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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