Any time stress afflicts the body, the response is the same. The hypothalamic-pituitary-adrenal (HPA) axis is activated, ending in the adrenal glands secreting cortisol, the stress-fighting hormone. As stress continues, the adrenals become less and less able to produce this hormone. Eventually, adrenal fatigue sets in and the vague symptoms of AFS begin. Due to the vagueness of the symptoms, they prove hard to evaluate clinically. If not assessed and addressed adequately, these symptoms will grow to the point of rendering the person suffering from them bedridden. Routine laboratory tests are not designed to pick up these vague symptoms.
The most common presenting complaints of Adrenal Fatigue are lack of energy, lethargy, dizziness, insomnia, hypoglycemia, low blood pressure, and anxiety. Routine conventional medicine laboratory testing for these in an otherwise healthy person commonly include:
- Hematology (full blood count (CBC) – red cells, white cells and platelets to make sure patient is not anemic.
- Biochemistry (liver and kidney function) to rule out systemic organ damage.
- Inflammation in the blood – ESR, C reactive protein, plasma viscosity to rule out autoimmune diseases, among others.
- Cancer markers for early detection of cancer.
- Blood Sugar level to rule out diabetes mellitus.
- Urine testing to rule out infection or kidney damage.
- Fecal occult blood to rule out bleeding from the gut and cancer screen.
- Electrolyte panel to assess kidney function.
- Thyroid stimulating hormone to rule out primary thyroid failure.
These tests are good in detecting macroscopic pathology such as major organ failure including anemia, heart disease, metabolic dysfunction, cancer, liver failure, kidney failure, thyroid diseases.
Unfortunately, these routine laboratory testing procedures do not detect organ dysfunction at the sub-clinical level such as those afflicted with sub-clinical hypothyroidism, Adrenal Fatigue, mild liver dysfunction, imbalanced electrolyte function, minor hormonal imbalance, estrogen dominance, and suboptimal detoxification capacity.
In addition, little if any attention is paid to laboratory values that lie close to or just outside of normal range. Low normal or high normal values are generally passed over as insignificant until the result is much higher or much lower than normal range.
Modern medicine has also ushered in a wide array of standardized protocols of testing in addition to the number of tests. These well-intended tracks are meant to efficiently and effectively handle most common medical problems with accuracy and speed. They are by definition fitting for the masses. Those whose response falls within the statistical norm but physically symptomatic will be inadvertently ignored as they will be considered normal when they are not. In these cases, conventional medicine has little to offer. Instead, normal laboratory values are used to justify why patients are sent home to self-navigate, and that nothing is wrong when the body continues to suffer.
Unusual and convoluted clinical states such as those suffering from chronic fatigue syndrome, Adrenal Fatigue Syndrome, tension myositis syndrome, and estrogen dominance are difficult to diagnose to start. Conventional physicians usually dismiss these conditions because routine test values are invariably within the standard laboratory reference range. This is why it is most frustrating to the patient—when they are told there is nothing wrong while they feel physically tired and lethargic.
Prior to the advent of modern medical laboratory tests, the astute physician had to rely on a detailed history and physical examination to assess the clinical state. Laboratory values are used only in case of doubt, or as a confirmatory tool. Unfortunately, this is fast becoming a lost art in the clinical practice of medicine. The failure of conventional medicine to be on alert and to recognize that a person can be ill but have normal laboratory blood test results is alarming. Many sufferers are sent home to self-navigate and are abandoned by the very health professionals who are supposed to help them recover.
To make matters worse, most conventional physicians are not nutritionally oriented or trained. Even if laboratory tests come back abnormal, they are at a loss on how to correlate it with clinical findings when the presentation is overwhelmingly convoluted as one sees commonly in Adrenal Fatigue.
In order to comprehensively understand and assess conditions like AFS, a different approach must be undertaken by healthcare professionals. Two major factors of the body’s response to stress must be combined: the typical neuroendocrine factor and the functional metabolic factor. Incorporating the systemic metabolic component with the organ-specific neuroendocrine component allows the healthcare professional to get to the root cause of symptoms and develop adequate remediation efforts. In this model, there are six circuits that all work interdependently in dealing with stress. These six circuits include the metabolic, detoxification, inflammation, cardionomic, neuroaffective, and hormone response circuits.
To illustrate how a normal laboratory test can be present in a body that is not well, let us consider the following:
- Most Adrenal Fatigue sufferers have low immune function present with frequent infections but normal white cell count. Low or low normal white cell count can be a sign of poor immune function. Nutritional deficiencies, such as low zinc, low magnesium,low B vitamins, and low essential fatty acids can contribute to this. Normal white cell count does not rule out these problems at the sub-clinical level.
- Normal platelet count does not rule out stealth viruses or a residual bacterial infection, such as that seen in post-acute Epstein-Barr virus infection. Low or low normal platelet count can be a sign of toxic stress from viral or emotional forces.
- Borderline or high mean cell volume (MCV) suggests B12 deficiency, folic acid deficiency, or hypothyroidism. Normal MCV can occur with sub-clinical B12 deficiency in those who are constitutionally weak or sensitive.
- A normal fasting blood sugar in absolute terms associated with clinical hypoglycemia is common in advanced stages of Adrenal Fatigue.
- Normal electrolyte levels do not rule out the presence of debilitating sub-clinical dilutional hyponatremia seen in advanced Adrenal Fatigue.
- A normal thyroid Free T3 and Free T4 do not rule out secondary subclinical hypothyroidism due to pituitary or adrenal dysfunction.
- Normal aldosterone level with salt craving and low blood pressure is commonly found in Adrenal Fatigue. Both serum aldosterone and sodium levels are usually within normal range.
- Normal potassium level does not rule out the need to reduce internal potassium load. In Adrenal Fatigue, sodium depletion is common, leading to a relative (and not absolute) potassium overload that is still within normal laboratory range on testing.
- High normal liver enzymes usually suggest liver dysfunction, typically from chemicals such as medications, or poor nutritional status. Normal liver enzymes are commonly associated with poor clearance of metabolites in Adrenal Fatigue as the body slows down to conserve energy.
- High normal or high total cholesterol could mean low levels of vitamin D or hypothyroidism commonly seen in Adrenal Fatigue and does not necessitate the administration of statin medications to normalize lipid level.
- A normal TSH can be present in those with clinical hypothyroidism. In other words, you can be suffering from hypothyroidism but have normal TSH levels.
Laboratory testing plays an important and significant part of assessing bodily function. It should not be disregarded. However, as you can see from the above, just because laboratory testing results are within normal range does not necessarily mean a person is free of illness. Many chronic illnesses, including Adrenal Fatigue, progress over time slowly. Sole reliance on routine blood serum laboratory tests for definitive assessment is a grossly incomplete approach to start in the case of Adrenal Fatigue.
The advent of functional and specialized laboratory testing now offers a window of insight into our body’s working well beyond regular standard testing. These tests generally focus on the endocrine system, gastrointestinal system, immunology system, metabolic system, and nutritional function of the body. It may seem these test could be of great help in exploring Adrenal Fatigue, but there are very important considerations.
The most popular tests (not necessarily what is needed in most cases) include:
- Organic acids urinary analysis to assess the efficiency of cellular energy production and metabolic toxicity.
- Neurotransmitter assessments to determine serotonin, dopamine, GABA, epinephrine and norepinephrine levels.
- Digestive stool analysis provides information about intestinal absorption, intestinal metabolism, enzymes level markers, stool pH, detection of pathogenic microorganisms, levels of beneficial bacteria, fecal color and occult blood, and gut immune function via IgA levels.
- Bacterial overgrowth of the Small Intestine Breath Test, BOSI, for assessment of bloating, gas, diarrhea, irregular abdominal pain.
- Intestinal Permeability Analysis for assessing leaky gut, irritable bowl, and malabsorption syndromes.
- Liver detoxification tests, including various challenge tests to evaluate the detoxification pathway and capacity.
- Immunoglobulin testing to evaluate the classical immediate reaction (IgE allergy) to pollen or the delayed reactions (IgG allergy) results from poor digestion and leaky gut syndrome. Both are prevalent in Adrenal Fatigue and environmental illnesses. These tests can also be helpful to assess toxic reaction from residual stealth virus overload such as that caused by Epstein-Barr virus and candida.
- Salivary C reactive protein biomarker for cardiac and inflammation
- Salivary IGA biomarker for gut and mucosal health. This advanced marker is a measure of antibodies the body produces in response to invading pathogens, such as bacteria or viruses. Their purpose is to destroy any of these invading organisms. The SIgA are the body’s first line of defense and prevent any foreign organisms from attaching to or infiltrating any of the mucosal membranes in areas such as the gut, the mouth, or the lungs. It’s thought SIgA decreases the body’s inflammatory response to some antigens and bacteria that could lead to allergic responses. Chronic stress decreases the production of SIgA – which may also decrease the body’s immune responses. Production of cortisol in response to stress also may decrease SIgA production. This could result in the body becoming more susceptible to infections. SIgA is a potential marker for immune system function.
- Salivary interleukin-1 Beta biomarker for inflammation. This marker is a substance released to boost the inflammatory response when the body is injured or is going through infection or allergic reaction. It’s a signal marker that something is wrong in the body. IL-1beta cytokine levels in saliva change when it comes in contact with stressors, microbes, infections, and inflammation. Because of these changes, IL-1 beta is a significant marker for the body’s detox and the circuits in the NEM stress response. If IL-1 beta is decreased, this has a negative impact on leaky gut, Type-1 diabetes, and age-related diseases, among others.
- Salivary alpha-amylase biomarker for autonomic nervous system health. This biomarker is most related to the hormonal, cardionomic, and neuroaffective NEM circuits. It is secreted when the body produces catecholamines found when there is stress present. It conveys an indication of the stress levels, either physical or psychological, by the way it interacts with the autonomic nervous system. The integrity of the Sympathoadrenal medullary Hormonal System (AHS) axis is seen in the level of alpha-Amylase in saliva. Research has shown alpha-Amylase to be sensitive to psychosocial stress in particular. This makes it a good additional marker for the presence of stress. Chronic life stressors such as poverty have been shown to affect levels of alpha-Amylase over the course of time. Research also suggests a relationship forming between stress, alpha-Amylase levels, and higher body mass index may begin early in life.
Other helpful tests may include:
- Dark field microscopy and dry blood analysis
- Lyme disease testing
- ATP/cellular energy tests to assess mitochondrial function
- Bone resorption assessment for early identification of bone loss
- Melatonin profile for assessment of circadian pattern and Seasonal Affective Disorder (SAD)
- Saliva female hormone profile such as estrogen and progesterone
- Amino acid analysis for assessment of chronic fatigue, depression, and immune problems;
- Essential and metabolic fatty acids analysis for assessment of inflammatory reaction
- Urine iodine with pre and post loading tests to identify iodine/iodide sufficiency
- Helicobacter pylori specific antigen (HpSA) stool tests to determine if the stomach and duodenum contains H. pylori, which is a major cause of peptic ulcer disease.
The major consideration here is the presence of estrogen dominance (that condition where levels of estrogen are high on a relative basis) but remain normal on an absolute basis. This imbalance is frequently seen in the NEM stress response. This may bring about mood swings and breast tenderness in both males and females as well as PMS, fibroid tumors, endometriosis, and cramps in women. Estrogen is critical in the sexuality of females and plays a major role in the menstrual cycle, sexual development, cognitive abilities, emotion, heart function, protein synthesis, and bone formation, among other functions.
There are three types of estrogen: estrone, estradiol, and estriol. Estradiol is the prominent form of estrogen in premenopausal women. Estriol is the mildest form of estrogen, has a brief impact, and appears to play a part in controlling the negatives of the other two forms.
Men also have estrogen, but their levels remain relatively stable. This is affected by age, however. The older men get, the higher their estrogen levels get due to a decrease in testosterone. Also, men who become obese typically have higher estrogen levels because the adipose tissue converts testosterone into estradiol.
Older adults, both men and women, have similar levels of estradiol. In women, this hormone plays a role in cognitive functioning, memory, and mood. In men, combined with testosterone, it affects cognitive functioning and memory.
Progesterone is important to evaluate because it is a precursor hormone to cortisol. Progesterone is crucial in several functions and processes in the body. Among these are reproduction and the menstrual cycle, and in the health of bone, brain, heart, and skin. It also influences mood, health of the adrenal glands, thyroid functioning, and libido. In women who have not gone through menopause, progesterone is produced in the ovaries. In women who are post-menopausal, it’s produced by the adrenal glands.
Men and women both have progesterone, but its function in men isn’t well known yet.
People who suffer from AFS and have a compromised NEM stress response will have lower levels of progesterone present. This results in an imbalance between progesterone and estrogen. When progesterone levels fall below optimum to balance estrogen, the condition of estrogen dominance prevails. This explains why estrogen levels can be measured as normal, but a person still has estrogen dominance. One reason progesterone levels can be low with AFS is that it is converted into cortisol, the stress-fighting hormone, during times of stress.
Common symptoms seen with low levels of progesterone include breast tenderness, lumps in the breasts, PMS, anxiety, atypical weight gain, and the increased risk of miscarriage in the early stages of pregnancy. Research strongly suggests, but has not come to a definitive consensus, that low progesterone levels may contribute significantly to female infertility.
High levels of progesterone have a sedative effect and can be used as a sleep aid. However, people with compromised liver function should be careful, since progesterone is metabolized in the liver. Higher levels of progesterone may bring on brain fog, fatigue, anxiety, and paradoxical reactions.
The progesterone to estradiol estrogen ratio is important, also. It should be about 200-300:1. In other words, for every one unit of estradiol, there should be 200-300 units of progesterone for balance. As with many body chemicals, this ratio is generally accurate, but individual ratios may vary.
Testing for testosterone levels may also give the healthcare professional valuable information. While testosterone is considered a male hormone, both males and females have it. It plays a role in libido, helps with the production of other hormones, and influences weight loss and muscle mass. This hormone typically lessens with age.
Testosterone typically fluctuates when AFS and a compromised NEM stress response are present. It is often converted into estrogen, which also may explain the fluctuation of testosterone levels. The use of DHEA or pregnenolone may increase the level of testosterone since they can be converted into it. There are testosterone hormone replacements available also. You should consult with your healthcare professional before trying hormone replacements.
As you can see, the list can be quite overwhelming. Again, while each functional test offers a narrow peek into the inner workings of the body from a specific perspective, these are seldom definitively diagnostic in and of themselves. Normal values do not rule out pathology, and abnormal values require clinical correlation to make sense. Abnormal laboratory value is not a mandatory requirement or prerequisite for therapy.
The rush to treat abnormal lab values rather than the whole person is a common clinical mistake. The reason is simple—as with regular blood tests, reference ranges for functional testing is not perfect. There is tremendous statistical variation among the general population. This needs to be factored in and examined on a case by case basis. What is applicable to a general population group may not be applicable to a person’s unique body. The bottom line—you need an astute clinician to know what test to order and to correlate the laboratory findings along with the clinical history in order to make sense of these test results under most situations.
The astute clinician will know what to look for, along with the pros and cons, before each test is ordered. A shotgun approach to laboratory testing is a sign of clinical inexperience. The following are common tests ordered but seldom necessary for assessment of Adrenal Fatigue for reasons outlined:
- Serum magnesium – does not tell us about the magnesium where it really counts—inside the cell. To really look at magnesium closely, an intracellular magnesium level should be ordered.
- Total T4 and total T3 – does not tell us the free amount which is what counts. A free T3 and free T4 are required.
- Tests for food allergy – at best these are 70 percent accurate. It is far less expansive to simply avoid the most common allergens—gluten, corn, and dairy to start.
- Serum Essential fatty acids – deficiency is a pandemic.
- Serum vitamins A, C and E – deficiency is a pandemic.
- Hair mineral analysis – does not reliably detect heavy metal toxicity and can be very misleading with trace elements.
- Vitamin B profile including Thiamin (B1), Riboflavin (B2), Niacin (B3), vitamin B6, Folic Acid, vitamin B12 – deficiency is a pandemic
- Serum test for estrogen and progesterone – does not tell us the free amount present which is what is important
As mentioned above, Adrenal Fatigue is difficult to diagnose with traditional blood tests; those available are designed to detect the severe, absolute deficiencies of adrenal hormones that characterizes Addison’s disease, which afflicts 4 out of 100,000 people. Addison’s disease often results from an autoimmune disease or originates from an infection. Blood testing also is useful to detect extreme, excessive levels of adrenal hormones associated with Cushing’s disease. In other words, available blood tests measure adrenal hormones only at the extremes.
For a minute, picture a bell curve. The ACTH (adrenocorticotropic hormone) challenge test reveals extreme underproduction or overproduction of hormone levels, as shown by the top and bottom 2 percent of the bell curve. This means adrenal function must be extremely low (the bottom 2 percent) in order to fit a recognized diagnosis. However, symptoms of non-Addison adrenal malfunction can begin to appear after a 15 percent deviation from the mean on the bell curve. Therefore, the adrenal glands could be functioning anywhere from 15 to 48 percent below the norm and not be detected by the ACTH test.
What this tells us is that a test result showing so-called normal levels of adrenal hormones does not mean that the patient is free from adrenal malfunction. As long as conventional doctors are not taught the significance of sub-clinical Addison’s disease, or Non-Addison’s Hypoadrenia (what we call Adrenal Fatigue), these blood tests lead to misguided interpretations. Patients tested for adrenal function are told the results are well within the normal range, but in reality, their adrenal glands are performing sub-optimally; meanwhile, clear signs and symptoms continue as the body cries out for help and attention.
- Serum laboratory studies of two surrogate markers of adrenal function, cortisol and DHEA (measured in the blood by way of DHEA-S) reveal a general picture that tells us if the body is in an anabolic state (build up) or catabolic state (breakdown). However, these blood levels alone do not provide clear evidence that leads to a diagnosis of Adrenal Fatigue.
Among the specific functions of DHEA in the body are aiding in the metabolism of proteins, fats, and carbohydrates; influencing blood pressure, weight, and immune system functioning; and aiding in the production of testosterone and estradiol. Working in conjunction with cortisol, it also aids in regulating blood sugar levels. When the balance between DHEA and cortisol is upset, some significant illnesses may result depending on the levels of the two substances.
In advanced AFS, levels of DHEA often decline because pregnenolone is shunted off for the production of cortisol, which is seen to be necessary for survival instead of producing hormones of lesser importance to the body. Higher levels of DHEA may be due to supplementation or androgen dysfunction.
In addition to being the stress-fighting hormone, cortisol is important to the body in several other ways. Most of the body’s functions depend on cortisol to an extent. It aids in metabolizing and using proteins, fats, and carbohydrates. Besides its role in helping the body deal with stress, cortisol also helps in maintaining appropriate blood sugar levels and in controlling inflammation. Other body processes need cortisol to operate at optimum levels. Blood pressure, nerve and brain activity, heart function, and the immune system need cortisol levels to be balanced.
Cortisol levels can be either elevated or decreased, depending on the level of a person’s AFS condition. A healthcare professional should not rely simply on laboratory results without combining them with clinical evaluation.
Saliva testing: We can also test adrenal health by measuring levels of key adrenal hormones such as cortisol and DHEA in the saliva. An saliva test is more accurate than serum for cortisol and DHEA as it measures the free and circulating amount of each of these, not the total bounded amount as measured by serum.
Research has shown that salivary cortisol determined by enzyme immunoassay is preferable to serum total cortisol for assessment of dynamic hypothalamic-pituitary-adrenal axis activity.
We can measure DHEA at any time during the day, but cortisol levels vary throughout the day, highest in the morning and lowest in the evening before bedtime. For this reason, the recommended tests require four saliva samples: 8 am, Noon, 5 pm, and before bedtime. The multiple samples give us the ability to map the daily diurnal curve of free cortisol in the body relative to DHEA levels, allowing us to have a much clearer picture of adrenal function.
The following are general correlations on how saliva cortisol and DHEA levels relate to Adrenal Fatigue.
- Normal cortisol, normal DHEA does not rule out Adrenal Fatigue.
- Normal cortisol, high DHEA points to early Adrenal Fatigue or excessive DHEA intake.
- High cortisol, normal DHEA points to early Adrenal Fatigue as the body puts out more cortisol relative to DHEA as part of the stress response.
- High cortisol, high DHEA is commonly associated with chronic stress.
- High cortisol, low DHEA usually points to early phases of Adrenal Exhaustion.
- Low cortisol, low DHEA usually is associated with late phases of Adrenal Exhaustion.
The above correlations are very general. There are many exceptions to the rule. Paradoxical values are common especially in those who have a sensitive body or in advanced Adrenal Fatigue. Delayed response needs to be factored in as well.
Do not rely on a single saliva snapshot to draw clinical conclusions. Serial studies are needed in most cases for best interpretation.
Saliva cortisol interpretation is also challenging. To be useful, saliva cortisol levels must be viewed in the proper context:
- Morning free cortisol level is indicative of peak cortisol output.
- Lunch cortisol level points more towards cortisol adaptability.
- Mid-afternoon cortisol is highly associated with metabolic issues such as blood sugar imbalances.
- Evening cortisol level refers to baseline adrenal cortisol function.
Computerized laboratory interpretation is therefore of limited value. In fact, it can be misleading if we fail to match the different cortisol values with the body’s symptoms throughout the day along with the clinical state.
Note: If you are taking oral hormones or applying topical supplemental hormone creams such as DHEA or pregnenolone, the saliva test results may be elevated immediately. Although blood test results also increase, it takes about three months to be reflected on the test.
Stress at the time of testing also influences adrenal hormone levels. Your cortisol level tested after a quiet and relaxing morning will differ from that taken when you are under tremendous stress.
Warning: Because individual variation is wide, and the body is in a constantly changing state, you should undergo these laboratory tests in an appropriate setting and only when needed in order to make sure they are both relevant and cost-effective. We often see Adrenal Fatigue symptoms in the presence of normal laboratory results, and vice versa. Furthermore, in advanced Adrenal Fatigue, the 24-hour saliva cortisol curve invariably becomes flattened most of the time and can stay that way for an extended period of time, even during recovery. Sometimes we see a delayed response, which means the test results may be confusing and misleading. Over-reliance on tests is a common adrenal recovery mistake.
Far better than any laboratory test is a thorough history taken by an astute and experienced clinician. This is the most accurate way to assess Adrenal Fatigue status, and knowledgeable health professionals use lab tests as supporting tools, rather than as the sole gauge of adrenal function and therapeutic options. Saliva testing is best used in serial studies performed regularly over time for comparative purposes.
Relying on a single hormonal snapshot is another common mistake in recovery. For example, patients may rely on laboratory tests without understanding their limitations. They then embark on a self-guided nutritional recovery program that eventually leads to improper use of nutrients, thus making the condition worse.
Routine serum based laboratory tests can be useful in the setting of confirming disease, measuring disease burden, and explaining unusual findings in a particular patient. However, its use in Adrenal Fatigue is severely limited due to the lack of sensitivity to detect subtle adrenal dysfunction. Normal serum laboratory tests therefore are seldom utilized as a diagnostic tool in Adrenal Fatigue. Saliva hormonal testing is better. However, it needs to be interpreted properly and clinically correlated with serial study to be of significant use.
Functional and specialized laboratory testing is often not helpful in the initial assessment of Adrenal Fatigue, though they may serve a role in helping our understanding of the inner workings of the body. When properly selected, they can be helpful in situations where further investigative study is warranted after a prolonged period of slow or failed recovery.
Due to the above constraints, the key to proper Adrenal Fatigue assessment lies in a detailed history of symptoms best carried out by an astute and experienced health care professional.