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In Brief: The Adrenal Glands and ME

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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 ...


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.


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.


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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@stridor

I was so bad I could only get out of bed to crawl to the bathroom. I would shower once a month. I was so dizzy I couldn't look down because the floor would fall out from under my feet and I would start throwing up. I've personally never met someone who had AF as bad as me that wasn't clinical Addisons. I personally hate the name adrenal fatigue because it sounds so minor.
I needed 20 mg hydrocortisone to get out of the hole but I made it. I feel that if I didn't get M.E. I would be healed by now.
 
@stridor, Stress dosing is hard. It has taken me years to get anywhere near reasonable at it. Steroid fear, for the most part; it's hard to get over.

I would suggest that if it is still taking you hours to get over a low cortisol episode that a) your daily dose is still insufficient or b) your stress dose is insufficient either in quantity or type of steroid.

I personally find that stress dosing with Medrol often works better than HC for other than out and out emergency situations (like a broken bone or car wreck) because it gives you a longer lasting baseline from which to re-build your reserves. You might ask your doctor to give you a trial to see if that helps.

It usually takes me at least 10-20 mg of HC (or 4 mg of Medrol) to get out of a low cortisol hole within 20-30 minutes. If I dribble in 5 mg over the course of the day, I never really get out of the hole. A bigger dose is required for me and then I'm pretty normal in a short amount of time. This took me a LONG time to learn.

The important thing to remember is that you will never hurt yourself short term by taking more steroid than you need. So you can feel free to experiment and find the dose that is right for you that gets you out of the hole without having to write off the rest of the day.

I also know many people that find themselves to be more stable on a combo of dex/Medrol and HC on a daily basis for exactly that reason as well. It's another thing to consider if you metabolize steroid quickly like I do as well.
 
@Aerose91 When I read your post I got that sinking feeling in my stomach. Took me back to 2011 when I couldn't get any help as Dr's kept saying that I was depressed. Finally, I bought hydrocortisone ointment and put that into capsules to swallow. That is how I finally got some HC on board. Man those were dark days....I hear you loud and clear.

@Ema Yep, I have steroid fear. Looking at what you do, I am being way too conservative with the stress dosing. This is precisely the type of information that I was looking for. My Dr is an HC guy but I can work with that at least for now. I have been under-treating these crashes. I take take HC 5 times a day to help stabilize levels (weighted towards the morning). Thanks a million for giving me the confidence to experiment more. brad
 
Pred and methyl Pred maybe better suited as they are more slowly broken down. Ema mentioned a possible combo, maybe 1mg methylpPred and 5mg of hc for a more quicker increase in cortisol on first awakening? The methyl Pred will taper off slower. Maybe just a once a morning appropriate dose of methyl pred and hc for stress dosing when required.

Some are fast and some are slow metabolizes of steroids? ?
 
I will mention to my Dr about the trouble I have been having. but honestly, I really can't wait to try some of the other ideas around stress-dosing. I was only using 5-6 mg. I have to read Safe Uses of Cortisol again now that I am not buried in illness.
My Dr has an open mind and if I need to change, he will think about it. but generally he is a HC guy.Maybe he would push me to 30 mg from 25.....brad
 
I will mention to my Dr about the trouble I have been having. but honestly, I really can't wait to try some of the other ideas around stress-dosing. I was only using 5-6 mg. I have to read Safe Uses of Cortisol again now that I am not buried in illness.
My Dr has an open mind and if I need to change, he will think about it. but generally he is a HC guy.Maybe he would push me to 30 mg from 25.....brad

Ask him about an equal strength dose of methyl pred and see if it makes a difference. Help tell if your a fast metabolizer of hc, so might not really need an increase in dose but just something that has a longer half life, then take it from there.

you might have mentioned this, but have u had other hormones checked like dhea and testosterone, these could also need to play a part.
 
I take testosterone as my levels were low. The Dr wanted me to try DHEA and Pregnenolone (sp?) at the same time. I did not respond well to them. I am high estrogen and really didn't care much about having success with DHEA anyway from that perspective. But it is supposed to help with age spots and I have lots but my real interest was whether it was generally good for skin as I have many skin ailments.
The pregnenolone gave me a good initial response but then went on to increase fatigue and brain-fog. I took this to mean that it was trying to push energy production somehow. I do not respond well to the traditional approaches to CFS like ribose or creatine. brad
 
I take testosterone as my levels were low. The Dr wanted me to try DHEA and Pregnenolone (sp?) at the same time. I did not respond well to them. I am high estrogen and really didn't care much about having success with DHEA anyway from that perspective. But it is supposed to help with age spots and I have lots but my real interest was whether it was generally good for skin as I have many skin ailments.
The pregnenolone gave me a good initial response but then went on to increase fatigue and brain-fog. I took this to mean that it was trying to push energy production somehow. I do not respond well to the traditional approaches to CFS like ribose or creatine. brad

with pregnenolone i think its tablet versions if dosed too high can cause a spacey type of feel as they can affect benzo receptor sites. Supposedly transdermal preg creams work better and best to start with low doses like 5-10mg and slowly increase from there. Dhea pills i think is best to start low also say 10mg pills and slowly increase to say 25mg, if more is needed then add some at night, i use 25mg twice a day and that has me in the upper third of the normal range. For me pregnenolone helped increase cortisol, didnt do alot for other hormones but i think its an individual thing.

U might also try looking into ways to help increase dopamine as this is normally low in us and can help with energy and pain etc??
 
Pred and methyl Pred maybe better suited as they are more slowly broken down. Ema mentioned a possible combo, maybe 1mg methylpPred and 5mg of hc for a more quicker increase in cortisol on first awakening? The methyl Pred will taper off slower. Maybe just a once a morning appropriate dose of methyl pred and hc for stress dosing when required.

Some are fast and some are slow metabolizes of steroids? ?

This is so true. I metabolized h/c too quickly, a dose of even 10 mg in the morning would run out well before midday and so would the next dose so my doctor said I would probably do better with Prednisolone and he was so right. That was in 2002 and I have been on it ever since. I take 2.5mg on waking around 5 am, go back to sleep and then when I wake around 6.30 am I take another 2.5 mg.Pred That will last me till about 3 pm and then I need another 1mg Pred and 2.5 mg h/c. However if I have done more physical stuff or have a virus then I will probably need another 2.5 mg h/c in the evening. It still takes me till about 9 am at the earliest to get any real energy through but this seems to be typical of the Addison sufferers too.

BTW I had a Dexa scan on my bone about 3 years ago and I had the bones of a young woman which is great seeing that I was 62 at the time! They said it was very unusual to see this but I have always taken lots of supplements and have carried on with some estrogen plus I take dessicated thyroid too so taking steroids if you need them doesn't mean you have to get osteoporosis. I think there is a lot more to it.

If you are too low on your dose of steroid then you will feel horrendous, I can always tell when I am running low. I agree it is really difficult to get the balance right as to what your body needs and not to overdose.

Pam
 
@bertiedog @heapsreal
I am feeling a bit foolish right now. I have been so focused on Mercury-detox and Freddd's protocol that I have made no effort to really understand what I can do for my adrenals. I just took my 25 mg/day with an occasional extra 5 mg when I was in trouble.
At this point I am unsure whether my adrenals have gotten worse or if now that I am recovering from ME, my activity level is revealing limitations that were there all along.
Yesterday I took an extra 10 mg HC before going outside to pull dandelions. I took another 7.5mg during and after the activity. I did need to rest for a while but the day was not a write-off. That's over 40 mg of HC.
I will ask the Dr what he thinks about other products with longer half-lives.
I read somewhere that oral DHEA is more likely to increase estrogen production and that transdermal is superior. I don't feel particularly led to take it either way. My DHEA levels were in the normal range. The Dr was trying to sort out why my testosterone was low and DHEA was an experiment. I am willing to look at the pregnenolone again.

I just did trial of tyrosine again and had an initial (+) response. I took it with tryptophan this time (as opposed to 5-HTP).
I was getting headaches and my hard to control blood pressure got worse so I took a break. Too bad, as my thinking improved otherwise.
BP is running in the 130-160 / 80-90 range right now with 3 meds on board. Looks like I will need one more increase. Was running 180/100 two months ago so definitely the meds help. If I push the adrenals it drops to 90/60 and I have a hard time standing as all the strength leaves me. I will dust off "Safe Uses of Cortisol". I have to get better at this. Thanks, brad
 
@stridor if your dhea levels are within normal range then i probably dont see a need for it and probably would increase your estrogen level, if your dhea was low though it probably wouldnt effect estrogen too negatively??

It can take alot of experimenting to find what helps you personally, we all seem to be slightly different.

good luck,
keep us posted,
cheers!!!
 
@bertiedog @heapsreal
I am feeling a bit foolish right now. I have been so focused on Mercury-detox and Freddd's protocol that I have made no effort to really understand what I can do for my adrenals. I just took my 25 mg/day with an occasional extra 5 mg when I was in trouble.
At this point I am unsure whether my adrenals have gotten worse or if now that I am recovering from ME, my activity level is revealing limitations that were there all along.
Yesterday I took an extra 10 mg HC before going outside to pull dandelions. I took another 7.5mg during and after the activity. I did need to rest for a while but the day was not a write-off. That's over 40 mg of HC.
I will ask the Dr what he thinks about other products with longer half-lives.
I read somewhere that oral DHEA is more likely to increase estrogen production and that transdermal is superior. I don't feel particularly led to take it either way. My DHEA levels were in the normal range. The Dr was trying to sort out why my testosterone was low and DHEA was an experiment. I am willing to look at the pregnenolone again.

I just did trial of tyrosine again and had an initial (+) response. I took it with tryptophan this time (as opposed to 5-HTP).
I was getting headaches and my hard to control blood pressure got worse so I took a break. Too bad, as my thinking improved otherwise.
BP is running in the 130-160 / 80-90 range right now with 3 meds on board. Looks like I will need one more increase. Was running 180/100 two months ago so definitely the meds help. If I push the adrenals it drops to 90/60 and I have a hard time standing as all the strength leaves me. I will dust off "Safe Uses of Cortisol". I have to get better at this. Thanks, brad
@stridor I don't take any extra DHEA as I don't seem to need it. When I did the last saliva test it was right in the middle of the range. I have heard that DHEA can deplete the benefits of cortisol as it sort of opposes it so if you aren't too low in it anyway then I wouldn't bother.

One other thing that I have found out so many times that makes me worse is taking herbal medicines although I like the idea of them. What seems to happen with me is that the herbs block the steroid so I don't do at all well. I think it is to do with the detoxification pathways being the same in the liver for both steroids and most herbs. Something else to onsider!

If your testosterone was low I would have thought you would do far better to just take a small amount of that rather than take pregnenolone because with that you don't know what it is going to convert into. Unless your liver is perfect you might well not get what you are hoping for. If you have adrenal and pituitary issues its better to get established on a basic regime that works before you start adding in other stuff then if you find you are worse you can always go back to the basic regime only.

Good luck with it all I know how difficult it can be to find out exactly what you need and how much of it!

Pam
 
@heapsreal @bertiedog
HOLD THE PHONE! After typing this mornings entry I went to set up the days meds and it seems that I miscounted. I stress dosed 12.5 mg yesterday = 5 mg extra before the activity + 5 mg when I first started to note symptoms = 1.5 hours later and 2.5 mg when I finished. I had a mild crash and stopped activity around noon. My spark returned around 3 pm.
This morning I added 10 mg and have taken breaks every hour. I am working harder and am definitely on the right track. I am a bit tired but not in trouble yet. My BP is 112/72 down from 160/88 this morning after meds. I will take another 5 mg and then hit the gardening again. So by 1 p.m my intake will be 30 mg for a total of 40 mg today. Very seldom can I go back out after lunch. This is great.
Thanks guys, I'm just going to keep mucking about with this. brad
 
A comment on the article, adding another hypothesis to Andrew Gladman's about cytokines as the potential source of trouble for the HPA axis--here is another hypothesis: Damage to the hypothalamus itself could result in underperformance.Dr. Richard Bruno who wrote about Post-Polio Syndrome said that in the course of an enterovirus infection, these viruses are carried up to the base of the brain. In some cases these spilled over into the spinal cord causing polio, but they also caused damage to both the hypothalamus and the dopamine-producing center there, which is called the Reticular Activating System. He wrote that upon autopsy this damage was always seen. He wrote that this part of the brain could have been damaged as a result of enteroviruses regardless of whether the patient became paralysed. Most who came down with polio did not become paralysed. Couldn't other viruses cause this same damage?

I relate this to the experience of both an underperforming HPA and to the slow brain phenonmena we have. This has recently been shown by research that there is inappropriate degree and location of Delta wave activity. Baruniak is, I believe, the name of the researcher, but maybe someone else can help me out with this. The study was reported in one of the San Francisco conferences last year.
 
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@stridor I had just written another post about not worrying about osteoporosis if you have to take physiological doses of steroids but hadn't realised I had already written a post saying this!

I will add though that I do take good quantities of magnesium daily and eat a calcium rich diet plus I have stayed on low dose estrogen since menopause and also take dessicated thyroid which gives me some T3. I believe if you have got everything on board then you shouldn't have to worry about osteoporosis and steroids. I am also able to exercise by walking for at least 20 minutes daily on the majority of days so I am sure this helps too.

Of course without taking steroids I wouldn't be able to walk at all and would spend my life in misery on the sofa and I couldn't tolerate the thyroid meds I need either.

I am also able to take quite a lot of herbal medications daily because I found out in July that I have late stage Lyme and this doesn't seem to have affected how I metabolise the steroids thankfully.

Hope you are able to sort out the stress dosing situation by now. I do think that for some of us we do much better with a longer lasting steroid.

Pam
 
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@bertiedog I have the same situation as you expressed minus, I hope, the Lyme disease.

@stridor I have found there is a big difference between generic hydrocortisone and brand name Cortef in efficacy. The generic seems to be a time release and somewhat lower dose, which doesn't help at all. You need cortisol when you need it, not hours later in a weak slow "drip". Imagine giving insulin at the wrong times and doses to a diabetic! Cortef made by Pfizer works in me within about 15 minutes, and wears off in 4-6 hours. (One caveat is that the chain drug store nearby had what appeared to be Cortef but acted like the generic. The pill itself looked slightly different too. So I only order Cortef from a more reputable pharmacy and this works exactly the way it is supposed to.)
 
@Sing My pills have "Cortef 10" stamped on them. The bottle has pfc in small letters beneath this. I don't know if this refers to a company or not. I have filled this script at 3 pharmacies and the pills always look the same. there could be one main supplier to Northern Ontario perhaps.

@bertiedog I read another post on here about someone who found bupropion helpful. Saw a video as well where this Dr was talking about symptoms related to low adrenaline. Never heard of that before but I was drawn to it. This got me thinking, "what if there is more wrong with the adrenals than just low cortisol output?".

Unlike most people with my degree of adrenal insufficiency, I have high BP treated with 3 types of meds. What if this was related to low aldosterone?
Anyway....I had some bupropion stashed in the back of a drawer (maybe not the freshest stuff in the world) and it has made a difference. Not a huge difference but perceivable.

Brain-fog decreased - initially by 50% but some crept back, still a welcomed net gain. I still tire and need to stress dose physical and emotional stress but I have not "crashed" to the point where I am basically incapacitated. My stamina has not improved and I am only allowed to be active for 2, 3 and sometimes 4 hours a day.

My Dr has OK'd 30 mg/day on my days at home. He also tells me to relax about the osteoporosis thing. I stood on one of those fancy and expensive "metabolic scales" that measure muscle, fat and bone through electrical resistance, I assume. It warned that I was low on bone density. Not very scientific - I will decide about a bone scan.

I diverted from my line of thought. What if I have low cortisol, low aldosterone and low adrenaline? Can the whole adrenal gland be pooched or would this point more to a hypothalamus problem? That's where I'm at right now.

Thanks for the help you guys. (I don't get notifications into my yahoo mailbox. I only pick up alerts when I come here. Glad I was "in the neighbourhood").
 
@stridor one symptom of low aldosterone is pissing like a race horse and drinking like a fish.

Hypertension could possibly be a way that your body is trying to compensate for low blood volume and or poor cerebral circulation and its possible to have hypertension with orthostatic intolerance. I think many seem to think one has to have low blood pressure to have pots/oi but i dont think this is the case.
 
@stridor Bupropion helps with norepinephrine or dopamine a little bit, doesn't it? Not just a straight SRI. I could use this too but just early in the day as it would interfere with sleep--always tending to touch and go for me. Yes, I agree that it is the whole adrenal gland which is underfunctioning. I don't have normal fight or flight at all, but instead feel either exhausted right away--on empty--or else have a buzz which is powerless then followed by extra tiredness. What works for me is to try to stay calm as much as possible and no matter what in order to conserve enough energy to function during the day mentally and physically.
 
@Sing Adrenal problems changes a personality - that's for sure. I am calmer, have a longer, slower burning fuse - I take time to gather all the facts and have a much higher threshold for what I think of as important. And yes, bupropion increases dopamine and norepinephrine. Pleasure, interest and drive.
We share some of the same responses to stress, I would say.

@heapsreal I had diabetes insipidus = 20+ urinations a day and 4-5 a night when I started mB12 and mfolate. It stopped in 3 days. It was like someone turned off the faucet. I used to go at least every 15 min after supper. I always had a water bottle back.
I would say that my aldosterone may be fine. I had pronounced OI back before the BP went back up. I have CCSVI which means there is blood flowing the wrong way in the veins of my neck. So yes, I have compromised blood flow to the brain.

I also have 7 ++ SNPs for glucocorticoid receptors and 1++ and 5 +- for corticotropin releasing hormone receptor but as these are reasonably common I basically ignore them.