What provokes Isenko-Cushing's disease?

Causes of Itenko-Cushing's disease are not established. In women, Itenko-Cushing's disease often occurs after childbirth. In the history of patients of both sexes there are head injuries, brain concussion, skull injuries, encephalitis, arachnoiditis and other CNS lesions.

Pathogenetic basis of the Itenko-Cushing disease is a change in the mechanism of control of ACTH secretion. Due to a decrease in the dopamine activity responsible for the inhibitory effect on the secretion of CRH and ACTH and an increase in the tone of the serotonergic system, the mechanism of the regulation of the function of the hypothalamic-pituitary-adrenal system and the daily rhythm of the secretion of KRH-ACTH-cortisol are disrupted; the principle of "feedback" with the simultaneous increase in the level of ACTH and cortisol ceases; the reaction to stress is lost - an increase in cortisol under the influence of insulin hypoglycemia.

In most cases, adenomas of the pituitary gland are found. Macadenomas are found in 10% of patients, in others - microadenomas that are not detected with the usual radiography of the Turkish saddle and can be diagnosed only with the help of computed tomography in surgical diagnostic adenomectomy (in a small part of the patients the tumors are not found, but the basophilic cells of the pituitary gland histological examination).

Tumor cells removed by the pituitary adenoma in Isenko-Cushing's disease give a positive immunocytochemical response to ACTH, beta-lipotropin, beta-endorphin, alpha-MSG and met-enkephalin.

At the present time, it is not conclusively proven whether the tumors of the pituitary gland are caused by a primary pituitary lesion in Isenko-Cushing's disease or their development is associated with a violation in the overlying sections of the central nervous system. The probability of the central origin of adenomas is a violation of the rhythm of secretion not only of ACTH and cortisol, but also of somatotropic hormone and prolactin, resistance to exogenous corticosteroids, and the absence of stage III and IV in the phase of slow sleep; against this - the restoration of daily secretion of ACTH and cortisol after removal of the pituitary tumor in a significant number of patients. Most ACTH-secreting adenomas are localized in the anterior pituitary (60%), the rest - in the posterior and middle part.

At the heart of the pathogenesis of the Itenko-Cushing disease lies both an increase in the secretion of ACTH by the pituitary gland, and the release of cortisol, corticosterone, aldosterone, androgens by the adrenal cortex. Chronic long-term cortisolism leads to the development of a symptom-complex of hypercorticism - the Itenko-Cushing's disease.

Violations of the hypothalamic-pituitary-adrenal relationships in the disease are combined with a change in the secretion of other tropic hormones in the pituitary gland. Significantly decreases the secretion of growth hormone, the level of gonadotropins and TSH decreases, and prolactin rises.

Atrophy of muscle tissue and the appearance of red bands on the skin of the abdomen, thighs are associated with a violation of protein metabolism. Atrophic processes affect the striated musculature and are particularly noticeable in the muscles of the upper and lower extremities. In the study of muscle tissue, there is a pronounced damage to the mitochondria.

Characteristic for the Itenko-Cushing's disease, reddening, marbling, thinning and dryness of the skin are associated with polycythemia and skin atrophy caused by increased catabolism and decreased collagen synthesis, which leads to the transmission of capillaries. Thinning of the skin and rapid deposition of fat lead to the appearance of stretch marks (striae). They are found in 77% of patients and usually occur earlier or simultaneously with other symptoms and are very typical for this disease. Their absence does not exclude Isenko-Cushing's disease.

The action in the body of excess of the main corticosteroid - cortisol - is that with the violation of enzyme systems, the processes of dissimilation and deamination of amino acids are accelerated. The result of these processes is an increase in the rate of disintegration of proteins and a slowdown in their synthesis. Violation of protein metabolism leads to an increase in the release of nitrogen in the urine, a decrease in the level of albumins.

A characteristic symptom of the disease is muscle weakness, which is due to dystrophic changes in muscles and hypokalemia. Hypokalemic alkalosis is associated with the action of glucocorticoids on electrolyte metabolism. Hormones contribute to the retention of sodium in the body, which leads to the removal of potassium salts. The content of potassium in plasma, red blood cells, muscle tissue and heart muscle is significantly reduced.

The pathogenesis of arterial hypertension in the Itenko-Cushing disease is complex and insufficiently studied. An indisputable role is played by violations of the central mechanisms of regulation of vascular tone. Important is also the hypersecretion of glucocorticoids with pronounced mineralocorticoid activity, in particular, corticosterone and aldosterone. Violation of the function of the renin-angiotensin system leads to the development of persistent hypertension. Prolonged hyperproduction of cortisol leads to an increase in the content of renin, which is involved in the formation of angiotensin I and causes an increase in blood pressure. The loss of potassium by muscle cells causes changes in vascular reactivity and an increase in vascular tone. A certain role in the pathogenesis of hypertension is also played by the potentiation of glucocorticoids by the effect of catecholamines and biogenic amines, in particular serotonin.

In the pathogenesis of osteoporosis in the Itzenko-Cushing disease, catabolic action of glucocorticoids on bone tissue is of great importance. The mass of bone tissue proper, as well as the content of organic matter and its components (collagen and mucopolysaccharides) in it decreases, the activity of alkaline phosphatase decreases. Due to the mass conservation and the structure of the protein matrix, the ability of bone tissue to fix calcium decreases. A significant role in the occurrence of osteoporosis belongs to a decrease in calcium absorption in the gastrointestinal tract, which is associated with inhibition of hydroxylation of calciferol. Destruction of the protein components of the bone and secondary demineralization lead to osteoporosis. The excretion of a large amount of calcium by the kidneys causes nephrocalcinosis, the formation of kidney stones, secondary pyelonephritis and kidney failure. Disturbances of carbohydrate metabolism in the case of Itenko-Cushing's disease are accompanied by an increase in the functions of alpha, beta and 6-cells of the pancreas. In the pathogenesis of steroid diabetes, relative insulin insufficiency, insulin resistance and an increase in the level of contrinsular hormones are of great importance.

Pathanatomy of Itenko-Cushing's disease

With Itenko-Cushing's disease, lesions are often localized in the paraventricular and supraoptic nuclei of the hypothalamus and lead to diffuse or focal hyperplasia of corticotrophs and / or their hyperfunction, as evidenced by the hypertrophy of cells and their organelles. This in more than 50% of cases leads to the formation of a microadene from ACTH-producing cells with a semi-autonomous functioning. Some of them are primary adenomas of the pituitary gland. In 5-15% of patients, adenomas are basophilic-cellular and represent small solitary tumors of the anterior lobe with specific neurosecretory granules 250-700 nm in diameter, located along the cell membrane, and bundles of microfilaments around the nucleus. The bulk of adenomas are mixed-cell (from basophils and chromophobes), less often - chromophobic-cellular. Tumor chromophobes are, obviously, a variant of basophils of the intermediate lobe of the pituitary gland, specializing in the formation of ACTH. Some corticotropinomas are tumors of the intermediate lobe. They are often multiple, contain and nervous tissue. In the tissue of the anterior lobe surrounding the tumor, there is a hyalinization of basophils, characteristic of an excess of corticosteroids of any origin. Part of the cells of paradenomatous tissue with degenerative changes, and the stroma is often fibrotic. Malignant variants of corticotropin with aggressive growth are possible.

Hyperproduction ACTH causes an increase in the mass of adrenal tissue and an increase in the functional activity of cells due to an increase in their number (hyperplasia) and hypertrophy. Most sharply, these phenomena are expressed with ectopic ACTH syndrome. In children, signs of an increase in the functional activity of adrenal cells predominate, in persons over 30 years of age - hyperplasia and hypertrophy of the organ. The adrenal glands removed at the second stage of surgical treatment are always more remote at stage 1. The weight of the adrenal gland does not depend on the age of the patients, nor on the weight of the previously removed one. Microscopically, they are characterized by a thickening of the beam and, to a lesser extent, mesh zones. Changes in the glomerular zone are diverse: from atrophic to focal hyperplastic. In 30% of patients, hyperplasia is diffuse-nodular. Nodules are formed mainly in the bundle zone, the capsule of the adrenal gland is often sprouted and form mushroom-like outgrowths on the surface. Their functional activity is comparable with the activity of the whole cortex. In individuals older than 40 years, nodules of pseudotubular structures with low functional activity are formed, cells of which are overfilled with lipids. Diffuse-nodular hyperplasia in 1/3 of patients develops in additional adrenal tissue.

With puberty and youthful, often family form of Itenko-Cushing's disease with pigmented multinodular dysplasia of the adrenal cortex, the latter are of normal size and mass. They are easily verified by the presence on the surface of the incision of numerous nodular inclusions of dark brown color; microscopically characterized by the presence of numerous nodular formations, surrounded by atrophied cortex and formed by large cells with hypertrophied, often polymorphic nuclei, the cytoplasmic oxyphilic, contains a brown pigment. The latter have an unusually high functional activity. Stroma of nodules is infiltrated by lymphoid elements and fat cells.

Violations of menstrual and genital functions in the Itenko-Cushing disease are caused by early onset, but reversible atrophic changes in the endometrium with thinning of the functional layer, a decrease in the number of glands and a cystic degeneration of the surviving ones. Changes in the ovaries occur later. They are reduced to atrophic changes due to the destruction of the follicular apparatus, impaired maturation of the surviving follicles, to the atrophy of the interstitial tissue, the disappearance of the hyloid cells and the reduction of the elements of the ovarian network.

Atrophic changes with a decrease in functional activity develop in other endocrine glands: testicles, parathyroid glands, etc.