It is no wonder our fatigued patients are sick and tired of being tired. Complaints of prolonged fatigue constitute up to 25% of all clinical consultations,6 with approximately half of these being labelled as idiopathic, or ‘cause unknown’.7 In fact, a number of drivers of fatigue have been identified, including stress, nutritional deficiencies, thyroid dysfunction, infections and toxicity. Natural Medicine encompasses a personalised approach that aims to identify and address the underlying causes of fatigue in your patients, to provide renewed vitality.

The damaging effects of stress can both drive and be a consequence of fatigue in patients. Over the years, stress-induced fatigue has become almost synonymous with the adrenal glands. At one time or another most Natural Medicine Practitioners will have referred to a patient as ‘adrenally exhausted’ or used ‘adrenal tonics’ to treat fatigued patients. However, is this terminology physiologically correct? Emerging understanding of stress-induced fatigue reveals a bigger picture; indicating the need to reframe the nomenclature.

Cortisol Regulation Occurs Beyond the Adrenals

Our patients’ stress response is primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis. Incoming sensory messages are screened by the limbic system in the mid-brain – this includes the hippocampus, amygdala and prefrontal cortex, as well as the hypothalamus. If these messages are recognised as stressful (e.g. neurotransmitter or blood sugar imbalance, nutrient deficiency, inflammation), the hypothalamus signals the pituitary to stimulate the adrenals to release cortisol as the primary response to maintain homoeostasis. Cortisol mobilises resources to cope with stress: increasing serum glucose via catabolism of fat stores (and eventually other tissue), and suppressing immune responses to control potentially damaging inflammation. This is fine in the short-term; however, if the stress is ongoing the effects of cortisol itself can become damaging, causing a loss of immune defence and maladaptive neuroplastic changes in the brain, leading to fatigue, neuronal damage and even brain atrophy.8

Long-term stress leads patients down the path of feeling ‘flat’ and exhausted. A common feature of chronic stress is low cortisol; and as such, it has always been assumed that this is due to an impaired or exhausted capacity of the adrenals to produce it. However, our more recent physiological understanding does not support this view. Whilst cortisol may be produced by the adrenals, it is the HPA axis that controls production.9 In fact, it now appears that cortisol production (within the adrenals) is deliberately down-regulated by the HPA axis to protect tissues from the damaging long-term effects of cortisol exposure.10 The concept of ‘adrenal fatigue’, as we knew it, does not exist (Figure 1).


Figure 1: No evidence for adrenal fatigue.11

The adrenals are merely ‘following orders’; acting under the direction of the central nervous system. This down-regulation of cortisol production is instigated by the HPA axis via increased central glucocorticoid negative feedback, rather than dysfunctional or ‘burnt out’ adrenal glands. Consequently, HPA axis dysfunction is more appropriate terminology.12

This describes any of the many consequences that link stress with the myriad of responses to it (allostasis)*; the majority of which can be linked to processes controlled by the HPA axis.12 Such consequences include the stress-induced neuroplastic remodelling of the hippocampus, amygdala and pre-frontal cortex,14, 15 that are implicated in mood disorders including anxiety and depression.

Treatment? Business As Usual

From a clinical perspective, the treatment of stress-induced fatigue remains the same – the actual physiology has not changed, merely our understanding of it. Technically ‘adrenal tonics’ such as licorice may need renaming in future, however their application remains unchanged, as does the use of adaptogenic herbs. This latter class of herbs are now understood to improve HPA axis self-regulation,16 helping explain how they are so effective during times of stress. Herbal and Nutritional Support for Adrenal Health combines a number of adaptogenic herbs including Siberian and Korean ginsengs, Withania and rhodiola to help increase patients resilience to both physical and mental stressors. Siberian and Korean ginseng aid patients’ stress management and energy production via the actions of ginsenosides; these constituents reduce inflammation and oxidative stress, protect the brain to improve neuroplasticity, and support mitochondrial function.17 With such a broad range of adaptogenic herbs, Herbal and Nutritional Support for Adrenal Health is ideal for supporting patients with physical and mental fatigue associated with stress. However, holistic treatment should also address the initiating causes of HPA axis dysfunction for each patient, for example, by implementing the Metagenics Stress Less Program.

Energetic Essentials

As a Practitioner, it is important to be familiar with the current scientific understanding of the stress response, allowing you to effectively and professionally communicate with your patients and other medical professionals using common terminology. By broadening your view of what was once referred to as adrenal fatigue, you can provide holistic and effective treatment to your patients to boost their energy levels. The new Metagenics Energy Program provides a step-wise, comprehensive treatment plan for fatigue, to help your patients regain their vitality and leap back into life. Core nutrients (e.g. magnesium, B vitamins and co-enzyme Q10) support ATP production in the first instance, whilst you identify and address the underlying causes of your patients fatigue for a long-term resolution.


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Yau JLW, Seckl JR. Local amplification of glucocorticoids in the aging brain and impaired spatial memory. Frontiers in Aging Neuroscience. 2012;4:24.
Fries E, Hesse J, Hellhammer J, et al. A new view on hypocortisolism. Psychoneuroendocrinology. 2005 Nov;30(10):1010-6.
Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC Endocr Disord. 2016 Aug 24;16(1):48.
Guilliams TG. The role of stress and the HPA axis in chronic disease management. Point Institute, Stevens Point, WI. 2015:22.
Guilliams TG. The role of stress and the HPA axis in chronic disease management. Point Institute, Stevens Point, WI. 2015:22.
Hyman SE. How adversity gets under the skin. Nat Neurosci. 2009 Mar;12(3):241-3.
Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci. 2009 Jun;10(6):423-33.
Asea A, Kaur P, Panossian A, et al. Evaluation of molecular chaperons Hsp72 and neuropeptide Y as characteristic markers of adaptogenic activity of plant extracts. Phytomedicine. 2013 Nov;20(14):1323-9.
Kim HJ, Kim P, Shin CY. A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system. J Ginseng Res. 2013 Mar;37(1):8-29.

*This article is issue by Metagenics

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