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 www.merrium- webster.com

TSH – the background Diagnose/ monitors the Hypothyroidism TSH is one of the best screening test for the diagnosis of the thyroid gland disorders and: 1 Monitors the treatment of hypothyroidism 2 Thyrotropin is released in response to hypothalamic hormones - 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 a glycoprotein having 2 chains with CHO moiety, produced in the RER of Thyrotropes – Ant.Pituary gland 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 www. slideshare.com

Structure of TSH

TSH - the target organs GPCR Target cells are the ones with TSH receptors – GPCR The major target organ is the thyroid gland TSH receptors are located on the plasma membrane of the thyroid follicular cells

Biosynthesis of TSH Thyrotropin is synthesized as Prohormone in the RER of the Thyrotropes of Ant. Pituitary Gland It loses signal sequence via peptidase in RER and CHO is added both in RER and Golgi apparatus Both α and β chain are interlinked and is important for the bioactivity of the TSH TSH undergoes post translational modification for the mature hormone

Regulation of TSH synthesis – 2 pathways TSH secretion is regulated essentially by the negative feed back mechanism This is achieved by 2 pathways Neuro endocrine/long loop/indirect regulation Pituitary – thyroid axis/ direct/short loop 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 Pituitary and circulating level of TH When TH level is high, it interacts with the TSH from the anterior pituitary and reduces TSH secretion 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 serum level of T3 and T4 inhibits TRH from the hypothalamus and TSH as result and 1 Stimulates the secretion of TIH from the hypothalamus 2 Opposite is true when TH level is Low (↑es TRH +TSH).

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 receptors over the plasma membrane of thyroid cells – GPCR Activation of G - protein leads to the separation of α subunit to bind with α- GDP for α- GTP

TSH mechanism of action – G- protein activation 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 to executes the actions of TSH

TSH – mechanism of action

TSH - Actions on thyroid cells As tropic hormone TSH increases the size and NO: of the thyroid cell by increasing the cellular DNA content - 1 ↑ mRNA and translation of proteins - 2 Promotes the growth /nutrition of thyroid gland

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 for elemental Iodine Iodination of Tyrosine Coupling of Iodotyrosines Release of T4 and T3 ↑ in the intracellular Ca++.↑ Glycolysis and NADFPH generation

TSH - Serum abnormalities The circulating level of TSH may be ↑or ↓giving rise to : important clinical conditions These conditions are usually associated with excess or reduction in TH levels - T4 and T3

TSH excess and normal TH - Hypothyroidism Cold intolerance High TSH level with normal T4 is hypothyroidism It is characterized by reduction in: BMR, O2 consumption and heat production - Increase in body weight, Diabetes and CVD and: Cold intolerance and Constipation

Hyperthyroidism - Low TSH and high T4 cold tolerance It is low/ normal TSH level with high T4 It is characterized by increase in : BMR,O2 consumption and heat production Reduction in body weight . ↑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