Cortisol

Cortisol is a 21-carbon steroid made in the zona fasciculata of the adrenal cortex, with 11-beta-hydroxylase performing the final step on 11-deoxycortisol. It acts through the glucocorticoid receptor, a cytoplasmic nuclear receptor that on ligand binding moves to the nucleus and changes transcription of a very large set of genes, so its effects appear over hours rather than seconds. It also binds the mineralocorticoid receptor, from which the kidney is protected only by 11-beta-hydroxysteroid dehydrogenase type 2 converting cortisol to inactive cortisone.

Secretion is pulsatile and diurnal, peaking within an hour of waking and reaching its nadir around midnight. Roughly nine-tenths of circulating cortisol is bound to corticosteroid-binding globulin and albumin, leaving a small free fraction as the active pool. The diagnostic tests are built on those two facts: late-night salivary cortisol and the overnight low-dose dexamethasone suppression test exploit the rhythm and the feedback loop, while a morning cortisol with ACTH addresses suspected insufficiency.

Timing decides interpretation more than the number does, and a mid-afternoon cortisol drawn without context is close to uninterpretable. Binding protein matters as much: pregnancy and oral estrogen raise CBG so total cortisol rises with no change in free hormone, while critical illness lowers albumin and CBG so a total cortisol can look unimpressive while free cortisol is high.

The error encountered most often is not clinical. Salivary cortisol curves are marketed to consumers as tests for adrenal fatigue, a construct the Endocrine Society has stated is unsupported by evidence, and the resulting graphs are used to justify supplements or peptides. Cortisol is also treated as a stress meter, as though one value quantified psychological load, when its variance across a normal day dwarfs the differences read into it.