Hypercortisolism
(Cushing syndrome: general overview)

Hypercortisolism is a state in which the body is exposed chronically and inappropriately to excessive cortisol or glucocorticoids with cortisol-like activity, with loss of the physiological circadian and pulsatile variability of secretion. The result is a continuous signal that reshapes energy homeostasis, cardiovascular function, immune and inflammatory balance, bone and muscle turnover, skin biology and neuropsychiatric function. Clinically, this condition corresponds to the spectrum of Cushing syndrome, in which the magnitude of hormonal excess and the duration of exposure determine a continuum of manifestations ranging from overt disease to subtler phenotypes dominated by cardiometabolic comorbidities and frailty.

From an etiological perspective, there are two major groups. The first is iatrogenic hypercortisolism, caused by glucocorticoid use, in which the hormonal excess is external and the hypothalamic-pituitary-adrenal axis is suppressed by feedback, with specific diagnostic and therapeutic implications. The second group is endogenous hypercortisolism, in which cortisol production is autonomous. It may be ACTH-dependent when the secretory drive arises from ACTH excess, most commonly due to a pituitary adenoma in Cushing disease, or ACTH-independent when the adrenal gland produces cortisol without ACTH stimulation and ACTH is suppressed. Although these forms share the same biological endpoint, they differ in clinical patterns, test interpretation, localisation strategies and the consequences for recovery of the axis after treatment.

The epidemiology of hypercortisolism depends primarily on whether exposure to prescribed glucocorticoids is included. Because glucocorticoids are used across a broad spectrum of inflammatory, autoimmune, allergic, respiratory, dermatological and oncological diseases, iatrogenic hypercortisolism is the most common form encountered in clinical practice. Risk is determined not only by the daily dose but also by the cumulative exposure, duration, drug potency, route of administration, combination of different formulations and pharmacological interactions that increase bioavailability. Even in the absence of high systemic doses, prolonged or repeated exposure may produce a clinically significant phenotype, with a gradient that varies according to individual glucocorticoid receptor sensitivity and the metabolic determinants of clearance.

Endogenous hypercortisolism is rare but highly clinically relevant because it is associated with increased morbidity and mortality and is frequently diagnosed late. Its rarity makes it more likely that individual signs will be interpreted as unrelated common conditions, whereas the syndrome becomes apparent when the combined progression of hypertension, metabolic dysfunction, musculoskeletal fragility and infectious vulnerability is recognised. Sex and age distributions reflect the predominant causes. Pituitary ACTH-dependent forms are more prevalent among women and typically develop in adulthood, whereas ACTH-independent adrenal forms and ectopic forms may show more variable patterns and, in some settings, greater clinical severity.

Strictly defined risk factors for endogenous hypercortisolism are less useful than an assessment of pre-test probability based on the clinical phenotype and context. Probability increases when common comorbidities appear at an early age or progress rapidly, when they are resistant to standard treatment or when they are associated with highly specific signs such as broad purple striae, easy bruising, proximal myopathy and vertebral fractures. Another epidemiologically relevant setting is the incidental discovery of an adrenal mass, in which even mild but persistent cortisol secretion may contribute to hypertension, diabetes and frailty and requires structured endocrinological assessment.

Temporal variability in cortisol excess also influences clinical epidemiology. In cyclic forms, periods of hypersecretion alternate with biochemically near-normal phases, which may cause patients to remain outside the diagnostic pathway if testing is performed at an unrepresentative time. In these cases, the natural history reported by the patient, including fluctuations in weight, neuropsychiatric symptoms and intermittent worsening of blood pressure or glycaemic control, may be more informative than a single laboratory snapshot.

Finally, vulnerability to adverse outcomes is modulated by functional reserves. Advanced age, heart disease, a history of thromboembolism, osteoporosis, sarcopenia and overall frailty amplify the impact of cortisol excess even when secretion is not extremely elevated. The epidemiology of clinically relevant hypercortisolism therefore overlaps with that of the major chronic diseases affecting adults and older people, in which cortisol acts as a pathogenic amplifier.

Cortisol is the final product of the hypothalamic-pituitary-adrenal axis and physiologically plays a central role in coordinating energy availability, immune responses and adaptation to stress. Its secretion is not constant. It follows a circadian rhythm, with a morning peak and a nocturnal nadir, and is organised into ultradian pulses that protect tissues from continuous glucocorticoid signalling. Hypercortisolism represents the loss of this architecture and its replacement by persistent exposure that increases the overall signalling burden on target tissues, transforming cortisol from an adaptive mediator into a factor of systemic toxicity.

In iatrogenic hypercortisolism, the excess originates externally and negative feedback suppresses CRH and ACTH, eventually causing functional atrophy of the zona fasciculata. This process explains two crucial differences from endogenous disease. Tests measuring endogenous production may be reduced or falsely reassuring if the exogenous source is not recognised, while inappropriate reduction or withdrawal of the glucocorticoid may precipitate adrenal insufficiency. In endogenous hypercortisolism, the pathophysiology is organised around ACTH control. In ACTH-dependent forms, ACTH is inappropriately elevated or not suppressed, stimulates both adrenal glands with functional hyperplasia and often produces a relatively dynamic excess with possible temporal variability, as is typical of Cushing disease. In ACTH-independent forms, ACTH is suppressed and autonomy resides in the adrenal gland, with cortisol production by an adenoma, carcinoma or adrenal hyperplasia, consistent with ACTH-independent hypercortisolism.

At the molecular and tissue levels, cortisol acts primarily through the glucocorticoid receptor, modulating gene transcription, intermediary metabolism and inflammatory programmes. In the liver, it increases gluconeogenesis and promotes the availability of energy substrates, while in peripheral tissues it reduces insulin sensitivity, causing insulin resistance and hyperglycaemia. In muscle, it promotes proteolysis and reduces protein synthesis, leading to loss of mass and strength with proximal myopathy. In adipose tissue, it promotes redistribution towards the visceral compartment in a setting in which cortisol and insulin cooperate in remodelling body composition. In connective tissue and skin, it inhibits collagen synthesis and repair, causing dermal fragility, striae and easy bruising.

The differences between forms concern not only the source of the excess but also its interaction with other hormones. In ACTH-dependent forms, chronically increased ACTH may also sustain greater production of adrenal androgens, contributing to manifestations such as acne or hirsutism in some women. In ACTH-independent forms, ACTH suppression reduces trophic stimulation of the contralateral adrenal cortex, and after surgical or pharmacological correction the patient may experience adrenal insufficiency until the axis recovers. In iatrogenic hypercortisolism, suppression is often more profound and the duration of recovery depends on the history of exposure, which is why the pathophysiology of glucocorticoid withdrawal is an integral part of the disease itself.

In the cardiovascular system, cortisol enhances vascular responsiveness to catecholamines and other vasoconstrictors, impairs endothelial function and promotes hypertension and increased cardiovascular risk. It also promotes a procoagulant state associated with increased thromboembolic risk, which is particularly relevant during the perioperative period and in severe disease. Its immunomodulatory and immunosuppressive effects reduce inflammatory responses and increase susceptibility to infections, which may present with attenuated signs. In the central nervous system, chronic cortisol excess disrupts sleep, mood, memory and stress regulation, producing a neuropsychiatric component that may dominate the clinical presentation and requires assessment alongside endocrinological treatment.

The clinical manifestations of hypercortisolism result from the combination of protein catabolism, metabolic dysfunction and vascular and immune vulnerability. During the medical history, patients may report progressive weight gain with predominantly truncal and visceral distribution, associated with reduced strength, easy fatigability and loss of physical performance. Sleep disturbances with poor-quality rest, irritability or depressed mood and a perception of reduced resilience to everyday stress are common. Polyuria and polydipsia may occur when hyperglycaemia develops, while recurrent skin or mucosal infections and delayed healing may emerge insidiously.

A common clinical feature is the dissociation between weight gain and fragility. Patients may appear physically larger but report marked weakness, particularly around the shoulder and pelvic girdles, with difficulty climbing stairs or rising from a seated position. Women may develop menstrual irregularities and signs of relative androgen excess, which are more likely when the secretory drive is ACTH-dependent because of the adrenal contribution to androgen production. In iatrogenic hypercortisolism, the medication history and axis suppression may produce a different chronology, with symptoms following exposure and overlapping with the underlying disease for which the glucocorticoid was prescribed.

During the physical examination, some signs have greater discriminatory value, including broad purple striae, thin skin with easy bruising, a rounded and plethoric face, cervicodorsal fat accumulation and proximal myopathy. Blood pressure is frequently elevated, and the presence of skin and connective-tissue fragility helps distinguish hypercortisolism from uncomplicated obesity. Bone involvement may occur early, with vertebral fractures that may cause few symptoms and back pain, while sarcopenia increases the risk of falls and disability.

The neuropsychiatric component is common and clinically relevant. Anxiety, depression, irritability, impaired concentration and memory disturbances may be integral features of the disease and may affect adherence and quality of life. Some symptoms may persist after correction of the hormonal excess and require a gradual recovery pathway. In severe disease, particularly in some non-pituitary ACTH-dependent forms, infections, hypokalaemia, rapid muscle deterioration and systemic instability may dominate. In milder forms, such as some autonomous adrenal cortisol secretions, a cardiometabolic phenotype may predominate with less evident skin manifestations.

In iatrogenic hypercortisolism, some signs may overlap completely with those of endogenous disease, but the distinguishing feature is their temporal relationship with therapy and, above all, the risk that opposite symptoms associated with axis insufficiency will emerge as the dose is reduced. This coexistence of excess and risk of deficiency over time is a structural clinical difference that directly affects management.

Clinical suspicion of hypercortisolism should arise when progressive and simultaneous features compatible with glucocorticoid excess are observed, particularly when they develop relatively rapidly or are disproportionately severe. Some findings have high discriminatory value, including broad purple striae, easy bruising with thin skin, overt proximal myopathy, vertebral fractures or osteoporosis in atypical patients and rapidly worsening hypertension or diabetes. The combination of truncal weight gain and reduced strength is particularly suggestive because it integrates the apparent anabolic effect on adipose tissue with the catabolic effect on muscle.

Suspicion should remain high even in subtler phenotypes. A patient with an adrenal incidentaloma and cardiometabolic comorbidities, or a patient with skeletal fragility and fractures in the presence of metabolic dysfunction and hypertension, may have less overt but clinically relevant cortisol excess. In these cases, the risk is not merely failing to recognise classic Cushing syndrome but underestimating persistent autonomous secretion that causally contributes to a cumulative risk profile.

It is also essential to recognise that some conditions may produce a similar phenotype and alter test results, creating pseudo-Cushing states. When the clinical probability is high, the most robust strategy is to consider the progression of signs, repeat tests in a reasoned manner and assess the pathophysiological consistency of the results, particularly when cyclic fluctuations are suspected. In this setting, the timing of symptoms and their response to intercurrent events become part of the diagnostic reasoning.

The first practical question must nevertheless concern exposure to glucocorticoids. Patients may not perceive their use as relevant, particularly when treatment consists of repeated courses, injections, inhaled preparations or topical formulations, or when prescriptions originate from different specialist pathways. When the history is compatible with glucocorticoid use, the clinical picture and test interpretation must be assessed in the context of iatrogenic hypercortisolism, because the principal short-term risk during dose reduction may become suppression of the hypothalamic-pituitary-adrenal axis.

The diagnosis of hypercortisolism consists of two complementary phases: confirmation of cortisol excess followed by identification of its source. The prerequisite is exclusion of exogenous glucocorticoid use, because the axis is suppressed in iatrogenic hypercortisolism and tests designed to demonstrate endogenous hypersecretion may be misleading. After this step, the major scientific societies recommend high-accuracy first-line tests, interpreted in context and, when necessary, repeated or confirmed with a second method to reduce false-positive and false-negative results.

The most commonly used tests include late-night salivary cortisol, 24-hour urinary free cortisol and low-dose dexamethasone suppression testing. These investigations assess different aspects of cortisol physiology, including loss of the nocturnal nadir, an increase in total daily secretion and impaired suppressibility. The choice must take into account renal function, adherence to urine collection, night-shift work, sleep disorders, medications that interfere with dexamethasone metabolism and conditions that transiently alter the axis, because diagnostic quality depends not only on the test but also on its suitability for the individual patient.

Diagnostic assessment of hypercortisolism

• Accurate reconstruction of glucocorticoid exposure and of conditions that may alter the axis or interfere with testing.
• Biochemical confirmation with one or more first-line tests, repeated when results are discordant or clinical suspicion remains high.
• Measurement of ACTH to distinguish ACTH-dependent from ACTH-independent forms by integrating the physiology of hormonal feedback.
• Localisation of the source through imaging and, when indicated, dynamic tests or sampling procedures to correctly establish the origin of the excess.

Once cortisol excess has been documented, measurement of ACTH determines the subsequent diagnostic branch. Suppressed ACTH points towards an adrenal source and therefore towards the spectrum of ACTH-independent hypercortisolism, whereas non-suppressed ACTH suggests an ACTH-dependent form, including Cushing disease and ectopic production. This distinction has immediate consequences for imaging. Pituitary magnetic resonance imaging is used in ACTH-dependent forms, whereas adrenal imaging is used in ACTH-independent forms, with the caveat that non-functioning incidentalomas may cause confusion and pituitary microlesions may be undetectable or unrelated to the disease.

In ACTH-dependent cases, localisation may require dynamic tests and, when discordance between the clinical findings, biochemistry and imaging persists, selective venous sampling procedures to distinguish a pituitary from an ectopic source. In ACTH-independent cases, in addition to identifying the responsible lesion, it is essential to anticipate the consequences of axis suppression after treatment. The contralateral adrenal gland may be hypofunctional and the patient may require glucocorticoid coverage until recovery. In iatrogenic disease, the diagnostic focus is instead recognition of axis suppression and management of drug reduction using a strategy that minimises the risk of adrenal crisis without perpetuating glucocorticoid excess, consistently with the physiology of iatrogenic hypercortisolism.

At the same time, diagnosis must include assessment of complications that determine therapeutic urgency and safety, including blood pressure, glycaemic profile, thromboembolic risk, infectious status, frequently paucisymptomatic vertebral fractures, muscle strength and neuropsychiatric impact. This assessment is not ancillary because hypercortisolism is a diffuse organ disease, and endocrinological correction must be accompanied by active management of its principal clinical targets.

The classification of hypercortisolism is clinically useful when it connects the underlying mechanism with decision-making. The first distinction is between iatrogenic and endogenous hypercortisolism. In iatrogenic disease, the defining feature is exposure to glucocorticoids and the resulting axis suppression, which creates a risk of adrenal insufficiency during drug reduction and makes the treatment history more informative than any individual test of hypersecretion.

Within endogenous hypercortisolism, classification into ACTH-dependent and ACTH-independent forms organises the entire diagnostic and therapeutic pathway. In ACTH-dependent disease, bilateral adrenal hyperstimulation is sustained by inappropriate ACTH secretion, and the most common cause is a pituitary adenoma, defining Cushing disease. Temporal fluctuations may be more likely, and some women may develop manifestations related to increased adrenal androgen production. In ACTH-independent disease, the adrenal gland becomes autonomous and ACTH suppression causes hypofunction of the unaffected gland, with a post-treatment transition that often requires temporary replacement therapy until physiological recovery occurs.

Severity does not always correspond to the visibility of the phenotype. Some patients develop severe systemic toxicity with infections, hypokalaemia, rapid muscular deterioration and thrombotic complications. Others have milder but persistent disease that progressively produces significant cardiovascular and skeletal morbidity. Temporal variability provides another basis for classification, as cyclic forms may be clinically intermittent and require a different diagnostic and follow-up strategy. Finally, in patients with adrenal incidentalomas, even modest autonomous secretion may be clinically relevant when associated with hypertension, diabetes and frailty, making classification an exercise in integrating biochemical findings with clinical impact.

Treatment of hypercortisolism aims to reduce tissue exposure to cortisol, correct the underlying cause whenever possible and control the comorbidities that sustain cardiovascular, skeletal and infectious risk. The clearest distinction is between the management of iatrogenic and endogenous forms. In iatrogenic hypercortisolism, the central intervention is gradual reduction of the glucocorticoid to the minimum effective dose or its discontinuation when compatible with the underlying disease, avoiding both continued excess and the development of deficiency caused by axis suppression.

In endogenous hypercortisolism, causal treatment is generally surgical and depends on the location of the source. In pituitary ACTH-dependent forms, removal of the adenoma is the main strategy and must be incorporated into a pathway that ensures correct identification of the ACTH source and continuity of follow-up. In ACTH-independent forms, treatment focuses on the responsible adrenal gland and requires post-treatment planning because suppressed ACTH and functional atrophy of the contralateral gland make a period of adrenal insufficiency likely until the axis recovers.

Medical treatment may be required as a bridge to surgery, as temporary control in severe disease or as an option when causal correction is not immediately feasible or when persistent or recurrent disease requires additional strategies. Medications that reduce cortisol synthesis, modulate ACTH secretion in selected settings or antagonise the peripheral action of glucocorticoids require close monitoring because overtreatment may cause iatrogenic adrenal insufficiency. The choice and sequence of therapies depend on clinical severity and the individual risk profile, with particular attention to infectious and thrombotic vulnerability.

Comorbidities must be treated actively in parallel. Hypertension and diabetes may require temporary intensification of therapy, skeletal fragility requires fracture prevention and correction of deficiencies, and sarcopenia requires nutritional and rehabilitative support. Because thromboembolic risk is increased, particularly in severe disease and during the perioperative period, risk assessment and preventive measures must be integrated into the overall plan. This approach is shared by all forms but has a different relative importance in each one. In iatrogenic disease, control of the underlying condition limits the speed of tapering, whereas in endogenous disease the rapidity of causal control may become the principal determinant of risk reduction.

Follow-up of hypercortisolism is prolonged because biochemical remission does not coincide with immediate normalisation of the affected systems. The objectives are to verify control or remission, detect persistent or recurrent disease early, manage any post-treatment adrenal insufficiency and monitor the trajectory of comorbidities. Assessments are more frequent during the initial period after surgery or while medical treatment is being adjusted and may be progressively spaced once stability has been established.

Differences between forms are particularly evident in management of the axis. After correction of endogenous disease, chronic axis suppression may cause transient or prolonged adrenal insufficiency requiring replacement therapy and education regarding stress dosing. In ACTH-independent disease, ACTH suppression often makes a period of contralateral adrenal hypofunction more likely, whereas in ACTH-dependent disease recovery may be influenced by the dynamics of remission and any persistence of central stimulation. In iatrogenic hypercortisolism, follow-up is intertwined with drug tapering and the stability of the underlying disease, and surveillance must prevent both the recurrence of excess and the emergence of symptoms of deficiency.

Monitoring of comorbidities is central. Blood pressure, glycaemic profile, body composition and muscle strength must be reassessed over time because they often improve gradually and not always completely. Skeletal follow-up must address vertebral fractures and bone mineral density, and fall prevention is an integral part of risk reduction. Thromboembolic risk may remain elevated even after correction, particularly during the perioperative period, and surveillance must be tailored to the individual risk profile.

Quality of life is an often underestimated domain. Sleep, mood and cognitive disturbances may persist and require specific management because they affect adherence and functional recovery. Continuity of care reduces the risk that residual symptoms will be attributed to unrelated causes and helps distinguish late consequences from recurrence or independent comorbidities. Follow-up is therefore part of treatment rather than a separate subsequent phase.

The prognosis of hypercortisolism depends on the duration of exposure, the intensity of the excess and the possibility of achieving stable causal control. In general, reducing cortisol improves mortality and comorbidities, although many consequences require time to regress and some may leave residual risk. Severe or prolonged disease is associated with a greater likelihood of cardiovascular and skeletal damage, infectious vulnerability and thrombotic complications, and these outcomes may persist after remission unless comorbidities are treated actively.

Cardiovascular complications include persistent hypertension, increased risk of atherothrombotic events and a procoagulant profile that promotes venous and arterial thromboembolism. Thrombotic risk is particularly important during active disease and the perioperative period, when immobility, infections and altered inflammatory status may coexist. Metabolically, diabetes and dyslipidaemia contribute to overall cardiovascular risk, while redistribution of adipose tissue towards the visceral compartment sustains a proinflammatory and proatherogenic state even when total body weight is not extremely elevated.

Musculoskeletal complications are among the most disabling. Osteoporosis and vertebral fractures may already be present at diagnosis, and proximal myopathy increases the risk of falls and loss of independence. Muscle recovery is often slow, and functional fragility may persist after normalisation of cortisol in the absence of rehabilitative intervention. Skin and connective-tissue abnormalities improve over time but may leave persistent signs that represent a biological record of the duration of exposure.

Infectious complications result from chronic cortisol-mediated immunomodulation, with increased susceptibility, attenuated presentations and slower recovery. Neuropsychiatric complications include depression, anxiety and cognitive impairment that may persist and require dedicated management. Prognosis therefore reflects two parallel trajectories: correction of the hormonal excess and reconstruction of the patient's functional reserves over time.

Treatment-related complications differ according to the form of disease. In iatrogenic hypercortisolism, the principal error is unprotected withdrawal or dose reduction, which may precipitate adrenal insufficiency. In endogenous disease, the post-treatment transition is frequently characterised by the need for temporary replacement until the axis recovers. ACTH suppression makes this phase more likely in ACTH-independent forms, whereas in ACTH-dependent disease prognosis is also influenced by the risk of persistence or recurrence and by the ability to maintain consistent endocrinological follow-up. Overall, the principal determinants of hypercortisolism are potentially reversible, but diagnosis and treatment must explicitly address both the shared characteristics and the structural differences between its various forms.