The two major components of the NeuroEndoMetabolic (NEM) Stress Response, the neuroendocrine and the metabolic, and their three respective circuits, vary in their degree of involvement as stages of stress. The body uses these two anti-stress components and their circuits to spread out the responsibility and workload of fighting stress.
Because stress resolution is critical for the survival of our species, the body has not one but two major systems to handle this. It makes perfect sense. Two army divisions are better than one when it comes to fight and winning an important war. Like an army, both components work concurrently. They not only act as back up systems for each other, but also as synergistic allies, fighting stress together as one unit.
The important question is, when stress arrives, how does the body know when to use each component, and to what degree? In other words, how is the NEM Stages of Stress Response regulated? What is the auto-regulation system that decides which component to activate, which takes center stage, and which needs rest or assistance? The body has a logical flow, and nothing is left to chance.
The research of conventional medicine over the past century has largely focused on the HPA hormonal axis and sympathetic nervous system, both of which fall within the neuroendocrine component of the NEM Stages of Stress Response. Some believe the body’s stress handling capability has been well dissected and mapped out. However, experience shows this model is clinically incomplete.
Instead, the body’s approach to stress is based on a duo-track, holistic response system. Depending on the stress level, the body automatically activates the component best suited for the job at hand. For example, in acute trauma such as a serious car accident, the neuroendocrine component is strongly activated, with the cardionomic circuit on full throttle to release adrenaline. Massive amounts of adrenaline flood the body, causing blood vessels to constrict and diverting blood to the brain to help reduce blood loss and ensure survival. In contrast, activation of the three circuits of the metabolic component is rather subtle and for good reason. In times of acute stress, metabolic circuits, such as the detoxification circuit, are of little help short term. The overall net dominance between the neuroendocrine and the metabolic component favors the former.
We will now examine how the body utilizes these two components as stress progresses.
In stage 1, NEM Response Activation, the metabolic component with its three circuits (metabolism, detoxification, and inflammation) takes center stage. It works behind the scenes as the neuroendocrine component remains relatively less active and dormant. The metabolic Stages of stress response is largely sufficient to reduce inflammation caused by stress and normalize homeostasis. There is no need for other systems to be prematurely activated. The body deploys only what is needed to “get the job done”. This ensures that our neuroendocrine responses are not overused at a time when they are not necessary. stage 1 is thus generally metabolic dominant. However, the symptoms are often so mild that no attention is paid to this, because the metabolism is so effective at subduing stress when it first arrives.
Signs and symptoms are often mild. Waking up sluggish is commonly experienced when one is under stress. Instead of tracing this symptom to its root, the sluggishness is commonly resolved with caffeinated drinks. Similarly, low energy in mid morning can be resolved by reaching for sugary donuts or other quick carbohydrates. Mild salt cravings can be satisfied by potato chips.
Stress triggers metabolic circuits to start working. Over time, metabolic derangement gradually worsens. This can go on for decades and escape detection. Some even attribute such symptoms to normal aging processes. Routine laboratory tests are usually normal. Only if more advanced and specialized functional medicine tests are run will problems be noticed. Advanced markers, such as rising C-reactive protein and triglyceride levels, serve as early warning signals of trouble within. Physicians, unaware of this, routinely send patients away with a clean bill of health without knowing the dangers that lie within. Many are told they need to exercise more to generate more energy.
In stage 2 of the NEM Stages of Stress Response, the neuroendocrine component and its three circuits (hormone, cardionomic, and neuroaffective) begin to take center stage. It goes into overdrive as this stage progresses.
The addition of the neuroendocrine system handling stress offers some relief to the metabolic component, whose burden continues unabated at the end of stage 1. Metabolic symptoms, such increased sugar and salt cravings, continue into stage 2.
As stage 2 begins, neuroendocrine disruptions start to gain prominence. The body recognizes an increased need for cortisol, the main anti-stress hormone. The HPA hormonal axis is called to action. Cortisol output from the adrenal gland surges and reaches its peak production in this stage. Symptoms become more serious. 
They act as a signal that the body has progressed to late stage 1 and early stage 2. For example, Polycystic Ovary Syndrome (PCOS), PMS, menstrual irregularity, low body temperature, and dry skin all reflect hormonal disruption in females. Low libido and fatigue from exercising affect both sexes. Sufferers notice something is wrong. Some take action to see their physician, but routine laboratory check ups reveal no abnormality. Meanwhile, symptoms become annoying, but not incapacitating. Stage 2 is called NEM Response Overdrive for good reasons. The body is working overtime to resolve stress overload and its damage within.
As stage 2 progresses, the metabolic disruptions typical of stage 1 continue unabated, but often ignored. For example, PCOS has a strong association with insulin resistance, a metabolic dysregulation. Unfortunately, laboratory test results generally appear normal or borderline, metabolically speaking. Abnormal lipid studies, if discovered, are often addressed with drugs rather than investigated to its root causes.
Symptoms, such as severe pain during the menstrual cycle, infertility, low libido, fibroids, endometriosis, and blood pressure instability, are annoying at the beginning of stage 2. By the end of this stage, they can start to disrupt daily living. Time off may be needed during menses to rest. A sense of uneasiness comes on. Something is not right but no one can put his or her finger on it. Because so many people have similar complaints, these are taken as a “normal” part of the aging process, even though some experience these symptoms as early as in their teenage years. Because the clinical focus is placed on hormonal issues by physicians, metabolic imbalances are often passed over as insignificant during this stage.
Stage 3 of the NEM Stages of Stress Response represents the deepest decline in vitality. The body’s signals, symptoms of hormonal imbalance due to a dysregulated endocrine system, have been unresolved. The ovarian adrenal thyroid (OAT) hormonal axis becomes damaged. Low thyroid symptoms surface, and many are now placed on thyroid replacement medication. Hashimoto’s thyroiditis is often determined, and patients are put on a variety of thyroid replacement medications, starting with T4 (commercially available as Synthroid). Over time, the tendency is to increase dosage or transition to a combination of T4 and T3 thyroid replacement drugs, such as Armour Thyroid. Finally, many are put on T3 alone (commercially available as Cytomel) to increase energy. The NEM Stages of Stress Response meanwhile approaches exhaustion.
Birth control pills may be recommended for those with menstrual irregularity. Low blood pressure emerges as an important disruptor of daily life, with dizziness on standing if one is not careful. Endometriosis may worsen and require surgery on the endocrine front. Fatigue intensifies and time off work increases. Weekends must be spent largely at home resting. Metabolic derangement continues, with central obesity, increasingly frequent infections, irritable bowel, weight gain, and reactive hypoglycemia becoming most bothersome. Having to eat snacks or a small meal every 2-3 hours becomes the norm when metabolic derangement becomes severe.
As stage 3 advances and stress goes unresolved, the body has no choice but to take stronger action. The alarm bells gets louder to catch our attention. The “neuro” portion of the “neuroendocrine “ components becomes the main executor of this responsibility in late stage 3. The built in autonomic nervous system is specifically designed for such an environment. It is activated only in times of severe stress, when the body perceives a threat to survival. When it is activated and becomes dominant in late stage 3, alerts can be felt throughout the entire body.
Symptoms such as heart palpitations, panic attacks, and severe insomnia render the sufferer in a state of incapacitation, leaving no doubt that the body is in trouble. Numerous physicians are sought by this time. Multiple conventional work ups continue to be negative. Most are sent home with sleeping medication. Those who complain most are given anti-depressants. Aggressive physicians may initiate multiple hormone replacements, including thyroid, estrogen, progesterone, and testosterone with the goal of accelerating metabolism to generate energy.
While stage 3 overall is neuroendocrine dominant, early stage 3 is biased towards the “endocrine” portion to alert us, while late stage 3 is biased towards the “neuro” portion as the flight or fight response takes precedent. The sympathetic portion of the autonomic nervous system accelerates and goes into overdrive if stress is unrelenting. PVCs, atrial fibrillation, sub-clinical POTS, severe anxiety, panic attacks, severe insomnia and multiple awakenings control life. One is homebound in severe cases.
Stage 4 of the NEM Stages of Stress Response is rare, fortunately. The body’s entire neuroendocrine system capitulates. Adrenaline floods the body, and the autonomic nervous system’s efforts have reached maximum output. All the anti-stress bullets available to the body have been fired. There is no ammunition left from the neuroendocrine perspective. Running out of bullets, the body has no choice but to capitulate.
The battle is lost as far as the body is concerned. It starts to downregulate metabolism to conserve energy as a last resort for survival. All but essential functions are put on a slow down or shut down mode. GI slowdown, weight loss, pain of unknown origin, electrolyte imbalances, and chemical sensitivities becomes the norm of daily living. The body’s strategy is simply to conserve what it has to its fullest capability. Without a steady energy supply, fatigue becomes extreme. As far as the body is concerned, this is still better than extinction. Most are bedridden much of the time. Ambulatory care may be needed for daily living, and multiple visits to the emergency room may be required as the body loses its stability. Stage 4 is metabolic-component dominant out of the necessity to conserve energy for survival, as all other avenues have been exhausted.
Our previous reference book, Adrenal Fatigue Syndrome, discusses these stages in great detail. Bear in mind that the NEM Stages of Stress Response largely follows the same progression as adrenal fatigue, but as the stages progress, the component dominance changes. Adrenal fatigue as a clinical condition follows largely the neuroendocrine component progression. The metabolic component and its many symptoms take center stage in late stage Adrenal Fatigue Syndrome (AFS), but this occurs outside the adrenal glands. That is why failure to change from a neuroendocrine focus to a metabolic focus is a major clinical mistake responsible for retarding recovery in advanced stages of AFS.
Failure to understand why the body changes course as stress progresses has been a repeated stumbling block in successful recovery programs.
When a patient complains of fatigue, the standard of care is to recommend metabolic stimulants, such as thyroid replacements. One need not have laboratory results indicating low thyroid to initiate such an intervention. Putting the body on metabolic stimulants often works in the short term. It’s akin to putting oil on the fire. Once the boost has been exhausted, however, more is needed to maintain the same increased energy level, and here lies the danger.
Over time more and more stimulants are required. Stronger medications, along with herbal and glandular compounds, are added to the plan. Eventually, the body becomes wired and tired. Severe insomnia, reactive hypoglycemia, and heart palpitations grip the body. Patients return asking for more stimulants. Physicians not on alert are easily misled into thinking that dosage increase will solve the problem. However, this may not work. The longer one is on stimulants, the bigger the risk of failure. You can only whip a tired horse to run further for so long. The body frequently develops tolerance or resistance to such stimulatory compounds over time. Physicians, therefore, have little option but to increase dosage. Unfortunately, what appears to work early on seems to backfire in later stages. Energy crashes become common, fatigue increases, and insomnia worsens.
Clinicians are usually at a loss at this point. Instead of pausing and questioning the approach, the tendency is to point a finger to an uncooperative body, instead of considering the appropriateness of the approach. Patients are generally abandoned and left to self navigate as physicians give up. The pursuit of healing with ever increasing doses of the same tactics, without realizing that the body demands a different focus at different stages, is a recipe for disaster. There is risk of making the condition worse.
The lesson is simple. Things will get worse if you do not listen to the body carefully. Symptoms occur with increasing severity as stress increases. Symptoms also change because they reflect different circuits activating during progression of the NEM Stages of Stress Response. This makes sense. You do not expect the body to send the same alert when it is mildly disturbed as when it perceives its survival is on the line. This is normal behavior as far as the body is concerned. Therefore, there is also a need for fluidly switching recovery approaches.
Symptoms are simply the body’s way of alerting and talking to us. They need to be listened to and not suppressed. Unfortunately, heroic measures by well-intentioned physicians are by and large focused on patching symptoms and relieving patients’ demand. When symptoms fail to resolve, the immediate, knee-jerk reaction is to increase the dosage, frequency, and intensity of medications that have worked before. Few take the time to step back, look at the entire body holistically, and put together a plan that supports the body as it switches from one dominant component to another as stress progresses.
Understanding component dominance, therefore, is not a theoretical academic exercise to satisfy the scientific mind. A strong, foundational understanding of how the NEM Stages of Stress Response behaves physiologically has important clinical significance in formulating a comprehensive and appropriate recovery plan.