What is Cushing's syndrome

This disorder occurs when the level of the hormone cortisol rises. It can also happen when taking drugs that contain it or any steroid hormones in large quantities.

Causes

As mentioned above, Cushing's syndrome is also caused by an excess of corticosteroids such as prednisone and prednisolone. These drugs are used to treat conditions such as asthma and rheumatoid arthritis. In other people, it can develop because their body gets too much cortisol. This hormone is usually produced by the adrenal glands. This phenomenon can be caused by:

• Cushing's disease, in which the pituitary gland produces a lot of the hormone ACTH, which signals the adrenal glands to produce cortisol. A similar condition can cause pituitary gland swelling.
• A tumor in the adrenal glands or other parts of the body that produce ACTH or cortisol (such as the lungs, pancreas, or thyroid gland).

1. The majority of those suffering from this condition will have:

• obesity of the upper body (above the waist), but thin arms and legs;
• round, red face;
• slow growth rates in children.

2. Skin lesions that are common:

• acne or skin infections;
• purple spots, called striae, on the skin of the thighs, abdomen and chest;
• thin skin with slight bruising.

3. Problems with the musculoskeletal system include:

• back pain that occurs even with minimal exertion;
• bone pain or fragility;
• accumulation of fat between the shoulders (the so-called bovine hump);
• Frequent fractures of the ribs and spine (caused by thinning of the bones);
• weakened muscles.

4. Women with Cushing's syndrome often suffer from:

• excess hair growth on the face, chest, neck, thighs, and abdomen;
• the menstrual cycle becomes irregular.

5. Men can have:

• decreased or lack of sexual desire;
• impotence.

6. In addition, you may experience:

• various mental changes, including depression, behavior changes, or anxiety;
• headache;
• fatigue;
• increased urination and thirst;
• blood sugar and white blood cell levels can be high, but potassium can be low;
• high cholesterol levels, including triglycerides, may be present.

1. Treatment of this disease depends on the cause of its occurrence. If it is caused by corticosteroid use:

• It is necessary to slowly reduce the dose of the drug (if possible) under medical supervision.
• If you cannot stop taking the drug, you need to carefully monitor blood sugar and cholesterol levels, as well as osteoporosis and bone thinning.

2. In Cushing's syndrome, which is caused by a pituitary tumor, are shown:

• Surgery to remove the tumor.
• You may need to take hydrocortisone (cortisol) as a replacement therapy after surgery, and may continue to take it for life.

3. In case of a disease caused by a tumor of the adrenal glands or other organs, it is necessary:

• Surgery to remove the tumor.
• If this is not possible, medications should be taken to help block the production of cortisol.

Forecast (prospects)

Removing the tumor may help you recover completely, but there is a small chance that the disease will return. The survival of patients with an ectopic tumor depends on its type. Untreated, Cushing's syndrome is life-threatening.

When characteristic symptoms are identified, laboratory tests are used to confirm the diagnosis.

The clinical picture of Cushing's syndrome is diverse and is determined by the duration and magnitude of excess cortisol. Many of these symptoms are common in the population; the diagnosis may be misdiagnosed in cases of mental illness, multiple metabolic disorder, anovulation, obesity, fibromyalgia, or acute illness. For example, in one study, among 250 women with hirsutism, Cushing's syndrome was identified in only one.

Cushing's syndrome is characterized by fat deposition over the collarbones and on the face (on the cheeks and temples), weakness of the proximal muscles of the extremities, wide (more than 1 cm) purplish striae, the appearance of mental disorders, cognitive impairment, and impaired short-term memory. The appearance of new symptoms characteristic of Cushing's syndrome also requires laboratory research.

Itsenko-Cushing's syndrome (SIK), or endogenous hypercortisolism, is a severe endocrine disease that develops as a result of exposure to the body of an excess of glucocorticoids due to primary damage or hyperplasia (micro-, macro-nodular) of the adrenal cortex.

In addition to endogenous hypercortisolism, exogenous (iatrogenic) is isolated, which is associated with excessive intake of glucocorticoids from the outside, and functional, or pseudohypercortisolism, which can develop in a number of physiological conditions and diseases (pregnancy, obesity, alcoholism, depression).

Classification of Itsenko Cushing's syndrome

According to the severity, SIC is divided into mild (mild or moderate symptoms), medium (detailed clinical picture without complications) and severe, when cardiovascular disorders, diabetes mellitus, fractures, mental disorders and other complications develop against the background of a pronounced clinical picture.

In ICD-10, endogenous hypercortisolism belongs to the E24 heading.

Causes of Itsenko Cushing's syndrome

Exogenous Syndrome: The most common cause of Cushing's syndrome. The consequence of taking glucocorticoids (by mouth, intramuscularly or by inhalation) or tetracosactide. May be iatrogenic or self-medicated with glucocorticoids.

Endogenous syndrome: Adrenal (20%). Adrenal cancer (40-50%). Adrenal adenoma (40-50%). Rare causes: nodular dysplasia of the adrenal cortex, McCune-Albright syndrome, nodular hyperplasia of the adrenal cortex. Activation of the adrenal glands by excess ACTH (80%). Ectopic secretion of ACTH (20%). Pituitary adenoma (80%) Ectopic secretion of corticoliberin (rare).

SIC develops due to various reasons. Itsenko-Cushing's disease is based on a tumor of the pituitary gland secreting ACTH (corticotropinoma). Usually it is a microadenoma of basophilic cells. ACTH-independent form of SIK is associated with a tumor from the fascicular area of ​​the adrenal cortex (corticosteroma, adrenal cortex cancer) or primary hyperplasia of the adrenal cortex, which can be small or large-nodular. Ectopic ACTH syndrome is caused by the secretion of corticotropin by neuroendocrine tumors (carcinoid of the bronchi or other localizations, thymoma, tumors from the pancreas islets, MTC, chromaffinomas).

Pathogenesis... In all forms of SIC, the key link in pathogenesis is the overproduction of cortisol, the main effect of which on metabolism is increased catabolism. Long-term exposure to excessive concentrations of glucocorticoids leads to disorders of the cardiovascular system (arterial hypertension, myocardial dystrophy), carbohydrate metabolism (increased glycogenolysis and gluconeogenesis), electrolyte balance (hypokalemia, hypernatremia), muscle and adipose tissue and skin (atrophy of the muscles of the extremities, centripetal redistribution , catabolism of skin proteins), bone tissue (osteoporosis), nervous system, weakening of the immune system.

Symptoms and signs of Itsenko Cushing's syndrome

The prevalence of various symptoms in Cushing's syndrome

Symptom	The proportion of patients,%
Decreased sex drive	100
Obesity or weight gain	97
Crimson blush	94
Moon face	88
Menstrual irregularities	84
Hirsutism	81
Arterial hypertension	74
Bruises	62
Drowsiness, depression	62
Striae	56
Weakness	56
ECG changes or atherosclerosis	55
Fat "hump" on the back	54
Edema	50
Impaired glucose tolerance	50
Osteopenia or fractures	50
Headache	47
Backache	43
Recurrent infections	25
Abdominal pain	21
Acne vulgaris	21
In women, hair thinning	13

On examination, attention is drawn to central obesity with relatively thin limbs. Characterized by the redistribution of subcutaneous fat with its deposition mainly in the abdomen, shoulder girdle, supraclavicular spaces, face, back in the interscapular region. Dry and thinning of the skin is noted. The patient's face becomes rounded ("moonlike" face), the cheeks become red, purple ("matronism").

Often, multiple bruises and petechiae are determined, hypertrichosis and fungal infections of the nails are noted. Progressive obesity and protein catabolism lead to the appearance on the skin of the abdomen, shoulders, thighs, buttocks, mammary glands and sometimes on the back of a kind of stretch stripes - stretch marks, mainly of a cyanotic or purple-red hue. As a result of osteoporotic damage to the spine, thoracic kyphosis increases and posture is impaired.

Changes in the cardiovascular system are expressed in persistent arterial hypertension, myocardial dystrophy due to direct exposure to glucocorticoids and electrolyte disturbances. An excess of adrenal androgens in women leads to the development of hirsutism and amenorrhea, and in men it can be accompanied by the development of erectile dysfunction. Mental disorders (from emotional lability and euphoria to depression and psychosis) can be observed. The consequence of the immunosuppressive action of corticosteroids is a decrease in the body's resistance to various infections.

With ectopic ACTH syndrome, in addition to the symptoms described above, hyperpigmentation of the skin (due to increased production of melanocyte-stimulating hormone), as well as various symptoms caused by a primary neuroendocrine tumor, can be observed.

Diagnostics of the Itsenko Cushing's syndrome

Laboratory tests are necessary to make a diagnosis, but the accuracy of commonly used methods is low. If sensitivity is taken as the main criterion (the proportion of positive results among all patients with Cushing's syndrome), the diagnosis often gives false positive results. To reduce their number, you can first observe the patient, prescribing laboratory tests only when new symptoms appear. Since Cushing's syndrome usually progresses over time, the absence of such symptoms speaks against this diagnosis.

Research includes the identification of excess cortisol secretion and feedback disturbances in the pituitary-adrenal system. The degree of hypercortisolemia can be assessed by the content of free cortisol in daily urine. It increases in Cushing's syndrome, as well as in depression, anxiety, obsessive-compulsive disorder, chronic pain, intense physical activity, alcoholism, decompensated diabetes mellitus and severe obesity. Apparently, in all these cases, central mechanisms stimulate the secretion of corticoliberin, which activates the hypothalamic-pituitary-adrenal system. Cortisol suppresses the secretion of corticoliberin and ACTH in a negative feedback loop, so the content of cortisol in urine increases at most fourfold. Therefore, if the level of free cortisol in the urine is normal, Cushing's syndrome is excluded (apart from cases of transient hypercortisolemia), and an increase in this indicator may be due to both Cushing's syndrome and other conditions in which the adrenal cortex is activated. In the latter case, the content of cortisol in daily urine, as a rule, exceeds the upper limit of the norm by less than four times, therefore, at higher rates, the presence of Cushing's syndrome (or a more rare disease - familial glucocorticoid resistance) is not in doubt.

The immunological methods for the determination of free cortisol in urine are gradually being replaced by methods of structural analysis. When immunologically determined, antibodies interact not only with cortisol, but also with its metabolites, as well as with other steroids of similar structure. In contrast, liquid chromatography-mass spectrometry detects only cortisol, which narrows the range of normal values ​​and increases the specificity of 1.58J. Because of these differences between methods, it is important when analyzing results to consider how they are obtained.

A good way to distinguish Cushing's syndrome from superficially similar conditions is to measure plasma cortisol levels at midnight; if the level of 7.5 μg% is taken as the limit exceeding which is regarded as Cushing's syndrome, the diagnostic accuracy of the method is 95%. It is equally reliable and more convenient to measure the level of cortisol in saliva before bedtime or at midnight. However, since different indicators were taken as the upper limit of the norm in different studies, methods for determining cortisol in saliva still need to be evaluated and standardized.

Sometimes in Cushing's syndrome, sensitivity to dexamethasone is close to normal; therefore, there is debate about how best to measure results. It has been suggested that cortisol levels below 1.8 μg% (50 nmol / L) be considered normal; this will increase sensitivity, but will greatly increase the number of false positives. Even with a higher limit value of the norm (5 μg%), the proportion of false-positive results (in chronic diseases, obesity, mental disorders, in healthy people) reaches 30%.

In a small study of 58 patients, administration of corticorelin (1 μg / kg IV) immediately after the end of the test and measuring the level of cortisol 15 minutes later increased the sensitivity and specificity of the method to 100%; the threshold level of cortisol, the excess of which was considered a sign of Cushing's syndrome, was taken as 1.4 μg% (38 nmol / l). Such a combined test has a very high diagnostic accuracy, but the cost of administering corticorelin is added to the disadvantages of a long test with dexamethasone. Due to these shortcomings, these tests in the United States are usually carried out only with dubious or unclear results of the determination of cortisol in daily urine or a short sample with dexamethasone.

Any test with dexamethasone can give a false positive result if the rate of elimination of the drug changes. Alcohol, rifampicin, phenytoin and phenobarbital induce liver microsomal enzymes that metabolize dexamethasone and accelerate its excretion, and in case of renal or hepatic insufficiency, the excretion of the drug, on the contrary, is slowed down. In such situations, it is advisable to measure the plasma level of dexamethasone in order to determine if its excretion from the body is impaired, and the above drugs should be canceled if possible.

SIC diagnostics consists of three main stages. At the first stage, the organic nature of hypercortisolism is confirmed.

At the next stage (with a positive small dexamethasone test), the form of endogenous hypercortisolism is determined. To do this, examine the content of ACTH in the peripheral blood. In Itsenko-Cushing's disease, the ACTH level is elevated or normal. In patients with ectopic ACTH syndrome, the excretion of cortisol and its metabolites also usually does not decrease, but the level of ACTH is increased, and often quite significantly.

At the last stage, topical diagnostics of the source of hyperproduction of cortisol or ACTH is carried out. In patients with ACTH-dependent SIC, diagnostic efforts are directed towards detecting a pituitary tumor, using MRI for this purpose. Since most of the corticotropin is microadenomas, contrast enhancement with gadolinium is often required to visualize them. In patients with ACTH-independent form of SIK, CT or M-RT of the adrenal glands is performed, which usually reveals a solitary tumor of one of the adrenal glands against the background of atrophy of the other, less often small- or large-nodular hyperplasia of the adrenal glands is detected. The greatest difficulties arise in the topical diagnosis of ectopic ACTH syndrome, since tumors of neuroendocrine origin can be very small in size and the most diverse localization. The most promising method for detecting them is scintigraphy with labeled octreotide, since most of these neoplasms have somatostatin receptors.

Differential diagnosis of Cushing's syndrome

Differential diagnosis is required to distinguish SIC and functional hypercortisolism (obesity, adolescent dyspituitarism, alcoholism, depression) and is based on the results of a small dexamethasone test - with SIC, there is a significant (50% or more) suppression of free cortisol excretion after taking dexamethasone.

Attempts to establish the etiology of Cushing's syndrome should be made only after it has been confirmed by the above methods. Endogenous Cushing's syndrome can be caused by adrenal hyperfunction (15% of cases) or excessive secretion of ACTH or corticoliberin by the tumor (85% of cases). Since the secretion of ACTH by corticotropic cells of the pituitary gland is suppressed in hypercortisolemia, with lesions of the adrenal glands (adenoma, cancer, or, less often, bilateral adrenal hyperplasia), the plasma ACTH level is low (less than 10 pg / ml). Therefore, the differential diagnosis of Cushing's syndrome begins with measuring the level of ACTH in plasma. The ACTH threshold is discussed; some authors use values ​​less than 9 pg / ml as an upper limit for the diagnosis of ACTH-independent endogenous Cushing's syndrome. Others recommend more stringent criteria, less than 5 pg / ml.

A higher ACTH level indicates a pituitary tumor (called Cushing's disease) or an ACTH / corticoliberin-secreting tumor of a different location. To establish the exact cause, requires complex laboratory and instrumental diagnostics, ideally under the guidance of experienced endocrinologists. The best method is to take blood from the lower stony sinuses; a long test with dexamethasone, a test with corticoliberin and MRI of the pituitary gland are also used.

Treatment of Itsenko Cushing's syndrome

The main treatment for Cushing's syndrome is to surgically remove the cause of the excess secretion of ACTH or cortisol. In adrenal Cushing's syndrome, adrenalectomy, unilateral or bilateral, is usually successful - except in cases of adrenal cancer, since the patient often already has metastases at the time of diagnosis. In Cushing's disease, transsphenoidal tumor resection is the treatment of choice. In case of ineffectiveness or impossibility of surgical treatment, as well as in cases where the tumor cannot be found, bilateral adrenalectomy is performed. Sometimes radiation therapy is used for Cushing's disease, after which, as a rule, drug suppression of steroidogenesis is carried out until radiation works. Drug suppression of steroidogenesis or adrenalectomy is also used for metastatic tumors that secrete cortisol or ACTH, or when an ectopic ACTH-secreting tumor cannot be found.

The treatment of SIK consists in the surgical removal of the tumor that caused it. In Itsenko-Cushing's disease, this is a transsphenoidal adenomectomy, in the ACTH-independent form of SIC - adrenalectomy, in the case of ectopic ACTH syndrome - the removal of the corresponding tumor. Drug therapy with steroidogenesis inhibitors (aminoglutethimide, ketoconazole), due to poor tolerance and insufficient clinical efficacy, is considered mainly as a preoperative preparation. If it is impossible or not radical to remove the corticotropinoma, radiation therapy can be used, with rapid progression of the disease - bilateral adrenalectomy. The same operation can be performed in case of rapid progression of SIC in the presence of an ACTH-secreting tumor with an inaccessible localization. If it is impossible to radically remove adrenal cortex cancer, mitotane is used. Octreotide or bilateral adrenalectomy may be used for conservative management of inoperable or cryptogenic ectopic ACTH syndrome.

Itsenko Cushing's forecast

The prognosis can be favorable with timely diagnosis and radically performed surgical treatment of a benign tumor. Most patients who have undergone corticosteroma removal develop transient, and some develop persistent secondary hypocorticism due to prolonged suppression of pituitary ACTH secretion and atrophy of the healthy adrenal cortex. With bilateral adrenalectomy, patients become disabled, and in patients with a pituitary-dependent form of SIK who underwent this operation, a pituitary adenoma develops after a few years. In the case of a late diagnosis of the disease, even radical surgical treatment does not lead to a complete recovery due to far-reaching complications.

Itsenko-Cushing's disease

What is Itsenko-Cushing's Disease -

Itsenko-Cushing's disease- a disease in which an excessive amount of adrenocorticotropic hormone (ACTH) is produced, which regulates work. With an excess of ACTH, the adrenal glands increase in size and intensively produce their own - corticosteroids, which leads to the disease.

The symptoms of this disease were described at different times by two scientists - the American neurosurgeon Harvey Cushing and the Odessa neuropathologist Nikolai Itsenko.

An American specialist associated the disease with, a Soviet scientist suggested that the cause of the disease lies in changes in the area of ​​the brain responsible for interaction and. Today, scientists have come to the conclusion that Itsenko-Cushing's disease occurs as a result of malfunctions in the hypothalamic-pituitary system - both researchers were right.

Itsenko-Cushing's disease, or otherwise hypercortisolism- a severe neuroendocrine disease that occurs in case of dysregulation of the hypothalamic-pituitary-adrenal system, when an excess of adrenal hormones - corticosteroids - is formed.

Distinguish Itsenko-Cushing's syndrome and Itsenko-Cushing's disease... Itsenko-Cushing's syndrome is called all pathological conditions with one common symptom-complex, which is based on hypercortisolism, that is, increased secretion of cortisol by the adrenal cortex.

Itsenko-Cushing's syndrome includes:

• Itsenko-Cushing's disease, resulting from an increase in the production of adrenocorticotropic hormone by the pituitary gland (pituitary ACTH-dependent syndrome).
• ACTH- or corticoliberin-ectopic syndrome.
• iatrogenic or drug syndrome various hyperplastic tumors of the adrenal cortex - adenomatosis, adenoma, adenocarcinoma.

What provokes / Causes of Itsenko-Cushing's disease:

The cause of Itsenko-Cushing's syndrome there can be various conditions, but most often hypercortisolism is caused by an increased production of adrenocorticotropic hormone of the pituitary gland (Itsenko-Cushing's disease). Adrenocorticotropic hormone can be produced by a microadenoma of the pituitary gland (microadenoma is a small mass in the pituitary gland, usually benign, not exceeding 2 cm in size, hence its name) or ectopic corticotropinoma - a tumor that produces large quantities of corticotropic hormone, but develops slowly. Ectopic corticotropinoma, which has an oncogenic or other malignant nature, can be located in the bronchi, testes, and ovaries.

Pathogenesis (what happens?) During Itsenko-Cushing's disease:

A cascade of hormonal changes in the body starts.

It all starts with the fact that mysterious nerve impulses are received in it, which cause its cells to produce too many substances that activate the release of adrenocorticotropic hormone.

In response to such a powerful stimulation, the pituitary gland releases a huge amount of this very adrenocorticotropic hormone (ACTH). He, in turn, affects: makes them produce in excess of their own - corticosteroids. This is where complete chaos begins, because corticosteroids affect all metabolic processes.

As a rule, with Itsenko-Cushing's disease, the pituitary gland is enlarged (tumor, or pituitary adenoma). As the disease progresses, the adrenal glands also enlarge.

Symptoms of Itsenko-Cushing's Disease:

Diagnosis of the disease, as a rule, is not very difficult, because the data of the physical examination of the patient are of paramount importance. More than 90% of patients are observed to one degree or another, and special attention is drawn to the distribution of fat - dysplastic (according to the cushingoid type): on the abdomen, chest, neck, face (a crimson-red moon-shaped face, sometimes with a cyanotic shade - t .n. matronism) and back (the so-called "climacteric hump"). Itsenko-Cushing's syndrome is distinguished from other forms of obesity by thinning, almost transparent skin on the back of the hand.

Amyotrophy- a decrease in the volume of muscle mass, accompanied by a decrease in muscle tone and muscle strength, especially the gluteal and femoral ("beveled buttocks") - a typical symptom of Itsenko-Cushing's syndrome. There is also atrophy of the muscles of the anterior abdominal wall ("frog belly"), over time, hernial protrusions appear along the white line of the abdomen.

Leather the patient becomes thinner, has a "marble" appearance with a clear vascular pattern, prone to dryness, interspersed with areas of regional sweating, flakes.

Very often on stretch marks appear on the skin- Stretch stripes of crimson or violet color. Basically, striae are located on the skin of the abdomen, inner and outer thighs, mammary glands, shoulders, can be from a few centimeters to several millimeters. The skin is replete with various acne-type rashes, manifested as a result of inflammation of the sebaceous glands, numerous subcutaneous microbleeds, vascular "asterisks".

In some cases, with Cushing's disease and ectopic ACTH syndrome, hyperpigmentation can be observed - an uneven distribution of pigment, manifested in the form of dark and lighter spots that differ from the main skin color. A disease associated with damage (thinning) of bone tissue, leading to fractures and deformation of bones - osteoporosis - is one of the most severe complications accompanying Itsenko-Cushing's syndrome. As a rule, osteoporosis develops in the vast majority of patients. Fractures and deformities of bones, accompanied by severe painful sensations, eventually lead to scoliosis and kyphoscoliosis.

With hypercortisolism, it often develops cardiomyopathy- a group of diseases in which the heart muscle primarily suffers, which is manifested by a violation of the function of the heart muscle.

There are several reasons that can cause cardiomyopathy, the main ones being the catabolic effects of steroids on electrolyte shifts and arterial hypertension. The manifestations of cardiomyopathy are cardiac arrhythmias and heart failure. The latter, in most cases, is capable of leading the patient to death.

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Most often, this syndrome develops with chronic glucocorticoid therapy. "Spontaneous" Cushing's syndrome can be a consequence of pituitary or adrenal diseases, as well as the secretion of ACTH or CRH by non-pituitary tumors (syndrome of ectopic secretion of ACTH or CRH). If the cause of Cushing's syndrome is excessive secretion of ACTH by a pituitary tumor, they speak of Cushing's disease. This section discusses the various forms of spontaneous Cushing's syndrome and how they are diagnosed and treated.

Classification and prevalence

Distinguish between ACTH-dependent and ACTH-independent Cushing's syndrome. ACTH-dependent forms of the syndrome include the syndrome of ectopic ACTH secretion and Cushing's disease, which are characterized by chronic hypersecretion of ACTH. This leads to hyperplasia of the fascicular and reticular zones of the adrenal glands and, consequently, to an increase in the secretion of cortisol, androgens and DOK.

The cause of ACTH-independent Cushing's syndrome may be a primary tumor of the adrenal glands (adenoma, cancer) or their nodular hyperplasia. In these cases, elevated cortisol levels suppress the secretion of ACTH by the pituitary gland.

Cushing's disease

This most common form of the syndrome accounts for about 70% of all cases described. Cushing's disease is 8 times more common among women than among men, and is usually diagnosed between the ages of 20-40, although it can manifest itself at any age up to 70 years.

Ectopic ACTH secretion

Ectopic ACTH secretion underlies approximately 15-20% of cases of Cushing's syndrome. ACTH secretion by non-pituitary tumors may be accompanied by severe hypercortisolemia, but in many patients the classic signs of glucocorticoid excess are absent, which is probably associated with the rapid course of the disease. This syndrome is most typical for small cell lung cancer (which accounts for about 50% of cases of ectopic secretion of ACTH), although among patients with small cell cancer it occurs only in 0.5-2% of cases. The prognosis of such patients is very poor, and they do not live long. The ectopic secretion of ACTH can also manifest itself as signs of the classic Cushing's syndrome, which significantly complicates the diagnosis, especially since by the time of visiting a doctor, these tumors are not always visible on X-ray examination. The syndrome of ectopic ACTH secretion is more common in men. Its maximum frequency occurs at the age of 40-60 years.

Primary adrenal tumors

In about 10% of cases, Cushing's syndrome is due to primary adrenal tumors. Most of these patients have benign adenomas of these glands. The incidence of adrenal cancer is about 2 cases per million population per year. Both adenomas and cancers of these glands are more common among women. The so-called adrenal incidentalomas are often accompanied by autonomous cortisol secretion without the classic signs of Cushing's syndrome.

Cushing's syndrome in children

Cushing's syndrome is extremely rare in childhood and adolescence. However, unlike adults, adrenal cancer is the most common cause (51%), while adenomas occur in only 14% of cases. These tumors are more common in girls and most often develop between the ages of 1 and 8. During adolescence, 35% of cases are due to Cushing's disease (the frequency of which is the same among girls and boys). At the time of diagnosis, the age of patients usually exceeds 10 years.

Causes and pathogenesis of Cushing's syndrome

Cushing's disease

According to the modern point of view, its primary cause is spontaneously developing corticotrophic adenomas of the pituitary gland, the hypersecretion of ACTH by which (and, accordingly, hypercortisolemia) leads to characteristic endocrine shifts and dysfunctions of the hypothalamus. Indeed, microsurgical resection of pituitary adenomas normalizes the state of the HPA system. In addition, molecular studies indicate the monoclonal nature of almost all corticotrophic adenomas.
In rare cases, as already noted, the cause of Cushing's disease is not an adenoma, but hyperplasia of the pituitary corticotrophs, which may be a consequence of excessive CRH secretion by a benign hypothalamic gangliocytoma.

Syndromes of ectopic secretion of ACTH and CRH

Non-pituitary tumors sometimes synthesize and secrete biologically active ACTH and related peptides rPLPH and β-endorphin. Inactive fragments of ACTH are also secreted. In tumors secreting ACTH, CRH can also be produced, but its role in the pathogenesis of ectopic ACTH secretion remains unclear. In some cases, only CRH was produced by non-hypophyseal tumors.

Ectopic ACTH secretion is characteristic only for some tumors. In half of the cases, this syndrome is associated with small cell lung cancer. Other such neoplasms include carcinoid tumors of the lungs and thymus, medullary thyroid cancer, as well as pheochromocytoma and related tumors. Rare cases of ACTH production by other tumors have also been described.

Tumors of the adrenal glands

Adenomas and adrenal cancer that produce glucocorticoids occur spontaneously. The secretion of steroids by these tumors is not controlled by the hypothalamic-pituitary system. In rare cases, adrenal cancer develops with chronic ACTH hypersecretion characteristic of Cushing's disease, nodular adrenal hyperplasia or their congenital hyperplasia.

Pathophysiology of Cushing's syndrome

Cushing's disease

In Cushing's disease, the circadian rhythm of ACTH secretion and, accordingly, cortisol is disrupted. The inhibitory effect of glucocorticoids on the secretion of ACTH by the pituitary adenoma (by the mechanism of negative feedback) is weakened, and therefore ACTH hypersecretion persists despite the increased level of cortisol. As a result, a chronic excess of glucocorticoids is formed. The episodic secretion of ACTH and cortisol determines fluctuations in plasma levels, which at times may be normal. However, the diagnosis of Cushing's syndrome is confirmed by elevated levels of free cortisol in urine or elevated serum or saliva levels in the late night hours. The general increase in the secretion of glucocorticoids determines the clinical manifestations of Cushing's syndrome, but the secretion of ACTH and R-LPH usually does not increase enough to cause hyperpigmentation.

1. Violation of ACTH secretion. Despite the increased secretion of ACTH, her response to stress is absent. Stimuli such as hypoglycemia or surgery do not further increase the secretion of ACTH and cortisol. This is probably due to the inhibitory effect of hypercortisolemia on the hypothalamic secretion of CRH. Thus, in Cushing's disease, ACTH secretion is not controlled by the hypothalamus.
2. Effects of excess cortisol. Excess cortisol not only inhibits the functions of the pituitary and hypothalamus, affecting the secretion of ACTH, TSH, GH and gonadotropins, but also determines all the systemic effects of glucocorticoids.
3. Excess androgens. In Cushing's disease, the secretion of adrenal androgens increases in parallel with the secretion of ACTH and cortisol. The content of DHEA, DHEA sulfate and androstenedione in plasma increases, and their peripheral conversion to testosterone and dihydrotestosterone causes hirsutism, acne and amenorrhea in women. In men, due to the inhibition of LH secretion by an excess of cortisol, testosterone production by the testicles decreases, which leads to a weakening of libido and impotence. The increased secretion of adrenal androgens does not compensate for the decrease in testosterone secretion by the sex glands.

In ectopic ACTH secretion syndrome, plasma ACTH and cortisol levels are usually higher than in Cushing's disease. The secretion of ACTH in these cases occurs chaotically and is not suppressed by cortisol through a negative feedback mechanism. Therefore, pharmacological doses of glucocorticoids do not reduce plasma ACTH and cortisol levels.

Despite a significant increase in the content and rate of secretion of cortisol, adrenal androgens and DOC, the typical manifestations of Cushing's syndrome are usually absent. This is probably due to the rapid development of hypercortisolemia, anorexia, and other symptoms of a malignant tumor. On the other hand, there are often signs of an excess of mineralocorticoids (arterial hypertension and hypokalemia), which is caused by increased secretion of DOK and the mineralocorticoid effects of cortisol. With ectopic CRH secretion, pituitary corticotrophic cells undergo hyperplasia, and ACTH secretion is not suppressed by cortisol through a negative feedback mechanism.

Tumors of the adrenal glands

1. Autonomous secretion. Benign and malignant adrenal tumors secrete cortisol autonomously. The concentration of ACTH in plasma is reduced, which leads to atrophy of the second adrenal cortex. Cortisol is secreted chaotically, and pharmacological doses of agents affecting the hypothalamic-pituitary system (dexamethasone and metirapone), as a rule, do not change its plasma level.
2. Adrenal adenomas. In Cushing's syndrome, caused by an adrenal adenoma, there are signs of an excess of glucocorticoids only, since such adenomas secrete only cortisol. Therefore, the manifestations of an excess of androgens or mineralocorticoids indicate not an adenoma, but a cancer of the adrenal cortex.
3. Adrenal cancer. Adrenal cancers usually secrete large amounts of various steroid hormones and their precursors. Excessive secretion of cortisol and androgens is most often observed. The production of 11-deoxycortisol, DOK, aldosterone and estrogens also often increases. Plasma cortisol and urinary free cortisol levels are often less elevated than androgen levels. Thus, in adrenal cancer, an excess of cortisol is usually accompanied by an increase in plasma concentrations of DHEA, DHEA sulfate and testosterone. Severe clinical manifestations of hypercortisolemia progress rapidly. In women, signs of an excess of androgens (virilization) are pronounced. Arterial hypertension and hypokalemia are usually caused by the mineralocorticoid effects of cortisol and, more rarely, by hypersecretion of DOK and aldosterone.

Symptoms and signs of Cushing's syndrome

1. Obesity... Weight gain is the most common and usually the initial symptom of Cushing's syndrome. The classic manifestation is central obesity, characterized by fat deposits on the face, neck and abdomen, while the arms and legs remain relatively thin. Just as often (especially in children) there is general obesity (with a predominance of central obesity). The typical symptom, "moon face", occurs in 75% of cases; most patients have a facial pletora. Fat deposits on the neck are especially pronounced in the supraclavicular region and on the back of the head ("bovine hump"). Obesity is absent in only a very small number of cases, but such patients usually have a central redistribution of fat and a characteristic facial appearance.
2. Skin changes. Skin changes are very common, and their appearance suggests excess cortisol secretion. Atrophy of the epidermis and connective tissue underneath leads to thinning of the skin, which becomes "transparent", and the facial pletore. In about 40% of cases, there is slight bleeding, resulting in bruising even with minimal trauma. In 50% of cases, there are stretch stripes (striae) of red or purple color, but in patients over 40 they are extremely rare. Due to connective tissue atrophy, striae are located below the level of the surrounding skin and, as a rule, are wider (up to 0.5-2 cm) pinkish striae observed during pregnancy or rapid weight gain. Most often they are localized on the abdomen, but sometimes on the chest, thighs, buttocks and armpits. Pustular acne is associated with hyperandrogenism, while papular acne is more characteristic of excess glucocorticoids. Small wounds and scratches heal slowly; sometimes there is a divergence of surgical sutures. The skin and mucous membranes are often affected by fungal infections, including pityriasis versicolor, onychomycosis, and candidal stomatitis. Hyperpigmentation of the skin with Cushing's disease or adrenal tumors is much less common than with ectopic ACTH secretion syndrome.
3. Hirsutism... Hirsutism due to hypersecretion of adrenal androgens occurs in about 80% of women with Cushing's syndrome. Facial hair growth is most common, but hair growth can also increase on the abdomen, chest and shoulders. Hirsutism is usually accompanied by acne and seborrhea. Virilization is rare, except in cases of adrenal cancer, in which it occurs in about 20% of patients.
4. Arterial hypertension. Hypertension is a classic symptom of spontaneous Cushing's syndrome. High blood pressure is recorded in 75% of cases, and in more than 50% of patients, diastolic pressure exceeds 100 mm Hg. Art. Arterial hypertension and its complications to a large extent determine the morbidity and mortality of such patients.
5. Dysfunction of the sex glands, due to increased secretion of androgens (in women) and cortisol (in men and, to a lesser extent, in women) occurs very often. Amenorrhea and infertility occur in about 75% of women. In men, libido is often impaired, and some people experience loss of body hair and softening of the testicles.
6. Mental disorders. Psychological changes are observed in most patients. In mild cases, emotional lability and increased irritability are observed. Anxiety, depression, impaired attention and memory are also possible. Many patients have euphoria and sometimes overt manic behavior. Sleep disturbances are common, manifested by insomnia or early awakening. Much less common are severe depression, psychosis with delusions and hallucinations, and paranoia. Some people are suicidal. The volume of the brain may decrease; correction of hypercortisolemia restores it (at least partially).
7. Muscle weakness. This symptom occurs in almost 60% of patients. The proximal muscle groups are more often affected, especially the leg muscles. Hypercortisolemia is associated with a decrease in lean body mass and total body protein.
8. Osteoporosis... Glucocorticoids have a pronounced effect on the skeleton, and osteopenia and osteoporosis are common in Cushing's syndrome. Fractures of the bones of the feet, ribs and vertebrae often occur. Back pain is the first complaint. Compression fractures of the vertebrae are radiographically detected in 15-20% of patients. Unexplained osteopenia in any young or middle-aged person, even in the absence of other signs of excess cortisol, should be a reason for assessing adrenal health. Although aseptic necrosis of bones was observed with the introduction of exogenous glucocorticoids, this is not typical for endogenous hypercortisolemia. It is possible that such necrosis is associated with the underlying disease for which glucocorticoids were prescribed.
9. Urolithiasis disease. About 15% of patients with Cushing's syndrome have urolithiasis, which develops as a result of the hypercalciuric effect of glucocorticoids. Sometimes renal colic is the reason for seeking help.
10. Thirst and polyuria. Hyperglycemia is rarely the cause of polyuria. More often it is due to the inhibitory effect of glucocorticoids on the secretion of ADH and the direct action of cortisol, which increases the clearance of free water.

Laboratory data

The results of routine laboratory tests are described here. Special diagnostic tests are discussed in the Diagnostics section.

Hemoglobin level, hematocrit and red blood cell count are usually at the upper limit of normal; in rare cases, polycythemia is found. The total number of leukocytes does not differ from the norm, but the relative and absolute number of lymphocytes is usually reduced. The number of eosinophils is also reduced; in most patients it is less than 100 / μL. With Cushing's disease, the serum electrolyte content, with rare exceptions, does not change, but with a sharp increase in steroid secretion (as is typical for ectopic ACTH secretion syndrome or adrenal cancer), hypokalemic alkalosis may occur.

Fasting hyperglycemia or overt diabetes occurs in only 10-15% of patients; more often postprandial hyperglycemia occurs. In most cases, secondary hyperinsulinemia and impaired glucose tolerance are found.

Serum calcium is normal, while phosphorus is slightly reduced. Hypercalciuria is noted in 40% of cases.

X-ray

Plain x-rays often reveal cardiomegaly due to hypertension or atherosclerosis and mediastinal dilatation due to fat deposition. Compression fractures of the vertebrae, fractures of the ribs and kidney stones may also be found.

Electrocardiography

On the ECG, changes associated with arterial hypertension, ischemia and electrolyte shifts can be detected.

Signs Indicating Causes of Cushing's Syndrome

Cushing's disease

Cushing's disease is characterized by a typical clinical picture: high prevalence among women, onset between the ages of 20 and 40, and slow progression. Hyperpigmentation and hypokalemic alkalosis are rare. Signs of androgen excess include acne and hirsutism. The secretion of cortisol and adrenal androgens is only moderately elevated.

Ectopic ACTH Secretion Syndrome (Cancer)

This syndrome occurs predominantly in men and is especially common between the ages of 40 and 60. The clinical manifestations of hypercortisolemia are usually limited to muscle weakness, arterial hypertension, and impaired glucose tolerance. There are often signs of a primary tumor. Hyperpigmentation, hypokalemia, alkalosis, weight loss, and anemia are common. Hypercortisolemia develops rapidly. Plasma levels of glucocorticoids, androgens, and DOC are usually equally and significantly elevated.

Syndrome of ectopic ACTH secretion (benign tumors)

In a smaller number of patients with ectopic ACTH secretion syndrome, caused by more "benign" processes (especially bronchial carcinoid), typical signs of Cushing's syndrome progress more slowly. Such cases are difficult to distinguish from Cushing's disease due to pituitary adenoma, and the primary tumor is not always possible to detect. The incidence of hyperpigmentation, hypokalemic alkalosis, and anemia is variable. Additional diagnostic difficulties are associated with the fact that in many patients the dynamics of ACTH and steroids is indistinguishable from that in typical Cushing's disease.

Adrenal adenomas

The clinical picture with adrenal adenomas is usually limited to signs of an excess of glucocorticoids only. There are no androgenic effects (such as hirsutism). The disease begins gradually, and hypercortisolemia is mild to moderate. Plasma androgen levels are generally slightly reduced.

Adrenal cancer

Adrenal cancer is characterized by an acute onset and rapid increase in clinical manifestations of excess glucocorticoids, androgens, and mineralocorticoids. Plasma cortisol and androgen levels are dramatically increased. Hypokalemia is often found. Patients complain of abdominal pain, palpation reveals volumetric formations, and often there are already metastases in the liver and lungs.

Diagnostics of the Cushing's syndrome

Suspicions of Cushing's syndrome must be confirmed by biochemical studies. First, you should exclude other conditions that manifest similar symptoms: taking certain medications, alcoholism or mental disorders. In most cases, biochemical differential diagnosis of Cushing's syndrome can be carried out on an outpatient basis.

Dexamethasone suppression test

An overnight suppressive test with 1 mg dexamethasone is a reliable method of screening patients with suspected hypercortisolemia. Dexamethasone 1 mg is given at 11 pm (before bedtime) and plasma cortisol levels are measured the next morning. In healthy people, this level should be less than 1.8 μg% (50 nmol / L). Previously, the criterion was cortisol levels below 5 μg%, but the test results often turned out to be false negative. False negative results are observed in some patients with mild hypercortisolemia and hypersensitivity of the pituitary gland to the action of glucocorticoids, as well as with periodic releases of cortisol. This test is performed only if Cushing's syndrome is suspected and should be confirmed by determining the urinary excretion of free cortisol. In patients taking drugs that accelerate the metabolism of dexamethasone (phenytoin, phenobarbital, rifampicin), the results of this test may be false positive. False positive results are also possible in cases of kidney failure, severe depression, as well as in cases of stress or severe illness.

Free cortisol in urine

Determination of the level of free cortisol in daily urine using HPLC or chromatography-mass spectroscopy is the most reliable, accurate and specific way to confirm the diagnosis of Cushing's syndrome. Frequently used drugs do not interfere with the determination results. An exception is carbamazepine, which elutes with cortisol and interferes with its determination by HPLC. When determined by this method, the level of free cortisol in daily urine is usually less than 50 μg (135 nmol). By the excretion of free cortisol in the urine, patients with hypercortisolemia can be distinguished from obese patients without Cushing's syndrome. A slight increase in the level of free cortisol in urine is found in less than 5% of patients with simple obesity.

Daily rhythm of secretion

Lack of circadian rhythm of cortisol secretion is considered a necessary symptom of Cushing's syndrome. Normally, cortisol is secreted sporadically, and the circadian rhythm of its secretion coincides with that for ACTH. Usually, the highest cortisol levels are found in the early morning; during the day it gradually decreases, reaching its lowest point in the late evening. Since the concentration of cortisol in plasma normally fluctuates widely, it can be normal in Cushing's syndrome. It is difficult to prove a violation of the circadian rhythm. Single definitions in the morning or in the evening are not very informative. However, serum cortisol levels above 7 μg% (193 nmol / L) at midnight are quite specific signs of Cushing's syndrome. Since cortisol is secreted in free form, it is easier to detect it in saliva at night. As recent studies show, the cortisol content in saliva in Kushink's syndrome at midnight usually exceeds 0.1 μg% (2.8 nmol / L).

Difficulties in diagnosis

It is most difficult to distinguish patients with mild Cushing's syndrome from healthy people with physiological hypercortisolemia ("pseudo-cushing"). These conditions include the depressive stage of mood disorders, alcoholism, and anorexia nervosa and bulimia nervosa. In these cases, biochemical signs of Cushing's syndrome may occur: an increase in the level of free cortisol in the urine, a violation of the circadian rhythm of cortisol secretion, and the absence of a decrease in its level after an overnight suppressive test with 1 mg of dexamethasone. Certain diagnostic indications can be obtained from the anamnesis, but the most reliable way to distinguish Cushing's syndrome from "pseudo-cushing" is a suppressive test with dexamethasone followed by the introduction of CRH. This new assay, which combines suppression with stimulation, has greater diagnostic sensitivity and accuracy for Cushing's syndrome. Dexamethasone is administered at 0.5 mg every 6 hours 8 times, and 2 hours after taking its last dose, CRH is administered intravenously at a dose of 1 μg / kg. In most patients with Cushing's syndrome, the plasma cortisol concentration 15 minutes after CRH administration exceeds 1.4 μg% (38.6 nmol / L).

Differential diagnosis

Differential diagnosis of Cushing's syndrome is usually very difficult and always requires the consultation of an endocrinologist. For this, a number of methods developed over the past 10-15 years are used, including the specific and sensitive IRMA method for ACTH, a stimulation test with CRH, blood sampling from the lower petrosal sinus (ICS), and MRI of the pituitary and adrenal glands.

Plasma ACTH

The first step is to differentiate ACTH-dependent Cushing's syndrome (caused by a pituitary or non-pituitary tumor that secretes ACTH) from ACTH-independent hypercortisolemia. The most reliable method is to determine the plasma ACTH level by the IRMA method. In adrenal tumors, their autonomous bilateral hyperplasia and artificial Cushing's syndrome, the ACTH level does not reach 5 pg / ml and reacts poorly to CRH [the maximum reaction is less than 10 pg / ml (2.2 pmol / l)]. In tumors secreting ACTH, its plasma level usually exceeds 10 pg / ml, and often 52 pg / ml (11.5 pmol / l). The main difficulty in the differential diagnosis of ACTH-dependent Cushing's syndrome is associated with the elucidation of the source of ACTH hypersecretion. The vast majority of these patients (90%) have a pituitary tumor. Although plasma ACTH levels are usually higher during ectopic secretion than when secreted by a pituitary tumor, these rates overlap to a large extent. In many cases of ectopic ACTH secretion, the tumor remains latent at the time of diagnosis and may not manifest clinically for many years after the diagnosis of Cushing's syndrome. An increased ACTH response to CRH is more common in pituitary Cushing's syndrome than in ectopic ACTH secretion syndrome, but the CRH test is much less sensitive than blood counts from the inferior petrosal sinuses.

MRI of the pituitary gland

In ACTH-dependent Cushing's syndrome, MRI of the pituitary gland with gadolinium enhancement reveals an adenoma in 50-60% of patients. In patients with classical clinical and laboratory signs of hypercortisolemia, dependent on pituitary ACTH, and obvious changes in the pituitary gland on MRI, the probability of the diagnosis of Cushing's disease is 98-99%. It should be emphasized, however, that in about 10% of people between the ages of 20 and 50, pituitary incidentalomas are found on MRI. Therefore, signs of a pituitary tumor can be detected in some patients with ectopic ACTH secretion syndrome.

Dexamethasone high dose suppressive test

This test has long been carried out for the purpose of differential diagnosis of Cushing's syndrome. However, its diagnostic accuracy is only 70-80%, which is significantly less than the actual incidence of Cushing's disease with pituitary adenomas (on average 90%). Therefore, it should hardly be used.

Blood from the lower stony sinus

If MRI fails to detect a pituitary adenoma, then the ACTH hypersecretion dependent on the pituitary adenoma from the one that depends on other tumors can be distinguished by bilateral catheterization of the NCC against the background of a CRH test. Blood flowing from the anterior lobe of the pituitary gland enters the cavernous sinuses, and then into the NCC and further into the bulb of the jugular vein. Simultaneous determination of ACTH in blood from the NCC and peripheral blood before and after CRH stimulation reliably confirms the presence or absence of an ACTH-secreting pituitary tumor. In the first case, the ratio of ACTH levels in the blood of NCS and peripheral blood after CRH administration should exceed 2.0; if it is less than 1.8, then the syndrome of ectopic ACTH secretion is diagnosed. The difference in the level of ACTH in the blood of the two NCCs helps to establish the localization of the pituitary tumor before surgery, although this is not always possible.

Bilateral blood sampling from the NCC requires a highly qualified radiologist. However, in experienced hands, the diagnostic accuracy of this approach approaches 100%.

Undetectable non-pituitary tumor secreting ACTH

If the results of determining ACTH in the blood from the NCS indicate the presence of a non-pituitary ACTH-secreting tumor, then it is necessary to find out its localization. Most of these tumors are located in the chest wall. More often than with CT, such neoplasms (usually small carcinoid tumors of the bronchi) are found on chest MRI. Unfortunately, the use of a labeled somatostatin analogue (octreotide acetate scintigraphy) does not always allow localization of such tumors.

Imaging of adrenal tumors

To identify the pathological process in the adrenal glands, CT or MRI is performed. These methods are used mainly to determine the localization of adrenal tumors in ACTH-independent Cushing's syndrome. Most adenomas are larger than 2 cm in diameter, while cancers are usually much smaller.

Treatment for Cushing's syndrome

Cushing's disease

The goal of treatment for Cushing's disease is to remove or destroy the pituitary adenoma in order to eliminate the hypersecretion of adrenal cortex hormones without creating hormonal deficiencies that would require constant replacement therapy.

Potential effects on the pituitary adenoma currently include microsurgical removal, various forms of radiation therapy, and drug suppression of ACTH secretion. Influences aimed at hypercortisolemia as such (surgical or pharmacological adrenalectomy) are used less frequently.

Syndrome of ectopic ACTH secretion

A complete cure of this syndrome can usually be achieved only with relatively "benign" tumors (such as carcinoid of the bronchi and thymus or pheochromocytoma). Particularly difficult cases are associated with severe hypercorticosolemia in malignant metastatic tumors.

Severe hypokalemia requires replacement administration of large doses of potassium and spironolactone, which blocks mineralocorticoid effects.

Drugs that block the synthesis of steroid hormones (ketoconazole, metyrapone and aminoglutethimide) are also used, but the resulting hypocorticism usually requires steroid replacement therapy. Ketoconazole in daily doses of 400-800 mg (divided) is usually well tolerated by patients.

Mitotane is used less frequently because it acts more slowly and causes severe adverse reactions. Mitotan often has to be administered for several weeks.

In cases of impossibility of correcting hypercortisolemia, bilateral adrenalectomy is performed.

Tumors of the adrenal glands

1. Adenomas... Unilateral adrenalectomy in such cases gives excellent results. For benign or small adrenal tumors, a laparoscopic approach is used, which significantly reduces the hospitalization period. Since long-term hypersecretion of cortisol inhibits the function of the hypothalamic-pituitary system and the second adrenal gland, adrenal insufficiency develops in such patients immediately after surgery, requiring temporary glucocorticoid replacement therapy.
2. Adrenal cancer. The results of treatment of patients with adrenal cancer are much worse, since by the time of diagnosis there are often already metastases (usually in the retroperitoneal space, liver and lungs). a) Surgical treatment. Surgery rarely leads to a complete cure, but resection of the tumor, reducing its mass, reduces the secretion of steroids. Preservation of unsuppressed steroid secretion in the immediate postoperative period indicates incomplete removal of the tumor or the presence of its metastases. b) Drug treatment. The choice is mitotane. It is prescribed inside in daily doses of 6-12 g (3-4 admission). In almost 80% of patients, these doses are associated with side effects (diarrhea, nausea and vomiting, depression, drowsiness). A decrease in the secretion of steroids can be achieved in about 70% of patients, but the size of the tumor decreases only in 35% of cases. If mitotane is ineffective, use ketoconazole, metirapone or aminoglutethimide (alone or in combination). Radiation and conventional chemotherapy for adrenal cancer are ineffective.

Nodular adrenal hyperplasia

In cases of ACTH-dependent macronodular hyperplasia of the adrenal glands, the same treatment is carried out as in classical Cushing's disease. With ACTH-independent hyperplasia (as in cases of micro- and some cases of macronodular hyperplasia), bilateral adrenalectomy is indicated.

Cushing's syndrome prognosis

Cushing's syndrome

In the absence of treatment, ACTH-secreting non-pituitary tumors and adrenal cancer inevitably lead to death of patients. In many cases, the cause of death is persistent hypercortisolemia and its complications (arterial hypertension, heart attack, stroke, thromboembolism, and infections). According to old observations, 50% of patients die within 5 years after the onset of the disease.

Cushing's disease

Modern microsurgical methods and irradiation of the pituitary gland with heavy particles make it possible to achieve success in the treatment of the vast majority of patients and to exclude surgical mortality and morbidity associated with bilateral adrenalectomy. These patients now live much longer than before. Nevertheless, the life expectancy of patients is still less than that of healthy individuals of the corresponding age. The cause of death is usually cardiovascular disorders. In addition, the quality of life of patients decreases, especially in connection with psychological changes. The prognosis for large tumors of the pituitary gland is significantly worse. The cause of death may be tumor invasion into adjacent brain structures or persistent hypercortisolemia.

Tumors of the adrenal glands

The prognosis for adrenal adenomas is good, but for cancer it is almost always poor, and the average survival rate of patients from the onset of symptoms is approximately 4 years.

Syndrome of ectopic ACTH secretion

In these cases, the prognosis is also poor. Often, the life expectancy of patients is limited to weeks or even days. Some people may be helped by tumor resection or chemotherapy. With ectopic ACTH secretion by benign tumors, the prognosis is better.

Itsenko-Cushing's disease (as well as the syndrome) develops either as a result of prolonged and frequent treatment with hormonal drugs, or occurs against the background of increased synthesis of corticosteroid hormones in the body. In this regard, a certain symptom complex appears.

This pathological condition is also characterized by the fact that the production of adrenocorticotropic hormone is significantly increased. And already a consequence of this is the excessive production of cortisol by the adrenal glands. This chain of hormonal disorders is hypercortisolism or cushingoid. It is necessary to know the main symptoms of Cushing's syndrome in women.

Description of the syndrome

As mentioned above, Cushing's syndrome is characterized by excessive activity of the adrenal glands, as a result of which the body is oversaturated with cortisol. This process is made possible by the control of the pituitary gland, which in turn produces adrenocorticotropic hormone. And already the hypothalamus, which produces liberins and statins, affects the activity of the pituitary gland. It turns out a kind of chain, the violation of which in any of its links and becomes the cause of increased secretion of the adrenal cortex. In connection with all this, Itsenko-Cushing's syndrome develops.

An excess of cortisol in the body provokes the breakdown and breakdown of protein compounds. Because of this, many tissues and structures undergo negative changes. Bones, skin, muscles and internal organs are primarily affected. The further the decay process goes, the more clearly the processes of dystrophy and atrophy in the body are manifested. The metabolism of fats and carbohydrates is also susceptible to disorders.

Women of reproductive age between 25 and 40 are much more likely to experience symptoms of Cushing's syndrome.

Forms of the syndrome

Reasons for development

The main reason	At-risk groups	Symptoms and manifestations
Tumor	Women with malignant tumors.	1-2% of cases of Cushing's syndrome. The reason is a tumor that produces the same hormones. The localization of the tumor can be very different - the gonads, lungs, liver and other organs.
Adrenal adenoma	Women with disorders in the functioning of the endocrine system.	14-18% of the total number of Cushing's syndrome. The reason lies in the tumor process of the adrenal cortex (adenoma and other formations).
Adrenal cancer	In women with a genetic predisposition.	It is very rare when a predisposition to the formation of endocrine tumors is transmitted from parents to a child. Because of this, the likelihood of neoplasms increases, which, in turn, will cause the development of Cushing's syndrome.
Itsenko-Cushing's disease	In women from 20 to 40 years old.	In 80% of cases of patients with Cushing's syndrome, it is Itsenko-Cushing's disease that becomes its cause. Then an excess amount of ACTH is produced by a pituitary microadenoma (a benign tumor of a very small size - up to 2 cm), while Itsenko-Cushing's disease arises in connection with a head injury and infections that adversely affect the brain. This disease can also develop in women immediately after childbirth.
Medicines	In women from 20 to 40 years old.	Taking medications containing glucocorticoid hormones. A vivid confirmation of this is the drugs Prednisolone and Dexamethasone, as well as other drugs used to treat lupus, bronchial asthma and other diseases. If the reason is precisely in the drugs, then it is necessary as soon as possible to reduce the dose of their use as much as possible. This must be done without much prejudice to the treatment of the underlying disease for which they were prescribed.

Symptoms and signs of Cushing's syndrome

Symptoms of Cushing's syndrome in women:

• Obesity. Such a symptom in women is quite simple to visualize, since at the same time its appearance changes greatly: abundant fat deposits on the face, neck, chest and abdomen. Significant weight gain is the very first and most common symptom of Cushing's syndrome. Surprisingly, the arms and legs with such fat deposits are quite thin and can even decrease in volume. Especially significant folds of fat are found on the neck and back of the head. It is extremely rare that there are no fat deposits.
• Another visible symptom is "Moon face" or cushingoid face- bright red complexion, sometimes even with signs of cyanosis.
  
• Symptom of changes in the skin. As a result of the development of the syndrome, the epidermis becomes thin and dry, it peels off strongly and under it the pattern of blood vessels in women becomes clearly pronounced. The skin is so thin and fragile that bruising is possible even as a result of minor trauma - this happens in 40% of cases with this syndrome. This syndrome is characterized by acne and hyperpigmentation in women. Any wounds and injuries heal very poorly; sutures may even sprawl after surgery. The mucous membranes are easily exposed to fungal infections (lichen, stomatitis, and others).
• Stretch marks- also a frequent symptom of the described syndrome (50%). Striae have a purple or red tint and are large (up to several centimeters). However, in women over 40, this phenomenon is quite rare. They usually occur on the abdomen, but they can also occur on the chest, buttocks, armpits, and thighs.
• Hirsutism- This is an excess growth of coarse dark hair on a male basis. This is due to the increased work of the adrenal glands and is observed in about 80% of cases in women with Cushing's syndrome. Hair growth mainly occurs on the face, but it can also affect the chest, shoulders and abdomen. A phenomenon like hirsutism often goes along with acne and even seborrhea in women. It is extremely rare to meet such a symptom of Cushing's syndrome as virilization - the appearance of masculine features in the appearance of a woman. Usually, it manifests itself in adrenal cancer.
• Hypertension- a common symptom associated with Cushing's syndrome (75% of cases). High blood pressure and especially the complications caused by it become a frequent cause of death in such patients.
• Dysfunction of the sex glands. It is also one of the most common symptoms of Cushing's syndrome. In women, it is expressed in. In this condition, 75% of women suffer from infertility or amenorrhea.
• Mental and related disorders- a frequent occurrence in such patients. Increased irritability, depressive states, changes in concentration and memory disorders, symptoms of insomnia - such signs are very common in Cushing's syndrome. Less often - manic manifestations, euphoric states, psychosis with delirium, suicide attempts. In especially severe cases, the volume of the brain may even decrease.
• Sensation muscle weakness takes place in 60% of patients. This symptom is especially noticeable on the muscles of the legs. This is due to the fact that the amount of protein in the body decreases and, as a result, the lean body mass.
• Decreased bone density (osteoporosis) caused by glucocorticoids. It is dangerous because of frequent fractures of ribs, limbs, vertebrae (compression fractures of the vertebrae occur in 15-20%). The first sign is back pain. Bone loss (osteopenia) in a patient of any age is a good reason for a thorough examination of the adrenal glands. Not an X-ray image can reveal "glass vertebrae", this is a phenomenon when individual vertebrae look completely translucent. Together with the atrophic state of the muscles due to this phenomenon, scoliosis often develops in women.
  
• Symptoms of urolithiasis is present in 15% of Cushing's syndrome. This is due to the fact that with an increased concentration of glucocorticoids in the body, an excess of calcium is observed in the urine. Oddly enough, some women were diagnosed with Cushing's syndrome precisely because of his visit to the doctor in connection with complaints of colic in the kidneys.
• Symptoms of Cushing's Syndrome in the form of intense thirst and increased production of urine (polyuria).
• Cardiomyopathy. Hormones negatively affect the middle muscle layer of the heart (myocardium). This can lead to irregular heartbeats and heart failure. This symptom is extremely dangerous and often becomes the cause of death in patients with Cushing's symptom.
  
• Emergence diabetes mellitus steroid type(10-20% of patients with Cushing's syndrome). The pancreas does not play any role in the occurrence of such diabetes mellitus (as in normal cases).

Complications of Cushing's Syndrome

Complications of Cushing's syndrome symptoms in women:

• the transition of the process and symptoms into a chronic form. Without qualified medical treatment in a woman for symptoms of Cushing's syndrome, this is often the cause of death. The chronic process is fraught with strokes, heart failure, serious disorders in the spine.
• an adrenal or adrenaline crisis is manifested by symptoms such as vomiting and abdominal pain, low blood sugar, high blood pressure, and impaired consciousness.
• fungal formations, boils and phlegmon, various processes of a purulent nature - all this may be due to a decrease in the body's resistance to various kinds of infections.
• symptoms of urolithiasis in a woman due to the increased excretion of calcium and phosphates from the body along with urine.

Pregnancy with Cushing's syndrome

The prognosis of the pregnancy rate in combination with such symptoms is extremely unfavorable. Very often, pregnancy terminates spontaneously already at the earliest possible date, or childbirth occurs ahead of time. The fetus greatly lags behind in development, which is why its death is possible during this period.

Miscarriage is associated with adrenal insufficiency in the embryo due to the same pathology in the mother.

It is safe to call pregnancy a factor in the development of complications of the symptoms of this syndrome in a woman. This is so dangerous that there may be an immediate threat to the patient's life.

If, nevertheless, the pregnancy proceeds according to the norms, it is very important to constantly be monitored by specialists and receive courses of symptomatic therapy to maintain the condition of the future woman in labor.

Diagnostics

Methods for diagnosing symptoms of Cushing's syndrome in women:

1. Screening test designed to detect the amount of cortisol in the daily urine dose. If, according to the test results, it turns out that the level of this hormone is increased by 3-4 times, then this is a clear symptom of Cushing's syndrome in women.
2. Small dexamethasone test - this study can accurately confirm or deny the endogenous nature of the symptoms of the syndrome in a woman. In the course of this study, in a healthy person, after taking the appropriate drug (used in the study), the concentration of cortisol in the blood will decrease by 2 times. If there is Cushing's syndrome, then such a decrease is not observed.
3. Large dexamethasone test (shown with a positive small test). She is able to accurately diagnose both Itsenko-Cushing's disease itself and the syndrome. The difference with a small sample is only in the amount of the injected drug - it is much larger. A 50% decrease in the level of cortisol in the blood means Itsenko-Cushing's disease, and the absence of any changes is a syndrome.
4. Blood and urine tests. A significant increase in hemoglobin, cholesterol and erythrocytes is noted in the blood. In the course of laboratory research, a high content of oxycorticosteroids and a low content of ketosteroids are noted.
5. MRI or CT of the adrenal glands to determine the location of tumors and other pathological processes is necessary to prescribe adequate treatment for a woman for the symptoms of Cushing's syndrome.
6. X-rays to detect symptoms of spinal deformities, rib fractures, and kidney stones in women.
7. An ECG is necessary to determine electrolyte processes and disturbances in the work of the heart.

Treating symptoms in a woman

Methods for treating women with symptoms of Cushing's syndrome:

1. Medical treatment. For this, drugs are used that act on the pituitary gland in such a way that there is a decrease in the production of adrenocorticotropic hormone, the high secretion of which is the cause of the syndrome. Simultaneously with such therapy, symptomatic treatment in a woman of the main symptoms of Cushing's syndrome is necessarily shown - a decrease in blood sugar, blood pressure. Drug treatment for symptoms of Cushing's syndrome in women necessarily includes taking antidepressants and drugs that increase bone density. Prescribing drugs is carried out only by a doctor after considering the results of the research and the symptoms themselves.
2. Surgical treatment of symptoms of Cushing's syndrome. If Itsenko-Cushing's disease is a consequence of a pituitary adenoma, then it is removed surgically. This is perhaps the most effective and, in fact, the only method to fix the problem. The operation is performed in the presence of clear tumor boundaries and the result of such an intervention is very good.
3. Radiation therapy is an effective method of dealing with the syndrome, which gives a good chance of recovery. Such treatment of the symptoms of Cushing's syndrome in women can be carried out in conjunction with surgical excision of the neoplasm.

Cushing's syndrome prognosis

In the absence of the necessary and timely treatment, the probability of death is 40-50% of all cases of Cushing's syndrome. This is due to irreversible changes in the patient's body.

If there are malignant neoplasms in Cushing's syndrome that caused this condition, then the prognosis cannot be good. Only in 20-25% of cases, after the operation and appropriate postoperative treatment, a more or less positive result is possible.

If the tumor in Cushing's syndrome was of a benign nature, then after its operative excision, a positive trend is observed in almost 100% of cases.