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What Is The Physiological Role Of Thyroid Hormones

Effects Of Iodine Deficiency

Thyroid Gland: Thyroid Hormone Function

If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormone. A lack of thyroid hormone will lead to decreased negative feedback on the pituitary, which in turn, will lead to increased production of thyroid-stimulating hormone, which causes the thyroid to enlarge .

This enlarged endemic colloid goiter has the effect of increasing the thyroids ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone.

How Is Thyroxine Controlled

The production and release of thyroid hormones, thyroxine and triiodothyronine, is controlled by a feedback loop system that involves the hypothalamus in the brain and the pituitary and thyroid glands. The hypothalamus secretes thyrotropin-releasing hormone which, in turn, stimulates the pituitary gland to produce thyroid stimulating hormone. This hormone stimulates the production of the thyroid hormones, thyroxine and triiodothyronine, by the thyroid gland.

This hormone production system is regulated by a feedback loop so that when the levels of the thyroid hormones increase, they prevent the release of both thyrotropin-releasing hormone and thyroid stimulating hormone. This system allows the body to maintain a constant level of thyroid hormones in the body.

Clinical Manifestation Of Th Signaling Related Mutations In Humans

The developing skeleton is sensitive to thyroid status and childhood hypothyroidism is characterized by growth retardation, delayed bone age and short stature, whereas juvenile thyrotoxicosis accelerates growth and advances bone age but results in persistent short stature due to premature fusion of the epiphyses . A loss of function mutation of the TSH -subunit results in TSH deficiency and congenital hypothyroidism. Two affected siblings received TH replacement from birth but despite the lifelong absence of TSH, their skeletal development and bone mineral density were normal . These findings suggest that TSH is not required for normal skeletal development and growth. TSHR mutations result in wide spectrum of clinical manifestations ranging from mild to severe hypothyroidism and hyperthyroidism . Up to this date more than 40 kinds of loss of function mutations in the TSHR gene have been reported as the causative defect in congenital hypothyroidism . By contrast, gain of function mutations in the TSHR gene were identified in familial non-autoimmune hyperthyroidism or sporadic non-autoimmune hyperthyroidism .

Table 2 Clinical manifestation of TH signaling related mutations in humans

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Functions Of Thyroid Hormones

The thyroid hormones, T3 and T4, are often referred to as metabolic hormones because their levels influence the bodys basal metabolic rate, the amount of energy used by the body at rest. When T3 and T4 bind to intracellular receptors located on the mitochondria, they cause an increase in nutrient breakdown and the use of oxygen to produce ATP. In addition, T3 and T4 initiate the transcription of genes involved in glucose oxidation. These mechanisms prompt cells to produce more ATP which causes an increase in heat production. This so-called calorigenic effect raises body temperature.

Disorders of theEndocrine System: Iodine Deficiency, Hypothyroidism, and Hyperthyroidism

Dietary iodine deficiency can result in the impaired ability to synthesize T3 and T4, leading to a variety of severe disorders. When T3 and T4 cannot be produced, TSH is secreted in increasing amounts. As a result of this hyperstimulation, thyroglobulin accumulates in the thyroid gland follicles, increasing their deposits of colloid. The accumulation of colloid increases the overall size of the thyroid gland, a condition called a goiter . A goiter is only a visible indication of the deficiency. Other symptoms include impaired growth and development, decreased fertility, and prenatal and infant death. Neonatal hypothyroidism is characterized by severe cognitive deficits, short stature, and sometimes deafness and muteness in children and adults born to mothers who were iodine-deficient during pregnancy.

What Happens If I Have Too Little Thyroxine

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Too little production of thyroxine by the thyroid gland is known as hypothyroidism. It may be caused by autoimmune diseases, poor iodine intake or caused by the use of certain drugs. Sometimes, the cause is unknown. Thyroid hormones are essential for physical and mental development so untreated hypothyroidism before birth or during childhood can cause mental impairment and reduced growth.

Hypothyroidism in adults causes reduced metabolism. It can result in symptoms such as fatigue, intolerance of cold temperatures, low heart rate, weight gain, reduced appetite, poor memory, depression, stiffness of the muscles and reduced fertility. See the article on hypothyroidism for more information.

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Developmental Effects Of Fetal Hypothyroidism

As in postnatal tissue , the current study shows that thyroid hormones are important metabolic regulators in fetal skeletal muscle. In late gestation, O2 consumption by TX muscles was lower than control values in a substrate-specific manner, consistent with the low whole body rates of O2 consumption in TX sheep fetuses . The lower rates of muscle O2 consumption after TX were accompanied by reductions in CS activity and the abundance of ETS complexes and ATP-synthase. These decrements were more pronounced at 143 than at 127 dGA. TX muscles also had lower HOAD activity and expression of ANT1 than control muscles by 143 dGA. In addition, TX abolished the developmental increase in mitochondrial oxidative capacity seen in control muscle between 127 and 143 dGA. Furthermore, TX was associated with a lower proportion of type I fibres and more undifferentiated muscle fibres in the BF at 143 dGA, in line with previous studies of other skeletal muscles in fetal sheep . Together, the current findings suggest that the effects of thyroid hormones on muscle mitochondrial function in utero may be mediated at least, in part, by their role in muscle fibre differentiation.

Functions Of T3 And T:

T3 and T4 are secreted from chief thyroid follicular cells.

The principal functions are given below:

On Carbohydrate Metabolism:

Enhances uptake of glucose in GI tract.

Promotes gluconeogenesis in liver by enhancing the activities of PEPCK and pyruvate carboxylase.

Causes insulin breakdown and increases blood glucose level.

On Protein Metabolism:

Thyroid hormone has a specific effect on the tissues to mobilize protein and thereby release amino acids into extracellular fluids.

It has anabolic effect, increase in RNA and protein synthesis.

In hyperthyroidism, there is excessive proteins catabolism leading to body wasting as evidenced by excessive nitrogen excretion in the urine.

On Lipid Metabolism:

The concentration of cholesterol in blood is inversely proportional with the level of thyroid activity.

Thyroid hormone stimulates the synthesis, metabolism and degradation of lipids.

It increases the oxidation of fatty acids.

On Vitamin Metabolism:

It is necessary for conversion of carotene to Vit. A and Vit. A to retinol.

Hyperthyroidism may cause Vit. D deficiency.

In increases the requirement of Vit. B6, B12 and Vit C.

On Iodine Metabolism:

Helps in the absorption of inorganic iodide from plasma and helps in oxidation of iodide into iodine for synthesis of thyroxine.

On Mineral Metabolism:

It causes increased metabolism of calcium and phosphorous from the bone.

Magnesium level in serum is increased in hyperthyroidism.

On Growth:

On Nervous System:

On Reproductive System:

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Data Collection And Laboratory Measurements

Trained interviewers obtained information on clinical characteristics. Body weight and height were measured with an automatic body composition analyzer to calculate BMI . Systolic blood pressure and diastolic blood pressure were recorded at rest.

A fasting blood sample was collected. TSH, free T3, and free T4 levels were measured using a chemiluminescent immunoassay at the LSI Medience Corporation . Normal ranges for free T3 , free T4 , and TSH based on this method were reported . Hemoglobin A1c , triglyceride , high-density lipoprotein cholesterol , and serum creatinine levels were measured using standard procedures at SRL, Inc. .

The presence of thyroid cysts was determined by experienced ultrasound technicians using a LOGIQ Book XP with a 10-MHz transducer . For the present study, a thyroid cyst was defined as a structure with a maximum diameter of ⥠2.0 mm and no solid components .

Spot urine dipstick was used to assess for the presence of proteinuria. Proteinuria was diagnosed as +1 or above.

Iii Multiple Thyroid Hormone Receptor Isoforms

Physiological Functions of the Thyroid Hormones

Fig. 3.Comparison of amino acid homologies and their functional properties among TR isoforms. The length of receptors is indicated just above the receptor diagrams, and the percent amino acid homology with TR-2 is included in the receptor diagrams.

There also are two TRs derived from the TR gene . This gene contains two promoter regions each of which is vital for the transcription of an mRNA coding for a distinctive protein. By the use of alternate promoter choice, one or both of the coding mRNAs are generated . The resultant TR isoforms are designated as TR-1 and TR-2. The amino acid sequences of the DNA binding, hinge region, and LBDs of these two TRs are identical, but the amino-terminal regions bear no homology . Both are authentic receptors as they bind TREs and TH with high affinity and specificity and can mediate TH-dependent transcription. The expression of the two TR isoforms may be regulated by pituitary-specific transcription factors such as Pit-1 .

Both TR-1 and TR-1 mRNAs and proteins are ubiquitously expressed in rat tissues . However, TR-1 mRNA has highest expression in skeletal muscle and brown fat, whereas TR-1 mRNA has highest expression in brain, liver, and kidney. In contrast to the other TR isoforms, TR-2 mRNA and protein have tissue-specific expression in the anterior pituitary gland and specific areas of the hypothalamus as well as the developing brain and inner ear . In the chick, TR-2 mRNA also is expressed in the developing retina .

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Skeletal Phenotype Of Th Signaling Related Mutant Mice

Mouse mutants with altered TSH or TH levels

Pax8/ mice lack the thyroid specific transcription factor Pax8 required for thyroid follicular cell formation and hyt/hyt mice have a loss-of-function mutation in the TSH receptor . Both mutants have a 2000-fold elevation of TSH and undetectable THs, but the TSHR is functional in Pax8/ mice whereas it is non-functional in hyt/hyt mice. Thus, the reciprocal relationship between THs and TSH remains intact in Pax8/ mice but is disrupted in hyt/hyt mice . Both mutants exhibited a similar skeletal phenotype of impaired linear growth, delayed endochondral ossification, impaired chondrocyte differentiation, reduced cortical bone, impaired trabecular bone remodeling and reduced bone mineralization . These data indicate that any action of TSH in bone is likely to be minor when compared to the effects of T3.

Table 1 Skeletal phenotype of TH signaling related mutant mice

TRa mutants

Mice harboring dominant-negative mutations of TRa1 in different genetic backgrounds have mild and transient systemic hypothyroidism but they also exhibit a more severe phenotype of delayed skeletal development than TRa0/0 mice. TRa1PV/+ mice are most severely affected, displaying persistent post-natal growth retardation and markedly delayed endochondral ossification and decreased mineralization .

TR mutants

Initiation Of Production In Fetuses

Thyrotropin-releasing hormone is released from hypothalamus by 6 8 weeks, and thyroid-stimulating hormone secretion from fetal pituitary is evident by 12 weeks of gestation, and fetal production of thyroxine reaches a clinically significant level at 1820 weeks. Fetal triiodothyronine remains low until 30 weeks of gestation, and increases to 50 ng/dL at term. Fetal self-sufficiency of thyroid hormones protects the fetus against e.g. brain development abnormalities caused by maternal hypothyroidism.

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If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormones. The lack of thyroid hormones will lead to decreased negative feedback on the pituitary, leading to increased production of thyroid-stimulating hormone, which causes the thyroid to enlarge . This has the effect of increasing the thyroid’s ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone.

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V Thyroid Hormone Response Elements

Steroid hormone receptors bind as homodimers to conserved palindromic hormone response elements that mediate hormone regulation of target genes . In contrast, TRs can bind to TREs as monomers, homodimers, and heterodimers in vitro. In general, most of these TREs are located upstream from the minimal promoter, but in certain cases, also can be located in 3-flanking sequences downstream from the coding region . Mutational analyses of the rat growth hormone gene TRE, and sequence comparison among known TREs from other T3-responsive genes, have suggested a putative consensus hexamer half-site sequence of GGTA . However, there can be considerable variation found in primary nucleotide sequences of TREs as well as the number, spacing, and orientation of their half-sites . In particular, TRs can bind to TREs in which half-sites are arranged as palindromes , direct repeats , and inverted palindromes . The optimal spacing for these half-site arrangements are zero, four, and six nucleotides, respectively . Almost all positively regulated target genes contain two or more half-sites however, TRs can activate transcription via an artificial single octamer half-site, perhaps even as monomers .

Fig. 8.Half-site orientation and optimal nucleotide spacing between half-sites. N refers to nucleotides, and arrows show direction of half-sites on the sense strand. TRE, thyroid hormone response element.

Detection Of Metabolisation Products

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In addition to T4 and T3, various TH metabolites circulate in blood, some of which mediate biological effects. Exact levels are not known due to cross-reactivity of TH metabolites in conventional immunoassays, and it is also clear that metabolites found in plasma do not reflect tissue concentrations . Uncertainties of exact levels are not restricted to TH metabolites but exist also for T3, fT4 and fT3 levels. Liquid chromatography-tandem mass spectrometry is the reference method for exact TH quantification but shows a general trend for overestimation, particularly of free TH . Based on LC-MS/MS data, 48% percent of patients were classified as hypothyroid compared to 11% by immunoassay. In another study, in a cohort of 40 patients diagnosed with subclinical hypothyroidism , 65% had fT4 and fT3 levels below the reference level. A major reason for the better performance of LC-MS/MS in the determination of fT4 and fT3 is the removal of TH binding proteins during sample preparation.

Figure 3 Generation of biologically active thyroid hormone metabolites from thyroxine. Circles mark agonists and boxes antagonistically acting metabolites. 3,5-T2, 3,5-diiodothyronine T1AM, 3-iodothyronamine rT3, reverse triiodothyronine TA4, tetraiodoacetic acid T0AM, thyronamine TA3, triiodoacetic acid.

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What Happens If I Have Too Much Thyroxine

The release of too much thyroxine in the bloodstream is known as thyrotoxicosis. This may be caused by overactivity of the thyroid gland , as in Graves’ disease, inflammation of the thyroid or a benign tumour. Thyrotoxicosis can be recognised by a goitre, which is a swelling of the neck due to enlargement of the thyroid gland. Other symptoms of thyrotoxicosis include intolerance to heat, weight loss, increased appetite, increased bowel movements, irregular menstrual cycle, rapid or irregular heartbeat, palpitations, tiredness, irritability, tremor, hair thinning/loss and retraction of the eyelids resulting in a staring appearance.

John R Counsell Errol Richardson & James V Gardiner

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Imperial College, London, UK.

The hypothalamo-pituitarythyroid axis serves to maintain appropriate systemic levels of thyroid hormone through a negative feedback pathway via the hypothalamic arcuate and paraventricular nuclei. However, the effects of TH in other hypothalamic regions are poorly understood. Triiodothyronine administration to the hypothalamic ventromedial nucleus induces a potent hyperphagic response, although it is unclear whether this is part of a novel physiological pathway or simply an additional component of the HPT axis.

This research investigates the physiological role of TH in the VMN through the use of a recombinant adeno-associated virus designed to locally inactivate TH. Activation and inactivation of TH is mediated by the iodothyonine deiodinases , where D2 functions to deiodinate tetraiodothyronine to produce the active T3 hormone, and D3 is the inactivating enzyme.

A plasmid encoding D3 cDNA under the control of a CMV promoter was packaged into rAAV to generate a viral titre capable of over-expressing D3 . Anaesthetised male Wistar rats received bilateral stereotactic injections of either rAAV-D3 or rAAV-GFP into the VMN. Both groups were dissected 78 days after surgery.

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Synthesis And Release Of Thyroid Hormones

Hormones are produced in the colloid when atoms of the mineral iodine attach to a glycoprotein, called thyroglobulin, that is secreted into the colloid by the follicle cells. The following steps outline the hormones assembly:

  • Binding of TSH to its receptors in the follicle cells of the thyroid gland causes the cells to actively transport iodide ions across their cell membrane, from the bloodstream into the cytosol. As a result, the concentration of iodide ions trapped in the follicular cells is many times higher than the concentration in the bloodstream.
  • Iodide ions undergo oxidation . The oxidation of two iodide ions results in iodine , which passes through the follicle cell membrane into the colloid.
  • In the colloid, peroxidase enzymes link the iodine to the tyrosine amino acids in thyroglobulin to produce two intermediaries: a tyrosine attached to one iodine and a tyrosine attached to two iodines. When one of each of these intermediaries is linked by covalent bonds, the resulting compound is triiodothyronine , a thyroid hormone with three iodines. Much more commonly, two copies of the second intermediary bond, forming tetraiodothyronine, also known as thyroxine , a thyroid hormone with four iodines.
  • X Resistance To Thyroid Hormone

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    RTH is a syndrome in which patients have hyposensitivity to TH, elevated circulating serum T3 and T4, and elevated or nonsuppressed TSH levels. Refetoff et al. first described this syndrome in two siblings who presented with deaf-mutism, delayed bone age with stippled epiphyses, goiter, and high protein-bound iodine levels. Since this initial report, over 350 subjects have been described who have RTH, with 80% of the subjects inheriting this disorder . The clinical manifestations are variable among families with RTH and also among affected family members. Additionally, patients can have clinical symptoms that have features of hypo- and hyperthyroidism, suggesting variable resistance in different tissues. Some of the clinical features that have been described include goiter, mental retardation, attention-deficit disorder, tachycardia, delayed bone growth and maturation, and hearing abnormalities. There also are examples of pituitary resistance to TH , in which patients have resistance predominantly in the pituitary and have signs and symptoms of hyperthyroidism in peripheral tissues .

    Fig. 13.Diagram of hot spots in the ligand-binding domain of TR where natural mutations have clustered. Shown are some representative mutations. For a more extensive listing of mutations, see Refs. , , and resistance to thyroid hormone registry at the University of Chicago .

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