Genetic disorders leading to infertility in humans. Such problems include

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

Causes of male reproductive disorders

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

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

excretory disorder. Violation of the patency (obstruction, obturation) of the vas deferens, resulting in impaired output constituent elements sperm into the urethra through the genital tract. It can be permanent or temporary, unilateral or bilateral. Semen contains spermatozoa, prostate and secret seminal vesicles.

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

Other reasons:

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

Causes of violations of female reproductive function

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

Treatment of female infertility

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

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

With obstruction of the tubes, laparoscopy is included in the treatment.

Endometriosis is also treated by laparoscopy.

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

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

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

Treatment male infertility

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

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

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

Causes of male reproductive disorders

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

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

Other reasons:

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

Causes of violations of female reproductive function

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

Treatment of female infertility

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

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

With obstruction of the tubes, laparoscopy is included in the treatment.

Endometriosis is also treated by laparoscopy.

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

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

It is most difficult to treat infertility if the causes cannot be accurately identified. As a rule, in this embodiment, IVF technologies are used - artificial insemination.

Treatment of male infertility

If a man has infertility, which is of a secretory nature, that is, associated with a violation of spermatogenesis, the beginning of treatment consists in eliminating the causes. Infectious diseases are treated, inflammatory processes are eliminated, hormonal agents are used to bring spermatogenesis back to normal.

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

Violations and their causes in alphabetical order:

reproductive dysfunction -

Reproductive dysfunction(infertility) - the inability of a married couple to conceive with regular unprotected sexual 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) this period increases to 1 year, and after 35 years - more than 1 year.

Approximately 35-40% infertile couples the cause of it is a man, in 50% - 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, heavy chronic diseases, vibration, overheating of the body (work in hot shops, sauna abuse, fever), hypoxia, hypodynamia
- 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 disorders - structural chromosomal aberrations - Klinefelter's syndrome, XYY syndrome, chromosomal translocations, autosomal aneuplodies) - 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 one's own immune cells production of antibodies to spermatozoa
o parotitis- "pig"
o testicular injury
o cryptorchidism (undescended testicles)
o operations on the organs of the scrotum
o passive homosexuals

II. Obstructive (excretory) violation of the reproductive function is associated, as a rule, with bilateral, temporary or permanent violation patency (obstruction, obstruction) of the vas deferens and a violation of the output of the constituent elements of sperm (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 its membranous part urethra, damage nerve centers regulating ejaculation.
- injuries of the genital organs, including during surgical interventions(for example, with hernia repair),
- consequences of vasectomy

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

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

V. Idiopathic reproductive dysfunction
The reason cannot be determined.

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

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

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What could be more enjoyable than happy marriage? Thinking logically, most come to an answer. The best thing is just the opportunity to become happy parents. Most often, each married couple sooner or later think about it 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, none of the spouses suffers from pathologies that can provoke infertility, but such a couple cannot have common children;

psychological aspects.

However, if a completely healthy woman does not get pregnant during regular sexual intercourse without the use of contraceptives for a year, 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 in last, is the presence bad habits. Smoking, alcohol abuse also adversely affect the body of a man in general 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

Consists of using medicines 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

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

Alternative Therapy

To this method resort when available 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 your own diet and rest and following simple rules reproductive function is normalized without additional interventions.

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 no mutations leading to cystic fibrosis were 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 that are characteristic of cystic fibrosis at once - 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, different variants, 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 mainly by the 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 faf gene in Drosophila). 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 Y-chromosome mutations 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:

they are found both in barren and in healthy men;
the presence of DAZ and RBMY clusters containing several copies of genes makes analysis difficult;
in various studies different parameters of sperm were studied;
the set of contig maps of the Y-chromosome was not complete due to the presence of repeated sequences;
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 conditions of deficiency folic acid however, 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 other family members may also be carriers: they may have sons with fragile X syndrome, which manifests itself mental retardation, characteristic features faces and macroorchism.

Secondary hypogonadism and Kalman syndrome in men

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