Cushing Syndrome

1. Exogenous Hypercortisolism:
   • The most common cause of Cushing syndrome.
   • Predominantly iatrogenic, resulting from prolonged administration of glucocorticoids for medical conditions.
2. Endogenous Hypercortisolism:
   • Caused by excessive cortisol production within the adrenal glands.
   • Further classified into ACTH-dependent and ACTH-independent forms:
     • ACTH-Dependent:
       • Represents 70–80% of endogenous cases.
       • Mainly caused by ACTH-secreting pituitary adenomas, termed Cushing disease.
       • Ectopic ACTH secretion from neoplasms, such as small-cell lung carcinoma or carcinoid tumors, accounts for the remaining cases.
       • Rarely, ectopic corticotropin-releasing hormone (CRH) secretion may stimulate ACTH production.
     • ACTH-Independent:
       • Includes adrenal adenomas, carcinomas, and bilateral adrenal hyperplasia.
       • Approximately 10% of cases involve adrenal adenomas, though only a small proportion autonomously secrete cortisol.
       • Adrenal carcinomas, while rare (1% of cases), cause ACTH-independent Cushing syndrome in a significant number of affected individuals.
         
         

Genetic Insights

• Mutations in USP8: Frequently observed in ACTH-secreting pituitary adenomas, highlighting its role in Cushing disease.
• cAMP/PKA Pathway Alterations: Associated with adrenal adenomas and hyperplasia, underlying many cases of primary adrenal hypercortisolism.
  
  

Cortisol Production and Transport

• Source and Binding:
  • Cortisol is synthesised in the zona fasciculata of the adrenal cortex and primarily transported bound to cortisol-binding globulin (CBG), which carries approximately 90% of circulating cortisol.
  • Free cortisol, representing 1%–10% of the total, is bioavailable and responsible for its physiological effects.
• Synthetic Corticosteroids:
  • These vary in potency and bioavailability but affect pathways similar to natural cortisol.
    
    

Metabolic Effects

1. Carbohydrate and Protein Metabolism:
   • Cortisol stimulates gluconeogenesis and glycogenolysis, raising blood glucose and exacerbating insulin resistance.
   • Protein catabolism generates amino acids for gluconeogenesis, causing muscle atrophy, thinning skin, and characteristic striae.
   • Long-term catabolism contributes to osteoporosis and delayed wound healing, primarily due to collagen depletion.
2. Lipid Metabolism:
   • Cortisol redistributes adipose tissue, leading to central obesity, moon facies, and dorsocervical fat pads.
     
     

Immune System Modulation

• Neutrophil Dynamics:
  • Cortisol mobilises neutrophils from the marginating pool into circulation, elevating the total count without increasing production.
• Lymphocyte Suppression:
  • Reduces lymphocyte proliferation, impairing cellular immune responses.
• Cytokine Inhibition:
  • Downregulates key inflammatory cytokines, including IL-2, TNF-α, and IFN-γ, further suppressing immunity.
    
    

Enzymatic and Molecular Regulation

• Cortisol alters enzyme activity, including NF-kB, AMP kinase, and glycogen phosphorylase.
• Downregulation of these pathways contributes to the anti-inflammatory and immunosuppressive effects of hypercortisolism.

Aetiological Variants

1. ACTH-Dependent Hypercortisolism:
   • Frequently caused by ACTH-secreting pituitary adenomas (Cushing disease).
   • Ectopic ACTH production, often from small-cell lung carcinoma or carcinoid tumors, accounts for additional cases.
2. ACTH-Independent Hypercortisolism:
   • Caused by adrenal adenomas, carcinomas, or bilateral adrenal hyperplasia.
   • Bilateral hyperplasia, whether micronodular or macronodular, is a rare but recognised cause.
     
     

Clinical Manifestations

• Mild Hypercortisolism:
  • Features include glucose intolerance, dyslipidemia, and modest weight gain, mimicking metabolic syndrome.
• Severe Hypercortisolism:
  • Prominent signs include purple striae, proximal muscle weakness, and significant fat redistribution.
  • Ectopic ACTH secretion often presents with rapid-onset, severe symptoms, such as muscle wasting and weight loss.
    
    

Frequency

1. General Incidence:
   • Endogenous Cushing syndrome has an estimated annual incidence of 1.8 to 3.2 cases per million people.
   • Exogenous cases, often due to prolonged glucocorticoid use, are significantly more common, although precise epidemiological data are not available.
2. United States Data:
   • Endogenous Cushing syndrome affects approximately 13 individuals per million annually.
   • Among these, 70% are caused by ACTH-producing pituitary adenomas (Cushing disease), 15% by ectopic ACTH production, and 15% by primary adrenal tumors.
     
     

Demographics

1. Gender Distribution:
   • Women are three times more likely to develop Cushing syndrome compared to men.
   • Cushing disease exhibits a female-to-male ratio of 3:1 to 5:1.
2. Age:
   • Most cases are diagnosed between the ages of 20 and 50, though Cushing syndrome can present at any age. Pediatric cases remain rare but well-documented.
3. Ethnic Distribution:
   • There is no significant variation in prevalence among different ethnic groups.
     
     

High-Risk Populations

1. Secondary Hypercortisolism Prevalence:
   • Hypercortisolism is reported in:
     • 0.5% to 1% of individuals with hypertension.
     • 2% to 3% of patients with uncontrolled diabetes.
     • 5% to 10% of individuals with adrenal masses.
     • 11% of patients with osteoporosis and vertebral fractures.
2. Testing and Diagnosis:
   • The reported prevalence in high-risk groups may be influenced by improved diagnostic sensitivity and increased recognition in these populations.
     
     

Common Symptoms

1. Weight Gain and Central Obesity:
   • Nearly all patients experience progressive weight gain, predominantly in the face, supraclavicular region, upper back, and torso.
   • The increasing prevalence of obesity in the general population makes this symptom less specific.
2. Skin Changes:
   • Thin, fragile skin with purplish stretch marks (violaceous striae), particularly on the abdomen, thighs, and breasts.
   • Easy bruising and delayed wound healing are common.
3. Muscle Weakness:
   • Proximal muscle weakness is prominent, often manifesting as difficulty climbing stairs, rising from a seated position, or raising arms.
4. Psychological Symptoms:
   • Depression, emotional instability, anxiety, and cognitive dysfunction occur in up to 70% of patients.
   • Severe cases may present with psychosis.
5. Reproductive Issues:
   • Women frequently report menstrual irregularities, amenorrhea, infertility, and decreased libido.
   • Men may experience decreased libido and erectile dysfunction due to gonadal dysfunction.
6. Cardiovascular and Metabolic Symptoms:
   • Hypertension and glucose intolerance or diabetes mellitus are common.
   • Patients may present with poorly controlled blood sugar levels.
7. Skeletal Issues:
   • Osteopenia or osteoporosis occurs in more than 50% of patients, increasing the risk of fractures.
   • Younger men with low bone density should be evaluated for hypercortisolism.
8. Immune Dysfunction:
   • Recurrent infections and poor wound healing are indicative of immune suppression caused by elevated cortisol levels.

Diagnostic Considerations

• Symptoms like rapid onset of virilisation in women (e.g., hirsutism, voice deepening) or feminisation in men suggest adrenal carcinoma as the underlying cause.
• ACTH-secreting pituitary adenomas (Cushing disease) may present with headaches, visual disturbances, or other signs of pituitary mass effects.
  
  

General Appearance

• Fat Redistribution:
  • Moon facies: Rounded facial appearance due to increased facial fat.
  • Buffalo hump: Prominent fat accumulation at the base of the neck.
  • Supraclavicular fullness: Fat deposition above the clavicles.
  • Central obesity: Disproportionate accumulation of adipose tissue in the trunk with relatively thin extremities.
    
    

Skin

1. Striae and Atrophy:
   • Wide, violaceous striae (>0.5 cm) on the abdomen, thighs, breasts, and arms.
   • Skin atrophy with a translucent appearance, exposing subcutaneous vasculature.
   • Easy bruising without significant trauma.
2. Other Features:
   • Facial plethora: Erythema, especially over the cheeks.
   • Acne: Papular or pustular lesions on the face, chest, and back.
   • Hirsutism: Excess hair growth in androgen-dependent areas in women.
   • Acanthosis nigricans: Hyperpigmented, velvety skin in areas prone to friction (e.g., neck, axillae).
     
     

Musculoskeletal System

• Muscle Weakness:
  • Proximal muscle weakness, especially in the shoulder and hip girdles, leading to difficulty performing activities like climbing stairs or rising from a seated position.
• Skeletal Findings:
  • Signs of osteoporosis: Reduced bone density, kyphosis, and increased risk of vertebral compression fractures.
  • Axial skeletal pain due to bone fragility.
    
    

Cardiovascular and Renal

• Hypertension:
  • Commonly observed due to cortisol’s activation of mineralocorticoid receptors, causing sodium and water retention.
• Oedema:
  • Present in severe cases of fluid overload.
    
    

Neuropsychological and Ocular

• Neurological:
  • Emotional lability, fatigue, and depression.
• Ocular:
  • Bitemporal visual field defects caused by compression of the optic chiasm from ACTH-secreting pituitary tumors.
    
    

Emergency Examination Findings

• Adrenal Crisis:
  • Hypotension, confusion, vomiting, and laboratory findings of hypoglycemia, hyperkalemia, and hyponatremia.
  • May follow abrupt steroid cessation or adrenal tumor resection.
    
    

Initial Screening Tests

1. Late-Night Salivary Cortisol (LNSC):
   • A highly sensitive and non-invasive test to detect loss of diurnal cortisol rhythm.
   • Patients collect saliva between 11 p.m. and midnight on at least two separate occasions.
   • Elevated cortisol above the upper assay-specific reference limit suggests hypercortisolism.
   • Smoking and licorice ingestion may interfere with results, and this test is less reliable in shift workers or erratic sleep schedules.
2. 1 mg Overnight Dexamethasone Suppression Test (DST):
   • A widely used initial test for hypercortisolism.
   • Procedure: 1 mg dexamethasone is taken at 11 p.m., and serum cortisol is measured at 8 a.m.
   • A cortisol level >50 nmol/L (>1.8 μg/dL) indicates abnormal suppression.
   • False positives may occur with drugs such as phenytoin, carbamazepine, or rifampin, which enhance dexamethasone metabolism.
3. 24-Hour Urinary Free Cortisol (UFC):
   • Measures the amount of cortisol freely filtered by the kidneys over 24 hours.
   • A level >4 times the upper limit of normal strongly suggests Cushing syndrome.
   • Renal dysfunction or improper collection can lead to false results, requiring careful patient instruction.
4. 48-Hour Low-Dose Dexamethasone Suppression Test:
   • Administers 0.5 mg dexamethasone every 6 hours for 48 hours, with cortisol measured 6 hours after the final dose.
   • Cortisol levels >50 nmol/L (>1.8 μg/dL) indicate hypercortisolism.
   • Useful in borderline cases or when more sensitive testing is required.
     
     

Confirmatory and Diagnostic Tests

1. Plasma Adrenocorticotropic Hormone (ACTH):
   • Differentiates between ACTH-dependent and ACTH-independent causes:
     • ACTH >4 pmol/L (>20 pg/mL): Suggests ACTH-dependent (pituitary or ectopic source).
     • ACTH <1 pmol/L (<5 pg/mL): Indicates ACTH-independent (adrenal) hypercortisolism.
   • ACTH is unstable at room temperature, necessitating prompt processing.
2. High-Dose Dexamethasone Suppression Test:
   • Used to distinguish pituitary ACTH secretion from ectopic ACTH production.
   • Procedure: 8 mg dexamethasone is given at 11 p.m., and cortisol is measured the following morning.
   • Suppression >50% of baseline cortisol supports a pituitary source.
3. Inferior Petrosal Sinus Sampling (IPSS):
   • Gold standard for distinguishing pituitary from ectopic ACTH secretion.
   • Measures the central-to-peripheral ACTH gradient:
     • Central/peripheral ACTH ratio >2:1 (baseline) or >3:1 (post-CRH stimulation) confirms a pituitary source.
   • Reserved for patients with equivocal pituitary imaging or normal MRI findings.
     
     

Imaging Studies

1. Pituitary MRI:
   • First-line imaging for ACTH-dependent Cushing syndrome.
   • Detects pituitary adenomas, though microadenomas (<1 cm) may be missed in up to 40% of cases.
2. Adrenal CT:
   • Initial imaging for ACTH-independent hypercortisolism.
   • Identifies adrenal adenomas, carcinomas, or bilateral hyperplasia.
3. Chest, Abdomen, and Pelvis Imaging:
   • Used to locate ectopic ACTH-producing tumors.
   • Includes CT, MRI, or gallium-68 DOTATATE PET/CT for detecting neuroendocrine tumors.
     
     

Special Considerations

• Physiological Hypercortisolism:
  • Mimics Cushing syndrome and includes conditions like pregnancy, severe obesity, poorly controlled diabetes, and major depressive disorder.
  • These conditions typically lack features like violaceous striae, proximal muscle weakness, or easy bruising, helping to differentiate them.
• Cyclic Cushing Syndrome:
  • Characterised by intermittent episodes of hypercortisolism.
  • Requires repeated testing during symptomatic periods for diagnosis.
• Subclinical Cushing Syndrome:
  • Common in adrenal incidentalomas with mild cortisol overproduction.
  • Best detected using the 1 mg overnight DST.
    
    

Laboratory Caveats

1. False-Positive Results:
   • Physiologic hypercortisolism (e.g., stress, obesity, or depression) may elevate cortisol levels.
   • Medications, excessive fluid intake, or improper collection can interfere with test results.
2. False-Negative Results:
   • Cyclic or mild Cushing syndrome may require multiple tests to capture intermittent hypercortisolism.
     
     

Adrenal Insufficiency Secondary to Adrenal Suppression

• Primary Adrenal Insufficiency (Addison’s Disease)
  • Autoimmune adrenal destruction with hyperpigmentation, mineralocorticoid deficiency, and electrolyte imbalances.
  • Investigations: Low cortisol and aldosterone, elevated ACTH, positive adrenal antibodies.
• Secondary Adrenal Insufficiency
  • Pituitary or hypothalamic dysfunction leading to ACTH deficiency, without hyperpigmentation.
  • Investigations: Low ACTH, low cortisol, normal aldosterone, abnormal insulin tolerance test or metyrapone challenge.
• Glucocorticoid Withdrawal Syndrome
  • Chronic exogenous steroid use suppressing the HPA axis, leading to transient adrenal insufficiency after cessation.
  • Investigations: Suppressed ACTH and cortisol levels, improvement with gradual steroid tapering.

Cardiovascular Disease

• Hypertensive Heart Disease
  • Chronic hypertension causing left ventricular hypertrophy, heart failure, and arrhythmias.
  • Investigations: Echocardiogram showing LV hypertrophy, BNP elevation.
• Atherosclerotic Cardiovascular Disease (ASCVD)
  • Coronary artery disease presenting with angina, myocardial infarction, or stroke.
  • Investigations: Lipid panel, ECG, coronary angiography.
• Dilated Cardiomyopathy
  • Heart failure with reduced ejection fraction, non-hypertensive causes.
  • Investigations: Echocardiogram, cardiac MRI, NT-proBNP.

Hypertension

• Primary Aldosteronism
  • Resistant hypertension with hypokalemia due to excessive aldosterone secretion.
  • Investigations: Plasma aldosterone-to-renin ratio, adrenal CT.
• Pheochromocytoma
  • Episodic hypertension, palpitations, sweating, and headaches due to catecholamine excess.
  • Investigations: Plasma metanephrines, adrenal MRI.
• Obstructive Sleep Apnea (OSA)
  • Nocturnal hypertension, daytime somnolence, and obesity-related hypoxia.
  • Investigations: Polysomnography, STOP-BANG questionnaire.
• Renovascular Hypertension
  • Hypertension due to renal artery stenosis, presenting with bruits and refractory hypertension.
  • Investigations: Renal Doppler ultrasound, CT angiography.

Diabetes Mellitus and Insulin Resistance

• Type 1 Diabetes Mellitus
  • Autoimmune beta-cell destruction causing insulin deficiency, presenting with weight loss, polyuria, and polydipsia.
  • Investigations: Fasting glucose, HbA1c, C-peptide, pancreatic autoantibodies.
• Type 2 Diabetes Mellitus
  • Insulin resistance-driven hyperglycemia, commonly associated with obesity.
  • Investigations: Fasting insulin, HOMA-IR, HbA1c.
• Acromegaly
  • Growth hormone excess leading to insulin resistance, associated with soft tissue overgrowth.
  • Investigations: IGF-1 levels, oral glucose suppression test.
• Pancreatic Diabetes (Type 3c Diabetes)
  • Secondary diabetes due to chronic pancreatitis or pancreatic resection.
  • Investigations: Fecal elastase, imaging for pancreatic calcifications.

Hypercoagulability and Thrombosis

• Antiphospholipid Syndrome (APS)
  • Autoimmune disorder causing recurrent arterial and venous thrombosis.
  • Investigations: Lupus anticoagulant, anticardiolipin antibodies.
• Factor V Leiden Mutation
  • Inherited thrombophilia increasing risk of deep vein thrombosis and pulmonary embolism.
  • Investigations: Genetic testing for factor V mutation.
• Paraneoplastic Hypercoagulability (Trousseau Syndrome)
  • Cancer-associated hypercoagulability with migratory thrombophlebitis.
  • Investigations: D-dimer, malignancy screening (CT, tumor markers).

Osteoporosis and Fractures

• Postmenopausal Osteoporosis
  • Estrogen deficiency accelerating bone resorption.
  • Investigations: Bone mineral density (BMD) scan, serum estrogen levels.
• Vitamin D Deficiency
  • Impaired calcium absorption leading to bone demineralization.
  • Investigations: Serum 25-hydroxyvitamin D, PTH, calcium levels.
• Multiple Myeloma
  • Lytic bone lesions causing fractures and hypercalcemia.
  • Investigations: Serum protein electrophoresis, skeletal survey.
• Renal Osteodystrophy (CKD-MBD)
  • Bone demineralization due to secondary hyperparathyroidism in chronic kidney disease.
  • Investigations: PTH, calcium, phosphorus levels.

Nephrolithiasis (Kidney Stones)

• Primary Hyperparathyroidism
  • Increased calcium excretion due to excess PTH.
  • Investigations: Serum calcium, PTH levels.
• Renal Tubular Acidosis (RTA)
  • Impaired acid excretion leading to stone formation.
  • Investigations: Urine pH, bicarbonate levels.
• Gout and Hyperuricemia
  • Uric acid stone formation due to excess purine metabolism.
  • Investigations: Serum uric acid, 24-hour urine uric acid.

Nelson Syndrome (Post-Adrenalectomy Pituitary Tumor Progression)

• Pituitary Macroadenoma
  • Non-ACTH-secreting tumor with mass effect and hormonal deficiencies.
  • Investigations: MRI, pituitary function tests.
• Craniopharyngioma
  • Suprasellar tumor leading to pituitary compression.
  • Investigations: Brain MRI, beta-hCG, AFP levels.
• Lymphocytic Hypophysitis
  • Autoimmune inflammation of the pituitary gland, often in postpartum women.
  • Investigations: MRI showing pituitary enlargement, autoimmune panel.

Treatment-Related Endocrine Deficiencies

• Primary Hypothyroidism (Hashimoto’s Thyroiditis)
  • Autoimmune thyroid destruction.
  • Investigations: Elevated TSH, low free T4, anti-TPO antibodies.
• Sick Euthyroid Syndrome
  • Transient thyroid hormone suppression during critical illness.
  • Investigations: Low T3, normal TSH, normal or low T4.

• Idiopathic Growth Hormone Deficiency
  • Childhood-onset short stature, delayed puberty.
  • Investigations: Growth hormone stimulation test, IGF-1.

• Nephrogenic Diabetes Insipidus
  • Renal resistance to vasopressin, often due to lithium toxicity.
  • Investigations: Water deprivation test, vasopressin challenge.
• Primary Polydipsia
  • Excessive fluid intake leading to dilute urine.
  • Investigations: Serum osmolality, urine osmolality.

General Principles

• Confirm Diagnosis Before Treatment:
  • Treatment is initiated only after the diagnosis of Cushing syndrome is firmly established and the source of hypercortisolism is identified (e.g., ACTH-dependent or ACTH-independent).
• Goals of Treatment:
  • Normalise cortisol levels to reverse the systemic effects of hypercortisolism.
  • Remove or control the source of excess cortisol production.
  • Minimise long-term dependency on medication or endocrine deficiencies.
• Comorbidity Management:
  • Hypertension, diabetes, osteoporosis, and psychiatric disturbances are common comorbidities that require active management.
  • Preventive measures, such as thromboprophylaxis, are vital due to the increased risk of thromboembolic events in these patients.
• Monitor and Address Recurrence:
  • Frequent follow-ups using biochemical tests, including 24-hour urinary free cortisol (UFC) and late-night salivary cortisol, are crucial to detect recurrence.
    
    

Cushing Disease (ACTH-Secreting Pituitary Adenomas)

• Transsphenoidal Surgery (TSS):
  • TSS is the treatment of choice for ACTH-secreting pituitary adenomas. Success rates are higher when performed by experienced neurosurgeons.
  • Surgical success is assessed postoperatively by morning cortisol levels:
    • Remission: Cortisol <55 nmol/L (<2 mcg/dL).
    • Persistent Disease: Cortisol >138 nmol/L (>5 mcg/dL).
    • Uncertain Outcomes: Cortisol levels between 55 and 138 nmol/L (2–5 mcg/dL) require further monitoring.
      
      

• Monitoring Cortisol Levels:
  • Some centers advocate withholding routine corticosteroid replacement immediately after surgery to monitor for adrenal insufficiency as a sign of remission.
  • In cases of adrenal insufficiency, hydrocortisone replacement is initiated and tapered within weeks to months.
• HPA Axis Recovery:
  • The hypothalamic-pituitary-adrenal (HPA) axis is reassessed 3 months postoperatively using stimulation tests.
  • A morning cortisol level >552 nmol/L (>20 mcg/dL) suggests HPA axis recovery.
    
    

• Reoperation: Recommended for patients with persistent or recurrent disease; success rates are lower than initial surgery.
• Radiotherapy:
  • Stereotactic radiosurgery (SRS) or fractionated radiotherapy is used for residual or inoperable tumors.
  • Hypercortisolism is controlled in 50–85% of patients within 3–5 years of therapy.
  • Long-term risks include hypopituitarism and optic nerve damage for tumors near the optic chiasm.
• Medical Therapy:
  • Steroidogenesis Inhibitors:
    • Ketoconazole: Effective but associated with hepatotoxicity.
    • Osilodrostat: Reduces cortisol production rapidly but requires careful monitoring for adrenal insufficiency and hyperandrogenism.
    • Levoketoconazole, metyrapone, and mitotane: Used as adjuncts or in cases of severe disease.
  • Corticotroph-Targeted Therapy:
    • Pasireotide: A somatostatin analog effective in 25–40% of patients but may cause hyperglycemia.
    • Cabergoline: A dopamine agonist with limited efficacy.
  • Glucocorticoid Receptor Antagonist:
    • Mifepristone: Used in cases of persistent hyperglycemia and severe hypercortisolism.
      
      

• Bilateral adrenalectomy is the last resort for refractory or life-threatening cases. Post-surgical complications include permanent adrenal insufficiency and Nelson syndrome, requiring long-term hormone replacement and monitoring.
  
  

ACTH-Independent Cushing Syndrome

1. Adrenal Adenomas:
   • Unilateral adrenalectomy is curative in most cases. Laparoscopic techniques are preferred for their minimally invasive nature.
   • Postoperative glucocorticoid replacement is typically required due to contralateral adrenal suppression but is tapered over months as the HPA axis recovers.
2. Bilateral Adrenal Hyperplasia:
   • Primary pigmented nodular adrenal disease (PPNAD) or macronodular adrenal hyperplasia often requires bilateral adrenalectomy.
   • In selected cases, aberrant receptor blockade (e.g., beta-blockers or dopamine antagonists) may reduce cortisol secretion without surgery.
3. Adrenocortical Carcinoma:
   • Surgical resection remains the mainstay of treatment. Mitotane is used as adjuvant therapy, but its toxicity and narrow therapeutic window limit its use.
     
     

Ectopic ACTH Syndrome

1. Tumor Resection:
   • Complete surgical excision of the ACTH-secreting tumor is the preferred treatment. However, many cases involve metastatic or inoperable disease.
2. Medical Therapy:
   • Steroidogenesis inhibitors or mifepristone are used to manage cortisol levels in unresectable cases.
   • Radiological imaging is often repeated periodically to monitor for tumor progression.
3. Bilateral Adrenalectomy:
   • Definitive therapy for severe cases where medical management fails to control hypercortisolism.
     
     

Exogenous Cushing Syndrome

• Gradual tapering of glucocorticoids is essential to allow adrenal recovery and avoid adrenal insufficiency.
• Patients often require hydrocortisone supplementation during the tapering process, especially if adrenal suppression is severe.
  
  

Long-Term Outcomes

• Resolution of Symptoms:
  • Physical signs like moon facies, striae, and central obesity improve within months to years, though hypertension and diabetes may persist.
  • Bone density begins to improve within 6–12 months but may not normalise.
• Quality of Life:
  • Despite biochemical remission, patients often experience persistent fatigue, depression, and cognitive impairments.
  • Long-term psychological and rehabilitative support is critical to improving health-related quality of life.
• Mortality and Recurrence:
  • Untreated Cushing syndrome has a high mortality rate due to cardiovascular complications and infections.
  • Regular monitoring is required, as recurrence rates can be as high as 20–50% in the years following treatment.
    
    

Natural History Without Treatment

• Untreated Cushing syndrome has a poor prognosis, with a five-year survival rate of approximately 50% due to the systemic complications of persistent hypercortisolism, particularly cardiovascular disease.
• Progression of the disease leads to worsening of the characteristic phenotype, including obesity, hypertension, diabetes, osteoporosis, and psychiatric disturbances.
  
  

Effect of Treatment on Prognosis

1. Improved Survival:
   • With effective therapy, normalising cortisol levels reduces mortality rates to levels comparable to the general population.
   • Early diagnosis and timely treatment significantly improve long-term outcomes.
2. Reversal of Symptoms:
   • Within the first year of achieving biochemical remission, many clinical features, including facial plethora, striae, and supraclavicular fat pads, show significant improvement.
   • Weight loss and better control of diabetes and hypertension are common in the months following treatment.
   • Bone density steadily improves once hypercortisolism resolves, but full recovery may take years, and complete normalisation is not guaranteed.
3. Residual Risks:
   • Despite biochemical remission, residual cardiovascular risk, hypertension, and obesity may persist in some patients.
   • Quality of life remains diminished in many cases, especially in patients with Cushing’s disease compared to other forms of Cushing syndrome.
     
     

Patient-Reported Outcomes

• Quality of life often remains impaired even after achieving biochemical normalisation, with symptoms such as fatigue, depression, and cognitive difficulties persisting.
• Outcomes tend to be worse in patients with Cushing disease compared to other aetiologies of hypercortisolism.
  
  

Prognosis Based on Aetiology

1. Cushing Disease (ACTH-Secreting Pituitary Adenomas):
   • Surgical Outcomes:
     • Remission rates vary based on tumor size:
       • Microadenomas (<1 cm): Superior outcomes with remission rates ranging from 48% to 100%.
       • Macroadenomas (>1 cm): Lower remission rates (<65%) and higher recurrence rates (12–45%).
     • Up to 75% of patients undergoing pituitary surgery eventually require second-line treatments due to recurrence or incomplete remission.
   • Recurrence and Long-Term Risk:
     • Recurrence rates are approximately 4% per patient per year for both endoscopic and microscopic surgical approaches.
   • Surgical Technique:
     • Endoscopic transsphenoidal surgery has shown favorable outcomes in younger patients, with lower retreatment rates compared to microscopic techniques.
   • Complications:
     • Temporary or prolonged hormone replacement therapy may be required due to deficiencies in pituitary hormones (e.g., thyrotropin, gonadotropin, growth hormone, or antidiuretic hormone).
2. ACTH-Independent Cushing Syndrome:
   • Unilateral Adrenalectomy:
     • Surgical removal of adrenal adenomas leads to a uniform cure, with recurrence being exceedingly rare.
   • Bilateral Adrenalectomy:
     • Patients require lifelong corticosteroid and mineralocorticoid replacement therapy.
   • Adrenal Carcinoma:
     • Prognosis depends on the stage at diagnosis. Early resection offers the best outcomes, but advanced-stage disease often has a poor prognosis.
3. Ectopic ACTH Syndrome:
   • Prognosis varies depending on the nature of the tumor:
     • Aggressive Tumors: Rapid growth and metastasis make complete surgical resection difficult, often leading to tumor-related mortality.
     • Indolent Tumors: These are more likely to be completely resectable, leading to resolution of hypercortisolism and improved survival.
       
       

Factors Influencing Prognosis

1. Tumor Characteristics:
   • Tumor size, invasiveness, and histopathological features influence surgical success rates and recurrence risks.
2. Delay in Diagnosis:
   • Delays in treatment contribute to disease progression and increased morbidity.
3. Comorbidities:
   • Conditions such as diabetes, hypertension, cardiovascular disease, and osteoporosis significantly impact long-term outcomes.
4. Hormonal Recovery:
   • Postoperative recovery of the hypothalamic-pituitary-adrenal (HPA) axis and resolution of hypercortisolism-associated complications improve prognosis.
     
     

Long-Term Monitoring

• Recurrence Detection:
  • Patients require lifelong follow-up due to high recurrence rates, especially within the first five years of treatment.
  • Biochemical tests such as late-night salivary cortisol or 24-hour UFC are used to monitor for recurrence.
• Quality of Life:
  • Persistent symptoms such as fatigue, depression, and cognitive impairment necessitate psychological support and rehabilitative therapies.
• Bone Health:
  • Bone density monitoring and treatment for osteoporosis should be part of long-term management.
    
    

Short-Term Complications

1. Adrenal Insufficiency Due to Adrenal Suppression:
   • Likelihood: High
   • Description: Post-treatment adrenal insufficiency can occur due to prolonged suppression of the hypothalamic-pituitary-adrenal (HPA) axis by hypercortisolism. This condition often necessitates glucocorticoid therapy until HPA axis recovery, which may take several months.
   • Management: Glucocorticoid replacement and monitoring of cortisol levels to ensure sufficient adrenal function.
2. Surgery-Related Hyponatremia:
   • Likelihood: Medium
   • Description: A known complication of pituitary surgery, particularly in older patients or those with larger tumors.
   • Management: Monitoring of sodium levels and prompt correction if symptomatic hyponatremia develops.
     
     

Long-Term Complications

1. Cardiovascular Disease:
   • Likelihood: High
   • Description: The leading cause of mortality in Cushing syndrome, driven by hypertension, diabetes, dyslipidemia, and direct effects of cortisol on vascular remodeling.
   • Management: Early intervention to normalise cortisol levels, aggressive management of cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia), and regular cardiovascular screening.
2. Hypertension:
   • Likelihood: High
   • Description: Affects 70-80% of patients and is typically mild to moderate, though severe cases may occur. Blood pressure often improves post-treatment but may persist due to vascular remodeling.
   • Management: Use standard antihypertensive therapies based on the patient’s comorbidities.
3. Diabetes Mellitus:
   • Likelihood: High
   • Description: Hypercortisolism-induced insulin resistance leads to diabetes in 20-60% of cases. Glycemic control can be challenging, often requiring insulin therapy.
   • Management: Focus on normalisation of cortisol levels, standard antidiabetic therapies, and close monitoring of blood sugar levels.
4. Hypercoagulability and Thrombosis:
   • Likelihood: High
   • Description: Patients experience increased thrombotic events due to endothelial dysfunction and hypercoagulable states. These include deep vein thrombosis and pulmonary embolism.
   • Management: Prophylactic anticoagulation in high-risk patients, particularly those undergoing surgery or with severe hypercortisolism.
5. Osteoporosis and Fractures:
   • Likelihood: Medium
   • Description: Glucocorticoid excess inhibits osteoblast function, enhances osteoclast activity, and reduces calcium absorption, leading to bone loss and fractures in about 50% of patients.
   • Management: Bone density assessments, bisphosphonates, calcium and vitamin D supplementation, and treatment of persistent hypercortisolism.
6. Nephrolithiasis:
   • Likelihood: Medium
   • Description: Calcium kidney stones can occur due to altered calcium handling by the kidneys.
   • Management: Treat hypercortisolism and use standard therapies for nephrolithiasis, including adequate hydration and dietary modifications.
7. Nelson Syndrome:
   • Likelihood: Low
   • Description: Progression of a pituitary adenoma following bilateral adrenalectomy, resulting in elevated ACTH levels and intracranial mass effects.
   • Management: Regular monitoring of plasma ACTH levels and pituitary imaging. Treatment includes repeat surgery, radiotherapy, or pharmacologic therapies.
     
     

Treatment-Related Complications

1. Central Hypothyroidism:
   • Likelihood: High
   • Description: Thyrotropin deficiency following pituitary surgery or radiotherapy necessitating thyroid hormone replacement.
   • Management: Levothyroxine therapy with regular thyroid function monitoring.
2. Growth Hormone Deficiency:
   • Likelihood: High
   • Description: Occurs in 53-93% of patients post-pituitary surgery or radiotherapy, requiring growth hormone replacement therapy.
   • Management: Symptom-guided therapy with dose titration based on insulin-like growth factor 1 (IGF-1) levels.
3. Adrenal Insufficiency:
   • Likelihood: Medium
   • Description: Permanent adrenal insufficiency may develop after pituitary or adrenal surgeries, necessitating lifelong glucocorticoid replacement.
   • Management: Hydrocortisone therapy with close monitoring of adrenal function.
4. Hypopituitarism:
   • Likelihood: Medium
   • Description: Damage to normal pituitary tissue during surgery or radiotherapy may result in hormone deficiencies, including gonadotropins, thyroid-stimulating hormone, or antidiuretic hormone.
   • Management: Hormone replacement therapies tailored to the specific deficiencies.
5. Diabetes Insipidus:
   • Likelihood: Medium
   • Description: Vasopressin deficiency occurs in over 25% of patients post-pituitary surgery, particularly after repeat surgeries.
   • Management: Desmopressin replacement with monitoring of hydration and serum sodium levels.
     
     

Other Long-Term Complications

• Infections: Increased susceptibility to bacterial and fungal infections, both during active disease and post-treatment due to immunosuppressive effects of glucocorticoids.
• Psychiatric and Cognitive Issues: Depression, anxiety, and cognitive impairments may persist despite biochemical remission of Cushing syndrome.
• Excess Hair Growth and Acne: Androgen excess in some patients with ACTH-dependent disease may lead to hirsutism and acne, requiring dermatologic interventions.
  
  

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