Transcript Mechanism of Thyroid Hormones

HPT axis
Review of HPA
Hypothalamus receives multiple
signals from various regions of the
brain
Hypothalamus can directly release
hormones into bloodstream in
posterior pituitary via neurons or;
Secrete hormones via portal system
(blood vessels) to anterior pituitary
that regulate hormone secretion from
anterior pituitary
HPT axis
Hypothalamic-pituitary-thyroid axis
Thyrotropin releasinng hormone (TRH) is released
from paraventricular nucleus of hypothalamus
TRH stimulates cells in the anterior pituitary, called
thyrotropes, to release thyroid stimulating hormone
(TSH)
TSH stimulates the thyroid gland to synthesize the
thyroid hormones (T3 and T4)
Anatomy of thyroid gland
Thyroid gland is an unpaired
endocrine gland surrounding
anterolateral (front and sides)
surface of trachea in the neck
Consists of two lateral lobes
with a connecting isthmus
(narrow strip)
Histology and Composition
•Composed of spherical follicles
•Follicles are surrounded by a
single layer of epithelial cells
called follicular cells
•Inner space is called follicular
lumen and is filled with a colloid
rich in thyroglobulin protein
•Parafollicular cells, or “C-cells”,
can be found scattered among
follicular cells or in spaces
between follicles
•TSH receptors are found on the
surface of follicular cells
Colloid
Thyroglobulin
Follicular
cell
Parafollicul
ar cell “Ccell”
Capillary
TSH
receptor
Thyroid hormone synthesis
Thyroglobulin (Tg) is made in the follicular cells and
released into the follicular lumen
Tg has a number of exposed tyrosine residues
An enzyme called thyroperoxidase (TPO) oxidizes an
iodide (I-) to I+ and adds it to the tyrosine rings of Tg to
get MIT and can do it a second time and form DIT
TPO can fuse a DIT and an MIT to form T3 or DIT and a
DIT to get T4
Thyroid hormone synthesis
Tg, along with the
attached T3, T4, DIT, and
MIT, is engulfed by the
follicular cell
Tg is broken down and
the T3 and T4 are
released into the
bloodstream
Iodide in thyroid hormone
synthesis
Iodide is essential to the synthesis of TH
On the external (non-lumenal) surface of follicular cells are
iodide pumps that actively transport iodide into cell at
concentrations 20-50 times of that outside the cell
Effect of TSH
Has multiple roles in increasing TH release
Increases activity of iodide pump such that the ratio of [I]IC:[I-]EC is 500:1
Affects DNA to increases production of the iodide pump
Activates TPO
Stimulates breakdown of Tg and release of T3 and T4
Where are thyroid hormones
stored?
Thyroid hormones are stored in the colloid inside the follicle
Stored in the form of iodinated thyroglobulin
Thyroid gland can store enough hormones to serve the body
for 2 – 3 months
Thyroglobulin
Glycoprotein (10% carbohydrate)
660 kDa, dimeric protein produced by and used only
within the thyroid gland
Produced by the follicular cells of the thyroid
During storage, T3 and T4 are attached to thyroglobulin
When thyroglobulin is endocytosed  hormones are
released
Hydrolysis releases thyroid hormones
Release of Thyroid Hormones
1.When TSH is released,
thyroglobulin molecules form colloid
droplets and are taken back up into
follicular cells by endocytosis
2.Colloid droplets fuse with
lysosomes  hydrolysis of Tg T3
and T4 are released
3.About 10% T4 converted to T3
before secretion
4.T4 and T3 containing vesicles are
excreted out to blood stream
Delivery of Thyroid Hormones to
Tissues
T3 and T4 are water-insoluble
Need to bind to a transport protein in
the serum to be transported to tissues
Thyroid Binding Globulin (TBG) =
produced by the liver
Transthyretin (TTR) = also secreted by
liver
Albumin = main protein in blood
http://www.anaesthetist.com/icu/organs/endocr/th
yroid/images/t3t4.gif
Thyroid Binding Plasma Proteins
Protein
Binding strength
Plasma concentration
Thyroid Binding
Globulin (TBG)
highest
lowest
transthyretin (TTR)
lower
higher
Albumin
poorest
much higher
http://en.wikipedia.org/wiki/Transthyretin
•In cerebrospinal fluid, TTR is the primary carrier
Thyroid Proteins in Plasma
Type
Percent
bound to Thyroxin Binding Globulin (TBG)
70%
bound to transthyretin (TTR)
10-15%
Albumin
15-20%
unbound T4 (fT4)
0.03%
unbound T3 (fT3)
0.3%
http://en.wikipedia.org/wiki/Thyroid_hormone
Conversion of T4 to T3
All T4 is converted to T3 in peripheral
tissues
More T4 is secreted by thyroid
But T3 works better than T4
This conversion is done by
Iodothyronine Deiodinase
http://www.anaesthetist.com/icu/organs/endocr/th
yroid/images/t3t4.gif
Mechanism of Thyroid Hormones
Thyroid hormones are hydrophobic 
readily cross lipid bilayer
Bind to receptor in cytoplasm
Enter nucleus
Bind to DNA in the nucleus
Change DNA expressions  change
specific mRNA level  change protein
level
Physiologic Effects of Thyroid
Hormones
Almost all cells in the body are targets for thyroid
hormones
Important for development, growth and metabolism
Deficiency and excess state lead to abnormal health
state
Thyroid Hormone and Metabolism
Stimulate metabolic activities in most tissues → lead
to increase in BMR (Basal metabolic rate)
BMR = the amount of energy a person expends daily
while at rest
Thyroxine increases the number and activity of
mitochondria in cells → increased body heat production
→ increased oxygen consumption and rates of ATP
hydrolysis
Effects on Lipid and Carbohydrate
Metabolism
Carbohydrate metabolism
Low amounts  glycogen synthesis (enhance insulin
dependent entry of glucose into cells)
High amounts  glycogenolysis and gluconeogenesis to
generate free glucose
Lipid metabolism
Deficient  serum cholesterol levels increase
High amount → fat mobilization and oxidation of fatty
acids in tissues → serum cholesterol levels decrease
Effects on Growth and
Development
Thyroid hormones are needed for normal growth in
children and young animals
Thyroid deficiency → growth-retardation
Tadpoles deprived of thyroid hormone → unable to
undergo metamorphosis into frogs
Normal levels of thyroid hormones are essential for
proper development and growth of fetus and neonatal
brain
Other Effects
Cardiovascular system
Thyroid hormones → increase heart rate, cardiac
output, and vasodilation → more blood flow to
organs
Increase transcription of myosin protein genes in
cardiac muscle → increased cardiac contractility
Central Nervous System
Too little → mentally sluggish
Too much → anxiety and nervousness
Reproductive System
Too little → infertility
Dysregulation - Hyperthyroidism
Too much = HyPERthyroidism = increased thyroid hormones in
blood
Non-functional negative feedback system
Graves Disease = autoimmune disease → antibodies bind to and
activate the thyroid-stimulating hormone receptor → continuous
stimulation of thyroid hormone synthesis
Common symptoms:
Nervousness, high heart rate, anxiety, weight loss but increased
food ingestion
Treatment: anti-thyroid drugs → suppress synthesis of thyroid
hormones by blocking thyroid peroxidase
Dysregulation - Hypothyroidism
Too little = HyPOthyroidism
Primary: Problem with the thyroid → part of the thyroid is
destroyed (95% cases) = Hashimoto's thyroiditis
Secondary: problem with pituitary → decreased TSH secretion
→ decreased production of T3 and T4
Tertiary: problem with hypothalamus → decreased TRH
hormone
Iodine deficiency → not enough thyroid hormones are made
Common symptoms:
Lethargy, fatigue, weakness, cold intolerance, reproductive
failure, weight gain but appetite decrease
Treatment = synthetic thyroid hormone