Causes and pathogenesis of congenital adrenal cortex dysfunction

Congenital adrenogenital syndrome is genetically determined and is expressed in the deficiency of enzyme systems that ensure the synthesis of glucocorticoids; it causes increased secretion of ACTH by the adenohypophysis, which stimulates the adrenal cortex, which secretes mainly androgens in this disease.

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

With a defect in the enzyme 20,22-desmolase, the synthesis of steroid hormones from cholesterol into active steroids is disrupted ( aldosterone, cortisol and androgens are not formed). This leads to salt wasting syndrome, glucocorticoid deficiency and insufficient sexual masculinizing development in male fetuses. While female patients have normal internal and external genitalia, boys are born with feminine external genitalia and pseudohermaphroditism is observed. The so-called congenital lipoid hyperplasia of the adrenal cortex develops. Patients die in early childhood.

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

Deficiency of 3β-ol-dehydrogenase leads to disruption of cortisol and aldosterone synthesis at early stages of their formation. Patients develop a clinical picture of salt-wasting syndrome. Due to partial formation of DHEA, virilization of the body in girls is weakly expressed. In boys, due to disruption of the synthesis of active androgens, incomplete masculinization of the external genitalia is observed (traits of external hermaphroditism). Most often, newborn boys have hypospadias and cryptorchidism, which indicates a disruption of enzymes not only in the adrenal glands, but also in the testicles. The level of 17-KS in urine is elevated mainly due to DHEA. The disease is severe. A high percentage of patients are mortal in early childhood.

Deficiency of 17a-hydroxylase causes disruption of the synthesis of sex hormones (androgens and estrogens) and cortisol, which leads to sexual underdevelopment, hypertension, and hypokalemic alkalosis. In 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 virilization syndrome, the so-called virilization (or uncomplicated) form of the disease. Since the hyperplastic adrenal cortex is capable of synthesizing adequate amounts of aldosterone and cortisol, salt loss is prevented and adrenal crises do not develop. Increased production of androgens from the reticular hyperplastic zone of the adrenal cortex leads to the development of masculinization in women and macrogenitosomy in men, regardless of the presence or absence of the salt-losing form of the disease. Virilization in female patients can be very pronounced.

With a complete block of the 21-hydroxylase enzyme, along with virilization of the patient's body, salt-wasting syndrome develops: a sharp loss of sodium and chlorides with urine. Potassium levels usually increase in the blood serum. Salt-wasting syndrome most often manifests itself in the first months of a 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 exsiccosis. Without treatment, such children usually die in early childhood.

The defect of the 11b-hydroxylase enzyme leads to an increase in the amount of 11-deoxycorticosterone, which has high mineralocorticoid activity, which causes sodium and chloride retention. Thus, along with virilization, high blood pressure is observed. In this form of the disease, the excretion of 11-deoxycortisol (Reichstein's "S" compound) in the urine increases significantly. Salt retention is the same as with 17a-hydroxylation disorder and is caused by DOC synthesis.

With a defect in the enzyme 18-oxidase, which is necessary only for the synthesis of aldosterone, salt-wasting syndrome develops. Since cortisol synthesis is not impaired, there is no stimulus for increased progesterone production and, accordingly, DOC synthesis. At the same time, there is no hyperplasia of the reticular zone of the adrenal cortex and, accordingly, no 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 severe salt-wasting syndrome, in which patients die in early childhood.

Several other forms have been described that are very rare: a form with attacks of hypoglycemia and a form with periodic etiocholanol fevers.

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Pathological anatomy

The majority of patients with congenital adrenogenital syndrome have hypertrophy of the adrenal cortex, the degree of which depends on the patient's gender, the severity of the congenital enzyme deficiency, and the age at which it manifested itself.

The average adrenal mass of children with the classic variant of congenital adrenogenital syndrome from birth to puberty is 5-10 times greater than the norm and reaches more than 60 g. In appearance, these adrenal glands resemble the cerebral cortex; when cut, their substance is brown. Microscopically, the entire thickness of the cortex, up to the glomerular zone, is formed by compact cells with eosinophilic cytoplasm with a few lipid droplets. Some cells contain lipofuscin. Sometimes the compact cells are separated from the glomerular zone by a thin layer of lipid-rich spongiocytes. They form the outer part of the fascicular zone. The degree of its expression depends on the level of circulating ACTH: the higher its concentration, the less expressed the outer part of the fascicular zone. The zona glomerulosa of the cortex is preserved in the virile form of congenital adrenogenital syndrome (with mild enzyme deficiency) and hyperplastic in severe defects, especially sharply (along with the zona fasciculata) in the salt-wasting form of congenital adrenogenital syndrome. Thus, in congenital dysfunction of the adrenal cortex caused by 21-hydroxylase deficiency, there is hyperplasia of the reticular and glomerular zones of the adrenal cortex, while the zona fasciculata is mostly hypoplastic. In some cases, adenomas and nodes in the adrenal glands are formed.

Similar changes in them are observed in patients with the hypertensive form of congenital adrenogenital syndrome caused by deficiency of 11b-hydroxylase. The defect of the 3b-oxysteroid dehydrogenase enzyme system is quite rare, but often fatal. It affects both the adrenal glands and the gonads. Isolated deficiency of As-isomerase in the adrenal glands is also possible. The adrenal glands of these patients are also characterized by pronounced hyperplasia of its elements with the loss of spongiocytes.

Changes in the adrenal glands with a defect of 20,22-desmolase are reduced to hyperplasia and overfilling of cells of all zones with lipids, mainly cholesterol and its esters. This is the so-called congenital "lipoid" hyperplasia of the adrenal cortex, or Prader syndrome. The testicles are also involved in the pathological process. Even from the intrauterine period of development, testosterone synthesis is disrupted, as a result of which the masculinization of the external genitalia is disrupted.

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

In the hypertensive form of the disease, changes characteristic of hypertension are observed in the internal organs: hypertrophy of the left ventricle of the heart, changes in the arterioles of the retina, kidneys, and brain. There is a known case of the development of an ACTH-secreting pituitary tumor in a patient with congenital adrenogenital syndrome due to 21-hydroxylase deficiency. In the salt-wasting form of congenital dysfunction of the adrenal cortex, specific changes occur in the kidneys: the juxtaglomerular apparatus hypertrophies due to hyperplasia and hypertrophy of the cells that form it, in which the number of renin granules increases. In parallel with this, there is an expansion of the mesangium due to an increase in the number of cells and the accumulation of granular material in the cytoplasm. In addition, the granulation of the interstitial cells, which are the site of prostaglandin synthesis, increases. In boys with the salt-wasting form of congenital adrenogenital syndrome, tumors form in the testicles weighing from several grams to several hundred grams (in adult men).

In the case of the disease, the ovaries are also involved in the pathological process. They usually undergo the same type of structural changes, regardless of whether the patients had spontaneous menstruation or not. Thickening and sclerosis of the protein membrane and thinning of their cortex are characteristic. Changes in the ovaries are secondary, they are associated with excess androgens in the body and with a violation of the gonadotropic function of the pituitary gland.