Cortisol stops inflammation, but suppresses the immune system.

To understand Adrenal fatigue, Chronic Fatigue Syndrome and Myalgic Encephalitis (“CFS/ME”), “burnout”, “long Covid”, Fibromyalgia, “Low T3 syndrome”, Intracellular Hypothyroidism and the tiredness and weakness which accompanies all severe illnesses, one needs to understand Cortisol.
To understand Cortisol, one needs to understand the adrenal glands.
Be warned! – it will be a long journey to understanding.
But there’s no other way, so, let’s begin with the adrenals, where cortisol is made.

CAVEAT

The major portion of this page is reasonably easy to read and understand. However the section on “adrenal insufficiency”, an explanation of situations in which the adrenal glands fail to produce enough cortisol, is complicated and difficult. If you don’t have a fairly extensive medical vocabulary, it may be frustrating.

Therefore, while I would encourage you to read this page on cortisol, if you can’t “stomach it”, you may find that all you really need is “the bottom line”.

So here’s the bottom line, in advance

Cortisol stops inflammation, but causes immune system suppression. It is an essential part of our metabolism and in an emergency, it is lifesaving. Synthetic Cortisol, which is much stronger than the natural hormone, is prescribed by doctors to control severe illness and save lives.

However the side effects of long-term treatment with synthetic cortisone can be severe and under some circumstances lethal, because it achieves its effects by shutting down important systems. In fact, it shuts down almost everything, causing diabetes, osteopenia (bone loss), Intracellular Hypothyroidism (IH) and loss of maintenance and repair facilities in many organs, including the joints.

THE ADRENAL GLANDS

Twin influencers; each in a privileged position in the middle of the body, atop a kidney, right and left.

This pair of tiny (5×3×1 cm, 5 Grams), complicated secretory glands sit, one on top of each kidney, in front of the 10^th-11^th rib on either side, where they are safe, protected from all trauma except for sharp, penetrating wounds.
Each is supplied with blood by three arteries (imagine – 3 arteries, for a 5Gram organ!) and each excretes its hormones directly into the big kidney vein, only an inch or two from the vena cava (the biggest vein in the body), about six inches from the heart.

INTERNAL STRUCTURE of the ADRENALS: amazing anatomy!

Each Adrenal has a capsule and within it, two layers: an outer, yellow ‘cortex” and an inner, red “medulla”.
The CORTEX, only 1 mm thick, has three layers, or “zones” and each zone makes a “Corticoid Hormone”.
The (outer) Zona glomerulosa makes mineralocorticoids, to control Sodium and Potassium in the urine.
The (middle) Zona fasciculata makes Cortisol, the “stress hormone”, which is the subject of this paper.
The (inner) Zona reticularis makes DHEA, the “mother of the steroids” and the raw material for many other hormones.
The MEDULLA makes “Catecholamines”, the “fight or flight”, adrenaline-type hormones epinephrine and norepinephrine, which control heart, skin, muscle, gut and emotional responses to acute emergencies.

Each gland is enclosed in an active capsule, which does its maintenance and repair. An active capsule is unique to the adrenals: every other capsule does nothing but separate the gland it encloses, from the surrounding tissues. (2).

Cortisol

Cortisol works primarily in the metabolism of fat, protein, and carbohydrates.
It is secreted in diurnal rhythm: a surge of cortisol is released in the morning, with a maximum at 8AM. Then it tapers through the day to an evening minimum.

THE DIURNAL RHYTHM OF CORTISOL

Cortisol, the Dr. Jekyll and Mr. Hyde hormone

In addition to the diurnal rhythm, the adrenals can produce a surge of cortisol at any time: it is released in response to physical, environmental or emotional stress, so it is called the “STRESS HORMONE”.

This is good, but Cortisol is, sort of, a “Dr Jekyll and Mr Hyde hormone“.
Its calming, soothing, painkilling, anti-inflammatory effects come at a cost.
Many of its effects are brought about by blocking “cytokines“, which are chemicals that our bodies make to activate our immune system. The cytokines attract specialised white blood cells to injured or infected areas, to fight germs, neutralise toxins and repair any damage which has been done, but some cytokines can cause inflammation elsewhere in the body.
Some of them are specialised for healing, for instance Interleukin 6 (IL-6): without IL-6, the large bowel can’t repair mechanical or infectious damage to the lining mucosa: if enough cortisol is made, or prescribed, it can block IL-6 completely and prevent the bowel from healing itself.

So cortisol can be helpful, but prolonged treatment with cortisol can cause trouble.

For example, here is what happened to one of my patients: he had IBS symptoms, but his actual problem was an infected diverticulum in the lower part of his bowel. His bowel lining was secreting Interleukin 6 (IL6, a cytokine), to heal itself, but IL-6, although a healer in the bowel, causes inflammation elsewhere. In his case, it caused Polymyalgia Rheumatica, with terrific shoulder pain.

His family doctor diagnosed the polymyalgia rheumatica amazingly quickly and prescribed prednisone (artificial cortisone), which blocks IL-6. The Polymyalgia Rheumatica pain stopped in two hours, but the infected diverticulum’s damaged lining couldn’t heal without IL6.
The prednisone also did two other things: it blocked other cytokines that would normally have called white blood cells to the infected diverticulum to kill the germs, and it raised his blood sugar. The sugar fed the germs and made the infection worse. Soon, he developed an abscess, which could have killed him.

The doctor diagnosed the abscess and tried treating it with a series of antibiotics, but that didn’t work. Eventually, after diagnosis with a CAT scan, the infected part of the bowel was removed surgically: the patient made a quick recovery and the polymyalgia rheumatica didn’t come back.

So in that case, the side effects of cortisone-type treatment could have killed the patient.

Summary of cortisol’s side effects

[1] Blocking “inflammatory cytokines” * results in immune system suppression, failure to attract white blood cells to fight infection and slow, inefficient wound healing.
[2] Cortisol supplies emergency Glucose from “Glycogen” stores, but if there isn’t enough glycogen, it converts muscle protein into amino acids, so that the liver can use them to make glucose. Thus, prolonged treatment with cortisol wastes muscle.
[3] Cortisol decreases bone formation and healing and can cause bone loss: the bones break more easily.
[4] The increased blood glucose that cortisol produces can cause temporary diabetes: diabetes can make curing an infection impossible.
[5] Cortisol slows down all body processes by preventing conversion of Thyroxine (“Thyroid 4”, or “T4”) to “Triiodothyronine” (“Thyroid-3”, or “T3”), producing “Intracellular Hypothyroidism”IH).
In IH, low T3 in the cells drops energy consumption and encourages fat formation. It slows the brain down, causing anxiety, confusion, depression and “burnout“. It causes weakness, muscle pain, fatigue and constipation. It can weaken the heart muscles, which can lead to heart failure.
In short, everything slows down, including cognition: the patient gets some mixture of hypothyroid symptoms, like weakness, tiredness, hair loss, brittle fingernails, swollen legs, puffy eyes, constipation, hoarseness, dry legs, memory loss, “fuzzy thinking”, anxiety and sometimes, depression.
[6] Cortisol even slows production of dehydroepiandrosterone (DHEA), so testosterone, progesterone and other “downstream hormones” which are made from DHEA, may become deficient.

The HPA axis

• The hypothalamus, pituitary, and Adrenals constitute the “Hypothalamo-Pituitary-Adrenal axis”, (HPA). The HPA controls Cortisol production.
• Emotional, physiological and physical stress – any kind of stress – causes a release of Corticotrophin-Releasing Hormone (CRH) by the Hypothalamus.
• CRH travels in the portal passages (tiny tubes carrying hormones from the Hypothalamus), to the anterior Pituitary gland (the “Adenohypophysis”).
  There, CRH stimulates production of ACTH (Adreno-CorticoTrophic Hormone).
• ACTH travels in the blood to the adrenal cortex, to stimulate production of cortisol.

ADRENAL INSUFFICIENCY (NOT “Adrenal Fatigue”)

Adrenal insufficiency can be divided into primary, secondary and tertiary.

Primary adrenal insufficiency (Addison’s disease), is caused by damage to, or dysfunction of, the adrenal glands.
Production of all Adrenal hormones falls.
Severe adrenal failure causes Addison’s disease, which can be lethal.

Addison’s disease can be caused by:
Surgical removal of both adrenal glands, or blockage of the arteries by blood clots.
Autoimmune Diseases (when the body’s own immune system attacks itself).
Granulomatous Diseases (e.g. tuberculosis and histoplasmosis infections).
Metastatic cancer, spread from Cancer in another organ, to the adrenal glands.
Pharmacological steroid therapy.
Haemorrhage (bleeding) in the adrenal gland, sometimes from blood thinners.
Septicaemia (infection in the blood) with low blood pressure to the adrenals.
Pneumocystis infection (as a complication of AIDS).
Rare hereditary diseases.
Note that these conditions, except surgery and embolism, develop slowly.

The most common signs and symptoms of Addison’s disease are:
Weakness
Fatigue
Nausea
Abdominal pain
Weight loss
Dehydration
Low blood pressure
Lethargy
Hyperpigmentation (darkening of the skin)

Secondary adrenal insufficiency results from low production of ACTH, by the pituitary gland. If your pituitary doesn’t send ACTH, your adrenal glands don’t make cortisol.
This is much commoner than the primary form.
The clinical features usually have a slow onset with many non-specific symptoms.

Tertiary adrenal insufficiency results from inadequate CRH (Corticotropin Releasing Hormone) being secreted from the Hypothalamus, with resultant decrease in ACTH release from the pituitary.
Causes include brain tumors and strokes, but the usual cause is sudden stoppage of long-term steroid use.

TREATING PRIMARY ADRENAL INSUFFICIENCY
The aim of therapy is to replace the glucocorticoids and in some cases, mineralocorticoids, for as long as necessary.
Synthetic “corticoids” are prescribed, rather than cortisol itself, because they last longer and are easier to control.
Extra glucocorticoid is given for any major stress (e.g. surgery, accident or infection).
The patient can lead a normal, active life, but must avoid infections and must take precautions against emergencies by taking prescriptions faithfully, wearing a medical alert bracelet and staying in contact with support systems.

SECONDARY AND TERTIARY INSUFFICIENCY
These occur with hypothalamic or pituitary damage from trauma, surgery, radiation, infection or tumours, or by suppression of the adrenals with long-term prescription of cortisone. (6)
The clinical features of secondary adrenal insufficiency are similar to those of primary insufficiency, except that hyperpigmentation is not present (because ACTH is not elevated) and dehydration does not occur.

ADRENAL CRISIS

Adrenal Crisis, in which the adrenals are unable to supply sufficient cortisone, is a life-threatening emergency and requires immediate treatment, with intravenous saline to correct low blood pressure and Hydrocortisone to replace cortisol.
In addition corrective treatment is given, for the cause of the Adrenal failure and any other problems.
Adrenal Crisis usually presents as sudden low blood pressure shock in three major groups of patients:
1. Previously undiagnosed patients subjected to major stress,
2. Previously diagnosed patients who fail to increase glucocorticoid replacement during a major illness.
3. Sepsis.

EARLY DIAGNOSIS OF ADRENAL INSUFFICIENCY (4)

Anyone presenting with fatigue should have an early morning Cortisol test at 8AM.
If the Cortisol is lower than normal and especially if Sodium is low and Potassium high, an “ACTH stimulation” test can be done, to show if the Adrenals can produce Cortisol.
This test shows whether the Adrenal function is normal or low and differentiates between primary and secondary failure, to allow early diagnosis and proactive, preventative therapy.

THE BOTTOM LINE

Cortisol stops inflammation, but causes immune system suppression.
Cortisol is an essential part of our metabolism and in an emergency, it is lifesaving.
Synthetic Cortisol, which is much stronger than the natural hormone, is prescribed by doctors to control severe illness and save lives.
However the side effects of long-term treatment with synthetic cortisone can be severe, because it achieves its effects by shutting down important systems, causing diabetes and loss of maintenance and repair facilities in many organs.

REFERENCES

(1) The endocrine surgeon, http://www.endocrinesurgeon.co.uk/index.php/adrenals-the-cortex-cortisol

(2) The adrenal capsule is a signalling centre controlling cell renewal and zonation through RSPO3
Genes Dev. 2016 Jun 15; 30(12): 1389–1394. doi: 10.1101/gad.277756.116, PMCID: PMC4926862, PMID: 27313319 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926862/

(3) Long-Term DHEA Replacement in Primary Adrenal Insufficiency: A Randomized, Controlled Trial: Eleanor Gurnell, Penelope Hunt, Suzanne Curran, Catherine Conway, Eleanor Pullenayegum, Felicia Huppert, Juliet Compston, Joseph Herbert, and V. Krishna K. Chatterjee J Clin Endocrinol Metab. 2008 Feb; 93(2): 400–409. Published online 2007 11 13. doi:10.1210/jc.2007-1134, PMCID: PMC2729149, PMID: 18000094

(4) Addison disease: early detection and treatment principles: A. Michels, MD, N. Michels, PhD, Am Fam Phys, 14/4/1 ;89 (7):563-568. see https://www.aafp.org/afp/2014/0401/p563.html and https://familydoctor.org/familydoctor/en/diseases-conditions/addisons-disease.html.

(5) Adrenal insufficiency in sepsis: Djillali Annane  1 , . 2008;14(19):1882-6. doi: 10.2174/138161208784980626. PMID: 18691099 DOI: 10.2174/138161208784980626

(6) Glucocorticoid therapy and adrenal suppression, Nicolas C Nicolaides, MD, PhD, Aikaterini N Pavlaki, MD, Maria Alexandra Maria Alexandra, MD, PhD, and George P Chrousos, MD, PhD, MACP, MACE, FRCP. Update: October 19, 2018, Bookshelf ID: NBK279156PMID: 25905379 https://www.ncbi.nlm.nih.gov/books/NBK279156/

(7) Burnout and metabolic syndrome among healthcare workers: Is subclinical hypothyroidism a mediator? By Meng‐Ting Tsou ^{1 , 2 , 3} and Jau‐Yuan Chen
In J Occup Health. 2021 Jan-Dec; 63(1): e12252. Published online 2021 Jul 19. doi: 10.1002/1348-9585.12252
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291686/