Patients with Cushing's disease who are otherwise healthy often experience metabolic responses that lead to localized obesity in the abdominal, neck, and face regions. This is accompanied by muscle wasting and weakness, particularly in the extremities. It is important to note that the chronically elevated cortisol in these patients is typically associated with an increased insulin/glucagon ratio. The elevated cortisol stimulates appetite, further increasing the insulin/glucagon ratio. The high levels of cortisol counteract insulin's effect on glucose uptake into skeletal muscle and adipose tissue, resulting in glucose intolerance. This contributes to hyperglycemia and hyperinsulinemia. Both cortisol and insulin promote the differentiation of preadipocytes into adipocytes and lipogenesis.

In individuals who are otherwise well-nourished but have chronically elevated cortisol levels, such as those with Cushing's disease, the metabolic actions of cortisol in response to stress differ from those seen in a healthy individual. The response to stress involves the integration of cortisol with catecholamines and glucagon, whereas chronically elevated cortisol integrates with insulin in an otherwise healthy individual.

The inflammatory response to injury involves the dilation of capillaries and increased capillary permeability, leading to local edema and accumulation of white blood cells. Prostaglandins, thromboxanes, and leukotrienes mediate these steps. Cortisol inhibits phospholipase A2, an important enzyme in the synthesis of prostaglandins, leukotrienes, and thromboxanes. Additionally, cortisol stabilizes lysosomal membranes, reducing the release of proteolytic enzymes that contribute to local swelling. Cortisol generally inhibits the migration of leukocytes from the vascular system to the site of injury and also inhibits the phagocytic activity of neutrophils. However, it stimulates the release of neutrophils from the bone marrow. Glucocorticoid analogues are frequently used pharmacologically due to their anti-inflammatory properties.

Cortisol has an inhibitory effect on the immune response, which is why glucocorticoid analogues are used as immunosuppressants in organ transplants. High cortisol levels decrease the number of circulating T lymphocytes, particularly helper T lymphocytes, and impair their ability to migrate to the site of antigenic stimulation. Glucocorticoids also promote atrophy of the thymus and other lymphoid tissue. While corticosteroids inhibit cellular-mediated immunity, they do not impair antibody production by B lymphocytes.

Reproductive behavior and function are dampened in response to stress. Cortisol decreases the function of the reproductive axis at the hypothalamic, pituitary, and gonadal levels.

Glucocorticoids increase bone resorption and have various effects on bone metabolism. They reduce intestinal calcium absorption and renal calcium reabsorption, leading to lower serum calcium levels. As serum calcium levels drop, the secretion of parathyroid hormone increases, which stimulates bone resorption. Additionally, glucocorticoids directly inhibit osteoblast bone-forming functions. While glucocorticoids can be beneficial in treating inflammation associated with arthritis, excessive use can result in osteoporosis.

Cortisol also influences connective tissue, but further details regarding its actions on connective tissue are not provided in this excerpt.
Metabolic responses to chronically elevated cortisol in patients with Cushing’s disease who are otherwise healthy tend to promote localized obesity (abdominal, neck, and face), with muscle wasting and weakness, especially at the extremities. Note that the elevated cortisol in this case usually occurs in the context of an elevated insulin/glucagon ratio. Elevated cortisol stimulates appetite, which increases the insulin/glucagon ratio. High levels of cortisol antagonize insulin’s effect on GLUT-4mediated glucose uptake into skeletal muscle and adipose tissue, so that glucose intolerance is frequently a symptom in patients with Cushing’s disease. This further contributes to hyperglycemia and hyperinsulinemia. Both cortisol and insulin promote the differentiation of preadipocytes into adipocytes, and lipogenesis.
Chronically elevated levels of cortisol in otherwise well-fed person (e.g., Cushing’s disease) •Fig. 43.10 Metabolicactionsofcortisol(integratedwithcatecholaminesandglucagon)inresponsetostress(upper panel) andcontrastedtotheactionsofchronicallyelevatedcortisol(integratedwithinsulin)inanotherwisehealthyindividual(lower panel). (ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)
The inflammatory response to injury consists of local dilation of capillaries and increased capillary permeability, with resultant local edema and accumulation of white blood cells. These steps are mediated by prostaglandins, thromboxanes, and leukotrienes. Cortisol inhibits phospholipase A2, a key enzyme in prostaglandin, leukotriene, and thromboxane synthesis. Cortisol also stabilizes lysosomal membranes, thereby decreasing release of the proteolytic enzymes that augment local swelling. In response to injury, leukocytes normally leave the vascular system and migrate to the site of injury. This complex process is generally inhibited by cortisol, as is the phagocytic activity of neutrophils, although release of neutrophils from bone marrow is stimulated. Analogues of glucocorticoid are frequently used pharmacologically because of their antiinflammatory properties.
Cortisol inhibits the immune response, and for this reason glucocorticoid analogues have been used as immunosuppressants in organ transplants. High cortisol levels decrease the number of circulating T lymphocytes (particularly helper T lymphocytes) and reduce their ability to migrate to the site of antigenic stimulation. Glucocorticoids promote atrophy of the thymus and other lymphoid tissue. Although corticosteroids inhibit cellular-mediated immunity, antibody production by B lymphocytes is not impaired.
Effects of Cortisol on the Reproductive Systems
Reproduction exacts a considerable anabolic cost on the organism. In humans, reproductive behavior and function are dampened in response to stress. Cortisol decreases the function of the reproductive axis at the hypothalamic, pituitary, and gonadal levels.
Effects of Cortisol on Bone
Glucocorticoids increase bone resorption. They have multiple actions that alter bone metabolism. Glucocorticoids decrease intestinal Ca++ absorption and renal Ca++ reabsorption. Both mechanisms serve to lower serum [Ca++]. As serum [Ca++] drops, secretion of parathyroid hormone (PTH) increases, and PTH mobilizes Ca++ from bone by stimulating resorption of bone. In addition to this action, glucocorticoids directly inhibit osteoblast bone-forming functions (see ). Although glucocorticoids are useful for treating the inflammation associated with arthritis, excessive use will result in bone loss (osteoporosis).
Actions of Cortisol on Connective Tissue