Stole this from somewhere else, very interesting info on T3 and T4 thought this could be interesting since summer is coming and I have seen the amount of T# cycles increase. Hope this is interesting.

Pain


BDS1 Course 2: Endocrinology and Nutrition
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The Thyroid Gland
Contents
Introduction
Storage, release and transport of thyroid hormones
The regulation of thyroid function
The mechanism of action of thyroid hormones
Thyroid Hormone Summary
Thyroid hormone deficiency
Hypothyroidism
Hyperthyroidism
Causes of abnormal thyroid function
Calcitonin
UMDS Physiology

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The Thyroid Gland
Introduction
The gross anatomy is shown in the first diagram. The thyroid gland has a characteristically high blood flow giving it a bright red appearance. When sectioned it has;


a lobular and follicular appearance
each follicle is a single layer of epithelia cells surrounding a cavity in which the thyroid hormones are stored

The main function of the thyroid gland is to manufacture and release the thyroid hormones thyroxine (T4) and triiodothyronine (T3). These two hormones, in the adult, maintain metabolic stability by regulating intermediate metabolism, body weight and oxygen requirements. They are also important in the normal growth and development of the body during childhood. Deficiencies in thyroid hormone production during critical periods of development can lead to permanent brain damage. A lack of thyroid hormone synthesis is usually the result of an inadequate supply of dietary iodine. Under normal circumstances 75µg/day iodine is required which is usually ingested as a result of addition to bread, salt and certain dairy produce. The majority of the stored "iodinated" compounds are found in the thyroid gland itself (8000µg) with only 250µg in the extracellular pool. The thyroid gland is able to concentrate inorganic iodide from the extracellular fluid by an active, saturable energy-dependent process, partly under the influence of thyroid stimulating hormone (TSH). This transport mechanism is influenced (inhibited) by certain anions, notably thiocyanate (increases iodide efflux) and perchlorate (inhibits trapping of I-).

The two principle thyroid hormones are thyroxine or T4 and triiodothyronine or T3. These hormone are produced from the precursor amino acids mono and diiodotyrosine which are synthesised following iodination and coupling of the tyrosine residues on the protein thyroglobulin synthesised by the follicular cells. The coupling reaction appears to occur separately from iodination and is catalysed by thyroid peroxidase. Thyroglobulin is a large molecule with a molecular weight of 660,000 and is present as a soluble protein in the lumen of the thyroid follicle.


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Storage, release and transport of thyroid hormones
In contrast to most endocrine glands the thyroid gland is able to store 2-3 months supply of thyroid hormones in the thyroglobulin pool. Thyroglobulin must be hydrolysed to release T4 and T3. The cleavage is accomplished by lysosomal proteases within the cells of the follicle. The process starts with the action of thyroid-stimulating hormone (TSH) which stimulates the endocytosis of luminal colloid and the fusing of lysosomal hydrolytic enzymes. The iodide released from monoiodothyrosine and diiodotyrosine is then available for reuse in the thyroid gland. The freed T4 and T3 diffuse from the cell into the circulation where approximately 70% are bound to thyroid-binding globulin (TBG) and the rest bound to either prealbumin or to albumin. The serum half life of T4 is about 7 days whereas the half life of T3 is less than a day. levels of T4 in the plasma are 65x higher than T3 majority of T4/ T3 bound to plasma proteins thyroxine binding protein, prealbumin and albumin however T3 is the most active and T4 is converted to T3 in most tissues suggesting that T4 is a prohormone. The fact that T4 is more tightly bound to serum proteins means that its half life is longer. A summary of bound/ unbound hormones in the plasma is shown below;

........TOTAL........FREE........%bound.....Half life.....Potency
T4...100nmol/l....0.04nmol/l......99.9..........7 days..........1
T3....1.5nmol/l....0.02nmol/l......98.7..........1 day...........10

The T4 is metabolised in the periphery to T3. Most of this conversion is the result of deiodinase activity in the liver and kidneys The deiodination process is inhibited by propylthiouracil so that T4 to T3 conversion is impaired.

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The regulation of thyroid function
The thyroid gland is mainly regulated by TSH from the anterior pituitary. TSH is a glycoprotein hormone with an alpha and beta subunit and a molecular weight of 28,000. The alpha subunit is identical to the alpha subunit of gonadotrophin and so hormonal specificity is conferred by the beta subunit. TSH acts on a membrane bound receptor on follicular cells (see lecture Introduction to hormones) to increase the concentration of the intracellular second messenger, cAMP. The release of TSH by the pituitary is under the control of the tripeptide hormone TRH (thyrotrophin releasing hormone) via the median eminence - pituitary portal blood system and the negative feedback influence of the thyroid hormones upon thyrotrophs. TRH acts to stimulate thyrotrophic exocytosis by elevating Ca2+ levels using an **3 mechanism (see lecture Introduction to hormones). The release of TSH is not wholly dependent upon TRH since there is some background release. TRH is released by neurones that project towards the median eminence and release their hormone in a pulsatile fashion. It is probable, but not proven, that the thyroid hormones also act to inhibit (possible -ve feedback) on TRH-producing neurones in the hypothalamus. TSH release, in addition to its tonic secretory control by TRH, is also under the inhibitory control of somatostatin (GHIH) and dopamine.


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The mechanism of action of thyroid hormones
The majority of biological actions of thyroid hormones appear to be mediated by an interaction of T3 with nuclear receptors (cf. steroid responses) and the resultant stimulation of transcription of specific mRNA's. Thyroid hormones stimulate the number of Na+/K+ ATPase "pump units" and thus increases oxygen consumption in those tissues that have nuclear thyroid hormone receptors (spleen and testes have very low levels of these). Protein synthesis and degradation are enhanced by thyroid hormones as are most aspects of carbohydrate metabolism. In this respect thyroid hormones may have a "permissive" action (cf. Introduction to hormones) in that they allow the actions of adrenaline and insulin to be maximised. The thyroid hormone effects on lipid metabolism is complex and is thought to involve the expression of low-density lipoprotein receptors on the cell membrane surface - a detailed knowledge is not required for BDS students. Thyroid hormone deficiencies or excesses are common and students should know the symptoms (which may be subtle - laboratory tests should be undertaken).


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Thyroid Hormone Summary;
T3/T4 are the most important hormones for determining basal metabolic rate (BMR)
increases O2 consumption & heat production except brain, lungs, spleen and sex organs
thermoregulatory effect is very long lasting (weeks)
released during stress
thyroid hormones are essential for normal growth because they are permissive for the growth promoting effects of GH.
decreased thyroid function (children/ infants) leads to retarded bone growth (development) and epiphyseal closure delayed (development)
CNS development during foetal life & first few months of life hypothyroid infants (cretins) are mentally retarded. Treatment for cretinism must be carried out very early.
thyroid hormones essential for normal mental function



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Thyroid hormone deficiency
Thyroid hormone deficiency, usually as a result of deficiencies in dietary iodine leads to profound developmental delay in children. Prolonged deficiency leads to cretinism and is characterised by physical and mental retardation. Epiphyseal development is also delayed so that chronological age is greater than "bone" age. In the adult thyroid deficiency is slow to show obvious clinical signs which may take several years to appear.


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Hypothyroidism (2% adult women, v. rare in males)
somnolence and sluggishness
poor mental function, impaired memory, slow speech
cold intolerance
decreased food intake and constipation
in women, abnormalities of menstruation, usually increased menstrual flow
hair loss, brittle nails, dry skin (NB. non-GH dependant growth impairment)
accumulation of mucopolysaccharides in subcutaneous tissues - myxoedema, general oedema with swelling of the hands and feet
eventually lack of iodine causes thyroid hyperplasia (enlargement of gland - goiter)



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Hyperthyroidism
In contrast to hypothyroidism (2% adult women, v. rare in males), overproduction of thyroid hormones (hyperthyroidism) leads to the following symptoms;


jittery, irritable
emotionally unstable
hyperactive or "impression of increased energy"
loss of sleep
exophthalmus - protruding eyes
increased food intake - common
loss of body weight - common
increased body temperature (vasodilatation/ sweating), heat intolerance
in women decreased or absent menstrual flow
eyelid retraction
stimulation of synthesis of beta receptors with a "pounding heart sensation" with
atrial arrhythmias



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Causes of abnormal thyroid function
The cause of abnormal function leads to either hyper or hypothyroidism. Inadequate production of thyroid hormone by the thyroid gland with a decrease in thyroid tissue or with thyroid enlargement is called primary hypothyroidism (95% of cases). This condition is probably due to an autoimmune thyroiditis whereas secondary hypothyroidism is due to a decrease in TSH secretion. Hyperthyroidism may go into remission but usually is recognisable from the above symptoms with goitre (Grave's disease) where there is an IgG immunoglobulin acting on the TSH receptor to cause profound excitation.


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Calcitonin
Calcitonin is a 32- amino acid peptide hormone synthesised by the parafollicular (C) cells of the thyroid gland. Calcitonin's main action is to inhibit bone resorption by acting on osteoclasts to inhibit their activity. The parafollicular C cells secrete calcitonin is response to an elevated serum calcium concentration or to gastrin levels. The importance of calcitonin in humans is questionable since neither excess or absence appears to do any harm. Further discussions over this hormone's role will be included with the "Calcium" lecture later in the course.




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