Chronic fatigue, low blood pressure, sleep alterations and digestive problems are just some of the health issues commonly associated with “adrenal fatigue”. While symptoms are real, what is research saying about this purported condition?
The condition commonly known as “adrenal fatigue” is not a medically recognised illness. However, the symptoms usually linked to adrenal fatigue are real and can be treated. People with “adrenal fatigue” often experience tiredness, brain fog, lack of motivation, low energy levels, anxiety, body aches, nervousness, sleep disturbances and digestive problems.
However, many of these conditions are linked to different underlying problems, and the adrenal glands may play an important role.
“Adrenal fatigue”: What are the adrenal glands?
The adrenal glands are two small, triangle-shaped organs located on top of each kidney. The adrenal glands produce hormones essential for regulating the metabolism, immune system, blood pressure, and response to stress, among other functions.
Each adrenal gland is composed of two key structures:
- The adrenal cortex – the outer and largest part of the adrenal gland;
- The adrenal medulla – the inner region of the gland;
These two structures have important and distinct physiological roles, each secreting different types of hormones.
The adrenal cortex produces three types of hormones: glucocorticoids, mineralocorticoids, and sex hormones (adrenal androgens).
- Glucocorticoids regulate fundamental processes, such as linking the endocrine and immune systems and ensuring the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination. They also regulate key cellular functions, such as cell metabolism, growth, differentiation, and apoptosis. The hypothalamus and the pituitary gland trigger glucocorticoids production;
- Mineralocorticoid hormones primarily act on the kidney, causing sodium and water retention, as well as excretion of potassium and protons. The kidney regulates mineralocorticoid production;
- Sex hormones are male and female-specific and are produced in small quantities by the adrenal cortex;
The adrenal medulla produces two key hormones involved in our body’s response to stress:
- Epinephrine, better known as adrenaline, is responsible for increasing the heart rate, blood flow to muscles and the brain, and blood sugar levels, all in response to stressful stimuli.
- Norepinephrine – also known as noradrenaline, this hormone works alongside adrenaline in response to stressful stimuli. Noradrenaline is known to cause high blood pressure due to the narrowing of the blood vessels.
A brief history of “Adrenal fatigue”
The idea of “adrenal fatigue” was originally based on general adaptation syndrome, which describes the changes that occur in our body in response to stressful situations. This stress response model was first proposed in 1936 by endocrinologist Hans Selye. In a series of experiments, Seyle noticed that, when exposed to stressful situations, rats exhibited physiological responses similar to those observed in humans. According to Seyle, the general adaptation syndrome is characterised by three distinct stages: alarm, resistance, and exhaustion.
In 1998, influenced by Seyle’s work, the chiropractor James Wilson invented the term “adrenal fatigue”. According to this model, chronic stress can cause the “overuse” of the adrenal glands, resulting in their functional failure or “adrenal fatigue”. The term “adrenal fatigue” is widely used by alternative medicine providers; however, there is no scientific evidence for the existence of such a condition3. Furthermore, to date, no endocrinology society has recognised “adrenal fatigue” as a real medical condition.
“Adrenal fatigue” and our stress response system
Our body responds to stress through two primary systems, depending on the type of stress. When facing a stress signal requiring immediate or short-term responses, the sympathoadrenal medullary system (SAS) comes into play. In contrast, when the stress signal requires an intermediate or long-term stress response, the hypothalamic–pituitary–adrenal axis (HPA axis) steps in.
The Sympathoadrenal system is a major regulator of body homeostasis, influencing blood pressure, heart rate, energy balance and intermediary metabolism. This system has been linked to regulating the body’s energy expenditure through stimulating β-adrenergic receptors (β-ARs). These receptors are a type of protein found in the heart, kidney and fat cells. β-ARs serve as targets for catecholamines like norepinephrine and epinephrine4. In animal models, it has been shown that mice genetically modified to lack β-ARs, exhibit accelerated weight gain, compared to normal mice, despite following a similar diet5.
The hypothalamic–pituitary–adrenal axis or HPA axis can be seen as an interactive neuroendocrine unit composed of the hypothalamus, the pituitary gland, and the adrenal glands. The hypothalamus is located in the middle of the brain, the pituitary gland at the base of the brain, and the adrenal glands can be found on top of the kidneys6. The interaction of these three organs of the HPA axis have important roles in maintaining basal homeostasis and regulating certain stress responses. The ultimate output of the HPA axis is the production and secretion of cortisol. The hypothalamus is the first responder in the HPA axis pathway, which increases the secretion of corticotrophin-releasing hormone (CRH) in response to stress signals. In response to increased levels of CHR, the pituitary gland secretes adrenocorticotropic hormone (ACTH), which reaches the adrenal cortex and stimulates the release of cortisol into the bloodstream.
To learn more about the HPA axis and the many ways it influences health, head to our research and innovation website.
Focus on Adrenal Fatigue and Cortisol levels
this hormone is responsible for various physiological changes meant to help our body respond to stress. When cortisol is produced, it increases glucose levels in the bloodstream, enhances the brain’s use of glucose, enhances the availability of biochemicals involved in tissue repair and reduces inflammation. Cortisol also inhibits certain non-essential functions that are not useful in a fight-or-flight situation, such as digestive and reproductive functions.
Altered cortisol levels – Optimal cortisol levels are required for the correct functioning of the body. Excessively low or high levels of cortisol result in detrimental consequences. For example,
- weight gain, particularly around the abdomen and face
- thin and fragile skin that is slow to heal
- acne
- for women, facial hair and irregular menstrual periods
- chronic tiredness
- nausea and vomiting
- weight loss
- muscle weakness
- pain in the abdomen
For more details on the role of cortisol in the body, see the healthdirect portal.
“Adrenal fatigue”, Stress and modern life
Our stress-response system was designed to help us survive stressful (and dangerous) situations. For example, fleeing an imminent danger or facing other potentially harmful situations. Our stress system made sense for our hunter-gatherer ancestors, who lived in an overall hostile environment. At that time, it was good to have an elevated heart rate, blood pressure and blood sugar, and tense muscles. Back then, this stress system would have helped our ancestors in many ways, making them efficient at conserving energy, combating dehydration, fighting injurious agents, anticipating adversaries, minimising exposure to danger and preventing tissue strain and damage.
But this was some 12,000 years ago. Our lifestyle has changed dramatically compared to that of our hunter-gatherer ancestors. For most people today, danger is not lurking on the next corner, nor do they have to run for their lives anytime during the week. Instead, today, our sources of stress are much different, more subtle than thousands of years ago. Our modern sources of stress are traffic, work stress, following a poor diet, sleeping late at night or being exposed to excessive white light/screen time during night-time. These stimuli reach our body as stress signals, activating the same stress-response system that once helped us run away from a wild animal.
This is an example of a biological adaptation that was beneficial but has now become harmful or maladaptive, especially in the long term. Constantly activating our stress-response system can lead to alterations to our body’s physiology and may explain why modern societies are plagued by disorders like:
- obesity
- metabolic syndrome
- type 2 diabetes mellitus
- hypertension
- autoimmunity and allergies
- anxiety
- insomnia
- depression
- pain and
- fatigue syndromes.
All of these conditions can be associated with dysfunction of the stress system7.
An important concept to understand in the context of dysfunction of our stress system is metabolic reserve, which explains how long our body can withstand stressful events.
Key points about stress
- Our stress response system involves the central nervous system and peripheral organs.
- Some key players of the stress response system are hormones like corticotropin-releasing hormone, cortisol and brainstem-derived norepinephrine
- Malfunction of the stress response system is associated with multiple behavioural and somatic disorders
- Stress is a major factor influencing psychosocial and physical pathologies
Focus on: Adrenal Fatigue, resilience and metabolic reserve
Resilience can be defined as our body’s capacity to respond to immediate stress inputs. In contrast, metabolic reserve can be defined as our body’s capacity to withstand long-term stress. In practice, metabolic reserve can be defined as the long-term capacity of cells, tissues, organs and organ systems to withstand repeated stressful signals, such as changes to physiological needs.
Some of the conditions associated with malfunctions of resilience and metabolic reserve include:
- depression
- obsessive-compulsive disorder
- alcoholism
- diabetes
- obesity
- PTSD
- hyperthyroidism
- hypothyroidism
- chronic fatigue syndrome
- fibromyalgia
- premenstrual tension syndrome
- rheumatoid arthritis
- asthma
- eczema
Building resilience and metabolic reserve requires significant changes to the various aspects of modern-day lifestyle for many people. Eating a healthy diet, reducing stress levels, getting plenty of sleep, and adequate exercise (not too little, not too much) are all well-established factors that can build your resilience and metabolic reserve. Even spending time in nature has been recently shown to have positive health effects.
A recent article that reviewed research from the past four decades concluded that there was significant evidence to support a link between diets low in saturated fats / high in omega-3 polyunsaturated fats and reduced risk of obesity, metabolic syndrome and stress-related psychiatric disorders. Diets rich in fruits, nuts, and vegetables and fish rich in omega-3 fatty acids are likely to have a beneficial effect on mental and physical health8. Our patients receive a personalised and well-balanced diet of macronutrients and micronutrients that matches their lifestyle. The goal of this diet is to help improve the functioning of the HPA Axis.
However, diet alone is not sufficient to attain a healthy body. Alongside a healthy diet, studies show that an active lifestyle is crucial to maintaining a healthy body and optimal metabolic functioning.
exercise exerts an important influence on the HPA axis. It has been shown to be efficacious in treating mild to moderate depression and anxiety. It has also been shown that physical exercise is beneficial for various chronic conditions through its role in regulating certain genes, like PGC1α. This gene is involved in the reduction of pro-inflammatory cytokines and the increase of anti-inflammatory cytokines9.
Both animal studies and human clinical studies suggest that the underlying mechanisms driving the effect exercise has on depression and anxiety involve multiple pathways, including regulation of the production of brain-derived neurotrophic factor (BDNF), D-β-hydroxybutyrate, synaptic transmission, hypothalamic pituitary adrenal (HPA) axis, tryptophan hydroxylase, GSK3β/β-catenin pathway, neuroinflammation, oxidative stress and PGC-1α1-PPAR axis9.
Finally, regular exercise is a well-established approach to activating the HPA axis and regulating levels of the glucocorticoid cortisol10. At a physiological level, the benefits of exercise have been linked to effects on the hippocampus and the prefrontal cortex, both regions implicated with cognition and regulation of diurnal cortisol levels11.
Is “adrenal fatigue” just HPA Axis Dysregulation?
An emerging question is whether the symptoms commonly framed around “adrenal fatigue” may more accurately describe alterations of the HPA axis and the hormone cascade it produces. Studies have shown that HPA dysfunction has an important role in the onset of anxiety. Long-term stress responses on the HPA axis, for example, can induce fear, sympathetic disorder and excessive vigilance, all symptoms associated with anxiety11-12. Other studies have found evidence that exercise can have beneficial effects on depression through different pathways reviewed here.
Like anxiety, most symptoms associated with adrenal fatigue, such as tiredness, brain fog, lack of motivation, low energy levels, body aches, nervousness, sleep disturbances and digestive problems, can all be traced to hormonal alterations occurring through a dysfunctional HPA axis.
Dysfunction of the HPA axis can generally be caused by four main factors:
- perceived stress – this can be financial stress, job stress, relationship stress or any other form of stress.
- Inflammatory inputs – anything that can cause inflammation in your body, having gut problems, Small intestinal bacterial overgrowth, obesity and following an inflammatory diet.
- High or low blood sugar – alteration to optimal blood sugar levels can influence insulin levels and leptin signalling levels, potentially affecting HPA axis functioning.
- Circadian disruption – alteration to our sleep/wake and light/darkness cycles can affect the functioning of the HPA axis, reviewed here13.
Modern Functional Medicine – a better approach to “adrenal fatigue”
At the Australian Centre for Functional Medicine, we conduct regular literature reviews to maintain an updated and accurate understanding of chronic conditions affecting our patients. For “adrenal fatigue”, we follow an evidence-based approach and focus on the symptoms experienced by the patient and the results obtained from clinical tests.
For patients suffering from symptoms commonly associated with “adrenal fatigue”, we conduct a comprehensive hormone test known as the DUTCH test. This urine-based test provides accurate measurements of hormones levels, including information about:
- 24-hour cortisol production;
- diurnal free cortisol;
- free cortisone rhythms;
- cortisol metabolites (indicating rate of cortisol metabolism);
- Dehydroepiandrosterone;
- Melatonin
- Six organic acids, and
- Sex hormones, such as Estradiol, Estrone, Estriol, Progesterone, Testosterone, DHEA estrogens, estrogen metabolites, progesterone metabolites, and androgens.
With these results at hand, we will be able to gain a better understanding of the potential mechanism driving your symptoms and design a personalised treatment plan.
Start your path to improved health
References
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- Annane D. Is there a mineralocorticoid deficiency in critically ill patients? How can it be diagnosed? Should it be treated?. InEvidence-Based Practice of Critical Care 2010 Jan 1 (pp. 521-524). WB Saunders. Read it!
- Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC endocrine disorders. 2016 Dec;16(1):1-6. Read it!
- Alhayek S, Preuss CV. Beta 1 Receptors. [Updated 2020 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Read it!
- Bell C. Regulation of Metabolism. InPrimer on the Autonomic Nervous System 2012 Jan 1 (pp. 253-255). Academic Press. Read it!
- Heaney J. (2013) Hypothalamic-Pituitary-Adrenal Axis. In: Gellman M.D., Turner J.R. (eds) Encyclopedia of Behavioral Medicine. Springer, New York, NY. Read it!
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- Ignácio ZM, da Silva RS, Plissari ME, Quevedo J, Réus GZ. Physical exercise and neuroinflammation in major depressive disorder. Molecular neurobiology. 2019 Dec;56(12):8323-35. Read it!
- Chen C, Nakagawa S, An Y, Ito K, Kitaichi Y, Kusumi I. The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels. Frontiers in neuroendocrinology. 2017 Jan 1;44:83-102. Read it!
- Tortosa-Martínez J, Manchado C, Cortell-Tormo JM, Chulvi-Medrano I. Exercise, the diurnal cycle of cortisol and cognitive impairment in older adults. Neurobiology of stress. 2018 Nov 1;9:40-7. Read it!
- Lopresti AL, Hood SD, Drummond PD. A review of lifestyle factors that contribute to important pathways associated with major depression: diet, sleep and exercise. Journal of affective disorders. 2013 May 15;148(1):12-27. Read it!
- Hu S, Tucker L, Wu C, Yang L. Beneficial effects of exercise on depression and anxiety during the Covid-19 pandemic: A narrative review. Frontiers in Psychiatry. 2020 Nov 4;11:1217. Read it!
- Kalsbeek A, Van der Spek R, Lei J, Endert E, Buijs RM, Fliers E. Circadian rhythms in the hypothalamo–pituitary–adrenal (HPA) axis. Molecular and cellular endocrinology. 2012 Feb 5;349(1):20-9. Read it!
