QUESTION FOR RICH: Thoughts on ACTH, HPA axis, n Growth Hormone?

Discussion in 'Fibromyalgia Main Forum' started by nitekitty, Jun 12, 2008.

  1. nitekitty

    nitekitty New Member

    What are your thoughts on how your protocol will affect ACTH levels and the HPA axis? In your hypothesis, how exactly are the ACTH levels affected through your protocol? or what mechanism or what biochemistry would change?

    Also, as a side note--- In theory, How would human growth hormone be affected by your protocol? While on a dysautonomia site recently a girl posted that she had tested abnormally low for human growth hormone. In theory, would the protocol increase human growth hormone production and if so, How?

    As always, I understand you cannot give medical advice. So all of these questions are completely hypothetical.


    [This Message was Edited on 06/12/2008]
  2. richvank

    richvank New Member

    Hi, Gen.

    I expect that treatment to lift the partial methylation cycle block and to restore glutathione to normal levels will correct the HPA axis dysfunction as well as the low human growth hormone.

    I have both specific and general reasons why I believe this. The general reason is that I currently believe that all the biochemical abnormalities and symptoms in most cases of CFS can be traced back to a partial block in the methylation cycle and glutathione depletion. But I realize that that is not a very satisfying answer for anyone who doesn't have this same belief! (;-)

    So, down to specifics. First I have to give some general background:

    Proteins consist of certain sequences of amino acids connected together in long chains.

    When connected together in a protein, the amino acids are called residues.

    One of the amino acids that is found in many proteins is cysteine.

    Cysteine contains a sulfur atom in a chemically reduced state.

    When cysteine is placed in a protein, it is always present in pairs of cysteine residues, often separated from each other in the amino acid chain.

    Proteins are made inside living cells.

    The amino acids are connected together within the cytosol, which is the general region inside the cell that is not contained within any of the organelles.

    The chemical environment in the cytosol is maintained in a reducing state by glutathione. Specifically, by maintaining the proper ratio of reduced to oxidized glutathione.

    This is particularly important for cysteine, because if the conditions become too oxidizing, each two cysteine molecules will join together to form cystine molecules before they are supposed to.

    After the amino acids are connected together, they pass into an organelle called the endoplasmic reticulum.

    The chemical conditions in the endoplasmic reticulum are maintained in a more oxidizing condition than in the cytosol.

    One of the things that happens in the endoplasmic reticulum is that the cysteine residues are joined together with their proper partner cysteines, to form cystines, which have disulfide bonds. This hooks the amino acid chain together on itself in certain places, and the result is that the protein molecule obtains its proper tertiary structure. This structure is important for the protein to be able to do its job.

    Some of the hormones are in the class called peptide hormones. That means that they are short proteins. They are also called secretory proteins, because they are made inside certain cells, but are then exported to influence cells in other parts of the body.

    Some of the hormones contain pairs of cysteine residues, connected together as cystine.

    The pituitary gland produces a molecule called POMC (proopiomelanocortin). This molecule is eventually broken up into pieces, which include ACTH, MSH, and endorphin.

    The initial POMC molecule has a “hook” at one end, which is formed by two sets of cystine disulfide bonds.

    This hook is used to route the molecule to the regulated secretory pathway, so that the export of the resulting hormones will be regulated properly.

    If this hook is not properly formed, the POMC molecule will be routed to the unregulated secretory pathway.

    O.K., so much for the background info. Now let’s talk about CFS.

    In most cases of CFS, there is glutathione depletion. This seems to affect the cells in the pituitary gland.

    When glutathione is depleted, cysteine molecules cannot be maintained in the cysteine state, but instead react to form cystine.

    When this happens, the cell is not able to make proteins that contain cysteine properly.
    Many of the malformed proteins will be detected and recycled by the cell, through what is called the proteosome. This organelle takes proteins apart, so that the amino acids can be used over.

    In the case of POMC, some molecules are probably made, but do not have their hook formed properly. The result is that they are routed to the unregulated secretory pathway.

    This causes whatever low amount of ACTH is produced to be secreted in a nonregulated way. I believe this explains the HPA axis dysfunction in CFS, because ACTH is what signals the adrenal cortices to secrete cortisol. In many cases of CFS, the cortisol levels are too low, and they do not have the normal diurnal variation.

    You also asked about human growth hormone. The explanation is a little different for hGH, but it still boils down to a problem with redox control, because of insufficient glutathione.

    This same mechanism explains the abnormalities with oxytocin, antidiuretic hormone (producing the high daily urine volume and constant thirst), and perforin (lowering the natural killer cell activity) in CFS. I think it explains some other endocrine problems in CFS, also, but I haven’t had time to track down all the biochemistry yet.

    I hope this helps.


    [This Message was Edited on 06/12/2008]
  3. nitekitty

    nitekitty New Member

    This is good stuff. Thanks for the long explanation. I really appreciate it.

    Some more side questions---
    Do you think long term Glucocorticoid use could cause further damage (whether temporary or permanently) to a CFS patient's HPA axis/ hormone systems? If so, how?

    In short--- I was put on Fludrocortisone (Florinef) for my Orthostatic Intolerance. This was particular for two reasons-- One, I desperately needed to gain weight at the time. and Two, I had been put on Toprol (Atenolol prior to that) which lessened my episodes of day to day pre-syncope but actually increased the frequency of actual syncope episodes. The Florinef was like a drug I had to take in order to lessen the horrible side effects of the beta blocker.
    Lovely I know.

    Anyway, On the Florinef I gained 30 lbs rapidly. I stopped it after a year (and lessened my dose of beta blocker significantly). Yet I continued to gain weight after stopping the Florinef. 6 months later I had gained another 20 lbs.

    I feel like the Glucorticoid to counteract the already awful beta blocker really screwed me up big time.

    CFS patients a lot of times have a tendency towards weight gain. Why?

    And How can a CFS patient have a low Cortisol level and yet gain extensive weight around the middle?

    I have not had my Cortisol tested. Yet I went from not being able to gain any weight, to gaining a ton of weight around the middle on Florinef, to now not being able to take the weight off a year after stopping the med.

    Not sure if you have any insight into any of this but if you do let me know! ;) :)

    Always a pleasure.......
    and Thanks again,
  4. Slayadragon

    Slayadragon New Member

    This is very interesting. Thanks for sharing!
  5. richvank

    richvank New Member

    Hi, Gen.

    I'll have to plead ignorance on the effects of Florinef on weight, but here is my hypothesis to explain the weight gain that most (but not all) PWCs experience, apart from issues associated with use of Florinef:

    It comes down again to the depletion of glutathione, which is present in most PWCs.

    Again, some background:

    Human beings are normally capable of burning carbohydrates, fats and protein as fuels.

    Carbohydrates are converted mostly to glucose by the gut and liver, and the glucose enters the blood. Glucose is blood sugar.

    The cells normally import glucose from the blood, and it is passed through the glycolysis chain (located in the cytosol of the cell), which produces some ATP, and it is converted to pyruvate.

    Pyruvate enters the mitochondria, which are the power plants of the cells. Most of the energy derived from food is converted to ATP by the mitochondria.

    Pyruvate passes through the pyruvate dehydrogenase complex and is converted to acetyl CoA. It enters the Krebs cycle (citric acid cycle) (located in the mitochondria) as acetyl CoA.

    Depending on the type of cell and also on the availability of carbohydrates, the cell will normally also use fat as a fuel. Fats are broken down into fatty acids, and they are imported into the mitochondria, ushered by carnitine. Inside the mitochondria, they undergo beta oxidation and are converted to acetyl CoA, which can enter the Krebs cycle.

    The important point for the present discussion is that both carbohydrates and fats must enter the Krebs cycle as acetyl CoA.

    Also in the mitochondria is what is called the respiratory chain or the electron transport chain. Energetic electrons derived from oxidation of fuels by the Krebs cycle are delivered to the respiratory chain by NADH and FADH2, and their energy is eventually used to produce ATP from ADP. ATP is used to power many of the biochemical reactions in the cell. The electrons are eventually used, together with hydrogen ions, to convert oxygen to water.

    In the course of the operation of the respiratory chain, a small fraction of the oxygen is converted to superoxide, which is an oxidizing free radical. These must be properly dealt with, or they will damage the lipid membranes, DNA and proteins in the cell. The free radicals are normally taken care of by the antioxidant enzyme system. The basis of this system is glutathione.

    Now, let's talk about CFS. In CFS, most of the cases involve glutathione depletion.

    When glutathione is depleted in the mitochondria, the oxidizing free radicals are not properly quenched. One of the enzymes in the early part of the Krebs cycle is very vulnerable to attack by oxidizing free radicals. It is called aconitase.

    When aconitase is attacked, it is not able to perform its normal function, and this introduces a partial block early in the Krebs cycle.

    Unfortunately, acetyl CoA must enter the Krebs cycle just a little way upstream of this partial block.

    The result is that PWCs are not able to burn either carbohydrates or fats very well as fuels in the mitochondria.

    When the mitochondria cannot accept pyruvate, it is converted to lactate and goes into the blood. Some of it can be burned by other cells that don't have the partial block. The rest goes to the liver, is converted back to glucose by the gluconeogenesis pathway, and is exported back to the blood.

    As you can see, there is no net place for the glucose to go in what has been described so far. So what does the body do with it? Well, the pancreas senses that the blood glucose level is too high, so it raises its output of insulin. When insulin gets high enough, the liver and fat cells accept the glucose, and convert it into stored fat.

    Hence the weight gain that occurs when a PWC continues to consume carbohydrates at usual levels, but can't burn it as fuel.

    The reason the weight gain is so stubborn, once a PWC has it, is that the cells can't burn fat very well, either, because it has to come into the Krebs cycle as acetyl CoA also, and there is a partial block just downstream of where it enters.

    So what's the solution? Well, ultimately, the methylation cycle block must be lifted, so that glutathione can rise up to normal and quench the free radicals, restoring aconitase to normal operation and opening up the partial block in the Krebs cycle.

    In the meantime, many PWCs switch to a high protein diet, lower in carbs and fats. The reason this gives them more energy, without the weight gain, is that some of the amino acids that make up protein can enter the Krebs cycle beyond the partial block, and they can thus be burned for fuel more efficiently than can carbs or fat, by the PWC. Amino acids can also be converted from one to another by transamination reactions, so this helps to feed them in beyond the partial block. This reaction requires vitamin B6, some of which is lost over time, and I think this is why many PWCs test low in B6.


    [This Message was Edited on 06/12/2008]
  6. nitekitty

    nitekitty New Member

    Extremely helpful. Thank you!

    by the way, you mentioned carnitine--
    quick question: In your opinion-- For supplementation is it best to supplement L-Carnitine, or Acetylcarnitine, or Both?
    Right now I'm taking AcetylCarnitine but thinking of getting also L-Carnitine.

    When supplementing Amino Acids a lot of times I see on the label to take them on an empty stomach. Just how important is this? I tend to nibble on a little something very frequently throughout the day to keep from getting hypoglycemia symptoms, so I rarely ever have an empty stomach.

    Thanks again,

  7. deliarose

    deliarose New Member

    So where do you stand on the B6 supplementation issue if one has a CBS upreg?


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