Thyroid-stimulating hormone explained

Thyroid-stimulating hormone, alpha
Hgncid:1885
Symbol:CGA
Altsymbols:HCG, GPHa, GPHA1
Entrezgene:1081
Omim:118850
Refseq:NM_000735
Uniprot:P01215
Chromosome:6
Arm:q
Band:14
Locussupplementarydata:-q21
Hgncid:12372
Chromosome:1
Arm:p
Band:13
Omim:188540
Entrezgene:7252
Refseq:NM_000549
Uniprot:P01222

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.[1] [2]

Physiology

Hormone levels

See also: Hypothalamic–pituitary–thyroid axis.

TSH (with a half-life of about an hour) stimulates the thyroid gland to secrete the hormone thyroxine (T4), which has only a slight effect on metabolism. T4 is converted to triiodothyronine (T3), which is the active hormone that stimulates metabolism. About 80% of this conversion is in the liver and other organs, and 20% in the thyroid itself.[3]

TSH is secreted throughout life but particularly reaches high levels during the periods of rapid growth and development, as well as in response to stress.

The hypothalamus, in the base of the brain, produces thyrotropin-releasing hormone (TRH). TRH stimulates the anterior pituitary gland to produce TSH.

Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.

The concentration of thyroid hormones (T3 and T4) in the blood regulates the pituitary release of TSH; when T3 and T4 concentrations are low, the production of TSH is increased, and, conversely, when T3 and T4 concentrations are high, TSH production is decreased. This is an example of a negative feedback loop.[4] Any inappropriateness of measured values, for instance a low-normal TSH together with a low-normal T4 may signal tertiary (central) disease and a TSH to TRH pathology. Elevated reverse T3 (RT3) together with low-normal TSH and low-normal T3, T4 values, which is regarded as indicative for euthyroid sick syndrome, may also have to be investigated for chronic subacute thyroiditis (SAT) with output of subpotent hormones. Absence of antibodies in patients with diagnoses of an autoimmune thyroid in their past would always be suspicious for development to SAT even in the presence of a normal TSH because there is no known recovery from autoimmunity.

For clinical interpretation of laboratory results it is important to acknowledge that TSH is released in a pulsatile manner[5] [6] [7] resulting in both circadian and ultradian rhythms of its serum concentrations.[8]

Subunits

TSH is a glycoprotein and consists of two subunits, the alpha and the beta subunit.

The TSH receptor

See main article: TSH receptor. The TSH receptor is found mainly on thyroid follicular cells.[11] Stimulation of the receptor increases T3 and T4 production and secretion. This occurs through stimulation of six steps in thyroid hormone synthesis: (1) Up-regulating the activity of the sodium-iodide symporter (NIS) on the basolateral membrane of thyroid follicular cells, thereby increasing intracellular concentrations of iodine (iodine trapping). (2) Stimulating iodination of thyroglobulin in the follicular lumen, a precursor protein of thyroid hormone. (3) Stimulating the conjugation of iodinated tyrosine residues. This leads to the formation of thyroxine (T4) and triiodothyronine (T3) that remain attached to the thyroglobulin protein. (4) Increased endocytocis of the iodinated thyroglobulin protein across the apical membrane back into the follicular cell. (5) Stimulation of proteolysis of iodinated thyroglobulin to form free thyroxine (T4) and triiodothyronine (T3). (6) Secretion of thyroxine (T4) and triiodothyronine (T3) across the basolateral membrane of follicular cells to enter the circulation. This occurs by an unknown mechanism.[12]

Stimulating antibodies to the TSH receptor mimic TSH and cause Graves' disease. In addition, hCG shows some cross-reactivity to the TSH receptor and therefore can stimulate production of thyroid hormones. In pregnancy, prolonged high concentrations of hCG can produce a transient condition termed gestational hyperthyroidism.[13] This is also the mechanism of trophoblastic tumors increasing the production of thyroid hormones.

Applications

Diagnostics

Reference ranges for TSH may vary slightly, depending on the method of analysis, and do not necessarily equate to cut-offs for diagnosing thyroid dysfunction. In the UK, guidelines issued by the Association for Clinical Biochemistry suggest a reference range of 0.4–4.0 μIU/mL (or mIU/L).[14] The National Academy of Clinical Biochemistry (NACB) stated that it expected the reference range for adults to be reduced to 0.4–2.5 μIU/mL, because research had shown that adults with an initially measured TSH level of over 2.0 μIU/mL had "an increased odds ratio of developing hypothyroidism over the [following] 20 years, especially if thyroid antibodies were elevated".[15]

TSH concentrations in children are normally higher than in adults. In 2002, the NACB recommended age-related reference limits starting from about 1.3 to 19 μIU/mL for normal-term infants at birth, dropping to 0.6–10 μIU/mL at 10 weeks old, 0.4–7.0 μIU/mL at 14 months and gradually dropping during childhood and puberty to adult levels, 0.3–3.0 μIU/mL.[16]

Diagnosis of disease

TSH concentrations are measured as part of a thyroid function test in patients suspected of having an excess (hyperthyroidism) or deficiency (hypothyroidism) of thyroid hormones. Interpretation of the results depends on both the TSH and T4 concentrations. In some situations measurement of T3 may also be useful.

Source of pathology TSH level Thyroid hormone level Disease causing conditions - Hypothalamus/pituitary High High - Hypothalamus/pituitary Low Low Secondary hypothyroidism or "central" hypothyroidism - Hyperthyroidism Low High - Hypothyroidism High Low Congenital hypothyroidism, Primary hypothyroidism i.e. Hashimoto's thyroiditis

A TSH assay is now also the recommended screening tool for thyroid disease. Recent advances in increasing the sensitivity of the TSH assay make it a better screening tool than free T4.[2]

Monitoring

The therapeutic target range TSH level for patients on treatment ranges between 0.3 and 3.0 μIU/mL.[17]

For hypothyroid patients on thyroxine, measurement of TSH alone is generally considered sufficient. An increase in TSH above the normal range indicates under-replacement or poor compliance with therapy. A significant reduction in TSH suggests over-treatment. In both cases, a change in dose may be required. A low or low-normal TSH value may also signal pituitary disease in the absence of replacement.

For hyperthyroid patients, both TSH and T4 are usually monitored. In pregnancy, TSH measurements do not seem to be a good marker for the well-known association of maternal thyroid hormone availability with offspring neurocognitive development.[18]

TSH distribution progressively shifts toward higher concentrations with age.[19]

Difficulties with interpretation of TSH measurement

Therapeutic

Inn:thyrotropin alfa
Tradename:Thyrogen
Atc Prefix:H01
Atc Suffix:AB01
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[27]
Cas Number:194100-83-9
Unii:AVX3D5A4LM

Synthetic recombinant human TSH alpha (rhTSHα or simply rhTSH) or thyrotropin alfa (INN) is manufactured by Genzyme Corp under the trade name Thyrogen.[28] [29] It is used to manipulate endocrine function of thyroid-derived cells, as part of the diagnosis and treatment of thyroid cancer.[30] [31]

A Cochrane review compared treatments using recombinant human thyrotropin-aided radioactive iodine to radioactive iodine alone.[32] In this review it was found that the recombinant human thyrotropin-aided radioactive iodine appeared to lead to a greater of thyroid volume at the increased risk of hypothyroidism. No conclusive data on changes in quality of life with either treatments were found.

History

In 1916, Bennett M. Allen and Philip E. Smith found that the pituitary contained a thyrotropic substance.[33] The first standardised purification protocol for this thyrotropic hormone was described by Charles George Lambie and Victor Trikojus, working at the University of Sydney in 1937.[34]

External links

Notes and References

  1. Book: The American Heritage Dictionary of the English Language, Fourth Edition. 2006. Houghton Mifflin Company. 0-395-82517-2. registration.
  2. Book: Sacher R, McPherson RA . Widmann's Clinical Interpretation of Laboratory Tests, 11th ed.. 2000. F.A. Davis Company. 0-8036-0270-7 .
  3. http://www.merckmanuals.com/home/hormonal_and_metabolic_disorders/thyroid_gland_disorders/overview_of_the_thyroid_gland.html?qt=thyroxine&alt=sh Merck Manual of Diagnosis and Therapy
  4. Estrada JM, Soldin D, Buckey TM, Burman KD, Soldin OP . Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice . Thyroid . 24 . 3 . 411–23 . Mar 2014 . 24073798 . 10.1089/thy.2013.0119 . 3949435.
  5. Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC . Pulsatile secretion of thyrotropin in man . The Journal of Clinical Endocrinology and Metabolism . 63 . 3 . 661–8 . Sep 1986 . 3734036 . 10.1210/jcem-63-3-661 .
  6. Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Mühlen A . Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman . The Journal of Clinical Endocrinology and Metabolism . 70 . 2 . 403–9 . Feb 1990 . 2105332 . 10.1210/jcem-70-2-403 .
  7. Samuels MH, Veldhuis JD, Henry P, Ridgway EC . Pathophysiology of pulsatile and copulsatile release of thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and alpha-subunit . The Journal of Clinical Endocrinology and Metabolism . 71 . 2 . 425–32 . Aug 1990 . 1696277 . 10.1210/jcem-71-2-425 .
  8. Hoermann R, Midgley JE, Larisch R, Dietrich JW . Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment . Frontiers in Endocrinology . 6 . 177 . 20 November 2015 . 26635726 . 10.3389/fendo.2015.00177 . 4653296. free .
  9. Lalli E, Sassone-Corsi P . Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor . Proceedings of the National Academy of Sciences of the United States of America . 92 . 21 . 9633–7 . Oct 1995 . 7568187 . 40856 . 10.1073/pnas.92.21.9633 . 1995PNAS...92.9633L . free .
  10. Porcellini A, Messina S, De Gregorio G, Feliciello A, Carlucci A, Barone M, Picascia A, De Blasi A, Avvedimento EV . The expression of the thyroid-stimulating hormone (TSH) receptor and the cAMP-dependent protein kinase RII beta regulatory subunit confers TSH-cAMP-dependent growth to mouse fibroblasts . The Journal of Biological Chemistry . 278 . 42 . 40621–30 . Oct 2003 . 12902333 . 10.1074/jbc.M307501200 . free .
  11. Parmentier M, Libert F, Maenhaut C, Lefort A, Gérard C, Perret J, Van Sande J, Dumont JE, Vassart G . Molecular cloning of the thyrotropin receptor . Science . 246 . 4937 . 1620–2 . Dec 1989 . 2556796 . 10.1126/science.2556796 . 1989Sci...246.1620P .
  12. Book: Boron W, Boulpaed E . Medical Physiology. 2012. Elsevier Saunders. Philadelphia. 978-1-4377-1753-2. 1046. 2nd.
  13. Fantz CR, Dagogo-Jack S, Ladenson JH, Gronowski AM . Thyroid function during pregnancy . Clinical Chemistry . 45 . 12 . 2250–8 . Dec 1999 . 10585360 . 10.1093/clinchem/45.12.2250. free .
  14. Web site: UK Guidelines for the Use of Thyroid Function Tests . Use of thyroid function tests: guidelines development group . 1 June 2008 . Web Page . 30 April 2018 .
  15. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruf J, Smyth PP, Spencer CA, Stockigt JR . Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease . Thyroid . 13 . 1 . 3–126 . Jan 2003 . 12625976 . 10.1089/105072503321086962 .
  16. Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, Segal RL . American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism . Endocrine Practice . 8 . 6 . 457–69 . 2002 . 15260011 . 10.4158/1934-2403-8.6.457 . 8 August 2015 . 8 December 2015 . https://web.archive.org/web/20151208150759/https://www.aace.com/files/hypo_hyper.pdf . dead .
  17. Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, Segal RL . American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism . Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists . 8 . 6 . 457–469 (462,465) . 2002 . 15260011 . American Association of Clinical Endocrinologists . 30 January 2013 . 15 September 2012 . https://web.archive.org/web/20120915230049/https://www.aace.com/files/hypo-hyper.pdf . dead .
  18. Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T, Tiemeier H, Peeters RP . Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study . The Lancet Diabetes & Endocrinology . Oct 2015 . 26497402 . 10.1016/S2213-8587(15)00327-7 . 4 . 1 . 35–43. 1765/79096 . free .
  19. Surks MI, Hollowell JG . Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism . The Journal of Clinical Endocrinology and Metabolism . 92 . 12 . 4575–82 . 2007 . 17911171 . 10.1210/jc.2007-1499 . free .
  20. Morton A . When lab tests lie ... heterophile antibodies . Australian Family Physician . June 2014 . 43 . 6 . 391–393 . 24897990 .
  21. Serum sample containing endogenous antibodies interfering with multiple hormone immunoassays. Laboratory strategies to detect interference . Garcia-Gonzaleza E, Aramendia M, Alvarez-Ballano D, Trincado P, Rello L . Practical Laboratory Medicine . 4 . 1 . April 2016 . 1–10 . 10.1016/j.plabm.2015.11.001 . 28856186 . 5574524 .
  22. Hattori N, Ishihara T, Shimatsu A . Variability in the detection of macro TSH in different immunoassay systems . European Journal of Endocrinology . Jan 2016 . 174 . 1 . 9–15 . 26438715 . 10.1530/EJE-15-0883 . free .
  23. Beck-Peccoz P, Persani L . Variable biological activity of thyroid-stimulating hormone . European Journal of Endocrinology . Oct 1994 . 131 . 4 . 331–40 . 7921220 . 10.1530/eje.0.1310331.
  24. Sergi I, Papandreou MJ, Medri G, Canonne C, Verrier B, Ronin C . Immunoreactive and bioactive isoforms of human thyrotropin . Endocrinology . Jun 1991 . 128 . 6 . 3259–68 . 2036989 . 10.1210/endo-128-6-3259.
  25. Midgley JE, Toft AD, Larisch R, Dietrich JW, Hoermann R . Time for a reassessment of the treatment of hypothyroidism . BMC Endocrine Disorders . 19 . 1 . 37 . April 2019 . 30999905 . 10.1186/s12902-019-0365-4 . 6471951 . free .
  26. Midgley JE, Larisch R, Dietrich JW, Hoermann R . Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency . Endocrine Connections . 4 . 4 . 196–205 . December 2015 . 26335522 . 10.1530/EC-15-0056 . 4557078 .
  27. Web site: Thyrogen EPAR . European Medicines Agency (EMA) . 9 March 2000 . 14 August 2024.
  28. Web site: Drug Approval Package: Thyrogen (Thyrotropin Alfa) NDA# 20-898 . U.S. Food and Drug Administration (FDA) . 10 September 2001 . 13 March 2020.
  29. Web site: Drugs@FDA: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 13 March 2020.
  30. Duntas LH, Tsakalakos N, Grab-Duntas B, Kalarritou M, Papadodima E . The use of recombinant human thyrotropin (Thyrogen) in the diagnosis and treatment of thyroid cancer . Hormones . 2 . 3 . 169–74 . 2003 . 17003018 . 10.14310/horm.2002.1197 . free .
  31. Web site: Thyrogen- thyrotropin alfa injection, powder, for solution Thyrogen- thyrotropin alfa kit . DailyMed . 1 October 2018 . 13 March 2020.
  32. Huo Y, Xie J, Chen S, Wang H, Ma C . Recombinant human thyrotropin (rhTSH)-aided radioiodine treatment for non-toxic multinodular goitre . The Cochrane Database of Systematic Reviews . 12 . 12 . CD010622 . December 2021 . 34961921 . 8712889 . 10.1002/14651858.CD010622.pub2 . Cochrane Metabolic and Endocrine Disorders Group .
  33. Magner J . Historical note: many steps led to the 'discovery' of thyroid-stimulating hormone . European Thyroid Journal . 3 . 2 . 95–100 . June 2014 . 25114872 . 4109514 . 10.1159/000360534 .
  34. Lambie CG, Trikojus VM . The preparation of a purified thyrotropic hormone by chemical precipitation . The Biochemical Journal . 31 . 6 . 843–847 . June 1937 . 16746406 . 1267016 . 10.1042/bj0310843 .

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