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 very high, about 4.1% in foreign countries, while the incidence reported in China is 5.7%, and increases with age. Therefore, more and more attention has been paid to the treatment of VC in adolescents. This article reviews the progress of research on VC in recent years.
I. Anatomy and etiology
The blood supply to the testis comes from the white testicular artery, the vas deferens artery, and the levator artery. The veins of the testis and epididymis converge to form a trapezoidal plexus, most of which travel up through the inguinal canal and converge 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 side joins the inferior vena cava at an acute angle to the second lumbar vertebra.
About 90% of VCs occur on the left side, less than 20% are bilateral, and those on the right side alone are even rarer. The high incidence on the left side is inextricably linked to the unique anatomy of the left testicular vein.
First, congenital venous valve deficiency and incomplete closure, which increases venous return pressure, are thought to be the main causes of VC, but autopsy also reveals that many normal testicular veins do not have valves.
Secondly, the left internal spermatic vein is approximately 8 cm longer than the lateral one and injects into the left renal vein at a right angle, thus increasing the resistance to blood flow.
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) even listed VC as the primary cause of male infertility, with about 35% of primary infertility patients suffering from VC and up to 75% of secondary infertility patients.
The exact mechanism by which VC causes male infertility is not yet clear. In recent years, with the continuous research, 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 the 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 affected side of VC through a large sample multicenter study. 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 for 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. Biopsy of testicular tissues before and after surgery revealed that a series of histological changes in VC patients mainly caused impaired germ cell maturation, including detachment of germinal epithelium, proliferation of Leydig cells, thickening of the basement membrane of germinal tubules, luminal narrowing, 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 confined to the left testis at the beginning of the disease, but as the disease progresses, it eventually involves the right testis as well, 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 kept in dynamic balance by the action of antioxidants (e.g. superoxide dismutase SOD, vitamin E, etc.). It was found that the concentration of ROS and RNS in the veins of male infertility patients 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 surgical treatment should be considered for testicular tissue with high levels of oxidative stress. Coenzyme Q10 is a common antioxidant, and Festa et al. proposed the feasibility of antioxidant therapy by giving oral coenzyme Q10 treatment to VC patients.
(2) Testicular hypoxia Recent studies have found that VC causes stagnant venous return and elevated hydrostatic pressure, which in turn causes local hypoxia in the testis and ultimately damages testicular tissue. Along with hypoxia, testicular tissue also upregulates the expression of VEGF and other active factors to compensate for tissue hypoxia by promoting neovascularization.
In recent years, hypoxia-inducible factor-la (HIF-la) has been extensively studied, and the expression of HIF-la increases in response to tissue hypoxia, promoting vascular wall remodeling and neovascularization to compensate for tissue hypoxia. In addition, Minutoli et al. found that polydeoxynucleotide (PDRN) binds to the A2A receptor during tissue hypoperfusion, which in turn promotes VFGF production. Further studies in ELV mice found 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, 1°C to 2°C lower than body temperature, while VC increases scrotal temperature by an average of 2.6°C through venous dilatation, and excessive scrotal temperature causes germ cell proliferation and impaired function, thus affecting fertility.
Kanter et al. found through mouse studies 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. noted that heat shock protein (HSP) 70 and 90 expression is upregulated at elevated scrotal temperatures and is closely associated with os, ultimately leading to apoptosis.
III. Diagnosis
1.Physical examination
Usually, juvenile VC is asymptomatic, and occasionally the diagnosis relies on routine physical examination because of scrotal swelling and testicular discomfort. 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 are like a mass of earthworms, which 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, 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 examination methods 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) × width (mni) × thickness (mm) × 0.521. The normal testicular volume in prepubertal period is about 1-2 ml and is usually considered to be the beginning of puberty when the volume exceeds 3 ml. The testicular volume can increase to 16 ml between the ages of 11 and 16 years. there can 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 surgical treatment 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 patients showed improvement in the above 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 recently been used to assess the function of the testes 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 remain for the analysis of adolescent semen: firstly, it is more difficult to obtain semen from adolescents. Secondly, spermatozoa in adolescence are in continuous maturation, and there is no specific semen indicator yet.
IV. Treatment
1. Timing and effect of treatment
(1) Effectiveness of treatment Some scholars have previously considered the efficacy of surgical treatment for 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 increased. 76.5% of children with VC had significant “catch-up” testicular growth after surgery.
(2) Timing of treatment Currently, the timing of surgery for VC in adolescents is still controversial. In recent years, there is a growing consensus that testicular damage from VC occurs early in the course of the disease and that effective treatment can reverse this damage. However, considering that not all VC can lead to infertility, and that there is a possibility of white “catch-up” growth of underdeveloped testes, and that the hypothalamic-pituitary gonadal axis of adolescents is not yet mature, and there are individual differences in semen indicators, the indications for surgical treatment of adolescent VC have not yet been standardized.
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 to undergo Palomo and selective arterial preservation, and performed semen analysis after the children reached 18 years of age.
(2) Laparoscopic/robotic/microscopic techniques 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 probability of postoperative complications of syringomyelia was as high as 24.5%. In response to this complication, staining techniques have been applied in recent years to better preserve the lymphatic vessels and thus maintain the patency of reflux and reduce the occurrence of syringomyelia.
Due to the presence of 3 incisions in the abdomen in traditional laparoscopic surgery. In recent years, a single-port laparoscopic technique has been invented, and Lee et al. confirmed its efficacy in a randomized controlled trial, noting that the latter was associated with less pain and faster recovery in children after surgery than the traditional laparoscopic technique. In addition, robot-assisted laparoscopy (RALV) has recently been tried in 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 sphingomyelia with microscopic subcircular spermatic vein ligation were 42.8%, 0.8%, and 0.6%, respectively, which were significantly better than several other procedures, and concluded that microscopic subcircular spermatic vein ligation can be used as a “gold standard” for the treatment of varicocele. “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 injury, quicker recovery, clear observation of intra-seminal venous reflux, and no 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. With the continuous 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 adult infertility in adolescent VC patients, so as to provide directions for better treatment of VC