creation date: 2026-06-13 03:31
tags: Pathologies
Cushing Syndrome
Background
Definitions
Cushing syndrome represents a characteristic set of manifestations arising from sustained hypercortisolism, either from exogenous or endogenous sources.
Etiology
Physiologic hypercortisolism (pseudo-Cushing syndrome)
Pseudo-Cushing syndrome refers to a clinical picture resembling Cushing syndrome due to hypercortisolism but is due to another disorder. These are listed as differential diagnoses.
ACTH-dependent Cushing syndrome
ACTH-dependent causes are associated with bilateral adrenocortical hyperplasia, owing to an inappropriately normal, or elevated, ACTH level:
- Cushing disease (pituitary hypersecretion of ACTH)
- Almost always pituitary adenoma; may not be visible on imaging if microadenoma
- Loss of circadian rhythm of ACTH levels
- Ectopic secretion of ACTH by nonpituitary tumours
- Malignant sources of ACTH not inhibited by cortisol or glucocorticoids
- Most commonly lung SCC, or other intrathoracic tumour
- Ectopic secretion of CRH by nonhypothalamic tumours
- Iatrogenic or factitious Cushing syndrome due to exogenous ACTH (not glucocorticoids)
ACTH-independent Cushing syndrome
Causes include:
- Iatrogenic or factitious Cushing syndrome
- Administration of excess synthestic glucocorticoid (most commonly prescribed prednisone)
- Adrenocortical adenomas and carinomas
- Primary pigmented nodular adrenocortical disease (bilateral adrenal micronodular hyperplasia)
- Bilateral macronodular adrenal hyperplasia
Pathophysiology
The development of hypercortisolism involves the excessive tissue exposure to glucocorticoids.
In normal physiology, the HPA axis stimulates cortisol production through CRH and ACTH. The system is intricately controlled with a circadian rhythm (when not under stress)—peak cortisol between 6-8 am and a low point near midnight—and an additional pulsatile ultradian rhythm.
Chronic hypercortisolism disrupts homeostatic regulation in many organ systems including metabolic, cardiovascular, musculoskeletal, immune, and neuropsychiatric systems.
Clinical Presentation
Signs & Symptoms
Cardiovascular
- Increased cardiovascular risk (lipid profiles, waist-to-hip ratios, carotid artery intima thickness; residual risk after cure from residual abdominal obesity and insulin resistance)
- Hypertension
- Thromboembolic events
Metabolic
- Glucose intolerance (cortisol induced gluconeogenesis; overt or poorly controlled hyperglycemia)
- Progressive central obesity (in children, generalized obesity and growth slowing)
- Sleep apnea
Musculoskeletal
- Proximal muscle wasting and weakness
- Bone loss (osteoporosis from decrease intestinal calcium absorption, decreased bone formation, increased bone resorption, decreased renal calcium resorption)
Dermatologic
- Easy bruisability
- Striae (wide, reddish-purple streaks where stretch occurs)
- Skin atrophy
- Fungal infections (especially tinea versicolor) - on trunk, some patients have nails
- Hyperpigmentation due to increased ACTH
Reproductive
- Menstrual irregularities (abnormal, oligomenorrhea, amenorrhea, variable)
- Adrenal androgen excess (hirsutism, acne, libido changes, virilization)
Neuropsychiatric
- Insomnia
- Depression and anxiety
- Irritability and emotional lability
- Memory loss
Infections
- Inhibited immune function (increased frequency of infections)
History & Physical Exam
History should include:
- History of malignancy, especially of bronchial origin
- Exogenous glucocorticoid use including oral, injected, topical, and intranasal glucocorticoids
- History of conditions that may cause physiologic hypercortisolism
Risk Factors
Diagnosis
Criteria
Diagnosis of Cushing syndrome is made with at least two different first-line tests with abnormal findings.
For low pre-test probability, test with one of the following:
- Bedtime salivary cortisol (2 measurements)
- 24-hour urinary free cortisol excretion (2 measurements)
- Overnight 1 mg dexamethasone suppression test (not preferred for pregnant)
For high pre-test probability, test with 2-3 of the above tests.
Negative tests (one for low PTP, 2+ for high PTP) is sufficient to rule out Cushing syndrome.
Work-up
Ruling out physiologic hypercortisolism
Consider conditions below.
Differential
Conditions associated with physiologic hypercortisolism with features of Cushing syndrome are:
- Pregnancy
- Severe obesity, especially with visceral obesity or polyendocrine metabolic ovarian syndrome
- Physiological stress (eg. severe MDD)
- Poorly controlled diabetes mellitus
- Chronic alcoholism
- Psychical stress (illness, hospitalization/surgery, pain)
- Obstructive sleep apnea
Red Flags / Complications
Untreated Cushing syndrome is often fatal. Now, patients rarely die from hypercortisolism as cortisol production can be controlled.
Major complications include:
- Opportunistic infections
- Deep vein thrombosis
- Cardiovascular disease
Management
The management of Cushing syndrome depends on the etiology. Signs and symptoms typically disappear over a period of 2-12 months following treatment.
Exogenous Glucocorticoid Cushing Syndrome
Treatment is to stop glucocorticoid use. Note that use sufficient enough to cause Cushing syndrome will have a period of HPA insufficiency, as such, a dose taper will be required.
Tumours
Cushing disease
Treatment of Cushing disease involves removal of ACTH-producing pituitary tumour.
- Transsphenoidal surgery
- Adrenal enzyme inhibitors (while waiting for surgery)
- Pituitary irradiation (if tumour is not found)
- Adrenalectomy with lifelong glucocorticoid and mineralocorticoid replacement
Ectopic ACTH and CRH
Ectopic tumours are excised. Nonresectable tumours can be controlled by adrenal enzyme inhibitors
Primary Adrenal Diseases
Adrenal adenomas can be cured by unilateral adrenalectomy (balances hypersecretion). In other cases,