Stress can be experienced by the body in a variety of forms and systems all interacting with each other. Please refer to the following model for a more detailed explanation: http://heathercarrdpt.com/integrative-systems-model/ Examples of stress include psychological; emotional; environmental; dietary; and/or physical (trauma, low blood sugar, abnormal pH, infections, etc). When the body perceives stress it typically reacts by activating the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Sympathetic Adrenal axis (SA). Via the HPA axis, the hypothalamus will release corticotropin releasing hormone (CRH) to the pituitary which will then secrete adrenal corticotropin releasing hormone (ACTH) to stimulate the adrenal glands to produce cortisol and other hormones and neurotransmitters with specific systemic effects directed against the stressor. When the SA axis becomes activated it can concurrently activate the adrenal glands. These reactive stress pathways originally evolved to protect us from immediate, acute threats temporary in nature. However, many of us have co-evolved with our modern culture to commonly be in a perpetual state of stress with chronic activation of these stress pathways and resulting undesirable physiological effects.
There are three layers within the adrenal cortex with the outermost being where the mineralcorticoid, aldosterone, is secreted. This hormone regulates electrolyte and fluid concentrations by retaining sodium (Na) and water and facilitating potassium (K) urinary excretion in an attempt to keep up blood pressure. Hydrogen ions are also excreted more via urine to decrease metabolic acidosis. With increased facilitation such as with chronic stressors, aldosterone will exaggerate these effects. In cases of adrenal and or HPA hypofunction there will be a reduction in aldosterone production resulting in sodium depletion, excessive potassium, increased water loss via urination, and low blood pressure.
The next layer of the adrenal cortex produces cortisol which has a huge impact on glucose regulation. Cortisol is normally synthesized as a result of low blood sugar such as in the morning upon waking from sleep. Cortisol stimulates the liver to break down glycogen (glycogenolysis) as well as form glucose from amino acids and fatty acids (gluconeogenesis). Muscle tissue will respond to cortisol by breaking down into amino acids for gluconeogenesis while adipose tissue will metabolize triglycerides. Cortisol also has anti-inflammatory effects and inhibits white blood cells. In chronic stress states excessive cortisol production will enhance these processes and higher reactive blood sugar levels putting increased pressure on insulin to counteract the blood sugar surge. This may create a reactive hypoglycemia depending on whether there is still cellular insulin sensitivity and pancreatic secretion. Over time, insulin resistance may eventually occur which would maintain elevated blood glucose levels. This blood sugar dysregulation may simultaneously be compounded by a diet that is heavily laden with sugar and carbohydrates and/or low in nourishing fats and protein. Please refer to this article: http://heathercarrdpt.com/uncategorized/blood-sugar-dysregulation/ for more information on these processes.
With adrenal hypofunction, individuals will present with reduced cortisol levels. In this situation, hypoglycemia will typically occur due to decreased gluconeogenesis and lipolysis (breakdown of adipose tissue). If insulin levels are high and there is still cellular sensitivity this will further contribute to hypoglycemia as glucose will be transported intracellularly for storage.
The 3rd layer of the cortex secretes the androgens, the sex hormones and their precursors (DHEA, pregnenolone, androstenedione, estrone, testosterone, estradiol) for both sexes. Proper function of this layer is important for post-menopausal women as well as assisting with endocrine regulation. The androgens balance the effects of cortisol and are anti-oxidants. Decreased androgen production is associated with adrenal hypofunction which can create symptoms of decreased libido, acne, hair loss, and endocrine imbalances. Decreased progesterone production in men can leave the prostate vulnerable.
The inner layer of the adrenal glands consists of the medulla which secretes norepinephrine and epinephrine serving to enhance sympathetic nervous system activity and parallel the blood sugar effects that cortisol and glucagon have, namely elevating blood glucose levels. Norepinephrine redirects blood flow to the lungs, muscles, and heart and away from the digestive and reproductive systems.
There are different patterns of hypo and hyper adrenal function which may also show cyclical relationships. Based on an individual’s physiological and psychological susceptibility to perceiving stress coupled with the dosage of stress they experience will determine their pattern. For example, it has been shown that certain behavioral coping styles in animals can result in different HPA and SA reactions. A proactive and more aggressive behavior pattern when faced with a challenge was associated with more SA but less HPA activity while a typical reactive less aggressive response correlated to more HPA, less SA activity, and more parasympathetic activity (the parasympathetic activity may be from the more primitive dorsal motor nucleus creating more of a freezing response. Refer to this article for more details on parasympathetic nervous system activity related to the vagus nerve. (http://heathercarrdpt.com/uncategorized/the-polyvagal-theory-and-the-pri-approach/). The bottom line is that it is one’s ultimate appraisal of a stressor that will determine how they process it. This appraisal process is a complex conglomeration of excitatory and inhibitory input from all different parts of the brain, neuroendocrine, and immune systems further influenced by environmental, genetic, and epigenetic factors.
The hypothalamus is the primary regulator of cortisol production with receptors for circulating cortisol levels to determine whether further production is needed. When cortisol levels become low the HPA axis is stimulated. If the brain is receiving chronic stress signals (in various psychological and/or physical forms and combinations) then there will be increased production of cortisol as well as aldosterone and androgens which can feature the symptoms described above. However, if there are prolonged elevated cortisol levels in the body, the hypothalamus and/or the pituitary may compensatorily downregulate and become less sensitive to cortisol resulting in decreased production of it. Glucocorticoid receptors on the hypothalamus may also become destroyed via chronic systemic inflammatory processes. It appears that a significant factor that facilitates the decreased HPA response is increased cytokine levels, in particular interleukin-6 (IL-6) in which the midbrain has a high number of receptors for. If the body has chronic levels of systemic inflammation such as through autoimmune processes and/or chronic infections the subsequent increased cytokine production can inhibit the effects of CRH and ACTH and thus decreased cortisol production will ensue. It is also worth noting that this may also impact other endocrine pathways such as with the thyroid and reproductive glands.
In addition to the hypothalamus and pituitary, the hippocampus and pineal gland are important regulators of cortisol’s release patterns. Dysfunction in these important parts of the brain may potentially impair cortisol regulation. Cortisol and melatonin (synthesized by the pineal) have an inverse relationship with one another and dysregulation of one will impact the other. Prolonged elevated systemic cortisol levels due to chronic stress have been shown to reduce the size of the hippocampus. Chronically high insulin levels and glycation related to excessive sugar and carbohydrate consumption can also damage the hippocampus. The pineal gland can become calcified due to excessive fluoride exposure or nutrient deficiencies impacting calcium levels such as magnesium, vitamin D and cofactors, and/or vitamin K-2. Lastly, anything that interferes with melatonin synthesis such as deficiencies of Vit B6, L-Tryptophan, serotonin, and/or systemic inflammation can also indirectly impact cortisol regulation.
Other possible nutrient deficiencies can also influence cortisol levels. Examples include vitamin B12, iron, omega 3s, arachidonic acid, CoQ10, methyl donors, choline, magnesium, vitamin D and cofactors, and cholesterol. Insufficient neurotransmitter levels may also be a part of the problem. Epigenetic issues could be involved such as the expression of the enzyme methylenetetrahydrofolate reductase which helps with creating L methyl folate (utilized for converting homocysteine into methionine). Without proper functioning of this metabolic pathway there may be increased homocysteine levels which are associated with neurodegeneration and inflammation. Other potential causes are free radical processes, cancer, use of stimulants, blood sugar dysregulation, chronic use of synthetic steroids, and hypothyroidism. Finally, adrenal autoimmunity may be a mechanism behind decreased adrenal hormone secretion.
In reality, there are likely numerous factors and interrelated pathological processes going on during cortisol dysregulation. It seems that a key element involved with the switch from elevated to depressed levels is the increased levels of cytokines as their presence has the ability to downregulate the HPA axis and/or destroy its receptors. This naturally brings up the question as to why there are elevated cytokines in the first place. One answer could to be related to systemic inflammation likely caused by gut dysfunction such as dysbiosis, leaky gut, and the subsequent autoimmune processes connected to them. Blood sugar dysregulation can also facilitate systemic inflammation. The autoimmune mechanisms that often accompany gut problems may manifest in autoimmune adrenal gland issues further impacting cortisol regulation. Finally, chronic stress and/or a brain that is highly sensitive to stress (as a result of chronic stress signaling) is associated with increased sympathetic nervous system tone and reduced parasympathetic nervous system activity. The vagus nerve is the primary parasympathetic regulator in addition to connecting the gut and the brain. If this nerve becomes inhibited via dysbiotic gut environments and/or excessive sympathetic activity it will also not be able fulfill its other primary role which is to dampen systemic inflammation via the cholinergic anti-inflammatory pathway. This will ultimately create elevated cytokine levels and thus a prime environment for cortisol downregulation processes to occur.
Clinical Implications for Healthcare Providers
- Whether an individual is in a hyper or hypoadrenal functional state may influence intervention strategies. Physical Therapists commonly encounter individuals who present with chronic inflammatory musculoskeletal issues. A typical treatment approach would be to address postural and mechanical issues related to the neuromuscular system. However, such a condition is likely associated with underlying decreased cortisol and increased systemic inflammatory processes occurring. As outlined above, there may be a variety of factors that can influence such a state. Common major ones that are typically related include gut dysfunction (maldigestion, malabsorption, and/or dysbiosis), nutritional deficiencies (from lack of intake and/or gut dysfunction) autoimmune issues, reduced vagal tone/elevated sympathetic tone, a sensitized limbic system (particularly the amygdala), blood sugar dysregulation, and environmental toxins. Breathing dysfunction as well as airway insufficiency may also be involved as well. An integrative approach to managing such an individual would consider all of these potential variables and their interactions with one another. For example, I am currently treating a woman in her 50s who presented with medial elbow pain for the past year. She had two cortisone injections that resulted in temporary relief. Upon assessment, I concluded that she was likely in a hypoadrenal state (the fact that she improved with cortisol supports this) coupled with blood sugar dysregulation, impaired digestion, breathing, and postural dysfunction that was mechanically straining her ulnar nerve. Therefore, my treatment intervention included addressing all of these issues via both dietary recommendations, breathing, and postural retraining. Within 1 month she has made excellent progress and is virtually symptom free.
- Healthcare providers are encouraged to seek out other like-minded integrative referral sources as specialists working in other systems of the body are frequently needed to fully support our patients and clients. One of the most challenging referrals to make is one that addresses underlying psychological maladaptive patterns.
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