Adrenal Fatigue vs Stress Response: Which Best Describes Stress-Related, Chronic Dysfunction?

Dr. Thomas Guilliams earned his doctorate from the Medical College of Wisconsin (Milwaukee) where he studied molecular immunology in the Microbiology Dept. Since 1996, he has spent his time studying the mechanisms and actions of natural-based therapies and is an expert in the therapeutic uses of nutritional supplements.

As the VP of Science and Regulatory Affairs for Ortho Molecular Products, he has developed a wide array of products and programs which allow clinicians to use nutritional supplements and lifestyle interventions as safe, evidence-based and effective tools for a variety of patients.

Tom teaches at the University of Wisconsin School of Pharmacy, where he holds an appointment as an Asst. Adjunct Professor and at the University of Minnesota School of Pharmacy. He is a faculty member of the Metabolic Medicine Institute (Formerly FAARM), through which he has an appointment as a Clinical Instructor at the George Washington University School of Medicine and Health Sciences. He lives outside of Stevens Point, Wisconsin with his wife and children.

Most of us are familiar with the K.I.S.S. principle; “keep it simple, stupid.” First coined in the engineering world, the idea is that simple designs and solutions are always preferred over complex ones. In the engineering world, these simpler solutions are then tested to see if they actually tackle the engineering problem they were designed to fix. Simple solutions are genius…..when they work. As you can imagine, it often takes a much more complex design to solve some of engineering’s most complex challenges.

In the world of medicine, the K.I.S.S. principle is quite often adopted to explain complex pathophysiology, especially when educating young medical students or busy clinicians, or in helping patients to understand what ails them. Quite often, these simple explanations out-live their usefulness and sometime can even create a barrier to explaining the true complexity behind the simplified explanation. Perhaps one of the best examples of this is “good” and “bad” cholesterol; sounds simple, like a Western movie that clearly tells us the intention of each cowboy based on the color of their hat. I witnessed the K.I.S.S. principle on full display during a commercial advertising one of the most recent cholesterol-lowering drugs. The woman in the ad was relieved to report her LDL-cholesterol (the bad guy) was below 10! In the simplistic world of good and bad cholesterol, the target for LDL-C must be zero, or so one is supposed to believe.

A second example is from a conversation I had a few years back when a friend of mine told me they had “MTHFR,” thinking this acronym defined some sort of disease. After explaining that we actually all have this gene, I further discussed the fact that one’s methylation status was a complex relationship between many factors for which her particular polymorphism (genotype) was but one part of the phenotypic picture. I cannot tell you how many similar conversations I have had with clinicians equally confused about the meaning and implication of knowing about MTHFR and its polymorphisms. The simplistic answers, which were common just a few years ago, made it difficult for many clinicians to deal with the nuances and complexities of methylation biology.

Such is the use of terms like “adrenal fatigue” (or “adrenal exhaustion”) to explain the complex dysfunctions related to the stress response. Though these terms may help dispel the notion that only extreme issues related to adrenal function (Addison’s or Cushing’s Disease) are of clinical importance, these terms have become ubiquitous within the functional and integrative medical community as a diagnosis or description of stress-related, chronic dysfunction. As with these other explanations, these terms need to be abandoned and replaced by more accurate and medically appropriate terms to focus attention on the primary etiology of stress-related, chronic dysfunction, which is controlled by the brain rather than the adrenal gland.

In recent years, the broader medical community (led primarily by The Endocrine Society) has targeted “adrenal fatigue” as a diagnostic myth and warned consumers about practitioners who use this term.123 Ironically, except for publications criticizing the term, the language “adrenal fatigue” is rarely even used in peer-reviewed published literature. Nonetheless, the term is widely embraced by many clinicians (and the public) as the primary root cause (or consequence) for stress-related, chronic dysfunction. The notion that chronic stress can exhaust the capacity of the adrenal glands to produce cortisol (likened to how the pancreas is exhausted to produce insulin in type 2 diabetes) is what drives this phenomenon. The common finding of low cortisol levels (most often using salivary cortisol testing) in subjects complaining of chronic stress is then often cited as evidence of “adrenal fatigue.”

While it is true the most common laboratory tests used to assess the function of the HPA axis measure hormones secreted by the adrenal glands, primarily cortisol and DHEA(S), the mechanisms which control the level of these hormones, resides mostly outside of the adrenal gland. Low cortisol and/or DHEA levels may indeed be related to chronic stress, but the root cause leading to reduced levels of these hormones is related to HPA axis adaption (i.e., downregulation). Perhaps this is intentional to protect sensitive tissues from excess cortisol; and has nothing to do with the intrinsic cortisol-producing capacity of a person’s adrenal glands.4 Therefore, while many clinicians (and even some laboratories) refer to this as “adrenal testing,” it is much more accurate to say that such tests assess the status of the HPA axis using adrenal hormone measurements as surrogate markers. This is only true if those test samples are collected in the appropriate manner and time.

Clinicians should change their nomenclature as it relates to stress-induced phenomena and move away from language which focuses on “adrenals” and, instead, focus on stress or the stress response (i.e., the HPA axis). Using descriptive and accurate terms helps clinicians and patients have a better understanding of the pathophysiology caused by stress and the stress-response system. Also, since most stress-related phenomena start with one of several key hypothalamic triggers such as perceived stress, glycemic dysregulation, inflammatory signaling, circadian disruption, or feedback inhibition issues (in the hypothalamus and/or pituitary), successful treatment protocols should be designed to target these root issues rather than to support the adrenal gland directly. The term stress-induced HPA-axis dysfunction (or HPA axis maladaption) is much more appropriate to describe the typical consequences which link stress with the myriad of measurable negative consequences related to the stress-response. The majority can be linked in some manner to processes controlled by the HPA axis. Alternatively, some refer to these as “disorders of the stress-response system” or the consequences from or maladaption to stress. Again, most of these terms are used, in various ways, by stress researchers in the peer-reviewed literature and help orient both clinician and patient to the role of stressors and the stress response as two modifiable components of therapy. By avoiding the use of oversimplified (and incorrect) terminology to describe these relationships, and instead choosing more appropriate descriptive terms, the clinician will enhance the credibility of these important relationships and be better equipped to incorporate therapies which address the complexity of the whole stress-response system.


[1] While we generally agree with the Endocrine Society that the term “adrenal fatigue” is problematic, we do not agree with their view that there is little evidence to connect chronic stress with adverse health outcomes; or that testing adrenal hormone output is of no value beyond diagnosing extreme adrenal disease conditions. Their public statement can be found here:
[2] Ross IL, Jones J, Blockman M. We are tired of ‘adrenal fatigue’. S Afr Med J. 2018 Aug 28;108(9):724-725
[3] Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC Endocr Disord. 2016 Aug 24;16(1):48
[4] Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view on hypocortisolism. Psychoneuroendocrinology. 2005 Nov;30(10):1010-6