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Section 2. Biology
https://doi.org/10.29013/AJT-20-9.10-6-10
Mardomi Farid Davoud, doctoral student at the Department of Genetics and Evolutionary Doctrine Baku State Universitye E-mail: mardomi.farid@mail.ru Deljavan-Nikouei Forough Hassan, doctoral student at the Department of Genetics and Evolutionary Doctrine Baku State University
E-mail: deljavan@mail.ru Babayev Medjnun Shikbaba, Doctor of Biological Sciences, Professor of the Department of Genetics and Evolutionary Doctrine Baku State Universitye
E-mail: babayev_1940@mail.ru
MAIN TRENDS OF THE GENETIC FACTOR OF MALE INFERTILITY
Abstract. For centuries, male infertility and problems with impaired fertility have been a problem around the world. It is also a serious clinical problem today, which affects 8-12% of couples worldwide. Of all cases of infertility, approximately 40-50% are associated with "male factor" infertility, and up to 2% of all men show sub-optimal sperm parameters. It can be one or a combination of low sperm concentration, poor motility, or abnormal morphology. Our review will help to find out some of the trends in male infertility and to elucidate in the future various factors that may be responsible for this pathology.
Keywords: male infertility, fertility, sperm, diagnostics, deletions, genes, mutation.
Introduction These include anomalies of the genitourinary sys-
Male infertility (MI) is a serious pathological tem, tumors, infections of the genitourinary tract,
condition that requires a comprehensive comprehen- endocrine disorders, immunological factors, genetic
sive diagnosis, urgent correction, and in some cases mutations, etc. In contrast to the above reasons, ge-
prevention. Infertility affects 15-20% of couples of netic ones do not always have clinical manifestations,
reproductive age. In half of the cases, it is associated but are extremely important for the diagnosis of MI
with the "male factor", manifested by deviations in in the subject. It is important to understand that the
the parameters ofthe ejaculate [1, p. 191-196]. diagnosis of"MI" and its forms can only be made by
The complexity of diagnosing male infertility a specialist doctor on the basis of anamnestic data,
is due to the large number of reasons that cause it. examination data, results of instrumental and labora-
tory studies [2, p. 9-16]. The following reasons may be the reason for going to the doctor:
• impossibility of conceiving a child within a year, provided that there are no signs of female infertility in the partner;
• violations of erectile and ejaculatory functions;
• concomitant diseases of the urogenital sphere (inflammatory, tumor, autoimmune, congenital, etc.);
• taking hormonal and cytostatic drugs;
• discomfort in the urogenital area.
Genetic causes of male infertility
Frequent causes of male infertility are disorders
in the structure and number of sperm, which affect their mobility and ability to fertilize.
The main genetic causes of male infertility development are:
1) deletion (removal of genetic fragments) of the AZF locus;
2) polymorphism (increased repeats of the genetic fragment - CAG) of the androgen receptor (AR) gene;
3) mutations (sequence disruption) of the CFTR gene.
Currently, these markers are an integral part of the standard criteria for the complex diagnosis of genetic manifestations of male infertility, occurring in a group ofpatients in 10-15% of cases [3, p. 28-30].
Deletions of the AZF locus and the SRY gene
An important role in the development of pathologies such as oligozoospermia and azoospermia is played by deviations in a specific region of the Y chromosome - the AZF locus (azoospermia factor). The genes included in it determine the normal course of spermatogenesis, and if the genetic structure of the AZF locus is disrupted, the formation of male germ cells can be seriously impaired.
The AZF locus is located on the long arm of the Y chromosome (Yq11). The genes located at this locus play an important role in the process of spermatogenesis. Microdeletion of the Y chromosome is the
loss of certain areas, is found on average in 10-15% of cases of azoospermia and in 5-10% of cases of severe oligozoospermia and causes impaired spermatogenesis and infertility in men [4, p. 218-220].
The AZF locus is divided into 3 sections: AZFa, AZFb and AZFc. In each of them, genes involved in the control of spermatogenesis have been identified. Deletions at the AZF locus can be complete, i.e. completely removing one of the AZF regions or more, and partial, when they do not completely cover any of its three regions.
With complete AZF deletions, there is a fairly clear dependence of the degree of spermatogenesis impairment on the size and location of the deletions, which may have a prognostic value in obtaining spermatozoa suitable for in vitro fertilization programs. The absence ofthe entire AZF locus, as well as deletions that completely cover the AZFa and / or AZFb regions, indicate the impossibility of obtaining spermatozoa.
Almost all patients with AZFb or AZFb + c deletions have azoospermia due to severe spermatogenesis disorders (Sertoli cell only syndrome). With complete deletions of the AZFc region, manifestations range from azoospermia to oligozoospermia. On average, in 50-70% of patients with a deletion that completely captures the AZFc region, it is possible to obtain spermatozoa suitable for artificial insemination. With partial AZF deletions, manifestations range from azoospermia to normozoospermia [5, p. 80-87].
Investigation of the state of the AZF locus of the Y chromosome in patients with azoospermia and severe oligozoospermia makes it possible to establish the genetic cause of spermatogenesis disorders, to carry out differential diagnostics of infertility in men and to adjust the treatment, to check the possibility of obtaining spermatozoa with testicular biopsy and the possibility of obtaining spermatozoa for ICSI (intracytoplasmic injection).
It should be borne in mind that in the case of successful use of assisted reproductive technologies, the deletion of the Y chromosome is transmit-
ted through the male line. This shows the need for dispensary observation of boys born after the use of ICSI in fathers with microdeletions in the Y chromosome in order to assess their fertile status. Indications for AZF deletions are based on sperm count and include azoospermia and severe oligozoosper-mia (<5 million sperm / ml ejaculate).
The SRY gene (Sex-determining Region Y) is especially important in the genetic control of male development. It was in it that the largest number of mutations associated with gonadal dysgenesis and / or sex reversal was found. In the absence ofa chromosome region containing the SRY gene, the phenotype will be female with a male karyotype of 46XY. This genetic study includes the analysis of the AZF locus of the chromosome - 13 clinically significant deletions: sY86, sY84, sY615, sY127, sY134, sY142, sY1197, sY254, sY255, sY1291, sY1125, sY1206, sY242, as well as determination of the SRY gene deletion.
Androgen receptor gene (AR)
Another determining factor in male infertility is a violation of the hormonal regulation of spermatogenesis, in which male sex hormones androgens play a key role. They interact with specific androgen receptors, determining the development of male sexual characteristics and activating spermatogenesis. Receptors are found in cells of the testes, prostate, skin, cells of the nervous system and other tissues. The androgen receptor gene is characterized by the presence of a sequence of CAG (cytosine-adenine-guanine) repeats, the number of which can vary significantly (from 8 to 25). The CAG triplet encodes the amino acid glutamine, and when the number of CAG repeats of nucleotides changes, the amount of the amino acid glutamine in the protein also changes. The sensitivity of the receptor to testosterone depends on the number of repeats in the AR gene, and the relationship is inversely proportional: the more repeats, the less sensitive the receptor. An increase in the number of CAG repeats in receptors reduces their activity, they become less sensitive to testosterone, which can lead to impaired spermatogenesis,
and the risk of developing oligozoospermia and azoospermia increases [6, p. 122-123].
There is also evidence that with a reduced number of CAG repeats (<18) in the AR gene, there is an increased sensitivity to androgens and an increased risk of prostate cancer in men. An increase in the number of CAG repeats up to 38-62 leads to spin-bulbar muscle atrophy, Kennedy type. The test result makes it possible to assess the activity of spermatogenesis and, if necessary, take appropriate measures to compensate for the pathology.
Male infertility with cystic fibrosis
Cystic fibrosis (synonymous with cystic fibrosis) (CF) is one of the most common autosomal recessive hereditary diseases in humans. It is characterized by dysfunction of the epithelium of the respiratory tract, intestines, pancreas, sweat and sex glands. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which encodes an ATP-binding protein that forms a channel for chlorine ions in the cell walls. Mutations lead to a disruption in the transport of electrolytes and chlorine ions across the membranes of epithelial cells, which is accompanied by increased secretion of thick mucus and blockage of the excretory ducts of various glands. In 98% of men with cystic fibrosis, reproductive function is impaired, as there is azoospermia or severe oligozoospermia (less than 5 million sperm in 1 ml of semen) [7, p. 226-239].
The membrane protein encoded by the CFTR gene functions as an ion channel while simultaneously influencing the formation of the ejaculatory ducts, seminal vesicles, vas deferens, and distal 2/3 of the epididymis. Due to the mutation, the transfer of chlorine through the channels to the cells that produce mucous secretions is disrupted. This is the reason for the dehydration of the secretion, it becomes thicker and more viscous.
In men with cystic fibrosis, the vas deferens are most often absent or blocked by a plug of thick mucus. Moreover, the disease does not interfere with the production of sex hormones and the function
of the gonads. Sexual development is normal, although it can be slowed down by pulmonary disease and poor digestion.
A mutation in the CFTR gene is associated with congenital bilateral absence of the vas deferens (CBAD). In some men, it is the congenital absence of both vas deferens that is the only symptom of the disease, or there are moderate clinical manifestations of cystic fibrosis (for example, a history of frequent infections with lung damage). Because the vas deferens in most men with CF is absent or not functional, sperm cannot pass through them. As a result, although the testes produce these cells, the sperm does not contain them. New technologies of in vitro fertilization (IVF / ICSI) allow many men with CF to have children, and in some sick men the ducts are still present and not blocked [8, p. 47-58].
The absence of the vas deferens is often undetectable, so all patients with azoospermia should be examined very carefully to rule out CBAD. Patients diagnosed with CBAD need to undergo CFTR gene analysis. Mutations can be found in both copies of the CFTR gene, however, in most men with CBAD, the mutation is found in only one allele. In such presumably heterozygous cases of carriage, an unknown or rare 2nd mutation may be present.
If a CFTR gene mutation is detected in a man during family planning, it is important to conduct molecular genetic testing of the partner. According to statistics, in the European population, on average, every 25th person is a carrier of CFTR gene mutations. If a woman and a man are carriers of the CFTR gene mutation, the probability of having a child with cystic fibrosis will be 25%.
If one of the future parents is sick with cystic fibrosis, and the other is a carrier, then the probability
of having a child with cystic fibrosis will be 50%. In the remaining 50% of cases, he will be a clinically healthy carrier of the disease. If one parent has cystic fibrosis and the other is neither sick nor carrier, then all children will be clinically healthy carriers of the disease. However, in the future, they and their partners may need genetic counseling to predict the birth of sick children in the next generation. If both parents are diagnosed with cystic fibrosis, then the child will inevitably be sick. In all cases of mutation carriage, medical genetic counseling is recommended for family planning [9, p. 324-332].
Conclusion
Successful treatment of infertility by methods of assisted reproductive technologies has led to the emergence of a new problem - obtaining healthy offspring. A necessary stage in the treatment of infertility should be medical and genetic counseling, on the basis of which the doctor receives information about the need for genetic research of a married couple.
Thus, the analysis of literature data indicates that in our time the diagnosis of male infertility is at a high level and there are many modern, hightech ways of diagnosis and therapy. We can say with confidence that genetic analysis can identify up to 95% of all possible patients. The totality of the results that can be obtained during genetic testing for the presence ofAZF deletions in a man, determination of the number of CAG repeats of the AR gene and mutations in the CFTR gene makes it possible to identify problems in the male line when planning pregnancy, make a decision on the tactics of patient management and, if necessary, choose the optimal scheme of assisted reproductive technologies (ART) [6, p. 122-123].
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