Adrenal Glands: Medulla & Cortex

• Each of the two adrenal glands weighs roughly 4 grams.
• The adrenal glands are positioned at the superior poles of the kidneys.
• Each adrenal gland has two distinct regions: the adrenal medulla and the adrenal cortex.

Adrenal Medulla

• The adrenal medulla makes up the central 20% of the adrenal gland.
• Sympathetic nervous system closely interacts with the adrenal medulla.
• Epinephrine and norepinephrine are released from the medulla in response to sympathetic stimulation.

Adrenal Cortex

• The adrenal cortex produces corticosteroids.
• Corticosteroids include glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgens.
• The adrenal cortex is the outer zone of the gland
• It has mesodermal origin and comprised of three layers.
• The adrenal cortex accounts for 80% of the adrenal tissue and secretes adrenocortical steroid hormones.
• At gestational week 8, the adrenal cortex begins to differentiate.
• In intrauterine life, it facilitates fetal adrenal steroid production.
• Post-birth, the fetal adrenal cortex begins to involute, disappears, and transitions into the three-layered adult adrenal cortex.
• The adrenal cortex has three distinct layers.

Zona Glomerulosa

• Zona glomerulosa is a thin layer located just below the capsule.
• Aldosterone is secreted by zona glomerulosa.

Zona Fasciculata

• Zona fasciculata is the middle and widest layer, constituting about 75% of the adrenal cortex.
• Cortisol and corticosterone are secreted by the zona fasciculata, along with small amounts of androgens and estrogens.

Zona Reticularis

• Zona reticularis is the deep layer of the cortex.
• Adrenal androgens like dehydroepiandrosterone (DHEA) and androstenedione are secreted by the zona reticularis.
• Small amounts of estrogens and some glucocorticoids are also secreted by the zona reticularis.

Synthesis of Adrenal Steroids

• All human steroid hormones, including those from the adrenal cortex, are synthesized from cholesterol.
• About 80% of the cholesterol for steroid synthesis comes from LDL in plasma.
• Cholesterol desmolase converts cholesterol into pregnenolone within the mitochondria.
• All synthetic pathways for adrenal steroids take place in the mitochondria and endoplasmic reticulum.
• The chemical structures are similar but slight molecular differences give them different functions

Adrenocortical Hormones and Plasma Proteins

• 90-95% of cortisol in the plasma is bound to plasma proteins, especially cortisol-binding globulin (transcortin), and, to a lesser extent, albumin.
• Cortisol's half-life in plasma is about 60-90 minutes due to the binding nature.
• About 60% of aldosterone combines with plasma proteins, with 40% circulating freely.
• Aldosterone has a relatively short half-life of about 20 minutes.

Mineralocorticoids

• Aldosterone is a very potent mineralocorticoid, accounting for 90% of mineralocorticoid activity.
• Deoxycorticosterone is 1/30 as potent as aldosterone and secreted in small amounts.
• Corticosterone has slight mineralocorticoid activity.
• Cortisol has slight mineralocorticoid activity but is secreted in large amounts.
• 9α-Fluorocortisol and cortisone are synthetic mineralocorticoids.

Glucocorticoids

• Cortisol is a very potent glucocorticoid, accounting for 95% of glucocorticoid activity.
• Corticosterone accounts for 4% of glucocorticoid activity.
• Synthetic glucocorticoids include cortisone, prednisone, methylprednisone, and dexamethasone.
• Synthetic glucocorticoids are more potent, have longer half-lives, and are more selective than cortisol or corticosterone.

Cortisol and Renal Epithelial Cells

• Renal epithelial cells express the enzyme 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2)
• 11β-HSD2 prevents cortisol from activating mineralocorticoid receptors and cortisol is converted to cortisone

Adrenocortical Hormone Metabolism

• Combination of adrenocortical hormones with plasma proteins helps to prevent large variations of these hormones in plasma
• Adrenocorticol hormones are metabolized in the liver
• Adrenocortical hormones are conjugated with glucuronic acid and to a lesser extent with sulfates
• About 25% of these conjugates are excreted into bile and then in the feces
• The remaining 75% conjugates are not bound to plasma proteins and therefore filtered by the kidneys and excreted in the urine

Physiological Actions of Cortisol

• Cortisol is a "stress hormone" with a broad range of actions.
• Function of cortisol is to maintain blood glucose levels, CNS function, and cardiovascular function during fasting.
• Cortisol increases blood glucose during stress, but at the expense of muscle protein.
• It protects the body against the self-injurious effects of inflammatory and immune responses.
• Cortisol affects bone, skin, connective tissue, the GI tract, and the developing fetus.
• These effects act independently of its stress-related functions.

Specific Actions of Cortisol

• Cortisol increases gluconeogenesis, proteolysis (catabolic), and lipolysis.
• Cortisol decreases glucose utilization and insulin sensitivity.
• Cortisol inhibits inflammatory and immune responses.
• Cortisol enhances vascular responsiveness to catecholamines.
• Cortisol inhibits bone formation.
• Cortisol increases GFR and decreases REM sleep.

Cortisol and Metabolism

• Cortisol and other glucocorticoids best known metabolic effects are to stimulate gluconeogenesis and storage of glycogen.
• Cortisol is catabolic and diabetogenic.
• Protein, fat, and carbohydrate metabolism is affected, with cortisol increasing glucose synthesis.

Cortisol's effects on carbohydrate metabolism

• Cortisol increases the enzymes needed to convert amino acids into glucose in liver cells.
• Amino acids are mobilized from extrahepatic tissues like muscles.
• Increased gluconeogenesis leads to increased glycogen storage in liver cells.
• Glucose utilization of cells is also reduced
• Elevated blood glucose concentration and can cause “adrenal diabetes"
  • Results in increased insulin secretion
  • Leads to insulin resistance developing in tissues

The effect of cortisol on protein metabolism

• Reduces cellular protein
• Increases liver and plasma proteins
  • Results in increased gluconeogenesis using amino acids -Increased deamination of amino acids
• Increases blood amino acids
  • Results in diminished transport of amino acids into extrahepatic cells
  • Enhances transport into hepatic cells

The effect of cortisol on fat metabolism

• Mobilisation of fatty acids
• Increased concentrations of free fatty acids in plasma
• Mobilization of fats
• Helps shift metabolic systems of the cells to utilization of fatty acids instead of glucose
• Can cause obesity

Stress and increased cortisol release

• Some of the different types of stress that increase cortisol release are:
  • Trauma
  • Infections
  • Extreme heat or cold
  • Sympathetic stimulation
  • Surgery
  • Restriction of movement
  • Debilitating disease

Inflammation

• Inflammation is characterized by tissue injury.
• Key characteristics are:
  • Vasodilation of local blood vessels
  • Increased permeability of blood capillaries
  • Leakage of a large amount of fluid and fibrinogen
  • Clotting of substances in the interstitial space
  • Migration of a large number of granulocytes
  • Swelling of the tissue cells

Effects of High Cortisol Levels on Inflammation

• Rapid resolution of inflammation and blocks factors that cause inflammation
• Stimulates recovery relating to:
  • Rheumatoid arthritis
  • Rheumatic fever
  • Acute glomerulonephritis
• Blocks inflammatory response to allergic reactions by:
  • Stabilizing the lysosome membrane
  • Decreasing the permeability of the capillaries
  • Decreasing migration of leukocytes into the inflamed area and phagocytosis of damaged cells
  • Suppressing the immune system which causes decreased T lymphocyte and antibody synthesis
  • Attenuating of fever by decreasing the release of IL-1
• Reduces all aspects of the inflammatory process globally

Regulation of Cortisol by ACTH

• In contrast to aldosterone secretion, which is controlled by potassium and angiotensin acting directly on adrenocortical cells.

Circadian Rhythm and ACTH/Cortisol

• CRF, ACTH, and Cortisol are secreted in high levels in the early morning and are low in the late evening