Causes and pathogenesis of congenital adrenal cortex dysfunction

Congenital adrenogenital syndrome - is genetically conditioned, expressed in the inadequacy of enzyme systems providing synthesis of glucocorticoids; causes increased excretion of adenohypophysis ACTH, which stimulates the adrenal cortex, secreting this disease mainly androgens.

In congenital adrenogenital syndrome, as a result of the recessive gene, one of the enzymes is affected. Due to the hereditary nature of the disease, the disruption of the corticosteroid biosynthesis process begins in the intrauterine period, and the clinical picture is formed depending on the genetic defect of the enzyme system.

When the defect of the enzyme 20,22-desmolase is broken, the synthesis of steroid hormones from cholesterol to active steroids ( aldosterone, cortisol and androgens are not formed). This leads to a syndrome of salt loss, glucocorticoid insufficiency and an insufficient sexual masculinizing development in male fetuses. If female patients have a normal structure of internal and external genitalia, then boys have at birth a feminine external genitalia, phenomena of pseudohermaphroditism are noted. Develops the so-called congenital lipoid hyperplasia of the adrenal cortex. Patients die in early childhood.

This form of the disease is identical to Prader-Gartner syndrome, or "feminizing hyperplasia of the adrenal cortex", described by E. Hartemann and I. V. Gotton as a special form of congenital adrenal hyperplasia, in the clinical picture of which the symptoms of incomplete masculinization prevailed in men.

Deficiency of 3b-ol-dehydrogenase leads to a disruption in the synthesis of cortisol and aldosterone in the early stages of their formation. Patients develop a clinical picture of the syndrome of salt loss. Due to the partial formation of DHEA, virilization of the body in girls is poorly expressed. In boys, due to a violation of the synthesis of active androgens, incomplete masculinization of the external genitalia (features of external hermaphroditism) is observed. Most often, newborn boys have hypospadias and cryptorchidism, which indicates a violation of enzymes, not only in the adrenal gland, but also in testicles. The level in urine of 17-CS is increased mainly due to DHEA. The disease is severe. There is a large percentage of deaths in early childhood.

Deficiency of 17a-hydroxylase causes a violation of the synthesis of sex hormones (androgens and estrogens) and cortisol, which leads to sexual underdevelopment, hypertension, hypokalemic alkalosis. With this pathology, a large amount of corticosterone and 11-deoxycorticosterone is secreted, which causes hypertension and hypokalemic alkalosis.

Moderate deficiency of the enzyme 21-hydroxylase is clinically manifested by the viral syndrome, the so-called viral (or uncomplicated) form of the disease. Since the hyperplastic adrenal cortex is able to synthesize an adequate amount of aldosterone and cortisol, loss of salt is prevented and adrenal crises do not develop. Increased production of androgens from the reticular hyperplastic cortex of the adrenal cortex leads to the development of masculinization in women and macrogensisomy in men, regardless of the presence or absence of a salt-losing form of the disease. Virilization in sick women is very pronounced.

With a full block of the enzyme 21-hydroxylase along with virilization of the patient's body develops a loss of salt syndrome: a sharp loss of sodium and chloride in the urine. The potassium content usually rises in serum. Soltering syndrome most often manifests itself in the first months of the child's life and acquires a leading role in the clinical picture of the disease. In severe cases, acute adrenal insufficiency develops. Vomiting and diarrhea lead to exsicosis. Without treatment, such children, as a rule, die in early childhood.

Defect of the enzyme 11b-hydroxylase leads to an increase in the amount of 11-deoxycorticosterone, which has a high mineralocorticoid activity, which causes a delay in sodium and chloride. Thus, along with virilization, high blood pressure is noted. With this form of the disease, the urinary excretion of 11-deoxycortisol is significantly increased (Reichstein's "S"). Salt retention is the same as for 17a-hydroxylation, and is due to the synthesis of MRL.

When a defect of the enzyme 18-oxidase, which is necessary only for the synthesis of aldosterone, develops a salt-losing syndrome. Since the synthesis of cortisol is not violated, there is no incentive to increase the production of progesterone and, accordingly, the synthesis of DOC. In this case, there is no hyperplasia of the reticular zone of the adrenal cortex and, accordingly, an increase in the production of adrenal androgens. Thus, the absence of the enzyme 18-oxidase can only lead to aldosterone deficiency. Clinically, this is manifested by a severe soltering syndrome, in which patients die in early childhood.

Several other forms are described that are very rare: a form with hypoglycemic episodes and a form with periodic etiocholanol fevers.

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

Pathanatomy

In the majority of patients with congenital adrenogenital syndrome hypertrophy of the adrenal cortex takes place, the degree of which depends on the sex of the patient, the severity of the congenital deficiency of enzymes, and the age when it manifests itself.

The average weight of the adrenal glands of children with a classical variant of congenital adrenogenital syndrome from birth to puberty is 5-10 times higher than normal and reaches more than 60 g. In appearance, these adrenals resemble the cerebral cortex, on the cut their substance is brown. Microscopically the entire thickness of the cortex, up to the glomerular zone, is formed by compact cells with an eosinophilic cytoplasm with a few lipid droplets. Some cells contain lipofuscin. Sometimes compact cells are separated from the glomerulus by a thin layer of spongiocytes, rich in lipids. They form the outer part of the beam zone. The degree of its expression depends on the level of circulating ACTH: the higher its concentration, the less pronounced the outer part of the beam zone. The glomerular zone of the cortex is preserved in the virile form of the congenital adrenogenital syndrome (with a slight deficit of the enzyme) and is hyperplasic in case of a severe defect, especially sharply (along with the bundle zone) with the salt form of the congenital adrenogenital syndrome. Thus, with congenital dysfunction of the adrenal cortex due to the deficiency of 21-hydroxylase, hyperplasia of the reticular and glomerular zones of the adrenal cortex takes place, while the bundle zone is mostly hypoplastic. In a number of cases, adenomas and nodes in the adrenal gland are formed.

Similar changes in them are observed in patients with hypertensive form of congenital adrenogenital syndrome, caused by deficiency of 11b-hydroxylase. The defect of the Zb-hydroxysteroid dehydrogenase enzyme system is rather rare, but often fatal. With it, both the adrenal glands and the gonads are affected. Isolated deficiency of As-isomerase in the adrenal glands is also possible. Adrenal glands of these patients are also characterized by pronounced hyperplasia of its elements with loss of spongiocytes.

Changes in the adrenal glands with a defect of 20,22-desmolase are reduced to hyperplasia and cell overflow of all zones by lipids, mainly cholesterol and its ethers. This is the so-called congenital "lipoid" hyperplasia of the adrenal cortex, or Prader's syndrome. In the pathological process, testicles are also involved. Even during the fetal development period, the synthesis of testosterone is disrupted, and as a result, the masculinization of the external genitalia is impaired.

At present, there is a view that virilizing and feminizing tumors of the adrenal cortex are a manifestation of congenital adrenogenital syndrome.

In the hypertensive form of the disease in the internal organs, there are changes characteristic of hypertensive disease: hypertrophy of the left ventricle of the heart, changes in retinal arterioles, kidneys, and the brain. There is a case of development of ACTH-secreting pituitary tumor in a patient with congenital adrenogenital syndrome on 21-hydroxylase deficiency soil. With the salt form of congenital adrenal cortex dysfunction, specific changes occur in the kidneys: the juxtaglomerular apparatus is hypertrophied due to hyperplasia and hypertrophy of the cells forming it, in which the number of renin granules increases. In parallel with this, mesangium is expanded due to an increase in the number of cells and the accumulation of granular material in the cytoplasm. In addition, the granularity of interstitial cells, which is the site of the synthesis of prostaglandins, increases. In boys with a salt form of congenital adrenogenital syndrome, tumors in testicles weighing from several grams to several hundred grams (in adult males) are formed.

When the disease is involved in the pathological process, the ovaries are also involved. Usually they undergo the same structural changes, regardless of whether the patients had spontaneous menstruation or not. Characteristic is the thickening and sclerosing of the belly coat and the thinning of their cortical layer. Changes in the ovaries are secondary, they are associated with an excess of androgens in the body and with a violation of the gonadotropic function of the pituitary gland.