Reposting this as seperate from the sleep thread. This is info from the methylation cycle theory/ treatment plan........



here's an answer from my questions to Rich Konenynburg a while back, that talks about HPA axis and methylation cycle connection: (I added some info in the brackets[ ] below.) HPA stands for Hypothalamus-Pituitary-Adrenal axis.

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 [a methylation cycle amino acid formed after homocysteine in the cycle].

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 [Adrenocorticotropic hormone or "corticotropin"], MSH, and endorphin. [The melanocyte-stimulating hormones (collectively referred to as MSH) are a class of peptide hormones produced by cells in the intermediate lobe of the pituitary gland. They stimulate the production and release of melanin (melanogenesis) by melanocytes in skin and hair. MSH is produced by a subpopulation of neurons in the arcuate nucleus of the hypothalamus. MSH released into the brain by these neurons has effects on appetite and sexual arousal.][ACTH acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. ACTH stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also sex steroids (androgens). ACTH is also related to the circadian rhythm in many organisms.]


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.

Rich