Cortisol, the main glucocorticoid (representing 75%-95% of the plasma corticoids), plays a critical role in glucose metabolism and in the body's response to stress.
The majority of cortisol circulates bound to corticosteroid-binding globulin (CBG) and albumin. Normally, less than 5% of circulating cortisol is free (unbound). Only free cortisol can access the enzyme transporters in liver, kidney, and other tissues that mediate metabolic and excretory clearance.
Both hypercortisolism (Cushing disease) and hypocortisolism (Addison disease) can cause disease.
Cortisol levels are regulated by adrenocorticotropic hormone (ACTH), which is synthesized by the pituitary in response to corticotropin releasing hormone (CRH). CRH is released in a cyclic fashion by the hypothalamus, resulting in diurnal peaks (6 a.m.-8 a.m.) and troughs (11 p.m.) in plasma ACTH and cortisol levels.
Adult Reference Ranges for Cortisol, MS, Free:
8:00 - 10:00 AM - 0.07-0.93 mcg/dL
4:00 - 6:00 PM - 0.04-0.45 mcg/dL
10:00 - 11:00 PM - 0.04-0.35 mcg/dL
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); 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 is then metabolized into 5-alpha-Tetrahydrocortisol (5a-THF) and 5-beta-Tetrahydrocortisol (5b-THF) and cortisone is metabolized into 5-beta-Tetrahydrocortisone (5b-THE).
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. 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 even though free cortisol does not correlate positively with adipose tissue or BMI. This insight is quite helpful for those looking to lose belly fat and suspect cortisol/stress is a major factor. These patients are often misdiagnosed as having low cortisol production when only free cortisol is measured. Increased cortisol clearance may also be seen in hyperthyroidism and is suspected to be part of the chronic fatigue story as well.
In patients with low thyroid, the opposite pattern is often seen. 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. As a result, free cortisol starts to increase and may show up elevated.
The metabolized cortisol and free cortisol markers are important to use both together and separately in order to tell a more detailed story about the patient. 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.
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