55: Thyroid Gland Flashcards
Describe the steps in the biosynthesis (including handling of dietary iodide), storage, and secretion of the thyroid hormones (TH) and their regulation by TSH and TRH.
The thyroid hormones (THs), T3 and T4 are synthesized from the amino acid tyrosine on thyroglobuin (TG) and require iodide (I-), provided in the diet. It sounds like THyrosine
Thyroxine and triiodothyronine are known as T4 and T3, respectively. They are synthesized from tyrosine residues on thyroglobulin. There is preferential synthesis of T4 -thyroxine. Reverse T3 is also produced, but is biologically inactive! THs are the only hormones that require an essential trace element, iodine, which normally exists as a salt, iodide (e.g. with sodium).
Most iodide is stored in the thyroid gland in association with thyroglobulin.
To remain in thyroid balance, it is necessary to ingest adequate quantities of dietary iodide.
Iodide (I-) is concentrated in the thyroid gland by a specific transport protein (2Na+/I- symporter) that uses the inwardly-directed electrochemical Na+ gradient as a driving force. It is not a “pump”, and thus does NOT use ATP directly.
The thyroid gland has some capacity to autoregulate iodide transport according to its needs (e.g., if dietary iodide is somewhat low, it will concentrate more, and vice versa. However, chronic iodide deficiency can lead to a form of hypothyroidism that can be corrected by providing adequate dietary iodide. This is especially true in ‘land-locked’ mountainous areas outside the USA. The majority of organic iodide in the body resides in the thyroid gland in association with colloidal TG. The remainder is present in target tissues or the circulation as organic and inorganic iodide. Ultimately, TH is metabolized & iodide is excreted in the urine & feces.
Synthesis and Regulation of Thyroid Hormones: The thyroid gland is composed of follicular epithelial cells that synthesize and store thyroxine (T4) and triiodothyronine (T3) and release these hormones into the circulation. The synthesis is controlled by release of thyroid-stimulating hormone (TSH from anterior pituitary), which is under negative feedback control by the thyroid hormones.
Synthesis and storage of the thyroid hormones:
1) In the endoplasmic reticulum, thyroglobulin (TG) molecules are produced, packaged in vesicles by the Golgi, and exocytosed into the lumen of the follicle.
2) Iodide (I-, from the diet) enters the thyrocyte via basolateral Na+/I- cotransporters (aka the I-trap). The iodide exits the cell on the apical side into the lumen via I-/Cl- antiporters.
3) In the follicular lumen, I- is oxidized to iodine by thyroid peroxidase and substituted for H+ on the benzene ring of tyrosine residues of thyroglobulin.
4) Binding of one iodine will form monoiodotyrosine (MIT), and binding of two iodine moieties will form diiodotyrosine (DIT). This reaction is termed organification. Thyroid peroxidase also catalyzes the coupling of DIT to another DIT, forming T4. Some DIT will also couple to an MIT, forming T3. These products remain attached to TG.
5) The mature TG, containing MIT, DIT, T4, and T3 (in order of greater to lesser abundance), is endocytosed back into the follicle cell and can be stored as colloid until secreted.
6) Colloid proteolysis is stimulated by TSH and constituent molecules released. MIT and DIT reenter the synthetic pool; T3 and T4 exit the basolateral membrane into the blood.
Explain the importance of TH binding in the blood on free and total TH levels, including the names of major TH binding proteins.
The thyroid gland secretes primarily T4 (~93%) compared to T3 and reverse T3 (~7%). The majority of circulating or tissue T3 (and biologically inactive reverse T3) is derived from T4 (often referred to as a prohormone). Most circulating TH is bound to thyroid-binding globulin (~70% TBG). Not to be confused with thyroglobulin or TG.
Other TH binding proteins are transthyretin and albumin. A small amount of TH circulates in the ‘free’ form (~0.03% of T4 & 0.3% of T3). This free/bioavailable form is able to enter target tissues and bind to TH receptors in the nucleus.
Protein-bound hormones are biologically inactive and cannot be metabolized. Thus, an increase in protein binding would tend to decrease hormone activity and plasma clearance and increase the half-life of the hormone. Free hormone is also responsible for negative feedback inhibition of hormone secretion. Therefore, a sudden increase in hormone binding to plasma proteins would decrease negative feedback & stimulate release of TRH & TSH to stimulate more TH production. Protein binding of hormones does, however, provide a reservoir for the rapid replacement of free hormone.
Note that T3 and T4 most biologically active in the UNBOUND state.
Describe the significance of peripheral conversion of T4 to T3 and reverse T3, including half- lives and biological importance of each.
THs are metabolized in tissues such as liver & kidney through the action of 5’ deiodinases.
Conversion of T4 to T3 produces a more biologically active/potent form. T4 is often referred to as a prohormone. Conversion deiodination of T3 produces inactive organic compounds. THs are also deaminated, conjugated & decarboxylated.
In target tissues, nuclear receptors for thyroid hormones have a greater affinity for T3 than for T4. The secretion rate, plasma concentration, half- life, and onset of action are all greater for T4 than for T3.
Some pharmacological agents inhibit conversion of T4 to T3 (e.g., propylthiouracil/PTU) thereby acting as antithyroid agents in the treatment of hyperthyroidism.
The half life of:
- T4 = 7 days & more stable
- T3 = 1 day & less stable
T4 is typically used to treat hypothyroidism because of its longer half-life & greater stability (tighter binding/lower metabolic clearance). In essence, it is a prohormone for the more biologically active T3
Explain the physiological effects and mechanisms of action of thyroid hormones at both the cellular and systems levels, including consequences of over secretion and under secretion.
The thyroid gland regulates vertebrate growth, development & metabolism.
Follicular epithelial cells (aka thyrocytes) are the sites of thyroid hormone synthesis/release
Stored form of TH is in association with thyroglobulin (TG) in the colloid (gelatinous inner area of follicles).
Thyroid contains scattered parafollicular C-cells, the sites of calcitonin synthesis/release.
The majority of TH is bound to thyroxine-binding globulin (TBG)
Unbound* hormone enters target tissues to activate intracellular receptors in the cell nucleus
Typically, TR (Thyroid hormone receptor) heterodimerizes with RXR to regulate genes containing TREs (thyroid response elements). TH receptors are expressed in virtually all tissues in the body. TH regulates the metabolism of carbohydrates, proteins and lipids. Thyroid hormone receptors bind to DNA in which of the following forms? A heterodimer with the retinoid X receptor (RXR)
Action of thyroid hormones on target cells. Free extracellular T4 and T3 enter the target cell. Once T4 is inside the cell, a cytoplasmic 5’/3’-monodeiodinase converts much of the T4 to T3
Therefore, cytoplasmic levels of T4 and T3 are about equal. TRs bind to nuclear DNA at thyroid response elements in the promoter region of genes regulated by thyroid hormones. The binding of T3 or T4 to the receptor regulates the transcription of these genes. Of the total thyroid hormone bound to receptor, is T3. The receptor that binds to the DNA is preferentially a heterodimer of the TR and RXR.
Thyroid hormones have a slow onset and long duration of action-like the rabbit who won the race!
T3 acts about 4x as rapidly as T4 (latency 6-12 hrs & max effect 2-3 days).
Administration of T4 in amounts that increase plasma levels of the hormone above normal would be expected to increase the metabolic rate, respiratory rate, heart rate, decrease plasma cholesterol and decrease TSH secretion.
Thyroid hormone has transcriptional effects in most issues, including tissues that regulate normal growth and development.
Thyroid Hormone Action: T4 is converted to active T3 at target tissue by 5’-deiodinase action. The T3 binds to nuclear receptors, initiating transcription of a variety of proteins and enzymes.
The overall effects of thyroid hormone are to increase metabolic rate and O2 consumption. Target organs:
THs act synergistically with growth hormone and somatomedins to promote bone formation. Somatomedin is a group of hormones that is produced, when stimulated by somatotropin, to promote cell growth and division. In this way, they mediate the effect of somatotropin (also known as growth hormone. They have simmilar effects to growth hormone (somatotropin).
THs promote ossification and fusion of bone plates and bone maturation.
In hypothyroidism, bone age is less than chronological age. In hypothyroidism, excessive replacement therapy with thyroxine can lead to bone loss/osteoporosis.
THs have multiple effects on the CNS and are essential for CNS development in the perinatal (around birth) period.
TH deficiency in infants results in mental retardation called cretinism (cretino = estupido o idiota) and growth retardation. The growth retardation can be attenuated (less worse) by treatment with thyroxine/T4. The mental retardation can be attenuated only if treatment is initiated shortly after birth.
Mechanism of action of thyroid hormones. Thyroxine (T4) is converted to triiodothyronine (T3) in target tissues.
The actions of T3 on several organ systems are shown. T3 increases Basal metabolic rate, is involved in maturation of CNS, is involved in growth & bone formation, & it increases cardiac output.
T3 increases metabolism by increasing: glucose absorption, glycogenolysis, lypolysis, protein synthesis & degradation (net catabolic). Think of skiny hyperctive people as hyperthyroid & jacked fat people as hypothyroid.
BMR increases in hyperthyroidism & decreases in hypothyroidism.
THs have both anabolic and catabolic effects on multiple tissues that are apparent when they are deficient or present in excess.
In hypothyroidism, increased serum cholesterol increases the risk for atherosclerosis (LDL receptor expression and cholesterol excretion in bile are decreased in hypothyroidism).
Hypothyroid women who take thyroxine must be carefully monitored as they approach the menopause to prevent osteoporosis.
In hyperthyroidism, muscle wasting occurs bc proteolysis outweighs synthesis = net catabolism.
In hyperthyroidism, increased expression of B-adrenergic receptors leads to enhanced sensitivity to circulating epi and norepi. THs interact with the sympathetic nervous system in ways that are not well understood. Thus, beta-adrenergic antagonists (e.g., propranolol) are effective in treating many of the symptoms of hyperthyroidism.
Thyroid function is regulated by thyrotropin-releasing hormone (TRH), a tripeptide hypothalamic releasing factor, thyroid stimulating hormone aka thyrotropin (TSH), an anterior pituitary thyroid-stimulating hormone, and negative feedback by circulating T3 (especially) and T4.
TRH stimulates TSH release by activating a GPCR linked to PLC, leading to generation of IP3 and mobilization of intracellular calcium.
TSH stimulates TH synthesis/release by activating a GPCR linked to adenylate cyclase, generating intracellular cAMP.
T3 (especially) and T4 act on target tissues and also exert negative feedback at the level of the anterior pituitary and hypothalamus.
Dopamine and somatostatin also exert inhibitory effects on TSH release.
Determination of serum TSH is commonly used to diagnose primary thyroid disease. TSH is significantly elevated in primary hypothyroidism (due to lack of negative feedback by low- circulating T3 & T4), and reduced in primary hyperthyroidism (due to excessive negative feedback by high circulating T3 & T4).
