Thyroid-stimulating hormone: Difference between revisions

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{{DrugProjectFormSinglePage
{{infobox protein
|authorTag={{Ammu}}
| Name = [[Chorionic gonadotropin alpha|Thyroid-stimulating hormone, alpha]]
|genericName=Thyrotropin alfa injection
| caption =  
|aOrAn=a
| image =  
|drugClass=antineoplastic
| width =  
|indicationType=treatment
| HGNCid = 1885
|indication=well Differentiated Thyroid Cancer,
| Symbol = [[Chorionic gonadotropin alpha|CGA]]
|adverseReactions=Nausea , Vomiting ,Headache , Paresthesia
| AltSymbols = HCG, GPHa, GPHA1
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span>
| EntrezGene = 1081
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
| OMIM = 118850
| RefSeq = NM_000735
| UniProt = P01215
| PDB =
| ECnumber =
| Chromosome = 6
| Arm = q
| Band = 14
| LocusSupplementaryData = -q21
}}
{{Infobox protein
  |Name=[[TSHB|Thyroid-stimulating hormone, beta]]
  |image=
  |caption=
  |Symbol=[[TSHB]]
  |AltSymbols=
  |HGNCid=12372
  |Chromosome=1
  |Arm=p
  |Band=13
  |LocusSupplementaryData=
  |ECnumber=
  |OMIM=188540
  |EntrezGene=7252
  |RefSeq=NM_000549
  |UniProt=P01222
  |PDB=
}}
'''Thyroid-stimulating hormone''' (also known as '''thyrotropin''', '''thyrotropic hormone''', '''TSH''', or '''hTSH''' for human TSH) is a [[pituitary hormone]] that stimulates the [[thyroid]] gland to produce [[thyroxine]] (T<sub>4</sub>), and then [[triiodothyronine]] (T<sub>3</sub>) which stimulates the metabolism of almost every tissue in the body.<ref name="Merck"/> It is a [[glycoprotein]] hormone produced by [[thyrotrope]] cells in the [[anterior pituitary gland]], which regulates the endocrine function of the [[thyroid]].<ref>{{cite book|title= The American Heritage Dictionary of the English Language, Fourth Edition|year= 2006|publisher= Houghton Mifflin Company|isbn= 0-395-82517-2}}</ref><ref name="Sacher">{{cite book |last= Sacher|first= Ronald|author2=Richard A. McPherson |title= Widmann's Clinical Interpretation of Laboratory Tests, 11th ed.|year= 2000|publisher= F.A. Davis Company|isbn= 0-8036-0270-7 | name-list-format = vanc }}</ref> In 1916, Bennett M. Allen and Philip E. Smith found that the pituitary contained a thyrotropic substance.<ref>{{cite journal | vauthors = Magner J | title = Historical note: many steps led to the 'discovery' of thyroid-stimulating hormone | journal = European Thyroid Journal | volume = 3 | issue = 2 | pages = 95–100 | date = June 2014 | pmid = 25114872 | doi = 10.1159/000360534 | pmc=4109514}}</ref>


* Content
== Physiology ==


<!--Adult Indications and Dosage-->
[[File:Thyroid system.svg|thumb|250px|The system of the [[thyroid hormone]]s [[triiodothyronine|T<sub>3</sub>]] and [[thyroxine|T<sub>4</sub>]].<ref>References used in image are found in image article in Commons:[[Commons:File:Thyroid system.png#References]].</ref>]]


<!--FDA-Labeled Indications and Dosage (Adult)-->
=== Hormone levels ===
|fdaLIADAdult=1.1 Adjunctive Diagnostic Tool for Serum Thyroglobulin Testing in Well Differentiated Thyroid Cancer
THYROGEN® is indicated for use as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy.


Limitations of Use:
{{see also|Hypothalamic–pituitary–thyroid axis}}


THYROGEN-stimulated Tg levels are generally lower than, and do not correlate with, Tg levels after thyroid hormone withdrawal [see Clinical Studies (14.1)].  
TSH (with a half life of about an hour) stimulates the thyroid gland to secrete the hormone [[thyroxine]] (T<sub>4</sub>), which has only a slight effect on metabolism. T<sub>4</sub> is converted to [[triiodothyronine]] (T<sub>3</sub>), 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.<ref name="Merck">[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], Thyroid gland disorders.</ref>
Even when THYROGEN-stimulated Tg testing is performed in combination with radioiodine imaging, there remains a risk of missing a diagnosis of thyroid cancer or of underestimating the extent of disease.
Anti-Tg antibodies may confound the Tg assay and render Tg levels uninterpretable [see Clinical Studies (14.1)]. Therefore, in such cases, even with a negative or low-stage THYROGEN radioiodine scan, consideration should be given to further evaluating patients.
1.2 Adjunct to Treatment for Ablation in Well Differentiated Thyroid Cancer
THYROGEN is indicated for use as an adjunctive treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for well-differentiated thyroid cancer and who do not have evidence of distant metastatic thyroid cancer.


Limitations of Use:
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 effect of THYROGEN on long-term thyroid cancer outcomes has not been determined. Due to the relatively small clinical experience with THYROGEN in remnant ablation, it is not possible to conclude whether long-term thyroid cancer outcomes would be equivalent after use of THYROGEN or use of thyroid hormone withholding for TSH elevation prior to remnant ablation.
The [[hypothalamus]], in the base of the brain, produces [[thyrotropin-releasing hormone]] (TRH). TRH stimulates the anterior [[pituitary gland]] to produce TSH.
2.1 Recommended Dosage
THYROGEN should be used by physicians knowledgeable in the management of patients with thyroid cancer.


THYROGEN is indicated as a two-injection regimen.  The recommended dosage of THYROGEN is a 0.9 mg intramuscular injection to the buttock followed by a second 0.9 mg intramuscular injection to the buttock 24 hours later.
[[Somatostatin]] is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.


THYROGEN should be administered intramuscularly only. THYROGEN should not be administered intravenously.
The concentration of thyroid hormones (T<sub>3</sub> and T<sub>4</sub>) in the blood regulates the pituitary release of TSH; when  T<sub>3</sub> and T<sub>4</sub> concentrations are low, the production of TSH is increased, and, conversely, when T<sub>3</sub> and T<sub>4</sub> concentrations are high,  TSH production is decreased. This is an example of a [[negative feedback]] loop.<ref name="pmid24073798">{{cite journal | vauthors = Estrada JM, Soldin D, Buckey TM, Burman KD, Soldin OP | title = Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice | journal = Thyroid | volume = 24 | issue = 3 | pages = 411–23 | date = Mar 2014 | pmid = 24073798 | doi = 10.1089/thy.2013.0119 | pmc=3949435}}</ref> Any inappropriateness of measured values, for instance a low-normal TSH together with a low-normal T<sub>4</sub> may signal tertiary (central) disease and a TSH to TRH pathology. Elevated reverse T<sub>3</sub> (RT<sub>3</sub>) together with low-normal TSH and low-normal T<sub>3</sub>, T<sub>4</sub> 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.


Pretreatment with glucocorticoids should be considered for patients in whom tumor expansion may compromise vital anatomic structures [see Warnings and Precautions (5.3)].  
For clinical interpretation of laboratory results it is important to acknowledge that TSH is released in a [[Pulsatile secretion|pulsatile manner]]<ref>{{cite journal | vauthors = Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC | title = Pulsatile secretion of thyrotropin in man | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 63 | issue = 3 | pages = 661–8 | date = Sep 1986 | pmid = 3734036 | doi = 10.1210/jcem-63-3-661 }}</ref><ref>{{cite journal | vauthors = Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Mühlen A | title = Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 70 | issue = 2 | pages = 403–9 | date = Feb 1990 | pmid = 2105332 | doi = 10.1210/jcem-70-2-403 }}</ref><ref>{{cite journal | vauthors = Samuels MH, Veldhuis JD, Henry P, Ridgway EC | title = Pathophysiology of pulsatile and copulsatile release of thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and alpha-subunit | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 71 | issue = 2 | pages = 425–32 | date = Aug 1990 | pmid = 1696277 | doi = 10.1210/jcem-71-2-425 }}</ref> resulting in both circadian and ultradian rhythms of its serum concentrations.<ref>{{cite journal | vauthors = Hoermann R, Midgley JE, Larisch R, Dietrich JW | title = Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment | journal = Frontiers in Endocrinology | volume = 6 | pages = 177 | date = 20 November 2015 | pmid = 26635726 | doi = 10.3389/fendo.2015.00177 | pmc=4653296}}</ref>


Routine measurement of serum TSH levels is not recommended after THYROGEN use.
=== Subunits ===


2.2 Reconstitution, Preparation, and Administration of THYROGEN
TSH is a glycoprotein and consists of two subunits, the ''alpha'' and the ''beta'' subunit.
The supplied lyophilized powder must be reconstituted with Sterile Water for Injection. THYROGEN should be prepared, and administered in the following manner:
* The [[Alpha subunit of glycoprotein hormones|α (''alpha'') subunit]] (i.e., [[chorionic gonadotropin alpha]]) is nearly identical to that of [[human chorionic gonadotropin]] (hCG), [[luteinizing hormone]] (LH), and [[follicle-stimulating hormone]] (FSH). The α subunit is thought to be the effector region responsible for stimulation of adenylate cyclase (involved the generation of [[Cyclic adenosine monophosphate|cAMP]]).<ref>{{cite journal | vauthors = Lalli E, Sassone-Corsi P | title = Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 21 | pages = 9633–7 | date = Oct 1995 | pmid = 7568187 | pmc = 40856 | doi = 10.1073/pnas.92.21.9633 | url = http://www.pnas.org/content/92/21/9633.full.pdf }}</ref> The α chain has a 92-amino acid sequence.
* The β (''beta'') subunit ([[TSHB]]) is unique to TSH, and therefore determines its receptor specificity.<ref>{{cite journal | vauthors = Porcellini A, Messina S, De Gregorio G, Feliciello A, Carlucci A, Barone M, Picascia A, De Blasi A, Avvedimento EV | title = 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 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 42 | pages = 40621–30 | date = Oct 2003 | pmid = 12902333 | doi = 10.1074/jbc.M307501200 }}</ref> The β chain has a 118-amino acid sequence.


Add 1.2 mL of Sterile Water for Injection to the vial containing the THYROGEN lyophilized powder.
=== The TSH receptor ===
Swirl the contents of the vial until all the material is dissolved. Do not shake the solution.  The reconstituted THYROGEN solution has a concentration of 0.9 mg of thyrotropin alfa per mL.
{{main|TSH receptor}}
Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration.  The reconstituted THYROGEN solution should be clear and colorless.  Do not use if the solution has particulate matter or is cloudy or discolored.
The [[TSH receptor]] is found mainly on thyroid [[follicular cells]].<ref name="pmid2556796">{{cite journal | vauthors = Parmentier M, Libert F, Maenhaut C, Lefort A, Gérard C, Perret J, Van Sande J, Dumont JE, Vassart G | title = Molecular cloning of the thyrotropin receptor | journal = Science | volume = 246 | issue = 4937 | pages = 1620–2 | date = Dec 1989 | pmid = 2556796 | doi = 10.1126/science.2556796 }}</ref> Stimulation of the receptor increases T<sub>3</sub> and T<sub>4</sub> 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 [[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]] (T<sub>4</sub>) and [[triiodothyronine]] (T<sub>3</sub>) 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]] (T<sub>4</sub>) and [[triiodothyronine]] (T<sub>3</sub>). (6) Secretion of [[thyroxine]] (T<sub>4</sub>) and [[triiodothyronine]] (T<sub>3</sub>) across the basolateral membrane of follicular cells to enter the circulation. This occurs by an unknown mechanism.<ref>{{cite book|last1=Boron|first1=Walter|last2=Boulpaed|first2=Emile | name-list-format = vanc |title=Medical Physiology|date=2012|publisher=Elsevier Saunders|location=Philadelphia|isbn=978-1-4377-1753-2|page=1046|edition=2nd}}</ref>
Withdraw 1 mL of the reconstituted THYROGEN solution (0.9 mg of thyrotropin alfa) and inject intramuscularly in the buttocks.
The reconstituted THYROGEN solution must be injected within 3 hours unless refrigerated; if refrigerated, the reconstituted solution may be kept for up to 24 hours.
Discard unused portions.  Do not mix with other substances.
2.3 Timing of Serum Thyroglobulin Testing Following THYROGEN Administration
For serum thyroglobulin testing, the serum sample should be obtained 72 hours after the final injection of THYROGEN [see Clinical Studies (14.1)].


2.4 Timing for Remnant Ablation and Diagnostic Scanning Following THYROGEN Administration
Stimulating antibodies to the TSH receptor mimic TSH and cause [[Graves-Basedow disease|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.<ref name="pmid10585360">{{cite journal | vauthors = Fantz CR, Dagogo-Jack S, Ladenson JH, Gronowski AM | title = Thyroid function during pregnancy | journal = Clinical Chemistry | volume = 45 | issue = 12 | pages = 2250–8 | date = Dec 1999 | pmid = 10585360 | doi = }}</ref> This is also the mechanism of [[trophoblastic tumor]]s increasing the production of thyroid hormones.
Oral radioiodine should be given 24 hours after the second injection of THYROGEN in both remnant ablation and diagnostic scanning.  The activity of 131I is carefully selected at the discretion of the nuclear medicine physician.


Diagnostic scanning should be performed 48 hours after the radioiodine administration.
== Applications ==
|offLabelAdultGuideSupport======Condition1=====


* Developed by:
=== Diagnostics ===


* Class of Recommendation:  
{{Main|Thyroid-stimulating hormone measurement}}
{{Further|Thyroid function tests}}
[[Reference range]]s 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 mIU/mL.<ref name="British Thyroid Foundation">{{cite web | url = http://www.btf-thyroid.org/information/leaflets/34-thyroid-function-tests-guide | title = UK Guidelines for the Use of Thyroid Function Tests | author = Use of thyroid function tests: guidelines development group | date = 2008-06-01  | format = Web Page | work = | publisher = | pages =  | accessdate = 2018-04-30 }}</ref> 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".<ref name="pmid12625976">{{cite journal | vauthors = 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 | title = Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease | journal = Thyroid | volume = 13 | issue = 1 | pages = 3–126 | date = Jan 2003 | pmid = 12625976 | doi = 10.1089/105072503321086962 | url = http://www.aacc.org/members/nacb/Archive/LMPG/ThyroidDisease/Pages/default.aspx }}</ref>


* Strength of Evidence:  
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.<ref name="aace">{{cite journal | vauthors = Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, Segal RL | title = American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism | journal = Endocrine Practice | volume = 8 | issue = 6 | pages = 457–69 | year = 2002 | pmid = 15260011 | doi =  | url = https://www.aace.com/files/hypo_hyper.pdf }}</ref>{{rp|Section 2}}


* Dosing Information
====Diagnosis of disease====


:* Dosage
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 T<sub>4</sub> concentrations. In some situations measurement of T<sub>3</sub> may also be useful.


=====Condition2=====
{| class="wikitable"
! Source of pathology    || TSH level || Thyroid hormone level || Disease causing conditions
|-
| Hypothalamus/pituitary || High || High || Benign [[tumor of the pituitary]] ([[adenoma]]) or [[thyroid hormone resistance]]
|-
| Hypothalamus/pituitary || Low  || Low  || [[Secondary hypothyroidism]] or "central" hypothyroidism
|-
| Hyperthyroidism                || Low  || High || [[Primary hyperthyroidism]] i.e. [[Graves' disease]]
|-
| Hypothyroidism                || High || Low  || [[Congenital hypothyroidism]], [[Primary hypothyroidism]] i.e. [[Hashimoto's thyroiditis]]
|}


There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
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 T<sub>4</sub>.<ref name="Sacher"/>


<!--Non–Guideline-Supported Use (Adult)-->
====Monitoring====
|offLabelAdultNoGuideSupport=Multinodular goiter; Adjunct<ref name="pmidPMID: 15008994">{{cite journal| author=Silva MN, Rubió IG, Romão R, Gebrin EM, Buchpiguel C, Tomimori E et al.| title=Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. | journal=Clin Endocrinol (Oxf) | year= 2004 | volume= 60 | issue= 3 | pages= 300-8 | pmid=PMID: 15008994 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15008994  }} </ref>
|fdaLIADPed=There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.


<!--Off-Label Use and Dosage (Pediatric)-->
The [[therapeutic target range]] TSH level for patients on treatment ranges between 0.3 and 3.0 μIU/mL.<ref name="aace1">{{cite web | url = https://www.aace.com/files/hypo-hyper.pdf | title =  AACE Medical Guidelines for Clinical Practice for Evaluation and Treatment of Hyperthyroidism and Hypothyroidism | author = Baskin | authorlink = | year = 2002 | format = | work = | publisher = American Association of Clinical Endocrinologists | pages = 462, 465 | archiveurl = | archivedate = | quote = | accessdate = |display-authors=etal}}</ref>


<!--Guideline-Supported Use (Pediatric)-->
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.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Contraindications-->
|contraindications=* None
|warnings=* 5.1 THYROGEN-induced Hyperthyroidism
When given to patients who have substantial thyroid tissue still in situ or functional thyroid cancer metastases, THYROGEN is known to cause a transient (over 7 to 14 days) but significant rise in serum thyroid hormone concentration.  There have been reports of death in non-thyroidectomized patients and in patients with distant metastatic thyroid cancer in which events leading to death occurred within 24 hours after administration of THYROGEN.  Patients with residual thyroid tissue at risk for THYROGEN-induced hyperthyroidism include the elderly and those with a known history of heart disease.  Hospitalization for administration of THYROGEN and post-administration observation in patients at risk should be considered.
 
5.2 Stroke
There are postmarketing reports of radiologically-confirmed stroke and neurological findings suggestive of stroke unconfirmed radiologically (e.g., unilateral weakness) occurring within 72 hours (range 20 minutes to three days) of THYROGEN administration in patients without known central nervous system metastases.  The majority of such patients were young women taking oral contraceptives at the time of their event or had other risk factors for stroke, such as smoking or a history of migraine headaches.  The relationship between THYROGEN administration and stroke is unknown.  Patients should be well-hydrated prior to treatment with THYROGEN.
 
5.3 Sudden Rapid Tumor Enlargement
Sudden, rapid and painful enlargement of residual thyroid tissue or distant metastases can occur following treatment with THYROGEN. This may lead to acute symptoms, which depend on the anatomical location of the tissue.  Such symptoms include acute hemiplegia, hemiparesis, and loss of vision one to three days after THYROGEN administration.  Laryngeal edema, pain at the site of distant metastasis, and respiratory distress requiring tracheotomy have also been reported after THYROGEN administration.
 
Pretreatment with glucocorticoids should be considered for patients in whom tumor expansion may compromise vital anatomic structures.
|clinicalTrials=6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
 
The data described below reflect exposure to THYROGEN in 481 thyroid cancer patients who participated in a total of 6 clinical trials of THYROGEN: 4 trials for diagnostic use and 2 trials for ablation.  In clinical trials, patients had undergone near-total thyroidectomy and had a mean age of 46.1 years.  Thyroid cancer diagnosis was as follows: papillary (69.2%), follicular (12.9%), Hurthle cell (2.3%) and papillary/follicular 15.6%.  Most patients received 2 intramuscular injections of 0.9 mg of THYROGEN injection given 24 hours apart [see Clinical Studies (14.1) (14.2)].
 
The safety profile of patients who have undergone thyroidectomy and received THYROGEN as adjunctive treatment for radioiodine ablation of thyroid tissue remnants for well-differentiated thyroid cancer did not differ from that of patients who received THYROGEN for diagnostic purposes.
 
Reactions reported in ≥ 1% of patients in the combined trials are summarized in Table 1.  In some studies, an individual patient may have participated in both THYROGEN and thyroid hormone withdrawal [see Clinical Studies (14.1) (14.2)].
 
Table 1: Summary of Adverse Reactions by THYROGEN and Thyroid Hormone Withdrawal in Pooled Clinical Trials (≥1% of Patients in any Phase)
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|postmarketing=5.1 THYROGEN-induced Hyperthyroidism
When given to patients who have substantial thyroid tissue still in situ or functional thyroid cancer metastases, THYROGEN is known to cause a transient (over 7 to 14 days) but significant rise in serum thyroid hormone concentration.  There have been reports of death in non-thyroidectomized patients and in patients with distant metastatic thyroid cancer in which events leading to death occurred within 24 hours after administration of THYROGEN.  Patients with residual thyroid tissue at risk for THYROGEN-induced hyperthyroidism include the elderly and those with a known history of heart disease.  Hospitalization for administration of THYROGEN and post-administration observation in patients at risk should be considered.
 
5.2 Stroke
There are postmarketing reports of radiologically-confirmed stroke and neurological findings suggestive of stroke unconfirmed radiologically (e.g., unilateral weakness) occurring within 72 hours (range 20 minutes to three days) of THYROGEN administration in patients without known central nervous system metastases.  The majority of such patients were young women taking oral contraceptives at the time of their event or had other risk factors for stroke, such as smoking or a history of migraine headaches.  The relationship between THYROGEN administration and stroke is unknown.  Patients should be well-hydrated prior to treatment with THYROGEN.
 
5.3 Sudden Rapid Tumor Enlargement
Sudden, rapid and painful enlargement of residual thyroid tissue or distant metastases can occur following treatment with THYROGEN. This may lead to acute symptoms, which depend on the anatomical location of the tissue.  Such symptoms include acute hemiplegia, hemiparesis, and loss of vision one to three days after THYROGEN administration.  Laryngeal edema, pain at the site of distant metastasis, and respiratory distress requiring tracheotomy have also been reported after THYROGEN administration.
 
Pretreatment with glucocorticoids should be considered for patients in whom tumor expansion may compromise vital anatomic structures.
|drugInteractions=<!--Use in Specific Populations-->
|FDAPregCat=C
|useInPregnancyFDA=* Animal reproduction studies have not been conducted with THYROGEN.
 
It is also not known whether THYROGEN can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. THYROGEN should be given to a pregnant woman only if clearly needed.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=n pooled clinical studies of THYROGEN, 60 patients (12%) were >65 years, and 421 (88%) were ≤ 65 years of age.  Results from controlled trials do not indicate a difference in the safety and efficacy of THYROGEN between adult patients less than 65 years and those over 65 years of age.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=Elimination of THYROGEN is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of TSH levels.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
 
<!--Administration and Monitoring-->
|administration=* Oral
 
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
 
 
 
<!--IV Compatibility-->
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
 
<!--Overdosage-->
|overdose=* In clinical trials of THYROGEN, three patients experienced symptoms after receiving THYROGEN doses higher than those recommended.  Two patients had nausea after a 2.7 mg IM dose (3 times the recommended dose), and in one of these patients, the event was accompanied by weakness, dizziness and headache.  Another patient experienced nausea, vomiting and hot flashes after a 3.6 mg IM dose (4 times the recommended dose).  There is no specific therapy for THYROGEN overdose. Supportive care is recommended.
|drugBox=<!--Mechanism of Action-->
|mechAction=* Thyrotropin (TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroid hormone.  Binding of thyrotropin alfa to TSH receptors on normal thyroid epithelial cells or on well-differentiated thyroid cancer tissue stimulates iodine uptake and organification, and synthesis and secretion of thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4).
 
The effect of thyroid stimulating hormone activation of thyroid cells is to increase uptake of radioiodine to allow scan detection or radioiodine killing of thyroid cells.  TSH activation also leads to the release of thyroglobulin by thyroid cells.  Thyroglobulin functions as a tumor marker which is detected in blood specimens.
 
<!--Structure-->
|structure=* Each vial of THYROGEN contains 1.1 mg thyrotropin alfa, 36 mg Mannitol, 5.1 mg Sodium Phosphate, and 2.4 mg Sodium Chloride.
 
THYROGEN (thyrotropin alfa for injection) contains recombinant human thyroid stimulating hormone (TSH).  Thyrotropin alfa is synthesized in a genetically modified Chinese hamster ovary cell line.
 
Thyrotropin alfa is a heterodimeric glycoprotein comprised of two non-covalently linked subunits, an alpha subunit of 92 amino acid residues containing two N-linked glycosylation sites and a beta subunit of 118 residues containing one N-linked glycosylation site. The amino acid sequence of thyrotropin alfa is identical to that of human pituitary TSH.
 
Both thyrotropin alfa and naturally occurring human pituitary TSH are synthesized as a mixture of glycosylation variants. Unlike pituitary TSH, which is secreted as a mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated but not sulfated. The biological activity of thyrotropin alfa is determined by a cell-based bioassay. In this assay, cells expressing a functional TSH receptor and a cAMP-responsive element coupled to a heterologous reporter gene, luciferase, enable the measurement of thyrotropin alfa activity by measuring the luciferase response.  The specific activity of thyrotropin alfa is determined relative to an internal Genzyme reference standard that was calibrated against the World Health Organization (WHO) human TSH reference standard.
 
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
 
<!--Pharmacodynamics-->
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
 
<!--Pharmacokinetics-->
|PK=The pharmacokinetics of THYROGEN were studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg IM dose.  Mean peak serum TSH concentrations of 116 ± 38 mU/L were reached between 3 and 24 hours after injection (median of 10 hours).  The mean apparent elimination half-life was 25 ± 10 hours.  The organ(s) of TSH clearance in man have not been identified, but studies of pituitary-derived TSH suggest the involvement of the liver and kidneys.
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term toxicity studies in animals have not been performed with THYROGEN to evaluate the carcinogenic potential of the drug.  THYROGEN was not mutagenic in the bacterial reverse mutation assay.  Studies have not been performed with THYROGEN to evaluate the effects on fertility.
 
13.2 Animal Pharmacology and/or Toxicology
Four toxicology studies, two in rodents and two in primates, have been conducted using both single and repeated daily injections of thyrotropin alfa.  In a single-dose study utilizing male and female rats bolus injections were given at levels up to 7.14 IU/kg (equivalent to 50 times the expected single human dose). There were no effects, either gross or microscopic, in this study which could be attributed to the administration of thyrotropin alfa.  In a repeated-dose study, rats were given thyrotropin alfa in the form of 5 daily intramuscular injections at levels up to 1.43 IU/kg (equivalent to 10 times the expected single human dose) without dose-related toxic effects observed.
 
A single-dose study in male and female cynomolgus monkeys used single intramuscular injections of thyrotropin alfa at levels equivalent to the expected dose and 0.25 and 4 times the expected single human dose.  There were no changes that were regarded as indicative of an adverse or toxic response to thyrotropin alfa.  Cynomolgus monkeys were also administered thyrotropin alfa as three consecutive daily bolus intramuscular injections at levels extending to 4 times the dose in humans.  There were no changes that are considered to indicate an adverse or toxic response to thyrotropin alfa.
|clinicalStudies=14.1 Clinical Trials of THYROGEN as an Adjunctive Diagnostic Tool
Two prospective, randomized phase 3 clinical trials were conducted in patients with well-differentiated thyroid cancer to compare 131I whole body scans obtained after THYROGEN injection to 131I whole body scans after thyroid hormone withdrawal. A cross-over, non-blinded design was used in both trials.  Oral radioiodine was given 24 hours after the second injection of THYROGEN, and scanning was done 48 hours after the radioiodine administration.  Each patient was scanned first following THYROGEN and then scanned after thyroid hormone withdrawal.  In both studies, the primary endpoint was the rate of concordant scans (scan findings in agreement in a given patient using each preparation method).
 
Study 1 (n=127) compared the diagnostic scanning following a THYROGEN regimen of 0.9 mg IM daily on two consecutive days to thyroid hormone withdrawal.  In addition to body scans, Study 2 (n=229) also compared thyroglobulin (Tg) levels obtained after THYROGEN to those at baseline and to those after thyroid hormone withdrawal.  All Tg testing was performed in a central laboratory using a radioimmunoassay (RIA) with a functional sensitivity of 2.5 ng/mL.  Patients who were included in the Tg analysis were those who had undergone total or near-total thyroidectomy with or without 131I ablation, had < 1% uptake in the thyroid bed on a scan after thyroid hormone withdrawal, and did not have detectable anti-Tg antibodies.  The maximum THYROGEN Tg value was obtained 72 hours after the final THYROGEN injection, and this value was used in the analysis.
 
Diagnostic Radioiodine Whole Body Scan Results
 
Study 1 enrolled 127 patients, 71% were female and 29% male, and mean age was 44 years.  The study included the following forms of differentiated thyroid cancer:  papillary cancer (88%), follicular cancer (9%), and Hurthle cell (2%).  Study results are displayed in Table 2.
 
In Study 2, patients with differentiated thyroid cancer who had been thyroidectomized (n = 229) were randomized into one of two THYROGEN treatment regimens:  THYROGEN 0.9 mg IM daily on two consecutive days (n = 117), and THYROGEN 0.9 mg IM daily on days 1, 4 and 7 (n = 112).  Each patient was scanned first using THYROGEN, then scanned using thyroid hormone withdrawal.  The group receiving the THYROGEN 0.9 mg IM x 2 regimen was 63% female/27% male, had a mean age 44 years, and generally had low-stage papillary or follicular cancer (AJCC/TNM Stage I 61%, Stage II 19%, Stage III 14%, Stage IV 5%).  The group receiving the THYROGEN 0.9 mg IM x 3 regimen was 66% female/34% male, had a mean age 50 years, and generally had low-stage papillary or follicular cancer (AJCC/TNM Stage I 50%, Stage II 20%, Stage III 20%, Stage IV 9%).  The amount of radioiodine used for scanning was 4 mCi ± 10%, and scanning times were lengthened in some patients to capture adequate images (30 minute scans, or 140,000 counts).  Scan pairs were assessed by blinded readers.  Study results are presented in Table 2.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
Across the two clinical studies, and scoring all false positives in favor of thyroid hormone withdrawal, the majority of positive scans using THYROGEN and thyroid hormone withdrawal were concordant.  The THYROGEN scan failed to detect remnant and/or cancer localized to the thyroid bed in 17% (14/83) of patients in whom it was detected by a scan after thyroid hormone withdrawal.  In addition, the THYROGEN scan failed to detect metastatic disease in 29% (7/24) of patients in whom it was detected by a scan after thyroid hormone withdrawal.
 
Thyroglobulin (Tg) Results
 
THYROGEN Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning: Comparison with Results after Thyroid Hormone Withdrawal
 
In anti-Tg antibody negative patients with a thyroid remnant or cancer (as defined by a withdrawal Tg ≥ 2.5 ng/mL or a positive scan [after thyroid hormone withdrawal or after radioiodine therapy]), the THYROGEN Tg was positive (≥ 2.5 ng/mL) in 69% (40/58) of patients after 2 doses of THYROGEN.
 
In these same patients, adding the whole body scan increased the detection rate of thyroid remnant or cancer to 84% (49/58) of patients after 2 doses of THYROGEN.
 
Among patients with metastatic disease confirmed by a post-treatment scan or by lymph node biopsy (35 patients), THYROGEN Tg was positive (≥ 2.5 ng/mL) in all 35 patients, while Tg on thyroid hormone suppressive therapy was positive ( ≥ 2.5 ng/mL) in 79% of these patients.
 
As with thyroid hormone withdrawal, the intra-patient reproducibility of THYROGEN testing with regard to both Tg stimulation and radioiodine imaging has not been studied.
 
Hypothyroid Signs and Symptoms
 
THYROGEN administration was not associated with the signs and symptoms of hypothyroidism that accompanied thyroid hormone withdrawal as measured by the Billewicz scale.  Statistically significant worsening in all signs and symptoms were observed during the hypothyroid phase (p<0.01)
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
Across the two clinical studies, and scoring all false positives in favor of thyroid hormone withdrawal, the majority of positive scans using THYROGEN and thyroid hormone withdrawal were concordant.  The THYROGEN scan failed to detect remnant and/or cancer localized to the thyroid bed in 17% (14/83) of patients in whom it was detected by a scan after thyroid hormone withdrawal.  In addition, the THYROGEN scan failed to detect metastatic disease in 29% (7/24) of patients in whom it was detected by a scan after thyroid hormone withdrawal.
 
Thyroglobulin (Tg) Results
 
THYROGEN Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning: Comparison with Results after Thyroid Hormone Withdrawal
 
In anti-Tg antibody negative patients with a thyroid remnant or cancer (as defined by a withdrawal Tg ≥ 2.5 ng/mL or a positive scan [after thyroid hormone withdrawal or after radioiodine therapy]), the THYROGEN Tg was positive (≥ 2.5 ng/mL) in 69% (40/58) of patients after 2 doses of THYROGEN.
 
In these same patients, adding the whole body scan increased the detection rate of thyroid remnant or cancer to 84% (49/58) of patients after 2 doses of THYROGEN.
 
Among patients with metastatic disease confirmed by a post-treatment scan or by lymph node biopsy (35 patients), THYROGEN Tg was positive (≥ 2.5 ng/mL) in all 35 patients, while Tg on thyroid hormone suppressive therapy was positive ( ≥ 2.5 ng/mL) in 79% of these patients.
 
As with thyroid hormone withdrawal, the intra-patient reproducibility of THYROGEN testing with regard to both Tg stimulation and radioiodine imaging has not been studied.
 
Hypothyroid Signs and Symptoms
 
THYROGEN administration was not associated with the signs and symptoms of hypothyroidism that accompanied thyroid hormone withdrawal as measured by the Billewicz scale.  Statistically significant worsening in all signs and symptoms were observed during the hypothyroid phase (p<0.01)
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|howSupplied=* THYROGEN (thyrotropin alfa for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available either in a two-vial kit or a four-vial kit. The two-vial kit contains two 1.1 mg vials of THYROGEN.  The four-vial kit contains two 1.1 mg vials of THYROGEN, as well as two 10 mL vials of Sterile Water for Injection, USP.
 
        NDC 58468-1849-4 (4-vial kit)
 
        NDC 58468-0030-2 (2-vial kit)
 
THYROGEN is for intramuscular injection to the buttock.  The lyophilized powder should be reconstituted immediately prior to use with 1.2 mL of Sterile Water for Injection, USP [see Dosage and Administration (2.2)].  Each vial of THYROGEN and each vial of diluent, if provided, is intended for single use.
 
THYROGEN should be stored at 2-8ºC (36-46ºF)
|storage=If necessary, the reconstituted solution can be stored for up to 24 hours at a temperature between 2ºC and 8ºC, while avoiding microbial contamination.
 
Protect from light.
|packLabel=<!--Patient Counseling Information-->
|fdaPatientInfo=If necessary, the reconstituted solution can be stored for up to 24 hours at a temperature between 2ºC and 8ºC, while avoiding microbial contamination.
 
Protect from light.
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
 
<!--Brand Names-->
|brandNames=*THYROGEN ®<ref>{{Cite web | title =THYROGEN- thyrotropin alfa injection, powder, for solution  | url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b52dfa36-f90b-4e19-9b5e-26db9d04df2b}}</ref>
 
<!--Look-Alike Drug Names-->
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>
 
<!--Drug Shortage Status-->
|drugShortage=
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For hyperthyroid patients, both TSH and T<sub>4</sub> are usually monitored. It must also be noted that 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.<ref>{{cite journal | vauthors = Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T, Tiemeier H, Peeters RP | title = Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study | journal = The Lancet Diabetes & Endocrinology | date = Oct 2015 | pmid = 26497402 | doi = 10.1016/S2213-8587(15)00327-7 | volume=4 | pages=35–43}}</ref>


TSH distribution progressively shifts toward higher concentrations with age.<ref>{{cite journal |vauthors=Surks MI, Hollowell JG |title=Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism |journal=The Journal of Clinical Endocrinology and Metabolism |volume=92 |issue=12 |pages=4575–82 |year=2007 | pmid=17911171 | doi=10.1210/jc.2007-1499 }}</ref>


<!--Label Display Image-->
====Difficulties with interpretation of TSH measurement====
* [[Heterophile]] antibodies (which include human anti-mouse antibodies (HAMA) and Rheumatoid Factor (RF)), which bind weakly to the test assay's animal antibodies, causing a higher (or less commonly lower) TSH result than the actual true TSH level.<ref name="afg">{{cite journal | vauthors = Morton A | title = When lab tests lie ... heterophile antibodies | journal = Australian Family Physician | date = June 2014 | volume = 43 | issue = 6 | pages = 391–393 | pmid =  24897990 | url = http://www.racgp.org.au/afp/2014/june/when-lab-tests-lie/ }}</ref><ref name="plm">{{cite journal | title = Serum sample containing endogenous antibodies interfering with multiple hormone immunoassays. Laboratory strategies to detect interference | vauthors = Garcia-Gonzaleza E, Aramendia M, Alvarez-Ballano D, Trincado P, Rello L | journal = Practical Laboratory Medicine | volume = 4 | issue = 1 | date = April 2016 | pages = 1–10 | doi = 10.1016/j.plabm.2015.11.001 }}</ref> Although the standard lab assay panels are designed to remove moderate levels of heterophilic antibodies, these fail to remove higher antibody levels.  "Dr. Baumann [from Mayo Clinic] and her colleagues found that 4.4 percent of the hundreds of samples she tested were affected by heterophile antibodies.........The hallmark of this condition is a discrepancy between TSH value and free T4 value, and most important between laboratory values and patient's conditions. Endocrinologists, in particular, should be on alert for this."
* Macro-TSH - endogenous antibodies bind to TSH reducing its activity, so the pituitary gland would need to produce more TSH to obtain the same overall level of TSH activity.<ref>{{cite journal | vauthors = Hattori N, Ishihara T, Shimatsu A | title = Variability in the detection of macro TSH in different immunoassay systems | journal = European Journal of Endocrinology | date = Jan 2016 | volume = 174 | issue = 1 | pages = 9–15 | pmid = 26438715 | doi = 10.1530/EJE-15-0883 }}</ref>
* TSH [[Isomer]]s - natural variations of the TSH molecule, which have lower activity, so the pituitary gland would need to produce more TSH to obtain the same overall level of TSH activity.<ref>{{cite journal | author = Beck-Peccoz P, Persani L | title = Variable biological activity of thyroid-stimulating hormone | journal = European Journal of Endocrinology | date = Oct 1994 | volume = 131 | issue = 4 | pages = 331–40 | pmid = 7921220 | doi=10.1530/eje.0.1310331}}</ref><ref>{{cite journal | vauthors = Sergi I, Papandreou MJ, Medri G, Canonne C, Verrier B, Ronin C | title = Immunoreactive and bioactive isoforms of human thyrotropin | journal = Endocrinology | date = Jun 1991 | volume = 128 | issue = 6 | pages = 3259–68 | pmid = 2036989 | doi=10.1210/endo-128-6-3259}}</ref>


=== Therapeutic ===


A synthetic drug called [[recombinant DNA|recombinant]] human TSH alpha (rhTSHα or simply rhTSH) or thyrotropin alfa ([[International Nonproprietary Name|INN]]) is manufactured by [[Genzyme|Genzyme Corp]] under the trade name Thyrogen. It is used to manipulate endocrine function of thyroid-derived cells, as part of the diagnosis and treatment of [[thyroid cancer]].<ref name="pmid17003018">{{cite journal | vauthors = Duntas LH, Tsakalakos N, Grab-Duntas B, Kalarritou M, Papadodima E | title = The use of recombinant human thyrotropin (Thyrogen) in the diagnosis and treatment of thyroid cancer | journal = Hormones | volume = 2 | issue = 3 | pages = 169–74 | year = 2003 | pmid = 17003018 | doi = 10.14310/horm.2002.1197 }}</ref>


== References ==
{{reflist}}


== External links ==
* TSH at [http://labtestsonline.org/understanding/analytes/tsh/tab/test Lab Tests Online]
* {{MedlinePlusEncyclopedia|003684}}
* {{MeshName|Thyrotropin}}


<!--Category-->
{{Hormones}}
{{Peptidergics}}


[[Category:Drug]]
[[Category:Glycoproteins]]
[[Category:Peptide hormones]]
[[Category:Anterior pituitary hormones]]
[[Category:Human hormones]]
[[Category:Thyroid]]
[[Category:Hormones of the hypothalamus-pituitary-thyroid axis]]

Latest revision as of 07:33, 18 January 2019

Thyroid-stimulating hormone, alpha
Identifiers
SymbolCGA
Alt. symbolsHCG, GPHa, GPHA1
Entrez1081
HUGO1885
OMIM118850
RefSeqNM_000735
UniProtP01215
Other data
LocusChr. 6 q14-q21
Thyroid-stimulating hormone, beta
Identifiers
SymbolTSHB
Entrez7252
HUGO12372
OMIM188540
RefSeqNM_000549
UniProtP01222
Other data
LocusChr. 1 p13

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, TSH, or hTSH for human 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.[1] It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.[2][3] In 1916, Bennett M. Allen and Philip E. Smith found that the pituitary contained a thyrotropic substance.[4]

Physiology

File:Thyroid system.svg

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.[1]

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.[6] 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[7][8][9] resulting in both circadian and ultradian rhythms of its serum concentrations.[10]

Subunits

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

The TSH receptor

Main article: TSH receptor

The TSH receptor is found mainly on thyroid follicular cells.[13] 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 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.[14]

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.[15] This is also the mechanism of trophoblastic tumors increasing the production of thyroid hormones.

Applications

Diagnostics

Main article: Thyroid-stimulating hormone measurement
Further information: Thyroid function tests

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 mIU/mL.[16] 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".[17]

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.[18]:Section 2

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 Benign tumor of the pituitary (adenoma) or thyroid hormone resistance
Hypothalamus/pituitary Low Low Secondary hypothyroidism or "central" hypothyroidism
Hyperthyroidism Low High Primary hyperthyroidism i.e. Graves' disease
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.[3]

Monitoring

The therapeutic target range TSH level for patients on treatment ranges between 0.3 and 3.0 μIU/mL.[19]

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. It must also be noted that 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.[20]

TSH distribution progressively shifts toward higher concentrations with age.[21]

Difficulties with interpretation of TSH measurement

  • Heterophile antibodies (which include human anti-mouse antibodies (HAMA) and Rheumatoid Factor (RF)), which bind weakly to the test assay's animal antibodies, causing a higher (or less commonly lower) TSH result than the actual true TSH level.[22][23] Although the standard lab assay panels are designed to remove moderate levels of heterophilic antibodies, these fail to remove higher antibody levels. "Dr. Baumann [from Mayo Clinic] and her colleagues found that 4.4 percent of the hundreds of samples she tested were affected by heterophile antibodies.........The hallmark of this condition is a discrepancy between TSH value and free T4 value, and most important between laboratory values and patient's conditions. Endocrinologists, in particular, should be on alert for this."
  • Macro-TSH - endogenous antibodies bind to TSH reducing its activity, so the pituitary gland would need to produce more TSH to obtain the same overall level of TSH activity.[24]
  • TSH Isomers - natural variations of the TSH molecule, which have lower activity, so the pituitary gland would need to produce more TSH to obtain the same overall level of TSH activity.[25][26]

Therapeutic

A synthetic drug called recombinant human TSH alpha (rhTSHα or simply rhTSH) or thyrotropin alfa (INN) is manufactured by Genzyme Corp under the trade name Thyrogen. It is used to manipulate endocrine function of thyroid-derived cells, as part of the diagnosis and treatment of thyroid cancer.[27]

References

  1. ↑ 1.0 1.1 Merck Manual of Diagnosis and Therapy, Thyroid gland disorders.
  2. ↑ The American Heritage Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company. 2006. ISBN 0-395-82517-2.
  3. ↑ 3.0 3.1 Sacher R, Richard A. McPherson (2000). Widmann's Clinical Interpretation of Laboratory Tests, 11th ed. F.A. Davis Company. ISBN 0-8036-0270-7.
  4. ↑ Magner J (June 2014). "Historical note: many steps led to the 'discovery' of thyroid-stimulating hormone". European Thyroid Journal. 3 (2): 95–100. doi:10.1159/000360534. PMC 4109514. PMID 25114872.
  5. ↑ References used in image are found in image article in Commons:Commons:File:Thyroid system.png#References.
  6. ↑ Estrada JM, Soldin D, Buckey TM, Burman KD, Soldin OP (Mar 2014). "Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice". Thyroid. 24 (3): 411–23. doi:10.1089/thy.2013.0119. PMC 3949435. PMID 24073798.
  7. ↑ Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC (Sep 1986). "Pulsatile secretion of thyrotropin in man". The Journal of Clinical Endocrinology and Metabolism. 63 (3): 661–8. doi:10.1210/jcem-63-3-661. PMID 3734036.
  8. ↑ Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Mühlen A (Feb 1990). "Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman". The Journal of Clinical Endocrinology and Metabolism. 70 (2): 403–9. doi:10.1210/jcem-70-2-403. PMID 2105332.
  9. ↑ Samuels MH, Veldhuis JD, Henry P, Ridgway EC (Aug 1990). "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. doi:10.1210/jcem-71-2-425. PMID 1696277.
  10. ↑ Hoermann R, Midgley JE, Larisch R, Dietrich JW (20 November 2015). "Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment". Frontiers in Endocrinology. 6: 177. doi:10.3389/fendo.2015.00177. PMC 4653296. PMID 26635726.
  11. ↑ Lalli E, Sassone-Corsi P (Oct 1995). "Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9633–7. doi:10.1073/pnas.92.21.9633. PMC 40856. PMID 7568187.
  12. ↑ Porcellini A, Messina S, De Gregorio G, Feliciello A, Carlucci A, Barone M, Picascia A, De Blasi A, Avvedimento EV (Oct 2003). "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. doi:10.1074/jbc.M307501200. PMID 12902333.
  13. ↑ Parmentier M, Libert F, Maenhaut C, Lefort A, Gérard C, Perret J, Van Sande J, Dumont JE, Vassart G (Dec 1989). "Molecular cloning of the thyrotropin receptor". Science. 246 (4937): 1620–2. doi:10.1126/science.2556796. PMID 2556796.
  14. ↑ Boron W, Boulpaed E (2012). Medical Physiology (2nd ed.). Philadelphia: Elsevier Saunders. p. 1046. ISBN 978-1-4377-1753-2.
  15. ↑ Fantz CR, Dagogo-Jack S, Ladenson JH, Gronowski AM (Dec 1999). "Thyroid function during pregnancy". Clinical Chemistry. 45 (12): 2250–8. PMID 10585360.
  16. ↑ Use of thyroid function tests: guidelines development group (2008-06-01). "UK Guidelines for the Use of Thyroid Function Tests" (Web Page). Retrieved 2018-04-30.
  17. ↑ 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 (Jan 2003). "Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease". Thyroid. 13 (1): 3–126. doi:10.1089/105072503321086962. PMID 12625976.
  18. ↑ Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, Segal RL (2002). "American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism" (PDF). Endocrine Practice. 8 (6): 457–69. PMID 15260011.
  19. ↑ Baskin; et al. (2002). "AACE Medical Guidelines for Clinical Practice for Evaluation and Treatment of Hyperthyroidism and Hypothyroidism" (PDF). American Association of Clinical Endocrinologists. pp. 462, 465.
  20. ↑ Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T, Tiemeier H, Peeters RP (Oct 2015). "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. 4: 35–43. doi:10.1016/S2213-8587(15)00327-7. PMID 26497402.
  21. ↑ Surks MI, Hollowell JG (2007). "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. doi:10.1210/jc.2007-1499. PMID 17911171.
  22. ↑ Morton A (June 2014). "When lab tests lie ... heterophile antibodies". Australian Family Physician. 43 (6): 391–393. PMID 24897990.
  23. ↑ Garcia-Gonzaleza E, Aramendia M, Alvarez-Ballano D, Trincado P, Rello L (April 2016). "Serum sample containing endogenous antibodies interfering with multiple hormone immunoassays. Laboratory strategies to detect interference". Practical Laboratory Medicine. 4 (1): 1–10. doi:10.1016/j.plabm.2015.11.001.
  24. ↑ Hattori N, Ishihara T, Shimatsu A (Jan 2016). "Variability in the detection of macro TSH in different immunoassay systems". European Journal of Endocrinology. 174 (1): 9–15. doi:10.1530/EJE-15-0883. PMID 26438715.
  25. ↑ Beck-Peccoz P, Persani L (Oct 1994). "Variable biological activity of thyroid-stimulating hormone". European Journal of Endocrinology. 131 (4): 331–40. doi:10.1530/eje.0.1310331. PMID 7921220.
  26. ↑ Sergi I, Papandreou MJ, Medri G, Canonne C, Verrier B, Ronin C (Jun 1991). "Immunoreactive and bioactive isoforms of human thyrotropin". Endocrinology. 128 (6): 3259–68. doi:10.1210/endo-128-6-3259. PMID 2036989.
  27. ↑ Duntas LH, Tsakalakos N, Grab-Duntas B, Kalarritou M, Papadodima E (2003). "The use of recombinant human thyrotropin (Thyrogen) in the diagnosis and treatment of thyroid cancer". Hormones. 2 (3): 169–74. doi:10.14310/horm.2002.1197. PMID 17003018.

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