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 2 Opposite is true when TH level is Low (↑es TRH and TSH).

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