Glucocorticoid

The major glucocorticoids secreted by zona fasciculata are cortisol (hydrocortisone), corticosterone, and cortisone. Cortisol is the most abundant hormone secreted by the zona fasciculata and accounts for 95% of glucocorticoid activity. The circulating glucocorticoids affect the entire body, including the CNS, via binding to glucocorticoid receptors (GR), and inducing gene transcription that alters protein expression and structure along with the functioning of target cells.

1.0Cortisol Glucocorticoid

• Long-term exposure to stress stimulates the release of cortisol, which in turn promotes an increase in blood glucose concentration at the expense of fat and proteins. 
• Glucocorticoids are also instrumental in counteracting increased stress, inflammatory, and immune responses.

2.0Effects of Glucocorticoid

1. Effect on carbohydrate metabolism 

• Cortisol has a dual role in carbohydrate metabolism and stimulates gluconeogenesis and glycogenolysis in the liver, depending on the need. In hepatic cells, cortisol facilitates the synthesis of carbohydrates from non-carbohydrate precursors like amino acids and increases the level of stored glycogen, which acts as a reservoir for glucose. 
• The cortisol further stimulates glycogenolysis (stimulates glucose-6- phosphatase) and augments energy requirements during low nutrient supply, fasting, or stress conditions. Cortisol controls these processes by acting on the hepatic cells to increase the enzymes required for gluconeogenesis. 
• It also ensures a sufficient supply of extrahepatic amino acids (mainly muscles) to the liver for gluconeogenesis and further promotes glucose formation. Stored glycogen inside the liver cells allows glycolytic hormones, epinephrine and glucagon to make glucose available in need. 
• Cortisol inhibits glucose uptake by most cells of the body except the brain. Increased gluconeogenesis and reduced cell uptake increase blood glucose levels by 50%, causing adrenal diabetes. Increased circulating glucose causes an increase in the level of plasma insulin and promotes glycogen synthesis.
• However, it has been observed that exposure to high levels of glucocorticoids reduces the sensitivity of many tissues, especially skeletal muscle and adipose tissue, to insulin. 
• However, exogenous insulin administration has effectively lowered the blood glucose level marginally in adrenal diabetes.

2. Effect on protein metabolism 

• Cortisol increases the rate of protein metabolism to liberate extra amino acids from extrahepatic tissues, especially from muscles. 
• The increased amount of amino acids is a raw material for gluconeogenesis in the hepatocytes. Cortisol decreases the rate of protein synthesis enzymes in almost all tissues except the liver. 
• It increases the same in the liver, thereby increasing the level of proteins in the liver and plasma.  

3. Effect on lipid metabolism 

• Cortisol is known to exert its effect on fatty tissue in the same manner as in muscles. 
• Still, it enhances lipolysis in fatty tissues to increase free fatty acids in the blood. 
• The increased fatty acids in the blood act as energy fuel in case of starvation. Thus, the brain cells use glucose exclusively. 

4. Resistance to stress

• Exposure to any stress (physical, emotional, chemical, physiological or social) causes a steep rise in cortisol levels. The increased cortisol provides the excess glucose required to combat stress. 
• It also helps mobilize amino acids and fats to meet the excess glucose demand to the brain and energy. 
• The other possible effects of cortisol are modulating the immune response, heart rate, blood pressure, and the response of the nervous system to overcome stress. 
• Cortisol also has permissive effects on the action of catecholamines, thereby causing vasoconstriction and increasing blood pressure.  

5. Anti-inflammatory effects 

• Glucocorticoids inhibit almost all the steps of inflammatory response in any tissue damage or infection to increase the healing rate. 
• They decrease the migration and phagocytosis phenomena of white blood cells participating in the inflammatory response. 
• Cortisol stabilizes the lysosomal membranes, reduces the permeability of the capillaries, and inhibits the immune system, causing lymphocyte reproduction to decrease markedly and attenuate fever. Although high doses are known to retard tissue repair, slow down the process of healing and cause mental disturbances. 
• Glucocorticoids are very useful in treating chronic inflammatory disorders such as rheumatoid arthritis. 

6. Depression of immune responses 

• Cortisol suppresses the immune response by affecting most cells (cellular and humoral immunity) participating in immune reactions. 
• The rate of lymphocyte proliferation goes down, along with an increase in the apoptosis rate. 
• The effectiveness of glucocorticoids (prednisone, prednisolone, etc.) in suppressing the immune system makes them ideal drugs to be prescribed during organ transplant surgeries to limit the chances of tissue rejection.  

7. Effects on the cardiovascular system

• Cortisol is a known vasoconstrictor, and by contracting the smooth muscles of blood vessels, it increases blood pressure. 
• The direct effect of cortisol on regulating sodium and potassium concentration in heart cells increases cardiac muscle strength.  

8. Effects on the central nervous system

• Cortisol affects the behavior, mood, and electrical excitability of the neurons. 
• It has been studied that any imbalance in cortisol levels causes symptoms of adrenal fatigue, leading to moodiness, decreased tolerance, decreased clarity of thought, and decreased memory. 
• The hippocampus of the temporal lobe is responsible for memory formation, has many glucocorticoid receptors, and is sensitive to stress; thus, glucocorticoids also play an important role in memory.  

9. Effects on water and electrolyte metabolism

• Deficiency causes increased production of ADH, which can decrease the glomerular filtration rate, causing water retention in the body. 

3.0Regulation of Cortisol Secretion

• The effects of ACTH on the adrenal gland are intensity and duration-dependent:
• Rapid effects due to transient increases in ACTH 
• Medium-term effects due to prolonged increases in ACTH (6 - 36 hours):
• Chronic stimulation of the adrenal by ACTH results in adrenal hyperplasia (months): 
• ACTH stimulation is required to prevent adrenal atrophy
• The increased cortisol level has direct negative feedback effects on (1) the hypothalamus to decrease the formation of CRH and (2) the anterior pituitary gland to decrease the formation of ACTH. Both of these feedbacks help regulate the plasma concentration of cortisol.

4.0Deficiency of Glucocorticoid

Glucocorticoids are involved in many essential bodily functions, and abnormalities in their levels either excess or deficiency can lead to various diseases. 

1. Cushing's Syndrome

• Cause: Cushing's syndrome is caused by prolonged exposure to high levels of glucocorticoids, either from excessive production by the adrenal glands or from taking corticosteroid medications (exogenous glucocorticoids).
• Symptoms: Weight gain (particularly around the abdomen and face), thinning skin, easy bruising, muscle weakness, osteoporosis, high blood pressure, diabetes, and mood changes.
• Diagnosis: Often involves blood tests to measure cortisol levels, imaging tests to identify adrenal or pituitary tumors, and sometimes a dexamethasone suppression test.
• Treatment: This may include reducing or stopping corticosteroid use, surgery to remove tumors, radiation therapy, or medications that inhibit cortisol production.

2. Addison's Disease 

• Cause: Addison's disease occurs when the adrenal glands produce insufficient glucocorticoids (often mineralocorticoids). This can result from autoimmune destruction of the adrenal cortex, infections, or other conditions that damage the adrenal glands.
• Symptoms: Fatigue, muscle weakness, weight loss, low blood pressure, salt craving, hyperpigmentation (darkening of the skin), and low blood sugar. In severe cases, an adrenal crisis can occur, which is life-threatening.
• Diagnosis: Blood tests to measure cortisol and ACTH levels, and sometimes an ACTH stimulation test to assess adrenal function.
• Treatment: Lifelong hormone replacement therapy with glucocorticoids (e.g., hydrocortisone) and sometimes mineralocorticoids (e.g., fludrocortisone).

3. Congenital Adrenal Hyperplasia (CAH)

• Cause: CAH is a group of genetic disorders that affect the adrenal glands' ability to produce glucocorticoids. The most common form involves a deficiency in the enzyme 21-hydroxylase, leading to reduced cortisol production and overproduction of androgens.
• Symptoms: In females, symptoms can include ambiguous genitalia at birth, early puberty, and excess body hair. In males, symptoms may consist of early puberty and rapid growth during childhood. Both sexes may experience salt-wasting, dehydration, and low blood pressure.
• Diagnosis: In some regions, genetic testing, hormone level measurement, and newborn screening.
• Treatment: Lifelong glucocorticoid replacement therapy to manage hormone levels and sometimes mineralocorticoid replacement for salt-wasting forms.

4. Secondary Adrenal Insufficiency

• Cause: Secondary adrenal insufficiency occurs when the pituitary gland fails to produce enough ACTH, which stimulates the adrenal glands to produce glucocorticoids. This can be due to pituitary tumors, surgery, radiation, or prolonged use of corticosteroids leading to suppression of the hypothalamic-pituitary-adrenal (HPA) axis.
• Symptoms: Similar to Addison's disease but typically without hyperpigmentation and with less severe mineralocorticoid deficiency.
• Diagnosis: Blood tests to measure cortisol and ACTH levels and an ACTH stimulation test.
• Treatment: Glucocorticoid replacement therapy, and treating the underlying cause of the pituitary dysfunction.

5. Iatrogenic Cushing's Syndrome

• Cause: This form of Cushing's syndrome results from prolonged use of glucocorticoid medications, which can lead to excess levels of glucocorticoids in the body.
• Symptoms: Similar to those of Cushing's syndrome from endogenous causes: weight gain, high blood pressure, diabetes, muscle weakness, and skin changes.
• Diagnosis: Based on a history of glucocorticoid use and clinical presentation.
• Treatment: Gradual tapering of glucocorticoid medication under medical supervision to prevent adrenal insufficiency.

6. Glucocorticoid Resistance

• Cause: A rare condition where body tissues are resistant to the effects of glucocorticoids, leading to compensatory overproduction by the adrenal glands.
• Symptoms: These may include features similar to Cushing's syndrome but with paradoxically normal or elevated cortisol levels.
• Diagnosis: Hormone level measurements and genetic testing.
• Treatment: Often challenging; treatment is aimed at managing symptoms and complications.

7. Pseudohypoaldosteronism Type II (PHAII)

• Cause: A rare genetic disorder characterized by high blood pressure and hyperkalemia (elevated potassium levels) despite normal or elevated aldosterone levels. It is sometimes associated with mutations affecting glucocorticoid receptor function.
• Symptoms: High blood pressure, elevated potassium levels, and metabolic acidosis.
• Diagnosis: Blood tests to assess electrolytes, aldosterone, and cortisol levels, along with genetic testing.
• Treatment: Includes dietary modifications, medications to control blood pressure, and management of electrolyte imbalances.