It results from chronic exposure to excessive levels of circulating glucocorticoids. Cushing’s syndrome may be ACTH dependent or ACTH independent, characterized by high or low levels of ACTH, respectively.
Cushing’s disease results from a pituitary adenoma and may be associated with MEN1 and 2 syndromes. It is the most common cause of endogenous Cushing’s syndrome. Overall, exogenous administration of steroids is the most common cause of Cushing’s syndrome.
Cushing’s syndrome presents with abdominal obesity, wasting of the limbs, round face, “buffalo hump”, hirsutism, frontal balding, muscle weakness, easy bruising, lethargy, depression, menstrual irregularities, proximal myopathy, vertebral stress fractures, osteoporosis, purplish abdominal striae, hyperpigmentation, hypertension, and glucose intolerance.
Adrenal adenomas generally secrete glucocorticoids. In ACTH-dependent disease, androgens are also elevated. Hypokalemic metabolic alkalosis may be seen due to excess aldosterone. Rapid onset is seen in carcinoma-associated Cushing’s syndrome.
Glucocorticoids inhibit GnRH pulsatility, which decreases secretion of FSH and LH. This leads to menstrual irregularities and decreased libido.
Infections are more frequent because glucocorticoids inhibit immune function. They decrease the number of CD4 cells and NK cells, inhibit transmigration of WBCs across the endothelium, and inhibit cytokine synthesis.
Physiologically, cortisol levels are highest in the morning and lowest at midnight. In Cushing’s syndrome, this circadian rhythm is lost.
Initial testing includes free cortisol levels and low dose dexamethasone suppression. Late night salivary cortisol, serum cortisol, and urinary free cortisol will be elevated. All cases of Cushing’s syndrome will show lack of suppression of cortisol levels to low dose (2 mg) dexamethasone, while healthy adults will show suppression.
ACTH levels, high dose (8 mg) dexamethasone suppression test (DST), and CRH stimulation test can be used to differentiate between causes of Cushing’s syndrome.
ACTH levels differentiate between:
High dose DST differentiates:
CRH stimulation physiologically causes a rise in serum ACTH and cortisol levels.
The bilateral inferior petrosal sinus sampling (BIPSS) test samples blood surrounding the pituitary, allowing accurate diagnosis of a pituitary origin of high ACTH. Adrenal or lung lesions can be visualized by CT or MRI, while pituitary MRI is recommended for evaluating Cushing’s disease.
Treatment depends on the underlying condition, such as adrenalectomy for adrenal adenomas and resection or chemotherapy for ectopic tumors. Cushing’s disease is treated with transsphenoidal surgery.
Cortisol levels can be decreased by ketoconazole, metyrapone, mitotane, and etomidate. ACTH modulators include dopamine agonists like bromocriptine, octreotide, and retinoic acid. Glucocorticoid receptor blockers like mifepristone are also used.
v) Hyperaldosteronism: It may be primary or secondary.
Primary hyperaldosteronism results from aldosterone excess due to an adrenal tumor secreting aldosterone, adrenal hyperplasia, or autonomous aldosterone production. If primary hyperaldosteronism is caused by an adenoma, it is known as Conn’s syndrome. Primary hyperaldosteronism is associated with low renin levels and is called hyporeninemic hyperaldosteronism.
Secondary hyperaldosteronism results from pathological activation of the renin-angiotensin-aldosterone system (RAS), seen in renal artery stenosis, coarctation of the aorta, renin secreting tumors, diuretics, Gittleman’s syndrome, and Bartter’s syndrome. It is a hyperreninemic hyperaldosteronism.
Mutations in cell membrane potassium channels resulting in increased sodium permeability have been associated with primary hyperaldosteronism.
Hyperaldosteronism is associated with hypertension, hypokalemia, hypernatremia, metabolic alkalosis, muscle weakness, cramps, insulin resistance, cardiac fibrosis, etc. Hypervolemia occurs without peripheral edema due to the effects of ANP (atrial natriuretic peptide). Secondary hyperaldosteronism may be normotensive or hypertensive and may present with clinical features of the underlying condition, such as heart failure.
Diagnosis is by serum aldosterone and renin levels. Titers of angiotensin II type I receptor autoantibodies are elevated in primary hyperaldosteronism.
Primary hyperaldosteronism (PA) is confirmed by captopril challenge test, intravenous saline infusion test, fludrocortisone suppression test, or oral salt suppression test. These tests show elevated aldosterone levels in spite of salt and fluid loading in PA. The captopril challenge test shows high serum aldosterone with renin suppression in PA.
Adrenal vein sampling (AVS) involves sampling from the right and left adrenal veins, as well as from the inferior vena cava, for measurement of aldosterone and cortisol concentrations. In unilateral adenoma or hyperplasia, aldosterone concentration in the same-sided vein will be high, while the contralateral side will be suppressed. CT or MRI can be used to detect adrenal masses.
Treatment is unilateral adrenalectomy in adrenal adenoma and unilateral adrenal hyperplasia. Radiofrequency ablation is an alternative.
Medical therapy is preferred in bilateral adrenal hyperplasia, using mineralocorticoid receptor antagonists such as spironolactone or eplerenone (which does not have anti-androgen effects like gynecomastia). Some cases respond to low dose glucocorticoids, which decrease ACTH by negative feedback. Secondary hyperaldosteronism is treated by managing the underlying condition.
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