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In Brief: The Adrenal Glands and ME

Discussion in 'Phoenix Rising Articles' started by Phoenix Rising Team, Apr 1, 2014.

  1. Phoenix Rising Team

    Phoenix Rising Team

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    The second in a new series of ‘In Brief’ articles, where Andrew Gladman provides a helpful insight into the science behind fairly common topics, exploring how they relate to ME/CFS. This time he discusses the adrenal glands and why they can be such a talking point ...

    [​IMG]
    Diagram showing the location of the adrenal glands, above the kidneys

    While the frequent topics of conversation relating to ME/CFS appear to now be infectious agents, autoimmunity and often a dysfunctional nervous system, many patients and researchers still turn their attention to problems within the endocrine system, namely the adrenal gland.

    As the gland within the body centred around stress responses, it is initially quite a logical place to look for problems. There can be no denying that patients suffering with diseases of the adrenal glands certainly do share many symptoms and complaints of those afflicted with ME/CFS.

    There is then good reason to query where the adrenal glands may relate to ME/CFS. While the initial reason for querying this may seem simple, the answers raise interesting questions for the potential pathophysiology and reasons for the symptomology of ME/CFS.

    What are the Adrenal Glands?

    The adrenal gland is one of the body's most vital endocrine glands. The adrenals are glands which secrete their hormone directly into the bloodstream, often as a result of the glands being innervated with blood vessels. Sitting above each kidney, these glands' primary function is releasing the hormones and chemicals which in turn stimulate a stress response, often known as a fight or flight reaction.

    However the adrenal glands do carry out numerous other functions.

    The stress response is initiated through the production and release of corticosteriods, such as cortistol, and a larger group of chemicals known as catecholamines of which adrenaline (epinephrine) and noradrenaline fall under.

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    Diagram showing the division between the adrenal medulla and cortex, along with the chemicals produced by each

    The adrenal gland is composed of numerous layers although it is often discussed simply as being split into two main regions, the medulla and the cortex.

    The medulla is the centre of the gland and the cortex is the outermost layers. The medulla is responsible for the production of adrenaline and noradrenaline. It achieves this through complex innervation with neurons of the sympathetic nervous system which stimulate the adrenal medulla in times of acute stress, increasing the rate of synthesis and release of these chemicals.

    The cortex, on the other hand, is tasked with the production of corticosteroids, including cortisol and aldosterone, along with androgen hormones (the male sex hormones). The cortex is further sub-divided into three separate layers differentiated by which of the discussed chemicals is being produced by the specialised cells in that region, although the specifics of this sub-division are very rarely discussed.

    [​IMG]
    The HPA axis

    Given the importance of the adrenal gland in producing these vital chemicals, there has evolved a complex set of interactions between other endocrine glands, the adrenal gland and the brain to help regulate one another through a process known as negative feedback.

    This set of interactions occurs between the hypothalamus (a region at the centre of the brain), the pituitary gland (a small gland located at the base of the brain) and the adrenal gland. This set of interactions between these three areas is known commonly as the hypothalamic-pituitary-adrenal axis, often abbreviated to HPA axis.

    It is this HPA axis that is frequently discussed in relation to ME/CFS.

    Given the wide range of chemical messengers produced by the adrenal gland through the complex interactions it shares within the HPA axis, it is clear that the gland has far-reaching consequences within the homeostasis of the body.

    These include playing roles in helping to control and regulate body temperature, digestion, immune system responses, mood sexuality and energy usage, along with the adrenal's primary function of controlling the physiological reaction to stress, trauma and injury.

    It is clear to see why any dysfunction in either the adrenal gland alone or in the HPA axis as a whole could potentially cause a plethora of problems and symptoms. Dysfunction in the HPA axis is well known to be involved in a wide variety of psychological illnesses and is now being understood to play quite a large role in many physiological conditions too -- understandably, given the stress that disease itself causes.

    Why are the Adrenal Glands important in ME?

    For many years now studies have indicated finding abnormalities in HPA axis function within the ME/CFS cohort. These abnormalities are often described in the literature to include mild hypocortisolism, heightened negative feedback, and blunted HPA axis responsiveness.

    Fundamentally, this means that in those patients observed, cortisol levels are persistently lower than is to be expected. This appears to be traced back to the hypothalamus and pituitary gland becoming somewhat unable to appropriately detect or respond to the low cortisol levels.

    Many studies have not just identified this as a fairly consistent finding in ME/CFS but have furthermore observed a correlation between this dysfunction and symptom severity. It is of note however that some studies dispute this finding.

    This dysfunction in the HPA axis has been used somewhat deviously by some groups to verify the effectiveness of talking-based therapies such as cognitive behavioral therapy (CBT).

    This is in part due to the effectiveness these therapies can appear to have in conditions such as anxiety disorders in which HPA axis dysfunction has also been proven to play a somewhat central role. However such a line of thought, while helpful in many diseases where HPA axis appears to be a disease mediator, is unlikely to be helpful in a disease where the HPA axis does not yet appear to be central.

    While there are a large number of studies confirming their independent findings of HPA axis dysfunction, few make the leap to develop a hypothesis for this being the central disease mechanism. This is likely a result of the multitude of other research indicating a deeper physiological defect in ME/CFS of which HPA axis may simply be an unfortunate by-product.

    One interesting study that bears thought as to HPA axis dysfunction developing as a secondary condition is a somewhat unrelated study by Dunn et al. This study focuses upon how cytokines can in turn activate the HPA axis, initiating a stress response. Cytokines are a rapidly emerging line of study in ME/CFS and we recently produced an article exploring why they are gaining increased exposure in the ME/CFS research field.

    It's an interesting notion that cytokines can directly influence the functioning of the HPA axis. When we consider the emerging results of researchers such as Prof. Lipkin outlining significant cytokine abnormalities in ME/CFS, perhaps we have a logical line of reasoning as to why the HPA axis appears somewhat blunted.

    If the observed cytokine abnormalities prove repeatable and appear chronic, then it stands to reason that the HPA axis is under significant strain for a prolonged period of time. This could account for lower cortisol levels as time progresses, alongside a blunting of the HPA axis response when challenged with a stressor.

    This hypothesis would also be supported by the HPA axis dysfunction seen in other chronic conditions with significant cytokine disturbance, such as lupus.

    Overall, while problems with the adrenal glands and HPA axis function don't yet appear to be a sole causative agent for ME/CFS, they do provide an interesting explanation for certain symptoms of ME/CFS from which patients suffer. As time progresses, and through the thorough research done every day, we learn more and more about the complex interconnections between different organs and systems such as the HPA axis.

    The connections between these systems, while seemingly unrelated to many diseases, appear to play quite a substantial role in the symptomolgy of ME/CFS, perhaps tying together with increasing evidence of autonomic dysfunction within ME/CFS.


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    Last edited by a moderator: Apr 1, 2014
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  2. Ema

    Ema Senior Member

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    The common line here is inflammation...cortisol is an extremely powerful anti-inflammatory agent - the main one that we have at our disposal. And it is exquisitely tied to the immune system by the modulation of thousands of genes that regulate the immune response.

    It seems quite clear now based on more recent studies that glucocorticoids both enhance and suppress immune function and are crucial for modulating inflammation. When the system is under constant stress of illness, it loses responsiveness to cortisol (resistance) and inflammation can run amok. And this does seem to happen mostly under the control of cytokines.

    The immune system eventually stops working and we suffer symptoms of low cortisol that then can cascade to the rest of the endocrine system and eventually cause all kinds of metabolic distress (thyroid and diabetes, for example). And the body becomes even more vulnerable to infectious assaults.

    The mistake many have made for years is assuming that the HPA axis dysfunction in ME/CFS *should* look exactly like the adrenal insufficiency of Addison's disease (an autoimmune disorder) or even like secondary AI which is a brain dysfunction. And it hardly ever does, though it is worth noting that infectious agents (such as CMV) can also cause adrenal insufficiency.

    We need a new paradigm to explain the low cortisol state caused by the immune dysfunction found in ME/CFS.
     
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  3. voner

    voner Senior Member

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    Andrew,

    Thx for the article. Clear and concise. Not an easy task!

    Any ideas on POTS and the adrenals/kidneys? I would love to see that as an article. Mineralcorticoids vrs glucocorticoids, etc.

    It looks like the feedback loops signaling could break and thus cause the cortisol insufficiencies?
     
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  4. Simon

    Simon

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    Thanks, Andrew - a very clear and helpful article.
     
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  5. Ema

    Ema Senior Member

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    Or possibly we just need to extrapolate the paradigm already explored in AIDS all the way back in 1992...these patients had hypercortisolism despite an Addison's type presentation due to peripheral glucocorticoid resistance.

    This also helps to possibly explain why some people have trouble with taking exogenous steroids...they already have enough but are just unable to use them properly so adding more is not helpful.

    http://www.ncbi.nlm.nih.gov/pubmed/1740494
     
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  6. Ema

    Ema Senior Member

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    So it turns out that our often low IgG levels may be due to low cortisol, as much or even more than defects in B cell production.



    Med Hypotheses. 1991 Mar;34(3):198-208.
    Cortisol and immunity.
    Jefferies WM.
    Abstract
    The relationship between adrenocortical function and immunity is a complex one. In addition to the well-known detrimental effects of large, pharmacologic dosages of glucocorticoids upon the immune process, there is impressive evidence that physiologic amounts of cortisol, the chief glucocorticoid normally produced by the human adrenal cortex, is necessary for the development and maintenance of normal immunity. This evidence is reviewed, and the importance of differentiating between physiologic and pharmacologic dosages and effects is discussed. The popular use of synthetic derivatives of cortisol, which differ greatly from the natural hormone in strength, and the dynamic nature of the normal adrenocortical response, which varies with the degree of stress being experienced, have contributed to the confusion. Further studies of the nature of the beneficial effect of cortisol, and possibly of other normal adrenocortical hormones, upon immunity in humans are needed, especially in view of recent evidence of a feedback relationship between the immune system and the hypothalamic-pituitary-adrenal axis, and with the increasing awareness not only that the immune process provides protection against infection, but also that its impairment seems to be involved in the development of autoimmune disorders, malignancies and the acquired immunodeficiency syndrome (AIDS).

    PMID:

    2062254

    [PubMed - indexed for MEDLINE]
     
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  7. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I wonder if the newer cfs people, the less than 3 years people have high cortisol and those long term cfs patients have low cortisol? Is there any studies showing this at all?
    Any ongoing stress can cause pregenolone steal i guess and then upset the apple cart of hormones??
     
  8. Ema

    Ema Senior Member

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    @heapsreal, this study shows a novel model for how cortisol may be affected over long term periods of stress similar to ME/CFS.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1804264/
     
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  9. Aerose91

    Aerose91 Senior Member

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    I have had ME for just over a year but before this had very severe adrenal fatigue which I think was a welcome mat for ME. Something very interesting happened though- the instant I got ME my adrenal fatigue nearly vanished. I mean I was as bad as they come, and instantly it almost completely went away. I have continued to do saliva cortisol tests throughout this past year as I have for the duration of my adrenal fatigue and my cortisol is still slightly low but not nearly as low as it was before ME. I have no explanation for this.
     
  10. stridor

    stridor Senior Member

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    My adrenal function has gotten worse and I have no talent for stress-dosing. Crashed them again on the weekend. I am on 25 mg daily. I have to get better at this - but I'm nervous about osteoporosis.
    At least in rats, mercury can permanently damage adrenals. These animals have normal a.m./p.m. cortisol levels but as soon as they are stressed the levels drop.
    I have a bunch of cortisol receptor SNPs which would make me resistant to cortisol. And I have some corticotropin releasing hormone receptor SNPS.
     
  11. Ema

    Ema Senior Member

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    I just read a journal article by a conservative endocrinologist who wrote that she has never seen a case of HC induced osteo under 30 mg/day. So stress dosing for activity every now and again (or even raising your dose slightly if you find your daily dose insufficient for your activity level) is not going to be a major player in the development of osteoporosis. For that, your Vit D, K2 and A status will prove to be much bigger factors.

    You'll learn to stress dose, it just takes time for everyone because there are no good hard and fast rules and we've all been brainwashed by the side effects of pharmacological doses opposed to physiological dosing. They just don't apply for the most part to us at all.
     
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  12. Aerose91

    Aerose91 Senior Member

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    I think the SNP's may be your underlying problem as adrenal fatigue is really just a signaling problem from the brain- the adrenal glands themselves are fine. Your brain has lost the ability to respond accordingly to the environment which is why small stressors cause huge deficits. There's also a theory out there that leptin plays a huge role in signaling to the hypothalamus and controlling these minute changes.that we can't get right. Try googling "leptin reset" and see what you think.
     
  13. Ema

    Ema Senior Member

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    What are the SNPs that you are referring to with regards to cortisol resistance?
     
  14. stridor

    stridor Senior Member

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    @Ema @Aerose91
    Thanks so much for the replies. I have to get this sorted out, as you seem to understand adrenal crashes are not any fun at all. I will look up leptin reset. I am delighted with the information on osteoporosis. I haven't been lucky in health and I get a bit too careful :)
    I discovered my adrenal panel through Nutrahacker.
    NR3C1 is the cortisol receptor = 7 ++
    CRHR1 is the corticotropin releasing hormone receptor 1 ++ and 5 +-
    My problem is that I think that I am only going to the garden for a minute and 2-3 hours later I notice that I feel a bit tired and by then it is too late. Nothing I can do will save me from the slide. Cortef will kick in hours later. brad
     
  15. Ema

    Ema Senior Member

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    @stridor, try chewing the HC or taking it sublingually. It should kick in within about 15-20 minutes. But better to take a slightly higher dose overall than let yourself get in the hole constantly. That is really hard on your QOL.
     
  16. Ema

    Ema Senior Member

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    What are the SNPs (rsid) that they are looking at on those genes?
     
  17. Aerose91

    Aerose91 Senior Member

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    @stridor

    Check this article out,
    http://jackkruse.com/brain-gut-16-adrenal-fatigue-rx/

    Dr. Jack Kruse is an extremely intelligent guy with very evolutionary ideas. Dr Romeo Mariano is another doctor who shares this theory of PVN signaling as the cause of adrenal fatigue.

    I have been to hell and back with AF. It is what brought me to ME. I was so bad at one point no doctor would treat me without getting verified by an endocrinologist to not have Addisons. The ideas in this article are the best I've seen
     
  18. Ema

    Ema Senior Member

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    I took Cycloset after reading Dr Jack Kruse for a while (or trying to read due to his ramblings and unwillingness to answer a straight question with a straight answer). It provoked a terrible crash that I'm still trying to recover from almost 9 months later.

    Turns out Cycloset can drop norepinephrine levels up to 50%...which was extremely detrimental to my health.

    I agree that he has some interesting ideas but be careful!
     
  19. Aerose91

    Aerose91 Senior Member

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    I like his adrenal fatigue protocol because it's situational and he doesn't promote drugs and supplements. He uses particular diets and circadian rhythms which have helped me.

    I feel you with crashing from random supplements, it has happened to me more times than I can count so I'm as careful as can be these days!

    He is definitely an eccentric guy
     
  20. stridor

    stridor Senior Member

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    @Ema I do take it sublingual but find that once I crash it takes a substantial amount of time (hours) to regain the ground I lost. It seems that either I will have to stress dose before working or I get to write off my day. Anyone else have this?
    Cortisol receptor site.
    NR3C1 rs2918419 ++
    rs860458 ++
    rs852997 ++
    rs6188 ++
    rs6198 ++
    rs1866388 ++
    rs258750 ++

    Corticotropin Releasing Hormone receptor
    CRHR1 rs173365 ++
    rs7209426 +-
    rs110402 +-
    rs242924 +-
    CRHR2 rs2267710 +-
    rs2284217 +-

    @Aerose91 I am going to look at the site. I don't have adrenal fatigue. I have "Chronic Adrenal Insufficiency" that seems to be slipping towards a close to Addison's presentation. I do have a bit of production left. I could go for a walk right now without any problem. A bit of work in the gardens for 2-3 hours is a problem.
    My adrenals just keep getting worse. It may have been adrenal fatigue 7 years ago. My Dr said that I was 10 years too late moving against mercury and that my adrenals are not treatable.
    I did 35-40 ACE and vitamin IV's at considerable expense. They did nothing but at least I can take comfort in knowing that I tried.
    There are no options, I have to get better with stress-dosing. brad
     

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