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Did I find the cause of my ME/CFS + POTS? Combined 3ß-HSD and 21-hydroxylase-deficiency

Messages
16
Recently, I wrote about the role of EZH2 in ME/CFS and POTS.

A study by Monash University states that there is an upregulation of EZH2 in POTS syndrome.https://forums.phoenixrising.me/threads/role-of-ezh2-in-me-cfs-and-pots.80229/#post- 2276535

Now to what is new: The study says that not only EZH2, but MECP2 and let-7i are upregulated as well.
As a consequence, I looked for causes for such upregulations.

One thing I found is that SSRI lead to upregulation of MECP2 and let-7i. So, these would be contraindicated in this subgroup.

Furthermore, I found out that NMDA-antagonists (Ketamine, Kynurenine-Acid, Magnesium, etc.) can downregulate MECP2. This is interesting, as some of these agents are being discusses concerning Glutamate in ME/CFS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377834/

Afterwards I looked for NMDA-agonists (I made the reverse conclusion that if NMDA- Antagonists can bring MECP2 down, NMDA-Agonists will probably lead to a rise in MECP2 expression.

I bumped on DHEA. Many years ago, I did those saliva tests (cortisol, DHEA, etc..) and DHEA was way above the upper limit:
9 am: 2200 pg/ml (normal range: 246-730 pg/ml)
9 pm: 1900 pg/ml (normal range: 120-365 pg/ml)

Doctors told me this would be nothing to concern about and that high DHEA levels are something positive.
Nevertheless, I did an ACTH-Test four years ago. The doctor said everything is perfectly normal and that I should rather see a psychologist. But now I looked at the laboratory result again and had an unpleasant surprise. The doctor wrote his final result, while the values for DHEA were still “pending”. So, I never got these results. Now, I phone called them and demanded the full result of the ACTH- test.

While basal DHEA at 0 minutes came back normal (6,2 ug/l), DHEA at 30 and 60 minutes was elevated (26 ug/l at 60 min.). It is said that if DHEA rises by more than 18,2 ug/l during an ACTH-Test, there is a so called 3ß-HSD-defect. This is a rare form of adrenal hyperplasia.
http://leistungsverzeichnis.labor-gaertner.de/entry/851
(Unfortunately, this source is in German, but maybe you can use google translator).

By now, there are officially only about 60 cases worldwide and all of them are extremely ill. In those cases, not enough testosterone etc. are made and boys are under-virilized and girls are over-virilized, so that this defect normally gets detected at a very young age. This is not the case with me and all other hormones (testosterone) are perfectly normal, except for the slight decrease in cortisol as it is often seen in ME/ CFS. So, probably there is a large number of unreported cases, where all (or almost all) problems are caused only by the excessive amount of DHEA (after stress).
https://en.wikipedia.org/wiki/3β-Hydroxysteroid_dehydrogenase

What are the consequences of very high DHEA?

1. Energy production: The transformation of glucose into ribose does not work anymore (DHEA suppresses Ribose-5-phosphate and glutathione) https://pubmed.ncbi.nlm.nih.gov/23282133/

2. Dose-dependent effect on ATP-production (small doses decrease ATP, high doses increase ATP). It is an interesting finding that ATP-levels in ME/CFS are actually increased.https://jme.bioscientifica.com/view...www.ncbi.nlm.nih.gov/pmc/articles/PMC5065105/

3. Increase in PDK4, which leads to a decrease in pyruvate dehydrogenase
https://rep.bioscientifica.com/downloadpdf/journals/rep/152/6/705.pdf

4. TH2/ Th1 switch as seen in ME/CFS (mast cells etc.)
https://pubmed.ncbi.nlm.nih.gov/11743142/

5. DHEA leads to a rise in NE and a stimulation of eNOS as seen in certain subgroups of POTS
https://pubmed.ncbi.nlm.nih.gov/12865324/ https://www.researchgate.net/figure/Effect-of-neuroactive-steroids-on-norepinephrine- production-PC12-cells-were-exposed-to_fig3_7876818/actions#reference https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191087/

6. activates 5a- Reductase
https://www.meridianvalleylab.com/clinical-significance-of-5a-reductase-activity/

7.Reduction in body weight

8. Extremely high DHEA levels lead to a lengthening of the circadian period
https://www.sciencedaily.com/releases/2018/04/180418100350.htm

9. DHEA rises with stress and physical exertion. So, all the processes stated above will be more significant after stress. The same applies to sleep deprivation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592957/ https://www.zrtlab.com/landing-pages/new-advancements-hpa-axis-dysfunction-qa/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353008/

There are probably many more effects of DHEA.

What is interesting is that DHEA consistently rises, beginning with puberty and reaches its peak between 25-30 years. I have seen a couple of patients here on Phoenixrising and on Dinet describing similar results in their DHEA saliva test. So, maybe some of you have the exact same problem as I do.

There is a study that resveratrol can lead to a reduction in DHEA (1g/ day).
https://pubmed.ncbi.nlm.nih.gov/25939591/

One other interesting finding I would like to mention is that another form of adrenal hyperplasia, 21-hydroxylase deficiency, is caused by a genetic defect in CYP21A2, which is flanked by TNXB. A mutation in TNXB leads to Ehlers-Danlos-Syndrome. So maybe, we will see more interactions between EDS and different forms of adrenal hyperplasia in the future. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565116/

I will now see an endocrinologist and keep you updated!

I would be interested, if there are more people with elevated DHEA levels or a rise in sebum production before their illness started, here on Phoenixrising. Maybe, some of you had to use Isotretinoine or 5a-Reductase Inhibitors because of associated problems.

Best wishes
Philipp
 
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Pearshaped

Senior Member
Messages
579
Interesting..@Philipp05
I have to look into this..
I am female but always joked about my scalp and actually whole upper body having excess sebum like a forehead of a male teenager..

Acth test ok,later in ilness ACTH to low.
Beta hydroxilase deficiency was strongly
suspected but test came back normal.


Yes please keep us posted about your appointment with Endo.

I hope your Endo is better than mine was.
 
Messages
16
Addition 2: This condition can lead to salt loss (too little aldosterone after stress) and hypovolemia, which is associated with both ME/CFS and POTS
 
Messages
16
Addition 3: I think I have found the answer to the question, why my testosterone levels are in the normal range. Here is a graph describing the synthesis of the adrenal gland hormones. The following hormones in my body are of interest: DHEA (after stimulation) is highly elevated, 17-Hydroxyprogesterone is mildly elevated after stimulation (3,71 ng/ml), cortisol and aldosterone do not rise as high as expected after stimulation, testosterone (6,87 ng/ml) is in the normal range.
https://www.msdmanuals.com/-/media/..._adrenal_hormone_synthesis_de.gif?la=de&thn=0

Let ́s start looking at what happens in the body, when the activity of 3ß-HSD is too low: 1.DHEA is very high, as it cannot be transformed into androstenedione. As a consequence, too little testosterone is produced.
2. Too little progesterone and 17-hydroxyprogesterone are produced.
3. At the end of the chain, there is too little aldosterone and cortisol.

If there is a 21-hydroxylase-deficiency, as you can see in certain forms of EDS, you would expect the following findings:
1.Progesterone and 17-hydroxy-progesterone accumulate, as the transformation into deoxycorticosterone and 11-deoxycortisol is reduced.
2. Instead, large amounts of androstenedione and testosterone are produced. Testosterone is expected to be highly elevated.
3.Too little aldosterone and cortisol are produced.
What happens, if there is a combined deficiency of 3ß-HSD and 21-hydroxylase?
  1. Too little progesterone and 17-hydroxyprogesterone is produced due to the 3ß-HSD- defciciency. But due to the fact that 21-hydroxylase does not work properly as well, there is a moderate accumulation of 17-hydroxyprogesterone, which now primarily gets transformed into testosterone.
  2. As above, 3ß-HSD-deficiency leads to a massive accumulation of DHEA. Too little androstenedione and consequently testosterone is produced. But in this case of a combined deficiency, this finding gets balanced (see above)
  3. Too little cortisol and aldosterone are produced (at least in after ACTH-test or with stress.
So actually, I think that my laboratory values can be explained by a combined deficiency of 3ß-HSD and 21-hydroxylase.
It is interesting that they partly mask each other!!! (especially concerning 17-hydroxy- progesterone and testosterone)
 
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Messages
16
A therapy would probably look like this: You suppress your DHEA production with dexamethasone. Additionally, you need an hormone replacement therapy including hydrocortisone, aldosterone and probably testosterone.
 

JES

Senior Member
Messages
1,320
I'm afraid this doesn't come close to attacking the root cause of POTS. Have you looked into the hypothesis that autoantibodies are responsible for maintaining this condition (e.g. described in this article)? I tested positive for all eleven antibodies in the CellTrend tests.

IMO it seems closer to the root cause that something with the immune system has gone haywire, as this condition is usually triggered by a virus. It could also be that all these autoantibodies found are just a consequence and of little significance, not a cause. The same applies to upregulations of genes. Optimistically, maybe they may offer a target for treatments, but they are almost certainly not the root cause. There are simply too many findings of this sort in POTS patients to really make much sense of what is significant and what is not, in my opinion.
 
Messages
16
I'm afraid this doesn't come close to attacking the root cause of POTS. Have you looked into the hypothesis that autoantibodies are responsible for maintaining this condition (e.g. described in this article)? I tested positive for all eleven antibodies in the CellTrend tests.

IMO it seems closer to the root cause that something with the immune system has gone haywire, as this condition is usually triggered by a virus. It could also be that all these autoantibodies found are just a consequence and of little significance, not a cause. The same applies to upregulations of genes. Optimistically, maybe they may offer a target for treatments, but they are almost certainly not the root cause. There are simply too many findings of this sort in POTS patients to really make much sense of what is significant and what is not, in my opinion.
Well, concerning to my theory, the epigenetic changes are a consequence of the 21-hydroxylase and 3ß-HSD deficiency as well. Furthermore, this form of adrenal hyperplasia causes several changes in the body such as low blood volume, stimulated eNOS and norepinephrine, a TH2-switch (immune system) and an upregulation of EZH2, which changes the way we are dealing with viruses.
I do have some of these autoantibodies as well:
This is a quote from Wikipedia :“Androgens (such as DHEA), but not estrogens, increase beta adrenergic receptors while decreasing alpha adrenergic receptors, which results in increased levels of epinephrine/ norepinephrine due to lack of alpha-2 receptor negative feedback and decreased fat accumulation due to epinephrine/ norepinephrine then acting on lipolysis-inducing beta receptors.“
In my opinion, the body could react to this changed environment by reorganizing the levels of those autoantibodies to counteract some of the effects of DHEA.
 
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Messages
16
I would be very interested in your DHEA saliva levels. My basal DHEA levels during the ACTH-Test at 0 minutes came back normal as well. Only after the ACTH-Test, there was a sharp increase in DHEA. Probably, the saliva test is more sensitive.
 

bread.

Senior Member
Messages
499
Well, concerning to my theory, the epigenetic changes are a consequence of the 21-hydroxylase and 3ß-HSD deficiency as well. Furthermore, this form of adrenal hyperplasia causes several changes in the body such as low blood volume, stimulated eNOS and norepinephrine, a TH2-switch (immune system) and an upregulation of EZH2, which changes the way we are dealing with viruses.
I do have some of these autoantibodies as well:
This is a quote from Wikipedia :“Androgens (such as DHEA), but not estrogens, increase beta adrenergic receptors while decreasing alpha adrenergic receptors, which results in increased levels of epinephrine/ norepinephrine due to lack of alpha-2 receptor negative feedback and decreased fat accumulation due to epinephrine/ norepinephrine then acting on lipolysis-inducing beta receptors.“
In my opinion, the body could react to this changed environment by reorganizing the levels of those autoantibodies to counteract some of the effects of DHEA.

did you reach out to doctors and researchers yet?