Pathogenesis of Cushing Syndrome
Cushing syndrome results from chronic excessive glucocorticoid exposure, either from exogenous corticosteroid administration or autonomous endogenous cortisol overproduction through ACTH-dependent or ACTH-independent mechanisms. 1
Primary Etiologic Mechanisms
ACTH-Dependent Causes (80-85% of endogenous cases)
Pituitary adenomas (Cushing's disease) represent the most common cause, accounting for 75-80% of cases in children/adolescents and 49-71% in adults, where corticotroph adenomas autonomously secrete ACTH, driving bilateral adrenal cortisol overproduction. 2, 3
Ectopic ACTH secretion occurs when non-pituitary tumors (lung, thymus, pancreas, or bowel) produce ACTH or corticotropin-releasing hormone (CRH), stimulating excessive adrenal cortisol production. 4, 5 Thymic sources account for up to 2% of cases. 2
ACTH-Independent Causes (15-20% of endogenous cases)
Adrenal tumors directly overproduce cortisol without ACTH stimulation. 6 These include:
- Benign adrenal adenomas: Unilateral cortisol-secreting tumors that suppress ACTH and are managed with laparoscopic adrenalectomy. 4
- Adrenal carcinomas: Malignancy should be suspected when tumors exceed 5 cm, demonstrate irregular margins, inhomogeneity, or local invasion. 4
- Bilateral macronodular hyperplasia: Rare cause where both adrenals are enlarged; may be controlled by aberrant membrane hormone receptors or altered eutopic receptor activity. 5, 4
- Primary pigmented nodular adrenal dysplasia: Associated with Carney complex, presenting with small bilateral adrenals. 3
Pathophysiologic Mechanisms of Hypercortisolism
Mineralocorticoid receptor activation by excess cortisol increases renal sodium absorption, contributing significantly to hypertension development. 4
Multiple additional pathways promote cardiovascular and metabolic dysfunction, including:
- Activation of the renin-angiotensin system 4
- Sensitization of vasculature to catecholamines 4
- Impairment of endogenous nitric oxide bioavailability 4
Clinical Consequences
Multisystem morbidity develops from chronic glucocorticoid excess, manifesting as weight gain, abdominal striae, hirsutism, dorsal and supraclavicular fat accumulation, fragile skin, mood disorders, menstrual irregularities, and muscle weakness. 4, 2
Metabolic syndrome mimicry occurs with hypertension (exceeding 80% prevalence in cohort studies) and glucose abnormalities being particularly common. 4
Increased mortality results from pulmonary emboli, infections, myocardial infarction, and cerebrovascular accidents. 1
Critical Diagnostic Distinction
Elevated ACTH levels indicate the excessive cortisol is not originating from the adrenal gland itself, pointing toward pituitary tumors or ectopic sources. 4
Suppressed ACTH levels indicate autonomous adrenal cortisol production, with the responsible unilateral adrenocortical tumor always visible on CT scan. 3