Thyroid-stimulating hormone (TSH) is crucial for the modulation of thyroid hormone release and growth of the thyroid gland. The hypothalamic-pituitary axis regulates TSH release. The hypothalamus releases thyroid-releasing hormone (TRH), which stimulates thyrotrophs of the anterior pituitary to secrete TSH. TSH is released by the anterior pituitary and stimulates the thyroid follicular cells to release thyroxine, T4 (80%) and triiodothyronine, or T3 (20%). When T4 is released into circulation, it can be converted to T3 through the process of de-iodination. T4 and T3 can then exert negative feedback on TSH levels with high levels of T3/T4 decreasing TSH and low levels of T3/T4 increasing TSH levels from the anterior pituitary. In this review, we discuss the physiology, biochemistry, and clinical relevance of TSH .
TSH is the accepted first-line screening test for the diagnosis of the majority of patients suspected of having hypothyroidism or hyperthyroidism and is measured by automated immunoassays.
In primary disease, the disease originates in the thyroid gland itself. If the thyroid gland is secreting high levels of T3/T4, this will negatively feedback on the anterior pituitary and thus, decrease the secretion of TSH. If the thyroid gland is secreting low levels of T3/T4, the absence of negative feedback on the anterior pituitary will increase TSH secretion from the anterior pituitary.
For secondary disease or central hyperthyroid or hypothyroid disease, the disease originates in the anterior pituitary itself. If a tumor in the anterior pituitary is secreting excessively high TSH, this will stimulate the thyroid follicular cells to secrete high levels of T3/T4. If the anterior pituitary is secreting low levels of TSH such as in panhypopituitarism, this lack of stimulation of thyroid follicular cells will cause them to secrete low levels of T4.
To assess whether thyroid disease is primary or secondary, the TSH must be evaluated in comparison to T3/T4 levels. If TSH and T3/T4 both increase or both decrease together, this indicates either secondary (central) hypothyroidism or secondary hyperthyroidism. However, if the TSH and T3/T4 change in the opposite directions, this indicates primary thyroid disease.
TSH is a peptide hormone produced by the anterior pituitary. Specifically, it is composed of 2 chains: 1 alpha, and 1 beta chain and has a molecular mass of approximately 28,000 Da. This also holds true for other glycoprotein hormones made by the anterior pituitary, including luteinizing hormone (LH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (HCG). This is important because TSH has the same alpha subunit as LH, FSH, and HCG. However, TSH has a different beta chain than LH, FSH, and HCG that confers biological specificity. Since TSH, LH, FSH, and HCG all have the alpha subunit, they all have the cyclic adenine monophosphate (cAMP) second messenger system. TSH also activates the IP3 signaling cascade. The cAMP second messenger system entails adenine monophosphate (AMP) conversion to cAMP, and the IP3 second messenger system involves calcium release from the sarcoplasmic reticulum. The cAMP and IP3/Ca2+ then leads to downstream physiological effects. There is a diurnal variation in TSH secretion with highest values between midnight and 4:00 am and lowest values in the late afternoon.
Thyroid hormone receptor subtypes are expressed in different tissues. The thyroid hormone receptor alpha (TRa) is predominantly expressed in the brain, heart, and bone. The thyroid hormone receptor beta (TRb1) is expressed in the liver, kidney, and thyroid. The TRb2 is primarily in the retina, cochlea, and pituitary. Mutations in TRa or TRb can result in disease which is beyond the scope of this review.
TSH modulates the release of T3/T4 from thyroid follicular cells. T4 is deiodinated to T3, which is a more potent thyroid hormone. While about 20% of T3 originates from the thyroid gland, 80% of T3 is produced by peripheral conversion via a deiodinase. More than 99% of thyroid hormone is protein bound to thyroid binding globulin, prealbumin, and albumin. T3 then binds to its receptor in the nucleus; this activates the transcription of DNA, which promotes translation of mRNA, which activates the synthesis of new proteins.
These new proteins influence many organ systems, promoting growth and bone maturation as well as maturation of the central nervous system (CNS). The basal metabolic rate is increased, with an increase in synthesis of Na+-K+ ATPases, increase in oxygen consumption, and increased heat production. Metabolism is activated as well, with an increase in glucose absorption, glycogenolysis, gluconeogenesis, lipolysis, and protein synthesis and degradation (net catabolic). These proteins also influence the cardiovascular system by increasing cardiac output by increasing the number of beta-1 receptors on the myocardium such that the myocardium is more sensitive to stimulation by the sympathetic nervous system, thereby increasing contractility.
The hypothalamic-pituitary axis regulates TSH release. The hypothalamus secretes the thyroid releasing hormone (TRH), which stimulates thyrotrophs in the anterior pituitary to secrete TSH. TSH is released by the anterior pituitary and stimulates the thyroid follicular cells to release thyroxine, or T4 (80%) and triiodothyronine, or T3 (20%). When T4 is released into circulation, it can be converted to T3 through the process of deiodination. T4 and T3 can then exert negative feedback on TSH levels, with high levels of T3/T4 decreasing TSH and low levels of T3/T4 increasing TSH levels from the anterior pituitary. T3 is the predominant inhibitor of TSH secretion. Because TSH secretion is so sensitive to minor changes in serum-free T4 through this negative feedback loop, abnormal TSH levels are detected earlier than those of free T4 in hypothyroidism and hyperthyroidism. There is a log-linear relationship between T3/T4 and TSH with minor changes in TH results in major changes in TSH.
TSH binds and activates the TSH receptor (TSHR), which is a G-protein coupled receptor (GPCR) on the basolateral surface of thyroid follicle cells. TSHR is coupled to both Gs and Gq G-proteins, activating both the cAMP pathway (via Gsa) and the phosphoinositol/calcium (IP/Ca2+; via Gq) second messenger signaling cascades. The Gs pathway activates iodide uptake, thyroid hormone secretion, and gland growth and differentiation. The Gq pathway is rate-limiting for hormone synthesis by stimulating iodide organification. A gain in function mutation of the TSH receptor can result in hyperthyroidism, while the loss in function mutations can result in hypothyroidism.
Testing for TSH is a first-line screening test for both hypothyroidism and hyperthyroidism. If values are outside the reference range of 0.4 to 4.5 uIU/ml, one reflex to measuring T4 if TSH is elevated, or T4 and T3 if TSH is decreased. However, TSH is the best first test in both the evaluation of hypothyroidism and hyperthyroidism as the test is more reliable than plasma T3/T4 which fluctuates. In hypothyroidism, if the cause is primary (originating in the thyroid gland itself), high TSH would be detected, and this is the best first-line test. This would be accompanied by low total T4, low free T4, hypercholesterolemia (decreased LDL receptor synthesis), and elevated creatinine kinase levels and thyroid antibodies in Hashimoto disease.
In hyperthyroidism, if the cause is primarily originating in the thyroid gland itself, for example, in patients with Graves disease with low TSH, this is the best first test. This would be accompanied by high total T4, high free T4, and elevated T3 levels. T3 levels increase before T4 levels in hyperthyroidism. However, when TSH is elevated for reasons other than subclinical (normal T4 and T3) and clinical hypothyroidism, one needs to consider a TSH-producing tumor. This is especially true if T4 and T3 are elevated, and the patient has features of hyperthyroidism including a goiter or selective pituitary thyroid hormone resistance syndrome due to a defect in the beta subunit of the thyroid hormone receptor. With a TSH tumor, there is an increase in alpha subunit/TSH molar ratio and the MRI scan can reveal a tumor. Also, interference by heterophile antibodies can result in a spurious isolated increase in TSH levels since TSH is now measured by third generation sensitive immunometric "sandwich" assays with a capture and detection antibodies. The most typical heterophile antibody that interferes with the TSH assay is a human anti-mouse antibody.
When TSH levels are low, the primary diagnosis is hyperthyroidism. However, patients treated with thyroxine can have low levels, for example, with thyroid cancer. If the clinical presentation is consistent with hypothyroidism, the clinician needs to consider secondary hypothyroidism and the most reliable test to confirm this diagnosis is a low T4 level since TSH levels can be normal or elevated due to a bioactive isoform of TSH. Also, patients on steroids, dopamine, and somatostatin analogs, or those with sick euthyroid syndrome can have low TSH levels. In the first trimester of pregnancy when HCG levels peak, TSH levels can be low since HCG can engage the TSH receptor and activate the thyroid possibly resulting in gestational hyperthyroidism. Also, TSH is an important screening test in neonates to diagnose hypothyroidism and prevent complications such as intellectual impairment.
When used in conjunction with physical exam and history, the TSH level can help determine the cause of hypothyroidism or hyperthyroidism. Symptoms of hyperthyroidism include increased metabolic rate, weight loss, negative nitrogen balance, increased heat production, excessive sweating, increased cardiac output, dyspnea (shortness of breath), tremor or muscle weakness, exophthalmos, and goiter. When a patient exhibits these symptoms, a decreased TSH would be indicative of feedback inhibition of T3 on the anterior lobe; while an increased TSH would be indicative of a defect in the anterior pituitary.
Hyperthyroidism can be caused by Graves' disease in which there is an increased thyroid-stimulating immunoglobulin, thyroid neoplasm (for example, toxic adenoma), excess TSH secretion, or exogenous T3 or T4. Treatment for this should include propylthiouracil (which inhibits peroxidase enzyme and thyroid hormone synthesis), thyroidectomy, radioiodine therapy which destroys the thyroid, and beta-adrenergic blocking agents (adjunct therapy).
Symptoms of hypothyroidism include decreased basal metabolic rate, weight gain, and nitrogen balance, decreased heat production, cold sensitivity, decreased cardiac output, hypoventilation, lethargy and mental slowness, drooping eyelids, myxedema, growth retardation, mental retardation in perinatal patients, and goiter. When a patient exhibits these symptoms, an increased TSH would indicate negative feedback if the primary defect is in the thyroid gland; while a decreased TSH would be indicative of a defect in the hypothalamus or anterior pituitary. Hypothyroidism can be caused by thyroiditis (autoimmune or Hashimoto thyroiditis), surgery for hyperthyroidism, iodine-deficiency, congenital (cretinism), or decreased TRH or TSH. Treatment for this should include thyroid hormone replacement.
|||Eghtedari B,Correa R, Levothyroxine 2019 Jan; [PubMed PMID: 30969630]|
|||Calsolaro V,Niccolai F,Pasqualetti G,Calabrese AM,Polini A,Okoye C,Magno S,Caraccio N,Monzani F, Overt and Subclinical Hypothyroidism in the Elderly: When to Treat? Frontiers in endocrinology. 2019; [PubMed PMID: 30967841]|
|||Wiersinga WM, Graves' Disease: Can It Be Cured? Endocrinology and metabolism (Seoul, Korea). 2019 Mar; [PubMed PMID: 30912336]|
|||Jannin A,Peltier L,d'Herbomez M,Defrance F,Marcelli S,Ben Hamou A,Humbert L,Wémeau JL,Vantyghem MC,Espiard S, Lesson from inappropriate TSH-receptor antibody measurement in hypothyroidism: case series and literature review. Clinical chemistry and laboratory medicine. 2019 Mar 8; [PubMed PMID: 30849043]|
|||Delitala AP,Capobianco G,Cherchi PL,Dessole S,Delitala G, Thyroid function and thyroid disorders during pregnancy: a review and care pathway. Archives of gynecology and obstetrics. 2019 Feb; [PubMed PMID: 30569344]|
|||Azim S,Nasr C, Subclinical hypothyroidism: When to treat. Cleveland Clinic journal of medicine. 2019 Feb; [PubMed PMID: 30742580]|
|||Leng O,Razvi S, Hypothyroidism in the older population. Thyroid research. 2019; [PubMed PMID: 30774717]|
|||Ehlers M,Schott M,Allelein S, Graves' disease in clinical perspective. Frontiers in bioscience (Landmark edition). 2019 Jan 1; [PubMed PMID: 30468646]|
|||Blick C,Jialal I, Thyrotoxicosis 2019 Jan; [PubMed PMID: 29489233]|
|||Mathew P,Rawla P, Hyperthyroidism 2019 Jan; [PubMed PMID: 30725738]|