For many years, I have been researching, writing, and teaching about the HPA axis, primarily in the context of the stress response and chronic disease. Along with others, I have been emphasizing that the primary focus of clinicians should not be the adrenal glands, but upon the brain and the stress signals that trigger the hypothalamus in the first place (perceived mental and emotional stress, circadian disruptors, inflammatory signals and glycemic dysregulation).

From a therapeutic perspective, I still think this is where most clinicians and health care professionals should begin: in learning how to assess the effects of stress on chronic disease, how to judge a person’s HPA axis reactivity and plasticity, and how to identify and modulate the modifiable stressors in their life. Few things are more important in building and preserving the buffering systems that maintain a patient’s resilience against chronic disease.

However, the HPA axis is more than a system designed to release cortisol when something goes awry. The HPA axis is one of the most critical surveillance systems in the body, designed to coordinate metabolic resources with metabolic needs.1 To do this, the HPA axis must calibrate the release of metabolic resources (glucose, amino acids, lipids, etc.) to the current and anticipated need for those resources. This appears to be main reason that the HPA axis maintains a tight circadian rhythm, anticipating the need for metabolic activity during the daylight hours, while resting and restoring during nighttime hours. Cortisol, through the glucocorticoid receptors within most cells, acts to regulate the expression of a myriad of genes on a circadian schedule. Stress, both acute and chronic, affects so many metabolic functions partly because it affects the harmony of the HPA axis’ ability to maintain this metabolic rhythm.2,3

Beyond this, meal timing also appears to be critical to strengthening overall circadian gene regulation, through a complex system of nutrient sensing.4 In other words, your peripheral cells know when you have been feeding and for how long you have been fasting; your brain (and your hypothalamus) knows, too. This feeding/fasting cycle controls a switch that acts to strengthen the circadian functions of the cell, along with the signals that come from light/dark cycles signaled through the hypothalamus. Chrono-nutrition is now a term used to describe this phenomenon and is even being looked at as a potential therapy for conventional adrenal dysfunction disorders.5,6

When clinicians begin thinking beyond the adrenal gland when it comes to stress (i.e., abandoning the term “adrenal fatigue”), they can then begin the process of thinking beyond “stress” when it comes to the HPA axis. This process will help focus on the importance of core lifestyle signals, which the HPA axis is designed to interpret, anticipate and attempt to modulate.


Thomas G. Guilliams, PhD (Tom) earned his doctorate in molecular immunology from the Medical College of Wisconsin in Milwaukee. For the past two decades, he has spent his time investigating the mechanisms and actions of lifestyle and nutrient-based therapies, and is an expert in the therapeutic uses of dietary supplements. Tom serves as an adjunct assistant professor at the University of Wisconsin School of Pharmacy and was the VP of Science for Ortho Molecular Products for 24 years (he now serves them as a consultant). Since 2014 he has been writing a series of teaching manuals (Road Maps) that outline and evaluate the evidence for the principles and protocols that are fundamental to the functional and integrative medical community.  He is the founder and director of the Point Institute, an independent research and publishing organization that facilitates the distribution of his many publications. A frequent guest-speaker, Dr. Guilliams provides training to a variety of health care disciplines in the use of lifestyle and natural medicines. He lives in the woods outside of Stevens Point, Wisconsin with his wife and children.




  1.  Cedernaes J, Waldeck N, Bass J. Neurogenetic basis for circadian regulation of metabolism by the hypothalamus. Genes Dev. 2019;33(17-18):1136-1158. doi:10.1101/gad.328633.119
  2. Agorastos A, Nicolaides NC, Bozikas VP, Chrousos GP, Pervanidou P. Multilevel Interactions of Stress and Circadian System: Implications for Traumatic Stress. Front Psychiatry. 2020;10:1003. Published 2020 Jan 28. doi:10.3389/fpsyt.2019.01003
  3. Spencer RL, Chun LE, Hartsock MJ, Woodruff ER. Glucocorticoid hormones are both a major circadian signal and major stress signal: How this shared signal contributes to a dynamic relationship between the circadian and stress systems. Front Neuroendocrinol. 2018;49:52-71.
  4. Reinke H, Asher G. Crosstalk between metabolism and circadian clocks. Nat Rev Mol Cell Biol. 2019;20(4):227-241. doi:10.1038/s41580-018-0096-9
  5. Hawley JA, Sassone-Corsi P, Zierath JR. Chrono-nutrition for the prevention and treatment of obesity and type 2 diabetes: from mice to men. Diabetologia. 2020;63(11):2253-2259. doi:10.1007/s00125-020-05238-w
  6. Minnetti M, Hasenmajer V, Pofi R, Venneri MA, Alexandraki KI, Isidori AM. Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy. J Endocrinol. 2020;246(2):R13-R31. doi:10.1530/JOE-20-0066