Antidiuretic Hormone/ vasopressin

 

Antidiuretic Hormone / vasopressin

Introduction

Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon terminating in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality).

Structure

The vasopressins are peptides consisting of nine amino acids (nonapeptides). The amino acid sequence of arginine vasopressin (argipressin) is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, with the cysteine residues forming a disulfide bond and the C-terminus of the sequence converted to a primary amide. Lysine vasopressin (lypressin) has a lysine in place of the arginine as the eighth amino acid, and is found in pigs and some related animals, whereas arginine vasopressin is found in humans. The structure of oxytocin is very similar to that of the vasopressins.

Production and secretion

The physiological stimulus for secretion of vasopressin is increased osmolality of the plasma, monitored by the hypothalamus. A decreased arterial blood volume, (such as can occur in cirrhosis, nephrosis, and heart failure), stimulates secretion, even in the face of decreased osmolality of the plasma: it supersedes osmolality, but with a milder effect. The AVP that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in the paraventricular nucleus of hypothalamus (PVN) and supraoptic nucleus (SON). It then travels down the axon through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood. It has a very short half-life, between 16 and 24 minutes.

Regulation

Vasopressin is regulated by AVP gene expression which is managed by major clock controlled genes. In this circadian circuit known as the transcription-translation feedback loop (TTFL). Many factors influence the secretion of vasopressin:

 

·       Ethanol (alcohol) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in neurohypophyseal nerve terminals in rats.

·       Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body.

·       Atrial natriuretic peptide(ANP) inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP secretion.

·       Cortisol inhibits secretion of antidiuretic hormone.

Functions

Vasopressin regulates the tonicity of body fluids. It is released from the posterior pituitary in response to hypertonicity and causes the kidneys to reabsorb solute-free water and return it to the circulation from the tubules of the nephron, thus returning the tonicity of the body fluids toward normal. An incidental consequence of this renal reabsorption of water is concentrated urine and reduced urine volume. AVP released in high concentrations may also raise blood pressure by inducing moderate vasoconstriction. Details as given below-

A.      Kidneys

ADH or Vasopressin has three main effects which are:

1.       Increasing the water permeability of cortical collecting tubules (CCT), as well as outer and inner medullary collecting duct (OMCD & IMCD) in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis. This occurs through increased transcription and insertion of water channels (Aquaporin-2) into the apical membrane of collecting tubule and collecting duct epithelial cells.[16][17] Aquaporins allow water to move down their osmotic gradient and out of the nephron, increasing the amount of water re-absorbed from the filtrate (forming urine) back into the bloodstream. This effect is mediated by V2 receptors. Vasopressin also increases the concentration of calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2 molecules in collecting duct cells.

2.       Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters,[19] which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct.

3.       Acute increase of sodium absorption across the ascending loop of Henle. This adds to the countercurrent multiplication which aids in proper water reabsorption later in the distal tubule and collecting duct.

B. Central nervous system

Vasopressin released within the brain may have several actions:

1.       Vasopressin is released into the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus.

2.       Vasopressin released from posterior pituitary is associated with nausea.

3.       Recent evidence suggests that vasopressin may have analgesic effects. The analgesia effects of vasopressin were found to be dependent on both stress and gender.

Medical uses

1.       Vasopressin is used to manage anti-diuretic hormone deficiency. Vasopressin is used to treat diabetes insipidus related to low levels of antidiuretic hormone. It is available as Pressyn.

2.       Vasopressin has off-label uses and is used in the treatment of vasodilatory shock, gastrointestinal bleeding, ventricular tachycardia and ventricular fibrillation.

3.       Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding.

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Growth hormone

 

Growth hormone

Introduction

Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. GH also stimulates production of insulin-like growth factor 1 (IGF-1) and increases the concentration of glucose and free fatty acid. It is a type of mitogen which is specific only to the receptors on certain types of cells. GH is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland. A recombinant form of HGH called somatropin (INN) is used as a prescription drug to treat children's growth disorders and adult growth hormone deficiency.

Genes for human growth hormone, known as growth hormone 1 (somatotropin; pituitary growth hormone) and growth hormone 2 (placental growth hormone; growth hormone variant), are localized in the q22-24 region of chromosome and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity.

Structure

The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of 22,124 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. Several molecular isoforms of GH exist in the pituitary gland and are released to blood. In particular, a variant of approximately 20 kDa originated by an alternative splicing is present in a rather constant 1:9 ratio.

Regulation

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides growth hormone-releasing hormone (GHRH or somatocrinin) and growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL Maximal secretion of GH may occur within minutes of the onset of slow-wave (SW) sleep (stage III or IV). Otherwise there is wide variation between days and individuals. Nearly fifty percent of GH secretion occurs during the third and fourth NREM sleep stages. Surges of secretion during the day occur at 3- to 5-hour intervals. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night.

A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones. Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day.[20] Sleep deprivation generally suppresses GH release, particularly after early adulthood.[21]

Stimulators[quantify] of growth hormone (GH) secretion include:

·       Peptide hormones

·       GHRH (somatocrinin) through binding to the growth hormone-releasing hormone receptor (GHRHR)

·       Ghrelin through binding to growth hormone secretagogue receptors (GHSR)

·       Sex hormones

o   Increased androgen secretion during puberty (in males from testes and in females from adrenal cortex)

o   Testosterone and DHEA

o   Estrogen

·       Clonidine, moxonidine and L-DOPA by stimulating GHRH release, α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine or moxonidine.[

·       Hypoglycemia,

·       arginine, pramipexole, ornitine, lysine, tryptophan, γ-Aminobutyric acid and propranolol by inhibiting somatostatin release

·       Deep sleep

·       Glucagon

·       Sodium oxybate or γ-Hydroxybutyric acid

·       Niacin as nicotinic acid (vitamin B3)

·       Fasting

·       Insulin

·       Vigorous exercise

Inhibitors[quantify] of GH secretion include:

·       GHIH (somatostatin) from the periventricular nucleus

·       circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus)

·       Hyperglycemia

·       Glucocorticoids

·       Dihydrotestosterone

·       Phenothiazines

Functions

Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other peptide hormones, GH acts by interacting with a specific receptor on the surface of cells. Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms-

1.       Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.

2.       GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin.[40] The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:

·       Increases calcium retention, and strengthens and increases the mineralization of bone

·       Increases muscle mass through sarcomere hypertrophy

·       Promotes lipolysis

·       Increases protein synthesis

·       Stimulates the growth of all internal organs excluding the brain

·       Plays a role in homeostasis

·       Reduces liver uptake of glucose

·       Promotes gluconeogenesis in the liver

·       Contributes to the maintenance and function of pancreatic islets

·       Stimulates the immune system

·       Increases deiodination of T4 to T3

·       Induces insulin resistance

Leptin

 

Leptin

Introduction

Leptin (from Greek λεπτός leptos, "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long-term energy balance.

As one of the major signals of energy status, leptin levels influence appetite, satiety, and motivated behaviors oriented toward the maintenance of energy reserves (e.g., feeding, foraging behaviors).

The amount of circulating leptin correlates with the amount of energy reserves, mainly triglycerides stored in adipose tissue. High leptin levels are interpreted by the brain that energy reserves are high, whereas low leptin levels indicate that energy reserves are low, in the process adapting the organism to starvation through a variety of metabolic, endocrine, neurobiochemical, and behavioral changes. Leptin is coded for by the LEP gene. Leptin receptors are expressed by a variety of brain and peripheral cell types. These include cell receptors in the arcuate and ventromedial nuclei, as well as other parts of the hypothalamus and dopaminergic neurons of the ventral tegmental area, consequently mediating feeding.

Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beyond hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be fully defined.

In obesity, a decreased sensitivity to leptin occurs (similar to insulin resistance in type 2 diabetes), resulting in an inability to detect satiety despite high energy stores and high levels of leptin.

Sites of synthesis

Leptin is produced primarily in the adipocytes of white adipose tissue. It also is produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow,[19] gastric chief cells, and P/D1 cells.

Blood levels

Leptin circulates in blood in free form and bound to proteins. Leptin levels vary exponentially, not linearly, with fat mass. Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night. The diurnal rhythm of blood leptin levels may be modified by meal-timing. Increased levels of melatonin causes a downregulation of leptin, however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping. Partial sleep deprivation has also been associated with decreased blood leptin levels.

Functions

1.       Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, and is thus labeled fat cell-specific. The central location of action (effect) of the fat cell-specific hormone leptin is the hypothalamus. The primary function of the hormone leptin is the regulation of adipose tissue mass through central hypothalamus mediated effects on hunger, food energy use, physical exercise, and energy balance.

2.       Outside the brain, in the periphery of the body, leptin's secondary functions are: modulation of energy expenditure, modulation between fetal and maternal metabolism, and that of a permissive factor in puberty, activator of immune cells, activator of beta islet cells, and growth factor.

3.       Leptin along with kisspeptin controls the onset of puberty. High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche. This may eventually lead to shorter stature as estrogen secretion starts during menarche and causes early closure of epiphyses.

4.       Leptin can affect bone metabolism via direct signalling from the brain. Leptin decreases cancellous bone, but increases cortical bone. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.

5.       Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the inflammatory response, it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory cytokines.

6.       Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, the size of individual fat cells, and overeating, it is not affected by exercise.

specific conditions

In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:

·       Leptin plays a critical role in the adaptive response to starvation.

·       Leptin level is decreased after short-term fasting (24–72 hours), even when changes in fat mass are not observed.

·       Serum level of leptin is reduced by sleep deprivation.

·       Leptin levels are paradoxically increased in obesity.

·       Leptin level is increased by emotional stress.

·       Leptin level is chronically reduced by physical exercise training.

·       Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels.

·       Leptin level is increased by insulin.

·       Leptin release is increased by dexamethasone.

·       In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure.[119][120] In non-obese individuals, h

Ghrelin

 

Ghrelin

Introduction

Ghrelin (/ˈɡrɛlɪn/; or lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is also dubbed the "hunger hormone" because it increases the drive to eat.[6] Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. 4Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid. Ghrelin activates cells in the anterior pituitary gland and hypothalamic arcuate nucleus, including neuropeptide Y neurons that initiate appetite. Ghrelin stimulates brain structures having a specific receptor – the growth hormone secretagogue receptor 1A (GHSR-1A). Ghrelin also participates in regulation of reward cognition, learning and memory, the sleep-wake cycle, taste sensation, reward behavior, and glucose metabolism.

Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHS-R) was determined in 1999. The hormone name is based on its role as a growth hormone-releasing peptide- gʰre-, meaning "to grow".

Ghrelin cells

The ghrelin cell is also known as an A-like cell (pancreas), X-cell (for unknown function), X/A-like cell (rats), Epsilon cell (pancreas), P/D sub 1 cell (humans) and Gr cell (abbreviation for ghrelin cell).

Ghrelin cells are found mainly in the stomach and duodenum, but also in the jejunum, lungs, pancreatic islets, gonads, adrenal cortex, placenta, and kidney. It has also been shown that ghrelin is produced locally in the brain. Additionally, research suggests that ghrelin may be produced in the myocardium and have an 'autocrine/ paracrine' like effect within the heart. Ghrelin cells are also found in oxyntic glands (20% of cells), pyloric glands, and small intestine.

Function and mechanism of action

1.       Ghrelin is a participant in regulating the complex process of energy homeostasis which adjusts both energy input – by adjusting hunger signals – and energy output – by adjusting the proportion of energy going to ATP production, fat storage, glycogen storage, and short-term heat loss. The net result of these processes is reflected in body weight, and is under continuous monitoring and adjustment based on metabolic signals and needs. At any given moment in time, it may be in equilibrium or disequilibrium. Gastric-brain communication is an essential part of energy homeostasis, and several communication pathways are probable, including the gastric intracellular mTOR/S6K1 pathway mediating the interaction among ghrelin, nesfatin and endocannabinoid gastric systems, and both afferent and efferent vagal signals.

2.       Ghrelin and synthetic ghrelin mimetics (growth hormone secretagogues) increase body weight and fat mass by triggering receptors in the arcuate nucleus that include neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons. Ghrelin responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin reduces the sensitivity of gastric vagal afferents, so they are less sensitive to gastric distension.

3.       In addition to its function in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic reward link in inputs to the ventral tegmental area and in the mesolimbic pathway, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food and addictive drugs such as ethanol. Ghrelin receptors are located on neurons in this circuit. Hypothalamic ghrelin signaling is required for reward from alcohol and palatable/rewarding foods.

4.       Ghrelin has been linked to inducing appetite and feeding behaviors. Circulating ghrelin levels are the highest right before a meal and the lowest right after. Injections of ghrelin in humans have been shown to increase food intake in a dose-dependent manner. So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number. Ghrelin also increases motivation to seek out food.

5.       Body weight is regulated through energy balance, the amount of energy taken in versus the amount of energy expended over an extended period of time. Studies have shown that ghrelin levels are positively correlated with weight. This data suggests that ghrelin functions as an adiposity signal, a messenger between the body's energy stores and the brain.

6.       Action on Glucose metabolism

The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a gluco-regulatory action,

7.       Effects of and on Sleep

Preliminary research indicates that ghrelin participates in the regulation of circadian rhythms. A review reported finding strong evidence that sleep restriction affected ghrelin or leptin levels, or energy expenditure.

8.       Effects on Cardiovascular system

Ghrelin functions as a cardio-protective peptide by being an anti-inflammatory agent, promoting angiogenesis, inhibiting arrhythmia, and improving heart failure.

 

Thyroid hormones

 

 

Thyroid hormones

Thyroid hormones are two hormones produced and released by the thyroid gland: triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, which is derived from food American chemist Edward Calvin Kendall was responsible for the isolation of thyroxine in 1915. Levothyroxine, a synthetic derivative of Thyroxine, is on the World Health Organization's List of Essential Medicines.

The major form of thyroid hormone in the blood is thyroxine (T4), whose half-life of around one week, is longer than that of T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-deiodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production. Calcitonin, a peptide hormone produced and secreted by the thyroid, is usually not included in the meaning of "thyroid hormone".

Thyroid hormones are one of the factors responsible for the modulation of energy expenditure. This is achieved through several mechanisms, such as mitochondrial biogenesis and adaptive thermogenesis.

Thyroid metabolism

Central metabolism

- Thyroglobulin is synthesized in the rough endoplasmic reticulum and follows the secretory pathway to enter the colloid in the lumen of the thyroid follicle by exocytosis.

- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide (I−) actively into the cell, which previously has crossed the endothelium by largely unknown mechanisms.

- This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin, in a purportedly passive manner.

- In the colloid, iodide (I−) is oxidized to iodine (I0) by an enzyme called thyroid peroxidase.

- Iodine (I0) is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain (in total containing approximately 120 tyrosyl residues).

- In conjugation, adjacent tyrosyl residues are paired together.

- Thyroglobulin re-enters the follicular cell by endocytosis.

- Proteolysis by various proteases liberates thyroxine and triiodothyronine molecules

- Efflux of thyroxine and triiodothyronine from follicular cells, which appears to be largely through monocarboxylate transporter 8 (MCT 8) and 10, and entry into the blood.

Thyroid hormones (T4 and T3) are produced by thyroid epithelial cells (a.k.a. thyroid follicular cells) and are regulated by thyroid-stimulating hormone (TSH) made by the thyrotropes of the anterior pituitary gland. The effects of T4 in vivo are mediated via T3 (T4 is converted to T3 in target tissues). T3 is three to five times more active than T4. T4, thyroxine (3,5,3′,5′-tetraiodothyronine), is produced by follicular cells of the thyroid gland. It is produced from the precursor thyroglobulin (this is not the same as thyroxine-binding globulin [TBG]), which is cleaved by enzymes to produce active T4.

The steps in this process are as follows:

The Na+/I− symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I− against its concentration gradient. This is called iodide trapping.[36] Sodium is cotransported with iodide from the basolateral side of the membrane into the cell,[clarification needed] and then concentrated in the thyroid follicles to about thirty times its concentration in the blood.

I− is moved across the apical membrane into the colloid of the follicle by pendrin. Hydrogen peroxide is also introduced into the follicle by the action of DUX (Dual Oxidase).

Iodide is non-reactive, and the reactive I2 species is required for the next step. Thyroid peroxidase (TPO) reduces hydrogen peroxide to water by transferring one electron from two I− atoms that react to form I2.

Iodine (I2) is converted into HOI, by hydration with water. Both I2 and HOI iodinate specific tyrosyl residues of the thyroglobulin within the colloid to form 3-monoiodityrosyl (MIT-yl) and 3,5-diiodityrosyl (DIT-yl) residues—introducting iodine atoms at one or both locations ortho to the hydroxyls of tyrosine. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.

TPO also converts tyrosyl, MIT-yl, and DIT-yl residues into their free radical forms. These forms attack other MIT-yl and DIT-yl residues. When a DIT-yl radical attacks a DIT, T4-yl (peptidic T4) is formed. When a MIT-yl radical attacks a DIT, T3-yl is formed. Other reactions are possible, but do not form physiologically active products.

Iodinated thyroglobulin binds megalin for endocytosis back into the cell.

TSH released from the anterior pituitary (a.k.a. the adenohypophysis) binds the TSH receptor (a Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.

The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave any MIT, DIT, T3, T4 as well as the inactive analogues from the iodinated thyroglobulin.

The thyroid hormones cross the follicular cell membrane towards the blood vessels by monocarboxylate transporter 8 (MCT 8) and 10 which play major roles in the efflux of the thyroid hormones from thyroid cells.

Thyroglobulin (Tg) is a 660 kDa, dimeric protein produced by the follicular cells of the thyroid and used entirely within the thyroid gland. Thyroxine is produced by attaching iodine atoms to the ring structures of this protein's tyrosine residues; thyroxine (T4) contains four iodine atoms, while triiodothyronine (T3), otherwise identical to T4, has one less iodine atom per molecule.[48] The thyroglobulin protein accounts for approximately half of the protein content of the thyroid gland.[49] Each thyroglobulin molecule contains approximately 100–120 tyrosine residues, a small number (<20) of which are subject to iodination catalysed by thyroperoxidase. The same enzyme then catalyses "coupling" of one modified tyrosine with another, via a free-radical-mediated reaction, and when these iodinated bicyclic molecules are released by hydrolysis of the protein, T3 and T4 are the result. Therefore, each thyroglobulin protein molecule ultimately yields very small amounts of thyroid hormone (experimentally observed to be on the order of 5–6 molecules of either T4 or T3 per original molecule of thyroglobulin).

Hydrolysis (cleavage to individual amino acids) of the modified protein by proteases then liberates T3 and T4, as well as the non-coupled tyrosine derivatives MIT and DIT. The hormones T4 and T3 are the biologically active agents central to metabolic regulation.

 

Peripheral metabolism

Thyroxine is believed to be a prohormone and a reservoir for the most active and main thyroid hormone, T3. T4 is converted as required in the tissues by iodothyronine deiodinase. Deficiency of deiodinase can mimic hypothyroidism due to iodine deficiency.T3 is more active than T4,[56] though it is present in less quantity than T4.

Initiation of production in fetuses

Thyrotropin-releasing hormone (TRH) is released from hypothalamus by 6–8 gestational weeks, and thyroid-stimulating hormone (TSH) secretion from the fetal pituitary gland is evident by 12 gestational weeks; fetal production of thyroxine (T4) reaches a clinically significant level at 18–20 weeks. Fetal triiodothyronine (T3) remains low (less than 15 ng/dL) until 30 weeks of gestation, and increases to 50 ng/dL at term. Fetal self-sufficiency of thyroid hormones protects the fetus against, for example, neurodevelopmental abnormalities caused by maternal hypothyroidism

 

Circulation and transport

Plasma transport

Most of the thyroid hormone circulating in the blood is bound to transport proteins, and only a very small fraction is unbound and biologically active. Therefore, measuring concentrations of free thyroid hormones is important for diagnosis, while measuring total levels can be misleading.

Thyroid hormone in the blood is usually distributed as follows:

Type	Percent
bound to thyroxine-binding globulin (TBG)	70%
bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA)	10–15%
albumin	15–20%
unbound T4 (fT4)	0.03%
unbound T3 (fT3)	0.3%

Despite being lipophilic, T₃ and T₄ cross the cell membrane via carrier-mediated transport, which is ATP-dependent

Membrane transport

thyroid hormones cannot traverse cell membranes in a passive manner like other lipophilic substances. The iodine in o-position makes the phenolic OH-group more acidic, resulting in a negative charge at physiological pH. However, at least 10 different active, energy-dependent and genetically regulated iodothyronine transporters have been identified in humans. They guarantee that intracellular levels of thyroid hormones are higher than in blood plasma or interstitial fluids.

Mechanism of action

The thyroid hormones function via a well-studied set of nuclear receptors, termed the thyroid hormone receptors. These receptors, together with corepressor molecules, bind DNA regions called thyroid hormone response elements (TREs) near genes. This receptor-corepressor-DNA complex can block gene transcription. Triiodothyronine (T3), which is the active form of thyroxine (T4), goes on to bind to receptors. The deiodinase catalyzed reaction removes an iodine atom from the 5′ position of the outer aromatic ring of thyroxine's (T4) structure. When triiodothyronine (T3) binds a receptor, it induces a conformational change in the receptor, displacing the corepressor from the complex. This leads to recruitment of coactivator proteins and RNA polymerase, activating transcription of the gene.

Functions of Thyroid Hormones

Thyroid hormones act on nearly every cell in the body. They act to

·       increase the basal metabolic rate

·       affect protein synthesis

·       help regulate long bone growth in synergy with growth hormone

·       effect neural maturation

·       increase the body's sensitivity to catecholamines (such as norepinephrine and epinephrine) by permissiveness, especially under cold exposure.

·       essential to proper development and differentiation of all cells of the human body.

·       These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds.

·       They  stimulate vitamin metabolism.

·       Thyroid hormones lead to heat generation in humans.

Functions of triiodothyronine

Effects of triiodothyronine (T3) which is the metabolically active form:

·       Increases cardiac output

·       Increases heart rate

·       Increases ventilation rate

·       Increases basal metabolic rate

·       Potentiates the effects of catecholamines (i.e. increases sympathetic activity)

·       Potentiates brain development

·       Thickens endometrium in females

·       Increases catabolism of proteins and carbohydrates.