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).

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.

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.