Risk factors associated with varicocele: a narrative review

Introduction

Varicocele is a condition characterized by the dilation and tortuosity of internal spermatic venous plexus, which impedes venous return, elevates testicular temperature, and ultimately compromises sperm quality (1). Moreover, varicocele can also cause significant sperm deoxyribonucleic acid (DNA) damage (2), leading to infertility or even abortion. Infertility is defined as the inability of a couple to achieve pregnancy after one year of regular, unprotected intercourse and it affects approximately 10–20% of couples of reproductive age worldwide (3). Even though varicocele is considered the leading cause of male infertility, the semen parameter abnormalities and high DNA fragmentation index caused by varicocele are considered correctable.

Most current research on varicocele has focused primarily on its effects on sperm quality and the outcomes of surgical interventions (4). However, there is a notable gap in the literature regarding a comprehensive review of the underlying mechanisms that contribute to varicocele formation. This review seeks to address this gap by exploring the pathophysiological mechanisms of varicocele and providing new insights that may inform future therapeutic strategies for the treatment and prevention of male infertility, particularly in cases involving varicocele (Figure 1). We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-120/rc).

Figure 1 Risk factors associated with varicocele [created in BioRender. šl, šl. (2025) https://BioRender.com/mm2mtmn]. COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; IL-6, interleukin-6.

Methods

We performed an extensive literature review on PubMed of the discussed topics, as well as factors related to varicocele. Keywords such as “varicocele”, “risk factors”, “male infertility”, “genetic predisposition”, “anatomical abnormalities”, and “oxidative stress” were employed. The summary of the search strategy is shown in Table 1.

The role of the spermatic cord in male reproductive system

The spermatic cord is a distinctive anatomical structure in males, essential for maintaining fertility. During early embryonic development, structures accompanying the testes converge at the deep inguinal ring to form the spermatic cord and it is approximately 11–15 cm in length and exhibits a round, cord-like shape. The spermatic cord is enveloped by three layers of fascia, from outermost to innermost: the external spermatic fascia, the cremaster muscle, and the internal spermatic fascia. Internally, the spermatic cord contains several key structures, including the vas deferens, arteries and veins, the pampiniform plexus of veins, testicular arteries and veins, cremasteric arteries and veins, nerves, lymphatic vessels, and other components (5).

The primary physiological functions of spermatic cord are to provide blood circulation, lymphatic drainage, and neural innervation to the testes and vas deferens. Notably, the countercurrent heat exchange between the internal spermatic artery and the pampiniform plexus of veins, along with the thermoregulatory role of the scrotum, ensures that the temperature of blood entering the testes remains 2–4 ℃ lower than the core body temperature. This temperature regulation is crucial for maintaining an optimal environment for spermatogenesis in testes (6).

Overview of varicocele

Varicocele is characterized by the abnormal tortuosity and dilation of the internal pampiniform venous plexus within the spermatic cord (7). It is recognized as a correctable cause of male infertility. The incidence of varicocele varies, with less than 1% of adolescents affected, approximately 15% in the general adult male population, 35% in men with primary infertility, and up to 80% in those with secondary infertility (8). Although epidemiological data consistently show an association between varicocele and male infertility, the majority of these correlations are reflected in abnormal semen parameters and DNA fragmentation index. This makes it difficult for epidemiological studies to establish a definitive causal relationship between varicocele and infertility (7).

Extensive research has been conducted on the mechanisms through which varicocele contributes to male infertility. The abnormal blood reflux within pampiniform venous plexus is thought to ultimately result in sperm abnormalities. However, the precise mechanisms remain poorly understood and generally considered multifactorial and complex (9). One of the most critical factors in varicocele-induced male infertility is oxidative stress (10). Reactive oxygen species (ROS) are primarily generated by mitochondria under both pathological and physiological conditions. These include superoxide radicals (O₂•⁻), hydrogen peroxide (H₂O₂), hydroxyl radicals (•OH), and singlet oxygen (11). Enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) catalyze reactions that convert ROS into less harmful molecules, thus reducing intracellular ROS levels. These enzymes serve as indicators of the body’s total antioxidant capacity (TAC) (12). An imbalance between ROS and TAC can lead to the oxidation of fatty acids in the sperm membrane, which subsequently results in alterations in sperm morphology, motility and fertilization capacity (13).

An elevated scrotal temperature is widely recognized as a contributing factor to decreased sperm quality. Spermatogenesis requires a cooler environment than the core body temperature; however, in patients with varicocele, impaired heat countercurrent exchange mechanisms result in an increase in scrotal temperature (14). Heat shock proteins (HSPs) are molecular chaperones that are induced under stress conditions, particularly hyperthermia, to assist in the proper folding of proteins and maintain protein homeostasis (15). A study investigating the expression of HSPs in the spermatozoa of varicocele patients identified 15 proteins through two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Of these, 11 proteins exhibited significantly higher expression levels compared to a control group, including HSP70 and HSP90 (16). Another study found that several HSPs and heat shock factors (HSFs), such as HSPA4, HSF1, and HSF2, were upregulated in the spermatozoa of men with varicocele and oligozoospermia, suggesting that the ejaculated spermatozoa were continually exposed to cellular stress. Interestingly, this study also observed an increased expression of HSP90 in patients with oligozoospermia, irrespective of varicocele (17). These findings indicate that under heat stress conditions, spermatozoa express HSPs and factors as a self-correction mechanism. However, the specific mechanisms underlying this response remain to be fully elucidated and warrant further investigation.

Sex hormones play a vital role as indicators of the function of Sertoli and Leydig cells in testes. Spermatogenesis occurs within the seminiferous tubules under the stimulation of follicle-stimulating hormone (FSH), while testosterone is produced by Leydig cells in response to luteinizing hormone (LH) (18). In a study by Nicola Zampieri on sex hormone levels in adolescents with varicocele, significant differences in FSH levels were observed across different clinical grades of varicocele and venous reflux severity in the spermatic cord. Specifically, patients with clinical grade 3 varicocele exhibited higher FSH levels compared to those with grades 1–2, and elevated FSH levels were also found in patients with more severe venous reflux (grade 4 versus grades 1–3) (19). These findings suggest that elevated FSH levels in varicocele patients may be associated with impaired fertility. Moreover, this biomarker can help identify individuals at increased risk for fertility impairment, thereby aiding in the early detection and selection of candidates who might benefit from surgical intervention.

Risk factors of varicocele

Anatomical factors

Anatomically, varicocele is primarily attributed to venous valve incompetence (20). The left spermatic vein is 8–10 cm longer than the right one and inserts into the left renal vein at a 90 angle, leading to increased hydrostatic pressure and a tendency for reflux (21). This is also the reason why almost varicoceles occur on the left side (22). Furthermore, certain abnormal anatomical factors can also contribute to the development of varicocele, such as the location of the left renal vein between the abdominal aorta and the superior mesenteric artery, which can lead to compression of the left renal vein and ultimately result in increased pressure in the ipsilateral spermatic vein, known as the nutcracker phenomenon (23).

The right testicular vein drains into the inferior vena cava, which makes it less prone to varicocele development (24). Thus, when varicocele occurs on the right side, especially in the case of isolated right-sided varicocele, ultrasound examination of the retroperitoneal cavity, followed by computed tomography (CT) scanning of the abdomen and pelvis, is typically required to assess and rule out the possibility of tumor compression or invasion of the related veins (25). In cases where men over 30, particularly elderly men, experience a sudden onset of varicocele, retroperitoneal imaging is advised to exclude the possibility of tumor-induced compression (26). However, recent clinical studies have questioned this approach, suggesting that isolated right-sided varicocele is either not associated or only weakly associated with abdominal malignancies (24,27).

Several anatomical abnormalities can also contribute to the development of varicocele. Early reports described three cases of complete situs inversus, with or without cardiac dysfunction, in which patients developed right-sided varicocele—a condition that was considered “normal” for them due to their unique anatomical structure (28). Additionally, there have been reports of patients with situs inversus totalis combined with inferior vena cava malformation, who presented with right-sided varicocele. Venographic imaging revealed that in these cases, the right internal spermatic vein drained into an anomalous venous ring surrounding the aorta (29).

Age factor

Multiple school-based studies in Europe have reported that the overall prevalence of varicocele among children and adolescents ranges from 4.1% to 35.1% and prevalence increasing with age (30). A study by Akbay and colleagues, focusing on children and adolescents in Turkey, found that the prevalence of varicocele was 0.8% among boys aged 2–6 years, 1.0% among those aged 7–10 years, 7.8% among those aged 11–14 years, and 14.1% among those aged 15–19 years (31).

While varicocele is well-documented in adolescents and children, studies on middle-aged and elderly individuals show conflicting results. Research by Canales et al. revealed that the morbidity rate of varicocele in elderly patients is higher than younger populations, yet no clear trend of increasing prevalence with age was observed (32). In contrast, a study by Besiroglu and colleagues found that individuals over 40 years old, the prevalence of varicocele among four age-stratified groups (40–49, 50–59, 60–69, and >70 years) was 44%, 40%, 51%, and 66%, respectively. Among these, patients older than 70 years had the highest prevalence of bilateral varicocele (33). This suggests that while the characteristic venous insufficiency of varicocele primarily develops during testicular maturation, aging is also a significant risk factor, with an approximate 10% increase in the incidence of varicocele for every decade of life，this is hypothesized to be associated with the anatomical architecture of the spermatic veins and mechanical wear-induced valvular dysfunction of unidirectional valves, secondary to chronic mechanical stress over prolonged physiological activity (34).

Genetic factors

A physical examination of the immediate family members of 88 patients who underwent surgical treatment for varicocele revealed a significantly higher detection rate of varicocele compared to a control group, suggesting a genetic predisposition to the condition (35). Similarly, Raman et al. found an increased prevalence of varicocele among first-degree relatives of affected patients. However, neither the grading of varicocele nor the presence of bilateral varicocele could predict hereditary patterns among these relatives (36). Luke Griffiths and colleagues also investigated the genetic aspects of varicocele, finding that fathers of patients with Grade 2 and Grade 3 varicocele were more likely to have varicocele compared to fathers of patients with Grade 1 varicocele. Furthermore, fathers of patients with Grade 2 varicocele had a higher likelihood of requiring surgical intervention than those with Grade 1 (37). Despite ongoing debate, there is growing recognition of a genetic component in the development of varicocele. However, current research remains largely based on epidemiological data, and the specific genetic factors responsible for the increased prevalence of varicocele among family members have yet to be fully identified.

Furthermore, a large-scale prospective study conducted by Philip Kumanov and colleagues in Bulgaria assessed the incidence of varicocele among 6,200 children from five regions of the country. The study identified several risk factors for varicocele, including height, penile length, and penile circumference, while body mass index (BMI) appeared to have a protective effect. Additionally, the prevalence of varicocele exhibited significant regional variations and was found to be more common among boys with dark-colored eyes (38).

Taymour Mostafa and colleagues have extensively examined the genetic variations in patients with varicocele, with glutathione S-transferase (GST) and nitric oxide synthase (NOS) being among the most studied (39), with GST and NOS being among the most extensively studied. Glutathione S-transferase plays a multifaceted role in male infertility (40), including its involvement in sperm detoxification by protecting sperm from damage caused by reactive electrophiles (41), regulating sperm signaling pathways, and facilitating fertilization (42). While the concept of regulating sperm signaling pathways has been proposed, there is currently no research specifically addressing this in the context of sperm. Despite several studies aiming to clarify its relationship with varicocele, research from various regions has consistently shown no significant difference in the genotype frequencies of GST enzymes, including GSTM1 and GSTT1, between varicocele patients and control groups (43-45). However, the GSTM1 genotype has been associated with increased oxidative stress damage in patients with varicocele (44). Interestingly, polymorphisms of both GSTT1 and GSTM1 have been significantly linked to improved outcomes following varicocelectomy (46).

The mechanisms involving NOS3 in varicocele primarily include observations of increased endothelial nitric oxide synthase (eNOS) expression in the spermatic veins of affected individuals, elevated nitric oxide (NO) levels in these veins, and the potential role of NO produced in the testes in promoting dilation of the internal spermatic veins (47-50). In a study on NOS genes, Omar et al. examined the rs1799983 locus of the NOS3 gene and found that the guanine-thymine (GT) and thymine-thymine (TT) genotypes were significantly more prevalent in varicocele patients (30% and 9%, respectively) compared to the control group, while the guanine-guanine (GG) genotype was more common in the control group (88%) than in varicocele patients (61%). For the rs2070744 locus, the thymine-cytosine (TC) genotype occurred significantly more frequently in varicocele patients (28%) than in the control group (10%), while the TT genotype was more prevalent in normal subjects (90%) than in varicocele patients (72%) (P=0.001) (51).

Lifestyle and environmental factors

The studies mentioned above also suggest that, in addition to eye color as a genetic factor, various lifestyle and environmental factors may be associated with the development of varicocele. For example, varicocele has been found to correlate positively with the degree of male sexual development. Sushil Prabakaran and colleagues conducted varicocele assessments on 1,200 males aged 0–19 years and found a positive correlation between height, penile length, and the presence of varicocele. Their findings indicate that males undergoing more rapid pubertal development are more likely to develop varicocele (52). Another contributing factor is that taller males tend to have a smaller angle between the superior mesenteric artery and the aorta, which increases the likelihood of compression of the left renal vein. Additionally, taller boys typically have a longer left testicular vein compared to the right, which raises the hydrostatic pressure in the distal portion of the left testicular vein (53).

Physical activity has also been associated with the incidence of varicocele. A study by Rigano et al. found that patients with longer weekly training durations (7–12 hours per week) had a higher prevalence of varicocele, additionally, studies indicate that exercise-induced varicoceles, if identified early and managed with cessation of athletic training, can lead to significant recovery of semen quality (54). However, the study also noted that general physical exercise does not affect the overall prevalence of varicocele (55). Interestingly, while general physical activity does not influence the prevalence, engaging in physical exercise may worsen symptoms in patients with varicocele, leading to increased pain and a deterioration in semen quality (56).

There is ongoing controversy regarding the relationship between BMI and the prevalence of varicocele. In a longitudinal follow-up study of 43 men, Daniel P. Delaney found no significant correlation between BMI and the prevalence of varicocele (57). Similarly, a comparative study by Süleyman Kiliç and colleagues, which involved 52 patients with varicocele and 100 without, also reported no association between BMI and varicocele (58). However, other studies have demonstrated a negative correlation between varicocele and BMI. A meta-analysis that included 13 articles—comprising 7 case-control studies and 6 cross-sectional studies, with a total of 1,385,630 subjects—revealed that patients with grade 3 varicocele had significantly lower BMI compared to those without varicocele. Moreover, a higher BMI was found to reduce the risk of developing varicocele, it is hypothesized to be associated with the nutcracker phenomenon, wherein increased adipose tissue may provide a cushioning effect, thereby preventing mechanical compression of the left renal vein between the superior mesenteric artery and aorta, then reduces pressure elevation in the left renal venous system (59).

As previously mentioned, regional variations and geographical environmental factors also play a role in the risk of developing varicocele. A study conducted in the Tibetan region of China found that, as altitude increases and the duration of stay extends for patients with varicocele, several factors—including the internal diameter of the spermatic vein at rest, the internal diameter during the Valsalva maneuver, peak reflux velocity, and reflux duration—gradually increased. Notably, in patients residing at altitudes above 4,500 meters, the incidence of clinical varicocele was higher than that subclinical varicocele (60).

Hematological factor

The external manifestations of varicocele are primarily observed in the venous blood vessels, and ultrasound examination remains a reliable diagnostic tool, particularly in assessing the type of blood reflux (61). However, an increasing research suggests that, in addition to oxidative stress indicators, other hematological markers may also play a role in the pathophysiology of varicocele. For instance, the presence of peripheral varicose veins has been positively correlated with an increased incidence of varicocele (58). Furthermore, Yetkin et al. found that patients with coronary artery dilation showed a higher incidence of varicocele, suggesting that both conditions may share a common underlying pathogenic mechanism (62).

As is well known, platelets are essential not only for hemostasis and coagulation (63), but play pivotal roles in the pathophysiology of various diseases, including vascular disorders, tumors, and allergic conditions (64-66). A systematic review and meta-analysis examining platelet indices in varicocele patients found significant differences in mean platelet volume (MPV) between patients with varicocele and healthy controls. Specifically, patients with varicocele exhibited significantly lower platelet counts compared to healthy individuals, and varicocele surgery was shown to reduce the preoperative elevation of MPV (67). Although the reasons behind the increased platelet count were not fully analyzed, the authors speculated that platelet activation leads to the release of cytokines, such as interleukin-6 (IL-6) and C-reactive protein (CRP), which may serve as mediators linking varicocele with changes in MPV (67,68). Furthermore, a study investigating the association between blood indices and infertility risk in varicocele patients, through multivariate logistic regression analysis, identified red blood cell count, platelet distribution width, neutrophil-to-lymphocyte ratio, and the systemic inflammatory response index as independent risk factors for infertility in these patients (69). This further underscores the involvement of inflammation-related factors in the onset and progression of varicocele.

Disease factors

Research conducted by Hideo Sakamoto and colleagues has demonstrated that men with bilateral varicocele exhibit larger mean diameters, higher peak values, and increased antegrade flow velocities in the prostatic venous plexus compared to men with unilateral varicocele or those without varicocele. Men with unilateral varicocele, in turn, display higher mean peak antegrade flow velocities of prostatic blood flow than those without varicocele. Furthermore, a positive correlation was found between the diameter of the prostatic venous plexus and the diameters of both the left and right pampiniform plexuses in all male subjects, suggesting that varicocele is associated with underlying venous abnormalities (70). As mentioned previously, patients with peripheral varicose veins and coronary artery dilation also exhibit a higher incidence of varicocele, and some of these associations may be explained by hematological indicators. In a study investigating the relationship between pulmonary artery hypertension and varicocele, Erdogmus et al. found that, after adjusting for smoking patterns, patients with chronic obstructive pulmonary disease (COPD) showed an elevated incidence of varicocele, with the prevalence increasing in parallel with the severity of COPD (71). This phenomenon may be attributed to the need for COPD patients to engage accessory muscles (particularly abdominal muscles) to overcome expiratory difficulties, resulting in prolonged expiratory time and increased intra-abdominal pressure (72). This elevated intra-abdominal pressure, in turn, impedes venous blood return from the scrotum and lower extremities. In addition, other diseases that elevate intra-abdominal pressure also increase the risk of varicocele. For instance, Kilciler et al. conducted an assessment involving 135 patients with varicocele or constipation and 120 healthy controls, revealing that chronic constipation serves as a contributing factor to varicocele (73). The compression of the left testicular vein by the overlapped and dilated distal colon due to chronic constipation is a major pathogenic factor. Furthermore, chronic and repeated exertion leading to increased intra-abdominal pressure is also among the contributing factors (74).

Behçet’s disease is an autoimmune disorder that can affect blood vessels, and its vascular involvement is classified as a form of unclassified vasculitis (75). There is a notable tendency for the formation of both superficial and deep venous thrombosis, with the veins of the lower extremities being the most commonly affected site. A study by Yilmaz et al. explored the relationship between Behçet’s disease and varicocele and found an increased incidence of varicocele in patients with Behçet’s disease (76). Although the exact mechanisms underlying this increased incidence have not been fully elucidated, several hypotheses have been proposed. First, Behçet’s disease tends to affect the venous system, resulting in endothelial cell damage or pathological activation. This leads to decreased synthesis of prostacyclin by endothelial cells, impaired fibrinolytic activity, and elevated levels of endothelin-1 (77). Second, the recurrent inflammation of blood vessels in Behçet’s disease may cause defects in the testicular venous valves, subsequently increasing the pressure within the pampiniform plexus and contributing to the formation of varicocele (76).

Another autoimmune disease that can affect blood vessels, ankylosing spondylitis, has been extensively studied, although the findings have been somewhat controversial. Breno Pires Almeida and colleagues conducted a comparative study between 20 patients with 24 healthy controls, and found no significant differences in sex hormone levels or semen parameters between the two groups (78). However, other studies have reported that patients with ankylosing spondylitis exhibit significantly larger diameters of the bilateral pampiniform plexus veins, a notably higher prevalence of varicocele, and abnormalities in semen parameters compared to the control group (79,80). These findings may be related to the chronic lumbar muscle weakness caused by low back pain in patients with ankylosing spondylitis, which leads to the compensatory use of the Valsalva maneuver, thereby increasing intra-abdominal pressure. Additionally, elevated NO levels in the blood of patients with spondyloarthritis may contribute to the dilation of the spermatic veins, promoting the formation of varicocele (81). Furthermore, treatment with tumor necrosis factor-alpha (TNF-α) antagonists for ankylosing spondylitis may also elevate the risk of varicocele (82).

Strengths and limitations

Our narrative review systematically synthesizes the risk factors associated with varicocele, including anatomical, genetic, lifestyle, hematological, and disease-related factors, providing clinicians and researchers with a comprehensive understanding of its pathogenesis. However, as a narrative review, it lacks systematic methodological design, which may introduce selection bias. Furthermore, quantitative synthesis is constrained by the heterogeneity of study designs in the cited literature. Although certain associations such as genetic polymorphisms and oxidative stress are well-established, causal relationships in some areas remain speculative and our review focus on risk factors rather than therapeutic strategies underscores the necessity for future research on treatment interventions.

Conclusions

Varicocele, as one of the reversible factors contributing to male infertility, necessitates a comprehensive understanding of its underlying risk factors to better facilitate its prevention and treatment. It is crucial to consider these risk factors comprehensively and adopt personalized intervention measures. These include improving lifestyle habits, engaging in moderate physical exercise, and avoiding prolonged exposure to unfavorable body positions. Meanwhile, individuals with a high risk due to anatomical abnormalities should undergo regular health examinations to facilitate early detection and adoption of appropriate treatment measures. Through comprehensive prevention and control strategies, the incidence of varicocele can be effectively reduced, thereby enhancing patients’ quality of life and male fertility.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-120/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-120/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-120/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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