Download Thyroid Stimulating Hormone

Thyroid Gland
Parts I and II
The Gentlemen's Guide
Like a Sir
Learning Objectives
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Identify the steps in the biosynthesis, storage, and secretion of tri-iodothyronine
(T3) and thyroxine (T4) and their regulation.
Describe the absorption, uptake, distribution, and excretion of iodide.
Explain the importance of thyroid hormone binding in blood on free and total thyroid
hormone levels.
Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in
extra-thyroidal tissues.
Describe the physiologic effects and mechanisms of action of thyroid hormones.
Explain what conditions can cause an enlargement of the thyroid gland.
Understand the causes and consequences of
A.
B.
over secretion of thyroid hormones
under secretion of thyroid hormones
Location of Thyroid Gland
Thyroid
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Located in the neck over the first part of the trachea
Humans-”butterfly” –two lateral lobes connect by an isthmus
Nodules on thyroid=parathyroid glands (2 superior/2 inferior)
Parafollicular (C cells)—major source for hormone calcitonin
canine
Chemistry of Thyroid Hormone
• Thyroid hormones are derivatives of the amino acid
tyrosine covalently bound to iodine
• Iodine bound at either 3 or 4 positions on two
linked tyrosines
• Other iodinated molecules can be generated
(example: rT3 but are inactive)
• T3 and T4 are poorly soluble in water (blood) so are
carried bound to proteins
• Principle binding protein is thyroid-binding
globulin
• Other important carrier proteins are albumin
and transthyrein
• Carriers allow a stable pool of hormone in blood that
can release free hormone to tissues (sites of action)
Steps in Biosynthesis, Storage
and Secretion of T3/T4
Raw materials:
1: Tyrosine-sourced from thyroglobulin in colloid
thyroglobulin secreted by thyroid epithelial cells
2: Iodide (I-)-uptake from blood by thyroid
epithelial cells (outer plasma membrane has a
Na+/I- symporter) once in cell transported to
colloid with thryoglobulin
Steps in Biosynthesis, Storage
and Secretion of T3/T4
1. Thyroid peroxidase adds the (iodide) I- to tyrosines on thyroglobulin (organifaction of
iodide).
2. Synthesis of thyroxine (T4) or tri-iodotyrosine (T3) from two iodotryosines
Remember that the hormone is still tied to the thyroglobulin ---needs to be liberated into
the circulation as needed
Thyroid Hormone Cycle
Steps in Biosynthesis, Storage
and Secretion of T3/T4
Release of T3/T4 from colloid:
1. Thyroid epithelial cells ingest iodinated
thyroglobulin from apical surface (endocytosis)
2. Colloid filled endosomes fuse with lysosomes
that contain hydrolytic enzymes that digest the
iodinated thyroglobulin
• Release of active thyroid hormone
3. Free thyroid hormone diffuses across the basolateral epithelial membrane into ECF (blood)
4. Free thyroid hormone quickly bound to carrier
proteins to be transported and release at target
cells.
Transport of Thyroid Hormone
• T3/T4 are highly bound to plasma protein carriers
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Major carrier is thyroxine–binding globulin (TBG)
Secondary carriers are albumin and thyroxine-binding prealbumin
Approximately 99.9% of T4 bound and <0.1% is free hormone
[T3]free in plasma <1% (more active than T4)
Because of tight binding to plasma proteins has long half life
• (T4=7 days)
• Free hormone is what is captured by target cells and
• exerts its biological effect before degradation
Transport of T4/T3 to peripheral tissues
• Increases (pregnancy) and Decreases (liver diseases) in circulating plasma
• TBG levels change the amount of TBG bound hormone
• However, They only transiently effect the amount of biologically active FREE
hormone because the negative feedback of free hormone on TSH levels
• Remember: TSH stimulates release of free hormone
• Example: In pregnancy, a fall in T3 levels, causes a compensatory increase in TSH
levels that in turn will increase production of free hormone in the circulation.
Increased thyroid hormone shuts off TSH
• But total [free hormone = T3] may be higher
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Thyroxine (T4) conversion to T3
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T4 is the dominant secreted/circulated form from the thyroid
However:
Most of the T4 secreted by thyroid is metabolized to T3
De-iodinated at the 5’ or 5 position in peripheral tissues to either T3 or rT3 (inactive)
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Since T4 is primarily converted to T3 that has a higher affinity for thyroid hormone receptors --sometimes T4 is considered a prohormone for T3
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Ratio of T4 to T3 is 5:1 in circulation
Potency of T4 to T3 is 1:10 (affinity)
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T4 is converted to T3 by peripheral peroxidase
Mechanism of Action and of T3/T4
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Receptors for thyroid hormone action are
INTRACELLUAR DNA-BINDING PROTEINS
Function as hormone responsive
transcription (HRE) factors
• Mode of action is similar to steroid
hormones
T3 binds to short repetitive sequences of DNA called Thyroid Response Elements (TRE)
TRE DNA sequence= AGGTCA
Can be arranged as direct repeats, pallindromes or inverted repeats.
Can be monomer (AGGTCA) homodimer (AGGTCANNNNAGGTCA) or a heterodimer
(T3+ another protein in complex) with the retinoic acid receptor (RXR) another member
of the nuclear receptor subfamily
Heterodimer is the high affinity form and thought to be the major functional entity
Mechanism of Action and of T3/T4
• Thyroid hormone receptors bind to the TRE DNA with and without T3
• Biological effects of T3 bound vs. T3 unbound receptor are dramatically different
Generally:
1: Binding of receptor w/o T3 to DNA transcriptional repression
results in compacted “turned off” chromatin
HDA=histone deactelyase
2: Binding of T3+receptor complex transcriptional activation
complex recruits different co-activators proteins –
conformational changesleads to gene activation
HAT=histone transacetylase
Thyroid Hormone Receptors
Structure
Mammalian Thyroid Receptors are
encoded by two genes α and β
Three Functional Domains:
1. Transactivation
• amino terminus---interacts
with other transcription factors
2. DNA Binding
• Recognition of HRE for binding
3. Ligand-Binding and dimerization
• T3 lignad binding at carboxy
terminus
Primary gene transcript for both forms
can be alternately spliced to form
multiple α and β isoforms.
Thyroid Receptors
The different isoforms of thyroid receptor have patterns of expression that differ
by tissue and developmental stage.
Examples:
• α1, α2 and β1 isoforms are expressed in virtually all tissues
• β2 found predominantly in hypothalamus, anterior pituitary and developing ear
• α1 first to be expressed in fetus and β1, β2 up-regulated in developing brain
after birth
• They activate several genes known to important in brain development such
as myelin basic protein
Regulation of Thyroid Hormone Secretion
Hypothalamic-pituitary-thyroid axis
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Control of thyroid hormone secretion is a NEGATIVE FEEDBACK LOOP
Binding of TSH on thyroid epithelia enhances all the processes for hormone
synthesis of
1. Iodide transporter
2. Thyroid peroxidase
3. Thyroglobulin
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Magnitude of the TSH signal sets the rate for endocytosis of colloid
 TSH Faster rates of colloid synthesis hence more
hormone in circulation
 TSH Decrease in colloid synthesis hence less
hormone in circulation
COLD Exposure can increase TRH release  enhanced thyroid hormone release
Degradation of Thyroid Hormone
These steps occur in peripheral tissues:
1. Deiodination and decarboxylation
2. Glucuronidation/Sulfonation in liver
3. Excretion into bile ducts
4. Excretion of glucuronide conjugate in urine
Thyroid Hormone and Cellular
Metabolic Rate
Many of the effects of T3 are secondary to increased BMR
•  sweating and thermogenesis – heat elimination from skin
•  Rate and depth of breathing – need for O2
•  Cardiac output – from increases in SV and HR and changes in
contractile force
• Improve memory and learning capacity
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Most tissues
– Increase in O2 consumption
– Increase in heat production
• Mitochondria increase in size and number
• Key respiratory enzymes increase
Physiological Effects of Thyroid
Hormone
Metabolism:
• Thyroid hormone stimulates most tissues of the body resulting in an increase of basal
metabolic rate
• This involves:
1. Increases body temperature
• O2 consumption and ATP hydrolysis
2. Stimulates fat mobilization leading to increases of [FA] in plasma
• FA oxidation is also increased
3. Increases in carbohydrate metabolism
• increased insulin dependent glucose entry into cells, gluconeogenesis
,glycogenolysis
Growth:
• Thyroid hormone synergistically combines with growth hormone to enhance grow
processes
Physiological Effects of Thyroid
Hormone
Development:
• Critical for development of fetal and neonatal brain
Cardiovascular:
• Promotes vasodilation ---increased vascular flow in organs
• Increases cardiac output, cardiac rate, and cardiac contractility
CNS:
• Decreased hormone sluggish mental activity
• Increased hormone related to anxiety
Reproduction:
• Low hormone levels frequently associated with infertility (female) (male?)
Thyroid and Bone
• Bone cells have receptors
for Thyroid hormone:
• Necessary for growth
and maturation of
the skeleton
• If thyroid hormone levels
are too high
• Osteoporosis and
bone loss
Thyroid and the Heart:
T3-Responsive Genes for Important Cardiac Proteins
Positive regulation-increased gene expression
• Sarcoplasmic reticulum calcium adenosine triphosphatase
• Myosin heavy chain α
• β1-Adrenergic receptors
• Guanine-nucleotide-regulatory proteins
• Sodium/potassium adenosine triphosphatase
• Voltage-gated potassium channels
Negative regulation-decreased gene expression
• T3 nuclear receptor α1
• Myosin heavy chain β
• Phospholamban
• Sodium/calcium exchanger
• Adenylyl cyclase types V and VI
Thyroid Function in Pregnancy
and Fetal Development
Maternal Thyroid Function in Pregnancy:
Normal changes in thyroid function during pregnancy include:
1a) 2-fold increase T4 (thyroxine) binding globulin (TBG) stimulated by increases in estrogen
1b) Increased levels of TBG decrease free T4 therefore more TSH is made, in turn, increasing T3 and T4
1c) Increased amounts of thyroid hormone balance reached at 20 weeks and maintained until parturition
2. Increased demand for iodine—significant increase in pregnancy clearance of I- by kidney and siphoning of Iby fetus from maternal circulation
3. Thyroid stimulation by hCG—TSH and hCG similar enough that hCG can increase mimics TSH at gland
receptor stimulates T3 release while TSH maybe suppressed (graph)
Some women may develop transient hyperthryoidosis in
pregnancy or if a woman has subclinical hypothryoidism the
demand of fetus can precipitate hypothyroidism.
Thyroid and Fetal Brain
Thyroid receptors present in brain tissue before fetus is
synthesizing its own hormone.
• During fetal brain development thyroid hormone assists in
activation of genes (HRE) involved with terminal stages of
brain differentiation
1. Synaptogenesis
2. Growth of dendrites and axons
3. Myelination
4. Neuronal migration
Thyroid Hormone Resistance
• Mutations in β receptor gene that abolish ligand-binding
• In most families transmitted as dominant trait
• Clinically:
• Hypothyroidism with goiter
• Elevated serum [T3] and [thyroxine] and normal or elevated serum
[TSH], significant number of pediatric patients show attention deficit
disorder.
– Activity is decreased because there is no receptor binding.
Graves Disease
– Most common form of hyperthyroidism
– Antibodies Thyroid stimulating immunoglobulins (TSIs)
form against the TSH receptor of the thyroid gland
– TSI’s bind to TSH receptor and mimic action of TSH
– Results in Goiter and increases thyroid hormone and
decreases in TSH because of negative feedback due to
increased thyroid hormone in plasma
Predicted Changes in Graves
1. Increased metabolic rate
2. Heat intolerance and sweating
3. Increased appetite but weight loss
4. Palpitations and tachycardia
5. Nervousness and emotional swings
6. Muscle weakness
7. Tiredness but inability to sleep
– Many patient’s develop protruding eyeballs (exopthalmos)
• Degenerative changes in extraocular muscles resulting from autoimmune reaction
Hypothyroidism
Hashimoto’s Thyroiditis
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Autoimmune destruction of gland
Also called Autoimmune Thyroiditis
Predicted changes
1) Decreased metabolic rate
2) Cold intolerance and decreased sweating
3) Weight gain w/o increased appetite
4) Bradycardia
5) Slowness of speech, thought and movement
6) Lethargy and sleepiness
Accummulation of mucoplysacchrides in interstial spaces----”puffiness” of skin myxedema
Decreased Thyroid hormone  increased TSH levels (may lead to compensatory goiter)
Thyroid Deficiency
In Fetus and Neonate
Fetus has two potential sources of thyroid hormone
Maternal
Fetal
• Fetus begins to make T3/T4 at approximately 12 weeks gestation
• Substantial transfer of hormone across the placenta
• placenta has a de-iodinases that converts T4 to T3
Three forms of hypothyroidism in Pregnancy:
1. Isolated Fetal Hypothyroidism
2. Isolated Maternal Hypothyroidism
3. Iodide Deficiency (combined maternal and fetal hypothyroidism)
Cretinism
• Severe hypothyroidism resulting stunted
growth and mental retardation
– Athyrotic cretinsim
• thyroid aplasia or Iodine deficiency in utero
– Endemic cretinism
• iodine deficiency
– Spasticity, deaf-mutism, motor dysfunction
• Symptoms
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Puffy face, short stature, protruding abdomen and
swollen tongue, slow reflexes
Iodide Deficiency
• Combined maternal-fetal hypothyroidism
• Most common cause of preventable mental retardation
world-wide
• Results in cretinism, mental retardation,deaf mutism and
spasticity
• Supplement with iodine in 1st and 2nd trimester (later will not
prevent defects)
• Endemic Goiter
– high plasma TSH stimulates gland
Hyperthyroidism in Pregnancy
Gestational Hyperthyroidism
• Increased risk for:
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– Preeclampsia
– Premature labor
– Fetal or perinatal death
– Low birth weight
May be caused by Grave’s Disease
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Auto-antibodies against TSH receptor
Fetal Hypothyroidism
Sporadic Congenital Hypothyroidism
• Fetal gland doesn’t produce enough hormone
– Normal at birth (maternal compensation)
• Needs rapid diagnosis shortly after birth or
risk child having permanent mental and growth
retardation
Maternal Hypothyroidism
• Female hypothyroidism frequently associated with
infertility
• If pregnancy does occur there is an increased risk of
fetal death and gestational hypertension
• Subclinical maternal hypothyroidism
– Diagnosed retrospectively
– Auto-antibodies to thyroid that can cross placenta
– Children with lower IQ scores
Hamburger Thyrotoxicosis
Rare Case
A 61 yr. old woman in Canada presented to physicians with intermittent hyperthyroidism that would resolve on
its own over 2-3 months. They saw rapid weight loss, increased sweating and palpitations, tremor in her hands
and a heart rate of 112 beats/minute.
Diagnosis was confirmed by and elevated free T4 (46 compared to 9-23) and a very low TSH. Within 2 months her
symptoms disappeared on their own and her T4 returned to normal range. She did not have thyroid antibodies.
The woman had 5 such episodes over an 11 year period. The physicians were left puzzled.
Resolution:
1. Patient indicated she did not take herbal supplements or thyroid supplements
2. Additional questioning about her dietary habits revealed the cause.
• She lived on a farm and every year a cow was slaughtered and the butcher packaged the meat for use.
It was discovered that the butcher did not know that “gullet trimming” was prohibited. Hence, muscles
from the larynx and thyroid were trimmed and used to make hamburger patties. The woman consumed
these (her husband did not) patties and had exposure to cow thyroid gland.
• 1984-85—similar cases seen in Minnesota, South Dakota and Iowa.
Key Concepts
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How is thyroid hormone regulated ?
Why is mode of action like a steroid hormone?
Over secretion of thyroid hormone has what consequences?
Under secretion of thyroid hormone has what consequences?
What is the active form of the hormone?
How does hormone reach tissues?
What are the actions at tissue level?
What amino acid forms the backbone of thyroid hormone?
Sample Board Question
Blood levels of ________would be decreased in
Grave’s Disease.
A. Tri-iodothyronine (T3)
B. Thyroxine (T4)
C. Diiodothyrosiine (DIT)
D. Thyroid Stimulating Hormone (TSH)
E. Iodide (I-)