Certainly, diseases occurring with disruption of the hypothalamic-pituitary-adrenal system are attracting more and more attention today. Itsenko-Cushing’s disease is no exception to the rule.
Itsenko-Cushing’s disease is a severe multi-symptomatic neuroendocrine chronic disease, in the pathogenesis of which the leading role belongs to the defeat of the hypothalamic-hypophyseal region, as well as to the violation of the regulatory mechanisms that control the hypothalamo-pituitary-adrenal system, the clinical picture of which is due to increased production corticosteroids (in particular, glucocorticoids) hyperplastic under the influence of increased secretion of ACTH by the adrenal glands. Hyperproduction of glucocorticoids can be a consequence of various pathogenetic changes, however, the clinical manifestations will be the same, since they do not depend on the cause of the hypersecretion of corticosteroids. In children, this disease is especially difficult, disfigures the appearance, leads the patient to disability. However, itsenko-Cushing’s disease is practically unusual for children. In adolescents, the disease often begins during puberty. Most often, this disease affects women aged 25-45 years. Itsenko-Cushing’s disease in the general population of people occurs in 0.1% of the population and determines the development of 0.5% of all cases of arterial hypertension. In 1932, H. V. Cushing described the clinical picture of this disease, but even earlier, in 1924, our domestic Voronezh neuropathologist N.M. Itsenko published his observations on patients. Along with the pronounced external manifestations of the disease, he found changes in the area of the gray tubercle and in other parts of the hypothalamus. The assumptions of N.M. Itsenko that the defeat of the hypothalamic region is the leading one in the development of this syndrome was fully confirmed. That is why this disease is rightly called “Itsenko-Cushing’s disease.” It is important to distinguish between such understood as illness and Itsenko-Cushing’s syndrome. The latter term is used for adrenal tumors or for ectopic tumors of various organs (bronchi, pancreas, liver).
Development reasons
It should be noted that questions about the causes of Itsenko-Cushing’s disease are not among the finally resolved. According to most scientists, this disease can arise under the influence of various factors, which, in turn, cause all kinds of changes in tissues and organs, leading to the development of pronounced manifestations of pathology. Factors that have a damaging effect include traumatic brain injury, inflammatory changes in the brain (including the part of the hypothalamus that produces corticoliberin), all kinds of neuroinfections. The development of the syndrome after encephalitis with damage to the diencephalic sphere in patients is not often observed.
It is possible that the disease occurs in bronchogenic cancer, cancer of the thymus, thyroid and pancreas, uterus and ovaries.
Also, Itsenko-Cushing’s disease can manifest itself in various stressful situations, during puberty, pregnancy, after childbirth (which is explained by the special vulnerability of the hypothalamic and other parts of the central nervous system of the female body) and in other situations, which, in turn, can lead to a violation of control secretion of ACTH. The role of the hypothalamus in Itsenko-Cushing’s disease is undeniable, since the production of not only ACTH, but also other hormones changes. A decrease in the production of growth hormone in children is the root cause of a strong lag in physical development, and this pathology is rarely amenable to correction. Of particular importance in the development and course of the disease is attached to tumors of the pituitary and adrenal glands, primary cancer of the thymus gland. Many foreign scientists attribute Itsenko-Cushing’s disease to pituitary pathologies, developing in the form of an adenoma from cells that produce ACTH.
Pathogenesis, clinical picture and diagnosis
Throughout the history of the development of the doctrine of Itsenko-Cushing’s disease, various data were obtained that significantly enriched knowledge about this pathology. However, many questions related to the pathogenesis of the disease remained unclear. The mechanism of development of Itsenko-Cushing’s syndrome to this day seems to be a rather controversial phenomenon. The study of the pathogenesis of this disease has come a long and difficult path in its development. Some researchers gave preference to the functional significance of the hypothalamic-hypo-fizar-adrenal system. The defining cause of the disease, in their opinion, is a violation of the functions of the pituitary gland or adrenal glands. Other researchers did not exclude the possibility of participation in the development of the syndrome of impaired activity of the central nervous system. Today, most authors tend to give preference to the pituitary theory of the formation of Itsenko-Cushing’s disease, according to which it appears due to macro- or microadenoma of the pituitary gland, which produces a large volume of the hormone ACTH. Studies have shown that hypercortisolism (excess production of the hormone cortisol in the human body) is invariably found in Itsenko-Cushing’s syndrome. Accordingly, all the main clinical manifestations of pathology are associated with hypercortisolism. In modern medicine, it is accepted that the hypothalamus, adenohypophysis and the adrenal cortex form a single functional system, which determines the development of Itsenko-Cushing’s syndrome. With excessive production of ACTH, the adrenal glands increase in size and begin to intensively synthesize glucocorticoids. As a result, significant hormonal changes occur in the patient’s body. Nerve impulses begin to enter the hypothalamus, which stimulate its cells to produce a huge amount of special substances that activate the release of ACTH (adrenocorticotropic hormone) in the pituitary gland. Thus, an increase in the production of ACTH, which occurs as a result of the disease, causes bilateral hyperplasia of the adrenal cortex, a more significant production of corticosteroids, which, disrupting the metabolism in the body, eventually lead to pathological abnormalities (Itsenko-Cushing’s disease). Of course, bilateral hyperplasia is quite common, but small-nodular hyperplasia of the adrenal cortex can also occur. It is the adrenal cortex under the influence of ACTH that secretes into the blood an increased amount of steroid hormones, primarily cortisol. As a result, the development of characteristic syndromes of the disease is realized. The secretion of ACTH by the adenohypophysis is stimulated by the hypothalamus. This is how these three components function, forming a single system. The hypothalamus, in turn, is structurally and functionally associated with the cerebral cortex. With Itsenko-Cushing’s syndrome, significant changes occur in the functioning of the hypothalamic-pituitary-adrenal system. For example, this is expressed not only in a violation of the feedback mechanism, but also in a violation of the circadian rhythm. The content of 17-OCS (oxycorticosteroid hormones) in blood plasma during the day does not decrease to those values that are characteristic of healthy people. The secretion of cortisol is increased, and at the same time, ACTH continues to be actively produced.
The diagnosis of Itsenko-Cushing’s syndrome in pronounced forms is not difficult, it is based on the clinical picture and the results of laboratory research. In addition, it is characterized by a rather pronounced symptomatology: an obese body with thin limbs, a round red face, a short neck, growth retardation and sexual development
with premature appearance of sexual hair growth , hypertension, osteoporosis (in particular, a change in the configuration of the vertebrae like fish vertebrae, spontaneous bone fractures), violation of fat, protein, carbohydrate and mineral metabolism. It is important to note that different clinical symptoms of the disease occur with different frequencies.
There are 2 degrees of severity of Itsenko-Cushing’s disease:
– mild form with moderately pronounced signs in the absence of complications;
– a severe form, which is distinguished by the severity of the symptoms and the presence of complications (cardiopulmonary failure, steroid diabetes, severe mental disorders).
Depending on the rate of development of clinical symptoms, a rapidly progressive (hypercorticism develops in 3-6 months) and torpid course of the disease (from one year or more) are distinguished. And finally, according to the international classification of diseases of the World Health Organization, Itsenko-Cushing’s disease is of the following types: unspecified, iatrogenic, idiopathic, pituitary origin, ectopic ACTH syndrome, cortisol hypersecretion.
When listing the complaints that lead the patient to see a doctor, it is probably necessary to highlight general weakness due to rapid fatigue, multiple changes in the skin. More rare are complaints associated with stomach ulcers and urolithiasis. Thus, complaints about a slowdown in age-related growth rates and sexual development in children and adolescents in combination with obesity with preserved normal mental development should lead a doctor to suspect that the patient has Itsenko-Cushing’s disease. Many children and adolescents may not have a clear centri-petal distribution of fat even in the presence of the disease. The suspicion is enhanced only with a combination of complaints of general weakness and rapid fatigue with a centripetal distribution of fat and characteristic changes in the skin and its appendages. The skin of patients is very thin, through it the subcutaneous vascular bed shines through, which is why the skin acquires a purple-cyanotic color (especially on the face). A marbled or reticular vascular pattern of the skin may be seen. For such patients, hypertrichosis (increased hairiness) on the face, chest and back is common, which occurs when exposed to an excess of androgens, the formation of which sharply increases with adrenal tumors and, for example, ovarian tumors. In children, increased hair growth appears on the forehead, cheeks, pubis, back and in the lumbar region. Fungal lesions of the skin and nails on the hands and feet are very common. It is important to note that in children and adolescents with Itsenko-Cushing’s syndrome, due to the high age-related metabolism, catabolic processes in the skin are much less pronounced than in adults, and this, in turn, greatly complicates the clinical diagnosis of the disease. As for obesity, excess fat accumulation occurs in 60-90% of patients with this syndrome, and in Itsenko-Cushing’s disease, the mass of adipose tissue is much higher than in patients with ordinary obesity, incorrect localization of fat cells in the body is formed: mainly on the abdomen, face, back, shoulders, neck, mammary glands, in the area of the collarbones. The face takes on characteristic puffy forms, there is a hyperemia of the skin of the cheeks. The cause of obesity in Itsenko-Cushing’s syndrome lies in the phenomenon of hypersecretion (excess production) of the hormone cortisol, which increases appetite, and also increases the formation of glucose, which is certainly necessary for the synthesis of fats. On the surface of the abdomen, shoulders and other surfaces, characteristic stains of all kinds of color are formed – striae. They are the result of stretching the skin from increased fat deposits. The color of the stretch marks is determined by the color of the vessels located directly under the skin. With this disease, the formation of striae also occurs due to a pathological violation of protein metabolism, as a result of which the skin acquires increased sensitivity and is easily injured (due to atrophy of the epidermis and connective tissue). Any wounds heal extremely slowly, and this is the source of various postoperative complications. Edema of the lower extremities is common, but the cause is not heart failure, but increased capillary permeability. Spontaneous tendon ruptures are very rare. Also, one of the early signs of the manifestation of this disease in children and adolescents is a slowdown in the age-related growth rate. Along with a decrease in anabolic processes of protein synthesis and an increase in catabolism, bone growth lags in length. The growth and differentiation of the forearm bones in children with Itsenko-Cushing’s syndrome are, on average, 3 years behind. Cortisol, by decreasing collagen synthesis, stimulates the excretion of calcium from the bone. In addition, the absorption of calcium in the intestine is greatly reduced and its loss in the urine increases. After successful treatment of the disease, an improvement in recovery processes is observed first in the lower extremities, lumbar vertebrae, gradually spreading upward. Such processes occur more intensively in children and adolescents.
An integral symptom of Itsenko-Cushing’s disease are diffuse atrophic processes in the striated muscles, which result from a decrease in the amount of amino acids in the muscles.
This can be especially clearly noted on the example of the leg muscles in the standing position. Reduced muscle strength in the upper extremities. The manifestation of muscle hypotonia can proceed so strongly that the patient is not able to rise to his feet from a sitting position without additional help. Atrophy of the muscles of the anterior abdominal wall leads to an increase in the size of the abdomen. In patients with severe symptoms of the syndrome, changes in the cardiovascular system are often manifested. This is indicated by multiple disturbances in hemodynamic parameters. They are the main cause of death in patients with Itsenko-Cushing’s syndrome. Some have tachycardia, which is the result of increased activity of the sympathoadrenal system. Muffled heart sounds are possible. With a long course of Itsenko-Cushing’s disease, changes are found that indicate a decrease in the contractility of the myocardium (muscle tissue of the heart). Another manifestation of this disease can rightfully be considered arterial hypertension. Moreover, it was noted that an increase in blood pressure in the syndrome is more typical for children than for adults. As a rule, arterial hypertension is stable. In medical practice, an increase in systolic pressure to 220-225 mm Hg was noted. Art. and diastolic up to 130-145 mm Hg. Art. Here the main role belongs to corticosteroids. With the help of the latter, the level of sodium in the body and the amount of water in the walls of argeriol increase, and at the same time their clearance decreases. All this leads to hypertension, which, with a prolonged course, contributes to left ventricular hypertrophy and the development of heart failure, as well as a violation of the heart rhythm. This syndrome often occurs due to altered carbohydrate metabolism (due to a large amount of glucocorticoids). They contribute to the development of hyperglycemia. Despite hyperglycemia, serum insulin levels are also elevated. The detection in patients with this pathology of diabetes mellitus (in 15-35% of patients) or glucose tolerance of the diabetic type (in 20-90% of patients). There are few examples of a certain tendency of such patients to pneumonia, their abscession and more severe course. Patients have described gingivitis, loosening and loss of teeth, atrophy and hemorrhage in the cancellous substance of the maxillary and mandibular bones. There is evidence of a decrease in the production of gastric juice and the acid-forming function of the stomach. X-ray observation reveals edema of the mucous membrane and submucosa of the stomach, as well as gastritis. In addition, patients have pylorospasm, decreased intestinal motor function, hypotension, and weakening of the contractility of the intestinal muscle layer. Lesions of the kidneys and urinary tract in Itsenko-Cushing’s disease are very diverse and occur quite often. Patients are diagnosed with disorders in the functioning of the excretory system (kidneys), manifested in albuminuria, hematuria, cylindruria. There is also a decrease in the concentration of the kidneys. Pathological changes are found in urine tests, in the release of phenolsulfaphthalein, in samples for urine concentration. Other examined patients have urolithiasis, accompanied by chronic, sluggish pyelonephritis. The occurrence of kidney stones occurs due to osteoporosis of the skeletal system and increased excretion of phosphates and calcium with urine flow, which contributes to the formation of phosphate ioxalate stones. In addition to hypercortisolism, in patients with Itsenko-Cushing’s disease, disorders of the functioning of other endocrine glands are very often revealed. Changes in the sex glands are usually reversible. In boys, underdevelopment of the testicles and penis is observed, in girls, the development of the mammary glands and the formation of the menstrual cycle are inhibited. In most cases, menstrual irregularities are one of the first signs of illness. As for hematological changes, many authors note the presence of erythrocytosis in the active form of the disease. Almost half of the observed increase the number of leukocytes and granulocytes in the peripheral blood. Polycythemia and an increase in hemoglobin in the general blood test are noted, which occurs due to too high levels of male hormones (androgens). Also, about 50% of those suffering from Itsenko-Cushing’s disease have all kinds of mental disorders of varying severity and severity. Sometimes they even precede various physical manifestations of Itsenko-Cushing’s disease. The most common disorders are depression, mania, paranoia, memory impairment, euphoria, sleep disturbances or depressions, irritability, emotional instability and sometimes psychosis. Depression becomes more pronounced with an increase in the patient’s body weight. Careful monitoring of such patients is required to prevent suicide attempts. Along with the definition of all of the above symptoms, when making the final diagnosis, first of all, laboratory research methods should be used, which allow fixing the increased function of the adrenal cortex, i.e., hypercortisolism. Such tests include, for example, the determination of the rate of cortisol secretion, the content of corticosteroids in the plasma, the excretion of total 17-hydroxycorticosteroids in the urine, the determination of the plasma concentration of corticotropin, etc. When conducting a test with ACTH, for example, in sick children, there is a significant increase in blood and urinary excretion of 17-hydroxycorticosteroids (in the presence of an adrenal tumor, the content of 17-OCS in daily urine does not change with the introduction of these substances). Due to the action of dexamethasone, there is a decrease in the secretion of hydrocortisone and adrenal androgens. Methapyrone, in turn, leads to disruption of the synthesis of hydrocortisone and corticosterone. As a result, an increase in the release of intermediate products of hydrocortisone and corticosterone is observed in the blood and urine. If, after a test with methapyrone, the child’s urinary excretion of total 17-hydroxycorticosteroids increases, therefore, in this case, we are dealing with Itsenko-Cushing’s disease. According to the scintigraphy of the adrenal glands, after the administration of 19-iodine-cholesterol, hypertrophy of the contours of both adrenal glands is revealed, and in the presence of a tumor, one of the adrenal glands. A blood test shows polycythemia, lymphocytopenia, eosinopenia, and neutrophilic leukocytosis. The content of electrolytes in the blood serum often fluctuates within normal limits (except for potassium, the content of which in the blood serum is low), and in severe cases hypokalemic alkalosis and hypernatremia are observed. In addition, it is necessary to conduct hormonal tests, the essence of which is as follows: first, patients donate blood for hormones (corticosteroids), then take the medicine (de-xamethasone, synacthen, etc.) and after a while they take the analysis again. For a full-fledged diagnostic study, it is necessary to clarify the nature of the disorders of the circadian activity of the hypothalamic-pituitary-suprarenal system. It is necessary to determine the binding capacity of trans-cortin (a protein that binds cortisol and transfers it to a temporarily inactive state). To confirm the diagnosis of Itsenko-Cushing’s disease, it is necessary to identify an increased secretion of ACTH and corticosteroids.
A radioimmunological method of blood examination reveals a slight increase in the level of the hormone.
With the presence of a pituitary adenoma in the history of the disease, the increase in this hormone becomes significant. However, along with ACTH in the blood plasma of persons with Itsenko-Cushing’s syndrome, the presence of all kinds of peptides, for example, / 3- and d-lipotrophins, is noted. In contrast to ACTH, these peptides are more stable, and their plasma level practically does not change. Therefore, the determination of their increased content in blood plasma is an important diagnostic sign of the presence of Itsenko-Cushing’s disease in a patient. Plasma cortisol levels are also significantly increased in the presence of this syndrome. An important role is played by special functional tests with stimulation and suppression of the activity of the hypothalamic-pituitary-adrenal system (metapyrone test, dexamethasone tests (Liddle’s test), insulin-tolerant test, test with corticotropin-releasing factor, test with lysine-vasopressticolib, proberin ), as well as other special research methods that provide topical diagnosis of changes in the adrenal glands. In controversial situations, to detect the presence of endogenous and functional hypercorticism, a small test with de-xamethasone is performed. A negative small test with de-xamethasone and a positive large test allow the diagnosis of a pituitary tumor. With the help of X-ray examination, osteoporosis of the bones of the skeleton is revealed. Over the past decade, the principles and methods for the detection and subsequent treatment of Itsenko-Cushing syndrome have undergone dramatic changes, primarily due to the emergence of the latest developments in imaging the pituitary and adrenal glands. So, useful information about the state of the adrenal glands can be obtained by radioisotope and ultrasound examination. In addition, angiographic studies and computed tomography are widely used. These methods make it possible to identify tumors in cases where all other research methods give negative results, as well as to establish the exact location of the tumor, its size, direction of growth and relationship with the surrounding tissues. The presence of a microadenoma characteristic of Itsenko-Cushing’s syndrome is detected only through the use of computed tomography or tomography based on magnetic resonance. To study the state of the adrenal glands, arterio- and venography is used, however, this test is associated with a certain risk due to the reduced resistance of the body to infections in such patients. Itsenko-Cushing’s disease must be distinguished from obesity. For these purposes, it is necessary to study the content of hormones in the blood and their excretion in the urine, including conducting a test with dexamethasone, methapyrone (in obese patients, they give the same results as in healthy people). Also, obese patients have moderate arterial hypertension, impaired carbohydrate metabolism, and sometimes moderate hirsutism; striae are white and very rarely pink, the skin is not thinned, there is no muscle atrophy. Obesity is uniform. Among other things, it is required to make a strict distinction (ie, differentiate) Itsenko-Cushing’s disease with hypothalamic syndrome that develops during puberty. In the presence of this syndrome, patients have an increase in adipose tissue, high growth, a slight increase in blood pressure, pathological changes in monthly menstruation, sometimes even a violation of the carbohydrate balance in the body.
Treatment
Treatment of Itsenko-Cushing’s disease in children, as well as in adults, is a very difficult problem. Itsenko-Cushing’s disease is accompanied by a decrease in the body’s resistance to infections, and if treatment is not carried out, about 50% of sick children die from infections concomitant with the disease. Therefore, it is very important to carry out diagnostics in a timely manner and begin to carry out effective therapy for this syndrome as soon as possible. Treatment in the presence of this disease is advised to be carried out under the supervision of the staff of the endocrinology department. For each patient with this syndrome, his own method of treatment should be selected, which would be the only necessary and final one. The main indicator of what kind of treatment is preferable is considered primarily the year of birth of the patient, the nature of the course of the disease, indicators of the boundaries of the pituitary adenoma, the presence or absence of its increase, etc. It is obvious that in Itsenko-Cushing’s disease, treatment is aimed at stabilizing the secretion of ACTH and cortisol. Thus, the main goal of treating children with this disease is to trigger the reverse mechanism, i.e., to reduce the main manifestations. The main goal is: stabilization of cortisol and ACTH indicators in blood plasma, as well as balancing their daily metabolism and stabilization of cortisol indicators in daily urine. If a patient, 6 months after complete remission of the disease, re-develops the clinical and hormonal picture characteristic of this disease, and there is a continued growth of the pituitary adenoma, then this condition is considered a relapse. In the middle of the XX century. the only treatment for this disease was X-ray irradiation of the interstitial pituitary region. Radiation therapy is currently considered the most common treatment for this pathology. The effectiveness of such a therapy is based on the direct effect on a specific lesion focus, i.e., the pituitary gland. Currently, along with rational irradiation, drug, combined (radiation therapy in combination with unilateral or bilateral adrenalectomy) and surgical treatment are widely used. Of course, each method has indications and contraindications in a particular clinical situation. However, despite the success in the treatment of Itsenko-Cushing’s disease in children, many of them remain disabled. X-ray therapy is carried out according to fractional-intensive technique with increasing doses. X-ray irradiation is effective only in 50% of cases; it gives a pronounced effect only in a small part of patients at the very beginning of the disease. When using y-therapy, a small number of side effects are observed, but the therapeutic effect is only slightly higher than that of X-ray therapy. Usually, after a course of u-therapy, patients are prescribed reserpine – 1 mg per day for 4-6 months. In recent years, irradiation of the pituitary gland has been carried out using special “proton beams”. This method is called pituitary adenoma radiosurgery. It is more gentle than X-ray yi therapy and also more effective. However, it is used only for the treatment of patients with endosellar adenomas of the pituitary gland (and the size of the sella turcica should not exceed 15 mm in diameter), and it is not recommended for the treatment of children under 8 years of age. Patients 10-25 years of age with minor changes in the body and small pituitary hypertrophy are prescribed therapy with the primary use of proton irradiation of the pituitary gland. The efficiency of proton irradiation can be adequately assessed only 8-12 months after irradiation. Doctors refer to the advantages of proton irradiation: the need for only a single procedure that gives maximum efficiency with minimal changes from nearby tissues, as well as the lowest risk of subsequent complications. Proton therapy as an autonomous method of therapy for Itsenko-Cushing’s disease gives especially good and rapid results at a young age, with slight pituitary hypertrophy and in the absence of complications of the disease. Another method of treating the disease is d-therapy (in this case, irradiation is carried out using a d-apparatus, in which the source of ionizing radiation is cobalt), but it cannot be used as the only method of therapy. In addition to all the listed methods of radiation therapy, the implantation of radioactive metals (yttrium or gold) directly into the concentration of the adenoma is often used. Resorption of pituitary neoplasms often occurs after exposure to very low temperatures (cryosurgery). When carrying out this type of treatment, it is necessary to pay great attention to the proper nutrition of the child. Sick children are recommended a protein-vegetable diet, fasting days, food intake with a sufficient content of vitamins and minerals, as well as exercise therapy and taking anabolic drugs with severe osteoporosis. In addition, symptomatic therapy with potassium preparations, antidepressants, sedatives is carried out. Drug treatment is prescribed either as an independent method of therapy, or as an additional one (for example, to radiation therapy). Its advantage is the absence of irreversible consequences, of course, with the correct selection of doses of the drugs used. Drug therapy is prescribed when the body is normal, without sharp manifestations of the disease and neoplasms in the structure of the pituitary gland. Drug treatment of patients with Itsenko-Cushing’s syndrome is aimed at reducing the secretion of hormones corticotropin or cortisol into the blood. However, drugs usually cause an improvement in the patient’s condition only during their use; they do not cure the disease. Drug treatment consists in the appointment of drugs that reduce the formation of ACTH, and blockers of the biosynthesis of steroid hormones in the adrenal glands. The drugs that reduce the activity of the secretion of hormones of the adenohypophysis include: diphenine, reserpine, sodium valproate, y-aminobutyric acid, antiserotonin drugs: cyproheptadine (peritol, deseril) and methergoline; parlodel (bromcrip-tin). The main side effects are changes in appetite and increased sleepiness. Treatment is indicated for children with Itsenko-Cushing’s disease in preparation for surgery on the pituitary gland or adrenal glands. Parlodel is also used to treat this syndrome, but the effectiveness of such therapy is low. The adrenal cortex function blockers include: chloditan, trilostane, aminoglutethimide (elipten, orimethene) and its derivatives (mamamit), ketoconazole derivatives. Chloditan is a persistent drug; it persists for a long time in the patient’s adipose tissue (even 22 months after stopping therapy). The standard dose of 5-6 g, which is taken within 48-50 days, is well tolerated. Increasing the dose can cause anorexia, vomiting, diarrhea, and other side effects. The main negative manifestation of chloditan is considered to be its significant toxicity, as a result of which many patients are stopped from treatment, even without having completed half of the main course.
Prescribing chloditan therapy is unacceptable in women of reproductive age who are planning to give birth to a child in the near future (4-6 years).
Trilostane, on the other hand, has less pronounced therapeutic properties, although it is used to treat Itsenko-Cushing’s syndrome along with other drugs. The daily dose is 30 mg 4 times a day. The dosage is gradually increased under the supervision of a physician. In the case of using aminoglutemide, only 42% of patients showed clinical improvement and normalization of blood biochemical parameters. In the first 10 days after taking the drug, a rash may appear as a side effect. These studies have reliably confirmed that the combined treatment with ketoconazole and aminoglutemid promotes particularly severe atrophy and deterioration of adrenal function. In the treatment of the disease, the fastest and most pronounced positive result is given by the appointment of hormone therapy (estrogen). As medications, non-steroidal drugs (amphenone, methapyrone) are used, which by the mechanism inhibit the functioning of the adrenal cortex and disrupt the synthesis of hydrocortisone. However, in children, amphenone has not received widespread use, since with prolonged use it has a toxic effect on the liver, kidneys and nervous system. Unlike amphenone, the toxicity of metapyrone is very small, and this allows it to be widely used to treat Itsenko-Cushing’s disease. The course of treatment ranges from 2 to 60 months. Imidazole derivatives – ketoconazole and eto-midate have also found wide application in the treatment of this syndrome. The first drug has long been used as an antimycotic (antifungal) agent, but it was later proved that ketoconazole is able to reduce blood cortisol by blocking cholesterol synthesis. Etomidate also inhibits the synthesis of cortisol, when administered intravenously, it very quickly reduces the level of cortisol in the blood serum. It is important to note that all of the above drugs are used to treat Itsenko-Cushing’s disease in combination with various types of radiation and surgical therapy. Itsenko-Cushing’s disease is a very serious disease, the main characteristic of which is its inevitable progression. The prognosis for this disease depends on the duration, severity of the disease and the patient’s age and is not always considered favorable. Early detection of the disease predicts the most favorable outcome from the prescribed treatment. The prognosis is unfavorable in the presence of such a pathology as a neoplasm of the thymus gland; improves when it is localized only in the interstitial space. Therefore, with a long and severe illness, children are shown surgical treatment. Surgical interventions on the adrenal glands are considered the most difficult to carry out and quite dangerous. The risk of complications in the early postoperative period is especially great. The indications for surgical intervention are the rapidly progressing course of the disease, as well as the lack of effect from conservative treatment methods. It gives a rather quick clinical effect, but it leads children to chronic hypocorticism, for which they must use glucocorticoid replacement therapy for life. Single or bilateral adrenalectomy should only be used in combination with radiation therapy. Very often, after bilateral adrenalectomy, patients develop chronic adrenal insufficiency. Today, transsphenoidal adenomectomy is widely used (it is considered the safest and most effective). Its introduction into clinical endocrinology opened a new era in the treatment of Itsenko-Cushing’s disease. The purpose of the use of adenomectomy is made in the presence of strict and clear boundaries of the pituitary neoplasm. It is unacceptable to use this method in the presence of the last degree of severity of the disease or in the presence of unfavorably predicted somatic abnormalities. This type of treatment for Itsenko-Cushing’s disease can be repeated at any time after a previous neurosurgical intervention, as well as in case of recurrence of a pituitary tumor. In the opinion of most scientists, adenomectomy in the coming years should gain particular popularity due to its rapid and beneficial effect (in most successfully operated patients, there is an improvement in well-being, a decrease in appetite, headaches and a decrease in the main clinical manifestations of the disease, i.e., a decrease in blood pressure, weight loss body, as well as a decrease in the level of cortisol in blood plasma and in daily urine), no need for long-term substitution treatment and a short rehabilitation period. The final assessment of the effectiveness of adenomectomy is carried out no earlier than 6 months after the operation. In recent years, the method of destruction of the adrenal glands has been widely used, usually in combination with radiation therapy or adenomectomy. Complications associated with surgical intervention on the adrenal glands can be divided into 2 groups; operating and postoperative. The most common surgical complications include opening the peritoneal cavity, opening the pleural sinus, bleeding from the central adrenal vein and inferior vena cava. Early postoperative complications: widespread suppuration of the surgical wound, limited suppuration of the surgical wound, acute cardiovascular failure, post-injection abscess, etc. However, such children cannot live a full life like their peers. Due to great weakness and rapid fatigability, the full school load is difficult for them. Children grow poorly, boys do not develop sexually. In the future, many sick children become disabled. With a prolonged course of the disease, patients often do not have pathological abnormalities in the cardiovascular and skeletal systems that require special therapy. In addition to lowering hormone levels, doctors are also involved in the treatment of clinical manifestations of the disease. So, for example, with severe obesity, the patient is prescribed a diet with limited consumption of carbohydrates, triiodothyronine, and sometimes diuretic drugs. For the treatment of arterial hypertension, antihypertensive drugs are used, for the treatment of diabetes mellitus – special hypoglycemic drugs, in case of osteoporosis, the patient is prescribed vitamin B preparations or fish oil. For the treatment of other manifestations of Itsenko-Cushing’s disease, diuretics are used, as well as cardiac
glycosides. In addition, some patients after total adrenalectomy develop a pituitary tumor. In the treatment of Itsenko-Cushing’s disease, great importance is attached to surgical intervention on the adrenal glands in combination with non-operative methods. Sometimes positive effects are achieved when using combined treatment – unilateral total adrenalectomy with further X-ray therapy or drug treatment. Observations prove that embolization of the adrenal gland vessels can eliminate the hyperfunction of its cortical layer and avoid suprarenectomy. This observation is an example of effective treatment of Itsenko-Cushing’s disease by means of combined therapy – embolization of the arterial system of one adrenal gland and surgical removal of the other. With the appointment of further courses of treatment, patients have a significant drop in body weight. At the same time, there is a visible improvement in physical and mental health.