Cortisol counteracts inflammation and soothes pain, but causes immune system suppression.
To understand and appreciate Adrenal fatigue, Chronic Fatigue Syndrome, burnout and Myalgic Encephalitis, one needs to understand and appreciate Cortisol.
To understand and appreciate Cortisol, one needs to understand and appreciate the adrenals.
Be warned!! – it will be a long journey to understanding, but there’s no other way.
So, let’s begin with the adrenals.
THE ADRENAL GLANDS
Twin influencers, each in its privileged position in the middle of the body!
This pair of tiny (5×3×1 cm, 5 grams), complicated secretory glands sit one atop each kidney, in front of the 10th-11th rib on either side, where they are nicely protected from trauma, each supplied with blood by three arteries and each outputting its products into the big kidney vein, only an inch or two from the vena cava.
INTERNAL STRUCTURE of the ADRENALS
Each Adrenal has an outer, yellow ‘cortex” and an inner, dark 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”.
The (inner) Zona reticularis makes DHEA and from it, many other hormones.
The MEDULLA makes “Catecholamines”, the “fight or flight”, adrenaline-type hormones such as 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 unusual, because every other organ’s capsule does nothing but separate it from the surrounding tissues. (2).
Cortisol (hydrocortisone), produced by the zona fasciculata, is called a “glucocorticoid”, because it raises the glucose (sugar) in the blood.
It does this by triggering conversion of glycogen (our glucose store) into glucose and when necessary, by converting proteins into glucose, in a process called gluconeogenesis, elsewhere (for example, in the muscles).
THE DIURNAL RHYTHM OF CORTISOL
When life is smooth and easy cortisol works in the metabolism of fat, protein, and carbohydrates.
A surge of cortisol is released in the morning, with a maximum at 8AM and tapering through the day to an evening minimum.
In addition, cortisol has a number of other functions.
It is released in response to Physical, Environmental or Emotional stress, so it is called
“THE STRESS HORMONE”.
All this is good, but Cortisol is, sort of, a “Dr Jekyll and Mr Hyde“: its calming, soothing, painkilling effects come at a cost: many of its effects are brought about by blocking “cytokines”, chemicals which our bodies make to activate our immune system and call up specialised white blood cells to repair damage caused by infection or injury.
 Reduces inflammation, but in doing so, suppresses normal repair processes.
 Supplies emergency Glucose, by changing muscle protein into amino acids, for the liver to use to make glucose……. So high cortisol leads to muscle wasting.
 Decreases bone formation and healing, and can cause bone loss.
 Counteracts inflammation produced by “inflammatory cytokines” *, but this results in immune system suppression.
 Increases the blood glucose, causing temporary diabetes, which can allow a mild infection to flare up into a severe problem.
 Slows all body processes by reducing conversion of Thyroxine (“T4”) to “Triiodothyronine” (“Thyroid-3”, “T3”), causing “Intracellular Hypothyroidism“.
– Low T3 in the cells drops energy consumption and encourages fat production. – Low T3 in the brain slows it down, causing anxiety, depression and “burnout“.
– Low T3 in the muscles causes weakness, fatigue, aches and constipation.
– Severe, chronic low T3 in the heart causes cardiomyopathy and heart failure.
 Cortisol blocks the Cytokines we need for repair processes, including summoning white blood cells to fight infection and heal wounds, so healing slows down.*
* For example:
– Interleukin 6 (IL6) is a cytokine made by the large intestine to heal any damage to its lining. Without IL6, the bowel can’t heal an infected diverticulum.
– IL6 causes muscle inflammation, such as Polymyalgia Rheumatica.
– Cortisol blocks IL6, so it stops Polymyalgia Rheumatica symptoms immediately.
– The infected diverticulum’s damaged lining can’t heal without IL6.
– Prescribed cortisol puts the blood sugar up and blocks the other cytokines that would call white blood cells to the infected area to kill germs. This makes the germs very happy.
– The diverticulum easily converts to an abscess, which can cause death.
- The hypothalamus, pituitary, and Adrenals constitute the “Hypothalamo-Pituitary-Adrenal axis”, (HPA). The HPA controls Cortisol production.
- Emotional, physiological and physical stressors cause a release of Corticotrophin Releasing Hormone (CRH) in the Hypothalamus.
- CRH travels in the portal passages of the Hypothalamus (tiny tubes carrying hormones from the hypothalamus to the pituitary, to tell the pituitary what to do), to the anterior pituitary (the “Adenohypophysis”).
In the Adenohypophysis CRH stimulates the making 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) results from damage to or dysfunction of the adrenal gland itself. Production of all Adrenal hormones falls. Severe adrenal failure causes Addison’s disease, which can be lethal.
Secondary adrenal insufficiency results from low production of AdrenoCorticoTropic Hormone (ACTH), by the pituitary gland. If your pituitary doesn’t make enough ACTH, your adrenal glands don’t make enough cortisol.
Tertiary adrenal insufficiency results from inadequate CRH release from the Hypothalamus, with resultant decrease in ACTH release. Causes include brain tumors, strokes and sudden stoppage of long-term steroid use, which is the usual cause.
PRIMARY ADRENAL INSUFFICIENCY:
Primary insufficiency is clinically distinct from secondary and tertiary insufficiency. In primary insufficiency there is a decrease in both mineralocorticoids (aldosterone) and glucocorticoids (cortisol), whereas in secondary and tertiary insufficiency the aldosterone levels are virtually normal (the zona glomerulosa is independent of ACTH).
The most common signs and symptoms are: Weakness Nausea Abdominal pain Weight loss Dehydration
Low blood pressure Lethargy Hyperpigmentation (darkening of the skin).
SECONDARY ADRENAL INSUFFICIENCY
This is much commoner than the primary form.
The clinical features usually have a slow onset with many non-specific symptoms.
WHAT CAUSES PRIMARY ADRENAL INSUFFICIENCY (ADDISON’S DISEASE)?
- Surgical removal of both adrenal glands
- Autoimmune Diseases (when the body’s own immune system attacks itself)
- Granulomatous Diseases (e.g. tuberculosis and histoplasmosis)
- Metastatic cancer (spread from (eg.) lung or breast cancer to the adrenal gland)
- Pharmacological steroid therapy
- Haemorrhage (bleeding in the adrenal gland, sometimes from blood thinners)
- Meningococcal septicaemia (Waterhouse-Friderichsen syndrome)
- Septicaemia (infection in the blood) with low blood pressure to adrenals (5)
- Rare hereditary diseases
- Pneumocystis infection (as a complication of AIDS)
Note that all of these conditions are of slow onset, except surgery.
TREATING PRIMARY ADRENAL INSUFFICIENCY
The aim of therapy is to replace the glucocorticoids and in some cases, mineralocorticoids, ongoing.
Extra glucocorticoid is given for any illness or major stress (e.g. surgery, accident or infection).
The patient can lead a normal active life, but must take precautions against emergencies by faithful compliance with prescriptions, wearing a medical alert bracelet and staying in contact with support systems.
SECONDARY AND TERTIARY INSUFFICIENCY
These occur with hypothalamic or pituitary lesions, from Trauma, Surgery, Radiation, Infection, Tumours, Suppression of the adrenals after long-term steroid use. (6)
The clinical features of secondary adrenal insufficiency are similar to those above except that hyperpigmentation is not present (because ACTH is not elevated) and dehydration does not occur.
Adrenal Crisis is a life-threatening emergency and requires immediate treatment, with intravenous saline to correct the low blood pressure and Hydrocortisone to replace the cortisol.
In addition corrective treatment is given, for the cause of the Adrenal failure and any other problems. Adrenal Crisis usually presents as sudden hypotensive shock in two 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.
The prevalence of Autoimmune adrenalitis is only one in 20,000 persons and the symptoms preceding crisis are subtle: hyperpigmentation, fatigue, anorexia, orthostasis, nausea, muscle pain, joint pain and salt craving.
Although surveillance and “a high index of suspicion” would lead to early diagnosis, this “prodrome” is often missed, but if the following protocol were applied to all patients presenting with fatigue, adrenal crisis would be truly rare:
DIAGNOSING ADRENAL INSUFFICIENCY (4)
Anyone presenting with fatigue gets a test for Cortisol done at 8AM.
If the Cortisol is lower than normal and especially if Sodium is low and Potassium high, an “ACTH stimulation” test is done to show whether the Adrenals can produce Cortisol.
This test shows whether the Adrenal function is normal or low and differentiate between primary and secondary failure is present, allowing early diagnosis and proactive, preventative therapy.
THE BOTTOM LINE
Cortisol is an essential part of our metabolism and in a “maximum emergency” it is lifesaving.
Cortisol and its synthetic forms, which are much stronger, are prescribed by doctors to control severe illness and save lives.
However the side effects of long-term treatment with Cortisol can be severe, because it achieves its effects by shutting down important systems, with resulting loss of maintenance and repair facilities in many organs.
(2) THE ADRENAL CAPSULE IS A SIGNALING CENTER 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.2007-1134PMCID: 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.
(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
ABSTRACT: Evidence suggests that subclinical hypothyroidism (SCH) is associated with burnout and metabolic syndrome (MetS). We examined the relationship between burnout and MetS among healthcare workers (HCWs) and investigated the potential mediation of SCH.