THYROID HORMONE Dr. Ayisha Qureshi MBBS, Mphil.. THE THYROID GLAND - The thyroid gland is the largest of the endocrine glands & is located at the base.

THYROID HORMONE

Dr. Ayisha Qureshi MBBS, Mphil.

THE THYROID GLAND

- The thyroid gland is the largest of the endocrine glands & is located at the base of the neck immediately below the Larynx on each side of & anterior to the Trachea.- The thyroid gland consists of two lobes of endocrine tissue (lying on either side of trachea) joined in the middle by a narrow portion of the gland called, the Isthmus.- In a normal adult male, it weighs 15-20 g but is capable of enormous growth, sometimes achieving a weight of several hundred grams.

LOCATION OF THE THYROID GLAND

THYROID GLAND

The thyroid gland consists of 2 types of cells:

1. Follicular cells: These are more abundant, and the major secretory cells. They secrete Thyroid hormone.

2. Parafollicular cells or C-cells: These are fewer in number & interspersed. They secrete calcitonin.

THYROID GLAND AS A FUNCTIONAL UNIT:

- The functional unit of the Thyroid Gland is a Follicle which is composed of cuboidal epithelial (follicular) cells arranged around hollow vesicles of various shapes (size: 0.02-0.3 mm in diameter). Each follicle is a closed structure filled with a glycoprotein colloid called Thyroglobulin.There are about 3 million follicles in an adult human thyroid gland.

THE THYROID HORMONE

THYROID HORMONES

The Thyroid gland secretes 2 major hormones:

1.Thyroxine or T4 having 4 atoms of Iodine &

2. Triiodothyronine or T3 having 3 atoms of Iodine

THYROID HORMONES

• About 93% of secreted hormone is T4,

while 7% is T3. However, almost all of the T4 is ultimately converted into T3.

• The functions of the 2 hormones are the SAME but they differ in rapidity & intensity of action.

• T3 is about 4 times as potent as T4, but is present in blood in much smaller quantities & for a much shorter time!

THYROID HORMONE BIOSYNTHESIS:

1. INGESTION OF IODINE

•Iodine in large amounts is required for thyroid hormone synthesis. This is acquired through diet & THERE IS NO OTHER USE OF THIS ELEMENT IN THE BODY!•50 mg of Iodine is required each year OR 1 mg/week.•To prevent deficiency, common table salt is iodized with about 1 part sodium iodide to every 100,000 parts sodium chloride.•Ingested iodide is absorbed from the GIT.

2. IODIDE TRAPPING• This is done with the help of an electrogenic “Iodide pump”

located in the thyroid cell membrane.

The Iodide pump is a Sodium Iodide Symporter (NIS) & is present in the follicular cell basolateral membrane.

↓This pump transfers 2 Na ions with each Iodide ion.

(Under normal circumstances, iodine is 25-50 times more concentrated in the cytosol of Thyroid follicular cells than in the

blood plasma. Iodine moves into the thyroid cells against a steep concentration gradient!)

↓Na/ K pump then extrudes 3 Na ions in exchange for 2 K ions to

maintain the electrochemical gradient for Na.NOTE: Other ions as percholate & thiocyanate compete for binding

sites on the symporter and can block the uptake of iodide.

3. THYROGLOBULIN SYNTHESIS

• It is the matrix for thyroid hormone synthesis & is the form in which the hormone is stored in the gland.

• It is a large glycoprotein with a m.w of 660,000 Da. And is synthesized in the Thyroid follicular cells.

• Tyrosine becomes incorporated into Thyroglobulin while it is being formed.

• Once produced, the tyrosine-containing thyroglobulin is exported from the follicular cells into the colloid by exocytosis.

• For hormone synthesis to take place, Iodine must also be delivered to the follicular lumen.

• The Iodine that has entered into the follicular cell from the blood stream diffuses across the follicular cell & exits it to enter the colloid of the Follicle. This is done with the help of a transporter protein called Pendrin.

4. OXIDATION OF THE IODIDE ION

• Iodide ion is oxidized to form either nascent iodine (I°) or I3− .

• This oxidation is catalyzed by the enzyme thyroid peroxidase and its accompanying hydrogen peroxidase.

• These enzymes are located in the apical membrane of the cell or attached to it.

5. ORGANIFICATION

• Addition of iodine molecules to tyrosine residues in the thyroglobulin is called Organification of thyroglobulin.

• This reaction is catalyzed by the enzyme Iodinase.

• Tyrosine + 1 Iodine = Monoiodotyrosine

(MIT)• Tyrosine + 2 Iodines = Di-iodotyrosine

(DIT)

6. COUPLING• It is the combination or coupling of 2 molecules of

iodinated tyrosine molecules to form thyroid hormone:

- DIT + DIT = Thyroxine (T4)- DIT + MIT = Tri-iodothyronine (T3)

COUPLING DOES NOT OCCUR B/W 2 MIT MOLECULES!

This mature hormone is formed while being a part of Thyroglobulin molecule, & remains a part of this large storage molecule till the stimulus for secretion arrives.

7. STORAGE

In normal individuals, approximately 30% of the mass of thyroid gland is thyroglobulin,

which is about 2-3 months supply of hormone.

8. SECRETION• Before their release, T4 & T3 are still bound with

the thyroglobulin molecule.• For secretion to occur, thyroglobulin must be

brought back into follicular cells by a process of endocytosis.

• Pseudopodia reach out form the follicular cells to engulf chunks of thyroglobulin, which are taken up in endocytic vesicles- this is also called “BITING OFF”.

• The endocytic vesicles fuse with the lysosomes.• Lysosomes release enzymes that split off the

biologically active hormones: T3 & T4, as well as the inactive iodotyrosines, MIT & DIT.

• The thyroid hormones being very lipophilic, pass freely through the outer membrane of the follicular cells & into the blood!

9. FATE OF MIT & DIT

The MIT & DIT are of no endocrine value.

↓

The follicular cells contain an enzyme

(deiodinase) that will swiftly remove the Iodine from MIT & DIT, allowing the freed

Iodine to be recycled for synthesis of more hormone.

PASSAGE THROUGH BLOOD

This highly lipophilic thyroid hormone molecule binds with several plasma proteins.

• The binding proteins are:1.Thyroxine binding globulin (TBG)2.Transthyretin (TTR)3.Albumin The majority (70%) bind to TBG, a plasma protein

that selectively binds only Thyroid hormone.Less than 0.1% of T4 and less than 1% of T3 is in

the unbound (free) form.

MECHANISM OF ACTION

M.O.A

• Thyroid hormone receptors are members of a large family of nuclear hormone receptors

Location: Thyroid hormone receptors are either attached to the DNA genetic strand or located in close proximity to them.

M.O.AThe receptor usually forms a heterodimer with retinoid X receptor (RXR) at

specific thyroid hormone receptor elements (THR) on the DNA. ↓

The thyroid hormone receptor binds to the response elements in the absence of the hormone.

↓ When the thyroid hormone becomes available, the receptor becomes activated

& initiates the transcription process. ↓

Large number of mRNA are formed↓

Within minutes or hours: RNA translation on the cytoplasmic ribosomes takes place ↓

Hundreds of new intracellular proteins are formed↓

Most of the actions are exerted through these proteins

ACTIONS OF THYROID HORMONE

1. GENES

• Thyroid hormone increases the transcription of large number of genes.

↓Thus, in all cells of the body, there is increased production

of:1. Protein enzymes

2. Structural proteins3. Transport proteins4. Other substances

↓Net result: there is generalized increase in functional

activity throughout the body!

2. GROWTH & MATURATION

• It stimulates growth of the skeletal system by affecting bone maturation.

• It stimulates normal synthesis & secretion of the GH.• It is essential for the normal growth of the children.• It stimulates & promotes normal growth & development

of the brain during the perinatal period (nerve myelination & brain vascularity).

• Its deficiency during postnatal period can lead to irreversible mental & physical retardation in infants & a small sized brain.

• In the adult, it has excitatory effects on the nervous system.

3. AUTONOMIC NERVOUS SYSTEM

• Interactions b/w thyroid hormone & ANS are important throughout life.

• ↑ secretion of thyroid hormone exaggerates many responses of the sympathetic neurons.

• It ↑ the number of receptors for epinephrine & NE (beta- adrenergic receptors) in the myocardium & other tissues.

• Thus, many symptoms of hyperthyroidism resemble sympathetic nervous system.

4. Carbohydrate metabolism

It stimulates all aspects of carbohydrate metabolism:1. ↑ hepatic glucose production2.↑ gluconeogenesis3.↑ glycogenolysis4.The plasma glucose levels remain normal provided the pancreas respond by ↑ Insulin secretion.

5. LIPIDS• It stimulates lipid mobilization from fat stores

of the body.• ↑ Lipogenesis• ↑ Lipolysis (to provide glycerol for

gluconeogenesis)• Increased levels of TH shift the balance in

favor of lipolysis, mobilizing fat stores. • ↑ secretion of cholesterol into bile, thus

decreasing the cholesterol levels in the blood.

6. PROTEIN METABOLISM

• ↑ Proteolysis (to provide the amino acids for gluconeogenesis)

• ↑ Protein synthesis

Usually the Proteolysis outweighs the protein synthesis and there is a net increase in Protein catbolism.

7. BASAL METABOLIC RATE

•BMR is highly sensitive to thyroid status.

HYPOthyroidism decreases BMR & HYPERthyroidism increases BMR.

•TH is “calorigenic” which means that it promoted heat production. •It is not surprising that one of the classical signs of hypothyroidism is decreased tolerance to cold, whereas excessive heat production & sweating are seen in hyperthyroidism.

8. HEART• Blood Flow & Cardiac Output:

Increased BMR↓

Increased & more rapid oxygen consumption by the tissues↓

Greater than normal metabolic end products↓

Vasodilatation in most tissues↓

Increased blood flow↓

Increased cardiac output• Increased Heart Rate• Heart Strength:

Small increase in thyroid hormone secretion: Increase in heart strength due to increased enzymatic activity (as occurs in mild fevers during exercise) Large increase in thyroid hormone secretion: heart strength becomes depressed b/c of long term protein metabolism

Some severely Thyrotoxic patients die of severe cardiac decompensation (due to myocardial failure b/c of increased cardiac output causing increased cardiac load)

9. RESPIRATION

Increased rate of metabolism

↓

Increased utilization of oxygen

+

Increased formation of carbon dioxide

↓

Increased rate & depth of Respiration

10. GASTROINTESTINAL TRACT

•Increased appetite•Increased food intake•Increased GI motility

•Increased GI secretions

SO, Hypothyroidism causes:__________ & Hyperthyroidism causes: __________

11. SLEEP

Increased thyroid hormone secretion

↓

Exhaustive effect on the musculature & CNS

↓

Constant tiredness

BUT, b/c of the excitable effects on synapses, IT IS DIFFICULT TO SLEEP

12. Effect on Other Endocrine Glands

Increased rate of secretion of thyroid hormones ↓

Increases the need of the tissues for the hormones↓

Increases the rate of secretion of various hormones

• For normal sexual development and function, thyroid hormone production needs to be normal.

THYROID HORMONE SECRETION

CONTROL & DIAGNOSIS

THYROID STIMULATING HORMONE (TSH)/ THYROTROPIN

• Is a glycoprotein with a mw of 28, 000 and secreted by the anterior pituitary.

• Main function: It increases the secretion of both T3 & T4by the thyroid gland.

• Mechanism of Action: TSH + TSH receptors on the thyroid follicular cell membrane

↓Adenylyl cyclase is stimulated

↓ATP→ cAMP

↓Protein kinase A is activated

↓Multiple phosphorylations throughout the cell

↓1. Immediate increase in thyroid hormone secretion2. Stimulates growth of the thyroid glandular tissue

THYROID STIMULATING HORMONE

EFFECTS ON THE THYROID GLAND:1. Increased proteolysis of the Thyroglobulin already

stored in the follicular cells2. Increased activity of the “Iodide pump”3. Stimulates Organification4. Increased size & secretory activity of the thyroid cells5. Increased number of the Thyroid cells (with change

into columnar from cuboidal) IN SUMMARY: TSH increases all the known secretory

activities of the thyroid gland!

MOST IMPORTANT IS PROTEOLYSIS WHICH CAUSES RELEASE OF THE TH INTO THE BLOOD STREAM

WITHIN 30 MINUTES!

• ANTERIOR PITUITARY SECRETION OF TSH IS REGULATED BY

THYROTROPIN-RELEASING HORMONE FROM THE HYPOTHALAMUS

THYROTROPIN RELEASING HORMONE (TRH)

• A tripeptide amide (pyroglutamyl-histidyl-proline-amide)• Secreted by the nerve endings in the median eminence

of hypothalamusMechanism of secretion:

TRH + TRH receptor in the pituitary cell membrane ↓

Phospholipase C second messenger system activated ↓

TSH released

HYPOTHALAMIC-HYPOPHYSIAL PITUITARY AXIS

Hypothalamus↓

TRH↓

Hypothalamic-Hypophysial portal blood system↓

Anterior pituitary↓

TSH↓

Thyroid gland↓

Tri-iodothyronine & Thyroxine Secretion

Hypothalamic-Hypophysial Feedback

System

IF TYROID HORMONE

DEFICIENT, THEN THE SECRETION IS STIMULATED THROUGH THIS

FEEDBACK SYSTEM!

&

VICE VERSA!