Structure of corticosteroid-binding globulin i...
Structure of corticosteroid-binding globulin in complex with cortisol. (Photo credit: Wikipedia)


Written by Dr Henry Lindner read more here

posted by dtbrents

Adequate levels of cortisol are essential to health and quality of life. This fact is becoming increasingly clear to doctors
who are trying to help people by natural scientific methods. In fact, cortisol is the foundation of the entire endocrine
It is essential for our adaptation to the demands of life, yet all other major hormones counteract it. If a person does not
make sufficient cortisol, their quality of life is low. They also cannot tolerate or benefit from the optimization of their thyroid,
estrogen, DHEAS or even testosterone levels. By trying to help patients with fatigue and pain with natural methods and by
performing saliva testing for cortisol levels, Dr. Lindner has learned that partial cortisol deficiency is common, especially among
women. Women have lower cortisol levels/effects and responses than men do. Cortisol deficiency accounts for women’s
much higher incidences of fatigue, anxiety, depression, fibromyalgia, and autoimmune diseases.
Indeed many studies
have demonstrated a hypoactive hypothalamic-pituitary-adrenal system in persons with these problems. Studies also show that
the SSRI anti-depressants (Prozac, Paxil, Lexapro, etc.) act upon the brain to increase ACTH production and cortisol levels. This
is one reason why they alleviate so many different kinds of symptoms, and also why it is so hard to stop taking them (cortisol
withdrawal). Indeed, many drugs of abuse have been shown to raise cortisol levels including amphetamines, marijuana, cocaine,
ecstasy, nicotine, and even caffeine! This fact is, no doubt, one reason that these drugs are so addictive–especially to persons
with low cortisol levels–and why stopping these drugs is so difficult.

The symptoms of partial cortisol deficiency are just milder versions of those found in severe adrenal insufficiency.  They include
fatigue, aches and pains, brain fog, allergies, frequent infections, low blood pressure, low stress tolerance,
anxiety, irritability, hypoglycemia, frequent nausea, PMS/PMDD, autoimmune diseases, excessive sweating, teeth
grinding, restless legs, hot flashes and insomnia.
Sufferers feel like they often have the flu. One of cortisol’s functions is to
maintain the blood sugar level throughout the day. Hypoglycemia causes irritability, confusion, headaches, hot flashes, sweating,
and palpitations and can trigger seizures. Hypoglycemia can also awaken a person from sleep at night with anxiety and sweating.
Cortisol deficiency is often unmasked when a person takes thyroid hormone. They higher thyroid levels increase both the
metabolism of cortisol and the need for cortisol. If a person feels worse taking thyroid doses that they need, they have
an underlying cortisol deficiency.
Higher estradiol and progesterone levels in the latter half of the menstrual cycle also block
cortisol’s effects in women; so cortisol deficiency is often the cause of severe PMS/PMDD and of intolerance of estradiol and
progesterone replacement in menopause. The nausea and vomiting of early pregnancy and post-partum depression have both
been associated with cortisol deficiency and have improved with cortisol supplementation. For those who need it, cortisol
supplementation improves mood, energy, mental functioning, sleep quality and the ability to handle physical and emotional
stress. It helps with allergies and autoimmune diseases. We all need optimal levels of this foundational hormone.

The most common form of cortisol deficiency is partial central adrenal insufficiency due to inadequate ACTH
production. It is not diagnosable by current conventional practices.
Most doctors think that all cortisol deficiency is
Addison’s Disease. However, the problem usually does not lie in failure of the adrenal glands. The brain-hypothalamic-pituitary
system is simply not secreting enough ACTH throughout the day to stimulate sufficient cortisol production by the adrenals. The
usual screening test for cortisol deficiency, a serum AM cortisol test , is insensitive for a number of reasons. It’s reported with a
reference range of 5 to 20mcg/dL, Yet experts know that a result under 14mcg/dL is suspicious. Even physicians suspect cortisol
deficiency, they believe that they can rule it in or out with an ACTH stimulation test. This is a false idea. It is superphysiological
test that proves only that the adrenal glands can make normal AM amounts of cortisol under maximal stimulation. The ACTH
stim. test is abnormal only in cases of nearly complete pituitary or adrenal gland failure.
It is normal in the much more
common partial central cortisol deficiency. This has been repeatedly documented. To diagnose cortsiol deficiency, the physician
must consider symptoms first and the free cortisol levels second. A serum cortisol test shows the total cortisol in the blood, but
this level is affected by the amount of cortisol-binding globulin. Serum free cortisol levels are available at some laboratories, but
one’s cortisol level prior to being stuck with a needle after driving to a lab is not likely to represent one’s usual level. The best
test of free cortisol levels in the blood throughout the day is a diurnal salivary cortisol profile.
These samples are
collected at home during a normal day. The accuracy of saliva cortisol testing is well established. Unfortunately, most doctors do
not do saliva testing, and the statistical ranges that most labs report have low lower limits of “0”, obviously incompatible with
health. So as it is, physicians have no way of seeing the low free cortisol levels in their patients with fatigue,
depression, hypoglycemia, and chronic pain.
Based on research done by ZRT Laboratories to create diagnostic saliva
cortisol reference ranges, published studies, and his own experience, Dr. Lindner uses these ranges for LabCorp/Quest LC/MS
saliva tests:

Morning: 0.25 – 0.60  mcg/dL   (30 mins after awakening)   Labcorp range   0.025 – 0.60
Noon:      0.08  -0.20  mcg/dL   (right before lunch)             Labcorp range <0.01 – 0.33
Evening: 0.04 – 0.13  mcg/dL   (right before dinner)            Labcorp range <0.01 – 0.20
Night:      0.02 – 0.07  mcg/dL   (right before bedtime)         Labcorp range <0.01 – 0.09

ZRT’s own ranges, and those of other labs that use immunoassays are about 50% higher. See Testing for more information
about testing for adrenal insufficiency. Notice that LabCorp’s lower ref. range for the AM saliva cortisol is almost zero, far below
the level of 1.8 or 2.0 mcg/dL advocated by some experts. It is, in fact, incompatible with life–yet this is what happens with
ranges when one performs a 2 standard-deviations-from-the-mean analysis on a population data set that is not a perfect bell-
shaped curve.

Even if physicians suspect cortisol deficiency, they are afraid to prescribe cortisol. They have no experience with
cortisol replacement, but have a lot of experience with the damaging effects of pharmacologic doses of powerful non-natural
“steroids” (e.g. prednisone, dexamethasone). They inappropriately generalize this negative experience to cortisol
supplementation. They believe that any dose of cortisol taken long-term will cause negative effects like Cushing’s syndrome.
They are not completely wrong, because they do not understand the importance of DHEA. Oral glucocorticoid therapy, whether
hydrocortisone (HC) or an artificial steroid, suppresses ACTH and therefore DHEA production, thus creating a severe
of a major anabolic hormone. DHEA is the body’s natural cortisol antagonist and prevents many of the
negative effects of cortisol.
DHEA has anabolic effects through conversion to estradiol and testosterone within tissues
throughout the body. DHEA is practically unknown to conventional medicine, even though it is the most abundant
steroid hormone in the human body
(20 times more abundant than cortisol, 8000 times more than estradiol or
testosterone!). There are thousands of studies detailing its contributions to health and the consequences of deficiency. For
instance, studies show that women on 10mg of prednisone daily start gaining bone mass when given DHEA. Again, it’s another
example of the use and misuse of pharmaceutical hormone substitutes causing doctors to overlook the benefits and safety of
balanced hormone restoration. Dr. Lindner prefers sublingual DHEA as it delivers more of the active hormone into the
circulation. People taking cortisol or any artificial steroid must restore their average DHEAS levels to those of a young
of the same sex: around 200mcg/dL in women, 300mgc/dL in men. This usually takes 10 to 25mg of sublingual DHEA for
women, 25 to 50mg for men. If DHEA is swallowed, the dose needs to be 25 to 50% higher.

Physiological cortisol supplementation accompanied by DHEA, by definition, does not produce any negative effects.
Since HC produces much more fluid retention than the artificial steroids, over-dosing is much easier to detect. A person will
notice fluid retention, weight gain, facial puffiness, higher blood pressure and increased blood sugar. The doctor and patient
simply have to look out for these signs and reduce the dose if they appear. HC is short-acting compared to the artificial steroids–
this also helps avoid overdosing. Dr. Jefferies popularized the ideas that people should take only 20 to 30mg of HC daily.
Conventional medicine gives 20 to 35mg/day to Addison’s disease patients. People with central cortisol insufficiency often also
need full replacement doses also since every dose they take further suppresses their already weak ACTH production. Higher
cortisol doses are needed in persons who are replacing their DHEA, as they must, and in those who are taking thyroid
hormone as both of these counteract cortisol strongly. Many people need 40-60mg/day. Cortisol supplementation,
optimized to the lowest dose that provides full clinical benefit, and combined with DHEA replacement, is just good
medical practice.
It is more effective and far safer for inflammatory conditions than the alien “steroids” and non-steroidal anti-
inflammatory medicines doctors prescribe every day (e.g. prednisone, methotrexate, Motrin®, Enbrel®, Humira®, Mobic®, etc.).

Hopefully we will have Plenadren here someday–it should greatly simplify cortisol replacement with a once-daily tablet that
provides both a quick-release of cortisol and a slow-release over 24 hrs.As it is, oral HC replacement therapy is a kind of
pulse therapy.
With the immediate-release HC tablets, cortisol levels peak at 1 hr at superphysiological levels, then drop
rapidly to pre-dose levels in several hours–how long depends upon the dose and the time of day. Generally it is best to take the
largest dose upon awakening, about half that dose at lunchtime, and, only if needed, half of the lunch dose at dinner time and at
bedtime. Daytime-only (morning-afternoon) dosing is preferable if it works as the person’s own ACTH-cortisol production then
must kick in overnight; so there is suppression of endogenous production.

While HC dosing must ultimately be guided by symptoms, seeking the lowest doses that eliminate symptoms, saliva testing is
accurate when a person is swallowing HC tablets and can be used to  help adjust the HC doses.
(Saliva tests are not
accurate if person is taking the HC sublingually or transdermally.) One can use ZRT’s ranges or Dr. Lindner’s Labcorp/Quest
ranges. Saliva cortisol levels just prior to the next oral dose should be low-normal or a bit low for that time of day–since the
level was much higher for a couple hours after the previous dose. For instance, if a saliva cortisol level prior to the noon or
dinner doses is high-normal or high for that time of day, then one should try reducing the previous dose. Conversely, the cortisol
dose may be too low if a peak saliva cortisol level at 1 to 2 hrs after a dose is just “normal”–since it will be much lower at 3 or 4
hrs when the next dose is due. If someone is taking HC, the awakening saliva cortisol, before the dose, will show how much
cortisol they are making on their own–since the bedtime dose will be long gone. If the AM saliva cortisol, before taking HC, is
very low, it does mean that there is marked suppression of their own ACTH/cortisol production. That is OK if that HC
regimen is what is necessary for that person–they will just  have to be more careful to stress dose and not to miss doses. Since
most cortisol insufficiency is central, in such persons oral HC doses can easily suppress the already weak ACTH production.
People vary a lot in the amount of HC and the number of doses that they need. Each person has to find out just what doses they
need, at what times, to eliminate their cortisol-deficiency symptoms–and the goal is always the lowest dose that still works.

Mild cortisol insufficiency, even if recognized, often does not require cortisol supplementation. A person can greatly
reduce their demand for cortisol by taking steps to eliminate stress in their life, by getting a good night’s sleep, by assuring that
they have time for enjoyable activities, by moderate daily exercise, by getting proper nutrition and taking supplements, by
eliminating any foods from their diet to which they are allergic (gluten, dairy, soy, eggs, etc.), by identifying and by identifying
and treating any ongoing infections in their body (root canal, H. Pylori, intestinal dysbiosis, etc.). The best physicians to help with
these kinds of problems are those trained in Functional Medicine.

Deciding to supplement with cortisol is a serious matter, as cortisol is the body’s major stress-reponse hormone. A
person who requires cortisol supplementation to function and feel well didn’t make enough cortisol prior to therapy, and will make
less cortisol in response to stress when they are taking cortisol–due to the suppression of their own already-weak ACTH
production. Therefore most people on long-term cortisol replacement need to take additional cortisol when ill and
prior to stressful activities.
The person must essentially take over their own cortisol regulation–increasing the dose
whenever they realize that they are under more stress, are more physically active, or are ill. They should wear some easily-
noticed medical alert jewelry stating that they have “Adrenal Insufficiency”. There are many options today, including USB drives
that contain all relevant medical history. See this site for examples.  The medical alert jewelry will prompt medical care
providers to look for a medical card, so patients should also carry a medical card containing the diagnoses, personal identifying
information, doctor’s names and contact numbers, and medications. One can create a medical card online. Patients can
obtain an emergency treatment card with specific recommendation for doctors here.