Varicocele (VC) is an obstruction of venous return to the spermatic cord that causes stagnation of blood, resulting in elongation, dilation and tortuosity of the trabecular plexus.
In recent years, most scholars believe that VC can occur as early as in childhood or adolescence, and the incidence is also high, with foreign statistics being about 4.1% and domestic reports being 5.7%, and the incidence increases with age. Therefore, more and more attention has been paid to the treatment of VC in adolescents. In this paper, we review the progress of research on VC in recent years.
I. Anatomy and etiology
The blood supply to the testis comes from the testicular artery, the vas deferens artery, and the levator artery. The veins of the testis and epididymis converge to form a trabecular plexus, most of which travels up through the inguinal canal and converges at the ventral ring to form a single vein called the internal spermatic vein. The left internal spermatic vein joins the left renal vein at a right angle to the lower edge of the first lumbar vertebra, while the right joins the inferior vena cava at an acute angle to the second lumbar vertebra.
VC occurs in about 90% of cases on the left side, less than 20% of cases bilaterally, and even more rarely on the right side alone. The high incidence on the left side is inextricably linked to the unique anatomy of the left testicular vein.
First, congenital venous valve defects and incomplete closure, which increase venous return pressure, are thought to be the main cause of VC, but autopsy also reveals that many normal testicular veins do not have valves.
Secondly, the left internal spermatic vein is approximately 200px longer than the lateral one and injects into the left renal vein at a right angle, thus increasing the resistance to blood flow; however, this anatomical structure is common, but not in all patients, so it is not the only cause.
Third, the nutcracker phenomenon, in which the left renal vein travels between the abdominal aorta and the superior mesenteric artery and is easily compressed (proximal nutcracker phenomenon), and the left common iliac vein is compressed by the left common iliac artery, blocking the return of the left spermatic vein (distal nutcracker phenomenon).
In conclusion, it is believed that the occurrence of VC is influenced by a variety of anatomical factors, and there is no clear single causative factor.
II. VC and male infertility
As early as the ancient Greek period, Celsus pointed out that VC affected testicular development. The World Health Organization (WHO) has listed VC as the leading cause of male infertility, with about 35% of primary infertility cases having VC and up to 75% of secondary infertility cases.
The exact mechanism by which VC causes male infertility is not yet clear. In recent years, as research has been intensified, it is believed that endocrine disorders, high testicular temperature, hypoxia, oxidative stress, circulating toxin accumulation, genetic disorders and autoimmunity can lead to decreased germ cell proliferation and apoptosis, ultimately leading to infertility, and oxidative stress is the main causative factor.
1. sequelae caused by VC
(1) Testicular dysplasia is the most significant effect of VC on the testes of adolescent patients. The difference in testicular volume between the two sides of a normal child should not exceed 2 ml. Considering the large individual differences in testes affected by sexual maturation during puberty, the testicular volume on one side is generally used as a normal control.
WHO has confirmed the reduction of testicular volume on the side affected by VC through a multicenter study with a large sample. Mo ri et al. further studied the relationship between different degrees of VC and testicular dysplasia and found that the incidence of reduced left testicular volume in children with degrees II and III was significantly higher than that in normal children, and there was no significant difference in the incidence between degrees II and III, suggesting that there was no significant relationship between testicular dysplasia and the degree of VC.
(2) Impaired spermatogenesis In adult patients, impaired spermatogenesis is mainly manifested by reduced sperm concentration and motility and increased morbid spermatozoa. Biopsies of testicular tissues before and after surgery revealed a series of histological changes in patients with VC, mainly causing impaired germ cell maturation, including detachment of germinal epithelium, proliferation of Leydig cells, thickening of the basement membrane of germinal tubules, narrowing of the lumen, and interstitial fibrosis.
Iafrate et al. found that in the veins of patients with VC, there was a progressive increase in fibrous connective tissue and a progressive decrease in trophoblastic vessels, or even absence. These changes are often limited to the left testis at the beginning of the disease, but as the disease progresses, the right testis is eventually involved, so early treatment is recommended.
2. Possible pathological mechanisms
(1) During oxidative stress spermatogenesis, highly active cells produce large amounts of reactive oxygen species (R()S) and reactive nitrogen species (RNS). The two are dynamically balanced by antioxidants (e.g. superoxide dismutase SOD, vitamin E, etc.). It was found that the concentration of ROS and RNS in the veins of infertile men with VC increased, while the concentration of antioxidants decreased, and the imbalance between the two led to oxidative stress (OS), which in turn damaged sperm and testicular tissue.
By comparing the expression levels of 4 HNE before and after VC surgery, Shiraishi et al. found that the expression of 4 HNE decreased significantly after surgery, and concluded that surgery should be considered for patients with high levels of oxidative stress in testicular tissue. Coenzyme Q10 is a common antioxidant, and Festa et al. suggested the feasibility of antioxidant therapy by giving oral coenzyme Q10 treatment to VC patients.
(2) Testicular hypoxia Recent studies have found that VC causes venous reflux stasis and elevated hydrostatic pressure, which in turn causes local hypoxia in the testis and ultimately damages testicular tissue. Along with hypoxia, testicular tissues also upregulate the expression of active factors such as vascular endothelial growth factor (VEGF) to compensate for hypoxia by promoting neovascularization.
In recent years, hypoxia-inducible factor-la (HIF-la) has been studied extensively, and HIF-la expression increases in response to tissue hypoxia, promoting vascular wall remodeling and neovascularization to compensate for tissue hypoxia. In addition, Minutoli et al. found that polydeoxyribonucleotide (PDRN) binds to A2A receptors during tissue hypoperfusion, which in turn promotes VFGF production. Further studies in ELV mice showed that exogenous application of PDRN was also effective in reducing VC-induced testicular damage.
(3) Elevated testicular temperature Elevated scrotal and testicular temperatures are recognized as the most likely cause of testicular dysfunction. Under normal conditions, testicular temperature is 35°C to 36°C, which is 1°C to 2°C below body temperature, while VC increases scrotal temperature by an average of 2.6°C through venous dilatation.
Kanter et al. found that high scrotal temperature decreased nuclear antigen expression in proliferating cells, increased terminal deoxyribonucleotidyl transferase-mediated in situ nick end labeling activity, and degraded mitochondria and swollen smooth endoplasmic reticulum in Sertoli cells and spermatocytes, which in turn affected spermatogenesis. In addition, Chan et al. showed that heat shock protein (HSP) 70, 90 expression is upregulated at elevated scrotal temperatures and is closely associated with os, ultimately leading to apoptosis.
Diagnosis
1. Physical examination
Usually, adolescents with VC are asymptomatic and occasionally present with scrotal swelling and testicular discomfort, so the diagnosis relies on routine physical examination. During the examination, the subject should be located in a warm room in the standing and supine positions to observe the change of symptoms. The common diagnostic criteria are: grade I (mild), which is not obvious on palpation, but the Valsalva test may be present; grade II (moderate), which has no obvious abnormality in appearance, but dilated veins are found on palpation; grade III (severe), in which the varicose veins look like a mass of earthworms and are extremely obvious on palpation and visual examination.
In primary VC, the symptoms are obvious in standing position and disappear after supine position, while in secondary VC, the symptoms do not change significantly after changing position. For those who do not have obvious local signs, the Valsalva method can be used for examination. In addition, physical examination can also be used to understand the texture and size of the testicles.
2.Auxiliary examination
Considering the subjectivity of physical examination, many objective examinations are often used to assist in the diagnosis of VC, such as color Doppler ultrasound, venography, radionuclide scrotal scintigraphy and other methods.
(1) Measurement of testicular volume can provide information about testicular damage. Most scholars believe that the more severe the VC, the smaller the testicle on the affected side. Measurement methods include visual comparison, sizing, Prader molds, Takihara molds, and ultrasound. Recently, B-mode ultrasound is considered to be the most accurate method for measuring testicular size.
The formula for calculating testicular volume is: testicular volume (ml) = testicular length (mm) x width (mun) x thickness (mm) x 0.521. The normal testicular volume in the prepubertal period is approximately 1-2 ml and is usually considered to be the onset of puberty when the volume exceeds 3 ml. The testicular volume may increase to 16 ml between the ages of 11 and 16 years, and there may be a difference in testicular size between the right and left side, but it is not statistically significant. The size of the right and left testes may vary but is not statistically significant.
In children with VC, the testicular atrophy index can be a useful indicator of testicular development. The atrophy index = (right testicular volume left testicular volume)/right testicular volume × 100%, and testicular atrophy is considered to exist when the atrophy index is >15%. Robinson et al. indicated that in adolescent patients, when the atrophy index is >20% and the maximum reflux velocity is >38 cm/s, waiting for observation is often ineffective and surgery should be performed.
(2) Semen analysis Semen analysis in adult VC patients shows a decrease in sperm concentration and motility and an increase in morbid sperm. After surgical treatment of VC, about 70% of the patients showed improvement in these indicators, and the improvement in sperm motility was particularly significant.
Most authors believe that the effect of VC on the semen of adolescents is similar to that of adults, and therefore semen analysis has been used to assess testicular function in adolescent patients. In addition, Zylbersztejn et al. recently examined the seminal plasma of adolescent patients at the proteomic level and found abnormal expression of proteins related to spermatogenesis and testicular function, providing a new direction for semen analysis.
However, the following problems still exist for the analysis of adolescent semen: firstly, it is more difficult to obtain adolescent semen. Secondly, the spermatozoa in adolescence are in continuous maturation, and there is no specific semen indicator yet.
IV. Treatment
1. Timing and effect of treatment
(Some scholars have previously considered the efficacy of surgical treatment of VC to be questionable. However, in recent years, several Meta-analyses have shown that the sperm concentration and motility of infertile men with VC significantly improved after surgical treatment, and the spontaneous pregnancy rate of their spouses also increased. . 5% of children with VC had significant “catch-up” testicular growth.
(2) Timing of treatment The timing of VC surgery in adolescents is still controversial. In recent years, there is a growing consensus that damage to the testis from VC occurs early in the disease and that effective treatment can reverse this damage. However, considering that not all VC can cause infertility, and that there is a possibility of white “catch-up” growth in the underdeveloped testes, and that the hypothalamic-pituitary gonadal axis is not yet mature in adolescents, and that there are individual differences in semen indicators, the indications for surgical treatment of VC in adolescents are not yet uniform.
Most studies have concluded that prophylactic surgery in adolescent children is not advisable. Surgical treatment should be considered only if the following conditions are present: (1) the affected testis is significantly reduced (atrophy index >20%, maximum reflux velocity >38 cm/s); (2) other testicular pathologies affecting fertility are combined; (3) varicocele is palpable bilaterally (grade III); (4) abnormal semen analysis is present (in older adolescents); (5) complaints of scrotal swelling and other discomfort are present.
2.Treatment methods
The treatment of VC includes surgical treatment and conservative treatment. Most scholars believe that surgical treatment is an effective and reliable method. The ideal surgical method should be able to cure VC, ensure that testicular function is not affected, and reduce postoperative complications and recurrence rate. There are three major types of surgical procedures in use, namely open surgical treatment, laparoscopic/robotic/microscopic techniques, and percutaneous spermatic vein puncture embolization. Complications of surgery include syringomyelia and testicular atrophy.
(The Palomo procedure has a lower postoperative recurrence rate than the other two procedures, and testicular atrophy is rare.
However, Zampieri et al. randomly divided 122 children aged 13-16 years with VC into two groups for Palomo and selective arterial preservation, and performed semen analysis after the children reached 18 years of age.
(2) Laparoscopic/robotic/microscopic technique In recent years, minimally invasive techniques have been increasingly used in clinical treatment because of their advantages of less injury and faster recovery. However, they also found that the postoperative complication of syringomyelia was as high as 24.5%. To address this complication, staining techniques have been used in recent years to better preserve the lymphatic vessels, thereby maintaining the patency of the reflux and reducing the occurrence of syringomyelia.
Due to the presence of 3 incisions in the abdomen in traditional laparoscopic surgery, the single-port laparotomy has been invented in recent years. In recent years, the single-port laparoscopic technique has been invented, and Lee et al. confirmed its efficacy in a randomized controlled trial, noting that the latter technique was associated with less pain and faster recovery than the conventional laparoscopic technique. In addition, robot-assisted laparoscopy (RALV) has recently been tried for the treatment of VC, but its efficacy needs to be further defined.
Microscopic techniques are another commonly used minimally invasive technique. Yu Nengwang et al: analyzed 35 papers with 4,555 patients and showed that the natural pregnancy rate, recurrence rate, and incidence of testicular syringomyelia with microscopic subcircular spermatic ligation were 42.8%, 0.8%, and 0.6%, respectively, which were significantly better than several other procedures, and concluded that microscopic subcircular spermatic ligation could be the “gold standard”.
(3) Percutaneous spermatic vein puncture embolization Percutaneous spermatic vein puncture embolization is also one of the commonly used methods, which is divided into two methods: paracentral and retrograde. The advantages of this method include less damage, faster recovery, and clear observation of the reflux of blood in the internal spermatic vein without accidental injury to the internal spermatic artery. However, considering the potential risks of radiation exposure, misembolization and displacement of the embolic agent, it is rarely used in adolescents these days.
V. Outlook
In summary, VC is a common cause of male infertility, and with the increasing research, people have more understanding of the etiology, diagnosis, and treatment of VC, and the application of minimally invasive techniques such as laparoscopy and microscopy has provided more options for VC treatment in recent years. Future research still needs to focus on the specific mechanisms of male infertility caused by VC and the predictive indicators of infertility in adolescent VC patients in adulthood, so as to provide directions for better treatment of VC.