Transcript Thyroid hormones

CHEMISTRY OF
HORMONES
Definition
• Hormones are organic substances,
produced in small amounts by specific
tissues (endocrine glands), secreted into
the blood stream to control the metabolic
and biological activities in the target cells.
• Hormones may be regarded as the
chemical messengers involved in the
transmission of information from one
tissue to another and cell to cell.
Chemical messengers
• Endocrine hormones:
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produced by ductless endocrine glands
mix to blood
have target organs
e.g. TH, LH, FSH
• Autocrine hormones:
– act on the same cells where they are synthesized. e.g.
interleukin-2
• Paracrine hormones:
– act on the cells adjacent/close to the cells from where
they are synthesized e.g. prostaglandins
• Neurotransmitters:
– released by nerve cells and usually act on the
adjacent cells. e.g. Catecholamines
• Pheromones:
– transmitted between the cells in the organisms of
opposite sex
– stimulates reproductive behavior and serve as sex
attractants.
CLASSIFICATION OF HORMONES
1. BASED ON CHEMICAL NATURE:
Peptide hormones :
Insulin
Glucagon
ADH
Oxytocin
Steroid hormones:
Sex hormones
Glucocorticoids
Mineralocorticoids
Amino acid derivatives:
Epinephrine
Norepinephrine
Thyroid hormones
2. BASED ON MECHANISM OF ACTION
GROUP I: intracellular receptor (Lipophilic)
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Hormones bind to intracellular receptors (HRE in
DNA) to form receptor hormone complexes to carry
out the biochemical functions. They are derivatives
of cholesterol, lipophilic in nature and possess long
half lives.
GROUP II: surface receptor (Hydrophilic)
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These hormones bind to cell surface receptors and
stimulate the release of second messengers which
in turn perform the biochemical function. They are
hydrophilic in nature and possess short half lives.
Group-I hormones
Hormones bind with HRE in DNA
– Estrogens
– Progestins
– Androgens
– Glucocorticoids
– Mineralocorticoids
– Calcitriol
– Thyroid Hormones
Group –II hormones
(a) The second messenger is cAMP
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Adrenocorticotropic hormone (ACTH)
Follicle stimulating hormone (FSH)
Leuteinzing Hormone (LH)
Thyroid stimulating hormone (TSH)
Chorionic gonadotropins (hCG)
 Endorphins & Enkephalins
Anti diuretic hormone (ADH)
Glucagon
Parathyroid hormone (PTH)
Calcitonin
Epinephrine
Nor-epinephrine
(b) The second messenger is cGMP
– Atrial natriuretic factor (ANF)
– Nitric oxide (NO)
(c) The second messenger is phosphotidyl
inositol/calcium (or both)
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Thyrotropin releasing hormone (TRH)
Gonadotropin releasing hormone (GnRH)
Gastrin
Cholecystokinin (CCK)
(d) The second messenger is unknown/
unsettled (Kinase/Phosphatase
cascade)
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Insulin
Growth hormone (GH)
Prolactin (PRL)
Oxytocin
Somatomedins (Insulin like growth factor)
(IGF-I, IGF-II)
MECHANISM OF HORMONE ACTION
Group I Hormones
– Lipophilic in nature  cross plasma membrane by
diffusion
– Act through intracellular receptors located either in
cytosol or nucleus
– Duration of action is hours to days
– Hormone first binds with receptor  forms HR-complex
 binds with the specific region on the DNA called
hormone responsive element (HRE)  causes
increased expression of specific genes  transcription
 translation  production of specific proteins  carries
biochemical action of hormone
HRE
HORMONE RESPONSE ELEMENT (HRE):– Specific sequence present in DNA which
binds HR complex during lipophilic hormone
action
– HRE hormone specific
RESULT:– Binding of HR complex to HRE 
transcription  mRNA  Translation
(specific protein)  Biochemical response
Hormone receptor interaction:
STRUCTURE OF RECEPTOR MOLECULES
– Large, integral membrane proteins with
specificity & high affinity for hormones.
– Hormone & receptor binding is reversible.
– Initiate response without entering the cell.
– Rapid response/ shorter duration of action
(seconds to hours).
– Mediate effect through second messengers.
MECHANISM OF HORMONE ACTION
GROUP II HORMONES
– These hormones are considered as first
messenger
– Hormone binds to surface receptors
– Carry the action through mediatory molecules
(second messengers)
– Hormones  First messenger  Second
messenger  Activation of protein kinase 
phosphorylation of enzyme  biochemical
action.
cAMP
• Cyclic adenosine 3’,5’-monophosphate (cAMP)
consists of adenine, ribose & a phosphate.
• Adenylate cyclase converts ATP to cAMP
• cAMP is a second messenger for majority of
polypeptide hormones
• cAMP binds with protein kinase and activates it
to carry out the phosphorylation for the
biochemical action of hormone
• cAMP degrades to 5’ AMP by
phosphodiasterase
Thyroid hormones
• Thyroid gland produces two principal
hormones T4 (3,5,3’,5’-tetraiodothyronine)
& T3 (3,5,3’-triiodothyronine)
• Calcitonin, a hormone of calcium
homeostasis is also produced by thyroid
gland.
Biosynthesis of T3 & T4
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T3 & T4 are synthesized from tyrosine
amino acid by the help of thyroglobulin
Biosynthesis covers the following steps
1. Uptake of iodine
2. Formation of active iodine
3. synthesis of T3 & T4
Biosynthesis (contd…)
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Uptake of iodine:
– Iodide uptake is done by thyroid gland
– Energy requiring process of Na+-K+ ATPase
against concentration gradient (≈ 20:1)
– Uptake is controlled by TSH
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Formation of active iodine:
– I- is converted to I+ by thyroid gland
– Reaction requires H2O2 & catalyzed by
thyroperoxidase
Biosynthesis (contd…)
• Synthesis of T3 & T4 :
– Thyroglobulin is required to synthesize T3 & T4
– Thyroglobulin contains many tyrosine residues
which serve as substrates for iodine to form
thyroid hormones
– Tyrosine becomes iodinated to form
monoiodotyrosine (MIT) & diiodotyrosine (DIT)
– MIT & DIT couple to form T3 and DIT & DIT to
form T4
Storage & release of T3 & T4
• Thyroglobulin containing T3 & T4 can be
stored in thyroid gland for several months
• Can meet the body requirements for 1-3
months
• T3 & T4 are released after proteolysis of
thyroglobulin by lysosomes
• MIT & DIT undergo deiodination by
deiodinase and iodine may be reutilized
Transport of T3 & T4
• Thyroxine binding globulin (TBG) &
thyroxine binding prealbumin (TBPA) are
responsible for transport
• T3 is biologically more active than T4
Regulation of T3 & T4 synthesis
• Synthesis is regulated by feedback regulation
• Production of TSH by pituitary causes TRH
production by hypothalamus which are inhibited
by T3
• If T3 & T4 are less then TSH & TRH will be
produced more and vice-versa
• Normal thyroid secretion rate is
– T4 = 100 g/day
– T3 = 7 g/day
– (Ratio of T4:T3 = 14:1 )
Biochemical functions of T3 & T4
1. Influence on the metabolic rate:
– Stimulate metabolic activities & increases
oxygen consumption
2. Effect on protein synthesis:
– Promotes protein synthesis by acting at the
transcriptional level.
– Cause positive nitrogen balance & promotes
growth and development
3. Influence on carbohydrate metabolism:
– Promote intestinal absorption of glucose and
its utilization
– Promote hyperglycemia (↑gluconeogenesis &
glycogenolysis)
4. Effect on lipid metabolism:
– Stimulates lipid turnover and utilization
Metabolic fate of T3 & T4
• They undergo deiodination in peripheral
tissues
• May get conjugated with glucuronic acid or
sulphate in liver and excreted through bile
• They may also form tetraiodothyroacetic
acid ( from T4) and triiodothyroacetic acid
(from T3) which then undergo conjugation
and excretion.
Abnormalities of thyroid function
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Three abnormalities are known
associated with thyroid hormones
1. Goiter
2. Hyperthyroidism
3. Hypothyroidism
Goiter
• Any abnormal increase in size of thyroid gland is
goiter
• Enlargement is mostly to compensate ↓ thyroid
hormones & ↑ TSH
• This is primarily due to a failure in the
autoregulation of T3 & T4 synthesis
• May be caused by deficiency or excess of iodine
• Goitrogenic substances: thiocyanates, nitrates &
percholates and drugs like thiourea, thiouracil,
thiocarbamide etc.
• Simple endemic goiter: due to iodine deficiency
in diet. Mostly found in those geographical
regions where iodine is less in soil & water
Hyperthyroidism
• Also known as thyrotoxicosis which is due to the
overproduction of thyroid hormones and ↓TSH
• Characterized by increased metabolic rate (↑
BMR), nervousness, irritability, anxiety, rapid
heart rate, loss of weight, weakness, diarrhea,
sweating, sensitivity to heat etc.
• Caused by either Grave’s disease (↑ thyroid
stimulating IgG) or increased intake of thyroid
hormones
• Diagnosed by scanning or thyroid hormones
estimation
Hypothyroidism
• May be due to an impairment in the function of
thyroid gland or disorders of pituitary or
hypothalamus as a result there will be ↓ T3 & T4
level and ↑ TSH
• Characterized by reduced BMR, slow heart rate,
weight gain, sluggish behavior, constipation,
sensitivity to cold, dry skin etc.
• Cretinism (physical & mental retardation) in
children and myxodema (bagginess under the
eyes, puffiness of face, slowness in physical &
mental activities) in adults.
Thyroid function test
• OBJECTIVES:
– To assess the functional status of the gland.
– To know anatomical features of thyroid gland.
– To evaluate possible cause.
– To confirm the biochemical response.
– To assess treatment (complications).
Serum TSH level
• Normal serum TSH = 0.4 – 5.0 U/ml (<10 U/ml)
• TSH  in case of:
– Primary hypothyroidism
– Recovery from severe illness
– Iodine deficiency (nontoxic goiter)
– Pituitary tumor, etc
• TSH  in case of:
– Hyperthyroidism
– Exogenous thyroid hormone excess
– Thyroiditis
– First trimester of pregnancy
Thyroxine (T4)
• Serum T4 levels:
– Serum total T4 (TT4) = 5-12μg/dL(65-156nmol/L)
– Serum free T4 (FT4) = 0.8-2.4ng/dl(10-30pmol/L)
• Interpretation:
– Serum T4  ( > 12 g/dL) – Hyperthyroidism
– Serum T4  ( < 2.5 g/dL) – Hypothyroidism
Triiodothyronine (T3)
• Serum T3 level:
– Normal serum T3: 80–220ng/dL(1.2-3.3mmol/L)
– Normal serum rT3: 30-80ng/dL(0.45-1.2nmol/L)
• Interpretation:
– Serum T3  ( > 300 ng/dL)  Hyperthyroidism
– Serum T3  ( < 70 ng/dL)  Hypothyroidism