Can Someone Explain Epinephrine Place in Adrenal-Pituitary Axis?

[pemone]

I had originally believed that stress creates adrenalin, which then stimulates hypothalamus which stimulates pituitary to create ACTH, which then stimulates adrenals to create cortisol. But this diagram seems to contradict that:
http://www.maryvancenc.com/wp-content/uploads/2011/08/HPA-and-HPT-Axes.jpg.jpg

This diagram seems to suggest that epinephrine is the end result of ACTH stimulation of the adrenals. If that is true, what is the input that stimulates the hypothalamus to start the whole sequence of chemicals in this axis?

Does someone have a pointer to a more complete diagram?

 

[JaimeS]

The diagram is correct. Another name for epinepherine is adrenaline. It's so named because it's made by the medulla of the adrenal glands. However, you are correct in believing that its affects are important higher 'up the chain' as well. Epinepherine in turn binds to beta-adrenergic receptors causing more ACTH to be produced in the pituitary gland. So there is no 'beginning' or 'first' chemical, no first-mover. Likewise, there is no 'end result': it's a cycle.

(Cue 'it's the Ciiiirrrcle of lifffeee' theme.)

If you're looking for what people typically put 'first' in the axis, perhaps you're thinking of CRH, or corticotropin-releasing hormone, which is produced in the hypothalamus and encourages production of ACTH in the pituitary.

Hope that helps!

-J

 

[pemone]

The diagram is correct. Another name for epinepherine is adrenaline. It's so named because it's made by the medulla of the adrenal glands. However, you are correct in believing that its affects are important higher 'up the chain' as well. Epinepherine in turn binds to beta-adrenergic receptors causing more ACTH to be produced in the pituitary gland. So there is no 'beginning' or 'first' chemical, no first-mover. Likewise, there is no 'end result': it's a cycle.

(Cue 'it's the Ciiiirrrcle of lifffeee' theme.)

If you're looking for what people typically put 'first' in the axis, perhaps you're thinking of CRH, or corticotropin-releasing hormone, which is produced in the hypothalamus and encourages production of ACTH in the pituitary.

So if epinephrine/adrenaline stimulate hypothalamus to stimulate pituitary to produce ACTH which stimulates adrenals to produce more epinephrine, how does this not become an out-of-control cycle that feeds on itself? Where are the brakes that bring epinephrine back to baseline?

It turns out I have persistently high adrenaline, and after searching through my metabolites what is unusual to my case is that my body is NOT metabolizing the adrenaline to either metanephrines or to its immediate metabolite Vanilmandelate (VMA) (aka Vanillyl-Mandelic Acid). Basically, once I get high adrenaline my body holds onto it and this is causing a lot of issues for me. They may have to rule out adrenalin-stimulating tumor as a possible cause for the high adrenalin, but I have this feeling that I may have had some form of this problem for more than a decade and there may be some error of metabolism here.

So, I'm trying to get smart about this whole pituitary-adrenal axis fast, so I can better participate with doctors. Thanks for your help.

 

[adreno]

So if epinephrine/adrenaline stimulate hypothalamus to stimulate pituitary to produce ACTH which stimulates adrenals to produce more epinephrine, how does this not become an out-of-control cycle that feeds on itself? Where are the brakes that bring epinephrine back to baseline?

Under normal circumstances, cortisol inhibits the release of CRH and ACTH through a negative feedback loop.

 

[JaimeS]

@pemone, funny you should mention...

I've recently been looking at NET deficiency as a potential contributor to what's going on with me, and if you can't 'clear' epinepherine or norepinepherine, that may interest you as a potential path of study.

Have you ever been given cortisol as part of a treatment plan?

If so, did it go quite badly for you? That could point to issues with NET deficiency.

Edit: eehhhh, NET is NORadrenaline deficiency, so probably not. By the way, I've been searching for a more integrative 'hormone map' for ages. I eventually came to the conclusion that I'd have to draw my own. If I ever do, I'll be sure to post it here for you guys.

-J

 

[adreno]

Edit: eehhhh, NET is NORadrenaline deficiency, so probably not.

Actually, NET is the Norepinephrine Transporter, responsible for the uptake of norepinephrine. NET deficiency would lead to higher levels of norepinephrine (and epinephrine, by conversion).

 

[JaimeS]

@adreno, Norepi is noradrenaline! Two names, same thing.

-J

 

[adreno]

@adreno, Norepi is noradrenaline! Two names, same thing.

-J

I'm aware of that, thank you.

 

[Jonathan Edwards]

In the physiology I remember ACTH stimulates the adrenal cortex to make cortisol and other steroids but I have not heard of it stimulating the adrenal medulla (which is really a different organ in the same capsule) to make adrenaline or noradrenaline (catecholamines). So to my mind catecholamines are not part of the HPA axis, although they do influence it. Cortisol of course has a negative effect on ACTH so there you have a homeostatic negative feedback system.

 

[pemone]

@pemone, funny you should mention...

I've recently been looking at NET deficiency as a potential contributor to what's going on with me, and if you can't 'clear' epinepherine or norepinepherine, that may interest you as a potential path of study.

I think my case may have genetic issues related to MAO-A and COMT SNP in my genetic structure. For my crude understanding of things, a diagnostic approach that is interesting is to follow all of the metabolites associated with adrenalin metabolism in a 24 hour urine study, and try to isolate the exact metabolite that fails to convert to the next appropriate step. That should give you some idea of which gene is causing the issue.

How do treat it once you identify the genetic defect? And of course you have to rule out adrenalin-stimulating tumor.

Have you ever been given cortisol as part of a treatment plan?

If so, did it go quite badly for you? That could point to issues with NET deficiency.

I was given adrenal support and various adaptogens and they all made me sicker. I end up having very high ACTH and cortisol, so of course stimulating these systems even further would be just bad. It would be throwing gas on a raging fire.

They ruled out autonomous secreting ACTH pituitary tumor. It's not clear at this point what the cause is.

 

[pemone]

Actually, NET is the Norepinephrine Transporter, responsible for the uptake of norepinephrine. NET deficiency would lead to higher levels of norepinephrine (and epinephrine, by conversion).

So measuring from my blood plasma, typical numbers I was getting before going off supplements (which made all of this condition worse) were:
adrenalin/epinephrine: 115 pg/mL (scale goes 0-62 pg/mL)
norepinephrine: 271 pg/mL (scale goes 0-874 pg/mL)

One source online contains the claim "The active secretion of the adrenal medulla contains approximately 80 percent epinephrine and 20 percent norepinephrine; but this proportion is reversed in the sympathetic nerves, which contain predominantly norepinephrine." Based on this, I don't understand the scales above at all. Why is norepinephrine on a scale that is 14 times higher than epinephrine?

What is consistent in my case is high adrenalin (on many tests) but low metanephrines and low VMA. High adrenalin should put VMA (it's direct metabolite) higher and should push the corresponding metanephrine higher. That does not happen with me, so there is a failure of metabolism here that accentuates the impact of high adrenalin. This may be independent of whatever causes the high adrenalin in the first place.

My 24 hour urine metanephrines are normal, but given the above that is what you would expect. I don't metabolize catecholamines to metanephrines correctly. I'm waiting back on the 24 hour urine catecholamines / epinephrine result. I'm hoping that will be high normal not well-into-redline area, because if it is too high then they start irradiating you everywhere looking for an adrenalin stimulating tumor.

A truly amazing thing to me is I went 14 months with this condition and never had a doctor think to check my pituitary hormones as a group. A Stanford endocrinologist checked just a few metabolites and remarked to me that I had high cortisol but then did not follow up on that at all. All of this could have been caught - and should have been caught - by allopaths right at the beginning of my illness. None of my osteopaths thought to check this. Nearly all of my osteopaths incorrectly diagnosed me with "adrenal fatigue" which was in fact a 100% incorrect diagnosis. My body was on fire from adrenalin and many pituitary hormones that were high, and they were trying to build the fire instead of putting it out.

You realize at some point that the medical system has become all about 15 minute shallow diagnosis. Get that patient in, run a few tests, do a few shallow passes on it, and then it is time for the next patient. What people with complex conditions need is a smart medically-trained doctor who will spend four hours of his time going through all of the tests and really thinking about possible causes. This will never happen, for almost any of us. If you are worth $100 million then I guess it will happen because you can buy a research staff. For ordinary humans, we are totally abandoned by this system, and we are 95% responsible for our own outcomes.

 

[adreno]

In the physiology I remember ACTH stimulates the adrenal cortex to make cortisol and other steroids but I have not heard of it stimulating the adrenal medulla (which is really a different organ in the same capsule) to make adrenaline or noradrenaline (catecholamines). So to my mind catecholamines are not part of the HPA axis, although they do influence it.

This is essentially correct. ACTH does not stimulate the medulla to secrete catecholamines, but it does increase their synthesis:

Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine-β-hydroxylase, two key enzymes involved in catecholamine synthesis. ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis.

http://en.wikipedia.org/wiki/Epinephrine

 

[Valentijn]

@pemone - It's also odd that they don't have a lower limit for epinephrine and norepinephrine. Those definitely need to be well above 0!

 

[pemone]

This is essentially correct. ACTH does not stimulate the medulla to secrete catecholamines, but it does increase their synthesis:

http://en.wikipedia.org/wiki/Epinephrine

So it's somewhat subtle and a little confusing. ACTH stimulates cortisol release, which then acts as a biofeedback to lower ACTH. That is the clear part.

But both ACTH and cortisol either release adrenalin precursors or increase synthesis. At minimum, this has to have the effect of upregulating adrenaline when it is produced?

And what would be the primary mechanism for sending adrenaline high? This is about about nerves in the body reacting to stimulus?

 

[adreno]

And what would be the primary mechanism for sending adrenaline high? This is about about nerves in the body reacting to stimulus?

I should say so. But remember we are talking about a normal functioning system here. Who the hell knows what happens when the system goes awry. My cortisol is too low, and I don't know the reason for that either.

 

[JaimeS]

@pemone,

I really sympathize with what you're going through. It SOUNDS as though you have issues metabolizing/breaking down catecholamines. NET deficiency would fit that. Here is an article on it, and here is another article on NE issues in general. There's also a great chapter on this kind of thing in a textbook on autonomic dysfunction I've been working my way through (slowly, slowly), which I hope to summarize on my blog here, eventually. Do you have dizziness and POTS-like issues as part of your symptom-picture? POTS can be caused by NET deficiency (amongst other things).

How's your dopamine? If your dopamine is low, that at least implies that dopamine is changing over to epinepherine rapidly. If your dopamine is within normal limits, it at least implies that you're making epinepherine at a regular rate but that you're not breaking it down properly once you do.

I keep saying 'it sounds' and 'it implies' because I always feel so shaky when it comes to hormones and neurotransmitters. What medicine understands about hormones and their interactions is really a very tiny piece of the larger puzzle, and every time I think I've got a handle on what is out there, I find another piece.

Good luck!

-J

 

[adreno]

NET deficiency would fit that.

I'm not sure how you got to that conclusion, when his NE readings are so low? Only his E is too high, not his NE. This doesn't fit NET deficiency to my eyes.

 

[pemone]

@pemone,

I really sympathize with what you're going through. It SOUNDS as though you have issues metabolizing/breaking down catecholamines. NET deficiency would fit that. Here is an article on it, and here is another article on NE issues in general. There's also a great chapter on this kind of thing in a textbook on autonomic dysfunction I've been working my way through (slowly, slowly), which I hope to summarize on my blog here, eventually. Do you have dizziness and POTS-like issues as part of your symptom-picture? POTS can be caused by NET deficiency (amongst other things).

How's your dopamine? If your dopamine is low, that at least implies that dopamine is changing over to epinepherine rapidly. If your dopamine is within normal limits, it at least implies that you're making epinepherine at a regular rate but that you're not breaking it down properly once you do.

Well, my norepinephrine is low end of the scale, so it doesn't sound like that is where my problem is.

Here is a diagram that shows the metabolic pathway leading to epinephrine:
http://intranet.tdmu.edu.ua/data/ka...s of the effect of protein.files/image073.jpg

Of course that confuses me a bit, because per adreno most of the epinephrine is apparently arising endogenously in the adrenal directly from nerve stimulation. I guess that makes sense since it is the flight or fight transmitter. It also confuses me because of the earlier ACTH diagram I shared that appears to further influence epinephrine. In short, it looks like a lot of signal boosters to epinephrine exist throughout the system, and tracing down which one is sending your adrenalin high looks like a non trivial undertaking.

Now look at how epinephrine breaks down:
http://4.bp.blogspot.com/-KtOcNL1yVPE/UJq31DQEogI/AAAAAAAAAB0/AELWBrrX5Xk/s1600/VMA.png

My metanephrine looks high normal, so it does look like some of the epinephrine gets there. But my VMA is near off the low end of scale. So I apparently have some defect in that metabolic breakdown pathway. I see in my 23andme data that I have the less active form of the enzyme to break down epinephrine in the MAO-A SNP. The MAO-A SNP codes the enzyme that is used to go from epinephrine to VMA.

Now a question I have is what kind of doctor even figures this stuff out? If you have 24 hour urine epinephrine off the red end of scale, then an endo will get involved and look for a tumor. If you are simply strung out by constantly high-normal adrenalin, due to a genetic influence combined with ???, then literally no one in the medical system cares about this. No one treats that as a disease, no matter how bad it might make you feel. Would a geneticist look at it? Allopaths will ignore it. Osteopaths will converse about it but probably most of them don't understand the genes involved well enough to really investigate the detailed cause. Most methylation practitioners have lots of opinions about these things but rarely trace through all the metabolites to nail a precise diagnosis.

Is there any practitioner out there that has a lot of expertise in MAO-A and COMT genes that could help me track down the details of this?

I obsess about this because so many of my symptoms seem to trace to high adrenalin: irregular heartbeats, strange blood sugar swings, and possibly even my metabolic collapse. It turns out that high adrenalin will dilate large vessels but close down peripheral vessels. So my version of chronic fatigue might end up being simple hypoxia to muscle tissue.

 

[pemone]

@pemone,

I really sympathize with what you're going through. It SOUNDS as though you have issues metabolizing/breaking down catecholamines. NET deficiency would fit that. Here is an article on it, and here is another article on NE issues in general. There's also a great chapter on this kind of thing in a textbook on autonomic dysfunction I've been working my way through (slowly, slowly), which I hope to summarize on my blog here, eventually. Do you have dizziness and POTS-like issues as part of your symptom-picture? POTS can be caused by NET deficiency (amongst other things).

How's your dopamine? If your dopamine is low, that at least implies that dopamine is changing over to epinepherine rapidly. If your dopamine is within normal limits, it at least implies that you're making epinepherine at a regular rate but that you're not breaking it down properly once you do.

Well, my norepinephrine is low end of the scale, so it doesn't sound like that is where my problem is.

Here is a diagram that shows the metabolic pathway leading to epinephrine:
http://intranet.tdmu.edu.ua/data/kafedra/internal/chemistry/classes_stud/en/stomat/ptn/2/08. Molecular mechanisms of the effect of protein.files/image073.jpg

Of course that confuses me a bit, because per adreno most of the epinephrine is apparently arising endogenously in the adrenal directly from nerve stimulation. I guess that makes sense since it is the flight or fight transmitter. It also confuses me because of the earlier ACTH diagram I shared that appears to further influence epinephrine. In short, it looks like a lot of signal boosters to epinephrine exist throughout the system, and tracing down which one is sending your adrenalin high looks like a non trivial undertaking.

Now look at how epinephrine breaks down:
http://4.bp.blogspot.com/-KtOcNL1yVPE/UJq31DQEogI/AAAAAAAAAB0/AELWBrrX5Xk/s1600/VMA.png

My metanephrine looks high normal, so it does look like some of the epinephrine gets there. But my VMA is near off the low end of scale. So I apparently have some defect in that metabolic breakdown pathway. I see in my 23andme data that I have the less active form of the enzyme to break down epinephrine in the MAO-A SNP. The MAO-A SNP codes the enzyme that is used to go from epinephrine to VMA.

Now a question I have is what kind of doctor even figures this stuff out? If you have 24 hour urine epinephrine off the red end of scale, then an endo will get involved and look for a tumor. If you are simply strung out by constantly high-normal adrenalin, due to a genetic influence combined with ???, then literally no one in the medical system cares about this. No one treats that as a disease, no matter how bad it might make you feel. Would a geneticist look at it? Allopaths will ignore it. Osteopaths will converse about it but probably most of them don't understand the genes involved well enough to really investigate the detailed cause. Most methylation practitioners have lots of opinions about these things but rarely trace through all the metabolites to nail a precise diagnosis.

Is there any practitioner out there that has a lot of expertise in MAO-A and COMT genes that could help me track down the details of this?

I obsess about this because so many of my symptoms seem to trace to high adrenalin: irregular heartbeats, strange blood sugar swings, and possibly even my metabolic collapse. It turns out that high adrenalin will dilate large vessels but close down peripheral vessels. So my version of chronic fatigue might end up being simple hypoxia to muscle tissue; at least that might have contributed something.

 

[adreno]

Is there any practitioner out there that has a lot of expertise in MAO-A and COMT genes that could help me track down the details of this?

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

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.