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Goals

  • Know the location and structure of the thyroid gland and parathyroid glands.
  • Know how the thyroid hormones are synthesized.
  • Understand how thyroid secretion is controlled.
  • Know the function of thyroid hormones.
  • Have an appreciation for hyperthyroidism and hypothyroidism.
  • Understand parathyroid hormone and calcitonin.

Thyroid gland

  • Thyroid gland wraps around the trachea anteriorly. Can't see normally, but easy to see externally when enlarged

Thyroid follicles and C cells

  • Made up of balls of cells; hollow like a tennis ball
  • Follicle is the ball of cells. Inside the ball is the colloid - protein/water suspension
  • Colloid is where the formation of the proteins we need occurs (aided by follicular cells)
  • C cells have lighter staining cytoplasm, interspersed between the other follicular cells between the balls. Secrete a different hormone

Hormones produced

  • Calcitonin from C cells, thyroid hormone from follicular cells
  • Follicular cells
    • synthesis of thyroglobulin
    • secretes it into the colloid
    • accumulate iodide
  • ‘C’ cells (parafollicular cells)
    • produce hormone calcitonin

Control of thyroid hormone secretion

Thyrotropin releasing hormone (TRH) *tripeptide hormone (pyro-Glu-His-Pro) Thyroid Stimulating Hormone (TSH)

  • large glycoprotein with an alpha and beta chain.

Actions of TSH:

  1. Promotes iodide uptake (iodide needed to make thyroid hormones in colloid)
  2. Promotes synthesis of thyroglobulin and of thyroid hormones.
  3. Stimulates the secretion of T3 and T4 (increases endocytosis of colloid by follicular cell)

Thyroid hormones

  • Synthesized from tyrosine.
  • Amine hormones, but are lipophilic.
  • T4 is produced and secreted at a rate ~10-times greater than T3. Called T4 because it has 4 I atoms; also called thyroxine.
  • T3 is more potent at target tissues.
  • T4 is converted to the more active T3 in target tissues, by an enzyme; deiodinase.

Although thyroid hormones are made from tyrosine (amino acid), they're not well soluble in water (they're slightly hydrophobic, so they need transport proteins to assist this)

T4 is produced and secreted 10x more than T3. But T4 is converted into T3 by enzymes in the periphery, by cutting off one I atom. T3 is actually the most potent one at the target tissues.

Accumulation of iodide and TH synthesis

  • I from diet, absorbed, accumulates in thyroid gland.
  • Essential for thyroid hormone synthesis
  • Thyroid hormone synthesis is catalysed by thyroid peroxidase
  • Apical membrane faces the colloid
  • Na-K ATPase establishes conc gradient of Na+, which we use to suck I- into cell.
  • Anion exchanger facilitates diffusion of ions down their concentration gradient - so Cl or bicarb swaps for iodide (no generation of membrane potential or movement of charge, just I- going into follicular lumen)
  • Once I is in the follicular space, it is rapidly acted on by the thyroid peroxidase, which is loosely associated with the apical membrane. This catalyses conversion of thyroglobin + I- to thyroglobin with T3 and T4 attached. This is called iodination and conjugation
  • The cell is acted upon by TSH, which initiates a cascade by cAMP to activate protein kinase A, to initiate many cellular changes, including endocytosis of the TG-T3-T4 complex.
  • Lysosome fuses with the endosome, containing lysozymes which cleave of T3 and T4. Because these are lipophilic, these can escape the cell.

Synthesis: Iodination and conjugation

  • Cluster of tyrosin residues, where thyroid peroxidase acts
  • Iodide is converted to iodine, then attached to the tyrosine residues (Iodination)
  • Then we conjugate,joining together two adjacent residues (OH group attacks indicated bond, to form the double ring structure that is T3 and T4)

Thyroid follicular cell

  • Apical surface blebs indicate the pseudopodia endocytosing the colloid to produce thyroid hormone. More active cells have more pseudopodia
  • Nucleus is active in the transcription of proteins
  • Vesicles are present - some are smaller (lysosomes), some are larger (endocytotic vesicles)
  • ER present for protein synthesis
  • Quiescent thyroid gland - cell height tends to decrease (less active endocytosis), cell is less active
  • Strong stimulation - higher cells and longer pseudopodia, more vesicles and lysosomes and endocytotic vesicles
  • Effects of TSH:
  1. Promotes iodide uptake (iodide needed to make thyroid hormones in colloid)
  2. Promotes synthesis of thyroglobulin and of thyroid hormones.
  3. Stimulates the secretion of T3 and T4 (increases endocytosis of colloid by follicular cell)
  • Gross effect of TSH: increase number of follicles and size of thyroid gland
  • Autoimmune diseases can produce autoantibodies that bind to TSH receptors, causing stimulation of this thyroid proliferation (goitre = large swelling due to thyroid enlargment
  • TSH stimulation produces smaller follicular lumen, and more fuzzy apical membrane (because of more endocytosis)

T3 and T4 transport

  • T3 and T4 are lipophilic.
  • Transported in the blood bound to specific carrier proteins-
    • Thyroxine-binding globulin (TBG)
    • Transthyretin
  • Non-specific binding to albumin.
  • T3, 99.5% bound to TBG, has a plasma half-life of 24 hours.
  • T4, 99.98% bound to TBG, has a plasma half-life of 8 days (probably why this is the principal way thyroid hormone is produced - once the extra I is cut off (more active form, T3), it's halflife is a bit shorter)
  • T4 provides a reserve pool available for conversion to biologically active T3 by the deiodinases in the periphery.

Binding of hormone to transporter is an equilibrium (on off on off): if it's off near a target cell, it may bind receptor and produce a response

We have a large pool of T3 and T4 in our blood that can be used to produce responses, can draw it from the blood and use it for our purposes

Actions of thyroid hormones

  • Don't act at cell surface receptors
  • Can move freely through the cell membrane, interacting with receptors either in cytoplasm or in nucleus. Either way, that receptor-hormone complex translocates into the nucleus, where it binds to specific sequences on the DNA to regulate gene expression
  • THR-TH complex binds with the retinoid X receptor (TXT), and together they bind to specific DNA sequence called the thyroid response element (TRE). Might increase gene expression of metabolic enzymes (increase metabolism). In other instances, it may downregulate expression of some genes.
  • Increases production of Na-K ATPase, gluconeogenic enzymes, respiratory enzymes (for oxidative phosphorylation in the mitochondria), myosin heavy chain (particularly in the heart, to increase its contractility), beta adrenergic receptors (increase heart rate; because more sensitive to sympathetic control), many others
  • Overall, there's an increase in basal metabolic rate. Slow onset reaction, but long lasting impacts. Increases utilisation of glucose to make new glycogen molecules, making new glucose molecules, increase lipolysis, increasing protein synthesis and degradation (to generate heat), increase Na-K-ATPase generates heat as well. Also stimulates growth and maintenance of tissue. Beta-adrenergic receptors and myosin filaments increase, resulting in greater sympathetic response of cardio-pulmonary system
  • Developmental effects: synaptogenesis and neurogenesis (not enough TH produces poorly-differentiated and poorly connected neural system. This is cretinism).

Control of thyroid hormone secretion

  • Negative feedback control
    • Circulating T3 and T4 have negative feedback upon hypothalamus and the thyrotrophs in the anterior pituitary
  • T4 is converted to T3 by a type 2 deiodinase (cuts of an iodine atoms;different to the peripheral type 1), which is only found inside the cytoplasm of cells of the hypothalamus and thyrotrophs. T3 has a stronger negative feedback effect on the hypothalamus
  • Cold can stimulate TRH production, to warm them up
  • Dopamine and somatostatin decrease TH and GH together (no need to have one high than the other)
  • Oestrogen upregulates TRH receptors- because oestrogen is a strong mitogen (stimulates growth of follicle - autocrine action of oestrogen back onto follicular cells to expand size); it is also important in stimulating osteoblasts to grow long bones -- therefore makes sense to upregulate metabolism as well (to support growth; make energy substrates available).

C cells (parafollicular cells)

  • Secrete calcitonin (CT) peptide hormone (32 aa)
  • Calcium sensing Receptor Protein (CasRP) on ‘C’ cells
  • Responds to the amount of calcium in the circulation
  • Calcitonin stimulates bone deposition (increases osteoblast activity, inhibits osteoclast activity).
    • Reduces the amount of calcium that is free in the plasma
    • Negative feedback

Parathyroid glands

  • Sit at the back of the thyroid gland

Four parathyroid glands

  • embedded on the posterior surface of each lobe of the thyroid gland.
  • Small ovoid bodies separated from the thyroid gland by connective tissue.

Composed of two cells types:

  • Chief cells (most of the cells - these produce parathyroid hormone)
  • Oxyphilic cells.

Chief cells secrete the parathyroid hormone.

Parathyroid hormone (PTH)

  • Parathyroid hormone (PTH)
    • Single chain protein, formed from pro-hormone
  • Calcium sensing Receptor Protein (CasRP) on the Chief Cells; modulates PTH secretion
  • Calcium needed for neurotransmission, muscle contraction, second messenger in cells
  • PTH acts to stimulate bone resorption (osteoclasts stimulated, osteoblasts inhibited), and in the kidney, reduces calcium clearance and increases phosphate clearance (don't want to form phosphate
  • Overall this elevates plasma Ca

Calcitonin- parathyroid hormone interaction

  • Together, these two work together to maintain calcium homeostasis
    • Calcitonin tones the calcium down

Summary

  • TRH > TSH > secretion of thyroid hormone.
  • Absolute requirement of iodide for synthesis of THs.
  • Synthesis of T3 and T4 in follicles, stored as thyroglobulin in colloid.
  • T3 and T4 transported on binding proteins.
  • T4 converted to the active T3 by deiodinases.
  • Important in metabolism, growth, foetal neuron development, maintaining normal tissue function.
  • Parathyroid hormone - increase in bone destruction. Calcitonin - stimulates uptake of Ca2+ and bone formation.