Learning Objectives
- At the end of the lecture all the students should be able to:
- Explain the site of release , mechanism of formation and general features of glucocorticoids.
- Know the different functions of glucocorticoids.
- Explain the regulation of adrenal hormones.
- Explain the features related to pathologies of glucocorticoids.
GLUCOCORTICOIDS
- Cortisol
- Corticosterone
- Cortisone
- Prednisolone
- Methylprednisolone
- Dexamethasone
- Cell?
- Type?
- Receptor site?
- Mechanism of action?
- Released from the adrenal gland: zona fasciculata
- Steroid Hormones
- GR in cytoplasm
- Nuclear and non-genomic
• Involved in many biological processes
– Metabolism, development, differentiation, immunity, reproduction and neural activity
• Depress immune response
– Immunosuppressive, anti-inflammatory and oncolytic therapy
Regulation of Cortisol Release
Cortisol release is regulated by ACTH
Release follows a daily pattern – circadian
Negative feedback by cortisol inhibits the secretion of ACTH and CRH
FUCTIONS OF CORTISOL
- Metabolism
- Growth
- Differentiation
- Inflamation
- Immunity
Glucocorticoids on Glucose Metabolism
- Glucocorticoids acts on all tissues
- Involved in glucose metabolism and increase &
maintain normal glucose levels in blood by other
processes
– Gluconeogenesis in the liver
– Stimulation of fat breakdown in adipose tissue
– Inhibition of use of glucose
– Inhibition of peripheral glucose uptake in muscle and
adipose tissue
Glucose metabolism
- Cortisol increases the enzymes required to convert amino acids into glucose in liver cells.
- Cortisol causes mobilization of amino acids from the extrahepatic tissues, mainly from muscle.
- Cortisol antagonizes insulin’s effects to inhibit gluconeogenesis in the liver.
- The net effect of cortisol is to increase glucose production by the liver.
- Decreases utilization of glucose by cells.
- Cortisol decreases translocation of the glucose
- transporters GLUT 4 to the cell membrane, especially in skeletal muscle cells, leading to insulin resistance.
- Glucocorticoids may also depress the expression and phosphorylation of other signaling cascades that influence glucose utilization directly or indirectly by affecting protein and lipid metabolism.
- insulin receptor substrate–1
- and phosphatidylinositol 3 kinase
Adrenal Diabetes
- The increase in blood glucose concentration is occasionally great enough (50 percent or more
above normal) that the condition is called adrenal diabetes.
Protein metabolism
- There is reduction in protein stores.
- Decreased protein synthesis
- Increased catabolism of protein
- Cortisol increases liver & plasma proteins
- Mobilizes aminoacids from non hepatic cells, thus
increase blood amino acid level. - ↑ amino acid transport to liver cells & ↓
transport of amino acids into other cells - In the presence of great excesses of cortisol, the muscles can become so weak that the
person cannot rise from the squatting position.
- The increased plasma concentration of amino acids and enhanced transport of amino acids into the hepatic cells by cortisol can cause:
(1) increased rate of deamination of amino acids by the liver,
(2) increased protein synthesis in the liver,
(3) increased formation of plasma proteins by the liver
(4) increased conversion of amino acids to glucose—that is, enhanced gluconeogenesis.
Fat metabolism
– They decrease hepatic lipogenesis and mobilize fat from adipose tissue so increase plasma lipids
and fatty acids.
– They also cause redistribution of fat.
- It potentiates the lipolytic effect of catecholamines and glucagon.
Excess Cortisol Causes Obesity.
- Despite the fact that cortisol can cause a moderate degree of fatty acid mobilization from adipose tissue, a peculiar type of obesity develops in many people with excess cortisol secretion.
- There is excess deposition of fat in the chest and head regions of the body, giving a buffalo- like torso and a rounded “moon face.”
Metabolic Effects of Glucocorticoids
Inflammation
- When large amounts of cortisol are secreted or injected into a person, the glucocorticoid has two basic anti-inflammatory effects:
- it can block the early stages of the inflammation process before noticeable inflammation even begins,
- if inflammation has already begun, it causes rapid resolution of the inflammation and increased rapidity of healing.
Anti-inflammatory effects
Cortisol stabilizes lysosomal membranes. Therefore, most of the proteolytic enzymes that are released by damaged cells to cause inflammation, which are mainly stored in the lysosomes, are released in greatly decreased quantities.
Cortisol decreases permeability of the capillaries, probably as a secondary
effect of the reduced release of proteolytic enzymes. This decrease in
permeability prevents loss of plasma into the tissues.
Cortisol decreases both migration of white blood cells into the inflamed area and phagocytosis of the damaged cells.
Cortisol suppresses the immune system, causing lymphocyte reproduction to decrease markedly.
Cortisol attenuates fever mainly because it reduces release of interleukin-1 from white blood cells.
Healing
Cortisol increases the rate of healing .
This probably results from
(1) The mobilization of amino acids and use of these acids to repair the damaged tissues
(2) The increased glycogenesis that makes extra glucose available in critical metabolic systems
(3) Increased amounts of fatty acids available for cellular energy
(4) Some effect of cortisol for inactivating or removing inflammatory products.
Other Effects of Cortisol
Reduces phagocytic action of white blood cells and reduced immunity.
Decreases lymphocytes and eosinophils.
Reduces fever
Suppresses allergic reactions
Causes RBC production
Cellular effects of glucocorticoids
Water and electrolyte metabolism
– They increase water excretion in urine as a result of accelerating inactivation of ADH in the liver. Increases GFR and so helps execration of water load.
Effect on calcium and bone
– Anti Vit. D so decrease calcium and phosphorus
absorption
– Demineralize bones.
– Catabolism of bone proteins
– So it produces osteoporosis by decreasing bone
matrix and bone mineralization
In the stomach
– Anti Vit. D so decrease calcium and phosphorus absorption
– Demineralize bones.
– Catabolism of bone proteins
– So it produces osteoporosis by decreasing bone matrix and bone mineralization
Cushing’s Syndrome
- Primary
- Secondary
Cushing’s Syndrome
- Hypersecretion by the adrenal cortex causes a complex cascade of hormone effects called Cushing’s syndrome.
- Many of the abnormalities of Cushing’s syndrome can be ascribed to abnormal amounts of cortisol, but excess secretion of androgens may also cause important effects.
- Hypercortisolism can occur from multiple causes:
(1) adenomas of the anterior pituitary that secrete large amounts of ACTH, which then causes adrenal hyperplasia and excess cortisol secretion;
(2) abnormal function of the hypothalamus that causes high levels of corticotropin releasing hormone, which stimulates excess ACTH release
(3) “ectopic secretion” of ACTH by a tumor elsewhere in the body, such as an abdominal carcinoma
(4) adenomas of the adrenal cortex.
(5) when large amounts of glucocorticoids are administered over prolonged periods for therapeutic purposes.
When Cushing’s syndrome is secondary to excess secretion of ACTH by the anterior pituitary, this condition is referred to as Cushing’s disease.
- Muscle weekness
- Diabetes
- Purplish striae
- osteoporosis
