M1: Endocrine System

Overview

• Endocrinology: scientific study of hormones.

• Endocrine system: communication network between cells and organs using chemical messengers.

• Regulated functions: metabolism, energy balance, growth, development, body temperature, water/electrolyte balance, smooth muscle contraction, and reproduction.

Endocrine Structure

Primary Focus

• Focus Glands: Pituitary, Thyroid, Parathyroid, and Adrenal glands.

• Focus Secretory Cells: Hypothalamus (brain) and Pancreas.

Other Endocrine Structures

• Other Glands: Pineal gland and Thymus.

• Other Secretory Cells: Heart, Liver, GIT / small intestine, Kidneys, Skin, Adipose tissue, Placenta, Ovaries, and Testes.

Hormone: Mode of Action

• Endocrine: secreted into interstitial fluid and blood to act on distant targets.

• Paracrine: released to act locally on nearby target cells.

• Autocrine: acts directly upon the secreting cell itself.

• Note: A single hormone can act via multiple modes depending on context.

Hormones: Chemical Classifications

Water-Soluble Hormones

• Types: Peptide/protein hormones, Eicosanoids (prostaglandins, leukotrienes), single amino acid derivatives (tyrosine/tryptophan).

• Examples: Insulin, Noradrenaline, Prostaglandins.

• Transport: Dissolves easily and travels freely in blood plasma.

 

Lipid-Soluble Hormones

• Types: Steroid hormones (cholesterol-derived), single amino acid derivatives (tyrosine/tryptophan).

• Examples: Thyroid hormone, Estrogen, Testosterone.

• Transport: Requires binding to transport proteins in blood plasma.

• Transport Protein Functions:

  1. Enhances hormone solubility in blood plasma.

  2. Slows rate of renal excretion.

Hormones: Target Cell Specificity

• Hormones exert effects by activating protein receptors located either on the cell membrane surface or inside the specific cell.

Water-Soluble Hormone Mechanism

Cell Surface Receptors

• cannot pass through the lipid cell membrane and must bind to surface receptors.

 

G-Protein Coupled Receptors (GPCR)

• When a hormone binds (first messenger) to a GPCR activates an intracellular G-protein.

• Activated G-proteins modulate ion channels or alter enzyme activity via second messenger systems (often involving cAMP).

• GPCR cascade mechanism: Hormone binds GPCR → G-protein activates adenylate cyclase → converts ATP to cAMP → cAMP activates protein kinases → phosphorylation of cellular proteins → physiological response.

 

 

Tyrosine Kinase Receptors

• Regulate cellular processes by activating or inactivating target enzymes via phosphorylation.

Lipid-Soluble Hormone Mechanisms

Intracellular Receptors

• Readily diffuse through the lipid plasma membrane into target cells.

• Receptors are located internally within the cytosol or nucleus.

• Examples: steroid hormones (estrogen, testosterone)

 

Steroid Hormone Signaling Pathway

• Free hormone dissociates from transport proteins in blood and diffuses across the target cell membrane.

• Hormone binds to its intracellular receptor —> forming an activated receptor-hormone complex.

• The complex binds directly to DNA in the nucleus to regulate gene expression.

• Newly synthesized mRNA directs the synthesis of specific proteins on ribosomes to alter cellular activity.

Hypothalamus

• regulating physiological functions + serves as the primary link between the nervous and endocrine systems

• Transmits nerve signals to brain regions while also synthesising and releasing regulatory hormones via the pituitary gland.

Pituitary Gland: Anatomical Structure

Consists of two anatomically and functionally distinct lobes in adults: the posterior pituitary and anterior pituitary:

Posterior Pituitary Gland

• Composed of neural tissue consisting of the pars nervosa (hormone release site) and infundibulum (contains neural axons).

• Does not synthesise hormones; contains axon terminals of neurons whose cell bodies reside within the hypothalamus.

• Hypothalamic neurosecretory cells synthesise Oxytocin and Antidiuretic hormone (ADH).

Anterior Pituitary Gland

• Functions as a true endocrine organ that synthesises and secretes hormones.

• Composed of the pars distalis (main hormone-producing site) and pars tuberalis (sheath surrounding the infundibulum).

Anterior Pituitary Gland: Cell Types

• Somatotrophs: Secretes human growth hormone (hGH).

• Thyrotrophs: Secretes thyroid-stimulating hormone (TSH).

• Gonadotrophs: Secretes gonadotropins, specifically luteinising hormone (LH) and follicle-stimulating hormone (FSH).

• Lactotrophs: Secretes prolactin (PRL).

• Corticotrophs: Secretes adrenocorticotropic hormone (ACTH).

Hypothalamic Regulatory Hormones

• Growth Hormone Releasing Hormone (GHRH): Stimulates growth hormone release from somatotrophs.

• Somatostatin: Inhibits growth hormone release from somatotrophs.

• Thyroid Releasing Hormone (TRH): Stimulates TSH release from thyrotrophs.

• Gonadotropin Releasing Hormone (GnRH): Stimulates FSH and LH release from gonadotrophs.

• Prolactin Releasing Hormone: Increases prolactin release from lactotrophs (chemical identity not yet fully clarified).

• Dopamine: Inhibits/decreases prolactin release from lactotrophs.

• Corticotropin Releasing Hormone (CRH): Stimulates ACTH release from corticotrophs.

Posterior Pituitary

• Stores and releases two primary hormones: Oxytocin (OT) and Antidiuretic Hormone (ADH / Vasopressin).

• Hormones are liberated into the capillary plexus of the posterior pituitary and enter systemic circulation via posterior hypophyseal veins.

Oxytocin (OT): Function + Regulation of Release

Functions

• Uterus: Stimulates forceful contractions of smooth muscle cells in the uterine wall during childbirth.

• Mammary Glands: Stimulates contraction of myoepithelial cells around secretory alveoli to induce milk ejection post-delivery.

Regulation of Release

• Cervical stretching activates stretch-sensitive nerve receptors, signaling the brain control center to trigger oxytocin secretion.

• Enhanced uterine contractions push the baby further, increasing cervical stretch and driving a positive feedback cycle.

• Childbirth terminates cervical distension, breaking the positive feedback loop.

Antidiuretic Hormone (ADH/Vasopressin)

Functions

• Kidneys: Conserves body water by decreasing urine volume.

• Sweat Glands: Decreases perspiration to reduce cutaneous water loss.

• Arterioles: Constricts blood vessels to raise blood pressure.

Regulation of Release

• Osmoreceptors in the hypothalamus detect blood solute concentrations (osmolality / osmotic pressure).

• Stimulatory Factors: High blood osmotic pressure (high osmolality), dehydration, decreased blood volume, low blood pressure, pain, and stress trigger synthesis and release.

• Inhibitory Factors: Low blood osmotic pressure (low osmolality), elevated blood volume, and alcohol suppress secretion.

Anterior Pituitary: Target Tissue and Hormone

• Thyroid-Stimulating Hormone (TSH): Acts on the thyroid gland to increase thyroid hormone synthesis and release.

• Luteinising Hormone (LH): In females, induces ovulation, corpus luteum formation, and release of estrogens and progesterone; in males, stimulates testosterone production.

• Follicle-Stimulating Hormone (FSH): In females, stimulates oocyte development and estrogen secretion; in males, induces sperm production.

• Prolactin (PRL): Acts on mammary glands to promote milk production.

• Adrenocorticotropic Hormone (ACTH): Acts on the adrenal cortex to induce release of glucocorticoids, such as cortisol.

Growth Hormone Clinical Conditions

Growth Hormone Deficiency

• Childhood Dwarfism: GH deficiency in childhood leads to dwarfism, characterized by a head, trunk, and limbs that are small but proportionate to each other.

• Etiology: Caused by genetic factors or damage to the pituitary gland that impairs GH production.

• Management: Treated with early recombinant Human Growth Hormone replacement therapy.

Growth Hormone Excess

• Childhood Gigantism: Excess GH during childhood results in gigantism, a rare condition (approx. 3 cases per million) causing extreme height growth.

• Etiology: Commonly caused by a pituitary adenoma (pituitary tumor).

• Adult Acromegaly: Excess GH in adulthood results in acromegaly ("large extremities"), characterized by lengthening of the jaw, growth of the hands and feet, and coarsening of facial features.

• Etiology: Caused by a pituitary adenoma.

• Management: Treated via somatostatin analogues, dopamine agonists, GH receptor antagonists, or surgical intervention.

Adrenal Gland: Location + Structure

Location

• Adrenal glands lie superior to the kidneys in the retroperitoneal space.

• Characterised by a triangular shape and small size (a few centimeters).

Structural Regions

• Encased by a protective outer capsule.

• Composed of two functionally distinct regions: outer adrenal cortex and inner adrenal medulla.

Adrenal Medulla

Organisation & Secretion

• Composed primarily of chromaffin cells.

• Produces and secretes catecholamines: ~80% adrenaline (ADR) and ~20% noradrenaline (NA).

Regulatory Stimuli

• Secretion is stimulated by increased sympathetic nerve activity.

• Key triggers: exercise or imminent danger (fight-or-flight response).

Receptor Activation & Actions

• Catecholamines activate widely distributed alpha and beta catecholaminergic receptors.

• Responses include increased heart rate and blood pressure, vasoconstriction in skin and GIT, bronchiole smooth muscle dilation, and increased adipose lipolysis.

Adrenal Cortex + Zona Glomerulosa

Cortex Zonation & Precursor

• Cholesterol is the essential precursor for all adrenal steroid hormones.

• Divided into three histological zones: zona glomerulosa, zona fasciculata, and zona reticularis.

Zona Glomerulosa

• Cells are closely packed in spherical clusters and arched columns.

• Secretes mineralocorticoids, primarily aldosterone.

Zona Fasciculata + COtrisol

Organisation & Glucocorticoids

• Largest zone of the cortex, cells arranged in long straight columns.

• Secretes glucocorticoids (GC), mainly cortisol (corticosterone is the primary GC in rodents).

• Inactive cortisone is the precursor to cortisol, while hydrocortisone is the chemical equivalent of cortisol.

Regulation of Cortisol Secretion

• Hypothalamic CRH travels via hypophyseal vessels to stimulate anterior pituitary ACTH release, which triggers adrenal cortex cortisol release.

• Negative Feedback: ACTH inhibits CRH release; Cortisol inhibits both CRH and ACTH release. Feedback regulation takes effect rapidly within minutes.

• Diurnal Rhythm: High levels in the morning after sleep, dropping low in the evening before sleep.

• Stimulatory Triggers: Short-term stress (brief spike), chronic stress (sustained high levels), low blood glucose, inflammation/infection, and intense exercise.

Actions of Cortisol

• Essential for life; influences all nucleated cells via cytoplasmic glucocorticoid receptors.

• Hormone-receptor complex translocates to the nucleus to regulate gene expression and protein synthesis over time.

• Immune System: Suppresses immune function (chronic stress reduces antibodies and lymphocytes).

• Liver: Increases gluconeogenesis (glucose production).

• Muscle: Increases protein catabolism, supplying amino acid substrates for glucose conversion.

• Adipose Tissue: Stimulates lipolysis, releasing free fatty acids for energy and glycerol for glucose production.

Zona Reticularis + DHEA

Synthesis & Precursors

• Cells arranged in branching cords synthesise and secrete dehydroepiandrosterone (DHEA), the major adrenal androgen.

• Cholesterol is the precursor to DHEA.

• DHEA acts as a precursor to small amounts of adrenal estrogens and testosterone.

• Plasma DHEA concentrations increase prior to and during puberty.

Roles of DHEA

• Pubertal development: contributes to axillary and pubic hair growth and the prepubertal growth spurt.

• Aging: plasma levels fall with age, suggesting potential involvement in aging processes.

• Immunomodulation: exerts a nuanced role, countering some immunosuppressive effects of cortisol.

• Cognition: acts on brain receptors in cognitive areas; plasma levels correlate with cognitive performance.

Thyroid Gland: Structure + Organisation

• Anatomy: A butterfly-shaped gland located caudal to the larynx and anterior to the trachea, consisting of left and right lateral lobes.

• Vascular Supply: Arterial blood is supplied by the superior and inferior thyroid arteries; venous blood is drained by the superior, middle, and inferior thyroid veins.

• Colloid Content: Contains thyroglobulin (TG) and enzymes required for the synthesis and storage of thyroid hormones.

• C-Cells (Parafollicular Cells): Larger clear cells scattered between follicles that synthesise and secrete calcitonin.

Thyroid Hormone Synthesis + Transport

Synthesis Pathway

1. Iodide Trapping: Iodide is actively transported from the blood into the follicular cell.

2. Thyroglobulin Secretion: Thyroglobulin (TG) protein is synthesised within follicular cells and secreted via vesicles into the follicle lumen.

3. Iodine Formation: Iodide is converted to iodine within the follicular cell and transported into the lumen.

4. Iodination (Thyroid Peroxidase): Thyroid peroxidase adds iodine to tyrosine amino acid residues on TG.

   • Attachment of 1 iodine = monoiodotyrosine (MIT).

   • Attachment of 2 iodines = diiodotyrosine (DIT).

5. Coupling Reaction: Conformational changes bring iodinated tyrosines together:

   • MIT + DIT = triiodothyronine (T3).

   • DIT + DIT = thyroxine (T4).

6. Endocytosis & Digestion: TG with attached T3 and T4 is taken back into the follicular cell via pinocytosis; vesicles merge with lysosomes to cleave T3 and T4 from TG.

7. Secretion & Transport: Free T3 and T4 diffuse into the blood and bind to thyroxine-binding globulin (TBG) for transport to target tissues.

Hypothalamic-Pituitary-Thyroid Axis

• TRH Secretion: The hypothalamus synthesises and releases Thyrotropin-Releasing Hormone (TRH) into the capillary network of the median eminence.

• TSH Secretion: TRH activates anterior pituitary thyrotrophs to release Thyroid-Stimulating Hormone (TSH).

• Thyroid Secretion: TSH induces the synthesis and release of thyroid hormones from the thyroid gland.

• Negative Feedback Control: Elevated blood levels of thyroid hormones inhibit further release of TSH from the anterior pituitary and TRH from the hypothalamus.

Thyroid Hormone: Effects

Mechanism of Action

• Highly lipid-soluble hormones that easily pass through plasma membranes to bind intracellular receptors.

• The hormone-receptor complex translocates to the cell nucleus and binds DNA to regulate gene expression in almost all body cells.

Effects in Adults

• Metabolism: Increases basal metabolic rate (elevated O2 consumption) and drives heat production (thermogenesis).

• Substrate Metabolism: Exerts catabolic actions on proteins and carbohydrates; elevates glucose production, promotes adipose lipolysis (increasing free fatty acids), and decreases blood cholesterol levels.

• Cardiovascular & Brain: Increases heart rate, blood pressure, and cardiac contraction force; influences mood in the brain.

Thyroid Hormones: Clinical Conditions of Dysfunction

Hyperthyroidism (Thyroid Hormone Excess)

• Graves' Disease: The most common cause of hyperthyroidism, occurring predominantly in females under age 40.

• Etiology: Autoimmune disorder in which autoantibodies bind and stimulate TSH receptors on follicular cells, inducing continuous TH production and gland enlargement (goitre).

• Symptoms: High basal metabolic rate, heat intolerance, increased O2 consumption, muscle catabolism/loss, CNS irritability, tachycardia, goitre, and exophthalmos (bulging eyes due to retro-orbital oedema).

Hypothyroidism (Thyroid Hormone Deficiency)

• Etiology: Inadequate dietary iodine intake (most common cause worldwide); can also stem from TRH or TSH deficiency.

• Adult Symptoms: Reduced metabolism, heat production loss (cold intolerance), weakness and fatigue (from decreased protein synthesis), coarse dry hair/hair loss, dry rough pale skin, and goitre.

• Developmental Impact: Hypothyroidism during pregnancy or infancy leads to congenital hypothyroidism, resulting in severe delays in physical growth and intellectual development.

Parathyroid Gland: Anatomy

• Four small parathyroid glands are partially embedded in the posterior surface of the thyroid gland, with two glands located on each lateral lobe.

• Chief Cells: Represent the most numerous cell type in the parathyroid gland and are responsible for producing and secreting parathyroid hormone (PTH).

• Oxyphil Cells: Cells that are larger than chief cells with unknown normal function, though they can secrete PTH under pathophysiological conditions.

Parathyroid Hormone (PTH): Actions

• PTH serves as a major regulator of calcium, magnesium, and phosphate ions, acting primarily to elevate plasma calcium ion levels.

• Kidneys: Increases renal calcium ion reabsorption, reducing the amount of calcium excreted in urine.

• Bone: Increases bone breakdown, leading to elevated resorption of calcium ions from bone into plasma.

• Small Intestine (via Calcitriol): Stimulates kidney production of calcitriol which increases calcium ion reabsorption in the small intestine.

• Calcitriol is the active form of vitamin D, and its release is also increased by prolactin.

Pancreas: Anatomy + Location

• The pancreas is located within the abdominal cavity, situated posterior to the stomach.

• Head: The expanded portion resting in the curvature of the duodenum.

• Body: The central horizontal extension spanning across the left side of the abdomen.

• Tail: The narrow, tapering end of the organ.

Exocrine + Endocrine Pancreas

EXOCRINE AND ENDOCRINE PANCREAS

Dual Organ Function

• Functions as both an exocrine and endocrine organ.

Exocrine Component (~98%)

• Consists of acini that produce bicarbonate ions and digestive enzymes secreted into the gastrointestinal tract via ducts.

Endocrine Component (~2%)

• Located within the islets of Langerhans, which are interspersed between exocrine acini.

Islet Cell Types

• Alpha Cells (~17%): Synthesise and release glucagon.

• Beta Cells (~75%): Synthesise and release insulin (and small amounts of amylin).

• Delta Cells (~5%): Secretes somatostatin.

• F Cells (~3%): Secretes pancreatic polypeptide.

Pancreatic Hormones: Insulin

• Chemical Structure: A 51-amino acid peptide synthesized as a prohormone, consisting of two amino acid chains linked by disulfide bonds.

• Secretion Trigger: Released by beta cells in response to elevated blood glucose levels to reduce circulating glucose.

• Metabolic Effects: Facilitates cellular glucose uptake, increases glucose utilization (glycolysis), promotes hepatic glucose storage (glycogenesis), increases amino acid uptake and protein synthesis, and enhances fat production (lipogenesis).

Pancreatic Hormones: Glucagon

• Chemical Structure: A 29-amino acid peptide produced by alpha cells.

• Secretion Trigger: Secreted in response to low blood glucose to raise circulating glucose levels and prevent hypoglycemia.

• Metabolic Effects: Acts primarily on the liver to stimulate glycogen breakdown (glycogenolysis), increase glucose synthesis from lactic acid and amino acids (gluconeogenesis), and promote ketogenesis (converting fatty acids into ketone bodies for energy during low glucose availability).

Diabetes Melitus

Overview & Symptoms

• Characterized by chronically elevated blood glucose levels resulting from insulin deficiency, insulin resistance, or both.

• Acute Symptoms: Increased urine output, thirst, and hunger.

• Long-Term Complications: Elevated risk of cardiovascular disease, kidney disease, eye disease, and neuronal dysfunction.

Type 1 vs Type 2 Diabetes

Type 1 Diabetes

• Etiology: Autoimmune destruction of pancreatic beta cells causing an absolute loss of insulin production, influenced by genetic and environmental factors.

• Management & Demographics: Requires lifelong replacement insulin; accounts for 95% of diabetes cases in Australian children.

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Type 2 Diabetes

• Etiology: Characterized by reduced target cell sensitivity to insulin (insulin resistance), requiring higher insulin levels; chronic cases may develop progressive beta cell dysfunction.

• Demographics & Risk Factors: Represents 85–90% of all diabetic cases; features a slow onset typically presenting in middle age, with a strong correlation to obesity, genetics, and environment.