Causes and pathogenesis of sexual dysfunction

On the etiology and pathogenesis of congenital forms of sexual dysfunction can be divided into gonadal, extragonadal and extraphetal, among the first two, a large proportion accounted for genetic pathology. The main genetic factors of the etiology of the forms of the congenital pathology of sexual development are the absence of sex chromosomes, an excess of their number or their morphological defects that can arise as a result of meiotic division of chromosomes (oogenesis and spermiogenesis) in the parents' body or in the defect of dividing the fertilized ovum (zygote) stages of crushing. In the latter case, there are "mosaic" variants of chromosomal pathology. In some patients, genetic defects manifest themselves as autosomal gene mutations and are not recognized by light microscopy of chromosomes. With gonadal forms, the morphogenesis of the gonad is impaired, which is accompanied by both the pathology of the antimulylerovoy activity of the testicles, and the hormonal (androgenic or estrogenic) function of the gonad. The decrease in tissue sensitivity to androgens, which may be due to the lack or inadequate number of receptors to them, a decrease in their activity and with defects in enzymes (in particular, 5-hydatase), which turn the less active forms of androgens into highly active , and also with excess production of androgens by the adrenal cortex. Pathogenetically, all these forms of pathology are associated with the presence of a gene imbalance that occurs with chromosomal pathology.

An extraphetal damaging factor can be: the use of any medications, especially hormonal, morphogenetic disorders of the reproductive system, radiation, various infections and intoxications during the early stages of pregnancy.

Pathanatomy of sexual development disorders. Gonadal agenesis includes two options - Shereshevsky-Turner syndrome and the syndrome of "pure" gonad agenesis.

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

I type: faces with infantile external genital organs, in the place of the usual location of the ovaries connective tissue strands are found. The uterus is rudimentary. Pipes thin, filiform, with hypoplastic mucosa.

II type: patients with signs of masculinization of the external genitalia. Gonads also lie in the place of the usual arrangement of the ovaries. Externally, they are similar to strands, but histologically consist of a cortical zone resembling the ovarian cortex, and from the medullary zone, in which clusters of epithelial cells, analogues of Leydig cells, can be found. In the medullar layer, the elements of mesonephros are often preserved. Near the tubes, structures that resemble the tubules of the appendage of the testis are sometimes found, that is, there are underdeveloped derivatives of both the wolf and the Muller channels.

Gonads of the III type of structure also localize in the location of the ovaries, but they are larger than the gonadal cords, with clearly distinguishable cortical and cerebral zones. In the former, primordial follicles are found in some cases, in others - underdeveloped seminiferous tubules without lumen, lined with undifferentiated Sertoli cells and extremely rarely - by single germ cells. In the second layer, there may be elements of the gonadal network and Leydig cell congestion. There are derivatives of the wolf and muller canals, the latter predominate: the uterus

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

The gonadal cords in patients with mixed testicular dysgenesis are diverse in structure: in some cases they are formed from coarse-fibrous connective tissue, while in others they resemble interstitial tissue of the ovarian cortex without germinative structures. In an insignificant part of the patients, the gonadal cord is similar to the interstitial tissue of the testicle cortex, contains either sexual strings, or single seminiferous tubules without gonocytes.

The high activity of enzymes of steroidogenesis (NADP- and NAD-tetrazolium reductase, glucose-6-phosphate dehydrogenase, 3R-oxysteroid dehydrogenase, alcohol dehydrogenase) is characteristic of the glandular cells of dysgenetic testes. Cholesterol and its esters are found in the cytoplasm of Leydig cells. As in any steroid-producing cells, they have an inverse relationship between the activity of enzymes involved in the processes of steroidogenesis and the content of lipids.

Approximately one-third of patients of any age in the testes and gonadal strands, especially those localized intraperitoneally, develop tumors from which the sex cells originate. Less often they are formed in persons with severe masculinization of the external genitalia and are identified by chance as an intraoperative or histological finding. Large tumors are extremely rare. More than 60% of patients have microscopic dimensions. With this pathology, there are two types of tumors from sex cells: gonadoblastoma and disgerminoma.

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. The tumor nodes are disgerminomas; in half of cases they are combined with gonadoblastomy of a diverse structure. Pathognomonic for them is lymphoid infiltration of the stroma. Malignant variants are extremely rare.

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

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

Morphological features of these confirm existing concepts of impaired functional activity, although there is evidence that some of the cells are hyperfunctioning. With age, their focal hyperplasia is so pronounced that it sometimes gives an impression of the presence of adenomas. In the final phase of the disease, the testicles degenerate and become hyaline.

Syndrome of incomplete masculinization. Gonads are located outside of the abdomen. The seminiferous tubules are large, they often show spermatogenic elements capable of reproduction and differentiation, although spermatogenesis never ends with spermiogenesis. When android form is rarely observed Leydig cells hyperplasia, for which, like the testicular feminization syndrome (STF), a defect of 3beta-hydroxysteroid dehydrogenase is characteristic. Apparently, a sufficient number of Leydig cells and their high functional activity, despite the violation of the nature of the biosynthesis, still provide sufficient androgenic activity of the testes. Tumors in the gonads of these patients, according to our data, are not formed.

The syndrome of testicular feminization. Histologically, the testicles show a thickening of the belly coat, the presence of a large number of fairly large, luminal seminiferous tubules with a thickened and hyalineized basal membrane. The epithelium is represented by Sertoli cells and the sex cells. The degree of development of the first depends on the number and state 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 it is considerably hyperplastic. The cytoplasm of these cells often contains lipofuscin. In the incomplete form of the syndrome, Leydig cells hyperplasia is present in more than half of the patients. The cells of both variants of the syndrome are characterized by a high activity of enzymes that ensure the processes of steroidogenesis: alcohol dehydrogenase, glucose-6-phosphate dehydrogenase, NADP- and NAD-tetrazolium reductase; however, the activity of the most specific for steroidogenesis enzyme, 3beta-hydroxysteroid dehydrogenase, is sharply reduced, , indicates a violation of one of the early stages of the biosynthesis of androgens. A defect of 17-ketosteroid reductase may be noted, the absence of which leads to a disruption in the formation of testosterone. Electron microscopically, Leydig cells are characterized as actively functioning steroid-producing cells.

Tumors in the testicles occur only with the full form of STF. Their source is the tubular apparatus. The initial stage of tumor development is nodular hyperplasia of the seminiferous tubules, which often has a multifocal character. In such gonads adenomas such as sertoli with their own capsule (tubular adenomas) are formed. Leydig cells are often localized in the foci of hyperplasia and in adenomas. In some cases, arenoblastomas of the trabecular or mixed structure are formed. Tumors are usually benign, although both malignant sertoliomas and gonadoblastomas are described. However, there is an opinion that tumors with STF should be referred to the group as a gametrum.

[1], [2], [3], [4], [5]