ACTH-independent hypercortisolism

ACTH-independent hypercortisolism is an endocrine disorder in which excess cortisol results from autonomous production by the adrenal cortex rather than from pituitary or ectopic stimulation through ACTH. From a pathophysiological perspective, the central feature is loss of central control of the hypothalamic-pituitary-adrenal axis: increased cortisol secretion suppresses ACTH through negative feedback, but the adrenal lesion continues to produce glucocorticoids independently of the body’s physiological requirements. The result is a clinical spectrum ranging from overt Cushing syndrome to subtler forms of autonomous secretion, which are often identified in the setting of incidentally detected adrenal masses.

The clinical importance of ACTH-independent hypercortisolism is not limited to the classic signs of cortisol excess. Even moderately increased and persistent cortisol levels may amplify cardiovascular and metabolic risk, promote skeletal fragility and sarcopenia, increase thromboembolic vulnerability and predispose to infection. Assessment therefore requires an integrated approach that accurately distinguishes the adrenal origin, degree of secretory autonomy and biological impact, because the choice between surgery, medical treatment and surveillance depends on the combination of aetiology and target-organ damage.

The epidemiology of ACTH-independent hypercortisolism is closely linked to two clinical settings: overt Cushing syndrome caused by adrenal disease and autonomous cortisol secretion identified in patients with an adrenal incidentaloma. Overt forms are relatively rare in the general population, but they account for a significant proportion of endogenous hypercortisolism, particularly because of the frequency of unilateral cortisol-secreting adenomas. Mild or subtle forms, in contrast, are increasingly identified because abdominal imaging has become common in internal medicine, emergency care and oncology, increasing the number of incidentally discovered adrenal masses undergoing hormonal evaluation.

In patients with incidentalomas, the identification of cortisol excess does not always correspond to an evident clinical syndrome. A substantial proportion have autonomous secretion without a complete Cushing phenotype, but with strong associations with hypertension, diabetes, visceral obesity, dyslipidaemia and reduced bone mineral density. In this setting, the apparent prevalence depends on the laboratory definition used, the cut-off applied to the dexamethasone suppression test and the characteristics of the study population, including age, comorbidities and inpatient or outpatient setting. The key epidemiological point is that the clinical impact is not binary: mild autonomous secretion may be more common than overt disease and, precisely because it is more widespread, may contribute substantially to the burden of cardiovascular and metabolic disease in the adult population.

The main risk factors are not uniform because they vary according to the underlying aetiology. Older age increases the likelihood of an incidentaloma and mild secretory autonomy, whereas some rare bilateral disorders may present at a younger age when associated with genetic predisposition or syndromic disease. The presence of cardiometabolic comorbidities is not merely a consequence of hypercortisolism, but also a factor that magnifies its clinical relevance. A patient with resistant hypertension, difficult-to-control diabetes, osteoporosis or fragility fractures is more vulnerable to even moderate cortisol excess and is more likely to undergo investigations that reveal the underlying adrenal disorder.

An important issue is the biological heterogeneity of adrenal lesions. Cortisol-secreting adenomas and nodular hyperplasias may develop in the setting of clonal instability and abnormalities in the intracellular signals regulating steroidogenesis. In some subtypes, a family history and the presence of other endocrine or neoplastic manifestations suggest a genetic background that modifies both risk and clinical presentation. A history of cancer is also a common context in which incidentalomas are identified, but a rigorous distinction must be made between non-functioning metastases and autonomous adrenocortical lesions, because their management differs radically and must be guided by integrated endocrine and radiological criteria.

Finally, clinical risk assessment must consider not only the likelihood of autonomous secretion, but also the likelihood of complications and progression over time. Some patients remain stable for years, whereas others develop worsening metabolic parameters or cardiovascular events, and in a minority cortisol secretion may become more pronounced. The epidemiology of ACTH-independent hypercortisolism is therefore inseparable from follow-up, cardiovascular prevention and systematic assessment of target-organ damage.

ACTH-independent hypercortisolism results from a primary abnormality of glucocorticoid production within the adrenal zona fasciculata. Under physiological conditions, ACTH binds to the melanocortin 2 receptor and activates the cAMP-PKA pathway, increasing the expression and activity of proteins that are crucial to steroidogenesis, including StAR, which transfers cholesterol into the mitochondrion, and the enzymes that catalyse the subsequent steps leading to cortisol synthesis. Adrenal autonomy develops when this pathway is mimicked or bypassed by intrinsic abnormalities of adrenocortical tissue, which maintain increased steroidogenesis even when ACTH is suppressed.

From an aetiological perspective, the principal causes include cortisol-secreting adrenocortical adenoma, adrenocortical carcinoma with glucocorticoid hypersecretion and unilateral or bilateral hyperplastic disorders. Among these, bilateral macronodular adrenal hyperplasia represents a model of progressive autonomy in which multiple nodules secrete cortisol under aberrant regulation, often related to ectopic or overexpressed receptors that respond to non-ACTH-dependent stimuli. Another paradigm is primary pigmented nodular adrenocortical disease and other micronodular disorders, in which multiple small nodules cause autonomous secretion, sometimes within a genetic syndrome. More rarely, cortisol production may arise from ectopic adrenal tissue or from variants of functional unilateral hyperplasia.

Molecular pathogenesis translates clinical concepts into biological mechanisms. In cortisol-secreting adenomas, abnormalities of the PKA pathway may constitutively increase steroidogenic activity, producing an ACTH-independent phenotype even in small lesions. In some subgroups, activating somatic mutations in the gene encoding the catalytic subunit of PKA are associated with greater secretory autonomy and often with a more evident clinical presentation. Interactions with other signalling pathways, including transcriptional regulation of steroidogenic genes and cellular proliferation pathways, help explain the variability between highly secreting adenomas and lesions with milder but persistent secretion.

In bilateral macronodular disease, the characteristic pathogenetic feature is the combination of nodular growth and non-canonical control of secretion. The hyperplastic cortex may express receptors that respond to catecholamines, vasopressin, incretins or other signals, causing cortisol increases related to meals, posture or stress. This dynamic pattern may obscure the diagnosis unless the hormonal profile is interpreted correctly. In a proportion of cases, germline or somatic mutations in genes involved in the regulation of adrenal growth and function promote a more severe phenotype and sometimes extra-adrenal manifestations, making broader assessment of the patient and, when appropriate, the family context necessary.

The pathophysiology of cortisol excess is multisystemic and depends on both the magnitude and duration of exposure. Metabolically, cortisol promotes gluconeogenesis and insulin resistance, redistribution of adipose tissue towards visceral compartments, protein catabolism and loss of muscle mass. This results in diabetes or impaired glucose tolerance, qualitative dyslipidaemia, sarcopenia and reduced physical performance. At the cardiovascular level, glucocorticoid excess enhances vasoconstrictor responses and promotes hypertension, endothelial dysfunction and myocardial remodelling, increasing the risk of major events and accelerating the progression of pre-existing heart disease.

The skeleton is a critical target because cortisol reduces bone formation and increases bone resorption, interferes with calcium absorption and gonadal function and promotes skeletal fragility. This leads to an increased risk of fractures, including subclinical vertebral fractures, which may be the first sign of disease in patients without a typical Cushing phenotype. At the same time, immune modulation and effects on the skin and microcirculation account for the increased incidence of infection, skin fragility, bruising and impaired wound healing. Neuropsychiatric consequences may include mood disorders, insomnia, anxiety and cognitive impairment, with substantial interindividual variability.

A distinctive feature of ACTH-independent disease is chronic suppression of the central axis, which may cause atrophy of the contralateral adrenal cortex in unilateral disease and a substantial risk of adrenal insufficiency after removal of the secreting lesion. This relationship between pathogenesis and clinical management is crucial: definitive treatment of cortisol excess may temporarily produce glucocorticoid deficiency requiring replacement therapy and monitoring until the axis recovers.

The clinical manifestations of ACTH-independent hypercortisolism reflect chronic exposure to glucocorticoids and are highly variable. In overt disease, the history often reveals progressive weight gain with fat redistribution, proximal muscle weakness and reduced exercise tolerance. Patients may report easy fatigability, difficulty climbing stairs or rising from a seated position and a general deterioration in quality of life, often accompanied by insomnia and irritability. The onset or worsening of hypertension and hyperglycaemia is also typical and may be more apparent than cutaneous signs.

Many patients, particularly those with mild autonomous secretion, do not have the classic phenotype. In these cases, the history is dominated by common comorbidities that are disproportionate in severity or resistance to treatment, including hypertension requiring multiple drugs, diabetes that becomes poorly controlled despite appropriate treatment, increased visceral fat accompanied by loss of lean mass and the occurrence of fragility fractures or vertebral pain caused by subclinical compression fractures. Neuropsychiatric manifestations may include depression, anxiety or impaired concentration and are often regarded as primary disorders. Only an integrated reconstruction of the course of symptoms makes hypercortisolism a plausible unifying factor.

On physical examination, overt disease may be associated with facial plethora, truncal adiposity, skin thinning, bruising and wide striae with capillary fragility. Proximal myopathy is an important and frequently underestimated functional sign. Loss of strength is not merely a symptom, but an indicator of protein catabolism and fall risk. Women may develop menstrual irregularities and reduced fertility, whereas gonadal dysfunction in both sexes contributes to osteoporosis and impaired overall well-being.

A crucial clinical issue is susceptibility to infection and thromboembolism. Cortisol alters the immune response and promotes skin and respiratory infections, while the combination of hypercoagulability, endothelial dysfunction and relative immobility caused by muscle weakness increases the risk of thrombotic events, particularly during active disease and the perioperative period. The psychological burden of the disorder, including changes in body image and persistent symptoms, may also affect treatment adherence and the patient’s perception of disease severity.

In ACTH-independent hypercortisolism, an adrenal mass may be known before the endocrine diagnosis is established. In other cases, the patient is evaluated because of fractures, difficult-to-control diabetes or resistant hypertension, and imaging subsequently reveals the lesion. The clinical pathway is therefore bidirectional: symptoms may lead to endocrine suspicion, or a radiological finding may require retrospective reconstruction of a clinical phenotype that had previously been divided into separate diagnoses.

ACTH-independent hypercortisolism should be suspected when signs and symptoms compatible with cortisol excess occur together with cardiometabolic and skeletal comorbidities that cannot be adequately explained by common causes or ageing alone. One clinical scenario is the presence of suggestive features such as proximal weakness, easy bruising, skin thinning and fragility fractures, particularly when they occur together or progress over a relatively short period. A second and more common scenario is the combination of resistant hypertension, rapidly worsening diabetes or prediabetes and increased visceral adiposity accompanied by loss of strength and physical performance.

The identification of an adrenal mass on imaging performed for another indication is a high-priority clinical setting. In this case, suspicion does not necessarily arise from Cushingoid features, but from the need to exclude hormonally active disease with systemic consequences even when the patient appears asymptomatic. Assessment must be particularly rigorous in patients with diabetes, hypertension, osteoporosis or previous cardiovascular events, because even a mild hormonal abnormality may be clinically important in an individual with reduced physiological reserve.

Suspicion should also be high in patients with multiple vertebral fractures or severe osteoporosis that is disproportionate to age and traditional risk factors. In many patients, the skeleton provides the first recognisable manifestation because cortisol-mediated impairment of bone formation and muscle function increases both falls and fragility. A history of recurrent infections, delayed wound healing or marked skin fragility may also suggest hypercortisolism, especially when associated with metabolic abnormalities.

Suspicion of an ACTH-independent form becomes stronger when features coexist that make a central cause less likely, but the distinction cannot be made from the clinical picture alone. In particular, a unilateral or bilateral adrenal lesion must be interpreted cautiously because non-functioning incidentalomas are common. Clinical suspicion must therefore lead to a diagnostic pathway that confirms hypercortisolism and assigns its origin using robust biochemical criteria.

Finally, in patients with rapid deterioration of their general condition, hypokalaemia in the setting of severe hypercortisolism, paradoxical weight loss with marked catabolism or evidence of malignancy, the differential diagnosis must include cortisol-secreting adrenocortical carcinoma. Prognosis in these cases depends on rapid assessment and multidisciplinary treatment. Endocrine evaluation therefore not only establishes the diagnosis, but also determines oncological and surgical priorities with a direct effect on survival.

Diagnosis of ACTH-independent hypercortisolism requires a sequential approach: confirmation of cortisol excess, demonstration of ACTH independence and identification of the adrenal aetiology using imaging and, when necessary, histopathological and genetic investigations. The first step is to establish that hypercortisolism is genuine and persistent while avoiding false-positive results related to acute stress, alcohol use, major depression, sleep disturbances or interfering medications. The most commonly used initial test, particularly in patients with an incidentaloma, is the low-dose dexamethasone suppression test, which evaluates loss of normal hypothalamic-pituitary feedback suppression caused by autonomous cortisol secretion.

Once an abnormality consistent with secretory autonomy has been confirmed, the decisive step is measurement of plasma ACTH. In ACTH-independent adrenal disease, ACTH is typically suppressed or inappropriately low relative to the cortisol concentration because central negative feedback remains intact. Indirect markers, such as reduced adrenal androgen levels, may support the presence of chronic axis suppression, although they are not diagnostic when considered in isolation. Identification of an adrenal source therefore requires rigorous integration of tests of cortisol autonomy with evidence of central suppression.

Diagnostic assessment of ACTH-independent hypercortisolism

• Confirmation of cortisol excess using validated screening tests interpreted in the clinical context and with consideration of possible pharmacological and biological interference.
• Demonstration of ACTH independence through identification of suppressed or inappropriately low ACTH in the presence of hypercortisolism.
• Identification of the adrenal source using dedicated imaging, with morphological characterisation and assessment of the likelihood of benignity or malignancy.
• Assessment of target-organ damage and complications to determine treatment priorities, perioperative risk and the need for immediate intervention.

Adrenal imaging has two functions: localisation of the lesion and estimation of the likelihood of malignancy. CT using a dedicated adrenal protocol and, when indicated, MRI can distinguish lipid-rich adenomas, indeterminate lesions and masses suspicious for carcinoma by integrating lesion size, attenuation, washout pattern and morphological characteristics. In unilateral disease, a mass consistent with an adenoma in a patient with hypercortisolism and suppressed ACTH is often sufficient to establish the clinical aetiology. Interpretation is more complex in bilateral disease because secretion may arise from both adrenal glands in the presence of multiple nodules or diffuse hyperplasia. Clinical reasoning must then focus on the degree of autonomy, disease severity and the most appropriate therapeutic strategy.

Systemic assessment of hypercortisolism is essential because management depends not only on biochemical findings but also on target-organ damage. Evaluation should include glycaemic status, blood pressure, overall cardiovascular risk, electrolyte balance, skeletal health with particular attention to vertebral fractures and fracture risk, and muscle function. In patients with more severe hypercortisolism, surveillance for infection and thromboembolism becomes an integral part of the evaluation, together with estimation of perioperative risk when surgery is being considered.

The differential diagnosis is based mainly on distinguishing adrenal causes from ACTH-dependent causes. When ACTH is not suppressed, hypercortisolism is likely to be ACTH-dependent and investigation should shift towards pituitary disease or ectopic ACTH production using specific tests and imaging. Conversely, suppressed ACTH suggests an adrenal source, but pre-analytical errors and laboratory variability must be considered. When biochemical findings are discordant or imaging is indeterminate, expert reassessment is necessary because premature interpretation may lead to inappropriate procedures or treatment delays in conditions associated with a poor prognosis.

Finally, some ACTH-independent disorders, particularly bilateral or micronodular forms, may benefit from genetic evaluation when the clinical context suggests a syndromic predisposition, young age at presentation, a family history or extra-adrenal manifestations. In these patients, diagnosis is not limited to locating and treating the lesion, but requires understanding the broader disorder in order to establish appropriate follow-up and prevent related manifestations over time.

The classification of ACTH-independent hypercortisolism has clinical value because it links the intensity of cortisol excess, anatomical origin and risk of complications. A first classification axis distinguishes overt Cushing syndrome from mild autonomous cortisol secretion associated with an incidentaloma. Overt disease is characterised by more pronounced cortisol excess and often evident clinical manifestations, whereas mild forms may lack a typical phenotype but still have a measurable effect on blood pressure, metabolism and the skeleton. Severity therefore does not always correspond to clinical appearance, because a patient without classic signs may still have increased risk when exposure is chronic and clinically relevant comorbidities are present.

A second axis is anatomical and distinguishes unilateral from bilateral disease. Unilateral forms include cortisol-secreting adenomas, unilateral hyperplasia and carcinomas. In these conditions, cortisol excess may suppress and cause atrophy of the contralateral adrenal gland, with important postoperative consequences. Bilateral forms include macronodular hyperplasia and micronodular disorders, in which cortisol production may be distributed unevenly. This makes the choice between partial, unilateral or bilateral surgery and medical control more complex.

A third axis concerns the probability of malignancy and the presence of hormonal co-secretion. Adrenocortical carcinoma may produce cortisol and, in some cases, other steroids, resulting in a more aggressive clinical profile and oncological implications that extend beyond endocrinology. Benign adenomas, in contrast, may be highly secreting or may produce moderate but persistent hormonal excess. This distinction determines not only the therapeutic strategy but also the type of follow-up and the need for management in centres with specific expertise.

From a functional perspective, disease can be classified according to target-organ impact. Low-impact forms are those in which comorbidities are absent or well controlled, whereas high-impact forms are characterised by resistant hypertension, difficult-to-control diabetes, osteoporosis with fractures, clinically significant sarcopenia or cardiovascular complications requiring more urgent reduction of cortisol exposure. Within this model, classification is not intended merely to assign a label, but to predict risk and select the treatment offering the greatest net clinical benefit.

Finally, some ACTH-independent forms require contextual classification when they occur as part of a genetic syndrome or multisystem disorder. In these cases, severity is determined not only by the quantity of cortisol, but by the combined burden of hypercortisolism and other associated risks requiring multidisciplinary management and targeted long-term surveillance.

Treatment of ACTH-independent hypercortisolism is based on a fundamental principle: reducing tissue exposure to cortisol and treating the underlying adrenal cause whenever possible. The strategy must be individualised according to aetiology, clinical severity, perioperative risk, probability of malignancy and the effect on comorbidities. In patients with overt disease caused by a benign unilateral lesion, the standard approach is adrenalectomy of the secreting gland after appropriate clinical optimisation. Lesions suspicious for carcinoma require a dedicated oncological and surgical pathway aimed at complete resection and, when indicated, planning of adjuvant treatment.

In patients with mild autonomous cortisol secretion associated with an incidentaloma, treatment decisions are more nuanced and must balance benefits and risks. In patients with comorbidities potentially attributable to cortisol excess, particularly difficult-to-control hypertension, poorly controlled diabetes and osteoporosis, surgery may improve metabolic and cardiovascular outcomes in selected subgroups. In others, active surveillance with intensified cardiovascular prevention and treatment of comorbidities is appropriate. The crucial clinical objective is to avoid both therapeutic inertia in high-risk patients and unnecessary surgery in patients with minimal autonomy and high operative risk.

Medical treatment has an important role in several settings: as a bridge to surgery, as treatment for patients who are not surgical candidates or as a control strategy in severe disease while oncological or surgical management is being planned. Steroidogenesis inhibitors reduce cortisol production by acting on key enzymes in its biosynthetic pathway. Drug selection and dose titration depend on disease severity, the required speed of control and the safety profile. In severe or rapidly evolving disease, rapidly acting agents may stabilise the patient by reducing cardiovascular, metabolic and infectious complications. In selected settings, glucocorticoid receptor antagonism may attenuate the peripheral effects of cortisol, particularly on glycaemic control, but requires careful monitoring because cortisol concentrations remain elevated and therapeutic efficacy cannot be assessed using hormone levels alone.

In cortisol-secreting adrenocortical carcinoma, control of hypercortisolism is often necessary because glucocorticoid excess worsens functional prognosis and increases infectious and thromboembolic risk. In these patients, medical treatment may be essential even when surgery is planned and must be integrated with specific oncological strategies and careful general medical support. The aim is to reduce the toxicity of hypercortisolism rapidly without compromising the safety or timing of definitive procedures.

In bilateral disease, the strategy may include unilateral adrenalectomy directed at the functionally dominant side or more extensive surgery in severe cases. Bilateral adrenalectomy resolves hypercortisolism but causes permanent adrenal insufficiency, requiring lifelong replacement therapy and management of the risk of adrenal crisis. Whenever possible, a balance is therefore sought between controlling cortisol excess and preserving some adrenal function, especially in patients for whom total definitive treatment would create a substantial long-term management burden.

Treatment of complications is an integral component of management. Blood pressure control, diabetes treatment, prevention and treatment of osteoporosis, rehabilitation of muscle function and assessment of thromboembolic risk must begin early. Reducing cortisol is necessary but not sufficient. Clinical prognosis also depends on restoring the functional reserve impaired by chronic exposure and preventing acute events during the transition towards remission.

Follow-up of ACTH-independent hypercortisolism has three objectives: confirming remission or control of cortisol excess, detecting recurrence or progression and managing the long-term consequences of both the disease and its treatment. After adrenalectomy for unilateral secreting disease, the principal clinical issue is management of the suppressed hypothalamic-pituitary-adrenal axis. Removal of the autonomous source may cause expected transient adrenal insufficiency because the remaining adrenal gland requires time to recover after a period of functional atrophy. This requires individualised glucocorticoid replacement and gradual dose reduction guided by clinical assessment and dynamic testing, together with patient education on stress dosing during fever, surgery or trauma.

Endocrine monitoring should include periodic assessment of cortisol and, when appropriate, tests documenting recovery of the circadian rhythm and the stress response. During the early postoperative period, symptoms may reflect glucocorticoid withdrawal or relative hypocortisolism. Interpretation must distinguish slow physiological recovery from clinically significant deficiency. Recovery may require several months and, in some cases, longer, particularly after prolonged and severe hypercortisolism.

In patients undergoing surveillance for mild autonomous cortisol secretion, follow-up focuses on comorbidities and stability of secretion. Periodic assessment of blood pressure, glycaemia, lipid profile, body weight, muscle strength and fracture risk is essential because the clinical objective is prevention of cardiovascular and skeletal events. Repeat hormonal testing should be guided by clinical changes, progression of comorbidities and the characteristics of the adrenal mass, avoiding both excessive low-value testing and failure to recognise functional progression.

Radiological follow-up depends on the probability of benignity or malignancy and the characteristics of the initial imaging. Lesions with typical features of a benign adenoma and stable clinical findings may be managed conservatively, whereas indeterminate masses or lesions with suspicious features require reassessment at appropriate intervals. In patients with carcinoma, structured oncological follow-up is required to detect local recurrence and metastatic disease. In all forms, the frequency of follow-up should reflect biological risk and clinical impact, avoiding a fragmented surveillance pathway that loses sight of the overall clinical picture.

An often underestimated issue is global functional recovery after remission. Normalisation of cortisol does not produce immediate recovery of muscle mass, bone density or psychological well-being. A prolonged recovery phase is common, during which interventions involving physical activity, nutrition, osteoporosis prevention and psychological support may improve outcomes and quality of life. Effective follow-up extends beyond laboratory testing and supports the patient during the transition from active disease to stability, preventing late complications and reducing the risk of unrecognised recurrence.

The prognosis of ACTH-independent hypercortisolism depends on the adrenal cause, the intensity and duration of exposure to cortisol and the extent of target-organ damage at diagnosis. In benign unilateral disease treated surgically, remission is often achievable and improvement in comorbidities may be substantial, particularly when diagnosis is made early. However, many consequences of cortisol excess resolve slowly. Sarcopenia and skeletal fragility may require prolonged recovery, and residual cardiovascular risk may persist in patients with long-standing exposure or pre-existing disease.

In mild autonomous cortisol secretion, prognosis is determined less by immediate survival than by the long-term risk of cardiovascular, metabolic and skeletal events. Even moderate but persistent cortisol excess may increase the likelihood of hypertension, diabetes, atrial fibrillation, heart failure and fractures, especially in older adults and patients with reduced functional reserve. Prognosis in this setting depends on identifying patients in whom hypercortisolism makes a substantial contribution to comorbidities and in whom treatment of the underlying cause could reduce overall risk.

In cortisol-secreting adrenocortical carcinoma, prognosis is less favourable and depends on stage, completeness of surgical resection and response to oncological treatment. Hypercortisolism in this setting is not merely a symptom, but a factor that increases infectious and thromboembolic complications and may reduce treatment tolerance. Effective control of cortisol therefore becomes part of the prognostic strategy because reducing immunosuppression and improving metabolic stability may affect the patient’s ability to undergo complex treatment.

The most important complications include cardiovascular events, venous thromboembolism, infection, fragility fractures and neuropsychiatric deterioration. Muscle weakness increases the risk of falls and loss of independence, whereas skin fragility and impaired wound healing increase perioperative risk. A specific complication of surgical treatment is postoperative adrenal insufficiency, which is often expected but may be dangerous if not recognised and treated because it can progress to adrenal crisis during physiological stress. This risk is particularly relevant in unilateral disease with axis suppression and in bilateral disease treated with extensive surgery.

Overall, ACTH-independent hypercortisolism has a substantial clinical impact because it combines the transformation of a powerful adaptive hormone into a cause of systemic injury with marked variability in presentation. Prognosis improves considerably when the aetiological assessment is accurate, treatment is proportionate to risk and follow-up addresses not only biochemical control, but also event prevention and restoration of global function over time.