Vasectomy is a congenital malformation of the male reproductive system and is an important cause of obstructive azoospermia and male infertility.
Overview.
Vasectomy is a congenital malformation of the male reproductive system and is an important cause of obstructive azoospermia and male infertility. It was identified as early as the mid-18th century, but due to limitations in diagnostic tools, only 25 cases were reported worldwide until the first half of the 20th century. Subsequently, with the improvement of male infertility diagnosis and treatment techniques, the number of reported cases has been increasing. Since 1985, more than 170 cases and treatment studies have been reported in China. However, the etiology of the disease has not yet been elucidated. In the past 10 years or so, as the etiology of the disease has been gradually explored, the relationship between vas deferens and cystic fibrosis has received widespread attention. The in-depth study of the latter has led to the initial revelation of the molecular biological basis of congenital vas deferens.
Epidemiology
Vasectomy is the most common type of vas deformity. Since it was first discovered by John Hunter in 1755, the number of reported cases has increased year by year and so far about 200 cases have been reported in China, and foreign reports of obstructive azoospermia account for 6%-14% of male infertility health search, while vas deferens accounts for 18%-50% of obstructive azoospermia. In 1985, China reported 1,310 cases of male infertility in which vasectomy accounted for 1.15%, while in 1989, 250 cases of azoospermia reported vasectomy accounted for 24%, which is similar to This is similar to foreign reports. This shows that congenital vasectomy is not rare in clinical practice.
Etiology
Congenital vas deferens, a congenital malformation of the male reproductive system, has been suspected to be related to genetic factors. For example, it has been found that the disease is clustered in some families, and the finding that cystic fibrosis and congenital vasectomy are closely related clinically provides a strong basis for the important role of genetic factors. The genetic basis of congenital vas deficiency has been initially elucidated. Cystic fibrosis is a common lethal autosomal recessive disorder with a prevalence of 1 in 2000 live births in Caucasians with a carrier frequency of 1 in 22.
The main clinical manifestations are
The main clinical manifestations are chronic lung disorders, pancreatic exocrine insufficiency, increased sweat electrolyte concentration and male infertility. The causative gene was identified in 1989 in the long arm of chromosome 7, region 3, band 1 (7q31), and was cloned and sequenced. The gene is 250kb long, has 27 exons, and the eDNA is 6129bp long, encoding a protein called cystic fibrosis transmembrane transport regulator (CFTR) exercising a functional health search for chloride channels. More than 600 mutations and variants have been identified in this gene, covering the entire CFTR gene region, with 70% of the mutations △F508 in Caucasians, i.e., base pair 1653 to l655 in exon 10 missing a codon encoding a phenylalanine at position 508 of the peptide chain.
In studies of cystic fibrosis, the majority of male patients were found to be infertile due to congenital vas deficiency, suggesting that mutations in this gene are closely related to abnormal vas deferens development, and studies have confirmed that category 1 congenital vas deficiency patients are caused by mutations in the CFTR gene. It is unclear whether this is related to a congenital vas deferens without typical cystic fibrosis symptoms, which was first reported by Petit et al. in 1983 with chromosome 7 abnormalities, inv(7) (p15, q32) and inv(9) (p11, q13).
At that time, because the CF gene had not been localized, its association with cystic fibrosis was not considered. it is now known that the CFTR gene is localized exactly at 7q31. The interchromosomal arm inversion in this case may have disrupted the structure of the CFTR gene adjacent to it on chromosome 7, thus causing the development of congenital vas deferens. This case suggests a possible correlation between the occurrence of class 2 congenital vas deferens and CFTR gene abnormalities.
Secondly, as the clinical and molecular genetics of cystic fibrosis have been studied in depth, the diversity of clinical manifestations of cystic fibrosis and the close correlation between mutant genotypes and phenotypes have become increasingly evident, i.e., different mutant genotypes may lead to different clinical manifestations, and the same mutant genotype may have different clinical manifestations in different individuals. Many researchers have performed extensive mutational screening of exons and exon-intron shear sites of the CFTR gene in such CBAVD patients and found that such CBAVD is indeed closely associated with CFTR gene mutations Health Search. At least 50-70% and sometimes up to 86% of these patients carry a CFTR mutation, and 10% of them are complex heterozygotes for CFTR mutations, i.e., one CFTR mutation on each of the two chromosomes 7. This is a highly significant difference compared to the frequency of CFTR mutation carriers in the normal population of only 4% and a prevalence of 0.2%. In addition, many new or relatively rare mutations in the CFTR gene were found in these CBAVD patients, which differed from the type and frequency of mutations carried by typical cystic fibrosis patients. This further confirms the relationship between the mutation genotype and the phenotype of cystic fibrosis disease, in that the more common mutations cause the typical cystic fibrosis disease symptoms, whereas some relatively rare mutations more often cause only CBAVD.
In summary, there is a consensus that a significant proportion of men with CBAVD without typical cystic fibrosis symptoms are a distinct genetic group of cystic fibrosis, and that CBAVD is an important phenotype of cystic fibrosis mutations along with pulmonary disorders and pancreatic insufficiency. mutations in the coding region of the CFTR gene are one of the most important genetic causes of class 2 CBAVD.
In addition, in studies of CUAVD, researchers have found that when patients with unilateral vas deficiency have non-medical atresia of the contralateral vas deferens at the inguinal or pelvic level, the CFTR gene mutation rate is often as high as 89%, similar to that of CBAVD and very significantly different from that of the normal population. Fibrosis gene expression studies have not only involved the coding region of the gene, but also included a few non-coding regions, such as poly(T) of intron 8. In the study of CFTR gene expression in respiratory epithelium, it was confirmed that allele 5T can affect the normal shearing of exon 9 of this gene, which decreases the transcription level and leads to incomplete expression of CFTR gene, causing a decrease in CFTR protein level and a series of clinical symptoms. Therefore, the 5T mutation of introne8 is considered to be one of the causes of the diversity of clinical manifestations of cystic fibrosis.
In order to investigate the relationship between CBAVD and 5T mutation, some authors divided the results of CBAVD into 3 groups according to the mutation status of cystic fibrosis genes: group 1, accounting for about 15%, were complex heterozygotes with CFTR gene mutation, all without 5T mutation; group 2, accounting for about 60%, had a CFTR gene mutation, of which more than 60% were accompanied by 5T mutation on another CFTR gene; Group 3, which accounted for about 25%, had no other CFTR gene mutation, while its 5T mutation carrier frequency was about 25%, and even 5T pure congeners appeared. This shows that when both CFTR genes are mutated, the occurrence of CBAVD may be related only to the former but not to the 5T mutation; while the carrier frequency of 5T mutation in the latter two groups was significantly higher than the carrier frequency of 5% in the normal population, showing a highly significant difference, suggesting that the presence of 5T mutation on CFTR gene introne8 may be another genetic cause for the occurrence of congenital vas deferens In addition, a mutation in the coding region of the CFTR gene combined with a 5T mutation in the non-coding region of another healthy CFTR gene may be the most common cause of congenital vas deferens. The transcriptional product of a pure heterozygote with a 5T mutation is only 24% of normal.
This further provides a theoretical basis for the important role of the 5T mutation in the development of congenital vas deferens, and reveals to some extent that cystic fibrosis, which is autosomal recessive, is also responsible for congenital vas deferens when there is only one mutation in the coding region of the gene. In addition, there is some tissue specificity in the transcription of this gene, such as higher levels of respiratory epithelial transcription than epididymal epithelium, which may be one of the reasons for the absence of other clinical manifestations in patients with congenital vas deferens carrying the CFTR gene mutation Health Search.
A significant proportion of simple congenital vas deferens are the result of CFTR gene mutations and are a specific phenotype of cystic fibrosis disease. However, CFTR gene mutations are not found in another proportion of CBAVD and CUAVD patients, which may be due to.
①The CFTR gene is larger current techniques such as polymerase chain reaction-single strand conformational polymorphism are still difficult to detect all mutations;
(ii) Only exons, shear sites and very few endosomes of the CFTR gene have been analyzed for mutations so far, and the existence of mutations in the promoter region or other regulatory sites cannot be ruled out yet, while the existence of the latter is possible;
(iii) In some families in which the father and siblings carry the same mutation, only one of them develops CBAVD, suggesting that there may be other genetic and environmental factors in addition to CFTR gene abnormalities in the development of congenital vas deficiency;
In patients with congenital vasectomy combined with other urological malformations (e.g., renal malformations, etc.) and CUAVD with a normal vas deferens, no mutations in the CFTR gene were found, suggesting that such congenital vasectomy is not related to the CFTR gene, and supporting the role of other etiological factors. Therefore, in addition to continuing to detect more mutations in the coding region of the CFTR gene, we should gradually extend the screening to the promoter region and other regulatory regions of the gene and investigate the health search for genes other than the CFTR gene that may be associated with the development of congenital vas deferens to more fully reveal the molecular genetic basis of congenital vas deferens.
Pathogenesis
Congenital vas deferens can be divided into.
1, bilateral vas deferens (CBAVD) Because both middle renal ducts are undeveloped or underdeveloped, it may be accompanied by epididymal and seminal vesicle agenesis, rarely accompanied by bilateral renal malformation or agenesis.
2.Unilateral vas deferens (CUAVD) is caused by undeveloped or underdeveloped unilateral middle renal duct, often accompanied by ipsilateral ureteral buds that do not develop, resulting in renal underdevelopment and ipsilateral renal, ureteral vas deferens and epididymal ducts are absent.
Partial vas deferens can also be divided into vas deferens scrotal section and vas deferens pelvic section, which may be caused by the sudden suspension of the middle renal duct in the process of derivation into vas deferens. Other vas deformities include atresia of the lumen of a segment of the vas deferens in the form of a fibrous cord and the development of a duplicate vas deferens from a branch of the mesonephric duct, and in most of the reported cases of duplicate vas deferens, there are two testes on the duplicate side and the vas deferens are each connected to one testis. In addition, the vas deferens may deviate from the spermatic cord and open ectopically at other sites. In 1978, Kaplan reported eight patients with ectopic vas deformities, six of which were combined with other urogenital malformations and three with congenital anal atresia because the testes develop from the genital crest, so the testes are usually not abnormal in vas deformities.
According to the clinical manifestations and the relationship with cystic fibrosis disease, congenital vas deficiency can be divided into 2 categories: Category 1 is clearly associated with cystic fibrosis disease, and patients mostly present with chronic pulmonary disorders and pancreatic insufficiency. On examination, typical symptoms of cystic fibrosis such as elevated electrolyte concentration in sweat can be found; category 2 has an unknown etiology and is often diagnosed as infertility, while no other abnormalities are seen on physical examination.
Laboratory tests
Low semen volume, low pH no sperm seminal plasma fructose deficiency or low content (<0.87g/ml or <13μmol/1 ejaculation) in CBVAD.
Other ancillary tests.
1, Testicular tissue examination Its varicocele can produce sperm, and there are live sperm in the epididymal head puncture fluid.
2. Imaging examination B ultrasound, CTMRI, etc. can be seen in some cases with absence or dysplasia of seminal vesicles; renal malformation dysplasia, absence of one kidney, etc. >pH(urine) >Fructose >Seminal fluid volume(semen) >Vitamin A
Clinical manifestations: Bilateral vas deferens is often seen for post-marital infertility. The patient is healthy, has a normal sex life and can ejaculate. The vas deferens cannot be found within the spermatic cord on scrotal palpation. Unilateral vas deficiency does not affect normal fertility because the vas deferens of the opposite testicle is normal, so there is no need to treat repeated vas deformity without clinical symptoms, and normal sex life is usually detected during scrotal exploration surgery.
Complications: Unilateral vas deficiency can be accompanied by ipsilateral renal deficiency, and vas deficiency is often accompanied by seminal vesicle and partial epididymal deficiency, but vas deficiency is not accompanied by testicular deficiency, because the testis comes from the primitive gonads, while the epididymis, vas deferens, seminal vesicle and ejaculatory duct come from the middle renal duct.
Diagnosis
1. Medical history Infertility.
2.Physical examination The vas deferens cannot be palpated in the scrotum bilaterally or unilaterally, and the head of the epididymis is enlarged and the body is absent caudally.
3. Partial agenesis is sometimes found incidentally during surgery
Differential diagnosis: No relevant information is available
Treatment.
Studies have shown that mutations in the CFTR gene, the main genetic cause of congenital vas deficiency, do not affect the function of the sperm itself or the success rate of artificial insemination. However, treatment of the disease remains quite difficult. In the past, sperm could be aspirated by puncturing an artificial sperm reservoir for artificial insemination. 1955 Hanly was the first to create a reservoir with amniotic membrane and impregnated the patient’s wife. In the past, artificial sperm receptacles were made by puncturing the testicular sheath and silicone rubber, but they could not be promoted; Cruz (1980) reported 4 pregnancies and 1 spontaneous abortion in 25 cases; Kelaml (1982) reported 2 pregnancies and 1 spontaneous abortion in 23 cases; Silber et al. (1985) reported 24 cases but no pregnancy, which proved that the success rate was too low to be promoted in a healthy way. The search for clinical replication.
Recently, Tournaye et al. recommended microsurgicalepididymalspermaspiration (MESA) in combination with intracytoplamicsperminjection (ICSI) as an effective treatment to improve fertility rates. . The prognosis for cystic fibrosis is mainly symptomatic treatment with antibiotics and dietary therapy to facilitate food digestion and absorption: At present, congenital vas deficiency itself is not treatable. However, with the development of assisted reproductive technology ART), fertility has become possible for patients.