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 axis and glucocorticoid signaling

Cortisol production is normally governed by the hypothalamic–pituitary–adrenal (HPA) axis, in which hypothalamic and pituitary signals regulate adrenal steroidogenesis, while circulating glucocorticoids provide negative feedback. Disruption at any level can produce clinically relevant hypercortisolism. Endogenous Cushing syndrome is conventionally divided into corticotropin-dependent and corticotropin-independent disease according to whether cortisol excess is driven by ACTH or occurs despite ACTH suppression. Exogenous glucocorticoid exposure represents a separate mechanism and may arise from prescribed drugs, adulterated herbal or traditional remedies, supplements, or other unrecognized sources. ^[27]D5[28]D5

Cortisol acts principally through the glucocorticoid receptor (GR), a ligand-activated transcription factor that modifies gene expression and cellular metabolism. GR signaling suppresses inflammation but also promotes adverse metabolic effects during sustained exposure. Glucocorticoid effects are tissue-specific and depend on receptor activity, exposure intensity and duration, and local metabolic pathways. Chronic cortisol excess is associated with adipose-tissue dysfunction, altered adipokine secretion, visceral adiposity, insulin resistance, hypertension, and cardiovascular risk. ^{[20]D5[27]D5[147]D[148]D}

Adrenal–adipose communication is bidirectional: adrenal glucocorticoids influence lipid storage, adipose distribution and thermogenic programs, whereas adipose tissue participates in systemic metabolic regulation. In Cushing syndrome, disruption of this relationship contributes to central fat accumulation and an adverse cardiometabolic phenotype. Experimental evidence further implicates serum- and glucocorticoid-induced kinase 3 (SGK3) in glucocorticoid-driven adipogenesis; inhibition or genetic loss of SGK3 reduced adipogenesis in murine models and conferred resistance to glucocorticoid-induced obesity. ^[20]D5[147]D

Pathophysiological mechanisms and etiologic spectrum

The clinical phenotype varies with the source, severity and duration of cortisol excess. Overt disease classically produces centripetal adiposity, proximal muscle weakness, skin fragility, hypertension and glucose dysregulation, although milder autonomous secretion may lack the typical phenotype. ^[27]D5 Mild autonomous ACTH secretion (MAAS) is described as autonomous pituitary-derived hypercortisolism without overt Cushing features. A literature review of 52 cases found MAAS across ages 18–83 years, with women comprising 60% of cases; it was reported in approximately 5% of patients with pituitary adenomas and was associated with substantial metabolic morbidity, including hypertension in 56% of reported cases. ^[204]D

Adrenal disease may be unilateral or bilateral. Primary bilateral macronodular adrenal hyperplasia is increasingly detected through imaging, including in asymptomatic individuals, and requires biochemical evaluation for steroid excess because many patients exhibit mild autonomous cortisol secretion. Severe phenotypes are frequently associated with ARMC5 abnormalities, whereas KDM1A has been implicated particularly in food-dependent forms. Aberrant adrenal hormone-receptor expression and intra-adrenal ACTH production by steroidogenic cells may contribute to cortisol dysregulation. ^[31]D5

Molecular abnormalities in cAMP/PKA signaling can promote adrenal steroidogenesis and endocrine hypertension. Activating GNAS variants increase signaling through the stimulatory G-protein α-subunit; mosaic variants may cause McCune–Albright syndrome with ACTH-independent Cushing syndrome, while somatic GNAS alterations have also been linked to cortisol excess. ^[146]D Thymic neuroendocrine tumors are a rare potential source of ectopic endocrine syndromes; in a French multicenter cohort of 74 locally advanced or metastatic tumors, 34% of patients had multiple endocrine neoplasia type 1, and the cohort included both atypical carcinoids and highly proliferative neuroendocrine tumors. These findings support consideration of tumor-associated endocrine dysregulation in selected ACTH-dependent presentations. ^[26]C4[30]D5

Biochemical signature

Biochemical assessment should establish endogenous cortisol excess, determine ACTH dependency, and distinguish autonomous secretion from altered glucocorticoid sensitivity or exogenous exposure. Commonly used assessments include urinary free cortisol, dexamethasone-suppression testing, midnight salivary cortisol and plasma ACTH; however, the supplied evidence emphasizes interpretation in clinical context rather than providing universal numeric diagnostic cutoffs. ^{[12]C4[27]D5[204]D}

Discordant results require consideration of glucocorticoid resistance. A reported NR3C1 missense variant caused primary generalized glucocorticoid resistance, with elevated urinary free cortisol and an abnormal low-dose dexamethasone-suppression test despite normal ACTH and midnight salivary cortisol. Such biochemical discordance can mimic Cushing syndrome and may lead to inappropriate pituitary surgery if receptor resistance is not considered. ^[12]C4

In ACTH-dependent disease, localization may require functional imaging because corticotroph tumors can be small or anatomically inconspicuous. A novel 68Ga-labeled desmopressin analogue targets V1b receptors overexpressed in tumoral corticotrophs and was investigated in patients with ACTH-dependent Cushing syndrome. ^[150]D In contrast, oncocytic thyroid adenoma has been reported in a patient with ACTH-independent Cushing syndrome; dual-tracer FDG and octreotide-receptor PET/CT was used to characterize the lesion, illustrating that incidental or coexisting tumors may complicate source attribution. ^[4]C4

Clinical consequences and treatment-related physiology

Excess cortisol impairs glucose homeostasis through mechanisms that contribute to difficult-to-control diabetes, obesity, hypertension and cardiovascular disease. ^[148]D Medical therapy may target adrenal steroidogenesis, pituitary ACTH secretion or peripheral GR signaling. Available approaches include steroidogenesis inhibitors, pituitary-directed agents and the GR antagonist mifepristone; treatment may be required before surgery, after persistent or recurrent disease, or when definitive treatment is not feasible. ^[24]D5 Relacorilant is another nonsteroidal selective GR antagonist under development for Cushing syndrome, although its first reported US approval was for combination treatment of platinum-resistant gynecologic cancer rather than Cushing syndrome. ^[29]D5

Reduction of chronic glucocorticoid exposure can produce glucocorticoid withdrawal syndrome, with musculoskeletal, gastrointestinal, neuropsychiatric, cardiovascular and metabolic symptoms that may resemble adrenal insufficiency or recurrence of the underlying disease. ^[23]D5

Epidemiology and spectrum

Cushing syndrome (CS) is an uncommon but clinically heterogeneous disorder caused by prolonged exposure to excessive glucocorticoids. The clinical spectrum includes mild autonomous cortisol secretion (MACS) and overt CS, and hypercortisolism may be under-recognized in people with obesity or diabetes because its manifestations overlap with common metabolic disease. ^[44]A1a A 2026 systematic review and meta-analysis identified 39 original studies involving 14,995 screened participants and specifically evaluated first-line screening—particularly the dexamethasone suppression test (DST)—and subsequently confirmed CS in patients with obesity or diabetes. ^[44]A1a These data support targeted case-finding rather than assuming that obesity or diabetes alone establishes CS. ^[44]A1a

In a nationwide matched-cohort study, 540 patients with endogenous CS were predominantly female (64.44%), with a mean age of 47.79 ± 17.01 years; each patient was matched with five controls. ^[153] A separate population-based cohort included 609 patients with CS and 3,018 matched controls, providing contemporary epidemiologic data on cardiovascular manifestations across etiologic subgroups and remission status. ^[35]B2b Pediatric CS also shows substantial phenotypic variability: among 273 patients with onset by 18 years, 189 (69%) had obesity and 84 (31%) did not. ^[41]C4 Children without obesity were more often female and had an older age at onset than children with obesity. ^[41]C4

Etiology

Endogenous CS is conventionally categorized by adrenocorticotropic hormone (ACTH) dependence: pituitary ACTH excess (Cushing disease), ectopic ACTH secretion, or ACTH-independent adrenal cortisol excess. In a 214-patient Polish tertiary-center cohort, pituitary CS accounted for 53%, adrenal CS for 25%, and ectopic CS for 22%. ^[154] In a European survey of 222 newly diagnosed patients, Cushing disease accounted for 64%, adrenal CS for 31%, and ectopic CS for 5.4%; the differing distributions likely reflect referral and case-ascertainment patterns rather than a directly comparable population prevalence. ^[159]C

Exogenous glucocorticoid exposure is also an important cause of Cushing syndrome; a nationwide claims-based study described CS as resulting primarily from chronic steroid use, while noting that pituitary tumors are an endogenous cause. ^[156] The available references do not provide a reliable population-level estimate separating exogenous from endogenous disease. ^[156]

Adrenal etiologies include unilateral cortisol-producing tumors and bilateral adrenal disease. Bilateral macronodular adrenocortical disease (BMAD) is a rare disorder characterized by bilateral adrenal nodules and variable cortisol excess. ^[42]C4 ARMC5 is an established genetic driver of BMAD; a Korean series enrolled 69 patients, and whole-exome sequencing was performed in 35, highlighting the relevance of inherited or somatic genetic assessment in selected patients with bilateral disease. ^[42]C4

Risk factors and associated clinical context

Obesity and diabetes are important contexts for detecting otherwise unrecognized cortisol excess, but they are also major sources of diagnostic overlap and potential false-positive screening results. ^[44]A1a In patients with CS, obesity and metabolic dysfunction may coexist with hepatic steatosis: a French study of 49 patients with CS who had abdominal imaging at diagnosis assessed metabolic dysfunction-associated steatotic liver disease using computed tomography. ^[112]B3b Because the study was single-center and retrospective, its findings should not be interpreted as a population prevalence estimate. ^[112]B3b

Long-term glucocorticoid excess is associated with clinically important skeletal risk. In a US insurance-claims study of 53,101 patients with CS, only 6.40% underwent bone-mineral-density measurement, indicating substantial underassessment of osteoporosis risk; testing was particularly underused among males and older adults. ^[156] These findings identify age and sex as care-gap modifiers rather than established causes of CS. ^[156]

The hypercortisolemic state is associated with thromboembolic risk. In a tertiary-center 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 patients with nonfunctioning pituitary macroadenomas undergoing similar surgery. ^[155]C A European registry survey included 222 new patients and examined venous thromboembolism and thromboprophylaxis during a mean post-diagnosis follow-up of 15 months. ^[159]C In another cohort of 70 adults with ACTH-dependent CS, routine rivaroxaban prophylaxis was introduced in 2019 and outcomes were compared between 29 pre-implementation and 41 post-implementation patients; this evidence concerns management of thrombotic risk, not disease etiology. ^[66]B2b

Cancer risk is an emerging epidemiologic consideration. A Taiwanese nationwide cohort identified 1,278 newly diagnosed patients with endogenous CS during 2006–2017; 1,246 without prior malignancy were included for cancer-incidence analyses. ^[33]B2b A separate retrospective cohort included 347 patients with endogenous hypercortisolism—138 with overt CS and 209 with MACS—excluded active malignancy at baseline, and evaluated incident cancers against age- and sex-specific national rates. ^[152] These studies address possible cancer associations but do not establish malignancy as a cause of CS. ^[33]B2b[152]

Persistent endocrine and psychiatric manifestations may remain relevant after biochemical remission. In a nationwide matched cohort, treated depression and anxiety were evaluated in 540 patients with endogenous CS versus 2,517 controls, with analyses stratified by etiology and remission status. ^[153] In a study of 93 women treated for CS, 68% had menstrual dysfunction, demonstrating that reproductive manifestations are common but not specific etiologic markers. ^[205] Long-term sarcopenia also occurs after remission: a pilot study compared 36 women in sustained remission for 13 ± 7 years with 36 matched controls and identified sarcopenia in 7 patients. ^[160]C

Practical interpretation

The principal risk for exogenous Cushing syndrome is chronic glucocorticoid exposure, whereas endogenous disease reflects pituitary, ectopic ACTH, adrenal, or genetically influenced bilateral adrenal pathology. ^{[156][154][159]C[42]C4} Obesity, diabetes, hypertension-like metabolic presentations, osteoporosis, hepatic steatosis, psychiatric disease, menstrual dysfunction, and thromboembolism should increase clinical vigilance but are consequences or overlapping features rather than specific causes. ^{[44]A1a[112]B3b[153][155]C[156][205]} Screening is most informative when clinical features are disproportionate, progressive, clustered, or otherwise unexplained, particularly in patients with obesity or diabetes. ^[44]A1a

Overview

Cushing syndrome (CS) is a clinical constellation caused by excessive exposure to exogenous or endogenous glucocorticoid hormones. Endogenous disease results from autonomous cortisol production by one or both adrenal glands, pituitary ACTH secretion (Cushing disease), or ectopic ACTH secretion from a non-pituitary tumor. ^[166]D The phenotype is heterogeneous, and clinical manifestations may be subtle, atypical, or shared with common disorders; this overlap contributes to underdiagnosis and delayed recognition. ^{[53]D5[165]D[166]D[168]C}

CS produces multisystem morbidity, particularly impaired cardiovascular and metabolic function, increased susceptibility to infection, and neuropsychiatric disease. ^[166]D Reported serious complications include pulmonary embolism, myocardial infarction, and cerebrovascular accidents, which contribute to increased mortality. ^[166]D Excess cortisol also disrupts adipose-tissue function and is associated with visceral adiposity, adverse adipokine profiles, and insulin resistance. ^[20]D5

Common and characteristic features

A characteristic facial phenotype may occur, including a rounded “moon face” and increased facial fat accumulation. Three-dimensional facial analysis has been used to distinguish cortisol-associated facial morphology from that of common obesity, indicating that facial changes are clinically relevant but not necessarily specific to CS. ^[163]D Weight gain and facial rounding are particularly important clues in children; a pediatric case of adrenocortical carcinoma presented with rapid weight gain and moon face over approximately 10 months. ^[171]C

Metabolic and cardiovascular manifestations are prominent. Hypertension and impaired glucose regulation or diabetes may accompany endogenous hypercortisolism, and difficult-to-control diabetes should raise consideration of CS when routine treatment is inadequate or only partially effective. ^[149]D[168]C In ACTH-dependent disease caused by an ACTH-secreting pheochromocytoma, refractory hypertension and hypokalemia were presenting findings in both reported cases; one patient developed symptoms during pregnancy with atypical clinical manifestations. ^[57]C4 These findings emphasize that severe hypertension or hypokalemia may dominate the presentation even when the classic CS phenotype is incomplete. ^[57]C4

Reproductive, androgenic, and pediatric presentations

Young women may present with menstrual abnormalities and/or clinical hyperandrogenism. Because these findings overlap with common gynecologic and endocrine disorders, they may represent a high-risk clinical context in which endogenous hypercortisolism is missed unless specifically considered. ^[165]D In children and adolescents, CS is uncommon and may be associated with growth or pubertal abnormalities; pediatric adrenocortical tumors classically present with virilization or hypercortisolism, but nonclassical presentations can delay diagnosis. ^[55]C4

Pediatric adrenocortical tumors may instead present with bilateral disease, hypertensive crisis with acute stroke, incidental discovery after trauma, misleading hormonal investigations, gradual premature pubarche, or hemorrhage. ^[55]C4 A reported child with adrenocortical carcinoma had rapid weight gain, moon face, and increased chest and back hair, with elevated cortisol, 17-hydroxyprogesterone, and testosterone. ^[171]C Thus, rapid somatic change, virilization, premature pubertal development, or unexplained severe hypertension warrants attention even when the presentation is not typical. ^{[55]C4[149]D[171]C}

Mild, atypical, and cyclic disease

Mild autonomous cortisol secretion or mild autonomous ACTH secretion may lack the overt physical signs traditionally associated with CS. Mild autonomous cortisol secretion is commonly identified biochemically after a low-dose dexamethasone-suppression test, with a reported definition of post-dexamethasone serum cortisol >1.8 μg/dL in patients with adrenal nodules and no signs of overt CS. ^[161]C Mild autonomous ACTH secretion is likewise described as autonomous pituitary-derived hypercortisolism occurring without overt signs or symptoms of CS. ^[204]D Despite subtle clinical expression, mild disease may be associated with hypertension and other cardiometabolic complications; in a literature review of 52 cases of mild autonomous ACTH secretion, hypertension occurred in 56% of patients. ^[204]D

Cortisol excess may also be cyclic or fluctuating. Primary pigmented nodular adrenocortical disease in Carney complex can cause ACTH-independent cyclic CS, with reported pediatric complications including obesity, depression, and short stature. ^[169]C A single clinical assessment may therefore underestimate disease burden when cortisol excess is intermittent. ^[53]D5[169]C

Special situations and mimics

Pregnancy can obscure recognition because normal pregnancy-related physiologic changes overlap with the clinical features of adrenal disorders, including CS. ^[58]D5 Pregnancy-associated presentations may therefore be atypical, and early recognition is clinically important. ^[58]D5 Ectopic ACTH production by pheochromocytoma is rare and may lack the typical features of CS, creating risks of delayed diagnosis or misdiagnosis. ^[57]C4

Exogenous glucocorticoid exposure must be considered when the phenotype suggests CS. CS includes both endogenous disease and excessive exposure to exogenous glucocorticoids. ^[166]D A pediatric case initially resembling endogenous CS was ultimately associated with prolonged use of an anti-lice foam; the clinical condition gradually and completely reversed after discontinuation. ^[59]C4 Medication, topical-product, and other nonclassic exposures should therefore be reviewed carefully. ^[59]C4

Clinical recognition

Because no single manifestation is diagnostic and many features overlap with common obesity, diabetes, hypertension, reproductive disorders, pregnancy-related changes, and medication effects, suspicion should be based on the overall pattern and progression of findings. ^{[53]D5[58]D5[165]D[166]D} Particular attention is warranted for combinations of rapid weight gain, moon face, hypertension, hypokalemia, difficult-to-control diabetes, menstrual or androgenic abnormalities, pediatric virilization or premature pubarche, neuropsychiatric symptoms, or an atypical presentation associated with an adrenal or ectopic tumor. ^{[55]C4[57]C4[163]D[168]C[171]C} Biochemical evaluation is essential because CS is characterized not only by excessive daily cortisol production but also by disruption of the normal circadian rhythm of cortisol secretion. ^[53]D5

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 spectrum-based treatment

The modern treatment history of Cushing syndrome (CS) reflects a progressively broader understanding of pathological cortisol excess, extending from classic overt presentations to milder and clinically heterogeneous states. More than a century after Harvey Cushing’s original description, contemporary interpretation recognizes that clinically important cortisol dysregulation may be subtle and that restricting the diagnosis to “Cushing syndrome” can delay treatment and increase morbidity. ^[118]D5 The supplied evidence does not document a complete chronology of early operative or pharmacologic milestones; instead, it illustrates the current transition toward etiology-specific, severity-adjusted, and comorbidity-directed management. ^[118]D5

Adrenal surgery and mild autonomous cortisol secretion

Adrenalectomy remains a central treatment strategy for cortisol excess arising from the adrenal gland, but its role has increasingly been evaluated in mild autonomous cortisol secretion (MACS), previously often managed conservatively. ^[114]A1b The COAR study was a prospective, multicenter randomized trial of patients with adrenal incidentaloma, no overt CS features, and cortisol >50 nmol/L after a 1-mg overnight dexamethasone suppression test. ^[114]A1b Of 132 randomized participants, 66 underwent adrenalectomy and 66 were assigned to control; 118 participants completed the study. ^[114]A1b The study specifically assessed changes in body weight, glucose, and blood pressure, and its reported findings support metabolic benefit from adrenalectomy in appropriately selected patients with MACS. ^[114]A1b

This evidence represents an evolution from treating surgery primarily as correction of overt hypercortisolism toward considering preventive or risk-reducing intervention when autonomous cortisol secretion contributes to cardiometabolic disease. ^[114]A1b A prospective cohort published subsequently evaluated cardiometabolic outcomes after surgical remission in 357 adults with endogenous hypercortisolism, including 49% with MACS and 36% with pituitary CS, with outcomes assessed at baseline and 3 and 12 months after remission. ^[73]B2b The cohort examined changes in hypertension, diabetes, hyperlipidemia, and obesity and sought factors associated with improvement, reinforcing that treatment success is now judged not only by biochemical remission but also by recovery of cortisol-related comorbidities. ^[73]B2b

Laparoscopic adrenal surgery has also become relevant to operative planning in patients with obesity. In a retrospective series of 90 patients with CS undergoing unilateral transabdominal lateral laparoscopic adrenalectomy, obesity was specifically analyzed in relation to operative time, conversion to open surgery, complications, and hospital stay. ^[138]C The available abstract supports the importance of body habitus in evaluating surgical outcomes but does not provide sufficient results to define a treatment threshold or contraindication. ^[138]C

Bilateral and rare adrenal causes

Treatment has also evolved for bilateral adrenal disorders, in which unilateral resection may be inadequate. Primary bilateral macronodular adrenocortical hyperplasia can range from subclinical disease to severe CS and is associated with ARMC5 mutations in approximately 20–55% of cases; a 2025 report describes bilateral adrenalectomy in a patient with severe hypercortisolism, hypokalemia, hypertension, and diabetes. ^[192]C Primary pigmented nodular adrenocortical disease, frequently associated with Carney complex and PRKAR1A abnormalities, remains a rare pediatric cause of ACTH-independent CS; a reported 10-year-old boy presented with severe obesity, illustrating the need to consider genetic adrenal disease in children with atypical presentations. ^[119]C4 Carney complex may include endocrine overactivity, cardiac myxomas, characteristic pigmentation, and other tumors, so treatment planning requires attention to the multisystem disorder rather than the cortisol excess alone. ^{[117]C4[119]C4}

Pediatric adrenal tumors require individualized management because benign adenomas, adrenocortical carcinoma, borderline lesions, micronodular disease, and other adrenal tumors occur across childhood and adolescence. ^[191]C A pediatric case series emphasized that bilateral tumors, hypertensive crisis, incidental discovery, misleading hormonal testing, gradual premature pubarche, and hemorrhagic lesions can complicate diagnosis and delay treatment. ^[55]C4 These reports support early endocrine assessment and multidisciplinary management when cortisol excess or an adrenal mass is suspected. ^[55]C4[191]C

Medical treatment, peri-treatment risk, and exogenous disease

Pharmacologic cortisol-lowering therapy remains important when rapid control is required, when surgery is delayed, or when malignancy and severe complications are present. ^[104]C4 In a reported case of adrenocortical carcinoma with CS and immune thrombocytopenia, metyrapone and tumor resection reduced cortisol but were followed by relapse of thrombocytopenia, requiring concurrent exogenous steroids and close monitoring during rapid cortisol fluctuations. ^[104]C4 This case highlights that correcting hypercortisolism can expose or worsen conditions previously modified by cortisol’s immunosuppressive effects. ^[104]C4

Recognition of exogenous CS has likewise become an essential treatment step: management requires identifying and stopping the glucocorticoid source while preventing adrenal insufficiency. ^{[28]D5[87]C4[116]C4[193]C} Hidden glucocorticoids have been reported in adulterated supplements, including Artri King or Artri Ajo King products containing undeclared dexamethasone; abrupt discontinuation may produce secondary adrenal insufficiency requiring hydrocortisone replacement. ^{[87]C4[116]C4} Persistent exposure can also follow undocumented intramuscular dexamethasone injections retained in gluteal abscesses, even when routine serum testing is unrevealing. ^[193]C Reviews classify rare exogenous causes as including adulterated herbal or traditional remedies and other atypical glucocorticoid sources. ^[28]D5

Outcomes beyond cortisol normalization

The contemporary treatment paradigm increasingly includes long-term surveillance of metabolic, hepatic, psychiatric, oncologic, and quality-of-life outcomes. ^{[73]B2b[112]B3b[153][33]B2b} MASLD was investigated at CS diagnosis in a retrospective study using liver imaging and fibrosis scores, reflecting recognition of hepatic steatosis as part of the metabolic burden of cortisol excess. ^[112]B3b Nationwide data from Taiwan investigated cancer incidence after endogenous CS, addressing whether the associated obesity and diabetes translate into excess malignancy risk. ^[33]B2b A matched-cohort study also evaluated depression and anxiety treatment patterns and medication discontinuation by CS etiology and remission status, emphasizing that psychological morbidity may persist beyond biochemical control. ^[153] Finally, recommendations against low-value or unproven interventions underscore the modern emphasis on benefit-risk balance, cost-effectiveness, and avoidance of iatrogenic harm. ^[115]A1c

Multiglandular and genetic context

Cushing syndrome (CS) may occur within a broader endocrine or genetic disorder rather than as an isolated adrenal, pituitary, or ectopic process. Multiple endocrine neoplasia type 1 (MEN1) is a particularly difficult context because synchronous neuroendocrine tumors (NETs) can coexist, and ACTH-dependent CS is a rare MEN1 manifestation. In a reported MEN1 patient with severe hypercortisolism, urinary free cortisol exceeded 25 times the upper limit of normal; rapid biochemical control required intensive medical treatment while the ACTH source was investigated. A literature review restricted to documented MEN1 cases emphasized that ectopic CS may originate from different NETs, making anatomical attribution hazardous and requiring biochemical, functional, radiological, and pathological correlation. ^[172]C

Ectopic ACTH secretion should remain in the differential when pituitary testing or surgery is inconclusive. In a long-term series of rigorously defined MRI-negative presumed Cushing disease, 5 of 57 patients (8.8%) were ultimately diagnosed with ectopic ACTH-secreting tumors after transsphenoidal surgery; one patient had initially been considered to have cyclic disease. These findings support prolonged surveillance when postoperative remission is absent, transient, or atypical. ^[175]C Desmopressin-stimulated bilateral inferior petrosal sinus sampling (BIPSS) can help distinguish Cushing disease from ectopic ACTH syndrome, but prospective data indicate that optimized, lower ACTH-gradient cutoffs may improve diagnostic performance compared with traditional basal and stimulated thresholds. ^[70]B2b

Pheochromocytoma is an uncommon but clinically important ectopic ACTH source. Reported cases presented with severe or refractory hypertension and hypokalemia, and one occurred during pregnancy with atypical CS manifestations; the diagnosis may therefore be delayed when the phenotype is not classically cushingoid. ^[57]C4 In patients with NETs, ectopic CS is not merely a biochemical accompaniment: a propensity-matched international database study found that CS-compatible ectopic ACTH syndrome was associated with worse survival and greater morbidity than in matched patients with NETs without CS. ^[182]

McCune–Albright syndrome (MAS) is a mosaic genetic disorder characterized by fibrous dysplasia, skin pigmentation, and endocrine hyperfunction. A national survey reported substantial diagnostic delay, misdiagnosis, and psychosocial burden among affected individuals, reinforcing the need to interpret hyperfunctioning endocrine phenotypes within a syndromic context rather than as isolated gland disease. ^[72]B2c

Pituitary–adrenal and adrenal–pituitary relationships

Mild autonomous ACTH secretion (MAAS) represents a mild pituitary form of autonomous hypercortisolism without overt cushingoid features. A literature review of 52 cases found that MAAS occurred across ages 18–83 years, affected women somewhat more often than men, and was identified in approximately 5% of pituitary adenoma cases. Hypertension and other metabolic complications were frequent, and MAAS should not be overlooked in patients with acromegaly, where more than one pituitary hormonal disorder may coexist. ^[204]D

The broader spectrum of cortisol excess includes mild autonomous cortisol secretion (MACS), which may be clinically subtle and enriched among patients with obesity, diabetes, resistant hypertension, or progressive cardiometabolic disease. A systematic review and meta-analysis of 39 studies involving 14,995 screened individuals evaluated screening in obesity and diabetes, particularly the dexamethasone suppression test (DST), and confirmed CS; the authors concluded that hypercortisolism is likely under-recognized in these populations, although diagnostic certainty varies by population and testing strategy. ^[44]A1a Reviews of type 2 diabetes similarly emphasize that overt CS is rare, whereas milder cortisol excess may be more frequent in selected high-risk groups. ^[178]D

Adrenal imaging findings must be integrated with hormonal phenotype. A retrospective study of 171 patients with adrenal adenomas compared overt CS, MACS, nonfunctioning adenomas, and primary aldosteronism using CT-derived L3 body-composition measures; hormonal subtypes differed in skeletal-muscle parameters after adjustment for age, sex, and body mass index, supporting assessment of muscle as a clinically relevant co-axis effect. ^[206] Another adrenal-lesion series evaluated preoperative hormonal, biochemical, imaging, surgical, and histopathological characteristics in 157 adrenalectomy patients, but its single-center observational design limits generalization. ^[208]C

Gonadal, metabolic, muscular and psychological co-axis effects

Cortisol excess suppresses reproductive function through hypothalamic–pituitary–gonadal-axis disruption. In a retrospective study of 137 women with adrenal CS, Cushing disease, or ectopic ACTH syndrome, reproductive hormone profiles differed across CS subtypes and suppression was related to disease severity. ^[82]B3b Menstrual dysfunction affected 68% of 93 women in another tertiary-center cohort; restoration after treatment was variable, indicating that gonadal recovery may lag behind biochemical remission. ^[205]

The metabolic phenotype may be present without classic Cushingoid appearance. Chronic cortisol excess promotes insulin resistance, hepatic gluconeogenesis, visceral adiposity, hypertension, dyslipidemia, cardiovascular disease, muscle loss, and bone complications. ^[202]D These effects can obscure the underlying diagnosis because obesity, diabetes, and hypertension are common in the general population. ^{[44]A1a[178]D} Body-composition findings in adrenal adenoma cohorts further link cortisol activity with reduced skeletal-muscle measures. ^[206]

Neuropsychiatric effects may persist after treatment. In a nationwide matched cohort of 540 patients with endogenous CS and 2,517 controls, treated mood and anxiety disorders were assessed over a median follow-up of 13.2 years, with analyses stratified by etiology and remission status. ^[153] Among 90 biochemically controlled patients, abnormal late-night salivary cortisol or continued glucocorticoid replacement was associated with differences in quality of life and psychological outcomes, indicating that restoration of cortisol circadian rhythm may matter in addition to conventional biochemical control. ^[105]B3b

HPA-axis recovery after adrenal treatment

Unilateral adrenalectomy for MACS or adrenal CS may be followed by prolonged suppression of the contralateral hypothalamic–pituitary–adrenal axis. A multicenter cohort included 139 MACS and 280 adrenal CS patients requiring postoperative glucocorticoid replacement and separately evaluated time to HPA-axis recovery, defined as discontinuation of replacement. Recovery duration differed between MACS and overt adrenal CS, demonstrating why replacement should be individualized and continued until biochemical recovery is documented. ^[207]

Finally, cortisol excess may have consequences beyond classical endocrine morbidity. In a cohort of 347 patients with endogenous hypercortisolism, including 138 with overt CS and 209 with MACS, incident malignancy was evaluated after exclusion of baseline active cancer, with standardized incidence ratios and Cox models used to identify predictors. ^[152] These data are observational and do not establish causality, but they support long-term, multisystem follow-up across genetic, tumor, metabolic, reproductive, muscular, psychological, and adrenal-axis domains.

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

Endogenous hypercortisolism spans overt Cushing syndrome (CS) and milder autonomous cortisol excess, commonly termed mild autonomous cortisol secretion (MACS); the latter may lack classic cushingoid features and can present through progressive metabolic, cardiovascular, musculoskeletal or neuropsychiatric disease. ^{[202]D [178]D} Chronic cortisol excess is associated with insulin resistance, increased hepatic gluconeogenesis, visceral adiposity, hypertension, dyslipidaemia, cardiovascular disease, impaired bone and muscle health, reproductive dysfunction and increased mortality. ^[202]D Selected populations with obesity or diabetes may therefore contain more unrecognised hypercortisolism than would be suggested by the rarity of overt CS, although the systematic review and meta-analysis identified substantial heterogeneity among screening studies. ^[44]A1a

Patients with neuroendocrine neoplasms (NENs) who develop ectopic CS have particularly adverse outcomes: in a large international electronic-record cohort, code-defined ECS was evaluated against overall survival and morbidity after propensity matching, supporting ECS as a clinically important adverse complication of NENs. ^[182] Thymic NENs are an ultrarare subgroup in which MEN1 was present in 34% of 74 patients with locally advanced or metastatic disease; the study assessed survival prognostic factors and treatment across 20 French centres, underscoring the need for specialist longitudinal management. ^[26]C4 ACTH-dependent CS may also occur in MEN1, where synchronous neuroendocrine tumours complicate localisation; a reported patient had UFC >25 times the upper limit of normal and achieved biochemical control within 10 days with high-dose medical treatment. ^[172]C

Cardiometabolic, cardiovascular and skeletal outcomes

Cardiometabolic morbidity can improve after definitive treatment, but recovery is incomplete or variable and requires follow-up. A prospective cohort of 357 surgically treated adults with endogenous hypercortisolism included 49% with MACS and 36% with pituitary CS and assessed hypertension, diabetes, hyperlipidaemia and obesity at baseline, 3 months and 12 months after remission. ^[73]B2b The principal prognostic consideration is that remission should be followed by active reassessment rather than assuming immediate normalisation of all comorbidities. ^[73]B2b

Population-based data indicate excess atrial arrhythmia risk: pre-existing atrial fibrillation/flutter occurred in 3.6% of patients with CS versus 2.1% of matched controls, with an odds ratio of 1.70; the study also examined new-onset arrhythmia by aetiology and remission status. ^[35]B2b These findings support cardiovascular risk-factor control and rhythm surveillance when clinically indicated. ^[35]B2b

Cortisol excess increases osteoporosis risk, yet a US insurance-claims analysis found that only 6.40% of 53,101 patients with CS underwent bone-mineral-density measurement; testing was particularly underused in males and older adults. ^[156] Prevention of fracture-related morbidity therefore requires systematic assessment of skeletal health rather than relying on overt skeletal symptoms. ^[156]

Psychological, reproductive and functional recovery

Psychiatric morbidity may persist after biochemical remission. In a matched nationwide cohort of 540 patients with endogenous CS and 2,517 controls followed for a median of 13.20 years, depression and anxiety were assessed using affective-drug dispensations, including differences by aetiology and remission status. ^[153] A German registry study of 90 patients with CS and 200 clinically suspected controls evaluated depression using validated questionnaires and examined pain and body-image measures as potential prognostic markers; depression was specifically recognised as potentially persistent despite remission. ^[190]

Menstrual dysfunction is common: in a retrospective series of 93 women treated for CS, 68% had affected menses, and the study measured the rate and time to return of menstrual function after restoration of eucortisolism. ^[205] Reproductive recovery should consequently be reviewed after treatment rather than presumed to be immediate. ^[205]

Natural history, recurrence and surveillance

Diagnostic uncertainty can influence long-term prognosis. Among 57 rigorously defined MRI-negative patients who underwent transsphenoidal surgery for presumed Cushing disease, 5 were subsequently diagnosed with ectopic ACTH-secreting tumours during long-term follow-up; the authors therefore highlight the need for prolonged surveillance when the pituitary lesion is not identified. ^[175]C In ACTH-dependent disease, prospective data from 181 patients showed that lower ACTH-ratio thresholds during desmopressin-stimulated bilateral inferior petrosal sinus sampling improved diagnostic performance compared with traditional cutoffs; the study compared basal >2.0 and stimulated >3.0 ratios with optimised thresholds for distinguishing pituitary disease from ectopic ACTH secretion. ^[70]B2b Prolactin-adjusted sampling has also been investigated in patients with inconclusive pituitary MRI, although evidence from the available retrospective series was limited to 19 patients, including 16 with pituitary disease and 3 with ectopic ACTH secretion. ^[195]C

Postoperative adrenal insufficiency is an expected determinant of recovery after unilateral adrenalectomy. A multicentre cohort followed 139 adults with MACS and 280 with adrenal CS who required glucocorticoid replacement and defined hypothalamic–pituitary–adrenal-axis recovery as discontinuation of replacement; recovery duration and associated factors differed sufficiently between clinical groups to justify individualised endocrine follow-up. ^[207]

Rare bilateral adrenal disorders require family-based surveillance. A long-term study of 17 familial and 9 sporadic cases of bilateral macronodular adrenocortical disease followed patients for 8–410 months and evaluated clinical, hormonal, imaging and genetic variability; ARMC5 and KDM1A were identified as the most frequently implicated genes in familial disease. ^[194] Primary pigmented nodular adrenocortical disease is another bilateral cause of ACTH-independent CS; a single-centre series of 10 patients assessed adrenal volume and adrenal venous sampling to inform surgical choice, reflecting the absence of a universally established operative strategy. ^[196]

Prevention and early detection

There is no demonstrated population-level strategy that prevents endogenous CS, but earlier recognition may reduce cumulative morbidity. Screening should be considered selectively in patients with disproportionate, progressive or treatment-resistant diabetes, hypertension, obesity or other compatible comorbidities, because milder hypercortisolism may occur without classic physical findings. ^{[44]A1a [178]D} UFC reference interpretation requires assay-specific validation: a Canadian study used 4,830 non-CS results and prospective comparison with 120 evaluated patients to derive a liquid-chromatography–mass-spectrometry reference interval, while also demonstrating a correlation between UFC and 24-hour urine volume. ^[43]B2c Prevention of avoidable complications depends on timely biochemical evaluation, definitive treatment when indicated, monitoring for recurrence or delayed alternative diagnoses, assessment of bone and cardiovascular risk, and structured psychological, reproductive and adrenal-axis follow-up. ^{[35]B2b [73]B2b [153] [156] [175]C [190] [205] [207]}

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