What are three fundamental physiological processes affected by thyroid hormones?
What are the major hormones produced by the thyroid glands and the parathyroid glands?
T3 - tri-iodo-thyronine
T4 - thyroxine
What are the cells in the thyroid responsible for producing hormone & how are they arranged?
Thyroid epithelial cells produce thyroid hormone. They're arranged in spheres called thyroid follicles, which are filled with colloid.
Colloid is a proteinaceous depot of thyroid hormone precursor. In standard histologic preparations such as these, colloid stains pink.
Aside from thyroid epithelial cells, what other types of cells in the thyroid synthesize & secrete hormone?
C cells synthesize & secrete calcitonin. C cells are also called parafollicular cells as they're nestled between the colloid-filled follicles.
Describe the chemical structure of the thyroid hormones T3 (triiodothyronine) & T4 (thyroxine).
They are derivatives of tyrosine bound covalently to iodine. They are also known as amine hormones.
They are two tyrosines linked together with iodine at three or four positions on the aromatic rings.
Several other iodinated molecules are generated that are inactive, such as "reverse T3".
They are lipid soluble, like steroid hormones, and thus they use facilitated diffusion to get across the target cell's plasma's membrane bind to intracellular receptors.
More than 99% of T3 & T4 are bound to carrier proteins:
- thyroxine-binding globulin, a glycoprotein synthesized in the liver
Carrier proteins allow maintenance of a stable pool of thyroid hormones from which the active, free hormones are released for uptake by target cells.
Thyroid hormones are synthesized by mechanisms fundamentally different from what is seen in other endocrine systems. Thyroid follicles serve as both factory and warehouse for production of thyroid hormones.
What are the three main steps of thyroid-hormone synthesis?
1. Production and accumulation of the raw materials - iodide-trapping & synthesis of thyroglobulin by thyroid epithelial cells to harvest tyrosine; thyroglobulin contains 134 tyrosines
2. Synthesis of the hormones on a backbone or scaffold of precursor
3. Release of the free hormones from the scaffold and secretion into blood
What is the enzyme necessary for the synthesis of thyroid hormones?
Where does the tyrosine come from to make thyroid hormones?
Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin, which is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle - colloid is essentially a pool of thyroglobulin.
A molecule of thyroglobulin contains 134 tyrosines, although only a handful of these are actually used to synthesize T4 and T3.
Where does the iodine come from to make thyroid hormones T3 & T4?
Iodine, or more accurately iodide (I-), is avidly taken up from blood by thyroid epithelial cells, which have on their outer plasma membrane a sodium-iodide symporter or "iodine trap".
Once inside the cell, iodide is transported into the lumen of the follicle along with thyroglobulin.
Where is thyroid peroxidase, the enzyme necessary for synthesis of thyroid hormone T3 & T4, located in thyroid cells?
What does it do?
It is an integral membrane protein in the apical (colloid-facing) plasma membrane of thyroid epithelial cells.
Thyroid peroxidase catalyzes two sequential reactions:
1. Iodination of tyrosines on thyroglobulin;
2. Synthesis of thyroxine (T4) or triiodothyronine (T3) from two iodotyrosines.
How is thyroid hormone, T3 or T4, released into the blood stream from the colloid in follicles on the surface of thyroid epithelial cells?
Remember that thyroid hormone is still tied up in molecules of thyroglobulin - the task remaining is to liberate it from the scaffold and secrete free hormone into blood.
Thyroid hormones are excised from their thyroglobulin scaffold by digestion in lysosomes of thyroid epithelial cells:
1. Thyroid epithelial cells ingest colloid by endocytosis from their apical borders - that colloid contains thyroglobulin decorated with thyroid hormone.
2. Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic enzymes that digest thyroglobluin.
3. Free thyroid hormones apparently diffuse out of lysosomes, through the basal plasma membrane of the cell, and into blood where they quickly bind to carrier proteins for transport to target cells.
How is thyroid-hormone synthesis & secretion controlled?
Binding of TSH, synthesized by the thyrotrophs of the anterior pituitary, to its receptors on thyroid epithelial cells in the thyroids stimulates synthesis of the iodine transporter, thyroid peroxidase and thyroglobulin.
How do thyroid hormones affect metabolism?
Thyroid hormones lead to an increase in basal metabolic rate. One consequence is to increase body heat production, which seems to result from increased oxygen consumption and rates of ATP hydrolysis.
Lipid metabolism: Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance oxidation of fatty acids in many tissues. Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated with thyroid hormone levels - one diagnostic indiction of hypothyroidism is increased blood cholesterol concentration.
Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose.
How do thyroid hormones effect growth?
Thyroid hormones are clearly necessary for normal growth in young animals, as evidenced by the growth-retardation observed in thyroid deficiency.
How are thyroid hormones important for development?
Of critical importance in mammals is the fact that normal levels of thyroid hormone are essential to the development of the fetal and neonatal brain.
What effect do thyroid hormones have on heart rate?
Thyroid hormones increases heart rate, cardiac contractility and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs.
What is Graves disease?
(Karen: Think of Tobel!)
A form of hyperthyroidism found in humans. It's an immune disease in which auto-antibodies bind to and activate the TSH receptor on thyroid epithelial cells, leading to continual stimulation of thyroid hormone synthesis.
What is hypothyroidism and what are two examples of the condition?
Any condition that results in thyroid hormone deficiency.
Iodine deficiency - can lead to goiter, as thyroid becomes enlarged
Primary thyroid disease: Inflammatory diseases of the thyroid that destroy parts of the gland are clearly an important cause of hypothyroidism.
What is cretinism?
A form of irreversible growth and mental retardation seen in young children with congenital thyroid deficiency (hypothyroidism) that was not treated by supplemental therapy soon after birth.
What is calcitonin? Compare & contrast its synthesis, structure and section to that of thyroid hormones T3/T4.
Calcitonin is produced in the thyroid glands, like T3 & T4, but it isn't an iodinated derivative of tyrosine like they are.
Unlike T3/T4, which are synthesized by thyroid epithelial cells in colloid-filled follicles, calcitonin is synthesized by C cells in the thyroid gland.
it is also synthesized in the lung and intestinal tract. In birds, fish and amphibians, calcitonin is secreted from the ultimobrachial glands.
Unlike T3/T4, which are tyrosine-derived amine hormones that are bound to carrier proteins in circulation and bind to intracellular receptors in target cells, calcitonin is a protein hormone cleaved from a larger prohormone. It binds to a cell-surface GPCR.
What does calcitonin do?
It plays a role in calcium and phosphorus metabolism.
In particular, calcitonin has the ability to decrease blood calcium levels at least in part by effects on bone & the kidney:
Bone: Calcitonin suppresses resorption of bone by inhibiting the activity of osteoclasts, a cell type that "digests" bone matrix, releasing calcium and phosphorus into blood.
Kidney: Calcium and phosphorus are prevented from being lost in urine by reabsorption in the kidney tubules. Calcitonin inhibits tubular reabsorption of these two ions, leading to increased rates of their loss in urine.
How is calcitonin secretion controlled?
The most prominent factor controlling calcitonin secretion is the extracellular concentration of ionized calcium (Ca++).
Elevated blood calcium levels strongly stimulate calcitonin secretion, and secretion is suppressed when calcium concentration falls below normal.
What is the most important endocrine regulator of calcium and phosphorus concentration in extracellular fluid?
Parathyroid Hormone (PTH)
What is parathyroid hormone? How is it synthesized & secreted?
Like other protein hormones, parathyroid hormone is synthesized as a preprohormone.
After intracellular processing, the mature hormone is packaged within the Golgi into secretory vesicles, then secreted into blood by exocytosis.
Where are PTH's target cells and what does it do? What are its effects?
PTH's major target cells are in bone and kidney.
If Ca++ concentrations in extracellular fluid fall below normal, PTH brings them back within the normal range.
In conjunction with increasing calcium concentration, the concentration of phosphate ion in blood is reduced.
How does PTH regulate Ca++ concentrations in extracellular fluid?
Mobilization of calcium from bone: Stimulates osteoclasts to reabsorb bone mineral, liberating calcium into blood.
Enhancing absorption of calcium from the small intestine: Stimulates production of the active form of vitamin D in the kidney; Vit. D induces synthesis of a calcium-binding protein in intestinal epithelial cells that facilitates efficient absorption of calcium into blood.
Suppression of calcium loss in urine: Puts a brake on excretion of calcium in urine, thus conserving calcium in blood. This effect is mediated by stimulating tubular reabsorption of calcium. Another effect of PTH on the kidney is to stimulate loss of phosphate ions in urine.
NB: phosphate causes reabsorption of Ca++ by bone, so you want to decrease phosphate if you're trying to release Ca++ from bone.
Explain what is happening in this graphic.
PTH helps restore calcium levels in ECF back to normal by stimulating osteoclasts to reabsorb calcium in the bones to release it into the blood; increasing Ca++ absorption from the GIT through Vit. D activation; suppressing Ca++ loss in urine; and to reduce plasma phosporous ion concentration.
How is parathyroid-thyroid hormone (PTH) secretion controlled?
Parathyroid hormone is released in response to low extracellular concentrations of free calcium.
Changes in blood phosphate concentration can be associated with changes in parathyroid hormone secretion, but this appears to be an indirect effect and phosphate per se is not a significant regulator of this hormone.
When calcium concentrations fall below the normal range, there is a steep increase in secretion of parathyroid hormone.
Low levels of the hormone are secreted even when blood calcium levels are high.