Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study [...], 2025, Thomas, Armstrong, Bergquist et al

[MelbME]

I think you may have missed my point. I thought I was clear. I am saying that the researchers here did not gather crucial information about the participants in this study e.g. menopausal, having regular periods, taking hormonal contraceptives. They did not ensure that samples were taken at the same time in the menstrual cycle.


I don't think that is true. We know that oral contraceptives fundamentally change hormonal levels. They do that because they have to change an aspect of the way the female body works, to make it not fertile.

We know that hormonal levels vary greatly during the menstrual cycle.

So, if in one sample you have 50% of the females taking oral contraceptives, and 30% were sampled during their period, and, in the other sample, only 10% of the females were taking oral contraceptives and only 10% were sampled during their period, then the average ratio of various hormones for the cohorts will be substantially different.






I do understand this, and I am sure that securing more funds was a major motivation for publishing the study. And, that is a big part of my concern here.

The researchers have said 'Hey, here is a problem! Please give us money to study it further.' And yet, you have not established that there really is a problem, because the participants were not adequately characterised. You have drawn conclusions that may or may not be true. We cannot know if the finding is true at this point. This study's abstract makes the case for studying hormones in ME/CFS more compelling, and may result in other studies that perhaps are more likely to bear fruit being delayed.

I might try use an analogy to help. If one car in traffic breaks down then the cars behind it are also stopped in their progression. This outcome highlights a relationship in progression. This is relevant to OCP impact on controlling steroid production. Even in this instance you expect relationships to be maintained to a degree that it's statistically significant. What you are arguing is why us saying that we didn't see differences in cortisol or other steroid levels between ME and controls is weak. I agree, without accounting for the factors you highlight it's not going to be rigorous enough to say we can rule out cortisol belong low in ME because we found no such change.

Track record is a major reason everyone publishes every paper, it's the only way to survive in academia, it's why so few researchers exist in ME/CFS and such little research gets done (it's hard to build a track in this field). You are concerned we are trying to secure grants to do more research? Why? That doesn't make sense to me.

 

[Hutan]

More from AI, this time on the menstrual cycle:

"The ratio of female hormones, particularly estrogen and progesterone, changes significantly throughout the menstrual cycle. Estrogen levels are generally higher during the first half of the cycle (follicular phase), including a peak before ovulation, and then drop after ovulation. Progesterone levels are low during the first half of the cycle and then increase significantly during the second half (luteal phase), after ovulation. The ratio shifts dramatically, with estrogen dominating before ovulation and progesterone becoming dominant after ovulation."

Here's an analogy. It's like you put an assortment of fruit in one basket, with a random but unknown quantity of oranges, red apples, green apples and bananas, and another assortment in another basket, possibly with quite a different mix. Then you averaged the colour of the fruit in one basket and said 'this is normal fruit colour', and said of the other basket, 'the average fruit colour is different', so the fruit in the second basket must be abnormal.


Even for the men, there are things that will change the ratio of hormones
"Hormone levels in men, particularly testosterone, fluctuate throughout the day. Testosterone levels typically peak in the morning and gradually decline throughout the day, reaching their lowest point in the evening."

There are lots of papers on how one-off and regular physical activity changes levels of various hormones. We know that higher levels of physical activity increases levels of cortisol, for example. I think differences in physical activity probably account for a lot of the reported differences in hormone levels in ME/CFS.

 

[MelbME]

More from AI, this time on the menstrual cycle:

"The ratio of female hormones, particularly estrogen and progesterone, changes significantly throughout the menstrual cycle. Estrogen levels are generally higher during the first half of the cycle (follicular phase), including a peak before ovulation, and then drop after ovulation. Progesterone levels are low during the first half of the cycle and then increase significantly during the second half (luteal phase), after ovulation. The ratio shifts dramatically, with estrogen dominating before ovulation and progesterone becoming dominant after ovulation."

Here's an analogy. It's like you put an assortment of fruit in one basket, with a random but unknown quantity of oranges, red apples, green apples and bananas, and another assortment in another basket, possibly with quite a different mix. Then you averaged the colour of the fruit in one basket and said 'this is normal fruit colour', and said of the other basket, 'the average fruit colour is different', so the fruit in the second basket must be abnormal.


Even for the men, there are things that will change the ratio of hormones
"Hormone levels in men, particularly testosterone, fluctuate throughout the day. Testosterone levels typically peak in the morning and gradually decline throughout the day, reaching their lowest point in the evening."

There are lots of papers on how one-off and regular physical activity changes levels of various hormones. We know that higher levels of physical activity increases levels of cortisol, for example. I think differences in physical activity probably account for a lot of the reported differences in hormone levels in ME/CFS.

If one tree existed that made all fruit and the type of fruit created were separated by a few enzymes then that also works as an analogy for what I'm trying to describe.

 

[Hutan]

Track record is a major reason everyone publishes every paper, it's the only way to survive in academia, it's why so few researchers exist in ME/CFS and such little research gets done (it's hard to build a track in this field). You are concerned we are trying to secure grants to do more research? Why? That doesn't make sense to me.

There are a couple of responses to this.

One is that if a funder is actually doing their job properly and checking past papers by the research team, they will look at this one and say 'this team don't seem to be thinking carefully enough', and won't fund the research you are proposing. Low quality research can also affect reputations and possibly even put funders off the whole ME/CFS research field.

The other point is that one that I already made above. That is, if a funder is convinced by the definitive language used in this abstract that there is a real problem with hormone ratios in people with ME/CFS, and is convinced that the people who did the research are the ones to back, then they may fund this research, instead of other research, perhaps put forward by researchers who make more cautious statements about their hypotheses, that may actually be more likely to move the field forward.

Look Chris, I'm a big supporter of you and your work. I want your research to get funded and I want the studies you do to be good. But this paper just was not up to standard, and that, one way or another, hurts us all. If more research is done in this area, it needs to be hugely better, with lots of attention to the many factors that affect hormone levels.

 

[Hutan]

I don't know can someone else help? Which bit of the following do you disagree with?

Individuals have different levels of hormones at a particular point in time due to things like activity levels, oral contraceptive use, stage of the menstrual cycle and whether they are menopausal or not. They also have different ratios of hormones, again due to those things, (and also the time of day when the sample is taken).

Therefore, it stands to reason that two cohorts with different numbers of people affected by those factors will produce different average ratios of hormones. If you don't know how many people with those attributes you have in each cohort, you can't say anything certain about whether one cohort has abnormal ratios or not.

 

[MelbME]

There are a couple of responses to this.

One is that if a funder is actually doing their job properly and checking past papers by the research team, they will look at this one and say 'this team don't seem to be thinking carefully enough', and won't fund the research you are proposing. Low quality research can also affect reputations and possibly even putting funders off the whole ME/CFS research field.

The other point is that one that I already made above. That is, if a funder is convinced by the definitive language used in this abstract that there is a real problem with hormone ratios in people with ME/CFS, and is convinced that the people who did the research are the ones to back, then they may fund this research, instead of other research, perhaps put forward by researchers who make more cautious statements about their hypotheses, that may actually be more likely to move the field forward.

Look Chris, I'm a big supporter of you and your work. I want your research to get funded and I want the studies you do to be good. But this paper just was not up to standard, and that, one way or another, hurts us all. If more research is done in this area, it needs to be hugely better, with lots of attention to the many factors that affect hormone levels.

In my experience, track record isn't a big factor in securing philanthropic grants. You're not out competing other ME/CFS researchers with quantity of publications. I think it helps to have at least a paper on ME/CFS that shows your understanding of the disease and a proven source of sample (could be a biobank or known clinician support). But after that I think philanthropy grants are usually based on reviewers knowing the area well and being intrigued by your idea. Many philanthropic grants are given to people with no track record in ME/CFS.

I can't imagine this paper, where we say we didn't see differences in hormone levels, is going to be convincing to a philanthropic funder. As a grant writer I wouldn't base a grant around this paper. We do have current projects in this space that I would though.

Number of publications is really just important for government grants when we are competing with all other diseases. The panels have diverse knowledge but not expertise in ME. For us to compete for the billions in funding we rely on track record for reviewers to feel confident we know what we are doing in an area. And you would agree that any research funded from this global pool is found money. This is a main motivation to publish beyond dissemination of information.

Yes the paper is limited and we write that out in the paper itself. I understand you're unhappy about the abstract. The intention was to highlight that steroid dynamics appeared worthwhile following up in ME/CFS. I guess it can be difficult to write from one perspective and read from another. I can try improve on this.

 

[SNT Gatchaman]

I haven't read the paper but the analogy for what I think is being said might be to equate cyclical hormone changes with tides. The water level still goes up and down but the water surface is not uniformly horizontal in ME, but "tilted", so their boats (individual steroids) are now floating at different levels with respect to the tide level. Or alternatively, some boats are now underwater and some in mid air above the water, while HCs' boats are all floating on the surface as usual.

 

[MelbME]

I don't know can someone else help? Which bit of the following do you disagree with?

Individuals have different levels of hormones at a particular point in time due to things like activity levels, oral contraceptive use, stage of the menstrual cycle and whether they are menopausal or not. They also have different ratios of hormones, again due to those things, (and also the time of day when the sample is taken).

Therefore, it stands to reason that two cohorts with different numbers of people affected by those factors will produce different average ratios of hormones. If you don't know how many people with those attributes you have in each cohort, you can't say anything certain about whether one cohort has abnormal ratios or not.

Individuals have different levels of steroids at a particular point in time due to things like activity levels, oral contraceptive use, stage of the menstrual cycle and whether they are menopausal or not. Some steroids will change in ratio differently to other steroid during different times but majority of steroids will stay in similar ratio. The outcome as a whole is that steroids are expected to maintain a relationship with each other across a cohort.

 

[Utsikt]

The intention was to highlight that steroid dynamics appeared worthwhile following up in ME/CFS. I guess it can be difficult to write from one perspective and read from another.

That isn’t what was written, though. It’s not a matter of interpretation or perspectives, it’s a matter of clearly going beyond the evidence:

These findings illustrate the importance of hormone network dynamics in ME/CFS pathophysiology

The above statement from the abstract simply isn’t true.

I think it helps to have at least a paper on ME/CFS that shows your understanding of the disease

The introductions isn’t doing you any favours then, because it goes way beyond the evidence wrt what we know about ME/CFS. As you surely know better than me, things aren’t so just because a paper says it is - and the sources for the claims you make in the introduction don’t hold up under scrutiny.

For us to compete for the billions in funding we rely on track record for reviewers to feel confident we know what we are doing in an area.

How do you think a reviewer will feel about a paper that clearly goes beyond the evidence?

 

[Hutan]

If one tree existed that made all fruit and the type of fruit created were separated by a few enzymes then that also works as an analogy for what I'm trying to describe.

In my analogy, the colours are the different ratios that are associated with a particular category.

I'll make it more concrete.

Say that healthy women in their reproductive years on a particular type of oral contraceptive have a ratio of a couple of hormones of 1.0. (Actually different contraceptives will have different effects, and I think even the number of years that a woman is on the contraceptive can change hormone levels too).
And healthy women in their reproductive years not on oral contraceptives and at a certain point in the menstrual cycle (A) have a ratio of 0.6.
And healthy women in their reproductive years not on oral contraceptives and at another point in the menstrual cycle (B) have a ratio of 0.4.
And post-menopausal women have a ratio of 0.9

Then, if you have 15 women, and 10 are on the oral contraceptive, 3 happen to be at point A in their menstrual cycle and two are post-menopausal, then the average ratio is 0.9.

But if you have 15 women and 3 are on the oral contraceptive and 2 are at point A and all the rest are at point B in their menstrual cycle, then the average ratio is 0.55.

(I may have the maths wrong, I haven't checked, the point is the principle.)

The problem comes when you have 15 women with a disease, and 15 healthy women and no idea whatsoever whether the women were on any oral contraceptive, let alone a specific one. And you have no idea if they were getting periods and, if so, at what point in the cycle they were. So, if you get a ratio of 0.55 for the women with the disease and 0.9 for the healthy women, does this mean that women with the disease have dysregulated hormones?

If you don't have data about attributes that fundamentally affect hormone levels and will confound your analysis, then, unless you have found a wildly abnormal ratio, you cannot claim the cohort has dysregulated hormones.

If average levels of the hormones themselves were not found to be different between the two cohorts (as was the case in this paper), then it's very unlikely that ratios between the hormones will be wildly abnormal to the point that confounding factors can't explain the difference.