Critical of past research: cortisol studies

I have been reading a bit into the three cortisol studies that have been done in the 90’s.

I would like to discuss the ideas that come out of a critical evaluation of these studies.
A lot of it is stating the obvious in my mind, but I still think it’s worth discussing. How could we repeat these studies and how would we do them differentely with the knowledge we have now? What lessons can we learn from these studies?

Why I personally read into these studies, is because I have found a lot of benefit from taking low dose cortisol. I take a physiological dose of 25mg spread over 4 or 5 time a day to avoid peaks. This seems to be the newest way that low cortisol in panhypopituatory disease is managed. Taking this treatment has helped a few very annoying symptoms (nausea, weakness) and gave me a much more steady energy during the day. So this is in no way a cure, but it did help me start work again for 10 hours a week.

Use of cortisol is specifically discouraged in the dutch guidelines. A lot of doctors I meet have been very negative towards my use of cortisol, they all cite different dosages as low dose cortisol and frequentely state the negative effects it can have and the suppresion on the adrenal glands it can cause. (We know from panhypopituatory studies that physicological doses do not have the risks that higher doses (given in inflammatory disease) do have).

Do I think low cortisol treatment could treat Me/cfs? No, I do not. If low cortisol was me/cfs we would have known by now. My personal hypothesis though is that me/cfs is probably 2 or more diseases, it’s also mutisystemic in nature, so I hypothesise that (as long as we don’t find a cure where the primary problem is adressed) different treatments are necessary to alleviate symptoms in one person and we will be needing a combination of different treatments in different people as well.

First thing that is interesting, is that at least two of the three studies have been done by fierce proponents of CBT type treatment.
In reading the studies, I imediately spotted a few problems that we have found in the CBT/GET studies as well:

• Use of fukuda criteria, not very strict criteria, no way of knowing who had PEM as a symptom.
• Subjective outcomes only, all different kind of depression, mood and anxiety scales are measured (nothing I would find relevant in the disease I experience)
• Where are patients recruited? At GP’s? In third line psychiatric clinics? (Two studies are done by welknown psychiatrist..) I couldn’t find the details, but I think these biases are particularly important in this disease.

Other than that: I found the length of one study very short. They gave the treatment for one month, in a group where people were ill for more than 4-5 years and for a disease where symptoms are pretty erratic (people experiencing good days and bad days).

Average illness duration is 4 years in one study, it’s not clear how many people were ill for a long time or how many people were ill for just 6 months. It is not clear how that differed in the active arm and the placebo arm?

The dosage that was used was different in every study. One study used 5 mg (no effects were noted), one study used 5-10mg (study had a postive outcome), the third used 25-35mg (study had a positive outcome). In the last study they found some evidence of suppresion of the adrenal glands, which comes as no suprise as the dose is really high and they gave a morning dose of 20-30mg, which is (with the knowlegde we have today) extremely high.

Thoughts I had:

• This very simple and cheap treatment is discouraged in the guidelines. Why are these recommendations in the guidelines? The conclusion to discourage this possibillity of treatment is not supported by these studies at all.
• It’s interesting to see that these medical studies suffer fom exactly the same problems as the cbt/get studies.
• Yes, we would need more studies to support the (broad) use of this treatment. I’m thinking of ways how you would do such a study now: Objective outcomes (stepcount, hours spend upright, hours worked. as well as daily measuring of important physical symptoms (headache, nausea etc)
• I would think that actually measuring if these patients had low cortisol, when you want to correct it with medication is important. One of the selection criteria should include, people having some kind of test of low cortisol (there is a lot of discussion about the right way to test low cortisol). They did measure this in one of the studies, but there was no comparison made between people responding to the treatment, who had low cortisol in the first place vs. people who did not have low cortisol.

I get why some people would not find these kind of studies very interesting, it will not give us a cure and it seems a bit simplistic. I feel that these cheap and easy ways of treating symptoms could give us some options, while at the same time getting the disease out of the cbt/get hands and into the hands of internal medicine specialists. Positive results could therefore also spark interest in specialist, researchers and pharmaceutical companies.
I feel that a lot of studies into me/cfs are very fundamental, theoretical and not likely to produce some kind of benefit for patients in the short term.

I would very much like to see this kind of simple research repeated in ways that will actually give us interesting results. Research that will give us some short term benefits and treatments.

What do you think about this kind of research? Interesting? Not interesting? Do you see any flaws in this kind of thinking, any suggestions?

What kind of other simple treatments are discouraged in this way in guidelines? Do you see any other kind of simple treatment where it could be benificial to repeat research on with knowledge we have today?

I am writing this down, partly because reading about these kinds of studies frustrates me enormously. Partly because I am thinking of ways in which I could be participating in me/cfs research.

 

Forgot to attach a link: The three clinical trials are mentioned on the me-pedia cortisol page.
https://me-pedia.org/wiki/Cortisol

 

Is it always low cortisol that is associated with ME/CFS? Or is high cortisol a known feature in some cases too?

 

Cort Johnson wrote about Cortisol studies and their history in ME/CFS this week. It lists several studies for those interested in learning more.
Low Dose Hydrocortisone: Flare Buster for Fibromyalgia and Chronic Fatigue Syndrome?

 

A personal story: Our family member has always had low morning cortisol since contracting ME. And the ME doctors in the USA and two we saw in Europe prescribed hydrocortisone. She has been on a variety of doses, from 5mg to 20mg over the course of this long illness. It was given to her because when she first became ill with this nightmare she was unable to get up; she was just flat out on the bed. So, initially in the illness the hydrocortisone helped her to get up a bit, but not to be functional in any normal way, and to still be severe--but she was able to walk into another room. However, what has now happened is osteopenia has made its appearance. But that was on the last test, who knows, what a current result would show! Thus, she has now weaned down to 2.5mg, yes, that is a small dose, but she is unable to got off the substance, try as she does. There doesn't seem to be a difference in the set point at present regarding the severity of the illness.

 

Thanks! This is from yesterday, I hadn’t read it yet. More people thinking along the same line, that’s really cool!

 

There is nothing simple about treatment with hydrocortisone, as @Perrier suggests.

The basic bind is that if you give a small dose the adrenals and hypothalamus just adjust to offset it. If you give more you produce osteoporosis, diabetes, mood disturbance, acne, fragile skin and muscle wasting. Managing corticosteroid therapy was always one of the most difficult tasks for me as a specialist in diseases traditionally treated with corticosteroids.

 

Which doses are you talking about? I just want to ask, because I see low dose cortisol being described as somewhere between 5-35mg, where 5mg is probably too low to work and 35mg is suppressing your own adrenals and probably already works as an anti-inflammatory treatment.

In one of the trials, we see no response. They used only 5mg, which is probably too low to do anything. I agree that in these doses, your body is probably responding for a short while until your body adjust to this dose and makes less cortisol by itself.

In one of the positive studies, they used 5-10 mg. We know (from different studies) that people with me/cfs have a blunted morning peak. It could be that the 10mg is treating the lack of a morning peak, which helps with the symtoms.

The third study was positive. It used doses of 25-35mg and used morning doses of 20-30mg. It could be that this works as a high enough physiological dose ór these doses will go towards anti-inflammatory treatment.
I think both theories will be valuable. I would like to know if (a subgroup with) me/cfs responds to a anti-inflammatory treatment. It would also be interesting to know if people with me/cfs would benefit from a physiological dosis which is around 25mg.

I agree that we need to be careful. We can learn a lot from studies done in addison patients or panhypopituatory patient, as we know they substitute cortisol life long. We do have to make sure to separate the negative effect for anti-inflammatory treatments (high) and physiological doses (low).

I have read a very interesting article (it was in dutch, adressed to the adrenal patient groups) from a specialist, where they have now personalised the treatment with cortisol. They measured bloodlevels and output continuously for 24 hours. They found that the right physiological dose was very specific for different people. A lot of woman found optimal doses at 15mg a day and some men needed 35mg. One woman who had a bariatric surgery needed even more because the uptake was very impaired. She was experiencing hypo symptoms at a very high dose. Some woman in the study had hyper symptoms at 35mg, while that could be the optimal dose for a man. Two times a day intake was not optimal for anyone, three times a day minimum and for some people even four times a day.

 

Daughter had an overenthusiastic endo who tried 5mg hydrocortisone based on slight blunting.

Unmitigated disaster .

 

I was put on a lowish dose of prednisone for a few months a couple of years back. I started on 10mg, stayed on it for a few weeks, and then slowly tapered down first dropping 1mg every few days then towards the end, 0.5mg every few days (if I recall correctly, the equivalent of a 10mg dose of hydrocortisone is a 2.5mg dosage of prednisone, so you need to take into account its around 4x stronger). The whole thing was spread out over several months. I was given additional medications to offset the osteoporosis risk (some form of vitamin D if I remember rightly, and calcium too - sorry, I can't remember more)

I won't talk about the benefits too much, as they might be unique to me (because I have a confirmed autoinflammatory diagnosis). But even in my case, the modest relief I initially got petered out after the first 5-6 weeks, and then I was still stuck with finishing the long taper. I got really fat, and my face blew up like a balloon. All this fat collected on the back of my neck, it was gross. Then about a year later, I ended up having to have cataract surgery. Apparently, cataracts are a known but unusual side effect corticosteriod use, I got unlucky apparently.

I was really sick at the time I started the prednisone, and would have gladly accepted all those shitty side effects in exchange for genuine relief and some real functionality. But the relief was too short-lived to make it all worth it.

I've since got a new specialist (an immunologist), and he still prescribes prednisone for my condition, but to use as rarely as possible when I have a severe flare, and only in high, short doses of two days max at a time. Like @Jonathan Edwards says, to avoid the way the body compensates for it.

 

Just an n=1 anecdote but I had my cortisol tested to eliminate Addisons during diagnosis and my cortisol profile morning midday and late afternoon was normal ...no low cortisol in the morning in particular. In fact my 9am level was on the high end of the range.

I still feel awful in the morning however (nausea, aching joints, brain fog that lasts for 1-2 hrs upon waking). I don’t think this is cortisol related.

I have also subsequently read a few studies on cortisol levels with PWME and found them unconvincing.

 

I think anything above 15mg is toxic long term.

Cataract is quite common.

There are quite a few 'specialists' like that about in Belgium and Holland in particular. I doubt there is any basis to the claim that doses can be titrated. There is a substantial folklore in endocrine support groups about this sort of thing.

 

Are there any studies on how peripheral nerve receptors respond to hydrocortisone?

 

I have tried to find the article again, but I can not find it. It was definitly not some fringe doctor, but an established professor at one of the universities here.

I realize that treatment is not without risks, it never is. The alternative is spending my life in a bed, risk free.

I think the risks can be lower when people are taken seriously and treatment is wel thought out and measured. Apparently there has been talk about low cortisol in ME/CFS since the 90, so much so that even 2 psychiatrists did a clinical trial with it.
I think it would be well worth finding out: who would benefit, who wouldn't and what the proper treatment then would be.

 

Established professors are quite often fringe doctors, unfortunately.
I think we know that corticosteroid does not produce dramatic benefit and since the adverse effects are so pervasive and long term I can see no justification for further studies.

 

So, that pretty much makes everyone a fringe-doctor?

I really would like to know what kind of evidence you have for it not producing drastic benefit? Two out of three clinical trials that were done, were positive? In a disease where we literally have no treatment, no biomarker, no nothing, I think that would give at least a justification for further studies.

I also think the criteria for drastic benefit are really high in this disease. People seem to be only interested in a cure. Which is strange, because people are so debilitated by this disease, that I think every procent of benefit is gain.

I do agree that the adverse effects of higher doses of prednisone are pervasive and long term, that doesn't hold doctors back with literally any other disease.

 

I completely understand where you're coming from, @unicorn7. I certainly also feel that people underestimate the degree of disability and suffering PwMEs experience, and they don't take that into account when weighing up pro's and con's of medications.

But I've been there, and corticosteroiods give with one hand, and take away with the other. You can end up worse than when you started. And yes, a person who takes a low enough dose might avoid some of the worst of the side effects, but they'll miss out on any benefits as well, because their body will soon adjust by making less cortisol itself. Then when they try to stop, they can be worse off than before they started.

I think we imagine that people with "legitimate" diseases get access to all these drugs because people take them seriously (e.g. RA, MS). But I'm noticing more and more that even in these diseases, the focus is often on stopping measurable decline, and the person is left pretty much to their own devices to deal with debilitating fatigue and malaise (or worse, given psychological treatment). Pretty much like us.

 

PS I think any benefit that PwMEs might get from corticosteroids probably has nothing to do with "correcting" morning cortisol, but stems from the direct antinflammatory properties of the drugs. Which is the main thing for which its prescribed in other illnesses.