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How to lower norepinephrine

dbkita

Senior Member
Messages
655
http://www.ncbi.nlm.nih.gov/pubmed/19000920 -- abstract

http://www.kksphotos.com/media/trhtheory.pdf -- full paper

"Decades of research have established that the biological functions of thyrotropin-releasing hormone (TRH) extend far beyond its role as a regulator of the hypothalamic-pituitary-thyroid axis. Gary et al. [Gary, K.A., Sevarino, K.A., Yarbrough, G.G., Prange, A.J. Jr., Winokur, A. (2003). The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics. J Pharmacol Exp Ther 305(2):410-416.] and Yarbrough et al. [Yarbrough, G.G., Kamath, J., Winokur, A., Prange, A.J. Jr. (2007). Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Med Hypotheses 69(6):1249-1256.] provided a functional framework, predicated on its global homeostatic influences, to conceptualize the numerous interactions of TRH with the central nervous system (CNS) and endocrine system. Herein, we profer a similar analysis to interactions of TRH with the immune system. Autocrine/paracrine cellular signaling motifs of TRH and TRH receptors are expressed in several tissues and organs of the immune system. Consistent with this functional distribution, in vitro and in vivo evidence suggests a critical role for TRH during the developmental stages of the immune system as well as its numerous interactions with the fully developed immune system. Considerable evidence supports a pivotal role for TRH in the pathophysiology of the inflammatory process with specific relevance to the "cytokine-induced sickness behavior" paradigm. These findings, combined with a number of documented clinical actions of TRH strongly support a potential utility of TRH-based therapeutics in select inflammatory disorders. Similar to its global role in behavioral and energy homeostasis a homeostatic role for TRH in its interactions with the immune system is consonant with the large body of available data. Recent advances in the field of immunology provide a significant opportunity for investigation of the TRH-immune system homeostatic hypothesis. Moreover, this hypothesis may provide a foundation for the development of TRH-based therapeutics for certain medical and psychiatric disorders involving immune dysfunction."
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Methylation is both the gateway to the production and the catabolism of many neurotransmitters. Certainly serotonin and the catecholamines. Remember though it must seem like I rail against NE, you need some NE to function and feel good, else you would just be depressed.

The problem is when it gets out of balance and hyperstimulates the SNS. You don't want sympathetic nervous overload. That is a beast of an issue and very destructive if chronic. NE also factors into the immune system and inflammation. Heck I just saw my neuroendocrinologist today and he was reminding me that my pain increase when I increase certain supplements if from increased inflammation tied into higher NE. Sigh.
I think my recent depression these past few months is due to inflammatory cytokines since it seems to be triggered by anything that causes a herx (either probiotics or supplements with antibacterial/microbial/fungal/viral properties) and prior to that my antidepressant was working very well so I don't think it's a failure of my meds. The recent depression starting a few months ago was what actually prompted me to start taking B12 again. If methylation is increasing inflammation though it might be counterproductive to take B12 for my mood. I suppose I could try just taking adenosylcobalamin since that's supposed to help inflammation, but since hydroxocobalamin was what I was taking I don't know if it was methylcobalamin or adenosylcobalamin that was helping my mood.
 

invisiblejungle

Senior Member
Messages
228
Location
Chicago suburbs
My brother is the one who went to see him first. Took me five more years to make it to him only because I was stubborn. Very bad decision on my part. What was special in his case is when I was on the brink (don't want to relive those memories) he was suitably aggressive in taking action. Still it took two more years to get the right diagnosis. Then things really started to change. So yeah guess who I was referring to about wanting me on Florinef well before I started taking it? Not only due to my labs and symptoms but because it hugely helped my brother with his dysautonomia. Shared genetics :)

Hey Dbkita,

What kind of dosing schedule do you and your brother use for medrol? I'm going to give HC another shot, but if I need something stronger medrol will be a back-up.
 

dbkita

Senior Member
Messages
655
Medrol is roughly 24 hour half-life so you take normally in the morning. Physiological replacement is 6 mg medrol equivalent to 30 mg hydrocortisone spread throughout day. I take 4 mg medrol but also prednisone. My brother does 6 mg medrol only. Both of us do NOT do well on hydrocortisone no matter how carefully we dose. I tried twice with supposedly equivalent dose amounts over a doctor appeoved protocol. Gah not good. Note medrol though has long term effects. Still 5-6 mg is not too bad with the exception avascular necrosis of the hip which very rare but need not require high doses. The osteoporosis is dose dependent and usually manageable with vitamin d and k and calcium.
 

Emootje

Senior Member
Messages
356
Location
The Netherlands
Increasing SAM and decreasing SAH will probably lower norepinephrine by stimulating the degradation of norepinephrine by COMT:

comt sah sam.JPG

comt.JPG


http://www.hh.um.es/pdf/Vol_17/17_4/Zhu-17-1283-1291-2002.pdf

Effects of S-adenosyl-methionine on plasma norepinephrine, blood pressure, and heart rate in healthy volunteers.
S-adenosyl-methionine (SAMe) is currently undergoing trials as a possible antidepressant. Because SAMe's mechanism of action is obscure and norepinephrine (NE) is often implicated in affective disorders, we studied the effects of SAMe on this neurotransmitter in volunteers. Plasma NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the supine and standing position were studied before and after acute placebo or a single 400 mg dose of SAMe and following seven daily administrations; concomitant measures were heart rate (HR) and blood pressure. Subjects were unable to distinguish acute drug from placebo, and although chronic SAMe administration was open, they reported no behavioral effects. Standing HR and plasma NE were reduced following chronic SAMe. Qualitatively similar changes are obtained following chronic treatment with monoamine oxidase inhibitors (MAOIs). However, unlike MAOIs, chronic SAMe treatment was not associated with changes in plasma MHPG. Exaggerated standing NE is found in depressed patients; SAMe may reduce this abnormal response, providing a clue for its mechanism of action in depression.
http://www.ncbi.nlm.nih.gov/pubmed/3961029

Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia.
S-adenosyl-methionine (SAM-e), functions as a primary methyl group donor for several metabolic compounds. Since SAM-e is involved in several metabolic processes, its administration may have a role in the amelioration of several disorders. In addition, SAM-e increases catechol-O-methyltransferase (COMT) enzyme activity, which may ameliorate aggressive symptoms in certain patients. We have therefore investigated the efficacy of SAM-e in managing schizophrenia symptomatology in patients with the low activity COMT polymorphism. Eighteen patients with chronic schizophrenia were randomly assigned to receive either SAM-e (800 mg) or placebo for 8 weeks in double-blind fashion. Results indicated some reduction in aggressive behavior and improved quality of life following SAM-e administration. Female patients showed improvement of depressive symptoms. Clinical improvement did not correlate with serum SAM-e levels. Two patients receiving SAM-e exhibited some exacerbation of irritability. This preliminary pilot short-term study cautiously supports SAM-e as an adjunct in management of aggressive behavior and quality of life impairment in schizophrenia.
http://www.ncbi.nlm.nih.gov/pubmed/18824331
 

invisiblejungle

Senior Member
Messages
228
Location
Chicago suburbs
Medrol is roughly 24 hour half-life so you take normally in the morning. Physiological replacement is 6 mg medrol equivalent to 30 mg hydrocortisone spread throughout day. I take 4 mg medrol but also prednisone. My brother does 6 mg medrol only. Both of us do NOT do well on hydrocortisone no matter how carefully we dose. I tried twice with supposedly equivalent dose amounts over a doctor appeoved protocol. Gah not good. Note medrol though has long term effects. Still 5-6 mg is not too bad with the exception avascular necrosis of the hip which very rare but need not require high doses. The osteoporosis is dose dependent and usually manageable with vitamin d and k and calcium.

Man, the once-a-day dosing sounds nice... Sticking to a HC schedule makes life a little less "life-like." :balloons: Seems like it would offer a smoother rhythm compared to the jagged ups-and-downs of HC.

Just curious, what is your complete HRT protocol?
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Absolutely. In chronic immune scenarios ne is made in the ans directly from tyrosine et al and not dopamine. I lived in a low dopamine high ne state for years till I got on hrt.
You said earlier that there wasn't an accurate test for neurotransmitters, so how do you know if you have low dopamine?
 

dbkita

Senior Member
Messages
655
Muscle tremors, pseudo parkinson's symptoms, restlessnes, restless leg syndrome, the feeling you can't sit still or you will die so you keep moving all the time, bad mood, no happiness, no passion, no appetite, no desire, no joy, all focus turned inward, muscle fasciculations, poor balance and coordination .... I am probably missing some. In my case I was first mis diagnosed with parlinson's (long painful story) then low dopamine due to anemia and low iron. The real culprit is my autoimmune disease which attacks the mid brain area, specifically the basal ganglia within which 95% of all dopamine in the cns is made.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Something I don't think I mentioned in this thread, but was actually discussing earlier with the person who started this thread who was having a similar problem. My adrenal symptoms these past few months seem to be almost identical to my overmethylation symptoms. I know the difference because I wasn't having the adrenal symptoms back in the fall when I had my first experience with methylfolate. It does seem like methylation might be triggering my adrenal symptoms to a certain extent.

If Rich's theory about excitoxicity during methylation being partially due to a decrease in glutathione then that might be a component to my symptoms. I rarely take glutathione anymore, but when I have taken it these past few months it sometimes seems to calm me down.

I've backed down on hydroxocobalamin to just 500 mcg, while I'm experimenting with increasing adenosylcobalamin. I just ordered some Anabol. Before buying it, I searched this forum for any mention of it. I think I only found 3-4 people saying it worked better than Source Naturals and then another 3 who said they didn't experience side effects with Anabol as they did with Source Naturals. But Vitacost was selling both brands for the same price so I figured why not? I've also increased my dose of LCF and ALCAR. I think they're actually calming me down, but it's hard to say since there are so many variables.
 

dbkita

Senior Member
Messages
655
Something I don't think I mentioned in this thread, but was actually discussing earlier with the person who started this thread who was having a similar problem. My adrenal symptoms these past few months seem to be almost identical to my overmethylation symptoms. I know the difference because I wasn't having the adrenal symptoms back in the fall when I had my first experience with methylfolate. It does seem like methylation might be triggering my adrenal symptoms to a certain extent.

If Rich's theory about excitoxicity during methylation being partially due to a decrease in glutathione then that might be a component to my symptoms. I rarely take glutathione anymore, but when I have taken it these past few months it sometimes seems to calm me down.

I've backed down on hydroxocobalamin to just 500 mcg, while I'm experimenting with increasing adenosylcobalamin. I just ordered some Anabol. Before buying it, I searched this forum for any mention of it. I think I only found 3-4 people saying it worked better than Source Naturals and then another 3 who said they didn't experience side effects with Anabol as they did with Source Naturals. But Vitacost was selling both brands for the same price so I figured why not? I've also increased my dose of LCF and ALCAR. I think they're actually calming me down, but it's hard to say since there are so many variables.

My bet would still be that high methylation for you translates into NE and inflammation which are exactly are what in play when adrenals are in trouble. Excitoxicity due to glutamate has some decidedly different symptoms.

Note when you take glutathione it is not absorbed as one molecule but is disassociated into glutamate, cysteine and glycine. It is reassembled either in the liver or intracellularly via two reaction steps both requiring ATP. So if you wanted to increase glutathione, provided your Krebs cycle works then add glutamate, NAC, etc.

Personally I think this is a bad idea. When I have glutathione IVs, it still must disassociate before transport into the cell. All I ended up with was ludicrously bad reflux, pain and excitoxicity since I was adding a glutamate load on top of already high glutamate levels.

I don't doubt it is calmative for you, but that is then your body doing a nice thing with the constiuents as it either reassembles and or recycles efficiently or other reactions benefit. People with autoimmune diseases usually benefit from glutathione as well as those with bad infections. In my case my particular autoimmune disease meant taking in glutathione in any form was really not a good idea. But I did not it at the time. Remember you need glutamate. Glutamate is normally not a bad guy. you need it for mental energy, drive, mental acuity, healthy ANS, etc.

I would bet my mortgage that a large fraction of people who blame their excitoxicity and anxiety on glutamate and looking in completely the wrong place.

On another note do you still really badly to even small doses of mb12? Just curious.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
My bet would still be that high methylation for you translates into NE and inflammation which are exactly are what in play when adrenals are in trouble. Excitoxicity due to glutamate has some decidedly different symptoms.

Note when you take glutathione it is not absorbed as one molecule but is disassociated into glutamate, cysteine and glycine. It is reassembled either in the liver or intracellularly via two reaction steps both requiring ATP. So if you wanted to increase glutathione, provided your Krebs cycle works then add glutamate, NAC, etc.

Personally I think this is a bad idea. When I have glutathione IVs, it still must disassociate before transport into the cell. All I ended up with was ludicrously bad reflux, pain and excitoxicity since I was adding a glutamate load on top of already high glutamate levels.

I don't doubt it is calmative for you, but that is then your body doing a nice thing with the constiuents as it either reassembles and or recycles efficiently or other reactions benefit. People with autoimmune diseases usually benefit from glutathione as well as those with bad infections. In my case my particular autoimmune disease meant taking in glutathione in any form was really not a good idea. But I did not it at the time. Remember you need glutamate. Glutamate is normally not a bad guy. you need it for mental energy, drive, mental acuity, healthy ANS, etc.

I would bet my mortgage that a large fraction of people who blame their excitoxicity and anxiety on glutamate and looking in completely the wrong place.
Yeah, I only take glutathione once in awhile. I thought glutathione was made of cysteine, glycine, and glutamine (not glutamate). Either way, I take glycine every day and I don't notice any benefit. And the amount of glutathione I take is 50 mg sublingually. I was referring specifically to anxiety when I mentioned glutathione and not my adrenal symptoms even though I sort of lumped them together in one post. Norepinephrine does lower GABA, but I have no idea if it's significant enough to make a difference. This is what I was referring to as far was what Rich said. Do you disagree with it and do you have an alternate theory?
A lot of people experience it when they start this protocol. It's due to too much glutamate in the synapses of the neurons in the brain. The glutamate is supposed to be pumped out and converted to glutamine by the astrocytes, and sent back to the neurons for re-use, but this takes ATP, and when glutathione is low, the mitochondria do not produce ATP as fast as normal. When this protocol is started, I suspect that glutathione initially drops even more, and that is what causes the excitotoxicity.
On another note do you still really badly to even small doses of mb12? Just curious.
There was one day a few weeks ago I increased my hydroxocobalamin from 1000 mcg to 1500 mcg and also started taking folinic acid the same day (around 150 mcg). I did experience symptoms, but I need to do more tests before I can say anything conclusively. My guess is that I could probably tolerate low doses of methylcobalamin. There's been a couple days where I've taken a small amount (less than 250 mcg) without any problems. I had actually considered transitioning over to methylcobalamin to save money (especially since I have a nearly full bottle of Enzymatic), but then I remembered what people said about hydroxocobalamin using up methyl groups which seems like a good thing for me at this point. I do plan on doing tests with hydroxocobalamin, methylcobalamin, folinic acid, and methylfolate at some point, but my health is too poor right now. I haven't left my house in the past 5-6 months except to go to doctor appointments. I am taking a small amount of folinic acid right now (less than 200 mcg). Not wanting to increase my methylation doses has nothing to do with being afraid of enduring discomfort. I know you've never suggested it, but other people have. I've gotten bee venom injections before. Prolotherapy injections in my hands and feet were even worse though.
 

dbkita

Senior Member
Messages
655
Yeah, I only take glutathione once in awhile. I thought glutathione was made of cysteine, glycine, and glutamine (not glutamate). Either way, I take glycine every day and I don't notice any benefit. And the amount of glutathione I take is 50 mg sublingually. I was referring specifically to anxiety when I mentioned glutathione and not my adrenal symptoms even though I sort of lumped them together in one post. Norepinephrine does lower GABA, but I have no idea if it's significant enough to make a difference. This is what I was referring to as far was what Rich said. Do you disagree with it and do you have an alternate theory?
A lot of people experience it when they start this protocol. It's due to too much glutamate in the synapses of the neurons in the brain. The glutamate is supposed to be pumped out and converted to glutamine by the astrocytes, and sent back to the neurons for re-use, but this takes ATP, and when glutathione is low, the mitochondria do not produce ATP as fast as normal. When this protocol is started, I suspect that glutathione initially drops even more, and that is what causes the excitotoxicity.

There was one day a few weeks ago I increased my hydroxocobalamin from 1000 mcg to 1500 mcg and also started taking folinic acid the same day (around 150 mcg). I did experience symptoms, but I need to do more tests before I can say anything conclusively. My guess is that I could probably tolerate low doses of methylcobalamin. There's been a couple days where I've taken a small amount (less than 250 mcg) without any problems. I had actually considered transitioning over to methylcobalamin to save money (especially since I have a nearly full bottle of Enzymatic), but then I remembered what people said about hydroxocobalamin using up methyl groups which seems like a good thing for me at this point. I do plan on doing tests with hydroxocobalamin, methylcobalamin, folinic acid, and methylfolate at some point, but my health is too poor right now. I haven't left my house in the past 5-6 months except to go to doctor appointments. I am taking a small amount of folinic acid right now (less than 200 mcg). Not wanting to increase my methylation doses has nothing to do with being afraid of enduring discomfort. I know you've never suggested it, but other people have. I've gotten bee venom injections before. Prolotherapy injections in my hands and feet were even worse though.

Norepinephrine and GABA are antagonists for sure. But that is not what Rich Vank was talking about in the snippet you posted. He is talking about the glutamate to glutamine conversion in the CNS when glutathione levels are low. Yes low glutathione can bottleneck ATP but so can a lot of things. And tons of reactions in the body require ATP. While his logic is not incorrect, I am don't think it is the main player for perceived excitotoxicity. I say 'perceived' since many people who have posted on here about excitotoxicity due to glutamate are not maybe describing glutamate overload at all. Doesn't mean it doesn't happen but I think glutamate gets blamed when other culprits may actually be the cause in many instances. Anxiety is hardly the province of glutamate alone. Wish it were that easy.

It is foolish imo to "judge" people for their "threshold" for pain and suffering. These can only be truly evaluated by the individual who is suffering. My own pain and suffering taught me that lesson the very hard way.

My concern is if you are essentially housebound for six months except for doctor visits and you have been trying methylation, isn't that a sign that something else is the real problem?

Prolotherapy injections directly in my costosternal joints and sternoclavicular joints sucked for sure. Nothing compared to my 2008-2009 pain though. Don't even want to think of that.
 

Lotus97

Senior Member
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United States
Norepinephrine and GABA are antagonists for sure. But that is not what Rich Vank was talking about in the snippet you posted. He is talking about the glutamate to glutamine conversion in the CNS when glutathione levels are low. Yes low glutathione can bottleneck ATP but so can a lot of things. And tons of reactions in the body require ATP. While his logic is not incorrect, I am don't think it is the main player for perceived excitotoxicity. I say 'perceived' since many people who have posted on here about excitotoxicity due to glutamate are not maybe describing glutamate overload at all. Doesn't mean it doesn't happen but I think glutamate gets blamed when other culprits may actually be the cause in many instances. Anxiety is hardly the province of glutamate alone. Wish it were that easy.
Norepinephrine and GABA are antagonists for sure. But that is not what Rich Vank was talking about in the snippet you posted.
I probably should have been more clear in my post. Those aren't related other than both being possible causes of anxiety/wiredness in myself. I wanted to ask you what you thought about the cause of anxiety/excitotoxicity in methylation and whether Rich's assessment was accurate. That's separate from my NE issues possibly being a contributing factor so I probably should have put it in another paragraph.
My concern is if you are essentially housebound for six months except for doctor visits and you have been trying methylation, isn't that a sign that something else is the real problem?
I agree with you there which is why I'm doing methylation very slowly. I have thought about stopping altogether, but I'm not sure I'd be any better off. As for the real problem, I don't have many options right now. My doctor did run some tests over my last visit, but I'm not sure they're going to yield anything. They had trouble drawing blood for some reason so they only filled 3 out of 6 vials. They sent me the results and she tested T4 and TSH again, but not T3. When I spoke with her it sounded like she was also going to get T3. If I got results back from T4 and TSH it seems like I should have gotten T3 too if she ordered the test unless that was one of the vials that wasn't filled. My creatinine has been low for the past few years. My iron was a little low. My D 25 hydroxy was 30.2 even though I've been taking 6000 iu vitamin D a day including 5000 a few hours before the test. I have no idea what's going on there. I started a thread and adreno suggested gut dysbiosis which is a possibility considering I've been having problems with probiotics these past few months. There was also some information about certain newer tests being inaccurate. Another thing is that with certain illnesses, including Lyme, a person could have a low D 25 hydroxy, but a high 1,25 dihydroxy. Hopefully my doctor will test for it. I'm not sure I should be taking 6000 iu of vitamin D even if my D 25 hydroxy is low since that could screw up my immune system (which is already screwed up). Another thing that I'm curious about is my monocytes, eosinophils, rheumatoid factor, and sedimentation rate were all high when I've been tested in the past, but since I wasn't able to get all the tests done I don't know what they are now. I'm happy my doctor is doing tests (which are thankfully covered by insurance btw), but based on what I've heard from other members here the tests my doctor has done so far are only scratching the surface as to what needs to be done. I wouldn't mind paying for some tests if I thought they were important, but I don't think I can afford seeing a new doctor and tests (my doctor is covered under insurance too). And paying a lot of money for a doctor doesn't guarantee good service. I spent thousands of dollars with my previous doctor and my health actually got worse during that period.
 

xjhuez

Senior Member
Messages
175
Fortunately my (supposed) NE issue isn't chronic, but I get acute "attacks", usually at night. Take last night for example, I wake up at 2:45am to my heart beating and the need to get up out of bed and do something - I absolutely could not lay there, roll over or think. My strictly mental "excitotoxicity" (racing thoughts/angst) has been eased of late with yucca, but I have no idea how to address this issue. I wonder if it's tied to cortisol somehow - isn't it supposed to be ramping up in the wee hours of the morning to a peak when you awake?
 

dbkita

Senior Member
Messages
655
Fortunately my (supposed) NE issue isn't chronic, but I get acute "attacks", usually at night. Take last night for example, I wake up at 2:45am to my heart beating and the need to get up out of bed and do something - I absolutely could not lay there, roll over or think. My strictly mental "excitotoxicity" (racing thoughts/angst) has been eased of late with yucca, but I have no idea how to address this issue. I wonder if it's tied to cortisol somehow - isn't it supposed to be ramping up in the wee hours of the morning to a peak when you awake?
Yoyr night attack is not due to cortisol. If your cortisol were high you would have not wanted to go to bed and sone insomnia. Are the acute attacks at night only after fallung asleep? When you woke up did you have sweats ir feel real warm temporarily?
 

xjhuez

Senior Member
Messages
175
Yoyr night attack is not due to cortisol. If your cortisol were high you would have not wanted to go to bed and sone insomnia. Are the acute attacks at night only after fallung asleep? When you woke up did you have sweats ir feel real warm temporarily?
I was warm, but not sweating. They are always after falling asleep, usually 1-3am. They're very inconsistent, I've not had one for 2 weeks. I did have alcohol before bed, but I don't see how that could cause it 4 hours later, my liver should have taken care of it by then. It could conceivably be caused by nightmare I suppose - I wouldn't know as I have absolutely zero dream recall.
 

heapsreal

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To summarize some issues a lot (since the actual mechanisms can be mind-bogglingly complex):

Chronic or traumatic stress may lead to hypothalamic-pituitary-adrenal axis dysregulation (the term which I believe is more accurate to use than the term "adrenal fatigue"), HPA dysregulation for short.

HPA dysregulation leads to lower production of adrenal cortex signals/hormones. This includes lower cortisol and/or DHEA, progesterone, pregnenolone, testosterone, estradiol, or aldosterone.

The primary signal for stress is norepinephrine. Norepinephrine is in a positive feedback loop with corticotropin releasing hormone. This positive feedback loop is interrupted by cortisol signaling. To increase norepinephrine, the brain has to also reduce production of some or all of the control signals that suppress norepinephrine signaling. These include reductions in serotonin, dopamine, GABA, etc.

Stress (particularly if it is a perceived threat), may lead to an increase in pro-inflammatory cytokine signaling from the brain and from the immune system (which is directly innervated by neurons of the sympathetic nervous system - the primary norepinephrine-releasing neurons of the nervous system). Stress may also lead to an increase in histamine signaling from brain mast cells. These changes lead to an activation of the immune system. These changes in large excesses may lead to an increase in inflammatory processes. The loss of anti-inflammatory signaling - which includes cortisol, DHEA, progesterone and testosterone - exacerbates these pro-inflammatory changes.

Excessive pro-inflammatory cytokine signaling may trigger automatic defensive programs in the brain. Defensive programs may induce behavioral changes including depressed mood, loss of interest or motivation in activities, loss of enjoyment from activities, social isolation, changes in sleep including the desire to sleep excessively.

There may be a loss of energy from excessive pro-inflammatory cytokine signaling. The actual mechanisms of the loss of energy are not clear. I currently speculate that perhaps there may be impaired brain astrocyte conversion of thyroxine (T4) to triiodothyronine (T3) - which leads to a hypothyroid central nervous system with a euthyroid body (as in Alzheimer's disease). Perhaps the increase in pro-inflammatory cytokines is one of the signaling problems leading to HPA dysregulation, aside from excessive norepinephrine signaling. However, other regulatory systems may also be involved - such as the opiate signaling systems (which also involve dopamine signaling).

HPA dysregulation, from whatever cause, leads to a loss of energy. The loss of energy production, however, under some circumstances. These circumstances include bipolar disorder and attention deficit/hyperactivity disorder with hyperactivity. In these cases, norepinephrine production is an effective signal for energy.

Nutrition plays a large role in the development of HPA dysregulation. Omega 3 vs. Omega 6 balance helps determine the balance between inflammation and anti-inflammation. Various nutrients (such as the B-vitamins, fat soluble vitamins, magnesium, etc) are cofactors for many of the processes involving signal production. Vitamin A and D are generally anti-inflammatory signals. Vitamin D reduces insulin resistance (which helps the body tolerate low blood sugar from impaired cortisol signaling), increases serotonin and dopamine production. Vitamin A helps regulate the sensitivity to various hormones/signals such as thyroid hormone.

The other endocrine signaling systems such as the reproductive system are in play. Testosterone helps reduce norepinephrine, increases dopamine production. It also suppresses adrenocorticotropin releasing hormone and directly inhibits adrenal cortex activity - this may be significant depending on the sum of signaling interactions and problems a person has. Estrogen acts similarly to a monoamine oxidase inhibitor - thus increasing serotonin, norepinephrine and dopamine (but serotonin primarily). Estrogen in relative excess may be pro-inflammatory, reduces free thyroid hormone. Thyroid hormone signaling loss is compensated by an increase in norepinephrine production with simultaneous activation of adrenal cortex signals. Over time, however, this compensation may fail as HPA dysregulation occurs. Insulin, glucagon, the incretins, etc. also have a role. Insulin, itself, is pro-inflammatory. Growth hormone has a calming effect and is anti-inflammatory. Etc. etc. etc. etc.

The entry point of all these processes is stress. This is represented primarily by norepinephrine signaling. However histamine (from brain mast cells) and pro-inflammatory cytokines (from brain microglia) are also involved in the process. Stress induces responses that are ostensibly designed to improve survival. The problem is that in the modern world, these responses may be dysfunctional instead.

===

Given the complexity of the interactions involved, a single intervention may or may not work. Which direction an intervention goes depends on the sum of the changes that occur as a result of that intervention. In psychiatry, the usual answer to a question is "It depends."

Stress is the entry point. Environmental and behavioral interventions would clearly help with few downsides.

Low dose testosterone may help, particularly in women, by helping to reduce norepinephrine and increasing dopamine signaling, and helping to reduce pro-inflammatory signaling. Low dose testosterone would not help in men since it may do nothing or it would suppress endogenous production of testosterone, leading to lower overall testosterone levels. Men would need replacement doses of testosterone. Testosterone, however, may also worsen adrenal cortex function depending on a person's susceptibility to this. In men, exogenous testosterone treatment also suppresses testicular thyroid releasing hormone production, leading to a loss of thyroid hormone production, which then leads to an increase in norepinephrine production. This is why in certain men, even if hypogonadal, testosterone treatment is intolerable. The rest of the system has to be optimized before testosterone treatment can be done.

Tamoxifen (I would prefer this to Clomiphene due to the visual changes that can occur with Clomiphene) is a weak estrogen. This blocks the stronger estrogens from being sensed by the brain. This then causes the brain to release more Luteinizing Hormone to stimulate testosterone production, leading to estrogen production. The increase in testosterone would have the effects listed previously. The problem is that Tamoxifen also blocks estrogen. This leads to lower estrogen signaling activity. Estrogen helps control norepinephrine by increasing serotonin and dopamine production. Estrogen is also needed to improve sensitivity to testosterone by increasing testosterone receptor production. Estrogen is also important in generating energy, motivation, drive, competitiveness, sex drive (libido). Estrogen (particularly in women) is important for neuron growth and memory. The loss of estrogen signaling, depending on the balance with testosterone, may lead to negative effects. If testosterone production is driven high enough, then perhaps this would improve things overall. This is particularly true in men. However, in women, this may not occur and destabilization of the system and dysfunction may occur instead. This is why many women do not like treatment with Tamoxifen or Arimidex for breast cancer.

Cortisol treatment alone may or may not work. Cortisol treatment in sub-replacement doses helps because it helps break the norepinephrine-CRH positive feedback loop. Cortisol also acts in the brain to improve concentration/focus by allowing the brain to ignore emotionally distracting memories or information. Cortisol also is the most important anti-inflammatory signal that reduces immune system activity. Cortisol triggers gluconeogenesis - helping improve blood sugar production. etc. etc. Thus it can be a useful component of treatment. However, Cortisol treatment alone also suppresses adrenal cortex activity. Thus, there is also a loss of pregnenolone, progesterone, DHEA, testosterone, estradiol, aldosterone, etc. If this loss is large enough, then the person may be worse off than without treatment. Since the majority of these other signals are calming, help control norepinephrine, are anti-inflammatory signals, a significant loss may cause the opposite intended effect of cortisol treatment. This is where some people become more tired, get "brain fog", become more anxious, etc. on cortisol monotherapy.

A systematic treatment has to be considered to address the multiple issues that invariably occur, contributing to HPA dysregulation. Single modality treatments may help - particularly in those people who don't have large problems in the rest of their system. But often, in more severe cases, they don't. A systemic approach would then be needed. I would count the person who responds to monotherapy as very fortunate.
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Romeo B. Mariano, MD, physician, psychiatrist
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