Adrenal Gland: Zones and Cortisol

Divisions and Layers of the Adrenal Gland

• Adrenal glands comprise the cortex and medulla, each with distinct functions.
• The adrenal cortex, surrounded by a capsule consists of the zona glomerulosa, zona fasciculata, and zona reticularis.
• The zone glomerulosa produces mineralocorticoids, mainly aldosterone.
• The zone fasciculata produces glucocorticoids like cortisol.
• The zone reticularis produces androgens.
• The adrenal medulla produces catecholamines (epinephrine and norepinephrine).

Zona Fasciculata and Glucocorticoids (Cortisol)

• The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol.
• Cortisol is the primary glucocorticoid, regulating: Metabolism, immune system, cardiovascular function, growth, reproduction, and circadian/diurnal rhythm.
• The HPA axis begins with the hypothalamus releasing corticotropin-releasing hormone (CRH).
• CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH).
• ACTH then prompts the adrenal cortex to secrete cortisol.
• This cascade is stimulated by stressors.
• Cortisol secretion follows a circadian rhythm, peaking in the morning.
• Physiological stress is the body’s response to internal or external factors that disrupt homeostasis.
• Stressors include hypoglycemia, inflammation, pathogens, physical trauma and emotional stress.
• Cortisol is lipophilic and bounds to plasma proteins for transport in the blood.
• Corticosteroid-binding globulin (CBG) transports the majority of cortisol.
• Transcortin transports approximately 75% of cortisol.
• About 15% of cortisol is bound to albumin.
• Approximately 10% of cortisol remains unbound in a free state.
• Free cortisol binds to receptors in the cytosol.
• The hormone-receptor complex migrates to the nucleus, affecting gene expression.

Effects of Cortisol on Protein Metabolism

• Proteins are catabolized and amino acids are mobilized from extrahepatic tissues, especially from skeletal muscles.
• Amino acids serve as substrates for enzyme manufacturing and gluconeogenesis.
• Cortisol reduces cellular protein synthesis and may cause muscle wastage and osteoporosis in the long term.

Effects of Cortisol on Lipid Metabolism

• Fatty acids are mobilized from the adipose tissue.
• Metabolism shifts from glucose to fat utilization.
• Oxidation of FFAs in cells is enhanced.
• Glucose transport into fat cells is reduced.
• Long-term increased cortisol release can cause potbelly obesity, depleting peripheral fat and increasing visceral (abdominal) fat.

Effects of Cortisol on Carbohydrate Metabolism

• Blood glucose is increased by stimulating gluconeogenesis (GNG) and glycogenolysis.
• Substrates from extrahepatic tissues are mobilized for GNG.
• Synthesis of enzymes involved in GNG is stimulated.
• Cortisol generally antagonizes insulin's inhibitory effect on GNG and glycogenolysis in the liver.
• Cortisol potentiates the action of glucagon and epinephrine on glucose metabolism, through a permissive effect.

Effects of Cortisol on the Immune System

• Stabilizes lysosomal membranes, reducing the release of proteolytic enzymes from damaged cells.
• Synthesis of prostaglandins and leukotrienes is supressed and vasodilation reduced.
• Secretion of histamine by mast cells is reduced.
• Phagocytosis is reduced and antibody formation is suppressed.
• Connective tissue collagen synthesis is prevented.

Additional Effects of Cortisol

• Secondary functions that are not necessary for survival are inhibited.
• Reproductive system suppressed.
• Growth processes are suppressed.
• Cardiovascular system is affected.
• Sensitivity of vascular smooth muscle to vasoconstrictors is increased.
• Helps maintain blood pressure.
• Release of vasodilators is suppressed.

Common diseases related to the adrenal cortex

• Hyperactive adrenal cortex can lead to Cushing's disease.
• Hypoactive adrenal cortex results in Addison's disease.

Zona Reticularis and the Production of Androgens

• Androgens interact with male sex hormone receptors.
• Dehydroepiandrosterone (DHEA) is an androgen produced in this zone.
• DHEA is converted to androstenedione, which is used by the testes and ovaries to produce testosterone and estrogens, respectively.
• Adrenal androgens action is not significant in most animals.

Adrenal Medulla and Catecholamines Production

• The chromaffin cells of the adrenal medulla are neuroendocrine cells that secrete catecholamines in response to stimuli.
• Short-term (acute) stress prompts acetylcholine release from pre-ganglionic sympathetic neurons.
• Acetylcholine binds to nicotinic receptors on the chromaffin cells → promoting secretion of catecholamines.
• The catecholamines secreted are epinephrine (80%) and norepinephrine (20%).

Catecholamine Synthesis and Metabolism

• L-tyrosine is converted to L-DOPA inside chromaffin cells.
• L-Dopa becomes dopamine, then norepinephrine (NE) within the chromaffin granules.
• NE is converted to epinephrine (EPI) in the cytosol.
• Epinephrine is then stored in granules before release.
• L-tyrosine to L-DOPA is the reaction inside the chromaffin cells (cytosol).
• Norepinephrine exerts negative feedback on pre-ganglionic sympathetic receptors.
• Liver and kidney metabolize catecholamines, which are then excreted in urine as VMA.
• Key enzymes include COMT and MAO.
• Norepinephrine's clearance half-life is 2-2.5 minutes, while epinephrine's is 1-2 minutes.

Catecholamines Actions and Adrenergic Receptors

• Catecholamines trigger fight or flight response.
• Energy availability and overall metabolism are increased.
• Adjustment to situations is facilitated.
• The major types of adrenergic receptors (GPCR) are Alpha (a) – a1 and a2 Beta (β) → β1, β2 and β3.
• Alpha 1 receptors in the arterioles stimulate smooth muscle contraction in most visceral organs.
• Beta 1 receptors stimulate increased heart rate and stronger contractions.
• Beta 2 receptors promote vasodilation in skeletal muscle and liver arterioles, while beta 3 receptors stimulate lipolysis in adipose tissue.
• Basal metabolic rate also rises to facilitate fight or flight.