Pathophysiology and Pathogenesis
What hormone is elevated in all forms of Cushing syndrome?
What is cortisol?
What is the most common overall cause of Cushing syndrome?
What is iatrogenic—due to exogenous glucocorticoids?
What is the definitive treatment for an adrenal mass causing Cushing syndrome?
What is laparoscopic adrenalectomy?
Name one test used to confirm hypercortisolism.
What is low-dose dexamethasone suppression test or late-night salivary cortisol?
A 43-year-old woman presents with fatigue, proximal muscle weakness, and weight gain. Physical exam reveals central obesity, facial plethora, and violaceous striae. Labs show elevated 24-hour urinary free cortisol. Plasma ACTH is low. A CT scan shows a 3.5 cm left adrenal mass. Histopathology post-adrenalectomy shows cortical atrophy sparing the zona glomerulosa. Which of the following best explains the spared zona glomerulosa?
A. It is not under ACTH regulation
B. It produces cortisol instead of aldosterone
C. It has higher levels of 11β-hydroxylase activity
D. It is the only adrenal zone that undergoes hyperplasia in Cushing disease
E. It is regulated by CRH from the hypothalamus
A. It is not under ACTH regulation
The zona glomerulosa is regulated by the renin-angiotensin-aldosterone system (RAAS), not ACTH. In ACTH-independent Cushing syndrome due to adrenal adenoma, high cortisol suppresses ACTH, leading to atrophy of the ACTH-dependent zona fasciculata and zona reticularis, but the zona glomerulosa is spared.
How does cortisol contribute to insulin resistance in Cushing syndrome?
What is by promoting hepatic gluconeogenesis and antagonizing insulin's peripheral actions?
Which is more common: ACTH-dependent or ACTH-independent Cushing syndrome?
What is ACTH-dependent?
What steroid is administered perioperatively during adrenalectomy for Cushing syndrome?
What is intravenous hydrocortisone?
What imaging study is used for suspected adrenal cause of Cushing syndrome?
What is CT or MRI of the adrenal glands?
A 38-year-old man presents with new-onset diabetes, hypertension, and mood swings. He has central adiposity, a rounded face, and dorsocervical fat pad. Initial labs show elevated late-night salivary cortisol on two occasions and failure to suppress cortisol on low-dose dexamethasone testing. Plasma ACTH is elevated. High-dose dexamethasone partially suppresses cortisol. MRI of the pituitary is inconclusive. What is the next best step in evaluation?
A. Repeat MRI with gadolinium contrast
B. CT scan of the chest to rule out ectopic ACTH production
C. Inferior petrosal sinus sampling
D. Serum DHEA-S level
E. 24-hour urine metanephrines
C. Inferior petrosal sinus sampling
Explanation: In ACTH-dependent Cushing syndrome, if the pituitary MRI is inconclusive, the gold-standard test to localize the source of ACTH secretion is inferior petrosal sinus sampling. It distinguishes between pituitary and ectopic ACTH production.
In ACTH-independent Cushing syndrome, where does the excess cortisol come from?
What is the adrenal cortex?
What is the most common endogenous cause of Cushing syndrome?
What is a pituitary adenoma (Cushing disease)?
Why must hydrocortisone be tapered postoperatively in patients treated for Cushing syndrome?
To allow gradual recovery of the HPA axis and avoid adrenal insufficiency.
What is the expected effect of chronic cortisol excess on serum glucose and lipids?
Hyperglycemia and hyperlipidemia, as seen in elevated glucose, triglycerides, and cholesterol
A 40-year-old woman is evaluated for fatigue, weight gain, and hypertension. Her labs show hyperglycemia, hypokalemia, and metabolic alkalosis. Serum cortisol is elevated and not suppressed by low- or high-dose dexamethasone. Plasma ACTH is markedly elevated. Chest CT reveals a hilar mass. Which of the following additional findings is most likely present?
A. Bitemporal hemianopsia
B. Elevated aldosterone
C. Hyperpigmentation
D. Elevated LH and FSH
E. Atrophic adrenal glands
C. Hyperpigmentation
Explanation: In ectopic ACTH syndrome (e.g., small cell lung cancer), very high levels of ACTH stimulate melanocortin-1 receptors, causing hyperpigmentation. This distinguishes it from adrenal Cushing syndrome, where ACTH is low and no hyperpigmentation occurs.
What is the mechanism by which cortisol leads to hypertension?
What is increased sensitivity to catecholamines and mineralocorticoid receptor activation?
True or False: Adrenal adenomas causing Cushing syndrome are typically bilatera
What is false? They are usually unilateral.
What condition is monitored postoperatively due to potential glucocorticoid therapy side effects?
What is hydrocortisone-induced hypothyroidism?
What is the role of the low-dose dexamethasone suppression test in diagnosing Cushing syndrome?
To confirm hypercortisolism by assessing whether cortisol is suppressed by dexamethasone; failure to suppress indicates Cushing syndrome.
A 35-year-old man with new-onset diabetes and proximal muscle weakness is diagnosed with ACTH-independent Cushing syndrome. His CT scan shows a 4 cm right adrenal mass. He undergoes unilateral adrenalectomy. Postoperatively, he develops nausea, fatigue, hypotension, and hyponatremia. Which of the following best explains this complication?
A. Rapid onset of mineralocorticoid deficiency
B. Suppression of CRH due to adrenal cortical atrophy
C. Increased ACTH from the contralateral adrenal gland
D. Surgical injury to the pituitary gland
E. Activation of 11β-hydroxysteroid dehydrogenase type 2
B. Suppression of CRH due to adrenal cortical atrophy
Explanation: Chronic cortisol excess from the adrenal adenoma suppresses CRH and ACTH, leading to atrophy of the contralateral adrenal cortex. After adrenalectomy, the remaining gland is temporarily insufficient, causing adrenal insufficiency.
Name one type of tumor (other than pituitary) that can cause ectopic ACTH production.
What is small cell lung carcinoma?
Which condition/findings in children may suggest Cushing syndrome?
What is weight gain without height gain?
What is a key post-op monitoring target following adrenalectomy for Cushing syndrome?
Pituitary corticotroph function and signs of adrenal insufficiency.
On pathology, what finding supported autonomous cortisol production from the adrenal mass?
Cortical atrophy in surrounding adrenal tissue, sparing the zona glomerulosa.
A patient with Cushing disease is started on metyrapone prior to definitive surgery. Which of the following best describes the mechanism of action of metyrapone in this setting?
A. Directly inhibits ACTH secretion
B. Stimulates hepatic metabolism of cortisol
C. Inhibits 11β-hydroxylase, reducing cortisol synthesis
D. Blocks glucocorticoid receptors in peripheral tissues
E. Inhibits mineralocorticoid receptor activity in the kidney
C. Inhibits 11β-hydroxylase, reducing cortisol synthesis
Explanation: Metyrapone is a steroidogenesis inhibitor that blocks 11β-hydroxylase, which converts 11-deoxycortisol to cortisol. It reduces cortisol production and is used as temporary medical therapy in Cushing syndrome.