Continuing Education Activity

Hypercortisolism is a clinical state caused by prolonged exposure to excess cortisol or related glucocorticoids from endogenous or exogenous sources. Sustained hypercortisolism leads to characteristic clinical manifestations collectively known as Cushing syndrome. The condition’s complexity arises from its wide spectrum of causes, including iatrogenic glucocorticoid use, pituitary adenomas, adrenal tumors, and ectopic adrenocorticotropic hormone (ACTH) production. This course explores the accurate diagnosis of this condition, which demands a high index of clinical suspicion, comprehensive history-taking, physical examination, and confirmatory biochemical testing, given presentations that range from overt Cushing syndrome to subclinical or pseudocushing states. The timely management of hypercortisolism, crucial to reducing associated cardiovascular, metabolic, musculoskeletal, and psychiatric complications, is also discussed.

This activity equips clinicians with advanced knowledge to enhance diagnostic accuracy and evidence-based management of hypercortisolism. Participants will learn to differentiate ACTH-dependent from ACTH-independent etiologies, interpret dynamic testing results, and select appropriate imaging modalities. This activity for healthcare professionals is designed to enhance the learner's competence in identifying hypercortisolism, performing the recommended evaluation, and implementing an appropriate interprofessional approach to manage this condition, optimizing patient outcomes, mitigating comorbidities, and reducing morbidity and mortality associated with delayed or missed diagnoses of hypercortisolism.

Objectives:

• Identify the clinical features associated with hypercortisolism to improve early recognition.
• Evaluate the diagnostic algorithms for hypercortisolism.
• Implement current evidence-based treatment for hypercortisolism.
• Develop interprofessional team approaches by integrating various clinical specialists to manage hypercortisolism and improve outcomes.

Introduction

Hypercortisolism is the clinical state resulting from excessive tissue exposure to cortisol or other glucocorticoids, from exogenous or endogenous sources. When sustained over time, hypercortisolism produces the distinctive constellation of clinical signs and symptoms known as Cushing syndrome. While all patients with Cushing syndrome have hypercortisolism, not all patients with hypercortisolism meet diagnostic criteria for Cushing syndrome. Hypercortisolism may also occur with transient or physiologic states such as severe stress, depression, alcoholism, and poorly controlled diabetes mellitus.

Exogenous hypercortisolism typically results from the iatrogenic or surreptitious administration of glucocorticoids. Endogenous hypercortisolism encompasses 2 major subtypes: adrenocorticotropic hormone (ACTH)–dependent and ACTH-independent.[1] This clinical syndrome is associated with Harvey W. Cushing, MD, whose original description of patients with endogenous hypercortisolism due to pituitary adenoma remains a seminal classic. Pituitary-based ACTH–dependent hypercortisolism is still referred to as Cushing disease.

The difficulty in recognizing, diagnosing, and managing hypercortisolism stems from its wide range of clinical presentations. While classic, overt Cushing syndrome presents with characteristic clinical features and pathognomonic biochemical abnormalities, this phenotype is relatively uncommon. In contrast, other forms of hypercortisolism, including subclinical Cushing syndrome, iatrogenic and exogenous Cushing syndrome, factitious disorder, cyclical and intermittent Cushing syndrome, and pseudo-Cushing states (physiologic hypercortisolism), are more frequently encountered in clinical practice and often pose greater diagnostic and therapeutic challenges.[2]

Etiology

The etiology of hypercortisolism includes exogenous and endogenous sources. The most common cause is iatrogenic due to the exogenous administration of oral, inhaled, topical, or parenteral glucocorticoids. Conservative estimates indicate that more than 10 million people in the United States receive pharmacologic doses of glucocorticoids annually. Although not all develop hypercortisolism, evidence strongly suggests significant underreporting of the prevalence and incidence of iatrogenic Cushing syndrome.[3][4][5][6][7]

Among endogenous causes, hypercortisolism is further divided into 2 subcategories: ACTH-dependent and ACTH-independent. Once this determination of ACTH dependency has been made, targeted imaging and dynamic testing are performed to localize the source of the ACTH dependency further. Cushing disease (pituitary ACTH-secreting adenoma) accounts for 60% to 70% of endogenous cases, adrenal causes (ACTH-independent) account for 10% to 20% of cases, and ectopic ACTH production accounts for 6% to 10% of cases. Less than 1% of cases are due to ectopic production of corticotropin-releasing hormone (CRH).[8]

Epidemiology

Due to the difficulty in recognizing and diagnosing hypercortisolism, estimates of its exact prevalence and incidence vary widely. Most cases are diagnosed between ages 30 and 49 years, but the syndrome can occur from childhood through older adulthood. Women are affected approximately 3 to 4 times more often than men in pituitary and adrenal etiologies, while ectopic ACTH secretion affects both sexes equally.[8]

Estimates from one Danish series indicated that over 11 years, the incidence of Cushing syndrome was 1.2-1.7 cases per million person-years (Cushing disease), 0.6 cases per million person-years (adrenal adenoma), and 0.2 cases per million person-years (adrenal carcinoma).[2] More recent estimates from a US-based population ranged from 39.5 to 48.6 per million person-years.[9] Some evidence suggests that ectopic Cushing syndrome (ECS), or ectopic ACTH syndrome (EAS), is more common than reported. Still, most series indicate a prevalence of approximately 10% to 15% of all Cushing syndrome cases. Small-cell lung cancer is the most common cause of this form of Cushing syndrome. Only 1% of patients with small-cell lung cancer have ECS, suggesting an incidence of approximately 300 new cases annually in the US.[10]

Adrenal mass lesions causing ACTH-independent Cushing syndrome have a higher prevalence and incidence. Adrenal incidentalomas have become more prevalent with the widespread use of powerful imaging modalities such as CT and MRI scans for the evaluation of various abdominal conditions. Depending on whether radiologic or autopsy-based data are used, adrenal incidentalomas have a prevalence of approximately 1.2% to 8.7%.[11][12][13] All other etiologies, including macronodular adrenal hyperplasia, micronodular adrenal hyperplasia (including primary pigmented nodular adrenocortical disease), and ectopic CRH syndrome, are rare; however, clinicians should consider these diagnoses in atypical clinical presentations.

Pathophysiology

Central to the development of hypercortisolism is the presence of clinical features resulting from excessive tissue exposure to glucocorticoids (particularly cortisol). Exaggeration of physiologic states known to be associated with hypercortisolemia or pseudocushing syndrome results in physiologic hypercortisolism. This distinction from pathologic hypercortisolism is important because pseudocushing syndrome is generally transient, typically resolving with the underlying cause, and is generally not associated with the overt cutaneous or muscular manifestations commonly seen in pathologic hypercortisolism.[14][15][16]

Derangement of the hypothalamic-pituitary-adrenal (HPA) axis is central to the development of hypercortisolism. Disruption may result from exogenous, endogenous, or combined insults. The HPA axis is primarily responsible for maintaining baseline, continuous cortisol production, and for provocative secretory responses to various stressful stimuli. CRH is the highest-level hormone in this axis and is produced tonically by the hypothalamus. CRH acts on the basophilic corticotrophs of the adenohypophysis (anterior pituitary) to produce ACTH (corticotropin). ACTH is then secreted from the pituitary into the general circulation, where it acts on the adrenal cortex to produce cortisol, the primary endogenous glucocorticoid. Circadian and stress-related inputs modulate CRH production from parvicellular neurons of the paraventricular nucleus of the hypothalamus. Notably, many of these neurons concomitantly produce arginine vasopressin, which has a similar, albeit less dominant, modulatory effect on ACTH production from the adenohypophysis.[16]

ACTH is produced by posttranslational modification of the precursor protein proopiomelanocortin (POMC). ACTH stimulates the production of cortisol from the adrenal cortex in the free form; most is then bound by carrier proteins, with cortisol-binding globulin (CBG) accounting for approximately 95%. At target tissues and organs, cortisol dissociates from its carrier protein and exerts its dominant effects by binding to the glucocorticoid receptor (and to a lesser degree, the mineralocorticoid receptor), which is then transported to the nuclear ribosomal complex of target cells to alter DNA transcription and protein production. Cortisol also has some nongenomic effects. The mechanisms mediating these effects are still under study. Cortisol, in both physiologic and pathologic settings, exerts negative feedback on further cortisol production by inhibiting pituitary ACTH secretion and hypothalamic CRH secretion, in addition to other central nervous system (CNS) modulatory effects.

This intricately orchestrated system has a well-defined circadian rhythm when not under stress. Peak levels usually occur soon after early morning awakening, typically between 6 and 8 am, with a nadir near midnight. Superimposed on this circadian baseline rhythm is an additional pulsatile ultradian rhythm. Various endogenous and exogenous stimuli can perturb this system, leading to either excessive or deficient cortisol production. Chronic hypercortisolism disrupts homeostatic regulation across multiple organ systems, including metabolic, cardiovascular, musculoskeletal, immune, and neuropsychiatric systems. These alterations contribute to visceral adiposity, proteolysis, insulin resistance, arterial hypertension, decreased bone mineral density with increased fracture risk, immunosuppression, and a spectrum of cognitive and mood disorders.[17]

Histopathology

The histologic findings in hypercortisolism are variable. Some of the tissue findings are directly caused by hypercortisolism, while others result from the complications and comorbidities associated with it. The histopathologic changes of the primary disease depend on the underlying etiology. For CNS primary ACTH-dependent hypercortisolism, the most common histologic finding is pituitary microadenomas with basophilic staining properties on routine hematoxylin-eosin sections, as first described by Harvey Cushing.[18] These benign tumors often demonstrate ACTH and other neuropeptide production on histochemistry. Pituitary carcinomas presenting with hypercortisolism are much less common. Other neuroendocrine tumors (often benign but sometimes malignant), resulting in ectopic CRH production, can also present with secondary adenohypophyseal hyperplasia and diffuse pituitary enlargement rather than adenomatous lesions. These tumors include carcinoid tumors, medullary thyroid carcinoma, functional ovarian tumors, pheochromocytomas, and hypothalamic neuroendocrine tumors.[19][20][21]

ACTH-dependent Cushing syndrome, whether of pituitary, hypothalamic, or ectopic origin, often results in secondary adrenocortical hyperplasia, which is generally diffuse but can be nodular in gross and histologic appearance. Most surgical adrenal samples obtained in patients with hypercortisolism are typically from ACTH-independent adrenal disease. The histopathologic findings can range from diffuse adrenal hyperplasia to micro- or macronodular adrenal hyperplasia, lone adrenal incidentaloma lesions (often benign adrenal adenomas), to adrenocortical carcinoma.[18][22] The distinction between micro- and macronodular adrenal disease is based on the macroscopic size of the nodules; nodules larger than 1 cm are macronodules, and those smaller than 1 cm are micronodules. The coexistence of macro- and micronodules within a single specimen is common. Awareness of the distinctive micronodular hyperplasia of primary pigmented nodular adrenocortical hyperplasia and its association with a paradoxical cortisol response on the 6- to 8-day Liddle test, as well as with Carney complex, is important.[23] Recognition of the unique form of bilateral macronodular adrenocortical hyperplasia associated with the McCune-Albright syndrome is also notable.[24][25][26]

History and Physical

While the clinical presentation of classic Cushing syndrome is distinctive, the vast majority of patients with hypercortisolism do not present this way, making a high index of clinical suspicion central to the diagnosis. The possible signs and symptoms of hypercortisolism are numerous and individually are not pathognomonic. Many of these findings are nonspecific, making hypercortisolism both overdiagnosed and underdiagnosed, depending on the clinical context.

The history and physical examination findings are often insufficient for diagnosing hypercortisolism, and diagnostic laboratory tests are typically required for accurate diagnosis. A subset of high-risk patients requires careful screening to diagnose hypercortisolism. Among these are young adults with osteoporosis, early-onset hypertension, hyperglycemia or diabetes mellitus, facial plethora, proximal myopathy, the presence of distinctive, pigmented, palpable, wide (greater than 1 cm) striae, easy cutaneous bruising (especially in young patients), and patients with adrenal incidentalomas.[17][18]

History must include careful questioning regarding exogenous glucocorticoid exposure, including topical and inhalational glucocorticoids (iatrogenic Cushing syndrome), as well as recreational and factitious abuse.[27][28] A detailed medication reconciliation history is a critical part of the evaluation of potential hypercortisolism, as is a prior history of psychopathology and occupational history that may identify potential occupational access to and misuse of glucocorticoids.

Symptoms that must be assessed during the history include: 

• The most common clinical symptom is progressive weight gain, which is typically centrally dominant. The weight gain can also be generalized and similar to that seen in nonsyndromic obesity.[29] 
• Symptoms related to hypertension include headaches, dizziness, and visual blurring.
• Symptoms due to worsening hyperglycemia, such as polyuria, polydipsia, and either polyphagia or anorexia.
• Reproductive dysfunction often manifests with various menstrual irregularities, including oligomenorrhea, amenorrhea, subfertility, or infertility. Pregnancy in the setting of hypercortisolism is uncommon. Among men, reduced libido and symptoms consequent upon secondary hypogonadism, such as lower energy levels, fatigue, nonspecific weakness, and erectile dysfunction, can occur.
• Easy bruising is more characteristic of the syndrome.
• Muscle weakness, especially in the proximal extremity muscle groups, is also a more specific symptom of hypercortisolism and can manifest as difficulty climbing stairs, difficulty rising unaided from low-set chairs, and an inability to perform standard squats.
• In children and adolescents, the coexistence of reduced or arrested linear growth and significant excess weight gain is suggestive of hypercortisolism. The discordance between progressive weight gain that crosses percentile lines on the child's weight growth chart, as compared to declining or arrested linear growth on the corresponding height charts, should raise suspicion of hypercortisolism and spur appropriate diagnostic testing.
• Sleep disturbance is common, as are vivid dreams and nightmares.
• Mood disorders and depression are also more common in patients with hypercortisolism. Others present with worsening episodes of mood swings ranging from wild elation to sudden dysthymia akin to manic-depressive states. Some patients can also present with severe psychotic episodes in the absence of a prior history of established psychiatric pathology.
• Among women, hirsutism and marked acne are relatively common findings. Frank virilization should raise the suspicion of a malignant neoplastic disease like adrenal carcinoma. 
• Osteoporosis associated with hypercortisolism is more common in older patients and those with chronic, long-standing illness. Such patients may present with chronic back pain, loss of height due to vertebral collapse, low-impact fragility fractures, or local bone pain.

Typical physical examination findings are:

• Facial rounding (moon facies)
• Facial flushing, including marked malar telangiectasia
• Enlarged dorsocervical pad (buffalo hump) and supraclavicular fat pads. The supraclavicular fat pads are more specific for hypercortisolism than the dorsocervical fat pads.
• Hypertension
• Cutaneous atrophy with wide (>1 cm) violaceous striae typically on the abdomen, thighs, or breasts, and ecchymoses with minimal trauma.
• In women, alopecia can occur.
• Diffuse cutaneous hyperpigmentation in the setting of hypercortisolism should suggest the possibility of ACTH-dependent forms of Cushing syndrome.

Patients with hypercortisolism can also present with clinical features of the comorbidities and complications associated with hypercortisolism. Hypercortisolism can impact virtually every organ system of the body. Clinical presentations may be consequent upon reproductive, dermatologic, orthopedic, metabolic, cardiovascular, neuropsychiatric, infectious, and bariatric comorbidities.

Ultimately, hypercortisolism is associated with considerable morbidity and mortality risk, necessitating early recognition and appropriate management. Hypercortisolism is associated with excess cardiovascular risk consequent upon its association with hypertension (which can be severe and resistant at presentation), heart failure, or the development of dilated cardiomyopathy. Other complications include dysglycemia, diabetes mellitus, and increased risk for thromboembolism.[30] 

Evaluation

Because the clinical presentation of hypercortisolism is often nonspecific, and a delay in diagnosis can lead to significant morbidity and possible mortality, the diagnostic evaluation comprises an initial screening protocol designed to have a high sensitivity and a lower specificity.

The first step of diagnostic evaluation involves broad screening, followed by diagnostic confirmation, and then anatomic localization of the etiology. The diagnosis of hypercortisolism is confirmed when at least 2 different first-tier screening tests are unequivocally elevated.[31] These first-tier screening tests include:

1. Salivary cortisol tests: At least 2 measurements to evaluate the early morning and late-night levels of absolute cortisol levels and the preservation of the normal diurnal rhythm.
2. 24-hour urinary free cortisol: The collection should start with an empty bladder (discard the first morning void). Collect all urine for 24 hours. Abnormally low or high urine volume can lead to false-negative or false-positive results, respectively. A low eGFR (less than 60 mL/min/1.73 m²) can falsely lower urine cortisol levels. 
3. 1 mg dexamethasone suppression test: Administer 1 mg dexamethasone at 11 PM and measure serum cortisol at 8 AM; a value above the assay-specific cutoff (commonly 1.8 µg/dL) is considered an abnormal result. An essential component of the test is confirmation that the patient actually took the dexamethasone tablet and adequately absorbed it; this can be objectively confirmed by concurrently measuring serum dexamethasone levels the morning after.[17] 

These screening tests may need to be repeated multiple times in cases of high clinical suspicion, even if the initial results are negative. Patients with variable or discordant results, or those with a consideration of intermittent or cyclical hypercortisolism, may also require retesting.

There are at least 5 clinical practice guidelines regarding hypercortisolism.[17][17][32][33][34][35] Overall, the guidelines of the Endocrine Society and the Italian Association of Medical Endocrinologists are well accepted. When discordance is observed between screening tests, especially on repeat testing, the possibility of cyclical, intermittent, iatrogenic, and even factitious Cushing syndrome merits consideration. A list of other potential variables that can affect the accuracy of these screening tests includes concomitant medication use, variations in dexamethasone metabolism, night shift work, states of cortisol-binding globulin excess or deficiency, and coexistence of sleep disorders.[36]

The combined dexamethasone-CRH test is generally considered the best dynamic test for distinguishing pathologic hypercortisolism from physiologic hypercortisolism. Patients with the latter tend to have a blunted cortisol response (and less consistently) ACTH response to CRH after dexamethasone suppression (using the standard 2-day low-dose dexamethasone administration protocol) compared to patients with pathological hypercortisolism. This testing remains controversial, with concerns regarding the sensitivity and specificity distinguishing pseudocushing syndrome from true pathologic Cushing syndrome. 

The next diagnostic branch point is to ascertain whether the hypercortisolism is ACTH-dependent or ACTH-independent. Because ACTH secretion is pulsatile and diurnal, this measurement often needs to be repeated to reach consensus. Persistently low serum ACTH levels (<5 pg/mL) are very strongly predictive of ACTH-independent hypercortisolism, including exogenous hypercortisolism. Similarly, a serum ACTH level greater than 20 pg/mL is highly suggestive of ACTH-dependent hypercortisolism, which then brings up the clinical decision branch point of distinguishing between pituitary-based hypercortisolism versus ectopic ACTH syndrome (EAS) through additional dynamic tests (eg, high-dose dexamethasone suppression, CRH stimulation) and advanced imaging (eg, chest/abdominal CT, fluorodeoxyglucose-positron emission tomography).

For patients with persistent serum ACTH levels between 5 and 20 pg/mL, further dynamic testing is necessary. These could include the CRH stimulation test, the vasopressin (or desmopressin [DDAVP]) stimulation test, or the metyrapone stimulation test. All these tests tend to cause a postprovocative increase in ACTH secretion in patients with pituitary-based hypercortisolism but not in adrenal hypercortisolism or ECS. Measurement of serum dehydroepiandrosterone sulfate (DHEA-S) has some diagnostic utility in repeat testing, as it tends to be reduced in ACTH-independent hypercortisolism but increased or normal in ACTH-dependent hypercortisolism.[37] The specificity and sensitivity of these tests are insufficient to localize the source of ACTH excess. In such settings, direct measurement of central and peripheral ACTH production may be necessary. The most validated strategy is inferior petrosal sinus sampling.[38][39][40]

Once the biochemical diagnosis and the anatomic location are determined, imaging is pursued. For pituitary and other CNS causes of hypercortisolism, pituitary MRI is the preferred imaging modality for lesion localization. Dynamic contrast-enhanced, high-resolution pituitary MRI scans may improve detection, but even the best MRI systems cannot detect all functional pituitary microadenomas causing hypercortisolism. In contrast, their high sensitivity has led to the detection of nonfunctional pituitary microadenomas in 10% to 20% of healthy volunteers.[41] In patients with unique limitations, an open MRI or cranial CT with pituitary tomographic imaging may be necessary. However, these imaging modalities have significantly lower sensitivity for detecting small pituitary or other brain lesions that may be etiologic in pituitary hypercortisolism; therefore, the primacy of establishing a biochemical diagnosis before imaging is emphasized. In patients with negative imaging test results despite positive biochemical diagnosis of pituitary-based hypercortisolism, because of the considerable morbidity and potential mortality associated with this condition, neurosurgical intervention with pituitary exploration and hemihypophysectomy may be necessary. Pituitary imaging misidentifies a pituitary lesion in approximately 18% of patients who have EAS. Caution in treatment decision-making is essential.

For patients whose biochemical and dynamic testing is suggestive of EAS, the process of anatomical localization of the responsible lesion can be particularly challenging. The optimal imaging strategy for these patients is not clearly defined, and decisions are often made on a case-by-case basis. Targeted imaging using CT, MRI, positron emission tomography, and specialized nuclear medicine, including octreotide scintigraphy and Gallium-68 DOTATATE imaging, is complementary. As most EAS lesions are found in the chest, chest-based imaging may be the best place to begin in the absence of clinical clues from the history and physical examination. Most malignant etiologic lesions are relatively easy to detect with these imaging modalities, but benign carcinoids are notoriously challenging to detect and may require multiple imaging studies over time.

For patients with ACTH-independent hypercortisolism, imaging is generally focused on the adrenal glands. However, there have been a few rare cases described of tumors in other organs (mainly ovarian) associated with ACTH-independent cortisol overproduction. The best imaging study for visualizing the adrenal glands remains the adrenal-dedicated, thin-section CT scan, with or without contrast. Subsequent decisions regarding diagnosis and management depend on whether bilateral or unilateral nodularity is detected, the size of the nodule(s) (micronodules vs macronodules), and the patient's age. The absence of any obvious nodules in patients with biochemical evidence of ACTH-independent hypercortisolism may require bilateral adrenal venous sampling. The presence of multiple nodules in both adrenals, or a single nodule in patients older than 65 years, should prompt adrenal venous sampling, as the possibility of a nonfunctional adenoma rather than the cause of the hypercortisolism can be as high as 25%. In cases of adrenomedullary lesions (a few instances of adrenal pheochromocytomas associated with ACTH-independent hypercortisolism have been reported), obtaining an I-123 meta-iodobenzylguanidine (MIBG) scintigram may provide additional diagnostic information. 

Treatment / Management

The management of hypercortisolism encompasses strategies to mitigate its metabolic and clinical effects, target the specific causes of the hypercortisolism state (including medical and surgical interventions), and manage the complications and comorbidities associated with hypercortisolism. The general principles of effective management are to reverse the clinical and metabolic consequences of hypercortisolism by restoring endogenous cortisol production, eliminating any neoplastic source of cortisol excess, minimizing medication replacement, and preventing long-term secondary hormone deficiency. These goals are not always attainable for various reasons.[42]

In patients with an unknown underlying etiology of hypercortisolism, modulation of hypercortisolism and its complications (such as management of hyperglycemia, diabetes mellitus, hypertension, osteoporosis, and hypercoagulopathy) may take priority while definitive diagnosis is pursued, enabling more permanent and curative treatment.[42][43][44][45][46]

• When hypercortisolism is due to exogenous glucocorticoid use, the central management strategy is a carefully monitored reduction in glucocorticoid use, with the ultimate aim of total withdrawal. Depending on the initial indication for their use, the glucocorticoid duration and dose, and evidence of secondary adrenal cortical atrophy, this may or may not be possible. Exogenous hypercortisolism can create hypercortisolism with secondary adrenal insufficiency from cortical atrophy. Serial monitoring of serum DHEA-S and ACTH levels, as well as serial ACTH (cosyntropin) stimulation tests, may be required while reducing the glucocorticoid dose to the closest physiologic replacement dose necessary to prevent symptoms and signs of adrenal insufficiency.
• Medical therapy strategies: While surgical treatment strategies offer the potential for permanent metabolic resolution and cure, it is often delayed or unsuccessful. Among the interventional strategies are the glucocorticoid (and progesterone) receptor antagonist mifepristone (RU-486) and adrenal synthetic enzyme inhibitors, such as ketoconazole, levoketoconazole, metyrapone, and mitotane. Mitotane is restricted for use in adrenocortical carcinoma due to its significant toxicity profile.[47][48][49] Medical therapy for pituitary adenomas causing hypercortisolism or neuroendocrine tumors causing EAS has been described and includes cabergoline, pasireotide, and other somatostatin analogs such as octreotide. However, the therapeutic effects can be variable.[42][49][50][51][52] In patients for whom oral therapies are impossible or contraindicated, parenteral use of the imidazole anesthetic agent etomidate has some utility in managing hypercortisolism by blocking the 11β-hydroxylation of deoxycortisol to cortisol.[53] Osilodrostat is the latest medication with the same mechanism of action and has shown benefit in patients with resistant hypercortisolism.[54][55][56][57] Further studies are ongoing to explore the potential utility of other medications in managing resistant hypercortisolism, including the novel glucocorticoid receptor modulators CORT-108297 and CORT-125134.[58][59][60][61][62]
• For pituitary adenomas causing hypercortisolism (Cushing disease), the vast majority (approximately 60% to 70%) are local microadenomas; however, nearly 30% may be locally invasive, and 0.2% to 2% are due to carcinomas that may be associated with central nervous system or systemic metastases. In such patients, surgical treatment is rarely curative, and the prognosis is often poor, with the need for systemic adjunctive chemotherapy.[63] For Cushing disease, the best potential for cure remains early surgical intervention, usually by transsphenoidal surgery. Identifying a skilled pituitary neurosurgeon in a clinical facility with appropriate support staff and clinical resources is critical to achieving this goal. Referral to well-established pituitary surgical centers that meet this high standard is a worthwhile consideration.
• Pituitary irradiation therapy is helpful in cases of well-documented and proven biochemical hypercortisolism when radiologic imaging, and possibly neurosurgical exploration, reveals no apparent tumor. This treatment can also serve as adjunctive therapy following debulking, noncurative pituitary surgery. This treatment option is deliverable by standard conventional brachytherapy or, more precisely, by stereotactic radiotherapy, radiosurgery, or gamma knife therapy, which requires high-level technical expertise and nuclear medicine imaging resources.
• In some scenarios where all other efforts to achieve control of the hypercortisolism fail, bilateral adrenalectomy with subsequent lifelong glucocorticoid and mineralocorticoid repletion therapy may be the last resort. Subsequent follow-up is essential to prevent the development of Nelson syndrome.
• The management of EAS depends on the location of the lesions. Surgical resection offers the best chance of a cure. Concomitant medical treatment to control the hypercortisolism is often required until the etiologic lesion is identified and may be required thereafter if curative surgical resection is not feasible.
• For patients with adrenal-based hypercortisolism due to identified unilateral adrenal adenomas, unilateral adrenalectomy is the best strategy for a cure, and the laparoscopic approach is the preferred approach as long as the adenoma is less than 6 cm in diameter. The role of adrenocortical sparing surgery in this setting is still evolving and is not the standard of care at this time.
• While hypercortisolism is typically associated with subfertility/infertility, the uncommon scenario of hypercortisolism in pregnancy occasionally arises. Medical therapy in such settings is often not feasible because of the potential teratogenic effects of most available treatment options. Metyrapone is the best medical adjunctive treatment option in this setting, but ideally, surgical intervention, generally in the second trimester of pregnancy, is the preferred therapeutic intervention strategy.

Differential Diagnosis

Among the differential diagnoses in patients with suspected hypercortisolism are all the possible causes of the pseudocushing states (physiologic hypercortisolism) including pregnancy, morbid obesity, melancholic depression, chronic alcoholism, poorly controlled diabetes, eating disorders such as bulimia nervosa and the night eating disorder, chronic lymphedema, lipedema, partial lipodystrophy syndromes (both congenital and acquired), Dercum disease, and syndromes of hypothalamic obesity including Prader-Willi syndrome, Fröhlich's syndrome, and the Bardet-Biedl syndrome. Other rare considerations, especially in children, include POMC and leptin-deficient obesity syndromes as well as cerebral gigantism (Sotos syndrome). Other diagnostic considerations are associated with anasarca, including generalized protein-energy malnutrition (kwashiorkor in children), congestive heart failure, cirrhosis of the liver with ascites, and nephrotic syndrome.

Biochemical evidence suggestive of possible hypercortisolism without concordant physical findings may occur with exogenous glucocorticoids, factitious Cushing syndrome (including abuse of various glucocorticoids, anabolic steroids, and peptides like adrenocorticotropic hormone [ACTHAR], desmopressin [DDAVP], and corticorelin [CRH] among patients with severe factitious disorders), severe physical stress, severe malnutrition, anorexia nervosa, hyperexercise syndrome, (including the female athlete triad of eating disorders, amenorrhea, and osteoporosis) hypothalamic amenorrhea, and glucocorticoid resistance states. There are also reports of rare disorders that can present similarly to hypercortisolism, including ectopic nonadrenal cortisol secretion, "normal Cushing" syndrome, and biochemical hypercortisolism in the absence of Cushingoid features.[64][65][66] 

Prognosis

Hypercortisolism, when untreated, correlates with marked morbidity and is often fatal. The prognosis depends on the underlying etiology, the duration and severity of hypercortisolism, the timeliness and efficacy of treatment, and the patient's age and overall health status. The most common causes of increased mortality in these patients are cardiovascular disease, infection, and thromboembolic events. 

Most cases of pituitary hypercortisolism are curable, and hypercortisolism should be manageable even if it requires the most drastic strategies of bilateral adrenalectomy or mitotane therapy to achieve that goal. The underlying etiology plays a considerable role in the ultimate prognosis, with malignant lesions such as small-cell lung carcinoma and adrenocortical carcinoma having the poorest prognosis. In contrast, patients with benign adrenal adenomas or benign carcinoids with EAS have the best prognosis.

Curative treatment, particularly surgical resection of the source of hypercortisolism, significantly improves prognosis; however, patients often experience persistent comorbidities such as hypertension, diabetes, osteoporosis, and neuropsychiatric disorders. Normalization of cortisol reduces, but does not eliminate, excess morbidity and mortality, and the quality of life frequently remains below that of age- and sex-matched controls for years after remission. Some complications, such as bone loss and cognitive dysfunction, may be irreversible.[67]

Children with hypercortisolism often have a residual decline in intelligence quotient and cognitive functional indices even after cure, which persists in the absence of any psychopathology and even with reversal of prior noted cerebral atrophy.[68] Children tend to show improvement in bone density and growth velocity following hypercortisolism treatment; however, a residual deficit may persist. Even after successful treatment, there is a 35% chance of recurrence, necessitating lifelong surveillance and management of residual comorbidities.

Complications

Hypercortisolism is a clinical syndrome that affects virtually every organ system either directly or indirectly.[44][46][45] The associated comorbidities and complications of hypercortisolism include:

• Osteopenia, osteoporosis, or osteonecrosis are particularly associated with exogenous rather than endogenous hypercortisolism, with the hips most commonly affected.
• Cardiovascular disease, including hypertension, accelerated atherosclerotic vascular disease (coronary artery disease, acute coronary artery syndromes, cerebrovascular disease, and peripheral vascular disease), and dilated cardiomyopathy.
• Dyslipidemia, including hypertriglyceridemia and hypercholesterolemia
• Metabolic syndrome
• Impaired glucose tolerance or diabetes mellitus with attendant complications and comorbidities
• Obesity is usually truncal dominant with relative atrophy of the extremities (apple on sticks phenotype), but can be associated with generalized adiposity
• Linear growth impairment in children
• Proximal myopathy
• Hypogonadism and subfertility or infertility
• Increased predisposition to cutaneous and systemic infections, usually bacterial and fungal
• Dyspepsia and gastroesophageal reflux disease
• Nephrolithiasis
• Cutaneous manifestations, including cutaneous atrophy, ecchymoses, striae, recurrent cutaneous infections, hyperpigmentation (in patients with pituitary Cushing syndrome, EAS, and ectopic CRH syndrome states), alopecia, hirsutism, hypertrichosis, poor wound healing, acanthosis nigricans, and acne
• Ophthalmic complications, most commonly cataracts and open-angle glaucoma. Exophthalmos has also been described, particularly with exposure to exogenous glucocorticoids
• Neuropsychiatric syndromes, including steroid psychosis, depression, bipolar state, dysthymia, and chronic anxiety
• Cognitive decline, including progressive memory loss and a dementia-like illness in the most severe cases, with associated brain cortical atrophy
• Reduced quality of life
• Prothrombotic state with increased risk for deep venous thrombosis and pulmonary embolism
• Secondary or primary adrenal insufficiency and glucocorticoid withdrawal syndrome following successful treatment
• Nelson syndrome after bilateral adrenalectomy
• Sleep disorders, including sleep deprivation, chronic insomnia, obstructive sleep apnea, and obesity hypoventilation syndrome
• In pregnancy, impaired glucose tolerance or gestational diabetes, hypertensive disorders of pregnancy, preeclampsia, congestive heart failure, psychiatric disorders, and increased fetal loss. While the fetus tends to be somewhat protected from the maternal hypercortisolism because of the effects of placental 11β-hydroxysteroid dehydrogenase, which converts approximately 85% of the maternal cortisol reaching the placenta to relatively inert cortisone, this protective system can be overwhelmed, resulting in fetal loss, intrauterine growth retardation, premature delivery, and neonatal adrenal insufficiency.[69][70]

Consultations

All patients with suspected or confirmed hypercortisolism should be referred to an endocrinologist for further diagnostic evaluation, etiologic determination, and initial management. Additional specialist consultations are determined by the underlying cause. Neurosurgery is indicated for patients with pituitary adenomas (Cushing disease), while general surgery or surgical oncology is indicated for adrenal or ectopic tumors. If malignancy is suspected, involvement of an oncologist is warranted. Interprofessional care is often required to address the multisystem comorbidities of hypercortisolism, and may include cardiology for hypertension and cardiovascular risk, psychiatry for mood and cognitive disorders, and orthopedics for osteonecrosis and fracture risk.

Deterrence and Patient Education

Patient education is a crucial component in the management of hypercortisolism, whether caused by exogenous glucocorticoid exposure or endogenous factors. Education should focus on explanation of the underlying etiology, potential complications, appropriate diagnostic evaluation, treatment options, and the necessity of long-term monitoring. Exogenous glucocorticoid use, including oral, inhaled, injectable, or topical formulations, remains the most common cause of hypercortisolism. Patients prescribed these agents must be thoroughly counseled on their indications, potential adverse effects, and the importance of minimizing duration and dose. Long-term glucocorticoid therapy can lead to dependence, misuse, and factitious Cushing syndrome. Importantly, abrupt discontinuation of exogenous glucocorticoids is dangerous and may precipitate secondary adrenal insufficiency, which can be life-threatening. Patients should be clearly instructed never to stop these medications suddenly and to follow tapering protocols under medical supervision. Clinicians should coordinate care across specialties to consider steroid-sparing alternatives when feasible, ensure the use of the lowest effective dose, and guide safe tapering strategies to minimize the risk of adverse effects. For patients who require chronic glucocorticoid therapy, clinicians must remain vigilant for complications and implement ongoing surveillance to mitigate long-term adverse effects.

Endogenous hypercortisolism, arising from pituitary (Cushing disease), adrenal, or ectopic sources, is less common but poses diagnostic and therapeutic challenges. Patients should be informed about appropriate diagnostic testing, including late-night salivary cortisol testing, 24-hour urinary free cortisol testing, and dexamethasone suppression testing. Clinicians should emphasize the multisystem impact of cortisol excess, including central obesity, hypertension, glucose intolerance or diabetes, osteoporosis, skin fragility, mood disturbances, and an increased risk of infection. Notably, these complications may persist even after biochemical remission has been achieved.

First-line therapy for most forms of endogenous Cushing syndrome is surgical resection of the causative lesion. However, patients may require adjunctive medical therapy, radiotherapy, or bilateral adrenalectomy. Education should include a discussion of treatment goals, risks, and the potential transition from cortisol excess to adrenal insufficiency following intervention. Lifelong follow-up is essential to monitor for recurrence and manage residual comorbidities. Ultimately, clinicians must partner closely with patients, providing clear, accessible information to empower informed decision-making and support adherence. Ongoing education and interprofessional coordination are key to optimizing outcomes in individuals affected by hypercortisolism.

Pearls and Other Issues

Hypercortisolism is a complex clinical syndrome due to multiple different etiologies that has considerable potential for morbidity and mortality. Early recognition of hypercortisolism is important to limit morbidity and avoid complications. Exogenous causes of hypercortisolism should be carefully excluded before investigating endogenous etiologies.

The diagnosis of endogenous hypercortisolism involves a 3-tiered approach: comprehensive screening, confirmation of the diagnosis, and anatomic localization of the causative lesion(s). While surgical intervention generally offers the best potential for cure, several medical adjunctive treatment options can enable management of the metabolic state of hypercortisolism even if surgery is not feasible or curative.

Enhancing Healthcare Team Outcomes

Hypercortisolism represents a clinical state resulting from excessive cortisol exposure, leading to metabolic, cardiovascular, musculoskeletal, and psychological complications. The causes may be exogenous or endogenous, including pituitary, adrenal, or ectopic sources. Because clinical presentations vary widely—from overt Cushing syndrome to subclinical or pseudocushing states—accurate diagnosis demands comprehensive evaluation, biochemical testing, and imaging correlation. Early recognition and appropriate treatment are essential to reduce morbidity, prevent complications, and restore hormonal balance.

Effective management of hypercortisolism requires coordinated, interprofessional care. Clinicians must identify early signs, initiate timely referrals, and lead evidence-based evaluation. Endocrinologists oversee diagnostic confirmation and treatment selection, while radiologists and surgeons collaborate in localization and intervention. Nurses monitor symptoms, medication responses, and patient education, and pharmacists ensure safe prescribing by evaluating potential drug interactions and optimizing dosing regimens. Mental health professionals, nutritionists, and rehabilitation specialists support recovery and long-term wellness. Interprofessional communication, case conferences, and continuity of follow-up are crucial for detecting recurrence and managing complications, enhancing patient-centered care, safety, and long-term outcomes, especially within specialized or interprofessional centers.

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Disclosure: Tara John declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.