Download Thyroid Stimulating Hormone TSH Lecture NO. 2nd

Thyroid Stimulating Hormone - TSH
Lecture NO: 2ndMBBS
Dr Muhammad Ramzan
Thyroid Stimulating Hormone (TSH) – the definition
• TSH is the formal name of a protein hormone from the
anterior pituitary gland
• It is also called Thyrotropin
• Thyrotropin regulates the endocrine functions of the
thyroid gland
TSH – the background
Diagnose/ monitors the Hypothyroidism
• TSH is one of the best screening test for the diagnosis
of the thyroid gland disorders (like hypothyroidism) and: 1
• Monitors the treatment of hypothyroidism
2
• Thyrotropin is released in response to the signals from
the Hypothalamus (TRH and TIH)
• It is a tropic hormone that regulates the growth, nutrition
and functions of the thyroid gland
TSH and hypothalamus
TSH - the structure
A Glycoprotein- 210 AA.
• TSH is secreted by the Thyrotropes from Ant. pituitary .
• It is a glycoprotein having 2 chains ,synthesized in the
RER of Thyrotrope cells with CHO moiety
•
α = 98 AA and β = 112 AA = 210 AA
•
α - chain is common to all Glycoproteins (FSH and LH)
• β chain determines the Receptor Specificity
• Separation of both the chains makes TSH as inactive
TSH – the structure
TSH - the target organs
GPCR
• Target cells are the ones with TSH receptors - GPCR
• TSH receptors are mainly found on the plasma membrane of
Thyroid Follicular cells - the Target cells
• TSH stimulates G - Protein Coupled Receptors on thyroid
cells to↑ the production of Thyroid hormones (TH)
Synthesis of TSH
• Thyrotropin is synthesized by the RER of the thyrotropes
of the ant. Pit. as Prohormone
• It loses signal peptidase in RER and carbohydrate is
added both in RER and Golgi
• Both α and β chain are interlinked which is important for
the bioactivity of the TSH
• TSH undergoes post translational modification for the
mature hormone
Regulation of TSH secretion – 2 pathways
TH as key player
• TSH secretion is regulated essentially by the negative
feed back mechanism
• This is achieved by 2 methods
• Direct or short loop /Pituitary - thyroid axis
• Indirect or long loop / Neuro - endocrine regulation
• The major player is the circulating level of TH
Regulation of TSH – Direct pathway
Pituitary - thyroid axis
• It is the interaction B/W TSH from Ant. Pituitary and
circulating level of Thyroid hormones
• When TH level is high, it inhibits the Ant. Pit. to
synthesize and release TSH that:
•
Lowers/brings TH level from thyroid gland to normal
• Opposite is true when TH level is low
TSH – Direct Regulation
Pituitary- thyroid axis
TSH - Neuroendocine /Indirect/
long loop regulation
• Hypothalamic- Pituitary- thyroid axis
• It is the interaction B/W the circulating level of TH and
Hypothalamus – TRH and TIH
• High level of T3/T4 inhibits TRH from the hypothalamus and
TSH as result (as well as Hypothalamic Somatostatin ) and :
1
• It also Stimulates the secretion of TIH from the hypothalamus to
• Bring back TH to normal
• Opposite is true when TH level is Low (↑es TRH and TSH).
2
TSH – Neuroendocrine regulation
TSH – Neuro - endocrine regulation/Indirect
Long loop – inhibition/stimulation
Mechanism of action of TSH -- GPCR
GPCR binding with β- subunit of TSH
• Mechanism of action of TSH is similar to the rest of the
protein/peptide hormones
•
β - subunit of the TSH binds to the receptor over the
plasma membrane of thyroid cells
• Activation of G- protein leads to the separation of α subunit
from other subunits to bind with α- GDP for α- GTP
TSH mechanism of action cont.
• Membranous Adenylate Cyclase is activated by binding
of α- GTP to the enzyme which produces:
• cAMP from ATP - the 2nd messenger
• cAMP causes Phosphorylation of intracellular protein/
enzymes via protein Kinase A to :
• execute the actions of TSH
TSH mechanism of action
TSH - Metabolic actions
As tropic hormone
• TSH increases the size and NO of thyroid cells by ↑
the DNA replication and its content 1
• ↑ mRNA and translation of proteins
2
• Promotes the growth, development and nutrition of the
thyroid gland and rest of the tissues. 3
Metabolic actions of TSH
Centered at Thyroid gland
• All the endocrine functions of thyroid are carried out by
the Thyroid Stimulating Hormone - TSH
• These include:
• Thyroglobulin synthesis
• Iodine trapping
Metabolic actions of TSH cont.
• Oxidation of Iodide to produce elemental Iodine
• Iodination of Tyrosine - Organization
• Coupling of Iodotyrosines
• Release of T4 and T3
• ↑ in the intracellular Ca++.↑ Glycolysis and NADFPH generation
TSH - Serum abnormalities
• TSH may be secreted in excess or there may be
deficiency of TSH for the body requirements
• Both the conditions give rise to different clinical conditions
• These conditions are usually associated with excess or
deficiency of thyroid hormones - T4 and T3
Hypothyroidism - TSH excess and normal TH Cold intolerance
•
↑ in TSH level with normal T4 is called hypothyroidism
• It is characterized by reduction in:
• BMR, O2 consumption and heat production
• Increases the body weight, Diabetes and CVD
•
Produces Cold intolerance and Constipation
Hyperthyroidism – T4 excess with normal /↓TSH
cold tolerance
•
It is characterized by low/ normal TSH level with high T4
• It increase in BMR,O2 consumption and heat production
• Reduction in body weight .
• Increase in heart rate and arrhythmias
• Cold tolerance and GIT disturbances
TSH – Normal serum levels
• Prevalent Normal serum level of TSH in adults is:
•
0.4- 4.5UIu/L
• Recent/new TSH recommendations
• .4 - 2.5uIU/L
• Normal serum level of T4 for adults
• 11.5 to 23.5 pmol/L
Why TSH normal levels are reduced
• NACB (National Academy of clinical Biochemistry) has suggested :
• to reduce the normal range of TSH for adults to .4 - 2.5uIU/L
• Adults with an initially measured TSH level of over 2uIU/L
• Had an increased odds ratio of developing hypothyroidism
• over (following) 20 years especially with ↑ thyroid antibodies