ObjectivesFormation of Thyroid hormonesPeripheral ConversionHormonal transportActions of Thyroid hormonesRegulation of Thyroid hormones

ThyroidEssential for:

Development & Regulation of Metabolism

Constant supply is essential for

Normal growth Brain development Maintenance of

metabolism Functional activity

of many organs

Follicles: the Functional Units of the Thyroid Gland

Follicles Are the Sites Where Key Thyroid Elements Function:

• Thyroglobulin (Tg)

• Tyrosine

• Iodine

• Thyroxine (T4)

• Triiodotyrosine (T3)

Iodine Necessary – synthesis – thyroid

hormones.Iodine → iodide & absorbed

SI – stomach & jejunum

90-95% - absorbed iodide taken up by

thyroid

Iodine SourcesAvailable through certain foods (eg,

seafood, bread, dairy products, eggs), iodized salt, or dietary supplements, drinking water as a trace mineral

The recommended minimum intake

is 0.1mg/day

Biosynthesis of T4 and T3

1. Iodide Trapping Dietary iodine (I) ingestionActive transport and uptake of

iodide (I-) by thyroid gland – First step

Dehalogenase enzymeThiocyanates + Perchlorates ≠

block

Biosynthesis of T4 and T3

2. Oxidation

Iodide → Inorganic iodine Thyroperoxidase (TPO) enzymeThioamides ≠ block Sulphonamides / PAS / Carbimazole / PT

Biosynthesis of T4 and T3

3. Binding - Iodination

Binding with tyrosine Formation of iodotyrosines Thyroperoxidase (TPO) enzymeIodine + tyrosine ═ MIT & DIT Thiourea groups ≠ block Carbimazole

Biosynthesis of T4 and T3

4. Coupling

2 molecule – DIT ═ T41 molecule ═ T3Dehalogenase enzyme Thiourea groups ≠ block Carbimazole

Biosynthesis of T4 and T3

5. Proteolysis / Hydrolysis

Hormones + globulin ═ colloid ( Tg )

Stored in thyroid gland Proteolysis of Tg with release of

T4 and T3 into the circulation - required

Plasma iodide enters through the sodium iodide symporter (NIS).

•Thyroglobulin (Tg), a large glycoprotein, is synthesized within the thyroid cell.

•Thyroid peroxidase (TPO) sits on the lumenal membrane. It iodinates specific tyrosines in Tg, creating mono-and di-iodotyrosines.

•The iodotyrosines combine to form T3 and T4 within the Tg protein

TSH

TSH receptor

Iodination ofTyr residues of Tg

COLLOID

TPO

THYROGLOBULIN SYNTHESIS IN THETHYROID FOLLICULAR CELL

In response to TSH, pseudopodia form and endocytose colloid.

•In the cell, colloid droplets fuse with lysosomes and thyroid hormone is cleaved enzymatically from Tg.

•T4 and T3 are released into the circulation.

•TSH stimulates iodide trapping, as well as thyroid hormone synthesis and secretion

Active Transport and I- Uptake by the Thyroid

Dietary iodine reaches the circulation as iodide anion (I-)

The thyroid gland transports I-

to the sites of hormone synthesis

I- accumulation in the thyroid is an active transport process that is stimulated by TSH

NIS is a membrane protein that mediates active iodide uptake by the thyroid

ION TRANSPORT BY THETHYROID FOLLICULAR CELL

I- I- organification

Propylthiouracil (PTU) blocks iodination of thyroglobulin

COLLOID

BLOOD

NaI symporter (NIS)

Thyroid peroxidase (TPO)

ClO4-, SCN-

Proteolysis of Tg With Release ofT4 and T3

T4 and T3 are synthesized and stored within

the Tg moleculeProteolysis is an essential step for releasing

the hormonesTo liberate T4 and T3, Tg is resorbed into the

follicular cells in the form of colloid droplets, which fuse with lysosomes to form phagolysosomes

Tg is then hydrolyzed to T4 and T3, which are then secreted into the circulation

THYROID HORMONE SECRETION BY THETHYROID FOLLICULAR CELL

COLLOID

TSH

TSH receptor

DITMIT I-

T4T3

Production of T4 and T3

T4 is the primary secretory product of the

thyroid gland, which is the only source of T4

The thyroid secretes approximately 70-90 g of T4 per day

T3 is derived from 2 processesThe total daily production rate of T3 is about 15-30 g

About 80% of circulating T3 comes from deiodination of T4 in peripheral tissues

About 20% comes from direct thyroid secretion

Sites of T4 Conversion

The liver is the major extrathyroidal T4 conversion site for production of T3

Some T4 to T3 conversion also occurs

in the kidneys / heart / muscle and other tissues

Peripheral Conversion - processAlthough T4 is the principal hormone from

Thyroid, T3 is the main hormone for regulation of metabolism

T3 is produced by de-iodination of T4, by the enzymes T4 -5’De-iodinase Type I & Type II

Type I T4 -5’De-iodinase is found in the Liver & Kidneys. It is responsible for the production of ⅔ of the total T3 in the body

Type II T4 -5’De-iodinase is responsible for most of the T3 found in the Pituitary, Brain & Brown Fat

T3 either enters the cell or locally produced, which is transported into the nucleus

Type III – which converts T4 → rt3 which is biologically inactive

THYROID HORMONE DEIODINASESThree deiodinases (D1, D2 & D3) catalyze

the generation and/disposal of bioactive thyroid hormone.

D1 & D2 “bioactivate” thyroid hormone by removing a single “outer-ring” iodine atom.

D3 “inactivates” thyroid hormone by removing a single “inner-ring”iodine atom.

All family members contain the novel amino acid selenocysteine (SeC) in their catalytic center.

OO

H

NH 2

II

I

IO

H

O

T4

I

I

OH

OR

3,3’-T2

II

I

OH

O

R

T3

“Step up”

I

I

IO

H

O

R

rT3

“Step down”

THYROID HORMONE METABOLISM

OO

H

NH 2

R =

Thyroxine (T4 )3,5,3’,5’ tetraiodo-L-thyronine

THYROID HORMONES

•Derived entirely from the thyroid gland

•Is a pro-hormone

THYROID HORMONES

*Is the biologically active thyroid hormone*•20% of plasma T3 comes from thyroidal secretion•80% comes from T4 5’-deiodination in peripheral organs

T3 & T4Iodinated aminoacidsWith in thyroid, integral part of TG, in which

they are synthesized & storedIn plasma, circulate as free amino acids in

equilibrium with THBPFree forms:

Penetrate cells-induce & stimulate Oxygen consumption,Body heat,Metabolism of CHO/Fat/ProteinStimulates feedback mechanisms with Pituitary

T4 DispositionNormal disposition of T4

About 41% is converted to T3

38% is converted to reverse T3 (rT3), which is metabolically inactive

21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bile

Normal circulating concentrations T4 4.5-11 g/dL

T3 60-180 ng/dL (~100-fold less than T4)

Carriers for Circulating Thyroid Hormones

More than 99% of circulating T4 and T3 is bound to plasma carrier proteinsThyroxine-binding globulin (TBG), binds about

75%Transthyretin (TTR), also called thyroxine-

binding prealbumin (TBPA), binds about 10%-15%

Albumin binds about 7%High-density lipoproteins (HDL), binds about 3%

Carrier proteins can be affected by physiologic changes, drugs, and disease

Free Hormone ConceptOnly unbound (free) hormone has

metabolic activity and physiologic effects Free hormone is a tiny percentage of total

hormone in plasma (about 0.03% T4; 0.3% T3)

Total hormone concentration Normally is kept proportional to the

concentration of carrier proteins Is kept appropriate to maintain a constant free

hormone level

Thyro-GlobulinIt is a dimeric Glyco-ProteinM.wt: 660000Contains about 120 Tyrosyl units30% of Tyrosyl will undergo iodinationAfter the synthesis of the Hormones

and its intracellular transport, exophytic residues discharge their contents in the Folliclle

TG accumulates in the lumenColloid, which fills the Follicular lumen

is almost exclusively composed of Iodinated TG

Thyroid PhysiologyHormone Binding proteins are the

principal factors influenzing total hormone concentration, which is normally maintained at a level appropriate for the concentration of carrier proteins, to maintain a constant free hormone level

Various factors may cause changes in the concentrations of TBG & changes in TBG level may alter the total hormone concentration, irrespective of the metabolic status or free hormone level

TBG estimation is a more accurate indicator of the Thyroid Hormone dependant metabolic state

Changes in TBG Concentration Determine Binding and Influence T4 and T3 Levels

Increased TBG Total serum T4 and T3 levels increase

Free T4 (FT4), and free T3 (FT3)

concentrations remain unchangedDecreased TBG

Total serum T4 and T3 levels decrease

FT4 and FT3 levels remain unchanged

Drugs and Conditions that Increase Serum T4 and T3 Levels by Increasing TBG

Drugs that increase TBGOral contraceptives and

other sources of estrogen

MethadoneClofibrate5-FluorouracilHeroinTamoxifen

Conditions that increase TBGPregnancyInfectious/chronic active

hepatitisHIV infectionBiliary cirrhosisAcute intermittent

porphyriaGenetic factors

Drugs and Conditions that Decrease Serum T4 and T3 by Decreasing TBG Levels or Binding of Hormone to TBG

Drugs that decrease serum T4 and T3

GlucocorticoidsAndrogensL-AsparaginaseSalicylatesMefenamic acidAntiseizure medications,

eg, phenytoin, carbama-zepine

Furosemide

Conditions that decrease serum T4 and T3

Genetic factorsAcute and chronic illness

ACTIONS BMR due to O2, Heat, Temp & Heat

intolerance. Optimum level is necessary for balanced growth & maturation

Stimulates Lipogenesis & Lipolysis, Lowers serum Cholesterol by enhancing

Excretion thro’ FaecesConversion to Bile Acids

Catecholamine effect Brain / retina / lungs / spleen & testes

are unaffected by thyroid hormones

ACTIONS

Site Actions Outcomings

Brain Effects on activity & mood

Hyperactivity & Mood changes

Pituitary ↓TSH release ↓TSH level

Heart Rate; changes in proteins

Tachycardia, Arrhythmia, Failure

Liver LDL Receptors, Cholesterol synthesis, Cholesterol excretion & conversion to Bile acids

↓Cholesterol

Muscle Changes in Protein Myopathy

Bone Osteoblastic & 2º Osteoclastic activity

Osteoporosis

ACTION OF THYROID HORMONES Parameter/ organ system

Action

Developmental Essential for normal neural and skeletal development

Calorigenesis Oxygen consumption

Basal Metabolic Rate

Intermediary Metabolism Protein Synthesis

Synthesis/ Degradation of cholesterol

Lipolysis

Glycogenolysis

Cardiovascular Heart rate and myocardial contractility

Sympathetic Nervous System Sensitivity to catecholamines

Catecholamine receptors in cardiac muscle

Amplification of catecholamine effects at postreceptor site

Endocrine Steroid hormone release

Hematopoietic Erythropoiesis

2,3 DPG production

Maintain hypoxic and hypercapnic drives

Musculo skeletal Bone turnover

Urinary hydroxy proline excretion

Increased rate of muscle relaxation

REGULATION OF THYROID HORMONE SECRETION

Classic feed back loop that involves pituitary and hypothalamus

Intrinsic thyroid autoregulatory process

FEEDBACK REGULATIONTHE HYPOTHALAMIC-PITUITARY-THYROID AXIS

Hormones derived from the pituitary that regulate the synthesis and/or secretion of other hormones are known as trophic hormones.

Key players for the thyroid include:

TRH - Thyrophin Releasing Hormone

TSH - Thyroid Stimulating Hormone

T4/T3 - Thyroid hormones

TSHTSH (Thyroid Stimulating Hormone or Thyrotrophin)

Normal Level = 0.5 to 4.5 μUnits/MLNormal daily production & degradation is 40 to 150

μUnitsCircardian rhythm-raise 2 hours after sleep, peak

from 2 to 4 AMInitial effect of TSH is in Iodide transportGlycoproteinLike LH / FSH / HCG, TSH also has α & β subunitsα subunits of all the said hormones are identicalβ subunits of each are responsible for biological &

immunological specificitiesTSH is required for normal production & secretion of

T3 & T4

Mostly influezed by tonic stimulation by TRH and feedback inhibition by T3 & T4

T3 regulates the transcription of the GENES for both the subunits of TSH

Effects of TSH Iodine binding to TG coupling of MIT & DITActivation of Exocytosis Transfer of proteins into the follicles Secretion of T3 & T4

Major factor in the growth of thyroidIodine↓& Drugs blocking the binding of Iodine to TG

cause TSH & diffuse enlargement of ThyroidWhen TSH is low or absent (Hypophysectomy, inactive

TSH) the Thyroid gland ↓ in sizeProlonged TSH administration will the ↑ weight of

the Thyroid GlandChronic TSH leads to: proliferation of capillaries &

fibroblasts rather than Follicles

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.

TSH REGULATION OF THYROID FUNCTION

TRHTripeptide- (pyroglutamyl-histidyl-proline

amide)First Hypothalamic hormone isolatedProduced at Supra-Optic & Para-Ventricular

NucleiPasses thro’ their axons to median eminence

and storedReach the Pituitary via hypophyseal portal

vessels & binds to receptor sitesIncreases the synthesis & secretion of TSHIncreases the synthesis & secretion of

ProlactinTonic stimulation of TSH producing cells

Auto-RegulationIn Humans, the Wolff-Chaikoff’s

block(acute block of Iodide binding) is induced by elevated plasma iodide level to ≥ 25 μGm%

Aftert the critical level of iodide, there is a progressive inhibition of iodide binding to tyrosyl residues in TG

Iodide adminisration leads to:↓Iodine containing compounds from thyroid↓ serum T3 & T4↓in Hypervascularity Seen in ↓in Hyperplasia HyperthyroidismMay induce HyperthyroidismMay cause Nodularity in Goitres

WOLFF CHAIKOFF’S EFFECTTSH independent manner by availability

& glandular content of iodideIodide depletion enhances iodide

transport & stimulate hormone synthesisIn the presence of excess iodide, iodide

causes suppression of both transport & hormone synthesis

Hypothalamic-Pituitary-Thyroid AxisNegative Feedback Mechanism

CALCITONINSecreted By: Parafollicular cells of Thyroid

glandRegulation: Negative feedback mechanism

High calcium levels in blood stimulated

secretion & vice versaAction: Decrease blood level of ionic Ca2+

& PO4 by inhibiting bone reabsorption by osteoclasts and uptake of Ca & PO4 in bone matrix.

ANTI THYROID COMPOUNDS

PROCESS AFFECTED

EXAMPLES OF INHIBITORS

Active Transport of Iodide Complex anions: Perchlorate, fluoborate, pertechnetate, thiocyanate

Iodination of thyroglobulin Thionamides: Propylthiouracil, methimazole, carbimazole.

Thiocyanate, Aniline derivatives, Sulphonamides, Iodide.

Coupling reaction Thionamides, Sulphonamides,

Hormone release Lithium salts, Iodide

Iodotyrosine deiodination Nitrotyrosines

Peripheral iodothyronine deiodination

Oral cholecystographic agents

Thiouracil derivatives, Amiodarone

Hormone excretion/ inactivation

Inducers of Hepatic drug metabolizing enzymes: Phenobarbital, rifampin, carbamazepine, phenytoin

Hormone Action Thyroxine analogs, Amiodarone, Phenytoin,

Binding in gut: Cholestyramine.