Can Someone Explain Epinephrine Place in Adrenal-Pituitary Axis?

[Gondwanaland]

However, if this was simply a genetic issue, you would have had the symptoms all your life.

There seems to be some point in life, either merely age related or triggered by some environmental cause, that our bodies stop coping with genetic disadvantages and these genes become expressed and take over...

Which version of the MAO snp do you have? If it's the one that Yasko terms +, then this is simply the common variant, and not likely to cause problems.

This very common variant has been causing me real problems since early age due to aluminum and mercury (amalgams) exposure. Much worse now that my body seems less and less capable to deal with it.

 

[Valentijn]

@pemone - One of the exercise physiology groups have found overexpression of ADRA2A in ME patients following maximal exertion. ADRA2A can inhibit the release of norepinephrine, which might be causing low-ish levels.

In my case, I had low levels of norepinephrine (despite normal dopamine and epinephrine) in serum both times it was tested. An NRI and then an ADRA2A antagonist have been quite helpful for me in controlling orthostatic intolerance.

 

[JaimeS]

There seems to be some point in life, either merely age related or triggered by some environmental cause, that our bodies stop coping with genetic disadvantages

Nail, meet head. I suspect I always had some kind of minor adrenal issue, but it really was minor most of my life (I'm not a member of the, I had a flu and from then on... patient subgroup.)

I wish I could recommend a doctor who's actually fully versed in this sort of thing, but I've got nothin'. Just idea-wise, I might look for a doctor who specializes in the genetics of metabolic illness, but that's still a crap-shoot. Most of us here are in the same boat - consulting with an expert when we can, but essentially figuring things out on our own.

This is not fair, or right, but it is the situation as I see it right now.

Earlier, you said that what we really need is a doctor who can spend hours upon hours on our case, and I agree. It's what is needed, but as you said, it's not what we're going to get unless we're far wealthier than the average citizen. We can spend hours and hours on our own cases and, if we're lucky, find a doc willing to listen to our findings for a half an hour or even an hour, and help us make decisions.

I was lucky enough to find a GP like this. She said, "I will work very hard for you, but I do not think I will catch this fish." Then she suggested that I keep researching, and I might be able to 'catch' it. It seems like someone willing to listen to you and work with you is the holy grail in this mess.

-J

 

[pemone]

Functional medicine practitioners might look into this. However, if this was simply a genetic issue, you would have had the symptoms all your life.

The interesting thing is I have been pretty energetic and high strung my entire life, so it wouldn't surprise me that I might have lived with high adrenalin for a long time. It might just be that the adrenalin *combined with some mitochondrial insult* take me to a very bad place. Maybe before when I got high adrenalin I was simply able to produce a lot of energy aerobically, so somehow metabolically it was tolerable.

Which version of the MAO snp do you have? If it's the one that Yasko terms +, then this is simply the common variant, and not likely to cause problems.

Here are the three MAO A SNPs where I have the risk allele:

rs6323 MAOA R297R/G492T/T941G T T +
rs1137070 MAOA T1011C/1460C C C +
rs2072743 MAOA T89113C C C +

I have only researched RS6323 and that one the T allele encodes a low activity form of the MAO A enzyme. That seems partly consistent with my high adrenalin not metabolizing to VMA. I have a feeling more than one gene is involved in that.

If you have insights on any of these please let me know.

 

[pemone]

@pemone - One of the exercise physiology groups have found overexpression of ADRA2A in ME patients following maximal exertion. ADRA2A can inhibit the release of norepinephrine, which might be causing low-ish levels.

In my case, I had low levels of norepinephrine (despite normal dopamine and epinephrine) in serum both times it was tested. An NRI and then an ADRA2A antagonist have been quite helpful for me in controlling orthostatic intolerance.

What is the RS ID of the ADRA2A SNP?

What were your typical values for norepinephrine?

My dopamine is kind of unknown. The range for that metabolite in serum was 0 to 48, and my test came back as <30. So in other words the precision of the test is very low. I'm going to get a 24 hour urine, and it will be very interesting to see where that places my dopamine. Several osteopaths tried giving me tyrosine to stimulate my dopamine and it made me very uncomfortable and together with B6 seems to overstimulate whatever is causing the adrenalin to go high.

 

[pemone]

Nail, meet head. I suspect I always had some kind of minor adrenal issue, but it really was minor most of my life (I'm not a member of the, I had a flu and from then on... patient subgroup.)

I wish I could recommend a doctor who's actually fully versed in this sort of thing, but I've got nothin'. Just idea-wise, I might look for a doctor who specializes in the genetics of metabolic illness, but that's still a crap-shoot. Most of us here are in the same boat - consulting with an expert when we can, but essentially figuring things out on our own.

I am going to see a mitochondrial geneticist. In theory they should be able to give a lot of useful information. In practice, it looks like there are fewer than 30 of these people in the entire US and most of their efforts are in finding mitochondrial genetic defects in children. I have my doubts that they are interested or willing to finding mitochondrial "inefficiency" in adults.

Earlier, you said that what we really need is a doctor who can spend hours upon hours on our case, and I agree. It's what is needed, but as you said, it's not what we're going to get unless we're far wealthier than the average citizen. We can spend hours and hours on our own cases and, if we're lucky, find a doc willing to listen to our findings for a half an hour or even an hour, and help us make decisions.

I was lucky enough to find a GP like this. She said, "I will work very hard for you, but I do not think I will catch this fish." Then she suggested that I keep researching, and I might be able to 'catch' it. It seems like someone willing to listen to you and work with you is the holy grail in this mess.

We have a $70 medical system. What I mean by that is the average doctor gets compensated less than $100 for a patient office visit. Their motivation is therefore to make the visit as short as possible. They will be glad to find any all diseases they can locate with 15 minutes invested into your case. Borderline useless, actually. Dysfunctional. At this point I see the main value of allopaths being help you order specific tests. They have very little correlation to making health better. As you say, you are lucky if you can find a doctor who will work with you and will be pretty liberal about ordering new tests.

Then you have osteopaths, who will charge you by the hour and gladly talk endlessly. They run a few expensive tests but then they don't have the time to actually sit down for four hours and tie together all of the metabolites. They don't think through careful experiments to actually diagnose how your system functions or malfunctions. You end up taking dozens of supplements and not getting cured.

At the end of the day, the system as designed now leaves the patient to become a biochemist or doctor without any training. You are responsible for your own outcome and have to piece together all of the different labs and point doctors in potentially useful directions.

In my own case, it feels like allopaths did zero for me. Osteopaths hurt me by putting me on supplements that made me worse. But the testing that was done was useful and I'm starting to put pieces together in useful ways. Now that I get closer to diagnosing causes, it is great to have the osteopath relationships, because you can validate or dismiss ideas using them as a sounding board. But it is very painful to be sick and realize at some point that you have no doctor.

 

[Valentijn]

What is the RS ID of the ADRA2A SNP?

It's a gene, not a SNP. And its expression is pretty normal in us prior to exertion, so it's unlikely to the source of the problem. If you want to know the SNPs on it, as well as your genotype, you can log on to https://www.23andme.com/you/explorer/ and enter "ADRA2A" into the "Jump to a gene" box.

What were your typical values for norepinephrine?

Pretty well below the reference range. Once I think it was at about 50% of the lowest value, then a little higher a year later. But still below range.

 

[pemone]

It's a gene, not a SNP. And its expression is pretty normal in us prior to exertion, so it's unlikely to the source of the problem. If you want to know the SNPs on it, as well as your genotype, you can log on to https://www.23andme.com/you/explorer/ and enter "ADRA2A" into the "Jump to a gene" box.

It's interesting that SNPedia and MTHFR Support Sterling's App Version 2 do not mention that gene at all.

Thanks for the reference to 23andme. Unfortunately the links to Google Scholar are pretty overwhelming. There would be a day or two of work to go through 40+ studies across the three SNPs that 23andme is describing for ADRA2A.

I think my problem is probably not low norepinephrine.

 

[adreno]

Here are the three MAO A SNPs where I have the risk allele:

rs6323 MAOA R297R/G492T/T941G T T +
rs1137070 MAOA T1011C/1460C C C +
rs2072743 MAOA T89113C C C +

I have the same variants. The thing is that these variants are the dominant ones in the western population, so how does this help to explain symptoms? If these variants caused problems, half the population should be sick. So logic dictates there must be more to the story.

 

[nandixon]

It's interesting that SNPedia and MTHFR Support Sterling's App Version 2 do not mention that gene at all.

Thanks for the reference to 23andme. Unfortunately the links to Google Scholar are pretty overwhelming. There would be a day or two of work to go through 40+ studies across the three SNPs that 23andme is describing for ADRA2A.

SNPedia gives links for 4 SNPs for ADRA2A, including the 2 that 23andMe gives for me. (I was tested on their earlier v3 chip, which gave rs11195419 & rs553668. From what you say, it seems a third SNP may have been added with the v4 chip.) See:

http://www.snpedia.com/index.php/ADRA2A

 

[wastwater]

Is epinephrine linked to cAMP PKA pathways

 

[adreno]

@pemone

According to the following diagram, the metabolism of E to VMA requires COMT.

SAM-e is needed for COMT to methylate E to metanephrine. How is your methylation status?

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

 

[pemone]

I have the same variants. The thing is that these variants are the dominant ones in the western population, so how does this help to explain symptoms? If these variants caused problems, half the population should be sick. So logic dictates there must be more to the story.

I don't view the high adrenalin as the cause of my condition. I view it as something that is aggravating it.

As I said previously, it might be I have been running high adrenalin my whole life. Maybe what changed is that my metabolism stopped being able to absorb that.

What is clear is that when I get these adrenalin surges, I get a very strange pulse (jumping from 70 to 110 without any real reason), brain fog, and higher blood sugars. It might be that higher-than-normal adrenalin levels, combined with poor aerobic metabolism, is creating some of these symptoms. And the "cure" might ultimately be to improve the aerobic metabolism rather than to fixate on the adrenalin (which may not be curable). Then again, if my supplements were causing the adrenalin to go much higher, then I do get some palliative benefit from stopping the supplements.

At this point I'm still at the stage where I am trying to follow through the metabolites and just understand the condition.

 

[pemone]

SNPedia gives links for 4 SNPs for ADRA2A, including the 2 that 23andMe gives for me. (I was tested on their earlier v3 chip, which gave rs11195419 & rs553668. From what you say, it seems a third SNP may have been added with the v4 chip.) See:

http://www.snpedia.com/index.php/ADRA2A

Sorry, I wasn't very clear. What I meant to say was that the SNPedia page has no real information on the gene. They list the four SNPs but there is no text in the main part of the page.

 

[pemone]

@pemone

According to the following diagram, the metabolism of E to VMA requires COMT.

SAM-e is needed for COMT to methylate E to metanephrine. How is your methylation status?

http://data:image/png;base64,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

I have both COMT and MAO-A defects and tracing through all of that is going to take some time.

Here is the diagram I have been using, which seems to contradict yours. Probably the truth is some combination of the two to create a third diagram:

Some things I wonder about from this diagram:

* Tyrosine makes me feel stimulated in a very bad way. My HMA is staying low, so dopamine is not metabolizing to HMA. What is the 3-Methoxy-tyramine metabolite doing when dopamine goes high? Is all of my dopamine metabolizing to adrenalin? It would be easy enough to design an experiment to capture those. I'm just not sure if one vendor measures all of the required metabolites.

* My norepinephrine is never very high. But my VMA is always very low. That seems to imply that the pathway from norepinephrine to VMA is either not used at all or being blocked. So it would be interesting to capture 3,4 DHPG aldehyde and 3,4 DHM and figure out is it the MAO-A or COMT that is not working. Or maybe it is all dumping to epinephrine.

* On the epinephrine pathway to VMA, my metanephrine seems to get created. But what about the subsequent steps to MHPG under action of MAO-A. The VMA never goes high, so something must be getting blocked.

As you say, even if you figure this all out, it doesn't necessarily mean it can be treated, and it also does not mean it is a cause of my condition. But it is aggravating things, and maybe once I understand it I can tweak it to give a better outcome.

 

[adreno]

As you say, even if you figure this all out, it doesn't necessarily mean it can be treated, and it also does not mean it is a cause of my condition. But it is aggravating things, and maybe once I understand it I can tweak it to give a better outcome.

I'd be surprised if you can trace and treat the system in such detail. Diagrams are simplifications, testing is often unreliable, biology in general is dirty and too many factors are unknown. We don't even have a full understanding of these processes yet. But I wish you good luck in your endeavor.

 

[pemone]

I'd be surprised if you can trace and treat the system in such detail. Diagrams are simplifications, testing is often unreliable, biology in general is dirty and too many factors are unknown. We don't even have a full understanding of these processes yet. But I wish you good luck in your endeavor.

All true. But I view having a complete map of metabolites being like having a very imprecise map. A good map reader can usually navigate by a bad map, albeit imperfectly. If you reject having a map and just try to navigate by intuition, it seems to me you will almost always get a bad result.

A lot of the practitioners out there try to navigate SNPs and methylation issues by just winging it. They don't test completely. They don't really look for the specific metabolite that is high or low for you. They don't retest. They just blab a lot of theory and then prescribe a lot of supplements, for pretty much everyone, in pretty much the same way.

In truth, to do this all correctly would probably require a skilled geneticist 40 hours of time, and lots of testing. And none of us will ever get that. So it's lot of slop and imprecision and chasing after wrong leads.

 

[wastwater]

Does anyone know what the name of these pathways is Adenylyl cyclase and beta adrenergic receptor kinase http://en.wikipedia.org/wiki/Beta_adrenergic_receptor_kinase

 

[Valentijn]

Does anyone know what the name of these pathways is Adenylyl cyclase and beta adrenergic receptor kinase http://en.wikipedia.org/wiki/Beta_adrenergic_receptor_kinase

KEGG is great for finding pathways:
http://www.kegg.jp/dbget-bin/www_bget?ko:K08048 lists a ton of pathways for Adenylate Cyclase (the more common name).

http://www.genome.jp/dbget-bin/www_bget?ko:K00910 lists "Chemokine signaling pathway" for beta adrenergic receptor kinase, which is also near the top of the list for Adenylate Cyclase.

Both also list "glutamatergic synapse", though a bit further down the list.

The full pathway of chemokine signaling is at http://www.genome.jp/kegg-bin/show_pathway?ko04062

The full pathway for glutamatergic synapse is at http://www.genome.jp/kegg-bin/show_pathway?ko04724

 

[JaimeS]

I was traveling when I wrote some of these responses, and clearly a little brain-foggier than I thought. Sorry for any wrenches in the works, guys.

-J