Chapter 15 Adrenal exhaustion
AETIOLOGY
Stress
Hans Selye, in 1935, was the first to develop a theory of stress. When he imposed different types of physical stressors on rats he discovered that, regardless of the kind of stressor, the same physiological response was the result: hypertrophied adrenal glands, atrophied lymphatic organs (lymph nodes, spleen and thymus) and bleeding gastric ulcers. These symptoms developed over time. He called this the ‘general adaptation syndrome’ (GAS), stating ‘stress is the nonspecific response of the body to any demand made upon it’.1 This requires adjustment or adaptation to a new situation.
From his observations he hypothesised three stages: alarm, resistance and exhaustion. The alarm stage was characterised by hormonal changes such as increased sympathetic nervous system (SNS) activity, with its typical fight or flight response and noradrenaline secretions, and up-regulated cortisol. In the resistance stage the body had adapted to the stressor, the above symptoms had disappeared and body metabolism had returned to normal. In the exhaustion stage the stress triad of hypertrophied adrenals, atrophied lymph organs and gastric ulcers were noticed, together with an initial increase in cortisol, which later declined to below normal. Only in this stage, with severe stress over prolonged periods of time, did the body lose its ability to cope and eventually death ensued. However, in general the physiological changes mentioned above were thought of as being protective to ensure the animal’s survival.1,2 Therefore, stress is actually a positive occurrence needed for protection (readiness for action when in danger, increased immune particles when injured). It becomes pathological only if it is protracted or uncontrolled.3–5
Physiologically, a stressor causes disruptions in homeostasis, leading to neural and endocrine changes known as the ‘stress response’ or ‘stress cascade’ (Figure 15.1).6,7 Mental and emotional stressors stimulate the hypothalamus via the limbic system (the hippocampus and amygdala),6–8 whereas physical and physiological processes, such as injury or hypoglycaemia, can stimulate the hypothalamus directly.
The first (and immediate) reaction to a stressor is caused by imbalances in the central nervous system (CNS) through overstimulation of the SNS and suppression of the parasympathetic nervous system (PNS). The SNS stimulates the adrenal medulla to secrete the catecholamines noradrenaline and adrenaline. They are produced from phenylalanine and hence tyrosine (Figure 15.2). These hormones lead to heightened alertness to quickly judge a situation regarding its potential danger. Blood pressure, breathing and heart rate are accelerated for fight or flight, for which glycogenolysis (release of glycogen from the liver) provides the extra fuel. Endorphins are released to dampen pain from a potential injury. Digestion, relaxation and sleep are suppressed. In other words, the body is prepared for swift action needed for survival.3,6,9,10
Stimulation of the anterior pituitary gland is achieved through secreting corticotrophin releasing hormone (CRH), and to a lesser extent arginine vasopressin (AVP), which leads to the release of adrenocorticotropic hormone (ACTH). ACTH triggers the release of vast amounts of cortisol glucocorticoid and moderate amounts of aldosterone a mineralo corticoid from the adrenal cortex. Both these hormones are made (a minerale certicoid) from cholesterol (Figure 15.3).
Under normal circumstances cortisol levels are highest in the morning and lowest in the evening. Its physiological actions control carbohydrate, protein and fat metabolism, and it inhibits prostaglandin synthesis and contributes to emotional stability.
In stress, however, cortisol levels in blood are elevated, triggering an increase in protein breakdown and mobilisation of fatty acids (gluconeogenesis) in order to provide glucose for the fight or flight response. This results in a hyperglycaemic state in the liver with peripheral hypoglycaemia, temporarily leading to moderate insulin resistance. High cortisol also decreases lymphocyte and eosinophil counts, effectively dampening any inflammation or immune response.2,6,7 Moreover, elevated glucocorticoids influence reproduction, growth and thyroid functions by inhibiting gonadotropin-releasing hormone (GnRH) and luteinising hormone (LH), growth hormone (GH) and thyroid-stimulating hormone (TSH), respectively.6 As a result, these functions are suppressed because the body deems them to be of minor importance in the face of an acute stressor.6,11–14
Cortisol, adrenaline and glucagon all have the ability to raise blood glucose levels. Due to their hyperglycaemic action they have a catabolic effect on the body. Cortisol is involved in replenishing depleted energy stores; hence it converts food into glycogen and fat, and initiates hunger. Adrenaline increases mental alertness, blood pressure, breathing and heart rate, muscle tone, glycogenolysis and the release of endorphins. Simultaneously, it down-regulates appetite, digestion, elimination, relaxation and sleep.3 Glucagon opposes insulin by mediating the release of glucose from storage.
The second hormone released by the adrenal cortex—aldosterone—retains sodium and water in the body. In addition, stimulation of the posterior pituitary gland by the hypothalamus results in antidiuretic hormone (ADH) secretion. The combined result of these actions is fluid retention and increased blood volume, which can lead to increased blood pressure.2
The secretion and interplay of the stress hormones will vary, depending on the type, intensity and duration of the stressor as well as its hormonal regulation.15,16 High amounts of circulating cortisol will, via negative feedback loops, shut off the release of hormones from the hypothalamus and anterior pituitary glands. Therefore, once the acute stressor has subsided, the stress cascade abates and the physiology of the organism returns to normal. The individual becomes more resilient as a result of successful adaptation to a new situation in which wear and tear are minimised.17 This memory is stored in the hippocampus and readily accessible when a similar stressful situation arises, so the learning from the first event can guide the (re)actions when it recurs. The role of the amygdala is to retain the emotional impact of the stressor and, together with the hippocampus, will ensure a better memory of an emotionally charged event. Both cortisol and adrenaline are needed for this memory to happen.3 Thus mind and body can both be strengthened from a stressful experience, becoming more resilient to future stressors.
Distress
If, however, stress is chronic or intense and exceeds the person’s mental and physical resources, it becomes distress. This is the case in adrenal exhaustion which corresponds to the final stage of Selye’s GAS. The circulating hormones will not return to their normal levels and initially stay in a state of hyperarousal.6,8 As a result, CRH, AVP and ACTH are no longer inhibited via negative feedback (leading to dysregulation of the HPA axis), target organs become overstimulated, receptors possibly become desensitised and tissue damage ensues.4 This ‘wear and tear’ or ‘cost’ of adaptation or allostasis has been termed ‘allostatic load’. It is implicated in numerous disease processes4,18–20 and has been associated with an energy-deficiency state of the body.14 It is mediated by adrenaline and cortisol. Both hormones actually serve to imprint the stressful event into long-term memory, but prolonged action will cause damage to the part of the brain that should shut them off. This in turn leads to higher levels of these hormones circulating in the blood (‘cortisol resistance’), which can do more damage to the brain, especially the hippocampus. High levels of cortisol have been linked to the conditions outlined in Table 15.1.
Table 15.1 Chronic diseases caused by high cortisol3
| HORMONAL DYSREGULATION | DISORDER |
|---|---|
| General effects | |
| Lowered serotonin levels | Anxiety, panic disorder and melancholic depression5,6,25–27 |
| High cytokines leading to oxidative stress | |
| Suppression of immune function | Infections31,32 |
| ↑ bone demineralisation | Reduction in bone mass and osteoporosis6,27 |
| ↑ storage of fat around abdomen → ↑ gluconeogenesis from protein (loss of muscle mass) to meet energy demands → ↑ insulin → ↑ cortisol → ↑ eating energy-dense foods → ↑ storage of fat | |
| Shrivelling of dendrites → destruction of neurons → ↓ neurogenesis → cerebral ischaemia → ↓ hippocampus size | Impaired memory and loss of cognitive function, acceleration of ageing28 |
| Impaired conversion of T4 to T3 | Thyroid dysfunction6 |
| Dysregulation of reproductive hormones37 | Hormonal disturbances6,13 |
However, with time there is a blunted response before cortisol levels will decline or the diurnal rhythm will flatten.20 With lowered cortisol levels, endogenous glucose production is compromised, and sugar and stimulant cravings are likely as a consequence of the resultant hypoglycaemia. If untreated, this can lead to adrenal burnout and chronic fatigue.34 The results of low cortisol are shown in Table 15.2.
Table 15.2 Chronic diseases caused by low cortisol (insufficient HPA response to stress)3
| HORMONAL DYSREGULATION | DISORDER |
|---|---|
| General | |
| Unresponsive HPA, low (exhausted) cortisol levels and blunted response to exercise, disturbances in serotonergic neurotransmission and AVP | |
| Flat cortisol rhythm | |
| Burnout → loss of regulation in limbic system → brain damage and atrophy | |
| Depleted adrenaline | |
| Hypoarousal | Non-melancholic depression3 |
The flow-on effect of these disturbances in neurotransmitters and stress hormones can lead to exhausted serotonin levels as well, potentially resulting in anxiety and sleep disturbances. The precursor of serotonin is tryptophan (Figure 15.4). The established link between carbohydrate cravings and depression is thought to be due to its tryptophan-increasing properties,42,43 with mood-elevating results.44
Agitation and anxiety can also be caused by glutamatergic activation. Note that the precursor for both the inhibitory and the excitatory pathways is the same amino acid: glutamine (Figure 15.5). If zinc or vitamin B6 are in short supply then adequate amounts of GABA, the inhibitory neurotransmitter, cannot be formed. Instead, glutamate, the excitatory neurotransmitter, accumulates, leading to the above-mentioned symptoms.45
Testing for adrenal exhaustion
Adrenal exhaustion is a vague term that is not generally used in medicine. ‘Adrenal fatigue’ has been used to describe hypoadrenia. It is therefore important to assess HPA axis dysregulation before treatment is instigated.46 The tests in Table 15.3 have been shown to be useful in diagnosing HPA axis dysregulation. The information gleaned from these tests will indicate not only the level of cortisol excess or depletion but also any concomitant health conditions that may have developed as a result of stress, such as insulin resistance, hypopituitarism and inflammation.
Table 15.3 Pathology tests for evaluating stress markers47
| TEST | TISSUE | COMMENTS |
|---|---|---|
| Cortisol | Serum | Cortisol is diurnal—it is highest in the morning at 6 to 8 a.m. and drops throughout the day, with lowest levels occurring around midnight. Therefore, tests should be performed at around 8 a.m. and again at 4 p.m., with the morning readings close to the maximum and the afternoon values closer to the lower end of the reference range. |
| Urine | 24-hour readings indicate whether adequate amounts of cortisol have been produced overall. | |
| Saliva | Several readings can be taken throughout the day to determine the diurnal variation. | |
| ACTH | Serum | ACTH needs to be present to stimulate cortisol release and is therefore following the same diurnal variation as cortisol. If both cortisol and ACTH are low, an ACTH stimulation test should be performed to determine whether cortisol is low because of lack of ACTH. |
| ACTH stimulation | Serum | A synthetic form of ACTH (cosyntropin) is injected after taking a blood sample for baseline cortisol measurements. Blood samples are taken in half-hourly intervals for the following 1–2 hours. If cortisol is still low, adrenal exhaustion or Addison’s disease (primary hypoadrenalism) is the likely cause. |
| GTT (glucose tolerance test) | Serum | A 3-hour glucose tolerance test can be performed, with half-hourly measurements of glucose, insulin and cortisol. If hypoglycaemia is present, then cortisol levels should increase to activate glucose release from glycogen stores. Both the hypoglycaemia and low cortisol in response are indicative of adrenal exhaustion. |
| ITT (insulin tolerance test) | Serum | This test is usually used for identifying patients with growth hormone (GH) deficiency, but it has also been used to determine HPA status.48 Hypoglycaemia is induced by the IV infusion of insulin and/or arginine. Blood samples for growth hormone, glucose and cortisol are taken at regular intervals for 90 minutes. |
| Inflammatory markers | Serum | ESR, CRP, homocysteine and antibodies should all be tested, as low cortisol reduces the ability of the body to control inflammatory processes. |
| Electrolytes | Serum | Altered aldosterone levels due to mineralocorticoid insufficiency (as part of glucocorticoid insufficiency) can lead to imbalances in electrolytes, notably sodium. |
| Aldosterone | Blood and urine | Aldosterone can be altered due to adrenal pathology. However, this test is mainly used to diagnose hyperaldosteronism and may not be relevant in this scenario. |
| Lipid studies | Serum | Cortisol is made in the body from cholesterol. Further, in an insulin-resistant state it is likely that triglycerides and possibly LDL are elevated, with insufficient amounts of HDL. |
| Viruses | Serum | To rule out any viral causes of fatigue. |
RISK FACTORS
While the SNS is responsible for arousal, for fight and flight, the PNS facilitates rest, relaxation and healing (repair), it slows heart rate and promotes digestion and elimination. Neurotransmitters activated by the SNS include adrenaline and noradrenaline, whereas acetylcholine is the predominant neurotransmitter of the PNS. In a healthy state there is balance between the SNS and PNS. However, during stress the SNS is dominant, suppressing the actions of the PNS. This can lead to digestive and sleep disturbances and agitation.49 Repercussions of this may include reduced absorption of nutrients through diminished production of digestive juices, anxiety and further drain on energy through lack of restful sleep.
The use of stimulants such as coffee increases the stress response and adrenal output, as shown by elevated catecholamines, notably adrenaline, in urine.50,51 If coffee is used as a pick-me-up without having an effect, leading to increasingly greater consumption, it begs the question as to whether adrenaline production ability has been exhausted. This kind of stimulation may therefore hasten the decline in adrenal function, thus being a stressor in its own right. Adrenal exhaustion can be the result of multiple stressors, each of them not being enough to cause HPA dysfunction. However, the additive effects (if not addressed) can weaken the system to such an extent that other health problems could arise, such as chronic fatigue, clinical depression, hypothyroidism, inflammatory and autoimmune conditions, and hormonal disturbances, as outlined in Table 15.2.
CONVENTIONAL TREATMENT
The diagnosis of adrenal exhaustion is not often made in conventional medicine, and if it is made, it is from a different perspective to what naturopaths consider. Primary hypoadrenalism (Addison’s disease) is rare. If it is part of an autoimmune endocrine disease,53 where adrenal function has been maintained through endogenous up-regulation of corticotropic hormone stimulation, treatment may not be required. If secondary hypoadrenalism has been diagnosed, glucocorticoids are the drugs of choice,54,55 with mineralocorticoids if needed.56 DHEA has been trialled, with mixed results.56,57 Apart from the removal of the adrenals like in Cushing’s syndrome, hypoadrenalism is mainly recognised in the medical literature as being the result of brain injury,58 tumours, endocrine disorders or critical illness,59,60 where adrenal crisis has either happened or may be imminent.61 In any case, the diagnosis seems to be thought of only at a very late stage.53 Where naturopaths use the diagnosis of adrenal exhaustion, conventional treatment would therefore focus on the symptoms, with antidepressants being the most likely prescription.62–64 Other interventions may include beta-blockers65,66 and glutamatergic agents.63 Novelty treatments trialled are glucocorticoid receptor antagonists and atrial natriuretic peptide receptor agonists.64
KEY TREATMENT PROTOCOLS
The aim of treatment is to repair suboptimally functioning cells, thus increasing the energy and wellbeing in the patient. Since the HPA axis is stimulated by mental and emotional as well as physical events, giving the patient resources requires not only support with nutrients but also teaching better coping strategies.46
Modulation of the HPA axis
The HPA axis activates and is inactivated by cortisol (Figure 15.1).67 In the case of low cortisol, the negative feedback is impaired, leading to dysregulation of other stress hormones. Diet, lifestyle and thought patterns have a key influence on the HPA axis. Adjusting these are the primary concerns as they will need to be the first line of defence for future stressors. Herbs have been used traditionally to modulate the nervous system and the stress response.
Diet
Reduction or avoidance of stimulants such as tea and coffee, so commonly used to keep up alertness and functioning in today’s hectic life, will prevent further drain on the adrenals. These beverages can be replaced with decaffeinated coffee or tea, herb teas and filtered water. The change is best done slowly to reduce the risk of caffeine withdrawal symptoms such as headache and further fatigue.51
Stress is often accompanied by carbohydrate cravings, which can lead to blood sugar imbalances, especially if they are high in sugar and refined starches. Fruit is best limited to two pieces a day as it may increase glycaemic load. Whole grains are preferable due to their fibre content, thus slowing down the release of sugar,68 and their B vitamin content. B vitamins are essential in the Krebs cycle for energy production.45 Carbohydrates are commonly craved during stress due to their tryptophan-serotonin enhancing qualities.42,43 This partially explains the weight gain experienced by some people when under stress.43 High cortisol is also known to lead to weight increases and potentially to metabolic syndrome,69,70 although in adrenal exhaustion cortisol is usually low (depleted). High-protein foods and snacks for amino acids, especially fish as the latter also contributes to a favourable EFA balance, may decrease carbohydrate cravings while at the same time providing the necessary amino acids as precursors for neurotransmitter synthesis. Protein powders can be used in smoothies to provide additional amino acids for neurotransmitter production and to help reduce hypoglycaemic episodes.
Lifestyle
Balance of work, relaxation and sleep, socialising, physical activities and daily chores is difficult to achieve in modern life. However, it is important to be aware of a person’s commitments and how these influence their life. Chronic stress has been linked to premature death,71 and social support networks are related to positive states of health and reduced disease burden.72
The importance of physical activity cannot be underestimated. Since the body is geared up for action when under stress (‘fight or flight’), exercise is a potent tool to bring stress hormones back under control.73 Regular physical activity has been shown to help in reducing stress, depression and anxiety.74
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