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Lack of sexual development (gonad dysgenesis)

Gonad dysgenesis (DG) is a congenital defect in the development of the gonads or their complete absence, which is often caused by chromosomal abnormalities (quantitative or structural pathology of the sex chromosomes). Patients have an incomplete set of chromosomes (45X instead of 45XY), mosaicism (X0 / XX, X0 / XY, etc.), a defect in the short arm of the X chromosome, etc. In this case, due to the suppression of meiosis, the ovaries do not develop (in their place, ribbon-like strips of whitish tissue form), and the oocytes from them disappear even in fetal development or immediately after birth.

It is believed that with DG in the chromosomes, genes or loci can be damaged in the groups responsible for sexual development (J), for the normal development of musculoskeletal, cardiovascular, urinary and other systems (A), as well as for growth (S). Depending on the combination of damage to these structures, different forms of the disease arise: sexual infantilism without developmental abnormalities with high growth, dwarfism with sexual infantilism and developmental abnormalities, infantilism with small growth and the absence of developmental abnormalities of organs and systems, etc.

Follicular development and estrogen production are absent, which leads to sexual infantilism and amenorrhea. In some cases, it is possible to preserve oocytes and mature follicles until menarche, and then the occurrence of premature ovarian failure and secondary amenorrhea. Such a variety of forms of gonadal dysgenesis can be associated with the timing of the adverse effects of harmful factors during the period of differentiation or formation of the gonads. Damaged gonad tissue during the differentiation period dies, replaced by connective tissue, with the subsequent formation of a neutral female phenotype due to the lack of secretion of the "organizer" of the male type, even in cases of chromosomal determination of the male type. Dysgenesis of gonads due to pathology of the sex chromosomes that occurred in the early stages of ovogenesis and spermatogenesis can be considered hereditary.

Sex chromatin with DG in most patients (80% or more) is absent. In this case, the correct male set of chromosomes (XY) may occur. With positive sex chromatin, the correct female chromosome set (XX) is noted. The mosaic set of chromosomes is accompanied by negative or positive sex chromatin in DG.

With DG there is no proper reaction of the ovaries to gonadotropins, which is accompanied by their high level, to a greater extent FSH, as well as sharp hypoestrogenia.

A “pure” form of gonadal dysgenesis is characterized by pronounced sexual infantilism in women with normal or high growth in the absence of somatic developmental abnormalities. First described in 1955 by Swyer. Patients have a female phenotype with a dysplastic physique according to the intersexual (enlarged chest circumference and decreased transverse body size) or eunuchoid (enlarged chest and legs and reduced pelvis sizes) types. Secondary sexual characteristics are absent or significantly underdeveloped: scanty hair growth in the pubic and axillary areas, the mammary glands, external genitalia, uterus, and atrophic mucous membrane of the genital organs are underdeveloped. The karyotype in patients is most often 46 XX with normal or reduced sex chromatin content. The karyotype 46 XY (Swyer syndrome) with a sharp decrease or absence of sex chromatin is possible. The level of gonadotropic hormones is sharply increased, mainly due to FSH (8-15 times) and to a lesser extent due to LH (4-5 times). The content of testosterone and excretion of 17-KS is within the normal range or with a tendency to increase with Swyer syndrome. The pathomorphological picture is characterized by the female type of genital organs: the uterus and tubes are determined, in the place of the ovaries - oblong whitish formations, often with single primordial follicles (often with various degenerative changes). With Swyer syndrome, hormone-active tumors are often formed in dysgenetic gonads, which is the basis for the removal of gonads in this pathology (karyotype 45 XY, negative sex chromatin).

Shereshevsky-Turner syndrome (a typical form of DH) is characterized by total sexual infantilism in women with short stature and often the presence of many somatic developmental anomalies. It was first described by N. A. Shereshevsky in 1926. Such patients are born with low body weight, swelling of the arms and legs (Ulrich syndrome). Subsequently, their growth is slowed down (up to 50–55% of the age norm) and reaches no more than 150–155 cm. They are characterized by a stocky physique, a disproportionately large chest and a short neck. In addition to a small body length, other somatic anomalies are noted: folds on the neck, low line of hair growth on the neck, deformation of the skull and elbow joints, low-lying ears with a defect in the cartilage of the auricle, flat chest, defects in the cardiovascular system (valve atresia, atrial septal defect, coarctation of the aorta, stenosis of the pulmonary artery, etc.), urinary tract (horseshoe-shaped kidneys, ureteral bifurcation), osteoporosis, and bone shape disturbances, especially tubular ones. At puberty, patients do not have secondary sexual characteristics: there is no hair growth in the axillary and pubic areas, the mammary glands, the labia minora, the uterus and the vagina, and the atrophic mucosa of the genital organs are undeveloped. Characteristic of Shereshevsky-Turner syndrome is mosaicism of chromosomes: X0 / XY, X0 / ХХХ, Х0 / ХХ, etc. In Shereshevsky-Turner syndrome, significant hormonal disorders are noted: high levels of FSH (10-20 times higher than normal), LH (in 3-4 times higher than normal), various abnormal levels of 17-KS excretion (peaks increase - decrease). The uterus and tubes are in the form of rudimentary structures, next to which whitish connective tissue cords (rudimentary gonads) are defined. Various variants of the pathological structure of the gonads are described: ordinary fibrous tissue; connective tissue stroma with interstitial cells, dysgenetic gonads with parts of the cortical zone and primary degenerative follicles, as well as with the seminiferous tubules; rudimentary male gonads. A “mixed” form of gonadal dysgenesis is one of the forms of intersexuality (hermophroditism), also called asymmetric. It was isolated in the nosological form of Sohval DG in 1905. It is characterized by an indefinite phenotype, with a predominance of female in some cases, in other cases for men. With the female phenotype, there is an intersexual structure of the genital organs and clitoral hypertrophy. With the male phenotype, the uterus with tubes is determined in the abdominal cavity. Gonads in such patients have a mixed structure: on the one hand, a gonad is rudimentary in the form of a connective tissue strand, and on the other, an underdeveloped testicle with Sertoli or Leydig cells, as well as undifferentiated gonads and the uterus (gonocytes). A dysgenetic testicle can be located in the ovary on one side, as well as in the inguinal canal or vestigial scrotum. This was the reason for the name of the "mixed" form of gonadal dysgenesis (or "gonadal dysgenesis"). Patients with a "mixed" form of DH have high growth (although there are also stunts). Somatic anomalies are more often absent, less often the same as with Shereshevsky-Turner syndrome.
In patients with DG, the mammary glands are undeveloped, pubic hair is expressed, hypertrichosis and a low voice timbre are noted. Sex chromatin in most cases is not detected, the karyotype is more often with a normal male set (XY) or in the form of mosaicism like X0 / XY, and other options are noted. It is believed that the pathology of the sex chromosomes always takes place, which explains the violation of the differentiation of the sex glands with functional insufficiency already in embryogenesis. Patients have a high level of gonadotropins with the content of female and male sex steroid hormones at the level of the lower boundary of the male norm. Often in a degenerative testicle, tumors such as gonocytoma or gonadoblastoma develop, leading to severe virilization.

In the diagnosis of gonad dysgenesis, general clinical data, examination results and additional research methods are important: ultrasound, determination of sex chromatin and karyotype, laparoscopy and laparotomy with a gonad biopsy, hormonal studies with functional hormonal tests.

The treatment of gonadal dysgenesis should be carried out together with an endocrinologist, geneticist, surgeon, urologist and psychologist. Such an integrated approach is especially important when choosing tactics and methods of treatment for severe genital intersexuality. The main goal of treatment is to prevent psychosexual conflicts. And for this, violated genitals should be correctly formulated or corrected as far as possible and conditions (possibilities) for sexual activity should be created. This is what should be the basis for the choice of tactics and gender during treatment (and not the chromosomal sex). This is also confirmed by the current tendency towards transsexualism.

The main directions in the treatment of gonadal dysgenesis: surgical correction of somatic developmental abnormalities; measures to correct low growth; the formation of secondary sexual characteristics; psychotherapeutic effects; hormone replacement therapy. During the treatment, deontology should be carefully observed in terms of proper relationships with patients, their parents and everyone else. Many issues should be discussed and agreed only with patients, especially when they reach puberty. In Shereshevsky-Turner syndrome, when the diagnosis is established immediately after birth, a plan is drawn up and timelines for surgical corrective interventions to eliminate somatic developmental abnormalities (bone, cardiovascular and other malformations) are outlined. This stage of treatment is performed by pediatric surgeons. The next most important task is to stimulate growth when it is delayed, which should be carried out as soon as possible. For this purpose, thyroid hormones, thyroid drugs (thyroidin 50-100 mg, thyrocomb 50-100 mg, triiodothyronine 20-25 micrograms, lyiotironin 20 micrograms, etc.) and anabolic hormones (methylandrostenolone 0.1 mg) are recommended. / kg per day, nerobolil 1 ml intramuscularly 1 time per month, retabolil 1 ml 1 time in 3 months). They are applied in courses of 4-5 months with 2-3-month breaks. To stimulate growth, insulin therapy is also carried out (2-10 units per day) in 2-month courses, 2 times a year. For the same purpose, growth factors (somatomedins and growth factors with insulin-like activity) can also be used. Such treatment is carried out up to 13-15 years of age of patients. This stage is carried out under the control of endocrinologists, during which the evaluation of ossification processes is especially important.

Timely resolution of the question of the timing of gonadectomy is very relevant for the following reasons: in connection with the potential blastomatous activity of dysgenetic gonads, such patients constitute an increased risk group in the oncological aspect; gonadectomy, apparently, should precede cyclic hormonal therapy with sex steroid hormones. Gonadectomy is widely used in Shereshevsky-Turner syndrome and in the "mixed" form of gonadal dysgenesis, especially with karyotypes 45 X0, in the presence of the Y-chromosome or its fragments in the karyotype. The solution to this issue is carried out jointly with urologists and geneticists.

The next stage is the induction and development of primary and secondary sexual characteristics. Initially (from 13-15 years), estrogen preparations are prescribed in courses of 20-21 days with 6-7-day intervals, lasting from 6 months to 2 years. Premature use of estrogen leads to ossification of the epiphyseal bones and stunted growth. Therefore, individual authors recommend starting their use from 16-17 years old, which, apparently, is not entirely justified in terms of the development of primary and secondary sexual characteristics. However, sex steroid hormones can also be prescribed from 11-12 years old to patients with a tendency to gigantic growth to stop it (with clean and mixed forms of DH). Under the control of TFD, ultrasound and other examination methods, the effectiveness of estrogenic compounds (growth of the uterus, mammary glands, mucous membranes, the appearance of menstrual bleeding, etc.) is evaluated to switch to cyclic hormonal therapy. Estrogenic drugs are prescribed parenterally, orally (folliculin, ethinyl estradiol, premarin, sinopause, dimestrol, etc.). The timely transition to cyclic hormone therapy using progestogens to simulate the second phase of the cycle is also necessary for the prevention of hyperplastic processes in hormone-dependent organs (uterus and mammary glands). At the same time, a complex of vitamins is recommended for the phases of the cycle (C, B, E, folic acid, etc.), as well as physiotherapeutic procedures to improve blood supply to the pelvic organs, electroanalgesia, acupuncture, sedatives.

With the development of secondary sexual characteristics (spontaneous or induced), only cyclic hormone replacement therapy with imitation of the phases of the cycle (microfollin, pregnin, etc.) is indicated; carried out regardless of the form of gonadal dysgenesis. It helps to eliminate psychopathological conditions, improve the general condition, normalize working capacity and eliminate other psycho-emotional, vegetovascular and metabolic-endocrine disorders. Therapy also includes the prevention of osteoporosis and cardiovascular diseases characteristic of hypoestrogenemia. In the process of hormone therapy, dynamic control (TFD, ultrasound, cytology, etc.) should be carried out. Complications of hormone replacement therapy (mastopathy, uterine fibroids, endometrial hyperplasia) are eliminated by an increase in the gestagen component. Hormone replacement therapy is carried out for a long time, possibly throughout the childbearing period.

The prognosis for gonad dysgenesis in the aspect of the restoration of specific female functions is ambiguous. Such patients should be classified as an absolute risk group for infertility. If in some cases with a pure form of DG even ovulatory processes can be achieved, therapy for infertility is unlikely to be carried out, since the probability of having healthy children in these patients is very low. In the event of pregnancy, a thorough genetic examination should be carried out.
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Lack of sexual development (gonad dysgenesis)

  1. Violation of puberty during puberty by the type of "worn out" virilization
    When a viril syndrome occurs in prepubertal age, the clinic is usually so pronounced that the diagnosis of such conditions does not cause special difficulties. In clinical practice, patients with erased virilization are much more common, the symptoms of which in most patients appear after menarche, due to the activation of the hypothalamus – pituitary – ovary – adrenal system. IN
  2. Classification and etiology of delayed sexual development in girls (by Lee P., 1999)
    I. Delayed sexual development and incomplete sexual development. A. Primary (hypergonadotropic) hypogonadism. 1. Congenital anomalies of the ovaries: a) typical gonadal dysgenesis in Turner syndrome (45, X) or mosaicism (45, X / 46, XX); b) erased dysgenesis of gonads 46, XX; c) pure dysgenesis of gonads 46, XY; Endocrine gynecology d) mixed gonadal dysgenesis 45X / 46, XY;
  3. Pathology of sexual development
    Of the disorders of sexual development, the following varieties are more common: delay and lack of puberty, premature sexual development, menstrual irregularities and abnormalities in the development of genital organs. These are the main endocrine diseases in children.
  4. Sexual Development Violations
    Solsky, Y.P., Reged SI. NDISCUSSION of sexual development includes premature sexual development and delayed sexual development. Premature sexual development (SPD) is the appearance of all or some secondary sexual characteristics (and in some cases, menarche) in girls under 8 years old. Currently, it is customary to distinguish two large groups of diseases accompanied by SPD syndrome.
  5. Delayed sexual development
    ZPR - this is the underdevelopment of secondary sexual characteristics by 13 years and the absence of menarche by 15 years and older. If sexual development begins in a timely manner, but menstruation does not occur within 5 years, they speak of an isolated delay in the menarche. In addition, there is incomplete sexual development. It is characterized by the timely appearance of some and the lag of other secondary sexual characteristics and, as
  6. Delayed sexual development
    Delay in puberty, as a rule, is a consequence of a violation of the correct relationships between the various links that regulate the process of puberty. In this case, there may be an underdevelopment or absence of all the main secondary sexual characteristics (development of the mammary gland, hairiness in the pubic and axillary cavities, menstruation) or only the absence of menarche. Delay
  7. Incomplete sexual development
    With incomplete sexual development, separate secondary sexual characteristics appear, but then their formation slows down. The period between the onset of puberty and the onset of menarche is lengthening. Incomplete sexual development is often constitutional (a variant of the norm), but can be caused by primary or secondary hypogonadism. Incomplete sexual development should be distinguished from the late onset of menarche.
  8. Periods of puberty and development
    Based on the anatomical, physiological and psycho-emotional changes that occur in humans during puberty and development, which is the topic of our lecture, it is necessary to recall 5 large periods of a person's LIFE: childhood, adolescence, youth, adulthood and old age. The most preferable scheme of sexual development in humans is described by I. Yunda, Yu. Skripkin, E. Maryasis
  9. Periods of puberty and development
    Based on the anatomical, physiological and psycho-emotional changes that occur in humans during puberty and development, which is the topic of our lecture, it is necessary to recall 5 large periods of a person's LIFE: childhood, adolescence, youth, adulthood and old age. The most preferable scheme of sexual development in humans is described by I. Yunda, Yu. Skripkin, E. Maryasis
  10. Male sexual development
    The period of development of the reproductive system in boys under 9 years of age is called asexual (asexual), since the functional state of sex hormones in them does not differ from those in girls. In a 6-month-old baby, the testes do not differ in structure from the testicles of the fetus. Gradually, from 7 months to 4 years, there is a slight increase in seminal epithelial cells. However, the gaps of the seminiferous tubules are almost not
  11. False premature sexual development
    False premature sexual development is due to autonomous excessive secretion of estrogen in the adrenal glands or ovaries, or the intake of estrogen or gonadotropic hormones. False premature sexual development, as well as true, is accompanied by accelerated growth (Bailey PE, 1997). Unlike true, false premature sexual development is always incomplete (premature
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