Reproductive dysfunction in men. Such problems include

The population of many developed countries is faced with the acute problem of male and female infertility. 15% of married couples in our country have a violation reproductive function. Some statistical calculations say that the percentage of such families is even higher. In 60% of cases, the reason for this is female infertility, and in 40% of cases, male infertility.

Causes of male reproductive disorders

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

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

excretory disorder. Violation of the patency (obstruction, obturation) of the vas deferens, as a result of which the exit of the components of the sperm into the urethra through the genital tract is disturbed. It can be permanent or temporary, unilateral or bilateral. The composition of semen includes spermatozoa, the secret of the prostate gland and the secret of the seminal vesicles.

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

Other reasons:

• Sexy. Erectile dysfunction, ejaculation disorders.
• Psychological. Anejaculation (lack of ejaculation).
• Neurological (due to damage spinal cord).

Causes of violations of female reproductive function

• Hormonal
• Tumors of the testicles (cystoma)
• Consequences of inflammatory processes in the small pelvis. These include the formation of adhesions, tubal-peritoneal factor, or, in other words, obstruction fallopian tubes.
• endometriosis
• Tumors of the uterus (myomas)

Treatment of female infertility

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

In the case of endocrine pathology, treatment consists in normalizing hormonal background, as well as in the use of ovarian stimulating drugs.

With obstruction of the tubes, 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 identified. As a rule, in this embodiment, ECO technologies are used - artificial insemination.

Treatment male infertility

If a man has infertility, which is of a secretory nature, that is, associated with a violation of spermatogenesis, the beginning of treatment consists in eliminating the causes. are being treated infectious diseases, are eliminated inflammatory processes, apply hormonal agents to normalize spermatogenesis.

If a man has diseases such as inguinal hernia, cryptorchidism, varicocele and others, surgical treatment is prescribed. Surgical intervention is also indicated in cases where a man is infertile due to obstruction of the vas deferens. The greatest difficulty is the treatment of male infertility in case of exposure to autoimmune factors, when sperm motility is impaired, antisperm bodies act. In this option, assign hormonal preparations, use laser therapy, as well as plasmapheresis and more.

Most of the known mutations lead to the absence or delay of puberty and, as a result, to infertility. However, people who have normal sexual development turn to the doctor about infertility. Examination for the majority of mutations that lead to infertility has no practical meaning now. However, some cases deserve special mention because they occur frequently in everyday practice.

Bilateral aplasia of the vas deferens

Bilateral aplasia of the vas deferens is present in 1-2% infertile men. According to most data, in 75% of cases, mutations in the CF gene are found, leading to cystic fibrosis. The main risk in such cases is the possibility of giving birth to a child with cystic fibrosis. It is necessary to examine for the presence of mutations in both partners, and then conduct appropriate counseling. If both partners are carriers of cystic fibrosis, its risk in a child reaches 25% (depending on the nature of the mutation). Even if only one mutation is found in a man, leading to cystic fibrosis, and the woman is not a carrier, it is better to play it safe and send the couple for a consultation with a geneticist. In about 20% of cases, bilateral aplasia of the vas deferens is accompanied by malformations of the kidneys, and in one study in such patients, mutations leading to cystic fibrosis were not detected (although the number of mutations analyzed was small).

It should be emphasized that the purpose of a mass examination is to identify cystic fibrosis, and not aplasia. The combinations of mutations leading to aplasia of the vas deferens are varied and complex, making counseling difficult in this disease. In the first studies on the genetics of bilateral vas deferens aplasia, there was not a single participant homozygous for the AF508 mutation, the most common mutation in the CF gene, which occurs in 60-70% of cases in the classic form of cystic fibrosis. Approximately 20% of patients immediately find two mutations in the CF gene characteristic of cystic fibrosis - in many cases these are missense mutations (a combination of two alleles that cause a mild form of cystic fibrosis, or one allele that causes a mild form of the disease and one severe). A polymorphism was also found in intron 8, in which the number of thymines in different alleles is 5, 7, or 9. In the presence of the 5T allele, exon 9 is skipped during transcription, and the mRNA, and subsequently the protein, are shortened. The most common genotype in bilateral aplasia of the vas deferens (about 30% of cases) is a combination of an allele carrying a mutation that causes cystic fibrosis and the 5T allele.

The R117H mutation is included in the screening because its combination with other, more severe mutations in the CF gene can cause cystic fibrosis. If the R117H mutation is detected, a derivative test is performed for the presence of the 5T/7T/9T polymorphism. When the 5T allele is detected, it is necessary to establish whether it is on the same chromosome with R117H (i.e., in the cis position) or on the other (in the trans position). The 5T allele in the “c-position relative to R117H causes cystic fibrosis, and if a woman is also a carrier of one of the alleles, disease-causing, the risk of cystic fibrosis in a child is 25%. The complexity of the genetics of cystic fibrosis becomes apparent when looking at the diversity of phenotypes in homozygotes for the 5T allele. The presence of the 5T allele reduces the stability of mRNA, and it is known that in patients whose level of unchanged mRNA is 1-3% of the norm, cystic fibrosis develops in the classical form. At the level of unchanged mRNA, which is more than 8-12% of the norm, the disease does not manifest itself, and at intermediate levels, various options are possible, from the complete absence of manifestations of the disease to bilateral aplasia of the vas deferens and mild form cystic fibrosis. It should also be noted that aplasia of the vas deferens in mild cases can also be unilateral. Among the general population, the 5T allele occurs with a frequency of about 5%, with unilateral aplasia of the vas deferens - with a frequency of 25%, and with bilateral aplasia - with a frequency of 40%.

American College medical geneticists and the American College of Obstetricians and Gynecologists recommend identifying only 25 mutations that have a prevalence of at least 0.1% in the US population, and testing for 5T/7T/9T polymorphisms only as a derived test. However, in practice, many laboratories can reduce costs by including this assay in their main program, which, as shown above, can lead to enormous difficulties in interpreting the results. It should be remembered that the purpose of a mass examination is to identify cystic fibrosis.

Genes that regulate spermatogenesis

The genes presumably responsible for spermatogenesis are mapped on the Y chromosome in the AZF region located at the Yq11 locus (the SR Y gene is located on the short arm of the Y chromosome). In the direction from the centromere to the distal part of the arm, the AZFa, AZFb, and AZFc regions are successively located. The AZFa region contains the USP9Y and DBY genes, the AZFb region contains the RBMY gene complex, and the /4Z/c region contains the DAZ gene.

Some of the genes involved in the regulation of spermatogenesis are represented in the genome by several copies. Apparently, there are 4-6 copies of the DAZ gene and 20-50 genes or pseudogenes of the RBMY family in the genome. DBY and USP9Y are represented in the genome by one copy. Due to the large number of repetitive sequences and differences in the design of studies, the analysis of the regions of the Y chromosome that control spermatogenesis is fraught with considerable difficulties. For example, the detection of deletions in the AZF region was carried out mostly by analysis of DNA-marking sites, short DNA sequences with a known chromosomal location. The more of them analyzed, the higher the probability of detecting deletions. In general, deletions in the AZF region are more common in infertile men, but have been reported in healthy men as well.

Evidence that the AZF region contains genes regulating spermatogenesis was an intragenic deletion in the USP9Y gene, also called DFFRY (because it is homologous to the corresponding Drosophila faf gene). An infertile man had a four base pair deletion that his healthy brother did not have. These observations, coupled with in vitro data, suggested that a mutation in the USP9Y gene impairs spermatogenesis. When reanalyzing previously published data, the researchers identified another single deletion in the USP9Y gene that disrupts spermatogenesis.

A review of data from a survey of nearly 5,000 infertile men for mutations in the Y chromosome showed that approximately 8.2% of cases (compared to 0.4% in healthy ones) have deletions in one or more regions of the AZF region. In individual studies, rates ranged from 1 to 35%. According to the mentioned review, deletions are most common in the AZFc region (60%), followed by AZFb (16%) and AZFa (5%). The remaining cases are a combination of deletions in several regions (most often involving deletions in AZFc). Most mutations were found in men with azoospermia (84%) or severe oligozoospermia (14%), defined as a sperm count of less than 5 million/ml. The interpretation of data on deletions in the AZF region is extremely difficult because:

1. they are found both in infertile and in healthy men;
2. the presence of DAZ and RBMY clusters containing several copies of genes makes analysis difficult;
3. different studies have studied different parameters of sperm;
4. the set of contig maps of the Y-chromosome was not complete due to the presence of repeated sequences;
5. there was not enough data on healthy men.

In a double-blind study of 138 male IVF couples, 100 healthy males and 107 young Danish military personnel, sex hormone levels, semen parameters, and AZF area analysis were performed. To study the AZF region, 21 DNA-marking sites were used; with normal sperm parameters and in all cases where the number of spermatozoa exceeded 1 million/ml, no 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 in the AZFc region were detected. Interestingly, none of the study participants had deletions in the AZFa and AZFb regions. This suggests that the genes located in the AZFc region are most important for spermatogenesis. Later there were more major study, which gave similar results.

If deletions are detected in the Y chromosome, this should be discussed with both future parents. The main risk to offspring is that sons may inherit this deletion from their father and be infertile - such cases have been described. These deletions do not appear to affect IVF efficacy and pregnancy rates.

Fragile X syndrome in women with premature ovarian failure

In sporadic cases of premature ovarian failure, approximately 2-3% of women are found to have a premutation in the FMR1 gene responsible for the occurrence of fragile X syndrome; in women with hereditary premature ovarian failure, the frequency of this premutation reaches 12-15%. A fragile region at the Xq28 locus can be detected by karyotyping of cells grown under folic acid deficiency conditions, but DNA analysis is usually performed. Fragile X syndrome refers to diseases that are caused by an increase in the number of trinucleotide repeats: normally, the FMR1 gene contains less than 50 repeats of the CCG sequence, in carriers of the premutation their number is 50-200, and in men with fragile X syndrome - more than 200 ( complete mutation). Fragile X syndrome is characterized by an X-linked dominant inheritance pattern with incomplete penetrance.

It is important to identify carriers of the premutation, since they may be other family members: they may have sons with fragile X syndrome, which manifests itself mental retardation, characteristic features faces and macroorchism.

Secondary hypogonadism and Kalman syndrome in men

Men with Kalman syndrome are characterized by anosmia and secondary hypogonadism; also possible defects of the face in the midline, unilateral agenesis kidneys and neurological disorders- synkinesis, oculomotor and cerebellar disorders. Kalman syndrome is characterized by an X-linked recessive type of inheritance and is caused by mutations in the KALI gene; suggest that Kalman's syndrome is due to 10-15% of cases of isolated deficiency of gonadotropic hormones in men with anosmia. Recently, an autosomal dominant form of Kalman syndrome has been discovered, which is caused by mutations in the FGFR1 gene. With an isolated deficiency of gonadotropic hormones without anosmia, mutations in the GnRHR gene (gonadoliberin receptor gene) are most often found. However, they account for only 5-10% of all cases.

Violations and their causes in alphabetical order:

reproductive dysfunction -

Reproductive dysfunction(infertility) - inability married couple to conception with regular unprotected intercourse for 1 year (WHO).

In 75-80% of cases, pregnancy occurs during the first 3 months of regular sexual activity of young, healthy spouses, that is, when the husband's age is up to 30, and the wife's - up to 20 years. In the older age group (30-35 years old), this period increases to 1 year, and after 35 years - more than 1 year.

Approximately 35-40% infertile couples it is caused by a man, in 50% - by a woman, and in 15-20% there is a mixed factor of reproductive dysfunction.

What diseases cause reproductive dysfunction:

Causes of reproductive dysfunction in men

I. Parenchymal (secretory) violation of reproductive function - a violation of spermatogenesis (production of spermatozoa in the convoluted seminiferous tubules of the testicles), which manifests itself in the form of aspermia (absence of spermatogenesis cells and spermatozoa in the ejaculate), azoospermia (absence of spermatozoa in the ejaculate when spermatogenesis cells are detected), oligozoospermia , decreased mobility, impaired structure of spermatozoa:

1. Testicular dysfunction:
- cryptorchidism, monorchism and testicular hypoplasia
- orchitis (viral etiology)
- testicular torsion
- primary and secondary congenital hypogonadism
- elevated temperature - violation of thermoregulation in the scrotum (varicocele, hydrocele, tight clothing)
- Sertoli cell-only syndrome
- diabetes
- excessive physical stress, psychological stress, severe chronic diseases, vibration, overheating of the body (work in hot shops, sauna abuse, fever), hypoxia, physical inactivity
- endogenous and exogenous toxic substances(nicotine, alcohol, drugs, chemotherapy, occupational hazards)
- radiation therapy
- mutations: mutation of the gene for muscoviscidosis ( congenital absence vas deferens - obstructive azoospermia, determined by polymerase chain reaction; microdeletion of the Y chromosome (impaired spermatogenesis various degrees severity of karyotype disorder - structural chromosomal aberrations - Klinefelter syndrome, XYY syndrome, chromosomal translocations, autosomal aneuploidies) - fluorescent hybridization method (FISH) using probes labeled with fluorochromes to different chromosomes

2. Hormonal (endocrine) reproductive dysfunction - hypogonadotropic hypogonadism - deficiency of luteinizing (LH) and follicle-stimulating (FSH) hormones of the pituitary gland, which play a role in the formation of testosterone and spermatozoa:
- Pathology of the hypothalamus
o Isolated gonadotropin deficiency (Kalman syndrome)
o Isolated luteinizing hormone deficiency ("fertile eunuch")
o Isolated FSH deficiency
o Congenital hypogonadotropic syndrome
- Pathology of the pituitary gland
o Pituitary insufficiency (tumors, infiltrative processes, operations, radiation)
o Hyperprolactinemia
o Hemochromatosis
o Influence of exogenous hormones (excess estrogens and androgens, excess glucocorticoids, hyper- and hypothyroidism)

3. autoimmune processes - the destruction of spermatozoa by their own immune cells, the production of antibodies to spermatozoa
o parotitis- "pig"
o testicular injury
o cryptorchidism (undescended testicles)
o operations on the organs of the scrotum
o passive homosexuals

II. Obstructive (excretory) violation of the reproductive function is associated, as a rule, with bilateral, temporary or permanent violation patency (obstruction, obstruction) of the vas deferens and a violation of the output of the constituent elements of sperm (sperm, prostate secretion, secretion of seminal vesicles) through the genital tract into the urethra:
- congenital underdevelopment or absence of the vas deferens, violation of its patency, lack of connection between the tubule of the epididymis of the vas deferens and the vas deferens
- Mullerian duct cysts of the prostate
- inflammatory process in the genital organs, complicated by obliteration of the vas deferens - chronic epididymitis, deferentitis, spermatocele
retrograde ejaculation - aspermatism (lack of ejaculate during intercourse) with congenital or cicatricial changes in the urethra at the level seed tubercle, stricture of its membranous part urethra, damage nerve centers regulating ejaculation.
- injuries of the genital organs, including during surgical interventions (for example, with hernia repair),
- consequences of vasectomy

III. Mixed violation of reproductive function (excretory-toxic, or excretory-inflammatory) is the result of mediated toxic damage spermatogenic epithelium, impaired synthesis and metabolism of sex hormones and the direct damaging effect of pus and bacterial toxins on spermatozoa biochemical characteristics of sperm:
- vulnerability of spermatozoa to immune system due to a violation of maturation, enveloping with protection from proteins in the appendages of the ovaries (epididymitis)
- changes in the composition of the secretion of the prostate gland, seminal vesicles (prostatitis, vesiculitis), STIs
- other inflammatory diseases male reproductive system (urethritis)

IV. Other causes of reproductive dysfunction
- sexual problems - erectile dysfunction, ejaculation disorders
- anejaculation, aspermia - psychological, neurological (spinal cord injuries)

V. Idiopathic reproductive dysfunction
The reason cannot be determined.

Causes of reproductive dysfunction in women
- inflammatory processes and their consequences ( adhesive process in the pelvis and obstruction of the fallopian tubes - "tubal-peritoneal factor)
- endometriosis
- hormonal disorders
- uterine tumors (myomas)
- ovarian tumors (cystomas)

Which doctors to contact if there is a violation of the reproductive function:

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Reproductive dysfunction This is the inability of a married couple to conceive with regular unprotected intercourse for 1 year. In 75-80% of cases, pregnancy occurs during the first 3 months of regular sexual activity of young, healthy spouses, that is, when the husband is under 30 and the wife is under 25. In the older age group (30-35 years old), this period increases to 1 year, and after 35 years - more than 1 year. Approximately 35-40% of infertile couples are caused by a man, in 15-20% there is a mixed factor of reproductive dysfunction.

Causes of reproductive dysfunction in men

Parenchymal (secretory) violation of reproductive function: violation of spermatogenesis (production of spermatozoa in the convoluted seminiferous tubules of the testicles), which manifests itself in the form of aspermia (absence of spermatogenesis cells and spermatozoa in the ejaculate), azoospermia (absence of spermatozoa in the ejaculate when spermatogenesis cells are detected), oligozooism, decrease motility, violations of the structure of spermatozoa.

Violations testicle functions:

cryptorchidism, monorchism and testicular hypoplasia;

orchitis (viral etiology);

testicular torsion;

primary and secondary congenital hypogonadism;

elevated temperature - violation of thermoregulation in the scrotum (varicocele, hydrocele, tight clothing);

syndrome "only-cells-Sertoli";

diabetes;

excessive physical stress, psychological stress, severe chronic diseases, vibration, overheating of the body (work in hot shops, sauna abuse, fever), hypoxia, physical inactivity;

endogenous and exogenous toxic substances (nicotine, alcohol, drugs, chemotherapy, occupational hazards);

radiation therapy;

Mutation of the muscoviscidosis gene (congenital absence of the vas deferens: obstructive azoospermia, determined by polymerase chain reaction; microdeletion of the Y chromosome (violations of spermatogenesis of various degrees of severity of karyotype disorders - structural chromosomal aberrations - klinefelter syndrome, XYY syndrome, chromosomal translocations, autosomal aneuploidies) - a method of fluorescent hybridization (FISH) using probes labeled with fluorochromes to different chromosomes.

Causes of reproductive dysfunction in women

Inflammatory processes and their consequences (adhesions in the pelvis and obstruction of the fallopian tubes - "tubal-peritoneal factor);

endometriosis;

hormonal disorders;

uterine tumors (myomas).

ovarian tumors (cystoma).

Less common are hormonal and genetic disorders. It should be noted that thanks to the achievements of genetics, it has become possible to diagnose a number of previously unknown causes of male reproductive dysfunction. In particular, this is the definition of AZF - a factor - a locus in the long arm of the Y chromosome responsible for spermatogenesis. With its loss in the spermogram, gross violations are revealed 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 reduced fertility. Idiopathic decline in fertility in the proportion of male infertility takes an average of 25-30% (According to various sources, from 1 to 40%). Obviously, such a large discrepancy in the assessment of etiology is due to the lack of uniformity in the examination and the difference in the interpretation of the obtained clinical and anamnestic data, which also confirms the complexity and insufficient knowledge of the problem of male infertility.

Infertility treatment

Today reproductive medicine has a solid store of knowledge on the treatment of infertility of all types and forms. The main procedure for more than three decades has been in vitro fertilization (IVF). The IVF procedure is well established by physicians around the world. It consists of several stages: stimulation of ovulation in a woman, control of maturation of follicles, subsequent collection of eggs and sperm, fertilization in laboratory conditions, observation of the growth of embryos, transfer of the highest quality embryos to the uterus in the amount of not more than 3.

The stages of treatment are standard, but the characteristics of the body and indications for IVF require individual approach, as in the appointment special medicines, and in setting the timing of each stage of treatment.

New methods are offered by almost all clinics of reproductive medicine, their effectiveness in treatment has been proven by tens and hundreds of thousands of children born into the world. But still, the efficiency of using only one IVF is no more than 40%. Therefore, the main task of reproductologists around the world is to increase the number of successful cycles of artificial insemination. Yes, in Lately, in clinics of reproductive medicine, the replanting of five-day embryos (blastocysts) is practiced instead of more “young”, three-day ones. The blastocyst is optimal for transfer, since at this time it is easier to determine the prospects of such an embryo for further development in the mother's body.

Other methods of auxiliary methods also help to improve the statistics of successful fertilizations. reproductive technologies, the list of which may be different in different clinics of reproductive medicine.

A common method for the treatment of infertility is ICSI (ICSI), which means the direct injection of sperm into the egg. Usually ICSI is indicated for male infertility of the secretory type, and is often combined with IVF. However, ICSI, which involves an increase of 200-400, allows you to assess the state of spermatozoa only superficially, with especially severe pathologies sperm is not enough. Therefore, in 1999, scientists proposed a more innovative method of IMSI (IMSI). It involves an increase of 6600 times and allows you to evaluate the smallest deviations in the structure of male germ cells.

For risk assessment genetic abnormalities in the fetus, methods such as pre-implantation genetic diagnosis(PGD) and comparative genomic hybridization (CGH). Both methods involve the study of the embryo for the presence of pathological changes in the genome of the embryo, even before transferring it to the uterus of a woman. These methods not only increase the effectiveness of in vitro fertilization and are indicated for genetic disorders in the couple's genotype, but also reduce the risk of self-abortion and the birth of children with genetic abnormalities.

Total information

The reproductive process or human reproduction is carried out by a multi-link system reproductive organs, which provide the ability of gametes to fertilize, conception, preimplantation and implantation of the zygote, 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 external environment.

Ontogeny 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 is identified that is responsible for ontogeny and the formation of organs of the reproductive system. It includes: 1200 genes involved in the development of the uterus, 1200 prostate genes, 1200 testicular genes, 500 ovarian genes and 39 genes that control germ cell differentiation. Among them, genes were identified that determine the direction of differentiation of bipotential cells either according to the male or female type.

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

ONTOGENESIS OF THE ORGANS OF THE REPRODUCTIVE SYSTEM

Early ontogeny

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

stage of a two-week embryo. Gonocytes migrate from the intestinal ectoderm region through the endoderm yolk sac in the region of the rudiments of the gonads or genital folds, where they divide by mitosis, forming a pool of future germ cells (up to 32 days 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 the organs of the urinary system and adrenal glands, which together form the sex.

At the very beginning of ontogenesis, in a three-week-old embryo, in the region of the nephrogenic cord (a derivative of the intermediate mesoderm), a rudiment of the tubules of the primary kidney (pronephros) or pronephros. At 3-4 weeks of development, caudal to the tubules of the pronephros (the area of ​​the nephrotome), the rudiment of the primary kidney or mesonephros. By the end of 4 weeks, on the ventral side of the mesonephros, the rudiments of gonads begin to form, developing from the mesothelium and representing indifferent (bipotential) cell formations, and the pronephrotic tubules (ducts) are connected to the tubules of the mesonephros, which are called wolf ducts. In turn, paramesonephric, or müllerian ducts are formed from sections of the intermediate mesoderm, which are isolated under the influence of the wolffian duct.

At the distal end of each of the two wolf ducts, in the zone of their entry into the cloaca, outgrowths are formed in the form of the rudiments of the ureters. At 6-8 weeks of development, they germinate 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 wolf channels and nephrogenic tissue of the posterior mesonephros.

Let us now consider the ontogeny of the human biological sex.

Formation of the male sex

The formation of the male sex begins at 5-6 weeks of embryo development with the transformation of the wolf ducts and ends by the 5th month of fetal development.

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

the beginning of the seminal tubes of the testes. Excretory paths are formed from the wolf ducts. The middle part of the wolf ducts elongates and transforms into efferent ducts, and seminal vesicles form from the lower part. The upper part of the duct of the primary kidney becomes an appendage of the testis (epididymis), and the lower part of the duct becomes the efferent canal. After that, the Müllerian ducts are reduced (atrophied), and only the upper ends (blinking of the hydatid) and the lower ends (the male uterus) remain of them. The latter is located in the thickness of the prostate gland (prostate) at the confluence of the vas deferens into the urethra. The prostate, testicles and Cooper (bulbourethral) glands develop from the epithelium of the wall urogenital 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 mature male, which ensures masculinization of the genital organs.

Under the control of testosterone, the structures of the internal male genital organs develop from the wolf 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 lumen of the prostate is formed after birth in the pubertal period. The penis is formed from the rudiment of the head of the penis in the genital tubercle. At the same time, 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 at the 12-week-old 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. In the case of a delay in lowering the testicles into the scrotum (due to various reasons, including genetic ones), unilateral or bilateral cryptorchidism develops.

Formation of the female

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

upper two-thirds of the vagina. Sewerage 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 sexual cords.

The medulla of the ovaries is formed from the remnants of the body of the primary kidney, and from the genital ridge (the rudiment of the epithelium), the ingrowth of the sex cords into the cortical part of the future ovaries continues. As a result of further germination, these cords 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. Ingrown sex cords continue after the birth of a girl (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 (protein) membrane of the ovary, on top of which the remains of the genital ridges remain in the form of an inactive rudimentary epithelium.

Levels of sex differentiation and their violations

The gender of a person is closely related to the characteristics of ontogeny 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 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 the individual;

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

Civilian sex, or sex registered at the time of issuing a passport. It is also called the parenting gender.

With the coincidence of all levels of sex differentiation and the normalization of all parts of the reproductive process, a person develops with a normal biological male or female sex, normal sexual and generative potencies, sexual self-awareness, psychosexual orientation and behavior.

The scheme of 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 growth of the 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 are transformed into either the scrotum or the labia. In the second case, the primary genital opening opens between the genital tubercle and genital folds. Any level of sex differentiation is closely associated with the formation of both normal reproductive function and its disorders, accompanied by complete or incomplete infertility.

genetic gender

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 a whole gene network, including genes located both on gonosomes and on autosomes.

As of the end of 2001, 39 genes were assigned to the genes that control the ontogeny of the reproductive organs and the differentiation of germ cells (Chernykh V.B., Kurilo L.F., 2001). Apparently, now there are even more of them. Let's consider the most important of them.

Undoubtedly, the central place in the network of genetic control of male sex differentiation belongs to the SRY gene. This single-copy, intron-free gene is located on the distal short arm of the Y chromosome (Yp11.31-32). It produces testicular determination factor (TDF), which is also found in XX males and XY females.

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 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 the effect

Initially, SRY gene activation occurs in Sertoli cells, which produce anti-Mullerian hormone, which acts on sensitive Leydig cells, which induces the development of the seminiferous tubules and the regression of the Müllerian ducts in the emerging male body. This gene has a large number of point mutations associated with gonadal dysgenesis and/or sex inversion.

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 translocate to the X chromosome or any autosome, which also leads to gonadal dysgenesis and/or sex inversion.

In the second case, the body of an XY-woman develops, which has streak-like gonads with female external genitalia and feminization of the physique (see below).

At the same time, the formation of an XX-male organism, characterized by a male phenotype with a female karyotype, is probably the de la Chapelle 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 impairment of spermatogenesis.

In recent years, it has been noted that in the process of sexual differentiation according to male type a number of genes located outside the SRY locus zone (several dozens) are involved. 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 disturbances in spermatogenesis; with them, both an almost normal sperm count and oligozoospermia are noted. An important role belongs to the genes located on the X chromosome and autosomes.

In the case of localization on the X chromosome, this is the DAX1 gene. It is located at Xp21.2-21.3, the so-called dose-sensitive sex inversion locus (DDS). It is believed that this gene is normally expressed in men and is involved in the control of the development of their testes and adrenal glands, which can lead to adrenogenital syndrome (AGS). For example, DDS duplication 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 hypoplasia of the testicles due to impaired differentiation.

renation of steroidogenic cells during the ontogenesis of the adrenal glands and gonads, which is manifested by AGS and hypogonadotropic hypogonadism due to deficiency of glucocorticoids, mineralocorticoids and testosterone. In such patients, severe violations 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, however, 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 belongs to the genes of early development (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 the HMG box. The gene is located on the long arm of chromosome 17 (17q24-q25). Its mutations cause campomelic dysplasia, which is manifested by multiple anomalies of the skeleton and internal organs. In addition, mutations in 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 (strands).

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

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

Let's take a 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 repressor of transcription, which is necessary already at the stage of bipotential cells (before the stage of activation of the SRY gene), has been shown.

It is assumed that the WT1 gene is responsible for the development of the pudendal tubercle and regulates the exit 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 inversion when there is a deficiency of regulatory factors involved in sexual differentiation. Often these mutations are associated with syndromes characterized by autosomal dominant inheritance, including WAGR syndrome, Denis-Drash syndrome and Frazier syndrome.

For example, WAGR syndrome is caused by a deletion of the WT1 gene and is accompanied by Wilms tumor, aniridia, birth defects development of the genitourinary system, mental retardation, gonadal dysgenesis and a 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 an early manifestation of severe nephropathy with protein loss and impaired sexual development.

Frazier syndrome is caused by a mutation in the donor splicing site of exon 9 of the WT1 gene and is manifested by gonadal dysgenesis (female phenotype with 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 the transcription of genes involved in the biosynthesis steroid hormones. The product of this gene activates the synthesis of testosterone 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, in which the SF1 site is found in the promoter. It is assumed that during ovarian morphogenesis, the DAX1 gene prevents the transcription of the SOX9 gene through repression of the transcription of the SF1 gene. Finally, the CFTR gene, known as the cystic fibrosis gene, is inherited in an autosomal recessive manner. This gene is located on the long arm of chromosome 7 (7q31) and encodes a protein responsible for the transmembrane transport of chloride ions. Consideration of this gene is appropriate, since males carrying the mutant allele of the CFTR gene often have bilateral absence of the vas deferens and anomalies of the epididymis, leading to obstructive azoospermia.

Chromosomal level

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

is stolen by a spermatozoon with the X chromosome, then the female sex is formed in the future organism (karyotype: 46, XX; contains two identical gonosomes). If the egg is fertilized by a sperm with a Y chromosome, then a 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. In sex differentiation, the Y chromosome plays a decisive role. If it is absent, then sex differentiation follows 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, on the long arm of this chromosome are localized:

GBY (gonadoblastoma gene) or tumor-initiating oncogene 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 the Yq11 part; its loss or violation of sequences causes short stature;

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

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

Now consider the violations of the genetic sex at the chromosomal level. Such disorders are usually associated with incorrect chromosome segregation in the 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 chromosome anomalies, in which one or more additional gonosomes or autosomes are detected in the karyotype, 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 originating 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 anomalies 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 region long shoulder Y chromosome (locus Yq11) and associated loss of the AZF locus or azoospermia factor, as well as deletion of the SRY gene, leading to impaired 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. There are three active subregions in the locus: a, b, and c. The locus is present in all cells except erythrocytes. However, the locus is only active in Sertoli cells.

It is believed that the mutation rate of the AZF locus is 10 times higher than the mutation rate in autosomes. Cause of male infertility is high risk transfer to sons of Y-deletions affecting this locus. In recent years, locus research has become binding rule with 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), Wolff-Hirschhorn syndrome (46, XX, 4p-), cat cry syndrome (46, XY, 5p-), syndrome of partial monosomy of chromosome 9 ( 46, XX, 9p-). For example, de la Chapelle syndrome is hypogonadism with a male phenotype, male psychosocial orientation and female genotype. Clinically, it is similar to Klinefelter's syndrome, combined with testicular hypoplasia, azoospermia, hypospadias (testosterone deficiency due to intrauterine insufficiency of its synthesis by Leydig cells), moderately severe 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 the chromosome turns over 180 ° inside the chromosome with the involvement of the centromere or inside the arm without involving the centromere). According to the latest chromosome nomenclature, inversion is denoted by the symbol Ph. Patients with infertility and miscarriage often have mosaic spermatogenesis and oligospermia associated with inversions of the following chromosomes:

Chromosome 1; often observed Ph 1p34q23, causing a complete block of spermatogenesis; less often Ph 1p32q42 is detected, 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 the chromosomes of all classified groups. An example of a reciprocal translocation is a Y-autosomal translocation, accompanied by a violation of sex differentiation, reproduction and infertility in men due to aplasia of the spermatogenic epithelium, inhibition or blockage of spermatogenesis. Another example is rare translocations between gonosomes X-Y, Y-Y. The phenotype in such patients may be female, male, or dual. In males with a Y-Y translocation, oligo- or azoospermia is observed as a result of a partial or complete blockage of spermatogenesis at the stage of formation of spermatocyte I.

A special class is Robertson type translocations between acrocentric chromosomes. They occur more frequently in men with impaired spermatogenesis and/or infertility than reciprocal translocations. For example, Robertsonian translocation between chromosomes 13 and 14 leads either to the 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 have a block in spermatogenesis at the stage of spermatocytes. 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 impaired reproduction. The latter are structures closed in a ring with the involvement of the centromere. Their formation is associated with damage to both arms of the chromosome, as a result of which the free ends of its fragment,

gamete sex

For illustration possible causes and the mechanisms of violations of the gamete level of sex differentiation, we will consider, on the basis of electron microscopy data, the process of gamete formation during normal meiosis. On fig. Figure 57 shows a model of the synaptonemal complex (SC), which reflects 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 the interphase (proleptotene stage), homologous parental chromosomes are decondensed, and axial elements beginning to form are visible in them. Each of the two elements includes two sister chromatids (respectively 1 and 2, as well as 3 and 4). 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 the zygotene, synapsis or conjugation(sticking on

Rice. 57. Model of the synaptonemal complex (according to Preston D., 2000). Numbers 1, 2 and 3, 4 denote sister chromatids of homologous chromosomes. Other explanations are given in the text.

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

During the passage of the zygoten, homologous chromosomes are oriented with their telomeric ends to 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 a haploid number of sexual bivalents is formed as a result of the conjugation process. 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 sexual body. In the case of male meiosis, this will be the first order spermatozoon. At the next (fifth) stage - diplotene - the synapsis of homologous chromosomes is completed and their desynapsis or mutual repulsion occurs. At the same time, the SC is gradually reduced and is preserved only in the chiasm areas or zones in which the crossing-over or recombination exchange of hereditary material between chromatids directly occurs (see Chapter 5). Such zones are called recombination nodules.

Thus, chiasm is a section 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 keep homologous chromosomes in one pair and ensure the divergence of homologues to different poles in anaphase I. The repulsion that occurs in the diplotene continues at the next (sixth) stage - diakinesis, when the axial elements are modified 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.

On fig. 58 shows a schematic representation of the axial elements or two lateral (oval) strands - 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 lateral rods, a dense zone of superposition of transverse lines is visible, and chromatin loops extending from the lateral rods are visible. A lighter ellipse in the central space of the SC is a recombination knot. In the course of further meiosis (for example, male) in the onset of anaphase II, four chromatids diverge, forming univalents in separate X and Y gonosomes, 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.

At puberty male body spermatids enter into spermatogenesis and, thanks to a series of morphophysiological transformations, turn into functionally active spermatozoa.

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

As a rule, gamete sex disorders are caused by chromosome anomalies in the gametes themselves, which, for example, in the case of male meiosis is manifested by oligo-, azoospermia, and teratozoospermia, which adversely affects the male reproductive ability.

It has been shown that chromosome anomalies in gametes lead to their elimination, death of the zygote, embryo, fetus and newborn, cause absolute and relative male and female infertility, are the causes of spontaneous abortions, miscarriages, stillbirths, births of children with malformations and early infant mortality.

Gonadal sex

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

With changes in the gonadal sex caused by the action of genetic and environmental factors, the main disorders are:

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. 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 laying of the reproductive system in the form of coelomic epithelium occurs in the embryo on the surface of the primary kidney - the wolf body. Then comes the stage of gonoblasts (epithelium of genital ridges), from which gonocytes develop. They are surrounded by follicular epithelial cells that provide trophism.

In the stroma of the primary kidney from the genital folds, strands consisting of gonocytes and follicular cells go, and at the same time from the body of the primary kidney to the cloaca goes the Mullerian (paramesonephric) duct. Next comes the separate development of male and female gonads. The following happens.

A. Male gender. Mesenchyme grows along the upper edge of the primary kidney, forming the sex cord (cord), which splits, connecting with the tubules of the primary kidney, which flow into its duct, and gives rise to the seminiferous tubules of the testes. In this case, the efferent tubules form 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 testicles and prostate develop from the wall of the urogenital sinus.

The action of the hormones of the male gonads (androgens) depends on the action of the hormones of the anterior pituitary gland. The production of androgens is provided 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 lobules and an isthmus (middle lobule). There are about 30-50 glands in the prostate, their secret is released into the vas deferens at the time of ejaculation. To the products secreted by the seminal vesicles and the prostate (primary sperm), as they move through the vas deferens and urethra, 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, in which spermatozoa are located and contain the substances necessary for their functioning: fructose, citric acid,

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

B. Female. The mesenchyme develops at the base of the body of the primary kidney, which leads to the destruction of the free ends of the sex cords. In this case, the duct of the primary kidney atrophies, and the Mullerian duct, on the contrary, differentiates. Its upper parts become the uterine (fallopian) tubes, the ends of which open in the form of funnels and cover the ovaries. The lower parts of the Müllerian ducts merge and give rise to the uterus and vagina.

The remnants of the body of the primary kidney become the brain part of the ovaries, and from the genital ridge (the rudiment of the epithelium), the growth of the sex cords into the cortical part of the future ovaries continues. 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 ratios (shifts) between the gonadotropic hormones of the pituitary gland and specific activators of the adrenohypophysotropic 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, craniocerebral injuries, infection, intoxication or psycho-emotional stress, upset sexual function and become the causes of premature puberty or menstrual irregularities.

Hormonal sex

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

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

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

Testosterone biosynthesis is activated in Leydig cells under the action of a transcription activator encoded by the SF1 gene (9q33).

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

Thus, an important role in the final formation of the external male genital organs 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 the secondary determination of sex in men. They are necessary to improve their reproductive function: the maturation of spermatozoa (improving 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 leads to 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 according to female type with 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, which manifests itself 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. The derivatives of the Mullerian ducts - the uterus, the fallopian tubes - are absent, the vaginal process is shortened and ends blindly.

Derivatives of the wolf ducts - the vas deferens, seminal vesicles and epididymis - are hypoplastic in varying degrees. At puberty, patients have normal development mammary glands, with the exception of pallor and a decrease in the diameter of the areolas of the nipples, sparse hair growth of the pubis and armpits. Sometimes there is no secondary hair growth. 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's syndrome. It is typically a male phenotype with hypospadias, gynecomastia, male karyotype, and infertility. However, there may be a male phenotype with significant masculinization defects (micropenis, perineal hypospadias, and cryptorchidism), as well as a female phenotype with moderate cliteromegaly and slight labial fusion. In addition, in phenotypic men with full masculinization, soft shape testicular feminization syndrome with gynecomastia, oligozoospermia or azoospermia.

Mental, social and civil gender

Consideration of violations of the mental, social and civil sex in a person is not the task of this textbook, since such violations relate to deviations in sexual self-awareness and self-education, sexual orientation and gender role of the individual, and similar mental, psychological and other socially significant factors of sexual development.

Consider the example of transsexualism (one of frequent violations mental sex), accompanied by a pathological desire of the individual to change his gender. Often this syndrome

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

Self-identification and sexual behavior of an individual are laid down even in the prenatal period of development of the organism 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. Such duality leads to incorrect registration of civil (passport) sex. Leading symptoms: inversion of gender identity and socialization of the personality, manifested in the rejection of one's gender, psychosocial maladjustment and self-destructive behavior. The average age of patients, as a rule, is 20-24 years. Male transsexualism is much more common than female transsexualism (3:1). Family cases and cases of transsexualism among monozygotic twins are described.

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

The causes of transsexualism can be viewed from two perspectives.

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

Second position- this is a violation of the differentiation of the biological sex and the formation of subsequent sexual behavior as a result of a defect in the receptors of sex hormones or their abnormal expression. It is possible that these receptors may be located in the 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 the female sex. In addition, this syndrome should be distinguished from transvestism syndrome as a psychiatric problem.

Classifications genetic disorders reproductions

Currently, there are many classifications of genetic disorders of reproduction. As a rule, they take into account the features 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. Consider one of the latest, most complete classifications (Grumbach M. et al., 1998). It highlights the following.

I. Disorders of differentiation of the gonads.

True hermaphroditism.

Gonadal dysgenesis in Klinefelter's syndrome.

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

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

II. Female false hermaphroditism.

Androgen-induced.

Congenital hypoplasia of the adrenal cortex or AHS. This is a common autosomal recessive disease, which in 95% of cases is the result of a deficiency of the enzyme 21-hydroxylase (cytochrome P45 C21). It is subdivided into the "classic" 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 isolated - a functionally active CYP21B gene and a pseudogene CYP21A, 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 impaired pairing of chromosomes in meiosis and, consequently, to gene conversion (moving a fragment of the active gene to a pseudogene) or deletion of a 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 gene - aromatase), is localized in the 15q21.1 segment.

The intake of androgens and synthetic progestogens from the mother.

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

III. Male false hermaphroditism.

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

2. birth defects biosynthesis of testosterone.

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

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

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

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

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

■ CYP 17 deficiency (cytochrome P450C176 gene);

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

2.3. Defects in sensitivity of target tissues to androgens.

■ 2.3.1. Insensitivity (resistance) to androgens:

syndrome of complete testicular feminization (syndrome

Morris);

syndrome of incomplete testicular feminization (Reifenstein's disease);

androgen insensitivity in phenotypically normal men.

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

■ 2.3.3. Dysgenetic male pseudohermaphroditism:

incomplete XY-dysgenesis of the gonads (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; deletion of the WT1 gene or WAGR syndrome; mutation of the SOX9 gene or campomelic dysplasia; mutation of the SF1 gene;

X-linked testicular feminization or Morris syndrome.

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

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

■ 2.3.6. Exposure-induced dysgenetic male pseudohermaphroditism 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 are: 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, which leads to the masking and disappearance of conjugation initiation points and, consequently, meiosis errors that occur in any of its phases and stages. An insignificant part of the disturbances is due to synaptic defects in the prophase of the first division in

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

More frequent are desynaptic mutations that block gametogenesis up to the metaphase I stage, causing SC defects, including its fragmentation, complete absence or irregularity, and chromosome conjugation asymmetry.

At the same time, partially synapted bi- and multisynaptonemal complexes can be observed, their associations with sexual XY-bivalents, not shifting to the periphery of the nucleus, but "anchoring" in its central part. Sex bodies are not formed in such nuclei, and cells with these nuclei are selected at the pachytene stage - this is the so-called foul arrest.

Classification of genetic causes of infertility

1. Gonosomal syndromes (including mosaic forms): Klinefelter's syndromes (karyotypes: 47,XXY and 47,XYY); YY-aneuploidy; sex inversions (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 Y-chromosome heterochromatin (Ygh+); increased or decreased pericentromeric constitutive heterochromatin; enlarged or duplicated satellites of acrocentric chromosomes.

5. Chromosomal aberrations in spermatozoa: severe primary testiculopathy (consequences radiotherapy or chemotherapy).

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

7. Mutations of X-linked genes: androgen insensitivity syndrome; Kalman and Kennedy syndromes. Consider Kalman's syndrome - a congenital (often familial) disorder of gonadotropin secretion in 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), there is no color vision, there are congenital deafness, cleft lip and palate, cryptorchidism, and bone pathology with shortening of the IV metacarpal bone. Sometimes there is gynecomastia. Histological examination reveals immature seminiferous tubules lined with Sertoli cells, spermatogonia, or primary spermatocytes. Leydig cells are absent; instead, mesenchymal precursors develop into Leydig cells upon administration of gonadotropins. The X-linked form of Kalman syndrome is caused by a mutation in the KAL1 gene encoding 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 in 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 a leading symptom: lack of 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; 45X/46,XX; 45,X/47,XXX; Xq-isochromosome; del(Xq); del(Xp); r(X).

2. Gonadal dysgenesis with a cell line carrying a Y chromosome: mixed gonadal dysgenesis (45,X/46,XY); gonadal dysgenesis with 46,XY karyotype (Swyer's syndrome); gonadal dysgenesis true hermaphroditism with a line of cells carrying a Y chromosome or having 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 the age of 35, as well as in the oocytes of women with a normal karyotype, in which 20% or more of the oocytes may have chromosomal abnormalities.

5. Mutations in X-linked genes: full form testicular feminization; fragile X syndrome (FRAXA, fraX syndrome); Kalman's 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 syndromes (blepharophimosis, ptosis, epicanthus), Denis-Drash and Frazier.

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

However, this classification does not take into account a number of hereditary diseases associated with male and female. female infertility. In particular, it did not include a heterogeneous group of diseases united by the common name "autosomal recessive Kartagener's syndrome", or the syndrome of immobility of cilia of cells of the ciliated epithelium of the upper respiratory tract, flagella of spermatozoa, fibrias of the villi of the oviducts. For example, more than 20 genes have been identified to date 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 reversal of the 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 fibriae of the oviduct villi. In addition, patients have secondary developed anosmia, moderate hearing loss, and nasal polyps.

CONCLUSION

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

It is characterized by a number of features.

The gene network involved in the ontogeny 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 organs of the reproductive system will take second place in terms of the number of genes after the network of neuroontogenesis (where there are 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 nondisjunction of chromosomes in the anaphase of mitosis and prophase of meiosis, numerical and structural anomalies 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.