Thyroid Hormones

•    Thyroid gland is a bow shaped bi-lobular gland located below the larynx on each side of trachea

 

•    Each lobule of thyroid gland consist of a large number of thyroid follicles

–  Structural and functional unit of thyroid gland

•    Thyroid follicle are spherical units filled with colloid and made up of cuboidal cells called follicular cells

•    In between thyroid follicles, small C cells are also present called parafollicular cells

 

•    It functions under the influence of TSH from pituitary gland.

•    Major hormones secreted by thyroid gland are

–  Thyroxine (T₄ or Tetra iodo thyronin) and Tri iodo thyronin (T₃) secreted by follicular cells

–  Calcitonin secreted by parafollicular cells

•    Calcitonin is involved in Ca²⁺ homeostasis while other two regulate metabolic rate of the body Chemistry:

•    Chemically thyroid hormones are iodinated derivatives of tyrosine aminoacid

–  Containing more than half of the body’s total iodine

Biosynthesis & Release of Thyroid Hormones:

•    The raw materials required for thyroid hormones are:

–  Thyroglobulin

–  Iodine

i) Thyroglobulin:

•    Precursor glycoprotein found in follicular cells and contains about 120 tyrosine residues

–  Tyrosine residues serves as substrate for iodine 

•    Iodinated tyrosine compounds are:

–  Mono-iodo tyrosine (MIT) and 

–  Di-iodo tyrosine (DIT)

•    MIT&DIT coupled with each other to form T₃ & T₄

 

ii) Iodine metabolism:

•    Iodine is essential for thyroid functioning

•    Normally approximately 50mg iodine is present in the body

–  Normal daily intake of iodine is 100 to 200 μg

–  2/3 of iodine is excreted by kidneys and remaining

1/3 is taken up by thyroid gland

•    Iodine is incorporated in hormones in 3 steps

a) Uptake of iodine

•    Actively taken up by Na⁺-K⁺ ATPase pump under the influence of TSH

b)  Organification • Oxidation of I^- to active iodine by thyroperoxidase in the presence of H₂O₂

•     Iodinium ion (I⁺) orhypoiodite (HIO) or free iodine radicle (I)

•     Active iodine is incorporated into the tyrosine residues to form MIT and DIT

c)   Coupling of iodotyrosines

•     MIT and DIT molecules each condenses to form T₃ & T₄ molecules in the presence of enzyme thyroperoxidase

•     1 MIT and 1DIT combines to form T₃ & reverse T₃

•     2DIT undergo oxidative condensation to form T₄ (Thyroxin)

•     Each thyroglobulin contains about 6 to 8 molecules of Thyroxin (T₄)

– Ratio of T₃ & T₄ in thyroglobulin in 1:10

•    Prepared hormones are stored in thyroid gland

–  Freed hormones are released into blood stream under the stimulation of pituitary through TSH

–  90% T₄ (Thyroxin) and 10% T₃

•    In plasma mostly T₃ & T₄ are transported by thyroxin binding proteins

–  Thyroxine-binding Globulin (TBG)

–  Thyroxine binding Pre-Albumin (TBPA)

•    After their saturation excessive hormones can bind to albumin

•    The unbound (free) hormones are metabolically active hormones in the plasma

–  Plasma half-life of T3 is about 1 day

–  T₄: 4 to 7 days

•    Thyroid hormones are de-iodinated in the peripheral tissues by de-iodinase (dehalogenase)

–  Iodine removed is recycled and utilized by the gland again

 

Regulation of Thyroid Hormones:

•    The synthesis is controlled by feedback regulation

•    T₃ is more actively involved in regulation than T₄

–  TSH from pituitary and TRH from hypothalamus are inhibited by T₃ and to a lesser extent by T₄

–  Decreased levels of T₃ & T₄ stimulate TRH and TSH

•    Thyroid hormones are stored for several weeks

–  It takes months to observe thyroid functional deficiency Target sites:

•    Liver, Kidneys, Adipose tissue, heart, neurons (brain etc.

–  Carrier mediated (TBG, TBPA) transport to target cells

                                                    

Mechanism of Action of Thyroid Hormones:

•    Act through binding the intracellular DNAbinding proteins

–  Hormone-responsive transcription factors

–  Similar to steroidal hormone receptors

•    Crosses the membrane by trans-membrane carriers

–  Binds to receptors in the nucleus

•    Hormone receptor complex binds to DNA and modulate gene expression

–  Enhance mRNA synthesis through DNA-dependent

RNA polymerase

–  Increase Protein synthesis

–  Increased enzyme production

•    Functions of Thyroid Hormones:

•    Thyroid hormones (T₃ & T₄) show similar biological functions however

–  Affinity of T₃ to thyroid receptors is 10 times greater than

T4

–  Biological activity is T₃ is 4 times more than T₄ – T₃ has more rapid onset of action and degradation kinetics than T₄

–  About 80% of the T₄ is de-iodinated to T₃ in the peripheral tissues

•    Effect on BMR:

•    They increase the overall metabolic rate of the body

–  Increase oxygen consumption in most tissues

–  Except Brain, lungs, testes, uterus, lymph nodes etc.

•    This increase heat production and an overall increase in basal metabolic rate (BMR)

–  Increase mitochondrial oxidation

•    Induction of Glycerol-3-P-dehydrogenase 

–  Increase number and activity of Na⁺-K⁺ ATPase pumps

•    Hydrolyses ATPs to transport Na+ across membrane

•    Lack of energy utilization or Na⁺-K⁺ ATPase activity may lead to obesity in some individuals

•    Effect on Proteins:

•    Promote proteins synthesis

–  Cause positive nitrogen balance • Promote growth and development

•    Effects on Carbohydrates:

•    Promotes utilization of glucose in the body and increase blood glucose level (Hyperglycemia)

–  Increase absorption from intestine

–  Increase gluconeogenesis

–  Increase glycogenolysis

•    Thyroid hormones act antagonistic to insulin

–  DM is aggravated by thyrotoxicosis

•    Stimulate oxidative metabolism of carbohydrates

–  Stimulate glycolysis, TCA, HMP shunt pathways

•    Effects on Lipids:

•    Increase lipolysis in adipose tissue – Increase plasma free fatty acids

•    Increase rate of degradation of cholesterol, formation of bile acids and bile excretion

•    Hypothyroidism increases

–  plasma cholesterol

–  Plasma lipoproteins (LDL)

•    Hyperthyroidism decreases these both of these

–  In thyrotoxicosis or thyroid hormone administration Disorders of Thyroid Gland:

•    Among all endocrine glands thyroid is most susceptible of hypo or hyper function

•    Three abnormalities are associated mostly with thyroid function

–  Goiter

–  Hyperthyroidism (Thyrotoxicosis)

–  Hypothyroidism

i) Goiter:

•    Abnormal increase in the size of thyroid is called goiter

•    Failure in the auto-regulation of T₃ & T₄ synthesis leads to elevated TSH levels

–  Thyroid gland is enlarged to compensate the decrease synthesis of thyroid hormones

•    Main cause of Goiter is deficiency of iodide caused by Thiocyanates, nitrates and perchlorates (Goitrogenic factors)

•    Certain foods like cabbage, cauliflower and turnip contain thiocyanate

 

•    Endemic goiter can be prevented by taking iodized table salt

–  Common salt is mixed with potassium iodide, sodium iodide or sodium iodate

ii) Hyperthyroidism: (thyrotoxicosis)

•    Associated with overproduction of thyroid hormones

•    Caused by Grave’s disease or increased thyroid hormone intake

•    Grave’s disease is due to elevated levels of thyroid stimulating IgG (Long acting thyroid stimulator)

–  Activates TSH that results in the increased hormone production

•    The general symptoms of thyrotoxicosis are:

–  Increased BMR

–  Nervousness

–  Irritibility, anxiety, rapid heartrate

–  Loss of weight, increased appetite

–  Diarrhea, sweating, weakness

–  Sensitivity to heat

–  Exophthalmos

•    Protrusion of eyeballs

•    Hyperthyroidism is treated with 

–  Antithyroid drugs like thiocarbamides, aminobenzene etc.

–  Surgical removal of thyroid gland

iii) Hypothyroidism: • Impaired thyroid function

– Decreased levels of T₃ & T₄

•    Disorder of pituitary or hypothalamus may contribute to hypothyroidism

•    Typical symptoms are:

–  Reduced BMR, 

–  slow heart rate,

–  Weight gain,

–  Sluggish behavior, – Sensitivity to cold etc.

•    In adults it cause myxoedema

–  Bagginess under eyes, puffiness of face and slowness in physical and mental activities

•    In children it causes cretinism 

–  (Physical & mental retardation)

•    Calcitonin (CT):

•    Secreted by parafollicular cells of thyroid gland

–  Also called C-cells present in thyroid, parathyroid and thymus glands

•    Calcium regulating hormone

–  Act antagonistic to parathormone from parathyroid

•    Chemistry:

•    Single chain lipophilic polypeptide with 32 aminoacids

–  Disulfide linkage between two cysteine residues at 1^st and 7^th position

–  High contents of aspartic acid and threonine is present

Mechanism of Action:

•    Binds to calcitonin receptors on plasma membrane of osteoclasts and renal tubular epithelial cells

–  Activates adenylyl cyclase that increase cAMP level

•    cAMP mediate hormone action Functions:

•    Acts on bones and kidneys

•    Cause Hypocalcaemia (decreased blood calcium)

i)     Bones

–  Promotes calcification by increasing osteoblast activity

–  Decrease osteoclast activity

• Bone resorption and Ca²⁺ and PO₄^3- mobilization from bones to blood

ii)   Kidneys:

•    Act on DCT and ascending loop of Henle

•    Decrease tubular reabsorption of calcium (Ca²⁺) and inorganic phosphate (PO₄^3-)

– Increased excretion of Ca²⁺ (Calcinuria) and PO₄^3-

(phosphaturia)

•    Also decrease Ca²⁺ absorption from intestine