Cortisol is a vital glucocorticoid hormone synthesized by the adrenal cortex. It plays important functions in maintaining metabolic homeostasis and coordinating physiological responses to stress. This chapter provides a comprehensive review of cortisol metabolism, encompassing its synthesis through the hypothalamicpituitary-adrenal (HPA) axis, steroidogenic pathways, and circadian regulation. The complex transport mechanisms involving corticosteroid-binding globulin and albumin ensure appropriate hormone distribution, while the free hormone hypothesis governs tissue accessibility and biological activity.

Cortisol exerts its effects through precise cellular mechanisms involving glucocorticoid receptors, operating via both genomic and non-genomic pathways to regulate gene expression and cellular signaling. The hormone's metabolic effects span glucose homeostasis through gluconeogenesis and glycogen regulation, protein catabolism for amino acid mobilization, and lipolysis with characteristic fat redistribution patterns. These actions are coordinated through complex interactions with insulin and other hormonal systems.

Cortisol clearance occurs primarily through hepatic metabolism and 11β-hydroxysteroid dehydrogenase enzyme systems, which provide tissue-specific modulation of glucocorticoid activity. Clinical implications are profound, with hypercortisolism leading to metabolic syndrome and cardiovascular complications, while hypocortisolism results in life-threatening metabolic instability. Understanding cortisol metabolism is essential for developing targeted therapeutic interventions and optimizing treatment strategies for endocrine disorders while minimizing adverse effects.

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