Production, Regulation, and Action

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

• Between follicles are clear parafollicular cells, which produce calcitonin.

The Thyroid Gland – Histology

I

Why is Iodine Important in Thyroid Hormone Production?

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

• Thus, adequate iodine intake (diet, water) is required for normal thyroid hormone production.

• Major sources of iodine:- iodized salt

- iodated bread - dairy products

- shellfish• Minimum requirement: 75- 80

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).

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

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 its tyrosine residues are iodinated by I+.

This results in tyrosine residues which have one or two iodines attached (monoiodotyrosine or diiodotyrosine).

Thyroid Hormone Synthesis

Thyroid Hormones There are two biologically active thyroid

hormones: - tetraiodothyronine (T4; usually called

thyroxine)- triiodothyronine (T3)

Derived from modification of tyrosine.

Differences between T4 and T3The thyroid secretes about 80 micro gm of

T4, but only 5 micro gm of T3 per day.However, T3 has a much greater biological

activity (about 10 X) than T4.An additional 25 microg/day of T3 is

produced by peripheral monodeiodination of T4.

T4

thyroid

I-

T3

TRIIODOTHYRONINE

TETRAIODOTYROSINE

RAPID ACTION AND DEGRADATION

SLOW TO RESPOND

10 x MORE RAPIDLY BINDS TO RECEPTORS

SLOW BINDING

METABOLICALLY ACTIVE

INACTIVE,CONVERTS TO T3

DIFFERENCE IN ACTIONS OF T3 & T4

Transport of Thyroid Hormones

• Thyroid hormones are not very soluble in water (but are lipid-soluble).

• Thus, they are found in the circulation associated with binding proteins:- Thyroid Hormone-Binding Globulin (~70% of hormone)- Pre-albumin (transthyretin), (~14%)- 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.

One Major Advantage of this System

The thyroid gland is capable of storing many weeks worth of thyroid hormone (coupled to thyroglobulin).

If no iodine is available for this period, thyroid hormone secretion will be maintained.

Regulation of Thyroid Hormone Levels

Thyroid hormone synthesis and secretion is regulated by two main mechanisms:- an “autoregulation” mechanism, which reflects the available levels of iodine.- regulation by the hypothalamus and anterior pituitary.

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

LHFSH TSH

LH FSH TSH

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 TSHTSH binds to a plasma membrane-bound,

G protein-coupled receptor on thyroid follicle cells.

Specifically, it activates a Gs-coupled receptor, resulting in increased cAMP production and PKA activation.

TSH

Gsa

Adenylyl Cyclase

ATP cyclic AMP

Protein kinaseA

Follicle cell

Thyroid Follicles

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.

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 increase 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 (Pit)

conversion T4 can convert to T3 through

deniodenation in peripheral tissues as well as in the thyroid.

(catalyzed by deiodinase).

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 basal metabolic rate.

Actions of Thyroid HormoneRequired for GH and prolactin

production and secretionRequired for GH actionIncreases intestinal glucose

reabsorption (glucose transporter)Increases mitochondrial oxidative

phosphorylation (ATP production)Increases activity of adrenal medulla

(sympathetic; glucose production)Induces enzyme synthesisResult: 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)

Expression and Regulation of Thyroid Hormone ReceptorsThyroid hormone receptors are found

in many tissues of the body, but not in adult brain, spleen, testes, uterus, and thyroid gland itself.

Thyroid hormone inhibits thyroid hormone receptor expression (TRE on THR genes).

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.

T3 also acts on mitochondria to increase ATP synthesis

The resulting increased metabolic rate increases thermogenesis (heat production).

Thyroid hormones:Key Points

• Held in storage• Bound to mitochondria, thereby increasing ATP

production• Bound to receptors activating genes that

control energy utilization• Exert a calorigenic effect

Thyroid Hormone Actions which Increase Oxygen Consumption Increase mitochondrial size, number and key

enzymesIncrease plasma membrane Na-K ATPase

activityDecrease superoxide dismutase activity T3 /T4 can increase oxygen consumption,

promote metabolism and BMR （ basal metabolic rate ） ,↓utility.

Effects of Thyroid Hormones on the Cardiovascular SystemIncrease heart rateIncrease force of cardiac contractionsIncrease stroke volumeIncrease Cardiac outputUp-regulate catecholamine receptors

Effects of Thyroid Hormones on the Respiratory SystemIncrease resting respiratory rateIncrease minute ventilationIncrease ventilatory response to hypercapnia

and hypoxia

Effects of Thyroid Hormones on the Renal SystemIncrease blood flowIncrease glomerular filtration rate

Effects of Thyroid Hormones on Oxygen-Carrying Capacity

Increase RBC massIncrease 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 receptorsIncrease substrate availability

Effects Thyroid Hormones in Growth and Tissue Development

Increase growth and maturation of boneIncrease tooth development and eruptionIncrease growth and maturation of

epidermis,hair follicles and nailsIncrease rate and force of skeletal muscle

contractionInhibits 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 alertnessEnhances memory and learning capacityRequired for normal emotional toneIncrease 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

Calcium metabolism.Adrenal cortex.

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.

Many causes (insufficient iodine, lack of thyroid gland, lack of hormone receptors, lack of TH binding globulin….)

Hypothyroidism SymptomsTiredness and weaknessDry skinFeeling coldHair lossDifficulty in concentrating and poor memoryConstipation

Weight gain with poor appetite

Hoarse voice Menorrhagia, later

oligo and amenorrhoea

Paresthesias Impaired hearing

Hypothyroidism SignsDry skin, cool extremitiesPuffy face, hands and feetDelayed tendon reflex

relaxationCarpal tunnel syndrome BradycardiaDiffuse alopeciaSerous cavity effusions

Causes of HypothyroidismAutoimmune

hypothyroidism (Hashimoto’s, atrophic thyroiditis)

Iatrogenic (I123treatment, thyroidectomy, external irradiation of the neck)

Drugs: iodine excess, lithium, antithyroid drugs, etc

Iodine deficiencyInfiltrative disorders

of the thyroid: amyloidosis, sarcoidosis,haemochromatosis, scleroderma

Causes of HyperthyroidismMost common causes

Graves diseaseToxic multinodular

goiterAutonomously

functioning nodule

Rarer causesThyroiditis or other

causes of destructionThyrotoxicosis factitiaIodine excess (Jod-

Basedow phenomenon)Struma ovariiSecondary causes (TSH

or ßHCG)

Hyperthyroidism SymptomsHyperactivity/ irritability/ dysphoriaHeat intolerance and sweatingPalpitationsFatigue and weaknessWeight loss with increase of appetiteDiarrhoeaPolyuriaOligomenorrhoea, loss of libido

Hyperthyroidism SignsTachycardia (AF)TremorGoiterWarm moist skinProximal muscle

weaknessLid retraction or

lagGynecomastia