Stress and You – NeuroEndoMetabolic Symptoms of Stress

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM

Living in the modern world and dealing with symptoms of stress is no easy task for the body. Ever increasing pressure emotionally to excel in our endeavors, along with an increasingly toxic environment and inadequate rest, put tremendous strain on the body and create symptoms of stress. Scientists and researchers have been studying stress, the symptoms of stress, and our body’s response for decades. Many of us don’t even realize just how many symptoms of stress our bodies experience on a regular basis in our daily lives or attribute the root of these symptoms of stress to something different entirely.

Conventional Stress Model

The body responds to mitigate effects of stress, but too much stress can overwhelm these responses and lead to unpleasant symptoms of stressThe fact that our neuroendocrine system is in charge of much of our stress response is well established. Much of this burden falls on the hypothalamic-pituitary-adrenal (HPA) hormone axis. This is the primary neuroendocrine highway where our brain receives stress signals through our senses, interprets them, and converts them into chemical messengers called neurotransmitter and hormones. These compounds are delivered to the proper target organ to effect further targeted action. They keep the brain on high alert and ready the heart to pump more blood in times of threat or while experiencing symptoms of stress. The main stress response control center and organ outside the central nervous system is the adrenal glands. Resting on top of our kidneys, these two walnut-sized glands secrete over fifty hormones that help us deal with stress as well as the symptoms of stress. The most important anti-stress hormone of all is cortisol. Proper adrenal function is, therefore, essential for life and wellbeing.

Without a properly functioning HPA axis and proper levels of cortisol output by the adrenals, the body will not be able to handle stress well. The slightest stress can be intolerable. Daily living becomes overburdened just with keeping up routine chores. Excessive or chronic stress can overburden the adrenals so that their hormonal output becomes dysregulated over time. In the early stages of the stress response, cortisol levels rise as the adrenals put out more anti-stress hormones to help return us back to normal. As stress increases and becomes persistent, cortisol output ultimately drops after maximum output is reached. The adrenals now are unable to keep up with the cortisol demand. The clinical presentation of fatigue accompanied by the initial rise and subsequent fall of cortisol and other anti-stress hormones is popularly known as adrenal fatigue. There are four stages to this progression as the body gradually weakens with unrelenting stress. Fatigue becomes more prominent with each advancing stage from 1 to 4. During this progressive decompensation process, the adrenal glands remain pathologically intact, and traditional laboratory tests are often normal.

As symptoms of stress and fatigue advance to the later stages (3 and 4), new and more advanced symptoms of stress start to emerge. In addition to low blood pressure, salt craving, insomnia, and fatigue, new symptoms include anxiety, panic attacks, heart palpitations, reactive hypoglycemia, brain fog, low libido, paradoxical reactions, hypersensitivity to medications and supplements, and food sensitivities. These advanced symptoms of stress can be quite debilitating. The body is engaged in a state of persistent fatigue that defies all medical logic. Conventional medical workups continue to be largely normal, with no gross multi-system failure in sight pathologically. Sufferers, however, can in fact be bedridden and incapacitated by these symptoms of stress.

Tracing the pathophysiology of these advanced symptoms of stress and fatigue to their root cause is challenging. Some of them can be indirect results of a dysregulated HPA axis. However, it is clear that not all of these advanced symptoms of stress can be explained by a dysfunctional HPA axis alone. A myriad of seemingly unrelated symptoms of stress and fatigue arise from a variety of different organs and systems outside the neuroendocrine system, which conventional medicine focuses on.

Symptoms of Stress and Severe InsomniaIn particular, the simultaneous presence of depression, panic attacks, severe insomnia, brain fog, multiple chemical sensitivities, and paradoxical reactions are hard to explain without involving other systems. It is obvious that the traditional model of stress response as a neuroendocrine driven event controlled by the adrenals is incomplete when stress is severe and persistent. There are missing pieces to the puzzle. The compartmentalized approach to understanding our stress response from the organ-oriented conventional medicine model focusing on the neuroendocrine system leaves much to be desired. Questions quickly come to mind as to whether we are indeed looking at the whole picture of stress response utilizing the HPA axis as our viewfinder, or if we are just looking at part of the overall picture.

Functional Medicine’s Approach to Symptoms of Stress

To solve this problem, we begin to look at the body’s overall stress response from a different perspective, that of functional medicine. Core imbalances that underlie the expression of disease are examined. These imbalances are the precursors to the signs and symptoms of stress through which we detect and identify organ system disease commonly used in conventional medicine. To look at a disease process functionally is to investigate and address the underlying causes that influence the body’s stress response using a system-oriented approach rather than an organ-oriented approach. Symptoms are expressions of underlying pathology and thus should be used to trace the root cause rather than suppressed and masked. Imbalances arise from environmental inputs such as diet, nutrition, exercise, toxins, and trauma. They are then processed through an individualized set of genetic dispositions, beliefs, attitudes, and lifestyle factors. This requires the investigator to back away from a compartmentalized focus. Instead of looking at trees close up for clues, one has to back off to a distance far enough to see the entire forest.

The functional approach, therefore, takes an intentional bird’s eye view that focuses on interactions between the environment and the gastrointestinal, endocrine, metabolism, and immune systems, for example, along with knowledge of how individual organs interact with these systems, as the foundational basis of a physiological construct for examining our body’s response to symptoms of stress. It cuts across an organ system approach to disease and allows health practitioners to see the full expression of disease and dysfunction from a systems approach in order to restore balance. It adopts a model of disease based on the interaction of underlying causes, triggers, constitutional parameters, immediate causes, and the particular characteristics of a person’s illness to arrive at the root cause. This approach to understanding the disease process and healing is holistic and comprehensive. Organs, systems, and their interactions are examined. Yet the field of investigation is much broader, yielding more data points that enable the construction of a more robust and comprehensive stress response model. Looking at the body’s stress response from a functional perspective allows the practitioner to fully comprehend and integrate a myriad of seemingly unrelated stress-induced symptoms into a coherent, logical flow that otherwise is convoluted and often defies the conventional medical construct when stress is severe.

Metabolism and Symptoms of Stress

metabolism processes help detoxify the body and ensure energy flow, but weak a metabolism fails to prevent symptoms of stressMetabolism in the context of symptoms of stress response refers not only to the way chemical reactions in each cell convert food into energy while dealing with symptoms of stress. It also governs our body’s inflammation responses and determines our body’s ability to detoxify itself. A healthy metabolism will defend the body against an insult from symptoms of stress and stress’ oxidative damage by reducing the body’s toxic load and preventing stress from damaging our cells. It will ensure a steady supply of glucose to keep our brain on alert during stressful events. On the other hand, a weak metabolism can cause an imbalance to the internal microbiome, congest the extracellular matrix, slow down the detoxification process, reduce nutrient delivery for optimum cellular respiration, and retard recovery from physical or emotional trauma. Ultimately, all chemical reactions of the hypothalamic-pituitary-adrenal (HPA) axis directed by the neuroendocrine (NE) system under the traditional symptoms of stress response model needs to be carried out by numerous metabolism pathways to produce the desired end results, whether it be fighting infection, avoiding mood swings, keeping us asleep when we are worried, or keeping us alert in times of stress.

Looking at our body’s stress response purely from a neuroendocrine perspective with the adrenals as the main stress response organ works well when stress is mild and intermittent (stages 1 and 2 of adrenal fatigue). However, a more comprehensive perspective is to see our body’s entire stress response from a NeuroEndoMetabolic (NEM) perspective, involving multiple organs, systems, pathways, and chemical reactions all working in unison on a functional level to combat stress when it arrives on our doorstep. This perspective allows us to explain the body’s pathophysiologic response in all stages of adrenal fatigue, from mild to severe.

The NEM stress response model, therefore, represents and describes the body’s response to stress from a functional medicine perspective. It represents a progressive approach and a paradigm shift in how stress should be evaluated. By incorporating the metabolism component, which is systemic in nature, into the traditional neuroendocrine stress response equation, which is mostly organ-specific, we see how the body uses both localized organ-specific responses as well as systemic responses to overcome stress. This makes perfect sense, because excessive stress threatens the very survival of our species. The body’s toolbox for stress removal is much bigger than can be contained in a compartmentalized approach, and rightfully so. This functional perspective to stress is an evolution in the practice of medicine because it recognizes the body as it truly is; a self-regulated and integrated system that cannot be compartmentalized.

Metabolic Dysregulation – Symptoms of Stress

The metabolism component has eluded our attention for decades because it is so subtle and seemingly innocuous. This leads us to think that its contribution to the stress response is limited. This cannot be farther from the truth. It is clear that metabolism regulation is one of the last remaining, little-understood frontiers of the body’s physiological response to stress. The reason is rather simple: it is well designed, so breakdown is unusual and often passed over as inconsequential. Connecting the dots between the metabolism and neuroendocrine systems, however, paints a very different picture when both are considered together as one overall stress response.

Sugar Cravings and Symptoms of StressWhile the metabolism is as involved throughout the stress response process as the hypothalamic-pituitary-adrenal (HPA) axis, its clinical expression is often hidden because the signs and symptoms of dysfunction are very subtle early on. Sugar craving, a sign of early metabolism derangement, for example, is seldom regarded as problematic by conventional medicine because it can be overcome by snacking frequently. Central obesity, a clear sign of metabolism derangement, is often passed over as caused by diet, without further investigation. Food sensitivity is seldom investigated from an inflammation perspective.

Unfortunately, unresolved metabolism derangements get worse over time and can be debilitating if stress as an aggravating factor is not resolved. Signs and symptoms of severe metabolic derangement can directly or indirectly lead to hypersensitivity to supplements, emergence of paradoxical reactions, recurrent crashes, intolerance to medications, severe constipation, or hypersensitivity to electromagnetic forces, just to name a few. Reactive hypoglycemia, a common sign of adrenal exhaustion, is a late sign. It can ruin one’s life. The exact pathophysiology pathways of some of these metabolic derangements are not fully known. Multiple metabolism pathways and resulting systemic dysfunctions are at play. Logic leads us to deduce that there may be associated involvement of intracellular space pollution, interstitium/extracellular matrix congestion, toxic reactive metabolite overload, reduced clearance, receptor site damage, and subprime hormonal levels, among others. Regardless of the actual pathophysiological pathways, which may not be known for decades, it is clear that collectively advanced metabolism derangement is involved in this final downward spiral of the decompensating cascade as the body runs out of tools to neutralize stress.

Sadly, by the time these metabolism symptoms surface, the body’s overworked neuroendocrine stress response is already severely compromised as well. Sufferers, therefore, also present with classic symptoms of a dysregulated HPA axis such as severe lethargy, reactive hypoglycemia, low blood pressure, dizziness, panic attacks, and gastric shutdown as the body enters a catabolic state to preserve whatever energy reserves remain.

Many are indeed housebound at this point. Fortunately, only a very small number of people advance to this state. Being in this state is to feel like the “living dead,” appearing well on the outside with normal routine laboratory results but “falling apart” internally. Many are incapacitated, unable to hold down any productive career. Some require ambulatory assistance to perform the chores of daily living such as cooking and housekeeping. Multiple specialists are sought, and after an exhaustive hunt for etiology, sufferers may be told that the root cause could be anything from gut dysbiosis or heavy metal toxicity to genetically linked conditions such as MTHFR and pyroluria or parasitic infections. Heroic efforts with prescription medications and nutritional supplementation are then attempted to normalize these conditions. Invariably, failure occurs as the body crashes and becomes more sensitive with less reserve after each crash. Eventually, the body may become intolerant of medications including steroids, glandulars, herbs, vitamins, and antibiotics. Any attempt to detox the body backfires. Sufferers are abandoned.

In response to extraordinary levels of stress, the body slows down unneeded functions, which is why fatigue is one of the most common symptoms of stressThe body’s signal is clear. It just wants to be left alone. Severe metabolic derangement, therefore, represents the final sign of a helpless body overwhelmed with stress. Clinical signs of metabolism derangement are often obvious only in retrospect as they are so subtle and are often ignored until too late. Experience shows that it can make a major difference to understand this significance and incorporate the metabolism component into our understanding early on. Clinically, it allows us to be on the alert and take proactive steps ahead of time.

The NeuroEndoMetabolic Stress Response

The entire NEM stress response, therefore, can be seen as a complex web consisting of systems and organs linked to each other forming a functional network. Its job is to act as a safety net when stress threatens our survival. It can be thought of as a home electrical circuit panel, with multiple circuits. Each circuit controls an area of the house, but collectively they are tied to one another as well.

Here is a graphical representation:
The body's NEM systems are interconnected systems that deal with stress. In attempting to deal with severe stress, symptoms of stress can arise.

There are two main components of independent but overlapping circuit breakers responsible for our body’s functional response to stress. They are the neuroendocrine and the metabolic components. Both are continuously working 24-7, though the degree varies depending on the severity of insult faced.

The neuroendocrine component consists of three circuits, involving the thyroid, adrenals, heart, autonomic nervous system, brain, and GI tract. They are called into action to help in the body’s anti-stress response when the hypothalamic-pituitary-adrenal (HPA) axis is activated.

The metabolic component also has three circuits, involving the pancreas, liver, extracellular matrix (interstitium), immune system, and microbiome. They are called into action at the same time as the neuroendocrine (NE) system.

Both the NE and the metabolic component work concurrently together and are inseparable. What happens in one component will affect all other organs and systems because the body is one closed ecosystem that cannot be compartmentalized when stress appears. The body’s response to stress is global in nature, utilizing the two components of the NEM response system at will. In its infinite wisdom, the body decides which pathways to activate, which organs to rest, and which hormones to put into overdrive as the stress reduction cascade is activated. This automatic process has served the survival of our species well.

These two components form the overall NEM response. Each has three circuits for a total of six functional circuits, all interconnected, working in unison. The three that fall into the neuroendocrine component are the hormone, cardionomic, and neuroaffect circuits. The three that fall into the metabolic component are the inflammation, detoxification, and bioenergetics circuits. Each circuit and its associated organs and systems are like a section of an orchestra, each with its own instruments and tools. The sum total of these six circuits and two components makes up the NeuroEndoMetabolic response to stress from a functional medicine perspective.

Normal activation of the NEM response is automatic and takes place 24-7 without us knowing. When stress is overwhelming or persistent, the NEM circuit breakers start to malfunction. Disruption within the NEM response can lead to negative consequences. The degree of damage to the NEM response will determine the degree of our body’s overall weakness and the degree of symptomatology seen clinically. The ultimate clinical presentation is also heavily influenced by our genetic backdrop and our lifestyle choices. Everyone’s clinical response to stress, therefore, is different. Some people can tolerate and in fact thrive on stress, whether physical or emotional. Others may have a nervous breakdown with the slightest insult.

NEM Circuit Dysfunction

The following are the six core clinical imbalances that arise from dysregulation of the NEM stress response. The function of each circuit in stress response will be considered as well as the consequences when it becomes disrupted or damaged.

They are discussed here in order of activation and clinical expression as stress increases and stress response dysfunction intensifies. Remember that only general patterns are presented here, with tremendous individual variations.

1. Hormone Circuit

The hormone response to stress is regulated primarily by the adrenals, thyroid, and gonads (female ovaries and male testis), with controlling signals starting in the brain. This area has been well studied. The HPA axis and the hypothalamic-pituitary-gonadal (HPG) axis are key pathway regulators.

Hormonal responses are some of the first to become deranged, leading to hormonal imbalances and associated symptoms of stress such as hair lossThe adrenal glands, sitting on top of the kidneys, are responsible for secreting cortisol, the most important anti-stress hormone in the body along with over fifty other hormones. Low adrenal function can lead to low thyroid function. The thyroid gland regulates our basal body temperature and the overall speed of stress response. When thyroid function is slowed, fatigue is inevitable. When a body is in a state of fatigue, reproduction is not a priority and libido is reduced. The ovarian-adrenal–thyroid (OAT) hormone axis plays an important balancing role to ensure the body has adequate hormones to deal with reproduction. Disruption of any part of the OAT axis will cause havoc in the other systems.

Disruption of the hormone circuit response can lead to symptoms such as fatigue, exercise intolerance, infertility, hair loss, afternoon slumps, PMS, low libido, dry skin, menses irregularity, feeling cold when others are warm, and low thyroid function despite thyroid replacement medication. Symptoms tend to be mild, starting with waking up unrefreshed, feeling tired in the afternoon, and a second wind in the evening. Women may also get fibrocystic breast disease, PMS, and menstrual irregularity. Low libido is common. As the NEM response becomes more disrupted, amenorrhea, infertility, and miscarriages can occur.

Thyroid function tends to slow as NEM response dysfunction progresses. The body tries to conserve energy, and slowing the basal metabolic rate by down-regulating thyroid function is effective. Unfortunately, many clinicians are unaware that low thyroid function is a compensatory response to stress and may initiate thyroid replacement therapy unnecessarily, masking the underlying pathology even more.

2. Metabolism Circuit

The bioenergetics regulatory organs are comprised primarily of the thyroid, pancreas, and liver. A proper bioenergetics response ensures the body gets the right amount of fuel it needs at the right time. It comes as no surprise that one of the body’s early defenses to stress, in addition to HPA axis activation, is activating the bioenergetics response to increase the basal metabolic rate, so the body is on ready mode, with increased glucose delivery to the brain to keep us alert.

The thyroid is the body’s main regulator of metabolism speed. A slow thyroid function will slow all metabolism pathways. The pancreas plays an important role by way of insulin, the all-important regulator of glucose, the fuel of our body. Least appreciated is the role of the liver, the master metabolite clearinghouse. Working together, they determine the effectiveness of metabolic pathways and reactions in the body.

A deranged bioenergetics response gives rise to many early warning signs of NEM disruption, such as sugar craving, dyslipidemia, and the central obesity commonly seen in stages 1 and 2 of adrenal fatigue. These are rather subtle and are often passed off as insignificant signs of aging by most clinicians. More advanced symptoms of metabolism disruption include reactive hypoglycemia, type 2 diabetes, and weight gain. These are often more present as the adrenals enter exhaustion in stage 3. In severe cases, weight loss and loss of muscle mass occur as the body surrenders after unsuccessful efforts to restore homeostasis. Eventually, the body enters a shutdown mode as the only way it sees fit for survival. The body is usually in late Stage 3 of adrenal fatigue at this time.

3. Neuroaffect Circuit

Mood swings, anxiety and brain fog are some of the symptoms of stress that affect cognition and mental capacityAs the bioenergetic and hormone circuits are fully engaged in the stress response, the central nervous system is inevitably involved as well. Complaints of insomnia, anxiety, depression, mood swings, and brain fog become more prevalent as stress increases.

Much of the neuroaffect response is regulated by the autonomic nervous system, brain, and microbiome. Stress responses are initiated in the brain, largely in the hypothalamus through the hormone circuit discussed earlier. A variety of neurotransmitters are released to different parts of the brain to maintain a balanced mood, keeping us alert to handle stress, but allowing us to rest when it is time to do so. Some neurotransmitters are transformed into or also act as hormones, regulated by the autonomic nervous system. Many of our body’s neurotransmitters are also made by the microbiome in the gut. The gut is often called the “second brain” for this reason. The microbiome-gut-brain axis is an important regulatory pathway of the body’s neurotransmitter pool. Inflammation of the gut microbiome can lead to depression, as we shall see below. Norepinephrine, for example, is an important neurotransmitter that helps support alertness within the brain. Symptoms of overactivation of norepinephrine include anxiety, panic attacks, and insomnia. The autonomic nervous system, however, is the conduit that allows norepinephrine to exert its effect outside the brain, such as on our heart and blood vessels, to get ready for stress. Symptoms of over activation of the autonomic nervous system can result in feeling the heart pounding as if it may “jump out of the body.”

The brain, microbiome, and autonomic nervous systems are, therefore, the all-important triad responsible for maintaining proper balance in our mood, sleep, and cognition. Dysregulation of this circuit can lead to sleep onset insomnia, sleep maintenance insomnia, anxiety, and panic attacks.

4. Cardionomic Circuit

As mentioned above, an important part of the body’s overall response to stress is to ready the heart, blood vessels and lungs with more blood filled with oxygen in case physical flight is needed. This function is not activated until the danger of survival becomes imminent. Key hormones required for this “fight-or-flight” response include both norepinephrine and adrenaline. Adrenaline is the body’s most powerful stimulatory hormone by far. It is also known as epinephrine, a hormone released and modulated by the adrenal glands and regulated by the sympathetic nervous system, part of our body’s autonomic nervous system. Excessive release can cause internal havoc. Perfect balance in this circuit, involving the heart, autonomic nervous system, and adrenal glands, is required.

Disruptions of the cardionomic response lead to high blood pressure, dizziness, heart palpitations, cardiac arrhythmia, breathlessness, and shortness of breath. In advanced disruptions, POTS-like symptoms, PVCs, and atrial fibrillation may be experienced. These symptoms are normally seen in those with adrenal exhaustion (stage 3 or four of adrenal fatigue). An overactive cardionomic circuit puts the entire body’s metabolism on constant overdrive, instead of allowing the system to turn itself on and off at will with adequate time for rest and repair in between activations. This is a short-lived, temporary measure by design. Unrelenting stressors put this “fight-or-flight” response in a permanent “on” mode which can damage our heart’s normal function.

5. Inflammation Response

Inflammation is one of the body's responses to toxins or germs, but persistent inflammation responses as symptoms of stress are unpleasant.Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, toxins, and damaged cells. It is an integral part of our body’s defense apparatus to keep us safe. It involves immune cells, our microbiome, and the GI tract. Imbalanced gut flora and systemic inflammation are strongly associated. The purpose of inflammation is to eliminate the initial cause of cell injury, to clear out necrotic cells and tissues damaged from the original insult and the inflammation process, and to initiate tissue repair. Inflammation is tied, therefore, to our detoxification system as well.

In addition, inflammation affects our brain’s response to stress. For example, depression is associated with a chronic low-grade inflammatory response caused by cell-mediated immunity. When the gut is inflamed, gut permeability is increased. Gut cells are generally held tightly together to avoid leakage. Stress, infection, toxins, and antibiotics damage the tight junctions, leading to the leakage of proteins into the bloodstream, along with sugar and other toxins that trigger inflammation. Such toxins can lead to depression within the central nervous system and pain of unknown origin outside. Lipopolysaccharides (LPS) are an important marker of leaky gut and are prevalent in autism, depression, Lou Gehrig’s disease, and Alzheimer disease. Commonly used antidepressants called SSRIs have strong anti-inflammatory properties that can help reduce depression.

The body’s inflammation response to stress is activated early on, like the bioenergetics response. Signs and symptoms of inflammation, however, are often subtle and too minor to be detected. Inflammation markers, such as C-reactive proteins (CRP), can be elevated but are often passed over as insignificant. It is not until inflammation is rampant that the body begins to show clinical symptoms such as food sensitivity, leaky gut, inflammatory bowel disease, irritable bowel disease, and musculoskeletal pain of unknown origin. Joint surfaces are easy targets of inflammation and destructive processes that result in pain. Neurogenic and musculoskeletal inflammation is often mediated by the sensory nervous system through the release of pro-inflammatory compounds that arise from sensory nerves in tissue. These compounds are activated by a wide variety of triggers including allergens and environmental chemicals.

Failure to properly regulate and suppress excessive inflammation can ruin the body. Disruption of this system can lead to symptoms such as recurrent infections, frequent and longer colds, proliferation of autoimmune disorders, increased food sensitivities, stealth viruses, exacerbation of the Epstein-Barr virus, candida, failure to recover from Lyme disease, SIBO, IBS, leaky gut, and musculoskeletal pain.

6. Detoxification Response

Environmental toxins and excessive stress increase oxidative stress and rob our cells of necessary electrons, leading to premature cell death and excessive cellular debris. The body’s ability to clear metabolites, biotoxins, and toxic by-products in a timely manner is critical to avoiding congestion and toxin accumulation. The liver, interstitium/extracellular matrix, and immune system are the key players that ensure an unpolluted body with a clear sewage system. In particular, the liver, as the main clearance center of the body, must be kept in optimum shape. The interstitium, immune system, and liver support these processes, as does the lymphatic system and kidneys, which also play important roles.

Toxic and synthetic chemicals bombard our bodies, causing an unprecedented degree of stress and crippling us with symptoms of stressStress-induced oxidative damage and excessive metabolite overload can become toxic in the body if not promptly removed by the liver and the extracellular matrix. Toxins from everyday pollution, medications, alcohol, smoke, and hydrogenated fats accumulate in our extracellular matrix, causing congestion. They also cross into cells and damage intracellular organelles such as mitochondria. Cellular integrity is often compromised when the body is in a toxic environment. Both the intracellular space and extracellular matrix need to be optimized to remove toxins promptly and help in the detoxification process. Oxidative damage to cell walls by heavy metals in our water and gaseous pollutants in the air we breathe can damage cell health. Receptor sites can also be damaged by prescription medications and recreational drugs. The extracellular matrix response, for cell to cell signaling and transportation of intercellular messengers and scaffolding to support organ structure, can become congested, choking the cells’ respiratory and energy production chain. Without proper detoxification, the immune system is compromised, and premature cell death occurs.

It comes as no surprise that as the detoxification burden increases, symptoms of a toxic ecosystem emerges. They include the emergence of paradoxical reactions, hypersensitivity, supplement and medication intolerance, and chemical sensitivities.

Here is a table breaking down the six responses with the corresponding symptoms and organs involved.

Stress Response Circuit Primary Systems and Organs Involved NEM Response Activation and Overdrive NEM Response Exhaustion and Failure
Hormone Adrenal-Reproductive-Thyroidd estrogen dominance, low libido, premenstrual syndrome (PMS), endometriosis, polycystic ovary syndrome (PCOS), amenorrhea, erectile dysfunction low cortisol output, thyroid resistance, brittle adrenals
Bioenergetics Thyroid-Pancreas-Liver sugar cravings, salt cravings, dyslipidemia, weight gain, metabolic syndrome carbohydrate dependency, carbohydrate intolerance, catabolic state, liver congestion, organ resistance, reactive hypoglycemia
Detoxification Liver-Interstitium-Immune hypersensitivity to drugs and supplements, sensitivity to food, pain of unknown origin paradoxical reactions, electromagnetic field (EMF) sensitivity, chemical sensitivities, recurrent crashes, retoxification reaction, reactive metabolite overload
Inflammation Immune-Microbiome-GI tract food sensitivities, leaky gut, irritable bowel syndrome (IBS), recurrent infections, Epstein-Barr virus (EBV) recurrent and stealth infection, autoimmune disorders, systemic candida, small intestinal bacterial overgrowth (SIBO), inflammatory bowel disease (IBD)
Neuroaffect GI tract-Brain-ANS mood swings, anxiety, sleep onset insomnia (SOI), sleep maintenance insomnia (SMI), stress intolerance adrenaline rushes, panic attacks, depression, neurotransmitter imbalances
Cardionomic ANS-Cardiovascular-Adrenal heart palpitations, tachycardia, sub-clinical postural orthostatic tachycardia syndrome (POTS) shortness of breath, breathlessness, premature ventricular contractions (PVC), atrial fibrillation, clinical POTS

Testing the NeuroEndoMetabolic Stress Response

Testing the body’s stress response begins with the hypothalamic-pituitary-adrenal (HPA) hormonal axis. The organ responsible for HPA output is the adrenals, where multiple hormones are excreted. Three tests give you insight into the situation of your HPA axis function. They are the salivary DHEA (dehydroepiandrosterone – a hormone produced by the adrenal glands), salivary cortisol, and pregnenolone tests. These tests are, however, only indicative of a possible problem, and results cannot be seen as definite without clinical correlation. Only an experienced clinician is able to interpret tests because mistakes are possible, results can be confusing, and they may not necessarily reflect the underlying root cause of the problem. Because there is so much variance in results, the analysis made by a computer should not be regarded as final. Rather, it should only be used as a general guideline for educational purposes.

There are, however, a number of more advanced investigative (non-diagnostic) tests that give a more complete evaluation of your NEM stress response. These tests are:

The Salivary Secretory IgA (SIgA)

Your salivary immunoglobulin A, or SIgA, is a part of your immune system’s ‘first line of defense’ when your body is confronted with pathogens, bacteria, and viruses. SIgA is considered a reliable biomarker when discerning gastrointestinal (GI) health in regards to conditions such as allergies, leaky gut, candida, food sensitivities, and small intestinal bacterial overgrowth (SIBO).

Children and older people with saliva containing lower SIgA concentrations tend to have a higher risk of developing periodontal disease, caries, and upper respiratory tract infections. While there is no difference in SIgA levels between males and females, individual differences have been identified when infection responses occur and are thus a risk factor.

Although we tend to think of mucus as being found only in the nose and sinuses, your gut actually has a whole lot more. Your mucus lining is the body’s first line of defense when it comes to all gastrointestinal pathogens, including parasites, viruses, bacteria, fungi, toxins, and food proteins.

To put things in a nutshell, carcinogens, microorganisms, and food proteins are prevented from binding to absorptive cell surfaces because of the SIgA antibodies’ actions. The SIgA antibodies attach themselves to any invading pathogens, and in doing so, effectively trap the pathogens in mucus, thereby disabling their ability to move throughout the body. Toxins given off by the pathogens are then neutralized before being excreted from the body.

The SIgA antibodies also identify food that they deem to be acceptable and non-invasive. This leads us to the conclusion that lower SIgA levels may be instrumental in developing intolerances and allergies when it comes to certain foods.

Although SIgA and serum IgA are related, they are not the same. Serum IgA is often checked together with Immunoglobulin E ( IgE) and Immunoglobulin G (IgG) when blood tests are conducted in order to ascertain immunity and possible allergies. The two, SIgA and serum IgA, are independent of each other. If the levels of one are normal, it does not necessarily mean that the same is true for the other. You thus always need to check each independently of the other when doing blood tests.

People with a lower IgA tend to have a higher propensity for immune-related problems such as infections, chronic skin problems, and allergies and find it more difficult to control instances of candida. Those who are most at risk of contracting immune-related issues are those with chronic stress, those within the autistic spectrum, and those with ulcerative colitis or Crohn’s disease.

Lower IgA levels indicate a weakened body that has only a limited ability to overcome infections. The adrenals may be exhausted, as is shown by fatigue, crashes, relapses, and prolonged recovery. The immune system has difficulty coping.

High SIgA levels, on the other hand, are indicative of a sub-clinical system infection that points to leaky gut syndrome, irritable bowel syndrome (IBS), or possibly a hyperactive immune state.

Your SIgA levels can thus be regarded as an advanced marker when it comes to the NEM stress response of the inflammation, detoxification, immune, and gastric systems.

Salivary C-Reactive Protein (CRP)

Your body’s serum and salivary CRP levels are usually not very high under normal conditions although they sharply increase during the latter stages of adrenal fatigue. Research indicates that there may be a link between the occurrence of stroke and heart attack incidences and your body’s CRP levels. This thus suggests that CRP levels could be used as a yardstick to monitor your body’s cardiovascular health and to predict the possibility of any future coronary problems. Numerous research studies have taken a look at the correlation between CRP and diseases, including diabetes, autoimmune disorders, hypertension, and cancer. They have also indicated a strong possibility of a link between various health issues such as heart disease, oral health, inflammation, and chronic infections.

Salivary Alpha Amylase (sAA or α-amylase)

Salivary alpha-amylase (sAA) is a protein enzyme that may be used as a possible potential biomarker when it comes to the activation of the sympathetic (autonomic) nervous system. Autonomic nervous signals control the release of sAA secretion by the salivary glands. Much research points to the release of sAA when the body experiences stress. This stress may be due to physiological reasons, such as heat, cold, or exercise, or due to psychological reasons, such as the stress related to taking a written test. Interestingly, studies do not indicate that there is necessarily a correlation between sAA and cortisol during stressful conditions. This thus suggests that the sAA differences that are seen may mean that the protein enzyme’s stress response happens to be independent of the stress response of your HPA axis. Instead, sAA levels are often tied to the activity of the sympathetic adrenomedullary (SAM) hormone system.

High levels of sAA indicate that your body is undergoing high levels of stress. When your body’s sAA and cortisol levels are measured and compared, it gives you valuable insights into the nature of the different interactions between your HPA axis and your autonomic nervous system (ANS) in regards to the different types of stress responses or different psychological conditions. With regards to the NEM stress response, valuable insights are garnered when it comes to the cardionomic, neuroaffect, and hormone circuits.

Interlukine-1-Beta (Interleukin-1β or IL-1β)

The cytokine protein interlukine-1-beta is also known as a leukocytic endogenous mediator, lymphocyte activating factor, or leukocytic pyrogen. Cytokines are manufactured by many different types of cells in the body including monocytes, dendritic cells, fibroblasts, and macrophages. Interlukine-1-beta is a pro-inflammatory cytokine because of its involvement in your body’s inflammation response during chronic or acute infections or when it is subjected to conditions that result in it being exposed to constant low-grade inflammation, such as is the case with obesity. The interlukine-1-beta protein is thus a reliable indicator of whether inflammation is present.

The cytokine protein interlukine-1-beta is usually released after the body is subjected to antigens, or as a result of infections or injury. It is, in fact, a molecule that is released to signal the presence of infection, and usually from the body’s immune cells, although quite a number of other cell varieties present in your body’s tissue also secrete it. It is present, for example, in your saliva (because of the presence of and production by immune cells), in certain cells in the saliva glands, and in other tissues in the oral cavity. Some of this cytokine, by means of the gingival crevicular fluid (GCF) that is secreted by gum tissue next to the teeth, also ends up in your saliva.

The cytokine protein interlukin-1-beta is a marker for inflammation, one of the main circuits of your body’s NEM stress response system.

One needs to remember that the NEM stress response system’s advanced markers are investigative and not diagnostic in nature at this time. None of these markers are definitive. This is because each of them points to a certain function, giving but an indication of the body’s response to stress in general terms. You should not depend on only one test in order to make a concrete determination. Instead, for clinical reasons, you should make comparisons, using the different tests, while at the same time looking at the person in question’s medical history before coming to any form of specific, concrete conclusion.

Summary and Conclusion

In the modern world, stress has become an inescapable part of living. The body’s NeuroEndoMetabolic (NEM) stress response self-regulation system protects us from excessive stress. The two components are the neuroendocrine and the metabolic components, and the six stress response circuits are the neuroaffect, cardionomic, hormone, bioenergetics, detoxification, and inflammation circuits. Utilizing various organs and systems, an orchestrated anti-stress response is mounted. Together they work in unison to attempt to restore the body to normal function, provided the body has the tools to affect this. Because the natural progression is a downward or worsening cascade, failure to recover or severe disruption of the NEM stress response can cause great harm to the body. Incorporating this functional model into our understanding of the body’s stress response helps us to understand the pathophysiology of stress in our body.

© Copyright 2016 Michael Lam, M.D. All Rights Reserved.

Dr. Lam’s Key Questions

Get a good night rest, do more adrenal breathing exercises, keep well hydrated, and eat frequently.

If you have advanced stages of AFS and are on a budget, it is best to take the right nutrients to strengthen your body and the adrenals before you embark on a heavy duty detoxification program.

metabolism processes help detoxify the body and ensure energy flow, but weak a metabolism fails to prevent symptoms of stress
5 -
Dr Lam,

Your information resonates so much with what I see in myself and the patients I treat. You are the first medical doctor I can believe about this issue as it seems no one wants to acknowledge adrenal issues (except known ICD9 codes) except you.

I am only a nurse practitioner and I need to be treated myself because I own a small independent clinic with more stress than is humanly possible.

Thank you,


Daniele Perrelli Marsh, MSN, CNP


  • Laura says:

    Is it possible to experience temporary adrenal fatigue? Sometimes I feel so stressed I literally cannot do anything but it doesn’t usually last very long and really, other than that I have no other symptoms of AF.



    • Dr.Lam says:

      in early stages, symptoms do come and go and is transient and that is the danager because most people will not take it seriously

      Dr Lam

  • Tom says:

    I’ve heard of laughter / humor therapy being used in cancer patients. Could this also be effective in treating metabolic issues and stress?

  • Patti says:

    This one really hits home for me. Stress is so unpreventable sometimes but I can tell the long lasting effects it has on my body!

  • Anonymous says:

    The vast web of factors seems to beget critical timing for supports for a stronger NEM. What might be happening with the body before 6:30am and does something change after 6:30am?

  • Richard says:

    What if stress has pushed you to a level of emotional burnout, or numbness?

  • Erik says:

    Great article, now if we could just get more doctors on board with this knowledge!

  • victoria raines says:

    This is the best overall article and explanation of the NEM response I’ve ever read. Thank you, Dr. Lam, for making it so available to everyone and so readable. 🙂

  • Tom says:

    This article really hits homes. Now its time to figure it out.


  • Kenzie says:

    Wow, I have never seen or heard of anyone explain this!! It really does make sense when you look at the whole big picture. I’ve felt so stuck and like doctors just keep shoving pills in my face without even taking the time to figure out where it is all coming from. I wish more doctors uinderstood this concept.

  • Karol says:

    Amen D. Marsh and thank god for Dr. Lam. I know now I never had a thyroid problem it was adrenal fatigue and Dr. Lam is the only one I will believe about this subject and it resonates my whole life beginning in high school and being a type A person and perfectionist that has just compounded the normal stress from everyday living into a living hell! Thank you,

  • Andy says:

    As per various studies and studies, 65% of representatives feel amazingly distressing at work, while 25% of the workers believe that their occupations are the real stressor in their lives. The working environment stress can be felt inwardly, physically and rationally

  • Michelle says:

    What would you recommend to manage stress?

    • Dr.Lam says:

      Ultimately stressors have to be removed. Simplifying your life can be helpful, but it is easier said than done.

      Dr Lam

  • Lisa says:

    This article describes me perfectly – everything! My history strongly suggests that I have a long-standing viral infection with lots of inflammation (CRP is 17.3) and a collapsed methylation pathway leading to adrenal insufficiency. I am being treated with bioidentical thyroid hormones, cortisol, and iodine by my functional medicine practioner and low-dose antibiotics by my CFS specialist but my fatigue keeps worsening. Can you point me to a book that might help me begin to pull-out of this vicious cycle?

  • Martha says:

    Do certain Medications cause an immune response which can make my adrenals worse?

    • Dr.Lam says:

      Medications can generate reactive metabolites that attack the immune system and thus worse adrenals. All medications has the potential to do that. That is why the less medication you take the better. Pain meds especially are problematic.

      Dr Lam

  • Deborah Serra says:

    Dear Dr. Lam, I have Graves’ disease which came on after a particularly high stress event last year. I subsequently wen on beta blockers and anti thyroid meds for three months until my thyroid levels came down. Prior to the onset of this and ever since I suffer from high cortisol from four to ten or so in the morning. I thought this would go away after my TT but it persists. Obviously the thyroid was not the only organ out of balance. I believe there is another imbalance in the neuroendocrine system. But I don’t know what it is. My Graves was caused by a reactivated Epstein Barr virus I contracted fifty years ago. The virus also gives me times of fatigue; I am anxious and wired in the am and often fatigued later on. I started the adrenal breathing and yoga poses from your book. They seem to help. Do you know what’s going on here? How can I rebalance my body? Like adrenal fatigue sufferers I want to get my life back.

    • Dr.Lam says:

      Your clinical situation is complex. It is common when the thyroid is off balance that other organs and systems can be involved as well. Stealth infection as a cause is problematic. Re-balancing when it comes to this point needs a personalized approach and what works for one person can backfire on you. Do be very careful. We do have a telephone coaching program that may be helpful if you qualify.

      Dr Lam

  • George says:

    So if IBS is an inflammatory symptom of stress- does that mean if I lower my stress levels my IBS will improve?

  • Christiana says:

    Didn’t realize that stress affects our metabolism! Thank you for this valuable insight.

  • Laura says:

    Do canker sores comes from stress or overheating in the body?

  • Janie says:

    I have had so many issues with stress recently and im noticing im breaking out more and i feel like my hair is constantly falling out. My question is how can a person lower the hormonal response of stress on their body? Thanks

  • Ned says:

    i now have a clearer understanding of how stress affects your body. thank you for the article!

  • Lori says:

    Is it possible for hair loss to be associated with adrenal fatigue and not low thyroid levels? I have been experiencing more hair loss than usual and when i had my blood test my thyroid levels were normal.

  • Maria says:

    I have been trying different ways to alleviate stress. What do you think about float tanks?

    • Dr.Lam says:

      It is one of many tools, and can be considered with the right situation. Sensory deprivation can be very good but also can backfire on some people.

      Dr Lam

  • Darryl says:

    Great info Dr. Lam, thanks for writing!

  • Anthony says:

    Dr. Lamm,

    Great information. Thank you. I’m 46, male, 5’11 & 140lbs. Fatigue & muscuoskeletal pain I originally thought were myofascial/trigger point in nature doesn’t seem to be the case.

    I’ve been taking prescription meds for ADD for five years but sleep relatively well, maintain an appetite etc. I also supplement–maybe “over” supplement as I continually chase physical pain with no relief. I don’t do R&R & am continually moving at about Mach 10. Daily meditation, deep breathing, sound frequency “healing”, & long invigorating walks don’t seem to help at all. Any suggestion(s) greatly appreciated. Thanks again.

    • Dr.Lam says:

      Certain people are internally neurologically wired to go at high speed.Medications are indicated, and you need to be careful with supplemnentatioin as well as they can often conflict with each other if not careful. understanding the neuroaffective component takes a lot of experience. Try not to self navigate if you can find a professional to help you as the body is constantly changing and a moving target especially under stress .

      Dr Lam

  • Nicole says:

    For someone who’s stress response is metabolic, what to you recommend to reduce those symptoms?

    • Dr.Lam says:

      Metabolic imbalances needs to be identified first and foremost. There are many possibilities. For example, if glucose metabolism is off, then one can experienced fatigue from reactive hypoglycemia. So one has to systematically go thru a detailed history and determine what is the specific metabolic is off, and help the body repair. There may be multiple dysfunctions, so it can get rather complicated. Metabolic nutritional is a very complex matter requiring extensive clinical training. Click Adrenal Fatigue & Hypoglycemia for more information.

      Dr Lam

  • Cara Zaller says:

    So how does one heal from this? I am trying so hard and nothing is working. The main issue is that I can’t sleep more than 5-6 hours and then feel extreme fatigue all day every day.

    • Dr.Lam says:

      The best is through educating yourself the complexity of what is involved first. Then you can look for an experienced professional who understands and has the ability to put together a comprenhensive long term recovery program. Short term treatment for sleep with sleep aids and meds are temporaary solutions to deeper problems. Focus on the big picture with a broad vision to allow the body to heal itself slowly and properly , step by step, is the key.

      Dr Lam

  • Donna says:

    Hello Dr. Lam,

    Thank you so much for the video message (very quick response!) and the link above. Very very informative!

    The thing is I have always been healthy – I eat a lot of good food (fruits, veggies, whole foods). I do not drink alcohol and sodas, nor do I smoke. I exercise (walk/run) using the treadmill until just recently as I got busier with raising kids and running my household. I did not realize how much stress can affect the whole body! I gave birth naturally (without pain medications to two relatively big babies – 8.5lbs and 7.5lbs) and these were particularly taxing to the body, and I breastfed them both for about 18 months! Double whammy for me (but I do not regret breastfeeding my babies at all)!

    I saw my primary physician maybe 5 times last year complaining about little pains here and there, and about feeling fatigued, and she always discounted it and always said my blood work had always been good and that I am a healthy person. But deep inside, I know something is not right, that’s why I started searching for a Holistic Doctor and found one in my area. I saw him in Dec last year and did extensive blood work – which showed my cortisol level at 5.5 and DHEA at only 26. He was actually the one who mentioned something about my adrenals not functioning at their optimum level (which I have not heard of). But did not start my adrenal support regimen right away because at that time, I was still breastfeeding. Then I started having heart palpitations and anxious-like feelings – which are not fun! Then my insomnia got worse due to these palpitations waking me up prematurely at night. It is very debilitating and of course worrisome because I am not sure exactly what is going on and if I will ever get back to my normal, strong self. I am the type of person who hates medication – if can take something naturally, I usually go that route first before anything else. But, I need sleep to function properly during the day that is why I am taking the sleep aid (as much as I hate it, I feel like I do not have a choice at this point).

    Anyway, I am scheduled for an initial phone-in interview this coming Thursday and I can not tell you how much I can not wait to feel better.

    I thank you and your team for your assistance, in advance.

    Best regards,

    • Dr.Lam says:

      What you experienced is quite common and it reflects a body that does not like what you are currently doing with good reasons. Continue your search for knowledge, and that is the best beginning for your recovery.

      Dr Lam