The ratio of cortisol metabolites and cortisone metabolites best represent the overall dominance of either active cortisol or inactive cortisone.
B-Tetrahydrocortisol [aka 5-beta-Tetrahydrocortisol (5b-THF)] is a metabolite of cortisol.
Tetrahydrocortisone, Tetrahydrocortisol and Allo-Tetrahydrocortisol are cortisol metabolites that reflect approximately 50% of daily cortisone synthesis. These will often reflect a chronic adrenal picture if levels are out of normal limits.
Urine contains free cortisol, but it also contains many cortisol metabolites, like cortisone or 5-alpha- tetrahydrocortisol, 5-beta-tetrahydrocortisol, tetrahydrocortisone, etc.
Where is cortisol made? Free versus bound.
Cortisol is made from cholesterol in the Zona fasciculata layer of the adrenal cortex. 80-90% of cortisol is bound to cortisol-binding globulin (CBG) [L]; much like thyroid is bound to thyroid-binding globulin (TBG) and testosterone is bound to sex hormone-binding globulin (SHBG).
A very small percentage of cortisol is free and unbound, while the remaining is in transition. The human body produces cortisol first, and then different glands have the ability to keep it as cortisol or convert it into cortisone, which is biologically inactive, through the enzyme 11-beta-hydroxysteroiddehydrogenase (11bHSD).
Cortisol metabolization
Cortisol is metabolized into 5-alpha-Tetrahydrocortisol (5a-THF) and 5-beta-Tetrahydrocortisol (5b-THF) and cortisone is metabolized into 5-beta-Tetrahydrocortisone(5b-THE).
Since all production and output originally started as cortisol, the cortisone metabolites are added to the cortisol metabolites when evaluating the “total metabolized cortisol”. It essentially reflects how much cortisol was made in the body and has been processed out through the liver, into the kidney, and into the urine.
The amount of cortisol produced and the amount of free cortisol available can be very different in some scenarios. Measuring both allows for insight into the rate of cortisol clearance/metabolism.
The importance of looking at free and metabolized cortisol
The metabolized cortisol and free cortisol markers are important to use both together and separately in order to tell a more detailed story. Metabolized cortisol answers the question of how much cortisol is being made in total and clearing through the liver. Whereas free-cortisol results tell us how much cortisol is free to bind to receptors and allows for assessment of the circadian rhythm.
The metabolites of cortisol also give insight into the relative activity of 11b-HSD types I and II, which controls the activation and inactivation (to cortisone) of cortisol.
References:
– Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamic–pituitary–adrenal axis. [L]
– Cortisol, obesity, and the metabolic syndrome: a cross-sectional study of obese subjects and review of the literature. [L]
– Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients. [L]
– Serum cortisol level variations in thyroid diseases [L]
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