Infertility is a common clinical disease, although the disease does not endanger health and life, but it brings the patient great mental pain, affecting the relationship between husband and wife, and even lead to family breakdown. Infertility is not effective and takes a long time to treat, which is a heavy burden for the country and the individual and should be taken seriously.
The World Health Organization has clearly pointed out that a history of sexual intercourse without contraception for more than 12 months and still no conception can be diagnosed as infertility, unlike the previous belief that 2 or 3 years after marriage without pregnancy is infertility, this change is based on a large number of population survey of marriage and childbirth history, and this shortening of the time is conducive to the early diagnosis and treatment of infertility.
In addition, the development of assisted reproductive technology and the use of molecular biology in male medicine have promoted the study of male infertility. In addition, the development of assisted reproductive technology and the use of molecular biology in male medicine have promoted the study of male infertility and made some progress in the etiology, diagnosis and treatment of infertility.
I. Etiology of male infertility
Male infertility is not an individual disease, but a clinical manifestation caused by a variety of disease factors acting on various parts of the male reproductive axis.
(i) Hypothalamic/pituitary level lesions
The main lesions in this area are: Kalman’s syndrome and idiopathic hypogonadotropic hypogonadism, hyperprolactinemia and other congenital and secondary (e.g., tumor, trauma-induced) disorders of gonadotropin-releasing hormone secretion.
Kallmannsyndrome is a syndrome of hypogonadotropic hypogonadism. The disease was reported by Kallmann in 1944. The lesion is located in the hypothalamus and is secondary to hypogonadotropic hypogonadism due to impaired secretion of hypothalamic gonadotropin-releasing hormone (GnRH). The pathogenesis of this disease is well understood, because the precursors of GnRH-releasing hormone neurons are transferred from the olfactory epithelium of the nose to the hypothalamus during normal embryonic development, but in patients with Kalman syndrome, this transfer is not completed during embryonic development, and the hypothalamus does not have such neurons and therefore cannot secrete GnRH, which leads to reduced GnRH secretion and secondary hypogonadism. This is followed by reduced gonadotropin secretion and secondary hypogonadism. KALIG-1 is a large gene with about 200,000 base pairs and is associated with deletion or mutation of this gene. Those with normal olfaction used to be called idiopathic hypogonadotropic hypogonadism due to mutations in the gene for gonadotropin-releasing hormone, which is located on the short arm of chromosome 8.
The clinical manifestations of this syndrome are hypogonadism and olfactory impairment or normal olfaction, and infertility due to azoospermia caused by testicular dysplasia.
(ii) Lesions at the testicular level
There are more lesions at the testicular level, such as cryptorchidism, varicocele, Klinefelter’s syndrome (Klinefelter’s syndrone), orchitis, testicular spermatogenic arrest, round-headed spermatorrhea, ciliated immobility syndrome, testicular tumor, etc.
According to statistics, cryptorchidism accounts for about 8.5% of male infertility, and it is believed that 10-20% of unilateral cryptorchidism is infertile, while 40-80% of bilateral cryptorchidism is infertile. The etiology and pathogenesis of cryptorchidism are not clear at present, but it may be related to reproductive endocrine hormone disorder.
The normal development of the testes is affected due to the high temperature of the cryptorchid testis compared with the scrotum for a long period of time, resulting in sperm production disorders, which can be manifested as oligospermia, oligozoospermia and azoospermia. Cryptorchid testes are prone to cancer, and the possibility of developing testicular tumors is 4-5 times higher than that of normal people, so timely surgery should be performed to prevent testicular tumors.
Varicocele is a common cause of male infertility, and the incidence of varicocele is 10-15% in young male adults, and up to 40% in infertile patients. If a patient comes to the clinic for infertility, physical examination can reveal varicocele on one side or both sides and semen examination can be azoospermia, oligospermia or oligozoospermia, the diagnosis of this disease can be considered, but it should be noted that only varicocele with semen abnormality can be considered as the cause of infertility. The mechanism of infertility caused by varicocele may be due to blood reflux and stagnation, which increases the temperature in the scrotum and brings toxic substances in the renal and adrenal veins, as well as altered testicular hemodynamics, resulting in damage to the testicles and epididymis. However, varicocele as a cause of infertility has been controversial, and so far no conclusive evidence has been found that this disease affects fertility.
Klinefelter’s syndrome and other chromosomal abnormalities.
Klinefelter’s syndrome (Klinefelter’s syndrone) is the most common clinical disorder of male hypogonadism, with an incidence of about 0.2% of the male population. If the sex chromosomes of the egg and sperm do not divide during meiosis, the fertilized zygote will have extra X chromosomes, forming XXY, and this extra X chromosome can come from the sperm or the egg, in addition to the X not dividing during oogenesis, there can also be extra X chromosomes. The typical karyotype of Creutzfeldt-Jakob syndrome is 47,XXY, and the cause of its development may be related to the older age of the mother at the time of pregnancy.
Chromosomal disorders associated with male infertility can manifest not only as numerical abnormalities but also as structural abnormalities, such as reciprocal translocations, Robertsonian translocations, and inversions. Chromosomal abnormalities can occur with abnormal chromosome numbers, but more often with sex chromosomes.
In the process of spermatogenesis, there are many genes involved, and if these genes are abnormal, it will lead to sperm disorders. Since 1976, Tiepoio et al. found the deletion of the long arm of Y chromosome in 6 cases of azoospermia during the karyotype examination of 1170 male infertility patients and proposed the existence of azoospermia factor, and since then a large number of studies, especially in 1994, Kobayashi In 1994, Kobayashi et al. used PCR to determine the region on the Y chromosome associated with spermatogenesis, which is called AZF, and is divided into AZFa, AZFb, AZFc, and later AZFd regions on the proximal side of AZFc. The incidence of Y chromosome microdeletion in azoospermia is reported to be 10-15%, while the incidence of microdeletion in severe oligospermia is 5-10%, and similar results have been obtained from studies by scholars in China. The study of spermatogenesis-related genes such as Y chromosome microdeletions is a significant development in recent years, thus giving us a closer understanding of the etiology and pathogenesis of some unexplained so-called idiopathic azoospermia and oligospermia.
(iii) Vas deferens and accessory gonadal lesions
Sperm duct obstruction is one of the most important causes of male infertility, with obstructive azoospermia accounting for nearly 7%-10% of male infertility patients. Obstruction can occur anywhere in the vas deferens, from the testicular network, epididymis, vas deferens to the opening of the ejaculatory duct. Vasectomy is the common cause of obstruction, followed by congenital anomalies such as vasectomy defects, or obstruction of the vas deferens due to infection or injury. Obstruction of the ejaculatory duct is less common and often causes a significant decrease in semen volume and a decrease in semen pH.
Male genital tract infections: including specific and non-specific infections, specific infections: testicular atrophy due to mumps combined with orchitis and azoospermia and oligospermia due to epididymal, vas deferens and prostatic seminal vesicle lesions caused by Mycobacterium tuberculosis and Dictyococcus gonorrhoeae. The patient may have an increase in prostatic fluid leukocytes, accompanied by painful urination or painful ejaculation, etc. Some patients have other prostatitis symptoms in addition to infertility. The first is that the male genital tract is not a place for the male genital tract.
The diagnostics of male infertility
The diagnosis of male infertility addresses two main issues: the assessment of male fertility and the etiological diagnosis of male infertility. In order to obtain a correct diagnosis, a detailed history, physical examination and necessary laboratory tests must be taken, which are described here according to recent advances.
History taking: History taking is particularly important for the diagnosis of infertility and has a value that cannot be replaced by other examinations, which can provide etiology and other important diagnostic clues for one quarter of patients, so it should be given full attention.
Physical examination: In addition to the general condition, the genital organs should be carefully examined, the contents of the scrotum should be carefully touched, the room temperature and the thickness of the scrotum can easily affect the results of the examination, requiring the patience, time and experience of the examiner, too fast examination is often the reason why varicocele is neglected, because the time is too short, the varicose veins are not ready to fill, the lack of vas deferens in the scrotum is not found, it is inexcusable negligence This is not uncommon in patients with varicocele.
Laboratory tests: There are no less than dozens of laboratory tests related to reproduction, and quite a few of them have poor specificity and sensitivity, which should be noted by clinicians when evaluating the clinical significance of experimental parameters.
1, semen routine examination: is the most important and practical test to estimate male fertility, because the World Health Organization only provides reference values for semen variables, not “normal values”, and the existence of sampling errors and testing errors in semen testing, also affect the accuracy of the test results, so we should be the results of semen analysis, should be The results of semen analysis should be interpreted correctly. The semen parameters only provide the tendency of fertility or infertility, but cannot make a definite conclusion on fertility. In recent years, due to the rapid development of assisted reproduction techniques such as microinjection single sperm insemination, higher requirements have been put forward for the diagnosis of azoospermia, such as the use of nuclear solid red – bitter indigo carmine staining, which can detect very few sperm in the semen, and can further understand the spermatogenic state of the testes, which is beneficial to the development of assisted reproduction techniques.
Electronic computerized automatic sperm analyzer
In order to improve the accuracy of semen analysis, the sperm counting plate has been improved in recent years, from blood cell counting plate – Makler counting plate – Microcell counting plate, reducing the depth of the sperm counting pool from 100μm to 10μm (or 20μm), avoiding the counting error caused by overlapping sperm. The Microcell count tray is closed, and the semen is sucked into the counting cell through the capillary tube, ensuring the accuracy of the specimen volume. The invention and application of electronic computerized sperm auto-analyzer has a long history and has made great progress in recent years. This instrument can determine many parameters such as sperm density, sperm movement and even morphology, and can also understand the trajectory of sperm movement, but there is still a certain error in the identification of sperm in this instrument, and it can be disturbed by many factors. The operator should make appropriate interventions and carefully adjust the threshold to improve the accuracy of the equipment.
2, reproductive endocrine hormone determination: FSH is elevated, is an indicator of impaired testicular spermatogenesis, and can even replace testicular biopsy, in recent years found that the relationship between inhibin B and spermatogenesis, more closely than FSH. To determine whether spermatogenesis is impaired, the accuracy of the use of FSH is only 80%, while inhibin B is up to 95%, it seems that the role of FSH in the diagnosis, will probably be replaced by inhibin B.
3, anti-sperm antibody test: as a diagnosis of male immune infertility, anti-sperm antibody test.
In China, the enzyme-linked immunosorbent assay (ELISA) is used more often, and this method may be less specific, while WHO still recommends IBT and MAR tests, which are more expensive reagents and require live fresh sperm for testing, so its use is limited, so antibody testing is difficult to provide accurate information, and in addition, because immune infertility is relatively sterile, it is difficult to estimate the incidence of immune infertility. According to statistics, anti-sperm antibodies are detected in about 10%-30% of infertile couples, and in <2% of normal fertility couples. The diagnosis of immune infertility should be considered in conjunction with clinical considerations. The testers should indicate the method of testing and the establishment of controls while reporting the results, in order to facilitate the judgment of the results.
4, biochemical testing of semen: determination of neutral alpha-glucosidase: this enzyme can be considered as a functional indicator of the epididymis, and can now be used to identify obstructive and non-obstructive azoospermia.
The standard method for calculating the number of leukocytes in semen is the peroxidase method, in addition to immunohistochemical methods such as the use of monoclonal antibodies against leukocytes and their subclasses. The accuracy of these methods has yet to be further improved due to the influence of various factors, but the garden cells in semen should never be considered as leukocytes or pus cells, let alone diagnosed as male genital infection. The clinical significance of leukocyte spermatozoa is less clear at this time and can be seen in the semen of patients with infections, autoimmune diseases, smoking, alcohol abuse, and spinal cord injury. If infection is suspected, a microbiological examination of semen may be performed, but it should be noted that although many microorganisms can be found in semen, they may not be the pathogenic bacteria that cause reproductive tract infections, and perhaps bacteria from the skin or the front of the urethra contaminate the semen specimen. Mycoplasma humanum and Mycoplasma decidua can also be isolated from semen, but for both, there is still considerable doubt as to whether they can actually cause damage to the reproductive tract and thus lead to infertility. Chlamydia trachomatis can be found in semen and is increasingly becoming a common cause of epididymitis and orchitis in young people. Chlamydia trachomatis infection can cause obstructive azoospermia, where patients can be asymptomatic and have significant changes in semen parameters.
Semen routine laboratory test
Special tests
1.”B” type ultrasonography: In recent years, due to the development of ultrasound medicine, it has a very important use and value in the examination and diagnosis of male genital system.
(1) Application in the diagnosis of varicocele: Although the diagnosis of varicocele can be determined by using physical examination, sometimes there is a big difference due to the different methods of each examiner. Especially for mild varicose veins, “B” ultrasound is used to determine the internal diameter of the vein in both standing and lying position, and if the internal diameter is significantly widened, such as >3 mm, it can provide clear information for diagnosis.
(2) Examination of scrotal content: It can clearly examine the lesions of testes and epididymis, measure the volume of testes, and also understand the blood flow supply of testes and epididymis through color Doppler ultrasound to estimate the spermatogenic status of testes.
(3) Detection of obstructive azoospermia: The patency of the seminal tract can be checked by using a rectal probe, and the residual traces of the vas deferens can be found in the case of congenital vas deferens lesions. For vas deferens or ejaculatory duct obstruction, ductal dilatation and other corresponding pathological changes can be found at the proximal end of the obstruction, such as: vas deferens or ejaculatory duct stones, calcification, fibrosis, lesions of the seminal vesicles seminal vesicle dilatation, seminal vesicle dysplasia, etc.
2, testicular biopsy testicular biopsy is one of the important means of examination for male infertility, which can be used to understand the pathological changes in the testes, the status of spermatozoa, clarify the lesion site, quantitative histological analysis, and assess the prognosis. The material can be obtained by puncture and needle aspiration or by surgical incision. In recent years, due to the widespread use of ICSI, sperm retrieval from the testis (epididymis) has become an important means of testicular biopsy (puncture), and percutaneous epididymal sperm extraction (PESA) and testicular sperm extraction (TESE) have become routine methods of sperm retrieval.
The therapeutics of male infertility
(A) Drug therapy.
1, endocrine drug therapy are gonadotropin-releasing hormone (GnRH), gonadotropin (HCG/HMG), Kallmann’s syndrome and other hypogonadotropic hypogonadism, can receive good results, but the number of such patients is very small.
Clomiphene and Tamoxifen compete with estradiol in the body and bind to its receptors to act as antagonists of estrogen, causing LH and FSH levels to rise. The blood FSH and LH should be checked before using the drug, and if they are increased, it is not suitable for treatment with this drug.
2, immune infertility drug treatment is the first is for infection, the use of appropriate antibacterial drugs, followed by the use of immunosuppressive drugs to reduce the titer of anti-sperm antibodies in the patient. Adrenocorticotropic hormone is commonly used as an immunosuppressant, but its side effects, such as femoral necrosis, discourage people, immune infertility using semen preferences, intrauterine insemination can sometimes receive very good results.
(B) Surgical treatment
1.Surgical treatment of cryptorchidism: the implementation of testicular descending and fixing surgery, which has long been affirmed for everyone’s surgical methods, different opinions are the time of surgery, in recent years, the surgery time of cryptorchidism, there is an increasing trend of advance, based on the cryptorchid testis at the age of 1 year, has produced ultrastructural pathological changes, so advocate surgery at the age of 2-3 years, and even advocate surgery before the age of 2 weeks, but There are also different opinions, some people think that as long as the surgery is performed before the age of 6, the effect is the same.
2.Surgical treatment of varicocele: Since it has been debated whether varicocele is the cause of infertility, some people think that surgical treatment is ineffective. In contrast, others believe that varicocele is the main cause of male infertility, and therefore patients should undergo surgical treatment. Although the effectiveness of surgery has been debated, a study by the WHO organization concluded that surgery is effective, with an average pregnancy rate of 35% after surgery, although there is much controversy over this study.
3, surgical treatment of sperm duct obstruction: there are vasectomy, vasovaginal epididymal anastomosis, ejaculatory duct obstruction through the urethra to perform urethroscopic incision, etc., except for the latter, for such procedures should be microsurgical approach to improve the recanalization rate. Scrotal exploratory surgery can also be used to make the examination and diagnosis and treatment solved at one time and avoid repeated damage to the seminal tract.
(C) Assisted reproductive technology
After the success of in vitro fertilization and embryo transfer, the technology in this area has developed rapidly and the focus of research has shifted to the treatment of severe male infertility factors, such as obstructive and non-obstructive azoospermia, severe oligospermia, weak and teratospermia. In order to overcome the obstacles to sperm-egg union, microinsemination techniques such as partial zona pellucida excision (PZD) and sub-Zona Zona Infusion (SUZI) were developed, and in 1992 Palemo et al. achieved a successful delivery by injecting sperm directly into the oocyte plasma. After more than ten years of continuous improvement, ICSI technology has become the most effective technical method for the treatment of male infertility and has gradually gained popularity. However, we should also see the possible risks of ICSI technology, as the implementation of ICSI technology bypasses the normal fertilization process of natural selection, so that some lives could not be born, and there is a risk that some disease factors (or genes) can be inherited, such as Y chromosome microdeletion, which can harm future generations. In addition, single sperm microinjection operation may damage the structure of gametes, congeners and even chromosomes, in the injection may also be some impurities such as: PVP, cellulose, oil droplets injected into the cells, so the safety of ICSI treatment should be taken seriously, in the selection of indications should take a cautious attitude.
2, artificial insemination: artificial insemination is generally divided into artificial insemination by sperm donation (AID), artificial insemination by husband semen (AIH). According to the method of using semen, there are frozen semen artificial insemination, fresh semen artificial insemination and preferential semen artificial insemination; according to the site of insemination is divided into: intravaginal, intracervical, intrauterine, intra-fallopian tube, intra-abdominal artificial insemination. Although we have now entered the era of “in vitro fertilization”, artificial insemination still occupies an important position in the treatment of infertility, because
(1) The efficacy of artificial insemination is sure and reliable.
(2) The treatment is simple, natural, and relatively inexpensive.
(3) It is the only treatment for some patients, such as: azoospermia, those who cannot get sperm through the testes and epididymis; male spouses who have genetic diseases and are not suitable for childbirth, etc.