Effects of the Environment, Chemicals and Drugs on Thyroid Function


Revised by David Sarne, October 10, 2004

Chapter 5b-- The Non-Thyroidal Illness Syndrome
Revised by Leslie J. De Groot, M.D., 1 January 2005

The sensitive and tightly regulated feedback control system, thyroid gland autoregulation, and the large intrathyroidal and extrathyroidal storage pools of thyroid hormone serve to provide a constant supply of thyroid hormone to peripheral tissues in the face of perturbations imposed by the external environment, chemicals and drugs, and a variety of diseases processes. The thyroid is subject to a great number of exogenous and endogenous perturbations. The same agent may produce alterations in various aspects of thyroid hormone economy. For this reason, it is difficult to precisely classify all external and internal influences according to their mode of action. This chapter reviews effects on the thyroid produced by changes in the external environment, chemicals and drugs. The effects of non-thyroidal illness are reviewed in Chapter 5b. The effects of the more important factors and chemical agents and drugs are discussed individually.

Environmental Temperature

Changes in environmental temperature may cause alterations in TSH secretion and in the serum concentration of thyroid hormones and their metabolism. The changes are probably mediated through the hypothalamus and the pituitary and by peripheral effects on the pathways and rates of thyroid hormone degradation and fecal losses and alterations in thyroid hormone action. The in vitro effects of temperature on the firmness of binding of T4 to its transport serum proteins conceivably also play a role in vivo.1 The overall effects of environmental temperature have been more obvious and easier to demonstrate in animals than in humans but differences in thermal regulation 1a may mean that findings in animal models may not apply to humans. Additionally, studies of individuals with prolonged residence in Arctic and Antarctic regions may be confounded by other alterations in daylight, activity levels, living conditions and sleep deprivation. 1b,1c

Effects of Cold

Dramatic, although transient, increases in serum TSH levels have been observed in infants and young children during surgical hypothermia.2 Also, a prompt and important secretion of TSH occurs in the newborn, in the first few hours after birth, accompanied by an increase in thyroid hormone secretion and clearance.3,4 Since this TSH surge is partially prevented by maintaining infants in a warm environment, postnatal cooling appears to be responsible in part for the rise in TSH secretion. In most studies, exposure of adults to cold or even intensive hypothermia has produced no changes,5,6 or at best minimal increases7 in serum TSH. More prolonged exposure to cold generally results in maintenance of the total T4 (TT4) and free T4 (fT4) levels with maintenance of a normal or decreased total T3 (TT3) and free T3 (fT3) levels. 7a,7b , however, others have shown prolonged arctic residence leads the increase in TSH to be associated with an increase in, thyroglobulin and T3.7c These alterations may be partly the consequence of a direct effect of temperature on the rate and pathways of thyroid hormone metabolism with more rapid production and clearance of T3. Altered kinetics have been demonstrated in humans 7d, but have been more thoroughly studied in animals.8,9,9a,9b It has been more difficult to show a clear seasonal variation in serum hormone concentration. However, the variation demonstrated in several studies10,11 has been that T4 and T3 values are higher during the colder months.

Cold exposure in animals leads to thyroid gland hyperplasia, enhanced hormonal secretion, degradation, and excretion, accompanied by an increased demand for dietary iodine. All of these effects are presumably due to an increased need for thyroid hormone by peripheral tissues. The prompt activation of pituitary TSH secretion after cold exposure of the rats12,13 is possibly due in part to a direct effect on the hypothalamus.14 Exposure to cold has also resulted in augmented TRH production, and serum levels,16 and blunted responses of TSH to exogenous TRH.17 These effects have not been reproduced by other laboratories13,18 although an increase in thyroid hormone secretion has been clearly demonstrated.6,19,20 In the rat, it is associated with augmented rates of T4 and T3 deiodination, increased conversion of T4 to T3, and enhanced hepatic binding and biliary and fecal clearance of the iodothyronines.8,9,9a,21,22 Finally, thyroid hormone effects may be enhanced by alterations in co-activators which enhance the activity of thyroid hormone receptors on gene activation. 22a

Effects of Heat

In general, an increase in ambient temperature has produced effects opposite to those observed during cold exposure, although the effects of heat have not been extensively investigated. As indicated above, thyroid hormone levels in serum tend to be lower during the summer months. A decrease in the serum T3 concentration, with reciprocal changes in the levels of rT3, have been observed in normal subjects acutely exposed to heat and during febrile illnesses.23,24 In the latter condition, the contribution of the rise in body temperature relative to other effects of systemic illness cannot be dissociated. A decrease in the elevated serum TSH level associated with primary hypothyroidism has been induced by increases in body temperature.25
High Altitude and Anoxia

Acute elevations in serum T4 and T3 concentrations occur in humans during the early period of exposure to high altitude.26 Increases in the rate of T4 degradation and thyroidal RAIU have also been reported.27,28 At very high elevations (5400-6300 m), elevations in T4, fT4, T3, and TSH with a normal fT3 have been reported.28a When compared to those residing at sea level, individuals adapted to altitude were noted to have a lower T4 with higher fT4 and fT3 levels and a normal TSH response to TRH.28b Moderate, transient increases in oxygen consumption, not a result of sympathetic activation, were found in one study.28

The responses of rats exposed to high altitude or anoxia seem to be quite different. Thyroidal iodinative activity and T4 formation are diminished.29-31 The partial reversal of these changes by the administration of TSH led the authors of these studies to conclude that the primary effect is probably diminished TSH secretion.
Alterations in Light

Pinealectomy induces a moderate increase in thyroid weight,32 and continuous light exposure33 increases the T4 secretion rate of rats by about 20%. In squirrels, continuous darkness produces a decrease in thyroid weight and T4 levels33a, but this effect is blocked by pinealectomy.33a These studies suggest that melatonin has an inhibitory effect on thyroid gland function.33a,34 A nocturnal increase in Type II deiodinase activity Is blocked by exposure to continuous light.34a Although the retinas of rat pups reared in total darkness are totally devoid of TRH, the content of TRH in the hypothalamus remains unaltered.35 The diurnal variation in hypothalamic TRH content, reflecting both rhythmic synthesis and secretion, is, however, blunted in the absence of cyclical light changes. Little is known about the effect of light on the thyroid in humans. The normal TSH rhythm can be reset by a pulse of light.35a

Since thyroid hormone plays a central role in the regulation of total body metabolism, it is not surprising that nutritional factors may profoundly alter the regulation, supply, and disposal of this thermogenic hormone. Although many dietary changes can affect the thyroid economy, the most striking and important effects are related to alterations in total caloric intake and the supply of iodine. The changes associated with caloric deprivation appear homeostatic in nature producing alterations in thyroid hormones which would conserve energy through a reduction in catabolic expenditure. The changes observed with a deficiency or excess of iodine supply generally serve to maintain an adequate synthesis and supply of thyroid hormone, principally through modifications in thyroidal iodide accumulation and binding.
Starvation and Fasting

Multiple alterations in thyroid hormone regulation and metabolism have been noted during caloric restriction. The most dramatic effect is a decrease in the serum TT3 within 24-48 hours of the initiation of fasting.36-40b Because changes in the free T3 fraction are usually small, the absolute concentration of FT3 is also reduced, clearly into the hypothyroid range The marked reduction in serum T3 is caused by a reduction in its generation from T4 rather than by an acceleration in its metabolic clearance rate.41,42 The decline in T3 concentration is accompanied by a concomitant and reciprocal change in the concentration of total and free rT3. The increase in the serum rT3 concentration tends to begin later and to return to normal at the time serum T3 is being maintained at a low level with continuous calorie deprivation.38,39 Little change occurs in the concentrations of TT4 and FT4 and the production and metabolic clearance rates of T4.38,39,41,42 When small changes have been observed, they were generally in the direction of an increase in the FT4 concentration. They are attributed to decreased concentration of the carrier proteins in serum, as well as to their diminished association with the hormone caused by the inhibitory effect of free fatty acids (FFA) the level of which increases during fasting.40,43

Decreased outer ring monodeiodination (5'-deiodinase activity) would explain both the decreased generation of T3 from T4 and the excess accumulation of rT3. This hypothesis seems to be fully supported by in vitro studies using liver tissue from fasted fats.44 It is further supported by the finding of increased generation and serum concentration of 3',5'-T2 and 3'-T1 and decreased 3,5-T2 and 3,3'-T2.44-47 However, a less important increase in the monodeiodination of the inner ring of T4 (5-deiodination)42 explains the temporal dissociation of changes in serum T3 and rT3 concentration. A decrease in plasma T3 after fasting with an increase in hepatic type III deiodinase activity and mRNA has also been noted in chickens. 47a An increase in the nondeiodinative pathway of T4 degradation with the formation of Tetrac has been also reported.48

Considerable controversy remains regarding the mechanisms responsible for the observed changes in the rates of the deiodinative pathways of iodothyronines. Decreased generation of nonprotein sulfhydryls (NP-SH) as a cause of the reduction in 5'-deiodinase activity was suggested on the basis of the observed enhancement in enzyme activity by the in vitro addition of dithiothreitol. Reduced glutathione and NADPH had a similar effect.49 Although Chopra's50 direct measurements of NP-SH in tissue during fasting seemed to confirm this hypothesis, the precise mechanism is likely more complex. Decreased tissue NP-SH content does not always correlate with the inhibition of T3 generation, which may be restored by glucose refeeding independently of changes in NP-SH content.50,51

Composition of the diet rather than reduction in the total calorie intake seems to determine the occurrence of decreased T3 generation in peripheral tissues during food deprivation. The dietary content of carbohydrate appears to be the key ingredient since as little as 50 g glucose reverses toward normal the fast-induced changes in T3 and rT3.52 Replacement of dietary carbohydrate with fat results in changes typical of starvation.39,53 Refeeding of protein may partially improve the rate of T3 generation, but the protein may be acting as a source of glucose through gluconeogenesis.54 Yet, dietary glucose is not the sole agent responsible for all changes in iodothyronine metabolism associated with starvation. For example, the increase in serum rT3 concentration may not be solely dependent on carbohydrate deprivation since a pure protein diet partially restores the level of rT3 but not that of T339 (Fig. 5-1). The composition of the antecedent diet also has an effect on the magnitude of the serum T3 fall during fasting.39,52 It is possible that the cytoplasmic redox state, measured in terms of the lactate/pyruvate ratio rather than glucose itself, regulates the rate of deiodinative pathways of iodothyronines.55
Figure 5-1. The effect of food deprivation and diet composition on the serum concentration of T3 and rT3 in humans. Data represent means ± SEM for six subjects. Fasting produces reciprocal changes in these thyronines that are reversed by refeeding a mixed diet. A protein diet has no effect on the concentration of T3 but partially restores that of rT3. (Drawn from data published by F. Azizi, Metabolism, 27: 935, 1978, with permission of the author)

The basal serum TSH level during calorie deprivation is either normal or low, the response to TRH is blunted37-39 and the normal nocturnal rise in TSH is blunted.40a These changes are quite surprising given the consistent and profound decrease in serum FT3 levels. Several hypothesis have been proposed to explain this paradox. Because the pituitary is able to continue to respond appropriately during fasting to both suppressive and stimulatory signals,56 it has been suggested that starvation only "resets" the set point of feedback regulation. A more plausible hypothesis, supported by experimental data,57,58 proposes that the pituitary is regulated by the intracellular concentration of T3, which may remain unaltered through factors ensuring its continuous local generation during starvation, whereas a decrease is typically found in other tissues. Further support for this hypothesis comes from a recent study demonstrating that fasting produces a marked increase in hypothalamic Type II Deiodinase mRNA58a which would enhance local T3 production. This hypothesis gives credence to the preservation of a closer inverse relationship between serum FT4 and TSH than between FT3 and TSH. Hypothalamic TRH content in starved rats has been reported to be normal,59 low60 or even elevated.60a The elevation of TRH was accompanied by normal levels of proTRH mRNA and decreased pituitary TSH; it was suggested that this represented decreased TRH release. 60a In a different study of starved rats, the hypothalamic proTRH mRNA and the TRH content were both decreased,60b but these effects were reversed by adrenalectomy suggesting that they were secondary to increased glucocorticoid levels.60b Neonatal starvation in rats leads to diminished TRH and TSH production, with resultant hypothyroidism and growth retardation.61

Starvation produces a greater than 50% decrease in the maximal binding capacity of T3 to rat liver nuclear receptors within 48 hours.62 Although accompanied by a diminution of almost equal magnitude in the nuclear T3 content, it is unlikely that the observed change represents an alteration of the receptor content by the hormone as the more profound diminution of nuclear T3 content associated with hypothyroidism does not produce changes in the maximal binding capacity of T3 in rat liver nuclei. The reduction in maximal binding capacity has been demonstrated to coincide with a reduction in the level of the thyroid hormone receptors.62a The affinity of the rat liver T3 receptor is not affected by starvation.62,63 Studies in humans have used circulating mononuclear cells and, probably due to the limited choice of tissue, results have been either equivocal or negative.64

Other hormonal and metabolic changes during fasting may account for the observed alterations in the regulation and metabolism of thyroid hormones. Among them are the increase in plasma cortisol and suppression of adrenergic stimuli.65 Both changes are known to induce independently a decrease in the serum T3 concentration by inhibition of T4 to T3 conversion in peripheral tissues (see below). Accordingly, they may be partly responsible for the decrease in T3 neogenesis during starvation. There is likely a highly complex interplay between the changes in thyroid hormone and the many metabolic changes of starvation. In addition to a direct effect of glucose, changes in FFA, ketosis, and the redox state may influence thyroid hormone metabolism, while T3 itself may impact hepatic glucose production.40b

Two major issues of theoretical and practical importance remain unresolved - do the observed changes in thyroid function produce some degree of hypothyroidism, and is this state beneficial to the energy-deprived organism? Although the suppressed serum TSH response to TRH suggests that the starving organism does not suffer from a significant deprivation in thyroid hormone, other observations indicate the contrary. The decreased pulse rate, systolic time interval, oxygen consumption, and decrease in activity of some liver enzymes are suggestive of hypothyroidism at the level of peripheral tissues.66 Furthermore, administration of T3 to restore its serum level to normal during fasting increased the production and excretion of urea and 3-methylhistidine.56,67 Larger doses of T3, given during fasting, had even more profound effects. These effects included dramatic increased in the excretion of urea and creatine, and increased plasma levels of ketones and FFA indicating an accelerated protein and fat breakdown.68 Such evidence leaves little doubt that the decrease in T3 generation during calorie deprivation has an energy- and nitrogen-sparing effect. It is tempting to speculate that the result is beneficial in the adaptation to malnutrition through reduction in metabolic expenditure.

Fasting is not only a useful model for studying the effects of calorie deprivation on thyroid hormone but is also the prototype of the "low T3 syndrome".69 The latter is produced by a number of chemical agents and drugs, and accompanies a variety of nonthyroidal illnesses. It is possible that malnutrition, concomitant in a number of acute and chronic illnesses, is in part responsible for some of the observed changes in thyroid physiology.
Protein-Calorie Malnutrition (PCM)

As in the case of starvation, PCM is associated with a low serum T3 concentration and increased rT3 levels, probably due to similar changes in iodothyronine monodeiodination. However, important differences exist between the abnormalities in thyroid function observed in PCM and acute calorie deprivation. Most reports indicate important decreases in TBG and TTR concentrations, and there are also indications of hormone binding abnormalities.70,71 As a consequence, the free concentrations of both T4 and T3 are usually normal.70,72,72a Recovery is associated with restoration of the level of serum thyroid hormones and binding proteins. Despite an accelerated turnover time, the absolute amount of extrathyroidal T4 disposed each day is reduced. Refeeding restores the T4 kinetics to normal.70 The thyroidal RAIU is reduced due to a defect in the iodine-concentrating mechanism.73 The most striking difference between starvation and PCM is the finding the latter of an exaggerated and sustained TSH response to TRH, with basal TSH levels either elevated or normal.70,72,72a,72b,74

The experimental model of protein malnutrition in the rat yielded different results from those observed in humans. Serum T4 and T3 levels were found to be both elevated.75 However, in the lamb, as in humans, chronic malnutrition leads to a lower rate of T4 utilization.76
Overfeeding and Obesity

Overfeeding produces an increase in the serum T3 concentration as a result of an increased conversion of T4 to T3. It is particularly marked when the excess calories are given in the form of carbohydrates.77 Thus, it appears that the effect of overnutrition on iodothyronine metabolism is the opposite of that of starvation. This finding gives further credence to the speculation that changes in thyroid hormone may serve to modulate the homeostasis of energy expenditure.

Although it has been reported that serum T3 concentrations correlate with body weight,78 it appears that this phenomenon reflects the effect of an increase in caloric intake on T3 production. Most studies find that obese subjects have normal thyroid function and hormone metabolism.79 Furthermore, no abnormalities in the hypothalamic-pituitary-thyroid axis have been demonstrated in obese subjects.

Iodine. Of the many minerals that may affect thyroid function, iodine is the most important. It is an essential substrate for thyroid hormone synthesis and also interacts with the function of the thyroid gland at several levels.

Acute administration of increasing doses of iodide enhances total hormone synthesis until a critical level of intrathyroidal iodide is reached. Beyond this level, iodide organification and hormone synthesis are blocked (the acute Wolff-Chaikoff block). Chronic or repeated administration of moderate to large doses of iodine causes a decrease in iodide transport resulting in a decrease in its intrathyroidal concentration. The latter relieves the Wolff-Chaikoff block and is known as the escape or adaptation phenomenon. Although the exact mechanisms of the block and escape remain unknown, they appear to be autoregulatory in nature since they are independent of pituitary TSH secretion. Iodoloactones may play a role in the induction of the Wolff-Chaikoff block.80 One mechanism through which iodide acts is via desensitization of the thyroid gland to TSH. In TSH stimulated glands, iodine rapidly reduces the level of the mRNA for thyroid peroxidase (TPO) and the Na/I symporter (NIS) but not for thyroglobulin (Tg) or the TSH receptor (TSHr).80a Iodine also antagonizes TSH stimulated thyrocyte proliferation.80a In FRTL-5 cells, iodine blocks the TSH stimulation of Tg synthesis but does not alter the level of the Tg mRNA.80b These actions occur without a change in TSH receptor number, and may, in part, be via an action on adenylyl cyclase.80c More detailed description is provided in Chapter 2.

Another effect of large doses of iodine, apparently independent of TSH and hormone synthesis, is the prompt inhibition of hormone release. It has been exploited to achieve rapid amelioration of thyrotoxicosis in Graves' disease and toxic nodular goiters (see Chapters 11 and 13). In normal persons, the inhibitory effect of large doses of iodine on thyroid hormone release produces a transient decrease in the serum concentration of T4 and T3. It causes, in turn, a compensatory increase in serum TSH, which stimulates hormone secretion and thus counteracts the effect of iodine.81,82 The mechanisms of thyroidal autoregulation are believed to serve the purpose of accommodating wide and rapid fluctuations in iodine supply.

The most intriguing effects of iodine are the involution of hyperplasia and the decrease in vascularity that occur when the ion is administered to patients with diffuse toxic goiter. Iodine may be able to induce apoptosis in thyroid cells. 82a,82b Under different circumstances, iodide may intensify the hyperplasia and produce a goiter (Chapter 20).

Iodine deficiency used to be the leading cause of goiter in the world and still remains so in certain regions. When severe, it can cause hypothyroidism and cretinism, described in detail in Chapter 20 . In the United States and the rest of the developed world, untoward effects from excess iodine supplementation or the use of iodine-containing compounds are more common than problems related to iodine deficiency.

Excess iodine can be responsible for the development of goiter, hypothyroidism, and thyrotoxicosis. However, it should be emphasized that these complications usually occur in persons with underlying defects of thyroid function who are unable to utilize the normal adaptive mechanisms. Iodide-induced goiter (iodide goiter), without or with hypothyroidism (iodide myxedema), is encountered with greater frequency in patients with Hashimoto's thyroiditis or previously treated Graves' disease.83,84 Other predisposed persons include those who have undergone partial thyroid gland resection, patients with defects of hormonogenesis, and some with cystic fibrosis.85 Drugs such as phenazone,86,87 lithium,88 sulfadiazine,89 and cycloheximide90 may act synergistically with iodide to induce goiter and/or hypothyroidism.

More rarely, ingestion of excess iodide may cause thyrotoxicosis (iodide-induced thyrotoxicosis or Jodbasedow).90a This was initially observed with the introduction of iodine prophylaxis in areas of endemic iodine deficiency.91,92 It has also been observed after the administration of iodide in excess to patients with nodular thyroid disease residing in areas of moderate iodine deficiency or even iodine sufficiency.93,94 Although the exact mechanism of induction of thyrotoxicosis remains obscure, it may be related to the stimulation of increased thyroid hormone synthesis in areas of the gland with autonomous nodular activity.

Ingestion of excess iodide by a gravid woman may cause an iodide goiter in the fetus, and if the gland is large enough it may result in asphyxia during the postnatal period (Chapter 20). Consumption of Kombu, the iodine-rich seaweed, is responsible for the occurrence of endemic goiter in the Japanese island of Hokkaido.95 It has also been suggested that the increase in dietary iodine content in the United States during the last three decades is responsible for the higher recurrence rate of thyrotoxicosis in patients previously treated with antithyroid drugs.96

Calcium. Calcium is said to be goitrogenic when in the diet in excess. Administration of 2 g calcium per day was associated with decreased iodide clearance by the thyroid.97 The action is unknown, but it may in some way make overt a borderline dietary iodine deficiency. Calcium also acutely and chronically reduces the absorption of thyroxine It has been recently shown that calcium reduces the absorption of thyroxine. 97a, 97b

Nitrate. Nitrate in the diet (0.3 - 0.9%) can interfere with 131I uptake in the thyroid of rats and sheep.98 This concentration is found in some types of hay and in silages.

Bromine. Bromine is concentrated by the thyroid and interferes with the thyroidal 131I uptake in animals99,99a and humans, possibly by competitive inhibition of iodide transport into the gland. Bromine can also induce alterations in cellular architecture, blood supply and can lead to a reduction in T4 and T3 levels.99b

Rubidium. Rubidium is goitrogenic in rats.100 However, the mechanism of action is unknown.

Florine. Fluorine is not concentrated by the thyroid but has a mild antithyroid effect, possibly by inhibiting the iodide transport process.101 In large amounts, it is goitrogenic in animals. The amounts of fluorine consumed in areas with endemic fluorosis are not sufficient to interfere with thyroid function or to produce goiter.102,103 However, other data suggest that dietary fluorine may exacerbate an iodine deficiency and thus modulate the distribution of goiter in areas with low iodine intake.104

Cobalt. Cobalt inhibits iodide binding by the thyroid.105 The mechanism is unknown. Cobalt deficiency is associated with a reduction in type I monodeiodinase activity and a fall in T3105a while cobalt excess may produce goiter and decreased thyroid hormone production. 105b It is sufficiently active to have been used in the treatment of thyrotoxicosis.106

Cadmium. Administration of cadmium to rats or mice decreases serum levels of T4 and T3. 106a,106b It also decrease the activity of hepatic Type I - 5’Deiodinase.106a,106c

Lithium Ion. Lithium ion is goitrogenic when used in the treatment of manic-depressive psychosis and can induce myxedema.107 Experimentally, lithium increases thyroid weight and slows thyroid iodine release.108 When lithium carbonate was given to human subjects in doses of 900 mg four times daily, there was a significant decrease in the rate of release of thyroidal iodine in euthyroid and hyperthyroid subjects.109 Lithium also decreases the rate of degradation of T4 in both hyperthyroid and euthyroid subjects.110 Inhibition of thyroid hormone release may be the dominant effect of the ion.110a Therefore, the decrease in serum T3 concentration is greater in hyperthyroid patients, and changes in the rT3 level, if any, are minimal.111-113

A number of mechanisms have been suggested for the effects of lithium. One well-documented phenomenon is a potentiation of an iodide-induced block of binding and hormone release,88,114 perhaps because lithium is concentrated by the thyroid115 and increases the intrathyroidal iodide concentration109,111 (Fig. 5-2). Although it has been shown that lithium inhibits the adenylate cyclase activity in the thyroid gland as well as in other tissues,116 it also blocks the cAMP-mediated translocation of thyroid hormone. The latter effect, which is probably responsible for the inhibition of hormone release, appears to be due to the stabilization of thyroid microtubules promoted by lithium.117 In rat brain, lithium administration decreased both the levels of the Type II 5’Deiodinase and the Type III 5 Deiodinase.117a In the rat, lithium may also lead to an alteration in the distribution of thyroid hormone receptors with the alpha 1 isoform being increased in the cortex and decreased in the hypothalamus while the beta isoform was also decreaseed in the hypothalamus. 117b

An exaggerated response of TSH to TRH may be seen in a majority of lithium treated patients110a but an elevated basal TSH is usually absent. An increase in the basal serum TSH concentration and its response to TRH most likely represents an early manifestation of hypothyroidism rather than a direct effect of lithium on the hypothalamic-pituitary axis.118 The prevalence of goiter has been reported to be as high as 60%.110a Based on studies in FRTL-5 cells, lithium may have direct mitogenic effects on the thyroid that are independent of TSH and cAMP. 110b The occurrence of hypothyroidism during lithium therapy occurs in 10-40% of lithium treated patients and is far more frequent in women than men.110a,118a, 118b,118c
Figure 5-2. The potassium perchlorate discharge test was carried out in a euthyroid patient during lithium treatment with serum lithium concentrations of 0.8 - 1.3 mEq/liter and during a period without lithium for 10 days. After the administration of radioiodide thyroidal isotope, content was measured for three hours before and 90 minutes after the administration of 200 mg perchlorate. The iodide perchlorate discharge test result was negative in patients not receiving lithium (B) but was strongly positive in patients under lithium (A) treatment. (From B.F. Andersen, Acta Endocrinol., 73: 35, 1973, with permission of the author and publisher)

Although much less frequent, lithium therapy has been associated with the development of thyrotoxicosis.110a Lithium is also reported to produce exophthalamos during chronic therapy; the condition regresses when treatment is stopped. The phenomenon is a protrusion of the globe but does not involve the other changes of infiltrative ophthalmopathy of Graves' disease.118,119

Selenium. Selenium is a component of the enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase, both enzymes responsible for protection against free radicals. In addition, Type I 5’Deiodinase also contains selenium.119a Thus, a deficiency of selenium could predispose the thyroid to oxidative injury and lead to decreased peripheral T3 production. In the elderly, reduced selenium levels have been associated with a decreased T3/T4 ratio.119b It has been postulated that the combined deficiency of iodine and selenium in Zaire results in myxedematous rather than neurologic cretinism because the decrease in peripheral conversion to T3 results in greater delivery of T4 into the neonatal developing brain.119c In rats, selenium deficiency led to a decrease in renal but not hepatic Type I 5’ Deiodinase activity and serum T3 levels were unaffected.119d Selenium deficiency led to decrease GSH-Px activity in the liver, kidney and rbc’s but not the thyroid.119d Serum T4 was normal when both dietary iodine and selenium were both deficient, but was reduced when either was deficient alone.119d In other studies, brain GSH-Px and Type I deiodinase activity were normal in the presence of iodine or selenium deficiency while brain Type II Deiodinase activity was increased by iodine deficiency and unaffected by selenium deficiency.119e In contrast in brown adipose tissue (BAT), both selenium and iodine deficiency led to decreased deiodinase activity and decreased production of the uncoupling protein.119e

Treatment of goitrous children with combined seleium and iodine deficiency leads to a reduction in serum TSH and goiter size.119f The response, however, was correlated with the selenium level with both the goiter and TSH responses being correlated with the baseline selenium level. 119f
Physical and Emotional Stress

Perhaps the most dramatic study of emotional stress is that reported by Kracht,120 who found that stress provoked thyrotoxicosis in wild rabbits. Although some stress models may prompt secretion of thyroid hormone in animals,120,121 this effect is unlikely to occur in humans, at least for a sustained period of time. The stress-induced increase in adrenocortical activity tends not only to suppress TSH release but also to inhibit T3 production. A major problem in the analysis of available date is the difficulty in separating effects produced by non-specific stress from the effects caused by the agents used to induce the stress. Many of the changes in thyroid function described in this chapter under the headings starvation, temperature, altitude and anoxia may be due, in part, to stress.

Surgery has been used as a means to study the effect of stress on thyroid physiology in animals.122 Studies in humans have been prompted by the suspicion that thyroid hormone may mediate the postoperative metabolic changes leading to increased oxygen consumption and protein wastage. Some discrepancies in available data stem from lack of uniformity in the groups of patients studied in terms of preoperative state or disease, type of surgery, types of anesthetic agents and other drugs used, and the postoperative course, including nutrition and the period of recovery.

The most striking change in thyroid function is a decrease in the serum TT3 and FT3 concentrations shortly after surgery; rT3 concentrations are elevated in the postoperative period.123,124 The combined findings suggest a diversion in the normal deiodinative pathways of T4. FT4 levels may also be depressed in the postoperative period, but to a lesser degree.124 The TTR but not the TBG level is sharply reduced.125 This clear reduction in the concentration of the active forms of thyroid hormone during the postoperative period is preceded by a small, short-term increase in FT4 and FT3 concentrations during surgery.123,124 The magnitude of the subsequent reduction in T3 level appears to correlate with the severity of trauma and the morbidity during the postoperative course.123 The serum TSH concentration also tends to diminish,124 except during surgery performed in children under the conditions of hypothermia.2

Because surgical trauma produces a prompt elevation in plasma cortisol levels and food intake is curtailed during the pre-, intra-, and postoperative periods, the possibility that glucocorticoids and starvation are the principal contributors to the observed changes in thyroid function has been given strong consideration. However, Brandt et al.126 showed equally profound diminution in the serum T3 concentration when surgery was carried out with epidural anesthesia, which abolishes the plasma cortisol surge. Similarly, the almost routine use of glucose infusion should have been able to prevent the changes in serum T3 and rT3 levels if starvation played a major role in producing the changes observed during surgery.
Acute Mental Stress

Data on the effect of emotional stress on thyroid function in humans are principally derived from studies in patients with psychiatric disturbances. Thus, even if only patients with acute psychiatric decompensation are considered, the results are colored by the nature of the mental illness, its antecedent history, and the use of drugs. An early suggestion of enhanced hormonal secretion came from the observation of elevated protein-bound iodine (PBI) levels in the serum of psychiatric patients presumably under emotional stress and in medical students in the course of examinations.127 In more recent studies, elevations of the FT4I have been consistently found during admission of acute psychiatric patients. The incidence ranged from 7 to 18%.128-130 In one study, an equal number of patients (9%) had a low FT4I.128 In most instances, values became normal with time and treatment of the psychiatric illness. The TSH response to TRH is blunted or even absent in most psychiatric patients with elevated FT4I.130 Significant abnormalities in the serum T3 concentration are rare.
Table 5-1. Agents Inhibiting Thyroid Hormone Synthesis and Secretion
Substance Common Use
Block iodide transport into the thyroid gland
Monovalent anions (SCN-, Cl04-, N03-)a
Complex anions (monofluorosulfonate,difluorophosphate, fluoroborate)a
Not in current use; Cl04- test agent
(KClO4 contaminates some water supplies. Braverman et al found that doses up to 3 mg/day did not alter thyroid function in healthy volunteers.(130a)
Minerals (bromine, fluorine) In diet
Lithiuma Treatment of manic-depressive psychosis
Ethionamide Antituberculosis drug
Impair TG iodination and iodotyrosine coupling
Thionamides and thiourylenes, (PTU, methimazole, carbimazole)a Antithyroid drugs
Sulfonamides (acetazolamide, sulfadiazine, sulfisoxazole)a Diuretic, bacteriostatic
Sulfonylureas (carbutamide, tolbutamide,metahexamide, ?chloropropamide)a Hypoglycemic agents
Salicylamides (p-aminosalicylic acid, p-aminobenzoic acid)a Antituberculosis drugs
Resorcinol[Bull, 1950 #667] Cutaneous antiseptic
Amphenone [Selenkow, 1957 #668] and aminoglutethimide [Pittman, 1966 #669; Rallison, 1967 #670] Antiadrenal and anticonvulsive agents
Thiocyanatea No current use; in diet
Antipyrine (phenazone)a Antiasthmatic
Aminotriazole[Jukes, 1960 #671] "Cranberry poison"
Amphenidone[Pittman, 1962 #672] Tranquilizer
2,3-Dimercaptopropanol (BAL)[Current, 1960 #673] Chelating agent
Ketoconozole Antifungal agent
Inhibitors of thyroid hormone secretion
Iodide (in large doses)a Antiseptic, expectorant, and others
Lithiumaa See above
Mechanism unknown
p-bromdylamine maleate[Sharpe, 1961 #674] Antihistaminic
Phenylbutazone[Linsk, 1957 #675] Antiinflammatory agent
Minerals (calcium, rubidium, cobalt)a -----
Interleukin II Chemotherapeutic agent
g-Interferon Activiral and chemotherapeutic agent
aReferences given in the text

Table 5-2. Compounds that Affect Thyroid Hormone Transport Proteins in Serum
Substance Common Use
Increase TBG concentration
Estrogensa Ovulatory suppressants, anticancer agents
Heroin and methadone206 Opiates (in addicts)
Clofibrate207 Hypolipemic agent
5-Fluorouracil208 Anticancer agent
Perphe****ne209 Tranquilizer
Decrease TBG concentration
Androgens and anabolic steroidsa Virilizing, anticancer, and anabolic agents
Glucocorticoidsa Antiinflammatory, immunosuppressive,and anticancer agents; decrease intracranial pressure
L-Asparaginase210 Antileukemic agent
Nicotinic acid210a ,210b Hypolipidemic agent
Interfere with thyroid hormone binding to TBG and/or TTR
Salicylates and salsalatea Antiinflammatory, analgesic, antipyrexic, and antituberculosis agents
Diphenylhydantoin and analogsa Anticonvulsive and antiarrhythmic Antianxiety agent
Furosemide211 Diuretic
Sulfonylureasa Hypoglycemic agents
Heparina Anticoagulant
Dinitrophenola Uncouples oxidative phosphorylation
Free fatty acids212,213 --------
o,p'-DDD214 Antiadrenal agent
Phenylbutazone215 Antiinflammatory agent
Halofenate216 Hypolipemic agent
Fenclofenac217 Antirheumatic agent
Orphenadrine218 Spasmolytic agent
Monovalent anions (SCN-, C104-)a Antithyroid agents
Thyroid hormone analogs, including dextroisomers219 Cholesterol reducing
aReferences given in the text

Table 5-3. Agents that Alter the Extrathyroidal Metabolism of Thyroid Hormone
Substance Common Use
Inhibit conversion of T4 to T3
PTUa Antithyroid drug
Glucocorticoids (hydrocortisone, prednisone, dexamethasone)a Antiinflammatoryand immunosuppressive; decrease intracranial pressure
Propranolola ß-Adernergic blocker (antiarrhythmic, antihypertensive)
Iodinated contrast agents [ipodate (orgrafin), iopanoic acid (Telepaque)]a Radiologic contrast media
Amiodaronea Antianginal and antiarrhythmic agent
Clomipramine234 Tricylic antidepressant
Stimulators of hormone degradation or fecal excretion
Diphenylhydantoina Anticonvulsive and antiarrhythmic agent
Carbamazepine235 Anticonvulsant
Phenobarbitala Hypnotic, tranquilizing, and anticonvulsive agent
Cholestyramine236 and colestipol237 Hypolipemic resins
Soybeans151 152 Diet
Rifampin238a Antituberculosis drug
Ferrous Sulfate238 Iron therapy
Aluminum hydroxide238b Antacid
Sucralfate 238c Antiulcer therapy
aReferences given in the text

Table 5-4 Agents that May Affect TSH Secretion
Substance Common Use
Increase serum TSH concentration and/or its response to TRH
Iodine (iodide and iodine-containing compounds)a Radiologic contrast media, antiseptic expectorants, antiarrhymic and antianginal agents
Lithiuma Treatment of bipolar psychoses
Dopamine receptor blockers (metclopramide,252,253 domperidone253 254 ) Antiemetic
Dopamine-blocking agent (sulpiride255 ) Tranquilizer
Decarboxylase inhibitor (benserazide256 ) -----
Dopamine-depleting agent (monoiodotyrosine253 ) -----
L-Dopa inhibitors (chloropromazine,257 biperidine,258 haloperidol258 ) Neuroleptic drugs
Cimetidine (histamine receptor blocker)259 Treatment of peptic ulcers
Clomifene (antiestrogen)260 Induction of ovulation
Spironolactone261 Antihypertensive agent
Amphetamines262 Anticongestants and antiappetite
Decrease serum TSH concentration and/or its response to TRH
Thyroid hormones (T4 and T3) Replacement therapy, antigoitrogenic and anticancer agents
Thyroid hormone analogs (D-T4,263 3,3',5-Triac,264 etiroxate-HCl,265 3,5 dimethyl-3-isopropyl-L-thyronine266 ) Cholesterol-lowering and weight reducing agents
Dopaminergic agents (agonists)
Dopaminea Antihypotensive agent
L-Dopaa (dopamine precursor) Diagnostic and anti-Parkinsonian agent
2-Brom-a-ergocryptinea Antilactation and pituitary tumor suppressive agent
Fusaric acid (inhibitor of dopamine ß-hydroxylase267 ) ------
Pyridoxine (coenzyme of dopamine synthesis268 ) Vitamin and antiheuropathic agent
Other dopaminergic agents (perbidil,269 apomorphine,269 lisuride270 ) Treatment of cerebrovascular diseases and migraine
Dopamine antagonist (pimozide)a Neuroleptic agent
a-Noradrenergic blockers (phentolamine,271 thioridazine272 ) Neuroleptic agents
Serotonin antagonists (metergoline,273 cyroheptadine,274 methysergide275 ) Antimigraine agents and appetite stimulators
Serotonin agonist (5-hydroxytryptophan276 ) -----
Glucocoricoidsa Antiinflammatory, immunosuppressive, and anticancer agents
Reduction of intracranial pressure
Acetylsalicylic acida Antiinflammatory, antipyrexic and analgesic agent
Growth hormone277 b Growth-promoting agent
Somatostatin278,279 -----
Octreotide 279a Treatment of carcinoids, acromegaly and other secretory tumors
Opiates (morphine,280 leucine-eukephaline,281 heroin282 ) Analgesic agents
Clofibrate283 Hypolipemic agent
Fenclofenac216 Antirheumatic agent
aReferences given in the text