Disorder of Sex Development - Overview of Information

Gender is a complex concept consisting of several interconnected links of the reproductive system: the genetic structure of the sex cell (genetic gender), the morphostructure of the gonads (gonadal gender), the balance of sex hormones (hormonal gender), the structure of the genitals and secondary sexual characteristics (somatic gender), psychosocial and psychosexual self-determination (mental gender), a certain role in the family and society (social gender). Ultimately, gender is a biologically and socially determined role of the subject in the family and society.

The formation of human sex occurs in several stages during ontogenesis.

• Stage I. The sex of the future organism is determined at the moment of fertilization and depends on the combination of sex chromosomes in the zygote: XX set corresponds to the female sex, XY - to the male sex. The activity of the gene-activator of HY genes, determining the development of the primary gonad in the male direction, is associated with the Y chromosome. They trigger the synthesis of the HY antigen and receptor proteins to it, the genes of which are localized in other chromosomes. Another system of genes of the Y chromosome ensures the development of the epididymis, seminal vesicles, vas deferens, prostate gland, external genitalia in the male direction, as well as the involution of the Müllerian derivatives.
• In the germ cells of the primary gonad (both XY and XX chromosome sets) there are receptors for the HY antigen, while in somatic cells they are present only in the XY set; the structure of somatic receptors for the HY antigen includes a special type of beta-microglobulin, while the receptors of germ cells for the HY antigen (both XY and XX) are not associated with this specific protein. This probably explains the bipotentiality of the primary gonad.
• Stage II. Between the 7th and 10th week of intrauterine development, the formation of the sex glands occurs in accordance with the set of sex chromosomes.
• Stage III. Between the 10th and 12th week of embryogenesis, internal genitalia are formed. Functionally complete testicles during this period secrete a special peptide hormone that causes the resorption of Müllerian derivatives. In the absence of testicles or in case of their pathology with a violation of the production of anti-Müllerian hormone, internal female genital organs (uterus, tubes, vagina) develop even in an embryo with a genetic male sex (46.XY).
• Stage IV. Between the 12th and 20th weeks of embryogenesis, the external genitalia are formed. The determining role in male development at this stage is played by androgens (regardless of their source) - testicular, adrenal, coming from the mother's body (in the presence of androgen-producing tumors in the mother or in connection with the intake of androgenic drugs). In the absence of androgens and with a violation of receptor sensitivity to them, the external genitalia are formed according to the female ("neutral") type, even in the presence of a 46,XY karyotype and normal function of the embryonic testicles. The development of intermediate variants (incomplete masculinization) is also possible.
• Stage V. Descent of the testicles into the scrotum. Occurs between the 20th and 30th week of embryogenesis. The mechanism that causes or disrupts the advancement of the testicles is not completely clear. However, it is certain that both testosterone and gonadotropins are involved in this process.
• The sixth stage of sexual differentiation occurs already in puberty, when the connections in the hypothalamus-pituitary gland-gonads system are finally formed, the hormonal and generative function of the gonads is activated, and social and sexual self-awareness is consolidated, determining the role of the subject in the family and society.

Causes and pathogenesis of disorders of sexual development. According to etiology and pathogenesis, congenital forms of disorders of sexual development can be divided into gonadal, extragonadal and extrafetal; among the first two, a large share falls on genetic pathology. The main genetic factors of the etiology of forms of congenital pathology of sexual development are the absence of sex chromosomes, their excess number or their morphological defects, which can occur as a result of disorders of meiotic division of chromosomes (oogenesis and spermatogenesis) in the body of the parents or with a defect in the division of the fertilized egg (zygote) at the first stages of cleavage. In the latter case, "mosaic" variants of chromosomal pathology occur. In some patients, genetic defects are manifested in the form of autosomal gene mutations and are not recognized by light microscopy of chromosomes. In gonadal forms, the morphogenesis of the gonad is disrupted, which is accompanied by both pathology of the anti-Müllerian activity of the testicles and the hormonal (androgenic or estrogenic) function of the gonad.

Causes and pathogenesis of disorders of sexual development

Clinical characteristics of the main forms of congenital pathology of sexual development

When singling out a clinical form as a specific nosological unit, one should always take into account that between types of pathology that are closely located on the scale of stages of embryogenesis, there may be intermediate types that in some features bear the characteristics of neighboring forms.

The main clinical signs of congenital pathology.

1. Pathology of the formation of the gonads: complete or unilateral absence, disruption of their differentiation, the presence of gonadal structures of both sexes in one individual, degenerative changes in the gonads, undescended testicles.
2. Pathology of the formation of internal genitalia: simultaneous presence of derivatives of the Müllerian and Wolffian ducts, absence of internal genitalia, discrepancy between the sex of the gonads and the structure of the internal genitalia.
3. Pathology of the formation of external genitalia: discrepancy between their structure and the genetic and gonadal sex, gender-indeterminate structure or underdevelopment of the external genitalia.
4. Disorder of development of secondary sexual characteristics: development of secondary sexual characteristics that does not correspond to the genetic, gonadal or civil sex; absence, insufficiency or prematurity of development of secondary sexual characteristics; absence or delay of menarche.

Symptoms of Sexual Development Disorders

Diagnostics of various forms of congenital pathology of sexual development

The main principle of diagnostic studies for congenital pathology of sexual development is to determine the anatomical and functional state of all links that make up the concept of sex.

Examination of the genitals. At birth, the doctor determines the sex of the child based on the structure of the external genitalia ("obstetric sex"). In case of gonadal agenesis and complete testicular feminization, the structure of the external genitalia is always female, so the question of choosing the female civil sex is decided unambiguously, despite the genetic and gonadal sex, which in the latter case will be male. In case of testicular feminization syndrome, the diagnosis can in some cases be established at prepubertal age in the presence of testicles in the "large labia" or inguinal hernias. Palpation of the extra-abdominal testicles allows us to determine their size, consistency, and to assume the possibility of tumor changes.

In abdominal cryptorchidism in boys and severe forms of congenital dysfunction of the adrenal cortex in children with female genetic and gonadal sex, the structure of the penis may be normal, which often leads to an erroneous assessment of a newborn girl as a boy with cryptorchidism. In Klinefelter syndrome, the structure of the external genitalia at birth is normal male, which does not allow a diagnosis to be made based on a routine examination.

Diagnosis of disorders of sexual development

Treatment of congenital pathology of sexual development consists of several aspects. The main issue is to establish the civil sex of the patient, adequate to his biological and functional data, taking into account the prognosis of the possibility of sexual life.

In cases of underdeveloped genitalia corresponding to a certain sex, absence or surgical removal of gonads, as well as growth disorders, it is necessary to carry out hormonal correction of development, forming a phenotype approaching the norm and ensuring a normal level of sex hormones.

Surgical sex reassignment involves the formation of external genitalia depending on the chosen sex (feminizing or masculinizing reconstruction), as well as the decision on the fate of the gonads (their removal, removal from the abdominal cavity, or lowering the testicles into the scrotum). When choosing the male sex for patients with testicular dysgenesis, from our point of view, removal of the rudimentary uterus is not necessary, since its presence does not cause any complications in the future. Some patients with incomplete masculinization syndrome and testicular feminization require the creation of an artificial vagina.

Treatment of disorders of sexual development