CFIDS: Hormones: HPA Axis

One of the larger studies that has been carried out is that by Dr. Lucinda Scott for her PhD thesis, ‘The role of the HPA axis in Chronic Fatigue Syndrome.’ Her main findings were:

  1. Low levels of DHEA and Cortisol

This chronic depression of cortisol and DHEA is not seen in depressive illnesses. It probably emanates from a failure of ACTH drive from the hypothalamus. The postulate is that chronic depression of ACTH causes target organ atrophy. Perhaps the most significant finding was that there was a blunted response by the pituitary to the release of corticotrophic releasing hormone, (CRH).  Normally, the pituitary releases ACTH under the influence of CRH and Vasopressin (antidiuretic hormone). It would seem that in CFS/ME, there is a specific problem with the CRH receptor, with it being down-regulated, or the V1b receptor, which is the one that Vasopressin acts on, being upregulated. In humans, Vasopressin is not as effective an ACTH releasing agent. Therefore, in CFS/ME, where people are unable to use this as their main hypothalamic pituitary stress-releasing hormone, homeostasis cannot be maintained in the presence of any form of biological stress.

This finding is completely different to any illness otherwise described, and goes a long way to explaining many of the symptoms in CFS/ME. It is postulated that the use of Desmopressin may be helpful. Certainly, giving boluses of CRH and Desmopressin intravenously acutely restored the normal HPA balance and normalised the stress responses. Augmentation of the Vasopressin with its synthetic analogue seemed to regulate this receptor dysfunction at the pituitary level.

Another explanation would be that constant biological stress causes adrenal fatigue, i.e. constant output causes depletion of the functional reserve of the gland. We have the same basic stress response system as all mammals. We should only be stressed for short periods with a chance to recover in-between. Remember, cholesterol is the precursor to steroid hormones and in the adrenals this is converted into pregnenolone. Initially, both cortisol and DHEA rise. Then the adrenals, faced with a constant message to produce steroids, have to ‘make a choice’. There then follows a diversion of pregnenolone production into cortisol preferentially, resulting in low levels of DHEA. This is called the ‘cortisol steal’.

Eventually, the production of Cortisol also fails and it begins to fall and lose its rhythmicity. Paradoxically, you see a rise in DHEA, as cortisol becomes very low. This is partly because ACTH is not the only stimulus to DHEA release. They both then fall to almost Addisonian levels. This follows the Dr. Selye model of adaptation to any biological stress. Of course, both the central downregulation of the Adrenals and Adrenal fatigue could happen together. Certain premorbid cofactors such as psychological difficulties, or excessive exercise, can initiate adrenal fatigue, which may then set you up for problems if central down regulation occurs.

     2. Inadequate neuroendocrine tests

Scott also looked at the common neuroendocrine tests, which are often normal in people with CFS/ME, and concluded they were inadequate. It would seem that the most reliable test to try is a 1mcg ACTH stimulation test, as opposed to the normal 250mcg ACTH stimulation test we routinely use. This far more physiological dose of ACTH stimulus unmasks the neuroendocrine abnormalities. This is because the higher dose was used to identify primary adrenal failure before ACTH assays were available (i.e. the dose was a guess), and not to assess whether or not the adrenals are receiving adequate stimulus from endogenous ACTH. The higher dose standard test produces falsely reassuring results. Unless the adrenal has been destroyed by tumour, TB or autoantibodies, you will get a response in poorly functioning adrenals. Other studies have not been as clear cut on this question though, and more research is needed about Synacthen testing.

     3. Depressed central (brain) opioid tone

She then went on to look at central opioid tone in Chronic Fatigue Syndrome and found that using Naloxone to induce ACTH and cortisol release produced a blunted response. This would suggest depressed central opioid tone in chronic fatigue syndrome, which may account for some of the pain and immune dysfunction in CFS

     4. Adrenal gland atrophy

Finally, she looked at CT and MRI imaging studies of the adrenal gland and found consistently atrophied adrenals in CFS/ME. She performed this study with 8 patients who showed a poor response to the 1 mcg. Synacthen Test. A 50% reduction in adrenal size was seen. Therefore, the principal findings of her study were:

There is a reduction in adrenal gland size and secretory reserve.
End organ hypofunctioning occurs which is probably due to a deficiency of ACTH.
Under activity of this is not explained by increased opioid tone.
An increased contribution of Vasopressin to adrenal regulation is probable.

Finally, before finishing with the adrenals, it is also postulated that another steroid,

     5. ‘Ouabain-like’ steroid, (OLS), is low in CFS/ME.

OLS has mainly been researched with regards to hypertension.  It is produced, along with aldosterone, by the zona glomerulosa of the adrenal cortex.  It may be that the atrophy of the gland also causes reduction in OLS levels. It plays an important role in modulating the Na-K-ATPase pump in cell membranes. This is vital for maintaining the electrical homeostasis of the cell membrane. Failure of this regulatory enzyme has profound effects on cell energetics and may in part also account for many of the symptoms found in this illness.

Certainly, studies have shown that by using techniques such as cardiac-thallium SPECT scans in people with chest pain and CFS/ME. The results obtained are consistent with other ion channel disorders, e.g. Syndrome X. CFS can also begin following after exposure to toxins including Organophosphates and chlorines, which are known to produce abnormal sodium ion channels. Finally, CFS/ME patients have increased resting energy expenditure, a state influenced by abnormal transmembrane ion transport.

It may be that down regulation of the adrenals is an attempt by the body to downregulate a system that is constantly receiving stress messages from the brain, because of sympathetic overdrive. The body can take no more and it puts you flat on your back to enforce rest. Alternatively it could be seen as part of a general downregulation secondary to hypothalamic dysfunction.

One of the other problems is the effect of the illness on thyroid functioning. It has long been noted that people are often functionally hypothyroid. That is, they produce enough thyroid hormones from the thyroid gland, as measured by levels in the blood, but:

     6. they appear to be hypothyroid at a cellular level.

Numerous effects could explain this:

  1. The blood test for thyroid function is not a dynamic test, unlike, e.g. HbA1c. It simply represents what is in the blood, and not what is active at a cellular level. It is based on population sampling and would therefore include people with subclinical hypothyroidism. We will have to wait until the development of the nuclear membrane thyroid receptor volume test before we have a dynamic test of thyroid function. In medicine we tend to treat extremes and not subtle alterations in physiology. This means that people at the lower end of ‘normal’ are not treated. They may actually need to be at the upper end of normal, but the test will not tell you that. The body also has the ability, it seems, to keep the blood levels normal despite cellular thyroid problems. This can happen in any chronic illness.
  2. In cytokine mediated illness the production of central and locally generated cytokines can affect the de-iodination pathways of thyroid hormones. It seems that high level of rT3, and low levels of T2 may ensue. Reverse T3 is a non-competitive inhibitor of T3 and is raised in stress situations. T2 is thought to be important for the functioning of mitochondria. High levels of rT3 have been found in post-operative patients subsequent to high cortisol output. It is thought to be an adaptive response in order to conserve energy. The situation of poor conversion of serum T4 to cellular T3, for whatever reason, has been called Wilson’s Thyroid Syndrome.
  3. Other hormones affect thyroid functioning. Cortisol is permissive for hormone uptake into cells and low cortisol levels can therefore have an effect on this.  High cortisol can also inhibit functioning through its action on rT3 as mentioned above.
  4. There is hypothalamic downregulation of the thyroid axis with altered sensitivity to TRH and TSH at their receptors

     7. Low GH/IGF-1 levels may affect hormone receptors.

Dr Cheney reports improvement in thyroid hormone effectiveness with GH replacement.

Dr. Gordon Skinner has recently published his findings on treating clinically hypothyroid, but biochemically euthyroid patients, with low dose thyroxine. In 139 patients, 64 of whom had a diagnosis of CFS/ME, he looked at the improvement in 16 of the recognised criteria for hypothyroidism, e.g. energy loss, cold extremities, poor concentration, weight gain, constipation etc. Complete resolution of all symptoms was noted in 22% of patients and more than 12 out of 16 features in 76% of patients. What seemed to be the best indicator of clinical response was thyroid dosage and not pre or post treatment levels of T4 or TSH.

     8. Importantly, some suffer from low Pregnenolone levels, which can affect brain functioning. 

     9. Low VIP Neuropeptide: A Promising Treatment Developed

If you suffer from this illness, you probably don’t have enough VIP.  98% of people with CFIDS don’t.  When you learn what this neuropeptide does, you’ll probably surmise that low levels play a big role in that syndrome as well.

In Ritchie Shoemaker’s 2011 IACFS paper, “Vasoactive intestinal polypeptide (VIP) lowers C4a and TGF beta-1, corrects refractory symptoms and normalizes abnormal biomarkers in patients with CFS”, the role of VIP is elaborated in detail.

He wrote:  “VIP raises cAMP; lowers pulmonary artery (PASP) responses to exercise, blocks peripheral innate immune activation; reduces apoptosis of glial cells undergoing oxidative stress; raises VEGF; restores circadian rhythm; regulates response to olfactory stimuli in the suprachiasmatic nucleus; regulates dendritic calls; regulates Th17 function in autoimmunity; enhances IL-10 production; and modulates innate immunity.”

Let’s put that into lay person’s terms.

  1. Raises cAMP, short for cyclic Adenosine Mono Phosphate.This molecule is one step away from ATP, the energy molecule, the one that mitochondria make in great abundance when they work properly.  All of us with fatiguing illnesses have low ATP, some from mitochondria damage, as Dr. Sarah Myhill has shown, some from interference in the citric acid cycle due to heavy metals (especially mercury and aluminum), some from poor metabolism of sugars that feed the citric acid cycle with pyruvate, some from a deficiency of oxygen transport into the mitochondria, etc.   From Wikipedia we read, “cAMP is… used for … transferring the effects of hormones like glucagon and adrenaline, which cannot pass through the cell membrane. It is involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon. It also regulates the passage of calcium ions through ion channels.”   If you have issues with sugar metabolism (but not diabetes) and with adrenaline, you probably have low cAMP and would benefit from raising it.  In addition, cAMP affects cognitive function (not a big surprise since those brain cells of ours need to work properly.  By researchers have found a specific relationship between low cAMP and the cognitive deficits in age-related illnesses and ADHD.
  2. PASP (pulmonary artery response to exercise) may contribute to our exercise intolerance.Shoemaker found that patients on VIP could tolerate more exercise.  It still remains to be seen if raising VIP eliminates the phenomenon Drs Snell and VanNess documented at Pacific Fatigue Lab, results unique to CFS in which repeating a stress test within 24 hours showed markedly reduced capacity to produce energy and metabolize oxygen.  It would also be valuable to know if the changes in receptor activity in CFS patients during exercise, documented by Drs. Kathleen and Alan Light, ceases to operate after normalization of VIP levels.
  3. Peripheral innate immune activation makes us itch, swell from bugbites and scratches, get extreme reactions to poison ivy.
  1. Reduces apoptosis of glial cells undergoing oxidative stress. Apoptosis is another way of saying that brain cells which have been damaged by free radicals commit suicide (a normal process to make way for new, healthy cells).  Yet when there is more death than replacement, cognitive function deteriorates.  It’s been said that we don’t notice cognitive deficiencies until we’ve lost about 70% of our brain cells.  Good to reduce this depletion of our brains by restoring optimal levels of VIP.  If the cells don’t commit suicide, they can be repaired and restored to optimal health with reduction in toxins and inflammation and increase in nutrients.
  2. Raises VEGF, a molecule which helps us build new blood vessels.  When too high, VEGF can support the growth of cancer.  Too low means less repair of damaged vessels, especially those tiny capillaries which feed every cell in our body.  Hence degeneration as tissues which are deprived of the blood bath bringing oxygen and nutrients hold onto the toxins that reduce optimal function.
  3. Restores circadian rhythm, the daily rhythm of hormones like cortisol, an important adrenal hormone which serves as a buffer against stress and inflammation.  Cortisol is highest in the early morning, drops to about half by noon, and then slowly declines in the evening until we are desirous of sleep.   Good to reverse an inverted or flat rhythm; the former keeps us up late at night, the latter leaves us in perpetual lethargy.  Disturbed adrenal circadian rhythms have been found in CFS-ME, as documented by data at Sabre Sciences, Inc, a lab which offers salivary testing of the circadian rhythm.  The majority of indexed studies on adrenal issues in this illness looked a total serum cortisol, finding no pattern other than disturbed regulation of the hypothalamic-pituitary-adrenal axis, while salivary hormone testing measures free cortisol inside the cells.  If cAMP is low, cortisol transfer into the cells will suffer.  Consequently, when I tested an 8 am serum cortisol and did an 8 am saliva sample at the same time, we found a very high normal serum level and a below normal salivary level.  My adrenals were working fine, but my cortisol was all bound by globulins as it couldn’t be transported into the cells which needed it.  No wonder I couldn’t tolerate taking Cortef (a cortisol replacement).
  4. Regulates response to olfactory stimuli in the suprachiastic nucleus, e.g. to smells and chemicals that we breath.   Those with MCS are hyper-sensitive and get the kind of response to 1/10000th of a scent or odorless chemical that normals get to amounts 10,000 times greater than normal.  (From Martin Pall, whose theory of MCS involves upregulation of OH and ONOO with NMDA receptor hyper-response.)
  5. Regulates dendritic cells, immune cells which present antigens to other immune cells so that these antigens can be eliminated.  Dendritic cells are found everywhere the body is in contact with the external environment: on the skin and in the inner lining of the nose, lungs, stomach and intestines.
  6. Regulates Th17 function in autoimmunity, a type of T cell makes interleukin 17 which is found in excessive amounts in MS, psoriasis, rheumatoid arthritis, and other autoimmune disease.  They serve an important function at the mucosal barrier by producing cytokines which stimulate these cells to produce chemicals to fight candida, staph, and other microbes.  Without Th17 cells, there are more opportunistic infections.
  7. Enhances IL-10, an important anti-inflammatory cytokine which plays a role in the gut-based immune system.
  8. Modulates innate immunity.  This is the part of the immune system that we are born with, our first line of defense against invading pathogens.  It is the part that goes wacky in CIRS, and presumably also in CFS.

From a study of 1682 patients meeting the criteria for CFS, 98% had low VIP.  In comparison, fewer than 10% of controls have low VIP.  The range for VIP that Shoemaker uses is 23-63 pg/ml.  Shoemaker is working with VIP replacement, as a patented hormone replacement has been produced by Hopkinton Drug.  A talk he gave to other physicians used to be available at . It can still be accessed as streaming video on Shoemaker’s site at

But beware of the fact that taking VIP right away doesn’t do any good.  As Shoemaker states repeatedly in his book, Surviving Mold, it’s crucial to eliminate environmental mold toxins, detoxify the mycotoxins in the body, and lower inflammation before you take VIP.  It might also be helpful to first balance some of the upstream regulatory hormones, such as ADH and cortisol.


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