Stress and fatigue are some of the most common issues that patients mention, with an estimated 75-90% of visits to primary care physicians being related to stress.  While some stress can be beneficial, excessive stress can lead to adrenal fatigue and cause numerous health issues. [3, 4, 6]
Basic Mechanism of Stress
The adrenal glands are attached above each kidney. These two triangular-shaped glands include the medulla at the core, which is innervated by sympathetic nerves from the central nervous system, and the adrenal cortex, surrounding the core. The medulla produces norepinephrine and epinephrine which initiate the nervous system’s stress response. The adrenal cortex produces sex hormones, mineralocorticoids (such as aldosterone), and glucocorticoids (cortisol and DHEA).
Many different types of stimuli can cause the stress response: emotions, strenuous exercise, allergens, sleep deprivation, and so on. These stimuli are referred to as stressors. The stressors activate the HPA axis to produce the endocrine part of our stress response. The HPA axis is under feedback control, which helps to maintain homeostasis. [3, 4]
When the body detects a stressor, the sympathetic neurons signal the medulla to begin norepinephrine and epinephrine production. This is a major part of the “fight or flight” response. Signals are also sent from the amygdala to the hypothalamus, which supplies corticotrophin-releasing factor, or CRF. CRF then sends a signal to the pituitary gland, which releases adrenocorticotropic hormone (ACTH). ACTH stimulates glucocorticoid production in the adrenal cortex. The HPA feedback mechanism eventually signals the hypothalamus to stop producing CRF, allowing cortisol levels to return to normal. [4, 7]
At normal levels, cortisol is a protective anti-inflammatory hormone; it is involved with the immune response. Additionally, cortisol aids in the conversion of norepinephrine to epinephrine in the adrenal medulla. Cortisol also plays a role in the metabolism of carbohydrates, fat, and protein. It increases gluconeogenesis (production of glucose from protein), helping to maintain blood sugar homeostasis. This is especially helpful when sleeping. When in a fasting state such as during the night, cortisol increases glucose availability for the body to use for energy and repair. Cortisol levels are highest in the morning after waking. Cortisol is secreted in a circadian rhythm; after the morning peak, it gradually decreases to its lowest around midnight. This pattern is controlled by the hypothalamus; however, the levels are determined by the strength of the adrenal glands. Additionally, abnormal stress disrupts the circadian rhythm of cortisol, and can have physiological and psychological effects that continue past the elimination of the stressor. 
With chronic stress, adrenal gland function can diminish. This mechanism is best described by Hans Selye’s General Adaptation Syndrome. The General Adaptation Syndrome has three phases: alarm, resistance, and exhaustion. [1, 3, 6, 7]
In the alarm phase, cortisol is elevated in response to the stressor. DHEA is often elevated also. With continued alarm and elevated cortisol levels, DHEA may begin to decrease, as the adrenal hormone production pathway shifts to preserve cortisol production at the expense of DHEA. This is called the “pregnenolone steal.” This signals the beginning of the resistance phase, in which the body attempts to adapt to the stressor. The typical pattern of adrenal hormones at this stage is elevated cortisol levels throughout the day with low DHEA. These constant high cortisol levels often cause sleep difficulties and can contribute to irritability. Sex hormone levels may also decrease, as DHEA is the precursor to the sex hormones. Patients in this stage may note low libido or disrupted cycle. The resistance phase may last indefinitely; however, some individuals may move on to the exhaustion phase. 
Adrenal fatigue may occur in the exhaustion phase, where the adrenals are “worn out” by the continued attempt to sustain cortisol levels in response to chronic stress. The adrenal glands are no longer able to produce adequate cortisol. Typical measurements at this stage show low cortisol, low DHEA, and low epinephrine. Patients in the exhaustion phase may present with severe fatigue, allergies, poor sleep, and salt cravings.
Impact of Adrenal Fatigue
The impact of adrenal fatigue is not limited to patient concerns including profound fatigue, decreased stamina, and low libido. The effects of adrenal fatigue may be widespread, as research shows many negative consequences of excess cortisol and stress. High stress levels can lead to many health issues over time, including a higher risk for cardiovascular disease, impaired immunity, and disruptions in the intestinal microflora. [1, 4, 7]
Due to cortisol’s role in metabolism, high cortisol often increases blood sugar levels; insulin levels consequently rise. Sustained high cortisol levels may thus cause insulin and leptin receptor resistance.
High cortisol can also cause thinning of epithelial tissue. Internally, this may lead to ulcers in the GI tract, capillary damage, and connective tissue damage. 
Elevated cortisol may also heighten the risk for osteoporosis, as cortisol has been shown to decrease osteoblast function (and thus, new bone formation). Additionally, high cortisol may decrease absorption of calcium in the gut and reabsorption in the kidneys.
High cortisol levels can also damage the hippocampus. This may lead to short-term memory issues, as well as overall HPA axis dysregulation. The hippocampus may lose its control of the hypothalamus, thus, altering the HPA axis feedback mechanism. This can lead to chronic upregulation of the HPA axis, allowing for more cortisol, which causes more damage, in a vicious cycle. [2, 5]
Adrenal fatigue may also have a detrimental effect on inhibitory neurotransmission. Cortisol helps regulate serotonin transporter gene expression. Excess cortisol may lead to increased serotonin transporter levels, thus increasing serotonin reuptake. High cortisol levels may also cause decreased sensitivity of serotonin 1A autoreceptors. 
Addressing Adrenal Fatigue in Your Patients
While the effects of chronic stress plague patients, practitioners using an integrative approach may be able to address adrenal fatigue. Understanding adrenal fatigue in a holistic manner may provide treatment options such as supplementation that can help to restore the patient. [3, 4]
Non-pharmaceutical approaches may offer benefits to patients to help restore the adrenals in tandem with balancing neurotransmitters and lifestyle changes in diet, sleep, and stress management. This may include adaptogens such as Panax ginseng, Eleutherococcus senticosus, glycyrrhiza species, and Withania somnifera. These adaptogens increase the resistance to a variety of stressors and promote recovery from stress.  Assessing hormones and neurotransmitters of the HPA axis can help practitioners to identify and address adrenal fatigue, and create a protocol that can stabilize and improve the individual’s adrenals and ability to respond to stress.
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