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