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Adrenal Fatigue or HPA Axis Dysregulation?

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Do patients come to you complaining of adrenal fatigue? While widespread in popular health media, the term “adrenal fatigue” is not supported by the scientific literature. Read on to learn why “HPA axis dysregulation” is a much more accurate and useful diagnostic term.


Patients complaining of fatigue make up more than 20 percent of all patient contacts in primary care, which amounts to 18 million physician visits annually in the United States (1,2). Seventy-five to 90 percent of primary care visits have been reported to be stress related (3). Despite these statistics, conventional medicine is often at a loss as to how to care for these patients.

If you work in the integrative or functional medicine worlds, you are surely familiar with the terms “adrenal fatigue,” “adrenal stress,” and “adrenal exhaustion.” These terms are often used to explain not only fatigue and stress, but also a broad array of symptoms including sleep disturbance, low libido, poor exercise tolerance and recovery, weak immune function, and brain fog.

The common argument is that these symptoms—and the many others attributed to so-called adrenal fatigue—are caused by chronically low cortisol levels. This idea has become so widely accepted that it’s not uncommon for patients to include “low cortisol” as a complaint on the intake paperwork they fill out before they see me.

Are you still calling it “adrenal fatigue”?

You might be surprised, then, to learn that the concept of adrenal fatigue—and the resulting low levels of cortisol it’s purported to cause—is not consistent with our current scientific understanding of the stress response and how it affects human physiology.

In this article, I’ll discuss why the term “HPA axis dysregulation (HPA-D)” is a more accurate description of the signs and symptoms referred to as “adrenal fatigue.” I’ll also explain how chronic stress contributes to disease (via dysregulation of the HPA axis) and why addressing stress-related pathology in our patients is so important.

The Stress–Response Mismatch

One of the central themes of evolutionary medicine is that there’s a profound mismatch between our genes and the modern environment and that this mismatch is driving the current epidemic of chronic, inflammatory disease (4).

Our diet is one of the most frequently mentioned examples of this mismatch, but there is another example that I believe is every bit as important (but far less commonly recognized): our stress–response system.

The stress response is primarily governed by the hypothalamic–pituitary–adrenal (HPA) axis. Stress activates the HPA axis and sets off a cascade of neuroendocrine signals that ultimately leads to the release of hormones and neurotransmitters like cortisol, norepinephrine (noradrenaline), and epinephrine (adrenaline).

Over time, the chronic activation of our stress–response system erodes resilience and depletes metabolic reserve. Resilience is the immediate capacity of cells, tissues, and organ systems to respond to changes in physiological need. Metabolic reserve refers to the long-term capacity of our body to respond to these changes.

The loss of resilience and the depletion of metabolic reserve lead to changes in cortisol output (most commonly too much, but sometimes too little), disruption of the diurnal cortisol rhythm (too little cortisol in the morning or too much at night), and changes in the production of other hormones and neurotransmitters related to the HPA axis, such as DHEA, melatonin, and epinephrine.

As you can see, this is not simply a problem of cortisol deficiency due to weak adrenal glands. It’s a syndrome characterized by a mismatch between our modern diet and lifestyle and our innate stress–response system (5). All of these modern stressors impact the HPA axis, which in turn affects nearly every organ and system of the body, including the gut, brain, thyroid, metabolism, catabolism, and male and female reproductive system. This explains why the symptoms of HPA-D are so diverse and its effects can be so devastating.

Terminology: HPA-D or Adrenal Fatigue?

The concept of adrenal fatigue is loosely based on Hans Selye’s “general adaptation syndrome,” or G.A.S., which predicts changes in levels of stress hormones over time in response to chronic stress (6).

According to this theory, in a healthy stress response, cortisol, DHEA, and pregnenolone are within the normal range. In Stage 1, cortisol increases while DHEA decreases. In Stages II and III, cortisol, pregnenolone, and DHEA progressively diminish until they are totally depleted in the final stage, “failure,” or “exhaustion.”

The idea is that cortisol levels initially rise in response to stress but eventually decline as the adrenals become “fatigued” and unable to continue to produce it. However, there are three major problems with this theory:

  • Many (if not most) people with so-called “adrenal fatigue” don’t have low cortisol levels. Their free cortisol, when measured in saliva, may be low, but their total cortisol production (including cortisol breakdown products measured in urine) is often normal or even high.
  • Even when cortisol is low, it is rarely because the adrenals are “fatigued” and unable to produce it. Cortisol production is governed primarily by the brain, central nervous system, and tissue-specific regulatory mechanisms, not the adrenal glands themselves. The vast majority of people with low cortisol have normally functioning adrenal glands; the problem is further “upstream,” in the brain and CNS.
  • The adrenal fatigue concept is not supported by peer-reviewed, scientific evidence, nor does it align with our current understanding of HPA axis physiology. If you search for “adrenal fatigue” in PubMed, you’ll find only 12 results—and one of them is a systematic review published in 2016 called “Adrenal Fatigue Does Not Exist”! In contrast, if you search for “hypothalamic pituitary adrenal axis” in PubMed, you’ll see more than 19,000 search results, featuring studies linking changes in the HPA axis to everything from Alzheimer’s to obesity (7,8).

In my ADAPT Practitioner Training Program, I go into much more detail on the shortcomings of the “adrenal fatigue” model, the problems with the “adrenal stress index” test commonly used to diagnose adrenal fatigue, and a more evidence-based approach to diagnosing and treating HPA axis dysregulation and stress-related pathology. This is such an important area to master in functional medicine that we spend nearly one-third of the 12-month course covering it.

As a functional medicine practitioner and a teacher of other clinicians, I believe it’s crucial to bring ourselves into closer alignment with the current evidence base. This allows us to leverage the vast amount of research connecting HPA axis dysfunction with chronic disease. It provides a more accurate framework for understanding our patient’s condition, which enables us to focus on the many underlying causes of HPA-D (instead of myopically, and often mistakenly, assuming that low cortisol is to blame). And finally, it leads to better outcomes and reduces the likelihood that we’ll cause harm (e.g., by prescribing hydrocortisone to a patient that we assume has low cortisol, but actually has high cortisol).

35 Comments

  1. Thank you for this article! The tests I’ve done shie that I have a “suboptimal diurnal cortisol pattern” that is “consistent with evolving (phase 2) HPA axis dysfunction.”

    Your article mentions-but does not go into detail regarding- the connection with cortisol and the brain and central nervous system. What kinds of tests should I ask my HMO to perform? A brain scan? Thank you so for your advice and insight for so many “lost” people. HMO’s have failed too many people; we desperately need your help.

    With thanks,
    Laura Gerlach

  2. If my 4-point saliva tests show that my cortisol is low, how do I know if is actuallly high? I don’t want my ND to prescribe HC or other supplementation if my urine cortisol is actually high? This seem like a multi-step test and multi-faceted situation.

    What to do?

  3. I was premed and opted out of going into medicine due to my family friends that were old timers concerned about the direction of medicine in the mid1980s. Since that time I have coached from business, family and health. If Functional Medicine was available I would have become a doctor. I did not have Mono all through my childhood, and was diagnosed with CFS in my early 20s. My father and daughter have been as well. Since 2009, I have had extreme cycle of HPA-D and was finally diagnosed in 2013. Life management is vital and can function symptom free with management. When life happens in extreme ways my system crashes. Different protocols allow me to get back on my feet. Thus, a maintenance protocol and crisis protocol is just part of my lifestyle management plan. The insight about HPA-D and working with a variety of stealth microbes has helped me with the navigation of my own functionality. I believe that more information is needed into extreme chronic stress, early childhood trauma and complex PTSD and the effects on the system to include HPA-D, PAN, PANDAS and other neuroimmunological concerns. My personal theory is that since psychological abuse is not illegal or criminal, and used in war, government and the private sector, there has not been enough public funding to understand, protect against and heal from these kinds of stressors. The link of toxicity, stress and trauma has not organically expanded in our cultural consciousness due to the top secret nature of stealth operations. Now we have a health crisis from this artificial manipulation and control of stress thresholds and systems fallout. Now we are scrambling to catch up on things that have been withheld. Thank you!