THYROID HORMONES
• The thyroid hormones are secreted by thyroid glands
located on top of the trachea [butterfly shaped gland].
• There are several follicles [thyroid follicles] filled with
colloid like substances which are thyroid hormones.
When the gland is stimulated by TSH, it secretes
T4-Thyroxine [tetra-iodothyronine]
T3 [tri-iodothyronine]
Thyroid hormones [T3&T4] are the iodine containing hormones [iodinated
thyronines].
• TRH released from hypothalamus activate thyrotropes to release TSH
which bind to receptors on the membrane of follicular cells.
• This binding activates the
i. PLC &
ii. PKA
Signaling pathways activated by TSH
TH synthesis involves various
steps;
1. Thyroglobulin formation
2. Uptake of Iodide ions & conversion to Iodine
3. Formation of T3 & T4 [Iodination & Coupling]
4. Storage & Release
1. The glycoprotein thyroglobulin (TG) is synthesized in 4. Iodine then combines with tyrosine located on
the nucleus and RER and then packaged into a vesicle the thyroglobulin molecule forming MIT, DIT.
by the Golgi apparatus to then be secreted into the
5. As well as oxidizing iodide to iodine, TPO is
follicular lumen by exocytosis.
the enzyme that catalyzes the reaction that
2. On the basolateral membrane of the follicular cell there
binds MITs with DITs together to create T3
are Na /K pumps that use ATP to pump 3 Na out of the
+ + +
and T4.
cell and 2 K+ in). The NIS utilizes secondary active
transport by using the energy of moving Na+ from high • T3 (active form 10%)
to low concentration to move iodide (I-) from low to
• T4 (inactive form 90%)
high concentration into the cell.
6. The newly formed thyroid hormone is then
3. pendrin then transports iodide into the lumen. An
taken into the cell through receptor mediated
enzyme called thyroid peroxidase (TPO) that is also on
endocytosis via a receptor called megalin.
the apical membrane then oxidizes iodide into iodine.
6. Once the thyroglobulin complex is in the
cell, a lysosome fuse with the vesicle and 10. Inside the capillary, T3 and T4 bind
break it down into MITs, DITs, amino acids,
T3, and T4. to thyroid binding globulin (TBG) for
7. In the cytoplasm of the cell there transport in the circulatory system.
is intracellular deiodinase which removes
the iodine from the MITs and DITs and 11. In the peripheral tissue, inactive T4 is
recycles it.
converted to active T3 by peripheral
8. The amino acids are also recycled to make
more thyroglobulin. deiodinase. T3 then binds to its receptors
9. On the basolateral membrane there is a and exerts its action to increase growth and
T3/T4 transporter that moves the newly
synthesized thyroid hormones across the metabolism.
membrane to the blood. 12. In the peripheral tissue, inactive T4 is converted
to active T3 by peripheral deiodinase. T3 then
binds to its receptors and exerts its action to increase
growth and metabolism.
Mechanism of action of T3 & T4
• TH bind transmembrane transporter & enter
the cells by active transport, combine with a
nuclear thyroid hormone receptor (TR). It is
bound to the thyroid hormone
response element (TRE) in the enhancer region
of the target genes. The corepressors keep the
gene transcription suppressed.
• When T3 binds to TR, it heterodimerizes with
retinoid X receptor (RXR) and undergoes a
conformation change releasing the corepressor
and binding the coactivator.
• This induces gene transcription → production of specific mRNA and a specific
pattern of protein synthesis → Increases Na+/K+ ATPases →decrease in cellular
ATP → so more O2 & macronutrients utilized to overcome the deficiency of ATP
through cellular respiration→
• Glucose +6 O2 ----------------→ ATP + 6 CO2 + 6 H2O + Heat
• Mitochondriogenesis & heat production.
Regulation
TH are under the direct control of TSH & indirect
control of TRH.
Raised plasma thyroid hormone level decreases TSH
release & vice versa.
T3 has 40 times more inhibitory effect on thyrotropes
[TSH releasing cells] than T4.
One molecule of TRH can release 100,000 molecules
of TSH.
• Electrical stimulation and cooling of hypothalamus
increases the release of TRH while heat suppresses
the release of TRH.
Metabolic Fate & Normal Serum levels
• T3 and T4 may get conjugated with glucuronic acid or sulfates in the liver
and excreted through bile.
• The concentration of free T3, T4, and TSH are measured for laboratory
diagnosis of thyroid function [TFT].
• Free T3 220 ng/dl
• Free T4 0.8-2.4 ng/dl
• TSH <10 mU/ml
Biochemical Functions
1. Effect on metabolism
• Thyroid hormones stimulate the metabolic activities and increases the oxygen
consumption in most of the tissues of the body.
• TH increases the activity of Na+/K+ ATPase pump by consuming ATP.
Calorigenic/Thermogenic effect
TH control the basal metabolic rate [minimum number of calories required for basic functions at rest]
and calorigenesis through increased oxygen consumption in tissue via the effects of thyroid
hormone on membrane transport (increased Na+/K+ ATPase activity with increased synthesis and
consumption of ATP) and mitochondriogenesis.
TH uncouple oxidative phosphorylation. Increased uncoupling appears to be responsible for
some of the hypermetabolic effects of thyroid hormones.
2. Protein Metabolism [Muscles]
TH keep balance between anabolism & catabolism.
Like steroid hormones, it has anabolic effect causing increased synthesis of
proteins and RNA. Hyperthyroidism has opposite effect. i. e, increased protein
breakdown and negative nitrogen balance. Skeletal muscle wasting and
weakness associated with hyperthyroidism is the result of protein breakdown.
• It synthesizes;
i. sex hormone binding globulin. ii. Angiotensin converting enzyme [converts the
hormone angiotensin I to the active vasoconstrictor angiotensin II] & iii. ferritin
3. Carbohydrate metabolism
Promotes glycogenolysis, gluconeogenesis & intestinal absorption of glucose.
All this increases blood glucose level [hyperglycemia].
But it also increases insulin secretion and peripheral utilization of glucose. These
effects tend to lower the blood glucose.
Clinically hyper and hypothyroidism show hyperglycemia and hypoglycemia
respectively.
4. Lipid metabolism [Adipose Tissues]
Increased lipolysis of TG into glycerol & FA.
Increased synthesis of cholesterol but its fecal excretion and conversion to bile acids
is also increased. Increased formation of LDL receptors in liver which take up
cholesterol from plasma LDL.
The net effect is decreased plasma cholesterol level.
Clinically high plasma cholesterol is found in hypothyroidism and low plasma
cholesterol in hyperthyroidism.
5. Action on Heart
• TH stimulate beta1-adrenergic receptors, there is increased binding of
epinephrine/nor-epinephrine →more cardiac contractility/cardiac output → high B.P.
• Transcription of some myosin genes is stimulated by thyroid hormones and the
net effect is increased contractility →high B.P.
6. Action on CNS
• TH increases dendrides [conduct impulses towards cell body] of neuron
• Increases myelination [myelin layers wrap around the neuronal axon, act as insulator for
transmission of AP down the neuronal axon].
• Increase in number of synapses [neuronal junction-the site of transmission of electric
nerve impulses between neurons]
leading to increase action potential, so a person with hyperthyroidism is
more anxious, anxiety, irritability etc.
7. Action on Skin
• TH increases catecholamines sensitivity which act on sweat glands to prduce
sweat for overcoming the heat produced.
• Hyperthyroidism → thick hair & Hypothyroidism → thin hair
probably by effecting hair follicles
8. GIT
• TH acts on GI smooth muscles → increases GI motiloity → increases GI
secretions → diarrhoea.
9. Thyroid hormone increases conversion of carotenes to vitamin A and in its deficiency
carotenemia along with vitamin A deficiency may develop.
It is also required for the conversion of riboflavin [B 2] to its coenzyme forms; FMN, FAD.
10. Calcium metabolism [Action on Bones]
• It mobilizes bone Ca+ by increasing osteoclastic activity [bone resorption].
• Normally, TH keep balance [bones remodeling] between osteoblasts [bone deposition] &
osteoclasts.
• Hyperthyroidism may cause hypercalcemia and the bones may become porous.
HYPERTHYROIDISM
Increased synthesis & secretion of TH by TG
Graves disease. [common cause of hyperthyroidism]
Grave’s disease is an autoimmune disorder. There is formation of
autoantibodies [thyroid stimulating Ig/TSI also known as long acting thyroid stimulator-LATS]
that bind to TSH receptors and stimulate the gland to hyperfunction.
The disease is associated with marked eye changes. There is bulging of the eye
balls because of hyperplasia of tissues behind eye balls. Therefore also called
ophthalmic goiter .
Graves Disease
• Hyperthyroidism may also be caused
by overactive nodules in thyroid gland.
It is called toxic nodular goiter.
• Other causes include thyroiditis,
excessive intake of iodine and
exogenous TH (thyrotoxicosis facticia).
Clinical Features of hyperthyroidism
• CVS
• High BMR (7100KJ/d, 5900 KJ/d)
• Tachycardia even at sleep
• Tolerance to cold, intolerance to heat.
• Cutaneous vasodilation and sweating to • High BP
lower body temp. • Atrial fibrillation (irregular heart
• Decrease in body weight/increased beat).
appetite, anxiety • Murmors (heart sounds produced when
• Diarrhoea. blood is pumped across a heart valve)
CNS EYE
Conjunctivitis, corneal ulceration, optic neuritis etc.
• Tremors, nervousness, anxiety,
Eye changes are produced by cytotoxic antibodies
irritability
produced against antigens common to the eye muscles
• Brisk tendon reflexes- an above average and thyroid.
response during a reflex test [muscle Skin changes
contracts more strongly or more often than Thickening of skin [stimulate dermal fibroblasts],
normal] & vitiligo (autoimmune disorder).
others
Reaction time of ankle jerk is shortened
Impotence, loss of libido [due to depression, fatigue]
[hyperthyroidism breakdown muscle fibers quickly
gynecomastia may occur [aromatization of
HYPOTHYROIDISM
When present in infants, called CRETINISM.
When present in adults, called MYXEDEMA.
CRETINISM
Sign/Symptoms
Causes 1. Stunted growth, mental retardation.
2. Low feed, low body temperature, severe
Endemic goiter (iodine deficiency goiter constipation, skin is cold and dry.
occur in areas where iodine content of soil is 3. Umbilical hernia (abnormal bulge at umbilicus)
[impaired gastric empting-abdominal distention] .
very low) OR 4. Calm and uninterested in his surroundings.
5. Enlarged tongue [macroglossia-increase
Congenital deficiency of thyroid gland. accumulation of adipose tissues in tongue] & jaundice [low
bilirubin conjugation].
6. Delayed sexual maturation [low Testosterone,
estradiol].
MYXEDEMA
Primary: due to Thyroid disease
Secondary: insufficiency of pituitary or
hypothalamus.
The most common cause is Hoshimoto’s
Thyroiditis (auto-immune disease, in which
immune system produces antibodies
against thyroid gland and destroy tissues).