corticosteroid-binding globulin

**Structure/synthesis:** CBG (transcortin) is a ~50–60 kDa glycoprotein made by hepatocytes. It is encoded by SERPINA6 and belongs to the serine protease inhibitor (serpin) family, but it has no protease-inhibitor activity. It binds cortisol with high affinity and low capacity.

**Function:** - It transports cortisol in plasma. About 80–90% of cortisol is bound to CBG, ~5–10% to albumin (low affinity, high capacity), and ~5–10% is free. Only free cortisol is biologically active, enters cells, and is filtered into urine (urinary free cortisol). - It acts as a reservoir that prolongs the half-life of cortisol and buffers fluctuations in free cortisol. - It may deliver cortisol to inflammatory sites. Neutrophil elastase cleaves CBG's reactive center loop and releases cortisol locally. - It also binds progesterone (lower affinity) and, to a lesser extent, aldosterone and other steroids.

**Conditions that increase CBG (↑ total cortisol, normal free cortisol):** - Estrogen states: pregnancy, oral contraceptives, hormone replacement therapy, and hyperthyroidism. - Others: mitotane and some congenital CBG excess variants. - Clinical consequence: total serum cortisol (and the dexamethasone suppression test and morning cortisol) can be falsely elevated, giving a false-positive screen for Cushing syndrome. Patients lack true hypercortisolism features. Free cortisol measures (late-night salivary cortisol, 24-h urinary free cortisol) remain normal. Women on estrogen may need to stop it ~6 weeks before testing, or you can use salivary or urinary testing.

**Conditions that decrease CBG (↓ total cortisol, normal free cortisol if the HPA axis is intact):** - Cirrhosis/liver failure (↓ synthesis), nephrotic syndrome (urinary loss), protein-losing states, and malnutrition. - Critical illness/sepsis (↓ synthesis and cleavage by elastase), so free cortisol may be higher than expected from total levels. - Hyperandrogenic states, glucocorticoid excess, and rare inherited CBG deficiency (can cause fatigue and hypotension).

**Key points for the boards:** - Pregnancy raises both total cortisol and CBG, and free cortisol also rises modestly. Urinary free cortisol can be elevated in the 2nd–3rd trimester. - Free hormone is the active form, as with thyroid hormone binding proteins (TBG) and sex hormone-binding globulin (SHBG). A change in the binding protein changes total hormone but not free hormone, because negative feedback maintains free levels. - Compare: TBG (thyroxine), SHBG (testosterone/estradiol), and CBG (cortisol) are all increased by estrogen. - When the HPA axis is intact, ↑ CBG does not cause Cushing syndrome. Always interpret total cortisol in light of binding protein status, and prefer free cortisol measures (salivary, urinary) when CBG is altered. - Synthetic glucocorticoids differ in binding. Prednisolone binds CBG with substantial affinity, and dexamethasone binds negligibly, so dexamethasone is largely unaffected by CBG changes.