Symptoms of the disease - violations of the reproductive function. Levels of sex differentiation and their violations

Comprehensive study, which allows you to determine the leading genetic causes of male infertility and choose the appropriate tactics for managing the patient.

The study included the most common genetic causes of male infertility: detection of deletions in the region of the locus AZF that affect spermatogenesis, determination of the number of CAG repeats in the gene AR associated with changes in androgen sensitivity and the search for mutations in the gene CFTR, responsible for the development of the disease, the clinical manifestation of which is obstructive azoospermia.

What biomaterial can be used for research?

Buccal (buccal) epithelium, venous blood.

How to properly prepare for research?

No preparation required.

General information about the study

Male infertility (MB) is a serious pathological condition requiring complex comprehensive diagnostics, urgent correction, and in some cases prevention.

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

The difficulty in diagnosing MB is in large numbers the reasons for it. These include anomalies genitourinary system, tumors, urinary tract infections, endocrine disorders, immunological factors, genetic mutations etc. Unlike the above reasons, genetic ones do not always have clinical manifestations, however, are extremely important for the diagnosis of MB in the subject.

It is important to understand that the diagnosis of "MB" and its forms can put only specialist doctor on the basis of anamnestic data, examination data, results of instrumental and laboratory research. The following reasons may be the reason for visiting a doctor:

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

Frequent causes of male infertility are violations of the structure and quantity of spermatozoa, affecting their mobility and ability to fertilize.

The main genetic causes of MB development are:

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

2) polymorphism (increased repeats of the genetic fragment - CAG) of the gene AR;

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

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

Deletions of the AZF locus and the SRY gene

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

AZF- locus is in long shoulder Y chromosomes (q11). Genes located at this locus play an important role in the process of spermatogenesis.

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

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

At full AZF-deletions, there is a fairly clear dependence of the degree of impairment of spermatogenesis on the size and localization of deletions, which may have predictive value in obtaining spermatozoa suitable for programs in vitro fertilization.

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

State research AZF- locus of the Y-chromosome in patients with azoospermia and severe oligozoospermia makes it possible to establish the genetic cause of spermatogenesis disorders, to differential diagnosis infertility in men and adjust treatment, check the possibility of obtaining spermatozoa for testicular biopsy and the possibility of obtaining spermatozoa for ICSI (intracytoplasmic sperm injection).

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

Screening indications AZF-deletions are based on sperm count and include azoospermia and severe oligozoospermia (

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

At present genetic research includes analysis AZF-chromosome locus - 13 clinically significant deletions: sY86, sY84, sY615, sY127, sY134, sY142, sY1197, sY254, sY255, sY1291, sY1125, sY1206, sY242, as well as determining the gene deletion SRY.

Androgen receptor gene AR

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

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

Male infertility in cystic fibrosis

luteinizing hormone (LH)

Follicle stimulating hormone (FSH)

Common prostate-specific antigen (PSA common)

Karyotype study

Important Notes

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

Literature

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

What could be more enjoyable than happy marriage? Thinking logically, most come to an answer. The best thing is the opportunity to become happy parents. Most often, every married couple sooner or later thinks about such important step like the birth of a child. However, to our great regret, not everyone manages to carry out their plans on the first attempt, and for 15% of couples, such efforts are doomed to failure. What can cause such a situation?

Faced with a similar problem, do not panic. If the desire to have a child has not come true within 2-7 months, this is not scary. You need to calm down and not dwell on it. There are many reasons for not getting pregnant: from simple psychological factor before serious problems develop.

To similar problems include:

male infertility;

female infertility;

immunological incompatibility (allergy in a woman to the components male sperm) - at the same time, neither of the spouses suffers from pathologies that can provoke infertility, but such a couple cannot have common children;

psychological aspects.

However, if completely healthy woman with regular sexual intercourse without the use of contraceptives for a year, pregnancy does not occur, then it's time to think about the fact that it could be a man. It is worth talking about this situation in more detail - what is it? How to diagnose? How to treat?

Male infertility - despite regular sexual intercourse - is the inability of a man's sperm to fertilize a woman's egg. Ideally, in the spermogram of a healthy man, 1 ml of semen should contain about 20 million spermatozoa, which are rapidly moving forward and are capable of fertilization. Also, about 50% of sperm must have the correct structure.

The reasons

The reasons that can provoke infertility in men can be:

complication after mumps;

inflammation of the organs of the genitourinary sphere;

diabetes mellitus (disorders of ejaculation);

a small amount and sluggish activity of spermatozoa in semen (the complete absence of "tadpoles" is also not excluded);

psychological infertility (when a man on a subconscious level is subject to fear of future responsibility that will arise with the birth of a baby or in the presence of other obsessive fears and arguments);

immunological infertility (the formation of antibodies that prevent spermatozoa from performing their normal functions).

Well, the simplest and most common reason that comes to mind last is the presence bad habits. Smoking, alcohol abuse also adversely affect the body of a man as a whole and reproductive function in particular.

Diagnostics

Male infertility is divided into:

primary - in which the man could not fertilize any representative of the opposite sex;

secondary - when at least one woman became pregnant from a particular man.

Reveal this pathology in a man and determine the cause of this condition, a urologist-andrologist and an endocrinologist-andrologist will help. The beginning of research is to pass a semen analysis. Such an analysis is commonly called a spermogram. It determines the activity and viability of spermatozoa, in addition, an assessment of other pathological changes is carried out.

Doctors may also recommend other studies to determine exact reason or pathology:

Ultrasound of the prostate;

hormone analysis;

diagnosing immune infertility– MAR test;

bacteriological culture for detection infectious pathologies urinary area.

Depending on the results of the tests, the specialist will prescribe treatment. The therapy is divided into three methods, which will be discussed below.

Treatment Methods

Conservative therapy

It consists in the use of drugs in the presence of genital infections various genesis. Also, a similar type of treatment is often prescribed in the presence of infertility against the background of hormonal failure.

Surgery

Appointed in the presence of anomalies urethra, in the presence of inguinal hernias and other anatomical abnormalities that cannot be corrected without surgery.

Alternative Therapy

This method is used when there is serious violations reproductive function in the stronger sex. It consists in the artificial introduction of spermatozoa into the genital tract of a woman in order to achieve fertilization.

Treatment of infertility should be comprehensive and adequate. In addition, they presented the stronger sex (not only when making a diagnosis, but also when planning a pregnancy) should review their own rhythm of life and regulate it if necessary. It is worth giving up bad habits, start eating right and not forget about good rest. Solution of problems intimate nature in men can be achieved through the use of herbal remedies for the treatment and prevention of pathologies of the male reproductive system. Quite often, after normalizing one's own diet and rest and following simple rules, reproductive function normalizes without additional interventions.

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

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

Causes of male infertility

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

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

To a large extent, the state of reproductive function in men depends on development of the organs of the genitourinary system, puberty. Processes that control development reproductive system, start working in intrauterine period. Even before the laying of the sex glands, primary germ cells are isolated outside the tissues of the embryo, which move to the area of ​​\u200b\u200bthe future testicles. This stage is very important for future fertility, since the absence or insufficiency of primary germ cells in the developing testicles can cause serious disorders of spermatogenesis, such as the absence of spermatozoa in seminal fluid (azoospermia) or severe oligozoospermia (sperm count less than 5 million / ml ). Various violations The development of the sex glands and other organs of the reproductive system is often due to genetic causes and can lead to impaired sexual development and, in the future, to infertility or reduced fertility. An important role in the development and maturation of the reproductive system is played by hormones, primarily sex hormones. Various endocrine disorders associated with a deficiency or excess of hormones, impaired sensitivity to any hormone that controls the development of the organs of the reproductive system, often lead to reproductive failure.

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

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

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

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

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

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

Ways to overcome infertility

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

A cytogenetic study (analysis of a set of chromosomes) is prescribed for all couples with infertility or recurrent miscarriage. If indicated, additional genetic studies are recommended.

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

Regardless of age, couples planning a pregnancy and concerned about the health of future offspring, in particular the birth of children with genetic disorders, can seek appropriate help from medical genetic consultations. Conducting a genetic examination reveals the presence of factors that do not favor the birth of healthy offspring.

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

Undoubtedly, the biological components transmitted to the child from the parents are quite important. However, social factors also have a significant impact on the health and development of the child. Numerous studies have shown that the level intellectual abilities and the nature of a person to a certain extent due to genetic factors. However, it should be noted that the degree of development mental capacity largely determined precisely by social factors - upbringing. The age of the parents alone cannot affect the level of development of the children. Therefore, the widespread belief that geniuses are more often born to older fathers is unfounded.

Summing up, I would like to note that the health of the child equally depends on the health of both parents. And it's good if the future dad and future mom will keep that in mind.

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

Bilateral aplasia of the vas deferens

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

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

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

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

Genes that regulate spermatogenesis

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

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

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

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

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

In a double-blind study of 138 male IVF couples, 100 healthy males and 107 young Danish military personnel, sex hormone levels, semen parameters, and AZF area analysis were performed. To study the AZF region, 21 DNA-marking sites were used; with normal sperm parameters and in all cases where the number of spermatozoa exceeded 1 million/ml, no deletions were found. In 17% of cases of idiopathic azoospermia or cryptozoospermia and in 7% of cases with other types of azoospermia and cryptozoospermia, deletions in the AZFc region were detected. Interestingly, none of the study participants had deletions in the AZFa and AZFb regions. This suggests that the genes located in the AZFc region are most important for spermatogenesis. Later there were more major study, which gave similar results.

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

Fragile X syndrome in women with premature ovarian failure

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

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

Secondary hypogonadism and Kalman syndrome in men

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

Violations and their causes in alphabetical order:

reproductive dysfunction -

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

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

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

What diseases cause reproductive dysfunction:

Causes of reproductive dysfunction in men

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

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

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

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

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

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

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

V. Idiopathic reproductive dysfunction
The reason cannot be determined.

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

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

Have you noticed a violation of the reproductive function? Do you want to know more detailed information or do you need an inspection? You can book an appointment with a doctor– clinic Eurolaboratory always at your service! The best doctors will examine you, study external signs and help identify the disease by symptoms, advise you and provide needed help. you also can call a doctor at home. Clinic Eurolaboratory open for you around the clock.

How to contact the clinic:
Phone of our clinic in Kyiv: (+38 044) 206-20-00 (multichannel). The secretary of the clinic will select a convenient day and hour for you to visit the doctor. Our coordinates and directions are indicated. Look in more detail about all the services of the clinic on her.

(+38 044) 206-20-00

If you have previously performed any research, be sure to take their results to a consultation with a doctor. If the studies have not been completed, we will do everything necessary in our clinic or with our colleagues in other clinics.

Do you have reproductive dysfunction? You need to be very careful about your overall health. People don't pay enough attention disease symptoms and do not realize that these diseases can be life-threatening. There are many diseases that at first do not manifest themselves in our body, but in the end it turns out that, unfortunately, it is too late to treat them. Each disease has its own specific signs, characteristic external manifestations - the so-called disease symptoms. Identifying symptoms is the first step in diagnosing diseases in general. To do this, you just need to several times a year be examined by a doctor not only to prevent terrible disease but also to maintain a healthy mind in the body and the body as a whole.

If you want to ask a doctor a question, use the online consultation section, perhaps you will find answers to your questions there and read self care tips. If you are interested in reviews about clinics and doctors, try to find the information you need on. Also register for medical portal Eurolaboratory to be constantly up to date with the latest news and information updates on the site, which will be automatically sent to you by mail.

The symptom map is for educational purposes only. Do not self-medicate; For all questions regarding the definition of the disease and how to treat it, contact your doctor. EUROLAB is not responsible for the consequences caused by the use of the information posted on the portal.

If you are interested in any other symptoms of diseases and types of disorders or you have any other questions and suggestions - write to us, we will definitely try to help you.