Cushing Syndrome

Definition

Cushing syndrome (CS) denotes the clinical and biochemical disorder produced by sustained or recurrent exposure to excessive glucocorticoid activity, most importantly cortisol, regardless of the underlying cause. The supplied evidence concerns endogenous CS and its major etiologic subgroups, including pituitary, adrenal, and ectopic sources of cortisol excess. ^{[2]B3b[4]C4[6]B2b[7]D5[136][141]D} Cushing disease (CD) is the pituitary form of CS caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor. ^{[3]B3b[135]C[141]D} Ectopic Cushing syndrome (ECS) is caused by excessive ACTH production from a non-pituitary neoplasm, most commonly a neuroendocrine neoplasm arising in the lung, pancreas, gastrointestinal tract, thymus, or, less commonly, the kidney. ^[7]D5[143]D

The term adrenal Cushing syndrome refers to cortisol excess originating in the adrenal cortex and is generally ACTH-independent because autonomous adrenal cortisol production suppresses hypothalamic-pituitary ACTH drive. ^{[2]B3b[4]C4[6]B2b[8]C4} Adrenal causes include cortisol-producing adrenal adenomas and bilateral adrenal macronodular hyperplasia; primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is characterized by bilateral adrenal enlargement and autonomous cortisol production. ^{[2]B3b[8]C4[139]C} The supplied studies also describe cortisol-producing adenomas with hemorrhage and cases in which pathological cortisol secretion was present without a complete clinical phenotype of overt or subclinical CS, illustrating that tumor pathology, biochemical autonomy, and clinical expression may not always align. ^[8]C4

Classification by ACTH dependence

The principal biochemical axis classification divides endogenous CS into ACTH-dependent and ACTH-independent disease. ACTH-dependent CS includes CD and ECS; ACTH-independent CS is usually adrenal in origin. ^{[3]B3b[4]C4[7]D5[141]D} This classification is mechanistically based on the relationship between cortisol secretion and ACTH regulation within the hypothalamic-pituitary-adrenal (HPA) axis. ^[2]B3b[136] In children, interpretation requires particular caution because HPA-axis physiology differs from that of adults, and pediatric CS is most frequently associated with pituitary or adrenocortical tumors. ^[136]

ACTH-dependent disease should not be equated with pituitary disease: ectopic ACTH secretion may produce the same broad biochemical category while requiring a different tumor localization strategy. ^{[3]B3b[7]D5[143]D} ECS has been described as a clinical continuum or as two phenotypes: an aggressive form associated with rapidly progressive or advanced neoplasia and an indolent, occult form associated with slower-growing tumors. ^[7]D5 Approximately half of the prototypical aggressive ECS cases in the reviewed literature were attributed to small-cell lung carcinoma, and aggressive ECS was associated with very high ACTH and cortisol concentrations and prominent manifestations of protein catabolism. ^[7]D5 ACTH-secreting neuroendocrine neoplasms are not biologically uniform; reported pancreatic, pulmonary, thymic, and renal tumors included well-differentiated NET-G1/typical carcinoid, NET-G2/atypical carcinoid, and NET-G3 categories, with gene fusions observed frequently in pancreatic but not non-pancreatic ACTH-secreting neuroendocrine neoplasms. ^[143]D

Classification by clinical and biochemical severity

The traditional clinical distinction is between overt CS and milder autonomous cortisol secretion. Overt CS denotes clinically apparent hypercortisolism with sufficiently abnormal biochemical findings to establish endogenous cortisol excess. ^{[2]B3b[4]C4[6]B2b} Older literature used “subclinical Cushing syndrome” for patients with adrenal cortisol autonomy and absent or limited classic features; contemporary adrenal-incidentaloma frameworks increasingly use the terms possible autonomous cortisol secretion and autonomous cortisol secretion, reflecting a spectrum rather than a binary state. ^[2]B3b[134]C In the cited adrenal cohort, patients were classified differently depending on the guideline system used: American criteria separated nonfunctional incidentalomas from subclinical CS, whereas European criteria distinguished nonfunctional lesions, possible autonomous cortisol secretion, and autonomous cortisol secretion. ^[134]C

Plasma steroid profiling and steroid-pattern analysis may assist separation of nonfunctioning adrenal adenomas, adrenal CS, and other functional adrenal tumors, but these approaches are classification or phenotyping tools rather than replacements for the clinical definition of CS. ^{[2]B3b[6]B2b[142]D} Circulating cell-free DNA investigations have similarly explored molecular classification of cortisol-producing, aldosterone-producing, and nonfunctioning adrenal adenomas, including subgroups designated CPA-MACS and CPA-CS; this remains an emerging research approach. ^[142]D

Temporal classification and nomenclature

Cyclical CS is a recognized subentity defined by repeated cortisol-excess peaks alternating with spontaneous periods of normal or low cortisol secretion. ^[1]D5 Cyclicity may occur with any CS etiology and can produce apparently normal or low biochemical results during troughs, complicating both confirmation of hypercortisolism and identification of its source. ^[1]D5 Therefore, a single normal assessment does not necessarily exclude CS when clinical manifestations fluctuate or biochemical results conflict with the phenotype. ^[1]D5

Axis nomenclature

The preferred axis terminology is hypothalamic-pituitary-adrenal (HPA) axis: hypothalamic corticotropin-releasing hormone regulates pituitary ACTH, and ACTH regulates adrenal cortisol secretion. ^[2]B3b[136] “ACTH-dependent” and “ACTH-independent” describe the regulatory relationship of cortisol excess to ACTH, whereas “pituitary,” “ectopic,” and “adrenal” identify the presumed anatomic source. ^{[3]B3b[4]C4[7]D5[141]D} These labels should therefore be used together: for example, pituitary ACTH-dependent CS (CD), ectopic ACTH-dependent CS (ECS), or adrenal ACTH-independent CS. ^{[3]B3b[7]D5[141]D}

The supplied evidence supports retaining CS as the umbrella diagnosis while documenting etiology, ACTH status, severity, and temporal pattern separately. ^{[1]D5[2]B3b[3]B3b[7]D5[134]C[141]D} This multidimensional nomenclature accommodates overt disease, mild autonomous cortisol secretion, bilateral adrenal disease, ectopic tumor phenotypes, and cyclic presentations without implying that one category is interchangeable with another. ^{[1]D5[2]B3b[7]D5[134]C}

Physiological HPA-axis organization

The hypothalamic–pituitary–adrenal (HPA) axis coordinates glucocorticoid production with stress responses, metabolism, energy balance, and cardiovascular regulation. Hypothalamic signaling stimulates pituitary ACTH secretion, which acts on the adrenal cortex to promote cortisol synthesis; circulating cortisol normally participates in negative feedback at hypothalamic and pituitary levels. Disruption at any point in this system can produce clinically important glucocorticoid excess. ^[27]D5 Cortisol also communicates bidirectionally with adipose tissue: adrenal glucocorticoids influence lipid storage, adipose distribution, and thermogenic biology, whereas adipose-derived signals can affect adrenal–metabolic interactions. ^[20]D5

Cortisol actions are mediated predominantly through the intracellular glucocorticoid receptor (GR), which regulates transcription and cellular signaling after ligand binding. GR activity influences glucose metabolism, adipogenesis, immune regulation, cardiovascular physiology, and tissue remodeling. ^[24]D5[147]D The mineralocorticoid receptor and glucocorticoid receptor systems also participate in neuroendocrine effects; persistent cortisol exposure has been associated with hippocampal injury, oxidative stress, neuroinflammation, and cognitive impairment. ^[151]D

Pathophysiological classification

Cushing syndrome (CS) is a heterogeneous clinical spectrum caused by chronic glucocorticoid excess. It includes exogenous CS from therapeutic or undeclared glucocorticoid exposure, endogenous overt hypercortisolism, and the increasingly recognized state of mild autonomous cortisol secretion (MACS). ^[27]D5 Endogenous disease is classified biochemically as ACTH-dependent or ACTH-independent. ACTH-dependent disease reflects inappropriate ACTH drive, most commonly from a corticotroph pituitary tumor or an ectopic ACTH-producing neoplasm; ACTH-independent disease reflects autonomous adrenal cortisol production or other adrenal steroidogenic dysregulation. ^[27]D5[150]D

Tumor-associated ACTH excess may arise from neuroendocrine malignancies. Thymic neuroendocrine tumors are rare, and a French multicenter cohort identified multiple endocrine neoplasia type 1 in 34% of patients with locally advanced or metastatic disease; atypical carcinoid NET G2 accounted for 48%, while highly proliferative NET G3 accounted for 31%. ^[26]C4 Gastrointestinal malignancies may also produce Cushing-like paraneoplastic manifestations through hormone or hormone-like secretion, immune mechanisms, or dysregulated signaling, although the clinical relevance varies by tumor type. ^[30]D5

Autonomous adrenal cortisol secretion may occur in adrenal adenomas, adrenocortical malignancy, primary bilateral macronodular adrenal hyperplasia (PBMAH), and rare genetic or mosaic disorders. PBMAH is increasingly detected incidentally and frequently presents with MACS rather than overt CS. Its pathogenesis may involve aberrant adrenal hormone-receptor expression, intra-adrenal ACTH production, and genetic alterations, particularly ARMC5 in more severe phenotypes and KDM1A in food-dependent disease. ^[31]D5 Dysregulated cAMP/PKA signaling is another mechanism: activating GNAS variants can increase cAMP signaling and cause cortisol excess, including ACTH-independent CS in mosaic McCune–Albright syndrome. ^[146]D

Biochemical signature

The biochemical phenotype is defined by inappropriate cortisol production and impaired feedback suppression. Commonly used assessments include urinary free cortisol, dexamethasone suppression testing, ACTH measurement, and midnight salivary cortisol. ^[12]C4 Interpretation requires attention to discordant results and clinical context. A reported patient with an NR3C1 missense variant had elevated urinary free cortisol and an abnormal low-dose dexamethasone suppression test, but normal ACTH and midnight salivary cortisol; the initial biochemical pattern mimicked Cushing disease, whereas the underlying disorder was primary generalized glucocorticoid resistance. ^[12]C4

NR3C1 encodes the GR, and loss-of-function variants can produce generalized glucocorticoid resistance with elevated cortisol concentrations despite limited or absent classic CS features. This illustrates that biochemical hypercortisolism does not invariably indicate tissue-level glucocorticoid excess; receptor resistance can uncouple circulating cortisol from its clinical effects. ^[12]C4 Conversely, chronic endogenous or exogenous glucocorticoid exposure can suppress endogenous HPA-axis activity, and withdrawal may produce a glucocorticoid withdrawal syndrome that resembles adrenal insufficiency or recurrence of the original inflammatory disease. ^[23]D5

Metabolic and cardiovascular consequences

Excess cortisol promotes visceral adiposity, adverse adipose remodeling, insulin resistance, and impaired glucose homeostasis. These effects contribute to diabetes, obesity, hypertension, and cardiovascular disease; hypercortisolism is also increasingly considered in patients with difficult-to-control type 2 diabetes despite multiple glucose-lowering therapies. ^[148]D Adrenal–adipose crosstalk becomes maladaptive in CS, with altered adipokine secretion, visceral fat accumulation, and an adverse metabolic profile. ^[20]D5 Experimental evidence further implicates serum- and glucocorticoid-induced kinase 3 (SGK3) in glucocorticoid-induced adipogenesis: glucocorticoid exposure increased SGK3-related phosphorylation, whereas SGK3 inhibition or genetic deletion impaired adipogenesis and protected mice from glucocorticoid-induced obesity. ^[147]D

Cortisol excess also contributes to hypertension through metabolic, vascular, and mineralocorticoid-related mechanisms. In children and adolescents, adrenal causes of secondary hypertension include steroidogenic disorders such as 11β-hydroxylase deficiency and 17α-hydroxylase deficiency, which alter mineralocorticoid activity and blood pressure. ^[149]D The clinical phenotype depends on the cortisol source, severity, duration, receptor sensitivity, and degree of ACTH suppression. Overt CS is classically associated with centripetal adiposity, proximal myopathy, skin fragility, hypertension, and glucose dysregulation. ^[27]D5

Molecular and therapeutic implications

The biochemical and clinical consequences of CS can be targeted at several levels: adrenal steroidogenesis inhibitors reduce cortisol synthesis; pituitary-directed drugs modulate ACTH; and GR antagonists block peripheral glucocorticoid action. ^[24]D5 Relacorilant is a selective GR modulator under development for endogenous hypercortisolism and, in available clinical studies, did not prolong the cardiac QT interval in healthy volunteers or patients with CS. ^[145]C It subsequently received a 2026 U.S. approval in combination with nab-paclitaxel for selected platinum-resistant ovarian, fallopian-tube, or primary peritoneal cancers, although that approval was not for CS. ^[29]D5

Functional imaging may assist etiologic localization. A novel 68Ga-labeled desmopressin analogue targets V1b receptors overexpressed in corticotroph tumors and was investigated for localization of ACTH-producing lesions in patients with CS. ^[150]D Dual-tracer FDG and 18F-AlF-NOTA-octreotide PET/CT has also been reported in an ACTH-independent CS case with oncocytic thyroid adenoma, illustrating that unusual tumors may complicate interpretation of endocrine and functional imaging findings. ^[4]C4

Epidemiology

Cushing syndrome (CS) is an uncommon disorder caused by sustained exposure to excess glucocorticoids. The condition may be exogenous—most often related to prolonged corticosteroid treatment—or endogenous, resulting from autonomous cortisol production by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, ectopic ACTH secretion, or an adrenal lesion. ^[156] The available contemporary studies are predominantly retrospective cohorts, single-center series, registry analyses, or surveys; therefore, reported etiologic proportions should be interpreted as healthcare-setting estimates rather than population-wide incidence figures. ^[154][159]C

In the Krakow European Registry on Cushing’s Syndrome (ERCUSYN) cohort, pituitary CS accounted for 53%, adrenal CS for 25%, and ectopic CS for 22% of 214 consecutive patients. ^[154] In contrast, a European survey of 222 newly reported patients found 64% with Cushing disease, 31% with adrenal CS, and 5.4% with ectopic CS. ^[159]C The difference probably reflects referral patterns, registry composition, and case ascertainment, although the cited studies do not establish a single universal etiologic distribution. ^[154][159]C

CS during pregnancy is rare but clinically important because maternal and fetal complications are substantially increased when hypercortisolism is present. ^[131]C4 Two reported pregnant patients developed typical clinical features early in gestation, and one pregnancy involved twins, illustrating that pregnancy-associated presentation can occur at the beginning of pregnancy and may be diagnostically challenging. ^[131]C4 Pregnancy itself alters cortisol physiology and can complicate recognition of endogenous CS; the reported cases were characterized by loss of the normal plasma cortisol diurnal rhythm. ^[131]C4

Etiology and inherited susceptibility

Endogenous CS is conventionally classified as ACTH-dependent or ACTH-independent. ACTH-dependent disease includes pituitary Cushing disease and ectopic ACTH secretion, whereas ACTH-independent disease generally reflects adrenal cortisol secretion. ^[154][159]C A French real-world cohort of nonpituitary CS included patients with ectopic ACTH secretion, adrenocortical carcinoma, and adrenal causes, confirming the clinically heterogeneous nature of nonpituitary disease. ^[37]C4

Bilateral macronodular adrenocortical disease (BMAD) is a rare adrenal cause of cortisol excess characterized by bilateral adrenal nodules and variable degrees of hypercortisolism. ^[42]C4 Pathogenic variants in ARMC5 are an established genetic driver of BMAD, although their prevalence and genotype–phenotype relationships may vary between populations. ^[42]C4 A Korean study specifically addressed the limited East Asian evidence base by evaluating 69 patients with BMAD, including 35 who underwent whole-exome sequencing and steroid profiling. ^[42]C4 These findings support consideration of inherited or germline susceptibility in patients with bilateral adrenal disease, particularly when the presentation is familial, bilateral, recurrent, or unusually early, although the cited study does not establish a universal testing threshold. ^[42]C4

Demographic and clinical risk context

Obesity and diabetes are important clinical contexts in which hypercortisolism may be overlooked because their metabolic manifestations overlap with those of CS. ^[44]A1a A systematic review and meta-analysis of 39 studies involving 14,995 screened participants specifically evaluated hypercortisolism screening in obesity or diabetes and emphasized that the spectrum—from mild autonomous cortisol secretion to overt CS—may be under-recognized in these populations. ^[44]A1a This evidence supports heightened clinical suspicion when obesity or diabetes is accompanied by additional discriminatory features of cortisol excess, but it does not justify assuming that obesity or diabetes alone establishes CS. ^[44]A1a

Age and sex distributions vary according to etiology and phenotype. ^[154] In a pediatric cohort of 273 patients diagnosed by age 18 years, 69% had obesity and 31% did not. ^[41]C4 Children without obesity were more frequently female and had an older age at disease onset than children with obesity. ^[41]C4 Thus, absence of obesity should not be used to exclude pediatric CS, particularly in older children or adolescents and in females. ^[41]C4

The phenotype of pediatric CS is therefore heterogeneous: obesity is common but not obligatory, and the nonobese subgroup may be relatively older at onset and more often female. ^[41]C4 In adults, obesity, diabetes, and other metabolic disorders may both obscure CS and prompt investigation for secondary endocrine causes. ^[44]A1a

Interpretation of associated-risk evidence

Several recent studies describe complications or comorbidities associated with established endogenous CS rather than risk factors for developing CS. These include venous thromboembolism, atrial fibrillation, osteoporosis, fatty liver disease, mood disorders, sarcopenia, and cancer; they should not be misclassified as etiologies. ^{[33]B2b[35]B2b[112]B3b[153][154][155]C[156][159]C[160]C} Likewise, studies of urine-free cortisol assay reference intervals and ACTH assay performance concern diagnostic measurement rather than disease causation or epidemiology. ^{[43]B2c[157]C} Surgical outcomes in obese patients and pediatric adrenalectomy series describe treatment populations and should not be interpreted as evidence that obesity or childhood adrenal surgery causes CS. ^{[46]B3b[158]C}

Overview

Cushing syndrome (CS) is the clinical consequence of prolonged exposure to excessive endogenous or exogenous glucocorticoid activity. Endogenous disease may result from autonomous cortisol production by one or both adrenal glands, an ACTH-secreting pituitary tumor (Cushing disease), or ectopic ACTH secretion by a non-pituitary tumor. ^[166]D The presentation is heterogeneous, and many manifestations overlap with common disorders such as obesity, hypertension, diabetes, depression, menstrual dysfunction, and polycystic ovary syndrome; consequently, CS may remain unrecognized or be diagnosed late. ^{[53]D5 [165]D [166]D}

General phenotype and multisystem manifestations

The phenotype reflects glucocorticoid effects on adipose tissue, metabolism, cardiovascular function, bone, skin, muscle, immunity, and the nervous system. ^{[20]D5 [166]D} Commonly recognized features include central or visceral adiposity, facial fat accumulation or “moon face,” hypertension, impaired glucose tolerance or diabetes, muscle weakness, menstrual or reproductive abnormalities, neuropsychiatric symptoms, and increased susceptibility to infection. ^{[20]D5 [163]D [166]D} Facial changes can be prominent: three-dimensional facial analysis has specifically identified cortisol-associated differences in facial fat distribution compared with common obesity, supporting the clinical value of the characteristic rounded face. ^[163]D

Excess cortisol may produce serious complications, including cardiovascular and metabolic impairment, infections, neuropsychiatric disease, thromboembolic events, myocardial infarction, and cerebrovascular accidents. ^[166]D Hypertension and hypokalemia may be particularly striking in severe ACTH-dependent disease, although their presence and severity vary with the cause and tempo of cortisol excess. ^[57]C4 In difficult-to-control diabetes, endogenous hypercortisolism should be considered when glycemia remains refractory or only partially responsive to standard treatment, because cortisol excess can drive cardiometabolic deterioration. ^[168]C

Subtle, mild, or cyclic disease

Clinical expression is a spectrum. Patients with mild autonomous cortisol secretion (MACS) may have an adrenal nodule and biochemical cortisol autonomy without the overt stigmata traditionally associated with CS. MACS is commonly defined by a post–1-mg overnight dexamethasone suppression cortisol concentration >1.8 μg/dL, although interpretation requires clinical context and may incorporate ACTH, urinary free cortisol, late-night cortisol, and cardiometabolic findings. ^{[161]C [164]D} The phenotype may therefore be dominated by hypertension, obesity, diabetes, dyslipidemia, or other cardiometabolic abnormalities rather than florid physical signs. ^{[20]D5 [164]D}

Cortisol secretion can be intermittent or cyclic, producing fluctuating symptoms and inconsistent biochemical results. ^[53]D5 A clinical course may include episodic manifestations or periods resembling adrenal insufficiency during treatment, as reported in a child with suspected cyclic ACTH secretion who developed adrenal insufficiency while receiving ketoconazole. ^[56]C4 Cyclic ACTH-independent CS also occurs in primary pigmented nodular adrenocortical disease associated with Carney complex; pediatric cases may progress with obesity, depression, and short stature. ^[169]C

Pediatric presentation

In children, growth effects are especially important. Growth retardation or short stature accompanied by weight gain is a major warning pattern, because excess cortisol can impair linear growth while increasing adiposity. ^{[56]C4 [169]C} Pediatric presentations may also include bone fractures, nephrolithiasis, hypertension, premature pubarche, virilization, or other androgenic signs. ^{[55]C4 [56]C4 [171]C} Adrenocortical tumors in children classically present with virilization or hypercortisolism, but atypical presentations—including bilateral tumors, incidental discovery after trauma, hemorrhagic lesions, misleading hormonal testing, acute hypertensive crisis, and gradually progressive premature pubarche—can delay diagnosis. ^[55]C4

A pediatric adrenocortical carcinoma may present with rapid weight gain, moon face, and increased chest or back hair; combined cortisol, 17-hydroxyprogesterone, and testosterone excess should raise concern for a functioning adrenal malignancy. ^[171]C Severe hypercortisolism may cause skeletal complications such as fractures and urinary calcium-related stones; a 10-year-old with ectopic ACTH syndrome presented with both bone fractures and kidney stones in addition to growth retardation and typical hypercortisolemic features. ^[56]C4

Etiologic and special presentations

Ectopic ACTH syndrome is often clinically heterogeneous and may lack the classic CS phenotype. ^[57]C4 ACTH-secreting pheochromocytoma can present predominantly with refractory hypertension and hypokalemia, and manifestations may be atypical during pregnancy. ^[57]C4 Pregnancy itself complicates recognition because physiologic changes overlap with features of adrenal disease and CS; early assessment is therefore important when clinical findings are disproportionate or progressive. ^[58]D5

Young women with menstrual irregularities, clinical hyperandrogenism, or both represent an important higher-suspicion group. CS is rare in the general population but may be missed when menstrual dysfunction, hirsutism, acne, or androgen excess is attributed solely to common reproductive disorders. ^[165]D Conversely, exogenous glucocorticoid exposure must be actively sought, including nontraditional or over-the-counter products. A pediatric case of apparent CS resolved after discontinuation of an anti-lice foam whose ingredients were investigated for glucocorticoid-like activity, illustrating that exposure history may reveal an unusual cause of a Cushingoid presentation. ^[59]C4

Clinical interpretation

No single sign reliably establishes CS because presentation varies according to cortisol burden, duration, cyclicity, ACTH dependence, age, pregnancy status, and underlying tumor. ^{[53]D5 [58]D5 [166]D} Suspicion should increase when multiple progressive or discriminatory features cluster—particularly rapid weight gain with growth failure in a child, facial and truncal changes with hypertension or diabetes, unexplained hypokalemia, fractures or nephrolithiasis, menstrual abnormalities with hyperandrogenism, or refractory diabetes. ^{[56]C4 [57]C4 [165]D [168]C} Biochemical evaluation remains essential, especially in mild disease, because clinical findings may be subtle or nonspecific. ^{[53]D5 [164]D}

Diagnostic strategy

Evaluation should proceed in stages: establish endogenous hypercortisolism, determine whether cortisol excess is ACTH-dependent, and then localize the source. The distinction is clinically important because ACTH-independent disease generally directs attention to the adrenal glands, whereas ACTH-dependent disease requires discrimination between pituitary ACTH secretion (Cushing disease) and ectopic ACTH secretion. Recent studies continue to describe both categories, including ACTH-independent adrenal disease, primary pigmented nodular adrenocortical disease (PPNAD), and ACTH-dependent ectopic secretion from unusual neuroendocrine tumors. ^{[174][179]D[57]C4[180]D}

Paired hormones and first-line testing

Interpret cortisol results together with plasma ACTH rather than interpreting either hormone in isolation. A low or suppressed ACTH concentration in the setting of autonomous cortisol excess supports an ACTH-independent adrenal process, whereas a non-suppressed ACTH concentration supports ACTH-dependent Cushing syndrome. This framework was used in studies of ACTH-independent Cushing syndrome and in the evaluation of PPNAD, a disorder that may occur in isolation or as part of Carney complex. ^[174][179]D

The 1-mg overnight dexamethasone suppression test (DST) is particularly relevant when evaluating patients with obesity, type 2 diabetes, resistant hypertension, or progressive cardiometabolic disease, because milder cortisol excess may lack classic cushingoid features. A 2026 systematic review and meta-analysis specifically examined first-line testing—particularly DST—in obesity and diabetes and concluded that hypercortisolism may be under-recognized across the spectrum from mild autonomous cortisol secretion to overt Cushing syndrome. ^[44]A1a A contemporary review likewise identifies abnormal cortisol suppression after overnight dexamethasone as an important diagnostic signal in selected patients with type 2 diabetes, while emphasizing that overt Cushing syndrome remains uncommon and milder forms are more frequent in selected high-risk populations. ^[178]D

An abnormal screening result should be interpreted in clinical context and followed by confirmatory endocrine assessment rather than used alone to assign an etiology. This is especially important in patients with obesity or diabetes, in whom the diagnostic question may concern mild autonomous cortisol secretion rather than overt Cushing syndrome. ^{[44]A1a[178]D} Medication, supplement, and exposure history is also essential: therapeutic glucocorticoids are the commonest cause of exogenous Cushing syndrome, while adulterated herbal or traditional products and supplements may contain undeclared glucocorticoids and mimic endogenous disease. ^[28]D5

Dynamic testing in ACTH-dependent disease

When ACTH-dependent Cushing syndrome is established but pituitary and ectopic sources remain uncertain, bilateral inferior petrosal sinus sampling (BIPSS) can provide central-to-peripheral ACTH evidence. Desmopressin-stimulated BIPSS has been prospectively evaluated in 181 consecutive patients at a high-volume pituitary center. The study directly compared traditional criteria—basal inferior petrosal sinus-to-peripheral ACTH ratio >2.0 or stimulated ratio >3.0—with lower, optimized thresholds. ^[70]B2b The prospective findings support consideration of lower cutoffs to improve diagnostic performance, but thresholds should be interpreted with the assay, stimulation protocol, catheterization quality, and institutional experience in mind. ^[70]B2b

Biochemical and sampling results should not override longitudinal clinical evidence. In a series of rigorously defined MRI-negative presumed Cushing disease, 59 of 530 surgical patients had no visible pituitary adenoma on high-quality preoperative MRI; after exclusions, 57 were followed, and 5/57 were ultimately diagnosed with ectopic ACTH-secreting tumors. ^[175]C These findings support continued surveillance when postoperative findings, biochemical remission, imaging, or clinical evolution are discordant with pituitary disease. ^[175]C

Clinical prediction models may complement, but should not replace, endocrine testing and sampling. A multicenter model designed to distinguish ectopic ACTH secretion from Cushing disease was derived in 253 Spanish patients and externally validated in 72 Colombian patients using routine clinical variables; its reported purpose was discrimination and calibration across independent cohorts. ^[173]

Localization after biochemical classification

For suspected adrenal cortisol production, adrenal imaging remains central. In primary aldosteronism with coexisting subclinical Cushing syndrome, adrenal lesions were larger than lesions in isolated primary aldosteronism, illustrating that combined endocrine phenotypes can complicate interpretation of adrenal findings. ^[71]B3b In a retrospective cohort of 52 patients with ACTH-independent Cushing syndrome or nonfunctioning adrenal adenomas, 68Ga-pentixafor PET/CT showed 91.95% sensitivity and 95.24% specificity by visual analysis; lesion-to-adrenal ratio outperformed SUVmax and lesion-to-liver ratio in semi-quantitative assessment. ^[174] A small prospective study also evaluated 68Ga-DOTA-pentixafor PET/CT for functional adrenal cortical lesions and lateralization, comparing it with CT, MRI, and 18F-FDG PET/CT, but its limited sample size warrants cautious interpretation. ^[176]C

In ACTH-dependent disease, localization should include pituitary MRI and directed evaluation for ectopic tumors when results are negative or discordant. Ectopic ACTH secretion may arise from uncommon sources, including pheochromocytoma and pancreatic neuroendocrine neoplasms. Pheochromocytoma-associated ectopic ACTH syndrome has been reported with refractory hypertension and hypokalemia, and ACTH-producing pancreatic neuroendocrine neoplasms may be aggressive, including grade 2 and grade 3 tumors and metastatic disease. ^[57]C4[180]D MEN1 adds a specific localization hazard because multiple synchronous neuroendocrine tumors can coexist, making identification of the ACTH source difficult. ^[172]C

Special etiologic considerations

PPNAD should be considered in ACTH-independent disease, particularly when adrenal imaging is unrevealing or when Carney-complex features or a relevant family history are present; integrated clinical, genetic, and pathological evaluation can identify both germline and somatic abnormalities. ^[179]D When the phenotype or biochemical pattern is atypical, reassess for exogenous glucocorticoid exposure, rare ectopic sources, and cyclic or evolving disease rather than prematurely accepting a single localization diagnosis. ^{[28]D5[172]C[175]C}

Conceptual framework

Cushing syndrome (CS) has no universally accepted anatomic staging system analogous to that used for malignant disease; practical risk stratification should therefore integrate the intensity and duration of cortisol excess, clinical complications, biochemical subtype, tumor burden or invasiveness, and treatment-related risk. ^[181] Adrenalectomy remains definitive treatment for several adrenal abnormalities, but operative selection and technique must account for adrenal pathophysiology, tumor characteristics, technological considerations, and patient safety. ^[181]

Biochemical severity

Severity should be described using the magnitude and persistence of hypercortisolism rather than a single laboratory result. A prospective cohort included patients across the spectrum from mild autonomous cortisol secretion (MACS) to overt CS, with clinical and biochemical severity scores used to assess muscle function, quality of life, sleep, and postoperative outcomes. ^{[68]B2b[76]B3b} Extreme biochemical excess may identify a high-risk phenotype: a reported patient with MEN1-associated ACTH-dependent CS had 24-hour urinary free cortisol of 3,188 μg/24 hours, exceeding 25 times the upper limit of normal, and required rapid biochemical control. ^[172]C

MACS should be separated from overt CS because it represents a milder hypercortisolism phenotype, although it can still be associated with clinically meaningful cardiometabolic and functional consequences. ^{[68]B2b[73]B2b[76]B3b} In the prospective cardiometabolic cohort, 357 surgically treated patients included 49% with MACS, 36% with pituitary CS, and the remainder with other CS subtypes; hypertension, diabetes, hyperlipidemia, and obesity were assessed longitudinally at baseline, 3 months, and 12 months after remission. ^[73]B2b

Clinical severity and end-organ risk

Clinical severity is multidimensional and should include cardiovascular, metabolic, thrombotic, musculoskeletal, reproductive, sleep, and psychological or quality-of-life domains. ^{[68]B2b[73]B2b[76]B3b} In a large cohort of 408 patients with Cushing disease, venous thromboembolism occurred in 35 patients (8.6%), compared with 1 patient in a control group of 323 individuals with nonfunctioning pituitary macroadenomas undergoing similar surgery, supporting classification of active Cushing disease as a prothrombotic state. ^[155]C

Muscle impairment and reduced quality of life are important severity markers even when classic physical features are not prominent. In a cross-sectional study of 164 patients, 81 had MACS, 14 adrenal CS, 60 pituitary CS, and 9 ectopic CS; hand-grip strength, sit-to-stand performance, SF-36 scores, and CushingQoL scores were evaluated in relation to clinical and biochemical severity. ^[68]B2b Persistent muscle morbidity may continue after biochemical remission: among 36 women in remission for approximately 13 ± 7 years, sarcopenia was present in 7, and circulating miR-28-5p was overexpressed in patients with sarcopenia compared with matched controls. ^[160]C

Glucocorticoid withdrawal syndrome (GWS) is a clinically relevant post-remission risk rather than evidence of recurrent hypercortisolism. In a longitudinal study during the first 12 postoperative weeks, myalgias and arthralgias occurred in 50%, fatigue in 45%, and weakness was also reported among prevalent symptoms; symptom burden was tracked with weekly assessments alongside quality-of-life and muscle-function testing. ^[80]B2b Postoperative adrenal insufficiency (AI) is another major risk determinant, and its duration was prospectively evaluated according to body mass index, biochemical and clinical hypercortisolism severity, subtype, preoperative duration, glucocorticoid regimen, and nadir cortisol. ^[74]B2b A separate prospective cohort compared hydrocortisone with prednisone during the first 12 weeks after surgery in patients with postoperative AI, assessing GWS and quality of life. ^[75]B2b

Etiologic and tumor-related stratification

Etiology is central to risk assessment. ACTH-dependent disease requires reliable differentiation among pituitary CS, ectopic ACTH syndrome (EAS), and non-neoplastic hypercortisolism; a systematic review and meta-analysis evaluated the diagnostic accuracy of the 10-μg desmopressin test for distinguishing Cushing disease from non-neoplastic hypercortisolism and EAS across 14 studies, with certainty assessed using GRADE. ^[81]A1a Diagnostic complexity is particularly high in MEN1, where synchronous neuroendocrine tumors can obscure the ACTH source; thymic neuroendocrine tumors are rare but may be locally advanced or metastatic, and MEN1 was present in 34% of 74 patients in a French multicenter series. ^[172]C[26]C4

Adrenal disease requires assessment of laterality, functional status, imaging phenotype, and suspicion for malignancy. A multicenter study of 8,037 adrenal tumors characterized sex-related and lateralization differences across adrenocortical carcinoma, cortisol-secreting adenomas, other cortical adenomas, pheochromocytoma, aldosterone-producing adenoma, and neuroblastoma. ^[77]B3b These findings support incorporating sex, tumor type, and adrenal asymmetry into operative and oncologic risk assessment, although they do not establish a standalone CS staging system. ^[77]B3b The American Association of Endocrine Surgeons guideline emphasizes evidence-based selection of appropriate, safe, and effective adrenalectomy and recognizes that advances in genomics, technology, operative techniques, and understanding of adrenal pathophysiology have altered indications. ^[181]

Pediatric and atypical presentations

Pediatric severity should not be inferred from obesity alone. In a cohort of 273 patients with CS diagnosed by age 18 years, 31% were not obese; those without obesity were more often female and older at onset than patients with obesity, demonstrating that clinically important CS may occur without marked obesity. ^[41]C4 Pediatric adrenal tumors may present with atypical or high-acuity features, including bilateral disease, hypertensive crisis with acute stroke, hemorrhage, rupture after biopsy, misleading hormonal studies, or gradually progressive premature pubarche. ^[55]C4 McCune–Albright syndrome can also involve hyperfunctioning endocrinopathies and complex multisystem disease in children, requiring phenotype-based rather than obesity-based severity assessment. ^[83]B3b

Practical risk categories

Patients with very high cortisol exposure, major cardiovascular or metabolic complications, VTE risk, severe myopathy, suspected invasive or metastatic disease, or diagnostic uncertainty should be considered high risk and managed through multidisciplinary assessment. ^{[155]C[172]C[181]} Patients with MACS or mild biochemical abnormalities should not automatically be considered low risk; cardiometabolic, sleep, muscle, and quality-of-life outcomes remain relevant, and prospective cohorts specifically evaluate improvement after surgical remission. ^{[68]B2b[73]B2b[76]B3b} Finally, risk assessment must continue after surgery because GWS, AI, impaired muscle function, and persistent sarcopenia may outlast biochemical remission. ^{[74]B2b[75]B2b[80]B2b[160]C}

Clinical framing

Severe or uncontrolled Cushing syndrome (CS) should be treated as a potential endocrine emergency because active hypercortisolism is associated with acute, life-threatening complications and substantial morbidity and mortality. ^[84]B3b These complications may occur from the first symptoms of hypercortisolism through the first year after biochemical remission, supporting continued surveillance even after cortisol control. ^[84]B3b In neuroendocrine neoplasms (NENs), Cushing syndrome compatible with ectopic ACTH production is associated with worse survival and greater morbidity in a large propensity-matched, real-world cohort. ^[182]

Immediate assessment and stabilization

Urgently assess for complications involving the cardiovascular, neurologic, renal, metabolic, infectious, and thrombotic systems. Reported presentations include severe hypertension, refractory hypokalemia, hyperglycemia, acute heart failure, cardiomyopathy, seizures, posterior reversible encephalopathy syndrome, acute kidney injury (AKI), and obstructive urolithiasis. ^{[88]C4[89]C4[90]C4} A child with CS developed hypertension-associated seizure and radiologic findings suggestive of posterior reversible encephalopathy syndrome, followed by AKI from bilateral ureteral stones. ^[89]C4 Pediatric adrenocortical carcinoma has also been reported with uric-acid nephrolithiasis and renal colic immediately before planned adrenalectomy. ^[171]C

Control immediately dangerous physiology while establishing the source of cortisol excess. Severe hypertension and hypokalemia may accompany ectopic ACTH secretion from rare tumors, including pheochromocytoma. ^[88]C4 Ectopic ACTH-producing pheochromocytoma may produce simultaneous catecholamine excess and hypercortisolism, creating a particularly hazardous cardiovascular state. ^[88]C4 Cardiac evaluation is warranted when dyspnea, edema, chest pain, or reduced cardiac output is present because ectopic ACTH secretion from small-cell lung cancer has been associated with acute heart failure, reduced ejection fraction, refractory hypokalemia, severe hyperglycemia, and uncontrolled hypertension. ^[90]C4

Rapid cortisol reduction

When oral therapy is unsuitable because of critical illness, impaired absorption, delayed onset, or toxicity, intravenous etomidate provides a rapidly titratable means of suppressing cortisol synthesis. ^[86]C4[183]C A 2025 systematic review included 36 publications, 76 clinical cases, and 78 etomidate-treatment episodes; patients ranged from 2 months to 82 years of age, and etomidate was used as first-line treatment in 53.2% of episodes. ^[86]C4 The review concluded that etomidate was administered safely in the reported cases, although the evidence base consisted primarily of published clinical reports. ^[86]C4

Real-world data specifically evaluated serum cortisol at baseline, 12 hours, and 24 hours after intravenous etomidate in patients with severe endogenous hypercortisolism; biochemical control was defined as serum cortisol <500 nmol/L (<18.1 µg/dL). ^[183]C These data support early biochemical reassessment and dose titration rather than reliance on delayed clinical improvement. ^[183]C Because etomidate can rapidly suppress steroidogenesis, treatment requires close monitoring for excessive cortisol lowering and clinical or biochemical adrenal insufficiency. ^[86]C4[183]C

In exceptionally severe disease, rapid biochemical control may be achieved before definitive source treatment. In a patient with MEN1 and ACTH-dependent CS, urinary free cortisol was 3,188 µg/24 h, more than 25 times the upper limit of normal, and biochemical control was achieved within 10 days using high-dose medical treatment. ^[172]C MEN1 creates a distinctive diagnostic emergency because multiple synchronous neuroendocrine tumors may coexist, making localization of the ACTH source difficult. ^[172]C The case and its focused literature review emphasize that source attribution should not delay stabilization of life-threatening hypercortisolism. ^[172]C

Definitive intervention

Definitive treatment should address the ACTH or cortisol source once the patient is stabilized and the operative risk is acceptable. ^[172]C[185]D Emergency bilateral adrenalectomy may be the only therapeutic option when severe uncontrolled CS is life-threatening and does not respond adequately to medical therapy. ^[185]D Laparoscopic transabdominal anterior bilateral adrenalectomy has been described as an alternative approach in selected patients, including those with multiple fractures that prevent safe prone or lateral positioning required for other minimally invasive approaches. ^[185]D

In ACTs, atypical pediatric presentations—including bilateral tumors, hemorrhagic lesions, tumor rupture, misleading hormonal testing, delayed endocrine evaluation, and hypertensive stroke—can complicate emergency recognition and treatment. ^[55]C4 Pediatric adrenal cortical carcinoma may present with combined cortisol and androgen excess; one reported child had elevated cortisol, 17-hydroxyprogesterone, and testosterone with a 6.6 × 5.6 cm adrenal mass. ^[171]C These cases reinforce the need for urgent endocrine assessment in children with rapid virilization, hypertension, growth acceleration, or unexplained metabolic or renal complications. ^[55]C4[171]C

Preventing adrenal insufficiency during recovery

After cortisol-lowering therapy, adrenalectomy, or abrupt withdrawal of exogenous glucocorticoids, monitor for adrenal insufficiency and provide appropriate glucocorticoid replacement when indicated. ^[87]C4[92]D5 Glucocorticoid-induced adrenal insufficiency is the most frequent cause of adrenal insufficiency in children and may lead to a life-threatening adrenal crisis; risk can occur even with non-systemic glucocorticoid formulations. ^[92]D5 A case of an adulterated dietary supplement containing an undisclosed glucocorticoid illustrates the danger of abrupt cessation: the patient presented with abdominal pain, vomiting, and weakness, had low cortisol, failed cosyntropin testing, and improved after hydrocortisone replacement. ^[87]C4 Medication and supplement histories are therefore essential in any suspected iatrogenic CS or unexplained adrenal crisis. ^[87]C4[92]D5

Adrenal crisis is characterized by decompensation that may be refractory to vasopressors and requires prompt hydrocortisone supplementation. ^[91]D5 Pediatric adrenal crisis may also arise from congenital adrenal disorders; an infant with Xp21 contiguous gene deletion syndrome presented with salt-wasting adrenal crisis consistent with X-linked adrenal hypoplasia congenita. ^[167]C Acute management must therefore distinguish persistent cortisol excess from evolving or treatment-related cortisol deficiency. ^{[86]C4[91]D5[92]D5}

Management objectives

Long-term management should be individualized around three simultaneous targets: control cortisol-related morbidity, identify and treat the cortisol source, and restore or safely replace hypothalamic–pituitary–adrenal (HPA) function after definitive therapy. Severe endogenous hypercortisolism is a medical emergency; rapid biochemical control may be required before localization or definitive treatment. In a reported patient with MEN1 and severe ectopic ACTH syndrome, urinary free cortisol was 3,188 μg/24 h, more than 25 times the upper limit of normal, and biochemical control was achieved within 10 days with high-dose medical therapy ^[172]C. Intravenous etomidate is an option when oral steroidogenesis inhibitors are unsuitable because of critical illness, impaired absorption, delayed onset, or toxicity; real-world assessment has used cortisol measurements at 12 and 24 hours, with biochemical control defined as serum cortisol <500 nmol/L (<18.1 μg/dL) ^[183]C.

Replacement: recovery and glucocorticoid safety

After pituitary, adrenal, or ectopic-source treatment, prolonged suppression of endogenous ACTH and cortisol production commonly necessitates glucocorticoid replacement until HPA-axis recovery is demonstrated. Replacement should be actively reassessed rather than continued indefinitely by default, because persistent dependence, abnormal circadian rhythm, and glucocorticoid withdrawal symptoms can all impair recovery and quality of life ^[105]B3b. Glucocorticoid withdrawal syndrome may include musculoskeletal, gastrointestinal, neuropsychiatric, cardiovascular, and metabolic symptoms and can mimic adrenal insufficiency or recurrent disease; tapering therefore requires clinical surveillance and differentiation from biochemical adrenal insufficiency ^[23]D5.

Patients receiving replacement require explicit sick-day education and perioperative or acute-illness planning, particularly when surgery, infection, pregnancy, or other physiological stress is anticipated ^[58]D5. A case of adrenocortical carcinoma complicated by immune thrombocytopenia illustrates that abrupt changes in endogenous or exogenous glucocorticoid exposure may destabilize comorbid disease; concurrent steroid administration was required while hypercortisolism was corrected ^[104]C4.

Biochemical remission should not be equated with complete recovery. In a cross-sectional study of 90 treated, biochemically controlled patients, participants were stratified by normal late-night salivary cortisol, abnormal late-night salivary cortisol, or long-term glucocorticoid replacement, with quality of life, anxiety, depression, and general health assessed ^[105]B3b. Persistent depression, pain, and adverse body-image changes remain clinically relevant after remission, and body-image and pain measures were associated with depression in registry data ^[190]. These findings support long-term endocrine, metabolic, psychological, and functional follow-up even when cortisol targets are met ^{[105]B3b[190]}.

Suppression: bridging, persistent, or unresectable disease

Cortisol-lowering therapy is used as a bridge to surgery, for persistent or recurrent disease, when the source is occult, or when definitive treatment is unsuitable. Choice depends on the speed required, severity of hypercortisolism, hepatic and renal function, drug interactions, tumor biology, and the need to preserve interpretable biochemical monitoring ^[172]C[183]C. Ectopic ACTH syndrome carries substantial morbidity and is associated with worse survival in matched real-world neuroendocrine-neoplasm cohorts, supporting an aggressive, multidisciplinary strategy for cortisol control and oncologic treatment ^[182].

Thrombosis prevention must be considered during active ACTH-dependent disease because venous thromboembolism risk is markedly increased. A retrospective center experience compared 70 adults treated before and after routine rivaroxaban prophylaxis, introduced at 10 mg once daily in 2019; this supports consideration of protocolized thromboprophylaxis, but individualized bleeding-risk assessment remains necessary because the study was retrospective ^[66]B2b.

Source localization must remain dynamic. Among 57 patients with rigorously defined MRI-negative ACTH-dependent disease who underwent transsphenoidal surgery, 5 patients (8.8%) were subsequently diagnosed with ectopic ACTH-secreting tumors during long-term follow-up ^[175]C. Thus, apparent pituitary remission, recurrence, or unexplained biochemical persistence should prompt renewed evaluation for an occult ectopic source rather than indefinite empiric suppression alone ^[175]C. This issue is especially important in MEN1, where synchronous neuroendocrine tumors can complicate ACTH-source attribution ^[172]C. Pheochromocytoma is a rare ectopic ACTH source and may present with refractory hypertension, hypokalemia, pregnancy-associated atypical features, or limited classic Cushing phenotype ^[57]C4.

Definitive treatment and surveillance

Definitive treatment is source-directed surgery when feasible, including transsphenoidal surgery for confirmed Cushing disease, adrenalectomy for a cortisol-producing adrenal lesion, or resection of an ectopic ACTH/CRH-producing tumor. Surgical planning should incorporate tumor biology and perioperative risk: cortisol-producing oncocytic adrenocortical carcinoma may show invasive behavior and a high Ki-67 index, while pediatric adrenocortical tumors can present atypically, including bilateral disease, hemorrhage, or delayed endocrine recognition ^{[103]C4[55]C4}. Adrenalectomy outcomes are also influenced by obesity, although available laparoscopic data are retrospective ^[46]B3b.

Postoperative adrenal insufficiency is a predictable management issue. Even in mild autonomous cortisol secretion, unilateral adrenalectomy can produce postoperative adrenal insufficiency; one study defined suspected insufficiency as day-1 morning cortisol <10 μg/dL or a requirement for glucocorticoid replacement ^[106]B2b. This threshold is not a universal remission criterion, but it illustrates the need for postoperative cortisol assessment and a planned replacement pathway ^[106]B2b. Functional imaging, including 68Ga-DOTA-Pentixafor PET/CT, has been prospectively evaluated for characterization and lateralization of benign functional adrenal cortical lesions, but its role should be integrated with conventional imaging and biochemical assessment rather than used in isolation ^[176]C.

For adrenal disease, tumor size alone does not establish hormonal activity or malignant potential; retrospective adrenalectomy data emphasize heterogeneity in pathology, secretion, outcomes, and complications ^[189]. Patients with type 2 diabetes and resistant cardiometabolic disease may have unrecognized cortisol excess, although overt Cushing syndrome remains uncommon and mild autonomous cortisol secretion is more frequent in selected high-risk populations ^[178]D. Long-term surveillance should therefore include recurrence or persistence of hypercortisolism, adrenal insufficiency, cardiometabolic complications, bone and vascular health, thrombosis risk, tumor progression, and psychological recovery ^{[66]B2b[105]B3b[182][190]}.

From recognition of overt disease to a spectrum-based approach

Treatment has evolved alongside recognition that Cushing syndrome (CS) is not a single uniform disorder. More than a century after Harvey Cushing’s original description, contemporary understanding includes overt hypercortisolism as well as milder, clinically subtle states such as mild autonomous cortisol secretion (MACS); failure to recognize these nuances may delay diagnosis and increase morbidity. ^[118]D5 This broader spectrum has shifted management from treating only florid physical features to addressing biochemical cortisol autonomy, cardiometabolic disease, psychological burden, hepatic complications, and long-term risks. ^{[118]D5[73]B2b[153][112]B3b}

Surgical treatment and refinement of indications

For endogenous, surgically remediable hypercortisolism, definitive treatment has traditionally centered on removal of the cortisol-producing source. Recent evidence has strengthened the role of adrenalectomy in selected patients with MACS. In a prospective multicenter randomized trial, 132 patients with adrenal incidentaloma, no overt CS features, and serum cortisol >50 nmol/L after a 1-mg overnight dexamethasone suppression test were assigned to adrenalectomy or observation; 118 completed the study, with a median follow-up reported in the abstract. ^[114]A1b The trial’s stated objective was to assess metabolic effects, and its reported conclusion was that adrenalectomy improved control of body weight, glucose, and blood pressure, supporting surgery as a treatment option when cortisol autonomy coexists with clinically important metabolic disease. ^[114]A1b

Prospective evidence is also expanding beyond MACS. A 2019–2025 single-center cohort followed 357 adults with surgically remitted endogenous hypercortisolism, including 49% with MACS and 36% with pituitary CS, to assess changes in hypertension, diabetes, hyperlipidemia, and obesity at 3 and 12 months after remission. ^[73]B2b This reflects an evolution toward measuring treatment success by improvement in comorbidity severity rather than by biochemical remission alone. ^[73]B2b However, the supplied abstract does not provide the cohort’s numerical outcome estimates or the specific predictors of improvement, so these results should not be extrapolated beyond the reported study population. ^[73]B2b

Operative planning has also become more individualized. In a retrospective series of 90 patients with CS undergoing unilateral laparoscopic adrenalectomy, investigators specifically evaluated whether obesity affected operative time, conversion to open surgery, complications, and hospital stay. ^[138]C The study supports assessment of body habitus as part of perioperative risk stratification, although the supplied abstract does not include the comparative results. ^[138]C In children and adolescents, adrenal tumors are uncommon and may include adenoma, carcinoma, pheochromocytoma, isolated micronodular adrenocortical disease, and other pathology; a retrospective series of 31 patients examined endocrine, radiologic, histopathologic, and genetic outcomes. ^[191]C Pediatric adrenocortical tumors may present atypically, including with bilateral disease, hypertensive crisis, incidental discovery, misleading hormonal testing, premature pubarche, or hemorrhage, emphasizing early endocrine evaluation and multidisciplinary treatment. ^[55]C4

Bilateral adrenal disease requires a distinct surgical strategy. Primary pigmented nodular adrenocortical disease is a rare ACTH-independent cause of CS, often associated with Carney complex and pathogenic PRKAR1A variants; management must be integrated with surveillance and treatment of associated cardiac, cutaneous, and other endocrine manifestations. ^{[119]C4[117]C4} Primary bilateral macronodular adrenal hyperplasia is heterogeneous, ranging from subclinical cortisol excess to overt CS; ARMC5 variants occur in approximately 20%–55% of reported cases and may be associated with more severe disease. ^[192]C Bilateral adrenalectomy remains a treatment used for severe bilateral disease, as illustrated by a case involving refractory hypertension, hypokalemia, diabetes, and overt ACTH-independent hypercortisolism. ^[192]C

Treatment of exogenous and unusual cortisol excess

The management pathway begins by distinguishing endogenous CS from exogenous glucocorticoid exposure. Commonly overlooked sources include adulterated supplements, undocumented injections, and delayed release from injection-site lesions. Artri King and related products have been reported to contain undeclared dexamethasone; abrupt discontinuation after prolonged use can cause secondary adrenal insufficiency requiring hydrocortisone replacement. ^{[116]C4[87]C4} Persistent iatrogenic CS may occur after intramuscular dexamethasone, including delayed absorption from gluteal abscesses even when routine serum testing is unrevealing. ^[193]C Rare exogenous causes include herbal or traditional remedies adulterated with glucocorticoids and other atypical exposure mechanisms. ^[28]D5

Treatment withdrawal must therefore be supervised. Glucocorticoid withdrawal syndrome can produce musculoskeletal, gastrointestinal, neuropsychiatric, cardiovascular, and metabolic symptoms that resemble adrenal insufficiency or recurrence of the treated disease. ^[23]D5 A case of adrenocortical carcinoma-associated CS also illustrates that rapid cortisol reduction with metyrapone and surgery may destabilize coexisting immune thrombocytopenia, requiring concurrent steroid support and close monitoring. ^[104]C4

Comorbidity-directed and patient-centered treatment

The therapeutic goal has progressively broadened to include complications that may persist after cortisol normalization. Hepatic steatosis is common in metabolic disease accompanying CS; a retrospective study of 49 patients assessed metabolic dysfunction-associated steatotic liver disease at diagnosis using computed tomography and calculated fibrosis scores including FIB-4, the NAFLD Fibrosis Score, and eLIFT. ^[112]B3b A nationwide Taiwanese cohort identified 1,278 newly diagnosed endogenous CS patients, including 1,246 without previous malignancy, to examine subsequent cancer incidence, highlighting the need to consider cancer risk within long-term care. ^[33]B2b Depression and anxiety are also clinically relevant: a matched nationwide cohort of 540 patients with CS and 2,517 controls used affective-drug dispensations to compare treated mood and anxiety disorders and examined whether treatment discontinuation differed by etiology and remission status. ^[153]

Current practice consequently favors individualized, evidence-based intervention: definitive surgery when the source and patient profile make it appropriate, careful management of postoperative or withdrawal-related adrenal insufficiency, and active follow-up of metabolic, hepatic, cardiovascular, psychological, and oncologic consequences. ^{[73]B2b[23]D5[33]B2b[112]B3b[153]} The Spanish Society of Endocrinology and Nutrition has additionally emphasized avoiding diagnostic or therapeutic procedures that lack a favorable benefit–risk or cost-effectiveness profile, reflecting a modern move away from indiscriminate testing and overtreatment. ^[115]A1c

Inherited tumor syndromes and somatic genetic aberrations frequently drive the pathogenesis of Cushing syndrome (CS), necessitating a multidisciplinary approach to cross-axis surveillance. While most cases are sporadic, the clustering of adrenocortical tumors with other endocrine neoplasms often signals an underlying germline predisposition, such as Multiple Endocrine Neoplasia Type 1 (MEN1), Li-Fraumeni syndrome, or Beckwith-Wiedemann syndrome ^[5]D5[55]C4.

Genetic Drivers and Somatic Mutations

Somatic mutations are identified in approximately 71.8% of cortisol-producing adenomas (CPAs) ^[36]C4. The genetic profile differs significantly between overt Cushing syndrome (OCS) and mild autonomous cortisol excess (MACE). In OCS, the cyclic adenosine monophosphate-dependent protein kinase A (PKA) pathway is frequently activated via PRKACA mutations (43.8%), whereas CTNNB1 mutations (Wnt/β-catenin pathway) predominate in MACE (56.5%) ^{[36]C4[121]D5}. GNAS mutations, which also stimulate steroidogenesis, are more common in MACE (71.4% of all GNAS mutations) but have been reported in rare cases of oncocytic adrenocortical carcinoma ^{[36]C4[103]C4}.

Co-Axis Suppression and Hormonal Crosstalk

Chronic hypercortisolism exerts a severity-dependent suppression on the hypothalamic-pituitary-gonadal (HPG) and thyroid axes ^[82]B3b. The gonadal axis appears more susceptible to glucocorticoid excess than the thyroid axis ^[82]B3b.

• HPG Axis: Ectopic ACTH syndrome (EAS) causes the most profound suppression, characterized by markedly reduced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels ^[82]B3b. Conversely, EAS is associated with markedly elevated testosterone, which may aid in discriminating it from other subtypes ^[82]B3b.
• Hirsutism: Excess androgens contribute to hirsutism in approximately 10% of women globally, though CS remains a rare cause compared to polycystic ovary syndrome (80-90%) ^[18]D5.
• Pregnancy: ACTH-independent CS during pregnancy is often driven by adrenal adenomas aberrantly expressing LH receptors, which are activated by rising human chorionic gonadotropin (hCG) levels ^[17]D5.

Multiglandular and Syndromic Presentations

Ectopic ACTH or CRH production can arise from catecholamine-secreting pheochromocytoma , a rare but critical diagnostic consideration in patients with ACTH-dependent CS and an adrenal mass ^[50]A1a. In these cases, 93% of patients present with hypertension and 54% with diabetes ^[50]A1a. Furthermore, subclinical CS frequently coexists with primary aldosteronism (PA-SCS). These patients typically have larger adrenal lesions (2.24 cm vs 1.10 cm in isolated PA) and higher lesion-to-contralateral ratios on 68Ga-pentixafor PET/CT ^[71]B3b.

Systemic Metabolic and Tissue Effects

Glucocorticoid excess disrupts the bidirectional crosstalk between the adrenal cortex and adipose tissue, leading to visceral adiposity and insulin resistance ^[20]D5. In patients with obesity, the prevalence of an abnormal dexamethasone suppression test (DST) is 4.6%, with confirmed CS in 0.8% ^[44]A1a. Among patients with diabetes, the prevalence of an abnormal DST rises to 14.3%, with confirmed CS in 2.1% ^[44]A1a. Beyond metabolic dysfunction, even subtle endogenous excess is detrimental to bone health, increasing the risk of osteoporosis ^[25]D5. Cardiovascular surveillance is essential, as CS is associated with an increased risk of new-onset atrial fibrillation or flutter (HR 1.55, 95%), a risk that persists despite biochemical remission ^[35]B2b.

Pearl: Systematically screen for co-secretion and genetic syndromes in young patients or those with bilateral adrenal disease, as somatic CTNNB1 mutations or germline predispositions significantly alter the long-term surveillance strategy ^[36]C4[55]C4.

Overview

Chronic endogenous hypercortisolism produces multisystem morbidity through effects on glucose metabolism, lipid homeostasis, cardiovascular function, blood-pressure regulation, bone and muscle, reproductive function, immunity, and neuropsychiatric health. The burden extends across overt Cushing syndrome (CS) and milder phenotypes such as mild autonomous cortisol secretion (MACS), which may present without classic cushingoid features but with resistant diabetes, resistant hypertension, obesity, or progressive cardiometabolic disease ^{[202]D[178]D[27]D5}. Complications reflect cortisol exposure, disease duration, etiology, comorbidity burden, and the degree and speed of recovery after treatment ^[27]D5[202]D.

Cardiometabolic and cardiovascular complications

Hypertension, insulin resistance, hepatic gluconeogenesis, visceral adiposity, dyslipidemia, obesity, and cardiovascular disease are central consequences of hypercortisolism ^[178]D[202]D. A prospective cohort of 357 adults with CS or MACS undergoing surgical remission evaluated hypertension, diabetes mellitus, hyperlipidemia, and obesity at baseline, 3 months, and 12 months; the study was designed to identify which comorbidities improve after remission and which baseline factors predict recovery, although the supplied abstract does not report the numerical outcome estimates ^[73]B2b.

Dyslipidemia is clinically important because CS is associated with high cardiovascular mortality. A 2026 systematic review and meta-analysis identified 29 observational or interventional studies evaluating total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides before and after treatment; the supplied abstract confirms that before-after and subgroup analyses were performed but does not provide the pooled effect sizes ^[94]A1a. Lipid abnormalities should therefore be reassessed after biochemical remission rather than assumed to resolve completely ^{[94]A1a[73]B2b}.

Arrhythmia is an additional cardiovascular concern. In a population-based matched cohort comprising 609 patients with CS and 3,018 controls, pre-existing atrial fibrillation or flutter was more frequent in CS than in controls (3.6% vs 2.1%; OR 1.70, 95% CI [reported in the study]) ^[35]B2b. The study also assessed new-onset atrial fibrillation/flutter according to CS etiology and remission status, supporting attention to rhythm complications during active disease and follow-up after treatment ^[35]B2b.

In neuroendocrine neoplasms, a propensity-score-matched analysis of code-defined CS compatible with ectopic CS evaluated overall survival and clinical outcomes in a large international electronic-medical-record network; the supplied abstract identifies 265 patients in the ectopic-CS-compatible cohort before matching but does not provide the final hazard ratios or outcome frequencies ^[182]. The study’s premise and reported conclusion indicate that ectopic CS is associated with worse survival and greater morbidity in patients with neuroendocrine neoplasms ^[182].

Venous thromboembolism and infection

Endogenous CS creates an intrinsic hypercoagulable state and clinically important venous thromboembolism (VTE) risk ^{[155]C[66]B2b}. In a cohort of 408 patients with Cushing disease, VTE occurred in 35 patients (8.6%), compared with 1 patient in a comparator group of 323 patients with nonfunctioning pituitary macroadenomas undergoing similar procedures ^[155]C. This difference supports active perioperative VTE risk assessment, particularly when disease is severe or surgery and immobility add provocation ^[155]C.

A retrospective study of 70 adults with ACTH-dependent CS compared VTE outcomes before and after a center introduced routine rivaroxaban prophylaxis at 10 mg once daily in 2019; 29 patients were managed before implementation and 41 afterward ^[66]B2b. The supplied abstract reports no baseline-characteristic differences between groups but does not provide the comparative VTE or bleeding estimates; prophylaxis decisions should therefore remain individualized and guided by procedural, bleeding, and disease-specific risk ^[66]B2b.

Infection is another major complication of cortisol excess and may be particularly relevant around surgery. Among 113 patients with CS, 35 (31%) developed infection ^[132]B3b. In that study, the 1-mg dexamethasone-suppression-test result showed an area under the receiver-operating-characteristic curve of 0.852 for infection prediction; the prognostic nutritional index was also evaluated, although its complete performance estimate is not included in the supplied abstract ^[132]B3b.

Skeletal, muscular, reproductive, and treatment-related sequelae

Cortisol excess adversely affects bone and muscle, contributing to osteoporosis, fragility fractures, and proximal weakness ^[27]D5[202]D. A multicenter cross-sectional study assessed osteoporosis and symptomatic fragility fractures using questionnaires and dual-energy X-ray absorptiometry in adults with nonfunctioning adrenal adenomas, MACS, CS, and referent participants; the supplied abstract does not include the prevalence estimates or adjusted associations ^[201]. A population-level search-trend study reported correlations between osteoporosis and multiple comorbidities but was not a CS cohort and should not be used to quantify CS-specific skeletal risk ^[203]D.

Reproductive and sexual dysfunction is common and affects quality of life ^[82]B3b. A retrospective study of 137 women with adrenal CS, Cushing disease, or ectopic ACTH syndrome evaluated hypothalamic-pituitary-gonadal-axis suppression and compared reproductive hormone profiles across etiologic subtypes; the supplied abstract emphasizes severity-dependent suppression but does not provide the complete hormone results ^[82]B3b.

Correction of hypercortisolism can itself produce clinically significant sequelae. Glucocorticoid withdrawal syndrome may cause musculoskeletal, gastrointestinal, neuropsychiatric, cardiovascular, and metabolic symptoms that resemble adrenal insufficiency or recurrence of inflammatory disease ^[23]D5. Rapid cortisol reduction may also destabilize immune disorders: a case of adrenocortical carcinoma with CS and pre-existing immune thrombocytopenia described relapse of thrombocytopenia after metyrapone and tumor resection, requiring exogenous steroids while hypercortisolism was corrected ^[104]C4.

Perioperative considerations and evidence limits

Obesity increases concern for surgical complications, although a single-center retrospective study of 110 patients undergoing laparoscopic adrenalectomy compared obese patients (BMI ≥30 kg/m²) with nonobese patients and evaluated perioperative and postoperative outcomes; the supplied abstract does not report the comparative complication results ^[46]B3b. A separate retrospective analysis of 170 adrenalectomies examined tumor size, hormonal secretion, surgical outcomes, and complications, but the provided information does not give CS-specific long-term sequelae or complete results ^[189].

The broader literature also includes non-CS-specific evidence on shared genetic architecture between sleep traits and cardiometabolic diseases ^[10]B2c and a review of lung carcinoids that discusses neuroendocrine tumor classification and management ^[5]D5. These sources may provide background for sleep-related cardiometabolic risk or ectopic ACTH-producing tumors, respectively, but they do not establish CS-specific complication rates and should not be extrapolated without direct evidence ^[10]B2c[5]D5.

Overall prognosis and disease spectrum

Cushing syndrome (CS) is a heterogeneous disorder in which prognosis depends on the cause, magnitude and duration of cortisol excess, associated comorbidities, tumor biology, and the speed with which hypercortisolism is controlled. The spectrum extends from exogenous glucocorticoid exposure and overt endogenous CS to mild autonomous cortisol secretion (MACS), which may produce clinically important cardiometabolic disease despite limited classic cushingoid features. ^[27]D5 Chronic cortisol excess promotes insulin resistance, hepatic gluconeogenesis, visceral adiposity, hypertension, dyslipidaemia and cardiovascular disease. ^[178]D

Ectopic Cushing syndrome (ECS) arising from neuroendocrine neoplasms is particularly concerning because it combines the systemic complications of severe hypercortisolism with the prognosis of the underlying malignancy. In a large propensity-score-matched real-world cohort of patients with neuroendocrine neoplasms, code-defined ECS was specifically evaluated in relation to survival and morbidity, reflecting the clinically adverse nature of this complication. ^[182] Thymic neuroendocrine tumors are rare, frequently advanced, and may occur with multiple endocrine neoplasia type 1 (MEN1); a French multicentre study of 74 locally advanced or metastatic cases reported MEN1 in 34% of patients. ^[26]C4

Cardiometabolic, cardiovascular and skeletal outcomes

Surgical remission can improve cardiometabolic disease, but recovery is not necessarily complete or immediate. A prospective cohort of 357 patients with endogenous hypercortisolism, including 49% with MACS and 36% with pituitary CS, assessed hypertension, diabetes, hyperlipidaemia and obesity at baseline, 3 months and 12 months after remission, emphasizing the need for structured post-treatment assessment rather than assuming that biochemical cure immediately reverses comorbidity. ^[73]B2b

CS is associated with an increased burden of atrial fibrillation and atrial flutter. In a population-based matched cohort, pre-existing atrial fibrillation/flutter occurred in 3.6% of patients with CS compared with 2.1% of matched controls, corresponding to an odds ratio of 1.70; risk was also examined according to disease cause and remission status. ^[35]B2b Cardiovascular risk assessment should therefore remain part of long-term follow-up, including after treatment of hypercortisolism. ^[35]B2b

Skeletal complications are an important but under-recognized source of persistent morbidity. A US insurance-claims study including 53,101 patients with CS found that only 6.40% underwent bone mineral density measurement, demonstrating a substantial gap between osteoporosis risk and preventive evaluation, particularly among males and older adults. ^[156] Bone health assessment and fracture-risk management should consequently be incorporated into CS care rather than reserved for patients with overt skeletal symptoms. ^[156]

Neuropsychiatric and quality-of-life outcomes

Depression and anxiety are common clinically relevant consequences of endogenous CS and may persist after biochemical remission. A nationwide matched-cohort study of 540 patients with endogenous CS and 2,517 controls followed for a median of 13.20 years evaluated treated mood and anxiety disorders and medication discontinuation in relation to disease cause and remission status. ^[153] Prospective or registry-based assessment of mood, body image, pain and functional recovery is warranted because physical recovery may not parallel cortisol normalization. ^[190]

In a German Cushing registry analysis of 90 patients with CS and 200 clinically suspected controls, body image and pain were examined as potential predictors of depression, supporting attention to persistent psychological and somatic symptoms during long-term follow-up. ^[190]

Recurrence, diagnostic delay and surveillance

Long-term surveillance is necessary when the source of ACTH is uncertain, particularly in MRI-negative presumed Cushing disease. Among 57 rigorously defined MRI-negative patients who underwent transsphenoidal surgery, 5 were subsequently diagnosed with ectopic ACTH-secreting tumors during follow-up, demonstrating that an initially presumed pituitary source may later prove incorrect. ^[175]C Persistent, recurrent or discordant biochemical disease should prompt renewed evaluation for an occult ectopic tumor rather than being attributed automatically to recurrent pituitary disease. ^[175]C

Accurate biochemical interpretation is essential for distinguishing persistent disease from assay-related or physiological variation. A Canadian study derived and prospectively evaluated a mass-spectrometry reference interval for 24-hour urinary free cortisol using 4,830 non-CS results and 120 prospectively evaluated individuals in whom CS was excluded; urinary cortisol correlated with urine volume, highlighting the importance of validated, volume-aware interpretation. ^[43]B2c In ACTH-dependent disease, optimized lower cutoffs for desmopressin-stimulated bilateral inferior petrosal sinus sampling are being evaluated to improve discrimination between pituitary CS and ECS. ^[70]B2b Prolactin-adjusted sampling and alternative calculation methods have also been studied in patients with inconclusive pituitary MRI. ^[195]C

Prevention and early detection

Most exogenous CS is caused by therapeutic glucocorticoids, but adulterated herbal or traditional remedies and supplements may contain undeclared glucocorticoids. Prevention therefore includes medication reconciliation, review of non-prescription and traditional products, avoidance of unsupervised glucocorticoid use, and appropriate tapering and monitoring when clinically feasible. ^[28]D5

Routine population screening is not established, but targeted evaluation may be appropriate in selected patients with obesity, type 2 diabetes, resistant hypertension or progressive cardiometabolic disease, especially when classic cushingoid signs are absent. ^[44]A1a The rationale is that overt CS is uncommon whereas milder cortisol excess or MACS may be under-recognized in these high-risk groups. ^[44]A1a The 1-mg overnight dexamethasone suppression test is a principal first-line approach evaluated in obesity and diabetes populations. ^{[44]A1a[178]D}

Familial and syndromic causes require preventive surveillance rather than lifestyle prevention alone. Familial bilateral macronodular adrenocortical disease may involve ARMC5 or KDM1A and shows marked clinical and hormonal variability over follow-up periods of 8–410 months. ^[194] Primary pigmented nodular adrenocortical disease may occur in isolation or as part of Carney complex; integrated genetic evaluation and cascade screening can identify affected relatives before severe CS develops. ^[179]D MEN1 may create diagnostic complexity because multiple synchronous neuroendocrine tumors can coexist, making source localization and ongoing surveillance essential. ^[172]C

Practical follow-up priorities

After remission, follow-up should include biochemical surveillance for recurrence, reassessment of blood pressure and glycaemia, cardiovascular-risk review, lipid and weight management, bone mineral density evaluation, and screening for depression, anxiety, pain and body-image distress. ^{[35]B2b[73]B2b[153][156][190]} Patients with suspected ectopic, familial or syndromic disease require individualized tumor surveillance and, when appropriate, long-term genetic counseling and family testing. ^{[26]C4[172]C[179]D[194]}

Pregnancy: rarity, recognition, and maternal–fetal risk

Cushing syndrome (CS) during pregnancy is rare but is associated with substantial maternal and fetal morbidity; early recognition is important because clinical features may overlap with normal pregnancy changes or pregnancy-related hypertension and metabolic disease. ^{[131]C4[58]D5[197]D} In two reported pregnancies, including one twin pregnancy, typical clinical manifestations of hypercortisolism developed early in gestation, and the normal plasma cortisol diurnal rhythm was absent. ^[131]C4 The diagnosis was supported by cortisol testing and adrenocorticotropic hormone (ACTH) assessment, although interpretation requires pregnancy-specific expertise because physiological changes alter endocrine test results. ^{[131]C4[58]D5}

Pregnancy can complicate the recognition of CS because weight gain, hypertension, glucose intolerance, skin changes, and other findings may be attributed to gestation. ^[58]D5[197]D Secondary hypertension reviews specifically identify CS and ACTH-producing pheochromocytoma among uncommon but clinically important causes of hypertension in pregnancy; determining the cause is necessary to select appropriate maternal and fetal management. ^[197]D A case of ectopic ACTH syndrome caused by pheochromocytoma presented during pregnancy with atypical manifestations, refractory hypertension, and hypokalemia, illustrating that the absence of classic CS features does not exclude the diagnosis. ^[57]C4 ACTH-producing pheochromocytomas and paragangliomas are rare tumors that may co-secrete catecholamines and ACTH, producing a combination of CS and catecholamine-related cardiovascular risk. ^[199]D

Treatment and surveillance during pregnancy

Management should be individualized by a multidisciplinary team experienced in endocrinology, high-risk obstetrics, anesthesia, surgery, and neonatal care. ^{[131]C4[58]D5} The available pregnancy literature is dominated by case reports and small series, so treatment decisions must balance control of maternal hypercortisolism against fetal exposure and the risks of delaying definitive therapy. ^{[131]C4[58]D5} Adrenal disorders in pregnancy are diagnostically challenging, and CS and adrenocortical carcinoma are often managed surgically; early diagnosis, ideally before conception, is emphasized. ^[58]D5

Medical therapy may be required when surgery is not immediately possible, as a presurgical bridge, after persistent or recurrent disease, or while awaiting radiotherapy effects in pituitary CS. ^[24]D5 Available medical options include adrenal steroidogenesis inhibitors—ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate—pituitary-directed agents such as pasireotide and cabergoline, and the glucocorticoid-receptor antagonist mifepristone. ^[24]D5 However, the cited medical-treatment review is not a pregnancy-specific safety guideline; drug selection during gestation therefore requires specialist risk–benefit assessment rather than routine extrapolation from nonpregnant adults. ^[24]D5[58]D5

ACTH-dependent CS is associated with markedly increased venous thromboembolism (VTE) risk. ^[66]B2b In a retrospective study of 70 adults, a center introduced routine rivaroxaban prophylaxis at 10 mg once daily in 2019 and compared 41 subsequently managed patients with 29 earlier patients; the study evaluated safety and effectiveness but does not establish a pregnancy regimen. ^[66]B2b Anticoagulant choice in pregnancy and the peripartum period must therefore be determined by obstetric and hematology specialists, with attention to gestational timing, bleeding risk, delivery planning, and neuraxial anesthesia. ^[66]B2b

Fertility, bilateral adrenalectomy, and Nelson syndrome

Nelson syndrome is a rare, potentially life-threatening complication after total bilateral adrenalectomy for Cushing disease. ^[130]A1a A successful term pregnancy after fertility treatment has been reported in a woman with Nelson syndrome. ^[130]A1a A systematic review accompanying that case identified 50 pregnancies across 14 publications, but the literature remains limited and there are no universally accepted prenatal or intrapartum guidelines. ^[130]A1a Reported care emphasizes individualized prenatal monitoring and coordinated intrapartum management, reflecting the potential challenges of altered pituitary–adrenal physiology and adrenal-replacement requirements after bilateral adrenalectomy. ^[130]A1a

Preconception counseling should address disease control, the cause of CS, prior pituitary or adrenal surgery, adrenal-replacement needs, recurrence surveillance, thrombotic risk, and the limited evidence base for pregnancy-specific treatment. ^{[130]A1a[131]C4[58]D5[66]B2b}

Children and adolescents

Pediatric CS may present differently from adult disease. In a cohort of 273 patients with onset at ≤18 years, 84 patients (31%) did not have obesity, while 189 (69%) did; patients without obesity were more often female and had an older age at onset. ^[41]C4 Consequently, the absence of marked obesity should not be used to exclude pediatric CS. ^[41]C4

Pediatric adrenocortical tumors are rare and frequently functional. In a registry study of 155 children and adolescents, endocrine manifestations commonly preceded diagnosis by approximately 4–6 months, and their pattern varied with age, sex, and pubertal stage. ^[127]B3b Presentations may include hypercortisolism or virilization, but atypical presentations—including bilateral tumors, hypertensive crisis, misleading hormonal evaluation, trauma-associated discovery, gradual premature pubarche, and hemorrhagic lesions—can delay diagnosis. ^[55]C4 Distinguishing benign from malignant pediatric adrenocortical neoplasms remains difficult; a study of 92 pediatric tumors evaluated the modified reticulin algorithm alongside established pediatric criteria. ^[200]D

Other special populations

McCune–Albright syndrome is caused by somatic gain-of-function variants in GNAS, with variable involvement of bone, skin, and endocrine tissues; its broad phenotype may complicate evaluation of endocrine abnormalities in children. ^[83]B3b Chronic glucocorticoid exposure can suppress the hypothalamic–pituitary–adrenal axis in children and is the most frequent cause of adrenal insufficiency in this population, creating an important distinction between exogenous glucocorticoid effects and endogenous CS. ^[92]D5 Obesity may increase perioperative complexity, although a single-center study of laparoscopic adrenalectomy evaluated outcomes by a threshold of BMI ≥30 kg/m² and was not specific to pregnancy or CS. ^[46]B3b