Control of Thyroid Hormone Synthesis and Secretion
Aug 14, (,) Hypothalamic TRH synthesis is in turn regulated by thyroid At difference with the anterior pituitary, where ablation of TR β2 or the. Patients with central hypothyroidism have either a failure of the anterior Normally TSH is the more sensitive test due to the relationship between TSH and fT4. Apr 1, Central Regulation of Hypothalamic-Pituitary-Thyroid Axis Under the median eminence for conveyance to anterior pituitary thyrotrophs. .. There is a major difference between the human and the rodent pathways, however.
These cells combine iodine and the amino acid tyrosine to make T3 and T4. T3 and T4 are then released into the blood stream and are transported throughout the body where they control metabolism conversion of oxygen and calories to energy. Every cell in the body depends upon thyroid hormones for regulation of their metabolism.
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The thyroid gland is under the control of the pituitary gland, a small gland the size of a peanut at the base of the brain shown here in orange. Under the influence of TSH, the thyroid will manufacture and secrete T3 and T4 thereby raising their blood levels. The pituitary senses this and responds by decreasing its TSH production.
One can imagine the thyroid gland as a furnace and the pituitary gland as the thermostat.
Thyroid hormones are like heat. When the heat gets back to the thermostat, it turns the thermostat off. As the room cools the thyroid hormone levels dropthe thermostat turns back on TSH increases and the furnace produces more heat thyroid hormones.
The pituitary gland itself is regulated by another gland, known as the hypothalamus shown in the picture above in light blue.
Physiology of the Hypothalamic-Pituitary-Thyroid Axis - Endotext - NCBI Bookshelf
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. Cellular TSH is a peptide hormone produced by the anterior pituitary. Specifically, it is composed of 2 chains: This also holds true for other glycoprotein hormones made by the anterior pituitary, including luteinizing hormone LHfollicle-stimulating hormone FSHand human chorionic gonadotropin HCG.
TSH also activates the IP3 signaling cascade. There is a diurnal variation in TSH secretion with highest values between midnight and 4: Development 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.
- How Your Thyroid Works
- Hypothalamic–pituitary–thyroid axis
T4 is deiodinated to T3, which is a more potent thyroid hormone. 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.
Function These new proteins influence many organ systems, promoting growth and bone maturation as well as maturation of the central nervous system CNS.
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.
Mechanism The hypothalamic-pituitary axis regulates TSH release. The hypothalamus secretes the thyroid releasing hormone TRHwhich stimulates thyrotrophs in the anterior pituitary to secrete TSH. When T4 is released into circulation, it can be converted to T3 through the process of deiodination. 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. 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.
Related Testing Testing for TSH is a first-line screening test for both hypothyroidism and hyperthyroidism. If values are outside the reference range of 0. In hypothyroidism, if the cause is primary originating in the thyroid gland itselfhigh 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 synthesisand elevated creatinine kinase levels and thyroid antibodies in Hashimoto disease.
Pathophysiology 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. 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. Also, TSH is an important screening test in neonates to diagnose hypothyroidism and prevent complications such as intellectual impairment.