HPA Axis and CRH Functions

Hypothalamus-Pituitary-Adrenal (HPA) Axis

• The HPA axis is a major neuroendocrine system controlling reactions to stress.
• Stress is any stimulus disrupting the body's internal balance (physiological homeostasis).
• The HPA stress response is primarily driven by corticotrophin releasing hormone (CRH) release from the hypothalamic paraventricular nucleus (PVN).
• The HPA axis mobilizes energy reserves to ensure the organism has the resources to meet stress.

Structure and Function

• The paraventricular nucleus (PVN) of the hypothalamus synthesizes and secretes corticotropin-releasing hormone (CRH).
• CRH is transported to the anterior pituitary via the hypophyseal portal blood vessel system.
• CRH stimulates the secretion of stored ACTH from corticotrope cells in the anterior pituitary.
• ACTH is transported by the blood to the adrenal cortex of the adrenal gland.

Corticotropin-Releasing Hormone (CRH)

• CRH is a 41-amino-acid peptide hormone.
• CRH binds to G protein-coupled receptors on the corticotropic cell membrane.
• CRH stimulates cAMP production.
• Corticotrophs produce pro-opiomelanocortin (POMC), which is cleaved to release ACTH and melanocyte-stimulating hormone (MSH).

Adrenocorticotropic Hormone (ACTH)

• ACTH is a 39-amino-acid peptide hormone.
• ACTH stimulates secretion of glucocorticoid steroid hormones and androgens from adrenal cortex cells.
• ACTH receptor, also known as melanocortin receptor 2 (MC2), is a G protein-coupled receptor that activates adenylyl cyclase, increasing intracellular cAMP and activating protein kinase A.

ACTH Action

• ACTH stimulates cholesterol delivery to the mitochondria by steroidogenic acute regulatory (StAR) protein.
• P450scc catalyzes the first step of steroidogenesis.
• ACTH stimulates lipoprotein uptake into cortical cells to increase cholesterol bioavailability.
• ACTH stimulates transcription of genes coding for steroidogenic enzymes, especially P450scc.

Adrenal Gland

• The adrenal gland is a small gland atop each kidney, secreting steroid hormones, adrenaline, and noradrenaline.
• These hormones control heart rate, blood pressure, and other bodily functions.
• The adrenal cortex is the outer layer, divided into three zones. -Zona glomerulosa: mineralocorticoids (e.g., aldosterone). -Zona fasciculata: glucocorticoids (e.g., cortisol). -Zona reticularis: adrenal androgens (e.g., DHEA, DHEA-sulfate)
• The adrenal medulla is the inner core, secreting catecholamines (epinephrine, norepinephrine).

Steroid Hormone Synthesis

• Cholesterol is the starting material for steroid hormone biosynthesis, arriving at the adrenal cortex in the form of low-density lipoproteins.
• Receptor-mediated endocytosis takes up cholesterol.
• Adrenal cortex cells also synthesize cholesterol from carbohydrate or fatty acid precursors.
• Cholesterol is stored in steroid hormone-producing cells as fatty acid esters.

Adrenal Cortical Hormone synthesis Control

• ACTH stimulates steroidogenesis in the zona fasciculata and reticularis.
• This results in accelerated cholesterol deesterification, increased transport to mitochondria, and increased activity of StAR protein.
• ACTH accelerates cholesterol delivery to P450scc, initiating pregnenolone formation.
• ACTH also stimulates transcription of P450 enzymes, LDL receptors, and Star protein with continued stimulation.

Cortisol's Metabolic Effects

• Cortisol stimulates gluconeogenesis and glycogen storage.
• Cortisol is catabolic and diabetogenic.
• Cortisol increases protein catabolism in muscle, decreases protein synthesis, and provides amino acids for gluconeogenesis.
• Cortisol increases lipolysis, providing glycerol for gluconeogenesis.
• Cortisol decreases glucose utilization, insulin sensitivity of adipose tissue, and is essential for survival during fasting.
• Hypocortisolism causes hypoglycemia; hypercortisolism causes hyperglycemia.

Cortisol and Inflammation

• Cortisol induces lipocortin synthesis, inhibiting phospholipase A2.
• It decreases prostaglandin and leukotriene precursor synthesis.
• Cortisol inhibits IL-2 production and T lymphocyte proliferation.
• It inhibits histamine and serotonin release from mast cells and platelets.

Cortisol's Additional Actions

• Cortisol maintains normal blood pressure by up-regulating alpha-adrenergic receptors in arterioles.
• Cortisol inhibits bone formation by decreasing type I collagen synthesis, osteoblast production, and intestinal Ca²⁺ absorption.
• Cortisol increases glomerular filtration rate (GFR) by causing afferent arteriole vasodilation.
• Cortisol affects the limbic system, decreasing REM sleep, increasing slow-wave sleep, and increasing wake time.

Mineralocorticoid (Aldosterone)

• Promotes sodium reabsorption and potassium secretion in the distal convoluted tubules.
• Regulates total body sodium and controls plasma volume/arterial pressure.
• Absence of aldosterone causes sodium depletion and low arterial pressure.

Aldosterone Secretion

• Aldosterone is stimulated by decreased plasma sodium, increased plasma potassium, and decreased arterial pressure.
• ACTH has a minor effect on aldosterone secretion.

Renin-Angiotensin-Aldosterone System (RAAS)

• Regulates aldosterone secretion and blood pressure
• Involves interactions between the kidneys, angiotensin-converting enzyme (ACE), and other hormones.

Aldosterone Receptor Mechanism

• Aldosterone binds to its receptor, facilitating gene transcription and translation.
• Aldosterone-induced protein (permease) increases cell permeability to sodium.
• Increased sodium influx causes elevated sodium-potassium ATPase pump activity.

HPA Feedback System

• The HPA feedback system is regulated by the circulating level of plasma cortisol.
• Cortisol negatively feeds back on CRH and ACTH secretion.

Cushing's Syndrome

• A collection of signs and symptoms due to prolonged cortisol exposure.
• Excess cortisol, of any etiology, leads to this condition.
• Presenting symptoms may include; high blood pressure, abdominal obesity with thin arms and legs, reddish stretch marks, a round face, fat between shoulders, weak muscles, weak bones, acne, fragile skin.
• In women, it may manifest as excess hair and irregular menstruation.

Cushing's Disease

• Cushing's disease is a subtype caused by pituitary adenomas (tumors).
• Leads to excessive secretion of ACTH from corticotroph cells or due to increased CRH production by the hypothalamus.
• Exogenous steroid administration can also cause Cushing's syndrome, particularly with oral steroids, steroid injections into joints or steroid inhalers.

Adrenal Insufficiency (Addison's Disease)

• Characterized by weight loss, muscle weakness, fatigue, low blood pressure.
• Skin darkening (hyperpigmentation) often occurs.
• The problem can be due to either a primary disorder of the adrenal glands themselves or inadequate ACTH secretion by the pituitary.
• Around 70% of cases are due to autoimmune disorders, gradually destroying the adrenal cortex.

Adrenogenital Syndrome (AGS)

• Adrenal androgen hypersecretion, often concurrent with Cushing’s syndrome.
• Causes enlargement of external sexual organs in children, early onset of puberty, and masculinizing effects (e.g., deeper voice, beard growth) in women.

Pheochromocytoma

• A tumor of chromaffin cells, secreting catecholamines.
• Symptoms often include high blood pressure, heavy sweating, headache, rapid heartbeat (tachycardia), tremors, paleness, and shortness of breath (dyspnea).

Explore the essential components of the hypothalamus-pituitary-adrenal (HPA) axis and its role in stress responses. This quiz covers the structure and function of corticotropin-releasing hormone (CRH) along with its impact on physiological homeostasis. Test your knowledge on how this neuroendocrine system helps the body manage stress effectively.