Varicocele is a common urological condition that results in a series of clinical symptoms due to tortuous dilatation of the trabecular plexus of the testis, most commonly in adolescent males [1,2]. Varicocele has received widespread attention due to numerous studies showing that it can lead to structural and functional damage to testicular tissue and is significantly associated with male infertility. Especially, in the last three decades, the successful establishment of various experimental animal models of varicocele and the application of molecular biology techniques have led to greater progress in the study of varicocele. In this paper, we review the epidemiology, etiology, pathophysiology, diagnosis, treatment and prognosis of varicocele in order to provide readers with more information about this disease.
1.Epidemiological features
More than 90% of varicocele occurs on the left side, and the overall prevalence of varicocele in the male population is 10-15%, and approximately 30%-50% of men with primary infertility have varicocele [3-6]. Although varicocele can develop in all age groups, it is most common in adolescent males [1,2].
2, Associated vascular anatomical features
There are three main arteries that supply blood to the human testis [7-12].
(1) The testicular artery, also known as the internal spermatic artery: approximately 93.5% originate directly from the anterolateral wall of the abdominal aorta below the plane of origin of the renal artery, 5.6% from the renal artery, and only 0.9% from the middle adrenal artery; the origin has an external diameter of approximately 0.11 cm, the height of the origin is between L2-L3, and the distance from the terminal abdominal aorta is 7.29 cm (right) and 7.24 cm (left) from the The distance from the beginning of the superior mesenteric artery is 4.2cm both right and left, and the distance from the beginning of the inferior mesenteric artery is 2.93cm (right) and 2.96cm (left); after the testicular artery starts from the abdominal aorta, it descends obliquely outward, accompanies the internal spermatic vein in the retroperitoneum, passes through the ureter and the lateral external iliac artery, enters the groin from the internal ring of the inguinal canal (deep ring), accompanies the other components of the spermatic cord out of the superficial ring into the scrotum, and The vessels become curved near the testis and branch repeatedly after entering the testis. Some branches enter the lobular septum through the testicular longitudinal septum and some branches enter the lobular septum through the vascular membrane; the small arteries in the lobular septum enter the testicular lobules and form a capillary network that wraps around the seminiferous tubules and interstitial cells.
(ii) The levator artery: it is a branch of the inferior abdominal wall artery, which travels on the inner surface of the external fascia of the spermatic cord and extensively branches out into the surface of the spermatic cord, the scrotal sheath and the testis.
(iii) Vas deferens artery: it comes from the superior cystic artery and travels along the vas deferens to the epididymis, with branches supplying the testes.
(iv) In addition, the arteries of the testicular leads and the longitudinal scrotum also provide part of the blood supply to the testis. There are a large number of traffic branches between these arteries. Although there are several arteries in the testis, the testicular artery is always the largest, and its internal diameter is 50% larger than the combined internal diameter of the levator artery and the vas deferens artery, which is the main blood supply artery to the testis.
The venous blood of the human testis flows back through the spermatic veins. The spermatic veins can be divided into three groups [13-19].
(i) Posterior group: external spermatic vein → inferior abdominal wall vein → femoral vein → external iliac vein.
(ii) Middle group: vas deferens vein → superior vesical vein → internal iliac vein.
(③) Anterior group: the veins of testes and epididymis consist of 10-20 small veins anastomosing with each other in the spermatic cord to form a trapezoidal plexus, which merges into 2-4 veins in the inguinal canal and crosses the internal ring to the peritoneum, 91.6% of which are synthesized into one vein, and only 8.4% are 2-branched, called the internal spermatic vein. These veins have lateral circulation with each other, and the testicular venous blood is mainly drained by the internal spermatic vein. The left internal spermatic vein enters the left renal vein at a right angle, while about 72% of the right side infuses the inferior vena cava at an acute angle and 28% infuses the right renal vein at a right angle. In addition, venography shows the presence of traffic branches between the internal spermatic vein and the inferior vena cava and between the bilateral internal spermatic veins.
3.Etiology of varicocele
There are several theories about the causes of varicocele.
(i) The left internal spermatic vein is generally 8-10 cm longer than the right and injects into the left renal vein at right angles, causing an increase in hydrostatic pressure within the trabecular plexus of the testis [20];
(ii) Since the left renal vein is located within the angle formed by the superior mesenteric artery and the abdominal aorta, it is vulnerable to compression by the latter two, resulting in obstruction of blood return to the left internal spermatic vein, which is known as the “nutcracker phenomenon” [21,22];
(iii) The venous valve of the left internal spermatic vein is defective or incompetent, leading to the reflux of blood from the left renal vein [23];
④The left internal spermatic vein is locally compressed by the sigmoid colon and iliac vessels, which obstructs the return of blood to the testicular veins [24];
⑤ Recent studies have found defects in the structure of the internal spermatic veins in patients with varicocele [25];
(vi) Other studies have shown that varicocele has a congenital genetic trait [26];
(7) Some studies have also shown that varicocele is still significantly associated with obesity, excluding the factor of “nutcracker phenomenon” in obese individuals [27];
(8) A significant increase in testicular arterial blood flow during puberty, which exceeds the venous return load, leads to testicular venous stasis [28,29];
⑨ Other: hypoplastic levator muscle, spermatic fascia relaxation; prolonged standing, increased abdominal pressure, etc [24].
Although numerous theories have been proposed regarding the mechanism of formation of varicocele, there are still many debates. For example, studies have confirmed the presence of renal venous blood reflux in the left internal spermatic vein in normal men without varicocele, thus not supporting the “venous blood reflux theory”. In addition, some of these theories are based on animal studies; for example, a significant increase in arterial blood flow to the testes during pubertal development, which exceeds the venous reflux load and results in varicocele. Therefore, the formation of varicocele may be the result of the combined action of multiple factors, and its mechanism needs to be further explored.
4. Effects of varicocele on testicular tissue structure and function
4.1. Histological effects
Varicocele can cause growth arrest in the affected testis in both humans and experimental animals, and histopathological abnormalities have been observed in the testis on histological examination, and such alterations can be seen in both testes [30-34]. The most common pathological changes on testicular tissue biopsy in patients with varicocele are regression of one part of Leydig cells and hyperplasia of the other part; reduction in the number and disorganization of germ cells, shedding of a large number of germ cells in the lumen of the tubules, in severe cases only Sertoli cells remain; fibrosis of the peritubules and thickening of the lamina propria of the germinal tubules [34-38]. The germinal tubule is a vascularized area, and the uptake of various nutrients and excretion of metabolites required by the germinal epithelium depend on the integrity of the lamina propria structure; at the same time, the muscle-like cells within the lamina propria have a contractile function, thus facilitating the discharge of sperm from the tubular lumen to the epididymis [34,39]. Thus, damage to the intrinsic membrane structure will lead to the development and discharge of germ cells. Moreover, the observation by ultrastructural and immunohistochemical techniques revealed that the damage to the lamina propria in adult patients due to varicocele is far more severe than that in adolescent patients, with age dependency [40]. Myofibroblasts originating from the lamina propria of the seminiferous tubules in adolescent men with varicocele cannot be transformed into fibroblasts in vitro in culture, but can produce large amounts of extracellular matrix; whereas myofibroblasts from the lamina propria of adult men with varicocele are readily transformed into fibroblasts, which can lead to fibrosis of the seminiferous tubules [41]. This would explain why internal spermatic vein ligation reverses testicular growth arrest and repairs damage to testicular tissue structure in adolescent patients with varicocele; whereas, the surgical results are not satisfactory in adult patients. However, in animal models, the opposite has been observed: Saypol DC et al. reported that no morphological changes were found in the testicular tissue of adult rats with experimental varicocele [42]; whereas Choi H et al. observed histopathological changes in the testes of adolescent rats with experimental varicocele (degeneration of the germinal epithelium, atrophy of the germinal tubules, Sertoli cell hyper hyperplasia, etc.) and concluded that the testes of adolescent rats are more sensitive to the damage induced by varicocele [43]. It is evident that more in-depth studies are needed regarding the effects of varicocele on testicular tissue structure.
4.2. Effects on spermatogenic function
Although most patients with varicocele are still fertile, numerous studies have shown that varicocele can lead to a decrease in fertility due to damage to the spermatogenic function of the testis.Macleod first objectively described the abnormalities of semen parameters in patients with varicocele infertility in 1965, when he repeatedly observed the semen of 200 patients with varicocele infertility and found that the sperm count and viability of their semen and viability were significantly decreased, the number of immature and acinar sperm was significantly increased and in severe cases there were no spermatozoa [44].Steckel et al. reported that there is a varicocele degree – semen quality dependence of the effect of varicocele on semen (i.e. the more severe the varicocele, the worse the quality of semen) [45]. Moreover, studies have found that the damage of varicocele on testicular spermatogenesis is progressive [46].
On the other hand, there are some findings that do not support the above conclusions, but most of their studies lack systematic and rigorous controls; thus, these conclusions are not convincing.
4.3. effects on the testosterone synthesis function of Leydig cells
The two main functions of the testis are the production of spermatozoa and the synthesis of the androgen, testosterone. The findings suggest that varicocele, in addition to impairing the spermatogenic function of the testis as described above, may also lead to impairment of testosterone synthesis in Leydig cells.
Canales et al. found that varicocele did not cause significant changes in peripheral serum testosterone concentrations in patients [47]; whereas Andό S et al. found in their study that varicocele caused a significant decrease in peripheral serum testosterone concentrations and a negative correlation with the duration of varicocele [48]; and the World Health Organization found that varicocele caused a significant decrease in peripheral serum testosterone concentrations in patients [48]; a World Health Organization study based on 9000 men also showed a significant correlation between varicocele and decreased testicular Leydig cell function [49]. In contrast, Kass et al. showed that serum testosterone concentrations in patients with varicocele older than 30 years of age were significantly lower than those in patients with varicocele younger than 30 years of age, which was not found in men without varicocele, i.e., the effect of varicocele on serum testosterone concentrations was age-dependent [50]. The reasons for this controversial result may be multifactorial; perhaps due to the extremely low peripheral serum testosterone concentrations and the influence of multiple factors such as age and circadian rhythm fluctuations, which in turn make it difficult to standardize the test results [51].
The vast majority of testosterone is synthesized by testicular Leydig cells, and the concentration of testosterone in testicular tissue is much higher than that of peripheral serum testosterone, and testosterone in testicular tissue is directly involved in spermatogenesis and emission; therefore, changes in testosterone concentration in testicular tissue can better reflect the function of testosterone synthesis by testicular Leydig cells than changes in clear testosterone concentration, and has more physiological significance [48].
5, Pathophysiology of varicocele
The effects of varicocele on testicular structure and function in humans and experimental animals have been very widely recognized. At the same time, the pathophysiological mechanisms of testicular damage caused by varicocele have been thoroughly investigated by researchers and several theories have been proposed. The most important ones are as follows.
5.1. hyperthermia theory
Varicocele can cause an increase in the local temperature of the testes and scrotum [52]. Studies have shown that the optimal temperature environment for spermatogenesis is 2-3°C lower than body temperature, which is the ideal temperature for DNA synthesis during spermatogenesis in the testis; while elevated testicular temperature causes degeneration of Sertoli cells resulting in the destruction of the blood-testis barrier and the release of spermatozoa into the blood to produce anti-sperm antibodies, whose immune complexes are deposited in the testicular mesenchyme or spermatogonia through the damaged blood-testis barrier to induce testicular autoimmune reactions; In addition to inducing autoimmunity, high temperature degeneration of Sertoli cells can also lead to impaired sperm maturation because of their supporting and releasing spermatozoa and their trophic role; in addition, deposition of immune complexes on spermatogonia can directly lead to their death [53,54]. The natural position of the testis within the scrotum and the unique structure of the “countercurrent heat exchange apparatus” formed by the testicular artery and the tracheal plexus are conducive to providing an optimal temperature environment for spermatogenesis [55].
In varicocele, the accumulation of venous blood in the trabecular plexus and testis impairs the function of the “countercurrent heat exchange apparatus” formed by the testicular artery and the trabecular plexus and increases the testicular temperature, which in turn adversely affects spermatogenesis.
5.2. Testicular blood flow abnormalities theory
It has been found that testicular arterial blood flow increases significantly during puberty [28,29]. The abnormal increase in testicular arterial blood flow also increases the hydrostatic and capillary filtration pressure in testicular veins, which increases the testicular interstitial fluid and alters the concentration of various active substances in the testicular interstitial fluid, which in turn affects the paracrine regulation of testicular interstitial cells, myoid cells within the lamina propria of the germinal tubules, and Sertoli cells within the germinal epithelium, ultimately affecting spermatogenesis [42,56, 57].
5.3. Metabolic toxicity theory
It has been suggested that venous blood returning from the left internal spermatic vein carries metabolites secreted by the adrenal glands and kidneys such as steroids, catecholamines, and 5-hydroxytryptamine (5-HT) to the testes and impairs their structure and function [58]. Among these substances, 5-HT is currently more intensively studied.
5-HT is an important neurotransmitter that acts mainly on specific S2 receptors on vascular smooth muscle to constrict peripheral blood vessels, and is also a proplatelet aggregation substance that causes stagnation of blood flow around the testis. devoto E et al. suggested that an abnormal increase in 5-HT leads to excessive constriction of testicular microvessels, which directly affects testicular blood supply, interstitial fibrosis, and swelling and degeneration of interstitial cells, which in turn inhibits testicular androgen synthesis, i.e., inhibition of the conversion of progesterone to testosterone, leading to an increased ratio of androstenedione to testosterone and contributing to the premature shedding of immature sperm [59].
However, it has also been found that blood reflux within the internal spermatic veins is present in both patients with and without varicocele in the male population [60]; furthermore, testicular damage was not reduced in experimental varicocele rats with the left adrenal gland removed [61]. Thus, the theory of toxicity of adrenal and renal metabolites has been questioned.
5.4. Hypoxia and acidosis theory
Because venous stasis leads to hypoxia and acidosis of local tissues. Therefore, it has been proposed that in varicocele, venous blood stasis within the trabecular plexus of the spermatic cord alters the partial pressure of oxygen in testicular tissues, affecting their aerobic metabolism and ultimately causing damage to testicular tissue structure and function [62,
63].
5.5. Nitric oxide (NO) doctrine
NO is a free radical molecule produced by the oxidative decomposition of the nitrogen atom in the terminal guanidine group of L-arginine catalyzed by nitric oxide synthase (NOS), which has an important role in biological processes such as neural signaling, tumor cell killing, body immunity, and inflammatory response [64]. In addition, NO has a role in the regulation of sexual and reproductive functions [65].
The results showed that the effect of NO on sperm function is dual: low concentrations of NO inactivate superoxide anions, prevent lipid peroxidation, stimulate testosterone secretion, promote sperm activation and gain energy, and improve sperm motility; while high concentrations of NO reduce testicular blood supply, impair spermatogenesis, inhibit sperm motility, suppress sperm hyperresponsiveness and reduce acrosome reaction rate; this may be related to This may be related to the fact that high doses of NO inhibit the tricarboxylic acid cycle and prevent ATP production in spermatozoa [66]. It was found that NO, peroxynitrite and thionitrosol formation were increased in testicular tissue and peripheral serum of varicocele patients and animal models, and these chemical products are biologically active and may cause sperm damage; therefore, NO plays an important role in the pathophysiology of varicocele and may be an important cause of spermatogenic impairment in varicocele patients [67, 68, 69]. From clinical observations, semen analysis of patients with varicocele not only showed weak spermatozoa, but also reduced sperm count and more malformed sperm; and the more severe the degree of varicocele, the higher the NO level and the more severely the sperm quality was affected; this indicates that NO not only affects sperm motility, but may also affect sperm production and development [70]. As for how NO affects sperm growth and development, further studies are needed.
5.6. reactive oxygen species (ROS) and apoptosis theory
The reactive oxygen species family includes hydrogen peroxide (H2O2), superoxide anion (O2-) and hydroxyl group (OH-), among which H2O2 is the most toxic. It has been found that lipid peroxidation (LPO) of sperm membranes induced by reactive oxygen species is one of the causes of reduced sperm viability and fertilization ability during in vitro fertilization. The damage of reactive oxygen species on sperm function includes: (i) oxidative damage to DNA, causing DNA strand breakage, producing an abnormal increase in DNA fragments, affecting sperm development and maturation and leading to sperm-egg binding disorders; (ii) the human sperm plasma membrane is rich in polyunsaturated fatty acids, which are beneficial for maintaining membrane fluidity; this fluidity is necessary for fertilization processes such as acrosome reaction and sperm-egg binding; however, these fatty acids are extremely unstable in However, these fatty acids are extremely unstable under aerobic conditions, and are prone to interact with reactive oxygen species to undergo lipid peroxidation and activate phospholipase A2, leading to changes in membrane fluidity and permeability; (3) reactive oxygen species can cause lipid peroxidation of unsaturated fatty acids on the inner and outer mitochondrial membranes, and the inner membrane cristae are reduced, affecting the synthesis of ATP; and ATP is the energy source for maintaining sperm viability, and the reduction of ATP is bound to affect sperm viability; (4) at the same time , substances produced by lipid peroxidation such as malondialdehyde (MDA) are cytotoxic and can inhibit the function of mitochondria and the activity of many enzymes including adenylate cyclase [71-74]. Clinical experiments revealed that in sterile patients with elevated reactive oxygen species, oral administration of VitE, a lipid-soluble antioxidant, increased sperm fertility in vitro in patients by interrupting the chain of redox reactions and increasing membrane stability, which demonstrated the relationship between reactive oxygen species and sterility and provided a new way to treat this type of sterility.
Under normal conditions, sperm produce only small amounts of oxygen radicals, related to physiological functions such as sperm capacitation and acrosome reactions. At the same time, there are enzymatic scavenging systems in the seminal plasma that counteract reactive oxygen species; superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), whose main role is to scavenge oxygen radicals. Although the efficiency of these enzymes is low due to the limitation of concentration and distribution; however, experiments have shown that the production of oxygen radicals will be greatly increased after removing the enzyme scavenging system from the seminal plasma by washing. Under physiological conditions, oxygen radical generation and scavenging are in equilibrium, but in pathological conditions such as varicocele, the regulatory mechanism of reactive oxygen species is disrupted, the receptors for reactive oxygen species in sperm membranes are upregulated, and the production of reactive oxygen species increases abnormally due to the stimulation of cellular inflammatory factors; at the same time, the efficiency of the enzyme scavenging system is not correspondingly increased or even decreased; this imbalance leads to impairment of sperm function by reactive oxygen species, causing infertility [ 75]. Reactive oxygen species are one of the triggers of apoptosis [76], and Cam
K et al. also found a synchronous increase in the level of reactive oxygen species in testicular tissue and apoptosis of germ cells in rats with experimental varicocele [77].
5.7. The epididymal damage theory
The epididymis is an important site for sperm storage and maturation, and pathological changes in epididymal function due to varicocele will lead to impaired sperm maturation, decreased sperm motility, and insufficient energy supply for sperm metabolism [78,79]. Animal experiments have shown that varicocele can cause histological abnormalities such as disorganization of epididymal epithelial cells, thinning and shedding of microvilli [80]. It has been reported that a-glycosidase plays an important role in sperm maturation, sperm capacitation and fertilization process, and it mainly reflects the functional morphology of the epididymis. a-glycosidase activity is significantly decreased in patients with varicocele compared to normal subjects [78].
5.8. Immunological factors theory
With the increase in the detection of antisperm antibodies in the blood of patients with varicocele, immune factors began to receive attention. in 1999, Isitmangil et al. tested 30 patients and 30 normal controls using the complex lectin reaction (SMAR) with the peroxidase-labeled protein A method (POPA) and found that 15 patients were positive (50%) and no autoantibodies were detected in the control group It was suggested that this may be due to microangiopathy and hematotoxic substances that compromise the tight junctions between the testicular supporting cells and between the epithelial cells of the epididymis, leading to a breakdown of the blood-testis barrier and the attack of spermatozoa by immune factors in the blood and the production of autoantibodies [81].Gubin et al. studied 97 patients with varicocele and found that the relative risk of developing antisperm antibodies was five times higher than in normal subjects [82 ]. The mechanism of damage to testicular spermatogenesis by antisperm antibodies has also been discussed in the above-mentioned “hyperthermia theory”.
Carbone et al. concluded that varicocele is not associated with autoantibodies, and suggested that partial stenosis of the vas deferens is the main cause of autoantibodies, while the detection rate of antibodies in varicocele is very low, so the role of immune factors is still inconclusive [83].
5.9. Reproductive hormone theory
Among the microenvironment in which the whole process of spermatogenesis takes place, in addition to its physical and chemical factors, sex hormones are important components of the microenvironment for sperm survival, and they have an important role in gonadal development, spermatogenesis, and sperm maturation [84]. Studies have concluded that serum levels of testosterone (T) and dihydrotestosterone (DHT) are decreased in patients with varicocele compared with normal subjects, and levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are significantly higher than normal, and PRC levels are also significantly higher than normal; reflecting damage to testicular interstitial cells [85]. Moreover, the clinical application of human chorionic gonadotropin (HCG) for the treatment of reduced semen quality due to varicocele resulted in improved sperm viability. It can be speculated that endocrine hormone disorder caused by varicocele is one of the causes of impaired sperm production and low sperm motility.
5.10. Heat shock protein 60 (HSP60) theory
In a study by Wemer et al. in 1997, HSP60 was found to be associated with spermatogenic function: in varicocele, HSP60 is specifically expressed in the sperm cell stage in rat testes and impaired sperm maturation occurs at this stage, suggesting that HSP60 is associated with impaired sperm maturation due to varicocele [86].
6. diagnosis
6.1. physical examination
Patients with obvious signs and symptoms are easily diagnosed. During physical examination, the patient should be in a standing position and the examined room should be warm and brightly lit to facilitate relaxation of the patient’s scrotal muscles and accurate assessment of the degree of varicocele by the examiner; and both sides should be examined to prevent missed diagnoses. The degree of varicocele is usually clinically classified into three degrees: degree I: the varicose vein cannot be palpated locally, but can be palpated when the patient holds his breath and increases abdominal pressure, which is called the Valsalva test; degree II: the varicose vein can be palpated in the normal standing position, but has a normal appearance; degree III: the varicose vein is visible in the scrotum, and a soft earthworm mass can be palpated.
Primary varicocele may disappear in the horizontal position, if not it should be alerted to the possibility of secondary varicocele due to retroperitoneal tumor or renal tumor compression; in this case, careful examination of the ipsilateral lumbar abdomen and B-type ultrasound, IVU, CT, or MRI should be done to further clarify the diagnosis [87].
6.2. laboratory tests
Routine examination of semen in patients with varicocele reveals changes such as decreased sperm count, decreased sperm motility, decreased sperm survival, increased number of malformed sperm, and more immature or acromegalic sperm, or in severe cases, no sperm [24]. However, such changes lack specificity and some patients with varicocele may have no significant abnormalities in routine semen examination, so they are often used clinically only to assess the impact of varicocele and treatment on fertility.
6.3. Ancillary tests
In recent years, increasing attention has been paid to the study of subclinical varicocele at home and abroad [88]. In this group of patients, varicocele cannot be detected on physical examination and the Valsalva test is negative, but the diagnosis can be confirmed by ancillary examinations. The main examinations are: ① Color Doppler ultrasonography: it should be performed in the lying position, standing position, and when calm with the Valsalva test; usually the measured diameter of the spermatic vein is greater than 2 mm for diagnosis, but there are also those who advocate greater than 3 mm as the diagnostic criterion [89]; the latter or the average value is the recommended criterion in China; this method is a noninvasive examination, which is convenient, reproducible, high resolution, and accurate. This method is noninvasive, has the characteristics of convenience, good repeatability, high resolution and accurate diagnosis, and can be used as the preferred test method [90]. Scrotal thermometry: scrotal temperature recorder or infrared thermometer can be used for measurement, which is a noninvasive test; research shows that the local temperature of scrotum is proportional to the degree of varicose veins, but it is influenced by the temperature of surrounding tissues and environment, and the false positive rate is high [91]. (iii) Spermatic venography: under X-ray surveillance, the patient is placed in a lying position and is performed under local anesthesia with the Seldinger method via femoral vein cannulation to the internal spermatic vein. The imaging results can be divided into three degrees: mild: contrast reversal in the internal spermatic vein up to 5 cm in length; moderate: contrast reversal to the L4-5 level; severe: contrast reversal into the scrotum [92]. This method can be used to diagnose varicocele and guide the treatment, but this method is after all an interventional diagnostic tool, not particularly needed clinically, and generally not advocated to be carried out universally. ④Other tests: including radioisotope 99mTc scrotal blood pool scan and CT scan; there is less information on related studies, and its value needs to be further evaluated.
7. Treatment
7.1. Non-surgical treatment
For asymptomatic or mild symptoms, non-surgical treatment is recommended, such as scrotal brace, local cold compress and avoiding pelvic and perineal congestion caused by excessive sexual intercourse.
7.2. Surgical treatment
7.2.1. Indications for surgery
Those whose symptoms are severe enough to affect daily life and workers or whose symptoms cannot be relieved by non-surgical treatment should be treated surgically; those with significant varicocele or semen abnormalities or with infertility should also be considered as indications for surgery [24]. In the past, it was thought that some patients with mild varicose veins might resolve on their own after sexual maturity, therefore, mild varicose veins without symptoms and without affecting fertility could be left untreated. As the research on subclinical varicocele progresses, it is believed that subclinical varicocele can also affect testicular function, and therefore, patients with all types of varicocele should be treated actively. Some even advocate that adolescents should undergo surgery as early as possible once varicocele is detected to avoid affecting future fertility [24].
7.2.2. Surgical methods
Traditional treatment methods are based on open surgery. The surgical principle is to cut and ligate the internal spermatic vein at a high level at the level of the retroperitoneal, internal inguinal canal ring. Usually an oblique inguinal incision is used to perform a high ligation of the internal spermatic vein and to remove part of the dilated vein in the scrotum. In recent years, laparoscopic high ligation of the internal spermatic vein for varicocele has also become more common. In cases of combined male infertility, concomitant testicular biopsy is preferable.
In addition, since Palomo’s proposal in 1949 for the treatment of varicocele by high set ligation of the spermatic vessels via the retroperitoneal route, this procedure has also been accepted by some clinical urologists. However, the safety of ligation of testicular arteries has been questioned.
Internal spermatic vein embolization has also been reported for the treatment of varicocele, but it is not widely used because it requires special equipment and techniques, and there is a risk of spillage of the embolic agent into the circulatory system [93]. In addition, spermatic vein diversion and spermatic muscle duct folding are also available.
8.Prognosis
Timely surgical treatment has positive significance for the protection of testicular function and the improvement of sperm count and morphology, and the semen improvement rate of infertile patients undergoing high level ligation of the internal spermatic vein is about 80% and the conception rate is 50%, while the testicular growth can be improved and the damage to the tissue structure can be repaired, while the chances of postoperative conception in azoospermic patients are minimal [24,90, 94]. It has been suggested that subclinical varicocele is more effective than clinical varicocele and that early treatment is more effective than waiting for observation before treatment [90, 95].
9. Complications
9.1. hematoma
Hematoma formation is caused by incomplete intraoperative hemostasis or impairment of the patient’s coagulation mechanism. Therefore, the surgical operation should be performed meticulously, and local compression or application of hemostatic drugs should be given postoperatively for symptomatic treatment if necessary.
9.1. Scrotal edema
The incidence is reported in the literature to be about 7%, which is caused by ligation of the lymphatic vessels accompanying the spermatic cord during surgery, and most of them can disappear on their own.
9.2. testicular atrophy
Testicular atrophy is the most serious long-term complication after varicocele surgery and occurs far more frequently with transinguinal canal pathway surgery than with high retroperitoneal ligation. Studies have found that testicular artery injury can lead to testicular atrophy [97]; therefore, ligation of the varicocele internal spermatic vein, preserving the testicular artery, is accepted by most clinical urologists.
9.3. Recurrence
Recurrence is the most common long-term complication after varicocele surgery, and high ligation has a lower recurrence rate than low ligation and embolization therapy, which is mainly due to missed venous branches and the presence of collateral circulation veins below the ligation site [98].
10. Outlook
In conclusion, many scholars have studied the epidemiology, etiology, pathophysiology, diagnosis, treatment and prognosis of varicocele from different perspectives using various means. Although most of these studies are limited to one aspect and many of the theories are still controversial, they have deepened our understanding of varicocele from various aspects. We believe that with the widespread application of new experimental techniques and tools in this field of research, new ideas will be proposed to elucidate the pathophysiological mechanisms of varicocele and to provide new methods for the diagnosis and treatment of the disease.