Cortisol

Cortisol
Abbreviation	F
Molecular formula	C₂₁H₃₀O₅
Type	Glucocorticoid steroid hormone
Administration	Endogenous (produced by adrenal cortex); supplemental forms include oral hydrocortisone (Cortef), prednisone, dexamethasone
Bioavailability	Oral: ~96% for hydrocortisone; cortisol is slightly more water soluble than progesterone
Synonyms	Hydrocortisone, Compound F
Source	Produced by the adrenal cortex from cholesterol via pregnenolone → progesterone pathway; body makes ~`20 mg` daily
Ray's verdict	Negative, undamentally catabolic and aging, necessary for short-term survival but harmful when chronically elevated

Introduction

Cortisol is the main catabolic steroid in the human organism. In addition to tissue catabolism, cortisol plays a key role in virtually all chronic degenerative conditions, and the aging process in general.

It belongs to the glucocorticoid class of steroid hormones, synthesized in the adrenal cortex from cholesterol via the pregnenolone-progesterone pathway. Cortisol is the thing which has a short-term defensive reaction against stress. One of its main effects is to turn protein into sugar so that the sugar can be used for energy to increase adaptive ability to handle the stress.

History/Etymology

The understanding of cortisol emerged from Hans Selye's pioneering stress research in the mid-20th century. The whole stress hormone system, the things that Hans Selye popularized and studied for many years, he was concentrating on the steroid system, and that's the most powerful stress-induced system.

Hans Selye had the concept of catatoxic steroids. They destroyed the toxin effect. It isn't exactly the same as detoxifying, but they protect the organism by blocking the effect of a toxin.

Selye's adrenalectomy experiments demonstrated that animals without adrenal glands became acutely stress-sensitive: When Hans Selye was experimenting with removing adrenals, he found that after the tissue-stored steroids had dissipated, just a moderate amount of stress would kill the animals because they didn't have the adrenal resilience to meet the stress.

Felix Meerson later extended Selye's work to the mitochondrial level, exploring stress-limiting systems. Meerson's idea was that we have many layers of stress-limiting signals and hormones and processes, and it happens that the steroids are one major stress-limiting system where cortisol and serotonin and nitric oxide and estrogen activate the short-term stress reactions that can stimulate brief defense. If those continue, they destroy the organism.

Structure/Chemical properties

• Molecular formula: C₂₁H₃₀O₅
• Type: Glucocorticoid steroid (21-carbon structure)
• Solubility: Cortisol is a little more water soluble than progesterone, and a diurnal cycle can be seen in the saliva.

Biosynthesis pathway: The pituitary senses something wrong in the organism, increases its ACTH, which drives the adrenal glands in particular to take up cholesterol and to synthesize cholesterol from raw materials, and to direct the cholesterol into the mitochondrion to turn it into pregnenolone, progesterone, DHEA, and finally cortisol.

Before the cortisol stage of stress, the continuously activated adrenal tissue will be first producing pregnenolone, progesterone, and DHEA, and it's only when those aren't enough to handle the stress that the progesterone will be further converted into the cortisol.

Function/Mechanism of Action

Primary functions:

1. Blood sugar maintenance: When the adrenaline reaches a certain level and can't get the blood sugar up out of your storage, then you turn on the cortisol and that's the classic stress that can be harmful because the cortisol dissolves first tissues like the thymus which are very fragile that starts turning to sugar just immediately when you run out of stored glycogen.
2. Protein → glucose conversion: If your liver didn't have the glycogen stored to release glucose under the influence of adrenaline, then you depend on cortisol to keep your blood sugar steady, and cortisol activates the conversion of protein to sugar and fat.
3. Anti-inflammatory (acute): Progesterone and cortisol both prevent leakiness of capillaries and are antiinflammatory, though they are antagonists in other situations. They both stabilize mast cells, decreasing histamine and serotonin, and inhibit phospholipase and prostaglandin formation and release of various inflammatory cytokines, and protect the glycocalyx.
4. Detoxification (at physiologic levels): A physiologically balanced amount of cortisol induces enzymes of detoxification, for example in the intestine.

Receptor mechanism: Prednisolone, dexamethasone, and cortisol are all glucocorticoid receptor agonists. The cortisol-GR complex translocates to the cell nucleus to exert systemic effects.

Medical uses/Effects

Medical Uses/Effects

Legitimate uses:

• Addison's disease: Addison's disease, with adrenal cortex degeneration, can cause cortisol deficiency, in which case progesterone would compensate.
• Acute shock/stress: Short-term cortisol maintains capillary integrity and provides emergency fuel.
• ACTH suppression: Since ACTH can interfere with ovarian function, cortisol can sometimes help the ovaries to make progesterone, by suppressing ACTH.

Conversion relationships:

Cortisol works in the body although the body can convert cortisol to cortisone. Synthetic cortisol-like drugs, such as prednisone are more like cortisol. Also, hydrocortisone is a drug that acts like cortisol.

Dosing

Endogenous production:

The body makes 20 mg of cortisol daily.

Synthetic equivalence:

Taking 10 mg of prednisone is equivalent to about 50 mg of cortisol or 2.5 times the daily amount made in-vitro. Cortef is Hydrocortisone which acts like cortisol.

Ray Peat's caution on supplementation:

William Jefferies' book created a lot of interest in cortisol supplementation (Cortef). "I don't think his arguments are correct. The amounts he sometimes prescribed weren't always safe." He knew people who followed Jefferies' prescription and got Cushing's symptoms.

Diurnal rhythm:

Cortisol peaks ~8am and reaches its lowest between midnight and 4am.

Side/Adverse effects

Tissue catabolism (the hallmark problem):

"The main features of aging can be produced directly by administering excessive amounts of cortisol. These features include atrophy of skin, arteries, muscle, bone, immune system, and parts of the brain, loss of pigment (melanin), deposition of fat in certain areas, and slowed conduction velocity of nerves. The physiology of aging (especially reproductive aging) overlaps the physiology of stress."

Thymus destruction:

After the thymus is consumed and turned to sugar, then the cortisol starts breaking down your muscles and then the skin. The brain, lungs and heart are spared from stress partly because they are very saturated in a healthy person with androgens, testosterone and DHEA especially, which block the breakdown function of cortisol.

It only takes about three hours typically for the thymus gland to disappear during profound stress.

Brain damage:

It is now clear that both stress and an excess of the glucocorticoid hormones cause brain damage (as well as damage to all other organs). Nerve cells are replaced by connective tissue cells.

There are actually imaging studies of people who have been under tremendous stress and they show drastic shrinkage of the volume of the brain, so you are literally eventually running on empty.

Gut barrier compromise:

Cortisol compromises the gut barrier and increases the expression of the TLR4 receptors, meaning you're going to flood the blood with endotoxin and increase the reactivity of the body to the toxin.

An unopposed excess causes destruction of detoxification enzymes, eliminating much of the intestine's barrier function, and leading to allergies. Endotoxin is known to destabilize and inactivate the bowel's detoxifying enzymes, just as an overdose of cortisol does.

Adrenal suppression:

High cortisol or glucocorticoid use can cause your adrenals to shrink to the point that if you suddenly stop the supplement, you might die from the absence of adrenal production. But the adrenals will gradually over about a month recover if you are well nourished after you've totally suppressed them with too much cortisol.

Psychological effects:

Since cortisol has a destabilizing, pro-convulsant effect on the nervous system, there are likely to be psychological symptoms—anything from compulsive behavior to depression or seizures-associated with the other chronic conditions.