L36. Physiology - Adrenal Gland

Adrenal Gland Overview

• The adrenal glands produce steroid hormones (mineralocorticoids, glucocorticoids, and adrenal androgens) and catecholamine hormones (epinephrine and norepinephrine).
• Cortisol, a glucocorticoid, regulates carbohydrate and protein metabolism, and affects many bodily systems.
• Aldosterone, a mineralocorticoid, maintains salt and water balance.
• DHEA and androstenedione, adrenal androgens, affect secondary sex characteristics.
• Epinephrine (adrenaline) mediates 'flight-or-fight' responses to stress.

Session Learning Objectives

• Describe the adrenal gland anatomy and hormonal output of the cortex and medulla.
• Outline the biosynthesis pathways for cortical and medullary hormones.
• Explain ACTH's regulation of cortisol production, including cellular mechanisms and feedback loops.
• Detail the cellular actions and physiological effects of cortisol and aldosterone.
• Describe the receptors and signaling pathways used by cortical and medullary hormones.
• Explain the functional relationship between the adrenal medulla and the sympathetic nervous system, and hormone regulation.
• Describe the effects of epinephrine on the liver.
• Describe Cushing's syndrome and Addison's disease.

Session Outline

• Overview of the adrenal gland
• Biosynthesis of adrenal cortical hormones
• Corticoid steroid action
• Biosynthesis and regulation of catecholamines from the adrenal medulla
• Epinephrine action

Biosynthesis of Adrenal Cortical Hormones

• Biosynthesis begins with the enzymatic removal of the cholesterol side chain.
• Pregnenolone is converted into cortisol, aldosterone, or androgens via enzymatic steps.
• Mutations in enzymes reduce cortisol and aldosterone production, and increase androgen production.
• Reduced activity of 21-hydroxylase diminishes cortisol and aldosterone, and increases sex steroid production.

Regulation of Corticosteroid Production

• Cortisol secretion is primarily controlled by ACTH (adrenocorticotropic hormone).
• ACTH production is controlled by the hypothalamus.
• Cortisol exerts negative feedback on ACTH and CRF (corticotropin-releasing factor) release.

ACTH

• Cortisol is secreted in an episodic pattern following a 24-hour circadian cycle.
• ACTH is released in a highly pulsatile manner throughout the day, but with higher overall rate in the morning hours.
• ACTH is generated from proteolytic digestion of the POMC (proopiomelanocortin) precursor peptide.
• In adults, POMC yields ACTH and other peptides. In fetuses, different peptides (MSHs) are produced.

ACTH action in the adrenal cortex

• ACTH acts via a specific GPCR (the ACTH receptor) to stimulate hormone production via multiple mechanisms.
• It influences the rate-limiting step in cortisol synthesis, stimulates other enzymes needed, promotes cholesterol uptake, and other mechanisms.
• Chronic elevated ACTH levels can lead to adrenal cortex hyperplasia.
• Other factors besides ACTH, such as potassium/sodium levels and angiotensin II, affect aldosterone production.

Corticosteroid Action

• Cortisol acts through intracellular receptors (GRs) within target cells.
• The receptors translocate to the nucleus, bind to hormone response elements (HREs), and stimulate (or suppress) transcription of target genes.
• Different genes are activated in different tissues in response to cortisol.
• Cortisol receptor 'cross-talk' may occur due to structural similarity between cortisol and aldosterone.

Physiological Effects of Cortisol

• Carbohydrate metabolism- Increase blood glucose levels via stimulating gluconeogenesis and inhibiting peripheral glucose utilization.
• Protein metabolism - Cortisol inhibits protein synthesis and increases protein breakdown, especially in muscle and liver.
• Lipid metabolism - Increases lipolysis, raises circulating fatty acid levels.

Physiological effects of cortisol continued

• Cortisol affects inflammation and the immune response, and is used clinically to suppress these in certain situations.
• The immune suppression, and other effects of cortisol, come with an elevated risk for infections and Cushing's syndrome.

Biosynthesis and Regulation of Catecholamine production

• Adrenal medulla produces catecholamines (norepinephrine, epinephrine, dopamine).
• Norepinephrine is both a neurotransmitter and a hormone.
• Epinephrine's function is primarily as a hormone.
• Catecholamine release is controlled by the sympathetic nervous system and often associated with stress responses.
• Tyrosine hydroxylase, the rate-limiting enzyme in the pathway, is stimulated by sympathetic nerve action.
• Norepinephrine synthesis is converted to epinephrine via PNMT.

Catecholamine Action

• Norepinephrine and epinephrine act via α and β adrenergic receptors, resulting in various effects.
• These effects include; increased heart rate and contractility, constriction or dilation of blood vessels, elevation of blood glucose, and other responses.

Factors that stimulate catecholamine release

• Fight-or-flight stimuli
• Anxiety
• Pain
• Increased sympathetic nervous system tone
• Trauma
• Hypoglycemia
• Anoxia
• Exercise
• Extreme temperatures

Rapid degradation of catecholamines

• Catecholamines are rapidly degraded by enzymes, primarily COMT and MAO.
• Metabolites are converted into products such as vanillylmandelic acid (VMA).

Adrenal Gland Pathologies

• Glucocorticoid excess is associated with conditions like Cushing's syndrome.
• Symptoms including truncal obesity, hypertension, loss of subcutaneous fat, muscle weakness, and hyperglycemia.
• It can be caused by excess cortisol production due to primary adrenal tumors or secondary to pituitary adenomas (Cushing's disease).

Glucocorticoid & Mineralocorticoid Deficiency

• Deficiency of both cortisol and aldosterone is known as Addison's disease.
• Symptoms are hypotension, hyperkalaemia, hypoglycemia, and hyperpigmentation.
• Common causes are autoimmune reactions and infectious diseases.