values before the procedure. The analysis included 26 studies, for a total of 1991 patients, and resulted in a trend toward reduction (MD -0.37 IU/L, 95% CI: -0.74 to 0.01; p=0.06) (Fig. 5). Inter-study heterogeneity was found, as supported by the Q-test (Q-value=294.1; p<0.001) and I²=87.0%. At the sensitivity analysis, one study [69] was sensitive enough to change the conclusion that VR does not significantly decrease the LH level. Its removal led to significant lower levels of LH in VR patients compared to their baseline values (MD -0.39 IU/L, 95% CI: -0.76 to -0.01; p=0.045). Tests for funnel plot asymmetry found no evident indication of publication bias (Egger's test: intercept 1.9, 95% CI: -0.4 to 4.1; p=0.1), as shown also by the symmetry of the

funnel plot (Supplement Fig. 8).

When VR patients were compared to patients with unrepaired varicocele, 3 studies were included, totaling 366 patients and 202 controls. The analysis showed significantly lower serum LH levels in patients than controls (MD -0.96 IU/L, 95% CI: -1.56 to -0.35; p=0.002), indicating the efficacy of VR in reducing LH levels (Fig. 6). No evidence of inter-study heterogeneity was found, as indicated by the Q-test (Q-value: 6.5; p=0.09) and I² statistics (I²=54.0%). No study was found sensitive enough to alter the conclusion that LH levels are lower in VR patients than in patients with unrepaired varicocele. No publication bias was found at the Egger's test (Egger's test: intercept -2.9, 95% CI: -12.7 to 6.9; p=0.33), as derived also by the symmetry of the funnel plot (Supplement Fig. 9).

<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /></figure>

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<figure><img src="image_18.png" /><figcaption>Fig. 6. Serum luteinizing hormone in patients after varicocele repair (VR), compared to patients with unrepaired varicocele. SD: standard deviation, IV: inverse variance, CI: confidence interval.</figcaption></figure>

<figure><img src="image_19.png" /></figure>

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<caption>Fig. 7. Serum luteinizing hormone in patients after varicocele repair (VR), compared to men without varicocele. SD: standard deviation, IV: inverse variance, CI: confidence interval.</caption>
<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /><figcaption>**Fig. 8.** Serum follicle-stimulating hormone levels in patients after varicocele repair (VR) compared to before treatment values. SD: standard deviation, IV: inverse variance, CI: confidence interval.</figcaption></figure>
The comparison LH levels between VR patients and healthy men was possible on 3 studies (100 patients vs. 94 controls). Serum LH levels resulted not significantly different than healthy controls (MD 0.84 IU/L, 95% CI: -0.68 to 2.36; p=0.28), possibly suggesting that VR normalizes LH levels (Fig. 7). The Q-test indicated the presence of inter-study heterogeneity (Q-value: 24.4; p=0.001), as confirmed also by I² statistics (I²=92.0%). No study was found sensitive enough to alter the conclusion that LH levels are not significantly different in VR patients compared to healthy men without varicocele. No publication bias was found at the Egger's test (Egger's test: intercept 12.84, 95% CI: -149.0 to 174.7; p=0.49), as derived also by the symmetry of the funnel plot (Supplement Fig. 10).

### 3. Follicle-stimulating hormone

Thirty-six studies, with 2,818 patients, were available to compare FSH levels before and after VR (Fig. 8). VR resulted in a significant decrease in serum FSH levels compared to before VR (MD -1.43 IU/L, 95% CI: -1.82 to -1.04; p<0.00001). The analysis showed the presence of inter-study heterogeneity, as demonstrated by the Q-test (Q-value=552.0; p<0.001) and I²=91.0%. At the sensitivity analysis, no study was sensitive enough to change the conclusion that VR significantly decreases the FSH level (data not shown). Tests for funnel plot asymmetry provided no evident indication of publication bias (Egger's test: intercept 1.6, 95% CI: -0.7 to 3.9; p=0.2), as shown also by the symmetry of the funnel plot (Supplement Fig. 11).

When VR patients were compared to patients with unrepaired varicocele, 5 studies could be included, with a total of 468 VR patients and 287 controls (no VR). Serum FSH levels were found to be significantly lower in VR patients than the control group (MD -2.35 IU/L, 95% CI: -4.06 to -0.65; p=0.007), indicating the efficacy of VR in reducing FSH levels (Fig. 9). Inter-study heterogeneity was found both at the Q-test (Q-value=60.3; p<0.001) and at the I² statistics (I²=92.0%). No sensitive study was identified at the sensitivity analysis. Also, no evident publication bias was found (Egger's test: intercept 3.8, 95% CI: -5.7 to 13.3; p=0.3), as shown also by the symmetry of the funnel plot (Supplement Fig. 12).

VR patients were compared to healthy men, in an analysis including 4 studies (178 patients vs. 104 controls). Serum FSH levels were found significantly higher compared to the healthy controls (MD 2.71 IU/L, 95% CI: 1.12 to 4.31; p=0.0009), possibly indicating that the VR reduces but does not return FSH levels to normality (Fig. 10). Q-test and I² statistics suggested the presence of inter-study heterogeneity (Q-value=29.7; p<0.001; I²=90.0%). No study was sensitive enough to change the conclusion that FSH is higher in VR patients than healthy men without varicocele. No evident publication bias was found (Egger's test: intercept 9.3, 95% CI: -29.5 to 48.2; p=0.4), as shown also by the symmetry of the funnel plot (Supplement Fig. 13).

<figure><img src="image_22.png" /></figure>

<figure><img src="image_23.png" /><figcaption>**Fig. 9.** Serum follicle-stimulating hormone in patients after varicocele repair (VR), compared to patients with unrepaired varicocele. SD: standard deviation, IV: inverse variance, CI: confidence interval.</figcaption></figure>
<figure><img src="image_24.png" /></figure>

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<figure><img src="image_25.png" /><figcaption>**Fig. 10.** Serum follicle-stimulating hormone in patients after varicocele repair (VR), compared to men without varicocele. SD: standard deviation, IV: inverse variance, CI: confidence interval.</figcaption></figure>

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<caption>**Fig. 11.** Serum inhibin B levels in patients after varicocele repair, compared to before treatment values. SD: standard deviation, IV: inverse variance, CI: confidence interval.</caption>

## 4. Inhibin B

A total of 7 studies (302 patients) were included in the comparison analysis of serum inhibin B after VR vs. the values before the technique. Serum inhibin B levels did not significantly differ (MD 11.76 pg/mL, 95% CI: -3.83 to 27.35; p=0.14) (Fig. 11). Inter-study heterogeneity was found at I² statistics (80.0%), and Q-test as well (Q-value: 35.6; p<0.001). At the sensitivity analysis, no study was found sensitive enough to alter the conclusion that inhibin B levels do not change after VR compared to baseline values. No evidence of publication bias found (Egger's test: -0.15, 95% CI: -6.85 to 6.55; p=0.95), as shown also by the symmetry of the funnel plots (Supplement Fig. 14).

## DISCUSSION

Most of the research on varicoceles focuses on the role of varicoceles in diagnosis and prognosis of male infertility as well as the impact of VR on semen parameters [72]. The last decade has witnessed increasing evidence that varicoceles can promote Leydig cell dys-
function impacting testosterone production [73,74]. Fur-
thermore, there has been a growing interest recently
in addressing the impact of VR on levels of reproduc-
tive hormones [50,75]. The present systematic review
and meta-analysis including data from over 4,000 men
demonstrates a significant increase in serum testoster-
one levels following VR compared to pre-intervention
baseline levels. However, a significant heterogene-
ity was noted among the included studies. Serum TT
levels remained significantly higher also when com-
pared to values in patients with unrepaired varicocele
and did not differ from the levels of healthy controls
without varicocele, suggesting that VR is capable to
increase and restore TT levels to normal. Interestingly,
these results were not influenced by baseline testoster-
one values, showing an increase in both groups with
mean testosterone at baseline <300 ng/dL and >300
ng/dL. An increase in testosterone was detectable af-
ter 3 months of follow-up and persisted even after 24
months. Finally, the type of technique used for VR
did not influence testosterone increase. Expectably, an
opposite trend was found for LH. Although LH levels
after VR did not reach a significant decrease compared
to baseline, they were lower than those of untreated
controls and did not differ from healthy men without
varicocele. Moreover, the impact on serum FSH levels
was positive. Indeed, its levels decreased after VR com-
pared to both baseline and untreated controls, but re-
mained higher than in healthy men without varicocele.
Finally, no improvement was found in serum inhibin B.
Overall, these findings suggest a positive effect of VR
on Leydig cell function and a positive, but milder effect
on Sertoli cell function.

The literature presents conflicting findings regard-
ing changes in testosterone levels following VR. Earlier
studies examining serum testosterone concentrations in
varicocele patients have reported inconsistent results.
While some early reports rejected the idea that the
presence of varicocele decreased testosterone biosyn-
thesis [76], others reported that it can cause androgen
deficiency [77,78]. The association between androgen
deficiency and varicocele was evaluated in a compre-
hensive study of 9,034 infertile patients and demon-
strated the progressive, time-dependent adverse effect
of varicocele on Leydig cell function. However, other
studies showed the absence of an increase in serum
testosterone levels after VR, particularly in patients
without hypogonadism at baseline [79-81].

A more recent and more robust study has better em-
phasized the negative effects of varicocele on serum
testosterone levels and provide higher quality evidence
[10]. Meta-analytic studies also supported the increase
in testosterone levels after VR [74]. In the study by Li
et al (2012) [74], the mean increase of testosterone levels
was approximately 100 ng/dL. However, identification
of the optimal patient (age, varicocele grade, baseline
testosterone levels) was not defined in the latter study.
A meta-analysis of seven studies on the impact of VR
on baseline serum testosterone in 712 men indicated a
mean improvement of 34.3 ng/dL compared to the pre-
intervention levels [75]. In the latter study, subgroup
analysis of patients that underwent surgery vs. un-
treated controls showed that mean testosterone among
hypogonadal patients increased by 105.65 ng/dL (95%
CI: 77.99–133.32 ng/dL), thus favoring surgery.

Saylam et al [11], in their study examining the ef-
fect of microsurgical varicocelectomy on testosterone
levels in hypogonadal infertile patients, reported that
serum testosterone levels increased after surgery and
VR could be recommended in the presence of clinical
varicocele in hypogonadal patients. A similar conclu-
sion was reached in a review published by the same
group on this topic [8]. Additionally, the authors recom-
mended microsurgical approach as the technique for
VR with the best outcome. Despite growing evidence
of varicocele's impaired androgen production and the
effect of surgical repair in reversing it, some studies
continued to argue that there is no association between
varicocele and hypogonadism [12-14].

A previous meta-analysis that evaluated the effect
of surgical VR on testosterone production, testosterone
levels showed a statistically significant increase after
surgical repair [74]. Another meta-analysis evaluated
the effects of VR for the treatment of hypogonadism
in subfertile patients with clinical varicocele [75]. In
the latter study, the mean serum testosterone lev-
els significantly improved compared with their pre-
operative levels. In a subgroup analysis, improvement
of testosterone levels was more evident in the hypogo-
nadal group treated with VR (MD 123 ng/dL, 95% CI:
114.61–131.35; p<0.00001, I²=37%). A more recent meta-
analysis evaluating the impact of VR on testosterone
levels in patients with severe oligozoospermia failed to
find significant improvement [50]. Finally, the latest
meta-analysis on this topic confirmed the benefit of
VR on serum testosterone, gonadotropin, and inhibin B
levels [82].

The inconsistency observed in different meta-analyses addressing the changes in serum testosterone levels after VR may be related, at least in part, to the inclusion of different study populations. Furthermore, it must be considered that the above-mentioned meta-analyses [82] included up to 9 studies and used a before-after approach. Our study is the first one that analyses 48 studies with a before-after analysis and offers the comparison to untreated varicocele patients and to healthy men. It therefore represents the most reliable evidence on this topic to date.

Using a sub-analysis approach, the present study tried to identify the population that may benefit most from VR in terms of increase in serum testosterone levels. First, the increase does not depend on the mean pre-operative testosterone level. Indeed, both groups of patients, those with a mean pre-VR testosterone level ≤300 ng/dL and those with a value >300 ng/dL showed a significant increase in TT after VR. The value of 300 ng/dL was chosen since it was the most frequently used cut-off mentioned by the included studies aimed at identifying the effects of VR in patients with and without hypogonadism. There is no definitive agreement on the cut-off that should be used for the diag-

nosis of hypogonadism. The last guidelines from the Endocrine Society suggest a cut-off value of 264 ng/dL [1], while other societies suggest 346 ng/dL [2]. A comprehensive review of the testosterone thresholds used in the diagnosis of male hypogonadism has been provided by Park et al [83]. Similarly to pre-operative serum testosterone levels, times of follow-up, the type of technique used for VR, and fertility status appeared not to influence the VR-induced increase in testosterone, since no subgroup difference was found. However, the fertile subgroup had a low number of studies, suggesting the need for more studies evaluating the impact of VR on testosterone levels in fertile patients. Another factor that may discriminate the possibility to have an increase in testosterone could be the presence of varicocele-induced severe impairment of testicular function, i.e., in case of testicular atrophy. However, we could not sub-analyze the cohort based on testicular asymmetry or atrophy since testicular measurements were reported in only a few included articles.

Results emerging from the present systematic review and meta-analysis also showed the efficacy of VR on serum FSH levels. In contrast, a recent meta-analysis failed to find significant FSH improvement following VR in patients with severe oligozoospermia [50]. FSH

## SWOT Analysis

<table><caption>Fig. 12. Strengths, Weaknesses, Opportunities and Threats (SWOT) Analysis. VR: varicocele repair. RCT: randomized controlled trial.</caption><thead><tr><th>Strengths</th><th>Weaknesses</th><th>Opportunities</th><th>Threats</th></tr></thead><tbody><tr><td><ul><li>Methodologically conducted by a panel of experts in andrology</li><li>Results independently verified by two statisticians</li><li>Comprehensive meta-analysis of the broadest publication period (1978-2021)</li><li>Including the highest number of studies so far</li><li>Inclusion of comparison with untreated varicocele and with healthy subjects</li></ul></td><td><ul><li>Being restricted in its conclusions by the limited number of RCTs addressing the effect of VR on hormonal profiles of infertile men</li></ul></td><td><ul><li>Serve as a guide for andrologists/uroligists /reproductive medicine practitioners in advising and monitoring VR</li><li>Be referenced by international societies dealing with male infertility for the establishment of their future guidelines on clinical varicoceles and VR</li><li>Help researchers plan their future clinical trials by overcoming the weaknesses identified</li><li>Conduct additional studies to investigate the impact of VR on total testosterone</li></ul></td><td><ul><li>Given the recent update (2021) of the international guidelines, there is a risk of slow dissemination in the international scientific and medical community</li></ul></td></tr></tbody></table>
increases the number of spermatogonia and matura-
tion of spermatocytes and plays a relevant role in the
hypothalamic-pituitary-testicular axis function [84]. A
decrease in FSH secretion from the pituitary suggests
that spermatogenesis has improved at the testicular
level. Therefore, VR could counteract the testicular in-
sult caused by varicocele and improve testicular func-
tion sufficiently to decrease FSH levels.

Currently, there are no clear guidelines recommend-
ing VR to ameliorate testicular endocrine function in
patients with clinical varicocele. The recent guidelines
by the American Urological Association do not specifi-
cally address repairing varicoceles for the purposes of
improving serum testosterone [85], whereas the Euro-
pean Association of Urology guidelines suggest that it
can be considered [86]. Based on our findings, low tes-
tosterone could be considered as an indication for VR
in the future.

The highlights of the present study are summarized
in a SWOT analysis (SWOT stands for strengths [S],
weaknesses [W], opportunities [O], and threats [T]) (Fig.
12). Using the SWOT method, we summarize the main
benefits and limitations of our systematic review and
meta-analysis evaluating the impacts of VR on the en-
docrine profile in patients with clinical varicocele. Posi-
tioning ourselves in the international context, we also
summarize the negative perspectives that could limit
the impact of this study and address the opportunities
that could ensure the wide diffusion of the evidence
reported in this article in the medical and scientific
community.

CONCLUSIONS

In conclusion, this systematic review and meta-
analysis is the largest to date and shows that VR sig-
nificantly increases post-operative serum TT levels and
decreases serum LH and FSH levels. Particularly, VR
was found to increase and restore to normality serum
TT and LH levels. The positive impact on FSH levels
appears less marked as its levels are reduced, but do
not reach those found in healthy controls. No signifi-
cant change was observed in serum inhibin B levels.
Clinically, these results suggest that VR can reverse
the deleterious effects that varicocele exerts on Ley-
dig cell function. These findings have the potential to
reshape current guidelines by adding the presence of
hypogonadism among VR indications, as well as indi-

cating a role for the endocrinologist in the manage-
ment of varicocele. Accordingly, this evidence could be
of value considering the treatment of varicocele in pa-
tients with clinical varicocele and hypotestosteronemia
or those who show a progressive decline in testosterone
levels. However, the results of the current meta-analy-
sis are limited by the notion of the high heterogeneity
and the risk of publication bias among the included
studies, and the scarcity of well-designed RCTs on this
topic.

Conflict of Interest

The authors have nothing to disclose.

Funding

None.

Acknowledgements

None.

Author Contribution

Conceptualization: Global Andrology Forum. Methodology: Global Andrology Forum. Data curation: RC, R Singh, MG, TT, FB. Writing-Original draft preparation: RC, R Singh, MG, TT, FB. Supervision: Global Andrology Forum. Validation: all authors. Writing-Reviewing and Editing: RC, R Shah, AA, AEC, AC.

Supplementary Materials

Supplementary materials can be found via https://doi.
org/10.5534/wjmh.240109.

REFERENCES

1. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone therapy in men with hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2018;103:1715-44.

2. Isidori AM, Aversa A, Calogero A, Ferlin A, Francavilla S, Lanfranco F, et al. Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE). J Endocrinol Invest 2022;45:2385-
403.

3. Corona G, Rastrelli G, Maggi M. The pharmacotherapy of male hypogonadism besides androgens. Expert Opin Pharmacother 2015;16:369-87.

4. Ribeiro RS, Abucham J. Clomiphene fails to revert hypogonadism in most male patients with conventionally treated nonfunctioning pituitary adenomas. Arq Bras Endocrinol Metabol 2011;55:266-71.

5. Russo GI, Asmundo MG, Perelli S, Condorelli RA, Calogero AE, Cannarella R, et al. Relationship between varicocele and male hypogonadism: A review with meta-analysis. Endocrines 2022;3:100-6.

6. Damsgaard J, Joensen UN, Carlsen E, Erenpreiss J, Blomberg Jensen M, Matulevicius V, et al. Varicocele Is Associated with Impaired Semen Quality and Reproductive Hormone Levels: A Study of 7035 Healthy Young Men from Six European Countries. Eur Urol 2016;70:1019-29.

7. Ozturk MI, Koca O, Keles MO, Haklar G, Baykan O, Ercan F, et al. The impact of unilateral experimental rat varicocele model on testicular histopathology, Leydig cell counts, and intratesticular testosterone levels of both testes. Urol J 2013;10:973-80.

8. Çayan S, Akbay E, Saylam B, Kadioğlu A. Effect of varicocele and its treatment on testosterone in hypogonadal men with varicocele: Review of the literature. Balkan Med J 2020;37:121-4.

9. Clavijo RI, Carrasquillo R, Ramasamy R. Varicoceles: prevalence and pathogenesis in adult men. Fertil Steril 2017;108:364-9.

10. Gomaa MD, Motawaa MA, Al-Nashar AM, El-Sakka AI. Impact of subinguinal varicocelectomy on serum testosterone to estradiol ratio in male patients with infertility. Urology 2018;117:70-7.

11. Saylam B, Çayan S, Akbay E. Effect of microsurgical varicocele repair on sexual functions and testosterone in hypogonadal infertile men with varicocele. Aging Male 2020;23:1366-73.

12. Rodriguez Peña M, Alescio L, Russell A, Lourenco da Cunha J, Alzu G, Bardoneschi E. Predictors of improved seminal parameters and fertility after varicocele repair in young adults. Andrologia 2009;41:277-81.

13. Reşorlu B, Kara C, Sahin E, Unsal A. The significance of age on success of surgery for patients with varicocele. Int Urol Nephrol 2010;42:351-6.

14. Panach-Navarrete J, Morales-Giraldo A, Ferrandis-Cortés C, García-Morata F, Pastor-Lence JC, Martínez-Jabaloyas JM. Is there a relationship between varicocele and testosterone levels? Aging Male 2020;23:592-8.

15. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-12.

16. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015;350:g7647.

17. Cannarella R, Shah R, Boitrelle F, Saleh R, Durairajanayagam D, Harraz AM, et al. Need for training in research methodology prior to conducting systematic reviews and meta-analyses, and the effectiveness of an online training program: The Global Andrology Forum Model. World J Mens Health 2023;41:342-53.

18. da Costa Santos CM, de Mattos Pimenta CA, Nobre MR. The PICO strategy for the research question construction and evidence search. Rev Lat Am Enfermagem 2007;15:508-11.

19. Murray J, Farrington DP, Eisner MP. Drawing conclusions about causes from systematic reviews of risk factors: The Cambridge Quality Checklists. J Exp Criminol 2009;5:1-23.

20. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med 2010;8:18.

21. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.

22. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.

23. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I² index? Psychol Methods 2006;11:193-206.

24. Cochran WG. The combination of estimates from different experiments. Biometrics 1954;10:101-29.

25. Andrade C. Mean difference, standardized mean difference (SMD), and their use in meta-analysis: as simple as it gets. J Clin Psychiatry 2020;81.

26. Duval S, Tweedie R. A nonparametric "Trim and Fill" method of accounting for publication bias in meta-analysis. J Am Stat Assoc 2000;95:89-98.

27. Abdel-Meguid TA, Farsi HM, Al-Sayyad A, Tayib A, Mosli HA, Halawani AH. Effects of varicocele on serum testosterone and changes of testosterone after varicocelectomy: a prospective controlled study. Urology 2014;84:1081-7.

28. Bolat MS, Kocamanoglu F, Gulsen M, Sengul M, Asci R. The impact of age on fertility rate in patients who underwent mi-
crosurgical varicocelectomy. Andrologia 2019;51:e13234.

29. Bryniarski P, Taborowski P, Rajwa P, Kaletka Z, Życzkowski M, Paradysz A. The comparison of laparoscopic and microsurgical varicocoelectomy in infertile men with varicocele on paternity rate 12 months after surgery: a prospective randomized controlled trial. Andrology 2017;5:445-50.

30. Cantoro U, Polito M, Muzzonigro G. Reassessing the role of subclinical varicocele in infertile men with impaired semen quality: a prospective study. Urology 2015;85:826-30.

31. Cantoro U, Catanzariti F, Lacetera V, Quaresima L, Giovanni M, Polito M. Percentage change of FSH value: new variable to predict the seminal outcome after varicocelectomy. Andrologia 2015;47:412-6.

32. Cayan S, Kadioglu A, Orhan I, Kandirali E, Tefekli A, Tel-laloglu S. The effect of microsurgical varicocelectomy on serum follicle stimulating hormone, testosterone and free testosterone levels in infertile men with varicocele. BJU Int 1999;84:1046-9.

33. Hurtado de Catalfo GE, Ranieri-Casilla A, Marra FA, de Alaniz MJ, Marra CA. Oxidative stress biomarkers and hormonal profile in human patients undergoing varicocelectomy. Int J Androl 2007;30:519-30.

34. Di Bisceglie C, Bertagna A, Baldi M, Lanfranco F, Tagliabue M, Gazzera C, et al. Varicocele sclerotherapy improves serum inhibin B levels and seminal parameters. Int J Androl 2007;30:531-6.

35. Enatsu N, Yamaguchi K, Chiba K, Miyake H, Fujisawa M. Clinical outcome of microsurgical varicocelectomy in infertile men with severe oligozoospermia. Urology 2014;83:1071-4.

36. Fujisawa M, Dobashi M, Yamasaki T, Kanzaki M, Okada H, Arakawa S, et al. Significance of serum inhibin B concentration for evaluating improvement in spermatogenesis after varicocelectomy. Hum Reprod 2001;16:1945-9.

37. Gat Y, Gornish M, Belenky A, Bachar GN. Elevation of serum testosterone and free testosterone after embolization of the internal spermatic vein for the treatment of varicocele in infertile men. Hum Reprod 2004;19:2303-6.

38. Ghanem MA, Safan MA, Ghanem AA, Dohle GR. The role of varicocele sclerotherapy in men with severe oligo-asthenoteratozoospermia. Asian J Androl 2011;13:867-71.

39. Ghanem MA, Adawi EA, Hakami NA, Ghanem AM, Ghanem HA. The predictive value of the platelet volume parameters in evaluation of varicocelectomy outcome in infertile patients. Andrologia 2020;52:e13574.

40. Ghazi S, Abdelfattah H. Effect of microsurgical varicocelectomy on sperm DNA fragmentation in infertile men. Middle East Fertil Soc J 2011;16:149-53.

41. Grober ED, Chan PT, Zini A, Goldstein M. Microsurgical treatment of persistent or recurrent varicocele. Fertil Steril 2004;82:718-22.

42. Ito H, Kotake T, Hamano M, Yanagi S. Results obtained from microsurgical therapy of varicocele. Urol Int 1993;51:225-7.

43. Iwasaki M, Murakami K, Nozaki T, Akashi T, Okumura A, Furuya Y, et al. Treatment of male infertility in severe oligozoospermia with varicocele. Japanese J Fertil Steril 2003;48:7-12.

44. Jin L, Yao Q, Wu S, Dai G, Xiang H, Liu X, et al. Evaluation of clinical effects of microsurgical subinguinal varicocelectomy with and without testicular delivery. Andrologia 2020;52:e13605.

45. Kuroiwa T, Hasuo K, Yasumori K, Mizushima A, Yoshida K, Hirakata R, et al. Transcatheter embolization of testicular vein for varicocele testis. Acta Radiol 1991;32:311-4.

46. Lee RK, Li PS, Goldstein M. Simultaneous vasectomy and varicocelectomy: indications and technique. Urology 2007;70:362-5.

47. Li F, Yamaguchi K, Okada K, Matsushita K, Ando M, Chiba K, et al. Significant improvement of sperm DNA quality after microsurgical repair of varicocele. Syst Biol Reprod Med 2012;58:274-7.

48. Lu XL, Liu JJ, Li JT, Yang QA, Zhang JM. Melatonin therapy adds extra benefit to varicecelectomy in terms of sperm parameters, hormonal profile and total antioxidant capacity: A placebo-controlled, double-blind trial. Andrologia 2018;50:e13033.

49. Lv JX, Wang LL, Wei XD, Zhang Z, Zheng TL, Huang YH, et al. Comparison of treatment outcomes of different spermatic vein ligation procedures in varicocele treatment. Am J Ther 2016;23:e1329-e34.

50. Majzoub A, ElBardisi H, Covarrubias S, Mak N, Agarwal A, Henkel R, et al. Effect of microsurgical varicocelectomy on fertility outcome and treatment plans of patients with severe oligozoospermia: an original report and meta-analysis. Andrologia 2021;53:e14059.

51. Nuhoğlu B, Göçen A, Ersoy E, Ayyildiz A, Fidan V, Germiyanoğlu C. [Comparison of subinguinal microsurgery and inguinal varicoselektomy effects on sperm and hormone parameters: A 1-year follow-up]. Turkish J Urol 2004;30:302-7. Turkish.

52. Ozden C, Ozdal OL, Bulut S, Guzel O, Koyuncu HH, Memis A. Effect of varicocelectomy on serum inhibin B levels in infertile patients with varicocele. Scand J Urol Nephrol 2008;42:441-3.

53. Öztekin Ü, Caniklioglu M, Sarı S, Selmi V, Gürel A, Tastınar MS, et al. Evaluation of the influence of subinguinal varicoce-
lectomy procedure on seminal parameters, reproductive hormones and testosterone/estradiol ratio. Arch Ital Urol Androl 2020;92.

54. Pasqualotto FF, Lucon AM, de Góes PM, Sobreiro BP, Hallak J, Pasqualotto EB, et al. Relationship between the number of veins ligated in a varicocelectomy with testicular volume, hormonal levels and semen parameters outcome. J Assist Reprod Genet 2005;22:245-9.

55. Pasqualotto FF, Lucon AM, de Góes PM, Sobreiro BP, Hallak J, Pasqualotto EB, et al. Is it worthwhile to operate on subclinical right varicocele in patients with grade II-III varicocele in the left testicle? J Assist Reprod Genet 2005;22:227-31.

56. Pierik FH, Abdesselam SA, Vreeburg JT, Dohle GR, De Jong FH, Weber RF. Increased serum inhibin B levels after varicocele treatment. Clin Endocrinol (Oxf) 2001;54:775-80.

57. Prasivoravong J, Marcelli F, Lemaître L, Pigny P, Ramdane N, Peers MC, et al. Beneficial effects of varicocele embolization on semen parameters. Basic Clin Androl 2014;24:9.

58. Qu X, Shan Z, Zhang N, Guo L. Curative effect of surgery in combination with compound Xuanju capsule in treating subclinical varicocele induced infertility. Biomed Res 2017;28:1247-50.

59. Ramasamy R, Schlegel PN. Microsurgical inguinal varicocelectomy with and without testicular delivery. Urology 2006;68:1323-6.

60. Sathya Srini V, Belur Veerachari S. Does varicocelectomy improve gonadal function in men with hypogonadism and infertility? Analysis of a prospective study. Int J Endocrinol 2011;2011:916380.

61. Segenreich E, Shmuely H, Singer R, Servadio C. Andrological parameters in patients with varicocele and fertility disorders treated by high ligation of the left spermatic vein. Int J Fertil 1986;31:200-3.

62. Senturk AB, Cakiroglu B, Yaytokgil M, Aydin C, Sungur M, Akkoc A. Effect of venous reflux time on testosterone and semen parameters of infertile males after microscopic varicocelectomy. Andrologia 2020;52:e13583.

63. Shabana W, Teleb M, Dawod T, Elsayed E, Desoky E, Shahin A, et al. Predictors of improvement in semen parameters after varicocelectomy for male subfertility: A prospective study. Can Urol Assoc J 2015;9:E579-82.

64. Shinoda M. A pharmacological manipulation of testicular function for rational therapeutic approach to male infertility: experimental and clinical data. Keio J Med 1985;34:31-45.

65. Smit M, Romijn JC, Wildhagen MF, Veldhoven JL, Weber RF, Dohle GR. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. J Urol 2010;183:270-4.

66. Su LM, Goldstein M, Schlegel PN. The effect of varicocele tology on serum testosterone levels in infertile men with varicoceles. J Urol 1995;154:1752-5.

67. Tanrikut C, Goldstein M, Rosoff JS, Lee RK, Nelson CJ, Mulhall JP. Varicocele as a risk factor for androgen deficiency and effect of repair. BJU Int 2011;108:1480-4.

68. Vyas HG, Bhandari V, Kumar A, Nanda B, Singh H, Bhowmick S. A prospective randomized comparative trial between open subinguinal and loupe assisted subinguinal varicocelectome: a single center experience. Urol Ann 2017;9:13-7.

69. Younes AK. Improvement of sexual activity, pregnancy rate, and low plasma testosterone after bilateral varicocelectomy in impotence and male infertility patients. Arch Androl 2003;49:219-28.

70. Zheng YQ, Gao X, Li ZJ, Yu YL, Zhang ZG, Li W. Efficacy of bilateral and left varicocelectomy in infertile men with left clinical and right subclinical varicoceles: a comparative study. Urology 2009;73:1236-40.

71. Zohdy W, Ghazi S, Arafa M. Impact of varicocelectomy on gonadal and erectile functions in men with hypogonadism and infertility. J Sex Med 2011;8:885-93.

72. Agarwal A, Finelli R, Durairajanayagam D, Leisegang K, Henkel R, Salvio G, et al. Comprehensive analysis of global research on human varicocele: a scientometric approach. World J Mens Health 2022;40:636-52.

73. Hayden RP, Tanrikut C. Testosterone and varicocele. Urol Clin North Am 2016;43:223-32.

74. Li F, Yue H, Yamaguchi K, Okada K, Matsushita K, Ando M, et al. Effect of surgical repair on testosterone production in infertile men with varicocele: a meta-analysis. Int J Urol 2012;19:149-54.

75. Chen X, Yang D, Lin G, Bao J, Wang J, Tan W. Efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males with clinical varicocele: a meta-analysis. Andrologia 2017. doi: 10.1111/and.12778 [Epub].

76. Swerdloff RS, Walsh PC. Pituitary and gonadal hormones in patients with varicocele. Fertil Steril 1975;26:1006-12.

77. Hudson RW, Hayes KA, Crawford VA, McKay DE. Seminal plasma testosterone and dihydrotestosterone levels in men with varicoceles. Int J Androl 1983;6:135-42.

78. Younes AK. Low plasma testosterone in varicocele patients with impotence and male infertility. Arch Androl 2000;45:187-95.

79. Hsiao W, Rosoff JS, Pale JR, Powell JL, Goldstein M. Varicocelectomy is associated with increases in serum testosterone independent of clinical grade. Urology 2013;81:1213-7.

80. Hsiao W, Rosoff JS, Pale JR, Greenwood EA, Goldstein M. Older age is associated with similar improvements in semen
parameters and testosterone after subinguinal microsurgical
varicocelectomy. J Urol 2011;185:620-5.

81. Whelan P, Levine L. Effects of varicocelectomy on serum testosterone. Transl Androl Urol 2016;5:866-76.

82. Tian D, Yang C, Xie B, Li H, Li J, Yang D, et al. Effects of varicocele surgical repair on serum hormone and inhibin B levels for patients with varicocele: a systematic review and meta-analysis. Am J Mens Health 2023;17:15579883231199400.

83. Park HJ, Ahn ST, Moon DG. Evolution of guidelines for testosterone replacement therapy. J Clin Med 2019;8.

84. Recchia K, Jorge AS, Pessôa LVF, Botigelli RC, Zugaib VC, de

Souza AF, et al. Actions and roles of FSH in germinative cells. Int J Mol Sci 2021;22.

85. Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM Guideline Part I. J Urol 2021;205:36-43.

86. Salonia A, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al.; EAU Working Group on Male Sexual and Reproductive Health. European Association of Urology Guidelines on sexual and reproductive health-2021 update: male sexual dysfunction. Eur Urol 2021;80:333-57.