text:
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 associates 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
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. 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.
Fluorine. 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
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 119c 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 In an epidemeological study in China, low selenium levels were assocated with an increased ididence of goiter, sub-clinical and overt hypothryoidism and thyroiditis. 119g
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.
A number of compounds have the ability to inhibit thyroid hormone synthesis (Fig.5-3). Irrespective of their mechanism of action, they are collectively called goitrogens. As a result of a decrease in serum thyroid hormone levels, TSH secretion is enhanced, causing goiter formation. Some goitrogens occur naturally in food, and others are in drugs with goitrogenic side effects. The least toxic and those possessing the highest thyroid-inhibiting activity are used in the treatment of hyperthyroidism.
Dietary Goitrogens
The discovery of natural and synthetic substances that impair the synthesis of thyroid hormone are landmarks in the history of pharmacology.131 These substances are discussed in more detail in Chapter 20. Although iodide deficiency is, without doubt, the major cause of endemic goiter and cretinism throughout the world, dietary goitrogens may play a contributing role in some endemics, and may possibly be the dominant factor in certain areas. The dietary goitrogens fall into several categories, more than one of which may occur in the same food.
Certain foods contain cyanogenic glucosides,132 compounds that, upon hydrolysis by glucosidase, release free cyanide. These foods include almond seeds and such important dietary items as cassava, sorghum, maize, and millet. Cassava contains enough cyanogenic glucoside to be lethal if large quantities are consumed raw. Ordinarily, the root is extensively soaked, then dried and powdered. Most of the cyanide is lost in this process; that left in the root is liberated after ingestion and converted to SCN–. Chronic poisoning due to cassava is responsible for a tropical neuropathy in Nigeria133 and Tanzania, and is suspected of being a contributing cause of goiter in Central Africa.134,135
Other important classes of antithyroid compounds arise from hydrolysis of the thioglucosides.132,136,137 These compounds are metabolized in the body to goitrin or thiocyanates and isothiocyanates, and ultimately to other sulfur containing compounds, or are excreted as such. They are important in the goitrogenic activity of seeds of plants of the genus Brassica and the cruciferae, compositae, and unbelliferae. Among the plants containing these compounds are cabbage, kale, brussel sprouts, cauliflower, kohlrabi, turnip, rutabaga, mustard, and horseradish. Myxedema was reported in a woman without previous thyroid disease who consumed extremely large amounts of raw bok choy. 137b Cattle may ingest these goitrogens and pass them to humans through milk, as observed in Australia,138 Finland,139,140 and England.141 . The isothiocynate, cheiroline, occurs in the leaves of choumoellier and may be related to a focal area of endemic goiter in Australia. The goitrogen is thought to be transmitted from forage to cows, to milk, and finally to children. Although there is considerable circumstantial evidence relating these compounds to endemic goiter, it has been difficult to prove their role with certainty.
Thiocyanate is a well-known inhibitor of iodide trapping when in high concentration in blood. The blood levels obtained by ingestion of dietary goitrogens are rarely of this degree. Inhibition of iodide trapping, and thyroid peroxidase activity, and augmentation of urinary iodide loss, as demonstrated by Delange and Ermans and co-workers, all may play a role in the goitrogenic activity.132,134,135 Thiocyanate may also reduce the iodine content of breast milk or animal milk and thus indirectly impact the thyroid function of young children in areas of marginal iodine sufficiency.141a A study in Thailand found an association between thiocyanate levels and TSH in pregnant women with low iodine excretion. 141b
Astwood et al. and Greer142,143 found that turnips contain progoitrin, which is a mustard oil thioglycoside. It undergoes rearrangement by enzymes in human enteric bacteria, or in the turnip, to be converted to goitrin, an active goitrogenic thioglycoside, L-5-vinyl-2-thio-oxazolidone.144,145 Goitrin inhibits oxidation of iodine and its binding to thyroid protein in the same way as do the thiocarbamides.
Several endemics of goiter have been attributed to dietary goitrogens, usually acting together with iodine deficiency. Goitrin is apparently present in cow's milk in Finland.146 In the Pedgregoso region of Chile, pine nuts of the tree Araucaria americana are made into a flour and consumed in large amounts, and may be related to endemic goiter.147,148 In the Cauca river valley of Colombia, sulfur-containing compounds found in the water supply, derived from sedimentary rocks containing a large amount of organic matter, are believed to be responsible for endemic goiter.149 At least, extracts from these waters are goitrogenic in rats. Pearl millet has been reported to cause goiter development in goats. 149a
Other mechanisms may also contribute to dietary goitrogenicity. Thus, diets high in soybean components or other materials increasing fecal bulk may cause excess fecal loss of T4 and increase the need for this hormone.150-153 These diets are low in iodine content, and soybean has been thought but not proven to contain a goitrogen.
The goitrogens, by blocking hormone synthesis, deplete the thyroid of iodide; this reduction itself increases the sensitivity of the gland to TSH.154 This sensitivity, in turn, further promotes goitrogenicity.
Antithyroid Drugs
According to their principal mode of action on thyroidal iodine metabolism, antithyroid drugs are divided into two categories: (1) the monovalent anions, which inhibit iodide transport into the thyroid gland, and (2) a large number of compounds that act through inhibition of thyroidal iodide binding and iodotyrosine coupling. The most important representatives of this latter category of compounds are the group of thionamides. The effect of the drugs in the first category is counteracted by exposure to excess iodine, whereas iodine has no inhibition, and at times even potentiates, the action of drugs in the second category. Other drugs inhibit thyroid hormone secretion or act through yet unknown mechanism. A list of these agents is provided in Table 5-1.
Monovalent Anions. Certain monovalent anions (SCN–, Cl04–, NO3–) inhibit transport of iodide into the thyroid gland and thereby depress iodide uptake and hormone formation.164-166 Thiocyanate stimulates efflux of iodide from the thyroid as well,167 and also inhibits iodide binding and probably coupling.168,169 A large number of complex anions, such as monofluorosulfonate, difluorophosphate, and fluoroborate,170 inhibit iodide transport. Of these, fluoroborate,171 and perchlorate,172 are concentrated by the thyroid gland. These ions have a molecular volume and charge similar to those of iodide, and may compete with iodide for transport.170,171 Perchlorate is sufficiently active to be useful clinically.173 Perchlorate and thiocyanate also displace T4 from thyroid hormone-binding serum proteins in vivo and in vitro and cause a transient elevation of free T4.174 In contrast to the pharmacologic effects of perchlorate, concerns have been raised about the potential health effects of environmental perchlorate exposure, especially in municipal water supplies. Several studies have been unable to detect an increase in hypothyroidism 174a. 174b, congenital hypothyroidism 174c, or thyroid cancer 174d in exposed populations, but a study in Thailand found an association bwteen perchlorate levels and TSH in pregnant women. 141b
Thionamides. The thionamide and thiourylene drugs do not prevent transport of iodide into the thyroid gland, but rather impair covalent binding of iodide to TG.175-177 They may be competitive substrates for thyroid iodide peroxidase, preventing the peroxidation of iodide by this enzyme. In small doses, the thiocarbamides inhibit formation of iodothyronines from iodotyrosyl precursors. When slightly larger amounts are present, iodination of MIT and tyrosine is prevented.177,178 Minute amounts (10-8 M) have, paradoxically, a stimulatory effect on iodination in thyroid slices.179
The basic structure necessary for the antithyroid action of these drugs is
where X may be C, N, or O180,181 (Fig. 5-3). The thiocarbamides are metabolized in the thyroid gland by transsulfuration.182 The enzyme responsible may also be involved in the iodide peroxidase enzyme system.183 Glands under TSH stimulation metabolize the antithyroid drugs at an accelerated rate, as has been shown for thiourea.184
Iodide is released more rapidly from a gland blocked by PTU than from one blocked by perchlorate.165,185 This action occurs presumably because PTU prevents the utilization of all iodide available to the gland (transported from the blood or formed in the gland by deiodination of iodotyrosines), whereas potassium perchlorate prevents uptake of iodide but does not inhibit reutilization of iodide derived from within the gland. T4 disappears from the PTU-blocked rat thyroid at a faster rate than do iodotyrosines.185
In addition to the effects on the thyroid gland, PTU (and, to a much lesser extent, methimazole) partially inhibits the peripheral deiodination of T4186-191 and its hormonal action.188,192-194 PTU acts directly on body tissues to inhibit the normal formation of T3 from T4.191,195 Coincidentally, fecal excretion of T4 increases.186 In order to inhibit goiter induced by antithyroid drugs in rats, one must maintain the T4 concentration in blood at a higher level that is normal for the species.188,192 Presumably, inhibition of T4 monodeiodination by the antithyroid drug leads to a buildup of T4 in blood and diminishes the availability of T3 in the tissues.191 Higher doses of T4 or higher blood levels may be sufficient to push the reaction toward T3 and allow formation of quantities sufficient to prevent goiter.
Metabolism of the antithyroid drugs has been observed after administration of 35S-labeled drugs. Methimazole is rapidly absorbed from the gastrointestinal tract in humans. It reaches a peak plasma level about an hour after administration, and then declines gradually to near zero levels at 24 hours. These drugs are accumulated and degraded in the thyroid, since they are substrates of the peroxidase.196,197 Carbimazole is accumulated as its metabolic product, methimazole. The concentration ratio between thyroid and plasma for unmetabolized methimazole in rats may approach 25, eight hours after administration of the drug. The metabolic products derived from the drug are excreted in the urine, largely during the first day.
Other Goitrogenic Compounds
A number of other drugs, including the aminoheterocyclic compounds and substituted phenols, act as goitrogens principally by impairing TG iodination (Fig. 5-3). They are in general far less potent in their goitrogenic effect than the thionamides. None are used therapeutically as antithyroid drugs; rather, goitrogenesis is an undesirable side effect of their use. Some the compounds have multiple effects and thus influence thyroid physiology at various levels. These compounds are individually discussed in greater detail. A comprehensive list is provided in Table 5-1.
Table 5-1 Agents Inhibiting Thyroid Hormone Synthesis and Secretion
|Block iodide transport into the thyroid gland
|Common Use
|Monovalent anions (SCN–, Cl04–, N03–)a
|Not in current use; Cl04– test agent
|Complex anions (monofluorosulfonate,difluorophosphate, fluoroborate)a
|Minerals (bromine, fluorine)
|In diet
|Treatment of manic-depressive psychosis
|Antituberculosis drug
|Impair TG iodination and iodotyrosine coupling
|Common Use
|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
|Cutaneous antiseptic
|Antiadrenal agent
|No current use; in diet
|Antipyrine (phenazone)a
|"Cranberry poison"
|2,3-Dimercaptopropanol (BAL)
|Chelating agent
|Antifungal agent
|Inhibitors of thyroid hormone secretion
|Common Use
|Amiodarone a
|Antianginal and antiarrhythmic agent
|Iodide (in large doses)a
|Antiseptic, expectorant, and others
|Treatment of manic-depressive psychosis
|Cause Thryoiditis
|Common Use
|Amiodarone a
|Antianginal and antiarrhythmic agent
|Interleukin II a
|Cancer therapy
|g-Interferon a
|Antiviral and cancer therapy
|Sunitinib a
|Cancer therapy
|Sorafenib a
|Cancer therapy
|Ipilmumab a
|Cancer therapy
|Pembrolizumab a
|Cancer therapy
|Nivolumab a
|Cancer therapy
|Mechanism unknown
|Common Use
|p-bromdylamine maleate a
|Phenylbutazone a
|Antiinflammatory agent
|Minerals (calcium, rubidium, cobalt)a
|Cancer therapy
|aReferences given in the text
Sulfonamides. Sulfonamides, particularly those containing an aminobenzene grouping, have antithyroid activity. Acetazoleamide (Diamox), the diuretic agent, has a strong effect on animals and humans.198,199 Its action, prevention of intrathyroidal iodide binding, is not related to carbonic anhydrase inhibition. Sulfadiazine and sulfisoxazole have a similar action, probably through a synergistic effect on iodide.89
Sulfonylureas. Sulfonylureas, derivatives of sulfonamides and used as hypoglycemic-antidiabetic agents, also inhibit the synthesis of thyroid hormone. They include carbutamide, tolbutamide, methahexamide, and possibly chlorpropamide, but not the phenylethyl biguanide (Fig. 5-3). They impair thyroidal RAIU and cause goiter in the rat.200,201 Carbutamide is much more potent than tolbutamide. Carbutamide, 2 g/day (but not 1 g/day), may reduce the thyroidal RAIU in humans to 20% of control values, but the uptake gradually rises as treatment is continued and is normal after 20 weeks. From 1 to 2 g tolbutamide per day does not affect RAIU in humans.202 Thus, in the usual dose range, tolbutamide will not depress thyroid function.
Chlorpropamide in large doses (3-7 g) depresses the RAIU in humans; the common therapeutic doses (up to 1 g daily) usually have no effect on serum T4.203 A mild antithyroid action is often reflected in a rise in RAIU, which may be found after the agents are withdrawn.
These drugs inhibit hormone synthesis by inhibition of iodide binding. In most instances, the pituitary compensates for the effect and maintains a euthyroid state by increased synthesis of TSH. Nevertheless, hypothyroidism is said to be more common in diabetic patients on sulfonylureas than in patients treated by other means.204
Sulfonylureas also block binding of T4 to the carrier proteins in serum and thus depress the T4 concentrations.205 This effect is most pronounced after intravenous administration.
Polychlorinated Biphenyls Animal studies have suggested that polchlorinated bihenyls (PCBs) may reduce thyroid hormone levels by decreasing synthesis, increasing biliary excretion of conjugated metabolites and displacing T4 from binding proteins. 205a A review of studies in humans, did not find significant or consistent changes. 205a
Effects of Miscellaneous Compounds and Drugs
General Mechanisms of Action
A large number of substances may affect thyroid gland function and thyroid hormone metabolism and action. The list continues to grow with the introduction of new diagnostic agents, drugs, and food additives. Drugs affect the transport, metabolism, action and excretion of T4 and its derivatives as well as regulation at all levels of the hypothalamic-pituitary-thyroid axis. Some drugs may induce hypothyroidism or thyrotoxicosis, and if autoimmune mechanisms are involved, the thyroid dysfunction may not resolve with discontinuance of the drug. Some compounds may not have any direct effect on thyroid hormone economy or regulation, but have clinical relevance by interfering in specific diagnostic assays.
Compounds are discussed and listed below based on their major mechanisms of action. Many drugs have more than one mechanism of action and the explanation for observed abnormalities is not always known. Results of experiments conducted in animals or in vitro are not always applicable to human pathophysiology. Compounds which alter thyroid hormone secretion are generally goitrogens or anti-thyroid drugs and were discussed in the preceeding section. Selected compounds with significant effects on the thyroid, wide-spread use or that are of particular interest in understanding the mechanism of drug effects are described in greater detail.
Alterations of Thyroid Hormone Transport
Some hormones and drugs may affect thyroid hormone transport in blood by altering the concentration of the binding proteins in serum. Thyroid hormone transport may also be affected by substances that compete with the binding of thyroid hormone to its carrier proteins (Table 5-2). TBG synthesis is increased by estrogens220-223 and decreased by androgens and anabolic steroids.223,224 Estrogen's effect to increase TBG is blunted or reversed by tamoxifen and raloxifene.224a The most extensively studied compounds that interfere competitively with thyroid hormone binding to the carrier proteins in serum are salicylates, diphenylhydantoin, and heparin.212,225-231,231a,b A clinically significant effect of furosemide211 may only be seen with very high doses and with accumulation with renal failure.
Table 5-2 Compounds that Affect Thyroid Hormone Transport Proteins in Serum
|Increase TBG concentration
|Common Use
|Ovulatory suppressants, anticancer agents, hormone replacement
|Heroin and methadone206
|Opiates (in addicts)
|Hypolipemic agent
|Anticancer agent
|Decrease TBG concentration
|Common Use
|Androgens and anabolic steroidsa
|Virilizing, anticancer, and anabolic agents
|Antiinflammatory, immunosuppressive, and anticancer agents; decrease intracranial pressure
|Antileukemic agent
|Nicotinic acid210a ,210b
|Hypolipidemic agent
|Interfere with thyroid hormone binding to TBG and/or TTR
|Common Use
|Salicylates, 4 amino-salicylic acid and salsalatea
|Antiinflammatory, analgesic, antipyretic, antituberculosis agents
|Diphenylhydantoin and analogsa
|Anticonvulsive and antiarrhythmic agents
|Hypoglycemic agents
|Uncouples oxidative phosphorylation
|Free fatty acids212,213
|Antiadrenal agent
|Antiinflammatory agent
|Hypolipemic agent
|Antirheumatic agent
|Spasmolytic agent
|Monovalent anions (SCN-, C104–)a
|Antithyroid agents
|Thyroid hormone analogs, including dextroisomers219
|Cholesterol reducing agents
|aReferences given in the text
In general, the effect of increased hormone binding is an increase in the serum concentration of total (bound) T4 and of reduced binding is a decrease in the total (bound) T4, with T3 effected to a lesser extent. There is no significant effect on the absolute concentration of the metabolically active fractions of FT4 and FT3, or usually their free indices (FT4I and FT3I). In the steady state, the quantity of thyroid hormone reaching peripheral tissues and the pathways and amount of hormone degradation remain unaltered. However, before this steady state is reached, an acute perturbation in the equilibrium between free and bound hormone brings about transient changes in thyroid hormone secretion and degradation. The hypothalamic-pituitary-thyroid axis participates in the reestablishment of the new steady state. For example, as illustrated in Figure 5-4, an abrupt increase in the concentration of TBG shifts the equilibrium between total and bound hormone, causing a decrease in the concentration of free hormone. The consequences are fourfold. First, there is a shift in the exchangeable hormone from tissues to blood. Second, a decreased hormone content in tissues diminishes its absolute degradation rate. Third, a decline in hormone concentration in tissues activates the hypothalamic-pituitary axis, causing an increase in TSH secretion. Fourth, the latter acts on the thyroid gland to step up its hormonal secretion and reestablish an appropriate thyroid hormone/TBG ratio. Thus, a normal thyroid hormone concentration in serum and tissues and hormonal production and disposal rates are reestablished. TSH concentration returns to normal, and a new steady state is maintained at the expense of an increased intravascular pool and a decreased fractional turnover rate and total distribution space of thyroid hormone.232,233 The reverse sequence of events accompanies an acute decrease in TBG concentration or binding (Fig. 5-4).
Alterations of Thyroid Hormone Metabolism
Agents that may alter the extrathyroidal metabolism of thyroid hormone are listed in Table 5-3. Several drugs with wide use in clinical practice inhibit the conversion of T4 to T3 in peripheral tissues. Glucocorticoids,239,240 amiodarone,241,242 and propranolol243-245 are a few examples. As expected, their most profound effect on thyroid function is a decrease in the serum concentration of T3,239,241,243 usually with a concomitant increase in the rT3 level.239,241 An increase in the serum T4 concentration has also been observed on occasion.241,245 The serum TSH concentration may also occasionally rise,241 provided the drug does not have a direct inhibitory effect on the hypothalamic-pituitary axis.246 In the absence of inherent abnormalities in thyroid hormone secretion or in its regulation, TSH levels should return to normal and hypothyroidism should not ensue from the chronic administration of compounds the only effect of which is to interfere partially with T4 monodeiodination.
Other mechanisms by which some compounds affect the extrathyroidal metabolism of thyroid hormone are acceleration of the overall rates of deiodinative and nondeiodinative routes of hormone disposal. Examples of drugs acting principally through the former mechanism are diphenylhydantoin and phenobarbital,247-249 and via the latter, colestipol237, ferrous sulfate238a, aluminum hydroxide238b and sucralfate238c. Patients receiving these drugs should increase the secretion of hormone from the thyroid gland in order to compensate for the enhanced hormonal loss through degradation or fecal excretion. Thyroid hormone concentration in blood should remain unaltered. However, hypothyroid patients receiving such drugs may require higher doses of exogenous hormone to maintain a eumetabolic state (Chapter 9). In patients on thyroid hormone therapy who are also taking drugs which bind thyroid hormone in the gastrointestinal tract, the administration of the two drugs at different times will markedly reduce or eliminate the effect on thyroid hormone absorption.
Acute increases in serum T4 and FT4 concentration after the injection of insulin or during halothane anesthesia have been attributed to an enhanced release of T4 normally stored in the liver.250,251
Table 5-3 Agents that Alter the Extrathyroidal Metabolism of Thyroid
|Common Use
|Inhibit conversion of T4 to T3
|Antithyroid drug
|Glucocorticoids (hydrocortisone, prednisone, dexamethasone)a
|Antiinflammatory and
immunosuppressive; Decrease
intracranial pressure
|ß-Adernergic blocker
(antiarrhythmic, antihypertensive)
Iodinated contrast agents [ipodate
(orgrafin), iopanoic acid
|Radiologic contrast media
|Antianginal and antiarrhythmic agent
|Tricylic antidepressant
|Stimulators of hormone degradation or fecal excretion
|Anticonvulsive and antiarrhythmic agent
|Hypnotic, tranquilizing, and
anticonvulsive agent
|Cholestyramine236 and colestipol237
|Hypolipemic resins
|Soybeans151 152
|Antituberculosis drug
|Ferrous Sulfate238
|Iron therapy
|Aluminum hydroxide238b
|Sucralfate 238c
|Anti-ulcer therapy
|Imatinib 384
|Cancer therapy
|Bexarotene 387
|Cancer therapy
|Sevelemer 393
|Phosphate Binder
|Colesevelam 394
|Hypolipemic resin
|Lanthanum Carbonate 394
|Phosphate Binder
|Coffee 395
|aReferences given in the text
Alterations of Thyroid Hormone Regulation
The last two decades have seen a prodigious growth in the list of substances that can be shown to act on the hypothalamic-pituitary axis (Table 5-4). Although many of these compounds are used frequently, only a few have significant effects on thyroid function via this central mechanism. Furthermore, patients receiving these drugs rarely have any abnormality of serum TSH although the response of TSH to the administration of TRH may be altered. An effect of these drugs may be seen in patients with untreated or partially treated primary hypothyroidism. In patients with an elevated basal level of serum TSH, addition of these drugs may produce a further increase or a significant diminution.
Although the following paragraphs discuss the general mechanisms of action for these compounds, specific mechanisms are not always known. A major problem in interpretation is the variability of experimental designs. These variables include doses, routes of administration, duration and time of treatment, drug combinations, age and sex of subjects, hormonal status at the time of testing, and time of blood sampling. Furthermore, observed responses may be effected by the method of data analysis. For example, results of TSH responses to TRH have been expressed in terms of changes in the absolute value, increments or decrements from the basal level, and percent of the basal value at either the peak and nadir of the response or the integrated area over the duration of the response.
The most potent suppressors of pituitary TSH secretion are thyroid hormone and its analogs. They act on the pituitary gland by blocking TSH secretion through the mechanisms discussed in Chapter 4. Some TSH-inhibiting agents listed in Table 5-4, such as, fenclofenac and salicylates, may act solely by increasing the free thyroid hormone level through interference with its binding to serum proteins. Other agents appear to have a direct inhibitory effect on the pituitary and possibly on the hypothalamus. The most notable is dopamine and its agonists. They have been shown to suppress the basal TSH levels in euthyroid persons284,285 and in patients with primary hypothyroidism.267,284-286 More uniformly, they suppress the TSH response to the administration of TRH.268,285,287,288 In contrast, most dopamine antagonists increase TSH secretion.150-155 Increases in the basal TSH and in its response to TRH have been observed in euthyroid persons,252,255 as well as in patients with primary hypothyroidism250-256 who have been given these drugs. A notable exception to this rule, which casts some doubt on the assumed mechanism of action of dopamine antagonists, is neuroleptic dopamine blocker, pimozide, which has been reported to reduce the elevated serum TSH level in patients with primary hypothyroidism.289
Table 5-4 Agents that May Affect TSH Secretion
|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
|Treatment of bipolar psychoses
Dopamine receptor lockers (metclopramide,252,253 domperidone253 254)
|Dopamine-blocking agent(sulpiride255 )
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
|Antihypertensive agent
|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)
|Antihypotensive agent
|L-Dopaa (dopamine precursor)
|Diagnostic and anti-Parkinsonian agent
|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
|alpha-Noradrenergic blockers (phentolamine,271 thioridazine272)
|Neuroleptic agents
|Serotonin antagonists metergoline,273 cyroheptadine,274 methysergide275)
|Antimigraine agents and appetite stimulators
|Serotonin agonist(5-hydroxytryptophan276)
|Antiinflammatory, immunosuppressive, and anticancer agents. Reduction of intracranial pressure
|Acetylsalicylic acida
Antiinflammatory, antipyrexic and
analgesic agent
|Growth hormone277 b
|Growth-promoting agent
|Octreotide 279a
|Treatment of carcinoids, acromegaly and other secretory tumors
|Opiates (morphine,280 leucine- eukephaline,281 heroin282)
|Analgesic agents
|Hypolipemic agent
|Antirheumatic agent
|Bexarotene a
|Cancer therapy
|Metformin 392
|Anti-diabetic agent
|Ipilmumab a (autoimmune hypophysitis)
|Cancer therapy
|Pembrolizumab a (autoimmune hypophysitis)
|Cancer therapy
|Nivolumab a (autoimmune hypophysitis)
|Cancer therapy
aReferences given in the text
bIn hyposomatotrophic dwarfs
Iodine and some iodide-containing organic compounds cause a rapid increase in the basal and TRH-stimulated levels of serum TSH. This effect is undoubtedly due to a decrease in the serum thyroid hormone concentration either by inhibition of hormone synthesis and secretion by the thyroid gland81,82 or by a selective decrease in the concentration of T3.290 The latter effect is mediated through the inhibition of T3 generation from T4. A more selective, intrapituitary inhibition of T4 to T3 conversion appears to be responsible for the TSH-stimulating effect of the radiographic contrast agent iopanoic acid58 and amiodarone. Iodine does not stimulate TSH secretion in patients in whom it has produced hyperthyroidism. 94 A decrease in the free thyroid hormone concentration in serum, albeit minimal in magnitude, may also be responsible for the increase in TSH levels observed during treatment with clomifene.260
It has been postulated that some agents may act by modifying the effect of TSH on its target tissue. For example, theophylline may potentiate the action of TSH through its inhibitory effect on phosphodiesterase, which may lead to an increase in the intracellular concentration of cAMP.291 In fact, the presence of the pituitary is required to demonstrate that methylxanthines augment the goitrogenic effect of a low-iodine diet in the rat.292 One of the postulated effects of diethyl ether anesthesia in the rat is inhibition of the action of TSH on the thyroid gland,293 although it has also been reported to induce a transient redistribution of T4 between serum and tissues.294
Alterations of Thyroid Hormone Action
A handful of drugs seem to act by blocking some of the peripheral tissue effects of thyroid hormone. Others appear to mimic one or several manifestations of the thyroid hormone effect on tissues. Guanethidine releases catecholamines from tissues.295 It has a beneficial effect in thyrotoxicosis, including a decrease in BMR, pulse rate, and tremulousness.296,297 This agent has little effect on the thyroid gland, but depresses manifestations of thyrotoxicosis that are mediated by sympathetic pathways. The sympatholytic agents phentolamine and dibenzyline have been reported both to depress and to stimulate thyroid function in animals. Their action is not clear, and it is of minimal clinical significance.298-300 Among several α-adrenergic blocking agents tested, only phentolamine showed an inhibitory effect on the TSH response to TRH.271
Theoretically, thyroid hormone effects could be blocked by drugs which interfere with the tissue uptake of thyroid hormone or binding to its receptors. Inhibition of both cellular uptake and nuclear receptor binding has been demonstrated in vitro for amiodarone in hepatocytes and cultured pituitary cells. Inhibition of cellular thyroid hormone uptake has also been reported for calcium channel blockers and benzodiazapines. Furosemide and non-steroidal anti-inflammatory drugs reduce T3 binfding to cytosolic receptors. There is, however, no clear evidence that any of these drugs have a clinically significant effect on thyoid hormone action.
Among the multiple effects the ß-adrenergic blocker, propranolol, has on thyroid hormone economy, it appears to reduce the peripheral tissue responses to thyroid hormone (see also Chapters 3 and 11). Dinitrophenol enhances oxygen consumption by a direct effect on tissues and thus mimics one of the actions of thyroid hormone.301
Recent interest has been directed toward compounds which may share some but not all thyroid hormone actions by either selective tissue uptake or receptor binding. The general goal is to develop agents which promote weight loss or decrease lipids without adverse effects on the skeleton, heart (tachycardia) or pituitary (TSH suppression). 300a-300d Diiodothyropropanoic acid (DIPTA) in short term studies was found to decrease cholesterol and lead to weight loss. 300a However it was also found to increase bone turnover and reduce TSH, T3 and T4. 300a
The drug eprotirome was shown to reduce total and LDL cholesterol, triglyerides and Lp(a) lipoprotein. 300b,300c Eprotirome was not found to have adverse effects on the heart or bone and did not changed levels of TSH or T3 although mild, reversible dops in T4 levels were noted. 300b,300c In a controlled trial, that was terminated prior to completion when adverse cartilage effects were noted in dogs, several patients did devlop transaminase elevations. 300c
Specific Agents
Estrogens and selective estrogen receptor modulators (SERMs). Hyperestrogenism, either endogenous (caused by pregnancy, hydatidiform moles, or estrogen-producing tumors) or exogenous (due to the administration of estrogens), is accompanied by an increase in TBG and a decrease in TTR concentrations in serum.220-222 Estrogens are the most common cause of TBG elevation, and this effect can be produced even after their topical application. The magnitude of TBG increase is in part dose related and occurs in women as well as in men. While tamoxifen blocks the estrogen induced increase of TBG224a, tamoxifen alone in post-menopausal women increases TBG and T4 and 3 levels.301a . The selective estrogen receptor modulator (SERM) raloxifene, increases TBG, produces small increase in T4 and insignificant changes in free T4. 301b,301c In a single case report, raloxifene appeared to also alter thyroid hormone absorption. 301d Estrogen increases the complexity of oligosaccharide side chains and, as a consequence, the number of sialic acids in the TBG molecule which in turn prolongs its survival in serum.302 The concentrations of other serum proteins, including several that bind hormones, such as cortisol-binding globulin and sex-hormone binding globulin, are also increased.303
The consequences of increased TBG concentration in serum are higher serum levels of T4, T3 and rT3 and, to a lesser extent, other metabolites of T4 deiodination. The fractional turnover rate of T4 is depressed principally due to an increase in the intravascular T4 pool. On the other hand, the FT4 and FT3 concentrations and the absolute amount of hormone degraded each day remain normal.232,233 Transient changes in these parameters during the early changes in TBG concentration can be anticipated as described above. Some of the effects of pregnancy on thyroid function are also mediated by an estrogen-induced increase in the serum TBG concentration. The effects on thyroidal and renal iodide clearance and BMR are mediated by different mechanisms (see Chapter 3).
The effect of estrogen, if any, on the control of TSH secretion is controversial. Contradictory results suggesting a stimulatory304 and an inhibitory305,306 effect have been obtained by different investigators and both stimulation and inhibition has been shown in a single study depending on the dosage utilized.306a In a study of the effects of Tamoxifen, TSH was elevated at 3 months but not at 6 months.306b Although women show a greater TSH responsiveness to TRH than men,306-308 administration of pharmacologic doses of estrogens does not appear to have a significantly enhancing effect.309,310 During ovarian hyperstimulation for ovulation induction, an increase in TSH and fT4 has been observed and this has been attributed to the marked increase in estrogen. 310a
The effects of estrogens in the rat are not identical to those observed in humans. Estrogens do not induce changes in the concentration of serum T4-binding proteins in the rat.22 Thus, investigations carried out in this species are not always representative in interpreting the effects of estrogens observed in humans
Androgens. Androgens decrease the concentration of TBG in serum and thereby reduce the level of T4 and T3.223,311 The TTR concentration, however, is increased.223 As with estrogens, the concentration of free hormone remains unaffected, and the degradation rate of T4 is normal at the expense of an accelerated turnover rate.223 TSH levels are normal.305 Anabolic steroids with weaker androgenic action have the same effect, although similar changes observed during danazol therapy have been attributed to its androgen-like properties.224
Salicylates. Acetylsalycilic acid has been identified as the most commonly administered medication which may cause significant alterations in measured parameters of thyroid function.224b,224c Salicylate and its noncalorigenic congeners (Fig. 5-3) compete for thyroid hormone-binding sites on serum TTR and TBG.225-228 As a result, the serum concentrations of T4 and T3 decline and their free fractions increase.228 The turnover rate of T4 is accelerated, but degradation rates remain normal.225,226 Salicylate and its noncalorigenic congeners also suppress the thyroidal RAIU but do not retard iodine release from the thyroid gland.312 The impaired respone to TRH313 and the hypermetabolic effect314 of salicylates have been attributed to the increase in the FT4 and FT3 fractions. If this were correct, hormonal release from the serum-binding proteins should produce only a temporary suppression of the thyroidal RAIU and transient hypermetabolism, but both effects are observed during chronic administration of salicylates.225,226 In addition, this mechanism of action does not explain the lack of calorigenic effect of some salicylate congeners despite their ability to also displace thyroid hormone from its serum-binding proteins.
In vitro studies have demonstrated an inhibitory effect of salicylate on the outer ring monodeiodination of both T4 and rT3,315 but lack of typical changes in serum iodothyronine levels suggests that this action is less important in vivo.
Acetylsalicylic acid mimics some actions of thyroid hormone, but does not reverse classic manifestations of hypothyroidism. While salicylate administration may lower serum cholesterol levels,316 it does not provide a therapeutic effect in myxedema, or lower TSH levels.317 Administration of 8 g aspirin daily raises the BMR to normal in myxedema, accelerates the circulation, and increases sweating, but it has no effect on the skin change, the electrocardiogram, or the mental state.316
Because of some analogies between the effects of salicylates and nitrophenol, uncoupling of oxidative phosphorylation has been suggested as one of its possible mechanisms of action. If this were the case, direct chemical action does not appear to be involved since analogs of salicylate that do not uncouple oxidative phosphorylation in vitro are active in vivo.318
p-Aminosalicylic acid and p-aminobenzoic acid are closely related chemically to salicylate. They inhibit iodide binding in the thyroid gland and are goitrogenic.319,320 These agents also displace thyroid hormone from its serum protein-binding sites.321 Abnormalities of thyroid function tests have been also reported in patients treated with salsalate.322
Heparin. Patients receiving heparin chronically may have increased FT4 and FT3.230,231 Reciprocal changes in serum TSH have been reported.231 While it had been suggested that heparin might interact with the T4-binding proteins to alter the steric configuration of the binding sites and reduce the affinity of the proteins for T4 and T3210, it is now thought that heparin acts via the activation of lipoprotein lipase to increase free fatty acid levels which may displace T4 from binding proteins. This effect is most likely to be significant when the levels of albumin are low and triglycerides are high such as during hyperalimentation with lipid solutions. Even low doses of heparin may be sufficient to cause artifactual, in vitro, increase in T4 especially when measured by equilibrium dialysis.231a Although initially reported with crude heparin preparations, this heparin effect has also been noted with enoxaparin. 231b
Glucocorticoids. Physiologic amounts, as well as pharmacologic doses of glucocorticoids influence thyroid function. Their effects are variable and multiple, depending on the dose and on the endocrine status of the individual. The type of glucocorticoid and the route of administration may also influence the magnitude of the effect.323 Known effects include (1) decrease in the serum concentration of TBG and increase in that of TTR;324,325 (2) inhibition of the outer ring deiodination of T4 and probably rT3;239,240 (3) suppression of TSH secretion;246,326,327 (4) a possible disease in hepatic binding of T4; and (5) increase in renal clearance of iodide.328,329
The decrease in the serum concentration of TBG caused by the administration of pharmacologic doses of glucocorticoids results in a decrease in the serum total T4 concentration and an increase in its free fraction and the resin uptake test result. The absolute concentration of FT4 and FT4I remain normal. The more profound decrease in the concentration of serum T3 compared to T4 associated with the administration of pharmacologic doses of glucocorticoids cannot be solely ascribed to their effect on serum TBG. It is due to the decreased conversion of T4 to T3 in peripheral tissues. Thus, glucocorticoids reduce the serum T3/T4 ratio and increase that of rT3/T4 in hypothyroid patients receiving replacement doses of thyroid hormone.239 This steroid effect is rapid and may be seen within 24 hours.239,240 In rats, dexamethasone has been shown to decrease T4 to T3 conversion in liver homogenates. 329a
Earlier observations of cortisone-induced depression of uptake and clearance of iodide by the thyroid328,329 now are understood to be the result of steroid suppression of TSH secretion. Pharmacologic doses of glucocorticoids suppress the basal TSH level in euthyroid subjects and in patients with primary hypothyroidism, and decrease their TSH response to TRH.246,326,327,329b The latter effect is less marked in the presence of hypothyroidism.327 Administration of as little as 34 mg. of hydrocortisone over 24 hours can be shown to reduce the pulse amplitude and mean TSH release the nocturnal rise of TSH and the T3 and TSH response to TRH.329b Administration of the glucocorticoid antagonist, mifepristone, produces an increase in TSH that remains within the normal range accompanied by a transient decrease in total but not free T4.329c Normal adrenocortical secretion appears to have a suppressive influence on pituitary TSH secretion because patients with primary adrenal insufficiency have a significant elevation of TSH.330 In cultures from rat pituitary tumors, hydrocortisone increased the number of TRH receptors 331 Dexamethasone has also been shown to increase the transcription, translation and processing of TRH precursors. 331a,b The mechanism of glucocorticoid action on the hypothalamic-pituitary axis is covered in Chapter 4.
No single change in thyroid function can be ascribed to a specific mode of action of glucocorticoids. For example, a diminished thyroidal RAIU may be due to the combined effects of TSH suppression and increased renal clearance of iodide. Similarly, a low serum TT4 level is the result of suppressed thyroidal secretion due to diminished TSH stimulation as well as the decreased serum level of TBG. One of the common problems in clinical practice is to separate the effect of glucocorticoid action on pituitary function from that of other agents and those caused by acute and chronic illness. This situation arises often since steroids are commonly used in a variety of autoimmune and allergic disorders as well as in the treatment of septic shock. The diagnosis of coexisting true hypothyroidism is difficult, if not impossible. Due to the suppressive effects of glucocorticoids on the hypothalamic-pituitary axis, the low levels of serum T4 and T3 may not be accompanied by an increase in the serum TSH concentration, which would otherwise be diagnostic of primary hypothyroidism. In such circumstances, a depressed rather than an elevated serum rT3 level may be helpful in the detection of coexistent primary thyroid failure.
Pharmacologic doses of glucocorticoids induce a prompt decline in serum T4 and T3 concentrations in thyrotoxic patients with Graves' disease.239 Amelioration of the symptoms and signs in such patients may also be accompanied by a decrease in the elevated thyroidal RAIU and a diminution of the TSH receptor antibody titer.325,332 This effect of glucocorticoids may be due in part to its immunosuppressive action since it has been shown that administration of dexamethasone to hypothyroid patients with Hashimoto's thyroiditis causes an increase in the serum concentration of both T4 and T3.333
Iodinated contrast It is estimated that in the US in the past year more than 80 million CT scans were performed and more than half of those utilized iodinated contrast. Whether low or high ionic strength, low or high osmolality, all of these agents contain large amount of iodine ranging from 320 – 370 mg/ml. In a prospective study, 2.6% of adults receiving contrast developed hyperthyroidism although many of theses cases were transient. 333a In a study of hospitalized elderly patients with hyperthyroidism, 23% of them had a contrast CT performed in the preceeding months. 333b When Alexander et al examined a data base of 4,500,000 patients, they found that the likelihood of developing hyperthyroidism within two years of being euthyroid was doubled by having a recent contrast CT. 333c In a small study, pretreatment with thionamides reduced the incidence and severity of hyperthyroidism but did not always prevent it. 333d Since many episodes of hyperthyroidism after iodinated contrast are transient, mild and asymptomatic, this approach may only be appropriate for patients who had more severe episodes. Other options include avoidance of iodinated contrast and definitive treatment of any underlying thyroid disorder after the patient has recovered. In a study of newly diagnosed hypothyroidism in children, the risk was increased nearly three fold by recent administration of iodinated contrast, 333e while in adults, Kornelius et al found the risk was doubled. 333f
Ipodate and Iopanoic acid The principal effect of these iodine-containing radiologic contrast media is inhibition of T4 to T3 conversion by inhibiting both Type I and Type II 5'-deiodinase. In fact, they may be the most potent of all agents known to interfere with this step of iodothyronine metabolism. A triiodo-and a monoamino-benzene ring with a proprionic acid chain appear to be required because iodinated contrast agents without this chemical structure have little or no effect.334 Several of these agents, namely, ipodate (Oragrafin) and iopanoic acid (Telepaque), are used for oral cholecystography.
A decrease in the rate of deiodination of the outer ring of thyronines causes a profound decrease in the serum T3 concentration and an increase in the rT3 and T4 levels.334,335 The serum T4 concentration may reach values well within the thyrotoxic range.334 These changes are accompanied by an increase in serum TSH secretion.290 The latter is particularly notable, if not characteristic of these agents, probably because of their potent inhibitory effect on T3 generation in pituitary tissue.58 These agents have been used to study the regulation of thyroid hormone action via the process of iodothyronine deiodination.58,336 Changes persist for at least two to four weeks after their administration.334
Ipodate and iopanoic acid also decrease the hepatic uptake of T4337 and inhibit T3 binding to its nuclear receptors.338 These effects reduce both symptoms and thyroid hormone levels even when thyrotoxicosis occurs in settings where ongoing synthesis would be minimal such as thyrotoxicosis secondary to thyroid hormone ingestion338a , or sub-clinical hypothyroidism. 338b The antithyroidal effect of the iodine present in these agents is believed to be responsible for the falling T4 level and some of the amelioration of the symptoms and signs of thyrotoxicosis when they are administered to patients with Graves' disease338,338c,338d ,
Amiodarone. Most changes in thyroid function observed during the administration of this drug are similar to those seen with iodine-containing contrast agents. They include a marked decrease in serum T3, an increase in rT3, and a more modest elevation in the T4 concentration.241,339 Basal and TRH-stimulated TSH levels are increased. The principal mechanism of action is believed to be inhibition of both Type I and Type II 5'-deiodinase resulting in a marked reduction of T3 generation from T4. Amiodarone may reduce the entry of thyroid hormone into tissues339a, may reduce the binding of thyroid hormones to the receptor339b and may antagonize the effects of thyroid hormone at the cellular level.339c,339d The drug is used as an antianginal and antiarrhythmic agent and the bradycardia that almost invariably occurs when the drug is used in high doses, may suggest the presence of hypothyroidism.340
Amiodarone contains 37% iodine by weight. The major effects on thyroid function appear to be the result of its structural resemblance to thyroid hormone rather than its iodine content. In contrast to the typical alterations of thyroid hormone function, the more uncommon occurrence of frank hypothyroidism or thyrotoxicosis are products of the excess iodine released from the drug. The overall incidence of amiodarone induced thyroid disease is higher in areas of mild iodine deficiency340 as is the relative incidence of the thyrotoxic as compared to the hypothyroid form. 340 The iodine dependence of both of these diseases is confirmed by the improvement of both with the use of perchlorate to discharge iodine from the thyroid gland. 340a, 340b
Amoidarone induced thyrotoxicosis has been identified as having two main types; type 1 usually coccuring with underlying thyroid abnormalities and type 2 in normal glands with small goiters. 340a, 340b Type 1 is more common in area of iodine deficiency. Early onset of thyrotoxicosisis is more typical for Type 1 and later onset with Type 2, but either form may present after amiodarone was discontinued. 340c, 340d Type 1 is associated with increased blood flow while hypervasculaity is absent in Type 2. Radioacitve iodine uptake may be low-normal or normal in Type 1 (especially in areas with iodine deficiency) and is low in Type 2. Type 1 is treated with thionamides but patients may be realtively resistant while patients with Type 2 respond to glucocorticoids. Some patient will present with a mixed form. Surgery may be used in cases refractory to medical therapy. 340e
Measurement of serum TSH, remains the most useful test in the differential diagnosis of hypothyroidism or thyrotoxicosis in amiodarone treated patients but the mild TSH elevation seen in euthyroid patients may make the diagnosis of mild to moderate hypothyroidism more difficult. If hypothyroidism is suspected, it is appropriate to obtain a measurement of the serum rT3 concentration. The absence of an elevated serum rT3 level in a patient receiving amiodarone suggests the patient is hypothyroid.
Diphenylhydantoin (Dilantin). Diphenylhydantoin (DPH) (Fig. 5-3) competes with thyroid hormone binding to TBG.228,229 This effect of DPH and diazepam, a related compound, has been exploited to study the conformational requirements for the interaction of thyroid hormone with its serum carrier protein229,341 It appears that the angle formed between the two phenyls and the hydantoin group of DPH is nearly identical to that formed between the two phenyls linked by an ether bond in T4.229 Although the affinity of DPH for TBG is far below that of T4, when used in therapeutic doses the serum concentration achieved is high enough to cause a significant occupancy of the hormone-binding sites on TBG. This effect of DPH is only partly responsible for the decrease in the total concentration of T4 and T3 in serum.
DPH accelerates the conjugation and clearance of T4 and T3 by the liver and probably enhances the conversion of T4 to T3.247,342 The net result is a decrease in the serum concentration of T4 and rT3 and, less consistently, that of T3343,344,344a,344b because the enhanced degradation of T3 is compensated for by an increase in its generation from T4. Yet, basal TSH- and TRH-stimulated values remain within the normal range343,344,344a,344b or slightly elevated.235,345 Calculated indices of FT4 are usually reduced, but the FT4 measured by dialysis is normal.247,343
Both DPH and diazepam are commonly used in clinical practice, the former most commonly as an anticonvulsant and the latter as an anxiolytic. Reduced serum levels of thyroid hormone in patients having therapeutic blood levels of DPH should not be viewed as indicative of thyroid dysfunction unless the TSH level is elevated. Treatment with T4 in such patients with a low T4 and normal TSH did not alter parameters of cardiac function or symptoms which might have been considered indicative of hypothyroidism.344b DPH therapy may increase the required dose of thyroid hormone replacement in athyreotic individuals.346 .
Phenobarbital. Chronic administration of phenobarbital to animals induces increased binding of thyroid hormone to liver microsomes and increased deiodinating activity.248,249,347,347a Phenobarbital administration reduces the biologic effectiveness of the hormone by diverting it to microsomal degradative pathways. In humans, phenobarbital augments fecal T4 clearance by nearly 100%,348 but serum T4 and FT4 levels remain near no rmal because of compensatory increases in T4 secretion. It is not apparent that barbiturates have an important effect on thyroid mediated metabolic action in normal humans, but it may potentate the effects of dilantin or carbamazapine. 348a The augmented hepatic removal of T4 induced by phenobarbital lower the absolute T3 disposal by nearly 25%, increase T4 clearance, and lower T4 and FT4I in patients with Graves' disease but does not produce a clinical response.348
Propranolol. Propranolol, a ß-adrenergic blocker, is commonly used as an adjunct in the treatment of thyrotoxicosis Propranolol is usually used in the treatment of cardiac arrhythmias, angina and hypertension. Information regarding its effects on thyroid hormone action, and application in the symptomatic treatment of thyrotoxicosis is found in Chapters 3 and 11, respectively.
Propranolol does not affect the secretion or overall turnover rate of T4, nor TSH release or its regulatory mechanisms.349,350 A small to moderate lowering effect on serum T3 has been reported in euthyroid subjects as well as in patients with hyperthyroidism or with myxedema under L-T4 replacement therapy.243,245,351,352 Reciprocal increases in serum rT3 and 3′,5′-T2 levels have also been reported.352 Such data, combined with the finding by some investigators of minimal increases in serum T4245 levels, suggest a mild blocking effect of this drug on the 5′-deiodination of iodothyronines. This effect does not appear to be related to the ß-adrenergic-blocking action of propranolol, since other ß-blocking agents do not share the deiodinase-blocking property and yet are effective in treating symptomatic thyrotoxicosis.353,354 The beneficial effects include the reduction of tachycardia, anxiety, and tremor 355-357 although the metabolic effects of thyrotoxicosis remain unaffected.
Reserpine. Reserpine formerly had wide use as an antihypertensive agent but has been replaced by more effective agents. Reserpine alters the manifestations of thyrotoxicosis by reducing anxiety, tachycardia, and tremulousness.358 This effect may arise from depression of autonomic centers or possibly from depletion of catecholamines in the peripheral tissues.359 Reserpine may depress the formation of iodotyrosines in thyroid tissue in vitro, but this action does not seem to be important clinically. Reserpine does not alter the results of thyroid function tests other than the BMR.358
Nitrophenols. 2,4-Dinitrophenol (Fig. 5-3) elevates the BMR, lowers the serum concentration of T4, accelerates the peripheral metabolism of T4, and depresses the thyroidal RAIU and secretion.275,360,361 The action is probably complex. The drug stimulates the metabolism by uncoupling oxidative phosphorylation in mitochondria.362 T4 in vitro also uncouples oxidative phosphorylation. Part of the effect of dinitrophenol may be to mimic the action of thyroid hormone on hypothalamic or pituitary receptor control centers; this effect would account for the diminished thyroid activity. Dinitrophenol also displaces thyroid hormone from T4-binding serum proteins.227 This action could lower the total hormone concentration in serum but should have no persistent effect on thyroid function. Dinitrophenol increases biliary and fecal excretion of T4, and this action largely accounts for the rapid removal of hormone from the circulation.363 Deiodination of T4 is also increased.364 Both of these effects may be related to displacement of hormone from TTR or to changes in metabolism of hormone in the liver.
2,4-Dinitrophenol does not share some of the most important properties of T4. It cannot initiate metamorphosis of tadpoles365 or provide a substitute for hormonal therapy in myxedema.
Dopaminergic Agents. It is generally accepted that endogenous brain dopamine plays a physiologic role in regulating TSH secretion via an effect on the hypothalamic-hypophyseal axis.252,366,367 Dopamine exerts a suppressive effect on TSH secretion and can be regarded as antagonistic to the stimulatory action of TRH at the pituitary level.284,287,367 Much of the information regarding the role of dopamine on the control of TSH secretion in humans has been derived from observations made during the administration of agents with dopamine-agonistic and -antagonistic activity (see Table 5-4 and Chapter 4).
Dopamine infusion is commonly used in the care of acutely ill hypotensive patients. It lowers the basal serum TSH level in both euthyroid and hypothyroid patients and blunts its response to the administration of TRH.252,284,287,368,368a
L-dopa, the precursor of dopamine, used in the treatment of Parkinson's disease and as a test agent in the diagnosis of pituitary diseases, also suppresses the basal and the TRH-stimulated serum TSH level in euthyroid subjects as well as in patients with primary hypothyroidism285,288,368b (Fig. 5-5). Metoclopropamide, a dopamine antagonist used as a diagnostic agent and in the treatment of motility disorders, increased TSH secretion. 368c
A similar effect has been observed during the administration of 2-brom-ergocryptine (bromocryptine), a dopamine agonist used in the treatment of some pituitary tumors and to suppress lactation during the puerperal period. Although the agent has been shown definitely to diminish the high serum TSH levels in patients with primary hypothyroidism,286 a significant inhibitory effect on TRH-induced TSH secretion has not been clearly demonstrated,369,370
The exact mechanism whereby dopaminergic drugs inhibit pituitary TSH secretion remains unknown, although a direct interaction with pituitary receptors has been suggested.371 While some authors have cautioned that prolonged infusion of dopamine may induce secondary hypothyroidism and worsen the prognosis of severely ill patients,372 there is no evidence that chronic treatment with dopaminergic drugs induces hypothyroidism in less critically ill patients.288 These drugs have been used with variable success in the treatment of some rare pituitary-induced thyrotoxicoses.373,374 When measurements of the basal or stimulated serum TSH levels are used in the differential diagnosis of primary and secondary hypothyroidism, the concomitant use of drugs with dopamine-agonistic or -antagonistic activity should be taken into account in the interpretation of results.
Alterations of Immunity
A number of drugs including interferon and lithium affected thyroid function either in part or completely by inducing thyroid immunity. In the past few years a number of agents have been developed to treat cancer and multiple sclerosis by altering immune regulation. Unintended side effects or these drugs has been the development of hyperthyroidism from Graves' disease or thyroiditis and hypothyroidism as a consequence of autoimmune hypophyisitis or chronic thyroiditis.
Interferon and Interleukin These cytokines have been associated with the development of both hypothyroidism and thyrotoxicosis. 375-379 The overall rate of thyroid dysfunction induced by these agents is about 6%.379a They are used in the treatment of infectious diseases such as hepatitis, as well as malignancies including melanoma and renal cell carcinoma . Acute administration has been used as a model of illness as the effects are similar; interferon-a leads to a decrease in T3 an increase in rT3 and a fall In TSH. 380 In a group of euthyroid HIV infected patients, however, short term administration of interleukin-2 was observed to lead to an increase in TSH, T3, T4 and free T4. 381
Cytokine induced thyroid disease appears to be immune mediated. The incidence is much greater in females and in patients with positive anti-peroxidase and anti-TPO antibodies prior to the initiation of therapy. 375-377 During therapy, patients who were antibody positive may have a rise in titer, while antibody positivity may develop in previously negative patients.375 In patients treated for hepatitis with interferon, the incidence of thyroid disease is much higher in those with Hepatitis C than those with Hepatitis B.375 The thyrotoxicosis often occurs as a manifestation of a destructive thyroiditis.376-377 In many patients, the thyroid disease resolves within several months after stopping the cytokine therapy. 375,377
Anti CD 52 Antibody Alemtuzumab This monoclonal antibody reacts against CD52, a glycoprotein that is expressed on B cells and CD4+ T cells. It is approved by the FDA for the treatment of multiple sclerosis. It is initially dosed daily for five days and then a second course is given for three days, one year later.
Thyroid disease has been noted to occur in a third of treated patients with some cases seen within weeks of initiating treatment and most cases seen within the first three years but cases have been seen up to seven years after starting treatment. 376a,376b,377a
The most frequently observed disorder has been Graves' disease which affects almost a quarter of all treated patients. 376a,376b,377a Most affect patients develop antibodies. Most cases are overt and some patients have experienced significant ophthalmopathy. While as many as 35% of these patients have been reported to have spontaneous resolution, most have been treated medically. Hypothyroidism develops in 5-7% of patients. Most of these patients develop anti-thyroid antibodies and the deficits are usually permanent. Less than 5 % of patients will develop typical painless thyroiditis with transient hyperthyroidism sometimes followed by hypothyroidism. 376a,376b,377a
Check Point Inhibitors
These agents target systems that normally act to limit activation of the immune system but are utilized by cancer cells to block immune mediated destruction. Use of these agents allows the activated immune cells to kill tumor cells. . 377b- 377d The same mechanism of action, however, leads to activation of immune mediated damage to other cells including skin, liver and thyroid cells. . 377b- 377d
Antibody against CTLA-4 ipilimumab Co-stimulation via HLA and B7 expressed on antigen presenting cells (and tumor cells) interacting respectively with T cell receptors and CD 28 expressed on T-cells leads to T-cell activation. Activated T-cells then express CTLA-4 that competes with CD 28 for B7 binding and thus reduces T cell activation. The monoclonal antibody, ipilmumab, specifically binds to CTLA-4 markedly enhancing T cell activation. 377b- 377d This promotes immune-mediated destruction of tumor cells. This agent was approved by the FDA for the treatment of melanoma in 2011. Usual dosing is every three weeks for four doses. The drug also remains under investigation for treating other tumors.
The most common associated autoimmune disorder affecting the thyroid has been the development of hypophyisitis. 377b- 377f Prior to the introduction of this agent, autoimmune hypophyisitis was typically seen in women in late pregnancy or post-partum, while hypophysitis secondary to ipilimumab has been seen almost solely in men. Onset has been within weeks of initiating therapy until almost two years later. 377b- 377f Most patients present with systemic symptoms while some present with headaches or visual symptoms. MRI abnormalities are common and include pituitary enlargement and stalk thickening. Similar to post-partum hypophyisitis, the pituitary-adrenal axis is most commonly affected, but most deficits are permanent. 377b- 377f
Hypothyroidism occurs in 4-6% of treated patients from 2 months to 3 years after starting treatment. Fatigue is the most common presenting symptom. The hypothyroidism is usually permanent. Some 1-3 % of treated patients will develop typical painless, thyroiditis with transient hyperthyroidism. Onset is usually two to four months after starting treatment. 377b- 377f Hyperthyroidism is sometimes followed by hypothyroidism. The package insert advises checking thyroid function prior to starting therapy, before each dose and as "clinically indicated'" but does not recommend checking cortisol or ACTH.
Antibodies Against Programmed Death Receptor Ligand (PDL-1) Pembrolizumab and Nivolumab Recognition of tumor cells via MHC/T cell receptor interaction leads to T cell activation and interferon production which stimulates tumor cell production of the PD-1 ligand. This then binds with the PD-1 receptor on the T cell and inhibits activation. Dendritic cells also express this ligand to inhibit T-cell activation. Pembrolizumab and Nivolumab are monoclonal antibodies directed against the PD1 ligand that act to increase T-cell activity and thus promote immune-mediated destruction of tumor cells. 377d, 377g These drugs were approved by the FDA in 2014 for the treatment of melanoma. Pembrolizumab is administered intravenously every 3 weeks. Nivolumab is administered intravenously every 2 weeks. These drugs also remains under investigation for treating other tumors.
Both agents may lead to the development of immune mediated hypothyroidism, thyroiditis and hypophysitis with hypothyroidism being the most common problem. 377g-377i Hypothyroidism may occur within weeks of starting therapy or may not occur until after a year. It is usually permanent. 377g-377i In contrast, reported cases of hyperthyroidism from thyroiditis have occurred from 2 weeks to 5 months after initiating therapy and always resolves. 377g-377i
For pembrolizumab the occurrence of these complications has been reported as 8% for hypothyroidism, 2-3% for thyroiditis and 0.5% for hypophyisitis. For nivolumab the rate of occurrence of these complications have been reported as 4-8% for hypothyroidism and 1-3% for thyroiditis. For both drugs, it is recommended to check thyroid function tests prior to starting therapy and periodically afterwards.
Tyrosine Kinase Inhibitors Sunitinib maleate an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and gastrointestinal stromal tumors has also been associated with the development of hypothyroidism.381a In two studies, an elevated TSH has been seen in over 50% of patients treated with sunitinib. 382.383 In a prospective study, this was persistent in 36% and transient in 17%. 382 The mechanism remains unknown. 382a Antiperoxidase activity was demonstrated in vitro382, but other mechanisms include induction of destructive thyroiditis, 383 reduction of vascularity ot the gland, 383b and enhanced apoptosis. 383c
The thyroid effects are seen with other TK inhibitors as well although the frequency and severity of the effect may vary. Hypothyroidism has also been seen with Sorafenib, but the rate is about 1/3 of that seen with sunitinib.383d,383e In a few patients, transient thryotoxicosis has preceeded the hypothyroidism consistent with a destructive thyroiditis. 383d There is also evidence for enhanced thyroid hormone metabolism attributed to increased Type 3 deiodination. 383f This would also explain the need for increased thyroid hormone doses in athyreotic thyroid cancer patients.
Imatinib mesylate is a selective tryrosine kinase inhibitor used in the treatment of chronic mylogenous leukemia (CML) and other malignancies. Thyroidectomized patients being treated with imatinib were noted to have a rise in TSH and a fall in serum T4 levels which responded to an increase in the T4 dose, suggesting enhanced metabolism of thyroid hormone 384 but changes have also been seen in euthyroid patients. 384a In most, cases, these changes were transient (74%) but have persisted in others. 384a Even higher rates of thyroid dysfunction have been seen with the newer agents nilotinib (55%) and dasatinib (75%). 384a As with the other TK inhibitors some patients have had thyrotoxicosis and some have developed antithyroid antibodies. 384a
Retinoids Bexarotene is a retinoid which is specific for the retinoid X- receptor and is used for the treatment of lymphomas and other malignancies. Therapy has been reported to produce central hypothyroidism 376a,376b,385, and a single dose, leads to a decrease in T3, T4 and TSH. 386 In addition to suppression of TSH synthesis and secretion, bexarotene also increases the peripheral metabolism of thyroid hormone by a nondeiodinase mediated pathway. 387
TSH Receptor Agonists and Antagonists A number of small molecules that interact with the TSH receptor were identified and characterized to select compounds which could behave as TSH receptor agonists or antagonists. 387 These were then further modified to increase their activity. Of note, these molecules do not bind to the TSH ligand binding region but rather to the serpentine trans-membrane region of the receptor. These compounds have multiple potential uses including use as imaging agents for thyroid cancer and Graves' ophthalmopathy and as therapeutic agents for patients with Graves' or thyroid cancer.
A TSH receptor agonist has been developed that when added to primary cultures of human thyrocytes increased messenger RNA expression for thyroglobulin, the sodium-iodide symporter, thyroid peroxidase (TPO), and deiodinase 2 similar to TSH. 388 When administered orally to mice, this compound increased radioactive iodine uptake in the thyroid and serum T4. 388 As an oral agent, this compound could potentially be used for imaging and treatment of thyroid cancer rather than parenteral rTSH or thyroid hormone withdrawal.
A TSH receptor antagonist has also been developed that has activity both in cells overexpressing the human TSH receptor and in primary cultures of human thyrocytes. 389 The compound reduces both basal and TSH stimulated cAMP production. Recently it was demonstrated in cultured human thyrocytes to reduce basal TPO mRNA expression and to antagonize the effect of sera from Graves' patients to induce TPO mRNA expression. 389 As an oral agent, this compound could potentially be used for imaging, to treat Graves' patients or to suppress thyroid cancer without requiring use of supraphysiologic T4 doses.
Thyronamines Thyronamines are small molecules identical to thyroxine, triiodothyronine and all of the deiodinated thyroid hormone metabolites except that they lack a carboxyl moiety at the amino terminus (ethylamine rather than alanine group). 390 Each compound is identified similar to the corresponding thyroid hormone or metabolite as TX(AM) where X is the number of iodine molecules and ranges from zero, T0(AM), to four, T4(AM). Two of these compounds, [3-T1(AM) and T0(AM)], have been identified by liquid chromatography-tandem mass spectrometry as naturally present in small amounts in tissues and sera from hamsters, mice and rats. 390 They have been detected in both cardiac and brain tissue. 390 No published report has confirmed the presence of any of these compounds in humans. It has been speculated that some of these compounds could be directly produced by the decarboxylation of T4 or T3, but this has never been demonstrated. These compounds can be deiodinated, in vitro, by Deiodinases 1, 2 and 3. 390
These compounds can bind to a number of receptors and 3-T1(AM) binds strongly to APO B 100 in serum. Despite the structural similarities to thyroid hormones, the thyronamines do not bind to nuclear thyroid hormone receptors and they do not alter T3 binding to these receptors. 390 Several thyronamines bind to the beta-adrenergic receptor, but any effects on cAMP signaling remain unclear. 390 There is conflicting evidence regarding the ability of these compounds to signal via the trace amine associated receptor 1 (TAAR-1) or via the Alpha2A adrenergic receptor. 390 There is also conflicting evidence about the ability of these compounds to alter intracellular signaling via the cAMP or tyrosine phosphorylation or dephosphorylation pathways. 390
There are no known physiologic actions of any of these compounds. In animals, several of these compounds have been found to have pharmacologic activity both in vitro and after intraperitoneal or intraventicular injection. These observations include a reduction in cardiac contractility and rate, a reduction in the metabolic rate, a reduction in fat mass and the development of hypothermia, ketonuria and hyperglycemia. 390 Many of these activities are noted within minutes after injection and resolve after a few hours but the development of ketonuria and the reduction of fat mass occur later and persist longer. 390 Potential therapeutic uses of these compounds are being evaluated in animal models. The ability of these compounds to induce hypothermia, has been shown to decrease infarct size when they were administered 2 days before or 1 hour after the induction of a stroke in an animal model. 390
Metformin Metformin is a biguanide used in the treatment of diabetes mellitus as well as insulin resistance and polycystic ovary syndrome. In four patients with hypothyroidism on stable thyroxine therapy, TSH levels became markedly reduced with either no change in serum thyroid hormone levels or despite a reduction in the T4 dose and serum thyroid hormone levels suggesting a direct suppression of TSH release. 388 Subsequent studies have reported mixed effects, but a meta-analysis conluded that TSH alterations are seen in both overt and sub-clinical hypothryoidism but not in euthyroid patients suggesting an effect to suppress TSH that is not seen when the thyroid gland is able to respond to any change in TSH. 388b
Biotin Biotin is a B vitamin that acts as a cofactor for carboxylase enzymes involved in gluconeogenesis and fatty acid synthesis. It is produced by gut bacrteria and normal daily intake is 35-350 mcg daily. It is used in the treatment of biotinidase deficiency and proprionic acidemia and as a supplement for TPN. It is frequently used by individuals in doses of 5,000 to 10,000 mcg daily as a supplement to improve hair and nail growth and to treat hair and nail disorders
Many laboratory platforms for the measurement of fT4, fT3 TSH and thyroglobulin depend on the strong binding of biotin and strep avidin. If patients ingest biotin in doses of 5,000 to 10,000 mcg prior to blood being drawn for these analytes, measurements of fT4 and fT3 will be falsely high and thyroglobulin and TSH will be falsely low as biotin interferes in the assays. . 397,398 The combination of a high fT4 and low TSH mimics hyperthyroidism. 397-400 These effects correspond to the blood level of biotin with a peak effect seen several hours after ingestion and potentially even lasting until the next day. 398,400 Variable times between ingestion and blood measurements can results in confusing variations in these measurement not corresponding to patents clinical status. Confirmation of this effect can be made by measuring several hours after ingestion and after abstaining for 48 hours or by re-measuring in an assay not utilizing biotin. 397-400 This effect is not limited to thyroid hormone measurements but have also been reported for PTH, DHEA-sulfate, estradiol and ferritin. 398
This chapter considers the effects of various environmental factors, drugs and chemicals, and nonthyroidal diseases on thyroid function.
In animals, cold exposure causes a prompt increase in TSH secretion, which gives rise to thyroid hormone release and leads to thyroid gland hyperplasia. Part of this effect is due to an apparent increase in the need for thyroid hormone by peripheral tissues and to an excessive rate of hormone degradation and excretion. In humans, hypothermia causes a dramatic TSH secretion in the newborn, but this response is lost after the first few years of life. Exposure to heat has an opposite effect, although of lesser magnitude. A small seasonal variation in serum thyroid hormone levels that follow this general pattern has been reported.
Simulated altitude and anoxia depress thyroid hormone formation in rats, but in humans serum T4 and T3 concentrations, T4 degradation, and oxygen consumption are at least temporarily augmented by high altitude.
Starvation has a profound effect on thyroid function, causing a decrease in serum T3 concentration and a reciprocal increase in rT3 level. These changes are due to a selective inhibition of the 5′-monodeiodination of iodothyronines by peripheral tissues. Reduction in carbohydrate intake rather than total calorie deprivation appears to be the determinant factor. These alterations in thyroid function are believed to reduce the catabolic activity of the organism and thus to conserve energy in the face of decreased calorie intake. Chronic malnutrition is accompanied by similar changes. Overfeeding has opposite although transient effects.
Physical and emotional stresses can have variable and opposite effects. Increased thyroid hormone secretion and serum levels have been observed in stressed animals and in acute psychiatric patients on admission. The physical stress of surgery causes a prompt decrease in the serum T3 concentration, probably as a consequence of decreased T3 neogenesis. This effect of surgery cannot be fully explained on the basis of increased adrenocortical activity or calorie deprivation.
Many minerals alter the synthesis of thyroid hormone, mainly through their interference with iodide concentration and binding by the thyroid gland. The action of iodine is only briefly covered here since it is discussed in Chapters 2 and 13. Calcium, nitrate, bromine, rubidium, and fluorine are allegedly goitrogenic. Lithium carbonate, used in the usual doses for the treatment of affective disorders, can produce goiter in susceptible persons. It inhibits iodide binding and hormonal release from the thyroid gland, probably through a synergistic action with iodide.
Numerous dietary goitrogens, including cyanogenic glucosides, thioglucosides, thiocyanate, and goitrin, are present in a wide variety of foods, and are believed to contribute to the occurrence of endemic goiter in some areas of the world. Monovalent anions such as thiocyanate and perchlorate inhibit iodide transport into the thyroid and cause goiter.
Thionamide drugs such as PTU and the related compound, methimazole, inhibit thyroid peroxidase and thus prevent thyroid hormone synthesis. In addition, PTU but not methimazole inhibits the conversion of T4 to T3 in peripheral tissues. Under appropriate circumstances, sulfonamides, sulfonylureas, salicylamides, resorsinol, amphenone, aminoglutethamide, antipyrine, aminotriazole, amphenidone, 2,3-dimercaptopropanolol, and phenylbutazone have antithyroid action.
A growing list of drugs and diagnostic agents have been found to affect thyroid economy by modulating the regulation of the hypothalamic-pituitary-thyroid axis, as well as by interfering with thyroid hormone transport, metabolism, excretion, and action. Some drugs, such as salicylates, diphenylhydantoin, and glucocorticoids, act at several levels. Several compounds, most notably estrogens, diphenylhydantoin, diazepam, heparin, halophenate, fenclofenac, and some biologically inactive thyroid hormone analogs compete with binding of thyroid hormone to its carrier proteins in serum. The only consequence of drugs affecting hormone transport is a decrease or increase in the concentration of total but not free hormone in serum.
Glucocorticoids, drugs such as propranolol, and amiodarone and some iodinated contrast media inhibit the extrathyroidal generation of T3. The result is a decrease in serum T3 and an increase in rT3 concentrations, with a slight increase or no change in T4 values. Thyroid hormone disposal is accelerated by diphenylhydantoin and phenobarbital, which increase several of the pathways of hormone degradation, and by hypolipemic resins, which increase the fecal loss of hormone. Homeostasis is usually maintained by a compensatory increase in thyroid hormone secretion.
Some drugs act through inhibition or stimulation of TSH secretion. Most notable of the former effect are dopamine agonists such as L-dopa and bromocryptine, as well as some -adrenergic blockers, glucocorticoids, acetylsalicylic acid, and opiates. A variety of dopamine antagonists as well as cimetidine, clomifene, and spirolactone appear to increase TSH secretion. These compounds seem to interfere with the normal dopaminergic suppression of the hypothalamic-pituitary axis. Observed changes in TSH secretion are not associated with significant metabolic alterations. Some of the drugs have an apparent effect on TSH secretion through changes induced at the levels of the free and active forms of the thyroid hormone. A handful of drugs appear to block or antagonize the action of thyroid hormone on tissues. These drugs include guanethidine, propranolol, and dinitrophenol. Some drugs may induce autoimmune thyroid disease. Notably among these are lithium, interferon, interleukin, alemtuzumab. prembrolizumab and nivolumab.
The clinician should be thoroughly familiar with the effects of drugs, nonthyroidal illnesses, and other extraneous factors on thyroid function. These factors should all be taken into account in the differential diagnosis of primary thyroid disease.
- Bernstein G, Oppenheimer JH: Factors influencing the concentration of free and total thyroxine in patients with nonthyroidal disease. J Clin Endocrinol Metab 26:195, 1966.
1a. Silva JE, Larsen PR: Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats. J Clin Invest 76:2296-,1985.
1b. Hackney AC, Feith S, Pozos R, Seale J: Effects of high altitude and cold exposure on resting thyroid hormone concentrations. Aviat Space Environ Med 66:325-9,1995.
1c. Hackney AC, Hogdon JA, Hesslink R Jr, Trygg K: Thyroid hormone responses to military winter exercise in the Arctic region. Arctic Med Res 54:82-90,1995.
- Wilber JF, Baum D: Elevation of plasma TSH during surgical hypothermia. J Clin Endocrinol Metab 31:372-375, 1970.
- Fisher DA, Odell WD: Acute release of thyrotropin in the newborn. J Clin Invest 48:1670, 1969.
- Fisher DA, Oddie TH: Neonatal thyroidal hyperactivity. Response to cooling. Am J Dis Child 107:574, 1964.
- Hershman JM, Read DG, Bailey AL, Norman VD, Gibson TB: Effect of cold exposure on serum thyrotropin. J Clin Endocrinol Metab 30:430, 1970.
- Nagata H, Izumiyama T, Kamata K, et al: An increase of plasma triiodothyronine concentration in man in a cold environment. J Clin Endocrinol Metab 43:1153, 1976.
- Golstein-Golaire J, Van Haelst L, Bruno OD, Leclercq R, Copinschi G: Acute effects of cold on blood levels of growth hormone, cortisol, and thyrotropin in man. J Appl Physiol 29:622, 1970.
7a. Reed HL: Environmental Influences on thyroid hormone regulation. pp259-265 in Werner and Ingbar's The Thyroid , Seventh Edition Braverman LE, Utiger RD eds. JB Lippincot Philadelphia 1996.
7b. McCormack PD, Reed HL, Thomas JR, Malik MJ: Increase in rT3 levels observed during extended Alaskan field operations of Naval personnel. Alaska Med 38:89-97,1996.
7c. Van Do N, Mino L., Merriam G, LeMAr H, Case HS, Palinkas LA, Reedy K, Reed HL: Elevation in serum thyroglbulin during prolonged Antarctic residence: Effect of thyroxine supplement in the polar 3,5,3'-triidothyronine syndrome. J Clin Endocrinol Metab 89:1529-1533,2004
7d Reed HL, Silverman ED, Shakir KM et al: Changes in serum triodothyronine (T3) kinetics after prolonged antarctic residence: the polar T3 syndrome. J Clin Endocrinol Metab 70:965-,1990
- Balsam A, Sexton FC: Increased metabolism of iodothyronines in the rat after short-term cold adaptation. Endocrinology 97:385, 1975.
- Bernal J, Escobar del Rey F: Effect of the exposure to cold on the extrathyroidal conversion of L-thyroxine to triiodo-L-thyronine, and on intramitochondrial -glycerophosphate dehydrogenase activity in thyroidectomized rats on L-thyroxine. Acta Endocrinol 78:481, 1975.
9a. Tsukahara F, Uchida Y, Ohba K, Nomoto T, Muraki T: Defective stimulation of thyroxine 5'-deiodinase activity by cold exposure and norepinephrine in brown adipose tissue of monosodium glutamate-obese mice. Horm Metab Res 29:496-500,1997.
9b. Margarity M, Valcana T Effect of cold exposure on thyroid hormone metabolism and nuclear bindng in rat brain. Neurochem Res 24:423-6, 1999
- DuRuisseau JP: Seasonal variation of PBI in healthy Montrealers. J Clin Endocrinol Metab 25:1513, 1965.
- Smals AGH, Ross HA, Kloppenborg PWC: Seasonal variation in serum T3 and T4 levels in man. J Clin Endocrinol Metab 44:998, 1977.
- Panda JN, Turner CW: Effect of thyroidectomy and low environmental temperature (4.4C) upon plasma and pituitary thyrotrophin in the rat. Acta Endocrinol 54:485, 1975.
- Emerson CH, Utiger RD: Plasma thyrotropin-releasing hormone concentrations in the rat. J Clin Invest 56:1564, 1975.
- Andersson B: Hypothalamic temperature and thyroid action. C. F. S. G. 18 (eds), Brain-THyroid Relationships, pp. 35-50,1964.
- Montoya E, Seibel MJ, Wilber JF: Thyrotropin-releasing hormone secretory physiology: studies by radioimmunoassay and affinity chromatography. Endocrinology 96:1413, 1975.
- Szabo M, Frohman LA: Suppression of cold-stimulated thyrotropin secretion by antiserum to thyrotropin-releasing hormone. Endocrinology 101:1023, 1977.
- Hefco E, Krulich L, Illner P, Larsen PR: Effect of acute exposure to cold on the activity of the hypothalamic-pituitary-thyroid system. Endocrinology 97:1185, 1975.
- Jobin M, Ferland L, Coté J, Labrie F: Effect of exposure to cold on hypothalamic TRH activity and plasma levels of TSH and prolactin in the rat. Neuroendocrinology 18:204, 1975.
- Melander A, Rerup C: Studies on e thyroid activity in the mouse. Acta Endocrinol 58:202, 1968.
- Yamada T, Kajihara A, Onaya T, Kobayashi I, Takemura Y, Shichijo K: Studies on acute stimulatory effect of cold on thyroid activity and its mechanism in the guinea pig. Endocrinology 77:968, 1965.
- Balsam A Leppo, L.E.: Augmentation of the peripheral metabolism of L-triiodothyronine and L-thyroxine after acclimation to cold. Multifocal stimulation of the binding of iodothyronines by tissues. J Clin Invest 53:980, 1974.
- Galton VA, Nisula BC: Thyroxine metabolism and thyroid function in the cold-adapted rat. Endocrinology 85:79-, 1969.
22a. Puigserver p, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:892-39,1998.
- Epstein Y, Udassin R, Sack J: Serum 3,5,3′-triiodothyronine and 3,3′,5′-triiodothyronine concentrations during acute heat load. J Clin Endocrinol Metab 49:677, 1979.
- Ljunggren JG, Klalner G, Tryselius M: The effect of body temperature on thyroid hormone levels in patients with nonthyroidal illness. Acta Med Scand 202:459, 1977.
- O'Malley BP, Davies TJ, Rosenthal FD: TSH responses to temperature in primary hypothyroidism. Clin Endocrinol 13:87, 1980.
- Rastogi GK, Malhotra MS, Srivastava MC, et al: Study of the pituitary-thyroid functions at high altitude in man. J Clin Endocrinol Metab 44:447, 1977.
- Moncloa F, Guerra-Garcia R, Subauste C, Sobrevilla LA, Donayre J: Endocrine studies at high altitude. I. Thyroid function in seal level natives exposed for two weeks to an altitude of 4,300 meters. J Clin Endocrinol Metab 26:1237, 1966.
- Surks MI, Beckwitt HJ, Chidsey CA: Changes in plasma thyroxine concentration and metabolism, catecholamine excretion, and basal oxygen consumption in man during acute exposure to high altitude. J Clin Endocrinol Metab 27:789, 1967.
28a. Mordes JB, Blume FD, Boyer et al: High-altitude pituitary-thyroid dysfunction on Mount everest. N Engl J Med 308:1135-,1983.
28b. Ramirez G, Herrera R, Pineda D, Bittle PA, Rabb HA, Bercu BB: The effects of high altitude on hypothalamic-pituitary secretory dynamics in man. Clin Endocrinol (oxf) 43:11-18,1995.
- Mulvey PF, Macaione JMR: Thyroidal dysfunciton during simulated altitude conditions. Fed Proc 23:1243, 1969.
- Surks MI: Effect of hypoxia and high altitude on thyroidal iodine metaoblism in the rat. Endocrinology 78:307, 1966.
- Surks MI: Effect of thyrotropin on thyroidal iodine metabolism during hypoxia. Am J Physiol 216:436, 1969.
- Pazo JH, Houssay AB, Davison TA, Chait RJ: On the mechanism of the thyroid hypertrophy in pinealectomized rats. Acta Physiol Lat Am 18:332, 1968.
- Singh DV, Turner CW: Effect of light and darkness upon thyroid secretion rate and on the endocrine glands of female rats. Proc Soc Exp Biol Med 131:1296, 1969.
33a. Shavali SS, Haldar C: Effects of continuous light, continuous darkness and pinealectomy on pineal-thyroid-gonadal axis of the female Indian palm squirrel, Funambulus pennati. J Neurol Transm 105:407-13,1998.
- Singh DV, Narang GD, Turner CW: Effect of melatonin and its withdrawal on thyroid hormone secretion rate of female rats. J Endocrinol 43:489, 1969.
34a. Uchiyama M, Ishibashi K, Enomoto T, Nakajima T, Shibui K, Hirokawa G, Okawa M: Twenty-four hour profiles of four hormones under constant routine. Psychiatry Clin Neurosci 52:241-3,1998.
- Martino E, Seo H, Lernmark A, Refetoff S: Ontogenetic pattern of thyrotropin-releasing hormone-like material in rat hypothalamus, pancreas and retina: Selective effect of light deprivation. Proc Natl Acad Sci 77:4345, 1980.
35a. Allan JS, Czeisler CA: Persistence of the circadian thyrotropin rhythmn under constant conditions and after light-induced shifts of circadian phase. J Clin Endocrionol Metab 79:508-,1994.
- Portnay GI, O'Brian JT, Bush J, al: The effect of starvation on the concentration and binding of thyroxine and triiodothyronine in serum and on the response to TRH. J Clin Endocrinol Metab 39:191-194, 1974.
- Merimee TJ, Fineberg ES: Starvation-induced alterations of circulating thyroid hormone concentrations in man. Metabolism 25:79, 1976.
- Carlson HE, Drenick EJ, Chopra IJ, Hershman JM: Alterations in basal and TRH-stimulated serum levels of thyrotropin, prolactin, and thyroid hormones in starved obese men. J Clin Endocrinol Metab 45:707, 1977.
- Azizi F: Effect of dietary composition on fasting-induced changes in serum thyroid hormones and thyrotropin. 27:935-942, 1978.
- Scriba PC, Bauer M, Emmert D, et al: Effects of obesity, total fasting and re-alimentation of L-thyroxine (T4), 3,5,3′-L-triiodothyronine (T3), 3,3′,5′-L-triiodothyronine (rT3), thyroxine binding globulin (TBG), cortisol, thyrotrophin, cortisol binding globulin (CBG), transferrin, 2-haptoglobin and complement C'3 in serum. 91:629-643, 1979.
40a. Alvero R, Kimzey L, Sebring N, Reynolds J, Loughran M, Nieman L, Olson BR: Effects of fasting on neuroendocrine function and follicle development in lean women. JCEM 83:76-80,1998.
40b. Byerly LO, Heber D: Metabolic effects of triiodothyronine replacement during fasting in obese subjects. JCEM 81:968-76,1996.
- Vagenakis AG, Portnay GI, O'Brian JT, et al: Effect of starvation on e production and metabolism of thyroxine and triiodothyronine in euthyroid obese patients. J Clin Endocrinol Metab 45:1305, 1977.
- Suda AK, Pittman CS, Shimizu T, Chambers JB Jr.: The production and metabolism of 3,5,3′-triiodothyronine and 3,3′,5′-triiodothyronine in normal and fasting subjects. J Clin Endocrinol Metab 47:1311, 1978.
- Stokholm KH: Decrease in serum free triiodothyronine, thyroxine-binding globulin and thyroxine-binding prealbumin whilst taking a very-low-calorie diet. Int J Obest 4:133, 1980.
- Balsam A, Ingbar SH: The influence of fasting, diabetes, and several pharmacological agents on the pathways of thyroxine metabolism in rat liver. J Clin Invest 62:415, 1978.
- Chopra IJ, Geola F, Solomon DH, Maciel RMB: 3′,5′-diiodothyroxine in health and disease: Studies by a radioimmunoassay. J Clin Endocrinol Metab 47:1198-1207, 1978.
- Chopra IJ: A radioimmunoassay for measurement of 3′-monoiodothyronine. J Clin Endocrinol Metab 51:117-123, 1980.
- Pangaro L, Burman KD, Wartofsky L, et al: Radioimmunoassay for 3,5-diiodothyronine and evidence for dependence on conversion from 3,5,3′-triiodothyronine. J Clin Endocrinol Metab 50:1075-1081, 1980.
47a. Van der Geyten S, Van Rompaey E, Sanders JP, Visser TJ, Kuhn ER, Darras VM : Regulation of thyroid hormone metabolism during fasting and refeeding in chicken. Gen Comp Endocrinol 116:272-80,1999
- Pittman CS, Shimizu T, Burger A, Chambers JB Jr.: The nondeiodinative pathways of thyroxine metabolism: 3,5,3′,5′-tetraiodothyroacetic acid turnover in normal and fasting human subjects. J Clin Endocrinol Metab 50:712-716, 1980.
- Balsam A, Ingbar SH: Observations on the factors that control the generation of triiodothyronine from thyroxine in rat liver and the nature of the defect induced by fasting. J Clin Invest 63:1156, 1979.
- Chopra IJ: Alterations in monodeiodination of iodothyronines in the fasting rat: Effects of reduced nonprotein sulfhydryl groups and hypothyroidism. Metabolism 29:161, 1980.
- Gavin LA, McMahon FA, Moeller M: Dietary modification of thyroxine deiodination in rat liver is notmediated by hepatic sulfhydryls. J Clin Invest 65:943, 1980.
- Burman KD, Dimond RC, Harvey GS, et al: Glucose modulation of alterations in serum iodothyronine concentrations induced by fasting. Metabolism 28:291, 1979.
- Danforth E, Sims EAH, Horton ES, Goldman RF: Correlation of serum triiodothyronine concentrations with dietary composition. Diabetes 24:406, 1975.
- Harris ARC, Fang SL, Vagenakis AG, Braverman LE: Effect of starvation, nutriment replacement, and hypothyroidism on in vitro hepatic T4 to T3 conversion in the rat. Metabolism 27:1680, 1978.
- Burger AG, Berger M, Wimpfheimer K, Danforth E: Interrelationships between energy metabolism and thyroid hormone metabolism during starvation in the rat. Acta Endocrinol 93:322, 1980.
- Gardner DF, Kaplan MM, Stanley CA, Utiger RD: Effect of triiodothyronine replacement on the metabolic and pituitary responses to starvation. N Engl J Med 300:579, 1979.
- Silva JE, Dick TE, Larsen PR: The contribution of local tissue thyroxine monodeiodination to nuclear 3,5,3′-triiodothyronine in pituitary, liver and kidney of euthyroid rats. Endocrinology 103:1196, 1978.
- Cheron RG, Kaplan MM, Larsen PR: Physiological and pharmacological influences on thyroxine to 3,5,3′-triiodothyronine conversion and nuclear 3,5,5′-triiodothyronine binding in rat anterior pituitary. J Clin Invest 64:1402, 1979.
58a. Diano S, Naftolin F, Goglia F, Horvath TL: Fating-induced increase in Type II iodothyronine deiodinase activity and messenger ribonucleic acid levels is not reversed by thyroxine in the rat hypothalamus. Edocrinology 139:2879-84,1998.
- Harris ARC, Fang SL, Azizi F, Lipworth L, Vagenakis AG, Braverman LE: Effect of starvation on hypothalamic-pituitary-thyroid function in the rat. Metabolism 27:1074, 1978.
- Morley JE, Russell RM, Reed A, Carney EA, Hershman JM: The interrelationship of thyroid hormones with vitamin A and zinc nutritional status in patients with chronic hepatic and gastrointestinal disorders. Am J Clin Nutr 34:1489, 1981.
60a. von Haasteren GA, Linkels E, van Toor H, Klootwijk W, Kaptein E, de Jong FH, Reymond MJ, Visser TJ, de Greef WJ: Effects of long term food reduction on the hypothalamic-pituitary-thyroid axis in male and female rats. J Endocrinol 150:169-78,1996.
60b. von Haasteren GA, Linkels E, Klootwijk W, van Toor H, Rondeel JM, Themmen AP, de Jong FH, Valentijn K, Vaudry H, Bauer K, et al: Starvation induced changes in the hypothalamic content of prothyrotropin-releasing hormone (proTRH) mRNA and the hypothalmic release of proTRH derived peptides:role of the adrenal gland. J Endocrinol 145:143-53,1995.
- Shambaugh GE III, Wilber JF: The effect of caloric deprivation upon thyroid function in the neonatal rat. Endocrinology 94:1145, 1974.
- DeGroot LJ, Coleoni AH, Rue PA, Seo H, Martino E, Refetoff S: Reduced nuclear triiodothyronine receptors in starvation-induced hypothyroidism. Biochem Bioophys Res Commun 79:173, 1977.
62a. Tagami T, Nakamura H, Sasaki S, Miyoshi Y, Nakao K: Starvation-induced decrease in the maximal binding capacity for triiodothyronine of the thyroid hormone receptor due to a decrease on the receptor protein. Metabolism 45:970-3,1996.
- Schussler GC, Orlando J: Fasting decreases triiodothyronine receptor capacity. Science 199:686, 1978.
- Buergi V, Larsen PN: Nuclear triiodothyronine binding in mononuclear leukocytes in normal subjects and obese patients before and after fasting. J Clin Endocrinol Metab 54:1199, 1982.
- Jung RT, Shetty PS, James WPT: Nutritional effects on thyroid and catecholamine metabolism. Clin Sci 58:183, 1980.
- Huang HS, Pittman CS: Effects of thyroid hormone evaluated by cardiac systolic time interval in fasted subjects. J Formosan Med Ass 83:1087-93, 1994.
- Vignati L, Finley RJ, Haag S, Aoki TT: Protein conservation during prolonged fast: a function of triiodothyronine levels. Trans Assoc Am Physicians 16:169, 1978.
- Carter WJ, Shakir KM, Hodges S, Faas FH, Wynn JO: Effect of thyroid hormone on metabolic adaptation to fasting. Metabolism 24:1177, 1975.
- Wartofsky L, Burman D: Alterations in thyroid function in patients with systemic illness: The "euthyroid sick syndrome". Endocr Rev 3:164, 1982.
- Ingenbleek Y, Malvaux P: Peripheral turnover of thyroxine and related parameters in infant protein-calorie malnutrtion. Am J Clin Nutr 33:609, 1980.
- van der Westhuyzen JM: Plasma-T3 assay in Kwashiorkor. Lancet 2:965, 1973.
- Chopra IJ, Smith SR: Circulating thyroid hormones and thyrotropin in adult patients with protein-calorie malnutrition. J Clin Endocrinol Metab 40:221, 1975.
72a. Orbak Z, Akin Y, Varoglu E, Tan H: Serum thyroid hormone and thyroid gland weight measurements in protein-energy malnutrition. J Pediatr Endocrinol Metab 11:719-24,1998.
72b. Turkay S, Kus S, Gokalp A, Baskin E, Onal A: Effects of protein energy malnutrition on circulating thyroid hormones. Indian Pediatr 32:193-7,1995.
- Ingenbleek Y, Beckers C: Thyroidal iodide clearance and radioiodide uptake in protein-calorie malnutriton. Am J Clin Nutr 31:408, 1978.
- Pimstone B, Becker D, Hendricks S: TSH response to synthetic thyrotropin-releasing hormone in human protein-calorie malnutrition. J Clin Endocrinol Metab 36:779, 1973.
- Tulp OL, Krupp PP, Danforth E Jr., Horton ES: Characteristics of thyroid function in experimental protein malnutrion. J Nutr 109:1321, 1979.
- Falconer IR, Marchant B: Thyroxine utilization in lambs in natural and controlled environments. J Endocrinol 46:363, 1970.
- Danforth E Jr.,, Horton ES, O'Connell M, et al: Dietary-induced alterations in thyroid hormone metabolism during overnutrition. J Clin Invest 64:1336, 1979.
- Bray GA, Fisher DA, Chopra IJ: Relation of thyroid hormones to bodyweight. Lancet 1:1206, 1976.
- Glass AR, Burman KD, Dahms WT, Boehm TM: Endocrine function in human obesity. Metabolism 30:89, 1981.
- Robison LM, Sylvester PW, Birkenfeld P, Lang JP, Bull RJ Comparison of the effects of iodine and iodide on thyroid functioinn in humans. J Toxicol Environ Health 55:93-106,1998.
80a. Uyttersprot N, Pelgrims N, Carrasco N, Gervy C, Maenhaut C, Dumont JF, Miot F: Moderate doses of iodid in vivo inhibit cell proliferation and the expression of thyroperoxidase and the Na+/I- symporter mRNAs in dog thyroid. Moll Cell Endocrinol 131:195-203,1997.
80b. Pregliasco L, Bocanera L, Krawiec L, Siberschmidt D, Pisarev M, Juvenal G: Effects of iodid on thyroglobulin biosynthesis in FRTL-5 cells. Thyroid 6:319-23,1996
- Vagenakis AG, Downs P, Braverman LE, Burger A, Ingbar SH: Control of thyroid hormone secretion in normal subjects receiving iodides. J Clin Invest 52:528, 1973.
- Vagenakis AG, Rapoport B, Azizi F, et al: Hyper-response to thyrotropin-releasing hormone accompanying small decreases in serum thyroid hormone concentration. J Clin Invest 54:913-918, 1974.
82a. Vitale M, DiMatola T, D"Ascoli F, Salzano S, Bogazzi F, Frnzi G, Martino E, Rossi G. Iodide excess induces apoptosis through a p53 independent mechanism involving oxidative stress. Endocrinology 141:598-605, 2000
82b. Burikhanov RB, Matsuzaki S. Excess iodine induces apoptosis in the thyroid of goitrogen-pretreated rats in vivo. Thyroid 10:123-9,2000
- Braverman LE, Ingbar SH, Vagenakis AG, Adams L, Maloof F: Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J Clin Endocrinol Metab 32:515, 1971.
- Braverman LE, Woeber KA, Ingbar SH: Induction of myxedema by iodide in patients euthyroid after radioiodine or surgical treatment of diffuse toxic goiter. N Engl J Med 281:816, 1969.
- Azizi F, Bentley D, Vagenakis A, et al: Abnormal thyroid function and response to iodides in patients with cystic fibrosis. Trans Assoc Am Physicians 87:111, 1974.
- Begg TB, Hall R: Iodide goitre and hypothyroidism. Q J Med 32:351, 1963.
- Pasternak DP, Socolow EL, Ingbar SH: Synergistic interaction of phenazone and iodide on thyroid hormone biosynthesis in the rat. Endocrinology 84:769, 1969.
- Shopsin B, Shenkman L, Blum M, Hollander CS: Iodine and lithium-induced hypothyroidism. Documentation of synergism. Am J Med 55:695, 1973.
- Milne K, Greer MA: Comparison of the effects of propylthiouracil and sulfadiazine on thyroidal biosynthesis and the manner by which they are influenced by supplemental iodide. Endocrinology 71:580, 1962.
- Vagenakis AG, Ingbar SH, Braverman LE: The relationship between thyroglobulin synthesis and intrathyroid iodine metabolism as indicated by the effects of cycloheximde in the rat. Endocrinology 94:1669, 1974.
90a. Stanbury JB, Ermans AE, Bourdoux T, Todd C, Oken E, Tonglet R,Vidor G, Braverman LE, Medeiros-Neto G: Iodine induced hyperthyroidism: occurrence and epidemiology. Thyroid 8:83-100,1998.
- Jackson AS: Iodine hyperthyroidism: An analysis of fifty cases. Boston Med Surg J 193:1138, 1925.
- Vidor GI, Stewart JD, Wall JR, Wangel A, Hetzel BS: Pathogenesis of iodide induced thyrotoxicosis: Studies in northern Tasmania. J Clin Endocrinol Metab 37:901, 1973.
- Ermans AM, Camus M: Modifications of thyroid function induced by chronic administration of iodide in the presence of "autonomous" thyroid tissue. Acta Endocrinol 70:463, 1972.
- Vagenakis AG, Wang CA, Burger A, et al: Iodide-induced thyrotoxicosis in Boston. N Engl J Med 287:523-527, 1972.
- Suzuki H, Higuchi T, Sawa K, Ohtaki S, Horiuchi Y: "Endemic coast goitre" in Hokkaido, Japan. Acta Endocrinol 50:161, 1965.
- Wartofsky L: Low remission after therapy for Graves' disease: Possible relation of dietary iodine with antithyroid therapy results. JAMA 226:1083, 1973.
- Boyle JA, Greig WR, Fulton S, Dalakos TG: Excess dietary calcium and human thyroid function. J Endocrinol 34:532, 1966.
97a. Singh N, Singh PN, Hershman JM: Effect of calcium carbonate on the absorption of levothyroxine. JAMA 283:2822-5,2000
97b. Singh N, Weisler, SL, Hershman JM The acute effect of calcium carbonate on the intestinal absoprption of levothyroxine. Thyroid 11:967-971; 2001
- Bloomfield RA, Welsch CW, Garner GB, Muhrer ME: Effect of dietary nitrate on thyroid function. Science 134:1690, 1961.
- Clode W, Sobral JM, Baptista AM: Bromine interference in iodine metabolism and its goitrogenic action. R. Pitt-Rivers (eds), Advances in Thyroid Research, Pergamon Press, New York, pp. 65,1961.
99a. Vobecky M, Babicky A, Lerner J, Svandova E: Interaction of bromine with iodine in the rat thyroid gland at enhanced bromide intake. Biol Trace elem Res 54:207-12,1996.
99b. Velicky J, Titlbach M, Duskova J, Vobecky M, Strbak V, Raska I: Potassium bromide and the thyroid gland of the rat:L morphology and immunohistochemistry, RIA and INAA analysis. Anat Anz 179:421-31,1997.
- Bach I, Braun S, Gati T, Kertai P, Sós J, Udvardy A: Effect of rubidium on the thyroid. R. Pitt-Rivers (eds), Advances in Thyroid Research, Pergamon Press, New York, pp. 505,1961.
- Galletti PM, Joyet G: Effect of fluorine on thyroidal iodine metaoblism in hyperthyroidism. J Clin Endocrinol Metab 18:1102, 1958.
- Gedalia I, Brand N: The relationship of fluoride and iodine in drinking water in the occurrence of goiter. Arch Int Pharmacodyn Ther 142:312, 1963.
- Siddiqui AH: Incidence of simple goitre in areas of endemic fluorosis. J Endocrinol 20:201, 1960.
- Day TK, Powell-Jackson PR: Fluoride water hardness, and endemic goiter. Lancet 1:1135, 1972.
- Paley KR, Sobel ES, Yalow RS: Effect of oral and intravenous cobaltous chloride on thyroid function. J Clin Endocrinol Metab 18:850, 1958.
105a. Stangl GI, Schwartz FJ, Kirchgessner M. Cobalt deficiency effects on trace elements, hormones and enzymes involved in energy metabolsim in cattle. Int J Vitam Nutr Res 69:120-6,1999
105b. Barceloux, DG. Cobalt. J Toxicol Clin Toxicol 37:201-6,1999
- Pimentel-Malaussera E, Roche M, Lavrisse M: Treatment of eight cases of hyperthyroidism with cobaltous chloride. JAMA 167:1719, 1958.
106a. Gupta P, Kar A: Role of ascorbic acid in cadmium-induced thyroid dysfunction and lipid peroxidation. J Appl Toxicol 18:317-20,1998.
106b. Paier B, Pavia MA Jr, Hansi C, Noli MI, Hagmuller K, Zaninovich AA: Cadmium inhibits the in vitro conversion of thyroxine to triiodothyronine in rat brown adipose tissue. Bull Environ Contam Toxicol 59:164-70,1997.
106c. Gupta P, Chaurasia SS, Maiti PK, Kar A: Cadmium induces alterations in extrathyroidal conversion of thyroxine to triiodothyronine 5" monodeiodinase in male mouse. Horm Metab Res 29:151-2,1997
- Pousset GB J., Berthezene F, Tourniare J, Devic M: Myxoedeme au lithium. Ann Endocrinol 34:549, 1973.
- Berens SC, Bernstein RS, Robbins J, Wolff J: Antithyroid effects of lithium. J Clin Invest 49:1357, 1970.
- Spaulding SW, Burrow GN, Bermudez F, Himmelhoch JM: The inhibitory effect of lithium on thyroid hormone release in both euthyroid and thyrotoxic patients. J Clin Endocrinol Metab 35:905, 1972.
- Carlson HE, Temple R, Robbins J: Effect of lithium on thyroxine disappearance in man. J Clin Endocrinol Metab 36:1251, 1973.
110a. Lazarus, JH. The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. Thyroid 8:909-13,1998.
110b. Tasevski V, Been D, King M, Luttrell B, Simpson A: Mitogenic effects in FRTL-5 cells can be reversed by blocking de novo cholesterol synthesis and subsequent signal transduction. Thyroid 2000:305-11, 2000.
- Burman KD, Diamond RC, Earll JM, Wright FD, Wartofsky L: Sensitivity to lithium in treated Graves' disease: Effects on serum T4, T3 and reverse T3. J Clin Endocrinol Metab 43:606, 1976.
- Blomqvist N, Lindstedt G, Lundberg PA, Walinder J: No inhibition by Li+ of thyroxine monodeiodination to 3,5,3′-triiodothyronine and 3,3′,5′-triiodothyronine (reverse triiodothyronine). Clin Chim Acta 79:457, 1977.
- Linquette M, Lefebre J, Van Parys C, Wemeau JL: Le lithium dans le traitement des thyrotoxicoses. Ann d'Endocrinol 39:15, 1978.
- Andersen BF: Iodide perchlorate discharge test in lithium-treated patients. Acta Endocrinol 73:35, 1973.
- Berens SC, Wolff J, Murphy DL: Lithium concentration by the thyroid. Endocrinology 87:1085, 1970.
- Wolff J, Berens SC, Jones AB: Inhibition of thyrotropin-stimulated adenyl cyclase activity of beef thyroid members by low concentration of lithium ion. Biochem Biophys Res Commun 39:77, 1970.
- Bhattacharya B, Wolff J: Stabilization of microtubules by lithium ion. Biochem Biophys Res Commun 73:383, 1976.
117a. Baumgartner A, Pinna G, Hiedra L, Gaio U, Hessenius C, Campos-Barros A, Eravci M, Prengel H, Thoma R, Meinhold H. Effects of lithium and carbamazapine on thyroid hormone metabolism in rat brain. Neuropsychopharmacology 16:25-41,1997.
117b. Hahn CG, Pawlyk AC, Whybrow, PC Gyulai L, Tejani-Butt SM. Lithium administration affects gene expression of thyroid hormone receptors in rat brain. Life Sci 64:1793-802, 1999
- Lazarus JH, Joh R, Bennie EH, et al: Lithium therapy and thyroid function: A long term study. Psych Med 11:85-92, 1981.
118a. Kirov G. Thyroid disorders in lithium-treated patients. J Affect Disord 50:33-40,1998
118b. Johnston AM, Eagles JM. Lithium-associated hypothyroidism. Prevalence and risk factors. Br J Psychiatry 175:336-9,1999
118c. Kusalic M, Engelsmann F. Effect of lithium maintenance therapy on thyropid and parathyroid function. J Psychatry Neurosci 24:227-33,1999
- Segal RL, Rosenblatt S, Eliasoph I: Endocrine exophthalmos during lithium therapy of manic-depressive disease. N Engl J Med 289:136, 1973.
119a. Berry MJ, Banu L, Larsen PR: Type I iodothyronine deiodinase is a selenocystein-containing enzyme. Nature 349:438-,1991.
119b. Olivieri O, Girelli D, Stanzial AM, Rossi L, Bassi A, Corrocher R: Selenium, zinc and thyroid hormones in healthy subjects: low T3/T4 ratio in the elderly is related to selenium status. Biol Trace Elem Res 51:31-41,1996.
119c Duntas LH: Selenium and the thyroid: A close knit connection. JCEM 95:5180-5188, 2010
119d. Hotz CS, Fitzpatrick DW, Trick KD, L'Abbe MR: Dietary iodine and selenium interact to affect thyroid hormone metabolism. J Nutr 127:1214-8,1997
119e. Mitchell JH, Nicol F, Beckett GJ, Arthur JR: Selenium and iodine deficiencies: effects on brain and brown adipose tisse seleneoenzyme activity and expression. J Endocrinol 155:255-63,1997
119f. Zimerman MB, Adou P, Torresani T, Zeder C, Hurrell RF. Effect of iodized oil on thyroid size and thyroid hormone metabolism with concurrent selenium and iodine deficiency. Eur J Clin Nutr. 54:209-13, 2000
119f. Wu O, Rayman MP, Lv H, Schomburg L, Cui B, Gao C er al: Low population selenium status is associated with increased prevalence of thyroid disease. J Clin Endocrinol Metab 100:4037-4047, 2015
- Kracht J: Fright-thyrotoxicosis in the wild rabbit, a model of thyrotrophic alarm-reaction. Acta Endocrinol 15:355, 1954.
- Falconer IR, Hetzel BS: Effect of emotional stress and TSH on thyroid vein hormone level in sheep with exteriorized thyroids. Endocrinology 75:42, 1964.
- Haibach H, McKenzie JM: Increased free thyroxine postoperatively in the rat. Endocrinology 81:435, 1967.
- Hagenfeldt I, Melander A, Thorell J, Tibblin S, Westgren U: Active and inactive thyroid hormone levels in elective and acute surgery. Acta Chir Scand 145:77, 1979.
- Chan V, Wang C, Yeung RTT: Pituitary-thyroid responses to surgical stress. Acta Endocrinol 88:490, 1978.
- Socolow EL, Woeber KA, Purdy RH, Holloway MT, Ingbar SH: Preparation of I131 labeled human serum prealbumin and its metabolism in normal and sick patients. J Clin Invest 44:1600, 1976.
- Brandt MR, Skovsted L, Kehlet H, Hansen JM: Rapid decrease in plasma-triiodothyronine during surgery and epidural analgesia independent of afferent neurogenic stimuli and of cortisol. Lancet 2:1333, 1976.
- Tingley JO, Morris AW, Hill SR, Pittman JA: The acute thyroid response to emotional stress. Ala J Med Sci 2:297, 1965.
- Cohen KL, Swigar ME: Thyroid function screening in psychiatric patients. JAMA 242:254, 1979.
- Levy RP, Jensen JB, Laus VG, Agle DP, Engel IM: Serum thyroid hormone abnormalities in psychiatric disease. Metabolism 30:1060, 1981.
- Spratt DI, Pont A, Miller MB, McDougall IR, Bayer MF, McLaughlin WT: Hyperthyroxinemia in patients with acute psychiatric disorders. Am J Med 73:41, 1982.
- Chesney AM, Clawson TA, Webster B: Endemic goitre in rabbits. I. Incidence and characteristics. Johns Hospkins Hosp Bull 43:261, 1928.
- Ermans AM, Delange F, Van Der Velden M, Kinthaert J: Possible role of cyanide and thiocyanate in the etiology of endemic cretinism. J. B. Stanbury and R. L. Kroc (eds), Human Development and the Thyroid Gland. Relation to Endemic Cretinism, Plenum Press, New York, pp. 455,1972.
- Monekasso GL, Wilson J: Plasma thiocyanate and vitamin B12 in Nigerian patients with degenerative neurological disease. Lancet 1:1062, 1971.
- Delange F, Ermans AM: Role of a dietary goitrogen in the etiology of endemic goiter on Idjwi Island. Am J Clin Nutr 24:1354, 1971.
- Delange F, Thilly C, Ermans AM: Iodine deficiency, a permissive condition in the development of endemic goiter. J Clin Endocrinol Metab 28:114, 1968.
- Langer P, Greer MA: Antithyroid activity of some naturally occurring isothiocyanates in vitro. Metabolism 17:596, 1968.
- Langer P: Antithyroid action in rats of small doses of some naturally occurring compounds. Endocrinology 79:1117, 1966.
137b Chu M, Selzer TF: Myxedema coma induced by ingestion of raw bok choy. New Engl J Med 362:1945-1946, 2010
- Clements FW, Wishart JW: A thyroid-blocking agent in the etiology of endemic goiter. Metabolism 5:623, 1956.
- Peltola P: The goitrogenic effect of milk obtained from the region of endemic goitre in Finland. R. Pitt-RIvers (eds), Advances in Thyroid Research, Pergamon Press, New York, pp. 10,1961.
- Peltola P, Krusius FE: Effect of cow's milk from the goitre endemic district of Finland on thyroid function. Acta Endocrinol 33:603, 1960.
- Kilpatrick R, Broadhead GD, Edmonds CJ, Munro DS, Wilson GM: Studies on goitre in the Sheffield region. R. Pitt-Rivers (eds), Advances in Thyroid Research, Pergamon Press, New York, pp. 273,1961.
141a. Laurberg P, Andersen S, Knudsen N, Ovesen L, Nohr SB, Pedersen IB: THiocyanate in food and iodine in milk: From domestic animal feeding to improved understanding of cretinism. Thyroid 12:897-902; 2002
141b. Charatchaoenwitthaya N, Ongphiphadhanakul B, Pearce EC, Charintip S, Chanthasenanont A, He X, Chailurkit L and Braverman LE: The association between perchlorate and thiocyanate exposure and thyroid function in first trimester pregnant Thai women J Clin Endocrinol Metab 99:2365-2371, 2014
- Astwood EB, Greer MA, Ettlinger MG: L-5-Vinyl-2-thiooaxazolidone, an antithyroid compound from yellow turnip and from bassica seeds. J Biol Chem 181:121, 1949.
- Greer MA: The isolation and identification of progoitrin from bassica seed. Arch Biochem Biophys 99:369, 1962.
- Langer P, Michajlovskij N: Studies on the antithyroid activity of naturally occurring L-5-vinyl-2-thiooxazolidone and its urinary metabolite in rats. Acta Endocrinol 62:21, 1969.
- Krusius FE, Peltola P: The goitrogenic effect of naturally occurring L-5-vinyl- and L-5-phenyl-2-thio-oxazolidone in rats. Acta Endocrinol 53:342, 1966.
- Arstila A, Krusius FE, Peltola P: Studies on the transfer of thio-oxazolidone-type goitrogens into cow's milk in goiter endemic districts of Finland and in experimental conditions. Acta Endocrinol 60:712, 1969.
- Barzelatto J, Beckers C, Stevenson C, et al: Endemic goiter in Pedgregoso (Chile). I. Description and fuction studies. Acta Endocrinol 54:577, 1967.
- Linazasoro JM, Sanchez-Martin JA, Jiminez-Diaz C: Goitrogenic effect of walnuts. Lancet 2:501, 1966.
- Gaitan E, Wahner HW, Correa P, et al: Endemic goiter in the Cauca Valley: I. Results and limitations of twelve years of iodine prophylaxis. J Clin Endocrinol Metab 28:1730, 1968.
149a. Abel Gadir WS, Adam SE: Development of goitre and enterohepatonephropathy in Nubian Goats fed with pearl millet (pennisetum typhoides) Vet J 157: 178-85,1999
- McCarrison R: The goitrogenic action of soybean and ground-nut. Indian J Med Res 21:179, 1933.
- Van Wyk JJ, Arnold MB, Wynn J, Pepper F: The effects of a soybean product on thyroid functions in humans. Pediatrics 24:752-760, 1959.
- Pinchera A, MacGillivray MH, Crawford JD, Freeman AG: Thyroid refractoriness in an athyrotic cretin fed soybean formula. N Engl J Med 273:83-86, 1965.
- Yamada T: Effect of fecal loss of thyroxine on pituitary-thyroid feedback control in the rat. Endocrinology 82:327, 1968.
- Bray GA: Increased sensitivity of the thyroid in iodine-depleted rats to the goitrogenic effects of thyrotropin. J Clin Invest 47:1640, 1968.
- Bull GM, Fraser R: Myxedema from resorcinol ointment applied to leg ulcers. Lancet 1:851, 1950.
- Selenkow HA, Rivera A, Thorn GW: The effects of amphenone on thyroid function in man. J Clin Endocrinol Metab 17:1131, 1957.
- Pittman JA, Brown RW: Antithyroid and antiadrenocortical activity of aminoglutethimide. J Clin Endocrinol Metab 26:1014, 1966.
- Rallison ML, Kumagai LF, Tyler FH: Goitrous hypothyroidism induced by aminoglutethmide, anticonvulsant drug. J Clin Endocrinol Metab 27:265, 1967.
- Jukes TH, Shaffer CB: Antithyroid effects of aminotriazole. Science 132:296, 1960.
- Pittman JA, Brown RW: Antithyroid action of amphenidone. J Clin Endocrinol Metab 22:100, 1962.
- Current JV, Hales IB, Dobyns BM: The effect of 2,3-dimercaptopropanol (BAL) on thyroid function. J Clin Endocrinol Metab 20:13, 1960.
- Sharpe AR Jr.: Inhibition of thyroidal 131I uptake by parabromdylamine maleate. J Clin Endocrinol Metab 21:739, 1961.
- Linsk JA, Paton BC, Persky M, Isaacs M, Kupperman HS: The effect of phenylbutazone and a related analogue (G25671) upon thyroid function. J Clin Endocrinol Metab 17:416, 1957.
- Wyngaarden JB, Stanbury JB, Rapp B: The effects of iodide, perchlorate, thiocyanate, and nitrate administration upon the iodide concentrating mechanism of the rat thyroid. Endocrinology 52:568, 1953.
- Ermans AM, Goossens F: Influence du perchlorate et du methimazol sur l'excretion urinaire de l'iode chez l'homme. Arch Int Pharmacodyn Ther 132:487, 1961.
- Stewart RDH, Murray IPC: An evaluation of the perchlorate discharge test. J Clin Endocrinol Metab 26:1050, 1966.
- Scranton JR, Nissen WM, Halmi NS: The kinetics of the inhibition of thyroidal iodide accumulation by thiocyanate: A reexamination. Endocrinology 85:603, 1969.
- Frohman LA, Klocke FJ: Recurrent thiocyanate intoxication, with pancytopenia, hypothyroidism, and psychosis. N Engl J Med 268:701, 1963.
- Taurog A, Potter GD, Chaikoff IL: Conversion of inorganic 131I to organic 131I by cell free preparations of thyroid tissue. J Biol Chem 213:119, 1955.
- Anbar M, Guttman S, Lewitus Z: Effect of monofluorosulphanate, difluorophosphate, and F borate ions on the iodine uptake of the thyroid gland. Nature 183:1517, 1959.
- Anbar M, Guttman S, Lewitus Z: The accumulation of fluoroborate ions in thyroid glands of rats. Endocrinology 66:888, 1960.
- Chow SY, Chang LR, Yen MS: A comparison between the uptakes of radioactive perchlorate and iodide by rat and guinea-pig thyroid glands. J Endocrinol 45:1, 1969.
- Crooks J, Wayne EJ: A comparison of potassium perchlorate, methylthiouracil, and carbimazole in the treatment of thyrotoxicosis. Lancet 1:401, 1960.
- Michajlovskij N, Langer P: Increase of serum free thyroxine following the administration of thiocyanate and other anions in vivo and in vitro. Acta Endocrinol 75:707-716, 1974.
174a. Li FX, Squartsoff L, Lamm SH: Prevalence of thyroid disease in Nevada counties with respect to perchlorate in drinking water. J Occup Environ Med 43:630-4;2001
174b Pearce EN, Lazarus JH, Smyth PPA, He X, Dall'amico D, et al: Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women. JCEM 945:3207-3215, 2010
174c. Morgan JW, Cassady RE: Community cancer assessment in response to long-time exposure to perchlorate and trichloroethylene in drinking water. J Occup Environ Med 44:616-21;2002
174d. Kelsh MA, Buffler PA, Daaboul JJ, Rutherford GW, Lau EC, Barnard JC, Exuzides AK, Madl AK, Palmer LG, Lorey FW: Primary congenital hypothyroidism, newborn thyroid function, and environmental perchlorate exposure among residents of a Southern California community. J Occup Environ Med 45:1116-27;2003
- Rosenberg IN: The antithyroid activity of some compounds that inhibit peroxidase. Science 116:503, 1952.
- DeGroot LJ, Davis AM: Studies on the biosynthesis of iodotyrosines: A soluble thyroidal iodide-peroxidase tyrosine-iodinase system. Endocrinology 70:492, 1962.
- Yamazaki E, Noguchi A, Slingerland DW: Effect of methylthiouracil and iodide on the iodinated constitutents of thyroid tissue in Graves' disease. J Clin Endocrinol Metab 20:889, 1960.
- Iino S, Yamada T, Greer MA: Effect of graded doses of propylthiouracil on biosynthesis of thyroid hormones. Endocrinology 68:582, 1961.
- Mulvey PF Jr., Slingerland DW: The in vitro stimulation of thyroidal activity by propylthiouracil. Endocrinology 70:7, 1962.
- Selenkow HA, Collaco FM: Clinical pharmacology of antithyroid compounds. Clin Pharmacol Ther 2:191, 1961.
- Astwood EB: Mechanisms of action of various antithyroid compounds. Ann NY Acad Sci 50:419, 1949.
- Maloff F, Spector L: The desulfuration of thiourea by thyroid cytoplasmic particulate fractions. J Biol Chem 234:949, 1959.
- Maloof F, Soodak M: Cleavage of disulfide bonds in thyroid tissue by thiourea. J Biol Chem 236:1689, 1961.
- Mitchell ML, Sanchez-Martin JA, Harden AB, O'Rourke ME: Failure of thiourea to prevent hormone synthesis by the thyroid gland of man and animals treated with TSH. J Clin Endocrinol Metab 21:157, 1961.
- Mayberry WE, Astwood EB: The effect ofpropylthiouracil on the intrathyroid metaoblism of iodine in rats. J Biol Chem 235:2977, 1960.
- Escobar del Rey F, Morreale de Escobar G: The effect of propylthiouracil, methylthiouracil and thiouracil on the peripheral metabolism of L-thyroxine in thyroidectomized L-thyroxine maintained rats. Endocrinology 69:456-465, 1961.
- Van Middlesworth L, Jones SL: Interference with deiodination of some thyroxine analogues in the rat. Endocrinology 69:1085, 1961.
- Escobar del Rey F, Morreale de Escobar G, Garcia-Garcia MD, Mouriz Garcia J: Increased secretion of thyrotrophic hormone in rats with a depressed peripheral deiodination of thyroid hormone and a normal or high plasma PBI. Endocrinology 71:859, 1962.
- Slingerland DW, Burrows BA: Inhibition by propylthiouracil of the peripheral metabolism of radiothyroxine. J Clin Endocrinol Metab 22:511, 1962.
- Furth ED, Rives K, Becker DV: Nonthyroidal action of propylthiouracil in euthyroid, hypothyroid, and hyperthyroid man. J Clin Endocrinol Metab 26:239-246, 1966.
- Oppenheimer JH, Schwartz HL, Surks MI: Propylthiouracil inhibits the conversion of L-thyroxine to L-triiodothyronine. An explanation of the antithyroxine effect of propylthiouracil and evidence supporting the concept that triiodothyronine is the active hormone. J Clin Invest 51:2493-2497, 1972.
- Stasilli NR, Kroc RL, Edlin R: Selective inhibition of the calorigenic activities of certain thyroxine analogues with chronic thiouracil treatment in rats. Endocrinology 66:872, 1960.
- Bray GA, Hildreth S: Effect of propylthiouracil and methimazole on the oxygen consumption of hypothyroid rats receiving thyroxine or triiodothyronine. Endocrinology 81:1018, 1967.
- Ruegamer WR, Warren JS, Barstow M, Beck W: Effects of thiouracil on rat liver alpha-glycerophosphate dehydrogenase and serum PBI responses to L-thyroxine. Endocrinology 81:277, 1967.
- Chopra IJ, Solomon DH, Chopra U, Wu SY, Fisher DA, Nakamura Y: Pathways of metabolism of thyroid hormones. Recent Prog Horm Res 34:521, 1978.
- Pittman JA, Beschi RJ, Smitherman TC: Methimazole: Its absorption and excretion in man and tissue distribution in rats. J Clin Endocrinol Metab 33:182, 1971.
- Marchant B, Alexander WD, Lazarus JH, Lees J, Clark DH: The accumulation of 35S antithyroid drugs by the thyroid gland. J Clin Endocrinol Metab 34:847, 1972.
- Krieger DT, Moses A, Ziffer H, Gabrilove JL, Soffer LJ: Effect of acetazoleamide on thyroid metabolism. Am J Physiol 196:291, 1959.
- Gabrilove JL, Alvarez AA, Soffer LJ: Effect of acetazoleamide (Diamox) on thyroid function. J Appl Physiol 13:491, 1958.
- Brown J, Solomon DH: Mechanism of antithyroid effects of a sulfonylurea in the rat. Endocrinology 63:473, 1958.
- Tranquade RE, Solomon DH, Brown J, Greene R: The effect of ora hypoglycemic agents on thyroid function in the rat. Endocrinology 67:293, 1960.
- Nikkilä EA, Jakobson T, Josipii SG, Karlsson K: Thyroid function in diabetic patients under long-term sulfonylurea treatment. Acta Endocrinol 33:623, 1960.
- Skinner NS Jr., Hayes RL, Hill SR Jr.: Studies on the use of chlorpropamide in patients with diabetes mellitus. Ann NY Acad Sci 74:830, 1959.
- Hunton RB, Wells MV, Skipper EW: Hypothyroidism in diabetics treated with sulphonylurea. Lancet 2:449, 1965.
- Hershman JM, Konerding K: Effects of sulfonylurae drugs on the thyroid and serum protein binding of thyroxine in the rat. Endocrinology 83:74, 1968.
205a. Hagmer L: Polychlorinated biphenyls and thyroid status in humans: a review. Thyroid 13:1021-1028;2003
- Azizi F, Vagenakis AG, Portnay GI, et al: Thyroxine transport and metabolism in methadone and heroin addicts. Ann Intern Med 80:194-199, 1974.
- McKerron CG, Scott RL, Asper SP, Levy RI: Effects of clofibrate (Atromid S) on the thyroxine-binding capacity of thyroxine-binding globulin and free thyroxine. J Clin Endocrinol Metab 29:957-961, 1969.
- Beex L, Ross A, Smals P, Kloppenborg P: 5-Fluorouracil-induced increase of total thyroxine and triiodothyronine. Cancer Treat Rep 61:1291-1295, 1977.
- Oltman JE, Friedman S: Protein-bound iodine in patients receiving perphenazine. JAMA 185:726-727, 1963.
- Garnick MB, Larsen PR: Acute deficiency of thyroxine-binding globulin during L-asparaginase therapy. N Engl J Med 301:252-253, 1979.
210a. Cashin-Hemphill L, Spencer CA, Nocoloff JT, et al: Alterations in serum thyroid hormonal indices with colestipol-niacin therapy. Ann Intern Med 107:324-329, 1987.
210b. O'Brien T, Silverberg JD, Nguyen TT: Nicotinic-acid-induced toxicity associated with cytopenia and decreased levels of thyroxine-binding globulin. Mayo Clin Proc 67:465-468, 1992.
- Stockigt JR, Lim CF, Barlow JW, et al: Interaction of furosemide with serum thyroxine-binding sites: In vivo and in vitro studies and comparison with other inhibitors. J Clin Endocrinol Metab 60:1025-1031, 1985.
- Hollander CS, Scott RL, Burgess JA, et al: Free fatty acids: A possible regulator of free thyroid hormone levels in man. J Clin Endocrinol Metab 27:1219-1223, 1967.
- Tabachnick M, Hao YL, Korcek L: Effect of oleate, diphenylhydantoin, and heparin on the binding of 125I-thyroxine to purified thyroxine-binding globulin. J Clin Endocrinol Metab 36:392-394, 1973.
- Marshall JS, Tompkins LS: Effect of o,p'-DDD and similar compounds on thyroxine binding globulin. J Clin Endocrinol Metab 28:386-392, 1968.
- Abiodun MO, Bird R, Havard CW, Sood NK: The effects of phenylbutazone on thyroid function. Acta Endocrinol 72:257-264, 1973.
- Davis PJ, Hsu TH, Bianchine JR, Morgan JP: Effects of a new hypolipidemic agent, MK-185, on serum thyroxine-binding globulin (TBG) and dialysable fraction thyroxine. J Clin Endocrinol Metab 34:200-208, 1972.
- Taylor R, Clark F, Griffiths ID, Weeke J: Prospective study of effect of fenclofenac on thyroid function tests. Br J Med 281:911-912, 1980.
- Wiersinga WM, Fabius AJ, Touber JL: Orphenadrine, serum thyroxine and thyroid function. Acta Endocrinol 86:522-532, 1977.
- Pages RA, Robbins J, Edelhoch H: Binding of thyroxine and thyroxine analogs to human serum prealbumin. Biochemistry 12:2773-2779, 1973.
- Oppenheimer JH: Role of plasma proteins in the binding, distribution, and metabolism of the thyroid hormones. N Engl J Med 278:1153-1162, 1968.
- Man EB, Reid WA, Hellegers AE, Jones WS: Thyroid function in human pregnancy. III. Serum thyroxine-binding prealbumin (TBPA) and thyroxine-binding globulin (TBG) of pregnant women aged 14 through 43 years. Am J Obstet Gynecol 103:338, 1969.
- Glinoer D, Fernandez-Deville M, Ermans AM: Use of direct thyroxine-binding gloublin measurement in the evaluation of thyroid function. J Endocrinol Invest 1:329-335, 1978.
- Braverman LE, Ingbar SH: Effects of norethandrolone on the transport in serum and peripheral turnover of thyroxine. J Clin Endocrinol Metab 27:389-396, 1967.
- Graham RL, Gambrell RD: Changes in thyroid function tests during danazol therapy. Obstet Gyneocl 55:395-397, 1980.
224a. Draper MW, Flowers, DE, Neild JA, Huster WJ, Zerbe RL: Antiestrogenic properties of raloxifene. Pharmacology 50:209-17,1995
224b. Groonroos PE, Irjala KM, Selen GP, Forsstrom JJ: Computerized monitoring of potentially interfering medication in thyroid function diagnostics. Int j Clin Monit Comput 14:255-9,1997
224c. Amberson J, Drinka PJ: Medication and low serum thyroxine values in nursing home residents. South Med J 91:437-40,1998
- Austen FK, Rubini ME, Meroney WH, Wolff J: Salicylates and thyroid function. I. Depression of thyroid function. J Clin Invest 37:1131-1143, 1958.
- Wolff J, Austen FK: Salicylates and thyroid function. II. The effect on the thyroid-pituitary interrelation. J Clin Invest 37:1144-1165, 1958.
- Christensen LK: Thyroxine-releasing effect of salicylate and of 2,4-dinitrophenol. Nature 183:1189-1190, 1959.
- Larsen PR: Salicylate-induced increases in free triiodothyronine in human serum: Evidence of inhibition of triiodothyronine binding to thyroxine-binding globulin and thyroxine-binding prealbumin. J Clin Invest 51:1125-1134, 1972.
- Oppenheimer JH, Tavernetti RR: Displacement of thyroxine from human thyroxine-binding globulin by analogues of hydantoin. Steric aspects of the thyroxine-binding site. J Clin Invest 41:2213-2220, 1962.
- Schatz DL, Sheppard RH, Steiner G, et al: Influence of heparin on serum free thyroxine. J Clin Endocrinol Metab 29:1015-1022, 1969.
- Hershman JM, Jones CM, Bailey AL: Reciprocal changes in serum thyrotropin and free thyroxine produced by heparin. J Clin Endocrinol Metab 34:574, 1972.
231a. Jaume JC, Mendel CM, Frost PH, Greenspan FS, Laughton CW: Extremely low doses of heparin release lipase activity into the plasms and can thereby cause artifactual elevations in the serum-free thyroxine concentration as measured by equilibrium dialysis. Thyroid 6;79-83,1996
231b. Stevenson HP, Archbold GP, Johnston P, Young IS, Sheridan B: Misleading serum free thyroxine results during low molecular weight heparin treatment. Clin Chem 44:1002-7,1998
- Dowling JT, Frienkel N, Ingbar SH: The effect of estrogens upon the peripheral metabolism of thyroxine. J Clin Invest 39:1119-1130, 1974.
- Refetoff S, Fang VS, Marshall JS, Robin NI: Metabolism of thyroxine-binding globulin (TBG) in man: Abnormal rate of synthesis in inherited TBG deficiency and excess. J Clin Invest 57:485-495, 1976.
- Schlienger JL, Kapfer MT, Singer L, Stephan F: The action of clomipramine on thyroid function. Horm Metab Res 12:481-482, 1980.
- Rootwelt K, Ganes T, Johannessen SI: Effect of carbamazapine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans. Scand J Clin Lab Invest 38:731-736, 1978.
- Northcutt RC, Stiel MN, Nollifield JW, Stant EG Jr.: The influence of cholestyramine on thyroxine absorption. JAMA 208:1857-1861, 1969.
- Witztum JL, Jacobs LS, Schonfeld G: Thyroid hormone and thyrotropin levels in patients placed on colestipol hydrochloride. J Clin Endocrinol Metab 46:838-840, 1978.
- Isley WL: Effect of rifampin therapy on thyroid function tests in a hypothyroid patient on replacement L-thyroxine. Ann Int Med 107:517-518, 1987.
238a. Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong, NC: Ferrous sulfate reduces thyroxine efficacy in patietns with hypothyroidism. Ann Intern Med 117:1010-3,1992
238b. Liel Y, Sperber AD, Shany S: Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide. AM J Med 97:363-5,1994.
238c. Sherman SI, Tielens ET, Ladenson PW: Sucralfate causes malabsorption of L-thyroxine. Am J Med 96:531-5,1994.
- Chopra IJ, Williams DE, Orgiazzi J, Solomon DH: Opposite effects of dexamethasone on serum concentrations of 3,3′,5′-triiodothyronine (reverse T3) and 3,3′,5-triiodothyronine (T3). J Clin Endocrinol Metab 41:911-920, 1975.
- Duick DS, Warren DW, Nicoloff JT, et al: Effect of a single dose of dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab 39:1151-1154, 1974.
- Burger A, Dinichert D, Nicod P, et al: Effects of amiodarone on serum triiodothyronine, reverse triiothyronine, thyroxine and thyrotropin. J Clin Invest 58:255-259, 1976.
- Savoie JC, Massin JP, Thomopoulos P, Leger F: Iodine-induced thyrotoxicosis in apparently normal thyroid glands. J Clin Endocrinol Metab 41:685-691, 1975.
- Lotti G, Delitala G, Devilla L, Alagna S, Masala A: Reduction of plasma triiodothyronine induced by propranolol. Clin Endocrinol 6:405, 1977.
- Faber J, Kirkegaard C, Lumholtz IB, et al: Measurements of serum 3′,5′-diiodothyronine and 3,3′-diiodothyronine concentrations in normal subjects and in patients with thyroid and nonthyroid disease: Studies of 3′,5′-diiodothyronine metabolism. J Clin Endocrinol Metab 48:611-617, 1979.
- Wiersinga WM, Touber JL: The influence of ß-adrenoreceptor blocking agents on plasma thyroxine and triiodothyronine. J Clin Endocrinol Metab 45:293-298, 1977.
- Re RN, Kourides IA, Ridgway EC, et al: The effect of glucocorticoid administration on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab 43:338-346, 1976.
- Larsen PR, Atkinson AJ, Wellman HN, Goldsmith RE: The effect of diphenylhydantoin on thyroxine metabolism in man. J Clin Invest 49:1266-,1279, 1970.
- Schwartz HL, Kozyreff V, Surks MI, Oppenheimer JH: Increased deiodination of L-thyroxine and L-triiodothyronine by liver microsomes from rats treated with phenobarbital. Nature 221:1262-1263, 1969.
- Schwartz HL, Bernstein G, Oppenheimer JH: Effect of phenobarbital administration on the subcellular distribution of 125I-thyroxine in rat liver: Importance of microsomal binding. Endocrinology 84:270, 1969.
- Blum C, Corvette C, Beckers C: Effect of insulin induced hypoglycemia on thyroid function and thyroxine turnover. Eur J Clin Invest 3:124, 1973.
- Johnstone RE, Kennel EM, Brummond W Jr., Shaw LM, Ebersole RC: Effect of halothane anesthesia on muscle, liver, thyroid, and adrenal-function tests in man. Clin Chem 22:217, 1976.
- Scanlon MF, Weightman DR, Shale DJ, et al: Dopamine is a physiological regulator of thyrotropin (TSH) secretion in normal man. Clin Endocrinol 10:7-15, 1979.
- Scanlon MF, Rodriguez-Arnao MD, Pourmand M, et al: Catecholaminergic interactions in the regulation of thyrotropin (TSH) secretion in man. J Endocrinol Invest 3:125-129, 1980.
- Delitala G, Devilla L, Lotti G: Domperidone, an extracerebral inhibitor of dopamine receptors, stimulates thyrotropin and prolactin release in man. J Clin Endocrinol Metab 50:1127-1130, 1980.
- Massara F, Camanni F, Belforte L, et al: Increased thyrotropin secretion induced by sulpiride in man. Clin Endocrinol 9:419-428, 1978.
- Delitala G, Devilla L, Lotti G: TSH and prolactin stimulation by the decarboxylase inhibitor benserazide in primary hypothyroidism. Clin Endocrinol 12:313-316, 1980.
- Kirkegaard C, Bjoerum CN, Cohn D, et al: Studies of the influence of biogenic amines and psychoactive drugs on the prognostic value of the TRH stimulation test in endogeneous depression. Psychoneuroendocrinology 2:131-136, 1977.
- Kirkegaard C, Bjoerum N, Cohn D, Lauridsen UB: TRH stimulation test in manic-depressive illness. Arch Gen Psychiatry 35:1017-1021, 1978.
- Nelis GF, Van DeMeene JG: The effect of oral cimetidine on the basal and stimulated values of prolactin, thyroid stimulating hormone, follicle stimulating hormone and luteinizing hormone. Postgrad Med J 56:26-29, 1980.
- Feldt-Rasmussen U, Lange AP, Date J, Kern-Hansen M: Effect of clomifen on thyroid function in normal men. Acta Endocrinol 90:43-51, 1979.
- Smals AG, Kloppenborg PW, Hoefnagesl WH, Drayer JM: Pituitary-thyroid function in spirolactone treated hypertensive women. Acta Endocrinol 90:577-584, 1979.
- Morley JE, Shafer RB, Elson MK, et al: Amphetamine-induced hyperthyroxinemia. Ann Int Med 93:707-709, 1980.
- Gloebel B, Weinheimer B: TRH-test during D-T4 application. Nuc-Compact 8:44, 1977.
- Medeiros-Neto G, Kallas WG, Knobel M, et al: Triac (3,5,3′-triiodothyroacetic acid) partially inhibits the thyrotropin response to thyrotropin-releasing hormone in normal and thyroidectomized hypothyroid patients. J Clin Endocrinol Metab 50:223-225, 1980.
- Emrich D: Untersuchungen zum einfluss von Etiroxat-HCL auf den Jodstoffwechsel beim menschen. Arzneim Forsch 27:422-426, 1977.
- Tamagna EI, Hershman JM, Jorgensen EC: Thyrotropin suppression by 3,5-dimethyl-3′-isopropyl-L-thyronine in man. J Clin Endocrinol Metab 48:196-200, 1979.
- Yoshimura M, Hachiya T, Ochi Y, et al: Suppression of elevated serum TSH levels in hypothyroidism by fusaric acid. J Clin Endocrinol Metab 45:95-98, 1977.
- Delitala G, Rovasio P, Lotti G: Suppression of thyrotropin (TSH) and prolactin (PRL) release by pyridoxine in chronic primary hypothyroidism. J Clin Endocrinol Metab 45:1019-1022, 1977.
- Masala A, Delitala G, Devilla L, et al: Effect of apomorphine and peribedil on the secretion of thyrotropin and prolactin in patients with primary hypothyroidism. Metabolism 27:1608-1612, 1978.
- Delitala G, Wass JAH, Stubbs WA, et al: The effect of lisurgide hydrogen maleate, an ergot derivative on anterior pituitary hormone secretion in man. Clin Endocrinol 11:1-9, 1979.
- Nilsson KO, Thorell JI, Hökfelt B: The effect of thyrotrophin releasing hormone on the release of thyrotrophin and other pituitary hormones in man under basal conditions and following adrenergic blocking agents. Acta Endocrinol 76:24-34, 1974.
- Lamberg BA, Linnoila M, Fogelholm R, et al: The effect of psychotropic drugs on the SH-response to thyroliberin (TRH). Neuroendocrinology 24:90-97, 1977.
- Delitala G, Rovasio PP, Masala A, et al: Metergoline inhibition of thyrotropin and prolactin secretion in primary hypothyroidism. Clin Endocrinol 8:69-73, 1978.
- Ferrari C, Paracchi A, Rondena M, et al: Effect of two serotonin antagonists on prolactin and thyrotropin secretion in man. Clin Endocrinol 5:575-578, 1976.
- Collu R: The effect of TRH on the release of TSH, PRL and GH in man under basal conditions and following methysergide. J Endocrinol Invest 2:121-124, 1978.
- Yoshimura M, Ochi Y, Miyazaki T, et al : Effect of intravenous and oral administration of L-DOPA on HGH and TSH release. Endocrinol Jpn 19:543-548, 1972.
- Porter BA, Refetoff S, Rosenfield RL, et al: Abnormal thyroxine metabolism in hyposomatotrophic dwarfism and inhibition of responsiveness to TRH during GH therapy. Pediatrics 51:668-674, 1973.
- Siler TM, Yen SS, Guillemin R: Inhibition by somatostatin on the release of TSH induced in man by thyrotropin-releasing factor. J Clin Endocrinol Metab 38:742, 1974.
- Weeke J, Hansen AP, Lundbaek K: Inhibition by somatostatin of basal levels of serum thyrotropin (TSH) in normal men. J Clin Endocrinol Metab 41:168-171, 1975.
279a. Colao A, Merola B, Ferone D, Marzullo P, Cerbone G, Longbardi S, Di Somma C, Lombardi G: Acute and chronic effects of octreotide on thyroid axis in growth hormone-secreting and clinically non-functional pituitary adenomas. Eur J Endocrinol 133:189-94,1995
- Thomas JA, Shahid-Salles KS, Donovan MP: Effects of narcotics on the reproduction system. Avd Sex Horm Res 3:169-195, 1977.
- May P, Mittler J, Manougian A, Erte N: TSH release-inhibiting activity of leucine-enkephaline. Horm Metab Res 11:30-33, 1979.
- Chan V, Wang C, Yeung RT: Effects of heroin addiction on thyrotropin, thyroid hormones and prolactin secretion in men. Clin Endocrinol 10:557-565, 1979.
- Kobayashi I, Shimomura Y, Maruta S, et al: Clofibrate and a related compound suppress TSH secretion in primary hypothyroidism. Acta Endocrinol 94:53-57, 1980.
- Delitala G: Dopamine and TSH secretion in man. Lancet 2:760-761, 1977.
- Refetoff S, Fang VS, Rapoport B, Friesen HG: Interrelationships in the regulation of TSH and prolactin secretion in man: Effects of L-DOPA, TRH and thyroid hormone in various combinations. J Clin Endocrinol Metab 38:450-457, 1974.
- Miyai K, Onishi T, Hosokawa M, et al: Inhibition of thyrotropin and prolactin secretions in primary hypothyroidism by 2-Br--ergocryptine. J Clin Endocrinol Metab 39:391-394, 1974.
- Burrow GN, May PB, Spaulding SW, Donabedian RK: TRH and dopamine interactions affecting pituitary hormone secretion. J Clin Endocrinol Metab 45:65, 1977.
- Spaulding SW, Burrow GN, Donabedian RK, Van Woert M: L-dopa supression of thyrotropin releasing hormone response in man. J Clin Endocrinol Metab 35:182, 1977.
- Collu R, Jéquier JC, Leboeuf G, et al: Endocrine effects of pimozide, a specific dopaminergic blocker. J Clin Endocrinol Metab 41:981-984, 1975.
- Kleinman RE, Vagenakis AG, Braverman LE: The effect of iopanoic acid on the regulation of thyrotropin secretion in euthyroid subjects. J Clin Endocrinol Metab 51:399-403, 1980.
- Faglia G, Ambrosi B, Beck-Peccoz P, et al: The effect of theophylline on plasma thyrotropin response (HTSH) to thyrotropin releasing factor (TRF) in man. J Clin Endocrinol Metab 34:906-909, 1972.
- Wolff J, Varrone S: The methyll xanthines – A new class of goitrogens. Endocrinology 85:410-414, 1969.
- Oyama T, Potsaid MS, Slingerland DW: Effect of diethyl ether anesthesia on thyroid function of rats: Pituitary, adrenal and thyroid relationship. Endocrinology 65:459, 1959.
- Fore W, Kohler P, Wynn J: Rapid redistribution of serum thyroxine during ether anesthesia. J Clin Endocrinol Metab 26:821, 1966.
- Cass R, Kuntzman R, Brodie BB: Norepinephrine depletion as possible mechanism of action of guanethidine (SU 5864), a new hypotensive drug. Proc Soc Exp Biol Med 103:871, 1960.
- Gaffney TE, Braunwald E, Kahler RL: Effects of guanethidine on triiodothyronine induced hyperthyroidism in man. N Engl J Med 265:16-20, 1961.
- Lee WY, Bronsky D, Waldstein SS: Studies of thyroid and sympathetic nervous system interrelationships. II. Effect of guanethidine on manifestations of hyperthyroidism. J Clin Endocrinol Metab 22:879-885, 1962.
- Ramey ER, Bernstein H, Goldstein MS: Effect of sympathetic blocking agents on the increased oxygen consumption following administration of thyroxine. Fed Proc 14:118, 1955.
- Surtskin A, Cordonnier JK, Lang S: Lack of influence of the sympathetic nervous system on the calorigenic response to thyroxine. Am J Physiol 188:503, 1957.
- Schwartz NB, Hammond GE, Gronert GA: Interaction between thyroxine and dibenzyline on metabolic rate. Am J Physiol 191:573, 1957.
300a Ladenson PW, McCarren M, Morkin E, Edson RG, Shihs MC et al: Effects of the thyromimetic agent diiodothyropropanoic acid on body weight, body mass index and serum lipoproteins: A pilot prospective, randomized, controlled trial. JCEM 95:1349-1354, 2010
300b Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B et al: Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. NEJM 362:906-916, 2010
300c Sjouke B, Langslet G, Ceska R, Nicholis S, Nissen S, Ohlander M, Ladenson P, Olsson A, Hovingh G, Kastelen J Eprotirome in patients with familial hypercholesterolemia (the AKKA trial); a randomized, double-blind, placebo-controlled phase 3 study. The Lancet Diabetes & Endocrinology 2:455-463, 2014
300d Yehuda-Schnaidman E, Kalderon B and Bar-Tana J: Thyroid hormone, thryomimetics and metabolic efficiency. Endocrine Reviews 35:35-58, 2014
- Cutting WC, Rytand DA, Tainter ML: Relationship between blood cholesterol and increased metabolism from dinitrophenol and thyroid. J Clin Invest 13:547-552, 1934.
301a. Anker GB, Lonning PE, Aakvaag A, Lien EA: Thyroid function in postmenopausal breast cancer patients treated with tamoxifen. Scand J Lab Clin Invest 58:103-7,1998.
301b. Hsu SH, Cheng WC, Jang MW, Tsai KS: Effects of long term use of raloxifene, a selective estrogen receptor modulator, on thyroid function test profiles. Clin Chem 47:1865-1867;2001
301c. Ceresini G, Morganti S, Rebecchi I, Bertone L, Ceda GP, Bacchi-Modena A, Sgarabotto M, Baldini M, Ablondi F, Valenti G, Braverman LE: A one-year follow-up on the effects of raloxifene on thyroid function in post-menopausal women. Menopause 11:176-9;2004
301d Siraj ES, Gupta MK, Reddy SS Raloxifene causing malabsorption of levothyroxine. Arch Intern Med 9:1367-70;2003
- Ain KB, Mori Y, Refetoff S: Reduced clearance of thyroxine-binding globulin (TBG) with increased sialylation: A mechanism for estrogen induced elevation of serum TBG concentration. J Clin Endocrinol Metab 65:689-696, 1987.
- Doe RP, Mellinger GT, Swaim WR, Seal JS: Estrogen dosage effects on serum proteins: A longitudinal study. J Clin Endocrinol Metab 27:1081-1086, 1967.
- Ramey JN, Burrow GN, Polackwich RK, Donabedian RK: The effect of oral contraceptive steroids on the response of thyroid-stimulating hormone to thyrotropin-releasing hormone. J Clin Endocrinol Metab 40:712, 1975.
- Gross HA, Appleman MD, Nicoloff JT: Effect of biologically active steroids on thyroid function in man. J Clin Endocrinol Metab 33:242-248, 1971.
- Lemarchand-Beraud T, Rappoport G, Magrini G, Berthier C, Reymond M: Influences of different physiological conditions on the gonadotropins and thyrotropin responses to LHRH and TRH. Horm Metab Res 5 (suppl):170, 1974.
306a. Moreira RM, Lisboa PC, Curty FH, Pazos-Moura CC: Dose-dependent effects of 17-beta-estriol on pituitary thyrotropin content and secretion in vitro. Braz. J. Med. Biol. Res. 30:1129-34,1997.
306b. Zidan J, Rubenstein W: Effect of adjuvant tamoxifen therapy on thyroid function in postmenopausal women with breast cancer. Oncology 56:43-45, 1999.
- Haigler ED Jr., Hershman JM, Pittman JA Jr., Blaugh CM: Direct evaluation of pituitary thyrotropin reserve utilizing thyrotropin releasing hormone. J Clin Endocrinol Metab 33:573-581, 1971.
- Snyder PJ, Utiger RD: Response to thyrotropin releasing hormone (TRH) in normal man. J Clin Endocrinol Metab 34:380-385, 1972.
- Carlson HE, Jacobs LS, Daughaday WH: Growth hormone, thyrothyropin and prolactin responses to thyrotropin-releasing hormone following diethylstilbestrol pretreatment. J Clin Endocrinol Metab 37:488, 1973.
- Rutlin E, Haug E, Torjesen PA: Serum thyrotrophin, prolactin and growth hormone, response to TRH during oestrogen treatment. Acta Endocrinol 84:23-35, 1977.
310a Poppe K, Glinoer D, Tournaye H, Schiettecatte J, Devorey P et al: Impact of ovarian hyperstimulation on thyroid function in women with and without thyroid autoimmunity. JCEM 89:3808-3812, 2004
310 b Poppe K, Glinoer D, Tounaye H, Devroey P, Velkeniers B Impact of the ovarian hyperstimulation syndrome on thyroid function Thyroid 18:801-802, 2008
- Federman DD, Robbins J, Rall JE: Effects of methyl testosterone on thyroid function, thyroxine metabolism, and thyroxine-binding protein. J Clin Invest 37:1024, 1958.
- Woeber KA, Barakat RM, Ingbar SH: Effects of salicylate and its noncalorigenic congeners on the thyroidal release of 131I in patients with thyrotoxicosis. J Clin Endocrinol Metab 224:1163-1168, 1964.
- Dussault JH, Turcotte R, Guyda H: The effect of acetylsalicylic acid on TSH and PRL secretion after TRH stimulation in the human. J Clin Endocrinol Metab 43:232-235, 1976.
- Langer P, Földes O, Michajlovskij N, et al: Short-term effect of acethylsalicylic acid on pituitary-thyroid axis and plasma cortisol level in healthy human volunteers. Acta Endocrinol 88:698, 1978.
- Chopra IJ, Solomon DH, Chua Teco GN, Nguyen AH: Inhibition of hepatic outer ring monodeiodination of thyroxine and 3,3′,5′-triiodothyronine by sodium salicylate. Endocrinology 106:1728-1734, 1980.
- Alexander WD, Johnson KWM: A comparison of the effects of acetylsalicylic acid and DL-triiodothyronine in patients with myxoedema. Clin Sci 15:593-600, 1956.
- Yamamoto T, Woeber KA, Ingbar SH: The influence of salicylate on serum TSH concentration in patients with primary hypothyroidism. J Clin Endocrinol Metab 34:423-426, 1972.
- Woeber KA, Ingbar SH: The effects of noncalorigenic congeners of salicylate on the peripheral metabolism of thyroxine. J Clin Invest 43:931-942, 1964.
- Christensen K: The metabolic effect of p-aminosalicylic acid. Acta Endocrinol 31:608-610, 1959.
- MacGregor AG, Somner AR: The antithyroid action of para-amino salicylic acid. Lancet 2:931-936, 1954.
- Christensen LK: The metabolic effect of salicylate and other hydroxybenzoates. Acta Pharmacol Toxicol 16:129, 1959.
- McConnell RJ: Abnormal thyroid function in patients taking salsalate. JAMA 267:1242-1243, 1992.
- Gamstedt A, Jarnerot A, Kagedal B, Soderholm B: Corticosteroids and thyroid function. Acta Med Scand 205:379, 1979.
- Oppenheimer JH, Werner SC: Effect of prednisone on thyroxine-binding proteins. J Clin Endocrinol Metab 26:715-721, 1966.
- Werner SC, Platman SR: Remission of hyperthyroidism (Graves' disease) and altered pattern of serum-thyroxine binding induced by prednisone. Lancet 2:751, 1965.
- Otsuki M, Dakoda M, Baba S: Influence of glucocorticoids on TRF-induced TSH response in man. J Clin Endocrinol Metab 36:95, 1973.
- Dussault JH: The effect of dexamethasone on TSH and prolactin secretion after TRH stimulation. Can Med Assoc J 111:1195-1197, 1974.
- Berson SA, Yalow RS: The effect of cortisone on the iodine accumulating functions of the thyroid gland in euthyroid subjects. J Clin Endocrinol Metab 12:407, 1952.
- Ingbar SH: The effect of cortisone on the thyroidal and renal metabolism of iodine. Endocrinology 53:171-181, 1953.
329a. Kaplan MM, Utiger RD: Iodothyronine metabolism in rat liver homogenates. J Clin Invest 61:459,1978.
329b. Samuels MH, McDaniel PA: Thyrotrophin levels during hydrocortisone infusions that mimic fasting-induced cortisol elevations: a clinical research study. J Clin Endocrinol Metab 82:3700-4,1997.
329c. Heikinheimo O, Ranta S, Grunberg S, Lahteenmaki P, Spitz IM: Alterations in pituitary-thyroid and pituitary-adrenal axes—consequences of long-term mifepristone treatment. Metabolism 46:292-6,1997.
- Topliss DJ, White EL, Stockigt JR: Significance of thyrotropin excess in untreated primary adrenal insufficiency. J Clin Endocrinol Metab 50:52-56, 1980.
- Tashjian AH, Osborne R, Maina D, Knaian A: Hydrocortisone increases the number of receptors for thyrotropin-releasing hormone on pituitary cells in culture. Biochem Biophys Res Commun 79:333, 1977.
331a. Bruhn TO, Huang SS, Vaslet C, Nillni EA: Glucocorticoids modulate the biosynthesis and processing of prothyrotropin releasing hormone (proTRH). Endocrine 9:143-52.1998.
331b. Jackson IM, Luo LG: Antidepressants inhibit the glucocorticoid stimulation of thyrotropin releasing hormone expression in cultured hypothalamic neurons. J Investig Med 46:470-4,1998.
- Benoit FL, Greenspan FS: Corticoid therapy for pretibial myxedema. Observations on the long-acting thyroid stimulator. Ann Intern Med 66:711-720, 1967.
- Yamada T, Ikejiri K, Kotani M, Kusakabe T: An increase of plasma triiodothyronine and thyroxine after administration of dexamethasone to hypothyroid patients with Hashimoto's thyroiditis. J Clin Endocrinol Metab 46:784-790, 1978.
333a. Conn J, Sebiastain M, Deam D A prospective study of the effect of non-ionic contast media on thryoid function. Thyroid 6:107-110;1996
333b. Martin FI, Dream DR Hyperthyroidism in elderly hospitalized patients. Clinical features and treatment outcomes. Med j Aust 164:200-203,1996
333c. Rhee CM, Bhan I, Alexnader EK, Brunelli SM Association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism Arch Intern Med 172:153-159:2012
333d. Nolte W, Muller, R, Siggelkow H, Emrich D, Hufner M Prophylactic application of thyrostatic drugs during excessive iodine exposure in euthyroid patients with thyroid autonomy: a randomized study. Eur J of Endocrinol 134:337-41: 1996
333e. Barr ML,Chiu HK, Li N, Yeh MW, Rhee CM, Casillas J, Iskander PJ, Leung AM Thyroid dysfunction in children exposed to iodinated contrast material J Clin Endocrinol Metab 2016 101:2366-2370
333f. Kornelius E, Chiou JY, Yang YS, Peng CH, Lai YR and Huang CN: Iodinated contrast media increased the risk of thyroid dysfunction: A 6-year retrospective cohort study. J Clin Endocrinol Metab 100:3372-3379, 2015
- Burgi H, Wimpfheimer C, Burger A, Zaunbauer W, Rosler H, Lamarchand-Beraud T: Changes of circulating thyroxine, triiodothyronine and reverse triiodothyronine after radiographic contrast agents. J Clin Endocrinol Metab 43:1203, 1976.
- Wu SY, Chopra IJ, Solomon DH, Bennett LR: Changes in circulating iodothyronines in euthyroid and hyperthyroid subjects given Ipodate (Oragrafin), an agent for oral cholescystography. J Clin Endocrinol Metab 46:691-697, 1978.
- Larsen PR, Dick TE, Markovitz BP, Kaplan MM, Gard TG: Inhibition of intrapituitary thyroxine to 3,5,3′-triiodothyronine conversion prevents the acute suppression of thyrotropin release by thyroxine in hypothyroid rats. J Clin Invest 64:117, 1979.
- Felicetta JV, Green WL, Nelp WB: Inhibition of hepatic binding of thyroxine by cholecystographic agents. J Clin Invest 65:1032-1040, 1980.
- DeGroot LJ, Rue PA: Roentgenographic contrast agents inhibit triiodothyronine binding to nuclear receptors in vitro. J Clin Endocrinol Metab 49:538-542, 1979.
338a. Brown RS, Cohen JH, Braverman LE: Successful treatment of massive acute thyroid hormone poisoning with iopanoic acid. J Pediatr 132:903-05,1998.
338b. Arem R, Munipalli B: Ipodate therapy in patients with severe destruction induces thyrotoxicosis. Arch Intern Med 156:1752-7,1996.
338c. Chopra IJ, van Herle AJ, Korenman SG, Viosca S, Younai S: Use of sodium ipodate in management of hyperthyroidism in subacute thyroiditis. J Clin Endocrinol Metab 80:2178-80,1995.
338d. Fontanilla JC, Schnedier AB, Sarne DH: The use of oral radiographic Contrast agents in the management of hyperthyroidism. Thyroid 11:561-567: 2001
- Nademanee K, Piwonka RW, Singh BN, Hershman JM: Amiodarone and thyroid function. Prog Cardiovascul Dis 31:427-437, 1989.
339a. deJong M, Docter R, Van der Hoek H, et al: Different effects of amiodarone on transport of T4 and T3 into the perfused rat liver. Am J Physiol 266:E44, 1994.
339b. Vorperian VR, Havighurst TC, Miller S, January CT: Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 30:791-8,1997.
339c. Hudig F, Bakker O, Wiersinga WM: Tri-iodothyronine prevent the amiodarone-induced decrease in the expression of the liver low-density lipoprotein receptor gene. J Endocrinol 152:413-21,1997
339d. Guo W, Kamiya K, Toyama J: Evidences of antagonism between amiodarone and triiodothyronine on the K+ channel activities of cultured rat cardiomyocytes. J Mol Cell Cardiol 29:617-27,1997.
- Martino E, Safran M, Aghini-Lombardi F, et al: Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 101:28-34, 1984.
340a. Bartlena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E: Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 81:2930-3,1996.
340b Bogazzi F, Bartalena L, Martino E: Approach to the patient with amiodarone-induced thyrotoxicosis. JCEM 96:2529-2535, 2010
340c. Tomisits L, Rossi G, Baratalena L, Martino E Bigazzi F The onset of amiodzrone-induced thyrotoxicosis (AIT) depends on AIT type. Eur J Endocrinol 171:363-368, 2014
340d. Yagishita A, Hachiya H, Kawabata M, Nakamura T, Sugiyama K, Tanaka Y, Sasano T, Iasobe M, Hirao K Amiodarone-induced thyrotoxicosis late after amiodarone withdrawal Circ J 77:2898-2903, 2013
340e. Houghton SG, Farley DR, Brennan MD, van Heerden JA, Thompson GB, Grant CS Surgical management of amiodarone-associated thyrotoxicosis: Mayo Clinic experience World J Surg 28:1083-1087, 2004
- Schussler GC: Diazepam competes for thyroxine binding. J Pharmacol Exp Ther 178:204-209, 1971.
- Molholm Hansen J, Skovsted L, Birk Lauridsen U, Kirkegaard C, Stersbaek-Nielsen K: The effect of diphenylhydantoin on thyroid function. J Clin Endocrinol Metab 39:785, 1974.
- Heyma P, Larkins RG, Perry-Kenne D, Peter CT, Ross D, Sloman JG: Thyroid hormone levels and protein binding in patients on long term diphenylhydantoin treatment. Clin Endocrinol 6:369, 1977.
- Cavalieri RR, Gavin LA, Wallace A, et al: Serum thyroxine, free T4, triiodothyronine, and reverse-T3 in diphenylhydantoin treated patients. Metabolism 28:1161-1165, 1979.
344a. Surks MI, DeFesi CR: Normal serum free thyroid hormone concentrations in patients treated with phenytoin or carbamazapine, a paradox resolved. JAMA 275:1495-8,1996
344b. Tiihonen M, Liewendahl K, Waltimo O, Ojala M, Valimaki M: Thyroid status of patients receiving long-term anticonvulsant therapy assessed by peripheral parameters: a placebo-controlled thyroxine therapy trial. Epilepsia 36:1118-25,1995
- Hansen JM, Skovsted L, Lauridsen UB, Kirkegaard C, Siersbaek-Nielsen K: The effect of diphenylhydantoin on thyroid function. J Clin Endocrinol Metab 39:785-, 1974.
- Blackshear JL, Schultz AL, Napier JS, Stuart DD: Thyroxine replacement requirements in hypothyroid patients receiving phenytoin. Ann Intern Med 99:341-359, 1983.
- Oppenheimer JH, Shapiro HC, Schwartz HL, Surks MI: Dissociation between thyroxine metabolism and hormonal action in phenobarbital-treated rats. Endocrinology 88:115, 1971.
347a. Brookstaff RC, Murphy VA, Skare JA, Minnema D, Sangiri U, Parkinson A: Effects of doxylamine succinate on thyroid hormone balance and enzyme induction in mice. Toxicol Appl Pharmacol 141:584-94,1996.
- Cavalieri RR, Sung LC, Becker CE: Effects of phenobarbital on thyroxine and triiodothyronine kinetics in Graves' disease. J Clin Endocrinol Metab 37:308-316:1973.
348a. Rootwelt K, Ganes T, Johannessen SI: Effects of carbamazapine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans. Scan J Clin Lab Invest 38:731,1978.
- Wartofsky L, Dimond RC, Noel GL, et al: Failure of propranolol to alter thyroid iodine release, thyroxine turnover, or the TSH and PRL responses to thyrotropin-releasing hormone in patients with thyrotoxicosis. J Clin Endocrinol Metab 41:485-490, 1975.
- Woolf PD, Lee LA, Schalch DS: Adrenergic manipulation and thyrotropin releasing hormone (TRH)-induced thyrotropin (TSH) release. J Clin Endocrinol Metab 35:616-, 1972.
- Faber J, Friis T, Kirkegaard C, et al: Serum T4, T3, and reverse T3 during treatment with propranolol in hyperthyroidism, L-T4 treated myxedema and normal man. Horm Metab Res 11:34-36, 1979.
- Faber J, Kirkegaard C, Lumholtz IB, Siersbaek-Nielsen K, Friis T: Variations in serum T3, rT3, 3,3′-diiodothyronine and 3′,5′-diiodothyronine induced by acute myocardial infarction and propranolol. Acta Endocrinol 94:341, 1980.
- Murchison LE, How J, Bewsher PD: Comparison of propranolol and metoprolol in the management of hyperthyroidism. Br J Clin Pharmacol 8:581, 1979.
- How ASM, Khir AN, Bewsher PD: The effect of atenolol on serum thyroid hormones in hyperthyroid patients. Clin Endocrinol 13:299-302, 1980.
- Hadden DR, Bell TK, McDevitt DG, Shanks RG, Montgomery DAD, Weaver JA: Propranolol and the utilization of radioiodine by the human thyroid gland. Acta Endocrinol 61:393, 1969.
- Wilson WR, Theilen ED, Fletcher FW: Propranolol and its effects in thyrotoxicosis on heart at rest or exercise. J Clin Invest 43:1697, 1964.
- Das G, Krieger M: Treatment of thyrotoxic storm with intravenous administration of propranolol. Ann Intern Med 70:985, 1969.
- Canary JJ, Shaaf M, Duffy BJ Jr., Kyle LH: Effects of oral and intramuscular administration of reserpine in thyrotoxicosis. N Engl J Med 257:435, 1957.
- Waud DR, Kattegoda SR, Krayer O: Threshold dose and time course of norepinephrine depletion of mammalian heart by reserpine. J Pharmacol Exp Ther 124:340, 1958.
- Goldberg RC, Wolff J, Greep RO: Studies on the nature of the thyroid-pituitary interrelationship. Endocrinology 60:38, 1957.
- Goldberg RC, Wolff J, Greep RO: The mechanism of depression of plasma protein-bound iodine by 2,4-dinitrophenol. Endocrinology 56:560-566, 1955.
- Lardy HA, Wellman H: Oxidative phosphorylations: Role of inorganic phosphate and acceptor systems in control of metabolic rates. J Biol Chem 195:215-224, 1952.
- Escobar del Rey F, Morreale de Escobar G: Studies on the peripheral disappearance of thyroid hormone. IV. The effect of 2,4-dinitrophenol on the 131I distribution in thyroidectomized, L-thyroxine maintained rats, 24 hours after the injection of 131I-labeled L-thyroxine. Acta Endocrinol 29:161-175, 1958.
- Escobar del Rey F, Morreale de Escobar G: Studies on the peripheral disappearance of thyroid hormone. V. The effect of 2,4-dinitrophenol on the variations of the 131I distribution pattern with time, after the injection of 131I-labeled L-thyroxine into thyroidectomized, L-thyroxine maintained rats. Acta Endocrinol 29:176, 1958.
- Cutting CC, Tainter ML: Comparative effects of dinitrophenol and thyroxin on tadpole metamorphosis. Proc Soc Exp Biol Med 31:97-100, 1933.
- Reichlin S: Regulation of the hypophysiotropin secretion of the brain. Arch Intern Med 135:1350, 1975.
- Morley JE: Neuroendocrine control of thyrotropin secretion. Endocr Rev 2:396-436, 1981.
- Kaptein EM, Spencer CA, Kamiel MB, Nicoloff JT: Prolonged dopamine administration and thyroid hormone economy in normal and critically ill subjects. J Clin Endocrinol Metab 51:387-393, 1980.
368a. deZegher F, Van den Bershe G, Dumoulin M, Gewillig M, Daenen W, Deviliger H: Dopamine suppresses thyroid-stimulating hormone secretion in neonatal hypothyroidism. Acta Paediatr 84:213-4,1995
368b. Martignoni E, Horowski R, Liuzzi A, Costa A, Dallabonzana D, Cozzi R, Attanasio R, Rainer E, Nappi G. Clin Neuropharmacol 19:72-80, 1996
368c. Samuels MH, Kramer P: Effects of metoclopramide on fasting-induced TSH suppression. Thyroid 6:85-9,1996
- Benker G, Zäh W, Hackenberg K, Hamburger B, Gunnewig H, Reinwein D: Long-term treatment of acromegaly with bromocryptine: Postprandial HGH levels and response to TRH and glucose administration. Horm Metab Res 8:291, 1976.
- Köbberling J, Darrach A, Del Pozo E: Chronic dopamine receptor stimulation using bromocryptine: Failure to modify thyroid function. Clin Endocrinol 11:367-370, 1979.
- Foord SM, Peters J, Scanlon MF, Rees-Smith B, Hall R: Dopaminergic control of TSH secretion in isolated pituitary cells. FEBS Lett 121:257, 1980.
- Heinen E, Herrmann J, Konigshausen T, Kruskemper HL: Secondary hypothyroidism in severe non-thyroidal illness? Horm Metab Res 13:284-288, 1981.
- Weintraub BD, Gershengorn MC, Kourides IA, Fein H: Inappropriate secretion of thyroid stimulating hormone. Ann Intern Med 95:339-351, 1981.
- Chanson P, Weintraub BD, Harris AG: Octreotide therapy for thyroid hormone-stimulating hormone-secreting pituitary adenomas. Ann Int Med 119:236-240, 1994.
- Fernandez-Soto L, Gonzalez A, Escobar_jimenez F, Vazquez R, Ocete E, Olea N, Salmeron J: Increased risk of autoimmune thyroid disease in hepatitis C vs hepatitis B before, during and after discontinuing interferon therapy. Arch Intern Med 158:1445-8, 1998.
- Amenomori M, Mori T, Fukuda Y, Sugawa H, Nishida N, Furukawa M, Kita R, Sando T, Komeda T, Nakao K: Incidence and characteristics of thyroid dysfunction following interferon therapy in patients with chronic hepatitis C. Intern Med 37:246-52, 1998.
376a. Hamnvik OR, Larsen PR, Marquses E Thyroid dysfunction from antineoplastic agents J Natl Cancer Inst 103:1572-1587, 2011
376b. Torino F, Barnabel A, Paragliola R, Baldelli R, Appetecchuia M, Corsello SM Thyroid dysfunction as an unintended side effect of anticancer drugs Thyroid 231345-1366, 2013
- Koh LK, Greenspan FS, Yeo PP: Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature. Thyroid 7:891-6,1997.
377a. Daniels GH, Vladic A, Brinar V, Zavalishin, Valente W, Oyuela P, Plamer J, Margolin DH Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab 99:80-89, 2014
377b Ribas A Releasing the brakes on cancer immunotherapy NEJM 373:1490-1492
377c Tarhini A Immune-mediated adverse events associated with Ipuilmumab CTLA-4 blockade therapy: The underlying mechanisms and clinical management Scientifica Artcile 857519 2013
377d Corsello SM, Barnabel A, Marchetti P, Vecchis LD, Salvatori R, Torino F Endocrine side effects induced by immune checkpoint inhibitors J Clin Endocrinol Metab 98:1361-1375, 2013
377e Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A and Nachitgall L: Ipilumumab-induced hypophyisitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 99:4078-4085, 2014
377f Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution Endocrine-Related Cancer 21: 371-381, 2014
377g Ansell SM, Leshokin AM, Borrello I, Halwani A, Scott EC, Gutierrez, M, Schuster SJ, Millenosn MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy, B, Ligon AH, Zhu, L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma N Engl J Med 372:311-319, 2014
377h Orlov S, Salari F, Kashat L and Walfish PG: Case reports: Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab 100:1738-1741, 2015
377i Naidoo J, Page DB, Connell LC, Schindler L|KJ, Lacouture ME, Postow MA, Wolchok JD Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies Ann Onc 26:2375-2391, 2015
- Schuppert F, Rambusch E, Kirchner H, Atzpodien J, Kohn LD, von zur Muhllen A: Patients treated with interferon-alpha, interferon-beta, and interleukin-2 have a different autoantibody pattern than patients suffering from endogenous thyroid disease. Thyroid 7:837-42,1997.
- Krouse RS, Yoral RE, Heywood G, Weintraub BD, White DE, Steinberg SM, Rosenberg SA, Schwartzentruber DJ: Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. J Immunother Emphasis Tumor Immunol 18:272-8,1995.
379a. Prummel MF, Laurberg P: Interferon- and autoimmuine thyroid disease. Thyroid 13:547-551, 2003
- Corssmit EP, Heyligenberg R, Endert E, Sauerwein HP, Romijn JA: Acute effects of interferon-alpha on thyroid hormone metabolism in healthy men. J Clin Endocrinol Metab 80:3140-4, 1995.
- Witske O, Winterhagen T, Saller, B, Rogenbuck U, Lehr I, Phillipp T, Mann K, Reinhardt W: Transient stimulatory effect on pituitary-thyroid axis in patients treated with interleukin-2 Thyroid 11:665-670, 2001
- Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK: Hypothyroidism after suntinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145:660-4, 2006
382a Rogiers A, Wolter P, de Beeck KO, Thijs M Decallonne B, Schoffski P: Shrinkage of thyroid volume in sunitinib-treated patients with renal cell carcinoma: A potential marker of irreversible thyroid dysfunction? Thyroid 20:317-322, 2010
- Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M, Hershman JM: Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 17:351-5,2007
383b Makita N, Megumi M, Fujita T, IIri T: Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid 20:323-326, 2010
383c Hershman JM, Liwanpo L: How does sunitinib cause hypothyroidism? Thyroid 20:243-244 2010
383d Iavarone M, Perrino M, Vigano M, Beck-Peccoz P, Fugazzola L: Sorafenib-induced destructive thyroiditis. Thyroid 20:1043-1044, 2010
383e Tamaskar I, Bukowski R, Elson P, Ioachimescu AG, Wood L et al Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 19:265-268, 2008
383f Abdulrahman RM, Verloop H, Hoftijzer H, Verburg E, Hovens GC et al: Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination. JCEM 95:3758-3762, 2010
- DeGroot JW, Zonnenberg BA, Plukker JT, van DerGraaf WT, Links TP: Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Phamacol Ther 78:4334-8, 2005
384a Kim TD, Schwarz M, Nogai H, Grille P, Westermann J et al: Thyroid dysfunction caused by second generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia. Thyroid 20:1209-1214, 2010
- Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, Duvic M: Central hypothyroidism associated with retinoid X receptor selective ligands. N Engl J Med 340:1075-9, 1999
- Golden WM, Weber KB, Hernandez TL, Sherman SI, Woodmansee WW, Haugen BR: Single-dose rexinoid rapidly and specifically suppresses serum thryotropin in normal subjects. J Clin Endocrinol Metab 92:124-30, 2007
- Smit JWA, Stokkel MPM, Pereira AM, Romijn JA, Visser TJ: Bexarotene-induced hypothyroidism: Bexarotene stimulates the peripheral metabolism of thyroid hormones. J Clin Endocrinol Metab 92:2496-99, 2007
388 Neumann S, Raaka BM, Gershengon MC: Human TSH receptor ligands as pharmacologic probes with potential clinical application. Expert Rev Endocrinol Metab 4:669-671, 2009
388b. Lupoli R, Di Minno A, Tottora A, Amborsino P, Lupoli GA, Di Minno MND Effects of treatment with metformin on TSH Levels: A meta-analysis of literature studies. J Clin Endo Metab 99: E143-E148, 2014
389 Neumann S, Huang W, Titus S, Krause G, Kleinau G et al: Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. PNAS 106:12471-12476, 2009
390 Neumann S, Eliseeva E, McCoy JG, Napolitano G, Giuliani C et al: A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J Clin Endocrinol Metab 96:548-554, 2011
391 Piehl S, Hoefig CS, Scanlan TS, Kohrle J: Thyronamines – Past, present and future. Endocrien Reviews 32:64-80, 2011
392 Vigersky RA, Filmore-Nassar A, Glass AR: Thyrotropin suppression by metformin. J Clin Endocrinol Metab 91:225-7, 2006
393 John-Kalarickal J, Pearlman G, Carlson HE: New medications which decrease levothyroxine absorption. Thyroid 17:763-765, 2007
394 Weitzman SP, Ginsburg KC, Carlson HE: Coleselvam hydrochloride and lanthanum carbonate interfere with the absorption of levothyroxine. Thyroid 19:77-79, 2009
395 Benvenega S, Bartolone L, Pappalardo MA, Russo A, Lapa D Giogianni G et al: Altered intestinal absorption of l-thyroxine caused by coffee. Thyroid 18:293-301, 2008
396 Badros AZ, Siegel E, Bodenner D, Zangarui M, Zeldis J, Barlogie B, Tricot G: Hypothyroidism in patients with multiple myeloma following treatment with thalidomide. AM J Med 112:412-413, 2002
- Kwok JS, Chan IH, Chan MH Biotin interference of TSH and free thyroid hormone measurement. Pathology 44:278-285, 2012
- Wijeratne NG, Doery JCG, Lu ZX Positive and negative interference in immunoassays following biotin ingestion: a pharmacokinetic study. Pathology 44:674-675, 2012
- Kummer S, Hermsen D, Distelmaier F Biotin treatment mimicking Graves' Disease New Engl J Med 375:704-706, 2016
- Elston MS, Seghal S, Du Toit S, Yarndley T Conaglen JV Factitious Graves' disease due to biotin immunoassay interference – A case and review of the literature. J Clin Endocrinol Metab 101:3251-3255,2016

subset: commoncrawl