Cushing's syndrome: causes and treatment

Cushing's syndrome is a condition of chronic excess cortisol in the blood. It can occur due to excessive production of adrenocorticotropic hormone by the pituitary gland (known as Cushing's disease), ectopic production of adrenocorticotropic hormone by a tumor outside the pituitary gland, autonomous secretion of cortisol by the adrenal cortex, or as a result of external glucocorticoid medication. All variants result in "hypercorticism"—a multisystem disorder affecting metabolism, the cardiovascular system, bones, muscles, skin, immunity, and the psyche. Early diagnosis and complete elimination of the source of excess cortisol are key to reducing complications and mortality. [1]

Modern diagnostics rely on several "screening" laboratory tests confirming excess cortisol, followed by determination of the cause: adrenocorticotropic hormone dependence or autonomous cortisol secretion by the adrenal glands. This is followed by imaging (magnetic resonance imaging of the pituitary gland, computed tomography, and positron emission tomography) and, if necessary, invasive methods, such as blood sampling from the inferior petrosal sinuses. This algorithm is thoroughly standardized and supported by major clinical guidelines. [2]

In recent years, there have been significant advances in treatment. Classic methods remain fundamental: microinvasive endoscopic surgery through the nose to the pituitary gland for Itsenko-Cushing's disease, removal of the tumor source of ectopic adrenocorticotropic hormone production, and adrenalectomy for autonomous cortisol secretion. However, drug treatment has also expanded: new cortisol synthesis inhibitors have been approved, and the indications for glucocorticoid receptor antagonists have been clarified; in 2025, US regulatory authorities expanded the indications for osilodrostat to cover all forms of endogenous hypercortisolism when surgery is impossible or has not been curative. [3]

With timely etiotropic therapy, the prognosis improves; however, even after cortisol levels are normalized, some risks persist for years: an increased risk of thrombosis, cardiovascular events, infections, and a decreased quality of life. Therefore, all patients are recommended to undergo long-term follow-up with a structured plan for the prevention and secondary prevention of complications. [4]

Code according to ICD-10 and ICD-11

In the International Classification of Diseases, Tenth Revision, Cushing's syndrome is coded in group E24. Subcodes allow for the identification of the source of hypercortisolism: Cushing's disease (adrenocorticotropic hormone-dependent pituitary form), drug-induced hypercortisolism, ectopic adrenocorticotropic hormone syndrome, and other and unspecified forms. This is important for routing and statistics, but the codes do not replace clinical verification of the cause. [5]

In the eleventh version of the classification, Itsenko-Cushing syndrome is placed in the group "Disorders of the Adrenal Glands or Adrenal Hormonal System" with the code 5A70 and subcodes for other specified variants. In practice, a combination of the syndrome code and the specific cause code (e.g., pituitary tumor, neuroendocrine tumor of the lung, or adrenal cortex tumor) is often used, which improves the accuracy of medical information. [6]

Table 1. ICD-10 and ICD-11 codes for Itsenko-Cushing syndrome

Classification	Main code	Subcodes and decoding
ICD-10	E24	E24.0 - Itsenko-Cushing's disease (pituitary form); E24.1 - Nelson's syndrome; E24.2 - drug-induced hypercortisolism; E24.3 - ectopic adrenocorticotropic hormone syndrome; E24.4 - alcohol-induced "pseudo-Cushing"; E24.8 - other forms; E24.9 - unspecified
ICD-11	5A70	5A70 - Itsenko-Cushing syndrome; 5A70.Y - other specified forms; if necessary, additional cause codes (e.g., pituitary tumors, adrenal cortex tumors, neuroendocrine tumors)

Epidemiology

Cushing's syndrome is a rare disorder. For all endogenous forms, the estimated incidence is approximately 0.7 to 2.4 new cases per 1,000,000 people per year; children account for approximately 10% of all cases. Women are more commonly affected than men, especially in the pituitary form, which is associated with biological and diagnostic factors. [7]

In adults, adrenocorticotropic hormone dependence predominates among the causes: pituitary microdenoma and Itsenko-Cushing's disease account for the majority of cases, while ectopic adrenocorticotropic hormone production is less common but often more severe due to rapid metabolic disturbances. Autonomous adrenal cortex tumors are most often diagnosed as incidentalomas; mild autonomous cortisol elevation is referred to as "mild autonomous cortisol secretion," which is associated with increased cardiometabolic risk. [8]

Iatrogenic, or drug-induced, hypercorticism is statistically more common than all endogenous forms, as glucocorticoids are widely used in rheumatology, pulmonology, dermatology, and transplantation. This includes systemic, inhaled, topical, intra-articular, and epidural forms. Identifying the iatrogenic source is a mandatory first step in any diagnostic algorithm. [9]

Even after successful treatment, some patients continue to experience excess morbidity and an increased risk of adverse outcomes—stroke, thrombosis, sepsis—compared to the general population. This requires long-term monitoring, aggressive risk factor management, and individualized rehabilitation plans. [10]

Table 2. Epidemiology of endogenous hypercorticism (approximately)

Indicator	Grade
Incidence of all endogenous forms	0.7-2.4 cases per 1,000,000 per year
Proportion of children	about 10%
Predominance of women in the pituitary form	expressed
Iatrogenic hypercorticism	the most common "real" source in the clinic
Long-term "excess" morbidity after remission	persists for years

Note: Specific numbers depend on the accounting methodology and region. [11]

Reasons

The causes of Itsenko-Cushing's syndrome are classified according to their dependence on adrenocorticotropic hormone. Dependent forms include Itsenko-Cushing's disease (pituitary adenoma producing adrenocorticotropic hormone) and ectopic secretion of adrenocorticotropic hormone by neuroendocrine tumors (e.g., bronchial carcinoids, less commonly thymus, pancreas, or small cell lung cancer). Independent forms include adrenal cortex adenoma, adrenal cortex carcinoma, bilateral macronodular hyperplasia, and primary pigmented micronodular hyperplasia. [12]

In recent years, the genetics of some forms has been clarified. In bilateral macronodular adrenal hyperplasia, pathogenic variants in the ARMC5 gene are often detected; in primary pigmented micronodular disease, PRKAR1A mutations within the Carney complex are found in some patients. This knowledge is important for screening relatives and long-term prognosis.

A separate, large category is drug-induced hypercorticism, when external administration of glucocorticoids leads to the clinical picture of Itsenko-Cushing's syndrome. The source can be not only tablets and injections, but also inhalers, creams, eye drops, "folk remedies," and dietary supplements containing undeclared steroids. An assessment of all potential sources is mandatory at the first appointment. [13]

There are also rare hereditary syndromes with hypercortisolism: Carney complex, McCune-Albright syndrome, and multiple endocrine neoplasias. These occur in small numbers, but for young patients, those with multiple tumors, or those with a familial pattern of the disease, genetic testing is advisable.

Table 3. Main causes of Itsenko-Cushing syndrome

Category	Examples
Adrenocorticotropic hormone dependent	Pituitary adenoma; ectopic secretion of adrenocorticotropic hormone by a neuroendocrine tumor (bronchial carcinoid, thymus, pancreas, small cell lung cancer)
Adrenocorticotropic hormone independent	Adrenal cortical adenoma; adrenal cortical carcinoma; bilateral macronodular hyperplasia (often variants in ARMC5); primary pigmented micronodular disease (PRKAR1A mutations)
Iatrogenic	Any form of glucocorticoid administration: systemic, inhalation, local, intra-articular, etc.
Hereditary syndromes	Carney complex, McCune-Albright syndrome, multiple endocrine neoplasia

Risk factors

The main risk factor for the "exogenous" variant remains long-term or high-dose use of glucocorticoids in any dosage form. The risk is increased by combination forms, lack of monitoring for side effects, and drug interactions that affect the metabolism of dexamethasone and cortisol. [14]

For endogenous forms, specific modifiable risk factors are less well known. However, genetic variants, including alterations in the ARMC5 and PRKAR1A genes, increase the likelihood of developing autonomous cortisol secretion. A family history of hormonally active tumors or multiple endocrine tumors should prompt genetic counseling.

Certain behavioral and medical conditions often mimic Cushing's syndrome ("pseudo-Cushing"): chronic alcohol abuse, severe depression, obesity, obstructive sleep apnea, and uncontrolled diabetes. These are not risk factors for true hypercortisolism, but they complicate diagnosis and can lead to overdiagnosis. [15]

Finally, medical interventions: pituitary radiation therapy and repeat surgeries can alter hormonal profiles and obscure or complicate further diagnosis and treatment. When planning therapy, the cumulative "burden" of interventions and their long-term consequences should be considered. [16]

Table 4. Risk factors and "confounding factors"

Group	Examples and comments
Iatrogenic	Long-term use of glucocorticoids (any form)
Genetic	ARMC5 (bilateral macronodular hyperplasia), PRKAR1A (Carney complex) variants
Pseudo-Cushing	Alcohol use disorder, severe depression, obesity, obstructive sleep apnea, uncontrolled diabetes mellitus
Iatrogenic consequences of treatment	Radiation therapy of the pituitary gland, repeated surgeries - affect hormonal tests and tactics

Pathogenesis

The underlying mechanism is chronic tissue exposure to excess cortisol and the loss of the normal circadian rhythm of secretion. Cortisol has a catabolic effect on muscle and bone, increases gluconeogenesis and insulin resistance, promotes fat redistribution, increases blood pressure, and activates prothrombotic mechanisms. In adrenocorticotropic hormone-dependent forms, androgen secretion is additionally stimulated, which is significant in women. [17]

In the pituitary form, hypersecretion of adrenocorticotropic hormone causes bilateral hyperplasia of the adrenal cortex. With ectopic adrenocorticotropic hormone production, hormone levels are high, symptoms progress rapidly, and hypokalemic alkalosis often develops due to the mineralocorticoid effect of excess cortisol. In autonomous adrenal cortex tumors, cortisol is secreted independently of adrenocorticotropic hormone, leading to its suppression. [18]

Genetic forms are associated with disruption of intracellular signaling of the adenylate cyclase system and receptors, leading to autonomous cortisol secretion in the adrenal cortex. In some cases of bilateral macronodular hyperplasia, "foreign" regulatory receptors are detected, which trigger cortisol synthesis in response to atypical stimuli (e.g., meals).

The consequences of hypercortisolism are systemic: vascular remodeling and accelerated atherosclerosis, osteoporosis and fractures, sarcopenia, insulin resistance and diabetes mellitus, neuropsychiatric disorders, and immunosuppression with an increased risk of infection and thrombosis. Even after healing, some damage regresses slowly or incompletely, requiring long-term secondary prevention. [19]

Table 5. Where does excess cortisol hit?

System	Key effects of excess cortisol
Cardiovascular	Increased blood pressure, dyslipidemia, endothelial dysfunction, increased risk of thrombosis
Skeleton and muscles	Osteoporosis, vertebral fractures, proximal myopathy, sarcopenia
Metabolism	Insulin resistance, diabetes mellitus, centripetal obesity
Leather	Thin skin, easy bruising, purple wide stretch marks
Nervous system and psyche	Depression, anxiety, cognitive impairment
Immunity	Immunosuppression, susceptibility to infections

Symptoms

The clinical picture is variable: from the "classic" triad (moon facies, fatty deposits above the collarbones and in the neck area, wide purple striae) to vague manifestations with mild autonomous cortisol secretion. More specific for true hypercorticism are easy bruising, pronounced muscle weakness of the proximal regions, a bright vascular network on the face, wide purple striae more than 1 centimeter wide, and, in children, weight gain against the background of growth retardation. [20]

The frequency of individual features varies across different series, but large reviews indicate a high prevalence of obesity, hypertension, skin changes, myopathy, and carbohydrate metabolism disorders. It is important to evaluate not just individual features, but their combination and dynamics over time—serial photographs and questioning about "minor" changes (e.g., height loss due to compression fractures) are significantly helpful. [21]

Mental and cognitive symptoms are underestimated: depression, anxiety, mood lability, sleep and attention disorders are common and may precede somatic symptoms, which is why patients are observed by psychiatrists for a long time without hormonal examination. [22]

In patients with ectopic production of adrenocorticotropic hormone, symptoms develop rapidly, often with severe hypokalemia and pronounced metabolic shifts; in autonomous tumors of the adrenal cortex, manifestations develop gradually and are often first detected by changes in bone density or accidentally on computed tomography. [23]

Table 6. Prevalence of individual clinical signs (ranges for large series)

Sign	Estimated frequency
Weight gain/obesity	81-97%
Arterial hypertension	68-90%
Round "moon" face	88-92%
Thin skin, slight bruising	21-84%
Purple wide striae	35-84%
Proximal muscle weakness	40-70%
Carbohydrate metabolism disorders	43-50%
Fractures	21-56%
Infections	14-25%
According to the summary data of the endocrinology review textbook. [24]

Classification, forms and stages

Classically, adrenocorticotropic hormone-dependent forms (Itsenko-Cushing's disease, ectopic adrenocorticotropic hormone secretion) and independent forms (adenoma, adrenal cortex carcinoma, bilateral hyperplasia) are distinguished. Iatrogenic hypercorticism is considered separately. This approach reflects the logic of diagnosis and treatment. [25]

"Cyclic" hypercortisolism is distinguished, when phases of elevated cortisol levels alternate periodically with normal or low levels. This complicates diagnosis, can produce false-negative tests, and requires serial measurements, sometimes even hair cortisol analysis, to retrospectively assess changes. New reviews discuss standardizing criteria, as the frequency of cyclicity has been underestimated. [26]

For adrenal incidentalomas, the term "mild autonomous cortisol secretion" is used, where cortisol levels are not completely reduced after a low-dose dexamethasone test, and the clinical picture is subtle, but the cardiometabolic risks are higher. This area has received separate updated guidelines in Europe. [27]

There is no standardized "stage" for severity, but in practice, the degree of hypercortisolism is assessed based on the level of free cortisol in the urine, the level of cortisol at night, the severity of clinical manifestations, and the number of complications. This helps determine the order of treatment methods and plan for complication prevention. [28]

Table 7. Classification by the source of hypercorticism

Base	Forms
Adrenocorticotropic hormone dependence	Itsenko-Cushing's disease (pituitary adenoma), ectopic secretion of adrenocorticotropic hormone
Independence from adrenocorticotropic hormone	Adenoma, carcinoma of the adrenal cortex; bilateral hyperplasia (macronodular, micronodular)
Special options	Cyclic hypercortisolism; mild autonomic cortisol secretion
Artificial reasons	Drug-induced hypercorticism

Complications and consequences

The main risks are cardiovascular events (heart attack, stroke), venous thrombosis and pulmonary embolism, severe infections, fractures, and long-term cognitive and mental impairment. The risk of thrombosis in patients with active hypercortisolism is several times higher than in the general population and remains elevated after surgery. This requires well-developed thromboprophylaxis regimens in the perioperative and early postoperative periods. [29]

Even after complete biochemical remission, excess morbidity and mortality can persist for years, especially with prolonged time to cure and multiple interventions. An "earlier diagnosis, earlier treatment" strategy is directly linked to long-term prognosis. [30]

Cortisol withdrawal syndrome is common postoperatively: after a sharp drop in hormone levels, patients experience severe weakness, pain, and depressive symptoms. This requires careful hydrocortisone replacement therapy and a slow dose reduction, monitored by symptoms and laboratory tests. [31]

A special case is the progression of a corticotropic pituitary tumor after bilateral adrenalectomy (previously called Nelson's syndrome). European experts propose the more precise term "progression of a corticotropic tumor after bilateral adrenalectomy," which reflects the biology of the process and helps standardize criteria. [32]

Table 8. Common complications and what to do about them

Complication	Risk/Note	Tactics
Venous thrombosis and thromboembolism	The risk is several times higher in active hypercorticism and in the first months after treatment.	Individualized thromboprophylaxis with low molecular weight heparins: a dynamic review
Cardiovascular events	The risk persists after remission	Strict control of blood pressure, lipids, glucose, and body weight
Infections	Immunosuppression and catabolism	Vaccination, early diagnosis, caution with invasive procedures
Fractures	High incidence of compression fractures	Densitometry, calcium and vitamin D, anti-resorptive therapy when indicated
Mental disorders	Often saved	Psychoeducation, psychotherapy, and, if necessary, pharmacotherapy

When to see a doctor

You should consult a doctor if you experience a combination of centripetal weight gain, wide purple striae on the trunk, easy bruising, a "moon-shaped" facies, proximal muscle weakness, hypertension, and carbohydrate metabolism disorders. Rapid weight gain and deterioration in appearance over several months are particularly concerning. [33]

Seek immediate medical attention if you experience severe muscle weakness, sudden increases in blood pressure, hypokalemia, increased frequency of infections, or if you are already taking any glucocorticoids and notice signs resembling Cushing's syndrome. Unintentional steroid withdrawal is dangerous; a dose reduction plan should be developed by a doctor. [34]

If a child experiences weight gain with slow growth, stretch marks, acne, or frequent fractures, these are reasons to seek targeted testing for hypercorticism from a pediatric endocrinologist. Pediatric cases are rare, but require particularly prompt referral to a specialized center. [35]

People with adrenal "incidental" findings on CT or MRI are also advised to have cortisol secretion assessed even in the absence of overt symptoms, as mild autonomic cortisol secretion increases cardiometabolic risk.[36]

Diagnostics

Step 1. Exclude external glucocorticoids. All forms of administration are clarified: tablets, injections, inhalers, creams, eye drops, intra-articular injections, and dietary supplements. Without this, further testing is pointless. [37]

Step 2. Confirm excess cortisol using at least two different screening tests. These include: overnight salivary cortisol levels, 24-hour free urinary cortisol in two or more collections, and a 1-milligram dexamethasone challenge (the criterion is post-challenge cortisol levels above 1.8 micrograms per deciliter, which corresponds to 50 nanomoles per liter). Each test has limitations, so combining them improves accuracy. [38]

Step 3. Determine adrenocorticotropic hormone dependence. Morning adrenocorticotropic hormone is measured: low levels indicate autonomous cortisol secretion by the adrenal glands; normal or elevated levels indicate adrenocorticotropic hormone dependence. Next, a branching analysis is performed using visualization and dynamic tests. [39]

Step 4. Visualization and invasive methods. If the pituitary form is suspected, high-field magnetic resonance imaging of the pituitary gland with thin sections is performed. If the adenoma is not visible or is smaller than 6-10 millimeters, to accurately differentiate a pituitary source from an ectopic one, blood is drawn from the inferior petrosal sinuses and adrenocorticotropic hormone is measured before and after the administration of corticotropin-releasing factor or desmopressin. A sinus-to-periphery adrenocorticotropic hormone ratio of at least 2.0 at rest or at least 3.0 after stimulation is considered diagnostic; the use of concomitant prolactin measurement helps confirm the correctness of catheterization. [40]

Step 5. Search for an ectopic source. This begins with a CT scan of the chest and abdomen; positron emission tomography with gallium-68-DOTATATE, which is sensitive to neuroendocrine tumors and helps detect "hidden" lesions, is increasingly being used. Other radiopharmaceuticals are used if necessary. [41]

Step 6. In complex cases. In cases of "cyclical" catarrh, serial overnight salivary tests, repeated urine collections, and hair cortisol and cortisone analysis are performed, allowing one to "see" a retrospective curve of excess secretion by centimeters of hair growth. This approach has proven useful specifically in cases of intermittent catarrh. [42]

Table 9. Screening for hypercortisolism: what, how much, and how to interpret

Test	What is considered "positive"	Comments
Nocturnal salivary cortisol (2 pm)	Above the laboratory reference range	High sensitivity; liquid chromatography with tandem mass spectrometry is preferred; impaired by shift work, stress, and smoking
Daily free cortisol in urine (2-3 collections)	Above the upper limit of normal	False negative in mild forms, false positive in renal failure
Test with 1 mg dexamethasone	Morning cortisol > 1.8 mcg/dL (50 nmol/L)	The result is affected by estrogens and drugs that accelerate the metabolism of dexamethasone (for example, some anticonvulsants)
Nocturnal serum cortisol	Above reference values	Complements, but is less commonly used due to its invasiveness

Table 10. Differentiation of dependent and independent forms and localization methods

Step	Target	Key criteria
Morning adrenocorticotropic hormone	Assess adrenocorticotropic hormone dependence	Low - autonomous cortisol secretion; normal/high - dependence
Magnetic resonance imaging of the pituitary gland	Search for adenoma	Microadenoma is often < 6-10 mm
Blood sampling from the inferior petrosal sinuses	Distinguish between pituitary and ectopic forms	Sinus/periphery ratio ≥ 2.0 at rest or ≥ 3.0 after stimulation; correction for prolactin improves accuracy
Search for an ectopic source	Localize the neuroendocrine tumor	Computed tomography, positron emission tomography with gallium-68-DOTATATE

Differential diagnosis

"Pseudo-Cushing's syndrome" is a collective term for conditions with clinical and laboratory findings resembling hypercortisolism, without autonomous cortisol production. These include severe depression, alcohol abuse, obesity, obstructive sleep apnea, and poorly controlled diabetes. When the underlying cause is addressed, the hormonal profile normalizes. Dynamic testing, serial overnight salivary samples, and hair analysis help differentiate these conditions from the true syndrome. [43]

Distinguishing between pituitary and ectopic production of adrenocorticotropic hormone is a separate issue. Magnetic resonance imaging does not always detect microadenomas, and small neuroendocrine tumors can "hide." Therefore, the gold standard remains blood sampling from the inferior petrosal sinuses with pharmacological stimulation, which allows for highly accurate identification of the source. In recent years, the use of parallel prolactin measurement to verify the accuracy of sampling has been discussed. [44]

Low adrenocorticotropic hormone levels, visualization of adrenal nodules, and the absence of cortisol suppression in a dexamethasone test help differentiate autonomous from dependent adrenal cortisol secretion. In adrenal incidentalomas, it is important to assess "mild autonomous cortisol secretion," as even slight excesses are associated with risks. [45]

In some patients, hypercortisolism is cyclical. If test results are inconsistent and the clinical picture is compelling, serial overnight salivary tests and retrospective hair analysis are helpful. Performing invasive and imaging studies outside the hypercortisolism phase is a mistake: this increases the risk of incorrect localization and unnecessary surgery. [46]

Table 11. How does true syndrome differ from "pseudo-Cushing's"

Sign	True hypercorticism	Pseudo-Cushing
Nighttime saliva tests	Steadily elevated	Unstable causes that normalize after treatment
Dexamethasone test	No suppression	There is often suppression
Hair cortisol analysis	Reflects a long-term increase	Normalizes during remission of the initial condition
Dynamics	Progressing	Regresses after treatment of the underlying disease

Treatment

The first-line treatment for Itsenko-Cushing's disease remains endoscopic transnasal pituitary surgery with selective removal of the adenoma. In the hands of experienced neurosurgeons, early remission is achieved in most patients, although the success rate varies widely across different series due to differences in remission criteria, adenoma size, and invasion. Relapses are possible months or years later, so long-term monitoring of nocturnal salivary samples, urinary free cortisol, and, if necessary, dynamic testing is necessary. [47]

If surgery is not indicated or does not result in remission, radiation therapy to the pituitary gland is used: fractionated radiation therapy or stereotactic radiosurgery. These approaches are effective as a "delayed" option with a gradual onset of effect over months; they are often combined with drug-based cortisol control. The choice depends on the size and location of the adenoma tissue, the distance to the optic pathways, and the patient's overall condition. [48]

Ectopic adrenocorticotropic hormone syndrome is treated by resection of the primary neuroendocrine tumor and its metastases, if technically feasible. Computed tomography and positron emission tomography with gallium-68-DOTATATE are used for detection and staging; if inoperability is considered, drug control of cortisol excess and antitumor therapies are discussed. Rapid cortisol control is especially important in severe hypokalemia and metabolic decompensation. [49]

In cases of autonomous cortisol secretion by the adrenal cortex, removal of the corresponding adrenal gland is indicated in cases of clinically significant hypercortisolism or severe complications. In cases of mild autonomous cortisol secretion, particularly in patients at high surgical risk, the decision is individualized, taking into account diabetes, hypertension, osteoporosis, and cardiovascular events. After unilateral adrenalectomy, temporary hydrocortisone replacement therapy is often required while the hypothalamic-pituitary-adrenal axis recovers. [50]

Pharmacotherapy has become more precise. Steroidogenesis inhibitors reduce cortisol synthesis: ketoconazole, metyrapone, osilodrostat, and levoketoconazole. Osilodrostat blocks the enzyme 11-betahydroxylase; in 2025, the drug's indications were expanded in the United States to cover all forms of endogenous hypercorticism when surgery is impossible or has not provided a cure. It was previously approved for Itsenko-Cushing's disease and for endogenous hypercorticism in a number of countries. Levoketoconazole is approved for the treatment of endogenous hypercortisolism in adults when surgery is impossible or ineffective; both drugs require monitoring of liver function, an electrocardiogram, and individual dose titration. [51]

Of the centrally acting drugs, "anti-pituitary" agents are used: pasireotide (a somatostatin analogue with affinity for the type 5 receptor) is capable of suppressing the secretion of adrenocorticotropic hormone in Itsenko-Cushing's disease; the dopamine receptor agonist cabergoline is used as monotherapy in some patients or in combination. The effect is heterogeneous, but these options are useful as a "bridge" to surgery or after radiation therapy, when the latter's effect is realized gradually. [52]

Glucocorticoid receptor antagonists block the effects of cortisol on tissue. Mifepristone is indicated for the treatment of hyperglycemia in adults with Cushing's syndrome when surgery is impossible or ineffective. When used, blood cortisol levels do not reflect the clinical response, so monitoring is based on clinical criteria and carbohydrate metabolism parameters. Selective receptor modifiers are being developed, but their registration status as of 2025 varies by country. [53]

In real-world practice, drug combinations (e.g., a steroidogenesis inhibitor plus cabergoline or pasireotide) are widely used to achieve and maintain normocortisolemia. In severe hypercorticism, intravenous etamidate is used in hospital settings to rapidly control cortisol levels, with subsequent transition to oral regimens. For corticosteroid-secreting adrenal cancer, mitotane with antitumor combinations remains the mainstay of therapy; cortisol monitoring with mitotane is complex due to pharmacodynamic properties, so clinical evaluation and specialized laboratory panels are used as a guide. [54]

Bilateral adrenalectomy is a salvage procedure for intractable hypercortisolism when the source cannot be eliminated. It provides immediate relief from excess cortisol, but it leads to lifelong adrenal insufficiency, requiring ongoing replacement therapy and risking progression of corticotropic tissue in the pituitary gland. The choice of this approach requires careful discussion with the patient and the specialist team. [55]

Periprocedural management is a separate issue. Evidence is accumulating today in favor of a more "gentle" administration of glucocorticoids around pituitary and adrenal surgeries, with early assessment of morning cortisol and selective replacement therapy. In patients with active hypercortisolism and in the early postoperative period, a strategy for preventing venous thrombosis should be developed, beginning at diagnosis and continuing for several weeks and months after remission. [56]

Table 12. Drugs for cortisol control: guidelines for selection

Class	Example	Mechanism	Where it is especially appropriate	Key points
Steroidogenesis inhibitors	Osilodrostat	11-betahydroxylase enzyme unit	Itsenko-Cushing's disease and other endogenous forms when surgery is impossible or unsuccessful	Dose titration, electrocardiogram monitoring; expanded indications in the US from 2025
Steroidogenesis inhibitors	Levoketoconazole	Reduces cortisol synthesis	Endogenous forms when surgery is impossible	Monitoring liver function tests and drug interactions
Steroidogenesis inhibitors	Metyrapone, ketoconazole	Various enzymes of corticosteroidogenesis	Bridge to surgery, combined schemes	Dose selection, monitoring of electrolytes and liver function tests
Centrally acting drug	Pasireotide	Suppresses the secretion of adrenocorticotropic hormone	Itsenko-Cushing's disease	Glycemic control, gallbladder
Dopaminergic agent	Cabergoline	Suppresses the secretion of adrenocorticotropic hormone	Complement to other strategies	Variable response
Glucocorticoid receptor antagonist	Mifepristone	Blocks the action of cortisol on tissues	With severe hyperglycemia	Assessing the effect by clinical findings, not cortisol levels
Adrenergic blocker	Mitotane	Toxic effect on the adrenal cortex	Corticosteroid-secreting carcinoma	Complex monitoring, drug interactions

Table 13. Operations and expected results

Situation	Operation	Expected early remission	Comment
Itsenko-Cushing's disease	Endoscopic transnasal adenomectomy	In different series approximately 65-90%	Dependent on size, invasion, surgeon's experience; long-term monitoring required
Autonomic secretion by the adrenal glands	Unilateral adrenalectomy	High with adenoma	Often temporary replacement therapy
Ectopic secretion	Removal of the primary lesion	Depends on the location and resectability	Combination treatment is often required
Uncontrolled hypercorticism	Bilateral adrenalectomy	Immediate elimination of excess	Lifelong replacement therapy; risk of corticotropic tissue progression

Prevention

Prevention of drug-induced hypercorticism involves the rational use of glucocorticoids at the minimum effective dose and for the shortest possible duration, a tapering plan, patient education, and regular review of indications. It is important to monitor for hidden sources: topical medications, inhalers, ophthalmic drops, and "alternative" agents. [57]

Prevention of complications of active hypercortisolism includes early thromboprophylaxis in hospitalized patients and a well-thought-out strategy around surgery, vaccination, active correction of blood pressure, glucose, and lipids, osteoporosis prevention, weight loss, and treatment of sleep apnea. These measures improve short-term and long-term outcomes. [58]

After recovery, secondary prevention should be continued: monitoring cardiovascular risk factors, bone density, mental health, and thyroid function (there is evidence of a higher incidence of autoimmune diseases after successful treatment). Individualized monitoring plans should be long-term. [59]

For families with identified genetic variants, genetic counseling and screening of relatives at early stages are appropriate, which allows for earlier detection of autonomous cortisol secretion and reduces the burden of complications.

Table 14. Brief information on prevention

Direction	What to do
Iatrogenic hypercorticism	Minimum effective doses, clear withdrawal plan, consideration of all forms
Thrombosis	Prevention during hospitalization and around operations, individual risk assessment
Bone and muscle	Calcium, vitamin D, densitometry, physical activity
Cardiovascular risks	Blood pressure, lipids, glucose, weight, sleep apnea
Vaccination	Routine immunization taking into account immunosuppression

Forecast

The prognosis is largely determined by the speed of diagnosis and the completeness of elimination of the source of excess cortisol. In patients cured by a single selective pituitary surgery, long-term survival is comparable to the general population; with a protracted course and multiple interventions, the overall risk of death is higher, especially from cardiovascular causes. [60]

Even in remission, excess morbidity persists: strokes, thrombosis, and sepsis are more common than in the general population. This emphasizes the value of aggressive risk factor management, rehabilitation, physical training, psychotherapy, and systematic monitoring by an endocrinologist. [61]

The risk of recurrence after successful pituitary surgery varies widely depending on the criteria for remission and the duration of follow-up; half of the recurrences may occur after more than 5 years, so "lifelong control" is a reasonable standard. An early sign of recurrence is an increase in nocturnal salivary cortisol. [62]

In cases of ectopic adrenocorticotropic hormone production, the prognosis is determined by the biology of the primary tumor. In cases of corticosteroid-secreting adrenal carcinoma, outcomes depend on the stage, the possibility of radical resection, and the effectiveness of systemic therapy, where mitotane remains the cornerstone. [63]

FAQ

Is it curable? In many cases, yes: in Cushing's disease, selective surgery by an experienced team leads to remission in most patients, and in the case of an adrenal adenoma, its removal eliminates excess cortisol. However, long-term monitoring is required due to the risk of recurrence. [64]

If surgery is not possible, what next? Medication strategies that reduce cortisol synthesis or block its action are used; in 2025, the indications for osilodrostat were expanded to cover all endogenous forms when surgery is impossible or unsuccessful. Combinations of drugs are often used. [65]

Why do I have "normal" morning cortisol levels, but people are talking about hypercortisolism? Cushing's syndrome disrupts the circadian rhythm, so overnight salivary tests and dexamethasone tests are more sensitive than a single morning assessment. In mild and "cyclical" forms, serial measurements and hair analysis are needed. [66]

Are surgeries dangerous for this syndrome? Risks are increased due to hypercoagulability, hypertension, diabetes, and infections. Therefore, patients are prepared in advance, protected against thrombosis and infection, and meticulously managed in the postoperative period. [67]

When can I expect to feel better after treatment? Hormones return to normal quickly, but tissues "catch up" slowly: muscles and bones require months, sometimes years. Cortisol withdrawal syndrome, with a temporary deterioration in well-being, is possible—this is a normal recovery phase. [68]

Is it possible to achieve a permanent cure with medication? Some patients achieve stable cortisol control without surgery, but drug therapy is usually considered a bridge to the underlying cause or as a long-term strategy if surgery is not indicated or possible. The decision is individual. [69]

Why was I prescribed an inferior petrosal sinus blood test? This test differentiates between a pituitary source of adrenocorticotropic hormone and an ectopic source when magnetic resonance imaging (MRI) is inconclusive. It is highly accurate when performed correctly and interpreted correctly. [70]