Reproductive dysfunction. Causes of reproductive dysfunction in women

Total information

The reproductive process or human reproduction is carried out by a multi-link system of 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 environment external environment.

Ontogenesis of reproductive organs is component genetic program for 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 the male or female type.

All links 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 the organs of the 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 mesenchyme, and the lumens of the prostate form after birth in 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. We are talking 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 manifests itself as AGS and hypogonadotropic hypogonadism due to 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, congenital malformations 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 early manifestation of severe nephropathy with protein loss and disorders of sexual development.

Frazier syndrome is caused by a mutation in the splice donor site of exon 9 of the WT1 gene and is manifested by gonadal dysgenesis (female phenotype with a male karyotype), late onset 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 of 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 chloride 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;

Protein gene cell membranes or H-Y histocompatibility antigen, previously mistakenly 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 high risk transmission of Y-deletions affecting this locus to sons. In recent years, locus testing has become a 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

To illustrate the possible causes and mechanisms of violations of the gametic level of sex differentiation, let us 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 (PPC) into the gonad anlage, 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 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. Reproductive system both sexes develop 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. Subsequently, the upper part of the duct of the primary kidney becomes an appendage of the testis, and the lower part 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 of the mammary glands, with the exception of pallor and a decrease in the diameter of the nipple areolas, and sparse pubic and axillary hair growth. 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, a mild form of testicular feminization syndrome with gynecomastia, oligozoospermia or azoospermia is identified.

Mental, social and civil gender

Consideration of mental, social and civil gender disorders in a person is not the task of this teaching aid, since this kind of violation concerns 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. The average age of patients is usually 20-24 years. 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 relationship between the levels of sex hormones and neurotransmitters during critical periods development of a child 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, scant sexual hair growth, hypoplasia of the uterus 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. Congenital defects in testosterone biosynthesis.

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

■ 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 in 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, as well as 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 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 syndromes (blepharophimosis, ptosis, epicanthus), Denis-Drash and Frazier.

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, 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 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.

Baranov V.S.
Ailamazyan E.K.

Keywords

REPRODUCTION / ECOLOGICAL GENETICS/ GAMETHOGENESIS / TERATOLOGY / PREDICTIVE MEDICINE / GENETIC PASSPORT

annotation scientific article on medicine and healthcare, author of the scientific work - Baranov V. S., Ailamazyan E. K.

Review of data indicating the unfavorable state of reproductive health of the population of the Russian Federation. Endogenous (genetic) and damaging exogenous factors that disrupt human reproduction, the peculiarities of the action of damaging factors on the processes of spermatogenesis and oogenesis, as well as on human embryos at different stages of development are considered. The genetic aspects of male and female sterility and the influence of hereditary factors on the processes of embryogenesis are considered. The main algorithms for the prevention of hereditary and congenital pathologies before conception (primary prevention), after conception (prenatal diagnosis) and after birth (tertiary prevention) are presented. Existing successes noted early detection genetic causes of reproductive dysfunction and prospects for improving the reproductive health of the Russian population based on the widespread introduction of advanced technologies and achievements of molecular medicine: biochips, genetic map of reproductive health, genetic passport.

Ecological Genetic Causes Of Human Reproduction Impairment And Their Prevention

Review of the data which confirm unfavorable reproductive health of Russian populations are presented. Endogenous (genetic) and detrimental environmental factors contributing to reproductive health decline in Russia are outlined with special emphasis on their effects in oogenesis, spermatogenesis and early human embryos. Genetic aspects of male and female sterility as well as impact of inherited factors in human embryogenesis are presented. Basic algorithms adopted for prevention of inborn and inherited disorders before conception (primarily prevention), after conception (secondary prevention prenatal diagnostics) as well as after the birth (tertiary prevention) are surveyed. Obvious achievements in unrevealing the basic genetic causes of reproductive failure as well as the perspectives in improving of reproductive health in native population of Russia through the wide scale implementation of recent advances in molecular biology including biochip-technology, genetic charts of reproductive health and genetic passes are discussed.

Text of scientific work on the topic “Ecological and genetic causes of reproductive health disorders and their prevention”

CURRENT HEALTH PROBLEMS

REPRODUCTIVE HEALTH disorders

Research Institute of Obstetrics and Gynecology and THEIR PREVENTION

them. D. O. Otta RAMS,

Saint Petersburg

■ Review of data indicating the unfavorable state of reproductive health of the population of the Russian Federation. Endogenous (genetic) and damaging exogenous factors that disrupt human reproduction are considered, and the features of the action of damaging factors on the processes of spermatogenesis

and oogenesis, as well as on human embryos at different stages of development. The genetic aspects of male and female sterility and the influence of hereditary factors on the processes of embryogenesis are considered. The main algorithms for the prevention of hereditary and congenital pathologies before conception (primary prevention), after conception (prenatal diagnosis) and after birth (tertiary prevention) are presented. The existing successes in early detection of genetic causes of reproductive dysfunction and prospects for improving the reproductive health of the Russian population based on the widespread introduction of advanced technologies and achievements of molecular medicine: biochips, genetic map of reproductive health, genetic passport are noted.

■ Key words: reproduction; environmental genetics; gametogenesis; teratology; predictive medicine; genetic passport

Introduction

It is well known that human reproductive function is the most sensitive indicator of the social and biological health of society. Without touching on the complex and very intricate social problems of Russia, discussed in detail in the materials of the XVII session of the general meeting of the Russian Academy of Medical Sciences (October 4, 2006) and in the program of the joint scientific session of the Russian Academies of Sciences with state status (October 5-6, 2006), we only note that that in his message to the Federal Assembly in 2006, President V.V. Putin, as the main strategic task of the Russian state and society for the next 10 years, put forward a solution to the demographic issue, that is, the problem of “saving” the Russian people. The government and society as a whole are seriously concerned about the increasingly obvious “demographic cross”, when the mortality rate of the Russian population is almost 2 times higher than the birth rate!

In this regard, the birth of full-fledged healthy offspring and the preservation of the reproductive health of the Russian population are of particular importance. Unfortunately, existing statistical data indicate a very alarming state of reproductive health of the population of Russia, which is due to both unfavorable ecology and the presence of a significant genetic load of mutations in the inhabitants of our country.

According to official statistics, in the Russian Federation, for every thousand newborns there are 50 children with congenital and hereditary diseases.

At the same time, perinatal pathology is registered in 39% of children in the neonatal period and remains the main cause of infant mortality (13.3 per 1000). If we add to this that almost 15% of all married couples are infertile, and 20% of registered pregnancies end in spontaneous abortions, then the picture of the reproductive health of the Russian population looks completely depressing.

This review focuses on the biological component of reproductive function of both endogenous (genetic) and exogenous (ecological) nature and outlines the most realistic, from our point of view, ways to improve it, including the prevention of gametopathies, hereditary and congenital malformations.

1. Gametogenesis

Disturbances in the maturation of male and female gametes play an important role in the pathology of reproductive function. Primary and secondary infertility, caused respectively

unfavorable genetic and exogenous factors determines sterility in more than 20% of married couples. Without touching upon the issues of secondary infertility, which is a consequence of previous diseases, we will consider some pathogenetic mechanisms underlying male and female infertility.

1.1. Spermatogenesis

Spermatogenesis in humans takes 72 days and is a hormone-dependent process, in which a significant part of the genome is involved. So, if in the cells of the liver, kidneys and most other internal organs (with the exception of the brain) no more than 2-5% of all genes are functionally active, then the processes of spermatogenesis (from the stage of spermatogonia type A to the mature sperm) provide more than 10% of all genes. It is no coincidence, therefore, as shown by numerous experiments on laboratory animals (mice, rats), spermatogenesis, as well as brain function, is disrupted by a variety of mutations affecting the skeleton, muscles, and internal organs.

The genetic causes of primary male infertility are very diverse. It is often caused by chromosomal rearrangements such as translocations and inversions, leading to disruption of chromosome conjugation in meiosis and, as a consequence, to the massive death of maturing germ cells at the stage of meiotic prophase. Serious disturbances of spermatogenesis, up to complete sterility, are observed in individuals with chromosomal diseases, such as Kline-Felter syndrome (47,XXY), Down's disease (trisomy 21). In principle, any chromosomal rearrangements, as well as gene mutations that interfere with the process of conjugation of homologous chromosomes in meiosis, lead to a blockade of spermatogenesis. Gene mutations that disrupt spermatogenesis primarily affect the AZF locus gene complex, located in the long arm of the “male” Y chromosome. Mutations in this locus occur in 7-30% of all cases of non-obstructive azoospermia.

The AZF locus is not the only determinant of spermatogenesis. Block of spermatogenesis and sterility can be a consequence of mutations in the CFTR gene (locus 7q21.1), leading to a severe frequent hereditary disease - cystic fibrosis, mutations in the sexual differentiation gene SRY (locus Yp11.1), in the androgen receptor gene (AR ) (Xq11-q12) and others.

Some of the already known mutations in the CFTR gene lead to obstruction of the vas deferens and are accompanied by disorders of spermatogenesis of varying severity, often without

manifestations of other signs of cystic fibrosis. Among patients with bilateral vas deferens obstruction, the frequency of CFTR gene mutations is 47%.

Mutations in the AR gene make a significant contribution (> 40%) to male infertility. It is known that deletions and point mutations in the AR gene lead to testicular feminization (women with karyotype 46,XY) or Reifenstein syndrome. The frequency of AR gene mutations in spermatogenesis disorders has not yet been clarified, but the role of point mutations in the hormone-binding domain in the development of oligoasthenoteratozoospermia has long been proven.

As for the SRY gene, it is known to be the main gene-regulator of male-type development of the body. Mutations in this gene are accompanied by a wide range of clinical and phenotypic manifestations - from complete sex reversal to underdevelopment of the male gonads. The frequency of mutations in the SRY gene during sex reversal (women with karyotype 46,XY) is ~ 15-20%; in other deviations of sexual differentiation and disorders of spermatogenesis, it has not been precisely established, but molecular analysis of the SRY gene seems appropriate.

The algorithm we developed for examining male infertility includes karyotyping, quantitative karyological analysis of immature germ cells, microdeletion analysis of AZF loci and is widely used in practice to determine the causes of impaired spermatogenesis and determine tactics for overcoming infertility. 1.2. Oogenesis

Unlike spermatogenesis, human oogenesis lasts for 15-45 years, more precisely from the 3rd month of intrauterine life until the moment of ovulation of the egg ready for fertilization. Moreover, the main events associated with the conjugation of homologous chromosomes, the process of crossing over, occur in utero, while the pre-meiotic stages of maturation begin several days before the expected ovulation, and the formation of a haploid egg occurs after the sperm penetrates the egg. The complexity of the hormonal regulation of oogenesis processes and its long duration make the maturing human egg very sensitive to damaging exogenous factors.

It is important to pay attention to the amazing fact that each egg throughout its development is the connecting link of three successive generations: the grandmother, in whose womb the female fetus develops, and the

responsibly, in whose body important initial stages meiosis, the mother in whom the egg matures and ovulates, and, finally, the new organism that arises after the fertilization of such an egg.

Thus, unlike men, where the entire process of sperm maturation, including meiosis, lasts just over two months, female germ cells are sensitive to external influences for several decades, and the decisive processes of their maturation occur in the prenatal period. Moreover, unlike male gametes, the selection of genetically inferior gametes in women largely occurs after fertilization, and the vast majority (more than 90%) of embryos with chromosomal and gene mutations die in the earliest stages of development. Consequently, the main efforts to prevent hereditary and congenital pathologies, including those induced by unfavorable environmental factors, should be aimed specifically at the female body. Naturally, this does not mean ignoring the influence of exogenous and genetic factors on the reproductive health of men, however, thanks to the natural biological characteristics of the maturation and selection of male gametes, as well as the development of new assisted reproductive technologies (for example, the ICSI method). prevention of reproductive disorders in men is greatly simplified.

2. Intrauterine development

Intrauterine development is divided into preembryonic (the first 20 days of development), embryonic (up to the 12th week of pregnancy) and fetal periods. Throughout all periods, the human embryo exhibits high sensitivity to the action of a variety of damaging factors of both exogenous and endogenous nature. According to the theory of critical periods by Professor P. G. Svetlov, mass selection of damaged embryos occurs during implantation (1st critical period) and placentation (2nd critical period). The natural third critical period is the birth itself and the transition of the fetus to independent life outside the mother’s body. Naturally, the reproduction of healthy offspring as the most important component of reproductive function requires special attention.

2.1. Exogenous damaging factors

Damaging, that is, teratogenic for the human fetus, can be physical (irradiation, mechanical stress, hyperthermia), biological (toxoplasmosis, rubella, syphilis).

foxes) and chemical (industrial hazards, agricultural poisons, drugs) factors. These may also include some metabolic disorders in the mother (diabetes mellitus, hypothyroidism, phenylketonuria). A particularly important and most controversial group are medicinal substances, chemicals and some bad habits(alcohol, smoking).

There are relatively few substances, including drugs, with proven teratogenic activity for humans - about 30. These include antitumor drugs, some antibiotics, the notorious thalidomide, and mercury salts. Substances whose danger to the human fetus is great, although not definitively proven, include aminoglycosides, some anti-epileptic drugs (diphenylhydantoin), some hormones (estrogens, artificial progestins), polybiphenyls, valproic acid preparations, excess vitamin A, retinoic acid , erethinate (a drug for the treatment of psoriasis). More detailed information about these and other drugs often used during pregnancy can be found in a number of recently published domestic monographs on the problems of teratology in humans. There is no doubt about the pronounced damaging effect on the human fetus of such harmful factors as alcohol (fetal alcohol syndrome), smoking (general developmental delay) and maternal obesity (correlation with defects in the fusion of the neural tube). It is important to pay attention to the fact that the use of medications during pregnancy is a widespread phenomenon. As world statistics show, on average, every woman during pregnancy takes at least 5-6 different medications, including often those that can harm the developing fetus. Unfortunately, it is usually not possible to prove the presence of such an effect and assess its danger to the fetus. The only recommendation for such a woman is to carry out ultrasound examination fetus on different stages development.

Various industrial pollution and agricultural poisons also have an undeniable damaging effect on the development of the human fetus. It is quite difficult to prove the direct teratogenic activity of these substances, however, all indicators of reproductive function in residents of industrially polluted areas are, as a rule, worse than those in prosperous areas. There is no doubt that various diseases in women that prevent or make it impossible to become pregnant

problems (endometriosis, hormonal dysfunctions) and representing serious threat for its reproductive function in unfavorable environmental conditions are much more common. Therefore, improving the environmental situation, improving living conditions, and observing the necessary hygienic standards are important conditions for the normal reproductive function of the population of the Russian Federation.

2.2. Endogenous (genetic) factors of congenital pathology The contribution of hereditary factors to disorders of intrauterine development in humans is unusually high. It is enough to note that more than 70% of spontaneously aborted embryos in the first trimester of pregnancy have severe chromosomal aberrations. Only at these stages such numerical karyotype abnormalities as monosomies (the absence of one of the chromosomes) and trisomies of many, especially large chromosomes, occur. Thus, implantation and placentation are indeed strict barriers to the selection of embryos with chromosomal aberrations. According to our long-term observations, which are in good agreement with world data, the frequency of chromosomal aberrations in the first trimester is about 10-12%, while already in the second trimester this value decreases to 5%, decreasing to 0.5% in newborns. The contribution of mutations of individual genes and microaberrations of chromosomes, detection methods for which have appeared only recently, cannot yet be objectively assessed. Our numerous data, confirmed by studies of other authors, prove the important role of unfavorable allelic variants of individual genes and even gene families in the occurrence of endometriosis, preeclampsia, recurrent miscarriage, placental insufficiency and other serious disorders of reproductive function. These already proven gene families include genes of the detoxification system, blood coagulation and fibrinolysis, genes immune system and others .

Thus, the selection of genetically complete embryos occurs throughout intrauterine development. Prevention of such disorders and prevention of the birth of genetically defective fetuses constitute the most important task protection of reproductive function.

3. Ways to prevent hereditary and congenital diseases Possible ways diagnosis and prevention of reproductive dysfunction in men were discussed earlier (see 1.1). Prevention of reproductive function disorders in women largely concerns the elimination of disease

it, and sometimes congenital anomalies that prevent normal ovulation and egg implantation, prevention of diseases complicating pregnancy, as well as hereditary and congenital diseases in the fetus.

The actual prevention of hereditary and congenital diseases in the fetus belongs to the section of medical genetics and includes several successive levels: primary, secondary and tertiary.

3.1 Primary prevention

Primary prevention is also called preconception prevention. It is aimed at preventing the conception of a sick child and includes a set of measures and recommendations related to childbirth planning. This is a consultation with a fertility specialist at family planning centers, medical genetic counseling in prenatal diagnostic centers, supplemented, if necessary, with a genetic map of reproductive health.

Preconception prevention includes informing spouses on issues of marital hygiene, child planning, and prescribing therapeutic doses folic acid and multivitamins before conception and during the first months of pregnancy. As world experience shows, such prevention can reduce the risk of having children with chromosomal abnormalities and neural tube defects.

Medical genetic counseling is aimed at clarifying the characteristics of the pedigrees of both spouses and assessing the risk of the damaging effects of possible unfavorable genetic and exogenous factors. A fundamentally important innovation in primary prevention is developed at the Research Institute of Obstetrics and Gynecology named after. D. O. Otta RAMS genetic map of reproductive health (GKRZ). It involves studying the karyotypes of both spouses to exclude balanced chromosomal rearrangements, testing for the presence of carriage of mutations that lead, in the case of damage to the genes of the same name in both spouses, to the appearance of a severe hereditary disease in the fetus (cystic fibrosis, phenylketonuria, spinal muscular atrophy, adrenocortical -nogenital syndrome, etc.). Finally, an important section of the SCRP is testing a woman for a predisposition to such a serious and intractable disease as endometriosis, as well as a predisposition to frequent illnesses, often complicating pregnancy, such as recurrent miscarriage, gestosis, placental insufficiency. Testing for functionally unfavorable gene alleles

systems of detoxification, blood coagulation, folic acid and homocysteine metabolism allows one to avoid severe complications associated with the pathology of implantation and placentation, the appearance of chromosomal diseases in the fetus, congenital malformations, and to develop rational treatment tactics in the presence of the disease.

While the SCRP is still at the level scientific developments. However, extensive research has proven a clear association of certain alleles of these genes with the above-mentioned pregnancy complications, which leaves no doubt about the need for widespread implementation of SCHR to prevent complications and normalize the reproductive function of the Russian population.

h.2. Secondary prevention

Secondary prevention includes the entire complex of screening programs, invasive and non-invasive methods of fetal examination, special laboratory analyzes of fetal material using cytogenetic, molecular and biochemical research methods in order to prevent the birth of children with severe chromosomal, genetic and congenital malformations. Therefore, secondary

and, by the way, the most effective form of prevention at present actually includes the entire rich arsenal of modern prenatal diagnostics. Its main components are prenatal diagnostic algorithms in the first and second trimesters of pregnancy, discussed in detail in our guide. Let us only note that, as methods for assessing the condition of the fetus improve, prenatal diagnosis extends to increasingly earlier stages of development. Prenatal diagnosis in the second trimester of pregnancy is standard today. In recent years, however, it has become increasingly noticeable specific gravity prenatal diagnostics in the first trimester, more accurate diagnostics chromosomal and gene diseases of the fetus at 10-13 weeks of pregnancy. The combined version of ultrasonic and biochemical screening, which makes it possible already at these dates to select women at high risk for giving birth to children with chromosomal pathology.

Pre-implantation diagnostics can also make a certain contribution to reducing the incidence of hereditary malformations. The real successes of preimplantation diagnostics are very significant. Already now, at the pre-implantation stages, it is possible to diagnose almost all chromosomal and more than 30 gene diseases. This high-tech and organizationally quite complex procedure can be performed

only in an in vitro fertilization clinic. However, its high cost and lack of guarantees that pregnancy will occur in one attempt significantly complicate the introduction of pre-implantation diagnostics in clinical practice. Therefore, its real contribution to increasing reproductive function is still for a long time will remain very modest and, of course, will not in any way affect the demographic crisis in our country.

3.3. Tertiary prevention

Concerns the creation of conditions for the non-manifestation of hereditary and congenital defects, methods for correcting existing ones pathological conditions. It includes various norm-copying options. In particular, such as the use of special diets in case of congenital metabolic disorders, medications that remove toxins from the body or replace missing enzymes, operations to correct the function of damaged organs, etc., for example, a diet devoid of phenylalanine to prevent brain damage in patients with phenylketonuria, treatment with enzyme preparations for children with cystic fibrosis, hypothyroidism, hereditary diseases accumulation, various surgical operations to correct various malformations, including heart, kidney, skeleton and even brain defects.

Improving the quality of reproductive function can also be achieved by preventing serious somatic disorders, severe chronic diseases, such as cardiovascular, oncological, mental, etc. In this regard, pre-symptomatic diagnosis of hereditary predisposition to these diseases and their effective prevention. Large-scale population studies are currently underway to elucidate the association of allelic variants of many genes with severe chronic diseases leading to early disability and death. Gene networks, that is, sets of genes whose products determine the development of bronchial asthma, diabetes, early hypertension, chronic obstructive bronchitis, etc., have been analyzed in sufficient detail. This information is included in the so-called genetic passport, conceptual framework which was developed back in 1997.

Unfavorable ecological situation in many regions of the country, poor nutrition, poor quality of drinking water, and air pollution are the unfavorable background against which a decline in the quality of

life, reproductive health disorders and an increase in antenatal losses and postnatal pathology. All these demographic indicators were obtained by analyzing population samples of the population of various regions of the country. They, however, do not take into account the heterogeneity of the genetic composition of the studied groups of the Russian population. Such studies have so far been carried out without taking into account the unique ethnic and individual characteristics genome, which largely determine population and individual differences in sensitivity to action unfavorable factors external environment. Meanwhile, the experience of predictive medicine convincingly indicates that individual sensitivity can vary within very wide limits. As pharmacogenetics studies show, the same drug in the same dosage can have a therapeutic effect in some patients, be quite suitable for treatment in others, and at the same time have a pronounced effect. toxic effect still others. Such fluctuations in the reaction rate, as is now known, are determined by many factors, but primarily depend on the rate of metabolism of the drug and the time of its elimination from the body. Testing the corresponding genes makes it possible to identify in advance people with increased and decreased sensitivity not only to certain medications, but also to various damaging environmental factors, including industrial pollution, agricultural poisons, and other extreme conditions for humans environmental factors.

The widespread introduction of genetic testing into the field of preventive medicine is inevitable. However, today it gives rise to a number of serious problems. First of all, conducting population-based studies of hereditary predisposition is impossible without the introduction of new technologies that allow large-scale genetic tests. To solve this problem, special biochips are being actively created, and in some cases have already been created. This technology greatly simplifies the complex and very time-consuming procedure of genetic testing. In particular, a biochip has been created and is already being used in practice for testing 14 polymorphisms of eight main genes of the detoxification system, developed in our joint research with the Center for Biological Microchips of the Institute of Molecular Biology. V. A. Engelhardt RAS. Biochips for testing hereditary forms of thrombophilia, osteoporosis, etc. are at the development stage. Use of such biochips

and the introduction of other advanced genetic testing technologies gives reason to hope that in the near future, screening studies of polymorphisms of many genes will become quite possible.

Mass population studies genetic polymorphisms, comparison of allelic frequencies of certain genes in normal conditions and in patients with certain severe chronic diseases will make it possible to obtain the most objective assessment of the individual hereditary risk of these diseases and to develop an optimal strategy for personal prevention.

Conclusion

High performance mortality, combined with low birth rates and a high incidence of hereditary and congenital defects, are the cause of a serious demographic crisis in our country. Modern methods diagnostics and new medical technologies can significantly increase the efficiency of reproductive function. Important progress has been made in the diagnosis and prevention of male and female infertility. The main efforts to prevent hereditary and congenital pathologies induced by unfavorable exogenous and endogenous factors should be aimed specifically at the female body. Preconception prevention and medical genetic counseling, supplemented by a genetic map of reproductive health, the use of which can prevent the conception of genetically defective children, as well as the development of diseases that often complicate the course of pregnancy, can play a great role in improving a woman’s reproductive function. The impressive achievements of modern prenatal diagnostics are explained by the success of solving methodological problems associated with biochemical and ultrasound screening, obtaining fetal material at any stage of development, and its molecular and cytogenetic analysis. Promising are the introduction of molecular methods for diagnosing chromosomal diseases in the fetus, diagnosing the condition of the fetus using DNA and RNA of the fetus in the mother’s blood. As the experience of the prenatal diagnostic service in St. Petersburg shows, even today in the conditions successful solution organizational and financial issues can achieve a real reduction in the number of newborns with chromosomal and gene diseases. It is reasonable to expect an improvement in reproductive function with the widespread introduction of the achievements of molecular medicine into practical medicine, first of all, individual

th genetic passport. Pre-symptomatic diagnosis of hereditary predisposition to frequent severe chronic diseases in combination with effective individual prevention are essential conditions for increasing reproductive function. A genetic passport that has been developed and is already used in practice requires serious medical guarantees and official support from health authorities and the country’s government. Its mass use must be secured by relevant legal and legislative documents.

Literature

1. Ailamazyan E. K. Women’s reproductive health as a criterion for bioecological diagnostics and control environment/ Ailamazyan E.K. // J. obstetrician. wives sick - 1997. - T. XLVI, Issue. 1. - pp. 6-10.

2. Association of allelic variants of some detoxification genes with the results of treatment of patients with endometriosis / Shved N. Yu., Ivashchenko T. E., Kramareva N. L. [et al.] // Med. genetics. - 2002. - T 1, No. 5. - P. 242-245.

3. Baranov A. A. Mortality of the child population of Russia / Baranov A. A., Albitsky V. Yu. - M.: Litera, 2006. - 275 p.

4. Baranov V. S. Human genome and “predisposition” genes: an introduction to predictive medicine / Baranov V. S., Baranova E. V., Ivashchenko T. E., Aseev M. V. - St. Petersburg: Intermedica, 2000 - 271 p.

5. Baranov V. S. Molecular medicine - a new direction in diagnosis, prevention and treatment of hereditary and multifactorial diseases / Baranov V. S., Ailamazyan E. K. // Medical academic journal. - 2001. - T. 3. - P. 33-43.

6. Baranov V. S. Cytogenetics embryonic development human / Baranov V.S., Kuznetsova T.V. - St. Petersburg: Publishing house N-L, 2007. - 620 p.

7. Baranova E. V. DNA - getting to know yourself, or how to prolong youth / Baranova E. V. - M., St. Petersburg, 2006. - 222 p.

8. Bespalova ON V. S. // J. obstetrics. wives disease - 2006. - T. LV, Issue. 1. - pp. 57-62.

9. Bochkov N. P. Clinical genetics / Bochkov N. P. - M.: GEOTAR-MED, 2001. - 447 p.

10. Vikhruk T. I. Fundamentals of teratology and hereditary pathology/ Vikhruk T.I., Lisovsky V.A., Sologub E.B. - M.: Soviet Sport, 2001. - 204 p.

11. Genetic factors of predisposition to recurrent early pregnancy loss / Bespalova O. N., Arzhanova O. N., Ivashchenko T. E., Aseev M. V., Ailamazyan E. K., Baranov V. S. // Zh. obstetrics wives disease - 2001. - T. Ts. Issue. 2. - pp. 8-13.

12. Ginter E. K. Medical genetics / Ginter E. K. - M.: Medicine, 2003. - 448 p.

13. Gorbunova V.N. Introduction to molecular diagnostics and gene therapy of hereditary diseases / Gorbunova V.N., Baranov V.S. - St. Petersburg: Special literature, 1997. - 286 p.

14. Dyban A.P. Cytogenetics of mammalian development / Dyban A.P., Baranov V.S. - M.: Nauka, 1978. - 216 p.

15. Ivashchenko T. E. Biochemical and molecular genetic aspects of the pathogenesis of cystic fibrosis / Ivashchenko T. E., Baranov V. S. - St. Petersburg: Intermedica, 2002. - 252 p.

16. Karpov O. I. Risk of using drugs during pregnancy and lactation / Karpov O. I., Zaitsev A. A. - St. Petersburg, 1998. - 341 p.

17. Korochkin L. I. Biology individual development/ Korochkin L.I. - M.: Moscow State University Publishing House, 2002. - 263 p.

18. Brain E. V. Polymorphism of genes involved in the regulation of endothelial function and its connection in the development of gestosis / Mozgovaya E. V., Malysheva O. V., Ivashchenko T. E., Baranov V. S. // Med. genetics. - 2003. - T. 2, No. 7. - P. 324-330.

19. Molecular genetic analysis of Y-chromosome microdeletions in men with severe disorders of spermatogenesis / Loginova Yu. A., Nagornaya I. I., Shlykova S. A. [et al.] // Molecular biology. - 2003. - T. 37, No. 1. - P. 74-80.

20. About the genetic heterogeneity of primary hypogonadism

ma / Nagornaya I. I., Liss V. L., Ivashchenko T. E. [et al.] // Pediatrics. - 1996. - No. 5. - P. 101-103.

21. Pokrovsky V.I. Scientific foundations of children’s health / Pokrovsky V.I., Tutelyan V.A. // XIV (77) Sessions of the Russian Academy of Medical Sciences, M., 2004, December 9-11. - M., 2004. - P. 1-7.

22. Prenatal diagnosis of hereditary and congenital diseases / Ed. E.K. Ailamazyan, V.S. Baranov - M.: MEDpress-inform, 2005. - 415 p.

23. Puzyrev V.P. Genomic medicine - present and future / Puzyrev V.P. // Molecular biological technologies in medical practice. Issue 3. - Novosibirsk: Alfa-Vista Publishing House, 2003. - P. 3-26.

24. Svetlov P. G. The theory of critical periods of development and its significance for understanding the principles of the action of the environment on ontogeny / Svetlov P. G. // Questions of cytology and general physiology. - M.-L.: Publishing House of the USSR Academy of Sciences, 1960. - P. 263-285.

25. Creation of a biochip for the analysis of polymorphism in the genes of the biotransformation system / Glotov A. S., Nasedkina T. V., Ivashchenko T. E. [et al.] // Molecular biology. - 2005. - T. 39, No. 3. - P. 403-412.

26. Frequency, diagnosis and prevention of hereditary and congenital malformations in St. Petersburg / Baranov V. S., Romanenko O. P., Simakhodsky A. S. [et al.]. - St. Petersburg: Medical press, 2004. - 126 p.

27. Environmental doctrine of the Russian Federation. - M., 2003.

28. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif / Sinclair A. H., Berta P., Palmer M. S. // Nature. - 1990. - Vol. 346, N 6281. - R. 240-244.

29. Cameron F. J. Mutations in SRY and SOX9: testis-determining genes / Cameron F. J., Sinclair A. H. // Hum Mutat. - 1997. - Vol. 5, N 9. - R. 388-395.

30. Golubovsky M. D. Oocytes physically and genetically link three generations: genetic/demographic implications / Golubovsky M. D., Manton K. // Environment and perinatal medicine. - SPb., 2003. - P. 354-356.

ECOLOGICAL GENETIC CAUSES OF HUMAN REPRODUCTION IMPAIRMENT AND THEIR PREVENTION

Baranov V. S., Aylamazian E. K.

■ Summary: Review of the data which confirm unfavorable reproductive health of Russian populations are presented. Endogenous (genetic) and detrimental environmental factors contributing to reproductive health decline in Russia are outlined with special emphasis on their effects in oogenesis,

spermatogenesis and early human embryos. Genetic aspects of male and female sterility as well as impact of inherited factors in human embryogenesis are presented. Basic algorithms adopted for prevention of inborn and inherited disorders before conception (primarily prevention), after conception (secondary prevention - prenatal diagnostics) as well as after the birth (tertiary prevention) are surveyed. Obvious achievements in unrevealing the basic genetic causes of reproductive failure as well as the perspectives in improving of reproductive health in native population of Russia through the wide scale implementation of recent advances in molecular biology including biochip-technology, genetic charts of reproductive health and genetic passes are discussed.

■ Key words: human reproduction; ecological genetics; gametogenesis; teratology; predictive medicine; genetic passes

Reproductive dysfunction This is the inability of a married couple to conceive with regular unprotected sexual 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 years old. In the older age group (30-35 years), this period increases to 1 year, and after 35 years - more than 1 year. In approximately 35-40% of infertile couples, the cause is a man, in 15-20% there is a mixed factor of reproductive dysfunction.

Causes of reproductive dysfunction in men

Parenchymal (secretory) disorder of reproductive function: disturbance of spermatogenesis (sperm production in the convoluted seminiferous tubules of the testicles), which manifests itself in the form of aspermia (the absence of spermatogenesis cells and spermatozoa in the ejaculate), azoospermia (the absence of spermatozoa in the ejaculate when spermatogenesis cells are detected), oligozoospermia AI, reduction motility, disturbances in the structure of spermatozoa.

Violations testicular functions:

cryptorchidism, monorchidism 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, body overheating (work in hot shops, sauna abuse, fever), hypoxia, physical inactivity;

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

radiation therapy;

Muscoviscidosis gene mutation ( congenital absence vas deferens: obstructive azoospermia, determined by polymerase chain reaction; microdeletion of the Y chromosome (spermatogenesis disorders of varying degrees of severity; karyotype disorders - structural chromosomal aberrations - Klinefelter syndrome, XYY syndrome, chromosomal translocations, autosomal aneuploidies) - fluorescence hybridization (FISH) method using fluorochrome-labeled probes to various chromosomes.

Causes of reproductive dysfunction in women

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

endometriosis;

hormonal disorders;

uterine tumors (fibroids).

ovarian tumors (cystoma).

Hormonal and genetic disorders are less common. It should be noted that thanks to advances in genetics, it has become possible to diagnose a number of previously unknown causes of male reproductive dysfunction. In particular, this is the determination of the AZF factor locus in the long arm of the Y chromosome, responsible for spermatogenesis. When it falls out, gross abnormalities up to azoospermia are revealed in the spermogram.
In some cases, even with the most detailed examination, it is not possible to establish the cause of infertility.

In this case, we can talk about idiopathic decrease in fertility. Idiopathic decline in fertility accounts for an average of 25-30% of male infertility (According to various sources, from 1 to 40%). Obviously, such a large discrepancy in the assessment of etiology is caused by the lack of uniformity in the 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 has been well developed by doctors all over the world. It consists of several stages: stimulation of ovulation in a woman, control of follicle maturation, subsequent collection of eggs and sperm, fertilization in the laboratory, monitoring the growth of embryos, transfer of the highest quality embryos to the uterus in an amount of no more than 3.

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

New methods are offered by almost all reproductive medicine clinics; their effectiveness in treatment has been proven by tens and hundreds of thousands of children born. But still, the effectiveness of using only one IVF is no more than 40%. Therefore, the main task of reproductive specialists around the world is to increase the number of successful artificial insemination cycles. So, recently, reproductive medicine clinics have been practicing the transfer of five-day-old embryos (blastocysts) instead of the “younger”, three-day-old ones. A blastocyst is optimal for transfer, since at this stage it is easier to determine the prospects of such an embryo for further development in the mother’s body.

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

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

Methods such as preimplantation genetic diagnosis (PGD) and comparative genomic hybridization (CGH) are used to assess the risk of genetic abnormalities in the embryo. Both methods involve studying the embryo for the presence of pathological changes in the genome of the embryo, even before transferring it to the woman’s uterus. 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 disorders.

Classification of genetic causes of infertility

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.

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).

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).

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

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

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

It is characterized by a number of features.

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

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

Thus, in recent years, significant changes have occurred in research into the ontogenesis of the human reproductive system and progress has been achieved, the implementation of which will certainly improve methods of treatment and prevention of reproductive disorders, as well as male and female infertility.

Infertility has existed thousands of years ago and will continue to exist in the future. A leading researcher at the Laboratory of Genetics of Reproductive Disorders of the Federal State Budgetary Institution "Medical Genetics" told MedNews about the genetic causes of infertility, the possibilities of their diagnosis and treatment. science Center", Doctor of Medical Sciences Vyacheslav Borisovich Chernykh.

Vyacheslav Borisovich, what are the main causes of reproductive dysfunction?

— There are a lot of reasons and factors for reproductive dysfunction. These can be genetically determined disorders (various chromosomal and gene mutations), negative environmental factors, as well as their combination - multifactorial pathology. Many cases of infertility and miscarriage are caused by a combination of various genetic and non-genetic (environmental) factors. But most severe forms of reproductive system disorders are associated with genetic factors.

With the development of civilization and the deterioration of the environment, human reproductive health is also deteriorating. In addition to genetic reasons, fertility (the ability to have one’s own offspring) can be influenced by many different non-genetic factors: previous infections, tumors, injuries, surgeries, radiation, intoxication, hormonal and autoimmune disorders, smoking, alcohol, drugs, stress and mental disorders, unhealthy lifestyle , occupational hazards and others.

Various infections, primarily sexually transmitted ones, can lead to decreased fertility or infertility, fetal malformations and/or miscarriage. Complications from infection (for example, orchitis and orchiepididymitis with mumps in boys), as well as from treatment with drugs (antibiotics, chemotherapy) in the child, and even in the fetus during its intrauterine development (if the mother takes medications during pregnancy), can lead to to disruption of gametogenesis and be the cause of reproduction problems that he will encounter as an adult.

Over the past decades, the quality of seminal fluid in men has changed significantly, so the standards for its analysis - spermograms - have been revised several times. If in the middle of the last century the norm was considered to be a concentration of 100-60-40 million sperm per milliliter, at the end of the twentieth century - 20 million, now the lower limit of the norm has “descended” to 15 million per 1 milliliter, with a volume of at least 1.5 ml and a total number of at least 39 million. Indicators of sperm motility and morphology were also revised. Now they make up at least 32% of progressively motile sperm and at least 4% of normal sperm.

But, be that as it may, infertility existed thousands and millions of years ago, and will continue to occur in the future. And it is registered not only in the human world, but also in various living beings, including infertility or miscarriage may be associated with genetic disorders that block or reduce the ability to bear children.

What kind of violations are these?

Exists a large number of genetic disorders of reproduction, which may affect different levels of the hereditary apparatus - the genome (chromosomal, gene and epigenetic). They can negatively affect various stages of development or function of the reproductive system, stages of the reproductive process.

Some genetic disorders are associated with anomalies in sex formation and malformations of the genital organs. For example, when a girl’s reproductive system does not form or develop in utero, she may be born with underdeveloped or even absent ovaries or a uterus and fallopian tubes. A boy may have defects associated with abnormalities of the male genital organs, for example, underdevelopment of one or both testicles, epididymis or vas deferens, cryptorchidism, hypospadias. In especially severe cases, disturbances in the formation of sex occur, to the point that at the birth of a child it is even impossible to determine its gender. In general, malformations of the reproductive system are in third place among all congenital anomalies - after malformations of the cardiovascular and nervous systems.

Another group of genetic disorders does not affect the formation of the genital organs, but leads to delayed puberty and/or disruption of gametogenesis (the process of formation of germ cells), hormonal regulation of the functioning of the hypothalamic-pituitary-gonadal axis. This is often observed with damage to the brain, dysfunction of the gonads (hypogonadism) or other organs endocrine system, and can ultimately lead to infertility. Chromosomal and gene mutations can only affect gametogenesis - completely or partially disrupt the production of a sufficient quantity and quality of germ cells, their ability to participate in fertilization and the development of a normal embryo/fetus.

Genetic disorders are often the cause or factors of miscarriage. In general, most pregnancy losses occur due to newly occurring chromosomal mutations that are formed during the division of immature germ cells. The fact is that “severe” chromosomal mutations (for example, tetraploidy, triploidy, monosomies and most autosomal trisomies) are incompatible with the continued development of the embryo and fetus, so in such situations most conceptions do not end in childbirth.

How many married couples face this problem?

In general, 15-18% of married couples face the problem of infertility, and every seventh (about 15%) of clinically recorded pregnancies ends in miscarriage. Most pregnancies spontaneously end in the very early stages. Often this happens so early that the woman did not even know that she was pregnant - these are so-called preclinical losses (undocumented pregnancies). About two thirds of all pregnancies are lost in the first trimester - before 12 weeks. There are biological reasons for this: the number of chromosomal mutations in abortive material is about 50-60%, the highest in anembryony. In the first days - weeks, this percentage is even higher - reaches 70%, and mosaicism in the set of chromosomes occurs in 30-50% of embryos. This is also associated with the not very high efficiency (approximately 30-40%) of pregnancy in IVF/ICSI programs without preimplantation genetic diagnosis (PGD).

Who is more likely to be a carrier of a “defective” gene - a man or a woman? And how do you understand how genetically “compatible” spouses are?

— “Male” and “female” factors of infertility occur with approximately the same frequency. Moreover, a third of infertile couples have reproductive system disorders on the part of both spouses. They are all, of course, very different. Some genetic disorders are more common in women, while others are more common or predominantly in men. There are also couples with pronounced or severe disorders of the reproductive system of one of the partners, as well as decreased fertility in both spouses, while they have a reduced ability to conceive and/or an increased risk of pregnancy. When changing partners (when meeting a partner with normal or high reproductive potential), pregnancy may occur. Accordingly, all this gives rise to idle fiction about “incompatibility of spouses.” But as such, there is no genetic incompatibility among any married couples. In nature, there are barriers to interspecific crossing - different types there is a different set of chromosomes. But all people belong to the same species - Homo sapiens.

How then can a couple make sure that they are not infertile and, most importantly, can have healthy offspring?

It is impossible to say in advance exactly whether a given married couple will or will not have problems with childbearing. For this it is necessary to carry out comprehensive examination. And even after this, it is impossible to guarantee the success of pregnancy. This is due to the fact that the ability to fertility (have viable offspring) is a very complex phenotypic trait.

It is assumed that the human reproductive system and ability to have children is influenced by at least every 10th gene - approximately 2-3 thousand genes in total. In addition to mutations, the human genome contains a large number (millions) of DNA variants (polymorphisms), the combination of which forms the basis of genetic predisposition to a particular disease. The combination of different genetic variants that affect the ability to have offspring is enormous. Many genetic causes of infertility do not have clinical manifestations in the reproductive system. Many genetically determined disorders of the reproductive system clinically look the same for completely different reasons, including various chromosomal and gene mutations; many so-called non-syndromic disorders do not have a specific clinical picture, which would suggest a specific genetic effect. All this greatly complicates the search for genetic disorders and the diagnosis of hereditary diseases. Unfortunately, there is a huge gap between the knowledge of human genetics and its practical use in medicine. In addition, in Russia there is a significant shortage of geneticists, cytogeneticists and other specialists qualified in medical genetics.

However, with many hereditary diseases and reproductive disorders, including those associated with genetic factors, it is possible to have healthy children. But, of course, it is necessary to plan treatment and prevention in such a way as to minimize the risks of hereditary diseases and developmental defects in the offspring.

Ideally, before planning a pregnancy, any married couple should undergo a comprehensive medical and genetic examination and counseling. A geneticist will examine your medical history, pedigree and, if necessary, conduct specific tests to identify genetic diseases/disorders or their carriage. A clinical examination, cytogenetic examination, and chromosome analysis are carried out. If necessary, they are supplemented by a more detailed molecular genetic or molecular cytogenetic study, that is, a study of the genome for specific gene mutations or microstructural rearrangements of chromosomes. At the same time, genetic diagnostics is exploratory and confirmatory, but cannot completely exclude the presence of a genetic factor. It can be aimed at searching for mutations, and if found, then this great luck. But if mutations are not found, this does not mean that they do not exist.

If the diagnosis of genetic disorders itself is so difficult, then what can we say about treatment?

“It’s true that genetic changes themselves cannot be corrected. At least to date, gene therapy has only been developed for a small number of inherited diseases, and these diseases are predominantly not related to the reproductive system. But this does not mean that those affecting reproduction genetic diseases are not treatable. The fact is that treatment can be different. If we talk about eliminating the cause of the disease, then for now this is truly impossible. But there is another level of treatment - combating the mechanisms of disease development. For example, for diseases associated with impaired production of gonadotropic or sex hormones, replacement therapy or hormone stimulating therapy is effective. But if there is a defect in the receptor for the hormone (for example, for male androgens), treatment may be ineffective.

Many problems of childbirth can be successfully solved with the help of assisted reproductive technologies (ART), among which IVF methods - in vitro fertilization - occupy a special place. IVF gives a chance to have their own offspring for many married couples with severe forms of infertility and recurrent miscarriage, including those caused by genetic reasons.

With the help of assisted reproduction methods, it has become possible to overcome infertility, even with such severe fertility disorders in men as azoospermia, oligozoospermia and severe astheno-/teratozoospermia, with obstruction or absence of the fallopian tubes, and severe disorders of egg maturation in women. If your own gametes (mature germ cells) are absent or defective, you can achieve conception and give birth to a child using donor germ cells, and if it is impossible to bear, by resorting to a surrogacy program.

Additional methods of selecting germ cells make it possible to use higher quality male germ cells for fertilization. And preimplantation genetic diagnosis (PGD) of embryos, which is aimed at identifying chromosomal and gene mutations, helps to give birth to genetically healthy offspring that do not have the mutations carried by the parents.

Assisted reproductive technologies can also help couples with an increased risk of miscarriage or the birth of a child with an unbalanced karyotype and severe malformations. In such cases, an IVF procedure is performed with preimplantation genetic diagnosis, in which embryos with a normal set of chromosomes and no mutations are selected. New techniques for assisted reproduction are also emerging. For example, for women with poor quality oocytes (female reproductive cells during their growth in the ovary), oocyte reconstruction technology is used, which uses donor cells from which the nuclei have been removed. The recipient's nuclei are inserted into these cells, after which they are fertilized with the husband's sperm.

Are there any downsides to assisted reproductive technologies?

— Yes, this may have a negative impact on the demographic picture in the future. Among couples who have problems with childbearing and go for IVF, the frequency of genetic changes, especially those associated with disorders of the reproductive system, is increased. Including those that are not diagnosed and can be passed on to future generations. This means that future generations will increasingly bear the burden of gene mutations and polymorphisms associated with infertility and miscarriage. To reduce the likelihood of this, widespread medical genetic examination and counseling of married couples with fertility problems, including before IVF, is necessary, as well as the development and widespread use of prenatal (preimplantation and prenatal) diagnostics.