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REVIEW ARTICLE
Year : 2013  |  Volume : 3  |  Issue : 2  |  Page : 87-95

Thyroid: Disorders, disruptors and drugs


Department of Pharmacology, Government Medical College, Miraj, Sangli, Maharashtra, India

Date of Submission17-Apr-2012
Date of Acceptance11-May-2012
Date of Web Publication3-Jun-2013

Correspondence Address:
Suyog S Jain
Department of Pharmacology, Government Medical College, Miraj, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.112827

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   Abstract 

Thyroid disorders are one of the most common endocrine disorders. In India, estimated prevalence of thyroid disorders is more than 42 million, hypothyroidism being commonest. Drugs play an important role, both as adjuncts and as critical molecules, in managing thyroid problems including emergencies. This review emphasizes the role of drugs in the treatment of thyroid diseases. A detailed review of the symptomatology, investigations, and diagnosis of thyroid disorders is beyond the scope of this article. Hence, due consideration is give to the appropriate medical management of thyroid disorders with the help of goal-oriented algorithms. An additional note has been added on the concept of selective thyroid receptor modulators and thyroid disruptors. The cause of thyroid disease is more often primary in nature and originates from the thyroid itself. Hence, primary hypothyroidism and hyperthyroidism are considered in detail, and readers are referred to endocrinology reference books for a review of causes and treatment of secondary thyroid disorders. Medical management of thyroid disorders includes use of drugs, and drugs available for treatment of thyroid disorders are either synthetic preparations similar to natural hormones for replacement therapy in case of thyroid hypofunction or antithyroid drugs used to reduce the functional capacity of the gland during thyroid hyperfunction.

Keywords: Hyperthyroidism, hypothyroidism, selective thyroid receptor modulators, thyroid, thyroid disruptors, thyroid hormone analogues


How to cite this article:
Murthy MB, Jain SS, Ramteke KB, Raparti GT. Thyroid: Disorders, disruptors and drugs. Int J Nutr Pharmacol Neurol Dis 2013;3:87-95

How to cite this URL:
Murthy MB, Jain SS, Ramteke KB, Raparti GT. Thyroid: Disorders, disruptors and drugs. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2019 Dec 7];3:87-95. Available from: http://www.ijnpnd.com/text.asp?2013/3/2/87/112827


   Thyroid Hormone Preparations and Medical Management of Hypothyroidism Top


Hormonal preparations include triodothyronine (T3) called liothyronine, levothyroxine or the levo isomer of thyroxin (T4), and a 4:1 mixture of T3 and T4 called lithotrix.

Levothyroxine is the most commonly used preparation for therapy as it is readily available in the oral form (and less used parenteral form), with good oral bioavailability and sufficiently long duration of action to recommend once daily administration. Half life of 1 week allows dosage adjustments every 5 to 6 weeks. A practical advantage of long half life is that skipping a single dose by noncompliant patients does not adversely affect the therapeutic levels in patients on therapy with levothyroxine.

Liothyronine is less readily available in India. Although rapid acting and some prefer its use in thyroid emergencies in preference to levothyroxine, randomized controlled trials have not conferred any superiority to regimens containing liothyronine in the treatment of thyroid emergencies. For long-term treatment of hypothyroidism, its short duration of action requiring multiple daily administrations is a practical drawback.

Mixtures of T3 and T4 were prepared under the rationale that it would mimic physiological secretion from the gland, but the ratio between the two hormones in the mixture is far from physiological. It is also found that pharmacological administration of levothyroxine more closely mimics physiological concentrations of the hormone in vivo.


   Therapeutic Uses of Thyroid Hormone Preparations Top


Adult hypothyroidism

Most common cause of hypothyroidism in an adult is thyroid hypofunction following autoimmune thyroiditis or thyroid ablation by surgery or radioiodine. Iodine fortification of edible salt has reduced the incidence of thyroid hypofunction as a result of iodine deficiency.

Symptomatic adult hypothyroidism is commonly referred to as myxedema. Very rarely, patients of chronic hypothyroidism may present with muscle stiffness and muscle pseudo-hypertrophy known as Hoffmann's syndrome. [1] Increased oxidative stress in hypothyroidism may result in accelerated atherosclerosis, coronary artery diseases. [2] Hypothyroidism is characterized by increased levels of TSH (thyroid stimulating hormone) and normal or subnormal levels of T3 and T4. Treatment options are based on the patient's condition and goal of therapy is to maintain TSH levels in the reference range (0.4-4 mIU/L).

Treatment is usually begun with an initial suitable dose of T4 administered orally once a day. Dosage adjustments are made every 5-6 weeks based on serum TSH measurements. A level of TSH below 0.4 mIU/L warrants a reduction in levothyroxine dose while high TSH levels above 4 indicates increase requirement for increase in dose. (Refer to [Figure 1] for diagnosis and treatment of hypothyroidism.)
Figure 1: Hypothyroidism diagnosis and management

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Subclinical hypothyroidism

Some patients who are asymptomatic with mild increase in TSH levels and normal free serum T4 levels are classified as patients with subclinical hypothyroidism. Since patients are asymptomatic, diagnosis of subclinical hypothyroidism entirely depends on lab investigations to measure TSH and free T4 levels. Routine screening of all patients is not recommended because thyroid replacement therapy does not benefit all patients with subclinical hypothyroidism to the same extent. On the contrary, screening is recommended for high-risk patients with history of treatment for Graves' disease, elderly patients (above 60 years), and in pregnant women. These patients are more likely to be benefitted by thyroid replacement therapy since they have higher chances of developing overt hypothyroidism in the near future. Recently carried out studies highlight the association of subclinical hypothyroidism and obesity and dyslipidemia, thus enhanced risk of premature coronary artery diseases. [3] There is a consensus on treating patients of subclinical hypothyroidism with cardiovascular disease, hypercholesterolemia, and those with demonstrable thyroid peroxidase antibodies and pregnant women because many small clinical trials have demonstrated benefits of thyroid replacement therapy in these conditions. [4] Patients with subclinical hypothyroidism can be maintained on small doses equivalent to 25-50 mcg of levothyroxine daily as compared to thyroxine dose used for full replacement therapy. (Refer to [Figure 1] for diagnosis and treatment of subclinical hypothyroidism.)

Hypothyroidism during pregnancy

Hypothyroidism during pregnancy is of special concern because reduced availability of thyroxine to the fetus during early phases of development to a few months of extra-uterine life may have serious consequences on mental and physical development of the child. Hence, any degree of hypothyroidism during pregnancy as indicated by raised TSH levels should be an indication for replacement therapy in this group of patients. If a patient is already on replacement therapy, levothyroxine dosage has to be increased by 30% as soon as pregnancy is confirmed because thyroxine requirement increases during pregnancy. Further dosage adjustments are based on TSH measurements every 4-6 weeks with the goal of maintaining TSH levels in the lower half of reference range. (i.e., between 0.4-2.5 mIU/L.)

Congenital hypothyroidism

As stated above, thyroxine plays a very important role in mental and physical development of the child. Prognosis of treatment of congenital hypothyroidism depends on the degree of hypothyroidism (high in thyroid agenesis versus low in genetic abnormality of enzymes in the hormone synthetic pathway) and the age at which treatment is started. Normal mental and physical development can be achieved in such infants if treatment is started as early as 2 weeks of life. Goal of therapy is to maintain free T4 levels in the upper half of the reference range with a starting dose of 10-15 mcg/kg levothyroxine per day. Measurements of TSH and T4 concentrations are made for dosage adjustment, and thyroxine supplementation has to be given until the end of growth. Developmental milestones, physical appearance, and growth charts are a good guide to adequacy of treatment. However, it has to be kept in mind that the detrimental effects of congenital hypothyroidism are progressive and can only be prevented by therapy and damage that has already occurred cannot be reversed. Since most changes are irreversible by the time they become clinically detectable, early detection of hypothyroidism by measuring free T4 levels in blood collected from umbilical cord or by heel prick soon after birth is useful. Such measurements are not mandatory in India although are frequently practiced in developed countries.

Myxedema coma

A rare but a severe presentation of hypothyroidism is myxedema coma, which is a medical emergency. It is a triad of hypothermia, respiratory depression, and reduced consciousness occurring in patients of longstanding hypothyroidism with a precipitating cause like infection, trauma, or organ failure. Mortality is as high as 60% in untreated patients progressing from lethargy to coma and death. Mainstay of treatment lies in symptomatic management of the patient with warming blankets, ventilatory and circulatory support, with simultaneous treatment of the precipitating cause. A loading dose of 250-500 mcg of levothyroxine followed by 100 mcg daily by intravenous route is administered until the patient is capable of consuming oral medication. Levothyroxine is administered intravenously for rapid action and also because of inconsistent oral bioavailability in a patient of myxedema coma. Although T3 acts more rapidly in such a case, randomized controlled trials have not shown special benefits with T3 treatment. In fact, risk of arrhythmias and angina were found to be higher in such patients.

Thyroid nodules and nontoxic goiter

TSH is a stimulus for proliferation and enlargement of the thyroid gland. Levothyroxine given to a patient with diffuse or nodular thyroid enlargement suppresses growth by exerting negative feedback inhibition at the level of the pituitary, hence reducing TSH levels. Ultimately there is a regression in the size of benign functioning nodules and nontoxic goiter in patients with elevated TSH levels, but such use has been controversial in patients with normal serum TSH level coupled with thyroid enlargement. In any case, an indication to stop pituitary suppression by supplementing levothyroxine is when the nodule fails to regress during 6 months of therapy or when regression in size stabilizes, whichever happens earlier. However, nonfunctional nodules are not responsive to TSH stimulation and, hence, not benefited by levothyroxine therapy.

Thyroid papillary carcinoma

Thyroid papillary carcinoma is a TSH-dependant tumor. Well-differentiated tumors are amenable to surgical management with excellent prognosis. TSH suppression by levothyroxine is indicated in the presence of inoperable tumors or metastasis.

Synthetic thyroid hormones are reasonably safe and efficacious drugs. Over-replacement might sometimes lead to symptoms of hyperthyroidism like palpitations, heat intolerance, muscle weakness, osteoporosis, and anxiety. However, use of thyroid hormones for the conditions stated above has been quite successful as the availability of lab monitoring facilities has reduced chances of hypo or hyper correction.


   Antithyroid Drugs and Medical Management of Hyperthyroidism Top


Hyperthyroidism is a state resulting from increased functional capacity of the gland leading to high circulating levels of thyroid hormones and low TSH levels. Common causes for hyperthyroidism include autoimmune disease like Graves and toxic multinodular goiter.

Options available for treatment of hyperthyroidism include measures like surgical removal of thyroid gland or destruction of the gland using radioactive chemicals or use of drugs, which interfere with the synthesis, release, or action of thyroid hormones. This section is dedicated to medical management of hyperthyroidism using either drugs or radioiodine.


   Classification of Drugs Used Clinically for Treatment of Hyperthyroidism Top


Drugs inhibiting the synthesis of thyroid hormones (antithyroid drugs)-Propylthiouracil, methimazole, carbimazole.

Drugs inhibiting the release of thyroid hormones - Iodine.

Drugs causing destruction of the gland - Radioactive Iodine (I 131 ).

Ionic inhibitors, which act by competitively inhibiting the uptake of iodide like thiocyanate and perchlorates, were historically used for the treatment of hyperthyroidism but are currently considered too toxic for clinical use. However, they are common environmental pollutants capable of disrupting the function of thyroid gland and hence are considered under the section of thyroid disruptors.


   Pharmacology of Drugs Used for Treatment of Hyperthyroidism Top


Antithyroid drugs

Conventionally, drugs inhibiting the synthesis of thyroid hormones are classified under antithyroid drugs and they include Propylthiouracil, methimazole, and carbimazole. Drugs of this class act by inhibiting the enzyme, thyroid peroxidase, responsible for oxidation and coupling reactions during thyroxine synthesis. Thus, they interfere with the iodination of tyrosyl residues and coupling of iodotyrosines to form triodothyronine (T3) and tetraiodothyronine (T4). Inhibition of hormone synthesis results in depletion of the hormone and low circulating thyroxine levels once the stored hormone is exhausted. Additional mechanism of action of propylthiouracil is to prevent conversion of T4 to its active form T3 in the periphery. Some immunosuppressant action for all antithyroid drugs has been suggested since long-term treatment leads to reduced circulating antibody levels in patients of Graves' disease. [5]

All antithyroid drugs are well absorbed orally and more concentrated in the thyroid. Propylthiouracil has a short half life and has to be administered three times a day while methimazole and carbimazole are relatively longer acting and are available for once or twice daily administration. Carbimazole is the most commonly used drug in India. It is a prodrug with its therapeutic actions being attributed to its conversion into methimazole in the body.

Antithyroid drugs are indicated as definitive therapy to control hyperthyroidism in patients with Graves' disease until remission occurs. Since spontaneous remission is unlikely in patients with multinodular goiter, it can be used in patients in whom definitive therapy like surgery or use of radioiodine is not possible. Antithyroid drugs are also used as adjuncts prior to surgery and radioiodine therapy to achieve euthyroid state as either of the above attempts in a hyperthyroid patient with load of stored hormones may precipitate hyperthyroid crisis.

Common adverse reactions to antithyroid drugs are less serious and include rashes and joint pain. Hypothyroidism and goiter occur on overtreatment and can be dealt with by reducing the dose of the drug. Serious adverse reactions are very rare and include agranulocytosis with all drugs and hepatic necrosis with propylthiouracil. Frequent blood cell count monitoring is required as agranulocytosis is reversible upon drug withdrawal.

Certain practical considerations associated with the clinical use of antithyroid drugs.

There is a lag period of 3-6 weeks before the effects of antithyroid drugs are noticed, as preformed hormone stores have to be exhausted before the effect of drugs on prevention of new hormone synthesis are appreciable.

Patients of small goiter and mild and new-onset hyperthyroidism respond better to drugs as compared to patients with large goiters and longstanding hyperthyroidism.

Initial drug doses are always higher and maintenance doses are started once euthyroidism is achieved. Monitoring of therapy is done by measuring free T4 and T3 levels every 2-3 months. TSH monitoring cannot be relied upon as it remains suppressed for a long time in patients of hyperthyroidism. Staring dose of carbimazole is 5-15 mg three times a day initially followed by a maintenance dose of 2.5-10 mg daily. Usual starting dose for propylthiouracil is 100 mg three times a day followed by maintenance with 25-50 mg in three divided doses daily.

Reduction in the size of goiter and symptoms of hyperthyroidism in patients on small maintenance doses indicates remission. Increase in the size of goiter is often an indication of hypothyroidism and warrants reduction in dose of antithyroid drug and treatment with levothyroxine to suppress pituitary TSH secretion.

In a few patients of Graves' disease, remission occurs in 1-2 years and drug may be completely withdrawn. Otherwise, drug withdrawal is indicated only for severe adverse reactions like agranulocytosis or hepatic failure.

For fear of hepatic necrosis with propylthiouracil, methimazole or carbimazole are first-line drugs for treatment of hyperthyroidism. In cases of first trimester of pregnancy or thyroid storm, propyltiouracil is preferred due to lack of teratogenic effects and because of its ability to prevent peripheral activation of T4 to T3. However, during pregnancy once the period of organogenesis is over, methimazole is used.

Propylthiouracil is preferred in lactating women because its concentration in milk is lower than the other two drugs.

Iodine

It is in fact a paradox that in spite of being an indispensible constituent of thyroid hormone, iodide is the fastest acting thyroid inhibitor.

The mechanism of action of iodine is not well understood, but within 24 h of administration of iodine, it reduces the release of thyroid hormones from the gland. "Thyroid constipation" is the term used to describe effects of iodine where follicles are loaded with colloid but endocytosis and release of hormone are affected. Iodine reduces the vascularity of the gland and makes it firmer and less vascular. Complete spectrum of antithyroid effects are seen in 10-15 days a variable time after which thyrotoxicosis returns with increased vengeance. An acute effect of iodine on hormone synthesis inhibition has also been demonstrated.

Iodine for pharmacological administration is available as Lugol's iodine containing 5% iodine in 10% solution of potassium iodide, which yields a dose of 8 mg iodine per drop. It is well absorbed on oral administration and concentrated by the thyroid gland; 2-6 drops of Lugol's iodine is administered orally 3 times a day.

Therapeutic uses of iodine include preparation of the thyroid gland for surgery and in treatment of thyroid storm. When used for preoperative preparation, Lugol's iodine is administered 7-10 days before surgery to make the gland less vascular and less friable during surgery so as to decrease surgical complications. During thyroid storm, faster acting drugs and iodine-containing radio contrast media (iopanoic acid) are administered orally to reduce the release of hormone from the gland.

Adverse reactions to iodine can be in the form an acute anaphylactic reaction comprising of laryngeal edema or serum sickness-like syndrome. Chronic administration of iodine leads to iodism characterized by flaring of acne, inflammation of mucous membranes with rhinorrhea and lacrimation, bloody diarrhea, hypothyroidism, and goiter. All symptoms of chronic overdose regress on withdrawal of iodide.

Radioiodine

Radioactive isotope of iodine, I 131 , is an attractive option for permanent treatment of hyperthyroidism. Results almost similar to surgical thyroidectomy can be obtained by radioiodine, which achieves ablation of the thyroid gland by a nonsurgical economical and convenient way.

Upon oral administration in the form of a sodium salt, I 131 is taken up and concentrated by the thyroid similar to stable iodine. I 131 then emits β particles from within the gland. These β particles have the capacity to selectively ablate the thyroid tissue by penetrating to a depth of around 2 mm. Characteristic signs of radioiodine-mediated thyroid destruction include necrosis of the follicular cells followed by fibrosis of the gland without injury to the surrounding tissue. It is customary to calculate the dose of radioiodine by estimating the weight of the gland by ultrasonography. However, studies comparing the individualized dosage regimens with standard dose therapy have shown equivocal results. Hence, a standard dose of 4-15 mCi is administered.

Radioiodine therapy is indicated in patients of hyperthyroidism in whom surgery is risky, like in elderly with heart disease and in cases of multinodular goiter or Graves' disease where antithyroid drugs have failed to induce remission in spite of prolonged therapy.

Complete control of hyperthyroidism following radioiodine therapy requires 2-3 months. Monitoring free T3 and T4 concentrations gives a good estimate of success of therapy and need for a second dose of radioiodine. Assessment of TSH levels is not helpful as it remains elevated for several months following treatment of hyperthyroidism.

Major disadvantages of radioiodine therapy include a lag period of 2 months before symptomatic control is evident, hypothyroidism, and requirement for lifelong therapy with levothyroxine, radiation thyroiditis, worsening of thyroid ophthalmopathy following radioiodine administration, and salivary gland dysfunction. An increased incidence of some cancers of gastrointestinal tract, germ cell damage in young adults, and fetal thyroid destruction when administered to pregnant women form the basis for contraindication to the use of radioiodine in young adults and pregnant women.

Since radioiodine is taken by thyroid carcinoma and its metastasis, it is also used for destruction of thyroid tumors. Medullary carcinomas are resistant to such destruction as they do not accumulate radioiodine.

Adjuvant drugs for treatment of hyperthyroidism

β blockers and calcium channel blockers are useful adjuncts to therapy. β blockers act by cutting down the signs of sympathetic over-activity in hyperthyroidism like tachycardia, anxiety, and arrhythmias. Nonselective β blocker like propranolol in a dose of 40-60 mg 6 hourly is preferred in the management of patients with thyrotoxic crisis as it can additionally prevent the peripheral conversion of T4 to T3. Propranolol or atenolol are used to suppress sympathetic activity in patients of Graves' disease, multinodular goiter, and in the preoperative preparation for thyroidectomy. Calcium channel blockers like diltiazem are added when propranolol is alone insufficient to control sympathetic cardiac stimulation.

Amongst the multiple options available for treatment of hyperthyroidism, no single group can be said to be specifically efficacious in a particular patient. Selection of mode of therapy is based on relative indications and contraindications. Combinations are used many times for optimal control of hyperthyroidism. (Refer to [Figure 2] for individualized treatment of hyperthyroidism.)
Figure 2: Hyperthyroidism diagnosis and management

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Currently available thyroid inhibitors act by either inhibiting thyroid hormone synthesis or achieving gland destruction. Recent research has been directed towards development of selective thyroid receptor antagonists, which act by receptor-mediated antagonism of thyroid function. They would be welcome drugs for treatment of hyperthyroidism and associated cardiac arrhythmias. However, NH3, the only thyroid antagonist synthesized so far, has partial agonistic activity at high concentrations and success in trials has been limited. Availability of more selective antagonists devoid of partial agonistic activity would expand the spectrum of drugs available for treatment of hyperthyroidism.


   Thyroid Hormone Analogs and the Concept of Selective Thyroid Receptor Modulators (STRMS) Top


Thyroxine is a hormone performing versatile functions in the body, ranging from beneficial actions like regulation of body weight and plasma lipids to certain deleterious effects like cardiac stimulation, muscle wasting, and osteoporosis. Basis of thyroid hormone actions on the cell constitutes actions of active form of thyroid hormone T3 on specific nuclear receptors known as thyroid receptors (TRs), which regulate gene expression to ultimately cause the aforementioned effects. In spite of widespread beneficial actions of T3, it has not been possible to widely use its effects for therapeutic purposes in non-endocrine disorders because of nonselective actions. However, it has been noted that not all actions of T3 are brought about by one type of thyroid receptor. There are different isoforms of TRs, which are expressed to different extents in different tissues [Table 1] summarizes the TR isoforms with respect to their locations and functions]. Hence, selective modulation of thyroid hormone action can be achieved by designing drugs acting on specific isoforms so as to separate the therapeutic actions from the deleterious effects of thyroid hormone. Such drugs capable of modulating the function of specific thyroid receptor isoform are called as selective thyroid receptor modulators (STRMs).
Table 1: Thyroid receptor isoforms, location, and functions

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Cellular mechanism of action of STRMs

Agonists on a nuclear receptor act by recruiting specific co-activators to the promoter region of the gene causing gene expression while binding of antagonists to the ligand binding sites causes recruitm ent of co-repressors, thus negatively regulating gene expression. Selective thyroid receptor modulators are drugs acting intermediate between agonists and antagonists where they recruit co-activators in some tissues and co-repressors in other tissues, thus acting as agonists in some tissue and as antagonist on other tissues. Ultimate action on a particular tissue depends on the relative amounts of co-activators and co-repressors expressed in that particular tissue.

Possible clinical implications of STRMs

Using the concept of STRMs, it is possible to strategically design selective TRβ ligands capable of achieving reduced body weight and plasma LDL and total cholesterol levels without interfering with cardiac functions and TRα lignands as beneficial inotropic agents for treatment of heart failure. Although only poor or partially selective TRα ligands with no demonstrable efficacy are available till date, a few leading compounds with TRβ selectivity are under development. KB141 and GC1 are TRβ selective STRMs under trials and have shown significant lipid lowering and antiobesity effects in rodents and primates without remarkable effects on heart rate. [6],[7] KB141 has also shown favorable effects on glucose tolerance and insulin sensitivity. Such drugs would be welcome adjuncts for treatment of obesity, hyperlipidemias, and metabolic syndrome. [8] Eprotirome (KB2115), a TRβ thyromimetic evaluated in clinical trials, has been shown to reduce serum total cholesterol and triglycerides over and above lipid levels achieved with statins without significant adverse effects. However, the selectivity of currently available STRMs is limited and development of more selective compounds is essential to optimally exploit the therapeutic activity of these compounds.


   Thyroid Disruptors Top


The interference of xenobiotics with endocrine regulatory mechanisms is well known for the last two decades. Cumulating evidence favoring the existence of such xenobiotics gave rise to the concept of endocrine disruptors, which are chemicals, natural or synthetic, interfering with the synthesis, circulating levels, or peripheral action of hormones. Thus, thyroid disruptors (TDs) or thyroid disrupting chemicals (TDCs) are a subfamily of endocrine disruptors, which interfere with thyroid metabolism by affecting the hypothallamo-pituitary-thyroid axis or directly via thyroid hormone receptors. [9],[10],[11] Many drugs like iodine and antithyroid drugs act in a similar manner and are deliberately used for the treatment of thyroid disorders and are considered in the previous section. This section includes those thyroid disruptors which are widely prevalent in the ecosystem as pollutants arising from products of day to day use.

Exposure to TDCs can have varied effects in the host depending on many factors like age, status of iodine repletion, and number of disruptors to which the host is exposed at a given point of time. Following exposure, TDCs can interfere with any step of the thyroid axis to alter the hormonal milieu in such a way as to cause developmental defects, tumors, and hypo or hyper-thyroidism. [10] [Table 2] enumerates certain TDCs, their source, mechanisms of thyroid disruption, and implications of thyroid disruption in the host.
Table 2: Thyroid disrupting chemicals, their source, mechanisms of thyroid disruption, and implications on the host

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Possible implications of TDs on the host depend upon the phase of development of the host and role played by thyroid hormones during that particular phase. Thus, exposure to TDCs in adulthood cause an array of ill effects much different from effects during in utero exposure Thyroid hormones play a very important role in development of nervous and auditory systems. Exposure to TDCs resulting in thyroid hormone imbalance during pregnancy and early years of life, which are critical phases of such development, can lead to neurodevelopmental problems leading to low IQ scores, cognitive and behavioral defects, and deafness in such children. In adults, thyroid hormones are responsible for maintenance of cellular metabolism and maintenance of cardiovascular functions. Exposure to TDCs in adults has been linked to thyroid autoimmune disorders, thyroid neoplasms, subclinical and clinical hypothyroidism, and increased cardiovascular risk due to altered lipid metabolism. Thyroid homeostasis may overcome the effects of some thyroid disruptors like benzophenones, which inhibit thyroid peroxidase in an iodine-replete state but cause hypothyroidism in presence of iodine deficiency. Similarly, TDCs may be more harmful when the host is exposed to multiple disruptors at a point of time. TDs are ubiquitously distributed and there are higher chances of people coming into contact with mixtures of TDs at any point of time. The combined effects of such multiple exposures most often have synergistic action on thyroid axis. [9],[10],[11]

Most of the thyroid disruptors and their mechanisms have been well studied in vitro on special endocrine cell lines or recombinant enzymes and in animal experiments. These led to controversies regarding possible clinical impact of these endocrine disruptors on human endocrine systems. However, a large amount of data from epidemiological studies in humans exposed either accidentally or occupationally to TDs provides conclusive evidence of alteration of hormonal milieu by these agents. Thus, even in the incidence of minimal threat, it is necessary to probe into the role of TDs and possible ways of evading their effects to halt the menace of disruptor-induced endocrine disorders.


   Summary Top


Thyroid disorders are very common across all age groups. Most of the times, the presentation is, an obvious direct consequence of hypo or hyper levels of the thyroid hormones. These situations are easy to investigate, diagnose, and treat accordingly. Sometimes, the presentations of the patient may not be a classical one, therefore, necessitating detailed history taking including possible exposure to TDs and previous medications. Management plan involves frequent hormonal level estimation, symptomatic assessment, and readjustment of the pharmacotherapy if needed. With availability of STRM, it would be possible to exploit thyroid hormones selective beneficial action without being worried about the adverse effects. This review covers most of these aspects and may be useful for general physicians in treating thyroid patients in a better way.

 
   References Top

1.Praveen KA, Aslam S, Dutta TK. HoffMann's syndrome: A rare neurological presentation of hypothyroidism. Int J Nutr Pharmacol Neurol Dis 2011;1:201-3.  Back to cited text no. 1
  Medknow Journal  
2.Shanmugapriya V, Mohanty PK, Suganthy K. A study of oxidative stress as a cardiovascular Risk factor in hypothyroidism. Int J Nutr Pharmacol Neurol Dis 2011;1:23.  Back to cited text no. 2
    
3.Suganthy K, Mohanty PK, Shanmugapriya V. A study of lipid profile as a predictor of cardiovascular risk in women with subclinical hypothyroidism. Int J Nutr Pharmacol Neurol Dis 2011;1:21.  Back to cited text no. 3
    
4.Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-38.  Back to cited text no. 4
    
5.Cooper DS. Antithyroid drugs in the management of patients with Graves' disease: An evidence-based approach to therapeutic controversies. J Clin Endocrinol Metab 2003;88:3474-81.  Back to cited text no. 5
    
6.Ye L, Li YL, Mellström K, Mellin C, Bladh LG, Koehler K, et al. Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta 1. J Med Chem 2003;46:1580-8.  Back to cited text no. 6
    
7.Villicev CM, Freitas FR, Aoki MS, Taffarel C, Scanlan TS, Moriscot AS, et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J Endocrinol 2007;193:21-9.  Back to cited text no. 7
    
8.Grover GJ, Mellstrom K, Malm J. Development of the thyroid hormone receptor beta-subtype agonist KB-141: A strategy for body weight reduction and lipid lowering with minimal cardiac side effects. Cardiovasc Drug Rev 2005;23:133-48.  Back to cited text no. 8
    
9.Jugan ML, Levi Y, Blondeau JP. Endocrine disruptors and thyroid hormone physiology. Biochem Pharmacol 2010;79:939-47.  Back to cited text no. 9
    
10.Patrick L. Thyroid disruption: Mechanisms and clinical implications in human health. Altern Med Rev 2009;14:326-46.  Back to cited text no. 10
    
11.Miller MD, Crofton KM, Rice DC, Zoeller RT. Thyroid-disrupting chemicals: Interpreting upstream biomarkers of adverse outcomes. Environ Health Perspect 2009;117:1033-41.  Back to cited text no. 11
    


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