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What is Stress
- In its broadest meaning as a real or perceived threat to homeostasis.
- Thus, any change in external temperature, water intake, or other homeostatic factors sets into motion responses designed to minimize a significant change in some physiological variable.
- These threats to homeostasis comprise a large number of situations, including physical trauma, prolonged exposure to cold, prolonged heavy exercise, infection, shock, decreased oxygen supply, sleep deprivation, pain, and emotional stresses.
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Physiological response to stress
- In one respect the response to all these situations is the same: Invariably, the secretion from the adrenal cortex of the glucocorticoid hormone cortisol is increased.
- Activity of the sympathetic nervous system, including release of the hormone epinephrine from the adrenal medulla, also increases in response to many types of stress.
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Control of cortisol release
- The increased cortisol secretion during stress is mediated by the hypothalamus–anterior pituitary gland system.
- As illustrated in Figure 11.25, neural input to the hypothalamus from portions of the nervous system responding to a particular stress induces secretion of CRH.
- This hormone is carried by the hypothalamo–hypophyseal portal vessels to the anterior pituitary gland, where it stimulates ACTH secretion.
- ACTH in turn circulates through the blood, reaches the adrenal cortex, and stimulates cortisol release.
- The secretion of ACTH, and therefore of cortisol, is also stimulated to a lesser extent by vasopressin, which usually increases in response to stress and which may reach the anterior pituitary gland either from the general circulation or by the short portal vessels.
- Some of the cytokines (secretions from cells that comprise the immune system) also stimulate ACTH secretion both directly and by stimulating the secretion of CRH.
- These cytokines provide a means for eliciting an endocrine stress response when the immune system is stimulated in, for example, systemic infection.
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11.13 Physiological Functions of Cortisol (non-stress)
- Cortisol has permissive actions on the responsiveness to epinephrine and norepinephrine of smooth muscle cells that surround the lumen of blood vessels such as arterioles.
- Partly for this reason, cortisol helps maintain normal blood pressure; when cortisol secretion is greatly decreased, low blood pressure can occur.
- Likewise, cortisol is required to maintain the cellular concentrations of certain enzymes involved in metabolic homeostasis.
- These enzymes are expressed primarily in the liver, and they act to increase hepatic glucose production between meals, thereby preventing the plasma glucose concentration from significantly decreasing below normal.
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Two important systemic actions of cortisol are its anti-inflammatory and anti-immune functions.
- The mechanisms by which cortisol inhibits immune system function are numerous and complex.
- Cortisol inhibits the production of leukotrienes and prostaglandins, both of which are involved in inflammation.
- Cortisol also stabilizes lysosomal membranes in damaged cells, preventing the release of their proteolytic contents.
- In addition, cortisol decreases capillary permeability in injured areas (thereby decreasing fluid leakage to the interstitium), and it suppresses the growth and function of certain key immune cells such as lymphocytes.
- Thus, cortisol may serve as a “brake” on the immune system, which may overreact to minor infections in the absence of cortisol.
Thus, although it is common to define the actions of cortisol in the context of the stress response, it is worth remembering that the maintenance of homeostasis in the absence of external stresses is also a critical function of cortisol.
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Cortisol during fetal and neonatal life
- During fetal and neonatal life, cortisol is also an important developmental hormone.
- It has been implicated in the proper differentiation of numerous tissues and glands, including various parts of the brain, the adrenal medulla, the intestine, and the lungs.
- In the last case, cortisol is very important for the production of surfactant, a substance that decreases surface tension in the lungs, thereby making it easier for the lungs to inflate.
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11.14 Functions of Cortisol in Stress table
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11.14 Functions of Cortisol in Stress- effects on organic metabolism
- The effects on organic metabolism are to mobilize energy sources to increase the plasma concentrations of amino acids, glucose, glycerol, and free fatty acids.
- These effects are ideally suited to meet a stressful situation.
- First, an animal faced with a potential threat is often forced to forgo eating, making these metabolic changes adaptive for coping with stress while fasting.
- Second, the amino acids liberated by catabolism of body protein not only provide a potential source of glucose, via hepatic gluconeogenesis, but also constitute a potential source of amino acids for tissue repair should injury occur.
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11.14 Functions of Cortisol in Stress- vascular reactivity and protective effects against stress
- Cortisol has important effects during stress other than those on organic metabolism. For example, it increases the ability of vascular smooth muscle to contract in response to norepinephrine, thereby improving cardiovascular performance.
- We still do not know the other reasons that increased cortisol is so important for the body’s optimal response to stress.
- What is clear is that a person exposed to severe stress can die, usually of circulatory failure, if his or her plasma cortisol concentration is abnormally low; the complete absence of cortisol is always fatal.
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11.14 Functions of Cortisol in Stress- Inhibition of inflammation and specific immune responses
- Administration of large amounts of cortisol or its synthetic analogs profoundly reduces the inflammatory response to injury or infection.
- Because of this effect, the synthetic analogs of cortisol are useful in the treatment of allergy, arthritis (inflammation of the joints), other inflammatory diseases, and graft rejection.
- It is now clear that such effects also occur, albeit to a lesser degree, at the plasma concentrations achieved during stress.
- Thus, the increased plasma cortisol typical of infection or trauma exerts a dampening effect on the body’s immune responses, protecting against possible damage from excessive inflammation.
- This effect explains the significance of the fact, mentioned earlier, that certain cytokines (immune cell secretions) stimulate the secretion of ACTH and thereby cortisol.
- Such stimulation is part of a negative feedback system in which the increased cortisol then partially inhibits the inflammatory processes in which the cytokines participate.
- Moreover, cortisol normally dampens the fever an infection causes.
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Chronic stress
- Whereas the acute cortisol responses to stress are adaptive, it is now clear that chronic stress, including emotional stress, can have deleterious effects on the body.
- In some studies, it has been demonstrated that chronic stress results in sustained increases in cortisol secretion.
- In such a case, the abnormally high cortisol concentrations may sufficiently decrease the activity of the immune system to reduce the body’s resistance to infection.
- It can also worsen the symptoms of diabetes because of its effects on blood glucose concentrations, and it may possibly cause an increase in the death rate of certain neurons in the brain.
- Finally, chronic stress may be associated with decreased reproductive fertility, delayed puberty, and suppressed growth during childhood and adolescence. Some but not all of these effects are linked with the catabolic actions of glucocorticoids.
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Stress + cortisol summary
- In summary, stress is a broadly defined situation in which there exists a real or potential threat to homeostasis.
- In such a scenario, it is important to maintain blood pressure, to provide extra energy sources in the blood, and to temporarily reduce nonessential functions.
- Cortisol is the most important hormone that carries out these activities.
- Cortisol enhances vascular reactivity, catabolizes protein and fat to provide energy, and inhibits growth and reproduction.
- The price the body pays during stress is that cortisol is strongly catabolic.
- Thus, cells of the immune system, bone, muscles, skin, and numerous other tissues undergo catabolism to provide substrates for gluconeogenesis.
- In the short term, this is not of any major consequence.
- Chronic stress, however, can lead to severe decreases in bone density, immune function, and reproductive fertility.
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11.15 Adrenal Insufficiency
- The absence of cortisol leads to the body’s inability to maintain homeostasis, particularly when confronted with a stress such as infection, which is usually fatal within days without cortisol.
- Adrenal insufficiency: The general term for any situation in which plasma concentrations of cortisol are chronically lower than normal.
- Symptoms of adrenal insufficiency vary depending on the severity and cause of the disease.
- Symptoms include: weakness, fatigue, and loss of appetite and weight. Examination may reveal low blood pressure (in part because cortisol is needed to permit the full extent of the cardiovascular actions of epinephrine) and low blood sugar, especially after fasting (because of the loss of the normal metabolic actions of cortisol).
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11.15 Adrenal Insufficiency causes
- There are several causes of adrenal insufficiency.
- Primary adrenal insufficiency: is due to a loss of adrenocortical function, as may rarely occur, for example, when infectious diseases such as tuberculosis infiltrate the adrenal glands and destroy them.
- The adrenals can also (rarely) be destroyed by invasive tumors.
- Most commonly by far, however, the syndrome is due to autoimmune attack in which the immune system mistakenly recognizes some component of a person’s own adrenal cells as “foreign.”
- The resultant immune reaction causes inflammation and eventually the destruction of many of the cells of the adrenal glands.
- Because of this, all of the zones of the adrenal cortex are affected. Thus, not only cortisol but also aldosterone concentrations are decreased below normal in primary adrenal insufficiency.
- This decrease in aldosterone concentration creates the additional problem of an imbalance in Na+, K+, and water in the blood because aldosterone is a key regulator of those variables.
- The loss of salt and water balance may lead to hypotension (low blood pressure).
- Primary adrenal insufficiency from any of these causes is also known as Addison’s disease, after the nineteenth-century physician who first discovered the syndrome.
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Diagnosis of primary adrenal insufficiency + treatment
- The diagnosis of primary adrenal insufficiency is made by measuring the plasma concentration of cortisol.
- In primary adrenal insufficiency, the cortisol concentration is well below normal, whereas the ACTH concentration is greatly increased due to the loss of the negative feedback actions of cortisol.
- Treatment of this disease requires daily oral administration of glucocorticoids and mineralocorticoids.
- In addition, the patient must carefully monitor his or her diet to ensure an adequate consumption of carbohydrates and controlled K+ and Na+ intake.
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Secondary adrenal insufficiency
- Secondary adrenal sufficiency: adrenal insufficiency as a result of inadequate ACTH secretion, which may arise from pituitary disease.
- Its symptoms are often less dramatic than primary adrenal insufficiency because aldosterone secretion, which does not rely on ACTH, is maintained by other mechanisms.
- Adrenal insufficiency can be life threatening if not treated aggressively.
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Excess glucocorticoids syndrome and disease
- Excess glucocorticoids—is usually not as immediately dangerous but can also be very severe.
- In Cushing’s syndrome, even the non-stressed individual has excess cortisol in the blood.
- The cause may be a primary defect (e.g., a cortisol-secreting tumor of the adrenal) or may be secondary (usually due to an ACTH-secreting tumor of the anterior pituitary gland).
- In the latter case, the condition is known as Cushing’s disease [due to ACTH-secreting tumor], which accounts for most cases of Cushing’s syndrome.
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Cushing's Syndrome
- The increased blood concentration of cortisol, particularly at night when cortisol is usually low, promotes uncontrolled catabolism of bone, muscle, skin, and other organs.
- As a result, bone strength diminishes and can even lead to osteoporosis (loss of bone mass), muscles weaken, and the skin becomes thinned and easily bruised.
- The increased catabolism may produce such a large quantity of precursors for hepatic gluconeogenesis that the blood sugar concentration increases to that observed in diabetes mellitus.
- A person with Cushing’s syndrome, therefore, may show some of the same symptoms as a person with diabetes.
- Equally troubling is the possibility of immunosuppression, which may be brought about by the anti-immune actions of cortisol.
- Cushing’s syndrome is often associated with loss of fat mass from the extremities and with redistribution of the fat in the trunk, face, and the back of the neck.
- Combined with an increased appetite, often triggered by high concentrations of cortisol, this results in obesity (particularly abdominal) and a characteristic facial appearance in many patients.
- A further problem associated with Cushing’s syndrome is the possibility of developing hypertension (high blood pressure). This is due not to increased aldosterone production but instead to the pharmacological effects of cortisol, because at high concentrations, cortisol exerts aldosterone-like actions on
- the kidney, resulting in ion and water retention, which contributes to hypertension.
- Treatment of Cushing’s syndrome depends on the cause.
- In Cushing’s disease, for example, surgical removal of the pituitary tumor, if possible, is the best alternative.
- Of importance is the fact that glucocorticoids are often used therapeutically to treat inflammation, lung disease, and other disorders. If glucocorticoids are administered at a high enough dosage for long periods, the side effect of such treatment can be Cushing’s syndrome.
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11.16 Other Hormones Released During Stress
- Other hormones that are usually released during many kinds of stress are aldosterone, vasopressin, growth hormone, glucagon, and beta-endorphin (which is coreleased from the anterior pituitary gland with ACTH).
- Insulin secretion usually decreases.
- Vasopressin and aldosterone act to retain water and Na+ within the body, an important response in the face of potential losses by dehydration, hemorrhage, or sweating.
- The overall effects of the changes in growth hormone, glucagon, and insulin are, like those of cortisol and epinephrine, to mobilize energy stores and increase the plasma concentration of glucose.
- The function in humans, if any, of beta-endorphin in stress may be related to its painkilling effects.
- In addition, the sympathetic nervous system has a key function in the stress response. Activation of the sympathetic nervous system during stress is often termed the fight-or-flight response.
- A list of the major effects of increased sympathetic activity, including secretion of epinephrine from the adrenal medulla, almost constitutes a guide to how to meet emergencies in which physical activity may be required and bodily damage may occur.
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Actions of the Sympathetic Nervous System, Including Epinephrine Secreted by the Adrenal Medulla, During Stress
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