TSH

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.

Uses

Thyrogen (Genzyme).

Uses

Thyrotropic hormone from porcine pituitary can be used as a NCTC-135 medium supplement for isolating the thyroid cells which in turn is used for studying the impact of retinoids on non-transformed cells like thyrocytes. The product can also be used in cell proliferation experiment for studying the impact of increased IGF binding proteins 1 level on the function and growth of the thyroid gland in transgenic mice.

Definition

A hormone secreted by the anterior lobe of the pituitary gland. It increases the rate of removal of iodine from the blood by the thyroid gland, synthesis of the thyroid hormone, and its release into the bloodstream. The thyrotropic hormone is a protein with a low molecular weight (about 10,000) that contains some carbohydrate.

Indications

TSH, or thyrotropin, is a glycosylated protein of two subunits,  and . TSH stimulates the thyroid gland to produce thyroid hormones. Deficiencies are treated by giving thyroxine itself rather than TSH, but TSH is available for diagnostic purposes to differentiate between pituitary and thyroid gland failure as causes of hypothyroidism.

brand name

Thyrotrophin is INN and BAN.

General Description

The thyrotropic hormone, also called thyrotropin and thyroidstimulatinghormone (TSH), is a glycoprotein consisting oftwo polypeptide chains. This hormone promotes productionof thyroid hormones by affecting the kinetics of the mechanismby which the thyroid concentrates iodide ions from thebloodstream, thereby promoting incorporation of the halogeninto the thyroid hormones and release of hormones by thethyroid.
TSH (Thyropar) appears to be a glycoprotein (relativemolecular mass [Mr] 26,000–30,000) containing glucosamine,galactosamine, mannose, and fucose, whose homogeneityis yet to be established. It is produced by thebasophil cells of the anterior lobe of the pituitary gland.TSH enters the circulation from the pituitary, presumablytraversing cell membranes in the process. After exogenousadministration, it is widely distributed and disappears veryrapidly from circulation. Some evidence suggests that thethyroid may directly inactivate some of the TSH by an oxidationmechanism that may involve iodine. TSH thus inactivatedcan be reactivated by certain reducing agents.TSH regulates the production by the thyroid gland of thyroxine,which stimulates the metabolic rate. Thyroxinefeedback mechanisms regulate the production of TSH bythe pituitary gland.

Biochem/physiol Actions

Two-chain glycoprotein hormone. The α-chain is not active, biological specificity attributed rather to the β-chain. Activates adenylate cyclase in the thyroid gland, stimulating iodine uptake, thyroxine synthesis and release. Goitrogenic.

Clinical Use

Recombinant form of human thyroidstimulating hormone (rhTSH). Used diagnostically for serum thyroglobulin testing.

Clinical Use

TSH levels are measured as part of a thyroid function test in patients suspected of hyperthyroidism and hypothyroidism as the simplest and most sensitive indicator. Primary hypothyroidism/hypothyroidism is characterized by a high/low serum TSH concentration and a low/high serum free T4 concentration. Subclinical hypothyroidism/hypothyroidism is defined biochemically as a normal free T4 concentration in the presence of an increased/decreased TSH concentration. Central hypothyroidism is characterized by a low serum T4 concentration and a low or normal serum TSH concentration, whereas TSH-secreting pituitary adenomas may lead to the development of hyperthyroidism through a condition called the syndrome of the inappropriate secretion of TSH (SITSH). Recombinant human TSH is used in the follow up of patients with thyroid cancer to ablate the thyroid remnant following thyroid cancer surgery, and to obtain reliable diagnostic test results for the recurrence of differentiated thyroid cancer.

Veterinary Drugs and Treatments

The labeled indications for the formerly available veterinary product Dermathycin? (Mallinckrodt) was for “the treatment of acanthosis nigricans and for temporary supportive therapy in hypothyroidism in dogs.” In actuality however, TSH is used in veterinary medicine principally as a diagnostic agent in the TSH stimulation test to diagnose primary hypothyroidism.