“Every tenth gene affects the human reproductive system. Symptoms of the disease - reproductive dysfunction

A certain role is played by the abnormal condensation of chromosome homologues, leading to the masking and disappearance of the initiation points of conjugation and, consequently, meiosis errors that occur in any of its phases and stages. A small part of the disorders occurs due to synaptic defects in the prophase of the first division in

in the form of asynaptic mutations that inhibit spermatogenesis up to the pachytene stage in prophase I, which leads to an excess of the number of cells in leptotene and zygotene, the absence of a sex vesicle in pachytene, causing the presence of a non-conjugating bivalent segment and an incompletely formed synaptonemal complex.

More common are desynaptic mutations, which block gametogenesis until the metaphase I stage, causing defects in the SC, including its fragmentation, complete absence or irregularity, and asymmetry of chromosome conjugation.

At the same time, partially synapted bi- and multisynaptonemal complexes can be observed, their associations with sexual XY-bivalents, which are not shifted to the periphery of the nucleus, but “anchored” in its central part. Sex bodies are not formed in such nuclei, and cells with these nuclei are subject to selection at the pachytene stage - this is the so-called disgusting arrest.

Classification of genetic causes of infertility

1. Gonosomal syndromes (including mosaic forms): Klinefelter syndromes (karyotypes: 47,XXY and 47,XYY); YY-aneuploidy; gender inversion (46,XX and 45,X - men); structural mutations of the Y chromosome (deletions, inversions, ring chromosomes, isochromosomes).

2. Autosomal syndromes caused by: reciprocal and Robertsonian translocations; other structural rearrangements (including marker chromosomes).

3. Syndromes caused by trisomy of chromosome 21 (Down's disease), partial duplications or deletions.

4. Chromosomal heteromorphisms: inversion of chromosome 9, or Ph (9); familial Y chromosome inversion; increased heterochromatin of the Y chromosome (Ygh+); increased or decreased pericentromeric constitutive heterochromatin; enlarged or duplicated satellites of acrocentric chromosomes.

5. Chromosomal aberrations in sperm: severe primary testiculopathy (consequences of radiation therapy or chemotherapy).

6. Mutations of Y-linked genes (for example, microdeletion in the AZF locus).

7. Mutations of X-linked genes: androgen insensitivity syndrome; Kalman and Kennedy syndromes. Consider Kalman syndrome - this is a congenital (often familial) disorder of gonadotropin secretion in individuals of both sexes. The syndrome is caused by a defect in the hypothalamus, manifested by a deficiency of gonadotropin-releasing hormone, which leads to a decrease in the production of gonadotropins by the pituitary gland and the development of secondary hypogonadotropic hypogonadism. Accompanied by a defect olfactory nerves and is manifested by anosmia or hyposmia. In sick men, eunuchoidism is observed (testicles remain at the pubertal level in size and consistency), absent color vision, there is congenital deafness, cleft lip and palate, cryptorchidism and bone pathology with shortening of the IV metacarpal bone. Sometimes gynecomastia occurs. Histological examination reveals immature seminiferous tubules lined by Sertoli cells, spermatogonia or primary spermatocytes. Leydig cells are absent, instead there are mesenchymal precursors that, with the introduction of gonadotropins, develop into Leydig cells. The X-linked form of Kallmann syndrome is caused by a mutation in the KAL1 gene, which encodes anosmin. This protein plays a key role in the migration of secreting cells and the growth of olfactory nerves to the hypothalamus. Autosomal dominant and autosomal recessive inheritance of this disease has also been described.

8. Genetic syndromes in which infertility is the leading symptom: mutations of the cystic fibrosis gene, accompanied by the absence of vas deferens; CBAVD and CUAVD syndromes; mutations in genes encoding the beta subunit of LH and FSH; mutations in genes encoding receptors for LH and FSH.

9. Genetic syndromes in which infertility is not the leading symptom: insufficiency of the activity of steroidogenesis enzymes (21-beta-hydroxylase, etc.); insufficiency of reductase activity; Fanconi anemia, hemochromatosis, betathalassemia, myotonic dystrophy, cerebellar ataxia with hypogonadotropic hypogonadism; Bardet-Biedl, Noonan, Prader-Willi and Prune-Belli syndromes.

Infertility in women happens with the following violations. 1. Gonosomal syndromes (including mosaic forms): Shereshevsky-Turner syndrome; gonadal dysgenesis with short stature -

karyotypes: 45,X; 45Х/46,ХХ; 45,Х/47,ХХХ; Xq isochromosome; del(Xq); del(Xp); r(X).

2. Gonadal dysgenesis with a cell line carrying the Y chromosome: mixed gonadal dysgenesis (45,X/46,XY); gonadal dysgenesis with karyotype 46,XY (Swyer syndrome); gonadal dysgenesis with true hermaphroditism with a cell line that carries the Y chromosome or has translocations between the X chromosome and autosomes; gonadal dysgenesis in triplo-X syndrome (47,XXX), including mosaic forms.

3. Autosomal syndromes caused by inversions or reciprocal and Robertsonian translocations.

4. Chromosomal aberrations in the oocytes of women over 35 years of age, as well as in the oocytes of women with a normal karyotype, in which 20% of oocytes or more may have chromosomal abnormalities.

5. Mutations in X-linked genes: full form of testicular feminization; Fragile X syndrome (FRAXA, fraX syndrome); Kallmann syndrome (see above).

6. Genetic syndromes in which infertility is the leading symptom: mutations in the genes encoding the FSH subunit, LH and FSH receptors and the GnRH receptor; BPES (blepharophimosis, ptosis, epicanthus), Denis-Drash and Frazier syndromes.

7. Genetic syndromes in which infertility is not the leading symptom: lack of aromatic activity; deficiency of steroidogenesis enzymes (21-beta-hydroxylase, 17-beta-hydroxylase); beta thalassemia, galactosemia, hemochromatosis, myotonic dystrophy, cystic fibrosis, mucopolysaccharidosis; DAX1 gene mutations; Prader-Willi syndrome.

However, this classification does not take into account a number hereditary diseases associated with masculinity and female infertility. In particular, it did not include a heterogeneous group of diseases united by the common name “autosomal recessive Kartagener syndrome”, or the syndrome of immobility of cilia of ciliated epithelial cells of the upper respiratory tract, sperm flagella, and oviduct villous fibria. For example, to date, more than 20 genes have been identified that control the formation of sperm flagella, including a number of gene mutations

DNA11 (9p21-p13) and DNAH5 (5p15-p14). This syndrome is characterized by the presence of bronchiectasis, sinusitis, complete or partial inversion internal organs, bone malformations chest, congenital heart disease, polyendocrine insufficiency, pulmonary and cardiac infantilism. Men and women with this syndrome are often, but not always, infertile, since their infertility depends on the degree of damage to the motor activity of the sperm flagella or the fibria of the oviduct villi. In addition, patients have secondary developed anosmia, moderate hearing loss, and nasal polyps.

CONCLUSION

As an integral part of the general genetic development program, the ontogenesis of the organs of the reproductive system is a multi-link process that is extremely sensitive to the action of a wide range of mutagenic and teratogenic factors that determine the development of hereditary and congenital diseases and disorders reproductive function and infertility. Therefore, the ontogenesis of the organs of the reproductive system is the most clear demonstration of the common causes and mechanisms of development and formation of both normal and pathological functions associated with the main regulatory and protective systems of the body.

It is characterized by a number of features.

The gene network involved in the ontogenesis of the human reproductive system includes: female body- 1700+39 genes, in the male body - 2400+39 genes. It is possible that in the coming years the entire gene network of the reproductive system organs will take second place in the number of genes after the network of neuroontogenesis (with 20 thousand genes).

The action of individual genes and gene complexes within this gene network is closely related to the action of sex hormones and their receptors.

Numerous chromosomal disorders of sex differentiation associated with chromosome nondisjunction in anaphase of mitosis and prophase of meiosis, numerical and structural abnormalities of gonosomes and autosomes (or their mosaic variants) have been identified.

Disturbances in the development of somatic sex associated with defects in the formation of sex hormone receptors in target tissues and the development of a female phenotype with a male karyotype - complete testicular feminization syndrome (Morris syndrome) have been identified.

Genetic causes of infertility have been identified and their most complete classification has been published.

Thus, in last years In studies of the ontogenesis of the human reproductive system, significant changes have occurred and successes have been achieved, the implementation of which will certainly improve methods of treatment and prevention of reproductive disorders, as well as male and female infertility.

The population of many developed countries faces an acute problem of male and female infertility. 15% of married couples in our country experience reproductive dysfunction. Some statistics show that the percentage of such families is even higher. In 60% of cases, the cause is female infertility, and in 40% of cases - male infertility.

Causes of disorders of male reproductive function

Secretory (parenchymal) disorder, in which the production of spermatozoa in the seminiferous tubules of the testicles is impaired, which manifests itself in aspermia (there are no spermatogenesis cells in the ejaculate, as well as spermatozoa themselves), azoospermia (there are no spermatozoa, but spermatogenesis cells are present), oligozoospermia (the structure and motility of spermatozoa are changed).

1. Testicular dysfunction.
2. Hormonal disorder. Hypogonadotropic hypogonadism is a deficiency of pituitary hormones, namely luteinizing and follicle-stimulating hormones, which are involved in the formation of sperm and testosterone.
3. Autoimmune disorder. Own immune cells produce antibodies to sperm, thereby destroying them.

Excretory disorder. Impaired patency (obstruction, obstruction) of the vas deferens, resulting in impaired exit constituent elements sperm into the urethra through the genital tract. It can be permanent or temporary, one- or two-sided. The composition of semen includes sperm, prostate secretion and seminal vesicle secretion.

Mixed violation. Excretory-inflammatory or excretory-toxic. Occurs due to indirect damage to the spermatogenic epithelium by toxins, disruption of metabolism and synthesis of sex hormones, as well as the direct damaging effect of bacterial toxins and pus on sperm, leading to a deterioration in its biochemical characteristics.

Other reasons:

• Sexual. erectile disfunction, ejaculation disorders.
• Psychological. Anejaculation (lack of sperm release).
• Neurological (consequence of spinal cord damage).

Causes of disorders of female reproductive function

• Hormonal
• Testicular tumors (cystomas)
• Consequences of inflammatory processes in the pelvis. These include the formation of adhesions, tubo-peritoneal factor or, in other words, obstruction of the fallopian tubes.
• Endometriosis
• Tumors of the uterus (fibroids)

Treatment of female infertility

Based on the results of the tests, the doctor prescribes certain methods of treating infertility. Usually, the main efforts are aimed at correct diagnosis of the causes of infertility.

When endocrine pathology, treatment is to normalize hormonal levels, as well as in the use of ovarian stimulating drugs.

In case of tubal obstruction, laparoscopy is included in the treatment.

Endometriosis is also treated by laparoscopy.

Defects in the development of the uterus are eliminated using the possibilities of reconstructive surgery.

The immunological cause of infertility is eliminated by artificial insemination with the husband's sperm.

It is most difficult to treat infertility if the causes cannot be accurately determined. As a rule, in this case, IVF technology is used - artificial insemination.

Treatment of male infertility

If a man has infertility that is secretory in nature, that is, associated with impaired spermatogenesis, the beginning of treatment is to eliminate the causes. Are being treated infectious diseases, are eliminated inflammatory processes, apply hormonal agents to bring spermatogenesis back to normal.

If a man has diseases such as inguinal hernia, cryptorchidism, varicocele and others, is prescribed surgery. Surgery It is also indicated in cases where a man is infertile due to obstruction of the vas deferens. The greatest difficulty is caused by the treatment of male infertility in the case of exposure to autoimmune factors, when sperm motility is impaired, and antisperm bodies are affected. In this option, hormonal drugs are prescribed, laser therapy is used, as well as plasmapheresis and more.

Recently, in reproductive medicine, the influence of biological factors of the male body on its fertility (fecundity), as well as on the health of the offspring, has been actively studied. Let's try to answer some questions related to this topic. The ability to reproduce, or reproduce, is the main distinguishing feature of living beings. In humans, for the successful implementation of this process, the preservation of reproductive function is required - both on the part of the woman and on the part of the man. Totality various factors, influencing the reproductive ability (fertility) in men is called the “male” factor. Although in most cases this term refers to various circumstances that adversely affect male fertility, of course, the “male” factor should be considered as a broader concept.

Infertility in marriage, the ineffectiveness of its treatment, including with the help of assisted reproduction methods (in vitro fertilization, etc.), various forms of miscarriage (recurrent miscarriage), such as frozen pregnancy, spontaneous miscarriages, may be associated with negative impact"male" factor. If we consider the genetic contribution of parents to the health of their offspring, in general it is approximately the same for both women and men. It has been established that the cause of infertility in marriage in about a third of cases is a violation of reproductive function in a woman, in a third - in a man, and in a third of cases there is a combination of such disorders in both spouses.

Causes of male infertility

Infertility in men is most often associated with impaired patency of the vas deferens and/or sperm formation (spermatogenesis). Thus, in approximately half of cases of infertility in men, a decrease in the quantitative and/or qualitative parameters of sperm is detected. There is great amount causes of reproductive dysfunction in men, as well as factors that may predispose to their occurrence. These factors can be physical in nature (exposure to high or low temperatures, radioactive and other types of radiation, etc.), chemical (exposure to various toxic substances" by-effect medications, etc.), biological (sexually transmitted infections, various diseases of internal organs) and social (chronic stress). The cause of infertility in men may be associated with the presence of hereditary diseases, diseases of the endocrine system, autoimmune disorders- the production of antibodies in a man’s body to his own cells, for example to sperm.

The cause of reproductive problems in men can be genetic disorders, in particular changes in genes that are involved in the control of any processes occurring in the body.

To a large extent, the state of reproductive function in men depends on development of the genitourinary system, puberty. The processes that control the development of the reproductive system begin to operate during the prenatal period. Even before the formation of the gonads, primary germ cells are released outside the tissues of the embryo, which move to the area of ​​​​the future testicles. This stage is very important for future fertility, since the absence or insufficiency of primordial germ cells in the developing testes can cause serious violations spermatogenesis, such as the absence of sperm in the seminal fluid (azoospermia) or severe oligozoospermia (sperm count less than 5 million/ml). Various violations the development of the gonads and other organs of the reproductive system is often due to genetic reasons and can lead to impaired sexual development and, in the future, to infertility or decreased fertility. Hormones, primarily sex hormones, play an important role in the development and maturation of the reproductive system. Various endocrine disorders associated with deficiency or excess of hormones, impaired sensitivity to any hormone that controls the development of the organs of the reproductive system, often lead to insufficient reproductive function.

The central place in the male reproductive sphere is occupied by spermatogenesis. This is a complex multi-stage process of development and maturation of sperm from immature germ cells. On average, sperm maturation takes about two and a half months. The normal course of spermatogenesis requires the coordinated influence of numerous factors (genetic, cellular, hormonal and others). This complexity makes spermatogenesis an “easy target” for all kinds of negative influences. Various diseases, unfavorable environmental factors, unhealthy lifestyle (low physical activity, bad habits, etc.), chronic stressful situations, including those related to work, can lead to impaired spermatogenesis, and, as a consequence, to decreased fertility.

Over the past decades, there has been a clear deterioration in sperm quality. In this regard, standards for the quality of seminal fluid have been repeatedly revised. Plank normal amount(concentration) of sperm has been reduced several times and is now 20 million/ml. It is believed that the reason for this “decline” in sperm quality is primarily related to the deterioration of the environmental situation. Of course, with age there is a decrease in the quantity and quality of sperm (number, motility and proportion of normal sperm), as well as other sperm parameters that can affect male fertility. However, it should be noted that the state of spermatogenesis is largely determined by genetic factors, the presence of diseases and/or factors that adversely affect the formation of sperm.

Despite the use of numerous modern diagnostic methods, the cause of infertility remains unclear in almost half of all cases. The results of numerous studies indicate that genetic causes occupy one of the leading places among the causes of both infertility and recurrent miscarriage. In addition, genetic factors may be the root cause of abnormalities of sexual development, as well as a number of endocrinological, immunological and other diseases leading to infertility.

Chromosomal mutations (change in the number and/or structure of chromosomes), as well as disorders of genes that control reproductive function in men can cause infertility or miscarriage. Thus, very often male infertility, associated with a severe disorder of spermatogenesis, is caused by numerical abnormalities of the sex chromosomes. Abnormalities of the Y chromosome in a certain region are one of the most common genetic causes (about 10%) of infertility in men associated with azoospermia and severe oligozoospermia. The frequency of these disorders reaches 1 in 1000 men. Impaired patency of the vas deferens may be due to the presence of such a common genetic disease as cystic fibrosis (cystic fibrosis of the pancreas) or its atypical forms.

In recent years, the influence of epigenetic (supragenetic) factors on reproductive function and their role in hereditary pathology. Various supramolecular changes in DNA, not associated with a violation of its sequence, can significantly determine the activity of genes and even be the cause of a number of hereditary diseases (so-called imprinting diseases). Some researchers point to a several-fold increase in the risk of such genetic diseases after using the methods in vitro fertilization. Undoubtedly, epigenetic disorders can cause reproductive dysfunction, but their role in this area remains poorly understood.

It is important to note that genetic causes do not always result in primary infertility (when pregnancy has never occurred). In some cases of secondary infertility, i.e. when recurrent pregnancies do not occur, the cause may be due to genetic factors. Cases have been described in which men who have already had children subsequently experienced severe disturbances in spermatogenesis and, as a consequence, infertility. Therefore, genetic testing is carried out for patients or couples with reproductive problems, regardless of whether they have children or not.

Ways to overcome infertility

Overcoming infertility, including in some cases such severe forms of reproductive disorders in men as azoospermia (lack of sperm in the ejaculate), oligozoospermia (decrease in the number of sperm) and asthenozoospermia (decrease in the number of motile forms, as well as the speed of sperm movement in the semen) severe, became possible thanks to the development of in vitro fertilization (IVF) methods. More than ten years ago, an IVF method was developed, such as fertilization of an egg with a single sperm (ICSI, Intracytoplasmic Sperm Injection). Like conventional in vitro fertilization, this technique is widely used in IVF clinics. However, it should be remembered that the use of assisted reproductive technologies can not only solve the problem of childbearing, but also transmit genetic disorders, increasing the risk of inheriting mutations associated with reproductive pathology. Therefore, all patients, as well as germ cell donors, must undergo a medical genetic examination and counseling before IVF programs.

Cyto genetic research(chromosome set analysis) is prescribed to all married couples with infertility or recurrent miscarriage. If indicated, additional genetic studies are recommended.

Unlike women (especially those over 35 years old), men with age do not experience a significant increase in the number of germ cells with an incorrect set of chromosomes. Therefore, it is believed that a man’s age does not affect the frequency chromosomal abnormalities in the offspring. This fact is explained by the peculiarities of female and male gametogenesis - the maturation of germ cells. In women, at birth, the ovaries contain a final number of germ cells (about 450-500), which are used only with the onset of puberty. The division of germ cells and the maturation of sperm persists in men until old age. Most chromosomal mutations occur in germ cells. On average, 20% of all oocytes (eggs) of healthy young women carry chromosome abnormalities. In men, 5 - 10% of all sperm have chromosomal disorders. Their frequency may be higher if there are changes (numerical or structural chromosome abnormalities) in the man’s chromosome set. Severe disturbances in spermatogenesis can also lead to an increase in the number of sperm with an abnormal set of chromosomes. It is possible to assess the level of chromosomal mutations in male germ cells using a molecular cytogenetic study (FISH analysis) of sperm. Such a study on embryos obtained after in vitro fertilization makes it possible to select embryos without chromosomal abnormalities, as well as to select the sex of the unborn child, for example, in the case of hereditary diseases linked to sex.

Regardless of age, married couples planning a pregnancy and concerned about the health of their future offspring, in particular the birth of children with genetic disorders, can seek appropriate help from medical genetic consultations. Carrying out a genetic examination allows us to identify the presence of factors that are not conducive to the birth of healthy offspring.

If there is no reason to worry about this, any special preparation for future pregnancy is not carried out. And if necessary, given the duration of sperm maturation, such preparation should begin at least three months in advance, and preferably six months to a year. During this period, it is advisable not to use strong medications. A man should abstain or get rid of bad habits, if possible, eliminate or reduce the influence of professional and other harmful factors. A reasonable balance between physical activity and rest is very useful. It is important to remember that the psycho-emotional mood is of no small importance for a married couple planning a pregnancy.

Undoubtedly, the biological components transmitted to the child from the parents are quite important. However, social factors also have a significant impact on the health and development of the child. Numerous studies have shown that the level intellectual abilities and a person’s character are to a certain extent determined by genetic factors. However, it should be noted that the degree of development mental abilities is largely determined by social factors - upbringing. The age of parents in itself cannot influence the level of development of children. Therefore, the widespread belief that older fathers are more likely to give birth to geniuses is unfounded.

To summarize, I would like to note that the health of a child equally depends on the health of both parents. And it’s good if the future dad and future mom will keep this in mind.

A comprehensive study that allows you to determine the leading genetic causes of male infertility and choose the appropriate tactics for patient management.

The study included the most common genetic causes of male infertility: identification of deletions in the locus AZF affecting spermatogenesis, determining the number of CAG repeats in the gene AR associated with changes in sensitivity to androgens and search for mutations in the gene CFTR, responsible for the development of the disease, the clinical manifestation of which is obstructive azoospermia.

What biomaterial can be used for research?

Buccal (buccal) epithelium, venous blood.

How to properly prepare for research?

No preparation required.

General information about the study

Male infertility (MF) is a serious pathological condition that requires complex comprehensive diagnosis, urgent correction, and in some cases, prevention.

Infertility affects 15-20% of couples of reproductive age. In half of the cases it is associated with " male factor", manifested by deviations in the parameters of the ejaculate.

The difficulty of diagnosing MB lies in the large number of causes that cause it. These include anomalies of the genitourinary system, tumors, genitourinary tract infections, endocrine disorders, immunological factors, genetic mutations etc. Unlike the above reasons, genetic ones do not always have clinical manifestations, but are extremely important for diagnosing MB in the subject.

It is important to understand that the diagnosis of “MB” and its forms can be made only a medical specialist based on anamnestic data, examination data, results of instrumental and laboratory tests. The reasons for visiting a doctor may be the following:

• the impossibility of conceiving a child within a year, provided there are no signs of female infertility in the partner;
• erectile and ejaculatory dysfunction;
• concomitant diseases of the urogenital area (inflammatory, tumor, autoimmune, congenital, etc.);
• taking hormonal and cytostatic drugs;
• discomfort in the urogenital area.

Frequent causes of male infertility are disturbances in the structure and quantity of sperm, affecting their motility and ability to fertilize.

The main genetic reasons for the development of MB are:

1) deletions (removal of genetic fragments) of the locus AZF;

2) polymorphism (increase in repeats of a genetic fragment - CAG) of the gene AR;

3)m mutations (sequence violation) of a gene CFTR .

Currently, these markers are an integral part of standard criteria for complex diagnostics genetic manifestations of MB, occurring in a group of patients in 10-15% of cases.

Deletions of the AZF locus and the SRY gene

An important role in the development of pathologies such as oligozoospermia and azoospermia is played by deviations in a specific region of the Y chromosome - AZF- locus (azoospermia factor). Included in him determine the normal course of spermatogenesis, and in case of violation of the genetic structure AZF-locus, the formation of male germ cells can be seriously disrupted.

AZF- The locus is located on the long arm of the Y chromosome (q11). Genes located at this locus play important role during the process of spermatogenesis.

Microdeletion of the Y chromosome is the loss of certain areas, found on average in 10-15% of cases of azoospermia and in 5-10% of cases of severe oligozoospermia and causes spermatogenesis disorders and infertility in men.

AZF locus divided into 3 sections: AZFa, AZFb And AZF c. In each of them, genes involved in the control of spermatogenesis have been identified. Deletions in the AZF locus may be full, i.e. completely removing one of AZF-regions or more, and partial, when they do not completely capture any of its three regions.

When full AZF-deletions, there is a fairly clear dependence of the degree of impairment of spermatogenesis on the size and location of the deletions, which may have prognostic significance in obtaining sperm suitable for in vitro fertilization programs.

• Absence of the entire locus AZF, as well as deletions that completely cover regions AZFa and/or AZFb, indicate the impossibility of obtaining sperm.
• Almost all patients with deletions AZFb or AZFb+c Azoospermia is noted due to severe disorders of spermatogenesis (Sertoli cell only syndrome).
• With complete deletions of the region AZFc manifestations range from azoospermia to oligozoospermia. On average, 50-70% of patients with a deletion that completely involves AZF c-region, it is possible to obtain sperm suitable for artificial insemination.
• With partial AZF In c-deletions, manifestations range from azoospermia to normozoospermia.

State Research AZF- Y-chromosome locus in patients with severe azoospermia and oligozoospermia allows us to establish the genetic cause of spermatogenesis disorders and carry out differential diagnosis infertility in men and adjust treatment, check the possibility of obtaining sperm from testicular biopsy and the possibility of obtaining sperm for ICSI (intracytoplasmic sperm injection).

It should be taken into account that in case successful use assisted reproductive technologies, deletion of the Y chromosome is transmitted through the male line. This shows the need dispensary observation for boys born after the use of ICSI to fathers with microdeletions in the Y chromosome, to assess their fertility status.

Indications for screening AZF-deletions are based on sperm count and include azoospermia and severe oligozoospermia (

The gene is especially important in the genetic control of male-type development SRY(Sex-determining Region Y). It is in it that the largest number of mutations associated with gonadal dysgenesis and/or sex inversion were found. If there is no part of the chromosome containing the gene SRY, the phenotype will be female with a male karyotype of 46XY.

This genetic study includes analysis AZF-chromosomal locus – 13 clinically significant deletions: sY86, sY84, sY615, sY127, sY134, sY142, sY1197, sY254, sY255, sY1291, sY1125, sY1206, sY242, as well as determination of gene deletion SRY.

Androgen receptor gene AR

Another determining factor in male infertility is a violation of the hormonal regulation of spermatogenesis, in which the male sex hormones androgens play a key role. They interact with specific androgen receptors, determining the development of male sexual characteristics and activating spermatogenesis. Receptors are found in the cells of the testes, prostate, skin, cells nervous system and other fabrics. The androgen receptor gene is characterized by the presence of a CAG (cytosine-adenine-guanine) repeat sequence, the number of which can vary significantly (from 8 to 25). The CAG triplet encodes the amino acid glutamine, and when the number of CAG nucleotide repeats changes, the amount of the amino acid glutamine in the protein changes accordingly. From the number of repeats in the gene AR the sensitivity of the receptor to , and the relationship is inversely proportional: the more repeats, the less sensitive the receptor. An increase in the number of CAG repeats in receptors reduces their activity, they become less sensitive to testosterone, which can lead to impaired spermatogenesis, and the risk of developing oligozoospermia and azoospermia increases. There is also evidence that with a reduced number of CAG repeats (AR), there is increased sensitivity to androgens and an increased risk in men. An increase in the number of CAG repeats to 38-62 leads to spinobulbar muscle atrophy, Kennedy type.

The test result makes it possible to assess the activity of spermatogenesis and, if necessary, take appropriate measures to compensate for the pathology.

Male infertility in cystic fibrosis

Luteinizing hormone (LH)

Follicle stimulating hormone (FSH)

Prostate-specific antigen total (PSA total)

Karyotype study

Important Notes

Lifetime data genetic markers do not change, the study is carried out once.

Literature

1. Naina Kumar and Amit Kant Singh Trends in male factor infertility, an important cause of infertility: A review of literature J Hum Reprod Sci. 2015 Oct-Dec; 8(4): 191–196.

Total information

The reproductive process or human reproduction is carried out by a multi-link system reproductive organs, which ensure the ability of gametes to fertilize, conception, preimplantation and implantation of the zygote, the intrauterine development of the embryo, embryo and fetus, the reproductive function of a woman, as well as the preparation of the newborn’s body to meet new conditions of existence in the surrounding external environment.

Ontogenesis of the reproductive organs is an integral part of the genetic program of the overall development of the body, aimed at providing optimal conditions for the reproduction of offspring, starting with the formation of gonads and the gametes they produce, their fertilization and ending with the birth of a healthy child.

Currently, a common gene network responsible for ontogenesis and the formation of organs of the reproductive system is being identified. It includes: 1200 genes involved in the development of the uterus, 1200 genes of the prostate, 1200 genes of the testes, 500 genes of the ovaries and 39 genes that control the differentiation of germ cells. Among them, genes were identified that determine the direction of differentiation of bipotential cells either according to male or according to female type.

All parts of the reproductive process are extremely sensitive to the negative effects of environmental factors, leading to reproductive dysfunction, male and female infertility, and the appearance of genetic and non-genetic diseases.

ONTOGENESIS OF ORGANS OF THE REPRODUCTIVE SYSTEM

Early ontogeny

The ontogeny of the reproductive organs begins with the appearance of primary germ cells or gonocytes, which are detected already at

stage of a two-week embryo. Gonocytes migrate from the region of the intestinal ectoderm through the endoderm of the yolk sac to the region of the gonad primordia or genital ridges, where they divide by mitosis, forming a pool of future germ cells (up to day 32 of embryogenesis). The chronology and dynamics of further differentiation of gonocytes depend on the sex of the developing organism, while the ontogenesis of the gonads is associated with the ontogenesis of organs urinary system and adrenal glands, which together form the sex.

At the very beginning of ontogenesis, in a three-week embryo, in the area of ​​the nephrogenic cord (a derivative of the intermediate mesoderm), the rudiment of the tubules of the primary kidney (pre-kidney) or pronephros. At 3-4 weeks of development, caudal to the pronephros tubules (nephrotome area), the rudiment of the primary kidney is formed or mesonephros. By the end of 4 weeks, on the ventral side of the mesonephros, gonadal primordia begin to form, developing from the mesothelium and representing indifferent (bipotential) cell formations, and the pronephrotic tubules (ducts) connect with the mesonephros tubules, which are called Wolffian ducts. In turn, paramesonephric, or müllerian ducts are formed from areas of intermediate mesoderm, which are separated under the influence of the Wolffian duct.

At the distal end of each of the two Wolffian ducts, in the area of ​​their entry into the cloaca, outgrowths are formed in the form of ureteric rudiments. At 6-8 weeks of development, they grow into the intermediate mesoderm and form tubules metanephros- this is a secondary or final (definitive) kidney, formed by cells derived from the posterior parts of the Wolffian canals and nephrogenic tissue of the posterior part of the mesonephros.

Now let's look at the ontogeny of human biological sex.

Formation of the male gender

The formation of the male sex begins at 5-6 weeks of embryo development with transformations of the Wolffian ducts and is completed by the 5th month of fetal development.

At 6-8 weeks of embryo development, from the derivatives of the posterior parts of the Wolffian canals and the nephrogenic tissue of the posterior part of the mesonephros, mesenchyme grows along the upper edge of the primary kidney, forming a sex cord (cord), which divides, connecting with the tubules of the primary kidney, flowing into its duct, and gives

beginning of the seminiferous tubes of the testes. Excretory tracts are formed from the Wolffian ducts. The middle part of the Wolffian ducts lengthens and transforms into efferent ducts, and seminal vesicles are formed from the lower part. The upper part of the duct of the primary kidney becomes the epididymis (epididymis), and the lower part of the duct becomes the efferent canal. After this, the Müllerian ducts are reduced (atrophied), and only the upper ends (morgania hydatid) and lower ends (male uterus) remain. The latter is located in the thickness of the prostate gland (prostate) at the point where the vas deferens enters the urethra. The prostate, testes and Cooper's (bulbourethral) glands develop from the epithelium of the wall genitourinary sinus (urethra) under the influence of testosterone, the level of which in the blood of a 3-5 month old fetus reaches that in the blood of a sexually mature man, which ensures masculinization of the genital organs.

Under the control of testosterone, the structures of the internal male genital organs develop from the Wolffian ducts and tubules of the upper mesonephros, and under the influence of dihydrotestosterone (a derivative of testosterone), the external male genital organs are formed. The muscular and connective tissue elements of the prostate develop from the mesenchyme, and the lumens of the prostate form after birth during puberty. The penis is formed from the rudiment of the head of the penis in the genital tubercle. In this case, the genital folds grow together and form the skin part of the scrotum, into which protrusions of the peritoneum grow through the inguinal canal, into which the testicles are then displaced. The displacement of the testicles into the pelvis to the site of the future inguinal canals begins in the 12-week embryo. It depends on the action of androgens and chorionic hormone and occurs due to the displacement of anatomical structures. The testicles pass through the inguinal canals and reach the scrotum only at 7-8 months of development. If the descent of the testicles into the scrotum is delayed (due to various reasons, including genetic), unilateral or bilateral cryptorchidism develops.

Formation of the female gender

The formation of the female sex occurs with the participation of the Müllerian ducts, from which, at 4-5 weeks of development, the rudiments of the internal female genital organs are formed: the uterus, fallopian tubes,

the upper two thirds of the vagina. Canalization of the vagina, the formation of a cavity, body and cervix occur only in a 4-5 month old fetus through the development of mesenchyme from the base of the body of the primary kidney, which contributes to the destruction of the free ends of the reproductive cords.

The medulla of the ovaries is formed from the remains of the body of the primary kidney, and from the genital ridge (the rudiment of the epithelium), the genital cords continue to grow into the cortical part of the future ovaries. As a result of further germination, these strands are divided into primordial follicles, each of which consists of a gonocyte surrounded by a layer of follicular epithelium - this is a reserve for the formation of future mature oocytes (about 2 thousand) during ovulation. Ingrowth of the sex cords continues after the girl is born (until the end of the first year of life), but new primordial follicles are no longer formed.

At the end of the first year of life, the mesenchyme separates the beginning of the genital cords from the genital ridges, and this layer forms the connective tissue (albuginea) membrane of the ovary, on top of which the remains of the genital ridges are preserved in the form of inactive germinal epithelium.

Levels of sex differentiation and their disorders

Human gender is closely related to the characteristics of ontogenesis and reproduction. There are 8 levels of sex differentiation:

Genetic sex (molecular and chromosomal), or sex at the level of genes and chromosomes;

Gametic sex, or the morphogenetic structure of male and female gametes;

Gonadal sex, or morphogenetic structure of the testes and ovaries;

Hormonal sex, or the balance of male or female sex hormones in the body;

Somatic (morphological) sex, or anthropometric and morphological data on the genitals and secondary sexual characteristics;

Mental gender, or the mental and sexual self-determination of an individual;

Social gender, or determining the role of the individual in the family and society;

Civil gender, or gender recorded when issuing a passport. It is also called gender of education.

When all levels of gender differentiation coincide and all links of the reproductive process are normalized, a person develops with a normal biological male or female sex, normal sexual and generative potency, sexual identity, psychosexual orientation and behavior.

A diagram of the relationships between different levels of sex differentiation in humans is shown in Fig. 56.

The beginning of sex differentiation should be considered 5 weeks of embryogenesis, when the genital tubercle is formed through the proliferation of mesenchyme, potentially representing either the rudiment of the glans penis or the rudiment of the clitoris - this depends on the formation of the future biological sex. From about this time, the genital folds transform into either the scrotum or the labia. In the second case, the primary genital opening opens between the genital tubercle and the genital folds. Any level of sex differentiation is closely related to the formation of both normal reproductive function and its disorders, accompanied by complete or incomplete infertility.

Genetic sex

Gene level

The gene level of sex differentiation is characterized by the expression of genes that determine the direction of sexual differentiation of bipotential cell formations (see above) either according to the male or female type. It's about about an entire gene network, including genes located both on gonosomes and on autosomes.

As of the end of 2001, 39 genes were classified as genes controlling the ontogenesis of reproductive organs and differentiation of germ cells (Chernykh V.B., Kurilo L.F., 2001). Apparently there are even more of them now. Let's look at the most important of them.

There is no doubt that the central place in the network of genetic control of male sex differentiation belongs to the SRY gene. This single-copy, intronless gene is localized in the distal part of the short arm of the Y chromosome (Yp11.31-32). It produces testicular determination factor (TDF), also found in XX men and XY women.

Rice. 56. Scheme of relationships between different levels of sex differentiation in humans (according to Chernykh V.B. and Kurilo L.F., 2001). Genes involved in gonadal differentiation and ontogenesis of the genital organs: SRY, SOX9, DAX1, WT1, SF1, GATA4, DHH, DHT. Hormones and hormone receptors: FSH (follicle-stimulating hormone), LH (luteinizing hormone), AMH (anti-Mullerian hormone), AMHR (AMHR receptor gene), T, AR (androgen receptor gene), GnRH (gonadotropin-releasing hormone gene), GnRH-R (GnRH receptor gene), LH-R (LH receptor gene), FSH-R (FSH receptor gene). Signs: “-” and “+” indicate the absence and presence of an effect

Initially, activation of the SRY gene occurs in Sertoli cells, which produce anti-Müllerian hormone, which affects Leydig cells that are sensitive to it, which induces the development of seminiferous tubules and regression of the Müllerian ducts in the developing male body. A large number of point mutations associated with gonadal dysgenesis and/or sex inversion have been found in this gene.

In particular, the SRY gene can be deleted on the Y chromosome, and during chromosome conjugation in the prophase of the first meiotic division, it can be translocated to the X chromosome or any autosome, which also leads to gonadal dysgenesis and/or sex inversion.

In the second case, the organism of an XY woman develops, having cord-like gonads with female external genitalia and feminization of the physique (see below).

At the same time, the formation of a XX-male organism is likely, characterized by a male phenotype with a female karyotype - this is de la Chapelle's syndrome (see below). Translocation of the SRY gene to the X chromosome during meiosis in men occurs with a frequency of 2% and is accompanied by severe disorders of spermatogenesis.

In recent years, it has been noted that the process of male sexual differentiation involves a number of genes located outside the SRY locus (there are several dozen of them). For example, normal spermatogenesis requires not only the presence of male-differentiated gonads, but also the expression genes that control the development of germ cells. These genes include the azoospermia factor gene AZF (Yq11), microdeletions of which cause spermatogenesis disorders; with them, both an almost normal sperm count and oligozoospermia are observed. An important role belongs to genes located on the X chromosome and autosomes.

If localized on the X chromosome, this is the DAX1 gene. It is localized in Xp21.2-21.3, in the so-called dose-sensitive sex reversal locus (DDS). This gene is thought to be normally expressed in men and is involved in controlling the development of their testes and adrenal glands, which can lead to adrenogenital syndrome(AGS). For example, duplication of the DDS region has been found to be associated with sex reversal in XY individuals, and its loss is associated with a male phenotype and X-linked congenital adrenal insufficiency. In total, three types of mutations have been identified in the DAX1 gene: large deletions, single-nucleotide deletions, and base substitutions. All of them lead to hypoplasia of the adrenal cortex and testicular hypoplasia due to impaired differentiation

recruitment of steroidogenic cells during the ontogenesis of the adrenal glands and gonads, which is manifested by AGS and hypogonadotropic hypogonadism due to a deficiency of glucocorticoids, mineralocorticoids and testosterone. In such patients, severe disturbances of spermatogenesis (up to its complete block) and dysplasia of the cellular structure of the testicles are observed. And although patients develop secondary sexual characteristics, cryptorchidism is often observed due to testosterone deficiency during the migration of the testicles into the scrotum.

Another example of gene localization on the X chromosome is the SOX3 gene, which belongs to the SOX family and is one of the early developmental genes (see Chapter 12).

In the case of gene localization on autosomes, this is, firstly, the SOX9 gene, which is related to the SRY gene and contains an HMG box. The gene is localized on the long arm of chromosome 17 (17q24-q25). Its mutations cause campomelic dysplasia, manifested by multiple abnormalities of the skeleton and internal organs. In addition, mutations of the SOX9 gene lead to XY sex inversion (patients with a female phenotype and a male karyotype). In such patients, the external genitalia are developed according to the female type or have a dual structure, and their dysgenetic gonads may contain single germ cells, but are more often represented by streak structures (cords).

The following genes are a group of genes that regulate transcription during the differentiation of cells involved in gonadal ontogenesis. Among them are the genes WT1, LIM1, SF1 and GATA4. Moreover, the first 2 genes are involved in primary, and the second two genes - in secondary sex determination.

Primary determination of gonads by sex begins at 6 weeks of age of the embryo, and secondary differentiation is caused by hormones produced by the testes and ovaries.

Let's look at some of these genes. In particular, the WT1 gene, localized on the short arm of chromosome 11 (11p13) and associated with Wilms tumor. Its expression is found in the intermediate mesoderm, differentiating metanephros mesenchyme and gonads. The role of this gene as an activator, coactivator, or even a transcription repressor, necessary already at the stage of bipotential cells (before the stage of activation of the SRY gene), has been demonstrated.

It is assumed that the WT1 gene is responsible for the development of the genital tubercle and regulates the release of cells from the coelomic epithelium, which gives rise to Sertoli cells.

It is also believed that mutations in the WT1 gene can cause sex reversal when regulatory factors involved in sexual differentiation are deficient. These mutations are often associated with syndromes characterized by autosomal dominant inheritance, including WAGR syndrome, Denis-Drash syndrome, and Frazier syndrome.

For example, WAGR syndrome is caused by deletion of the WT1 gene and is accompanied by Wilms tumor, aniridia, birth defects development of the genitourinary system, mental retardation, gonadal dysgenesis and predisposition to gonadoblastomas.

Denis-Drash syndrome is caused by a missense mutation in the WT1 gene and is only sometimes combined with Wilms tumor, but it is almost always characterized by early manifestation of severe nephropathy with protein loss and disorders of sexual development.

Frazier syndrome is caused by a mutation in the donor splice site of exon 9 of the WT1 gene and is manifested by gonadal dysgenesis (female phenotype with a male karyotype), late start nephropathy and focal sclerosis of the glomeruli of the kidneys.

Let us also consider the SF1 gene, localized on chromosome 9 and acting as an activator (receptor) of transcription of genes involved in the biosynthesis steroid hormones. The product of this gene activates testosterone synthesis in Leydig cells and regulates the expression of enzymes that control the biosynthesis of steroid hormones in the adrenal glands. In addition, the SF1 gene regulates the expression of the DAX1 gene, which has an SF1 site in its promoter. It is assumed that during ovarian morphogenesis, the DAX1 gene prevents transcription of the SOX9 gene through repression of transcription of the SF1 gene. And finally, the CFTR gene, known as the cystic fibrosis gene, is inherited in an autosomal recessive manner. This gene is localized on the long arm of chromosome 7 (7q31) and encodes a protein responsible for the transmembrane transport of chlorine ions. Consideration of this gene is appropriate, since in male carriers of the mutant allele of the CFTR gene, bilateral absence of the vas deferens and abnormalities of the epididymis, leading to obstructive azoospermia, are often observed.

Chromosomal level

As you know, an egg always carries one X chromosome, while a sperm carries either one X chromosome or one Y chromosome (their ratio is approximately the same). If the egg is fertilized

is formed by a spermatozoon with an X chromosome, the future organism develops a female sex (karyotype: 46, XX; contains two identical gonosomes). If an egg is fertilized by a sperm with a Y chromosome, the male sex is formed (karyotype: 46, XY; contains two different gonosomes).

Thus, the formation of the male sex normally depends on the presence of one X and one Y chromosome in the chromosome set. The Y chromosome plays a decisive role in sex differentiation. If it is not there, then sex differentiation proceeds according to the female type, regardless of the number of X chromosomes. Currently, 92 genes have been identified on the Y chromosome. In addition to the genes that form the male sex, the following are localized on the long arm of this chromosome:

GBY (gonadoblastoma gene) or oncogene that initiates a tumor in dysgenetic gonads developing in mosaic forms with a 45,X/46,XY karyotype in individuals with a male and female phenotype;

GCY (growth control locus), located proximal to part of Yq11; its loss or disruption of sequences causes short stature;

SHOX (pseudoautosomal region I locus), involved in growth control;

The cell membrane protein gene or H-Y histocompatibility antigen, previously erroneously considered the main factor in sex determination.

Now let's look at genetic sex disorders at the chromosomal level. This type of disorder is usually associated with incorrect segregation of chromosomes in anaphase of mitosis and prophase of meiosis, as well as with chromosomal and genomic mutations, as a result of which, instead of having two identical or two different gonosomes and autosomes, there may be:

Numerical abnormalities of chromosomes, in which the karyotype reveals one or more additional gonosomes or autosomes, the absence of one of the two gonosomes, or their mosaic variants. Examples of such disorders include: Klinefelter syndromes - polysomy on the X chromosome in men (47, XXY), polysomy on the Y chromosome in men (47, XYY), triplo-X syndrome (polysomy on the X chromosome in women (47, XXX ), Shereshevsky-Turner syndrome (monosomy on the X chromosome in women, 45, X0), mosaic cases of aneuploidy on gonosomes; marker

Or mini-chromosomes derived from one of the gonosomes (its derivatives), as well as autosomal trisomy syndromes, including Down syndrome (47, XX, +21), Patau syndrome (47, XY, +13) and Edwards syndrome ( 47, XX, +18)). Structural abnormalities of chromosomes, in which a part of one gonosome or autosome is detected in the karyotype, which is defined as micro- and macrodeletions of chromosomes (loss of individual genes and entire sections, respectively). Microdeletions include: deletion of a section of the long arm of the Y chromosome (locus Yq11) and the associated loss of the AZF locus or azoospermia factor, as well as deletion of the SRY gene, leading to disorders of spermatogenesis, gonadal differentiation and XY sex inversion. In particular, the AZF locus contains a number of genes and gene families responsible for certain stages of spermatogenesis and fertility in men. The locus has three active subregions: a, b and c. The locus is present in all cells except red blood cells. However, the locus is active only in Sertoli cells.

It is believed that the mutation rate of the AZF locus is 10 times higher than the mutation rate in autosomes. The cause of male infertility is the high risk of transmitting Y-deletions affecting this locus to sons. In recent years, locus research has become mandatory rule during in vitro fertilization (IVF), as well as in men with a sperm count of less than 5 million/ml (azoospermia and severe oligospermia).

Macrodeletions include: de la Chapelle syndrome (46, XX-male), Wolf-Hirschhorn syndrome (46, XX, 4p-), “cry of the cat” syndrome (46, XY, 5p-), partial monosomy syndrome of chromosome 9 ( 46, XX, 9р-). For example, de la Chapelle syndrome is hypogonadism with a male phenotype, male psychosocial orientation and female genotype. Clinically, it is similar to Klinefelter syndrome, combined with testicular hypoplasia, azoospermia, hypospadias (testosterone deficiency due to intrauterine insufficiency of its synthesis by Leydig cells), moderate gynecomastia, ocular symptoms, impaired cardiac conduction and growth retardation. Pathogenetic mechanisms are closely related to the mechanisms of true hermaphroditism (see below). Both pathologies develop sporadically, often in the same families; most cases of SRY are negative.

In addition to micro- and macrodeletions, peri- and paracentric inversions are distinguished (a section of a chromosome turns over 180° inside the chromosome involving the centromere or inside an arm without involving the centromere). According to the latest chromosome nomenclature, inversion is indicated by the symbol Ph. In patients with infertility and miscarriage, mosaic spermatogenesis and oligospermia associated with inversions of the following chromosomes are often detected:

Chromosome 1; Ph 1p34q23 is often observed, causing a complete block of spermatogenesis; Ph 1p32q42 is detected less frequently, leading to a block of spermatogenesis at the pachytene stage;

Chromosomes 3, 6, 7, 9, 13, 20 and 21.

Reciprocal and non-reciprocal translocations (mutual equal and unequal exchange between non-homologous chromosomes) occur between chromosomes of all classified groups. An example of a reciprocal translocation is Y-autosomal translocation, accompanied by impaired sex differentiation, reproduction and infertility in men due to aplasia of the spermatogenic epithelium, inhibition or block of spermatogenesis. Another example is rare translocations between X-Y, Y-Y gonosomes. The phenotype in such patients can be female, male or dual. In men with Y-Y translocation, oligo or azoospermia is observed as a result of partial or complete block of spermatogenesis at the stage of formation of spermatocyte I.

A special class is Robertsonian-type translocations between acrocentric chromosomes. They occur in men with impaired spermatogenesis and/or infertility more often than reciprocal translocations. For example, the Robertsonian translocation between chromosomes 13 and 14 leads to either a complete absence of spermatogonia in the seminiferous tubules or to minor changes in their epithelium. In the second case, men can maintain fertility, although most often they exhibit a block of spermatogenesis at the spermatocyte stage. The class of translocations also includes polycentric or dicentric chromosomes (with two centromeres) 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 reproductive disorders. The latter are structures closed in a ring involving the centromere. Their formation is associated with damage to both arms of the chromosome, resulting in the free ends of its fragment

Gametic sex

For illustration possible reasons and the mechanisms of violations of the gametic level of sex differentiation, we will consider, based on electron microscopy data, the process of gamete formation during normal meiosis. In Fig. 57 shows a model of the synaptonemal complex (SC), reflecting the sequence of events during synapsis and desynapsis of chromosomes involved in crossing over.

At the initial stage of the first division of meiosis, corresponding to the end of interphase (proleptotene stage), the homologous parental chromosomes are decondensed, and axial elements are visible in them, beginning to form. Each of the two elements includes two sister chromatids (1 and 2, and 3 and 4, respectively). At this and the next (second) stage - leptotene - the direct formation of axial elements of homologous chromosomes occurs (chromatin loops are visible). The beginning of the third stage - zygotene - is characterized by preparation for the assembly of the central element of the SC, and at the end of zygotene synapsis or conjugation(sticking along

Rice. 57. Model of the synaptonemal complex (after Preston D., 2000). The numbers 1, 2 and 3, 4 indicate sister chromatids of homologous chromosomes. Other explanations are given in the text

length) of two lateral elements of the SC, together forming a central element, or a bivalent, including four chromatids.

During zygotene, homologous chromosomes are oriented with their telomeric ends towards one of the poles of the nucleus. The formation of the central element of the SC is completely completed at the next (fourth) stage - pachytene, when, as a result of the conjugation process, a haploid number of sexual bivalents is formed. Each bivalent has four chromatids - this is the so-called chromomeric structure. Starting from the pachytene stage, the sexual bivalent gradually shifts to the periphery of the cell nucleus, where it is transformed into a dense reproductive body. In the case of male meiosis, this will be a sperm of the first order. At the next (fifth) stage - diplotene - the synapsis of homologous chromosomes is completed and their desynapsis or mutual repulsion occurs. In this case, the SC is gradually reduced and is preserved only in areas of the chiasmata or zones in which crossing over or recombination exchange of hereditary material between chromatids directly occurs (see Chapter 5). Such zones are called recombination nodes.

Thus, the chiasm is a region of the chromosome in which two of the four chromatids of the sexual bivalent enter into crossing over with each other. It is the chiasmata that hold homologous chromosomes in one pair and ensure the divergence of homologues to different poles in anaphase I. The repulsion that occurs in diplotene continues at the next (sixth) stage - diakinesis, when modification of the axial elements occurs with separation of the chromatid axes. Diakinesis ends with the condensation of 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 the axial elements or two lateral (oval) strands - the rods of the central space of the SC with the formation of thin transverse lines between them. In the central space of the SC between the side rods, a dense zone of overlapping transverse lines is visible, and chromatin loops extending from the side rods are visible. The lighter ellipse in the central space of the SC is a recombination nodule. During further meiosis (for example, male) at the onset of anaphase II, four chromatids diverge, forming univalents along separate gonosomes X and Y, and thus four sister cells, or spermatids, are formed from each dividing cell. Each spermatid has a haploid set

chromosomes (reduced by half) and contains recombined genetic material.

During the period of puberty in the male body, spermatids enter spermatogenesis and, thanks to a series of morphophysiological transformations, transform into functionally active spermatozoa.

Gametic sex disorders are either the result of impaired genetic control of the migration of primordial germ cells (PPCs) into the gonad anlage, which leads to a decrease in the number or even complete absence Sertoli cells (Sertoli cell syndrome), or the result of meiotic mutations that cause disruption of the conjugation of homologous chromosomes in zygotene.

As a rule, violations of gametic sex are caused by abnormalities of chromosomes in the gametes themselves, which, for example, in the case of male meiosis is manifested by oligo-, azoo- and teratozoospermia, which negatively affects the reproductive ability of a man.

It has been shown that abnormalities of chromosomes in gametes lead to their elimination, death of the zygote, embryo, fetus and newborn, cause absolute and relative male and female infertility, and are the causes of spontaneous abortions, missed pregnancies, stillbirths, births of children with developmental defects and early infant mortality.

Gonadal sex

Differentiation of the gonadal sex involves the creation in the body of the morphogenetic structure of the gonads: either testes or ovaries (see Fig. 54 above).

When changes in gonadal sex are caused by genetic and environmental factors, the main disorders are: age-

Rice. 58. Schematic representation of the central space of the synaptonemal complex (according to Sorokina T.M., 2006)

nesia or gonadal dysgenesis (including mixed type) and true hermaphroditism. The reproductive system of both sexes develops at the beginning of intrauterine ontogenesis according to a single plan in parallel with the development of the excretory system and adrenal glands - the so-called indifferent stage. The first formation of the reproductive system in the form of coelomic epithelium occurs in the embryo on the surface of the primary kidney - the Wolffian body. Then comes the stage of gonoblasts (epithelium of the genital ridges), from which gonocytes develop. They are surrounded by follicular epithelial cells that provide trophism.

Strands consisting of gonocytes and follicular cells enter the stroma of the primary kidney from the genital ridges, and at the same time the Müllerian (paramesonephric) duct runs from the body of the primary kidney to the cloaca. Next comes the separate development of male and female gonads. What happens is this:

A. Male gender. Mesenchyme grows along the upper edge of the primary kidney, forming a sex cord (cord), which divides, connecting with the tubules of the primary kidney, flowing into its duct, and gives rise to the seminiferous tubules of the testes. In this case, the efferent tubules are formed from the renal tubules. Further top part The duct of the primary kidney becomes an appendage of the testis, and the lower one turns into the vas deferens. The testes and prostate develop from the wall of the urogenital sinus.

The action of male gonadal hormones (androgens) depends on the action of hormones of the anterior pituitary gland. The production of androgens is ensured by the joint secretion of interstitial cells of the testes, spermatogenic epithelium and supporting cells.

The prostate is a glandular-muscular organ consisting of two lateral lobes and an isthmus (middle lobe). There are about 30-50 glands in the prostate, their secretion is released into the vas deferens at the moment of ejaculation. To the products secreted by the seminal vesicles and prostate (primary sperm), as they move along the vas deferens and urethra, the mucoid and similar products of the bulbourethral glands or Cooper cells are added (in the upper part of the urethra). All these products are mixed and come out in the form of definitive sperm - a liquid with a slightly alkaline reaction, which contains sperm and contains substances necessary for their functioning: fructose, citric acid,

zinc, calcium, ergotonin, a number of enzymes (proteinases, glucosidases and phosphatases).

B. Female. Mesenchyme develops at the base of the body of the primary kidney, which leads to the destruction of the free ends of the reproductive cords. In this case, the duct of the primary kidney atrophies, and the Müllerian duct, on the contrary, differentiates. Its upper parts become the fallopian tubes, the ends of which open into funnels and enclose the ovaries. The lower parts of the Müllerian ducts merge and give rise to the uterus and vagina.

The medulla of the ovaries becomes the remains of the body of the primary kidney, and from the genital ridge (the rudiment of the epithelium) the genital cords continue to grow into the cortical part of the future ovaries. The products of the female gonads are follicle-stimulating hormone (estrogen) or folliculin and progesterone.

Follicular growth, ovulation, cyclic changes in the corpus luteum, alternation of estrogen and progesterone production are determined by the relationships (shifts) between the gonadotropic hormones of the pituitary gland and specific activators of the adrenohypophysiotropic zone of the hypothalamus, which controls the pituitary gland. Therefore, violations of regulatory mechanisms at the level of the hypothalamus, pituitary gland and ovaries, which have developed, for example, as a result of tumors, traumatic brain injuries, infection, intoxication or psycho-emotional stress, upset sexual function and become the causes of premature puberty or menstrual irregularities.

Hormonal gender

Hormonal sex is the maintenance of a balance of male and female sex hormones (androgens and estrogens) in the body. The determining beginning of the development of the body according to the male type are two androgenic hormones: anti-Müllerian hormone, or AMH (MIS factor), which causes regression of the Müllerian ducts, and testosterone. The MIS factor is activated by the GATA4 gene, located in 19p13.2-33 and encoding a protein - a glycoprotein. Its promoter contains a site that recognizes the SRY gene, which is bound by the consensus sequence AACAAT/A.

Secretion of the hormone AMN begins at 7 weeks of ebryogenesis and continues until puberty, then sharply drops in adults (maintaining a very low level).

AMN is believed to be necessary for testicular development, sperm maturation, and inhibition of tumor cell growth. Under the control of testosterone, the internal male genital organs are formed from the Wolffian ducts. This hormone is converted into 5-alphatestosterone, and with its help the external male genitalia are formed from the urogenital sinus.

Testosterone biosynthesis is activated in Leydig cells by the transcriptional activator encoded by the SF1 gene (9q33).

Both of these hormones have both local and general action on the masculinization of extragenital target tissues, which causes sexual dysmorphism of the central nervous system, internal organs and body size.

Thus, an important role in the final formation of the external male genitalia belongs to androgens produced in the adrenal glands and testicles. Moreover, it is necessary not only normal level androgens, but their normally functioning receptors, otherwise androgen insensitivity syndrome (ATS) develops.

The androgen receptor is encoded by the AR gene, located in Xq11. Over 200 point mutations (mostly single nucleotide substitutions) associated with receptor inactivation have been identified in this gene. In turn, estrogens and their receptors play an important role in secondary sex determination in men. They are necessary to improve their reproductive function: maturation of sperm (increasing their quality indicators) and bone tissue.

Hormonal sex disorders occur due to defects in the biosynthesis and metabolism of androgens and estrogens involved in the regulation of the structure and functioning of the organs of the reproductive system, which causes the development of a number of congenital and hereditary diseases, such as AGS, hypergonadotropic hypogonadism, etc. For example, the external genitalia in men are formed by female type with a deficiency or complete absence of androgens, regardless of the presence or absence of estrogens.

Somatic gender

Somatic (morphological) sex disorders can be caused by defects in the formation of sex hormone receptors in target tissues (organs), which is associated with the development of a female phenotype with a male karyotype or complete testicular feminization syndrome (Morris syndrome).

The syndrome is characterized by an X-linked type of inheritance and is the most common cause of false male hermaphroditism, manifested in complete and incomplete forms. These are patients with a female phenotype and a male karyotype. Their testicles are located intraperitoneally or along the inguinal canals. The external genitalia have varying degrees of masculinization. Derivatives of the Müllerian ducts - the uterus, fallopian tubes - are absent, the vaginal process is shortened and ends blindly.

Derivatives of the Wolffian ducts - the vas deferens, seminal vesicles and epididymis - are hypoplastic to varying degrees. During puberty, patients experience normal development mammary glands, with the exception of pallor and a decrease in the diameter of the nipple areolas, scanty pubic and axillary hair. Sometimes secondary hair growth is absent. In patients, the interaction of androgens and their specific receptors is disrupted, so genetic men feel like women (unlike transsexuals). Histological examination reveals hyperplasia of Leydig cells and Sertoli cells, as well as the absence of spermatogenesis.

An example of incomplete testicular feminization is Reifenstein syndrome. It is usually a male phenotype with hypospadias, gynecomastia, male karyotype and infertility. However, there may be a male phenotype with significant defects in masculinization (micropenis, perineal hypospadias and cryptorchidism), as well as a female phenotype with moderate clitoromegaly and slight fusion of the labia. In addition, in phenotypic men with complete masculinization, soft form testicular feminization syndrome with gynecomastia, oligozoospermia or azoospermia.

Mental, social and civil gender

Consideration of mental, social and civil gender disorders in humans is not the purpose of this textbook, since such disorders relate to deviations in sexual identity and self-education, sexual orientation and gender role of the individual, and similar mental, psychological and other socially significant factors of sexual development.

Let's consider the example of transsexualism (one of the common mental gender disorders), accompanied by an individual's pathological desire to change his gender. Often this syndrome

called sexual-aesthetic inversion (eolism) or mental hermaphroditism.

Auto-identification and sexual behavior of an individual are laid down in the prenatal period of the body’s development through the maturation of the structures of the hypothalamus, which in some cases can lead to the development of transsexuality (intersexuality), i.e. duality of the structure of the external genitalia, for example, with AGS. This duality leads to incorrect registration of civil (passport) gender. Leading symptoms: inversion of gender identity and socialization of the individual, manifested in rejection of one’s gender, psychosocial disadaptation and self-destructive behavior. Average age Patients are usually 20-24 years old. Male transsexualism is much more common than female transsexualism (3:1). Familial cases and cases of transsexualism among monozygotic twins have been described.

The nature of the disease is unclear. Psychiatric hypotheses are generally not confirmed. To some extent, the explanation may be hormone-dependent differentiation of the brain, which occurs in parallel with the development of the genitalia. For example, the level of sex hormones and neurotransmitters during critical periods of child development has been shown to be associated with gender identification and psychosocial orientation. In addition, it is assumed that the genetic background of female transsexualism may be 21-hydroxylase deficiency in the mother or fetus, caused by prenatal stress, the frequency of which is significantly higher in patients compared with the general population.

The causes of transsexualism can be viewed from two perspectives.

First position- this is a violation of the differentiation of mental sex due to a discrepancy between the differentiation of the external genitalia and the differentiation of the sex center of the brain (advance of the first and lag of the second differentiation).

Second position is a violation of the differentiation of biological sex and the formation of subsequent sexual behavior as a result of a defect in sex hormone receptors or their abnormal expression. It is possible that these receptors may be located in brain structures necessary for the formation of subsequent sexual behavior. It should also be noted that transsexualism is the opposite of testicular syndrome

feminization, in which patients never have doubts about their belonging to female. In addition, this syndrome should be distinguished from transvestism syndrome as a psychiatric problem.

Classifications of genetic disorders of reproduction

Currently, there are many classifications of genetic reproductive disorders. As a rule, they take into account the characteristics of sex differentiation, genetic and clinical polymorphism in disorders of sexual development, the spectrum and frequency of genetic, chromosomal and hormonal disorders and other features. Let's consider one of the latest, most complete classifications (Grumbach M. et al., 1998). It highlights the following.

I. Disorders of gonadal differentiation.

True hermaphroditism.

Gonadal dysgenesis in Klinefelter syndrome.

Gonadal dysgenesis syndrome and its variants (Shereshevsky-Turner syndrome).

Complete and incomplete forms of XX-dysgenesis and XY-dysgenesis of the gonads. As an example, consider gonadal dysgenesis with karyotype 46,XY. If the SRY gene determines the differentiation of gonads into testes, then its mutations lead to gonadal dysgenesis in XY embryos. These are individuals with a female phenotype, tall stature, male build and karyotype. They exhibit a female or dual structure of the external genitalia, there is no development of the mammary glands, primary amenorrhea, scanty sexual hair growth, uterine hypoplasia and fallopian tubes and the gonads themselves, which are represented by connective tissue cords located high in the pelvis. This syndrome is often called a pure form of gonadal dysgenesis with a 46,XY karyotype.

II. Female false hermaphroditism.

Androgen-induced.

Congenital adrenal hypoplasia or AHS. This is a common autosomal recessive disorder, which in 95% of cases results from deficiency of the enzyme 21-hydroxylase (cytochrome P45 C21). It is divided into the “classical” form (frequency in the population 1:5000-10000 newborns) and the “non-classical” form (frequency 1:27-333) depending on the clinical manifestation. 21-hydroxylase gene

(CYP21B) is mapped to the short arm of chromosome 6 (6p21.3). In this locus, two tandemly located genes have been identified - the functionally active CYP21B gene and the CYP21A pseudogene, which is inactive due to either a deletion in exon 3, or a frameshift insertion in exon 7, or a nonsense mutation in exon 8. The presence of a pseudogene leads to chromosome pairing disorders in meiosis and, consequently, to gene conversion (movement of a fragment of the active gene to a pseudogene) or deletion of part of the sense gene, which disrupts the function of the active gene. Gene conversion accounts for 80% of mutations, and deletions account for 20% of mutations.

Aromatase deficiency or mutation of the CYP 19 gene, ARO (P450 - aromatase gene), is localized in the 15q21.1 segment.

Receipt of androgens and synthetic progestogens from the mother.

Non-androgen-induced, caused by teratogenic factors and associated with malformations of the intestine and urinary tract.

III. Male false hermaphroditism.

1. Insensitivity of testicular tissue to hCG and LH (agenesis and cell hypoplasia).

2. Birth defects testosterone biosynthesis.

2.1. Defects of enzymes affecting the biosynthesis of corticosteroids and testosterone (variants of congenital adrenal hyperplasia):

■ STAR defect (lipoid form of congenital adrenal hyperplasia);

■ 3 beta-HSD deficiency (3 betahydrocorticoid dehydrogenase);

■ deficiency of the CYP 17 gene (cytochrome P450C176 gene) or 17alpha-hydroxylase-17,20-lyase.

2.2. Enzyme defects that primarily disrupt testosterone biosynthesis in the testes:

■ CYP 17 deficiency (cytochrome P450C176 gene);

■ 17 beta-hydrosteroid dehydrogenase deficiency, type 3 (17 beta-HSD3).

2.3. Defects in the sensitivity of target tissues to androgens.

■ 2.3.1. Androgen insensitivity (resistance):

syndrome of complete testicular feminization (syndrome

Morris);

syndrome of incomplete testicular feminization (Reifenstein disease);

Androgen insensitivity in phenotypically normal men.

■ 2.3.2. Defects in testosterone metabolism peripheral tissues- gamma reductase 5 deficiency (SRD5A2) or pseudovaginal perineoscrotal hypospadias.

■ 2.3.3. Dysgenetic male pseudohermaphroditism:

incomplete XY gonadal dysgenesis (mutation of the WT1 gene) or Frazier syndrome;

X/XY mosaicism and structural anomalies (Xp+, 9p-,

missense mutation of the WT1 gene or Denis-Drash syndrome; WT1 gene deletion or WAGR syndrome; SOX9 gene mutation or campomelic dysplasia; SF1 gene mutation;

X-linked testicular feminization or Morris syndrome.

■ 2.3.4. Defects in the synthesis, secretion and response to anti-Mullerian hormone - persistent Müllerian duct syndrome

■ 2.3.5. Dysgenetic male pseudohermaphroditism caused by maternal progestogens and estrogens.

■ 2.3.6. Dysgenetic male pseudohermaphroditism caused by exposure chemical factors environment.

IV. Unclassified forms of anomalies of sexual development in men: hypospadias, dual development of the genitals in XY men with mCD.

GENETIC CAUSES OF INFERTILITY

The genetic causes of infertility include: synaptic and desynaptic mutations, abnormal synthesis and assembly of SC components (see gametic sex above).

A certain role is played by the abnormal condensation of chromosome homologues, leading to the masking and disappearance of the initiation points of conjugation and, consequently, meiosis errors that occur in any of its phases and stages. A small part of the disorders occurs due to synaptic defects in the prophase of the first division in

in the form of asynaptic mutations that inhibit spermatogenesis up to the pachytene stage in prophase I, which leads to an excess of the number of cells in leptotene and zygotene, the absence of a sex vesicle in pachytene, causing the presence of a non-conjugating bivalent segment and an incompletely formed synaptonemal complex.

More common are desynaptic mutations, which block gametogenesis until the metaphase I stage, causing defects in the SC, including its fragmentation, complete absence or irregularity, and asymmetry of chromosome conjugation.

At the same time, partially synapted bi- and multisynaptonemal complexes can be observed, their associations with sexual XY-bivalents, which are not shifted to the periphery of the nucleus, but “anchored” in its central part. Sex bodies are not formed in such nuclei, and cells with these nuclei are subject to selection at the pachytene stage - this is the so-called disgusting arrest.

Classification of genetic causes of infertility

1. Gonosomal syndromes (including mosaic forms): Klinefelter syndromes (karyotypes: 47,XXY and 47,XYY); YY-aneuploidy; gender inversion (46,XX and 45,X - men); structural mutations of the Y chromosome (deletions, inversions, ring chromosomes, isochromosomes).

2. Autosomal syndromes caused by: reciprocal and Robertsonian translocations; other structural rearrangements (including marker chromosomes).

3. Syndromes caused by trisomy of chromosome 21 (Down's disease), partial duplications or deletions.

4. Chromosomal heteromorphisms: inversion of chromosome 9, or Ph (9); familial Y chromosome inversion; increased heterochromatin of the Y chromosome (Ygh+); increased or decreased pericentromeric constitutive heterochromatin; enlarged or duplicated satellites of acrocentric chromosomes.

5. Chromosomal aberrations in sperm: severe primary testiculopathy (consequences of radiation therapy or chemotherapy).

6. Mutations of Y-linked genes (for example, microdeletion in the AZF locus).

7. Mutations of X-linked genes: androgen insensitivity syndrome; Kalman and Kennedy syndromes. Consider Kalman syndrome - this is a congenital (often familial) disorder of gonadotropin secretion in individuals of both sexes. The syndrome is caused by a defect in the hypothalamus, manifested by a deficiency of gonadotropin-releasing hormone, 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 in the olfactory nerves and is manifested by anosmia or hyposmia. In sick men, eunuchoidism is observed (the testicles remain at the pubertal level in size and consistency), there is no color vision, there is congenital deafness, cleft lip and palate, cryptorchidism and bone pathology with shortening of the IV metacarpal bone. Sometimes gynecomastia occurs. Histological examination reveals immature seminiferous tubules lined by Sertoli cells, spermatogonia or primary spermatocytes. Leydig cells are absent, instead there are mesenchymal precursors that, with the introduction of gonadotropins, develop into Leydig cells. The X-linked form of Kallmann syndrome is caused by a mutation in the KAL1 gene, which encodes anosmin. This protein plays a key role in the migration of secreting cells and the growth of olfactory nerves to the hypothalamus. Autosomal dominant and autosomal recessive inheritance of this disease has also been described.

8. Genetic syndromes in which infertility is the leading symptom: mutations of the cystic fibrosis gene, accompanied by the absence of vas deferens; CBAVD and CUAVD syndromes; mutations in genes encoding the beta subunit of LH and FSH; mutations in genes encoding receptors for LH and FSH.

9. Genetic syndromes in which infertility is not the leading symptom: insufficiency of the activity of steroidogenesis enzymes (21-beta-hydroxylase, etc.); insufficiency of reductase activity; Fanconi anemia, hemochromatosis, betathalassemia, myotonic dystrophy, cerebellar ataxia with hypogonadotropic hypogonadism; Bardet-Biedl, Noonan, Prader-Willi and Prune-Belli syndromes.

Infertility in women happens with the following violations. 1. Gonosomal syndromes (including mosaic forms): Shereshevsky-Turner syndrome; gonadal dysgenesis with short stature -

karyotypes: 45,X; 45Х/46,ХХ; 45,Х/47,ХХХ; Xq isochromosome; del(Xq); del(Xp); r(X).

2. Gonadal dysgenesis with a cell line carrying the Y chromosome: mixed gonadal dysgenesis (45,X/46,XY); gonadal dysgenesis with karyotype 46,XY (Swyer syndrome); gonadal dysgenesis with true hermaphroditism with a cell line that carries the Y chromosome or has translocations between the X chromosome and autosomes; gonadal dysgenesis in triplo-X syndrome (47,XXX), including mosaic forms.

3. Autosomal syndromes caused by inversions or reciprocal and Robertsonian translocations.

4. Chromosomal aberrations in the oocytes of women over 35 years of age, as well as in the oocytes of women with a normal karyotype, in which 20% of oocytes or more may have chromosomal abnormalities.

5. Mutations in X-linked genes: full form of testicular feminization; Fragile X syndrome (FRAXA, fraX syndrome); Kallmann syndrome (see above).

6. Genetic syndromes in which infertility is the leading symptom: mutations in the genes encoding the FSH subunit, LH and FSH receptors and the GnRH receptor; BPES (blepharophimosis, ptosis, epicanthus), Denis-Drash and Frazier syndromes.

7. Genetic syndromes in which infertility is not the leading symptom: lack of aromatic activity; deficiency of steroidogenesis enzymes (21-beta-hydroxylase, 17-beta-hydroxylase); beta thalassemia, galactosemia, hemochromatosis, myotonic dystrophy, cystic fibrosis, mucopolysaccharidosis; DAX1 gene mutations; Prader-Willi syndrome.

However, this classification does not take into account a number of hereditary diseases associated with male and female infertility. In particular, it did not include a heterogeneous group of diseases united by the common name “autosomal recessive Kartagener syndrome”, or the syndrome of immobility of cilia of ciliated epithelial cells of the upper respiratory tract, sperm flagella, and oviduct villous fibria. For example, to date, more than 20 genes have been identified that control the formation of sperm flagella, including a number of gene mutations

DNA11 (9p21-p13) and DNAH5 (5p15-p14). This syndrome is characterized by the presence of bronchiectasis, sinusitis, complete or partial inversion of internal organs, malformations of the chest bones, congenital heart disease, polyendocrine insufficiency, pulmonary and cardiac infantilism. Men and women with this syndrome are often, but not always, infertile, since their infertility depends on the degree of damage to the motor activity of the sperm flagella or the fibria of the oviduct villi. In addition, patients have secondary developed anosmia, moderate hearing loss, and nasal polyps.

CONCLUSION

As an integral part of the general genetic development program, the ontogeny of the organs of the reproductive system is a multi-link process that is extremely sensitive to the action of a wide range of mutagenic and teratogenic factors that determine the development of hereditary and congenital diseases, reproductive dysfunction and infertility. Therefore, the ontogenesis of the organs of the reproductive system is the most clear demonstration of the common causes and mechanisms of development and formation of both normal and pathological functions associated with the main regulatory and protective systems of the body.

It is characterized by a number of features.

In the gene network involved in the ontogenesis of the human reproductive system, there are: in the female body - 1700+39 genes, in the male body - 2400+39 genes. It is possible that in the coming years the entire gene network of the reproductive system organs will take second place in the number of genes after the network of neuroontogenesis (with 20 thousand genes).

The action of individual genes and gene complexes within this gene network is closely related to the action of sex hormones and their receptors.

Numerous chromosomal disorders of sex differentiation associated with chromosome nondisjunction in anaphase of mitosis and prophase of meiosis, numerical and structural abnormalities of gonosomes and autosomes (or their mosaic variants) have been identified.

Disturbances in the development of somatic sex associated with defects in the formation of sex hormone receptors in target tissues and the development of a female phenotype with a male karyotype - complete testicular feminization syndrome (Morris syndrome) have been identified.