Cushing’s Syndrome

Cushing’s syndrome arises from prolonged exposure to excessive levels of circulating glucocorticoids. Among the endogenous causes, Cushing’s disease, also known as pituitary-dependent Cushing’s syndrome, stands as the most common source of hypercortisolism. Screening for this condition typically involves three key tests: the 1mg overnight dexamethasone suppression test, at least two late-night salivary cortisol samples, and a minimum of two 24-hour urinary free cortisol collections. If two of these tests yield positive results, the patient should be referred to an endocrinologist for further evaluation.

The next step involves measuring plasma ACTH levels at 9:00 a.m., which guides subsequent imaging and investigations. When ACTH levels are elevated or inappropriately normal, an MRI of the pituitary gland is warranted. Conversely, suppressed ACTH levels call for imaging of the adrenal glands. To differentiate pituitary from ectopic ACTH-dependent Cushing’s syndrome, corticotrophin-releasing hormone (CRH) or desmopressin tests can be utilized. Bilateral petrosal sinus sampling remains the gold standard for distinguishing these conditions and should be performed when available, except in cases where a pituitary macroadenoma is present.

For all patients, it is prudent to conduct a CT scan of the thorax, abdomen, and pelvis to identify potential ectopic sources of ACTH. Treatment options vary depending on the underlying cause. In Cushing’s disease, transsphenoidal surgery is the first-line treatment, with radiotherapy as a secondary option if surgery is unsuccessful. For adrenal ACTH-independent Cushing’s syndrome, adrenalectomy is the preferred treatment. When Cushing’s syndrome is caused by ectopic ACTH secretion, surgical resection of the source tumor is recommended whenever feasible, with bilateral adrenalectomy serving as a potential alternative in challenging cases.

Steroidogenesis inhibitors remain highly effective as medical therapies, particularly when surgery is delayed, unsuccessful, or when awaiting the effects of radiotherapy. These treatments play a vital role in managing cortisol levels and ensuring the best possible outcomes for patients.

What is Cushing’s Syndrome?

Cushing’s syndrome results from prolonged exposure to excessive circulating glucocorticoids, a condition first described by Harvey Cushing over a century ago. Despite the time that has passed since its discovery, the investigation and management of this syndrome remain a challenge, even for seasoned endocrinologists. While the diagnosis is unmistakable in its most severe presentations, the prevalence of non-specific symptoms such as obesity, muscle weakness, and depression compels clinicians to recognize and address the condition in its earlier stages. The diagnostic process often involves an array of tests, each requiring careful interpretation to distinguish between the various underlying causes. Left untreated, severe forms of Cushing’s syndrome carry a high mortality risk due to profound metabolic disturbances. Even mild cortisol excess can significantly impact blood pressure and glycemic control, contributing to substantial morbidity. Effective treatment is multifaceted, frequently necessitating a combination of surgical, radiological, and medical interventions.

Pathophysiology, Etiology, and Epidemiology of Cushing’s Syndrome

Under normal physiological conditions, the hypothalamo-pituitary-adrenal (HPA) axis regulates cortisol secretion, the primary glucocorticoid produced by the zona fasciculata of the adrenal cortex. Cortisol release is stimulated by adrenocorticotropic hormone (ACTH) from the pituitary gland, which, in turn, is regulated by corticotropin-releasing hormone (CRH) and vasopressin from the hypothalamus. Cortisol exerts negative feedback control over CRH, vasopressin, and ACTH to maintain balance within the HPA axis. Its secretion follows a circadian rhythm, peaking between 7:00 and 8:00 AM and reaching its lowest levels around midnight before beginning to rise again in the early morning hours.

Figure 1. Normal Hypothalamic Pituitary Adrenal Axis

Cushing’s syndrome arises when this finely tuned system is disrupted. Loss of the normal circadian rhythm and feedback regulation leads to sustained, elevated cortisol levels, which underlie the clinical manifestations of endogenous Cushing’s syndrome. Additionally, excessive administration of synthetic glucocorticoids, commonly used to treat chronic conditions such as asthma or autoimmune diseases, is the most frequent cause of exogenous Cushing’s syndrome in clinical practice. Physicians must thoroughly evaluate patients for potential exposure to topical, inhaled, or injected corticosteroids to identify this etiology.

The causes of Cushing’s syndrome are broadly classified into ACTH-dependent and ACTH-independent categories:

• ACTH-Dependent Cushing’s Syndrome:
  This form is driven by excessive ACTH secretion, which overstimulates all three layers of the adrenal cortex. This leads to bilateral adrenal hyperplasia and hypertrophy, often increasing adrenal gland weight. The glands frequently display micronodular or macronodular changes. Elevated circulating glucocorticoids are often accompanied by a rise in serum androgens due to overstimulation of the adrenal cortex.
• ACTH-Independent Cushing’s Syndrome:
  In this form, plasma ACTH levels are suppressed, either due to autonomous adrenal glucocorticoid hypersecretion or secondary to exogenous glucocorticoid administration. While adrenal adenomas typically secrete only glucocorticoids, other endogenous adrenal lesions may also produce androgens or steroid precursors. The appearance of unaffected adrenal tissue varies based on the underlying etiology, ranging from atrophy in cases of exogenous glucocorticoid use to nodular changes in primary adrenal diseases.

Understanding these distinct pathophysiological mechanisms is crucial for accurate diagnosis and tailored management, ensuring that treatment addresses both the underlying cause and the systemic effects of cortisol excess.

ACTH-Dependent Cushing’s Syndrome

Cushing’s Disease

Cushing’s disease, the pituitary-dependent form of Cushing’s syndrome, is the most common cause of endogenous hypercortisolism, accounting for 60-80% of all cases. Epidemiological data from Europe estimate an incidence of 0.7 to 2.4 cases per million annually. The condition is significantly more common in women, typically presenting between the ages of 25 and 40.

Cushing’s disease is almost always caused by a corticotroph adenoma, a benign tumor of the pituitary gland. Although rare cases of nodular corticotroph hyperplasia have been described, their existence is debated and seldom seen in large surgical series. Most corticotroph tumors are intrasellar microadenomas (less than 1 cm in diameter), while macroadenomas constitute approximately 5-10% of cases, occasionally extending beyond the sella or invading nearby structures. Extremely rare cases of pituitary corticotroph carcinomas with metastatic disease causing Cushing’s syndrome have also been reported.

The molecular mechanisms underlying corticotroph adenomas remain largely unknown. Evidence supports a primary pituitary origin rather than a hypothalamic disorder. Recent research has identified somatic mutations in the USP8 gene in about one-third of corticotroph adenomas. These mutations lead to the constitutive activation of a deubiquitinase enzyme, increasing EGF receptor expression on corticotroph cells. Rarely, these adenomas are linked to familial syndromes such as MEN1, MEN2, Carney Complex, or familial isolated pituitary adenoma syndrome, which are associated with mutations in genes like MEN1, RET, PRKR1A, and AIP. Very infrequently, Cushing’s disease has also been described in individuals with McCune-Albright or Beckwith-Wiedemann syndromes, although ACTH-independent Cushing’s syndrome is more common in these conditions.

In up to 40% of older patients with long-standing Cushing’s disease, ACTH-dependent macronodular adrenal hyperplasia can develop. This condition results in adrenal gland enlargement with occasional prominent nodules and internodular hyperplasia. In these cases, ACTH levels may be lower than expected, and recovery of hypercortisolemia can be delayed even after successful pituitary tumor resection.

Ectopic ACTH Syndrome and Ectopic CRH Tumors

The remaining cases of endogenous ACTH-dependent Cushing’s syndrome, excluding Cushing’s disease, are often caused by non-pituitary tumors secreting ACTH, collectively known as ectopic ACTH syndrome. These tumors originate from a wide variety of sources, which can be categorized into two groups: highly malignant carcinomas and more indolent neuroendocrine tumors. However, these categories are better understood as a spectrum rather than distinct classifications.

In clinical practice, bronchial neuroendocrine tumors are the most common ectopic ACTH source, accounting for up to 25% of cases. This is followed by small-cell lung carcinoma, which causes approximately 19% of ectopic ACTH syndrome cases. Around 16% of patients with ectopic ACTH syndrome have an occult source, necessitating repeated imaging and monitoring for tumor detection.

Ectopic ACTH syndrome is more prevalent in men and typically presents after the age of 40, though it should be considered at any age, including in children. The clinical presentation of ectopic ACTH syndrome can vary depending on the tumor’s characteristics, but prompt diagnosis and management are crucial to mitigate the effects of hypercortisolism and address the underlying malignancy.

Etiology of Ectopic ACTH Syndrome

• Lung carcinoma
• Bronchial neuroendocrine tumor
• Thymic neuroendocrine tumor
• Medullary cell carcinoma
• Pancreatic or gastrointestinal neuroendocrine tumor (NET)
• Phaeochromocytoma/paraganglioma
• NET of unknown primary
• Occult tumor
• Miscellaneous malignant tumors

POMC and Ectopic ACTH Production

The ACTH precursor molecule, pro-opiomelanocortin (POMC), is expressed not only in the normal pituitary but also in several extra-pituitary tissues and some tumors, such as those in the lung or testis. While the mechanisms by which non-corticotroph tumors express the POMC gene are not fully understood, it may involve hypomethylation of the POMC promoter. Unlike Cushing’s disease, these tumors often produce higher levels of POMC than ACTH. Additionally, they may secrete pre-ACTH precursor peptides, known as “big” ACTH, which could aid in differential diagnosis. However, assays for these peptides are not widely available in clinical practice.

Isolated ectopic CRH production is exceedingly rare and challenging to diagnose, with only a few confirmed cases in the literature. In most cases, tumors secreting CRH also produce ACTH, making the distinction clinically insignificant.

ACTH-Independent Cushing’s Syndrome

ACTH-independent causes of Cushing’s syndrome, aside from exogenous glucocorticoids, encompass a range of conditions:

1. Adrenal Adenoma and Carcinoma
   • Adrenal adenomas are most common in women around the age of 35, with an incidence of 0.6 per million per year.
   • Adrenocortical carcinomas, rarer with an incidence of 0.2 per million annually, are more common in women and exhibit a bimodal age distribution, peaking in childhood/adolescence and again between 40-50 years.
   • Approximately 50-60% of adrenal carcinomas secrete hormones, primarily glucocorticoids and androgens.
   • Carcinomas are distinguished from adenomas using features such as size (>100g), nuclear pleomorphism, necrosis, mitotic figures, and vascular/lymphatic invasion, as outlined in the Weiss score.
2. Bilateral Macronodular Adrenocortical Disease (BMAD)
   • Previously termed ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH), BMAD is characterized by large adrenal nodules (>1 cm) visible on imaging.
   • Most cases are sporadic, but some familial cases involve germline mutations, including ARMC5 or KDM1A.
   • Ectopic receptors, such as glucose-dependent insulinotropic polypeptide (GIP) receptors, may aberrantly stimulate cortisol production in food-dependent Cushing’s syndrome.
   • Other aberrant receptors implicated include vasopressin, β-adrenergic, luteinizing hormone, serotonin, and angiotensin receptors.
   • BMAD often presents as subclinical Cushing’s syndrome, and treatment options include receptor-targeted therapies, though their efficacy may diminish over time.
3. McCune-Albright Syndrome
   • Features include fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction.
   • Caused by an activating mutation of the GNAS gene, resulting in constitutive activation of adenylate cyclase, nodule formation, and glucocorticoid overproduction.
   • Treatment involves addressing hypercortisolism and related endocrine dysfunction.
4. Primary Pigmented Nodular Adrenal Disease (PPNAD)
   • Characterized by small or normal-size adrenal glands with dark, pigmented micronodules.
   • Often associated with Carney Complex, a syndrome involving myxomas, hyperpigmentation, and other endocrine tumors.
   • In most cases, mutations in the PRKAR1A gene are identified.
   • Bilateral adrenalectomy is curative, though other endocrine abnormalities may coexist.
5. Other Rare Causes
   • Ectopic cortisol production by ovarian carcinoma.
   • Adrenal rest tissue located in unusual sites, such as the liver or gonads, producing cortisol.
   • Missense mutations in the ACTH receptor causing constitutive activation and Cushing’s syndrome.

Pseudo-Cushing’s Syndrome

Pseudo-Cushing’s syndrome encompasses conditions that mimic true Cushing’s syndrome both clinically and biochemically but resolve once the underlying cause is addressed. The pathophysiology is not well understood. Depression and alcohol abuse are the most frequently reported conditions leading to this state. Both conditions can present with hypercortisolemia and clinical features resembling Cushing’s syndrome, which normalize upon resolution of the triggering condition.

Exogenous Cushing’s Syndrome

Exogenous or iatrogenic Cushing’s syndrome results from prolonged exposure to external corticosteroids, with the development of Cushingoid features depending on the dose, duration, and potency of the medication. Although ACTH administration is now rarely used, it can also lead to Cushingoid features when given long-term.

Certain complications, such as increased intraocular pressure, cataracts, benign intracranial hypertension, aseptic necrosis of the femoral head, osteoporosis, and pancreatitis, appear to be more prevalent in iatrogenic Cushing’s syndrome compared to its endogenous counterpart. Conversely, features such as hypertension, hirsutism, and menstrual irregularities (e.g., oligomenorrhea/amenorrhea) are less common. Whether these distinctions represent true differences or observational bias remains uncertain.

Clinical Manifestations of Cushing’s Syndrome

The clinical manifestations of Cushing’s syndrome arise from chronic exposure to excess glucocorticoids and can range widely from mild, subclinical disease to severe and florid presentations.

In its classical and most severe form, the syndrome is characterized by truncal obesity, wasting of the limbs, facial rounding (moon face), plethora, hirsutism with frontal balding, muscle weakness, spontaneous bruising, vertebral fractures, hypertension, and diabetes mellitus. However, this dramatic presentation has become less common in modern clinical practice. Instead, the diagnosis is often less clear due to the overlap of common symptoms, such as lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularity, with conditions frequently encountered in the general population.

For an accurate diagnosis, it is essential to focus on the more specific signs of glucocorticoid excess, particularly those reflecting its catabolic effects. Identifying the presence of multiple symptoms with a progressive clinical course is highly informative. Sequential photographs documenting physical changes over time can also provide valuable evidence of disease progression.

The manifestations of Cushing’s syndrome are influenced by the duration and severity of glucocorticoid exposure. In aggressive forms, such as those caused by ectopic ACTH secretion (e.g., small cell carcinoma), hypercortisolism symptoms may be overshadowed by signs of malignancy, including weight loss and anorexia. The average time to diagnosis varies by etiology, with the shortest duration seen in ectopic ACTH syndrome (14 months), followed by ACTH-independent Cushing’s syndrome (30 months), and the longest in Cushing’s disease (38 months).

The specific type of steroid excess also depends on the underlying condition. For example, adrenal adenomas primarily secrete glucocorticoids, whereas ACTH-dependent disease or adrenal carcinomas often result in hyperandrogenism in addition to glucocorticoid excess. Identifying these patterns is crucial for determining the cause and tailoring the management of Cushing’s syndrome.

Table 2. Frequency of physical examination findings in Cushings

Clinical Features and Variability in Cushing’s Syndrome

The combination of clinical features in Cushing’s syndrome is largely influenced by the natural course and underlying cause of the condition.

Ectopic ACTH Syndrome

• Patients with ectopic ACTH syndrome often present with severe and rapidly developing metabolic signs, including anorexia, myopathy, and glucose intolerance.
• Severe hypercortisolemia, often coupled with mineralocorticoid effects, results in hypokalemic alkalosis and peripheral edema.
• Key clinical indicators, such as rapid deterioration, hyperpigmentation, hypokalemia, and signs of mineralocorticoid excess, may point to small-cell lung carcinoma, high-grade bronchial carcinoid, or pancreatic neuroendocrine tumors.
• In contrast, low-grade bronchial carcinoids often exhibit the classical Cushingoid features due to prolonged hypercortisolism, complicating differentiation from Cushing’s disease.

Adrenal Carcinomas

• Patients with adrenal carcinomas typically present with rapid symptom onset, often accompanied by abdominal pain and a palpable tumor mass.
• These tumors frequently secrete mineralocorticoids and androgens, distinguishing them from benign adenomas, which usually produce cortisol alone.
• Acne and hirsutism are often prominent in women with androgen-secreting adrenal carcinomas.
• Increasingly, adrenal carcinomas are identified incidentally during routine imaging for unrelated conditions.

Mild Autonomous Cortisol Secretion (MACS)

• In about 10% of patients with adrenal incidentalomas, MACS (previously known as subclinical Cushing’s syndrome) is identified.
• This condition involves mild hypercortisolism without the overt clinical features of Cushing’s syndrome.

Androgen Hypersecretion in Women

• Unlike men, whose primary androgen source is the testes, women derive a significant portion of circulating androgens from the adrenal glands.
• Adrenal hyperandrogenism in women is often evident through hirsutism, acne, and occasionally virilization.

Obesity and Fat Redistribution

• Obesity and weight gain are among the most common features of Cushing’s syndrome.
• Typical fat redistribution includes truncal obesity, moon face, buffalo hump (dorsocervical fat pad), and supraclavicular fat pads.
• Rarely, fat deposition in the epidural space may cause neurological deficits, or retroorbital fat deposition may manifest as exophthalmos.
• In children, generalized weight gain combined with growth retardation is a strong indicator.

Myopathy

• Proximal muscle weakness, especially in the lower limbs and shoulders, occurs in 40-70% of patients due to the catabolic effects of glucocorticoids.
• Assessing myopathy includes evaluating activities such as climbing stairs or rising from a chair. Formal testing can involve leg extension while seated or rising unaided from a squatting position.
• Hypokalemia caused by mineralocorticoid effects may exacerbate muscle weakness.
• Recovery of muscle strength may be incomplete, even after successful treatment of hypercortisolism.

Osteoporosis and Bone Effects

• Osteoporosis is present in approximately 50% of adult patients and primarily affects trabecular bone, leading to vertebral fractures and height loss.
• Rib fractures, often painless, may show exuberant callus formation on imaging.
• Aseptic necrosis of the femoral head is more commonly associated with iatrogenic Cushing’s syndrome following prolonged glucocorticoid use.
• Bone density improves significantly after successful treatment of Cushing’s syndrome.

Skin Changes

• Thinning of the skin is a hallmark of Cushing’s syndrome and is most apparent on the dorsum of the hand, described as “cigarette paper” (Liddle’s sign).
• Easy bruising, due to subcutaneous fat and elastic tissue loss, may mimic senile purpura or a coagulation disorder.
• Violaceous striae, over 1 cm wide, are almost pathognomonic of Cushing’s syndrome and typically appear on the abdomen, thighs, breasts, or arms.
• Facial plethora (redness) occurs due to skin thinning and loss of facial subcutaneous fat.

Growth in Children

• In children, the combination of growth retardation and generalized weight gain should prompt consideration of Cushing’s syndrome as a diagnosis.

Hair and Skin Changes

• Hair Growth: Increased fine, non-pigmented vellus hair on the upper cheeks or forehead, along with terminal hair hirsutism on the face and body, reflects androgen excess.
• Skin Infections: Common cutaneous fungal infections include truncal tinea versicolor and onychomycosis.
• Hyperpigmentation: More frequently seen in ectopic Cushing’s syndrome (e.g., small-cell lung carcinoma) than in Cushing’s disease, it often accompanies profound weakness, minimal weight gain, and an absence of overt Cushingoid features.
• Severe Hirsutism and Virilization: Strongly suggestive of adrenal carcinoma.

Hormonal Suppression and Reproductive Effects

• Hypogonadotropic Hypogonadism: Common in both men and women due to glucocorticoid inhibition of gonadotropin-releasing hormone (GnRH) pulsatility, reducing LH and FSH secretion.
  • Women: Menstrual irregularities and decreased libido.
  • Men: Reduced libido and gonadal dysfunction.
• Polycystic Ovarian Syndrome (PCOS): Often coexists with Cushing’s syndrome.
• Growth Hormone (GH): Reduced secretion and blunted responses to stimulation tests.
• Thyroid Dysfunction: Impaired TSH release and nocturnal TSH surge, with increased prevalence of autoimmune thyroid disease following successful treatment of Cushing’s syndrome.

Metabolic and Cardiovascular Effects

• Electrolyte Imbalance: Hypokalemic metabolic alkalosis, more common in ectopic ACTH secretion, results from mineralocorticoid activity due to glucocorticoid saturation of renal 11β-hydroxysteroid dehydrogenase type 2.
• Glucose Metabolism:
  • Insulin Resistance and Hyperinsulinemia: Common, with glucose intolerance in 20-64% of cases and overt diabetes in 30-47%.
  • Mechanisms: Glucocorticoids promote gluconeogenesis, inhibit peripheral glucose uptake, and stimulate lipolysis.
  • Diabetes remission is frequent after treatment of hypercortisolism.
• Lipid Profile: Increased total cholesterol and triglycerides, with variable effects on HDL.
• Cardiovascular Risks:
  • Common causes of mortality include cardiovascular events, with persistent risks even after hypercortisolism resolution.
  • Markers of cardiovascular disease include increased carotid intima-media thickness, atherosclerosis, hypertension, and visceral obesity.
  • Severe hypertension, especially with hypokalemia, is more common in ectopic Cushing’s syndrome and responds well to spironolactone.

Coagulation and Thrombotic Risks

• Hypercoagulability: Elevated clotting factors and reduced fibrinolysis increase the risk of thrombotic events.
  • Venous thromboembolism (VTE) occurs in 20% of untreated cases, with persistent risks even after remission.
  • Thromboprophylaxis: Recommended for patients undergoing surgery or with additional risk factors.

Neurological and Psychiatric Effects

• Psychiatric Symptoms: Depression, anxiety, irritability, paranoia, and insomnia affect over half of patients, along with cognitive impairments in memory and learning.
• Autonomic Dysfunction: Abnormal sympathetic function is linked to prolonged QTc dispersion and left ventricular hypertrophy.
• Ophthalmic Complications: Glaucoma, exophthalmos from retroorbital fat deposition, and rare cataracts, often associated with diabetes.

Infections

• Increased susceptibility to bacterial and opportunistic infections due to glucocorticoid suppression of cell-mediated immunity (Th1 responses), with reductions in CD4 and NK cells.

Cyclic Cushing’s Syndrome

• Some cases involve periodic or cyclical cortisol secretion, with waxing and waning symptoms.
  • Diagnostic difficulty arises when tests are performed during periods of eucortisolism, necessitating regular re-evaluation with urinary free cortisol or late-night salivary cortisol.
  • Cyclicity may occur in all forms of Cushing’s syndrome.

Biochemical Confirmation of Cushing’s Syndrome

Cushing’s syndrome presents with a diverse combination of clinical features, but certain pathognomonic signs—such as myopathy, wide purple striae, skin thinning, and bruising—strongly indicate the need for biochemical testing. Confirming the diagnosis requires biochemical evidence of hypercortisolism, which precedes tests to determine the specific underlying cause.

The key biochemical abnormalities in Cushing’s syndrome include hypercortisolemia, loss of the normal circadian rhythm of cortisol secretion, and disrupted hypothalamic-pituitary-adrenal (HPA) axis feedback. Diagnostic tests are designed around these principles. Initial screening employs highly sensitive tests to detect even mild cases, followed by highly specific tests to exclude false positives. For patients with a moderate-to-high clinical probability of Cushing’s syndrome, 2–3 different screening tests are recommended. In cases of low probability, a single negative test, such as the overnight dexamethasone suppression test, is usually sufficient.

Important Considerations

• Validation of test criteria depends on the specific assay used; results should be interpreted with local assay validation.
• Cortisol secretion follows a circadian rhythm, peaking early in the morning (07:00–08:00h) and reaching a nadir at midnight (<50 nmol/L or 1.8 μg/dL). In Cushing’s syndrome, this rhythm is lost, with elevated nocturnal cortisol levels being most diagnostically significant.
• Exogenous estrogens, such as oral contraceptives or hormone replacement therapy, increase cortisol-binding globulin (CBG) and total cortisol levels, potentially affecting test results. These medications should be discontinued 4–6 weeks before testing.

Late-Night Salivary Cortisol

Late-night salivary cortisol is a widely used, non-invasive, and sensitive screening tool for detecting the loss of circadian rhythm in cortisol secretion. It reflects free cortisol levels, as CBG is absent in saliva. Saliva samples are ideally collected at bedtime, when cortisol levels are naturally at their lowest.

Advantages

• Simple and non-invasive collection, suitable for home use.
• Stable at room temperature, making it particularly useful for children or patients with cyclical Cushing’s syndrome.
• Highly sensitive (92%) and specific (96%) based on meta-analyses of multiple studies.

Collection Guidelines

• Collect at least two samples on separate days for accuracy.
• Avoid eating, drinking, smoking, or brushing teeth within 15 minutes before collection.
• Not recommended for night-shift workers or individuals with irregular schedules.

Applications

• Increasingly used: In a European registry of 1,341 patients with Cushing’s syndrome (ERCUSYN), it was used in 28% of cases diagnosed between 2000 and 2016.
• Valuable for detecting recurrence or treatment failure following pituitary surgery.

Limitations

• Diagnostic cut-offs vary between studies due to differences in assays and populations.
• Less effective in subclinical Cushing’s syndrome (mild autonomous cortisol secretion).
• Normal ranges differ between adults and pediatric populations and can be influenced by comorbidities such as diabetes or collection methods.

Urinary Free Cortisol (UFC)

Urinary free cortisol (UFC) measurement is a widely used, non-invasive screening test for Cushing’s syndrome, utilized in 78% of cases in the ERCUSYN registry. Normally, 5–10% of plasma cortisol is unbound, filtered by the kidney, with most reabsorbed in the tubules and the remainder excreted unchanged. In Cushing’s syndrome, as serum cortisol levels rise, cortisol-binding globulin (CBG) becomes saturated, leading to a disproportionate increase in UFC levels. A 24-hour UFC collection provides an integrated measure of serum cortisol, smoothing out diurnal variations.

• Sensitivity: UFC measurement has a sensitivity of 95% in diagnosing Cushing’s syndrome, though multiple collections (2–3) are recommended due to episodic cortisol secretion.
• Efficacy by Subtype: Sensitivity is 86% for adrenal and ectopic Cushing’s syndrome and 95% for Cushing’s disease.

Limitations

• Incomplete Collections: Written instructions should be provided to patients to ensure accurate 24-hour collection. Simultaneous creatinine measurement helps verify completeness, with a creatinine excretion target of ~1g/24 hours for a 70kg individual.
• Pseudo-Cushing’s States: UFC lacks value in differentiating Cushing’s syndrome from pseudo-Cushing’s states.
• Drug Interference: Medications like carbamazepine, digoxin, and fenofibrate may cause falsely elevated results.
• Advanced Assays: Modern high-performance liquid chromatography or tandem mass spectrometry techniques improve accuracy by reducing cross-reactivity with exogenous glucocorticoids.

Summary

UFC is a highly sensitive diagnostic tool when collected correctly, with levels exceeding four times the normal range strongly suggesting Cushing’s syndrome. Marginally elevated results require additional testing to confirm the diagnosis. While UFC is less commonly used as a first-line screening test, it remains valuable for assessing patients with episodic cortisol secretion or intermediate findings.

Low-Dose Dexamethasone Suppression Test (LDDST)

The LDDST operates on the principle that exogenous glucocorticoids suppress the HPA axis in normal individuals, whereas patients with Cushing’s syndrome exhibit resistance to this negative feedback. Dexamethasone, a potent synthetic glucocorticoid, is ideal for this test as it does not interfere with most cortisol assays.

Protocols and Performance

1. Overnight Dexamethasone Suppression Test (ONDST)
   • Patients take 1mg of dexamethasone at midnight, with serum cortisol measured at 09:00h the next morning.
   • Sensitivity: 98–99% for screening, based on European registry data.
   • A threshold of cortisol <50nmol/L (1.8 μg/dL) at 09:00h is highly reliable for ruling out Cushing’s syndrome, though false positives remain significant.
2. Two-Day LDDST
   • Dexamethasone is administered every 6 hours (0.5mg per dose) over 48 hours, with cortisol measured at the end of the test.
   • Sensitivity: Comparable to ONDST (98–100%).
   • Specificity: Higher for the two-day test (95–100%) compared to the overnight protocol (88%).

Considerations

• False Positives:
  • Medications acting as CYP3A4 inducers (e.g., certain antiepileptics) may accelerate dexamethasone metabolism, leading to false positives.
  • Elevated CBG levels (e.g., during pregnancy, estrogen use, or chronic liver disease) can also affect results. Measuring dexamethasone levels can help identify these issues, although this is not routinely available.
• PPNAD: Patients with primary pigmented nodular adrenal disease may exhibit a paradoxical rise in cortisol after dexamethasone administration.

The ONDST is an excellent first-line screening test due to its simplicity and high sensitivity, while the two-day LDDST provides superior specificity and is often used for confirmation. Both tests are foundational tools in diagnosing Cushing’s syndrome and differentiating it from other conditions affecting cortisol secretion.

Midnight Serum Cortisol

Before the advent of salivary cortisol measurement, midnight serum cortisol was the primary test used to detect loss of the circadian rhythm of cortisol secretion. It remains a valuable second-line test for cases where diagnostic uncertainty persists.

Protocol and Interpretation

• The test requires hospitalization for at least 48 hours to acclimate the patient to the hospital environment.
• The patient must be asleep prior to venipuncture, which should occur within 5–10 minutes of waking them.
• A midnight plasma cortisol level <50 nmol/L (1.8 μg/dL) effectively rules out Cushing’s syndrome, but false positives may occur in critically ill patients or those with conditions like acute infections, heart failure, or pseudo-Cushing’s states.
• An awake midnight cortisol >207 nmol/L (7.5 μg/dL) demonstrates high sensitivity (94%) and specificity (100%) for distinguishing Cushing’s syndrome from pseudo-Cushing’s states.

While this test was performed in 62% of cases in the ERCUSYN cohort, it has been largely replaced by late-night salivary cortisol (LNSC) due to the practicality of outpatient-based investigations.

Dexamethasone-CRH (Dex-CRH) Test

The Dex-CRH test, introduced in 1993, is used in challenging cases to distinguish between pseudo-Cushing’s states (non-neoplastic hypercortisolism) and true Cushing’s syndrome, especially in patients with mild hypercortisolemia and subtle clinical signs.

Protocol

• Dexamethasone: Administered at 0.5 mg every 6 hours for eight doses, ending 2 hours before CRH injection.
• CRH Injection: Ovine CRH (1 μg/kg intravenously) is given, and cortisol is measured 15 minutes afterward.

Diagnostic Performance

• Plasma cortisol levels <38 nmol/L (1.4 μg/dL) post-CRH effectively rule out Cushing’s syndrome, while higher levels confirm it.
• Early studies demonstrated sensitivity of 99% and specificity of 96%, but later studies have shown variability in diagnostic utility due to differences in protocols, definitions, and thresholds.
• Comparative studies indicate the low-dose dexamethasone suppression test (LDDST) has similar or superior specificity.

Limitations

• Variable dexamethasone metabolism among individuals and limited availability of CRH have made this test less commonly used.
• It is generally not recommended due to the availability of simpler and more reliable alternatives.

Desmopressin Test

The Desmopressin Test leverages the expression of V3 receptors on ACTH-secreting adenomas, which causes desmopressin to stimulate ACTH and cortisol secretion in patients with Cushing’s disease.

Protocol

• Intravenous Injection: Administer 10 mcg of desmopressin.
• ACTH Measurement: Measure ACTH every 15 minutes from -15 minutes to 90 minutes post-injection.

Diagnostic Performance

• A study of 173 subjects proposed a positive test cutoff for an ACTH increment >6 pmol/L (30 ng/L).
• A subsequent study suggested updated criteria of ACTH increment >4 pmol/L with basal cortisol >331 nmol/L, yielding sensitivity of 90.3% and specificity of 91.5%.
• Meta-analysis of three studies reported pooled sensitivity of 88% and specificity of 94% for distinguishing Cushing’s disease from non-neoplastic hypercortisolism.

Limitations

• High patient selection bias and variability in evidence limit the certainty of its utility.
• Further research is needed to standardize the test and its diagnostic thresholds.

Differential Diagnosis of Cushing’s Syndrome

Once Cushing’s syndrome is confirmed, the next step is differentiating between ACTH-dependent and ACTH-independent causes by measuring plasma ACTH levels. Modern two-site immunoradiometric assays provide superior sensitivity compared to older radioimmunoassays. Accurate sample handling is critical, as ACTH is rapidly degraded by peptidases. Samples must be kept in an ice-water bath and processed—centrifuged, aliquoted, and frozen—within two hours to ensure reliable results.

ACTH Measurement

• Timing: Optimal sampling occurs between 08:00 and 09:00h due to the loss of circadian rhythm in Cushing’s syndrome.
• Repetition: Measurements should be repeated on different days to account for episodic ACTH secretion.
• Interference: False elevations may occur due to heterophilic antibodies or ACTH fragments. If results are inconsistent, remeasurement using an alternative assay is advised.

Interpretation

• ACTH <10 ng/L (2 pmol/L): Confirms ACTH-independent Cushing’s syndrome, warranting adrenal imaging.
• ACTH >20–30 ng/L (4–6 pmol/L): Indicates ACTH-dependent Cushing’s syndrome, arising from either pituitary disease or ectopic ACTH secretion.
• Intermediate ACTH Levels: Additional tests, such as CRH or desmopressin stimulation, can aid in diagnosis.

Investigating ACTH-Independent Cushing’s Syndrome

Adrenal imaging is the primary method to evaluate ACTH-independent Cushing’s syndrome. High-resolution CT is preferred for its accuracy in detecting masses >1 cm and assessing the contralateral gland. MRI provides additional differentiation based on T2-weighted signals.

Findings by Cause

• Adrenal Tumors: Typically unilateral with contralateral gland atrophy. Tumors >5 cm are presumed malignant until proven otherwise.
  • Adenomas: Smaller, homogeneous, and hypointense on T1-weighted MRI, with low unenhanced CT attenuation (<20 HU).
  • Carcinomas: Larger, often >5 cm, with signs of necrosis, hemorrhage, and calcification, and frequently co-secrete androgens.
• Primary Pigmented Nodular Adrenal Disease (PPNAD): Normal or slightly lumpy adrenal glands without significant enlargement.
• Bilateral Macronodular Adrenocortical Disease (BMAD): Enlarged bilateral adrenal glands (>5 cm) with nodular configurations.
• Exogenous Glucocorticoid Use: Adrenal atrophy with small gland size on imaging.

Identifying the Source in ACTH-Dependent Cushing’s Syndrome

Diagnosing the source of ACTH-dependent Cushing’s syndrome is complex but has improved significantly in recent years. Cushing’s disease (pituitary origin) accounts for the majority of cases (85–90%). In the European registry, 92% of ACTH-dependent cases were pituitary in origin.

Pretest Probability

• Higher likelihood of Cushing’s disease in women (92%) compared to men (77%).
• Pretest probability must be considered when interpreting results, as testing should aim to avoid unnecessary pituitary surgery in cases of ectopic ACTH production.

ACTH and Cortisol Levels

• Levels are generally higher in ectopic ACTH syndrome, but overlap with Cushing’s disease limits diagnostic utility.
• Hypokalemia: More common in ectopic ACTH-dependent Cushing’s syndrome.

Role of Imaging

• Pituitary MRI: Used to identify microadenomas (<1 cm) or macroadenomas.
• CT for Ectopic Sources: Essential for locating tumors in the chest or abdomen, often responsible for ectopic ACTH secretion.

Invasive Testing for Cushing’s Syndrome

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard test for differentiating Cushing’s disease (pituitary source) from ectopic ACTH secretion. However, it is generally unnecessary if an MRI reveals a pituitary macroadenoma (≥10mm) and dynamic tests, such as CRH or desmopressin stimulation, support a diagnosis of Cushing’s disease.

Procedure Overview

The procedure involves inserting catheters into the inferior petrosal sinuses, which drain the pituitary gland, to sample ACTH levels. Blood is drawn simultaneously from each sinus and a peripheral vein:

• Baseline Samples: Taken before stimulation.
• Post-Stimulation Samples: Collected at 3–5 minutes and possibly 10 minutes after administering 100 mcg of CRH (if available) or 10 mcg desmopressin.

Diagnostic Criteria:

• Baseline Gradient: A central-to-peripheral plasma ACTH ratio of ≥2:1 is diagnostic of Cushing’s disease.
• Post-Stimulation Gradient: A ratio ≥3:1 after desmopressin or CRH further supports the diagnosis.

Diagnostic Performance

• Early studies demonstrated 100% sensitivity and specificity using CRH stimulation, though false negatives and positives are now recognized.
• A meta-analysis of 23 studies with 1,642 patients reported 94% sensitivity and 89% specificity, with an area under the ROC curve of 97%.
• Desmopressin stimulation achieves comparable results, with studies showing a sensitivity of 97.8% and specificity of 100% when an ACTH ratio >2.8 is applied.

Key Factors for Accuracy:

• Ensure the patient is actively hypercortisolemic at the time of testing.
• Confirm catheter placement bilaterally and assess venous drainage patterns with venography.

Lateralization of Pituitary Microadenomas

BIPSS can also help lateralize microadenomas within the pituitary by analyzing inter-sinus ACTH gradients:

• A basal or post-stimulation inter-sinus ratio of ≥1.4 suggests lateralization.
• Diagnostic accuracy varies between 59–83%, improving with symmetric venous drainage.
• In one study of 501 cases, lateralization was accurate in 69% of patients. Enhanced dynamic MRI improves lesion detection, identifying pituitary adenomas in 81% of cases.

Safety and Limitations

• Complications: Rare (<1%), but include transient ear discomfort, groin hematomas, and in rare cases, brainstem infarction. Early signs of complications require immediate cessation of the procedure.
• Technical Challenges: Requires experienced radiologists.
• Alternative Approaches: Internal jugular vein sampling is simpler but less sensitive than BIPSS.

Additional Considerations

• Prolactin Ratio: A baseline inferior petrosal sinus (IPS) to peripheral prolactin ratio >1.8 confirms successful catheterization. Including this metric improves diagnostic performance but is not universally adopted.
• Children: BIPSS has higher lateralization accuracy in children (90%) where imaging is often inconclusive.
• Imaging Correlation: Enhanced dynamic MRI has a better detection rate for pituitary microadenomas than conventional MRI and is particularly valuable for pre-surgical planning.

BIPSS remains the definitive diagnostic tool for distinguishing Cushing’s disease from ectopic ACTH secretion. When combined with advanced imaging techniques and dynamic testing, it provides critical information to guide treatment decisions and surgical planning.

Non-Invasive Tests for Cushing’s Syndrome

High-Dose Dexamethasone Suppression Test (HDDST)

The HDDST, first proposed by Liddle, helps differentiate ACTH-dependent Cushing’s disease from ectopic ACTH secretion. It operates on the principle that most pituitary corticotroph tumors retain some sensitivity to glucocorticoid feedback, while ectopic ACTH-secreting tumors, with some exceptions (e.g., bronchial neuroendocrine tumors), typically do not.

Protocol:

• Two-Day Test: 2mg dexamethasone every 6 hours for 2 days.
• Overnight Test: A single 8mg dexamethasone dose at 23:00h, with cortisol measured the next morning at 08:00h.

Diagnostic Criteria:

• Suppression of cortisol to <5 mcg/dL (140 nmol/L) supports Cushing’s disease.
• A >50% reduction in basal cortisol indicates a positive response, but this occurs in only ~80% of patients with Cushing’s disease.
• False positives are common (~10–30%) in ectopic Cushing’s syndrome.

Utility:

• HDDST has limited use due to reduced specificity and is generally reserved for cases where Bilateral Inferior Petrosal Sinus Sampling (BIPSS) is unavailable.
• In combination with dynamic MRI, HDDST achieves a 98.6% positive predictive value (PPV) for Cushing’s disease, though sensitivity is lower (69.6%).

CRH Test

The CRH test distinguishes between pituitary-dependent and ectopic ACTH-dependent Cushing’s syndrome by exploiting the responsiveness of pituitary corticotroph tumors to CRH.

Protocol:

• Agent: 100 µg of human-sequence CRH (hCRH) or ovine-sequence CRH (oCRH) administered as a bolus injection.
• Measurement: Changes in ACTH and cortisol are monitored at baseline, 15 minutes, and 30 minutes post-injection.

Diagnostic Performance:

• A ≥35% rise in ACTH and ≥14% rise in cortisol from baseline indicates Cushing’s disease, with sensitivity of 85–93% and specificity of 100%.
• The ACTH response to CRH is comparable for both hCRH and oCRH, though oCRH demonstrates higher sensitivity for cortisol responses (67% vs. 50%).

Limitations:

• Variability in protocols and diagnostic thresholds complicates standardization.
• The test is largely unavailable in most countries due to limited CRH supplies, with desmopressin serving as an alternative.

Desmopressin Test

Desmopressin, a synthetic vasopressin analogue, stimulates ACTH release in patients with Cushing’s disease through corticotroph-specific V3 receptors.

Protocol:

• Dose: 10 mcg of desmopressin intravenously.
• Measurement: ACTH and cortisol are measured before and at intervals up to 90 minutes post-injection.

Diagnostic Criteria:

• An ACTH increase >35% and cortisol increase >20% indicates Cushing’s disease, with pooled sensitivity of 88% and specificity of 74%.

Combined Testing:

• A strategy combining CRH and desmopressin stimulation tests achieves 100% PPV for diagnosing Cushing’s disease when pituitary MRI and ectopic source imaging are negative.
• Combining both tests can avoid BIPSS in nearly half of patients.

Summary of Non-Invasive Tests

Non-invasive tests like HDDST, CRH, and desmopressin play crucial roles in diagnosing Cushing’s syndrome, especially when invasive procedures are unavailable. While their individual sensitivities and specificities vary, combining these tests can enhance diagnostic accuracy, particularly in distinguishing Cushing’s disease from ectopic ACTH secretion.

Imaging in Cushing’s Syndrome Diagnosis

Pituitary Imaging

Imaging of the pituitary gland is essential in investigating ACTH-dependent Cushing’s syndrome, primarily to identify a pituitary lesion and guide surgical exploration. However, imaging results should always be interpreted in the context of biochemical findings, as up to 10% of healthy individuals may have pituitary incidentalomas detectable on MRI.

• Modern MRI Techniques: T1-weighted spin echo or spoiled gradient recalled acquisition (SPGR) techniques with 1mm slice thickness identify adenomas in up to 80% of patients with Cushing’s disease. These methods offer greater sensitivity but also increase false positives.
  • Typical Findings: 95% of microadenomas appear hypointense on T1-weighted images without post-gadolinium enhancement. The remaining 5% may be isointense, making pre-gadolinium imaging crucial.
  • Advanced Techniques: Delayed contrast washout on FLAIR MRI can detect microadenomas in patients with negative dynamic MRI findings.
• Alternative Imaging: If MRI fails to localize a lesion, 11C-methionine PET co-registered with 3D gradient echo MRI can be helpful, though it requires an on-site cyclotron due to the isotope’s short half-life.
• CT Scans: With a sensitivity of 40–50% for microadenomas, CT is significantly inferior to MRI and is typically reserved for patients who cannot undergo MRI.

Preoperative MRI localization has a reported positive predictive value (PPV) of 93% for identifying pituitary lesions, though other studies indicate variability, especially in pediatric patients where BIPSS is often more effective.

Imaging Ectopic ACTH-Secreting Tumors

Identifying ectopic ACTH-secreting tumors can be challenging. Imaging typically begins with CT or MRI of the chest and abdomen, targeting likely sites of ectopic production.

• Common Sites: The chest is the most frequent location, with small cell lung carcinomas and bronchial carcinoid tumors being common culprits. High-resolution CT with fine-cut slices and both supine and prone positioning improves differentiation between tumors and vascular shadows.
• MRI: Can detect chest lesions missed on CT, with tumors showing high signals on T2-weighted and STIR images.
• Functional Imaging:
  • Somatostatin Receptor Scintigraphy: Using radiolabeled analogues like 111In-pentetreotide, this method can help confirm tumor functionality or locate radiologically occult lesions.
  • 68Ga-DOTA-PET: Superior to conventional somatostatin scintigraphy, this technique is particularly effective for identifying primary occult neuroendocrine tumors (NETs) and bronchial carcinoids. Detection rates are 70% for 68Ga-labeled peptides versus 61% for 18F-FDG PET.
  • 18F-FDG PET: More effective for detecting aggressive tumors like small-cell lung cancer.

Diagnostic Strategy for Cushing’s Syndrome

Diagnostic consensus statements recommend a stepwise approach:

1. First-Line Screening Tests:
   • Urinary free cortisol (UFC, at least two measurements).
   • Low-dose dexamethasone suppression test (LDDST).
   • Late-night salivary cortisol (LNSC, two measurements).
2. Confirmation of Abnormal Results:
   • Use second-line tests if results are discordant.
3. Determine Etiology:
   • Measure ACTH levels and perform the desmopressin test.
   • Combine with imaging findings.
4. Invasive Testing:
   • BIPSS is recommended for ACTH-dependent Cushing’s syndrome with discordant biochemical or radiological results.
   • Dynamic testing and high-quality imaging may reduce the need for BIPSS in some cases.

Treatment of Cushing’s Syndrome

Treatment focuses on addressing the underlying cause of hypercortisolism, as untreated Cushing’s syndrome can lead to fatal complications.

Primary Treatments

• Surgery: First-line treatment for most cases, aiming for permanent resolution of hypercortisolism and its associated symptoms.
• Radiation or Medical Therapy: Used when surgery is not possible or as first-line treatment based on patient preference, clinical condition, or etiology.

Post-Treatment Management

• Correct adrenal insufficiency promptly with steroid replacement therapy.
• Manage associated conditions, such as diabetes, hyperlipidemia, osteoporosis, and hypertension, with the goal of reducing long-term dependence on therapy.

Managing Severe Cases

• Prioritize treating metabolic complications such as hypokalemia, hypertension, and hyperglycemia.
• Address infections promptly, with prophylactic antibiotics for severe hypercortisolism (>1000–1200 nmol/L).
• Perioperative Anticoagulation: Prophylactic low molecular weight heparin is recommended for all but the mildest cases to prevent thromboembolic events.

First-Line Treatment: Transsphenoidal Surgery

Transsphenoidal surgery is the gold standard for treating Cushing’s disease and offers the highest likelihood of remission. Reoperation may be considered for persistent disease but has a lower success rate and higher risk of pituitary hormonal deficiencies. Before reoperation, diagnostic tests should be repeated to rule out an ectopic ACTH source, particularly if no tumor was identified on pathological examination. Other options for persistent disease include radiotherapy, medical therapy, or bilateral adrenalectomy as a definitive treatment.

Transsphenoidal Surgery

Procedure Overview

Transsphenoidal surgery is the treatment of choice for ACTH-dependent Cushing’s syndrome. Both traditional microscopic and modern endoscopic approaches are effective, with the latter offering shorter hospital stays and better outcomes for pituitary macroadenomas. Surgery should be performed by experienced pituitary surgeons, ideally in Pituitary Tumor Centers of Excellence, to maximize success and minimize complications. Surgeons with over 200 transsphenoidal procedures achieve the best outcomes.

Outcomes

• Remission Rates: Approximately 70–79% overall, with higher rates (~90%) for microadenomas.
• Risks:
  • Perioperative mortality: 1.9%.
  • Major complications: 14.5%, including temporary or permanent diabetes insipidus (3–46%), hypogonadism (14–53%), hypothyroidism (14–40%), cerebrospinal fluid rhinorrhea (4.6–27.9%), and severe growth hormone deficiency (13%).

When no tumor is visible during surgery, subtotal resection of 85–90% of the anterior pituitary may be performed, though this carries a risk of panhypopituitarism.

Prognostic Factors

Better outcomes are associated with:

• Age >25 years.
• Detection of a microadenoma on MRI.
• Lack of tumor invasion into the dura or cavernous sinus.
• Histological confirmation of an ACTH-secreting tumor.
• Post-operative cortisol levels <50 nmol/L (1.8 μg/dL).
• Prolonged post-operative adrenal insufficiency.

Post-Operative Management

Monitoring and Evaluation

• Immediate Monitoring:
  Morning serum cortisol is measured on days 4–5 after surgery (20 hours post-glucocorticoid taper) to assess adrenal function.
  • Hypocortisolemia (<50 nmol/L) strongly predicts long-term remission.
  • Persistent cortisol levels >140 nmol/L (>5 μg/dL) after three months indicate persistent disease requiring further intervention.
• Adrenal Insufficiency:
  Patients with post-operative adrenal insufficiency require hydrocortisone replacement therapy (15–20 mg/day in divided doses). Patients should also be educated on managing stress and illness with glucocorticoid adjustments and provided with emergency hydrocortisone kits and medical alert identification.
• HPA Axis Recovery:
  Recovery typically occurs within 3–12 months. Testing with the insulin tolerance test or short Synacthen test can assess adrenal function. Hydrocortisone replacement can be discontinued if recovery is confirmed.

Management of Persistent or Recurrent Disease

• Options for Persistent Disease:
  • Repeat Surgery: Effective in ~50% of cases but carries a higher risk of hypopituitarism.
  • Radiotherapy: For cases with invasive tumors or poor surgical candidates.
  • Bilateral Adrenalectomy: A definitive option to control hypercortisolism but requires lifelong glucocorticoid and mineralocorticoid replacement.
• Recurrence:
  Recurrence occurs in 10–15% of patients within 10 years and up to 20% at 20 years. Long-term monitoring with late-night salivary cortisol, the 1mg dexamethasone suppression test, and 24-hour UFC is essential. Repeat surgery is effective if a recurrent tumor is visible on MRI.

Post-Surgical Complications and Management

Pituitary Hormone Deficiencies

• Evaluate and treat deficiencies in ACTH, TSH, LH/FSH, and growth hormone as needed.

Diabetes Insipidus and Hyponatremia

• Diabetes Insipidus: Transient DI occurs in ~20% of cases; permanent DI requiring desmopressin therapy is rare.
• Hyponatremia: Common within 10 days post-surgery due to SIADH or fluid overload. Restrict fluid intake as necessary.

Metabolic Abnormalities

• Preoperative treatments for hypertension, hyperglycemia, and hypokalemia often improve post-surgery and may require adjustment.

Bilateral Adrenalectomy

Bilateral adrenalectomy is a key therapeutic option for patients with ACTH-dependent Cushing’s syndrome that remains unresolved after other treatments. It is particularly suitable for younger patients desiring fertility, where radiotherapy might lead to hypopituitarism. However, the procedure necessitates lifelong glucocorticoid and mineralocorticoid replacement therapy and carries risks of peri-operative morbidity and mortality. In experienced centers, laparoscopic adrenalectomy minimizes these risks significantly. Despite this, the lifelong incidence of adrenal crisis post-adrenalectomy (9.3 events per 100 patients) exceeds that in Addison’s disease or ACTH deficiency (3–6 events per 100 patients).

Post-Operative Management

• Hydrocortisone Replacement: Post-surgery, hydrocortisone is initially administered at 50 mg four times daily via intravenous or intramuscular injection, or as a continuous infusion of 200 mg/day. After 48 hours without complications, the dosage is reduced to a double replacement dose (40 mg/day), and oral fludrocortisone (100–200 mcg daily) is introduced.

Nelson’s Syndrome

Nelson’s syndrome, or corticotroph tumor progression post-adrenalectomy, occurs in 28–53% of cases, typically within 5.3 years. Younger patients and those with confirmed pituitary adenomas from prior surgeries are at higher risk. Prophylactic pituitary radiotherapy may lower the risk, but regular MRI monitoring and ACTH measurements (progressive elevation between 200 and 700 pg/mL) are crucial for early detection. Initial management involves transsphenoidal surgery for tumor resection, followed by radiotherapy for extrasellar expansion.

Alternative approaches, such as unilateral adrenalectomy combined with pituitary irradiation, may be considered in select cases. Although medical therapies for Nelson’s syndrome are limited, temozolomide has shown potential in aggressive cases. Recurrence of hypercortisolism due to adrenal rest tissue occurs in fewer than 10% of cases.

Pituitary Radiotherapy

Radiotherapy is an option for patients where fertility is not a concern, or as a second-line treatment following unsuccessful surgery. It may also serve as primary therapy in pediatric patients, showing comparable outcomes to surgery with cure rates of approximately 80%. Radiotherapy offers additional benefits in reducing Nelson’s syndrome risk post-adrenalectomy.

Efficacy and Considerations

• Primary Therapy in Adults: Long-term remission rates are about 50%.
• Second-Line Therapy: For failed surgery, remission rates improve to around 80%.
• Time to Effectiveness: Remission typically occurs within 12 months for children but may take up to two years for adults. Medical therapy is often used to manage hypercortisolism during this period.

Techniques

• Conventional Radiotherapy: Involves a total dose of 45–50 Gy over 25 fractions. While growth hormone deficiency is common (36–68%), other pituitary deficiencies and cerebrovascular risks are less frequent.
• Stereotactic Radiotherapy (Gamma Knife, Cyber Knife): Provides targeted high-dose radiation to minimize surrounding tissue damage. It is most effective for small tumors located away from radiosensitive structures, such as the optic chiasm.

Treatment of Ectopic ACTH Syndrome

For non-metastatic ectopic ACTH-secreting tumors, such as bronchial carcinoids, surgical excision offers a high likelihood of curing hypercortisolism. Local radiotherapy may be considered in non-metastatic cases, though its necessity depends on tumor type and extent. Prognosis is largely dictated by the tumor’s nature, with small-cell lung cancers and medullary thyroid cancers associated with poorer outcomes.

Metastatic Disease

• In cases with liver-limited metastases, options include cryoablation, resection, or liver transplantation.
• For significant metastatic disease, surgical excision may not be curative but can still offer symptomatic relief.

Hyperplasia and Tumor Identification

Control of hypercortisolism with medical therapy is essential while awaiting tumor localization or addressing residual disease. Ectopic CRH syndromes follow similar principles, as they are usually associated with pulmonary carcinoid tumors.

ACTH-Independent Cushing’s Syndrome

Unilateral or bilateral adrenalectomy remains the treatment of choice, depending on the etiology:

• Adrenal Adenomas: Typically cured with unilateral adrenalectomy in experienced centers, with nearly 100% success rates.
• Bilateral Hyperplasia: May require bilateral adrenalectomy unless milder cases can be managed temporarily with unilateral removal.

Surgical Approaches

• Laparoscopic Adrenalectomy: Preferred for non-malignant disease due to lower complication rates and shorter hospital stays.
• Open Adrenalectomy: Reserved for lesions >6 cm or suspected malignancy.

For adrenal carcinomas, aggressive surgical strategies combined with adjuvant mitotane therapy offer the best outcomes. Although radiotherapy for carcinoma shows limited efficacy, it may reduce local recurrence in select cases.