Endocrine Lecture 2 (Part 2) – Thyroid, Growth Hormone & Pancreatic Hormones

Thyroid Hormone (TH) – Structure, Synthesis & Storage

• Nomenclature: “thyroxine” = umbrella term for thyroid hormones; two circulating forms – triiodothyronine (T₃, biologically active) and thyroxine (T₄, pro-hormone).
• Anatomical position: bilobed gland encircling the larynx (anterior neck).
• Histology keywords
– Follicular cells: cuboidal epithelium that synthesises thyroglobulin + enzymes.
– Colloid (lumen of each follicle): extracellular gel where iodinated thyroglobulin (TG) is stored—effectively an external storage tank for pre-hormone.
• Step-wise biosynthesis

1. Follicular cell synthesises TG (large glycoprotein rich in tyrosine).

2. I⁻ actively transported (Na⁺/I⁻ symporter) from blood → follicular cell → colloid.

3. Thyroid peroxidase (TPO) in colloid oxidises & organifies iodine, attaching 1 or 2 iodines to each tyrosine: MIT (mono-iodotyrosine) & DIT (di-iodotyrosine).

4. Coupling: DIT+DIT → T₄; MIT+DIT → T₃ (minor direct secretion).

5. Endocytosis of iodinated TG back into follicular cell, proteolysis in lysosomes liberates free T₃/T₄.

6. Secretion: basal, non-diurnal release of ~$90\%$ T₄, $~10\%$ T₃ into plasma (bound mainly to thyroxine-binding globulin, albumin, transthyretin).
   • Dietary iodine rationale: salt iodisation prevents iodide-deficiency goiter.

Regulation – Hypothalamic–Pituitary–Thyroid (HPT) Axis

• Tonic hypothalamic TRH → anterior-pituitary thyrotrophs.
• TRH stimulates release of TSH which binds TSH-R on follicular cells to ↑ all synthetic steps above.
• Peripheral conversion: $T<em>4 \xrightarrow{\text{deiodinase}} T</em>3$ inside most target cells.
• Negative feedback: plasma T₃/T₄ suppress both TRH & TSH (two-level feedback characteristic of axis hormones).

Cellular Mechanism of Action

• TH is lipid-soluble: diffuses through plasma & nuclear membranes.
• Receptor: heterodimeric thyroid hormone receptor (TR) bound to thyroid-response elements (TRE) on DNA.
• Binding modulates transcription of energy-related genes – e.g. Na⁺/K⁺-ATPase, mitochondrial enzymes, gluconeogenic enzymes.
• Net physiological role: maintain basal metabolic rate (BMR) & permit normal growth/development.

Dose–Response & Clinical Replacement

• Relationship: BMR falls steeply when TH below normal; rises modestly with excess TH (graph shown – asymmetric curve).
• Pharmacology: levothyroxine therapy employs T₄ (longer t½, tissue deiodination generates required T₃).

Thyroid Pathologies & Feedback Logic

• Hypothyroid spectrum
– Myxoedema (adult): lethargy, puffy sagging face.
– Iodine-deficiency goiter: ↓I⁻ ⇒ ↓T₃/T₄ ⇒ loss of feedback ⇒ ↑TRH, ↑TSH → trophic thyroid hypertrophy (visible neck swelling).
– Cretinism (foetal/neonatal): severe neurodevelopmental delay, short stature.
• Hyperthyroid spectrum
– Graves’ disease: autoimmune TSH-R–stimulating antibodies (IgG). Physiology: ↑T₃/T₄ despite ↓TSH/TRH. Clinical hallmark = exophthalmos (retro-orbital oedema/fat).

Growth Hormone (GH) Axis – Overview

• Actors
– Hypothalamus: GHRH (+) & somatostatin (SS, –) neurones.
– Anterior pituitary somatotrophs → secrete GH (peptide, half bound to GH-BP).
– Liver & peripheral tissues → produce insulin-like growth factors (IGF-1, IGF-2).
• Regulators of hypothalamus: circadian rhythm (peaks during deep sleep), stress, cortisol, fasting (all modulate GHRH/SS balance).
• Feedback: circulating IGF-1 inhibits GHRH neurones & somatotrophs (long-loop); GH exerts short-loop feedback.

Actions of GH / IGF-1

• Direct (GH-mediated)
– Lipolysis, ↓ glucose uptake (anti-insulin), ↑ hepatic gluconeogenesis → ↑ blood glucose.
• Indirect (IGF-1-mediated)
– Growth plate chondrocyte proliferation & differentiation (epiphyseal expansion).
– Protein synthesis in muscle, organomegaly.
– Net nitrogen retention.
• Bone microanatomy: pre-chondrocytes in epiphyseal plate respond to IGF-1 → cartilage expansion → ossification → longitudinal growth.

GH-Related Diseases

• Excess: Acromegaly (post-epiphyseal closure); gigantism (pre-closure).
– Often pituitary adenoma; phenotypes = enlarged jaw, hands, feet; increased height (gigantism), cardiometabolic morbidity, reduced life expectancy.
– Clinical photographs: siblings/twins show stark skeletal differences.
• Deficiency/Resistance: Congenital IGF-1 receptor mutation (e.g. V44M) → severe proportional dwarfism, mental retardation, delayed puberty, muscle immaturity.

Pancreatic Endocrine Physiology

• Anatomy: retroperitoneal organ adjacent duodenum.
– Majority exocrine (digestive enzymes).
– Islets of Langerhans = endocrine clusters (~1-2 % mass).
• Islet cell types
– $\beta$-cells (~60 %): synthesize & secrete insulin.
– $\alpha$-cells (~30 %): secrete glucagon.
– (δ-cells: somatostatin; PP-cells: pancreatic polypeptide – mentioned but not detailed.)

Fed–Fasted Switch

• Fed/Post-prandial (↑ glucose, amino acids):
– $\beta$-cell depolarisation → Ca²⁺ influx → insulin exocytosis.
– Insulin ↓ plasma glucose by promoting uptake & storage.
– $\alpha$-cells suppressed.
• Fasting (↓ glucose):
– $\alpha$-cell activation → glucagon.
– Glucagon triggers hepatic glycogenolysis, gluconeogenesis, lipolysis → ↑ plasma glucose & ketones.
– $\beta$-cell insulin release curtailed.

Molecular Mechanism – Insulin Signalling to GLUT4

1. Insulin binds tetrameric receptor (IR-A/B) possessing intrinsic tyrosine-kinase activity.

2. Autophosphorylation → recruits & phosphorylates insulin receptor substrates (IRS).

3. Downstream cascades (PI3K–Akt) → gene transcription plus acute trafficking of GLUT4.

4. Vesicular GLUT4 translocates and fuses with plasma membrane ⇒ facilitated diffusion of glucose into muscle & adipose.

Integrated Metabolism Flowcharts

• Insulin-dominant state
– Liver: glycolysis, glycogenesis, lipogenesis ↑.
– Muscle/adipose: GLUT4-mediated glucose uptake ↑; protein & fat synthesis ↑.
• Glucagon-dominant state
– Liver: glycogenolysis, gluconeogenesis, ketogenesis ↑.
– Muscle/adipose: fatty-acid mobilisation (hormone-sensitive lipase) ↑.

Additional Modulators of $\beta$-Cell Secretion

• Sympathetic (epinephrine) – inhibits insulin (needed in “run away from bear” fight-or-flight scenario).
• Incretins (gut peptides) – e.g. GLP-1 released during food intake enhances insulin; basis of antidiabetic drug Ozempic.
• Plasma amino acids – potentiate insulin directly.

Diurnal/Meal Patterns (Graph Recap)

• Breakfast-Lunch-Dinner spikes: each meal → ↑ glucose → matched insulin peaks; inter-meal troughs → modest glucagon rise. Not an intrinsic circadian rhythm – meal-driven.

Diabetes Mellitus

• Type 1 (≈10 %) – autoimmune destruction of $\beta$-cells ⇒ absolute insulin deficiency.
– Clinical trace: baseline hyperglycaemia; post-meal glucose skyrockets because no insulin surge.
• Type 2 (≈90 %) – lifestyle-related insulin resistance ± progressive $\beta$-cell dysfunction ⇒ relative insulin insufficiency.
– Eventually impaired glucose-stimulated insulin release.
• Cardinal complications
– Polyuria & polydipsia (osmotic diuresis of glucosuria).
– Microvascular: diabetic nephropathy (leading renal failure), diabetic retinopathy (major cause blindness).
– Macrovascular & neuropathic sequelae (note but not detailed).

Concept Links to Previous Material

• Like cortisol, TH influences energy metabolism but lacks the cortisol-like diurnal pulses.
• GH axis shares negative feedback logic seen in HPT & HPA axes.
• Fight/flight inhibitory pattern on insulin echoes adrenal catecholamine lecture.