Woman/Man exists by maintaining a complex and adaptive equilibrium (homeostasis) that is constantly
challenged by real or imagined, adverse forces: the stressors. Maintaining homeostasis and reestablishing
balance requires successful adaptation to stressors. All Stress, whether emotional or physical, activates a
wide array of behavioral and physiological responses that are collectively referred to as the Stress
Response System. A controlled initial adaptive response allows one to regain homeostasis and balance. A
maladaptive response induces uncontrolled responses that can trigger abnormalities in the Principal
Regulatory Systems of the body comprised of:
• Hypothalamic-Pituitary-Adrenocortical Axis (HPA) System • Catecholaminergic system
• Cholinergic & Serotonergic NT Systems • Immune & reproductive system • Inflammatory System
Hypothalamic-Pituitary-Adrenocortical Axis (HPA) System: In response to stress the Hypothalamus
produces corticotropin-releasing hormone (CRH), the principal hypothalamic regulator of the pituitaryadrenal
axis. CRH stimulates the pituitary gland to secrete adrenocorticotropin hormone (ACTH). ACTH
then stimulates the adrenal cortex to make and release cortisol hormones into the blood stream. The
release of glucocorticoids and mineralcorticoids from the adrenal cortex may increase heart rate, and
blood pressure, inhibit feeding and reproduction and has anxiogenic affects, including hyper
responsiveness to sensory stimuli.
CRH and CRH receptors have been detected in many extra hypothalamic sites of the brain, including
parts of the limbic system, the basal forebrain, and the LC-NE sympathetic system in the brainstem and
spinal cord. lntracerebroventricular administration of CRH results in a series of behavioral and peripheral
responses, as well as activation of the pituitary-adrenal axis and the sympathetic nervous system (SNS),
indicating that CRH has a much broader role in coordinating the stress response than initially recognized
(1-3).
Catecholaminergic system: Activation of the ceruleus-norepinephrine system (LC-NE) in the brain
stem, leads to release NE in the extremely dense network of neurons, resulting in enhanced arousal and
vigilance, as well as increased anxiety. It activates the mesocortical and mesolimbic dopamine systems,
which plays important role in cognitive function, in motivational/reinforcement/reward phenomena. The
amygdala/hippocampus is activated during stress primarily by norepinephrine neurons, affecting the
memory (1-3).
Cholinergic and Serotonergic NT System: Both serotonin and acetylcholine act excitatory to CRH
neurons, and LC-NE system, while both these systems respond to inhibition by GABAergic and opioid
peptidergic neurotransmission, and by glucocorticoids. It potentially leads number of biochemical defects
that could cause basal or stressor induced hyperactivity or hypoactivity of any systems (84-86).
Immune and reproductive system: The systems responsible for immunity and reproduction, growth are
directly linked to the stress system, and each is profoundly influenced by the effectors of the stress
response. Reproductive axis is inhibited by the many components of HPA system; CRH suppresses the
luteinizing hormone releasing hormone, the pituitary gonadotroph. The growth axis is also inhibited
during stress, prolonged activation of the stress systems leads to suppression of growth hormone secretion
and inhibition of somatomedin C, and other growth factor on their target tissues (87).
Inflammatory System: HPA System, Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS).
The Stress Response System has profound inhibitory effect on the inflammatory system, decreasing
production of proinflammatory cytokines. HPA axis dysfunction is not currently evaluated nor connected
to CSF and FM patients. Recent research clearly connects HPA axis responses to the symptoms
experienced by these patient groups (101). Additionally, interventions providing symptomatic
improvement in patients with FM and CFS affect the HPA axis. There are related major symptomatic
manifestations of pain, fatigue, sleep disturbance, and psychological distress (100). Since many of these
symptoms are present in other syndromes that exhibit HPA axis disturbances, we suggest a paradigm
exists between the dynamic functions of the HPA axis and the clinical manifestations of FM and CFS.
Adrenal Insufficiency Classification
Homeostasis through Stage 5 Stress Response Reference Chart
● Stage1 Initial Adaptive Response ● Stage2 Adrenal Adaption ● Stage3 Adrenal Maladaption
● Stage4 Adrenal Insufficiency ● Stage5 Adrenal Crisis
Overview
Cortisol is necessary for life. The H/P/A feedback mechanisms maintain a homeostasis of
glucocorticoids, mineralcorticoids and the CNS. Sustained physiological or emotional stress leads to
substantially increased circulating cortisol levels throughout the day. The Stress Response, which
occurs when homeostasis is threatened or perceived to be threatened, is mediated by the Stress
System. Prolonged stress alters the activity of the H/P/A system and influences the activity of multiple
homeostatic systems.
Stage 1: Initial Adaptive Response is the default result of a long term stress left unabated. This stage
can go on for years. At first stress levels increase dramatically. As stress continues, other systems are
affected. Repetitive asymptomatic short crashes and fast recoveries supported by OTC energy products,
caffeine and other stimulants. The 24 hr circadian cortisol patterns show erratic, up/down fluctuations.
Repeat salivary Adrenal Circadian and urinary Metabonomic Profile (HPA-4) testing shows steady down
regulation in cortisol, DHEAS, catecholamine and methylation markers. Stage 1 can last years.
Note: The illustrated patterns in this graph are an attemt to demonstrate the typical pattern markers in
stage 1. Look for multiple spikes, erratic up/down changes in both the Cortisol and DHEA-S patterns
Along with the clinical presentations listed above. This graphical representation is based on clinical
observation and is for educational purposes only. It is not intended to be used as a diagnostic tool.
Actual pattern progressions vary depending on patient’s overall health, diet, supplementation and
genetics.
Stage 2: Adrenal Adaption: Cortisol and DHEAS patterns become erratic, with high/low fluctuations
occurring throughout the 24hr Circadian Cycle. These level fluctuations are telling signs of reduced
precursor steroid activity. Pregnenolone (the master adrenal hormone and precursor/metabolic
intermediate used by the adrenal cortex in the biosynthesis of glucocorticoids and mineral corticoids)
levels will trend downward; reducing the adrenals’ sustained continued high activity capability. Once the
Collective Stress Response Mechanism becomes responsive, proinflammatory cytokines are released,
down-regulating the HPA axis and affecting all metabolic pathways and the symptomatic threshold into
Stage 2 Adrenal Adaption is penetrated. Multiple symptomatic crashes, with longer intervals between
recoveries, begin. Energy continues to drop. Hypoglycemia, weight loss, fatigue, insomnia, irritability,
depression anxiety, panic attacks, profuse sweating and more, are connected to the Collective Stress
Response Mechanism. Chronic fatigue, fibromyalgia and other inflammatory symptoms are a direct
consequence of an amplified Collective Stress Response Mechanisms’ self-destructive potential.
Note: The illustrated patterns in this graph are an attemt to demonstrate the typical pattern markers in
stage 2. The erratic up/down fluctuations in both the Cortisol and DHEAS patterns may or may not be
there; however, both the cortisol and the DHEAS will be trending lower, a spike can be present or
absent, the downward trend and additional symptoms, are a signal of the occurred Stage 2 Crash. This
graphical representation is based on clinical observation and is for educational purposes only. It is not
intended to be used as a diagnostic tool. Actual pattern progressions vary depending on patient’s overall
health, diet, supplementation and genetics.
Stage 3: Cortisol and DHEAS patterns become erratic, with high/low fluctuations occurring throughout
the 24hr Circadian cycle. These level fluctuations are telling signs of reduced precursor steroid activity.
Pregnenolone (the master adrenal hormone and precursor/metabolic intermediate used by the adrenal
cortex in the biosynthesis of glucocorticoids and mineral corticoids) levels will trend downward;
reducing the adrenals’ sustained continued high activity capability. Once the Collective Stress
Response Mechanism becomes responsive, proinflammatory cytokines are released, down-regulating
the HPA axis and affecting all metabolic pathways. Multiple symptomatic crashes with longer intervals
between recoveries become more common. Energy continues to drop. Hypoglycemia, weight loss,
fatigue, insomnia, irritability, depression, anxiety, panic attacks and more, are connected to the
Collective Stress Response Mechanism. Chronic fatigue, fibromyalgia and other inflammatory
symptoms are a direct consequence of an amplified Collective Stress Response Mechanisms’
destructive potential.
Note: The illustrated patterns in this graph are an attemt to demonstrate the typical pattern markers in
stage 3. At this point in time, there will be a significant reduction in both the Cortisol and DHEA-S
production. There will be major crashes. There may be some recovery, but the trend will continue
downward. This graphical representation is based on clinical observation and is for educational
purposes only. It is not intended to be used as a diagnostic tool. Actual pattern progressions vary
depending on patient’s overall health, diet, supplementation and genetics.
Adrenal Insufficiency Progression: Stage 4 Adrenal Insufficiency
Recovery is no longer available without full medical intervention. Adrenal production is absent. Patient is
bedridden. Severe fatigue, heart palpitations, hypoglycemia, low blood pressure, insomnia, joint and
muscle pain become the norm. Sudden crashes from the smallest stressor can occur. At this point in
time, setbacks and crashes are frequent. The patient has serious metabolic, hormonal and neurological
imbalances.
Note: The illustrated patterns in this graph are an attempt to demonstrate the typical pattern markers in in
Stage 4 . This graphical representation is based on clinical observation and is for educational purposes
only. It is This graphical representation is based on clinical observation and is for educational purposes
only. It is not intended to be used as a diagnostic tool. Actual pattern progressions vary depending on
patient’s overall health, diet, supplementation and genetics.
What is the Stress Response System?
The stress response is sub served by the stress system, which has both central nervous systems (CNS) and
peripheral components (l-3). The central components of the stress system are located in the hypothalamus
and the brainstem. The autonomic nervous system (ANS) responds rapidly to stressors and controls a
wide range of functions. cardiovascular, respiratory, gastrointestinal, renal, endocrine, and other systems
are regulated by the SNS and/or the parasympathetic system. In general, the parasympathetic system can
both assist and antagonize sympathetic functions by withholding or increasing its activity, respectively
(3).
Stress, whether severe, acute or chronic low-grade, can induce abnormalities in the principal regulatory
systems of the body, Adrenal insufficiency is an endocrine disorder that occurs when the Adrenal Stress
Response Mechanisms are triggered and continue over extended periods of time. These mechanisms
include:
l. Hypothalamic-Pituitary-Adrenocortical Axis (HPA) System.
2. Cholinergic and Serotonergic NT Systems stimulate both components of CNS while aminobutyric
acid/benzodiazepine
(GABA/BZD) & Arcuate nucleus of the Hypothalamus (POMC) Peptide Systems inhibit it. The latter is
directly activated by the stress response system and is important in the enhancement of analgesia that
takes place during stress.
3. Catecholaminergic system.
The Initial Adaptive Responses to Stress
The stress system receives and integrates a diversity of cognitive, emotional, neurosensory, and peripheral
somatic signals that arrive through distinct pathways. Activation of the stress system leads to behavioral
and physical changes. Behavioral adaptation includes increased arousal, alertness, and vigilance;
improved cognition: focused attention; euphoria; enhanced analgesia; elevations in core temperature;
inhibition of reproduction and appetite.
What is Adrenal Insufficiency?
Adrenal insufficiency can be primary or secondary. Addison’s disease, the common term for primary
adrenal insufficiency, occurs when the adrenal glands are damaged and cannot produce enough of the
adrenal hormone cortisol. The adrenal hormone aldosterone may also be lacking, Addison’s disease
affects 110 to 144 of every l million people in developed countries (1).
Secondary adrenal insufficiency occurs when the pituitary gland -a pea-sized gland at the base of the
brain- fails to produce enough adrenocorticotropin (ACTH), a hormone that stimulates the adrenal glands
to produce the hormone cortisol. If ACTH output is too low, cortisol production drops. Eventually, the
adrenal glands can shrink due to lack of ACTH stimulation. Secondary adrenal insufficiency is much
more common than Addison’s disease.
What do Adrenal Hormones do?
Adrenal hormones, such as pregnenolone, cortisol, DHEA, DHEAS and aldosterone, play key roles in the
functioning of the human body; including, regulating,: blood pressure, metabolism, the way the body uses
digested food for energy and the body’s response to stress. In addition, the body uses the adrenal hormone
dehydroepiandrosterone (DHEA) to make androgens and estrogens, the male and female sex hormones.
Cortisol
Cortisol belongs to the class of hormones called glucocorticoids, which affect almost every organ and
tissue in the body, cortisol’s most important job is to help the body respond to stress. Among its many
tasks, cortisol helps:
• Maintain blood pressure and blood vessel function
• Slow the immune system’s inflammatory response–how the body recognizes and defends itself
against bacteria, viruses, and substances that appear foreign and harmful.
• Glycemic regulation
The amount of cortisol produced by the adrenal glands is precisely balanced. Like many other hormones,
cortisol is regulated by the hypothalamus, which is a part of the brain, and the pituitary gland. First, the
hypothalamus releases a “trigger” hormone called corticotropin-releasing-hormone (CRH), which signals
the pituitary gland to send out ACTH. ACTH stimulates the adrenal glands to produce cortisol. Cortisol
then signals back to both the pituitary gland and hypothalamus to decrease these trigged hormones.
Aldosterone
Aldosterone belongs to the class of hormones called mineraloco1ticoids, also produced by the adrenal
glands. Aldosterone helps maintain blood pressure and the balance of sodium and potassium in the blood.
When aldosterone production falls too low, the body loses too much sodium and retains too much
potassium.
The decrease of sodium in the blood can lead to a drop in both: blood volume- the amount of fluid in the
blood- and blood pressure. Too little sodium in the body also can cause a condition called hyponatremia.
Symptoms of hyponatremia include feeling confused und fatigued and having muscle twitches and
seizures.
Too much potassium in the body can lead to a condition called hyperkalemia. Hyperkalernia may have no
symptoms; however, it can cause an irregular heartbeat, nausea, and a slow, weak, or an irregular pulse.
Dehydroepiandrosterone (DHEA)
Dehydroepiandrosterone is another hormone produced by the body’s adrenal glands. The body uses
DHEA to make the sex hormones, androgen and estrogen. With adrenal insufficiency, the adrenal glands
may not make enough DHEA. Healthy men
derive most androgens from the testes. Healthy women and adolescent girls get most of their estrogens
from the ovaries. However, women and adolescent girls may have various symptoms from DHEA
insufficiency, such as loss of pubic hair, dry skin
Epinephrine and Norepinephrine
Adrenal medulla, the inner part of the adrenal gland, controls hormones that help you to cope with
emotional and physical stress. The main hormones produced in medulla are epinephrine and
norepinephrine, which have similar function. They are capable of increasing heart rate, force heart
contraction, increase the blood flow into the brain and heart, relaxing smooth muscles, assisting in sugar
metabolism and control vasoconstriction.
Psychiatric Disorders
The syndrome of adult melancholic depression represents a typical example of dysregulation of the
generalized stress response system, leading to chronic dysphoric hyperarousal, activation of the HPA axis
and the locus ceruleus and relative immunosuppression (88, 89). Patients suffering from the condition
have hypersecretion of CRH, as evidenced by the elevated 24-hour urinary cortisol excretion, the
decreased ACTH responses to exogenous CRH administration, and the elevated concentrations of CRH in
the cerebrospinal fluid (CSF). They also have elevated concentrations of norepinephrine in the CSF,
which remain elevated even during sleep (90).
What are the symptoms of adrenal insufficiency and adrenal crisis?
Adrenal Insufficiency
The most common symptoms of adrenal insufficiency are:
• chronic, or long lasting, fatigue
• muscle weakness
• loss of appetite
• weight loss
• abdominal pain
Other symptoms of adrenal insufficiency can include:
● nausea
• vomiting
• diarrhea
• low blood pressure that drops further when a person stands up, causing dizziness or fainting
● irritability and depression
• craving salty foods
• hypoglycemia, or low blood sugar
• headaches
● sweating
• irregular or absent menstrual periods
• loss of interest in sex
Hyperpigmentation, or darkening of the skin, can occur in Addison’s disease, although not in secondary
adrenal insufficiency,
This darkening is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles,
and toes; lips; and mucous membranes such as the lining of the cheek.
The slowly progressing symptoms of adrenal insufficiency are often ignored until a stressful event, such
as surgery, a severe injury, an illness, or pregnancy, causes them to worsen.
Adrenal Crisis
Sudden, severe worsening of adrenal insufficiency symptoms is called adrenal crisis. If the person has
Addison’s disease, this worsening can also be called an Addisonian crisis. In most cases, symptoms of
adrenal insufficiency become serious enough that people seek medical treatment before an adrenal crisis
occurs. However, sometimes symptoms appear for the first time during an adrenal crisis.
Symptoms of adrenal crisis Include:
● sudden, severe pain in the lower back, abdomen, or legs
• severe vomiting and diarrhea
• dehydration
• low blood pressure
● loss of conscience
If not treated, an adrenal crisis can cause serious health risks!
Get Treatment for Adrenal Crisis Right Away
People with adrenal insufficiency who have weakness, nausea, or Vomiting need immediate emergency
treatment to prevent an adrenal crisis and possible death, An injection with a synthetic glucocorticoid
hormone called a corticosteroid can save a person’s life, People should make sure to have a corticosteroid injection with them at all times, and make
sure their friends and family know how and when to give the injection.
Adrenal Insufficiency and Addison’s disease?
Autoimmune disorders cause most cases of Addison’s disease. Infections and medications may also cause
the disease.
Autoimmune Disorders
Up to 80 percent of Addison’s disease cases are caused by an autoimmune disorder, which is when the
body’s immune system attacks the body’s own cells and organs (2). In Autoimmune Addison’s, which
mainly occurs in middle aged females, the immune system gradually destroys the adrenal cortex-the outer
layer of the adrenal glands (2).
Primary adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed
(1). As a result, both cortisol and aldosterone are often lacking. Sometimes only the adrenal glands are
affected.
Sometimes other endocrine glands are affected as well (1), as in Polyendocrine Deficiency Syndrome.
Polyendocrine Deficiency Syndrome is classified into type I and type 2. Type I is inherited and occurs in
children. In addition to adrenal insufficiency, these children may have:
● underactive parathyroid glands, which are four pea-size glands located on or near the thyroid
gland in the neck;
they produce a hormone that helps maintain the correct balance of calcium in the body.
• slow sexual development.
• pernicious anemia, a severe type of anemia; anemia is a condition in which red blood cells are
fewer than normal, which means less oxygen is carried to the body’s cells. With most types
of anemia, red blood cells are smaller than normal, however, in pernicious1anemia, the cells
are bigger than normal.
• chronic fungal infections.
● chronic hepatitis, a liver disease.
Researchers think type 2, which is sometimes called Schmidt’s Syndrome, is also inherited. Type 2
usually affects young adults and may include:
● an underactive thyroid gland
• slow sexual development.
• diabetes
• vitiligo, a loss of pigment on areas of the skin
Infections
Tuberculosis (TB), an infection that can destroy the adrenal glands, accounts for IO to 15 percent of
Addison’s disease cases in developed countries (117), When primary adrenal insufficiency was foot
identified by Dr. Thomas Addison in 1849, TB was the most common cause of the disease. As TB
treatment improved, the incidence of Addison’s disease due to TB of the adrenal glands greatly decreased.
However, recent reports show an increase in Addison’s disease from infections such as TB and
cytomegalovirus. Cytomegalovirus is a common virus that does not cause symptoms in healthy people;
however, it does affect
babies in the womb and people who have a weakened immune system, mostly due to HIV/AIDS (2).
Other bacterial infections,
such as Neisseria meningitidis, which is a cause of meningitis, and fungal infections can also lead to
Addison’s disease.
Other Causes
Less common causes of Addison’s disease are:
● cancer cells in the adrenal glands
• amyloidosis, a serious, though rare, group of diseases that occurs when abnormal proteins,
called amyloids, build up in the blood and are deposited in tissues and organs
• surgical removal of the adrenal glands
• bleeding into the adrenal glands
• genetic defects including abnormal adrenal gland development, an inability of the adrenal
glands to respond lo ACTH, or a defect in adrenal hormone production
• medication-related causes, such as from anti-fungal medications and the anesthetic etomidate,
which may be used when a person undergoes an emergency intubation – the placement of a
flexible, plastic tube through the mouth and into the trachea, or’ windpipe, to assist with
breathing
What causes secondary adrenal insufficiency?
A lack of CRH or ACTH causes secondary adrenal insufficiency. The lack of these hormones in the body
can be traced to several possible sources.
Stoppage of Corticosteroid Medication
A temporary form of secondary adrenal insufficiency may occur when a person who has been taking a
synthetic glucocorticoid hormone, called a corticosteroid, for a long time stops taking the medication.
Corticosteroids are often prescribed to treat inflammatory illness such as rheumatoid arthritis, asthma, and
ulcerative colitis. In this case, the prescription doses often cause higher levels than those normally
achieved by the glucocorticoid hormones created by the body. When a person takes corticosteroids for
prolonged periods, the adrenal glands produce less of their natural hormones. Once the prescription doses
of corticosteroid are stopped, the adrenal glands may be slow to restart their production of the body’s
glucocorticoids. To give the adrenal glands time to regain function and prevent adrenal insufficiency,
prescription corticosteroid doses should be reduced gradually over a period of weeks or even months.
Even with gradual reduction, the adrenal glands might not begin to function normally for some time, so a
person who has recently stopped taking prescription corticosteroids should be watched carefully for
symptoms of secondary adrenal insufficiency.
Surgical Removal of Pituitary Tumors
Another cause of secondary adrenal insufficiency is surgical removal of the usually noncancerous, ACTH
producing tumors of the pituitary gland that cause Cushing’s Syndrome. Cushing’s Syndrome is a
hormonal disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone
cortisol. When the tumors are removed, the source of extra ACTH is suddenly gone and a replacement
hormone must be taken until the body’s adrenal glands are able to resume their normal production of
cortisol. The adrenal glands might not begin to function normally for some time, so a person who has had
an ACTH producing tumor removed and is going off corticosteroid replacement hormone, should be
watched carefully for symptoms of adrenal insufficiency.
Changes in the Pituitary Gland
Less commonly, secondary adrenal insufficiency occurs when the pituitary gland either decreases in size
or stops producing ACTH. These events can result from:
• tumors or an infection in the pituitary
• loss of blood flow to the pilL1itary
• radiation for the treatment of pituitary or nearby tumors
• surgical removal of parts of the hypothalamus
• surgical removal of the pituitary
The Hypothalamic-Pituitary-Adrenal System (HPA)
Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the HPA
axis. In response to stress the Hypothalamus releases CRF, which initiates a cascade of events that
culminate in the release of glucocorticoids and mineralcorticoids from the adrenal cortex. Glucocorticoid
feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid
release. Through these mechanisms, stress can alter memory functions, reward, immune function,
metabolism and susceptibility to diseases.
How is adrenal insufficiency diagnosed?
A diagnosis of adrenal insufficiency is evaluated through Salivary, Urinary and Blood Testing.
The 24hr Circadian Salivary Profile, HPA-1 Urine Metabonomic Profiles, Blood HPA Axis Studies are
diagnostic tools utilized to determine the Adrenal Insufficiency Classification Stages.
24hr Salivary Circadian Testing – Why Saliva?
Saliva collection is simple, non-invasive and can be performed in the privacy of ones’ home. Saliva
testing measures the levels of circulating analytes available to body tissues in men and women. Saliva is
considered to be a better indicator of biologically active hormone levels than blood- more accurately
reflecting the body’s functional hormone status.
Saliva testing provides a simple noninvasive means of determining whether hormone levels are within the
expected normal range for one’s age and gender. It is also an accurate method of evaluating how hormone
replacement therapy, topical hormone creams, sublingual hormone drops, diet, herbal therapy and
exercise influence these levels. The Circadian Panel tests 6 collections in a 24hr period. Sabre evaluates
the dynamics and sequencing of adrenal activity, identifying 5 adrenal insufficiency stage progressions.
This alerts the health care provider as to the severity of the damage not only to the adrenals, but also to
the HPA status and physiological responses that are collectively referred to as the Stress Response
System.
A controlled initial adaptive response allows one to regain homeostasis and balance (Stages 1 & 2). These
2 stages are treatable with natural adrenal support (pregnenolone, DHEA and DHEAS).
Consistent 24hr Low cortisols levels with erratic fluctuations and inversions are signs of
significantly reduced precursor steroid activity. Here pregnenolone (the master adrenal hormone
and precursor/metabolic intermediate used by the adrenal cortex in the biosynthesis of
glucocorticoids and mineral corticoids) activity is very low, consistent with the Maladaptive Stages
3 – 4. Maladaptive Stages induce uncontrolled responses that can trigger abnormalities in the Principal
Regulatory Systems of the body comprised of:
1. Hypothalamic-Pituitary-Adrenocortical Axis (HPA) System
2. Catecholaminergic system
3. Cholinergic and Serotonergic NT Systems
4. Immune and reproductive system
5. Inflammatory System
Metabolic Balance and the HPA-1 Urine Test
The HPA-1 urine test examines the body’s metabolic expression. An important part of the puzzle to
identifying and successfully treating adrenal insufficiency is to evaluate and treat metabolic pathway
imbalances, Identifying deficiencies in cofactors, B vitamins and evaluating metabolic expression
influences targeted adrenal treatment.
Combining the Sabre HPA-1 Metabonomic Profile with the 24hr Salivary Circadian Panel combines
adrenal cortex
(glucocorticoids) studies, salivary electrolyte studies (mineral corticoids) and adrenal medulla studies
(catecholaminergic) supplying the perfect recipe for individual targeted intervention.
What We Learn from Your HPA-1 Urine Profile and How does it help?
This information allows specific supplementation, avoiding unnecessary burdens on your body’s natural
detoxification needs.
What can we affect?
• Adrenal Activity
• Amino acid levels
• Actual metabolic expression
• Detoxification deficiencies
Metabolic Balance and Metabolism is a twofold process
• Production
• Elimination
A balanced metabolism is one that produces what you need (called a substrate), when you need it (cortisol
for instance) and can break down and eliminate a metabolic bi-product. This Is known as bringing a
metabolic process to completion.
All bodily functions are affected by bio-accumulation -a result of the body’s inability to CLEAR
metabolic bi-products. This causes inflammation.
HPA System
Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the HPA
axis. In response to stress the Hypothalamus releases CRF, which initiates a cascade of events that culminate
in the release of glucocorticoids and mineralcorticoids from the adrenal cortex. Glucocorticoid feedback
inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release.
The central nervous system (CNS) effector of this response is the stress response system with its main
components, the corticotropin-releasing hormone (CRH)/arginine-vasopressin (AVP) and locus ceruleusnoradrenaline
(LC-NA)/autonomic (sympathetic) neurons of the hypothalamus and brain stem. These,
respectively, regulate the peripheral activities of the HPA axis and the systemic/adrenomedullary sympathetic
nervous systems (SNS). Activation of the HPA axis and LC-NA/autonomic system result in systemic
elevations of glucocorticoids and catecholamines (CAs), respectively, which act in concert to maintain
homeostasis. It is primarily through the stress system that stress influences the innate and specific immune
response.
Hormonal Blood Urine Tests
• ACTH stimulation test. The ACTH stimulation test is the most commonly used test for
diagnosing adrenal insufficiency. In this test, the patient is given an intravenous (IV) injection
of synthetic ACTH, and samples of blood, urine, or both are taken before and after the
injection. The cortisol levels in the blood and urine samples are measured in the lab. The
normal response after an ACTH injection is a rise in blood and urine cortisol levels. People
with Addison’s disease or longstanding secondary adrenal insufficiency have little or no
increase in cortisol levels.
• CRH stimulation test. When the response to the ACTH test is abnormal, a CRH stimulation test
can help determine the cause of adrenal insufficiency, In this test, the patient is given an JV
Injection of synthetic CRH, and blood is taken before and 30, 60, 90, and 120 minutes after the
injection, The cortisol levels in the blood samples are measured in a lab. People with Addison’s
disease 1·espond by producing high levels of ACTH, yet no cortisol. People with secondary
adrenal Insufficiency do not produce ACTH 01· have a delayed response, CRH will not
stimulate ACTH secretion if tl1e pituitary is damaged, so 110 ACTH response points to the
pituitary as the cause. A delayed ACTH response points to the hypothalamus as the cause.
Diagnosis during Adrenal Crisis
Although a reliable diagnosis is not possible during adrenal crisis, measurement of blood ACTH and
cortisol during the crisis- before treatment with corticosteroids is given- is often enough to make a
preliminary diagnosis, Low blood sodium, low blood glucose, and high blood potassium are also
sometimes present at the time of adrenal crisis. Once the crisis is controlled, an ACTH stimulation test
can be performed to help make specific diagnosis. More complex lab tests are sometimes used if the
diagnosis remains unclear.
How is adrenal insufficiency treated?
Adrenal insufficiency is treated by replacing or substituting, adrenal hormones, targeted amino acids for
catecholaminergic balance, B vitamins and co-factors and if indicated, methylation support is also
administered. The dose of each medication is determined and monitored by the patient’s HPA-4 Profile
results.
Researchers have found that using replacement therapy for DHEA in adolescent girls who have secondary
adrenal insufficiency and low levels of DHEA can improve pubic hair development and psychological
stress.
If the Adrenal Stress Response salivary tests indicate stage 4 progression, then cortisol is replaced with a
corticosteroid, such as hydrocortisone, prednisone, or dexamethasone, taken orally one to three times each
day, depending on which medication is chosen. If the Adrenal Stress Response salivary tests indicate
Stage 1, 2 or 3 Progression; then transdermal pregnenolone, DHEA and DHEAS is given. If the patient is
female, then transdermal progesterone is also added.
If aldosterone is also deficient, it is replaced with oral doses of a mineral corticoid hormone, called
fludrocortisone acetate
(Florinef), taken once or twice daily. People with secondary adrenal insufficiency normally maintain
aldosterone production, so they do not require aldosterone replacen1ent therapy.
During adrenal crisis, low blood pressure, low blood glucose, low blood sodium, and high blood levels of
potassium can be life threatening. Standard therapy involves immediate IV injections of corticosteroids
and large volumes of IV saline solution with dextrose. This treatment usually brings rapid improvement.
When the patient can take liquids and medications by mouth, the amount of corticosteroids is decreased
until a dose that maintains normal hormone levels is reached. If aldosterone is deficient, the person will
need to regula1arly take oral doses of fludrocortisone acetate.
What problems can occur with adrenal insufficiency?
Problems can occur in people with adrenal insufficiency that are undergoing surgery, suffer a severe
injury, have an illness, or are pregnant. These conditions place additional stress on the body, and people
with adrenal insufficiency may need additional treatment to respond and recover.
The following steps can help a person prevent adrenal crisis:
• Ask a health care provider about possibly having a shortage of adrenal hormones, if always
feeling tired, weak, or losing weight.
• Learn how to increase the dose of corticosteroid for adrenal insufficiency when ill. Ask a health
care provider for written instructions for sick days. First discuss the decision to increase the
dose with the health care provider when ill.
• When very ill, especially if vomiting and not able to lake pills, seek emergency medical care
immediately.
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