Causes and pathogenesis of disorders of sexual development

According to etiology and pathogenesis, congenital forms of sexual development disorders 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 disturbances in the meiotic division of chromosomes (oogenesis and spermiogenesis) in the body of the parents or in the case of 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, gonad morphogenesis 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. Extragonadal factors of sexual development disorders include decreased tissue sensitivity to androgens, which may be associated with the absence or insufficient number of receptors to them, decreased activity, and enzyme defects (in particular, 5-reductase) that convert less active forms of androgens into highly active ones, as well as excess production of androgens by the adrenal cortex. Pathogenetically, all these forms of pathology are associated with the presence of gene imbalance that occurs with chromosomal pathology.

Extrafetal damaging factors may include: the use of any medications by the mother in the early stages of pregnancy, especially hormonal ones that disrupt the morphogenesis of the reproductive system, radiation, various infections and intoxications.

Pathological anatomy of sexual development disorders. Gonadal agenesis includes two variants - Shereshevsky-Turner syndrome and "pure" gonadal agenesis syndrome.

In patients with Shereshevsky-Turner syndrome, there are 3 types of gonadal structure, corresponding to the degree of development of the external genitalia.

Type I: individuals with infantile external genitalia, connective tissue strands are found in the place of the usual location of the ovaries. The uterus is rudimentary. The tubes are thin, filiform, with a hypoplastic mucous membrane.

Type II: patients with signs of masculinization of the external genitalia. The gonads also lie in the usual location of the ovaries. Externally, they resemble cords, but histologically they consist of a cortical zone resembling the ovarian cortex and a medullary zone in which clusters of epithelial cells - analogues of Leydig cells - may be found. Elements of the mesonephros are often preserved in the medulla. Structures resembling the tubules of the epididymis are sometimes found near the tubes, i.e., there are underdeveloped derivatives of both the Wolffian and Müllerian ducts.

Gonads of type III structure are also localized in the location of the ovaries, but they are larger than the gonadal cords, with clearly distinguishable cortical and medullar zones. In the first, in some cases, primordial follicles are found, in others - underdeveloped seminiferous tubules without a lumen, lined with undifferentiated Sertoli cells and, extremely rarely, single sex cells. In the second layer, elements of the gonadal network and clusters of Leydig cells may be found. There are derivatives of the Wolffian and Müllerian canals, the latter predominate: uterus

Leydig cells appear on time or somewhat earlier, but already from the moment of their differentiation, diffuse or nodular hyperplasia is observed. Morphologically, they do not differ from Leydig cells of healthy people, but Reinke crystals are not found in them, and lipofuscin accumulates early.

Gonadal cords in patients with mixed testicular dysgenesis are diverse in structure: in some cases they are formed from coarse fibrous connective tissue, in others they resemble the interstitial tissue of the ovarian cortex without germinal structures. In a small proportion of patients, the gonadal cord is similar to the interstitial tissue of the testicular cortex, contains either sex cords or single seminiferous tubules without gonocytes.

The glandular cells of dysgenetic testes are characterized by high activity of steroidogenesis enzymes (NADP and NAD-tetrazolium reductases, glucose-6-phosphate dehydrogenase, 3P-oxysteroid dehydrogenase, alcohol dehydrogenase). Cholesterol and its esters are found in the cytoplasm of Leydig cells. As in any steroid-producing cells, there is an inverse relationship between the activity of enzymes involved in steroidogenesis processes and the lipid content.

Approximately 1/3 of patients of any age develop tumors in the testicles and gonadal cords, especially those localized intraperitoneally, the source of which are germ cells. Less often, they form in individuals with pronounced masculinization of the external genitalia and are detected accidentally as an intraoperative or histological finding. Large tumors are extremely rare. In more than 60% of patients, they are microscopic in size. In this pathology, two types of tumors from germ cells are encountered: gonadoblastomas and dysgerminomas.

In the majority of patients, gonadoblastomas are formed by both gonocytes and Sertoli cells. Malignant variants are extremely rare. All gonadoblastomas contain either highly differentiated Leydig cells or their precursors. Some tumors are dysgerminomas; in half of the cases, they are combined with gonadoblastomas of various structures. Lymphoid infiltration of the stroma is pathognomonic for them. Malignant variants are extremely rare.

Klinefelter's syndrome. The testicles are sharply reduced in size, sometimes they make up 10% of the volume of the testicles of healthy men of the corresponding age: dense to the touch. Histological changes are specific and are reduced to atrophic degeneration of the tubular apparatus. The seminiferous tubules are small, with immature Sertoli cells, without germ cells. Only in some of them can spermatogenesis be observed, and rarely - spermiogenesis. Their distinctive feature is thickening and sclerosis of the basal membrane with gradual obliteration of the cavity, as well as hyperplasia of Leydig cells, which is relative due to the small size of the gonads. The number of these cells in the gonad is actually reduced, at the same time their total volume differs little from that in the testicle of a healthy man; this is explained by hypertrophy of the cells and their nuclei. Electron microscopy distinguishes four types of Leydig cells:

• Type I - unchanged, often with Reinke crystals.
• Type II - atypically differentiated small cells with polymorphic nuclei and scanty cytoplasm with paracrystalline inclusions; lipid droplets are rare.
• Type III - abundantly vacuolated cells containing a large number of lipid droplets, but poor in cellular organelles.
• Type IV - immature, with poorly developed cellular organelles. More than 50% are Leydig type II cells, the least common are type IV cells.

Their morphological features confirm the existing ideas about the disruption of functional activity, although there is evidence that some cells are hyperfunctional. With age, their focal hyperplasia is so pronounced that sometimes it seems like adenomas are present. In the final phase of the disease, the testicles degenerate and become hyalinized.

Incomplete masculinization syndrome. The gonads are located extra-abdominally. The seminiferous tubules are large, and spermatogenic elements capable of reproduction and differentiation are often found in them, although spermatogenesis never ends with spermiogenesis. In the android form, hyperplasia of Leydig cells is rarely observed, which, like in testicular feminization syndrome (TFS), are characterized by a defect in 3beta-oxysteroid dehydrogenase. Apparently, a sufficient number of Leydig cells and their high functional activity, despite the disruption of the nature of biosynthesis, still provide sufficient androgenic activity of the testicles. According to our data, tumors do not form in the gonads of these patients.

Testicular feminization syndrome. Histologically, the testicles show thickening of the tunica albuginea, the presence of a large number of fairly large seminiferous tubules with a thickened and hyalinized basement membrane. Their epithelium is represented by Sertoli cells and sex cells. The degree of development of the former depends on the number and condition of the germinal elements: in the presence of a relatively large number of spermatogonia, Sertoli cells are predominantly highly differentiated; in the absence of gonocytes, spermatids are very rarely formed. The glandular component of the gonad is represented by typical Leydig cells, often significantly hyperplastic. The cytoplasm of these cells often contains lipofuscin. In the incomplete form of the syndrome, Leydig cell hyperplasia is present in more than half of patients. The cells of both variants of the syndrome are characterized by high activity of enzymes that ensure the processes of steroidogenesis: alcohol dehydrogenase, glucose-6-phosphate dehydrogenase, NADP and NAD-tetrazolium reductases, however, the activity of the most specific enzyme for steroidogenesis - 3beta-oxysteroid dehydrogenase - is sharply reduced, which obviously indicates a violation of one of the early stages of androgen biosynthesis. A defect of 17-ketosteroid reductase may be noted, the absence of which leads to a violation of testosterone formation. Electron microscopically, Leydig cells are characterized as actively functioning steroid producers.

Tumors in the testicles occur only in the complete form of STF. Their source is the tubular apparatus. The initial stage of tumor development is nodular hyperplasia of the seminiferous tubules, which is often multifocal. In such gonads, adenomas of the sertolioma type with their own capsule (tubular adenomas) are formed. Leydig cells are often localized in the foci of hyperplasia and in adenomas. In some cases, arrhenoblastomas of trabecular or mixed structure are formed. Tumors are usually benign, although malignant sertoliomas and gonadoblastomas have been described. However, there is an opinion that tumors in STF should be classified as hamartomas.

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