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There are two biologically active thyroid hormones: - tetraiodothyronine (T4; usually called thyroxine) - triiodothyronine (T3) Derived

from modification of tyrosine.

The thyroid secretes about 80 microg of T4, but only 5 microg 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
thyroid

T4
I-

T3

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 micrograms/day US intake: 200 - 500 micrograms/day

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:
Iperoxidase

I+

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

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).

Squamous epithelial cells, cuboidal cells (follicle cells)

Colloid fills the follicle cavities I Follicle cells produce thyroglobulin ---- TH

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), (~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.

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.

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.

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

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.

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 a receptor binding and biological activity
LHb FSHb TSHb

LH

FSH

TSH

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 INa+
K+

Na+

gene

ATP
I-

follicle cell

colloid droplet

thyroglobulin

endocytosis thyroglobulin

thyroglobulin
iodination

I+

I-

T3

T4

TSH 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 Adenylyl PKA activation. TSH
Cyclase
Gsa

ATP

cyclic AMP
Follicle cell

Protein kinase A

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
pituitary TSH synthesis

T3/T4

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

G protein-coupled receptor

IP3

calcium calmodulin

phospholipase C DAG

PKC

Thyroid hormones also inhibit TRH synthesis.

TRH synthesis hypothalamus + TRH -

TRH receptor
pituitary TSH synthesis TSH binds Thyroid gland follicle cell receptors

T3/T4

PITUITARY-THYROTROPE CELL

HM Goodman, BASIC MEDICAL ENDOCRINOLOGY 3rd E

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. Other stresses: increased or decreased? Any condition that increases body energy requirements (e.g., pregnancy, prolonged cold) stimulates hypothalamus TRH TSH (Pit)

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.

Mechanisms of Hormone Actions


1. 2. 3. 4. Nuclear (regulate gene transcription) protein synthesis Ribosomal (regulate gene translation) Regulate enzymatic activity membrane receptors Alter membrane characteristics

Thyroid hormones appear to act directly via T3 receptors, but also indirectly by altering expression of genes for neurotrophins or their receptors.

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 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)
-low doses of thyroid hormone increase glycogen synthesis (low metabolic rate; storage of energy)

Effects on carbohydrates:

- high doses increase glycogen breakdown (high metabolic rate; glucose production)

Thyroid 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).

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).

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

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

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

Increase blood flow Increase glomerular filtration rate

Increase RBC mass Increase oxygen dissociation from hemoglobin

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

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

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

Required for normal follicular development and ovulation in the female Required for the normal maintenance of pregnancy Required for normal spermatogenesis in the male

Specimen collection :

Specimens are routinely collected in a clot tube, although anticoagulants can be used . Specimens free of lipemia or hemolysis are preferred .

The tests used to investigate thyroid function can be grouped into:

Tests that establish whether there is thyroid dysfunction ( TSH,T4 and T3 measurements)

Tests to know the cause of thyroid dysfunction (thyroid auto-antibody and serum thyroglobulin measurements, thyroid enzyme activities, biopsy of the thyroid, ultrasound and isotopic thyroid scanning )

TSH :
- The single most sensitive, specific and reliable test of thyroid status . - In primary hypothyroidism, [TSH] is increased. - In primary hyperthyroidism, [TSH] is decrease or undetectable

Total T4 and Total T3 :


- More than 99% of T4 and T3 circulate in plasma bound to protein - Both [total T4] and [total T3] change if [TBG] alters, e.g. in pregnancy

Free T4 and Free T3


Free thyroid hormone concentrations are independent of changes in the concentration of thyroid-hormone binding proteins more reliable for diagnosis of thyroid dysfunction

Primary hyperthyroidism
- Plasma [TSH] : due to feedback inhibition on the pituitary - Plasma free and total T4 and T3 concentrations :
In a very small percentage of hyperthyroid patients, plasma [total T4] and [freeT4] are both normal, whereas both plasma [total T3] and [freeT3] are increased ; this condition is known as T3 hyperthyroidism or T3 thyrotoxicosis .

Primary hypothyroidism :
Plasma [TSH] : Plasma [free T4] and [total T4] : Plasma free T3 and total T3 measurements are of no value here, since normal concentrations are often observed .

Sub clinical primary thyroid disease


Plasma [TSH] : abnormal Thyroid hormone levels : normal [TSH] : low sub clinical hyperthyroidism [TSH] : elevated sub clinical hypothyroidism Before the diagnosis of sub clinical thyroid disease can be made, causes of an abnormal plasma [TSH] other than thyroid disease must be excluded eg : - pregnancy - drug treatment

Central (pituitary) hypothyroidism :


[TSH] & thyroid hormone levels low

Hyperthyroidism due to a TSH-secreting tumor


very rarely

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