Cortisol and nitric oxide ..missing link

[hardasnails1973]

Vicious Circle Theory of Chronic Fatigue Syndrome and
Fibromyalgia

Captain David Williamsdavidwms@interpoint.netUpdate: July 1999

In a healthy person, 80% of the T-cells are resting and 20%
are activated to fight off normallyencountered pathogens, but in a person with chronic fatigue
syndrome (myalgic encephalomyelitis),60-80% of the T-cells are activated. Simply put, the immune
system in chronic fatigue syndrome is inoverdrive.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6
(IL-6) are both upregulated in chronicfatigue syndrome (abstract) (abstracts). IL-6 is especially
upregulated after fatiguing activity(abstract).

Some researchers suggest the root cause of this hyperimmunity
might be a re-activating HHV-6Avirus (abstracts) (abstract). Others suggest an unknown virus.

Some believe a mycoplasma bacteriais responsible (abstracts). A few think it is a yeast
(abstracts). It might be an allergy (abstracts)according to other experts.

The Low Cortisol (Glucocorticoid) Connection

The term glucocorticoid applies to adrenal steroids with the
main action on cellular metabolism. Theprincipal glucocorticoid is cortisol (aka hydrocortisone). The

actions of the cortisol in the bodyinclude the regulation of protein, carbohydrate, fat, and
nucleic acid metabolism. Cortisol raise theblood glucose by acting as an insulin antagonist and by
suppressing the secretion of insulin, therebyinhibiting glucose uptake in peripheral tissues and promoting
the synthesis of glucose(gluconeogenesis) in the liver.

Depressed cortisol levels would result in excessive amounts of

insulin and contribute tohypoglycemia.

Cortisol also has anti-inflammatory properties (abstract),
which are probably related to their actionson the microvasculature as well as to cellular effects. The
anti-inflammatory action includes theinhibition of interleukin-6 (IL-6) (abstract), known to be
upregulated in chronic fatigue syndrome(abstract) and in fibromyalgia (abstract).

The hormone maintains normal vascular responses to
vasoconstrictors and opposes the increase incapillary permeability characteristic of acute inflammation.
Cortisol can cause an increase inleukocytes; the circulating leukocyte mass is increased due to

release from the bone marrow ofmature cells as well as to inhibition of their egress through
the capillary wall. Extra amounts of thehormone can also produce a depletion of circulating
eosinophils and of lymphoid tissue, specifically Tcells (thymus-derived lymphocytes). The mechanism is by
redistribution from the circulation into othercompartments. Thus excessive cortisol can impair
cellular-mediated immunity.

On the other hand, cortisol also inhibits the production or
action of the local mediators ofinflammation such as the lymphokines and prostaglandins. The
hormone also inhibits the action andproduction of immune interferon by T lymphocytes and the
production of lymphocyte-activatingfactor (interleukin 1) by macrophages. The action of cortisol
in suppressing fever may be explainedby the latter effect, since IL-1 appears to be identical to
endogenous pyrogen, which can activate thehypothalamic fever center. Cortisol can also inhibit the
production of T cell growth factor (IL-2) by Tlymphocytes. The hormone reverses macrophage activation and
antagonize the action ofmigration-inhibiting factor (MIF), leading to reduced
adherence of macrophages to vascularendothelium.

Cortisol also inhibits prostaglandin and leukotriene
production by inhibiting the activity ofphospholipase A2, thus blocking release of arachidonic acid
from phospholipids. Finally, cortisolinhibits the inflammatory actions induced by bradykinin and
serotonin, such as increased vascularpermeability. It is probably only at pharmacologic dosages
that antibody production is reduced andlysosomal membranes stabilized, thereby suppressing the
release of proteolytic acid hydrolasesstored in these cytoplasmic organelles.

Cortisol, with the help of thyroid hormones, also stimulate
the production of growth hormone(abstract) (abstract). Cortisol levels are responsive within
minutes to physical trauma,surgery, exercise and psychological stresses such as anxiety
and depression. Normaladrenal secretion on a tranquil day is 20 – 30 mg, but can
increase in a healthy person to200 – 300 mg under stress!

Hypoglycemia is also potent stimuli of ACTH and cortisol
secretion in healthy people, but, insomeone with a defective response in the hypothalmus/pituitary

axis, such as those with chronicfatigue syndrome and fibromyalgia, the cortisol response to
low blood sugar would be bluntedallowing insulin to over-control blood sugar, sending the
person with CFS and FM into ahypoglycemic attack! People with this illness are required to
reduce high glycemic index foods fromtheir diet in order to prevent low blood sugar. A high protein

diet is the number one recommendedchange in this recovery protocol (link). The stress of dealing

with a serious illness like chronic fatiguesyndrome or fibromyalgia requires lots of extra cortisol, yet
most doctors refuse to supplementhydrocortisone even though their patients show borderline low
levels and no cortisol reserve. If theirpatient suffer from trauma, they would quickly give
hydrocortisone yet they back away from the drugwith severely stress patients with a chronic illness. The
reasons why elevated glucocorticoid levelsprotect the organism under stress are not understood, but in
the absence of glucocorticoids, suchstresses may cause hypotension, shock, and death. For these
reasons, glucocorticoid administrationshould always be increased in individuals with hypofunction of

the pituitary-adrenal axis during stress.People with CFS and FM should wear a medical bracelet begging
for hydrocortisone in case ofemergency!

Cortisol also has a major action on the distribution and
excretion of body water. It subserves theextracellular fluid volume by retarding the flow of water into

cells. It promotes renal water excretionby suppressing the secretion of vasopressin, increasing the
rate of glomerular filtration, and actingdirectly on the renal tubule, the consequence being to guard
against water intoxication by increasingsolute-free water clearance. Glucocorticoids also have weak
rnineralocorticoid-like properties, andincreasing doses produce renal tubular sodium reabsorption and

increased urine potassium excretion.Glucocorticoids also can influence behavior; emotional
disorders may occur with either excesses ordeficits of cortisol. Lastly, cortisol suppresses the
secretion of pituitary POMC and peptides derivedfrom this precursor molecule (ACTH, P-endorphin, and
P-lipotropin) as well as the secretion ofhypothalamic CRH and vasopressin.

Cortisol also stimulates erythropoiesis (the building of new
red blood cells) which is extremelyimportant function in chronic fatigue syndrome and fibromyagia

(abstract). It could be suggested thatlow levels of serum cortisol might be a factor in the
borderline anemia observed in these illnessessince low levels of this important hormone has been noted
(abstracts).

In additon, glucocorticoids have been shown to enhance thyroid

releasing hormone (TRH) geneexpression in three different cell systems in vitro, an effect

that occurs, at least in part, throughtranscriptional activation (abstract). The synthetic
glucocorticoid dexamethasone substantiallyelevated the synthesis of TRH prohormone and its intermediate
products of processing in culturedanterior pituitary cells, an observation that is consistent
with an overall upregulation of both thesynthesis and degradation of the TRH precursor. Synthethic
cortisol caused a significant 75.7%increase in newly synthesized TRH prohormone, suggesting that
the glucocorticoid raised thetranslation rate.

Thyroid hypofunction has been noted in hypoadrenalism;
however, it has been found counterproductive to treat this dysfunction with thyroid hormones
(link). Rather, treating the glucocorticoiddeficiency in reported to be more succesful in raising thyroid

output.

Could low cortisol be the cause of the immune pattern observed

in chronic fatigue syndrome andfibromyalgia? In the opinion of this researcher, the answer
is, “Almost, but not quite!” If we alsoconsider the effects of low DHEA coupled with low cortisol,
the pattern of hyperimmunity that wouldemerge will fit the pattern observed in CFS and the mystery of

hyperimmunity in CFS is solved!

The Low DHEA Connection

DHEA levels are also controlled by the same factors that
control the production of cortisol so thatboth should be low is only a natural conclusion. If you have
low cortisol–you have low DHEA! Ifyou have low DHEA–you have low cortisol!

DHEA is much easier to measure than cortisol so if there is
any single test you should seek out itshould be plasma DHEA levels.

Fact is, findings of low levels of DHEA in CFS might even be
considered as a marker for CFSaccording to researchers at Trinity College Medical School in
Dublin, Ireland (abstract). It shouldalso come as no surprise that DHEA has been found low in this
illnesses by every effort to measurethe hormone to date(abstract)! A blunted DHEA response to ACTH

has also been noted in chronicfatigue syndrome (abstract).

DHEA is quantitatively the most abundant hormone in humans and

mammals, with a wide variety ofphysiological effects, including major regulatory effects upon

the immune system (abstract). Two ofthe most striking aspects of DHEA are a steady decline in DHEA

with age and a significantdeficiency in DHEA in patients with several major diseases,
including chronic fatigue syndrome,cancer, atherosclerosis, and Alzheimer’s disease. The hormone
is secreted in a non-sulfated (DHEA)and sulfated form (DHEA-S). The two are apparently
interchangeable, and it appears likely that itsphysiological effects are achieved by derivative molecules
that have yet to be identified. DHEA hasother positive effects on immunity (abstract). The
neurohormone also inhibits IL-6, known to beupregulated in CFS (abstract) (abstract). Research has shown
that DHEA benefits people withLupus (abstract).

The release of DHEA and cortisol from the adrenal glands is
controlled by ACTH. ACTH iscontrolled by CRH. Recent evidence has been published
indicating that there might be a defect inCRH secretion from the pituitary gland (abstract) in CFS.
Research done in women with fibromyalgiaalso indicates a HPA axis problem (abstract).

So, in summary, the evidence indicated that the hyperimmunity
in CFS is caused by secondaryhypoadrenalism due to a blunted response to CRH and
vasopressin and the resulting low cortisol andDHEA.

Yet, many doctors still refuse to supplement with
hydrocortisone and/or DHEA! They site a recentstudy sponsored by NIH which indicated that people with
chronic fatigue syndrome treated withdaily low doses of hydrocortisone fail to report a significant

recovery (link) (abstract).

A study done in the UK got better results, but still not a
remarkable recover as would be expected.(link)

[hardasnails1973]

Does this rule out hypoadrenalism in chronic fatigue syndrome
and fibromyalgia?

Absolutely not! Failure to respond to daily low doses of
hydrocortisone should have been expectedsimply because daily dosing with an external source of
cortisol would, via feedback mechanismswithin the HPA axis, lower the person’s own production by the
exact amount taken by mouth.Letters to the editor of JAMA about the article discuss all
the various ways that the study might havegotten better results (letters) but none of the authors seem
to address the problem straight forward.

The whole concept that low doses of hydrocortisone would
improve chronic fatigue syndrome andfibromyalgia, and yet not cause feedback to the adrenal gland
was promoted by Professor WilliamMcK Jefferies in his book, “Safe Uses of Cortisol”(Link). To a

certain extent, the evidence suggestthat he is right. Low dose cortisol did not cause measurable
adrenal suppression in ~30% of thesubjects in the studies mentioned above providing the doses
were kept below a certain level.

Was the non-suppressing dose high enough to reverse the
disease process? Likely not.

People with chronic fatigue syndrome and fibromyalgia do make
a remarkable and quick recoveryfor the first few days when first starting daily
hydrocortisone if the dose is high enough, indicating thatincreasing cortisol bioactivity eliminates most of the
symptoms of the illness. But these marvelousimprovements in health are quickly lost on a continued daily
schedule because feedback quicklylowers the production by the same amount taken daily in ~70%
of those studied.

In fact, the NIH scientists should have known the daily dosing

protocol used to increase cortisolactivity in a PWC was doomed to a high failure rate from the
beginning. The money to do the studyshould have been spent in a trial of EVERY THIRD DAY (ETD) .
Since ETD gives the patientone day off for every two days of increased cortisol
bioactivity, the chances of HPA axis suppressionare reduced to almost nil.

Alternated Day Therapy is a well known tool used for 30+ years

in hormone dosing (abstract).

Regardless, it’s not easy to get around feedback because most
fast acting synthetic cortisol drugs arebioactive for about 36 hours. Hydrocortisone, a natural
cortisol, is bioactive for about 24 hours, andmight be better for reducing feedback due to its shorter
bioactivity.

Recommended Dosing Schedule to Get Around Feedback Problems

Every Third Day (ETD) dosing is a more effective schedule than

Alternate Day Therapy. Throughtrial and error with daily and then with Alternate Day
schedules, it was found that ETD wasnecessary to get around feedback. The recommend dose of
hydrocortisone is 0.6 milligram perkilogram of body weight ( ~1/4 mg per pound) first thing in
the morning on day one. This dose isequal to the same given in the studies, only given in one dose

every three days verses dosing everyday.

At bed time that evening, take a small dose of valium or
klonopin to increases GABA receptors inthe brain if you can’t sleep (more on this later). Also, since

physical activity burns cortisol, make dayone you primary activity day, doing all your house cleaning,
shopping, mowing the lawn and etc. Youcan also schedule lots of exercise on this day. Fact is, start

planning an exercise program based onEvery Three Day schedule.

The hydrocortisone will naturally feedback and reduce the
production of cortisol the next day. Theincreased cortisol bioactivity on day one also sends a signal
to the brain to increase 11beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme
that deactivates cortisol (abstract).In other words, a person taking a large amount of cortisol on
day one, can expect to experience adrop in adrenal cortisol output the next day, along with an
increase in the production of the enzymethat deactivates cortisol. If you kept this high dose up for
two weeks, your adrenal glands will shutdown and be extremely difficult to restart. Because the
chronic use steroids can lead to detrimentalsystemic side effects due to feedback, many doctors are afraid

to give hydrocortisone to a chronicfatigue syndrome or fibromyalgia patient. There has been so
much publicity about permanent adrenalfailure (Addison’s Disease) due to steroid use, that most
doctors block out all conversation about aneffective way to take the hormone. They figure that there is
just no way around feedback!

But there is a simply way to prevent feedback and allow for
effective dosing of steroids! This is thegenius in the ETD protocol. Since 11 beta-HSD is the enzyme
that deactivates cortisol, if a personcould take an 11 beta-HSD inhibitor on day two, less of their
cortisol would be deactivated, allowthe lowered output to go much further than normal. An 11
beta-HSD inhibitor would not increase thecortisol level on day two, inhibiting the inhibitor of
cortisol would only extend the time that the lowlevel of cortisol remained bioactive. In other words, the low
cortisol would still be low, but it wouldlast much longer and be able to offer you more benefit.
Feedback mechanism would sense lowcortisol and signal the HPA axis to halt its cut in cortisol
production.

Author’s note: This researcher thought that he was allow in
seeing the value of combining an 11beta-HSD inhibitor within the context of a steroid treatment
protocol but recently found evidence thata similar meathod is being used at the University of Utah
School of Medicine to treat skin disease(abstract). It appears that the Utah researchers might have
got the idea from work done in the UKwith glycyrrhizic acid (abstract). Researchers in Berlin
working on breast cancer also show anunderstanding of the concept of extending cortisol bioactivity

via 11 beta-HSD inhibition (abstract).

Glycyrrhizic acid in licorice extract, progesterone, and
flavonoids in grapefruit, are the only knowneffective inhibitors of 11 beta-HSD readily available. (How
progesterone alters 11 beta-HSD is notunderstood by this researcher at this time.) You could eat 10
– 15 grapefruit or take about ~4 gramsof licorice extract on the morning of day two to inhibit the
enzyme. This method can potentiatecortisol bioactivity up to 10 fold, making it possible to get
great benefit from low levels on day two.Feedback mechanisms sense the lowered 11 beta-HSD activity on
day two and signal the body toincrease production. Similar mechanisms also sense the lower
cortisol on day two and tell the HPAaxis to increase production because the big blast of cortisol
on day one was just a fluke!

Things tend to balance out on day three and the person with
chronic fatigue syndrome or fibromyalgiafeels like they do normally. Since day three is an off day,
you plan your schedule so that you canrelax and conserve all the cortisol you can. Avoid physical
activity and stress as much as possible andday three will go great.

The recommended dose of licorice extract is based on your
response to the herb, and on the amountof glycyrrhizic acid in each gram of extract you use. Personal

experience indicates 5 to 6 milligramsper kilogram of body weight (2.27 mg per pound) or about 500
milligrams for a 220 pound man.You can also take a half-dose about 3 PM if you feel the need
for a little lift.

Day two should also be an activity day, doing all you can do
without over doing it. But be sure to beas physically active as your energy level will allow. In order

words, don’t lay around like normal–getup and get going!

Day three is off day for both hydrocortisone and glycyrrhizin,

and will reset both your cortisol and 11beta-hydroxysteroid dehydrogenase homeostasis and get you
ready for a return to high doses ofhydrocortisone on the next day.

As an extra precaution to make sure adrenal suppression is not

occurring, skip an extra day (4 days)every 9 days. You can also go off hydrocortisone and
glycyrrhizin completely for 1 week every 6-8weeks. Work with your doctor closely and, between the two of
you, work out a plan that will assureboth of you that feedback is not occurring. This protocol has
not been tested in large numbers ofpeople so make sure you use caution and go off often to insure

yourself and your doctor that thisprogram will be successful.

One other point should be made here if one is to get the
complete cortisol picture. Doctor PMStewart, a researcher at Queen Elizabeth Hospital in UK, feels

that medical professionals are missingthe boat by being obsessed with levels of hormones as now
measured. He makes a strong point thatthe bioactivity of cortisol, thyroid and other hormones is
controlled by the enzymes that deactivate thespecific hormone in the targeted organ (abstract).

As mentioned above, cortisol is converted to the inactivity
metabolite, cortisone, by 11 beta-HSD. Ifa PWC has high levels of 11 beta-HSD in the kidneys or other
targeted organs, more of their owncortisol will be converted to cortisone in less time than
someone with normal levels of 11 beta-HSD.Cortisol levels in blood or saliva of a someone with chronic
fatigue syndrome and/or fibromyalgiaoften show low normal levels, indicating low cortisol is not
causing the symptoms. However, cortisolmeasured in such a fashion does not determine cortisol
bioactivity in the targeted organ, especially thekidney. Simply measuring cortisol in the doctors office might
be a waste of time and money and couldbe very misleading, resulting in strong resistance to any
treatment program supplementinghydrocortisone. The best way to accurately measure cortisol
activity in a person with chronic fatiguesyndrome and fibromyalgia is to measure the ratio of free
cortisol to free cortisone in urine collectedover a 24 hour period (abstract). And, this must be done on a
day when the patient feels like crap.Run the test on a day when the patients feels great and
everything shows normal. My strong advice isto always INSIST on being tested when you feel the worse!
Getting a test done when you feel greatis like taking your car to the mechanic when its running
perfect! You might want to spend the daybefore your scheduled 24 hour urine cortisol test exercising
as much as you can to burn off somecortisol. Exercising before such a test is not cheating.
Healthy people can and do perform work andexercise the day before most test. Fact is, being underactive
before a cortisol test as most peoplewith chronic fatigue syndrome and fibromyalgia usually are,
could be a major factor is why cortisollevels sometimes are normal in people with this illness.

Copy this Physician’s Information sheet and discuss this issue

with your doctor!

NITRIC OXIDE

If the topic of nitric oxide is new to you, it will help a lot

if you take the time to review some generalbackground on this toxic agent. Click here for nitric oxide
basics!

An increase in nitric oxide during immune activation lowers
overall adrenal output and, coupled withlow DHEA, will cause the same clinical picture now evident in
chronic fatigue syndrome andfibromyalgia (abstracts). Read a few of the abstracts and you
will see that increased levels of NO willnot only lower cortisol, but also lower aldosterone, DHEA,
pregnenolone and catecholaminesecretion.

The most direct evidence that NO alter adrenal function comes
from work with rats. Dr. CBCymeryng, et al, at the University of Buenos Aires found that
NO significantly decreasedcorticosterone (the same as cortisol in man) production both
in unstimulated and incorticotropin-stimulated zone fasciculate adrenal cells, in a
dose-dependent manner. The productionof pregnenolone from cholesterol was also significantly
reduced. This effect was reversed by ferroushemoglobin (abstract).

But primary hypoadrenalism due to weakened adrenal glands is
not as much in evidence in CFS andFM, as is secondary hypoadrenalism (defect in
pituitary-hypothalmus axis). The evidence in chronicfatigue syndrome and fibromyalgia all point to a reduced ACTH
response to CRH and vasopressin.

But it does not matter in this theory whether you have primary

or secondary hypoadrenalism!Upregulated nitric oxide due to hyperimmunity (coupled with
another toxic gas, carbon monoxide)also alters hypothalmus-pituitary function and would create
the exact same pattern now evidenced inthese illnesses (abstract).

A vicious circle begins to form! Low cortisol and DHEA allows
the immune system to becomehyper; hyper immune response (upregulated nitric oxide and
other cytokines) alters HPA axisfunction, resulting in low cortisol.

If one were looking for a single factor that would completely
explain chronic fatigue syndrome,including every single crazy symptoms known to occur in this
illness, you would need only look atupregulated nitric oxide (NO).

Dr. AM Levin (Link) has examined this nitric oxide theory and
is able to tie it in seamlessly with yeastinfections. I suspect that he is on target, but I would also
add that I believe many other pathogens canalso connect and cause the same situation. Still, I do like
his work in this area. He is the first MD tojump on the bandwagon of upregulated NO as a major factor in
CFS.

As mentioned earlier, Tumor Necrosis Factor-alpha (TNF-a) is
known to be increased in CFS.(Taking DHEA supplements helps down-regulates TNF.
(abstracts))

Tumor necrosis factor-alpha and other Th1 cytokines
upregulates the production of nitric oxide (NO)and nitric oxide synthase (NOS) (abstracts) therefore, it is
safe to say nitric oxide is upregulated inCFS (abstract).

Even though no studies have been done to date about the strong

connection between TNF-alpha(known to be increased in CFS) and NO, there is evidence
showing a strong possibility ofupregulated NO is CFS. As a matter of fact, evidence suggest
that autoimmune pathogenesis initiatedby inflammatory responses within the CNS may result in part
from a vicious cycle in whichTNF-alpha and NO mutually provoke each other’s production
(abstract).

Another important body of evidence is that fact that natural
killer cell cytotoxicity, found low is CFS(abstract) (abstract), is also shown dose-dependently low when

chemical NO donors are addedduring afferent phase of NK stimulation with IL-12 and
TNF-alpha. Conversely, when an inhibitor ofNO synthase was added, a subsequent increase in the
cytotoxicity of the effector cells towards theNK-sensitive target cells (K562) was observed (abstract). In
other words, upregulated nitric oxidelowers natural killer cell activity and accounts for the
evidence found in CFS.

In support of this view of upregulated nitric oxide in CFS,
other medical researchers are alsobeginning to suspect this simple gas in playing a major role
in CFS. One theory involvesN-methyl-D-aspartate (NMDA) receptors in the brain. When brain

function is balanced, GABA andNMDA receptor activity is balanced. In CFS, however, NMDA
receptors become substantiallymore active than GABA receptors. HealthComm International
feels that a key component in theupregulation of NMDA receptors in CFS involves the
overproduction of nitric oxide. They state,”This molecule, itself a neurotransmitter, has been associated

with stimulation of the NMDA receptorsystem when released into the nervous system (Link).
HealthComm is using an aspect of nitric oxide’sfunction in the brain to show evidence of upregulation in CFS.

It look’s like they could be on to partof the problem in CFS–nitric oxide does upregulate NMDA
receptors (abstract). However, Isuggest this is a pattern that is more closely associated with

the symptoms of hypoadrenalism, than itis a single cause of CFS.

Here is were the valium every 3 days can help. The drug
enhances GABA binding and increasesGABA receptors (abstract), which, like a see saw, will lower
NMDA receptors, but tolerance doeshappen rapidly so dosing every third day is mandatory in the
benefit is to be continued.

One might also try low dose trazodone every day as a way of
down-regulating the NMDA receptors(abstract). This could also be the manner in which low doses
of selective serotonin reuptakeinhibitors (SSRIs) help some with CFS since these drugs also
down regulate NMDA receptors, atleast in the rat (abstract).

Recent research also shows that the amino acid homocysteine is

elevated in the spinal fluid and brainof PWC (abstract). This evidence supports the view that nitric

oxide is also elevated in CFS sincenitric oxide inhibits the enzyme that breaks down
homocysteine.

Nitric oxide is the most potent vasodilator known. Excessive
production of this simple moleculecauses the drastic fall in blood pressure during shock. Nitric

oxide is also now known to drasticallyreduce the pain threshold and to be responsible for increased
sensitivity to pain, especiallyfibromyalgia-like pain (references). Nitric oxide is
manufactured in cartilage cells (chondrocytes)(abstracts). Since nitric oxide stimulates the reception of
pain (abstracts), there can be little doubt thatNO is responsible for fibromyalgia pain in CFS!

NO also can stimulate insulin secretion by deenergizing
mitochondria (abstract). Insulin also increasethe release of NO in the vascular system (abstract)(abstract).

Since NO is a potent vasodilator,insulin produced in response to a high carbohydrate meal will
cause increased vasodilation making aPWCs with neurally mediated hypotension feel much worse. In
other words, insulin and NO have aclose association that will lead to hypoglycemic reactions in
PWCs, making a high protein dietmandatory in treating CFS. The activated immune system in
chronic fatigue syndrome andfibromyalgia also reduces the manufacture of new healthy red
blood cells (erythropoiesis) (abstract).A strong connection exist between the local activation of bone

marrow T-lymphocytes, increasedproduction of cytokines, and reduced levels of red blood
cells.

In additon, both inflammatory cytokines and nitric oxide (NO)
interfere with the way the bodymetabolizes iron (references) (abstract). Not only does NO
cause problems with iron metabolism,but defects in iron utilization and reutilization results in
reduced performance of many iron-requiringenzymes and proteins (references).

[hardasnails1973]

Research has found that when the immune system is activated
the critical period in the developmentof nutritional iron deficiency occurs after 30 to 40 days
without iron supplementation. The person isunable to maintain hemoglobin levels without endangering the
iron-requiring enzyme groups which areessential for life (abstract). This indicates that any single
illness or combinations of factors that canstimulate the immune system and increase nitric oxide
production for longer than 30 to 40 days, couldprogress into CFS in selected individuals.

A similar iron metabolizing problem exist in AIDS. As HIV
infection advances, progressive anemia isestablished. The study of iron metabolism in these patients
shows a pattern similar to that of theAnemia of Chronic Disease (see below). A group of Spanish
researchers think that these changes inAIDS might be due to iron sequestration in phagocytic cells
induced by release of cytokines from theimmune system (abstract).

Red cell hemoglobin is the most important iron-requiring
protein likely defective in CFS.Hemoglobin is the MAJOR scavenger of excessive NO, therefore,
an inability to remove this toxicimmune agent quickly before it vasodilates blood vessels
excessively and over reacts with healthycells can result in many of the symptoms, particularly
fatigue, neurally mediated hypotension, and jointpain. In addition, if nitric oxide is not being properly
scavenged, then problems with excessive NOcan occur even if NO is not upregulated.

As unbelievable as all this sounds, the very latest evidence
indicates that nitric oxide also controls theamount of oxygen reaching the cells. If you do not read any
link in this article, you shouldstruggle to read this one (Link) . The researchers found that
the loss of oxygen flips a switch thatreleases nitric oxide in the arteries to dilate blood vessels
and increase blood flow so that theremaining oxygen can be delivered to tissue. On the return
trip to the lungs, the oxygen that was lostin the arteries is recaptured in the veins, giving the
appearance of inefficient oxygen delivery. Theresearchers measured blood flow and oxygen concentration in
several regions of rat brain while therats breathed air with varying oxygen levels. They showed that

hemoglobin releases a form of nitricoxide in the small arteries that regulate blood flow, thus
promoting oxygen delivery. When the animalsbreathed oxygen under higher air pressure, oxygen levels
increased in tissue, and hemoglobincompensated by halting NO release and contracting blood
vessels.

The finding also clears up another puzzle. In test tube
experiments, hemoglobin scavenges NO andconstricts blood vessels. Yet in the body, hemoglobin does not

have this effect under normalconditions. “This tendency to constrict blood vessels seems to

oppose hemoglobin’s job of deliveringoxygen,” one researcher said. “Our findings explain why
hemoglobin doesn’t constrict blood vesselsin the body. It releases NO in the arteries to counteract the
NO it scavenges.”

But what if something goes wrong with this system? As
mentioned above, cortisol reversesmacrophage activation, therefore, it can be assumed that low
cortisol will allow macrophages to bemore easily activated by stimuli. Since these white cells dump

loads of NO into the system when theyare activated, maybe one major problem with chronic fatigue
syndrome is activated macrophages.Release of NO from macrophages has been visualized in the
mouse (abstract). Their activation inchronic fatigue syndrome is theorized to be similar to the
manner in which a cancer drug (Taxol)primes macrophages in cancer patients (abstract).

Nitric oxide primed macrophages are ready to dump their NO at
the least disturbance. This theorysuggest that increased stress of the faster blood flow through

the vessels, after isoproterenol isinjected in the TTT, releases this “primed” nitric oxide,
intensifying the effects of the drug causing theperson with activated macrophages to go into syncope rather
easily. The increased NO stimulates therelease of large amounts of prostacylin, which causes
bradycardia (slowing of heart rate)(references).

Physical activity would increased the release of NO from
primed macrophages simply because thestress of muscle activity would put pressure on the primed
macrophages causing them to dump theirNO. The action of the heart muscle would also place
alternating pressure on the macrophages. Flowstress of the blood flowing more rapidly through the vascular
system during exercise would alsorelease a lot of NO. So would a sudden drop in barometric
pressure. These factors would explainwhy chronic fatigue syndrome and fibromyalgia are noted for an

increase in symptoms after physicalactivity. Some with CFS and FM swear they feel worse just
before a weather front moves in, whichwould agree with the release of NO due to a drop in
atmospheric pressure.

Hemoglobin is not the only iron-requiring enzyme likely
defective in chronic fatigue syndrome andfibromyalgia. The cytochrome p450 liver enzyme system
(abstract) is also likely defective. Theseenzymes are responsible for metabolizing toxic chemicals and
drugs (most antidepressants) intometabolites that can then be removed from the body in the bile

or by the kidneys (link).

As mentioned earlier, inflammatory stimuli, such as TNF-alpha,

are increased in chronic fatiguesyndrome. TNF-alpha increases nitric oxide production and
nitric oxide reacts with the ironcomplexes in the cytochrome p450 enzymes thereby inhibiting
the action of these important liverenzymes. (abstracts) (abstract).

Defects in cytochrome p450 liver enzymes due to excessive
nitric oxide (abstract) will result in abuild up of environmental chemicals in the body and a
super-sensitivity to certain drugs. (references)

Most chemicals use in food processing do not cause problems
for healthy people simply becausehealthy people have normal liver enzymes and can metabolize
these chemicals and flush them out ofthe body. But in people with defective cytochrome p450
enzymes, these chemicals can build up inthe body to the point where they become toxic. Most chemicals
can cause this toxicity. (link)

The normal dosage of certain drugs can also cause toxic
reactions if they are not being properlymetabolized due to a defect in the p450 enzymes. (link) A
person with this illness might have toreduce dosages of certain drugs to as low as 1/10th of the
normal dose to avoid reactions. Otherdrugs might not work simply because they must be metabolized
into their bioactive metabolite inorder to become effective.

Fact is, the failure of the cytochrome p450 liver enzymes to
detoxify the body is likely somewhatresponsible for multiple chemical sensitivity and may even be
related indirectly to what is now thoughtto be responsible for Gulf War Syndrome. Researchers at the
University of Texas believe they knowwhat causes Gulf War Syndrome. A long term study of members of

an Alabama Seabee unit thatserved in the Persian Gulf War strongly indicated that many
veterans who became ill do not carry aspecific gene that attempts to neutralize the nerve gas Sarin.

That lends more support to the claim thatsoldiers in the Gulf War were exposed to small amounts of
nerve gas. (link) The genetic defect couldexplain why some soldiers were afflicted with the syndrome —
which has a wide range of symptomsresembling chronic fatigue syndrome. The biggest questions
about Gulf War syndrome has been whyone person got sick when the person next to him didn’t. But
now experts suspect a genetic reasonwhy some people got sick, linking the illness to damage from
certain chemicals.

Writing in the journal Toxicology and Applied Pharmacology,
the research team said a gene thatcontrols production of an enzyme known as type Q paraoxonase,
or PON-Q, which helps the bodydestroy toxins, might be responsible.

It is highly specific for the chemical nerve agents sarin and
soman as well as for the common pesticidediazinon. Fact is, several organophosphorus insecticides are
detoxified through the cytochromeP450/paraoxonase (PON1) pathway (abstract). The reaserchers
found strong statistical linksbetween Gulf War syndrome and veterans’ reports of exposure to

combinations of chemicals likepesticides and low-level chemical nerve agents. They predicted

in 1997 that it might be due to aPON-Q deficiency, and now that’s what they have found. Human
serum paraoxonase (PON 1)exists in 2 major forms (Q and R), which differ in the amino
acid glutamine and arginine, respectively.These PON allozymes hydrolyze organophosphates and aromatic
esters, and both also protect LDLfrom copper ion-induced oxidation.

The group had linked three different neurological syndromes to

the use of pesticide-containing fleacollars, highly concentrated insect repellent and pills
formulated with pyridostigmime bromide tocounteract the effects of nerve gas, as well as exposure to
low-level chemical nerve agents.

Other researchers have theorized about a similar mechanism in
chronic fatigue syndrome (abstract)involving toxicity through the GABAa receptor. Corrigan, et
al, discuss the possible involvement oforganochlorine compounds which are widespread in the
environment and may have similar toxiceffects through damaged cholinergic input to the dentate gyrus

of the hippocampus where cholinergicand GABAergic transmission are closely linked.

Researchers in Australia also found a close assoication
between organochlorines and chronic fatiguesyndrome(abstract) (abstract).

A defect in iron-requiring P450 liver enzymes might alter the
cytochrome P450/paraoxonase(PON1) pathway, affecting paraoxonase-Q in people with chronic

fatigue syndrome, but it will likelytake decades before researchers answer this question.

Liver enzymes might also play the major role in many food
allergies due to certain toxic compoundscontained naturally in some foods.

Food allergies are also likely due to Leaky Gut Syndrome
(link). In this illness, the stomach wall isweakened and allows tiny particles of undigested food and food

chemicals to enter into the bloodstream where they are picked up by immune cells as pathogens.
The immune reaction following theintrusion of food particles and food chemicals can cause
severe migraine type headaches, depressionand insomnia (link). The likely cause of this problem in
chronic fatigue syndrome is hyperimmunity,including upregulated IL-6 and nitric oxide.

The way it appears, anything that can activated the immune
system over a long period of time canlead to cytochrome p450 liver enzyme dysfunction and result in

chronic fatigue syndrome andfibromyalgia!

Since pregnenolone, progesterone, and DHEA are all
biosynthesized from cholesterol by p450iron-requiring enzymes, the failure of this enzyme system due
to an iron metabolizing problem causedby hyperimmunity can lead to low levels of these neurohormones

(abstracts). Low levels of theseneurosteroids are know to cause brain fog, especially
pregnenolone.

Problems with iron metabolism can also contribute to loss of
energy, reduced oxygen utilization,reduced blood pressure control, altered sleep, reduced brain
perfusion, difficulty in concentration,and many other symptoms noted in CFS.

At least one researcher is interested in the association
between a defect in iron metabolism andincreased nitric oxide production. (link)

The secondary and/or primary hypoadrenalism found in CFS
causes dehydration, decreasing thewater content in the blood by up to 40% in some individuals
(reference). When there is less water inthe body, there is an equal less amount of water in the blood
and the blood thickened! Since RBCand hemoglobin measurements are based on a percentage of drawn

blood, hemoconcentrated bloodis artificially increase in red cell numbers and hemoglobin,
causing an elevated reading in the drawnblood of a person with chronic fatigue syndrome. This false
increase in RDC indices prevents anyiron related blood problem from being detected. People with
chronic fatigue syndrome andfibromyalgia are anemic and neither they nor their doctor are
aware of it!

The type of anemia is called, Anemia of Chronic Disease (ACD)
(link) . ACD is common in patientswho have a long standing disease in which the immune system is

activated. The causes are complexand incompletely understood, but probably involve inflammatory

cytokines and nitric oxide. (link)

In ACD the production of new red cells is insufficient for the

degree of anemia and RBC length ofsurvival is shortened and there is an impaired re-utilization
of iron.

ACD is fairly easy to diagnose if iron deficiency anemia (IDA)

can be ruled out, and it is easy todiagnose IDA in an otherwise healthy person. But the
differential diagnosis of ACD and IDA in apatient who has a chronic disease like chronic fatigue
syndrome, who also has an iron metabolizingproblem, is extremely difficult. The differential diagnosis
requires assessment of iron status, but thatassessment is complicated by the fact that ACD causes changes
in the parameters of iron status.

With chronic disease, Total Iron Binding Capacity (TIBC)
decreases, counteracting the usualincrease due to iron deficiency. Serum iron decreases,
mimicking iron deficiency.

The single most important diagnostic mark of iron deficiency
is low serum ferritin, but ferritin ismarkedly elevated as an acute phase protein in a chronic
diseases, reaching many fold higher than thediagnostic point, even in clearly iron deficient patients.

Recent clinical studies demonstrate that serum transferrin
receptor (sTfR), an independent parameterof iron status, adds to the power of existing diagnostic tests

in diagnosis of iron deficiency in patientswith chronic disease. It is, in fact, comparable to marrow
aspiration, the gold standard for irondeficiency, in evaluating iron status.

Most doctors will not know how to diagnose borderline anemia
in CFS, and may simply dismiss it asnot possible. To get iron status properly evaluated, refer
your doctor to this web site (click here).

One other point should be made before leaving the subject of
iron in chronic fatigue syndrome andfibromyalgia. Not only does dehydration and low blood volume
mask the presents of anemia, it alsoalters the flexibility of red blood cells and their ability to

deform and travel through the tiny capillariesin the brain. Dehydrated red blood cells show signs of reduce
elasticity (abstract) and could be thecause of reduced blood flow in the brain noted in CFS. Tilt
Table Test

The results of Tilt Table Tests (TTT) in which 95% of CFS
patients are positive for neurally mediatedhypotension is likely due to increased nitric oxide production

in CFS coupled with certain factorsduring the administration of the TTT. The beta-adrenergic
agonist, isoproterenol, is injected toincrease heart rate and decrease the amount of time spent in
the tilted position. In healthy folks withnormal nitric oxide levels, the drug vasodilates the blood
vessels and speeds the heart rate. But thisvasodilation is nitric oxide dependent so that when NO is
inhibited, the vasodilation is decreased(abstracts). Conversely, when NO is upregulated as is
theorized here, the response to isoproterenolis greatly exaggerated and syncope can occur.

Many PWCs complain that the TTT cause the same type of flare
brought on by a period of intenseexercise. This is understandable since the same release of NO
by primed macrophages would occurwhen the heart rate increases during exercise. The flare from
post-exercise fatigue and a TTT wouldbe similar since they are both caused by the same phenomena.

[hardasnails1973]

The Aspirin Test High doses of aspirin is also known to
relieve a severe flare in symptoms afterexercise. Aspirin not only inhibits prostacylins, the drug is
also a nitric oxide inhibitor (abstracts).Taking 3-4 aspirin during a severe case of fatigue should
cause you to recover about 30 minuteslater. The aspirin test should reveal to you that your NO is
upregulated and causing your fatigue.Taking aspirin when you feel fine will do nothing so wait till

you feel your worse to conduct this test.

Taking aspirin before having a TTT would likely insure
negative results for NMH. Aspirin can alsohelp you reduce post-exercise fatigue.

But one caution here: If you suffer a lot of headaches that
seemed food related, you likely leaky gutsyndrome and taking aspirin can aggravate this condition and
bring on more headaches. Why AreSo Many Women Affected?

Chronic Fatigue syndrome and fibromyalgia are predominately
diseases of women because femalesnaturally have ~20% less red blood cells and ~20% less
hemoglobin than men. They also suffer a fargreater iron loss than men due to monthly blood loss. To make
matters worse for women, recentresearch shows that whole-body production of nitric oxide is
20+% greater in healthy women than inmen (abstract).

Estrogen is the likely culprit because this hormone also
stimulates nitric oxide production. Fact is,estrogen’s upregulation of nitric oxide, a potent vasodilator,

is likely the reason estrogen preventsheart attacks. (abstracts) I don’t know how much comforting it

is to tell a women with chronic fatiguesyndrome that she is less likely to have a heart attack due to

her illness. I would suppose that mostwould rather have the heat attack risk and manage it with
exercise.

In support of this theory, a recent correlation of serum
measures of nitric oxide production with lupusdisease activity has been discovered (abstracts). Lupus is
another mostly female illness, likely for thesame reasons above. Maybe a nitric oxide study in CFS/FM is
not far off? Certainly if Lupus wasshown to be associated with NO, some CFS researcher will soon
put two and two together.

Blacks and CFS

How many black people you know with CFS? None likely. Some
researchers says this is becauseblacks don’t complain to doctors, but that’s not true. Truth
is, blacks do not suffer CFS and FMnearly as often as whites simply because they respond much
differently to increased levels of nitricoxide (Link) (abstract) (abstract). Blacks also have higher
blood pressure and generally have highercortisol levels.

Serotonin

People with chronic fatigue syndrome may or may not be
deficient in serotonin. Upregulated nitricoxide does decreases serotonin levels by inactivating
tryptophan hydroxylase, the initial enzyme in thebiosynthesis of this important neurotransmitter (abstract).
And, since serotonin plays an importantrole in inhibiting the level of TNF-alpha (abstract), reduced
serotonin levels could explain the increasein this potent cytokine found in some with CFS.

But the serotonin picture is muddle. Many people with chronic
fatigue syndrome respond negativelyto antidepressants taken to increase serotonin levels. Several

researchers have also found evidence ofhigh serotonin levels in chronic fatigue syndrome. There is
also minor evidence that an allergicreaction to serotonin could be going on in some.

Taking 5-HTP (link), the amino acid precursor to serotonin,
might help restore serotonin and downregulate TNF-alpha is some PWCs. It should also improve sleep
and having a calming effect.Serotonin is an extremely important agent in chronic fatigue
syndrome and may or may not play a rolein many symptoms (link). This hypothesis takes the view of
individual need when it comes toserotonin. Try it, but don’t hesitate to stop taking serotonin

boosters if you feel worse.

Improving Red Cell Health

Eating calves liver and/or taking various vitamins and
supplements to improve red cell health after youhave been successful at lowering cytokine/nitric oxide output
with hydrocortisone (Every Third DayTherapy) will improve overall health. However, one must first
makes sure that they have controlledthe upregulated nitric oxide, before taking iron supplements.
The iron is sequestered away from nitricoxide in CFS for a reason. Iron forms potent and dangerous
oxygen radicals when exposed to highlevels of NO. Therefore, iron supplements are not recommended
until NO is brought under control.

Dopamine

Dopamine likely plays a big part in the symptoms of CFS
because phentermine and other dopaminestimulates (ritalin, cylert) are know to provide fantastic
short term relief of chronic fatigue syndromeand fibromyalgia symptoms. But this research effort has not
yet try to unravel anything meaningfulfrom the study of dopamine in these illnesses. Dopamine and
nitric oxide are mentioned associatedwith each other in over 100 recent medical abstracts so anyone

interested in looking into this mightfind some great info.

B-12

Vitamin B-12, especially hydroxocobalamin (B-12a), is known to

reduce the symptoms of chronicfatigue syndrome and fibromyalgia. B-12, especially
hydroxocobalamin, is also know as a nitric oxidescavenger (abstracts).

In summary

If you’ve got chronic fatigue syndrome, you have low cortisol
and DHEA due to a blunted ACTHresponse to CRH. You also suffer from increased cytokine
production, upregulated nitric oxide, poorred cell health, defective iron-requiring enzymes and proteins

and low pregnenolone. Due to youractivated immunity and liver enzyme problems, you also suffer
from chemical exposure and selectivedeficiency of certain amino acids and nutrients. These
problems are collectively responsible for allyour symptoms.

Since there are many different root causes, no particular
drug, herb, or nutrient by itself can addressall the problems. This wide variety of symptoms coming from
many different aspects of the sameillness has also made this an extremely difficult syndrome for

the medical community and your friendsand relatives to accept. They will tend to think you are
faking it simply because you suffer from somany different, seemingly unrelated, symptoms.

The average person (and doctor) does not realize that
dysregulated nitric oxide can cause so manydifferent medical problems!

The best things you can do to recover is increase your
cortisol bioactivity in order to lower cytokinesand nitric oxide, while at the same time slowly addressing all

the other medical problems. Not an easytask! You will need to go slow and by extremely patient.
Remember, you could begin one drug ornutrient to address one problem and, at the same time, suffer
an increase in symptoms from adifferent problem, causing you to think the new nutrient you
just started is not for you. Just theopposite could happen and likely has. You could try a new
product and have a natural reduction insymptoms not related to the new product, causing you to think
the new product is a wonder drug.

Pay close attention to the nutrients that have a proven tract
record for helping others. If you triedthem once and failed to improve–go back and try them again.

Spending the extra time to learn about the broad consequences
of increased nitric oxide activity willhelp you to understand you illness and accept this recovery
program. Click here for more nitric oxideinfo and links.

[Gardiner]

@hardasnails1973 2226 wrote:

Spending the extra time to learn about the broad consequences
of increased nitric oxide activity willhelp you to understand you illness and accept this recovery
program. Click here for more nitric oxideinfo and links.

Recently read a book (don’t recall the name at the moment) that recommends supplementing with large doses of arginine to increase nitric oxide production for the control of high blood pressure. Based on all the above, sounds like this would be a bad idea for a CFS patient, true?

[hardasnails1973]

People with CFS tend to produce more peroxtyl nitrates from argine ..giving the proper lysine:argine ratio can help lower cholesterol as this has been shown in several studies
For some reason the cycle tends to spin out of control causes excessive oxidative stress resultting in a vicious cycle. IT has to do with inflammation and cytokines and hormonal imbalances.

[Author]

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