Thyroid Gland• The largest endocrine

gland, located in the anterior neck, consists of two lateral lobes connected by a median tissue mass called the isthmus

• Composed of follicles that produce the glycoprotein thyroglobulin

Figure 17.8a

Thyroid Gland• Colloid

(thyroglobulin + iodine) fills the lumen of the follicles and is the precursor of thyroid hormone

• Other endocrine cells, the parafollicular cells, produce the hormone calcitonin

Figure 17.8a

Thyroid Hormone (TH)

• Thyroid hormone – the body’s major metabolic hormone

• Consists of two closely-related iodine-containing compounds– T4 – thyroxine; has two tyrosine molecules plus four

bound iodine atoms

– T3 – triiodothyronine; has two tyrosines with three bound iodine atoms

Thyroid hormones

• Tetraiodothyronine or thyroxine (T4) • Triiodothyronine (T3)• (T4) is converted to (T3) by target cells• T3 and T4 regulate the body’s metabolic

rate and are necessary for normal growth and development

• Calcitonin: Regulates calcium levels in the blood

Figure 5.3.3 Effect of TSH on the thyroid gland. A. Hypothyroid follicles. B. Euthyroid (normal) follicles. C. Stimulated hyperplastic follicles.

SYNTHESIS AND TRANSPORT OF THYROID HORMONES

• Thyroid hormone synthesis is unique because it takes place OUTSIDE the cell in the colloid

Synthesis of Thyroid Hormone

• Thyroglobulin is synthesized and discharged into the lumen

• Iodides (I–) are actively taken into the cell, oxidized to iodine (I2), and released into the lumen

• Iodine attaches to tyrosine, mediated by peroxidase enzymes, forming T1 (monoiodotyrosine, or MIT), and T2 (diiodotyrosine, or DIT)

• Iodinated tyrosines link together to form T3 and T4

• Colloid is then endocytosed and combined with a lysosome, where T3 and T4 are cleaved and diffuse into the bloodstream

Synthesis of Thyroid Hormone

Pathway of thyroid hormone synthesis.

Transport of thyroid hormones

T3/T4

thyroid

Bound>99%

freeblood

target tissues

response inactivation

Transport and Regulation of TH

• T4 and T3 bind to thyroxine-binding globulins (TBGs) produced by the liver

• Both bind to target receptors, but T3 is ten times more active than T4

• Peripheral tissues convert T4 to T3

• Mechanisms of activity are similar to steroids• Regulation is by negative feedback • Hypothalamic thyrotropin-releasing hormone

(TRH) can overcome the negative feedback

TSH REGULATION OF THYROID FUNCTION

• TSH binds to specific cell surface receptors that stimulate adenylate cyclase to produce cAMP.

• TSH increases metabolic activity that is required to synthesize Thyroglobulin (Tg) and generate peroxide.

• TSH stimulates both I- uptake and iodination of tyrosine resides on Tg.

Activation of T4 in Target Tissues

• While the major secretory product of the thyroid gland is T4, the most active form of thyroid hormone is T3.

• This "problem" is solved in the target issues by the enzyme 5'-iodinase, which converts T4 to T3 by removing one atom of iodine. The target tissues also convert a portion of the T4 to reverse T3 (rT3), which is inactive (??).

• Essentially, T4 serves as a precursor for T3, and the relative amounts of T4 converted to T3 and rT3 determine how much active hormone is produced in the target tissue

Mechanism of thyroid hormone action via its nuclear receptor. Thyroid hormone diffuses and/or is transported across plasma and nuclear membranes to bind to its receptor. The thyroid hormone receptor (striped) is localized almost exclusively in the nucleus where it associated with DNA as a homodimer or as a heterodimer with RXR (stippled). The hormone-activated receptor binds to thyroid hormone response elements (TRE’s) to alter rates of gene transcription and consequently levels of mRNA.

1. Mediates normal growth and development >TH is necessary for normal overall body growth, and the normal growth and development of essentially all organs.So TH mediates normal anabolic processes associated with growth and development. It is essential for the development of CNS.2. Maintains basal metabolic rate and

calorigenesis >high levels of hormone increase ATP utilization,

glycolysis and oxidative phosphorylation, and oxygen consumption.

>increased fuel consumption associated with these processes is associated with overall catabolism.

Thyroid hormone has two major physiological functions:

Thyroid Hormone Effects on Fuels Hormone effect on protein metabolism

>positive influence of TH on normal body growth is derived largely from increased protein synthesis >high TH stimulates protein degradation Hormone effect on carbohydrate metabolism >low TH potentiates effects of insulin glucose uptake and utilization (e.g. glycogen synthesis) >high doses stimulate glycogenolysis to support theincreased BMR >synergizes with catacholamines in stimulating liver glycogenolysis and gluconeogenesis Hormone effect on lipid metabolism >enhance adpiocyte lipolysis to provide fatty acid fuels >decreases the serum triglycerides and cholesterol concentrations (high levels).

Other Actions

heart rate and contraction strength. – GI – increased motility and absorption

Calcitonin

• A peptide hormone produced by the parafollicular, or C, cells

• Lowers blood calcium levels in children• Antagonist to parathyroid hormone (PTH)• Calcitonin targets the skeleton, where it:

– Inhibits osteoclast activity and thus bone resorption and release of calcium from the bone matrix

– Stimulates calcium uptake and incorporation into the bone matrix

• Regulated by a humoral (calcium ion concentration in the blood) negative feedback mechanism

Endemic Goiter

Hyperthyroidism

• Also called exophthalmic goiter and Grave’s disease

• Probably an autoimmune disease

• Goiter, weight loss, irritability

• Treat with carbimazole – inhibits incorporation of iodine into thyroglobulin

Hypothyroidism

• Cretinism– due to untreated congenital deficiency

of thyroid hormones due to maternal nutritional deficiency of iodine.

– Infancy and early childhood, retards growth and development

• Myxedema – Insufficient iodine in the diet .– Subcutaneous swelling, goiter, weakness.

Treat with oral T4 (100 – 200 g/day)

• Regulation of calcium

Regulation of calcium

• Calcium is important to bone structure, to neuromuscular function, and to intracellular events

• Total Ca concentration in blood is normally kept at 10mg/dL

• Total Ca concentration in blood is normally kept at 10mg/dL

• 40% bound to plasma proteins

• 10% complexed to anions (phosphate, citrate, sulfate)

• 50% is free, ionized – only this fraction is biologically active

Calcium homeostasis

• Calcium homeostasis involves THREE systems (bone, kidney and GI tract) and THREE hormones (parathyroid hormone, calcitonin and vitamin D)

• Sources of calcium are dietary (absorbed in the gut) and bone (a dynamically labile structure).

• Bone remodeling is constant – bone is formed and resorbed at the same rate

Calcium homeostasis

Calcium and phosphate

• Calcium and phosphate homeostasis are linked• Calcium complexes with phosphate; the more phosphate

present, the more calcium binds to it and reduces the free, ionized calcium fraction.

• The less phosphate present, the less calcium binds to it and this increases the free, ionized calcium fraction.

• Therefore, decreasing phosphate levels in blood (i.e. by excreting it) helps to increase plasma Ca levels

Bone

• Osteoclast : a large multinuceated cell which asborbs and removes bone tissue .

• Osteoblast: a type of cell involved in bone remodelling that helps to build bone .

• Bone resorption: a type of bone loss (resorption) due to osteoclastic activity.

PTH secretion is regulated by the plasma Ca concentration

• When the total Ca concentration is in the normal range (i.e., 10 mg/dL) or higher, PTH is secreted at a low (basal) level.

• However, when the plasma Ca^ concentration decreases to less than 10 mg/dL, PTH secretion is stimulated, reaching maximal rates when the Ca concentration is 7.5 mg/dL.

• The ionized Ca concentration regulates secretion by the parathyroid glands. The response of the parathyroid glands to a decrease in ionized Ca^ concentration is remarkably prompt, occurring within seconds. Furthermore, the faster the ionized Ca^ falls, the greater the PTH secretory response.

Actions of PTH

• The actions on bone and kidney are direct and are mediated by cAMP; the action on intestine is indirect, via activation of vitamin D.

Action of PTH on bone• In bone, PTH causes an increase in bone resorption. When PTH levels are

chronically elevated, as in hyperparathyroidism, the rate of bone resorption is persistently elevated, which increases the serum Ca concentration.

• The overall effect of PTH on bone is to promote bone resorption, delivering both Ca and phosphate to ECF. Hydroxyproline released from bone matrix is excreted in urine.

• Alone, the effects of PTH on bone cannot account for its overall action to increase the plasma-ionized Ca^ concentration. The phosphate released from bone will complex with Ca^ in ECF and limit the rise in ionized Ca^ concentration. Thus, an additional mechanism must coordinate with the PTH effect on bone to cause the plasma ionized Ca^ concentration to increase. (That additional mechanism is the phosphaturic action of PTH.)

Action of PTH on kidney

• (1) PTH inhibits phosphate reabsorption by inhibiting Na+-phosphate co-transport in the proximal convoluted tubule. As a result of this action, PTH causes phosphaturia, an increased excretion of phosphate in urine.

• (2) PTH stimulates Ca reabsorption. This second renal action of PTH is on the distal convoluted tubule and complements the increase in plasma Ca concentration that resulted from the combination of bone resorption and phosphaturia.

Action of PTH on small intestine

• PTH indirectly stimulates intestinal Ca^ absorption via activation of vitamin D.

• PTH stimulates renal l alpha -hydroxylase, the enzyme that converts 25-hydroxycholecalciferol to the active form, 1,25-hydroxycholecalciferol.

• 1,25-hydroxycholecalciferol promotes Ca uptake by the gut

Control of calcium

Calcitonin

• It is synthesized and secreted by the parafollicular or C ("C" for calcitonin) cells of the thyroid gland.

• The major stimulus for calcitonin secretion is increased plasma Ca concentration

• The major action of calcitonin is to inhibit osteoclastic bone resorption which decreases the plasma Ca- concentration .

• Decreases the reabsorption of phosphate and calcium from the kidney.• Net effect will be to reduce both plasma calcium and phosphate

concentration .• In contrast to PTH, calcitonin does not participate in the minute-to-minute

regulation of the plasma Ca concentration. In fact, a physiologic role for calcitonin in is uncertain because neither thyroidectomy (with decreased calcitonin) nor thyroid tumors (with increased calcitonin levels) causes a derangement of Ca- metabolism, as would be expected if calcitonin had important regulatory functions.

Vitamin D

• Vitamin D is the second major regulatory hormone for Ca and phosphate metabolism.

• The roles of PTH and vitamin D can be distinguished as follows. The role of PTH is to maintain the plasma Ca concentration, and its actions are coordinated to increase the ionized Ca concentration toward normal.

• The primary role of vitamin D is to promote mineralization of new bone, and its actions are coordinated to increase both Ca and phosphate concentrations in plasma so that these elements can be deposited in new bone mineral.

Synthesis of Vitamin D

• Vitamin D has formal "hormone" status . • There are two sources of cholecalciferol in the body: It is either ingested in the diet or

synthesized in the skin from 7-dehydrocholesterol in the presence of ultraviolet light. • Cholecalciferol itself is physiologically inactive. It is hydroxylated in the liver to form

25-hydroxycholecalciferol, which also is inactive. 25-hydroxycholecalciferol is bound to a globulin in plasma and is the principal circulating form of vitamin D.

• In the kidney, 25-hydroxycholecalciferol undergoes one of two routes of hydroxylation:

• It can be hydroxylated at the C1 position to produce 1,25-dihydroxycholecalciferol, which is the physiologically active form, or it can be hydroxylated at C24 to pro-duce 24,25-dihydroxycholecalciferol, which is inactive.

• C1 hydroxylation is catalyzed by the enzyme 1 alpha-hydroxylase, which is up-regulated by several factors, including the plasma Ca2- concentration and PTH.

• Increased 1 alpha-hydroxylase is induced by decreased plasma Ca, increased PTH and decreased plasma phosphate.

Actions of Vitamin D

• The overall role of vitamin D (1,25 dihydroxycholecalciferol) is to increase the plasma concentrations of both Ca and phosphate and to promote mineralization of new bone.

Intestine

• The major actions of 1,25-dihydroxycholecalciferol are on the intestine.

• 1,25-dihydroxycholecalciferol increases both Ca and phosphate absorption.

Kidney

• The actions of 1,25-dihydroxycholecalciferol on the kidney are parallel to its actions on the intestine — it stimulates both Ca and phosphate reabsorption.

• In the kidney, the actions of 1,25-dihydroxycholecalciferol differs from PTH.

• PTH stimulates Ca reabsorption and inhibits phosphate reabsorption, whereas 1,25 dihydroxycholecalciferol stimulates the reabsorption of both ions.

Bone

• 1,25-dihydroxycholecalciferol acts synergistically with PTH to stimulate osteoclast activity and bone resorption.

Parathyroid Glands: Disorders• Hyperparathyroidism - rare; caused by parathyroid gland tumor

– results in hypercalcemia (excess Ca2+ levels in blood) • effects include:

– depression of nervous system (because of effect on sodium permeability; increased Ca2+ decreases permeability), abnormal reflexes, skeletal muscle weakness

– nausea, vomiting, – kidney stones (due to increased Ca2+ in urine)– calcium deposits in soft tissues– bones become soft

Parathyroid Glands: Disorders

• Hypoparathyroidism - trauma to or removal of parathyroid gland

– results in hypocalcemia (low blood Ca2+)

• effects include:

– Neurons become too excitable muscle tetany spasms/cramps respiratory paralysis death.

– Latent tetany - Trousseau’s hand (Obstetrician hand)

– - Chvostek’s sign

– Tetany should be carefully distinguished from Tetanus (Clostridium tetani)