Thyroid stimulating hormone

Hormone levels

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.

TSH is secreted throughout life but particularly reaches high levels during the periods of rapid growth and development.

The hypothalamus, in the base of the brain, produces thyrotropin-releasing hormone (TRH). TRH stimulates the 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. 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 resulting in both circadian and ultradian rhythms of its serum concentrations.

Subunits

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

The TSH receptor

The TSH receptor is found mainly on thyroid follicular cells. 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.

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

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 0.4-4.5 µIU/mL. 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".

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.

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.

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.

Monitoring

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

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. TSH measurements could not be applied any more, however, treatment would have to be continued.

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.

TSH distribution progressively shifts toward higher concentrations with age.

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 treat thyroid cancer.