Cushing Syndrome

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

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.

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

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.

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, dyslipidaemia, 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

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.

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 tumours.

Demographics

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.

Age

• Most cases are diagnosed between the ages of 20 and 50, though Cushing syndrome can present at any age.
• Paediatric cases remain rare but well-documented.

Ethnic Distribution

• There is no significant variation in prevalence among different ethnic groups.

High-Risk Populations

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.

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

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.

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.

Muscle Weakness

• Proximal muscle weakness is prominent, often manifesting as difficulty climbing stairs, rising from a seated position, or raising arms.

Psychological Symptoms

• Depression, emotional instability, anxiety, and cognitive dysfunction occur in up to 70% of patients.
• Severe cases may present with psychosis.

Reproductive Issues

• Women frequently report menstrual irregularities, amenorrhoea, infertility, and decreased libido.
• Men may experience decreased libido and erectile dysfunction due to gonadal dysfunction.

Cardiovascular and Metabolic Symptoms

• Hypertension and glucose intolerance or diabetes mellitus are common.
• Patients may present with poorly controlled blood sugar levels.

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.

Immune Dysfunction

• Recurrent infections and poor wound healing are indicative of immune suppression caused by elevated cortisol levels.

Diagnostic Considerations

Adrenal Carcinoma

• Symptoms like rapid onset of virilisation in women (e.g. hirsutism, voice deepening) or feminisation in men suggest adrenal carcinoma as the underlying cause.

Pituitary Adenomas (Cushing Disease)

• ACTH-secreting pituitary adenomas 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

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.

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 tumours.

Emergency Examination Findings

Adrenal Crisis

• Hypotension, confusion, vomiting, and laboratory findings of hypoglycaemia, hyperkalaemia, and hyponatraemia.
• May follow abrupt steroid cessation or adrenal tumour resection.

Initial Screening Tests

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.

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.

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.

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

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.

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.

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

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.

Adrenal CT

• Initial imaging for ACTH-independent hypercortisolism.
• Identifies adrenal adenomas, carcinomas, or bilateral hyperplasia.

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

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.

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

Central Hypothyroidism

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.

Growth Hormone Deficiency

Idiopathic Growth Hormone Deficiency

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

Diabetes Insipidus

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)

Primary Therapy

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.

Postoperative Management

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.

Second-Line Treatments

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.

Definitive Therapy

• Bilateral adrenalectomy
  • 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

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.

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.

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

Tumor Resection

• Complete surgical excision of the ACTH-secreting tumor is the preferred treatment. However, many cases involve metastatic or inoperable disease.

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.

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

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.

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.

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

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).

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.

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

Tumor Characteristics

• Tumor size, invasiveness, and histopathological features influence surgical success rates and recurrence risks.

Delay in Diagnosis

• Delays in treatment contribute to disease progression and increased morbidity.

Comorbidities

• Conditions such as diabetes, hypertension, cardiovascular disease, and osteoporosis significantly impact long-term outcomes.

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

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.

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

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.

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.

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.

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.

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.

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.

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

Central Hypothyroidism

• Likelihood: High
• Description: Thyrotropin deficiency following pituitary surgery or radiotherapy necessitating thyroid hormone replacement.
• Management: Levothyroxine therapy with regular thyroid function monitoring.

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.

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.

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.

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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