The hypothalamus directs the body’s stress response. The nervous system sends information about the stressful condition to the hypothalamus, which then engages both the nervous and endocrine systems in response. The hypothalamus engages the sympathetic nervous system in a neural and endocrine response, the well-known fight-or flight response, which prepares the body for immediate physical action. In a combination of direct action by the sympathetic fibers and epinephrine from the adrenal medulla, cardiac output, CO, increases, ventilation increases, blood pressure rises and is maintained at a level adequate to drive blood to the working organs and blood flow is redirected from the GI system and other quiescent organs to skeletal muscle and the heart. Sweating is stimulated. Epinephrine reinforces the actions of the sympathetic system especially relaxation of the airways and dilation of blood vessels to skeletal muscle and the heart. Epinephrine directly stimulates tissues to meet increased metabolic needs. The major effects of epinephrine are: stimulation of glycogenolysis and liver and skeletal muscle gluconeogenesis in the liver and lipolysis in adipose tissue Glucose and fatty acids provide fuel for working organs. Notice that this metabolic pattern is similar to the pattern in the postabsorptive state. The activity of the sympathetic system and epinephrine inhibit the release of insulin and stimulate glucagon. Glucagon reinforces the fasting metabolic state and the active inhibition of insulin is essential to keep plasma glucose levels high. The fast-acting catecholamines initiate the stress response. They produce rapid short-term changes because they are secreted rapidly from storage vesicles and they act rapidly on target cells. The effects end quickly when catecholamines are removed. The hypothalamus stimulates release of corticotropin releasing hormone that causes secretion of ACTH and ultimately cortisol for a more prolonged response. Because its synthesis and release are slow and cellular responses require transcription and translation, the effects of cortisol occur after a lag of about 30 minutes. Adrenal cortical hormones maintain and amplify the effects of adrenal medullary hormones. Together the two parts of the adrenal gland act as a functional unit that first initiates, and then maintains and modulates, the response to stress. Remember that cortisol is a glucocorticoid named for its effects on glucose metabolism. Cortisol mobilizes energy stores and stimulates breakdown of protein providing amino acids to the liver to produce glucose. The amino acids can also be used to repair damaged tissue. Cortisol acts on the liver to both produce glucose and store it as glycogen. Cortisol stimulates breakdown of triglycerides in adipose tissue that increases fatty acids for fuel and glycerol for producing glucose in the liver. Fuels continue to be made available, glucose for the brain and fatty acids for other tissues, to ensure survival at a time when an individual may not be able to eat. In the presence of norepinephrine, cortisol enhances the constriction of blood vessels. This is an important contribution to maintaining blood pressure. Cortisol also inhibits inflammation and other aspects of the immune system keeping it in check. Aldosterone is secreted from the adrenal cortex in response to increased angiotensin. It promotes retention of salt and water to maintain blood volume and blood pressure. Vasopressin (ADH) is secreted from the posterior pituitary. It promotes water retention and with angiotensin directs vasoconstriction effects. This response becomes more complicated as combinations of the hormones we have discussed act to reinforce existing effects and add others. The nervous and endocrine systems maximize gas exchange mobilize fuel and maintain the necessary pressure to deliver blood to essential organs. These two systems work together to maintain high levels of oxygen and nutrients in the blood stream and to ensure their delivery to essential organs. Pathological changes in the secretory activity of the adrenal medulla are rare. There are no recognized pathologies that cause hyposecretion of the catecholamines from the adrenal medulla. Because the sympathetic nervous system may replace many of the functions of the adrenal catecholamines, an individual can live without the adrenal medulla as long as the sympathetic nervous system is intact and functioning. A rare tumor called a pheochromocytoma, usually found in the adrenal medulla, secretes large amounts of the catecholamines and is not controlled by the sympathetic nervous system. Symptoms associated with pheochromocytoma may be persistent or intermittent. Episodic symptoms can arise from probing the tumor, standing up or lying down, or abdominal pressure. This patient has a pheochromocytoma and has come to the doctor today because he feels very ill with many of the symptoms of hypersecretion of catecholamines. Based on what we know about the actions of catecholamines, especially epinephrine, here are the symptoms that the patient might have; high blood pressure, excessive sweating, palpitations, rapid heart rate, and high blood glucose. The most prominent feature in patients with a pheochromocytoma is hypertension. Catecholamines act on the cardiovascular system to maximize cardiac output by increasing heart rate and force of contraction. Catecholamines increase total peripheral resistance. Increases in cardiac output and peripheral resistance cause blood pressure to rise. The treatment of choice for a pheochromocytoma is surgical removal of the tumor. Secretion of catecholamine hormones then returns to normal and is again under the control of the sympathetic nervous system. One way that scientist learn about the endocrine system is to observe the symptoms of patient’s who secrete too much or too little of a particular hormone. Two relatively rare diseases of the adrenal gland help illustrate some of the functions of cortisol. Cushing's disease, or hypercortisolism, occurs when the body is exposed to high levels of cortisol for a prolonged period. Addison's disease, or primary adrenal insufficiency, occurs when the adrenal glands produce too little cortisol, and too little aldosterone. Cushing's disease is caused by tumors of the pituitary that secrete increased amounts of ACTH. It is the most common cause of hypercortisolism. Hypercortisolism from all other causes, such as glucocorticoid drugs, is called Cushing's syndrome. The glucocorticoid prednisone may be prescribed for asthma, rheumatoid arthritis, other inflammatory diseases, or for immunosuppression following and organ transplant. Addison's disease is caused by damage to the adrenal cortex inducing hyposecretion of both cortisol and aldosterone. Hyposecretion of cortisol from other causes such as pituitary damage and subsequent lack of ACTH produces similar symptoms. In this case aldosterone secretion is normal. Cushing's patients experience paradoxical accumulation of fat that produces a round ‘moon face’ and a buffalo hump' on the back. A cardinal symptom of Addison's disease is a change in skin pigmentation that produces a bronzed color. Based on what we have learned about cortisol, let’s answer the following question about the symptoms of Cushings and Addisons. Which patient has hypoglycemia? One function of cortisol is to promote production and release of glucose. Lack of cortisol in Addison’s patients results in low plasma glucose. Which patient may exhibit signs of steroid diabetes? Hyperglycemia in Cushing’s patients can lead to diabetes mellitus. The chronic increase in insulin levels induced by hyperglycemia can cause pancreatic beta cells to fail. These high levels of insulin might also explain the redistribution of body fat. The action of insulin on normal body fat stores is antagonized by cortisol. In other body areas like the face and upper back, insulin can promote lipogenesis. Which patient might get dizzy or faint due to low blood pressure? Cortisol promotes vasoconstriction. Insufficient amounts of cortisol in Addison’s patients can lead to dangerous low blood pressure. Both patients may feel fatigued, and have muscle weakness, but which one will have increased nitrogen breakdown products in the blood, and spindly arms and legs due to muscle loss? Cortisol promotes protein breakdown to supply amino acids to the liver where they are used to produce glucose. Loss of protein also accounts for the easy bruising and poor wound healing seen in Cushing's patients. Which patient may be at risk for overwhelming infections? Cortisol inhibits the inflammatory response and depresses the immune system. The risk of infection rises in patients who are taking prednisone and those with hypersecretion of cortisol. Which patient may show decreased plasma levels of sodium and dehydration, and therefore crave salty food? Loss of aldosterone accompanies the loss of cortisol in Addison's disease. Aldosterone acts to retain salt and water. Note that the loss of aldosterone contributes to the low blood pressure in Addison's patients. Both of these pathologies can be treated. Cushing's disease is treated by surgical removal of the tumor. When Cushing's syndrome is caused by therapeutic drugs, such as prednisone, treatment involves adjusting the dosage of the drug. Addison's disease is treated by replacement of cortisol and aldosterone. Secondary adrenal insufficiency is treated by replacement of cortisol.