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Thyroid hormone metabolism and excretion

Thyroid hormone metabolism and excretion



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My understanding is that hormones generated by the thyroid gland, including, for example, T4, are excreted and recirculated in the body through the digestive tract. The reason for thinking this is that bile acid sequestrants such as cholestyramine cause a lowering of serum T4. In fact, patients who have hypothyroidism are explicitly warned not to use sequestrants for this exact reason. Here is a statement from a clinical trial discussing the effect:

The enterohepatic circulation of thyroid hormones is increased in thyrotoxicosis.Bile-salt sequestrants (ionic exchange resins) bind thyroid hormones in the intestine and thereby increase their fecal excretion. Based on these observations, the use of cholestyramine has been tried. The present study evaluates the effect of low doses of cholestyramine as an adjunctive therapy in the management of hyperthyroidism. -- clinical trial NCT00677469

Therefore, there would appear to be a metabolic pathway in which T4 is being excreted into the digestive tract and then is later re-absorbed in the lower intestine somehow.

What is this metabolic pathway? How exactly does this mechanism work? Does it have a name?

For more information on thyroid hormone sequestration see:

https://clinicaltrials.gov/ct2/show/NCT00677469

http://www.ncbi.nlm.nih.gov/pubmed/8435884


I have partially answered this question by discovering that the metabolic pathway is called enterohepatic circulation. In this interaction bile salts are absorbed and transported out of ileal mucosal cells by binding to albumin.

However, it is still unkown to me exactly how it is that thyroxine and other hormones are moderated in this process and how it works. Does the albumin collect thyroxine as well as bile salts? How is the process moderated? In other words, bile salts are allowed to be excreted according to some moderated control mechanism. What is this mechanism?


Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

Thyroid hormones (THs) are secreted by the thyroid gland. They control lipid, carbohydrate, and protein metabolism, heart rate, neural development, as well as cardiovascular, renal, and brain functions. The thyroid gland mainly produces l-thyroxine (T4) as a prohormone, and 5'-deiodination of T4 by iodothyronine deiodinases generates the nuclear receptor binding hormone T3. In this Review, we discuss the basic aspects of the chemistry and biology as well as recent advances in the biosynthesis of THs in the thyroid gland, plasma transport, and internalization of THs in their target organs, in addition to the deiodination and various other enzyme-mediated metabolic pathways of THs. We also discuss thyroid hormone receptors and their mechanism of action to regulate gene expression, as well as various thyroid-related disorders and the available treatments.

Keywords: deiodinases iodine selenium thyroid hormones thyroxine.


The function of thyroxine in metabolism regulation

The primary function of the thyroid gland is the production of the non-steroid hormone thyroxine, a peptide molecule made from the amino acid tyrosine.

Each thyroxine molecule contains four atoms of iodine.

Receptors for thyroxine are found on most cells in the body.

The function of thyroxine is an increase basal metabolic rate and oxygen consumption, especially in the heart, skeletal muscle, liver, and kidney. It is essential for normal development, growth, and neural differentiation.

The increased oxygen demand is due to the stimulation of sodium potassium pump activity in the cell membranes of target cells.

The additional oxygen is consumed in the production of ATP that is required to drive the sodium potassium pump. Heat is given off as a byproduct of this process.

Thyroid hormones are carried through the blood by carrier proteins, as are steroid hormones.

About 30 percent of the iodine in blood is consumed by the thyroid gland to be used in the synthesis of thyroxine.

Regulation of thyroxine synthesis

Thyroxine secretion is governed by the anterior lobe of the pituitary gland, which produces thyroid-stimulating hormone (TSH). The two hormones, thyroxine and thyroid-stimulating hormone, interact to adjust the levels of thyroxine in response to the body’s constantly changing needs.

Caffeine in some beverages we consume reduces glucose metabolism in the cells of the body by inhibiting thyroid-stimulating hormone production, which in turn suppresses thyroxine secretion.

Thyroid hormones (circulating in the blood) then feed back to the pituitary gland, where they suppress the secretion of thyroid-stimulating hormone.

In the thyroid gland, thyroid-stimulating hormone stimulates an increase in iodine uptake from the blood, and the synthesis and secretion of thyroxine hormone.

Hyperthyroidism - an autoimmune disorder of an overactive thyroid

An excess of thyroxine production is referred to as hyperthyroidism, also known as Grave’s disease.

Hyperthyroidism is an autoimmune disorder in which antibodies attach to thyroid-stimulating hormone receptors on thyroid cells. This attachment puts receptors in a “perpetually on” mode that stimulates cell division and production of thyroid hormone.

Symptoms of an overactive thyroid

The excessive hormone production causes enlargement of the thyroid, muscle weakness, increased metabolic rate, excessive heat production, and sweating and warm skin due to dilation of blood vessels in the skin (vasodilation).


Thyroid Function

The primary function of the thyroid is to produce hormones that regulate metabolic function. Thyroid hormones do so by influencing ATP production in cell mitochondria. All cells of the body depend on thyroid hormones for proper growth and development. These hormones are required for proper brain, heart, muscle, and digestive function. In addition, thyroid hormones increase the body's responsiveness to epinephrine (adrenaline) and norepinephrine (noradrenaline). These compounds stimulate sympathetic nervous system activity, which is important for the body's flight or fight response. Other functions of thyroid hormones include protein synthesis and heat production. The hormone calcitonin, produced by the thyroid, opposes the action of parathyroid hormone by decreasing calcium and phosphate levels in the blood and promoting bone formation.


Hormone Metabolism and Excretion

A hormone's concentration in the plasma depends not only upon its rate of secretion by the endocrine gland but also upon its rate of removal from the blood, either by excretion or by metabolic transformation. The liver and the kidneys are the major organs that excrete or metabolize hormones.

The liver and kidneys, however, are not the only routes for eliminating hormones. Sometimes the hormone is metabolized by the cells upon which it acts. Very importantly, in the case of peptide hormones, en-docytosis of hormone-receptor complexes on plasma membranes enables cells to remove the hormones rapidly from their surfaces and catabolize them intra-cellularly. The receptors are then often recycled to the plasma membrane.

In addition, catecholamine and peptide hormones are excreted rapidly or attacked by enzymes in the blood and tissues. These hormones therefore tend to remain in the bloodstream for only brief periods—minutes to an hour. In contrast, because protein-bound hormones are less vulnerable to excretion or metabolism by enzymes, removal of the circulating steroid and thyroid hormones generally takes longer, often several hours (with thyroid hormone remaining in the plasma for days).

In some cases, metabolism of the hormone after its secretion activates the hormone rather than inactivates

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Major Form Location of Signal Transduction Rate of

Types in Plasma Receptors Mechanisms Excretion/Metabolism

Peptides and catecholamines Free Plasma membrane Receptors alter: Fast (minutes to

Channels intrinsic an hour)

to the receptors Enzymatic activity intrinsic to the receptor Enzymatic activity of cytoplasmic JAK kinases associated with the receptor G proteins in the plasma membrane. These control plasma-membrane channels or enzymes that generate second messengers (cAMP, DAG, IP3).

Steroids and thyroid Protein- Cell interior Receptors directly alter Slow (hours to days)

hormones bound gene transcription

Possible fates and actions of a hormone following its secretion by an endocrine cell. Not all paths apply to all hormones. % [<n>]

Possible fates and actions of a hormone following its secretion by an endocrine cell. Not all paths apply to all hormones. % [<n>]

it. In other words, the secreted hormone may be relatively or completely unable to act upon a target cell until metabolism transforms it into a substance that can act. We have already seen one example of hormone activation—the conversion of circulating T4 to the far more active T3. Another example is provided by testosterone, which is converted either to estradiol or dihydrotestosterone in certain of its target cells. These molecules, rather than testosterone itself, then bind to receptors inside the target cell and elicit the cell's response.

There is another kind of "activation" that applies to a few hormones. Instead of the hormone itself being activated after secretion, it acts enzymatically on a completely different plasma protein to split off a pep-tide that functions as the active hormone. The best known example of this is the renin-angiotensin system, described in Chapters 14 and 16 renin is not technically a hormone but an enzyme that participates in the generation of the hormone angiotensin.

Figure 10-7 summarizes the fates of hormones after their secretion.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition


Endocrine Controls

To control endocrine functions, the secretion of each hormone must be regulated within precise limits. The body is normally able to sense whether more or less of a given hormone is needed.

Many endocrine glands are controlled by the interplay of hormonal signals between the hypothalamus, located in the brain, and the pituitary gland, which sits at the base of the brain. This interplay is referred to as the hypothalamic-pituitary axis. The hypothalamus secretes several hormones that control the pituitary gland.

The pituitary gland, sometimes called the master gland, in turn controls the functions of many other endocrine glands. The pituitary controls the rate at which it secretes hormones through a feedback loop in which the blood levels of other endocrine hormones signal the pituitary to slow down or speed up. So, for example, the pituitary gland senses when blood levels of thyroid hormone are low and releases thyroid stimulating hormone, which tells the thyroid gland to make more hormones. If the level gets too high, the pituitary senses that and decreases the amount of thyroid stimulating hormone, which then decreases the amount of thyroid hormone produced. This back-and-forth adjustment (feedback) keeps hormone levels in proper balance.

Many other factors can control endocrine function. For example, a baby sucking on its mother's nipple stimulates her pituitary gland to secrete prolactin and oxytocin , hormones that stimulate breast milk production and flow. Rising blood sugar levels stimulate the islet cells of the pancreas to produce insulin . Part of the nervous system stimulates the adrenal gland to produce epinephrine .


Discovery illuminates how thyroid hormone 'dims' metabolism

It has been known for some time that the thyroid gland is a strong regulator of the body's metabolism, making it key to many health conditions. But the molecular details of how thyroid hormone acts on cells in the body have never been fully understood. Now researchers at the Perelman School of Medicine at the University of Pennsylvania have taken a big step toward the resolution of this mystery by showing that it doesn't operate as a straight on/off switch, but more like a dimmer.

Biologists have known that, in cells where thyroid hormone acts to regulate metabolism, it operates in the cell nucleus, increasing the activity of some genes and decreasing the activity of others. The details of how the hormone controls gene activity have been mostly unknown, due to technical hurdles that have made it difficult to study them. The Penn Medicine researchers, who report their discovery today in Genes and Development, were able to overcome many of these technical hurdles to provide a much clearer picture of thyroid hormone's basic mechanisms of action -- in the process overturning other prominent models of these mechanisms.

"We were able in this study to show that thyroid hormone doesn't just turn things on or off, as the canonical model suggests, but instead more subtly shifts the balance between the repression and enhancement of gene activity," said principal investigator Mitchell Lazar, MD, PhD, Ware professor of Diabetes and Metabolic Diseases, and the director of the Institute for Diabetes, Obesity and Metabolism, at Penn Medicine. "Yet, as people with hypothyroidism know, the lack of thyroid hormone can have profound effects on the body."

Diseases of the thyroid gland, including hypothyroidism, hyperthyroidism, and goiter, have been described for as long as there have been doctors. The thyroid-produced molecule thyroxine, the chemical precursor to the main active form of thyroid hormone, was identified in 1914.

Endocrinologists also have long recognized that thyroid hormone is an essential metabolism-enhancing regulator whose insufficiency can lead not only to obvious thyroid diseases but also to weight gain and related metabolic problems including diabetes, high cholesterol, and fatty liver disease. Thus, the hormone's mechanism of action, if understood, could be a drug target of enormous value for medicine.

But although scientists have known for almost 40 years that thyroid hormone acts in the cell nucleus to control gene activity by binding itself to special proteins called thyroid hormone receptors, how it all works has remained an enigma -- largely because the interactions of thyroid hormone and its receptors have been difficult to study. Among other challenges, the receptors normally are produced in relatively tiny quantities in cells, and scientists have lacked a good way to mark their binding sites on DNA -- and to see how these binding sites differ when thyroid hormone is present.

In the new study, for which Yehuda Shabtai, PhD, a postdoctoral researcher in the Lazar lab, served as lead author, the researchers developed a mouse model in which a special tag was added to TR&beta, the main thyroid hormone receptor in the liver -- where some of thyroid hormone's most important metabolic effects occur. The researchers used this tag for marking the thousands of locations on DNA where TR&beta binds, both in a condition when thyroid hormone was present and could bind to TR&beta and also when the hormone was largely absent. With these and other experiments, the team provided strong evidence that thyroid hormone works with TR&beta in an unexpectedly subtle way.

When it binds to a given site on coiled DNA in the nucleus, TR&beta will enhance or repress the activity of a nearby gene or genes. To achieve this, it forms complexes with other proteins called co-activators and co-repressors. The researchers showed when thyroid hormone is bound to TR&beta, it can shift the balance of these associated co-regulator proteins in favor of more gene activation at some sites, and more gene repression at others. This is in contrast to prior models of thyroid hormone / TR&beta function in which thyroid hormone has a more absolute, switch-like effect on gene activity.

The researchers acknowledge that more work needs to be done to elucidate why thyroid hormone's binding to TR&beta lowers gene activity at some sites on DNA, and increases gene activity at other sites. But they see the new findings as a significant advance in understanding a basic process in biology -- a process that future medicines may be able to target precisely to treat a variety of metabolic diseases.

Their work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK43806, DK19525) and the Cox Institute for Medical Research.


Endocrine Controls

To control endocrine functions, the secretion of each hormone must be regulated within precise limits. The body is normally able to sense whether more or less of a given hormone is needed.

Many endocrine glands are controlled by the interplay of hormonal signals between the hypothalamus, located in the brain, and the pituitary gland, which sits at the base of the brain. This interplay is referred to as the hypothalamic-pituitary axis. The hypothalamus secretes several hormones that control the pituitary gland.

The pituitary gland, sometimes called the master gland, in turn controls the functions of many other endocrine glands. The pituitary controls the rate at which it secretes hormones through a feedback loop in which the blood levels of other endocrine hormones signal the pituitary to slow down or speed up. So, for example, the pituitary gland senses when blood levels of thyroid hormone are low and releases thyroid stimulating hormone, which tells the thyroid gland to make more hormones. If the level gets too high, the pituitary senses that and decreases the amount of thyroid stimulating hormone, which then decreases the amount of thyroid hormone produced. This back-and-forth adjustment (feedback) keeps hormone levels in proper balance.

Many other factors can control endocrine function. For example, a baby sucking on its mother's nipple stimulates her pituitary gland to secrete prolactin and oxytocin , hormones that stimulate breast milk production and flow. Rising blood sugar levels stimulate the islet cells of the pancreas to produce insulin . Part of the nervous system stimulates the adrenal gland to produce epinephrine .


Thyroid hormones

Cells of the thyroid gland produce three hormones

(Photo Credit : Designua/Shutterstock)

T4 and T3 hormones are secreted by the follicular cells and calcitonin is secreted by the parafollicular cells. The majority of the secretions of the thyroid hormones consist of T4, with T3 constituting only about 9-10% of the total secretions.

Both T4 and T3 contain iodine as its core substance, which binds to the amino acid tyrosine, and since iodine is not something our body manufactures, we must rely on dietary supplements like iodized salt to keep our thyroid hormones flowing and balanced.

If there is any type of deficiency of thyroid hormones, a whole host of things in your body will go wrong, but you will be able to notice the effects of the hormone slump within four months of the thyroid hormone factory slowing down.

The symptoms of this deficiency will take about 4 months to show up, and with good reason&mdashthe thyroid gland is the only endocrine gland with a storage capacity of four months, so while you may think everything is hunky-dory, it may not be the case!


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Nutritional Epidemiology and Thyroid Hormone Metabolism

▪ Abstract Severe iodine deficiency was the main cause of endemic goiter and cretinism. Most of the previously iodine-deficient areas are now supplemented, mainly with iodized salt. The geographical distribution of severe endemic areas has been progressively reduced, and at present, approximately 200 million people living in remote places are still at risk of severe iodine deficiency. International public health programs should be focused first on reaching these populations, and second on auditing and monitoring the operational work of supplementation programs. This second point is essential to prevent iodine-induced hyperthyroidism or interruptions of iodine supplement distribution, which could be catastrophic for the fetus and the young infant. Echography brings a complementary tool to clinical assessment of goiter by palpation. Inductively coupled plasma–mass spectrometry brings at least a definitive gold standard for iodine measurement and thyroid hormone measurement. Thiocyanate overload has been clearly documented as a goitrogen in Central Africa, and when associated with selenium deficiency, it may be included as risk factor for endemic myxedematous cretinism. Variable exposure to different environmental risk factors is likely the explanation of the variable distribution of two types of endemic cretinism (neurological and myxedematous), and the clinical overlap of the pathogeny of both syndromes is more important than previously described. It is possible that Kashin-Beck osteoarthropathy is another evanescent endemic disease that will disappear with the correction of iodine deficiency.