zona fasciculata

The adrenal cortex is divided into three histologically distinct zones (from outer to inner): zona glomerulosa (mineralocorticoids, e.g., aldosterone), zona fasciculata (glucocorticoids, e.g., cortisol), and zona reticularis (androgens, e.g., DHEA). The zona fasciculata consists of large, lipid-laden cells arranged in columns/fascicles, giving it a 'spongy' appearance on histology due to high cholesterol content used for steroidogenesis. It is regulated by the hypothalamic-pituitary-adrenal (HPA) axis: CRH from the hypothalamus stimulates ACTH release from the anterior pituitary, which acts on melanocortin 2 receptors (MC2R) in the zona fasciculata to stimulate cortisol synthesis via cAMP/PKA pathway, upregulating StAR protein and cholesterol desmolase (the rate-limiting enzyme). Cortisol has widespread effects: increases gluconeogenesis, lipolysis, and proteolysis; suppresses immune function and inflammation; increases blood pressure by potentiating catecholamine effects; and exerts negative feedback on CRH and ACTH release. Clinically, zona fasciculata dysfunction is central to several conditions: Cushing syndrome (excess cortisol from adrenal adenoma, ACTH-secreting pituitary tumor, ectopic ACTH, or exogenous steroids) presents with central obesity, moon facies, buffalo hump, striae, hyperglycemia, hypertension, and immunosuppression. Primary adrenal insufficiency (Addison disease) involves destruction of all adrenal cortex zones (often autoimmune) leading to cortisol and aldosterone deficiency, causing hypotension, hyperkalemia, hyponatremia, and hyperpigmentation (due to elevated ACTH/MSH). Congenital adrenal hyperplasia (particularly 21-hydroxylase deficiency) affects steroidogenic enzymes shared with zona fasciculata pathways, leading to cortisol deficiency and shunting toward androgen production. Long-term exogenous corticosteroid use can cause zona fasciculata atrophy due to suppressed ACTH, risking adrenal crisis upon abrupt withdrawal.