THYROID HORMONE:

• Gross and Microscopic Anatomy of the Thyroid Gland.• Production of Thyroid Hormones.• Transport of T3 and T4• Actions of Thyroid Hormones.• Regulation of Thyroid Hormones.• Hyper- and Hypothyroidism

PREPARED BY:

Dr.Abdul Wahab Aslam

Histology of the Thyroid Gland

• The thyroid gland contains numerous follicles, composed of epithelial follicle cells and colloid.

Also, between follicles are Para-follicular cells, which produce Calcitonin.

The Thyroid Gland – Histology:

Squamous epithelial cells, cuboidal cells (follicle cells).Gland is composed of hollow spheres, called colloid follicles.Colloid fills the follicle cavities.Follicle cells produce thyroglobulin.

I

The Thyroid Gland:

Thyroid Hormones:

There are two biologically active thyroid hormones: - Tetraiodothyronine(T4; usually called thyroxine)

- Triiodothyronine (T3) Derived from modification of tyrosine(amino acid).

Differences between T4 and T3:

• The thyroid secretes about 80mg of T4, but only 5mg of T3 per day.

• However, T3 has a much greater biological activity about 10 folds than T4.

• An additional 25mg/day of T3 is produced by peripheral monodeiodination of T4 by enzyme called 5’ Monodeiodenase.

T4

thyroid

I-

T3

Major sources of iodine:

• Thyroid hormones are unique biological molecules in that they incorporate iodine in their structure.

• Thus, adequate iodine intake either through diet or water is required for normal thyroid hormone production.

• Major sources of iodine are:- iodized salt

- iodated bread - dairy products

- shellfish• Minimum requirement(RDA): 75 micrograms/day• US intake: 200 - 500 micrograms/day

Iodine Metabolism

• Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland (or removed from the body by the kidneys).

• About 80% of the iodine is lost in urine where as only 20 % is taken up by the Thyroid follicular cells.

• The transport of iodide into follicular cells is dependent upon a Na+/I- co-transport system.

• Iodide taken up by the thyroid gland is oxidized by peroxide in the lumen of the follicle:

PeroxidaseI- I+

• Oxidized iodine can then be used in production of thyroid hormones.

The Next Step: Production of Thyroglobulin:

Pituitary produces TSH, which binds to follicle cell receptors. The follicle cells of the thyroid produce thyroglobulin. Thyroglobulin is a very large glycoprotein. Thyroglobulin is released into the colloid space, where it’s

tyrosine residues are iodinated by I+. This results in formation of monoiodotyrosine or diiodotyrosine.

Thyroid Follicles with Activities:

REGULATION:

Thyroid Hormone Synthesis

Transport of Thyroid Hormones

• Thyroid hormones are lipid-soluble.• Thus, they are found in the circulation associated with binding

proteins:- Thyroid Hormone-Binding Globulin(TBG) (~70% of hormone)- Pre-albumin(Transthyretin) (~15%)- Albumin (~15%)

• Less than 1% of thyroid hormone is found free in the circulation.• Only free and albumin-bound thyroid hormone is biologically

available to tissues.• Among the amount of thyroid hormone production and release

T4 is approximately 95% and T3 is 5%. But biological active is T3 so T4 is converted to T3 in peripheral tissues by the enzyme 5’monodeiodinase and become active.

Conversion of T4 to T3

T3 has much greater biological activity than T4. A large amount of T4 (25%) is converted to T3 in peripheral

tissues. This conversion takes place mainly in the liver and kidneys. The

T3 formed is then released to the blood stream. In addition to T3, an equal amount of “Reverse T3” may also be

formed. This has no biological activity.

T3 MIT + DIT

Reverse T3 DIT + MIT

Regulation of Thyroid Hormone Levels:

• Thyroid hormone synthesis and secretion is regulated by two main mechanisms:

- An “auto regulation” mechanism, which reflects the available levels of iodine.

- Regulation by the hypothalamus and anterior pituitary.

Auto regulation of Thyroid Hormone Production

• The rate of iodine uptake and incorporation into thyroglobulin is influenced by the amount of iodide available:- Low iodide levels increase iodine transport into follicular cells

- High iodide levels decrease iodine transport into follicular cells

Thus, there is negative feedback regulation of iodide transport by iodide.

Neuroendocrine Regulation of Thyroid Hormones: Role of TSH

• Thyroid-stimulating hormone (TSH) is produced by thyrotroph cells of the anterior pituitary.

• TSH is a glycoprotein hormone composed of two subunits:

- alpha subunit (common to LH, FSH, TSH, hCG)

- TSH beta subunit, which gives specificity of receptor binding and biological activity.

Action of TSH on the Thyroid

TSH acts on follicular cells of the thyroid.- increases iodide transport into follicular cells

- increases production and iodination of thyroglobulin- increases endocytosis of colloid from lumen into follicular cells

Na+

I-thyroglobulinfollicle

cell

gene

I-

endocytosis

thyroglobulin

T3 T4

colloid droplet

I-I+iodination

thyroglobulin

Na+ K+

ATP

Mechanism of Action of TSH

• TSH binds to G protein-coupled receptor on thyroid follicular cells.

• Specifically, it activates a Gs-coupled receptor which leads to activation of Adenyl cyclase resulting in increased c-AMP production and PKA (Protein Kinase-A) activation.

TSH

Gsa

Adenylyl Cyclase

ATP cyclic AMP

Protein kinaseA

Follicle cell

Regulation of TSH Release from the Anterior Pituitary

• TSH release is influenced by hypothalamic TRH, and by thyroid hormones themselves.

• Thyroid hormones exert negative feedback on TSH release at the level of the anterior pituitary.

- inhibition of TSH synthesis

- decrease in pituitary receptors for TRH

hypothalamus

TRH

TRH receptor

TSH synthesispituitary T3/T4

+

--

Influence of TRH on TSH Release

• Thyrotropin-releasing hormone (TRH) is a hypothalamic releasing factor which travels through the pituitary portal system to act on anterior pituitary Thyrotroph cells.

• TRH acts through G protein-coupled receptors, activating the IP3 (Ca2+) and DAG (PKC) pathways to cause increased production and release of TSH.

TRH phospholipase C

G protein-coupledreceptor

IP3 calcium

DAG PKC

calmodulin

• Thyroid hormones also inhibit TRH synthesis.

Negative Feedback Actions of Thyroid Hormones on TSH Synthesis and Release

hypothalamus

TRH

TRH receptor

TSH synthesispituitary

T3/T4

+

-

-

-

TRH synthesis

Thyroid gland follicle cell receptors

TSH binds

Other Factors Regulating Thyroid Hormone Levels

• Diet: a high carbohydrate diet increases T3 levels, resulting in increased metabolic rate (diet-induced thermogenesis).

• Low carbohydrate diets decrease T3 levels, resulting in decreased metabolic rate.

• Cold Stress: increases T3 levels in other animals, but not in humans.

• Any condition that increases body energy requirements (e.g., pregnancy, prolonged cold) stimulates hypothalamus TRH TSH.

Actions of Thyroid Hormones:

Thyroid hormones are essential for normal growth of tissues, including the nervous system.

Lack of thyroid hormone during development results in short stature and mental deficits (cretinism).

Thyroid hormone stimulates or increase Basal Metabolic Rate(BMR).

• Required for GH and prolactin production and secretion• Required for GH action• Increases intestinal glucose reabsorption (glucose

transporter)• Increases mitochondrial oxidative phosphorylation (ATP

production)• Increases activity of adrenal medulla (sympathetic; glucose

production)• Induces enzyme synthesis• Result: stimulation of growth of tissues and increased

metabolic rate. Increased heat production (calorigenic effect)

Effects of Thyroid Hormone on Nutrient Sources:

• Effects on protein synthesis and degradation:-increased protein synthesis at low thyroid hormone levels (low metabolic rate; growth)-increased protein degradation at high thyroid hormone levels (high metabolic rate; energy)

• Effects on carbohydrates:-low doses of thyroid hormone increase glycogen synthesis

(low metabolic rate; storage of energy)- high doses increase glycogen breakdown (high metabolic rate; glucose production)

One Major Target Gene of T3: The Na+/K+ ATPase Pump:

Pumps sodium and potassium across cell membranes to maintain resting membrane potential

Activity of the Na+/K+ pump uses up energy, in the form of ATP About 1/3rd of all ATP in the body is used by the Na+/K+ ATPase T3 increases the synthesis of Na+/K+ pumps, markedly

increasing ATP consumption(BMR increases). T3 also acts on mitochondria to increase ATP synthesis(size and

number of mitochondria will increase). The resulting increased metabolic rate increases thermo genesis

(heat production).

Key Points:

Thyroid Hormone Actions which Increase Oxygen Consumption

• Increase mitochondrial size, number and key enzymes.• Increase plasma membrane Na-K ATPase activity.• Increase futile(ineffective) thermogenic energy cycles.• Decrease superoxide dismutase activity.

Effects of Thyroid Hormones on the Cardiovascular System

• Increase heart rate• Increase force of cardiac contractions• Increase stroke volume• Increase Cardiac output• Up-regulate catecholamine receptors

Effects of Thyroid Hormones on the Respiratory System

• Increase resting respiratory rate• Increase minute ventilation• Increase ventilatory response to hypercapnia and hypoxia

Effects of Thyroid Hormones on the Renal System

• Increase blood flow• Increase glomerular filtration rate(GFR)

Effects of Thyroid Hormones on Oxygen-Carrying Capacity

• Increase RBC mass• Increase oxygen dissociation from hemoglobin

Effects of Thyroid Hormones on Intermediary Metabolism

• Increase glucose absorption from the GI tract• Increase carbohydrate, lipid and protein turnover• Down-regulate insulin receptors• Increase substrate availability

Effects Thyroid Hormones in Growth and Tissue Development

Increase growth and maturation of bone. Increase tooth development and eruption. Increase growth and maturation of epidermis, hair follicles and

nails. Increase rate and force of skeletal muscle contraction. Inhibits synthesis and increases degradation of

mucopolysaccharides in subcutaneous tissue.

Effects of Thyroid Hormones on the Nervous System

• Critical for normal CNS neuronal development• Enhances wakefulness and alertness• Enhances memory and learning capacity• Required for normal emotional tone• Increase speed and amplitude of peripheral nerve reflexes

Effects of Thyroid Hormones on the Reproductive System

• Required for normal follicular development and ovulation in the female

• Required for the normal maintenance of pregnancy• Required for normal spermatogenesis in the male

Thyroid Hormone Deficiency: Hypothyroidism

Early onset: Delayed/incomplete physical and mental development.

Later onset(Youth): Impaired physical growth Adult onset(Myxedema) : Gradual changes occur. Tiredness,

lethargy, decreased metabolic rate, slowing of mental function and motor activity, cold intolerance, weight gain, goiter, hair loss, dry skin. Eventually may result in coma.

Causes: (a) Insufficient iodine. (b) Lack of thyroid gland. (c) Lack of hormone receptors. (d) Lack of TH binding globulin.

How is Hypothyroidism Related to Goiter?

• During iodine deficiency, thyroid hormone production decreases.

• This results in increased TSH release (less negative feedback).• TSH acts on thyroid, increasing blood flow, and stimulating

follicular cells and increasing colloid production.

Midwest – the Goiter Belt

• If goiter is due to decreased I, then thyroid gland enlarges – called endemic or colloidal goiter.

• Pituitary gland TSH stimulate thyroid gland to produce TH, but the only result is that the follicles accumulate more and more unusable colloid.

• Cells eventually die from over activity and the gland atrophies.

Thyroid Hormone Excess: Hyperthyroidism

• Emotional symptoms (nervousness, irritability), fatigue, heat intolerance, elevated metabolic rate, weight loss, tachycardia, goiter, muscle wasting, apparent bulging of eyes(exophthalmos), may develop congestive heart failure.

• Causes:

(a) Excessive TSH release.

(b) Autoimmune disorders.