# Motivation and emotion/Book/2015/Cortisol and stress

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## Overview

Stress is a physiological and psychological stimulus and response that presents itself in many different ways throughout the body. Stress or a stressor can be thought of as any stimulus that upsets the bodies natural balance or homeostasis. Throughout the body there are many chemicals and hormones encorporated[spelling?] to equalize our stressors and alleviate the tension they cause. Cortisol is known as the stress chemical due to is inflammatory abilities, involvement in anti stress responses, and the high presence of cortisol in stressed individuals.
This chapter will discuss and outline the prominence and functions of cortisol throughout the body, especially in relation to the stress response. This[what?] will also mention the debate of the detriment of excess cortisol, [grammar?]this may indicate as to why some physicians have questioned its clinical use as an anti-inflammatory.

## Cortisol

Cortisol, known clinically as ‘hydrocortisone’ is a steroid hormone of the ‘Glucocorticoids’. Glucocorticoid [missing something?] roughly derived from its key role in regulating glucose levels, synthesis within the ‘Adrenal Cortex’ and its steroidal chemical structure. Glucocorticoids are synonymous with anti-inflammation, within the immune system. Some stronger binding glucocorticoids, for example high doses of cortisol are even used in inhibiting inflammation of immunity zones from cancer cells (Rhen & Cidlowski, 2005). Although in a medical context, cortisol is most famous for inflammation, the main functions are blood glucose regulation, suppression of the immune system, reducing bone formation whilst down regulating collagen synthesis, and acts as a diuretic for water and electrolytes (Pazirandeh, 2002). Psychologically, cortisol acts on a particular aspect of memory, is present in high doses in those with clinical depression and of course plays a key part within stress mechanisms (Weitzman et al., 1971).

## Cortisol and Glucocorticoid Functions

Gluconeogenesis
Glucocorticoids have many metabolic functions, largely due to cortisol. The main portion of this role is that cortisol enhances the presentation of enzymes involved in gluconeogenesis, particularly within the liver. Gluconeogenesis is a metabolic pathway responsible for generating glucose from non carbohydrate based substrates, and is one of the two key mechanisms used by humans and most vertebrates in maintaining blood glucose levels through degradation of glycogen. Gluconeogenesis is also present in flora, fungi and other microorganisms (Tanaka, 1987). Gluconeogenesis is a main target in therapy of Type II Diabetes and thus cortisol is a common component in treatments of diabetes ((Sönksen et al., 1972) Cortisol’s second main metabolic function is the mobilization of amino-acids from tissue outside the liver, to serve as substrates for gluconeogenesis. Cortisol also plays a large part in the inhibition of glucose uptake to fatty tissue, in a bid to conserve it. Cortisol is also partially responsible for lipolysis within adipose tissue. Lipolysis releases fatty acids for use in muscle tissue and glycerol to re-provide another substrate for gluconeogenesis. Cortisol also facilitates the activation of ‘Glycogen Phosphorylase’, which is necessary and provides the first team exercise of Adrenaline or epinephrine and cortisol (Laskowski, Gerick and Thornton, 2009).
The HPA
Cortisol is the main product of the hypothalamic-pituitary-adrenal axis. The HPA axis is the determinate of cortisol’s diurnal release, and one of the key self-regulated feedback systems within the bodies[grammar?] stress response. Cortisol is pivotal part of the diuretic process because of its interaction with arginine vasopressin. The HPA axis contains various structures to trigger this cortisol release, starting with the periventricular nucleus of the hypothalamus, which releases corticotrophin releasing hormones and arginine vasopressin. These two hormones in turn release ACTH, Cortisol’s acting hormone on the Adrenal gland (Bao, Meynen, & Swaab 2008). The main function of arginine vasopressin or antidiuretic hormone is regulating water balance within the body by determining the amount of water is excreted in each urination. When an individual’s fluid intake is low, or depleted through a homeostatic process (i.e. sweating, diahrrea), the pituitary gland releases more AVP into circulation. Concentrated levels of the hormone then instruct the kidneys to reabsorb more water then in turn less urine. When fluid levels are sufficient in the body, low levels of the hormone have an opposite affect on the kidneys in creating more urine (Christensen et al., 2003).
Cortisol then acts as a negative feedback mechanism, regulated in conjunction with the Mineralocorticoid and Glucocorticoid receptors, which result in a decrease of AVP and CRH release (Pariante & Lightman, 2008).
Cortisol and Foetal Development:
Foetal cortisol secretion rises late in pregnancy until birth and is thought to enhance oestrogen secretion by the placenta. A recent study into correlations between cortisol levels and brain size or birth weight measured 430 Chinese mother/child pairs. Measure had to be taken to identify “no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking, no hypertensive disorders, no impairment of glucose tolerance and no use of steroid medication during pregnancy. Measures on salivary cortisol found significant negative correlation between all parameters of foetal brain size (late biparital diameter, late head circumference, middle biparietal diameter, middle cerebellum diameter and early biparietal diameter) and levels of cortisol. This of course gives weight to studies of hippocampal shrinking etc. and cortisol, but interestingly the same study found no correlation between cortisol levels and birth weight. Essentially this meant that there was an inverse relationship between maternal cortisol & foetal brain size but not cortisol and birth weight.
Table 1. Example Agent effects on Bone Metabolism
| Agent | Effects |
| Cortisol | Inhibits Osteoclast activity, but in excess (Cushing's disease) can cause osteoperosis by inhibiting cell division and protein synthesis, inhibiting growth hormone secretion and stimulating osteoclasts to resorb bone. |
| Estrogen | Stimulates osteoblasts and adolescent growth; prevents osteoperosis |
| Insulin | Stimulates bone formation; significant bone loss can occur in untreated diabetes mellitus |
| Testosterone | Stimulates osteoblasts and promotes protein synthesis, thus promoting adolescent growth and epiphyseal closure |

## Cortisol and Stress

Stress is defined as any situation that upsets homeostasis within the body and threatens ones emotional or physical wellbeing. Physical causes of stress include injury, haemorrhage, infection, temperature extremes, malnutrition or gorging, and intense exercise. Emotional causes include anger, depression, grief, anxiety or guilt (Burton, 2012).
Cortisol and stress in was one of the first phenomenon widely study interacting a physiological stimulant with an emotional response. Contemporary researchers generally agree that physiological arousal accompanies, regulates and propels emotion, but it does not directly cause it. The dominant modern perspective is that emotions recruit biological and psychological supporters to enable adaptive behaviours i.e. fighting, running or empathetic situations (Levenson, 1994). The two hormones of Adrenaline (Epinepherine) and cortisol support the ‘fight-or-flight’ stress reactive system (Kemeny & Shestyuk, 2008). Jeffery Gray’s (1994) findings (with non-human mammals) documented the existence of three distinct neural circuits in the brain, each of which regulates a distinctive pattern of emotional behaviour. First [grammar?] being the ‘behavioural approach system’ that readies the subject to seek out and interact with attractive ‘environmental’ opportunities. The second being the ‘behavioural inhibition system’ that readies the subject to freeze in aversive situations, and finally the ‘fight-or-flight’ system that readies the subject to flee from aversive events or act aggressively in other, similar situations. These three neural circuits underlined the framework four emotions of joy, fear, rage and anxiety.
GAS-General Adaption Syndrome
Whatever the cause may be, it is believed that the body responds to the stress in a fairly consistent pattern, known by researchers as General Adaption Syndrome or GAS. Pioneered by Hans Seyle (1946) GAS progresses in three stages; Alarm reaction, the stage of resistance, and the stage of exhaustion. The response typically involves elevated levels of adrenaline (epinephrine) and cortisol. Some researchers define stress as any situation involving the release of cortisol (Lindfors & Lundberg, 2002). The Alarm reaction stage is mediated mainly by norenephrine from the sympathetic nervous system and epinephrine from the adrenal medulla. This stage begins the heightening of blood pressure and burning of glycogen, water and sodium, to prepare for the stage of resistance. If the stressful situation continues for a few hours, glycogen levels become exhausted and the body enters the stage of resistance. From here the body focuses all energy to providing alternative fuels for metabolism, and thus this stage is dominated by the introduction of cortisol. Cortisol then promotes the breakdown of fat and protein to glycerol, fatty acids and amino acids, providing the liver with raw material for gluconeogenesis (See Functions). Finally cortisol and epinephrine inhibit most organs reuptake of glucose and protein to save amino acids availability for gluconeogenesis. Finally as this process begins and glycogen stores become critical, the body begins the burning of fat. A healthy human’s body fat reserves can endure the subject through months of stress, but when fat is finally depleted, stress quickly overwhelms homeostasis. With one’s fat stores removed, the body now relies primarily on protein breakdown to meet its now small energy requirements. Whilst muscles and bones then breakdown, the adrenal cortex may stop producing glucocorticoids; further inhibiting glucose homeostatic process. Whilst this occurs, Aldosterone then conserves sodium and increases the elimination of potassium & hydrogen ions. This increased water retention starts with hypertension, then develops into a state of ‘hypokalaemia (potassium blood deficiency) and alkalosis (excessively high blood pH). Upon reaching this stage immunity and overall health has dropped dramatically, nervous & muscular systems experience dysfunction, and the likelihood of the stress being terminally rises dramatically.
Within some species of fish cortisol’s main response is their saving grace, proceeding through seasons. During a process called ‘Smolitification’ cortisol shows its high permeability and anti-inflammatory properties to assist in acclimatising the fish from seawater to fresh water and vise versa. During this process, predominately within the gills, cortisol and growth hormone work individually and in conjunction to promote the differentiation of the ‘sea water chloride cell’, whilst interacting with prolactin, which inhibits seawater cells to create another negative feedback mechanism (McCormick, 2001).

## Cortisol Synthesis and Regulation

All hormones are based from cholesterol or amino acids. Though steroids are synthesized from cholesterol their differences are mainly in the functional groups attached to their ‘four-ringed steroid backbone’. All steroids are then derivatives of four similar structures; Cholestane, Androstane, Estrane and importantly Pregnane, cortisol’s main derivative. Steroid Hormones are derived from Cholesterol. They include sex steroids produced by the testes & ovaries (such as oestrogen, progesterone, & testosterone) and corticosteroids produced by the adrenal gland (such as cortisol, aldosterone, & DHEA) (Carson-Jurica, Schrader & O’Malley, 1990).
Cortisol is produced by the ‘Zona Fasciculata’, making up the medial section of the adrenal cortex, within the adrenal gland. Here the cells are arranged in parallel cords known as fascicles, separated by blood capillaries, perpendicular to the gland surface. The cells are called ‘spongiocytes’ because of the foamy appearance impaired by an ambulance of cytoplasmic lipid droplets (Saladin, 2012). The zona fasciculata is stimulated by the Adrenocorticotropic hormone (ACTH) to head the production of glucocorticoids. A tumour in the adrenal cortex leads to large over production of cortisol and the health complications attributed to glucocorticoid overexcess. Arguably the most well known of complications with cortisol excess is Cushing’s disease (Keller-Wood & Dallman, 1984).
Table 2. Hormones of the Adrenal Cortex
| Agent | Effects | Targets |
| Aldosterone | Kidney's | Promotes Na+(sodium) & water retention, and K+(potassium) excretion |
| Cortisol | Most Tissue's | Stimulates fat and protein catabolism, gluconeogenesis, stress resistance, tissue repair and effects bone density |
| Dehydroepiandrosterone | Bone, Muscle, Integument, brain and other tissues | Precursor of Testosterone; Indirectly promotes growth of bones, pubic and anxillary hair, apocrine glands, and foetal male reproductive tract |

## Implications of Excess Cortisol and Adrenal Disorders

Cortisol being released in conjunction with adrenaline; especially in relation to exercise, highlights cortisol’s benefit in moderation and extensive harm in excess. Studies on the effects of exercise training on salivatory cortisol measure have found cortisol’s release peaks roughly 10 minutes into moderate exercise as the body begins a relative numbing process. When the body is placed under stress, adrenaline is released in conjunction with oxytocin (the happy chemical) to produce a small euphoria or in a fear sense alertness and panic (Droste et al.). Shortly after this release, as explained by Seyle’s GAS, the adrenal cortex intensifies its release of cortisol around 10 minutes and beyond to direct energy away from relative nonessential processes (e.g. urinary production, ovulation, brain function i.e. memory) to provide energy for essential processes such as the ‘flight’ response (Shepard, 2006; Seyle, 1946). This is an extreme example of based on an extended stress response, but Seyle’s other work on the stress response suggests that it is a primal instinct, with the fight-or-flight response deriving from life threating[spelling?] situations (Selye, 1956). It helps to think of this extreme derivative in explaining why the body would shut down life maintaining (or in the case of sexual function, ‘life extending’) functions and processes, and thus why something as trivium as stress or exercise can then be incredibly detrimental over constant extended periods. Cortisol and its relationship with stress is then life threatening due to the bodies perfect system of siphoning resources or energy to continue immediate life.
Immunity
Cortisol inhibits T cell & macrophage activity, antibody production, and the secretion of inflammatory chemicals. It also induces atrophy of the thymus, spleen, & lymph nodes and reduces the number of circulating lymphocytes, macrophages, & eosinophilis. It is these affects, that dramatically increase the susceptibility of high-level stress sufferers, to severe infections and even cancer (Jefferies, 1991). This is often explained by stress drawing cortisol and other energy resources from fighting immediate pathogens etc. & the individual can be unaware of this new ailment as the cortex and other brain sensors are preoccupied. The interleukins & tumour necrosis factor (TNF) secreted by immune cells producing feelings of fatigue and lethargy when we are sick, and stimulate the hypothalamus to secrete CRH, leading to ACTH and cortisol secretion.
According to research into extended stress on the hippocampus has found a tissue or synapse “shrinking” affect associated with excess levels of cortisol. Some research suggests this derives from a misplaced negative effect in the HPA Axis. Specifically, as emphasised by previously discussed studies on mice; stress alters synaptic plasticity and firing functionality of hippocampal neurons. Further research into the human brain suggests that stress suppresses neuronal proliferation and reduces hippocampal volume (Kim, Pellman & Kim, 2015).
Adrenal Disorders
Cushing syndrome is excess cortisol secretion owing to any of several causes; including ACTH hyper secretion by the pituitary, ACTH secreting tumours, or hyperactivity of the adrenal cortex independently of ACTH Cortisol then indirectly has adverse reactions on carbohydrate and protein metabolism in moderate doses. In extreme excess of cortisol, namely Cushing’s leads to hypertension, hyperglycaemia, muscular weakness, overall fatigue, and edema. Muscle & bone mass takes massive declines as protein is catabolized, cell division is inhibited and osteoclasts are stimulated to resorb[spelling?] bone matrix. Possibly due to fat concentration to glands in trauma, or fat conservation amidst excess carbohydrate catabolism, many Cushing’s sufferers result in abnormal fat deposition between the shoulders behind the neck (“buffalo hump”) or in the face/neck (“moon face”) (betterhealth.vic.gov.au).
Adrenogenital Syndrome (AGS) is the hyper secretion of adrenal androgens, known to commonly accompany Cushing’s syndrome. AGS is prolific as a developmental disorder for often causing enlargement of the genitals and the early onset of puberty. AGS or adolescent AGS is then more associated with girls, as this masculinizing of the genitalia causes misidentification as males, characterized by increased body hair, deepening of the voice and facial hair growth (Nichols & Gibson, 1969).
Cortisol’s effect during the ‘Stage of Resistance’, especially in relation to carbohydrate and protein catabolism, mean that excess cortisol can indirectly lead to Diabetes Mellitus. Diabetes Mellitus is the world’s most prevalent disease, occurring in 9% of the world’s adults according to the World Health Organization. In relation to cortisol, diabetes occurs from disruption of these metabolisms leading to inaction or inproduction of insulin. This results in the worlds leading cause of adult blindness, gangrene, renal failure & necessary amputations (who.int).

## Cortisol as a Bridge between Systems

The medulla and cortex work individually and in stimulating one another. Without stimulation by cortisol, the adrenal medulla would atrophy significantly. When stress activates the sympathetic nervous system, these cells stimulate the cortex to secrete cortisol and other corticosteroids (Lupien et al., 2007). Walter Cannon was the American physiologist whom coined the terms ‘homeostasis’ and ‘fight-or-flight’, cortisol plays an integral part of both of these functions/responses (Cannon, 1932). Either in the pursuit of homeostasis, or as an almost immediate reaction to any selection of fighting, defending, or fleeing, cortisol is introduced. Pathophysiology is the study of ailments attributing to a homeostatic imbalance, and the study of glucocorticoids is common within. Cortisol plays a part in many of the functions of the divisions of the autonomic nervous system. The sympathetic division adapts the body in many ways for physical activity including the raising of blood pressure, heart rate, alertness, pulmonary airflow, blood glucose concentration, and blood flow to cardiac & skeletal muscles. Also at the same time, this division reduces blood flow to the skin and digestive tract (Janig, 2014). Cannon referred to extreme sympathetic responses as the “fight-or-flight” reaction because it comes into play when an animal must attack, defend, or flee from the situation. The parasympathetic division has a relative calming effect on many of these bodily functions. It is associated with reduced energy expenditure and normal bodily maintenance i.e. digestion and waste elimination. Normally both of these systems are active simultaneously, they exhibit a background rate of activity referred to as the ‘autonomic tone’, cortisol is thus a large part of the body dynamically balancing between the two divisions to suit its needs. Cortisol is also believed to be a pivotal chemical in the link between the autonomic nervous system and the limbic system (Delacour, 1977). The limbic system is a ring of structures on the medial side of the cerebral hemisphere, which encircles the corpus callosum and thalamus. The most prominent of these structures is the amygdala, the cingulate gyrus and the hippocampus. The exact structures and pathways of the limbic system have been debated beyond the mid-twentieth century, but the clear point with these structures is having centres for both gratification and aversion (Farel, 1971). This is where the extensive connections with the hypothalamus and the multi-facet nature of cortisol that indicates it so strongly with sensory and mental experiences likened to the limbic system.

## Definitions of Terms

HPA Axis: hypothalamic-pituitary-adrenal axis
ACTH: Adrenocorticotropic hormone
AVP: Arganine Vasopressin
CRH: Corticotropin-releasing hormone