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Questions And Answer

• Discovery

  This is a thyrotropic glycoprotein hormone secreted from the anterior pituitary. TSH stimulates thyroid growth and function as well as thyroid hormone secretion. Bovine TSH was the first purified TSH, and its primary structure was determined in 1971. The structure and full nucleotide sequence of the human TSH β-subunit gene was determined in 1985.;

• Structure

  TSH is a glycoprotein consisting of noncovalently linked glycoprotein hormone (GPH) α- and TSH β-subunits. The GPH α-subunit is common to the follicle-stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) . The TSH β-subunit contains a cysteine-knot motif, which is critical for the heterodimer assembly and its biological activity. The N-linked oligosaccharide chain is important for the intracellular folding, secretion, metabolic clearance, and biological activity of the hormone.  Mr 25,000–30,000, pI 6.8–8.5. Multiple isoforms exist due to the microheterogeneity of oligosaccharide chains. Soluble in water. Inactivated by heating; treatment with trypsin, chymotrypsin, and pepsin; and oxidation (potassium permanganate, elemental iodine).;

• Synthesis and release

  The synthesis and release of TSH are directly stimulated by thyrotropin-releasing hormone (TRH). The administration of estrogen and insulin, and cold exposure, have stimulatory effects on TSH release. Thyroid hormones (T3 and T4) inhibit the synthesis and release of TSH through binding to the thyroid hormone receptor. Somatostatin and melanin-concentrating hormone (MCH) also inhibit TSH release. In the pars tuberalis, TSH secretion is regulated by melatonin that transmits photoperiodic information to regulate seasonal reproduction in mammals.;

• Receptors

  The receptor of TSH (TSHR) is a glycoprotein that belongs to a subclass of the rhodopsin/β-adrenergic subfamily of the membrane-bound GPCR superfamily. The TSHR consists of around 770 aa residues containing a large N-terminal extracellular domain (~410 aa residues), seven transmembrane domains, and a C-terminal intracellular domain. TSHR is mainly coupled to Gs and Gq proteins, and TSH activates the cAMP and PLC cascades.;

• Agonist and antagonists

  Recombinant human TSH and small molecule TSHR ligands are agonists. Deglycosylated TSH7 and small molecule TSHR antagonist are antagonists.;

• Gene, mRNA, and precursor

  The human TSH β-subunit gene, TSHB, location 1p13, consists of three exons. Human TSH β-subunit mRNA has 867 b that encode a signal peptide of 19 aa residues and a mature protein of 119 aa residues.  The TSH β-subunit mRNA is present in the basophilic thyrotropes distributed in the pars distalis and pars tuberalis of the anterior pituitary.;

• Biological functions

  TSH derived from the pars distalis of the pituitary binds to the TSHR located on the membrane of thyroid follicular cells. TSH stimulates thyroid hormone production, iodine uptake and organification, and thyroid growth. TSH derived from the pars tuberalis of the pituitary binds to the TSHR in the ependymal cells and induces the expression of type 2 deiodinase (Dio2), which converts T4 into bioactive T3. This leads to seasonal reproduction. TSHR is also expressed in a variety of extrathyroidal tissues including fat, fibroblasts, bone, and cardiomyocytes. ;

• Clinical implications

  Familial TSH deficiency with point mutations in TSHB and numerous mutations in the TSHR gene have been identified and associated with thyroid diseases. Graves’ disease is an autoimmune thyroid disorder in which the body produces antibodies to TSHR (TSAbs) that mimic the effects of TSH. TSAbs induce increased metabolic rate, and the associated symptoms result in thyroid eye disease, exophthalmos (protuberance of one or both eyes), fatigue, weight loss with increased appetite, and other symptoms of hyperthyroidism.;

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