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Thyroid Hormones

Unique to Thyroid Hormones:

Thyroid hormones are iodinated amino acid derivatives.

Iodine (I-): Thyroid hormones, precursors and metabolites are the only iodine-containing compounds in the body.

Long-term Storage: Thyroid stores sufficient hormone precursor for several weeks of normal secretion, which buffers against fluctuation in available iodine supply

Thyroid Hormone Function

Regulates Basal Metabolic Rate Increases body temperature Increases O2 consumption Stimulates protein, carbohydrate & fat metabolism transcription of gene encoding Na/K ATPase, production

of mitochondria

Required for proper neuronal development

In amphibians, it is the signal for metamorphosis

Thyroid glandstructure & function

Normal gland weights ~20 g Derived from embryonic endoderm 2 lobes joined by a thin isthmus

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Regulate DNA transcription O2 and ATP consumption temperature basal metabolic rate

TSH (=Thyrotropin)

TRH

T3T4

Somatostatin

+

Target Cells:

Regulation of Thyroid Hormone

Slow Onset of Thyroid Hormone Action

T4 is the precursor for the active thyroid hormone T3

Slow action is consistent with transcriptional regulation

Thyroid Tissue

Composed of sacs called follicles

Follicular cells are epithelial cells that synthesize and secrete thyroid hormones thyroxine (T4) and triiodothyronine (T3)

Hormone precursors, coupled to the protein thyroglobulin, are stored in the jelly-like interior of the follicle, a substance called the colloid

Thyroid hormone precursors stored in colloid

Inactive Follicles Active Follicles

colloid

colloid

Upon stimulation by TSH, the follicular epithelial cells expand and actively synthesize thyroid hormones.

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In the colloid, the thyroid stores sufficient T3 and T4 precurors for several weeks of thyroid hormone usage

Long-term storage capacity protects the body from deficiencies that might occur due to fluctuations in available iodine.

Antithyroid drugs, which target the synthesis of thyroid hormones, are slow to show physiological effects because of large storage reserve of hormone precursor.

Thyroid has a large reserve of hormonePrecursors

(attached to thyroglobulin) Thyroid hormones

MIT DIT T4 T3

Thyroid HormonesIodinated derivatives of Tyrosine

Thyroglobulin

660 kDa glycoprotein (2 identical subunits of 330 kDa)

~115 tyrosines; ~20 are iodinated

MIT, DIT, T3 and T4 residues are attached to thyroglobulin inside the follicles (for storage)

Hormones are released after thyroglobulin is endocytosed and proteolyzed

Thyroid Follicular Epithelial Cell Follicle Lumen

Iodide uptake

Travel across epithelial cell

Iodination of tyrosines on thyroglobulin

Coupling

Storage in colloid

Reuptake

Proteolysis & release

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Synthesis of Thyroid Hormones

Thyroid follicular epithelial cell

Na+/I-co-transporter

T3 T4Na+ & I-

Iodide uptake

Iodide supplied in diet Iodized salt, fish Deficiency is endemic in

some areas

Iodide is concentrated into the epithelial cell via the Na+/I- cotransporter on basolateral membrane (Iodide Trap)

Uptake inhibited by percholate (ClO4-) and thiocyanide (SCN-)

Na+ I-

Na+ I-

Na+/I- Cotransporter

Basolateral membrane

Apical membrane

Follicle Lumen

l- CI-I-/Cl- Cotransporter

l- CI-

Oxidation of Iodide & Iodination of Thyroglobulin

Organification of iodide

Catalyzed by Thyroid Peroxidaseat the apical membrane of the epithelial cell

Requires H2O2 (hydrogen peroxide) as an oxidizing agent

Thyroid peroxidase oxidizes I-and iodinates tyrosine residues of thyroglobulin

MIT and DIT are formed, attached to thyroglobulin

MIT

Coupling of MIT and DIT

Coupling is also catalyzed by Thyroid Peroxidase at the apical membrane of the epithelial cell

While still attached to thyroglobulin, two DITs are coupled to form T4

or MIT & DIT are coupled to form T3

T3 and T4, still attached to thyroglobulin, are stored in the colloid

THYROGLOBULIN

MIT residue

DIT residue

DITresidue

T4residue

Tyrosyl residue

I- + H2O2

Thyroid Peroxidase

I

II

II

I

I

II

Thyroid Peroxidase

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Na+ & I-

Na+/I- co-transporter

Endocytosis & Proteolysis

Thyroglobulin is endocytosed from the colloid into the follicle cell

Endocytic vesicles fuse with lysozomes, and proteolytically degrade thyroglobulin

Free T4 and T3 are released into the plasma

MIT & DIT are deiodinated. Amino acids and I- are reutilized

Thyroid Peroxidase

THYROGLOBULIN

MIT residue

DIT residue

DITresidue

T4residue

Tyrosyl residueH2O2

Thyroid Peroxidase

I

II

II

I

I

II

Proteolysis

Thyroxine (T4)

I

II

I

I

I

I

I-

Iodine Cycle

MIT

DIT

Deiodinases

Travel to target tissues

Most of the hormone synthesized and released by thyroid is T4 (~20x more than T3)

T4 and T3 carried in plasma by thyroxine binding globulin and albumin

Deiodinases convert T4 T3 in target tissues

T3 is the active hormone, binds thyroid hormone receptor and regulates transcription

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Agents for treatment of hyperthyroid states

Thionamides (thioureylenes): Anti-thyroid drugs containing thiocarbamide group

Mechanism of action: Inhibit thyroid peroxidase

R

CN S

NH

NH3CH2CH2C S

O

H

Propylthiouracil

N

NCH3

S

Methimazole

N

NCH3

Carbimazole (UK)COOC2H5

S

Radioactive iodine (131I): complete or partial destruction of thyroid

High [iodide]: acute inhibition of iodide trap & hormone release

Causes:- Hashimotos disease (autoimmune)- Iodide deficiency- consumption of anti-thyroid compounds (cassava, brassica

(cauliflower, broccoli))Agents for treatment of hypothyroid states:

- Synthetic T4 (&/or T3)- Dietary iodide (to correct iodide deficiency)

stimulation of the thyroid causes growth & enlargement of thyroid gland (goiter)

Hyperthyroidism: Graves disease An antibody mimics TSH &

stimulates thyroid T3 & T4 The antibody is not subject to

feedback inhibition, so continues to stimulate thyroid & causes goiter

Hypothyroidism: Iodide deficiency Low I- causes T3 & T4, Lack of feedback inhibition

causes TSH TSH stimulates thyroid,

causes goiter

Goiter:

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Summary: Thyroid hormones T3 & T4 stimulate basal metabolic rate, O2

consumption, temperature, also needed for normal neuronal development

Iodide trap: Na+/I- co-transporter takes up iodide into follicle cells

Thyroglobulin is synthesized in follicle cells, exported to colloid. Tyrosines on thyroglobulin are iodinated (to MIT & DIT) and coupled (to T3 and T4), stored in colloid, later endocytosed into follicle cell & proteolyzed

Thyroid hormone precursors are stored in colloid, so drugs that hormone synthesis only slowly decrease T3 & T4

Thyroid hormone excess: warm, moist skin, restlessness, hyperactivity, rapid pulse, appetite, GI motility, diarrhea, weight loss,

Graves disease (autoimmune; antibody mimics TSH) Thyroid adenoma Chronic ingestion of T3/T4 to lose weight

Thyroid hormone deficiency: dry, cool, puffy skin, myxedema, hair thinning, appetite, weight, lethargy, weakness, sometimes goiter

Hashimotos disease (autoimmune destruction of thyroid) Low dietary iodine Ingestion of anti-thyroid compounds

Anti-thyroid drugs: thionamides (thiourylenes), 131I, excess I- Anti-thyroid drugs target hormone synthesis & release, not the thyroid hormone

receptor