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]
This metabolism process is slowed in cases of hypothyroidism, anorexia or impaired liver function.
Please consult with your health care provider about advice/treatment/diagnosis. The following statements are general informational statements.
Address the cause for the low cortisol levels, improve sleep quality, rest, vitamin C, B-vitamins, licorice root (warning: watch for high blood pressure and low potassium), glandular supplements, and HPA-axis support. Obviously taking cortisol supplementation will also increase cortisol levels. This should never be done without proper justification and a prescription from a healthcare provider.
Ex: High Free Cortisol and low Metabolized cortisol
When the thyroid slows down or if there is peripheral hypothyroidism where free T3 cannot get into the cells, the clearance (or metabolism) of cortisol through the liver slows down (“increase cortisol half life and decrease of metabolic clearance”). As a result, free cortisol starts to increase and may show up elevated on in your urine levels. The literature is more definitive for lower metabolized vs. higher “free”. [L, L]
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Cortisol and cortisone are metabolized by 5a-reductase and 5b-reductase (and then by another enzyme) to tetrahydrocortisol and tetrahydrocortisone for excretion.
This metabolism process is particularly increased (sped up) in obesity, high insulin and hyperthyroid. It may also be that long-term exposure to cortisol (long-term stress, supplementation) or other glucocorticoids speed this process up.
Please consult with your health care provider about advice/treatment/diagnosis. The following statements are general informational statements.
Address the cause of the high cortisol levels, improve sleep quality, rest, prayer/meditation, weight bearing or resistance training, lowering stress, eliminating inflammatory foods, reduce inflammation overall, weight loss, vitamin C, B-vitamins, phosphytidyl serine, HPA-axis support and herbs such as skullcap, magnolia, and zizyphus.
Ex: High Metabolized cortisol and low Free Cortisol
For example, higher levels of metabolized cortisol (compared to free cortisol) are often seen in obesity where adipose tissue is likely pulling cortisol from its binding protein and allowing for metabolism and clearance. The adrenal gland has to keep up with this cortisol sequestering and excretion, so cortisol production is often quite high (as seen in the levels of metabolized cortisol) even though free cortisol does not correlate positively with adipose tissue or BMI [L]. This insight is quite helpful for those looking to lose belly fat and suspect cortisol/stress is a major factor. Those people are often misdiagnosed as having low cortisol production when only free cortisol is measured. Increased cortisol clearance (again, this manifests by higher levels of metabolized cortisol) may also be seen in hyperthyroidism and is suspected to be part of the chronic fatigue story as well.
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