Infertility existed for thousands of years ago, and will meet in the future. On the genetic reasons for infertility, the possibilities of their diagnosis and treatment, a leading researcher of the laboratory of genetics of violations of reproduction of the FGBNU "Medical and Genetic Science Center", Doctor of Medical Sciences Vyacheslav Borisovich Blacks.
Vyacheslav Borisovich, what are the main causes of violation reproductive function?
- There are a lot of reasons and factors of violations of reproductive function. These can be genetically determined disorders (various chromosomal and gene mutations), negative media factors, as well as their combination - multifactorial (multifactorial) pathology. Many cases of infertility and non-navigation of pregnancy are due to a combination of various genetic and non-mental (medium) factors. But the majority heavy Forms Violations reproductive system associated with genetic factors.
With the development of civilization and the deterioration of ecology, the reproductive human health is worsening. In addition to genetic reasons for fertility (the ability to have their own offspring), many different non-mental factors can affect: transferred infections, tumors, injuries, operations, irradiation, intoxication, hormonal and autoimmune disorders, smoking, alcohol, drugs, stress and mental disorders, improper lifestyle , professional harm and others.
Various infections, primarily transmitted by sexually, are able to lead to a decrease in fertility or infertility, malformations of the fetus and / or non-obscure pregnancy. Complications from infection (for example, orchitis and orchoepididimitis with boys are pairing), as well as drug treatment with drugs (antibiotics, chemotherapy) in a child, and even in the fetus during its intrauterine development (when taking medicines by the mother during pregnancy), can lead To the disruption of gametogenesis and being the cause of the problems of reproduction with which he will face, already becoming an adult.
Over the past decades, the quality of seminal fluid in men has significantly changed, so the standards of its analysis have been revised several times - spermograms. If in the middle of the last century, a concentration of 100-60-40 million sperm in one millilitress was considered the norm, at the end of the twentieth century - 20 million, now the lower limit of the norm "descended" to 15 million in 1 millilitress, with a volume of at least 1.5 ml and total At least 39 million was also subject to the reference indicators and morphology of spermatozoa. Now they make up at least 32% of progressively moving and at least 4% of normal spermatozoa.
But, be that as it may, the infertility existed thousands and millions of years ago, and will meet in the future. And it is registered not only in the world of people, but also from different living beings, including infertility or non-pending pregnancy, can be associated with genetic disorders blocking or decreasing childbearing ability.
What is this violation?
There is a large number genetic violations Reproductions that can affect the different level of hereditary apparatus - genome (chromosomal, gene and epigenetic). They can negatively influence various stages development or function of the reproductive system, the stages of the reproductive process.
Some genetic disorders are associated with the anomalies of the formation of sex and vices of the development of genital organs. For example, when the girl has no intrauterine system or do not develop any reproductive system organs, it can be born with underdevelopment or even with the absence of ovaries or uterine and uterine pipes. The boy may have vices associated with the abnormalities of men's genital organs, for example, underdevelopment of one or both testicles, appendages or seed-winning ducts, cryptorchism, hypospadia. In particularly severe cases, there are infringement of sex formation, up to the fact that at the birth of a child, it is even impossible to determine its floor. In general, the malformations of the sexual system are in third place among all congenital anomalies - after the malformations of the cardiovascular and nervous system.
Another group of genetic disorders does not affect the formation of genital organs, but leads to a delay in puberty and / or to a disorder of gamenenesis (geometry formation process), hormonal regulation of the functioning of the hypothalamic-pituitary-gonodnaya axis. This is often observed in the lesion of the brain, with a violation of the function of the genital glands (hypogonadism) or other organs endocrine systemand can lead ultimately to infertility. Chromosomal and gene mutations may affect only gametogenesis - fully or partially disrupt the products of sufficient amounts and quality of genital cells, their ability to participate in the fertilization and development of a normal embryo / fetus.
Genetic disorders are often the cause or factors of non-obscure pregnancy. In general, most of the losses of pregnancy occur due to the newly arising chromosomal mutations, which are formed during the division of immature sex cells. The fact is that "heavy" chromosomal mutations (for example, tetraploidide, triploidy, monosomy and most trisomy on autosomas) are incompatible with the continuation of the development of the embryo and the fetus, so in such situations most of the exclisions do not end in childbirth.
How many married couple is faced with such a problem?
In general, the problem of infertility is facing 15-18% of married couples, and each seventh (about 15%) from clinically fixed pregnancies ends with unbearable. Most pregnancies spontaneously interrupts on the most early timing. Often it happens so early that the woman did not even know that she had a pregnancy - this is so-called preclinical losses (uncomposed pregnancy). About two thirds of all pregnancies are lost in the first trimester - on the period of up to 12 weeks. For this there are biological grounds: the number chromosomal mutations In abortigative material is about 50-60%, the most high with the anambria. In the first days, this percentage is even higher - reaches 70%, and mosaicism on a chromosome set is occurred in 30-50% of embryos. With this, not very connected high efficiency (approximately 30-40%) of pregnancy in the ECO / ICSIBS programs of pre-impalating genetic diagnostics (PGD).
Who is more often a carrier of the "flawed" gene - a man or a woman? And how to understand how genetically "compatible" spouses?
- "Male" and "female" infertility factors are encountered about the same frequency. At the same time, a third of fruitless marital couples have disorders of the reproductive system from both spouses. All of them, of course, are very different. Some genetic disorders are more common in women, others - more often or mainly in men. There are also pairs with severe or severe violations of the reproductive system of one of the partners, as well as a decrease in fertility from both spouses, while they reduce the ability to conceive and / or increased the risk of pregnancy. When changing partners (when meeting a partner with normal or high reproductive potential) may come pregnancy. Accordingly, all this gives rise to impact fiction about the "incompatibility of spouses". But as such genetic incompatibility, there are no married couples. In nature, there are barriers of interspecific crossing - different types have a different set of chromosomes. But all people belong to the same type - H.omo Sapiens..
How then can a couple make sure that it is not blunt and, most importantly, can have a healthy offspring?
It is impossible to say in advance to say for sure, will or will not be for this married couple. This requires a comprehensive examination. Yes, and then guarantee the success of the occurrence of pregnancy. This is due to the fact that the ability of fertility (to have viable offspring) is a very complex phenotypic sign.
It is assumed that the reproductive system of a person, its ability to have children affects at least every 10th gene - only about 2-3 thousand genes. In addition to mutations in the human genome, there is a large amount (millions) of DNA variants (polymorphisms), the combination of which is the basis of the genetic predisposition to one or another disease. The combination of various genetic options affecting the ability to have offspring is just huge. Many genetic causes of infertility do not have clinical manifestations from the reproductive system. Many genetically determined violations of the reproductive system clinically look the same when of various reasonsah, including at various chromosomal and gene mutations, many so-called uninforcement disorders do not have a specific clinical picture, which would be assumed to be a specific genetic effect. All this greatly complicates the search for genetic disorders and the diagnosis of hereditary diseases. Unfortunately, there is a huge abyss between the knowledge of human genetics and their practical use in medicine. In addition, in Russia a significant shortage of genetic doctors, cytogenetics and other specialists skilled in medical genetics.
However, with many hereditary diseases and impaired reproductions, including related to genetic factors, there is an opportunity to have healthy children. But, of course, it is necessary to plan so planning and prevention to minimize the risks of hereditary diseases and the defects of the development of offspring.
Ideally, any married couple before planning pregnancy should be a comprehensive, including medical and genetic examination and counseling. Geneticist will study history, pedigree and, if there is a need for specific tests to identify genetic diseases / violations or their carriages. A clinical examination is carried out, cytogenetic research, chromosome analysis. If necessary, they are complemented by a more detailed molecular genetic or molecular-cytogenetic study, that is, the study of the genome to some particular gene mutations or microstructure restructuring chromosomes. In this case, genetic diagnostics is a search confirming, but cannot completely eliminate the presence of a genetic factor. It can be aimed at finding mutations, and if found it, then it is a big luck. But if mutations did not find, this does not mean that they are not.
If the diagnosis of genetic violations is so complicated, then what to talk about treatment?
- Genetic changes themselves, indeed, cannot be corrected. At least today, gene therapy is designed only for not big number hereditary diseasesAnd these diseases are mainly not associated with the reproductive system. But this does not mean that affecting the reproduction genetic diseases Do not treat. The fact is that treatment can be different. If we talk about eliminating the causes of the disease, so far it is indeed impossible. But there is another level of treatment - the struggle with the mechanisms of development of the disease. For example, in diseases associated with violation of products of gonadotropic or sex hormones, the replacement or stimulating treatment of hormones therapy is effective. But with a receptor defect to hormone (for example, male - androgenam) treatment may be inefficient.
Many childbearing problems can be successfully solved with the help of auxiliary reproductive technologies (HRD), among which the methods of Eco-extracorporeal fertilization occupy a special place. Eco gives a chance to have his own offspring with many married couples with severe forms of infertility and the usual unbearable, including those caused by genetic reasons.
Using the methods of auxiliary reproduction, it became possible to overcome infertility, even with such severe fertility disorders in men, like azoospermia, oligozoospermia and astheno- / teratozoocompermia of severe, with obstruction or absence of uterine pipes, severe disorders of the ripening of eggs in women. In the absence or defectivity of own weights (mature genital cells), it is possible to conceive and give birth to a child when using donor sex cells, and if it is impossible to carry out - resorted in the surrogate motherhood program.
Additional methods of selection of genital cells make it possible to use higher-quality men's genital cells for fertilization. And the pre-imposing genetic diagnosis (PGD) of embryos, which is aimed at identifying chromosomal and gene mutations, helps to give birth to genetically healthy offspring, not having those mutations that have carried their parents.
Auxiliary reproductive technologies can help couples with an increased risk of unbearable, or the birth of a child with unbalanced karyotype and heavy defects. In such cases, the ECO procedure with pre-imposing genetic diagnostics is carried out at which embryos with a normal set of chromosomes that do not have mutations are selected. New methods of auxiliary reproduction appear. For example, for women with bad quality Oocytes (female genital cells during their growth in the ovary) uses the technology of reconstruction of the oocyte, which uses donor cells from which the kernels are removed. The cores of recipients are inserted into these cells, after which they are fertilized by sperm spermatozoa.
Are there any "minuses" at auxiliary reproductive technologies?
- Yes, it can negatively affect the demographic picture in the future. Among the pairs that have problems with childbearing and go to Eco, the frequency of genetic changes is raised, especially related to the violation of the reproductive system. Including, such that are not diagnosed and can be transmitted to future generations. And this means that future generations will increasingly carry the cargo of gene mutations and polymorphisms associated with infertility and non-obscure pregnancy. To reduce the likelihood of this, a widespread medical and genetic examination and consulting of marital couples with childbearing problems, including before conducting Eco, as well as the development and widespread use of prenatal (preplantation and prenatal) diagnostics.
What can be more a pleasant eventWhat is a happy marriage? Logically, the majority comes to answer. It is only best to become happy parents. Most often, every married couple is sooner or later thinking about such an important step as the birth of a child. However, to great unfortunately, not everyone turns out to be made conceived from the first attempt, and in 15% of the pairs, such efforts are doomed to failure. What could cause such a situation?
Faced with a similar problem, do not panic. If the desire to start a child has not been implemented within 2-7 months - it is not scary. Need to calm down and do not bike on it. The reasons for not the occurrence of pregnancy many: from simple psychological factor Before developing serious problems.
These issues include:
infertility of men;
infertility of women;
immunological incompatibility (Allergy in a woman on the components of men's sperm) - At the same time, none of the spouses suffers from pathologies capable of provoking infertility, but the general children cannot appear at such a pair;
psychological aspects.
However, if a completely healthy woman has a regular sexual contact without the use of contraceptive means during the year, pregnancy does not occur, then it's time to think about what the case can be in a man. About such a situation is worth talking more - what is it? How to diagnose? How to treat?
Male infertility - despite regular sex contacts - this is the inability of spermatozoa men to fertilize the female egg. Ideally, in a spermogram of a healthy man in 1 ml of sperm should be contained about 20 million spermatozoa, which are rapidly moving forward and are capable of fertilization. Also about 50% of spermatozoa must have the right structure.
Causes
Reasons that can provoke infertility in men may be:
complication after steaming;
inflammation of the organs of the urinary sector;
diabetes mellitus (violations of ejaculation);
small quantity and sluggish activity of sperm in sperm (also not excluded and the complete absence of "headastrics");
psychological infertility (when a man at the subconscious level is subject to fear before the future responsibility, which will arise with the birth of a baby or with other obsessive concerns and arguments);
immunological infertility (the formation of antibodies that interfere with spermatozoa normally perform functions on them).
Well, the simplest and most common reason that comes to the mind last is the presence of bad habits. Smoking, alcohol abuse also addicted to the man's body as a whole and on the reproductive function in particular.
Diagnostics
Male infertility is divided into:
primary - in which a man could not fertilize any representative of the opposite sex;
secondary - when, at least one woman got pregnant from a particular man.
To identify this pathology in a man and determine the cause of this condition will be helped by an urologist-andrologist and an endocrinologist-andrologist. The start of research is to pass the analysis of sperm. A similar analysis is called spermogram. It determines the activity and viability of spermatozoa, in addition, an assessment of other pathological changes is made.
Also doctors can advise other studies to determine accurate reason or pathology:
Prostate ultrasound;
hormone analysis;
diagnosis of immune infertility - mar-test;
bacteriological sowing on the identification of infectious pathologies of the urogenital sphere.
Depending on the results of the analyzes, the specialist will prescribe treatment. Therapy is divided into three methods that will be disassembled below.
Treatment methods
Conservative therapy
Is to use medicinal preparations In the presence of genital infections various origin. Also, a similar type of treatment is also prescribed in the presence of infertility against the background of hormonal failure.
Surgery
Assigns in the presence of anomalies ureyeing Canal, in the presence of inguinal gryzh and other anatomical deviations that cannot be corrected without surgery.
Alternative therapy
This method is resorted to the presence of serious disorders of the reproductive function in a strong floor. It lies in the artificial introduction of spermatozoa in the genital path of the woman to achieve fertilization.
The treatment of infertility should be complex and adequate. In addition, presented strong sexes (not only in diagnosis, but also when planning pregnancy) should revise their own rhythm of life and resolve it if necessary. It is worth abandoning bad habits, start well eat and not forget about a full-fledged vacation. The solution of intimacy problems in men can be achieved by using phytopreparations for the treatment and prevention of pathologies of the men's sexual system. Quite often after the normalization of your own power and recreation and rest simple rules Reproductive function is normalized without additional interventions.
Most of the famous mutations lead to the absence or delay of puberty and, as a result, to infertility. However, people who have sexual development are normally addressed to the doctor about infertility. The survey on the majority of mutations leading to infertility, the practical meaning now does not have. However, some cases deserve special mention because they are often found in everyday practice.
Bilateral seed applaus
Bilateral Aplasia of seed-winning ducts is available in 1-2% fruitless men. According to most data, in 75% of cases, the mutations are detected by the CF gene, leading to the fibrosis. The main risk in such cases is the possibility of the birth of a child with cystic fibrosis. It is necessary to examine the presence of mutations of both partners, after which it is necessary to conduct appropriate counseling. If both partners are carriers of the fibrosis, its risk in a child reaches 25% (depending on the nature of the mutation). Even if the man found only one mutation, leading to the fibrosis, and a woman is not a carrier, it is better to be restrained and send a couple for consultation to genetics. Approximately 20% of cases, a bilateral aplasia of the seed-handed ducts is accompanied by the deposit of the kidney development, and in one study, such patients did not identify mutations leading to the fibrosis (although the number of analyzed mutations was small).
It should be emphasized that the purpose of the mass examination is to identify the fibrosis, and not aplasia. The combination of mutations leading to aplasia of the seed-handing ducts is diverse and complex, which makes it difficult to counseling with the disease. In the first studies dedicated to the genetics of the bilateral aplasia of seed-handed ducts, there was not a single participant, homozygous by AF508 mutation, the most frequent from mutations in the CF gene, which, in the classical form of fibrosis, occurs in 60-70% of cases. Approximately 20% of patients are at once two mutations in the CF gene are characteristic of cystic fibrosis - in many cases it is a mismotation (a combination of two alleles causing light shape Mukobovidoza, or one allele, causing a light shape of the disease, and one is heavy). Also, polymorphism was found in the intron 8, in which the number of thimins in different alleles is 5, 7 or 9. If there is an allele 5t, the exon 9t is passed during transcription, and the mRNA, and in the future, the protein is shortened. The most common genotype with a bilateral aplasia of seed-handing ducts (about 30% of cases) is a combination of an allele that carrying a mutation that causes fibrosis, and allele 5t.
The R117H mutation is included in the mass examination, since its combination with other, heavier mutations in the CF gene may cause fibrosis. When the R117H mutation is detected, a derivative test for the presence of polymorphism 5t / 7t / 9t is carried out. When the allele 5t is detected, it is necessary to install whether it is on the same chromosome with R117H (i.e. in the cis-position) or another (in the trans position). Allel 5T in the "C-position relative to R117N causes fibrose, and if the woman is also a carrier of one of the alleles causing the disease, the risk of fibrosis in the child is 25%. The complexity of the genetics of the fibrosis becomes obvious, if you look at the diversity of phenotypes in homozygoths by allele 5t. The presence of allele 5t reduces the stability of mRNA, and it is known that in patients who have the level of unchanged MRNA is 1-3% of the norm, fibrosis develops in classical form. In the level of unchanged mRNA, which makes up more than 8-12% of the norm, the disease does not appear, and at intermediate levels different options are possible, from the complete absence of the manifestation of the disease to a bilateral aplasia of the seven-way ducts and the light form of fibrosis. It should also be noted that the aplasia of seed-handing ducts in light cases is also one-sided. Among the population as a whole, Allel 5T occurs with a frequency of about 5%, with a one-sided aplasia of seed-handing ducts - with a frequency of 25%, and with a bilateral aplasia - with a frequency of 40%.
The American College of Medical Genetics and the American College of Obstetricians and Gynecologists recommend to identify only 25 mutations, the prevalence of which among the US population is at least 0.1%, and the analysis of Polymorphism 5T / 7T / 9T is carried out only as a derivative test. However, in practice, many laboratories can reduce costs, including this analysis to the basic program, which, as shown above, can lead to colossal difficulties in interpretation of the results. It should be remembered that the purpose of the mass examination is to identify the fibrosis.
Genes regulating spermatogenesis
The genes that are presumably responsible for spermatogenesis are mapped on the Y-XPoosmos in the AZF area located in the Locus YQ11 (SR gene is located on the short shoulder Y-chromosome). In the direction of the centromer to the distal shoulder, sequentially sequentially, Azfa, AZFB and AZFC sections are located. The AZFA section contains USP9Y and DBY genes, on the AZFB section, the RBMY gene complex, and in the area / 4Z / C - the DAZ gene.
A part of the genes involved in the regulation of spermatogenesis is presented in the genome several copies. Apparently, in the genome there are 4-6 copies of the DAZ gene and 20-50 genes or pseudogenes of the RBMY family. DBY and USP9Y are presented in a single copy genome. Due to the large number of repeated sequences and differences in the design of research, the analysis of the areas of Y-chromosomes controlling spermatogenesis is conjugate with considerable difficulties. For example, detection of deletions in the field of AZF was carried out mostly by analyzing DNA labeling sites, short DNA sequences with known chromosomal localization. The more they are analyzed, the higher the probability to detect deletions. In general, a deletion in the field of AZF is found in fruitless men, but there are cases of their discovery and in healthy.
Proof of the fact that the AZF region contains genes regulating spermatogenesis, served as an intragenic deletion in the USP9Y gene, which is also called DFFRY (since the appropriate FAF genome in Drosophila is homologous). A fruitless man was discovered to deleting four pairs of grounds, which was not from his healthy brother. These observations are associated with in vitro analysis data made it possible to assume that the mutation in the USP9Y gene disrupts spermatogenesis. With a re-analyzing of previously published data, the researchers revealed another single deletion in the USP9Y gene, disturbing spermatogenesis.
An overview of the survey data of nearly 5,000 fruitless men on mutations in the Y-chromosome showed that in about 8.2% of cases (compared with 0.4% in healthy) there are deletions in one or several sections of the AZF region. In some studies, the indicators ranged from 1 to 35%. According to the reference, most often there are deletions in the AZFC site (60%), then in AZFB (16%) and AZFA (5%). The remaining cases are a combination of deletions in several sites (most often including deletions in AZFC). Most mutations were found in men with azoospermia (84%) or severe oligozoospermia (14%), defined as spermatozoa content of less than 5 million / ml. Interpretation of data on delegation in the field of AZF is extremely complex, since:
- they are found in both fruitless and healthy men;
- the presence of DAZ and RBMY clusters containing several copies of genes makes it difficult;
- in different studies, various sperm parameters were studied;
- the set of continigory cards Y-chromosomes due to the presence of repeated sequences was not complete;
- it was not enough data on healthy men.
In a double-blind study, 138 men from couples who applied to a doctor for ECO, 100 healthy men and 107 young Danish servicemen were identified levels of sex hormones, sperm parameters and an analysis of the AZF region was carried out. 21 DNA labeling site was used to study the AZF region; With normal sperm parameters and in all cases where the number of spermatozoids exceeded 1 million / ml, the deletions were found. In 17% of cases of idiopathic azoospermia or cryptozoospermia and in 7% of cases, with other types of azoospermia and cryptozoospermia, deletions were identified in the AZFC site. It is interesting to note that neither one of the research participants has not been deleted in the AZFA and AZFB sites. It makes it assume that the genes located in the AZFC site are most important for spermatogenesis. Later a larger study was conducted, which gave similar results.
When detecting deletions in the Y-chromosome, it should be discussed with both future parents. The main risk for the offspring is that sons may inherit this deletion from the Father and will be fruitless - such cases are described. On the effectiveness of the ECO and the frequency of pregnancy, these deletions seem to do not affect.
Lickening X-chromosome syndrome in women with premature ovarian failure
In sporadic cases of premature deficiency of ovaries, about 2-3% of women detect the presence of premutation in the FMR1 gene, which is responsible for the occurrence of the cross-chromosome syndrome; In women with hereditary premature ovarian failure, the frequency of this promotion reaches 12-15%. The fragile plot in the XQ28 locus can be revealed during karyotyping of cells grown under the conditions of folic acid deficiency, but DNA analysis is usually carried out. Syndrome is broken X-chromosome refers to diseases that are caused by an increase in the number of trinucleotide repetitions: Normally, the FMR1 gene contains less than 50 repetitions of the CHG sequence, their number is 50-200, and in men with a short-chromosome syndrome (more than 200 Full mutation). The syndrome of the brittle X-chromosome is characterized by a X-clutch dominant type of inheritance with incomplete penetrance.
It is important to identify carriers of promotion, since they may have other family members: they may have the birth of sons with a brittle X-chromosome syndrome, which manifests itself by mental retardation, characteristic features of the face and macroorphism.
Secondary hypogonadism and squid syndrome in men
For men with squid syndrome, anosmia and secondary hypogonadism are characterized; Defects of the middle line are also possible, one-sided kidney anesthesia and neurological disorders - synctaneses, glazic and cerebellar disorders. Salchean syndrome is characterized by a X-lucked recessive type of inheritance and caused by mutations in the Kali gene; It is assumed that the squid syndrome caused 10-15% of cases of the isolated shortage of gonadotropic hormones in men with an alimony. The outosomalic shape of the squid syndrome, which causes mutations in the FGFR1 gene is found. With an isolated shortage of gonadotropic hormones without anosmia, the mutations in the GNRHR gene (Gonadoliberin receptor gene) are most often found. However, they account for only 5-10% of all cases.
Violation of reproductive functionetopheat with a married couple to conception with regular sexual intercourse without protection for 1 year. In 75-80% of cases, pregnancy occurs during the first 3 months of regular sex life of young, healthy spouses, that is, when the age of her husband is up to 30, and wives up to 25 years old. In an older age group (30-35 years), this term increases to 1 year, and after 35 years - more than 1 year. Approximately 35-40% of fruitless steam causes him a man, 15-20% there is a mixed factor of violation of the reproductive function.
Causes of violation of reproductive functions in men
Parenchimato (secretory) violation of reproductive function: spermatogenesis (spermatozoa products in convicted seminal tubes), which is manifested in the form of aspermia (lack of cerematogenesis cells and spermatozoa cells), azoospermia (lack of spermatogenesis ejaculate when detecting sperm cells), oligozoospermia, reduction Mobility, disruption of the structure of spermatozoa.
Violations egg function:
cryptorchism, monorchism and egg hypoplasia;
orchit (viral etiology);
twisted the testicles;
primary and secondary congenital hypogonadism;
increased temperature - violation of thermoregulation in the scrotum (varicocele, hydrocele, tight clothing);
syndrome "only-cell-sulfur";
diabetes;
excessive physical stress, psychological stresses, severe chronic diseases, vibration, body overheating (work in hot shops, sauna, fever abuse), hypoxia, hypodynamia;
endogenous and exogenous toxic substances (nicotine, alcohol, drugs, chemotherapy, virtuality);
radiation therapy;
Mutation of a muscovisosis gene (congenital absence of seed-handed ducts: obstructive azoospermia is determined by a polymerase chain reaction; microdelization Y chromosome (violation of spermatogenesis of various degrees of the severity of karyotype disorders - structural chromosomal abberats - kleinfelter Syndrome, Hyy syndrome, chromosomal translocations, autosomal aneuplody) - method of fluorescent hybridization (Fish) using lagging probes to different chromosomes.
Causes of violation of reproductive function in women
Inflammatory processes and their consequences ( safety process in the small pelvis and obstruction of the uterine pipes - the "tube-peritoneal factor);
endometriosis;
tumors of uterus (misa).
ovarian tumors (cystoms).
Less often meet hormonal and genetic disorders. It should be noted that due to the achievements of genetics it became possible to diagnose a number of reasons for the violation of the male reproductive function unknown earlier. In particular, this is the definition of AZF - factor - Lokus in the long shoulder y chromosome responsible for spermatogenesis. When it falls out in the spermogram, coarse disorders are detected up to azoospermia.
In some cases, even with the most detailed examination, it is not possible to establish the cause of infertility.
In this case, we can talk about idiopathic decrease in fertility. Idiopathic decline in fertility in share male infertion On average, it takes 25-30% (according to various sources from 1 to 40%). Obviously, such a large discrepancy in the assessment of etiology is caused by the lack of uniformity in the survey and the difference in the interpretation of the obtained clinical and anamnestic data, which is also a confirmation of complexity and insufficient study of the problem of male infertility.
Treatment of infertility
Today reproductive medicine It has a solid luggage knowledge on the treatment of infertility of all kinds and forms. The main procedure for more than three decades is extracorporeal fertilization (ECO). The ECO procedure is well worked out by the doctors of the whole world. It consists of several stages: the stimulation of ovulation in a woman, the control of ripening of follicles, the subsequent fence of egg and sperm, fertilization in laboratory conditions, monitoring the growth of embryos, transfer the highest quality embryos in the uterus in the amount of no more than 3.
Stages of treatment are standard, but the characteristics of the body and the testimony to Eco require an individual approach, both in the appointment of special medicines and in establishing the timing of each stage of treatment.
New methods offer almost all clinics of reproductive medicine, their effectiveness in treatment is proved by tens and hundreds of thousands of children who appeared on the light of children. Nevertheless, the efficiency of using only one ECO is no more than 40%. Therefore, the main task of reproductologists of the whole world is to increase the number of successful cycles of artificial fertilization. So, B. recent timesIn the clinics of reproductive medicine, a subset of five-day embryos (blastocyst) is practiced instead of more "young", three days. The blastocyst is optimal for transfer, since this period is easier to determine the prospect of such an embryo to further development in the mother's body.
The other methods of auxiliary reproductive technologies are helped to improve the statistics of successful fertilization, which can be different in different reproductive medicine clinics.
The common method for the treatment of infertility is Ixi (ICSI), which means the immediate administration of the sperm in the egg. Usually, Ixi is shown in men's interference of a secretory type, and quite often combined with Eco. However, ICSI, which suggests an increase in 200-400 makes it possible to estimate the state of spermatozoa only superficially, with particularly severe sperm pathologies, this is not enough. Therefore, in 1999, scientists have proposed a more innovative IMSI (IMSI) method. It implies an increase of 6600 times and allows you to estimate the smallest deviations in the structure of men's genital cells.
To assess the risks of genetic anomalies, the embryo uses such methods as pre-imposing genetic diagnostics (PGD) and comparative genomic hybridization (CGH). Both methods involve the study of the embryo for pathological changes in the embryo genome, even before transferring it to a woman's uterus. These methods not only increase the efficiency of extracorporeal fertilization and are shown in genetic violations in the genotype of the pair, but also reduce the risk of self-charges and the birth of children with genetic deviations.
general information
The reproductive process or reproduction of a person is carried out by a multi-centered system of reproductive organs, which provide the ability of weights to fertilization, conception, preimplantation and implantation of zygotes, intrauterine development of the embryo, embryo and fetus, the childbearing function of a woman, as well as the preparation of the newborn body to meet new conditions in the environment external environment.
Ontogenesis of reproductive organs is an integral part of the general development program of the body, aimed at ensuring optimal conditions for the reproduction of offspring, starting with the formation of the gonad and they produced by them, their fertilization and ending with the birth of a healthy child.
Currently, a general gene network is identified, responsible for ontogenesis and the formation of the reproductive system bodies. It includes: 1200 genes involved in the development of the uterus, 1200 prostate genes, 1200 testicular genes, 500 ovarian genes and 39 genes controlling the differentiation of embryonic cells. Among them are generated genes that determine the direction of differentiation of bipotential cells or by male, or on the female type.
All the reproductive process links are extremely sensitive to the negative impact of environmental factors leading to violations of reproductive function, male and female infertility, the emergence of genetic and non-mental diseases.
Ontogenesis of the reproductive system
Early Ontogenesis
Ontogenesis of reproductive organs begins with the appearance of primary sex cells or gorocytes that are already detected on
stages of a two-week embryo. Hungary is migrated from the region of the intestinal ectoderma through the yolochemteh of the yolk bag in the region of adventures of the gonad or sex rollers, where they are divided by mitosis, forming a pool of future germ cells (up to 32 embryogenesis). The chronology and dynamics of further differentiation of GOCIDS depend on the floor of the developing organism, while the ontogenesis of the gonad is conjugate with the ontogenesis of the urinary system organs and adrenal glands jointly forming the floor.
At the very beginning of ontogenesis in a three-week embryo in the field of nephrogenic heavy tape (derived intermediate mesoderma), the primary kidney channels are formed (bidding) or pererestros.For 3-4 weeks the development of Kaudalnaya Verefros tube (nephrotoma region) is formed primary kidney purposes or mesonephros.By the end of 4 weeks on the ventral side of the mesonefros, the primitives of gonads, developing from the mesothelium and constituting indifferent (bipotential) cellular education, and the pronenectic tubules (ducts) are connected to the mesonefrosite tubules, which are called wolf ducts.In turn, paramzenephral, \u200b\u200bor mullerovy Docaforms from sections of intermediate mesoderm, which are isolated under the influence of the Wolf of the Duch.
At the distal end of each of the two Wolf ducts in the zone of their entry into the clock, the growing rises in the form of risers of uretera are formed. At 6-8 weeks, they germinate in the intermediate mesoderm and form the tubules metanephros- This is a secondary or final (definitive) kidney formed by cells derived rear parts Wolf channels and nephrogenous tissue of the back of the mesonephros.
Now consider the ontogenesis of the human biological floor.
Forming a male floor
The formation of male begins at 5-6 weeks of the development of the embryo with transformations of Wolf ducts and is completed by the 5th month of development of the fetus.
At 6-8 weeks of the embryo from the derivatives of the rear parts of the Wolf channels and the nephrogogenic tissue of the back of the mesonefros, the mesenchym forming sexual litter (cord), which is divided, connecting with the tubes of the primary kidney, flowing into its duct, and gives
the beginning of the seed tubes of the seeds. From the Wolf ducts are formed output paths. The middle part of the Wolf ducts is lengthened and converted to the delivering ducts, and seminal bubbles are formed from the bottom. The upper part of the primary kidney duct becomes an appendage of the seed (epididium), and the lower part of the duct turns into an endowed channel. After that, the ductures are reduced (atrophy), and only the upper ends (Morgana Gedatid) and the lower ends are left from them (Magnaya Gydatid). The latter is in the thickness of the prostate gland (prostate) at the location of the seven-way duct into the urethra. Prostate, seeds and coopers (bulburetral) glands are developing from the epithelium of the walls of the urinary sinus (urethra) under the influence of testosterone, the level of which in the blood of 3-5 months of the fetus reaches such in the blood of a semi-creation man, which ensures the masculinization of the genitals.
Under the control of testosterone from the Wolf Ducts and the Upper Mesonefrost Channels, the structures of internal male genital organs develop, and when exposed to dihydrotestosterone (testosterone derivative), outdoor men's genitals are formed. Muscular and connecting elements of prostate develop from mesenchym, and probas of prostate are formed after birth in the pubertal period. Sectional member is formed from the meeting of the head of a member in a penny tubercle. At the same time, sex folds grow together and form skin part The scrotum, in which the dusting of the peritoneum is rotated through the groin canal, in which the testicles are then shifted. The displacement of the testicles in the pelvis area to the place of future inguinal channels begins at the 12-week embryo. It depends on the action of androgens and the chorionic hormone and occurs due to the displacement of the anatomical structures. The testicles pass through the inguinal channels and reach the scrotum only at 7-8 months of development. In the event of a delay in the lowering of the testicles into the scrotum (due to different reasons, including genetic), two-way cryptorchism develops.
Formation of female
Female formation occurs with the participation of mulcher ducts, of which the primitives of domestic female genital organs are formed on 4-5 weeks: the uterus, foolopiev pipes,
upper two thirds of the vagina. The sewage of the vagina, the formation of the cavity, body and cervix takes place only in a 4-5-month fetus by developing a mesenchym from the base of the body of the primary kidney, which contributes to the destruction of the free ends of the genital cords.
The brain part of the ovaries is formed from the balance of the body of the primary kidney, and the rotation of the genital cords in the cortic part of the future ovaries continues from the sex roller (concurrent epithelium). As a result of further germination, these tramples are divided into priority follicles, each of which consists of a gorolocyte surrounded by a layer of follicular epithelium, is a reserve for education during the ovulation of future mature oocytes (about 2 thousand). Enterprise germ continues after the birth of the girl (until the end of the first year of life), but new priority follicles are no longer formed.
At the end of the first year of the life, the mesenchym separates the beginning of the genital cords from the sex rollers, and this layer forms a connective tissue (protein) membrane of the ovary, on top of which the remains of the genital rollers are preserved in the form of an inactive adherent epithelium.
Floor differentiation levels and violations
Hands are closely connected with the features of ontogenesis and reproduction. 8 floor differentiation levels are distinguished:
Genetic floor (molecular and chromosomal), or gender at the level of genes and chromosomes;
Gament floor, or morphogenetic structure of male and women's weights;
Gonadal floor, or morphogenetic structure of seeds and ovaries;
Hormonal floor, or the balance of men's or female sex hormones in the body;
Somatic (morphological) floor, or anthropometric and morphological data on genital organs and secondary sexual signs;
Mental sex, or mental and sexually self-determination of the individual;
Social floor, or identifying the role of an individual in the family and society;
Civilian floor, or gender, recorded when issuing a passport. It is also called half education.
While the coincidence of all levels of the differentiation of the floor and the normalization of all links of the reproductive process, a person is developing with normal biological male or female floors, normal sexual and generative potencies, sexual self-consciousness, psychosexual orientation and behavior.
The scheme of the relationship between different levels of the floor differentiation in humans is shown in Fig. 56.
The beginning of the floor differentiation should be considered 5 weeks of embryogenesis, when a sexy tubercle is formed by expanding the mesenchym, which potentially represents either the gear of the head of the penis, or the gentle of the clitoris is depends on the formation of the future biological gender. From this time, the sex folds are converted to either in the scrotum or in sexual lips. In the second case, the primary sexual opening is opened between the gender tuberculk and sex folds. Any level of differentiation of the floor is closely related to the formation of both the normal reproductive function and its violations, accompanied by full or incomplete infertility.
Genetic floor
Gene level
The gene level of the floor differentiation is characterized by the expression of genes that determine the direction of sexual differentiation of bipotential cell formations (see above) or by male, or on the female type. We are talking about a whole gene network, including genes located both on gonomons and autosomas.
As of the end of 2001, the genes controlling the ontogenesis of the reproductive organs and the differentiation of germinal cells were attributed to 39 genes (Chernykh VB, Kurilo L.F., 2001). Apparently, now there are even more. Consider the most important of them.
There is no doubt that the central place in the network of genetic control of the partitioning of sex on male type belongs to the Sry gene. This single-source, non-intronical gene, is localized in the distal part of the Y-chromosome short shoulder (YP11.31-32). It produces the determination factor of testicles (TDF), discovered also in XX men and XY women.
Fig. 56.The scheme of the relationship between different levels of the floor differentiation in humans (according to black V.B. and Kurililo L.F., 2001). Genes involved in the differentiation of gonad and ontogenesis of genital organs: Sry, SOX9, DAX1, WT1, SF1, Gata4, DHH, DHT. Hormones and receptors to hormones: FSH (follicle-sustimulating hormone), LH (luteinizing hormone), AMN (hormone antimulamullers), AMHR (AMHR receptor gene), T, Ar (androgenic receptor gene), GNRH (Gonadotropin-Rilizing Hormon gene), GNRH-R (GNRH receptor gene), LH-R (LH receptor gene), FSH-R (FSH receptor gene). Signs: "-" and "+" denote the absence and availability of effect
Initially, the activation of the Sry gene occurs in the cells of the sertoli producing antimulamullers hormone, which affects the lesidig cell sensitive to it, which induces the development of seed tubules and the regression of muller ducts in the formative male body. This gene discovered a large number of point mutations associated with dizgensia gonad and / or inversion of gender.
In particular, the Sry gene can be deleted on the Y-chromosome, and in the conjugation of chromosomes in the protopase of the first meiotic division can be translocked on a X-chromosome or any autosoma, which also leads to the dysgenezia of gonad and / or gender inversion.
In the second case, the organism of the XY-Woman, having drag-like cutters, with female external genitalia and physiciation of the physique (see below) develops.
At the same time, the formation of the body of a XX-man, characterized by a male phenotype with a female karyotype, is the syndrome of De La Shapella (see below). The translocation of the Sry gene on X-chromosoma during Maizo in men is found with a frequency of 2% and is accompanied by severe spermatogenesis.
IN last years It was noted that a number of genes located outside the Sry locus zone (their several dozen) are involved in the process of sex differentiation on male type. For example, for normal spermatogenesis requires not only the presence of gonads differentiated by male type, but also expression genes controlling the development of germinal cells.These genes include the AZF AZF (YQ11) factor gene, whose micride cause spermatogenesis disorders; They have almost a normal amount of spermatozoa, and oligozoosperm. An important role belongs to genes located on the X-chromosome and autosomes.
In the case of localization on the X chromosome, this is a DAX1 gene. It is localized in XP21.2-21.3, in the so-called dose-sensitive floor inversion locus (DDS). It is believed that this gene is normally expressed in men and participates in controlling the development of their seeds and adrenal glands, which can lead to adrenogenital syndrome. (AGS). For example, it was found that the DDS-site duplication is associated with the inversion of the floor in XY-individuals, and its loss is accompanied by a male phenotype and the X-linked congenital lack of adrenal cortex. In total, three types of mutations are highlighted in the DAX1 gene: large deletions, single-deactive deletions and replacement of grounds. All of them lead to hypoplasies of the adrenal and hypoplasia of the testicles due to the disorders of the diff-
recitting steroidogenic cells during the ontogenesis of adrenal glands and gonad, which is manifested by AGS and hypogonadotropic hypogonadism due to the deficiency of glucocorticoid, mineralocorticoids and testosterone. In such patients, severe spermatogenesis disorders are observed (up to its full block) and the dysplasia of the cellular structure of the testicles. And although patients develop secondary sexual signs, but cryptorchism is often observed due to testosterone deficiency during the migration of the testicles in the scrotum.
Another example of the localization of the gene on the X chromosome is the SOX3 gene belonging to the Sox family and related to genes early Development (See chapter 12).
In the case of localization of genes on autosomes, it is, firstly, the SOX9 gene, the Sry generic gene and containing HMG boxing. The gene is localized on the long shoulder of chromosome 17 (17Q24-Q25). Its mutations cause campomelic dysplasia, manifested by multiple anomalies of the skeleton and internal organs. In addition, the Mutation of the SOX9 gene leads to XY-inversion of the floor (patients with a female phenotype and a male karyotype). In such patients, the external genital organs are developed on the female type or have a dual structure, and their dispensary gonads may contain single sex cells, but are more often represented by starbs structures (heavy).
The following genes are a group of genes regulating transcription in the course of differentiation of cells involved in the ontogenesis of the gonad. Among them are WT1, Lim1, SF1 and Gata4 genes. Moreover, the first 2 genes participate in primary, and the second two genes in the secondary determination of the floor.
Primary determination Gonad on the floorit starts from a 6-week age of the embryo, and the secondary differentiation is due to hormones, which are produced by the seeds and ovaries.
Consider some of these genes. In particular, the WT1 gene localized on the short shoulder of chromosome 11 (11p13) and associated with Wilms tumor. Its expression is found in intermediate mesoderm, differentiating mesenchym metanephros and gonads. The role of this gene as an activator, coactivator or even the transcription repressor required already at the stage of bipotential cells is shown (to the Sry gene activation stage).
It is assumed that the WT1 gene is responsible for the development of sexual tuberca and regulates the output of cells from a niculic epithelium, which gives the beginning of the cells of the sertoli.
It is also believed that the mutations of the WT1 gene can cause gender inversion with a shortage of regulatory factors involved in sexual differentiation. Often, such mutations are associated with syndromes characterized by an autosomal dominant type of inheritance, including WAGR syndrome, Denis Drash syndrome and Fresier Syndrome.
For example, WAGR syndrome is due to the deletion of the WT1 gene and is accompanied by a Wilms tumor, aniridia, congenital defects of development gOOD SYSTEM, mental retardation, dysgenesis gonad and predisposition to gonadoblastomas.
Denis-Drash syndrome is due to Misens-mutation in the WT1 gene and only sometimes combined with the Wilms tumor, but for him the early manifestation of severe nephropathy with loss of protein and sexual development disorders is almost always characteristic.
The FREEZ syndrome is due to a mutation in the donor site of the exon splicing 9 of the WT1 gene and manifests the gonad dysgenesis (women's phenotype with a male karyotype), late start of nephropathy and focal sclerosis of the kidney glomulus.
We also consider the SF1 gene localized on chromosome 9 and acting as an activator (receptor) of gene transcriptions involved in the biosynthesis of steroid hormones. The product of this gene activates testosterone synthesis in lesig cells and regulates the expression of enzymes controlling the biosynthesis of steroid hormones in adrenal glands. In addition, the SF1 gene regulates the expression of the DAX1 gene, which in the promoter found the SF1 site. It is assumed that during the morphogenesis of the ovaries, the DAX1 gene prevents the transcription of the SOX9 gene through the repression of the transcription of the SF1 gene. Finally, the CFTR gene known as the fibrosis gene inherited by autosomal-recessive type. This gene is localized on the long shoulder of chromosome 7 (7q31) and encodes the protein that is responsible for the transmembrane transfer of chlorine ions. Consideration of this gene is appropriate, since Men's carriers of a mutant allele, the CFTR gene often observed a bilateral absence of seed-winning ducts and anomalies of the appendages of eggs, leading to obstructive azoospermia.
Chromosomal level
As is known, the egg cell always carries one x-chromosome, while the spermatozoic carries either one x-chromosome or one y-chromosome (their ratio is about the same). If the egg fell
a spermatozoa with a x-chromosome is grouped, then the future body is formed by the female floor (karyotype: 46, XX; contains two identical gamors). If the egg cell is fertilized with a sperm with Y-chromosome, then a male floor is formed (karyotype: 46, xy; contains two different hammonds).
Thus, male formation is normal depends on the presence in a chromosomal set of one x and one y-chromosome. In the differentiation of the floor, the decisive role belongs to the Y-chromosome. If it is not, then the floor differentiation goes on the female type, regardless of the number of X-chromosomes. Currently, 92 genes are identified on the Y-chromosome. In addition to genes forming a male floor, on the long shoulder of this chromosome are localized:
GBY (Gonadoblastoma gene) or oncogen, initiating a tumor in dysgenetic gonads, developing in mosaic forms with a karyotype 45, X / 46, XY in individuals with a male and women's phenotype;
Gcy (growth control locus), which is proximal than the part YQ11; His loss or violation of sequences causes lowness;
SHOX (Pseudo-Outosomal Lock I) participating in growth control;
The cell of the cell membrane cell or H-Y antigen of histocompatibility, previously erroneously considered the main factor in the determination of the floor.
Now consider impaired genetic gender on the chromosomal level. This kind of violations are usually associated with the incorrect discrepancy of chromosomes in the mitosis anafase and the MEIOS PROFACE, as well as with chromosomal and genomic mutations, as a result of which, instead of the presence of two identical or two different gams and autosomas, can be:
Chromosomal numerical anomalies, in which one and more additional gamons or autosomas are revealed in the karyotype, the absence of one of the two gams or their mosaic options. Among the examples of such violations: CHINTFELTER SYNDROMES - POLISOMIY IN THE H-chromosome in men (47, XXY), polybitomy on y-chromosome in men (47, xyy), Triplo-X syndrome (polisomy in X-chromosome in women (47, xxx ), Sherosezhevsky -Terner syndrome (monosomy in X-chromosome in women, 45, x0), mosaic cases of Aneuploidy on gamomulas; marker
Or mini-chromosomes originating from one of the hammer (its derivatives), as well as trisomy syndromes on autosomas, including Down syndrome (47, XX, + 21), Patau syndrome (47, XY, + 13) and Edwards syndrome ( 47, XX, + 18)). The structural anomalies of chromosomes, in which the karyotype is detected as part of a single gamoron or autosomes, which is defined as micro and maternity chromosomes (loss of individual genes and entire sections, respectively). Microdemelutions include: deletion of the Long shoulder section of the Y-chromosome (Locus YQ11) and the associated loss of AZF locus or azoospermia factor, as well as deletion of the Sry gene, leading to spermatogenesis disorders, gonading differentiation and inversion XY inversion. In particular, the AZF locus has a number of genes and gene families responsible for certain stages of spermatogenesis and fertility in men. In Locus, three active subregion: a, b and s. Lock is present in all cells, except erythrocytes. However, the locus is active only in cells of the sertoli.
It is believed that the frequency of the AZF location mutations is 10 times higher than the frequency of mutations in autosomes. The cause of male infertility is the high risk of transferring to Sons Y-deletions affecting this locus. In recent years, the Locus study has become a mandatory rule in the vitro fertilization (ECO), as well as in men with a sperm indicator of less than 5 million / ml (azoospermia and severe oligospermia).
Macrows include: Syndrome De La Shapella (46, xx-male), Wolf Hirschorn syndrome (46, XX, 4P-), Cat Creek syndrome (46, XY, 5P-), partial monosomy syndrome 9 ( 46, XX, 9P-). For example, De La Shapella syndrome is hypogonadism with a male phenotype, a male psychosocial orientation and women's genotype. The clinic has similarities with the clanfelter syndrome, combined with the testicular hypoplasia, azoospermia, hypospadhery (testosterone deficiency due to intrauterine deficiency of its synthesis by leildig cells), moderately pronounced gynecomastics, eye symptoms, heart rate impaired and height delay. Pathogenetic mechanisms are closely related to the mechanisms of true hermaphroditism (see below). And that, and other pathologies develop sporadically, often in the same families; Most cases of Sry are negative.
In addition to micro-and maternity, they allocate period and paracentric inversions (the sector of chromosome turns over 180 ° inside the chromosome with the involvement of centromeds or inside the shoulder without involving centromers). According to the last nomenclature of chromosomes, the inversion is indicated by the pH symbol. In patients with infertility and non-peculiarity of pregnancy, mosaic spermatogenesis and oligospermia associated with the inversions of the following chromosomes are often detected:
Chromosome 1; It is often observed pH 1p34q23, which causes a complete spermatogenesis unit; less often pH 1p32q42, leading to the spermatogenesis unit at the stage of phakiten;
Chromosome 3, 6, 7, 9, 13, 20 and 21.
Reciprocal and non-rocked translocations (mutual equal and unequal exchange between non-homosomes) are found between chromosomes of all classified groups. An example of reciprocal translocation is a Y-autosomal translocation, accompanied by a breakdown of floor differentiation, reproduction and infertility in men due to aplasia of spermatogenic epithelium, braking or spermatogenesis block. Another example is rare translocations between X-Y, Y-Y gamons. Phenotype in such patients can be female, male or dual. In men with y-y translocation, oligoyli azoospermia is observed as a result of a partial or full block of spermatogenesis at the stage of sperm formation I.
A special class is the translocation of Robertson type between acrcentric chromosomes. They are found in men with impaired spermatogenesis and / or infertility more often than reciprocal translocations. For example, Robertson translocation between chromosomes 13 and 14 leads either to the complete absence of sperm in seed canalians, or to minor changes of their epithelium. In the second case, men can preserve fertility, although most often they have a spermatogenesis block at the sperm stage. The class of translocations also also includes polycentric or dicentric chromosomes (with two centromers) and ring chromosomes (centric rings). The first arise as a result of the exchange of two centric fragments of homologous chromosomes, they are detected in patients with impaired reproduction. The latter are closed in the ring structure with the involvement of centromeds. Their education is associated with damage to both shoulders of chromosome, as a result of which the free ends of its fragment,
Gaming floor
To illustrate possible causes and mechanisms of violations of the guy level differentiation of the floor consider on the basis of the data of electron microscopy the process of formation of the Games during normal meiosis. In fig. 57 A model of a synaptonex complex (SC) is shown, reflecting the sequence of events in synapsees and the desigse of chromosomes participating in Crossingrad.
At the initial stage of the first division of MEIOS, corresponding to the end of the interphase (stage of rampant), the homologous parent chromosomes are deconed, and the axial elements are visible in them. Each of the two elements includes two nursing chromatids (respectively 1 and 2, as well as 3 and 4). On this and next (second) stage - leptoten - immediately formation occurs axial elements homologous chromosomes (visible chromatin loops). The beginning of the third stage - zygoten - is characterized by preparing for the assembly of the central element of the SC, and at the end of the zigoten begins synapse or conjugation(Camping in
Fig. 57.Model of the synaptone complex (Preston D., 2000). Figures 1, 2 and 3, 4 denote the nursing chromatids of homologous chromosomes. Other clarifications are given in the text.
length) of two side elements of the SC, sharing the central element, or a bivalent, including four chromatids.
During the passage of zigotes, homologous chromosomes are focused by the teelor \u200b\u200bends to one of the core poles. The formation of the central element of the SC is completely completed in the next (fourth) stage - patchythene, when a haploid number of genital bivalents is formed as a result of the conjugation process. In each bivalent, four chromatids are the so-called chromer structure. Starting from the phakiten stage, the sex bivalent gradually shifts to the periphery of the coder of the cell, where it is converted to a dense sexual body. In the case of a male meyosis, this will be spermatozoa I order. At the next (fifth) stage - diploten - the synapsis of homologous chromosomes is completed and their desigsess occurs or mutual repulsion. At the same time, the SC is gradually reduced and persisted only in areas of chiasm or zones, in which a crosslinker is directly occurring or a recombination exchange of hereditary material between chromatids (see chapter 5). Such zones are called recombination nodules.
Thus, the chromosome is a section of chromosome, in which two of the four chromatids of the sexual bival join the crosslinker. It is the chiazmes that hold homologous chromosomes in one pair and ensure the discrepancy between homologs to different poles in Anafase I. The repulsion in Dipllue continues continues on the next (six) stage - diakinesis when the axial elements are modified with the separation of chromatide axes. Diacines ends with condensation by chromosomes and the destruction of the nuclear membrane, which corresponds to the transition of cells to metaphase I.
In fig. 58 shows a schematic representation of axial elements or two side (oval) heavy - rods of the central space system with the formation of thin transverse lines between them. In the central space of the SC between the side rods, a dense zone of the overlay of transverse lines is visible, and the chromatin loops departed from the side rods are visible. Lighter ellipse in the central space SC is a recombination nodule. In the course of further meeiza (for example, male), four chromatides, forming univalents on individual gamons X and Y, and thus four nursing cells are formed from each cell cells, or sperm. Each sperm has a haploid set
chromosome (halved) and contains a recoming genetic material.
In the period of puberty male organism The spermatides are entering spermatogenesis and thanks to a series of morphophysiological transformations turn into functionally active spermatozoa.
Violations of the garment - this is either the result of the impaired genetic control of the migration of primary genital cells (PPK) in the gonad bookmark, which leads to a decrease in the amount or even the complete absence of sertoli cells (sinotic cell syndrome), or the result of the occurrence of meiotic mutations caused by a violation of the conjugation of homologous chromosomes in Zigoten.
As a rule, disorders of the govetal floor are caused by the anomalies of chromosomes in the govetakes themselves, which, for example, in the case of male meyosis, is manifested by oligo, AZOO- and teratozoospermia, which adversely affecting the reproductive ability of a man.
It is shown that the abnormalities of chromosomes in gates lead to their elimination, the death of the zygota, embryo, fetus and the newborn, determine the absolute and relative male and female infertility, are the causes of spontaneous abortions, frome pregnancies, stillbirths, children's births with defects and early child mortality.
Gonadal floor
Differentiation of the gonadal floor involves the creation in the organism of the morphogenetic structure of the gonad: or seeds, or ovaries (see Fig. 54).
With changes in the gonadal floor caused by the action of genetic and medial factors, the main disorders are: AGE-
Fig. 58.Schematic representation of the central space of the synaptone complex (according to Sorokina TM, 2006)
neugeni or gonad disgenesis (including mixed type) and true hermaphroditism. The sexual system of both sexes is developing at the beginning of intrauterine ontogenesis according to a single plan in parallel with the development of an excretory system and adrenal glands - the so-called indifferent stage.The first laying of the sexual system in the form of a nuclear epithelium occurs at the embryo on the surface of the primary kidney - the Wolf body. Then the stage of hosounders (the epithelium of the sex rollers) comes, of which Gonocytes are developing. They are surrounded by cells of follicular epithelium providing trophic.
In the stroma of the primary kidney from the genital rollers, there are trenches consisting of gorolocytes and follicular cells, and simultaneously from the body of the primary kidney to the cloake there are mullers (paramzenephral) duct. Next is the separate development of male and female gonad. The following occurs.
AND.Male gender. At the top edge of the primary kidney, a mesenchym is grouped, forming sexual litter (cord), which is separated, connecting with the tubes of the primary kidney, flowing into its duct, and gives the beginning of the seed tubes of the seeds. In this case, driven tubules are generated from the renal tubules. In the future, the upper part of the primary kidney duct becomes an appreciation of the seed, and the bottom turns into a seven-way channel. Tsemenities and prostate develop from the wall of the urinary sinus.
The action of hormones of men's gonad (androgen) depends on the action of the hormones of the front lobe of the pituitary. Androgen production is ensured by the joint secretion of interstitial cells of semennikov, spermatogenic epithelium and supporting cells.
Prostate is a iron-muscular organ consisting of two side lobes and a carriage (medium slices). In the prostate about 30-50 glands, their secret is ejected into the seed-to-bull-free duct at the time of ejaculation. To products, secreted by seed bubbles and prostate (primary sperm), as they are promoted over the seed-toe and urethra (in the upper part of the urethra) of the MUKOID and similar to the composition of the compositions of bulburetral glands or cooper cells. All these products are mixed and exited in the form of definitive sperm with a slightly alkaline reaction, in which spermatozoa is located and contains the substance necessary for their functioning: fructose, citric acid,
zinc, calcium, Ergotonin, a number of enzymes (proteinases, glucosidase and phosphatases).
B.Female. The development of mesenchyma at the base of the body of the primary kidney, which leads to the destruction of the free ends of the genital cords. At the same time, the primary kidney duct is atrophically, and Muller duct, on the contrary, is differentiated. Its upper parts become uterine (phallopy) pipes whose ends are revealed in the form of funnels and cover the ovaries. The lower parts of Muller ducts merge and give rise to the uterus and vagina.
The brain part of the ovaries become the remains of the body of the primary kidney, and the rustling of sex cords continues to the cortical part of future ovaries from the sex roller (incidents of the epithelium). Products of women's gonad are a follicle-stimulating hormone (estrogen) or folliculin and progesterone.
The growth of follicles, ovulation, cyclic changes of the yellow body, alternation of estrogen and progesterone products are determined by relations (shifts) between the gonadotropic hormones of the pituitary gland and the specific activators of the adrenogiipophysotropic zone of the hypothalamus controlling the hypophies. Therefore, violations regulatory mechanisms At the level of the hypothalamus, pituitary gland and ovaries, developed, for example, as a result of tumors, cranial injuries, infection, intoxication or psycho-emotional stresses, are upset by sexual function and become the causes of premature puberty or disorders of the menstrual cycle.
Hormonal floor
Hormonal floor is maintaining in the body of the balance of men's and female sex hormones (androgens and estrogen). The determining principle of development of the body of the male type serve two androgenic hormones: antimulam hormone, or AMN (MIS factor), which causes the regression of muller ducts, and testosterone. The MIS factor is activated under the action of Gata4 gene, localized in 19p13.2-33 and coding protein - glycoprotein. Its promoter contains a site that recognizes the Sry gene with which the consensus sequence is associated - AACAAT / A.
The secretion of the AMN hormone begins on 7 weeks of ebogenesis and continues to puberta, then drops sharply in adults (with a very low level).
It is assumed that the AMN is necessary for the development of testicles, the ripening of spermatozoa and inhibition of the growth of tumor cells. Under the control of testosterone from Wolf ducts, internal men's genitals are formed. This hormone turns into 5-alphaatestosterone, and with its help from the urinary sinus, outdoor men's genitals are formed.
Testosterone biosynthesis is activated in leydega cells under the action of the transcription activator encoded by the SF1 genome (9q33).
Both of these hormones have a local, and a general effect on the masculinization of extragnenitial target tissues than the political dysminphism of the central nervous system, internal organs and body sizes are caused.
Thus, an important role in the final formation of the outer male genital organs belongs to the androgens produced in adrenal glands and testicles. And not only necessary normal level Androgen, but their normally functioning receptors, as otherwise develops insensitivity syndrome to androgen (ATS).
Androgen receptor is encoded by the Ar gene localized in XQ11. In this gene, more than 200 point mutations are identified (mainly single-nucleotide substitutions) associated with the inactivation of the receptor. In turn, estrogens and their receptors play an important role in the secondary determination of sex in men. They are necessary to improve their reproductive function: maturation of sperm (increasing their quality indicators) and bone tissue.
Hormone disorders occur due to the defects of biosynthesis and metabolism of androgen and estrogen participating in the regulation of the structure and functioning of the bodies of the reproductive system, which causes the development of a number of congenital and hereditary diseases, such as AGS, hypergronadotropic hypogonadism, etc. For example, external genitals for men are formed by Female type with a deficiency or complete absence of androgen, regardless of the presence or absence of estrogen.
Somatic floor
Doubrition of somatic (morphological) gender may be caused by defects for the formation of receptors of sex hormones in tissues (organs) - targets, which is associated with the development of a female phenotype with a male karyotype or a complete tescular feminization syndrome (Morris syndrome).
The syndrome is characterized by a X-clutched type of inheritance and is the most common cause of false male hermaphroditism, manifested in full and incomplete forms. These are patients with a female phenotype and a male karyotype. They have an intraperitoneal eggs or in the inguinal channels. Outdoor genitals have a different degree of masculinization. Muller duct derivatives - uterus, phallopyes pipes are missing, the vaginal process is shortened and blindly ends.
Derivatives of Wolf Ducts - Seeding Doc, Seed Bubbles and Pods of Tsemennikov - hypoplasis in varying degrees. In Pubtatat in patients, the patients noted the normal development of the chest glands, with the exception of the pallor and the decrease in the diameter of the Nizhki, the scarce lobster and the axillary depression. Sometimes there is no secondary oversight. The patients with the interaction of androgens and their specific receptors are broken, so genetic men feel like women (unlike transgender). With histological examination, they detect the hyperplasia of lesidig cells and cells of the sertoli, as well as the absence of spermatogenesis.
An example of incomplete testicular feminization is Raftenstein syndrome. This is usually a male phenotype with hypontal, gynecomastia, male karyotype and infertility. At the same time, there may be a male phenotype with significant masculinization defects (microtine, crotch hypospadia and cryptorchism), as well as a female phenotype with moderate clikenegali and a minor battle of the genital lips. In addition, in phenotypic men with complete masculinization, the soft form of testing syndrome of testing feminization with gynecomastia, oligozoospermia or azoospermia is isolated.
Mental, social and civilian sex
Consideration of violations of the psychic, social and civilian sex in humans is not the task of this tutorialSince this kind of violations relate to deviations in sexual identity and self-education, sexual orientation and sexual role of the individual and the like of the psychic, psychological and other socially significant factors of sexual development.
Consider an example of transsexualism (one of the frequent disorders of the mental sex), accompanied by the pathological desire of an individual to change its gender. Often this syndrome
call sexually-aesthetic inversion (eulation) or mental hermaphroditism.
Autiaentity and sexual behavior of the individual are laid in the intrauterine period of development of the body through the maturation of the hypothalamus structures, which in some cases may cause the development of transgenderness (intersxuality), i.e. The duality of the structure of external genitalia, for example, with AGS. Such duality leads to incorrect registration of civil (passportable) gender. Leading symptoms: Inversion of the sexual identity and socialization of the individual, manifested in rejecting its gender, psychosocial disadaptation and auto-commodity behavior. The average age of patients, as a rule, is 20-24 years. Male transsexualism occurs significantly more than female (3: 1). Family cases and cases of transsexualism among monosic twins are described.
The nature of the disease is unclear. Psychiatric hypothesis are generally not confirmed. To some extent, the explanation can be a hormonally-dependent differentiation of the brain, which occurs in parallel with the development of genitals. For example, the connection of the level of sex hormones and neurotransmitters during critical periods of the child's development with sexual identification and psychosocial orientation is shown. In addition, it is assumed that the genetic prerequisite of female transsexualism may be the lack of 21-hydroxylase in the mother or fetus caused by prenatal stress, the frequency of which is significantly higher in patients compared with the usual population.
Causes of transsexuality can be considered from two positions.
First position- This is a violation of the differentiation of mental sex due to the inconsistency between the differentiation of external genitalia and the differentiation of the genital center of the brain (ahead of the first and lag of the second differentiation).
Second position- This is a violation of the differentiation of biological gender and the formation of subsequent sexual behavior as a result of a defect receptor receptors of genital hormones or their abnormal expression. It is possible that these receptors can be located in the structures of the brain necessary for the formation of subsequent sexual behavior. It should also be noted that transsexuality is opposite to the test syndrome
feminization, in which patients never have doubts about their belonging to the female floor. In addition, this syndrome should be distinguished from transvestism syndrome as a psychiatric problem.
Classifications of genetic reproduction disorders
Currently, there are many classifications of genetic reproduction disorders. As a rule, they take into account the peculiarities of sex differentiation, genetic and clinical polymorphism in sexual development violations, spectrum and frequency of genetic, chromosomal and hormonal disorders and other features. Consider one of the last, most complete classifications (Grumbach M. et al., 1998). It allocate the following.
I. Differentiation violations Gonad.
True hermaphroditism.
Dysgenezia gonad with clanfelter syndrome.
Disence Syndrome Gonad and its options (Sherosezhevsky-Turner syndrome).
Complete and incomplete forms of XX-dysgenesis and xy-dysgenezia gonad. As an example, consider the gonad dysgenezia during the karyotype 46, x If the Sry gene determines the gonad differentiation in the testicles, then its mutations lead to the gonad dysgenezia in XY-embryos. These are faces with a female phenotype, high growth, male physique and karyotype. They detect the female or dual structure of external genitals, there is no development of the mammary glands, the primary amenorrhea, a meager sexual oath, uterine hypoplascence and fallopian pipes And the gonads themselves, which are represented by connective tanks, located highly in a small pelvis. Often, this syndrome is called a pure dysgenesis gonad with a karyotype 46, XY.
II. Female false hermaphroditism.
Androheninduced.
Congenital hypoplasia of adrenal cortex or AGS. This is a common autosomal-recessive disease, which in 95% of cases is the result of a 21-hydroxylase enzyme deficiency (cytochrome P45 C21). Divided into a "classic" form (frequency in a population of 1: 5000-10000 newborns) and "non-classical" form (frequency 1: 27-333) depending on clinical manifestation. Gene 21-hydroxylase
(CYP21B) Maps on the short shoulder of chromosome 6 (6p21.3). Two tandemly arranged genes are isolated in this locus - functionally active CYP21B gene and pseudogen CYP21A, inactive due to either deletion in exon 3, or insertion with the shift of the reading frame in Exon 7, or nonsense mutations in exon 8. The presence of pseudogen leads to the mating disorders of chromosomes In meyosis and, consequently, to the conversion of the gene (moving the fragment of the active gene to pseudogen) or the deletion of a part of the semantic gene, which disrupts the function of the active gene. The fraction of the conversion of the gene accounts for 80% of mutations, to the share of deletions - 20% of mutations.
The lack of aromatase or mutation of the CYP 19 gene, ARO (P450 gene - aromatase gene), localized in segment 15q21.1.
Arrival of androgens and synthetic progestogenis from the mother.
Nonadrogeniducanted, caused by teratogenic factors and associated intestinal developmental disorders and urinary tract.
III. Male false hermaphroditism.
1. The insensitivity of the tissue of the testicles to xg and LG (ASHENESIA AND GIPOLES OF CELLS).
2. Congenital defects of testosterone biosynthesis.
2.1. Defects of enzymes affecting the biosynthesis of corticosteroids and testosterone (options for congenital hyperplasia of adrenal cortex):
■ Star defect (lipoid form of congenital hyperplasia of adrenal cortex);
■ deficiency 3 beta-HSD (3 betahydroorticoid dehydrogenases);
■ The insufficiency of the CYP 17 gene (P450C176 cytochrome gene) or 17 elf-hydroxylase-17,20-liases.
2.2. Defects of enzymes, primary violation of testosterone biosynthesis in the testicles:
■ CYP 17 deficiency (cytochrome gene P450C176);
■ Insufficiency 17 beta-hydrocereroid dehydrogenases, type 3 (17 beta-HSD3).
2.3. Defects of the sensitivity of target tissues to androgen.
■ 2.3.1. Insensitivity (resistance) to Androgen:
syndrome of complete testing feminization (syndrome
Morris);
incomplete testing syndrome (Raftenstein's disease);
insensitivity to androgens in phenotypically normal men.
■ 2.3.2. Testosterone metabolism defects in peripheral tissues are a deficiency of 5 gamma reductase (SRD5A2) or pseudovaginal perineosotal hypospadia.
■ 2.3.3. Dysgenetic male pseudo-heermifroditism:
incomplete xy-dysgenezia gonad (mutation of the WT1 gene) or FREZ syndrome;
X / XY-mosaicism and structural anomalies (XP +, 9P-,
missens-mutation of the WT1 gene or Denis Drash syndrome; Deletion of the WT1 gene or WAGR syndrome; Mutation gene SOX9 or Campomelic dysplasia; Mutation of the SF1 gene;
X-clutched testicular feminization or morris syndrome.
■ 2.3.4. Defects of synthesis, secretion and response to anti-flames hormone - Muller duct persistence syndrome
■ 2.3.5. Dysgenetic male pseudo-eroditism caused by mother-progestogencies and estrogens.
■ 2.3.6. Dysgenetic male pseudo-eroditism caused by influence chemical factors medium.
IV. Unclassified forms of sexual development anomalies in men:hypospadia, dual development of genitalia in XY-Men with IPPR.
Genetic causes of infertility
As genetic reasons, infertility is distinguished: synaptic and desigterative mutations, anomalous synthesis and assembly of components of the SC (see above the gaming floor).
An abnormal condensation of homologs chromosomes, leading to the disappearance and disappearance of conjugation initiation points to the disappearance and, consequently, meiosis errors arising in any phases and stages. A minor part of violations falls on synaptic defects in the first division program
the form of asynaptic mutations that slow down spermatogenesis to the phase stage in Proofase I, which leads to exceeding the number of cells in leptoten and zygothene, the absence of a sexual bubble in Patchithene causes the presence of a non-conjugating bivalent segment and a non-fully formed synaptone complex.
The desigterative mutations are more frequent, which block the gamentheses to the metaphase stage I, causing the defects of the SC, including its fragmentation, complete absence or irregularity, as well as the asymmetry of the chromosome conjugation.
At the same time, partially synapted bi- and multisinaputerines may be observed, their associations with sex xy-bivalents that are not shifting to the periphery of the nucleus, and "binding" in its central part. In such nuclei, sexual calves are not formed, and the cells with these nuclei are subjected to selection at the pachiten stage - this is the so-called patchy arrest.
Classification of genetic causes of infertility
1. Honor syndromes (including mosaic forms): Chaninfelter syndromes (karyotypes: 47, XXY and 47, XYY); Yy-aneuploidy; Floor inversion (46, xx and 45, x - men); Structural mutations Y-chromosome (deletion, inversion, ring chromosomes, isochromosomes).
2. Autosomal syndromes caused by: reciprocal and Robertson translocations; other structural rearrangements (including marker chromosomes).
3. Syndromes due to trisomy chromosome 21 (Down disease), partial duplications or deletions.
4. Chromosomal heteromorphisms: chromosome inversion 9, or pH (9); Family inversion Y-chromosome; increased heterochromatin y-chromosome (YGH +); increased or reduced percentrocery constitutional heterochromatin; Increased or dumpy satellites acrcentric chromosomes.
5. Chromosomal aberrations in spermatozoa: severe primary tesculopathy (effects of radiation therapy or chemotherapy).
6. Mutations of Y-clutch genes (for example, microdeption in AZF locus).
7. Mutations of X-clutch genes: insensitivity syndrome to androgen; Salman and Kennedy syndromes. Consider the squid syndrome - this is a congenital (often family) violation of the secretion of gonadotropins in persons of both sexes. The syndrome is due to the defect of the hypothalamus, manifested by the gonadotropin-rilizing hormone deficiency, which leads to a decrease in the production of gonadotropins by the pituitary gland and the development of secondary hypogonadotropic hypogonadism. It is accompanied by a defect of olfactory nerves and is manifested by an alimony or hyposmy. In patients with men, Enuchoidism is observed (the testicles in size and consistency remain on the pubertal level) is absent color vision, There are congenital deafness, lips and nose clefts, cryptorchism and bone pathology with shortening of the IV Metal bone. Sometimes gynecomastia is manifested. In histological examination, immature seed tubules, lined with cells, spermatogonium or primary spermatocytes, are revealed. Leesig cells are absent, instead of them, mesenchymal precursors, which, with the introduction of gonadotropins, develop into lesiga cells. The x-clutched shape of the squid syndrome is caused by the Mutation of the Kal1 gene encoding anosmine. This protein plays a key role in migrating secreting cells and an increase in the olfactory nerves to the hypothalamus. An autosomal dominant and autosomal inheritance inheritance of this disease is also described.
8. Genetic syndromes in which infertility is a leading symptom: mutations of the genes of the fibrosis, accompanied by the absence of VAS Deferens; CBAVD and CUAVD syndromes; mutations of genes encoding beta subunit LG and FSH; Mutations of genes encoding receptors to LG and FSH.
9. Genetic syndromes under which infertility is not a leading symptom: the insufficiency of the activity of steroid enzymes (21-beta-hydroxylase, etc.); lack of reductase activity; FanConi anemia, hemochromatosis, betatalassmia, petonic dystrophy, cerebelchik ataxia with hypogonadotropic hypogonadism; Barda-Bidle syndromes, Nunan, Prader-Willie and Prune-Belli.
Infertility in womenit happens with the following violations. 1. Honor syndromes (including mosaic forms): Sherosevsky-Turner syndrome; Dysgenesia gonad with low growth -
kariotypes: 45, x; 45x / 46, xx; 45, x / 47, xxx; XQ isochromosoma; DEL (XQ); Del (XP); R (x).
2. Dysgenezia Gonad with a line of cells serving Y-chromosomes: Mixed Dysgenezia Gonad (45, X / 46, XY); Dysgenezia gonad during karyotype 46, xy (swayer syndrome); Dysgenezia gonad with true hermaphroditis with a line of cells carrying y-chromosomes or having translocations between X-chromosome and autosomas; Dysgenezia gonad with triplo-x (47, xxx) syndrome, including mosaic forms.
3. Autosomal syndromes caused by inversions or reciprocal and Robertson translocations.
4. Chromosomal aberrations in oocytes of women over the age of 35, as well as in oocytes of women with normal karyotype, which have 20% of oocytes and more may have chromosomal anomalies.
5. Mutations in X-clutched genes: full form of testing feminization; Syndrome Broke X-Chromosome (Fraxa, Frax Syndrome); Salchean syndrome (see above).
6. Genetic syndromes in which infertility is a leading symptom: mutations in genes encoding the FSH subunit, receptors to LH and FSH and gonadoliberin receptor; BPES syndromes (blefrophimism, ptosis, epicanti), Denis Drash and Frese.
7. Genetic syndromes in which infertility is not a leading symptom: insufficiency of aromatic activity; The insufficiency of steroidogenesis enzymes (21-beta hydroxylase, 17-beta hydroxylase); beta-thalassemia, galactosemia, hemochromatosis, petonic dystrophy, fibrosis, mucopolysaccharideosis; mutations gene DAX1; Prader-Willy syndrome.
However, this classification does not take into account a number of hereditary diseases associated with male and female infertility. In particular, he did not enter a heterogeneous group of diseases combined by the overall name "autosomal-recessive Cartageger Syndrome", or the motionlessness syndrome of the ciliation of the cereal epithelium of the upper respiratory tract, flagella of spermatozoa, fibrius. For example, more than 20 genes that control the formation of sperm flavors are identified, including a number of gene mutations.
DNA11 (9P21-P13) and DNAH5 (5P15-P14). This syndrome is characterized by the presence of bronchiectasis, sinusitis, full or partial reference of internal organs, vices of the development of chest bones, congenital heart disease, polyendocrine insufficiency, pulmonary and heart infantilism. Men and women with this syndrome are often, but not always fruitless, since they are infertility dependent on the degree of damage to the motor activity of sperm flavors or fibrius. In addition, patients experience secondly evolved anosmia, a moderate decrease in hearing, a nasal cavity polyps.
Conclusion
As an integral part of the general genetic development program, the ontogenesis of the reproductive system organs is a multi-sized process, extremely sensitive to action wide spectrum mutagenic and teratogenic factors resulting in the development of hereditary and congenital diseases, violations of reproductive function and infertility. Therefore, the ontogenesis of the bodies of the reproductive system is the most visual demonstration of the generality of the causes and mechanisms of development and the formation of both normal and pathological functions associated with the main regulatory and protective systems of the body.
It characterizes a number of features.
In the gene network, which participates in the ontogenesis of the human reproductive system, has: in the female body - 1700 + 39 genes, in the men's organism - 2400 + 39 genes. It is possible that in the coming years, the entire gene network of the reproductive system authorities will be released in the number of genes for second place after the neuronogenesis network (where 20 thousand genes).
The effect of individual genes and gene complexes in the composition of the specified gene network is closely related to the action of sex hormones and receptors to them.
Numerous chromosomal disorders of floor differentiation are isolated associated with chromosomes in anafase mitosis and meiosis proofased, numerical and structural anomalies of gone and outos (or their mosaic options).
Disorders of the development of somatic gender associated with defects for the formation of receptors of sex hormones in tissues and the development of a female phenotype with a male karyotype - full test syndrome (Morris syndrome).
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